Women's Vitali-T by LifeSeasons Therapeutics

LIKELY EFFECTIVE

• Biotin deficiency. Oral and injectable biotin prevents and treats biotin deficiency. Details: Biotin up to 10 mg daily has been used to treat and prevent biotin deficiency. Injections of biotin 150 mcg daily for 3-5 days have been used in adults. Biotin deficiency might occur due to different etiologies such as inherited biotinidase deficiency, malnutrition, chronic use of anticonvulsants, pregnancy, and excessive and chronic raw egg consumption (6243,19347). A very small study in newborns aged 1-6 months shows that adding biotin to infant formula safely improves biotin status in formula-fed infants (111365). The validity of these findings is limited by a lack of blinding, no randomization, and the small sample size.

POSSIBLY INEFFECTIVE

• Multiple sclerosis (MS). In spite of contrary reports, high-dose biotin (300 mg daily) does not reduce disability in patients with progressive MS. It also does not seem to be linked to an increased risk for relapse. Details: Although most earlier research suggested benefit, the highest quality evidence shows that high-dose biotin does not improve outcomes in progressive MS (95662,102963,102966,104011). A large multi-centered randomized clinical trial (SPI2) in patients with progressive MS and high disability shows that taking biotin 100 mg three times daily for 15 months does not improve disability, as measured on the expanded disability status scale (EDSS), or 25-foot walking time, when compared with placebo. The SPI2 clinical trial also did not find that biotin increases the rate of relapse (104011), a concern raised in one observational study of high-dose biotin (104000). Also, a large observational study of adults with progressive MS failed to identity an increase in annualized relapse rates in patients that reported taking biotin when compared with controls (105716). Other observational research has also found no effect on the relapse risk (102963,102964). There is some speculation that any increased rate of relapse identified in some high-dose biotin cohorts might be due to detection bias or reduced compliance with disease-modifying therapies.
• Seborrheic dermatitis. Oral biotin doesn't seem to improve seborrheic dermatitis of infancy. Details: A clinical trial in infants with seborrheic dermatitis shows that biotin given by mouth does not improve symptoms when compared with placebo (8469).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alopecia areata. It is unclear if oral biotin is beneficial for alopecia areata. Details: A small clinical study in healthy adults with alopecia areata shows that weekly injections of intramuscular biotin 5 mg/1 mL and dexpanthenol 250 mg/2 mL for 6 weeks reduces hair fall count and transiently increases hair density compared with baseline (111366). The validity of these findings is limited by a lack of a placebo control group, small sample size, and short duration of treatment. It is unclear if the effects are due to biotin, dexpanthenol, or the combination. Another small clinical study in 9-year-old children with alopecia areata shows that taking biotin 20 mg with zinc aspartate 100 mg orally along with topical application of clobetasol propionate 0.025% daily for one year promotes hair regrowth in 33% of children, compared with 0% in the group receiving the steroid deflazacort (6932). It is unclear if these effects are due to biotin, zinc, topical clobetasol, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral biotin for ALS, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Biotin-thiamine-responsive basal ganglia disease. Adding oral biotin to oral thiamine does not seem to improve most symptoms associated with this condition, although it may slightly speed recovery from acute crisis in children. Details: A small case series in children ages 1-12 years with biotin-thiamine-responsive basal ganglia disease has found that adding biotin 5 mg/kg daily to thiamine 40 mg/kg daily for 30 months is not associated with additional symptomatic improvement in encephalopathy, seizures, dystonia, or other neurologic sequelae when compared with taking only thiamine. However, taking biotin with thiamine is associated with a 1-day reduction in recovery from acute crisis when compared with thiamine alone (95661).
• Brittle nails. Low quality clinical studies suggest that oral biotin might improve nail thickness and prevent the splitting of brittle nails. Details: Some small, low quality clinical studies in people with brittle nails shows that taking biotin 2.5 mg orally daily for 1.5 to 15 months increases nail thickness and decreases the splitting of fingernails and toenails in some people when compared with baseline (171,35593). The validity of these findings is limited by the small study sizes and the lack of a comparator group.
• Depression. Although there is interest in using oral biotin for mild depression, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Diabetes. It is unclear if oral biotin is beneficial for type 2 diabetes. Details: A meta-analysis of randomized controlled trials shows that taking biotin 1.5-15 mg orally daily for 1-3 months does not improve fasting blood glucose or serum insulin levels when compared with placebo. However, the validity of these results is limited by inclusion of subjects with and without diabetes (110044). A very small study in adults with type 2 diabetes also shows that taking biotin 5 mg three times daily for 28 days does not affect glucose or insulin levels when compared to baseline (11579). Biotin has also been studied in combination with other ingredients. Preliminary clinical research shows that a taking a specific supplement containing a combination of biotin 2 mg and chromium picolinate 600 mcg (Diachrome, Nutrition 21) can lower blood glucose and glycated hemoglobin levels in patients with type 2 diabetes who are poorly controlled on oral hypoglycemic drugs (12385,12390,15169). It is unclear if these effects are due to biotin, chromium, or the combination.
• Diabetic neuropathy. Although there is interest in using oral and intramuscular biotin for diabetic neuropathy, there is insufficient reliable information about the clinical effects of biotin for this condition.
• Muscle cramps. It is unclear if biotin is beneficial for improving muscle cramps in patients undergoing hemodialysis. Details: Patients undergoing hemodialysis are prone to muscle cramps. A small clinical study in patients with hemodialysis-related muscle cramps shows that taking biotin 1 mg in the morning daily for at least one week prevents and reduces severity of muscle cramps when compared to baseline. Cessation of biotin led to recurrence of cramps, and restarting oral biotin led to resolution of cramps during hemodialysis (89475). The validity of these findings is limited by the lack of comparator group. More evidence is needed to rate biotin for these uses.

(Read more about BIOTIN)

POSSIBLY EFFECTIVE

• Chronic venous insufficiency (CVI). Oral butcher's broom extract, taken in combination with hesperidin and vitamin C, seems to improve symptoms of CVI. It is unclear if oral butcher's broom alone is beneficial in these patients. Details: One clinical trial in females with CVI shows that taking a specific butcher's broom rhizome extract (Fagorutin Ruscus Kapseln, GlaxoSmithKline Consumer Healthcare) 36-37.5 mg twice daily for 12 weeks reduces leg edema and symptoms of fatigue, heaviness, and tension of the leg when compared with placebo (9932). A specific combination product (Cyclo 3 Fort, Pierre Fabre Laboratories) containing butcher's broom has also been evaluated. Several clinical studies and meta-analyses of clinical research in patients with CVI show that taking this product, providing butcher's broom root extract 150 mg, hesperidin methyl chalcone 150 mg, and vitamin C 100 mg per capsule, at a dose of 1-3 capsules, 1-3 times daily for up to 3 months, can reduce edema, fatigue, pain, paresthesia, pruritus, and leg fatigue when compared with baseline or placebo (10068,10070,37483,37498,94779). It is unclear if these findings are due to butcher's broom, other ingredients, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Diabetic retinopathy. It is unclear if oral butcher's broom extract is beneficial in patients with diabetic retinopathy. Details: A small clinical study in patients with diabetic retinopathy shows that taking a specific butcher's broom extract (Fagorutin-Ruscus, Fink GmbH) 37.5 mg orally twice daily for 3 months does not improve visual acuity when compared to baseline. However, there does appear to be some regression of changes in the fundus in 23% of patients, and an increase in oscillatory potentials, suggesting improvement in retinal blood circulation, in 15% of patients (37502).
• Hemorrhoids. Although there has been interest in using oral and topical butcher's broom for hemorrhoids, there is insufficient reliable information about the clinical effects of butcher's broom for this purpose.
• Lymphedema. Oral butcher's broom extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with arm lymphedema following breast cancer treatment shows that taking a specific combination product (Cyclo 3 Fort, Pierre Fabre Laboratories) providing butcher's broom root extract 150 mg, hesperidin methyl chalcone 150 mg, and vitamin C 100 mg per capsule, in a dose of three capsules three times daily for 90 days, reduces swelling in the arms and improves mobility and heaviness when compared with placebo. Edema was reduced by around 13% when compared with placebo (37494).
• Orthostatic hypotension. Although there has been interest in using oral butcher's broom for orthostatic hypotension, there is insufficient reliable information about the clinical effects of butcher's broom for this purpose.
• Varicose veins. Oral butcher's broom extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, uncontrolled study in 12 males aged 34 -75 years with varicose veins suggest that taking a specific combination product (Cyclo 3 Fort, Pierre Fabre Laboratories) containing butcher's broom root extract 150 mg, hesperidin methyl chalcone 150 mg, and vitamin C 100 mg per capsule in a dose of three capsules in the morning on the first day, followed by one capsule three times daily for 5-7 days, decreases the diameter of some veins in the leg while standing and increases flow rates in these veins when compared to baseline (37499). It is unclear whether these changes improve the appearance of varicose veins. More evidence is needed to rate butcher's broom for these uses.

(Read more about BUTCHER'S BROOM)

LIKELY EFFECTIVE

• Diabetic neuropathy. Applying a specific prescription patch containing capsaicin 8% or a specific cream containing capsaicin 0.075% can reduce pain in diabetic neuropathy. Details: Clinical research has evaluated the use of a specific patch (Qutenza, NeurogesX Inc.) containing capsaicin 8%, which is approved as a prescription medication by the US Food and Drug Administration (FDA) for the treatment of diabetic peripheral neuropathy. The research in this population shows that a single application of the patch on the painful parts of the feet for 30-90 minutes following pretreatment with topical anesthetics reduces pain for up to 12 weeks when compared with placebo (40719,96453). Patients using the patch experience reduced sleep interference and an average 28% reduction in pain, compared with a 21% reduction with placebo. Additionally, 50% of patients receiving the patch experience pain relief within 19 days, compared to 72 days for those receiving placebo (96453). A meta-analysis of the available clinical research for diabetic peripheral neuropathy found that one-time application of this patch is equally effective to duloxetine 20-120 mg daily, pregabalin 75-600 mg daily, and gabapentin 300-3600 mg daily in producing a 30% or 50% pain reduction. The dose of oral medication used in the evaluated studies did not impact the comparative efficacy of the capsaicin patch (96450). Other clinical research shows that applying cream containing capsaicin 0.075% four times daily for 8 weeks reduces pain intensity when compared with placebo in patients with diabetic peripheral neuropathy (40547,40592,40607). A meta-analysis of clinical research shows that applying cream containing capsaicin 0.075% reduces pain similarly to 5% lidocaine-medicated plaster (40674). Topical cream containing capsaicin 0.075% (Zostrix-HP, Link Medical Products Pty Ltd.) is FDA-approved as an over-the-counter (OTC) medication for this indication (272). However, applying a capsaicin lotion less frequently or with a lower concentration of capsaicin does not seem to be beneficial. A small clinical study in patients with diabetic neuropathy shows that applying a specific lotion (Capsika-75 lotion, Bangkok Drug Company) containing capsaicin 0.075% three times daily for 8 weeks improves pain to a similar degree as a placebo lotion (102277). This study was limited by a high dropout rate, high placebo effect, and poor adherence to therapy. Furthermore, cream or gel (such as Capsika-25 gel, Bangkok Drug Company) containing lower amounts of capsaicin do not appear to be effective for reducing diabetic peripheral neuropathy pain (92984).
• Pain (chronic). Topical cream containing capsaicin can reduce chronic pain associated with various conditions. Topical capsaicin is FDA-approved for this use. Details: Several clinical studies show that topically applying cream containing capsaicin, the active capsicum constituent, 0.05% to 0.075% temporarily relieves chronic pain from rheumatoid arthritis, osteoarthritis, back pain, jaw pain, psoriasis, and neuropathic conditions (12401,17701). Capsaicin, used in topical preparations, is FDA-approved for these uses (272). It can take up to 14 days for the full analgesic effect. For neuropathic pain, the number needed to treat using capsaicin 0.075% for eight weeks is 5.7 (12401). For musculoskeletal pain, for every 8.1 patients treated with capsaicin 0.025%, 1 patient would achieve at least a 50% reduction in pain (12401). Also, applying capsaicin 0.05% (Finalgon CPD Warmecreme) three times daily for 21 days seems to cause a 49% reduction in chronic soft tissue pain when compared with placebo (17701).
• Postherpetic neuralgia. Applying a specific prescription patch containing capsaicin can reduce postherpetic neuralgia pain, especially in patients with the lowest pain scores. Details: Clinical research has evaluated the use of a specific patch (Qutenza, NeurogesX Inc.) containing capsaicin 8%, which is approved as a prescription medication by the US Food and Drug Administration (FDA) for the treatment of postherpetic neuralgia. Research in this population shows that applying a single patch for 60-90 minutes reduces average pain over 24 hours by 27% to 37% for up to 12 weeks, compared to only 4.4% to 26% in patients in the control group (40659,40679,40686,40691,40719,40728,40800,92985,96451,96452). The number needed to treat to achieve at least a 30% or 50% reduction in pain intensity is 10 and 12, respectively; the number needed to treat to achieve an additional beneficial outcome over placebo at 8 weeks and 12 weeks is 9 and 7, respectively (40800,96451). The pain reduction with this patch has an onset of a few days after treatment and the effect lasts for about 5 months (92986). However, some evidence shows that the reduction in pain is only significant for patients who have had postherpetic neuralgia for at least 6 months (40686). Additionally, the reduction in pain and duration of response appears to be greatest for patients with lower pain scores and low sensitivity to light touch at baseline, as well as patients not using concomitant systemic neuropathic pain medications, whereas patients with high pain scores, high sensitivity to touch, or those using systemic neuropathic pain medications experience the smallest and least sustained reduction in pain (40728,96458). Also, other evidence suggests that this patch may be less effective at relieving postherpetic neuralgia when compared with 5% lidocaine-medicated plaster (40688).

POSSIBLY EFFECTIVE

• Back pain. Topical capsicum or capsaicin seems to be beneficial for reducing back pain. Details: A meta-analysis of generally low-quality clinical research, as well as individual studies, show that applying a capsicum-containing plaster providing 11 mg of capsaicin per plaster or 22 mcg of capsaicin per square centimeter of plaster to the back once daily in the morning for 4-8 hours reduces low back pain when compared with placebo (15259,15260,15261). Applying capsaicin 0.05% (Finalgon CPD Warmecreme) three times daily for 21 days seems to cause a 58% reduction in low back pain when compared with placebo (17701). Also, in a mixed group of patients with acute back or neck pain, a large clinical trial shows that four topical applications with a gel containing capsaicin 0.075% with diclofenac 2% every 12 hours modestly reduces pain on motion when compared with diclofenac alone or placebo. The number of patients with at least a 50% reduction in pain from baseline was modestly higher. Capsaicin 0.075% was similarly effective alone and when combined with diclofenac 2% (105202). However, only about half of the patients in this study had back pain.
• Cluster headache. Intranasal capsaicin seems to be beneficial for preventing cluster headaches. Its effect in the treatment of cluster headache is unclear. Details: Some clinical research shows that using the capsicum constituent capsaicin intranasally reduces the frequency of episodic or chronic cluster headache attacks (14323,14351,14352,14358). Capsaicin suspensions of 0.1 mL of a 10 mM suspension, providing 300 mcg/day of capsaicin, has been applied to the ipsilateral nostril. Applications are continued once daily until a burning sensation is no longer experienced (14351,14358). Intranasal application of capsaicin 0.025% (Zostrix, Rodlen Laboratories) might also decrease symptom severity during an acute cluster headache attack. Clinical research shows that daily treatment for 7 days decreases symptom severity over the following week (14353). Ipsilateral, or same side, nostril application of capsaicin appears to be more effective than contralateral application (14351). Due to severe pain associated with intranasal capsaicin administration, pretreatment with intranasal local anesthetic is usually used.
• Nonallergic rhinitis. Intranasal capsaicin in a dose of at least 0.1 mM seems to improve symptoms of nonallergic rhinitis. It is unclear if lower doses of capsaicin are beneficial. Details: Clinical research shows that repeated intranasal in-clinic treatments with capsaicin, the active capsicum constituent, or with capsicum oleoresin, over a period of one to three days, can significantly decrease symptoms of non-allergic, non-infectious perennial rhinitis symptoms (14328,14357,15016,40595,105204,105205). A decrease of symptoms has been observed for up to 6-9 months following these treatments (14328,14357). The following doses have been used: capsaicin 0.15 mg per dose for up to 7 doses over a 14-day period (14328), capsaicin 0.0033 mol once weekly for 5 weeks (14357), capsaicin 15 mcg/0.1 mL applied three times daily for 3 days (15016), and capsaicin 1-4 mcg per puff, applied 3 times in each nostril daily for 3 days (40595). Due to severe pain associated with intranasal capsaicin administration, pretreatment with intranasal local anesthetic is usually used. Personal use of an intranasal spray with a lower dose of capsaicin might also be effective. Clinical research shows that two 0.4 mL puffs with an intranasal spray in each nostril daily for 4 weeks providing capsaicin 0.01 mM, but not 0.001 mM, is more effective than placebo for reducing symptoms of idiopathic rhinitis. This benefit is maintained for an additional 8 weeks. This protocol was at least as effective as receiving five repeated hourly intranasal spray treatments in hospital with capsaicin 0.1 mM (105204).
• Osteoarthritis. The American College of Rheumatology (ACR) conditionally recommends topical capsaicin for knee osteoarthritis, but not for hip or hand osteoarthritis. Details: A meta-analysis of 4 preliminary clinical trials shows that using topical capsaicin 0.025% four times daily has modest benefit for osteoarthritis when compared with placebo. Using capsaicin 0.0125% doesn't seem to be effective (102408). The American College of Rheumatology (ACR) conditionally recommends topical capsaicin for knee osteoarthritis. However, it does not recommend its use for hip osteoarthritis due to the depth of the joint beneath the skin surface, nor for hand osteoarthritis, due to the risk for contamination of the eye (102114).
• Pain (acute). Topical capsicum seems to be beneficial for reducing acute pain due to trauma. Details: Clinical research in patients with trauma-related acute pain shows that topical application with a gel (Sanli Gel) containing capsaicin 0.05% three times daily for 3 days reduces pain by at least 50% in 87% of patients, compared with 63% of those using a piroxicam gel 0.5% (Felden). There was also a significantly greater number of patients with a final pain score of 4 or less. In the capsaicin group, only 12% of patients did not achieve either of these endpoints, compared with 31% in the group receiving piroxicam (105197).
• Postoperative nausea and vomiting (PONV). Applying topical capsicum to acupoints seems to be beneficial for preventing PONV. Details: Clinical research shows that applying a capsicum-containing plaster to acupoints on the hand and forearm 30 minutes prior to anesthesia and leaving in place for 6-8 hours daily for up to 3 days after surgery reduces the incidence of PONV by about 29% to 36% when compared to control (40405,40483,40610). Plasters used in these studies included Sinsin PAS (Sinsin Pharm Co.), which is standardized to contain capsicum 345.8 mg and capsicum tincture 34.58 mg per sheet (40405,40610); and Johnson's Perforated Capsicum Plaster (Johnson & Johnson Ltd.), which is standardized to contain capsicum oleoresin 1% w/w (40483).
• Postoperative pain. Applying topical capsicum-containing plaster to acupoints seems to be beneficial for reducing postoperative pain. It is unclear if a capsicum patch or capsaicin instillation prior to wound closure is beneficial for reducing postoperative pain. Details: Some clinical research shows that applying a capsicum-containing plaster to acupoints on the hands or near the knees of adults or children 30 minutes prior to anesthesia, and leaving in place for 6-8 hours daily for up to 3 days after surgery, reduces the amount of rescue analgesics needed by 29% to 39% within the first 24 hours and by 16% to 19% within the first 48 hours when compared to control (40405,40483,40520,40524,40610). The capsicum-containing plaster used in these studies (Sinsin PAS, Sinsin Pharm Co.) is standardized to contain capsicum 345.8 mg and capsicum tincture 34.58 mg per sheet (40520,40610). Other preliminary clinical research shows that applying a single patch containing the capsicum constituent capsaicin 8% (Qutenza, NeurogesX Inc.) for 30-60 minutes leads to an improvement in overall health status and an average 22% reduction in pain that lasts up to 12 weeks in patients with postoperative and posttraumatic neuropathic pain. Patches were applied to various parts of the body, including the legs, torso, feet, hands, arms, head, and neck, and the reduction in pain continued with the use of a second and third patch application. The validity of these findings is limited by the lack of a control group (96452). Other clinical evidence suggests that instilling capsaicin 15 mg during surgery immediately prior to wound closure reduces the need for pain medication for up to 2 weeks postoperatively when compared with placebo (40741).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if intranasal capsaicin is beneficial for preventing allergic rhinitis symptoms. Details: Preliminary clinical research shows that intranasal treatment with cotton wads soaked in the active capsicum constituent capsaicin 30 mcM, applied for 15 minutes and repeated over two days, reduces the severity of experimentally-induced allergic rhinitis. The severity of symptoms seems to be reduced for up to 2 months after treatment (14324). However, contradictory research shows that patients with allergic rhinitis caused by house dust mites do not have significantly improved symptoms after using a capsaicin solution providing 0.15 mg/dose for up to 7 doses over a 14-day period when compared with placebo (14360).
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Although there is interest in using oral capsicum for ALS, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Athletic performance. It is unclear if oral capsaicin is beneficial for improving athletic performance; the available research is limited to small, conflicting studies. Details: Several small clinical studies in physically active young adults show that taking capsaicin might improve some measures of athletic performance, but results are mixed overall (99409,99410,102276,105191,105198,105200). A meta-analysis of these and several other small clinical studies shows that taking the capsicum constituents capsaicin or capsiate 45 minutes before exercise improves measures of muscular endurance but does not improve aerobic endurance when compared with placebo. Doses of the capsicum constituents ranged from 1.2-24 mg, with most studies assessing a single 12 mg dose (111515). The included studies have a number of methodological problems that limit the validity of the findings, such as a small sample size, short study duration, and insufficient blinding. Also, most of the study participants were male. Other small clinical studies not included in the meta-analysis also show conflicting results. One small clinical study in untrained young adults undergoing resistance training shows that taking capsiate, a capsaicin analog, 6 mg orally twice daily for 6 weeks improves upper body, but not lower body, weightlifting performance when compared with placebo (109024). However, another small clinical trial in experienced male athletes shows that taking cayenne (GNC Nature's Fingerprint Cayenne Herbal Supplement) 3 grams, providing capsaicin 25.8 mg, daily for 7 days does not improve sprint time, rate of perceived exertion, or muscle soreness over three days when compared with placebo (105206). Capsicum has also been evaluated in combination with other ingredients. One small clinical study in untrained males shows that taking a supplement containing capsicum extract 66.7 mg, caffeine 400 mg, black pepper extract 10 mg, and niacin 40 mg prior to exercising does not improve strength, time to exhaustion, or maximal oxygen consumption when compared with placebo (37873).
• Burning mouth syndrome. It is unclear if applying topical capsaicin in the mouth is beneficial for burning mouth syndrome. Details: Preliminary clinical studies show that using 15 mL of a mouth rinse containing the active capsicum constituent capsaicin 0.02% for 30 seconds daily for 7-21 days modestly decreases burning discomfort when compared to baseline in patients with burning mouth syndrome (92991,105195). Other preliminary clinical research shows that applying 0.5 mL of a gel containing capsaicin 0.01% or 0.025% to the tongue three times daily for 14 days modestly reduces pain when compared to baseline in patients with burning mouth syndrome. The gel is spread with a cotton swab, and no food or drink is consumed for 30 minutes after application (96456). The validity of these findings is limited by the lack of a control group, the small number of patients, and occasionally unclear statistical comparisons.
• Cancer. It is unclear if eating more chili is beneficial for preventing mortality due to cancer. Details: Population research has found that consuming chili more than four times weekly is not associated with a reduced odds of cancer mortality (105208). Also, other population research has found that any consumption of hot red chili peppers is not associated with a reduced odds of mortality related to cancer (105210).
• Cannabinoid hyperemesis syndrome (CHS). Preliminary clinical research suggests that topical capsaicin might be beneficial for reducing symptoms of CHS. Details: One small clinical study in adults presenting to an emergency department (ED) with CHS shows that applying 5 grams of a cream containing capsaicin 0.1% to the abdomen modestly reduces nausea severity at 60 minutes, but not 30 minutes, when compared with a placebo cream. Nausea was completely resolved in 29% of patients, compared with 0% of those using the placebo cream. However, there was no difference in vomiting at 30 or 120 minutes (105193). This study may not have been adequately powered to detect a difference in some of these outcomes. A meta-analysis of two small, low-quality studies involving the topical use of capsaicin on the abdomen, chest, and possibly back, shows that the mean time to resolution of symptoms was 326 minutes and the mean length of stay in the emergency department was 379 minutes. However, it is unclear how these times compare to the use of placebo or standard antiemetics. This study also conducted a systematic review of the available literature, which indicates that the creams most commonly used in research provide 0.025% to 0.1% capsaicin (105201). Two low-quality, retrospective reviews also suggest that capsaicin cream may be beneficial for CHS. A retrospective review of patients in the ED with CHS has found that applying capsaicin cream 0.025% is associated with a 39% shorter time to discharge when compared with control. Patients treated with capsaicin also required fewer additional rescue treatments when compared with control (109021). Another retrospective review of patients in the ED with CHS also suggests that capsaicin cream 0.025% modestly reduces abdominal pain when compared with baseline. However, 47% and 28% of patients, respectively, received additional antiemetics or an opioid after the use of the cream (105345).
• Cardiovascular disease (CVD). It is unclear if eating more chili is beneficial for preventing mortality due to CVD. Details: Population research has found that consuming chili more than four times weekly is associated with a 34% reduced odds of CVD mortality when compared with never or rarely consuming chili, as well as 44% and 61% reduced odds of ischemic heart disease and cerebrovascular death, respectively (105208). Other population research has found that consumption of hot red chili peppers is not associated with a reduced odds of mortality related to CVD when compared with not eating hot red chili peppers (105210).
• Diabetes. It is unclear if oral capsaicin is beneficial for gestational diabetes. Details: Preliminary clinical research shows that taking chili powder containing capsaicin 5 mg daily for 4 weeks modestly reduces total cholesterol levels and reduces postprandial blood glucose levels by an average of 36 mg/dL and postprandial insulin levels by an average of 14 IU/L in patients with gestational diabetes. Compared to a placebo group, these changes are significant. However, capsaicin intake does not alter fasting plasma glucose or insulin levels (96457).
• Dry skin. It is unclear if oral capsicum is beneficial for dry skin. Details: Preliminary clinical research in adult females with low skin moisture shows that taking paprika oil extract 400 mg, standardized to include 9 mg of xanthophyll, orally daily for 4 weeks improves skin moisture and viscoelasticity scores, but not the number of wrinkles, when compared with control (109026).
• Dyslipidemia. It is unclear if oral capsicum is beneficial for reducing lipid levels. Details: A meta-analysis of three or four mainly small clinical trials in healthy adults shows that taking capsicum does not improve levels of triglycerides, total cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with no treatment or placebo. However, there was a small to moderate effect on levels of low-density lipoprotein (LDL) cholesterol. Freshly chopped chili or fermented red pepper were studied for 4 and 12 weeks, respectively (105194). It is unclear if capsicum can lower lipid levels in patients with dyslipidemia or hyperlipidemia.
• Dyspepsia. It is unclear if oral capsicum is beneficial for dyspepsia. Details: Preliminary clinical research shows that taking red pepper powder 2.5 grams daily in three divided doses for 5 weeks reduces symptoms of functional dyspepsia when compared with placebo. However, in some patients, there seems to be a worsening of symptoms prior to any improvement (12410).
• Fibromyalgia. It is unclear if oral capsicum is beneficial for fibromyalgia. Details: Preliminary clinical research shows that applying cream containing the active capsicum constituent capsaicin 0.025% four times daily to tender points for 4 weeks reduces localized tenderness in patients with fibromyalgia (7038). Other preliminary clinical research shows that applying capsaicin 0.075% cream (Sensedol) three times daily to tender points for 6 weeks in addition to standard therapy increases the pain threshold when compared with standard therapy in patients with severe fibromyalgia (92979). However, capsaicin does not appear to reduce overall pain or improve physical function in patients with fibromyalgia (7038,92979). Also, the long-term effects of capsaicin on fibromyalgia-related pain are unclear.
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral capsicum for GERD, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• HIV/AIDS-related peripheral neuropathy. It is unclear if topical capsaicin is beneficial for this condition. Details: There is conflicting evidence regarding the effects of Qutenza (NeurogesX Inc.), which contains the active constituent of capsicum, capsaicin 8%. Although some research shows it reduces pain in patients with HIV and peripheral neuropathy (22395), other research shows no significant benefit (40746). A meta-analysis of results from both of these studies shows that applying a single capsaicin 8% patch for 30-90 minutes reduces pain intensity by at least 30% in about 30% more patients when compared to control (40800). Additional meta-analyses of the results from these two studies suggests that pain reduction with capsaicin begins a few days after treatment and lasts for about 5 months, with a number needed to treat of 11 to achieve at least a 30% reduction in pain intensity (92986,96451). Reduction in pain and duration of response appears to be greatest for females with lower pain scores at baseline, whereas males with high pain scores at baseline experience the smallest and least sustained reduction in pain (96458). Some research has also evaluated topical capsaicin 0.075%. One small clinical study shows that applying this cream does not relieve symptoms of HIV-associated peripheral neuropathy when compared with placebo (3891).
• Hypertension. It is unclear if oral capsicum is beneficial for lowering blood pressure. Details: Two meta-analyses of small clinical trials show that taking capsicum as freshly chopped chili, fermented red pepper, red pepper capsules, or capsinoid capsules orally daily for 4-12 weeks does not reduce systolic or diastolic blood pressure when compared with control. However, most subjects included in these clinical trials did not have hypertension (105194,109025).
• Intermetatarsal neuroma. It is unclear if injecting capsaicin into the third intermetatarsal space is beneficial for intermetatarsal neuroma. Details: Clinical research in adults with intermetatarsal neuroma shows that a single injection of capsaicin 0.1 mg into the third intermetatarsal space 5 minutes after administration of 2 mL of lidocaine 2% with epinephrine leads to a modest reduction in pain at weeks 1 and 4, but not weeks 2 and 3, when compared with placebo. Capsaicin also reduces the extent to which pain interferes with walking and mood, but not with work, sleep, relationships, or general activity (96454).
• Irritable bowel syndrome (IBS). It is unclear if oral capsicum is beneficial for IBS. Details: Preliminary clinical research shows that taking ground guajillo chili 1 gram, containing capsaicin 0.112%, with each meal for 7 days does not reduce symptoms of IBS (12403). A small clinical study shows that taking chili (Nguan Soon Co., Ltd.) 2.1 grams, providing 2.5 mg capsaicin, daily before meals for 6 weeks does not improve abdominal burning, fecal urgency, or abdominal pain or bloating after a spicy meal. However, there was a modest reduction in abdominal burning after a spicy meal (105207). This study may not have been adequately powered to detect a difference in some of these outcomes.
• Laryngitis. Although there is interest in gargling with capsicum for laryngitis, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Motion sickness. Although there is interest in oral capsicum for motion sickness, there is insufficient reliable information about the clinical effects of capsicum for this condition.
• Myofascial pain syndrome. It is unclear if topical capsaicin is beneficial for myofascial pain syndrome. Details: Preliminary clinical research shows that applying a specific capsaicin cream (Dipental Cream, Dalim BioTech) containing capsaicin 0.25 mg/gram along with a ketoprofen 30 mg patch (KetotopVRPlaster, Pacific Pharma) to the trapezius does not reduce pain when compared with a ketoprofen patch alone in patients with myofascial pain (92983).
• Neck pain. It is unclear if topical capsaicin is beneficial for neck pain. Details: In a group of patients with acute back or neck pain, a large clinical trial shows that four topical applications with a gel containing capsaicin 0.075% with diclofenac 2% every 12 hours modestly reduces pain on motion when compared with diclofenac alone or placebo. The number of patients with at least a 50% reduction in pain from baseline was modestly higher. Capsaicin 0.075% was similarly effective alone or when combined with diclofenac 2% (105202). However, only about half of the patients in this study had neck pain.
• Neuropathic pain. It is unclear if topical capsicum is beneficial for neuropathic pain. Details: A very small study in adults with neuropathic pain secondary to spinal cord injury shows that applying a patch containing the capsicum constituent capsaicin 8% for 60 minutes daily to the affected area for 12 weeks reduces pain at weeks 2 and 4 and improves mobility, but not quality of life, for up to 12 weeks when compared with placebo (111517). The validity of these findings is limited by insufficient blinding and the small sample size.
• Obesity. It is unclear if oral capsicum is beneficial for obesity. Details: A meta-analysis of 3-5 small clinical trials shows that taking capsicum does not reduce body weight, body fat, or body mass index (BMI) in individuals with a BMI of at least 25 kg/m2 when compared with placebo or no treatment. Freshly chopped chili, fermented red pepper, or capsicum constituents were studied for 4-12 weeks (105194). In one clinical trial included in the analysis, taking capsinoids 3 mg twice daily 30 minutes prior to eating for 12 weeks reduced abdominal fat by about 1%, but did not significantly reduce body weight, when compared with placebo (40599). In overweight individuals, one small clinical trial shows that taking a specific chili extract 200 mg, formulated with fenugreek dietary fiber for sustained release (Capsifen, Akay Natural Ingredients), providing capsaicinoids 4 mg daily for 28 days reduces body weight and BMI by about 2% when compared with placebo. There was no effect on blood pressure (105196). Capsicum has also been evaluated in combination with other ingredients, with some evidence of benefit. One study evaluated a combination product (Prograde Metabolism) containing capsicum extract (Capsimax, OmniActive Health Technologies), raspberry ketone (Razberi K, Integrity Nutraceuticals), caffeine, garlic root extract, ginger root extract, bitter orange fruit (Advantra Z, Nutratech Inc), L-theanine, and black pepper fruit extract (Biperine, Sabinsa Corporation) twice daily for 8 weeks (40802).
• Overall mortality. Eating chili may be beneficial for preventing mortality. It is unclear if taking capsicum supplements is beneficial for preventing overall mortality. Details: Population research has found that consuming chili is associated with a reduced risk of overall mortality. In one study, eating chili more than four times weekly was associated with a 23% reduced odds of overall mortality when compared with never or rarely consuming chili (105208). Other population research has found that any consumption of hot red chili peppers is associated with a 13% reduced odds of mortality when compared with not eating these peppers (105210). Also, eating spicy foods at least once each week, consisting mainly of fresh chili pepper, dried chili pepper, chili sauce, or chili oil, was associated with at least a 10% reduced risk of death when compared with eating these foods less than once a week (105211).
• Peptic ulcers. It is unclear if oral capsicum is beneficial for peptic ulcers. Details: Population research has found that eating capsicum fruit (chili) an average of 24 times per month is associated with a reduced likelihood of having an ulcer when compared with eating chili an average of 8 times per month. This applies to chili in the form of chili powder, chili sauce, curry powder, and other chili-containing foods (12053). However, clinical research shows that consuming chili peppers 1 gram three times daily for 4 weeks does not improve duodenal ulcer healing when compared to control (40828).
• Peripheral neuropathy. Preliminary clinical research suggests that topical capsaicin might be beneficial for reducing peripheral neuropathy pain. Details: Preliminary clinical research shows that applying patches containing the capsicum constituent capsaicin 8% (Qutenza, NeurogesX Inc.) reduces pain in people with non-diabetic peripheral neuropathy (96452,111516). Up to four patches, applied to different painful areas, are used at one time and are left in place for 30 minutes on the feet, or 60 minutes on other parts of the body such as the legs, torso, hands, arms, head, or neck (96452). After an interval of at least 90 days, treatment can be repeated, with new patches applied for 30-60 minutes (99407). There is an average 27% reduction in pain when compared to baseline, lasting up to 12 weeks (96452). Another similar study reported a decrease of 1 point, on a 10-point pain scale, in the typical daily pain intensity (99407). The validity of these findings is limited by methodological problems, including the lack of control groups. Further research shows that using a single application of up to four capsaicin 8% patches for 30-60 minutes, or taking pregabalin orally, 150-600 mg in 2-3 divided doses daily for 8 weeks, reduces the intensity and area of dynamic mechanical allodynia (DMA, pain evoked by light brushing of the skin) in people with non-diabetic peripheral neuropathy. Complete resolution of DMA occurred in 24% of people using the patches, and 12% of those taking pregabalin (99408). The validity of these findings is limited by methodological problems, including a lack of blinding.
• Prurigo nodularis. It is unclear if topical capsaicin is beneficial for prurigo nodularis. Details: Preliminary clinical research shows that applying a cream containing the active capsicum constituent, capsaicin 0.025% to 0.3%, 4-6 times daily improves burning sensations, erythema, pruritus, and healing of skin lesions over a period of 2 weeks to 33 months when compared to baseline. Symptoms may return after discontinuation of therapy (10650).
• Sinonasal polyposis. It is unclear if intranasal capsaicin is beneficial for sinonasal polyposis. Details: Preliminary clinical research in patients with severe sinonasal polyposis shows that intranasal application of 0.5 mL of a 30 mmol/L capsaicin solution to each nostril for 3 days, followed by 0.5 mL of a 100 mmol/L capsaicin solution for 2 days, can cause significant subjective improvement in symptoms as well as objective improvement in nose/sinus air volume and endoscopy scores; however, capsaicin does not seem to significantly affect eosinophil cationic protein levels (14359).
• Swallowing dysfunction. Preliminary research shows that oral capsaicin might be beneficial for improving swallowing ability. Details: Preliminary clinical research shows that elderly patients at risk for aspiration pneumonia due to swallowing dysfunction have improved swallowing reflexes after dissolving a lozenge containing capsaicin 1.5 mcg in the mouth before each meal when compared with using a placebo lozenge (13100). Preliminary clinical research also shows that capsaicin may be beneficial in patients with swallowing dysfunction due to stroke (102278,105192). One study shows that taking 1 mL of nectar containing capsaicin 150 mcM/L with each meal daily for 3 weeks, in addition to thermal tactile stimulation, improves eating and swallowing when compared with using thermal tactile stimulation and placebo nectar (102278). Another study shows that 20 minutes of stimulation with an ice swab containing capsaicin 0.15 mM before lunch and dinner daily for three weeks modestly improves the ability to swallow water when compared with ice stimulation alone. After treatment, approximately 70% of those using the capsaicin ice were able to drink the water without choking, compared with only 33% in those using ice alone (105192). Capsaicin solution has also been administered by nebulizer. A clinical study in patients with swallowing dysfunction secondary to hemorrhagic stroke shows that inhaling capsaicin solution twice daily for one week reduces the incidence of post-swallow residue and pulmonary infection and increases number of coughs in response to capsaicin compared with placebo. However, treatment with nebulized capsaicin does not reduce the number of patients with swallow or cough reflexes compared with control (111518). More evidence is needed to rate capsicum for these uses.

(Read more about CAPSICUM)

POSSIBLY EFFECTIVE

• Cardiovascular disease (CVD). Dietary cocoa seems to be beneficial for CVD prevention. Oral cocoa extract may reduce the risk of CVD-related death, but it is unclear if it can prevent other CVD-related outcomes like myocardial infarction (MI) or stroke. Details: A large clinical trial in adults without CVD shows that taking a specific cocoa extract daily for around 3.5 years reduces the risk of CVD-related death by 27%, but does not reduce the risk of cardiovascular events, including MI or stroke, or overall mortality when compared with placebo. This specific cocoa extract contained 500 mg of flavanols, including 80 mg of epicatechins (108898). In 2023, the US Food and Drug Administration (FDA) approved a qualified health claim stating that very limited scientific evidence suggests that the cocoa flavanols in high flavanol cocoa powder, for products containing at least 4% naturally conserved cocoa flavanols, may reduce the risk of cardiovascular disease (110017). Observational research in adults without CVD has also found that consuming a higher amount of cocoa is associated with a 10% lower risk of CVD and an up to 50% lower risk of CVD-related mortality when compared with consuming lower amounts of cocoa. Consuming more than 90 grams of cocoa per week did not add further benefit (14288,97192). Additional clinical research shows that taking cocoa flavanols 450 mg twice daily for one month improves cholesterol levels and blood pressure values, resulting in improved Framingham Risk Scores in healthy patients. These scores correspond to a 21% decrease in the 10-year risk for coronary heart disease, a 22% decrease in the risk for CVD, a 31% decrease in the risk for MI, and a 30% decrease in the risk for CVD-related mortality (92273). There is also evidence that consuming cocoa might improve flow-mediated dilatation, a measure of endothelial dysfunction. Meta-analyses of clinical research have found that increased cocoa or chocolate intake significantly improves flow-mediated dilatation. This is seen with intakes of 19-54 grams of cocoa daily, 46-100 grams of dark chocolate daily, or cocoa products containing 16.6-1080 mg of flavonoids daily (17187,42059,42137).
• Hypertension. Oral cocoa seems to be beneficial for modestly decreasing blood pressure in hypertensive patients. It is unclear if dietary cocoa is beneficial for preventing hypertension. Details: Overall, clinical research shows that chocolate or cocoa containing 25-1080 mg daily of flavonoids modestly reduces blood pressure in hypertensive patients (14306,15655,15752,42092,42107,42169,97190,103247). Meta-analyses of clinical research show that consuming commercially available dark chocolate or flavanol-enriched chocolate/cocoa products daily for 2-8 weeks reduces systolic blood pressure (SBP) by around 4 mmHg and diastolic blood pressure (DBP) by around 2 mmHg in patients with hypertension when compared to control products with low levels of flavanols or no flavanols (42169,97190). Additionally, a meta-analysis of clinical trials in middle-aged and elderly patients with or without hypertension shows that consuming cocoa products daily for 4-18 weeks reduces SBP and DBP by around 3 mmHg and 1.5 mmHg, respectively, when compared with control products (103249). Blood pressure lowering seems to occur more readily in hypertensive or pre-hypertensive individuals when compared with normotensive individuals (14306,15655,15752,42092,42107,42169,97190,103247). Consumption of cocoa might also reduce the risk of developing hypertension in normotensive patients. Observational research has found that long-term consumption of moderate amounts of cocoa (2.2 grams to 6.1 grams daily) is associated with a 7% lower risk of hypertension when compared with consumption of less than 0.61 grams daily. However, consumption of amounts greater than 6.1 grams daily does not seem to reduce hypertension risk. Also, this benefit seems to be limited to patients consuming cocoa from plain chocolate, as consumption of cocoa from desserts was linked with a 9% greater risk of hypertension (103248).

POSSIBLY INEFFECTIVE

• Hypercholesterolemia. Oral cocoa does not seem to be beneficial for reducing cholesterol levels in patients with hypercholesterolemia. Details: Some preliminary clinical research in healthy, normocholesterolemic males shows that diets high in stearic acid from cocoa butter result in lower cholesterol levels when compared with diets high in myristic acid from dairy butter. However, a diet high in stearic acid from cocoa butter does not significantly lower cholesterol when compared to baseline in this population (15063). A meta-analysis of 10 clinical studies shows that cocoa or dark chocolate can reduce total cholesterol and low-density lipoprotein (LDL) cholesterol in normocholesterolemic patients (42125). However, some preliminary clinical research in patients with hypercholesterolemia shows that drinking a high-flavanol cocoa beverage daily for 6 weeks does not reduce cholesterol when compared with a low-flavanol cocoa beverage (42013). Also, while some clinical research shows that taking cocoa powder 26 grams with sugar daily for 12 weeks can increase high-density lipoprotein (HDL) cholesterol levels when compared with sugar alone in normocholesterolemic and hypercholesterolemic patients (42026), taking cocoa or dark chocolate 13-41 grams daily does not seem to lower total cholesterol or LDL cholesterol in these patients (42026,42029,42225).
• Stretch marks (striae distensae). Topical cocoa butter does not seem to be beneficial for preventing stretch marks. Details: Clinical research shows that topical application with a cream containing cocoa butter 25% to the abdomen daily, starting during the second and third trimesters and continuing until delivery, does not prevent stretch marks when compared with a placebo cream (105261). Other clinical research shows that topical application with a cream containing cocoa butter and vitamin E as tocopheryl acetate to the abdomen, breasts, and thighs, daily, starting during the second trimester and continuing until delivery, does not reduce the prevalence or severity of stretch marks when compared to a cream not containing these ingredients (105262). More research is needed in individuals of all skin types.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral cocoa is beneficial for improving cognitive function in healthy older adults. Details: Some small clinical studies in healthy adults over the age of 60 with or without existing cognitive impairment show that sub-chronic intake of cocoa at doses of 45 mg, 520 mg, or 990 mg once daily for 8 weeks, or as a cocoa drink containing flavanols 609 mg daily for 30 days, modestly improves some measures of cognitive function, including task switching, visual attention, and verbal fluency (42184,92269). However, it does not improve performance on the mini mental state exam (92269). Also, one clinical study in healthy adults aged 60 years and older shows that consuming a dark chocolate bar containing 11 grams of cocoa and drinking 237 mL of an artificially sweetened drink containing 11 grams of cocoa daily for 6 weeks does not improve neuropsychological function when compared with placebo (42050). Additional preliminary clinical research in postmenopausal females aged 50-64 years shows that adding chocolate 10 grams daily, containing 99% cocoa, for 6 months does not improve most measures of cognitive function when compared with not taking cocoa (105259). Reasons for the discrepancies are unclear but may relate to the dose of cocoa, the duration of intake, or the specific cognitive testing procedures conducted.
• Age-related testosterone deficiency. Oral cocoa has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy middle-aged adults shows that taking a combination product containing cocoa seed extract and pomegranate rind (Tesnor, Gencor) daily for 56 days increases serum testosterone levels and hand-grip strength and improves measures of sexual function and psychological well-being when compared with placebo (111527). It is unclear if these effects are due to cocoa, pomegranate, or the combination.
• Aging skin. It is unclear if oral cocoa is beneficial for aging skin. Details: Preliminary clinical research in adults with aging skin shows taking a specific product (GliSODin Skin Nutrients Advanced Anti-Aging Formula, Isocell North America Inc.) 780 mg three times daily, containing cocoa extract, as well as superoxide dismutase, krill oil, sea buckthorn, hyaluronic acid, and other nutrients, in combination with daily use of tazarotene cream 0.1%, for 90 days improves fine wrinkling, photodamage, and skin elasticity when compared with tazarotene cream and placebo (91778). Additional preliminary clinical research in patients with photoaged skin shows that drinking a cocoa drink containing 320 mg of flavanols daily for 24 weeks improves wrinkle depth and skin elasticity, but not skin hydration, when compared with placebo (92274).
• Asthma. Although there has been interest in using oral cocoa for asthma, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Athletic performance. Although there has been interest in using oral cocoa for improving athletic performance, there is insufficient reliable information about the clinical effects of cocoa for this use.
• Atrial fibrillation. It is unclear if dietary cocoa is beneficial for preventing atrial fibrillation. Details: Most population research has found that chocolate consumption is not associated with a reduced risk of atrial fibrillation (97188,97189).
• Chronic fatigue syndrome (CFS). It is unclear if oral cocoa is beneficial for CFS. Details: In patients with CFS, preliminary clinical research shows that consuming 45 grams of a polyphenol-rich chocolate in three divided doses daily for 8 weeks can reduce fatigue by 35%, anxiety by 37%, and depression by 45%, and can increase overall function by 30%, when compared with pretreatment (42116).
• Cirrhosis. It is unclear if oral cocoa is beneficial for cirrhosis. Details: Clinical research shows that consuming a liquid test meal (Ensure Plus) in addition to dark chocolate (Lindt Excellence 85% Cocoa, Lindt & Sprüngli) 0.55 grams/kg can reduce the postprandial increase in hepatic venous pressure gradient in patients with cirrhosis when compared with the test drink alone (42164).
• Cognitive function. Research on the use of oral cocoa for improving cognitive function in healthy adults is conflicting. Details: A large clinical trial in older adults shows that taking cocoa extract containing 500 mg of flavanols daily for 3 years does not improve measures of cognitive function including global cognition, episodic memory, and executive function when compared with placebo, even when taken with a multivitamin-mineral product (Centrum Silver) (111524). Also, in middle-aged participants, clinical research shows that taking 20 grams of a dark chocolate drink mix containing 250 mg or 500 mg of polyphenols as a single dose does not seem to improve measures of cognitive function (92272). In contrast, clinical research in healthy younger individuals shows that consuming a single dose of cocoa flavanols 520-994 mg as a specific powder (Cocoapro) improves some, but not all, measures of cognitive function when examined in a situation of sustained mental effort (42093). Additionally, consuming a single dose of cocoa flavanols 900 mg as a specific powder (Acticoa) seems to improve reaction time during cognitive testing when compared with placebo in healthy adults and patients with type 1 diabetes (103251). However, acute dosing with cocoa flavanols 374-747 mg as specific powders (Acticoa) or cocoa extract capsules (Naturex) does not seem to improve measures of cognitive function, visual working memory, or ability to focus during testing in young people (99984,99985,109448). Reasons for the discrepancies are unclear but may relate to the dose of cocoa, the duration of intake, the level of stress during cognitive testing, or the specific cognitive testing procedures conducted.
• Cognitive impairment. Oral cocoa flavanols have only been evaluated in combination with other ingredients; their effect when used alone is unclear. Details: A large clinical study in adults at least 55 years of age with subjective or mild cognitive impairment shows that consuming dark chocolate containing 500 mg cocoa flavanols and taking fish oil containing DHA 1.1 grams and EPA 0.4 grams daily for 12 months does not improve cognitive function scores when compared with placebo (111453).
• Constipation. Oral cocoa husk has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with chronic constipation shows that taking 2-4 sachets containing cocoa husk 8-16 grams and beta-fructosans 2-4 grams daily for 4 weeks can reduce hard stools by 45% and reduce transit time by 36 hours when compared with a placebo (42016).
• Diabetes. Several small clinical studies suggest that oral cocoa may cause small but clinically insignificant improvements in glycemic control in patients with diabetes. However, cocoa does not appear to be beneficial for the prevention of diabetes. Details: While some individual studies show conflicting results (97252,99982), two similar meta-analyses of 8-9 small clinical trials in patients with diabetes show that taking cocoa 1-54 grams daily for up to 52 weeks reduces fasting blood glucose by around 7-9 mg/dL and low-density lipoprotein (LDL) cholesterol by around 10-15 mg/dL, but does not improve glycated hemoglobin (HbA1c), insulin levels, blood pressure, total cholesterol, or high-density lipoprotein (HDL) cholesterol, when compared with control (109447,109449). This slight improvement in fasting blood glucose, along with a lack of effect on HbA1c, suggests that cocoa is unlikely to lead to clinically meaningful improvements in glycemic control. Population research has found that eating up to 60 grams of chocolate per week is associated with a lower risk of developing diabetes. Higher consumption was not found to affect diabetes risk (97192). However, secondary analysis of a large clinical study in adults aged 74 on average shows that taking an extract containing cocoa flavanols 500 mg daily, with or without a multivitamin, for about 3.5 years does not reduce the risk of developing self-reported type 2 diabetes when compared with placebo. Subgroup analysis based on body mass index, level of physical activity, or multivitamin consumption did not change results (111619).
• Exercise-induced muscle damage. It is unclear if oral cocoa flavanols are beneficial for preventing exercise-induced muscle damage. Details: Preliminary clinical research shows that taking a single dose of cocoa flavanols (Chococru Extraordinary Flavanol Cocoa) 830 mg or 1245 mg within 5 minutes of a strenuous exercise protocol does not reduce exercise-induced muscle damage over 72 hours when compared with a control providing no cocoa flavanols (105260).
• Fatigue. It is unclear if oral cocoa is beneficial for fatigue. Details: A moderate-size clinical study in otherwise healthy females aged 40-60 years with fatigue shows that consuming a beverage containing cocoa flavanols 240 mg daily for 8 weeks does not improve self-reported fatigue scores when compared with placebo (111620).
• Heart failure. It is unclear if dietary cocoa is beneficial for heart failure prevention. Details: Population research has found that consuming up to 250 grams of chocolate weekly is associated with reduced risk of heart failure. However, consuming 300 grams weekly or more does not appear to affect the risk of heart failure (97187,97191).
• HIV/AIDS-related dyslipidemia. It is unclear if oral cocoa is beneficial for HIV/AIDS-related dyslipidemia. Details: Preliminary clinical research in patients with HIV shows that consuming dark chocolate 65 grams containing cocoa 36 grams for 15 days does not affect low-density lipoprotein (LDL) cholesterol or total cholesterol levels when compared with a white chocolate placebo. However, it slightly increases levels of high-density lipoprotein (HDL) cholesterol (96472).
• Impaired glucose tolerance (prediabetes). It is unclear if oral cocoa is beneficial in patients with prediabetes. Details: A small clinical study in premenopausal adults with overweight or obesity and mild insulin resistance shows that drinking a cocoa drink high in flavanols twice daily for 4 weeks does not improve measures of insulin resistance or insulin-mediated glucose uptake when compared with a low-flavanol cocoa drink (111532).
• Influenza. Although there has been interest in using oral cocoa for influenza, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Insect repellent. It is unclear if topical cocoa oil is beneficial as an insect repellent. Details: Preliminary clinical research shows that topical application of cocoa oil, 1 mL on each leg and 0.5 mL on each forearm, reduces bites from black flies (Simulium damnosum) by 99% (41954).
• Isolated systolic hypertension. It is unclear if oral cocoa is beneficial for isolated systolic hypertension. Details: Preliminary clinical research shows that consuming 100 grams daily of cocoa polyphenol-rich dark chocolate might modestly reduce systolic and diastolic blood pressure in elderly patients with isolated systolic hypertension (13166).
• Menopausal symptoms. It is unclear if oral cocoa is beneficial for menopausal symptoms. Details: In postmenopausal individuals aged 50-64 years, preliminary clinical research shows that adding chocolate 10 grams daily, containing cocoa 99%, for 6 months reduces body fat mass by approximately 0.6 kg and body fat percentage by 0.8%, and modestly improves some measures of quality of life, when compared with no treatment (105255,105258). However, there was no effect on all measures of quality of life, general menopausal symptoms, weight, body mass index, or most measures of cognitive function (105255,105258,105259).
• Multiple sclerosis (MS). Although there has been interest in using oral cocoa for MS, there is insufficient reliable information about the clinical effects of cocoa for this condition.
• Muscle strength. Oral cocoa seed extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy males shows that taking a combination product containing cocoa seed extract and pomegranate rind extract 400 mg daily for 8 weeks increases testosterone levels, hand grip strength, and upper arm circumference when compared with placebo (108485).
• Nipple fissures. It is unclear if topical cocoa butter is beneficial for the treatment or prevention of nipple fissures. Details: A small clinical study in breastfeeding adults shows that applying topical cocoa butter to the nipple and areola after each breastfeeding session for 10 days immediately postpartum reduces nipple pain, rashes, and cracks when compared with the topical application of the mother's breastmilk (111525). The validity of this study is limited by a lack of blinding and a high dropout rate.
• Obesity. It is unclear if oral cocoa is beneficial for obesity. Details: Preliminary clinical research in overweight or obese premenopausal females shows that following a reduced-calorie diet in addition to consuming two squares of dark chocolate and drinking 8 ounces of a sugar-free cocoa beverage daily for 18 weeks does not increase weight loss when compared with the reduced-calorie diet plus a non-chocolate snack (42130,99983).
• Parkinson disease. It is unclear if oral cocoa is beneficial for Parkinson disease. Details: Preliminary clinical research shows that consuming a single dose of dark chocolate 200 grams containing approximately 80% cocoa does not improve motor function in patients with Parkinson disease when compared with a white chocolate control, although there seems to be some improvements after one hour when compared with baseline (42156).
• Peripheral arterial disease (PAD). It is unclear if oral cocoa is beneficial for PAD. Details: A small clinical study in patients with PAD shows that drinking a flavanol-rich cocoa beverage 15 grams daily for 6 months increases 6-minute walking distance by up to 43 meters when compared with placebo (103250). Cocoa has also been studied in adults with diabetes at risk for developing PAD, with conflicting results. A small clinical study in adults with and without diabetes shows that taking a single dose of cocoa flavanols 790 mg does not improve peripheral microvascular or macrovascular parameters compared with placebo (111529). However, another small clinical study in healthy adults and those with diabetes at risk for PAD shows that taking cocoa flavanols (CocoaVia, Mars Inc) 1350 mg improves endothelial function in the brachial and femoral arteries after 2 hours when compared with placebo, suggesting that cocoa flavanols might reduce the risk of developing PAD in both populations studied (111528). The validity of this study is limited by the small sample size and short study duration.
• Stroke. It is unclear if dietary cocoa is beneficial for stroke prevention. Details: Population research has found that the highest dietary intake of chocolate is associated with a 16% reduced risk of stroke when compared with the lowest intake (97192). More evidence is needed to rate cocoa for these uses.

(Read more about COCOA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. Although there has been interest in using oral damiana for asthma, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Cognitive function. Although there has been interest in using oral damiana for cognitive function, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Constipation. Although there has been interest in using oral damiana for constipation, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Depression. Although there has been interest in using oral damiana for depression, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Diabetes. Although there has been interest in using oral damiana for diabetes, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Dyspepsia. Although there has been interest in using oral damiana for dyspepsia, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Erectile dysfunction (ED). Oral damiana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized, open-label clinical study in adults with mild-to-moderate ED shows that taking a specific combination supplement (Icarifil, Anvest Health S.p.A) containing damiana 100 mg, panax ginseng, L-carnitine, L-citrulline, tribulus, and other ingredients daily for 3 months improves patient-reported erectile function when compared to baseline. Additionally, taking the supplement with tadalafil improves some, but not all, patient-reported assessments of erectile function when compared with taking tadalafil alone (114989). It is unclear if this effect is due to damiana, other ingredients, or the combination. Additionally, the interpretation of these results is limited by poor methodology, including the use of per-protocol analysis and lack of a placebo group.
• Headache. Although there has been interest in using oral damiana for headache, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Menopausal symptoms. Although there has been interest in using oral damiana for menopausal symptoms, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Obesity. Oral damiana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in overweight adults shows that taking a combination product containing damiana 36 mg, guarana 95 mg, and yerba mate 112 mg, orally three times daily for 45 days increases weight loss when compared with placebo (11866). It is unclear if this effect is due to damiana, other ingredients, or the combination.
• Nocturnal enuresis. Although there has been interest in using oral damiana for nocturnal enuresis, there is insufficient reliable information about the clinical effects of damiana for this purpose.
• Sexual dysfunction. Oral damiana has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing damiana, L-arginine, Panax ginseng, ginkgo, vitamins, and minerals (ArginMax for Women, Daily Wellness Co.) improves sexual satisfaction and desire, increases orgasm frequency, and reduces vaginal dryness when compared with placebo in females interested in improving their sexual function (46933). It is unclear if this effect is due to damiana, other ingredients, or the combination. More evidence is needed to rate damiana for these uses.

(Read more about DAMIANA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). Although there is interest in using oral dong quai for atopic dermatitis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Chronic kidney disease (CKD). There is limited evidence on the use of dong quai in patients with CKD. Details: A large propensity score-matched observational study over 15 years in Taiwanese adults with CKD suggests that taking dong quai is associated with a 5.1% risk of end-stage renal disease (ESRD) and 38% risk of overall mortality when compared with 7% and 56%, respectively, in controls. Higher cumulative doses (i.e., 15 grams or more) and longer duration of exposure (i.e., > 60 days) are also associated with fewer ESRD events (112362). However, the interpretation of these findings is limited by the lack of exact dosage information and retrospective study design.
• Coronary heart disease (CHD). Intravenous dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with CHD shows that injecting 20 mL of an intravenous solution containing dong quai, ginseng, and astragalus (Yi-qi Huo-xue Injection) daily for 2 weeks reduces the frequency and severity of angina episodes when compared with placebo. It also seems to increase exercise tolerance and improve left ventricular function when compared with placebo (33046). It is unclear if these benefits are due to dong quai, other ingredients, or the combination.
• Dysmenorrhea. Although there is interest in using oral dong quai for dysmenorrhea, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Hypertension. Although there is interest in using oral dong quai for hypertension, there is insufficient reliable information about the clinical effects of dong quai for this purpose.
• Idiopathic interstitial pneumonia. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of 17 studies conducted in China in patients with idiopathic interstitial pneumonia concludes that adding traditional Chinese medicine combinations containing dong quai root and astragalus root to treatment with conventional medicines improves pulmonary function index, six-minute walking distance, and the Borg scale of perceived exertion when compared with conventional treatment alone (103618). The included studies are of low quality, include a range of treatment durations from 1-12 months, and vary in the conventional medicines and Chinese herb combinations used. The doses of dong quai used were not stated.
• Infertility. Although there is interest in using oral dong quai for infertility, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Iron deficiency anemia. Although there is interest in using oral dong quai for iron deficiency anemia, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Menopausal symptoms. There is inconsistent and contradictory evidence about the effect of dong quai on menopausal symptoms. Benefits have only been seen when it is used in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research shows that taking dong quai, 1.5 grams three times daily for 24 weeks, does not affect menopausal symptoms (738). Other clinical research shows that dong quai improves menopausal symptoms when used in combination with other constituents. In one clinical trial, taking five chewable tablets of a specific combination of dong quai and chamomile (Climex) daily for 12 weeks reduced the frequency and severity of hot flushes when compared with placebo (48445). In another trial, taking a combination providing dong quai 75 mg, along with American ginseng, black cohosh, milk thistle, red clover, and vitex agnus-castus (Phyto-Female Complex) twice daily for 3 months reduces menopausal symptoms, including the number and intensity of hot flushes, the number of night sweats, and sleep quality (19552). Taking another combination product containing dong quai, burdock root, licorice root, motherwort, and Mexican wild yam root, 500 mg three times daily for 3 months, also reduces menopausal symptoms when compared with placebo (48522). It is unclear if the beneficial effects in these studies were due to dong quai, other ingredients, or a combination of ingredients.
• Migraine headache. Oral dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with menstrual migraine shows that taking a combination of soy isoflavones 60 mg, dong quai 100 mg, and black cohosh 50 mg daily for 24 weeks reduces the frequency of attacks when compared with placebo (35797). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
• Osteoporosis. Although there is interest in using oral dong quai for osteoporosis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Peptic ulcers. Although there is interest in using oral dong quai for peptic ulcers, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Premature ejaculation. Topical dong quai has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In one preliminary clinical trial in patients with premature ejaculation, a multi-ingredient cream preparation (SS Cream) containing dong quai, Panax ginseng root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, clove flower, Asiasari root, cinnamon bark, and toad venom was applied to the glans penis 1 hour prior to intercourse and washed off immediately before intercourse. Patients using the cream had significantly improved ejaculatory latency when compared with placebo cream (2537). It is unclear if this effect is due to dong quai, other ingredients, or the combination.
• Premenstrual syndrome (PMS). Although there is interest in using oral dong quai for PMS, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Psoriasis. Although there is interest in using oral dong quai for psoriasis, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Pulmonary hypertension. Preliminary clinical research shows that intravenous dong quai may be effective in patients with pulmonary hypertension. Details: Some preliminary clinical research in patients with chronic obstructive pulmonary disease (COPD) and pulmonary hypertension shows that intravenous administration of 250 mL of a solution containing dong quai 25%, once daily for 5-10 days, reduces pulmonary arterial pressure and pulmonary vascular resistance when compared to baseline (48438,48442,48443). The validity of these findings is limited by the lack of comparator groups.
• Rheumatoid arthritis (RA). Although there is interest in using oral dong quai for RA, there is insufficient reliable information about the clinical effects of dong quai for this condition.
• Stroke. Preliminary evidence does not support the use of intravenous dong quai for acute ischemic stroke. Details: Preliminary clinical research in patients with acute ischemic stroke shows that administering 200 mL of a solution containing dong quai 25% intravenously daily for 20 days does not improve neurological symptoms when compared with dextran-40 (48483). More evidence is needed to rate dong quai for these uses.

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EFFECTIVE

• Folate deficiency. Oral or intravenous folic acid is effective for the prevention or treatment of folate deficiency. Details: Administering folic acid orally or parenterally improves and prevents folate deficiency (505,8739). Clinical research shows that supplementation with folic acid 100 mcg to 5 mg daily during pregnancy decreases the risk of developing megaloblastic anemia by up to 79% (91307).

LIKELY EFFECTIVE

• Kidney failure. Taking folic acid orally reduces homocysteine levels in people with kidney failure who are on hemodialysis. Details: Over 85% of people with kidney failure have hyperhomocysteinemia. Treatment of hyperhomocysteinemia in kidney failure is often more difficult than with normal kidney function (1489,3324,7289,9413,9414,9416). The reasons for this are not fully understood; renal uptake and metabolism of homocysteine may be reduced in severe kidney failure, and hemodialysis may contribute to vitamin deficiencies (6884,9414,9417). Folic acid 0.8-15 mg daily or 3 times weekly is generally used, but the degree of homocysteine reduction varies between 12% to 50%, and normal homocysteine levels (less than 12 µmol/L) cannot always be achieved. Adding vitamin B12 400-1000 mcg daily and vitamin B6 20-50 mg daily produces an additional reduction in homocysteine (1489,6884,7289,7881,9322,9413,9414,9415,9416,9417). Folic acid doses greater than 15 mg daily do not seem to provide additional benefit. Also, doses of 30-60 mg might cause a rebound in homocysteine levels when treatment is stopped (9219). Despite the homocysteine-lowering effect of folic acid in kidney failure, the most robust meta-analysis of 11 clinical trials suggests that folic acid supplementation does not seem to reduce the risk of cardiovascular events (50527). A smaller meta-analysis of 7 clinical trials that used a different primary composite outcome suggests that folic acid might reduce the risk of cardiovascular events by 15% when compared with control (91311). There has also been interest in using a reduced form of folic acid, L-5-methyltetrahydrofolate (L-5-MTHF). One study in patients on hemodialysis suggests that taking L-5-MTHF 17 mg daily for 12 weeks might lower homocysteine levels to a greater extent than an equimolar 15 mg of folic acid (104908). Another clinical trial in patients on hemodialysis suggests that giving intravenous L-5-MTHF 50 mg three times weekly is associated with an increased survival of about 36 months, compared with about 26 months with folic acid 5 mg daily. There was no difference in homocysteine reduction between groups (104909). These results should be interpreted with caution because they have not been replicated, and there was no placebo control. Furthermore, survival may have been affected by the availability of kidney transplants.
• Hyperhomocysteinemia. Oral folic acid, taken alone or in combination with other B vitamins, lowers homocysteine levels in most patients. However, it is unclear if this has cardiovascular benefits. Details: Taking folic acid orally 0.4-5 mg daily lowers fasting homocysteine levels by 20% to 30% in people with normal to moderately elevated homocysteine levels at baseline. Folic acid 0.8-1 mg daily seems to provide maximal reduction (9307,9400,9401,9405,9408,11337,11338,50145). Doses above 1 mg daily do not seem to add benefit (9307), except in some people with certain gene mutations that cause homocysteine levels of 20 µmol/L or higher (9408). The higher the initial homocysteine levels, the lower the folic acid dose needed to attain maximum homocysteine reduction (9307). The effects of folic acid supplementation on homocysteine concentrations appear to be greater in females than males (50145). Adding vitamin B6 25-250 mg or vitamin B12 500 mcg seems to further reduce homocysteine levels (1489,9400,9405,9406,9408,107136). Some experts recommend routine use of vitamin B12 in homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Increasing folic acid intake with supplements or folate-fortified cereal products is more effective for reducing homocysteine levels than increasing intake of folate-rich foods (6367). Fortification of cereals and flour with 140 mcg folic acid per 100 grams reduces the mean homocysteine level in the general population by about 7% (7881,9404,9407). Elevated homocysteine levels are considered by some to be an independent risk factor for atherosclerosis progression, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, ischemic stroke, and other vascular complications (3886,3887,6236,7725,9314,9318,50509). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). Although folic acid lowers homocysteine levels, it is not yet known whether this reduces the risk of vascular disease. One meta-analysis shows that taking folic acid can reduce the risk of stroke by about 10% in patients with cardiovascular disease (CVD); the reduction is greatest in patients for whom homocysteine levels are lowered by at least 25% (96157). A meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). However other research does not agree. Meta-analyses of clinical research show that folic acid does not prevent CVD or coronary heart disease, in spite of lowering homocysteine by up to 55%, when individuals with normal or high levels of homocysteine are considered (50539,96147,97619). Furthermore, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or improve secondary prevention of cardiovascular events such as myocardial infarction in people with existing CVD despite a homocysteine-lowering effect (9313,11337,11387,13482,50437,97619). Some research even suggests an increase in CVD risk concurrent with homocysteine lowering (13482). Large randomized controlled trials are needed to confirm or refute these findings. Some researchers hypothesize that different genetic profiles might explain some of these conflicting results. For instance, individuals with a homozygous 677TT MTHFR genotype typically have increased homocysteine levels. However, a meta-analysis suggests that treatment with folic acid does not reduce the risk of ischemic heart disease despite reducing homocysteine levels in individuals with 677TT MTHFR (50456). It has also been theorized that a reduced form of folic acid, 5-methyltetrahydrofolate (5-MTHF) might work better in these individuals. Although [6RS]-5-MTHF has been shown to lower homocysteine levels (104915), studies assessing its cardiovascular benefits are lacking.
• Methotrexate toxicity. Oral folic acid reduces the severity of methotrexate toxicity. Details: Oral folic acid reduces methotrexate toxicity symptoms, such as nausea and vomiting, in the treatment of rheumatoid arthritis (RA) and psoriasis (768,2162,2163,2164,4492,4493,4494,9369,9419). Folic acid also seems to reduce methotrexate-induced hepatic side effects by approximately 36% (50320). Some research shows that a low, 0.8 mg weekly dose of folic acid is equally effective to a higher dose of 5 mg weekly for the prevention of methotrexate toxicity (102388).
• Neural tube birth defects. Oral folic acid helps to prevent neural tube birth defects in newborns. Details: Clinical practice guidelines recommend that anyone capable of becoming pregnant take folic acid 400 mcg daily from fortified foods or supplements to prevent neural tube birth defects in infants. Folic acid 600 mcg daily is advised during pregnancy (94811,96146). This recommendation is based on research showing that a higher intake of folic acid from food and supplements during pregnancy reduces the primary incidence of neural tube birth defects by 41% to 69% (3325,9309,50344,50403,50468,95156). Individuals with a history of children with neural tube birth defects usually take a higher dose of folic acid 4000 mcg daily starting one month before and continuing for up to 3 months after conception (96146). Evidence shows that, when used for secondary prevention, folic acid supplementation reduces the incidence of neural tube defects by 66% to 87% (21235,50263,50344,50403,95156). In the US, foods containing at least 60 mcg of folic acid can be labeled with a health claim stating that healthful diets with adequate folic acid intake may reduce the risk of having a child with a brain or spinal cord defect (102369).

POSSIBLY EFFECTIVE

• Cognitive impairment. Taking folic acid alone, with other B vitamins or with docosahexaenoic acid (DHA), might improve thinking and memory skills in older patients with cognitive impairment. Details: One clinical trial in patients aged 65 years and older with mild cognitive impairment (MCI) shows that taking folic acid 400 mcg daily for 2 years increases IQ scores when compared with placebo (100952). Two small, low-quality clinical studies in patients aged 70-90 years with cognitive impairment and low folate levels or folate deficiency shows that taking folic acid 5 or 15 mg daily for up to 63 days improves cognitive function, including measures such as memory and attention, when compared with placebo or baseline (50301,104911). Folic acid also appears to be beneficial when used in combination with other B vitamins or with DHA. A clinical trial in patients aged 70 years and older with MCI shows that taking folic acid 800 mcg, vitamin B6 20 mg, and vitamin B12 500 mcg daily for 2 years mitigates decline in executive function and, in patients with high baseline homocysteine levels, improves cognition and memory when compared with placebo (50480). Taking folic acid 800 mcg with or without DHA 800 mg daily for 6 months modestly improves cognition, as measured on the full-scale intelligence quotient, when compared with placebo (103978,109196). However, this benefit is no longer present at 6 months after treatment discontinuation (109196).
• Depression. Oral folic acid seems to modestly reduce depression severity when added to conventional antidepressant therapy. It is unclear if folic acid can reduce the prevalence of depression or the risk for suicide. Details: Observational studies suggest that depression is correlated with low folate status, particularly in females (50105,50127,50243). Taking folic acid 0.2-15 mg daily for up to 6 months with conventional antidepressants seems to improve treatment response in patients with major depressive disorder (3657,10884,10887,50566,109190). One meta-analysis shows that taking L-methylfolate or folic acid as an adjunct to treatment with conventional antidepressants modestly reduces depression severity when compared with placebo and conventional antidepressants. The response and remission rates were improved by 36% and 39%, respectively (109190). However, limited clinical research suggests that folic acid is not effective as a replacement for conventional antidepressant therapy (10886). Also, a small clinical study in adolescents at high familial risk for mood disorders suggests that taking folic acid 2.5 mg daily for up to 36 months does not prevent mood disorders when compared with placebo. However, in the patients that were eventually diagnosed with depression, the time of onset was delayed from 5 months to 15.5 months in the group using folic acid when compared with placebo (91313). Guidelines from The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce state that folic acid is not currently recommended as monotherapy treatment for unipolar depression (110318). Observational research has also evaluated the association between folic acid supplementation and suicidal events in patients with or without depression. One within-person cohort study, in which only 12% of patients were diagnosed with depression, has found that filling a folic acid prescription of 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a reduced risk for suicidal events during the following months when compared with months without a prescription (109201). It is unclear what percentage of these patients, if any, had folate deficiency at baseline.
• Hypertension. Oral folic acid seems to modestly reduce hypertension. Details: A meta-analysis of clinical research shows that taking folic acid 5-10 mg daily for at least 6 weeks reduces systolic blood pressure by 2mmHg and improves flow-mediated dilation by 1.6% in hypertensive individuals (50364). Some research has evaluated folic acid in hypertensive patients when used with antihypertensive drugs. Results show that taking folic acid 400-800 mcg in combination with enalapril 10 mg daily for about 4.5 years does not improve blood pressure when compared with enalapril alone (50302,96158). However, in hypertensive patients with heavy proteinuria, this combination seems to reduce the risk of all-cause mortality by about 41% when compared with enalapril alone (96158).
• Phenytoin-induced gingival hyperplasia. Topical folic acid seems to reduce gingival hyperplasia due to phenytoin. The effect of oral folic acid is unclear. Details: Applying folic acid topically seems to inhibit gingival hyperplasia secondary to phenytoin therapy (2151). However, taking folic acid orally does not seem to improve gingival hyperplasia secondary to phenytoin therapy in adults (2150,2151,2152), although some evidence suggests that taking folic acid 500 mcg daily reduces the risk of phenytoin-induced gingival hyperplasia by 33% in children when compared with placebo (50463).
• Stroke. Although some clinical research has shown that oral folate reduces stroke risk by a small amount, more research is needed to determine who is most likely to benefit. Most individual clinical trials show that folic acid seems to reduce stroke risk only in regions without food-fortification policies. Details: Multiple clinical studies have shown that folic acid supplementation reduces the risk of stroke by 10% to 25% in regions WITHOUT established policies mandating folic acid fortification of grain products (50240,50485,50525,50539,91325,96154,96157,96159,97308). The effect appears to be greatest when folic acid is taken in low doses (usually 0.8 mg daily or lower) (50525,96157,96159), in regions with a low prevalence of statin use (50525,96159), in patients with high cholesterol levels at baseline (96152), in patients who achieve homocysteine reduction of at least 20% (50407,96157), and in patients with the lowest folate levels at baseline (96154,96157). There is also some evidence that the effect of folic acid on stroke risk is greatest in patients with low baseline levels of vitamin B12 (96159). In 2001, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Most research shows that folic acid supplementation does not reduce the risk of stroke in regions WITH established policies mandating folic acid fortification (50240,50485,50525,50539,96157,96159,97308). However, there is some evidence that folic acid may reduce the risk of stroke in patients from regions with folic acid fortification who have recently had a stroke or transient ischemic attack and are not using antiplatelet drugs (90379). Meta-analyses of clinical research have been conducted. However, possible confounding due to the presence or absence of folic acid fortification is unclear. A meta-analysis of the available research in adults with existing CVD shows that folic acid supplementation at a daily dose of less than 2 mg reduces the risk for stroke by about 10% (102386). Also, a meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation, including folic acid, reduces the relative risk of stroke by 10% when compared with placebo (97619). In patients with a history of stroke, a meta-analysis shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136). It is unclear if folic acid reduces the stroke risk in patients with impaired kidney function. Some research shows that taking folic acid in combination with high doses of vitamin B12 (cyanocobalamin) does not reduce the risk of stroke in these patients (11387,96150). However, there is concern that the lack of benefit may have been due to the decline in kidney function from high doses of cyanocobalamin (96150). Additional research is needed to determine if folic acid supplementation is beneficial in patients with impaired kidney function when used with other forms of vitamin B12 such as methylcobalamin or hydroxycobalamin.
• Vitiligo. Oral folic acid seems to improve vitiligo symptoms. Details: Taking folic acid orally seems to improve symptoms of vitiligo (2153,2154). This finding is supported by a meta-analysis of observational research which shows that patients with vitiligo have higher serum homocysteine levels when compared with patients without vitiligo (100951).

POSSIBLY INEFFECTIVE

• Anemia. Adding oral folic acid to oral iron therapy does not seem to improve hematologic parameters in patients with anemia. Details: In postpartum patients with anemia, clinical research shows that taking iron as ferrous fumarate 600 mg and folic acid 1 mg daily is no more effective than iron alone for improving hemoglobin status (91319). Also, clinical research in non-pregnant menstruating females shows that taking folic acid 0.4 mg daily or 2.8 mg once weekly for 16 weeks with iron 60 mg daily does not reduce anemia or improve iron status when compared with iron alone (109193). During pregnancy, clinical research shows that folic acid supplementation does not decrease the risk of pre-delivery anemia or low hemoglobin levels (91307).
• Age-related cognitive decline. Oral folic acid does not seem to prevent cognitive decline in healthy elderly adults. Details: Most clinical research shows that taking folic acid, alone or in combination with other B vitamins, does not improve cognitive function, including memory, language, or executive function, in elderly adults with age-related cognitive decline (50318,50412,50510). In fact, a large-scale observational study in the US has found that people over 65 years of age who consume large amounts of folic acid (median of 742 mcg daily) have cognitive decline at a rate twice as fast as those consuming smaller amounts (median of 186 mcg daily) (13068). While most research on folic acid for age-related cognitive decline lacks positive findings, many of the studies are small, short-term (<1 year), underpowered to detect significant differences, and not specific to patients with high homocysteine levels. Population research has found that high homocysteine levels are associated with decreased cognition in older adults, suggesting that using folic acid to lower homocysteine levels might mitigate cognitive decline in these patients (50094). Two long-term clinical trials examining the effects of folic acid in elderly adults with high homocysteine levels show mixed results. A large-scale clinical trial of patients aged 50-70 years from the Netherlands who have high homocysteine levels shows that taking folic acid 800 mcg daily for 3 years increases memory, information processing, and other measures of cognitive function when compared with placebo (15271). However, another large-scale clinical trial of patients aged 65 years and older from the Netherlands who have high homocysteine levels shows that taking folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years lowers homocysteine levels, but does not appear to improve overall measures of cognitive function, when compared with placebo (90392). The reasons for the discrepant findings in these two studies are not clear but might relate to differences in the dose of folic acid, duration of treatment, and age of patients included.
• Cataracts. Oral folic acid does not seem to reduce cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or with risk factors for CVD shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of developing cataracts. Furthermore, the risk of cataract extraction was increased by 28% in these patients (96149).
• Diarrhea. Oral folic acid does not seem to reduce the risk of diarrhea, and might even increase the incidence of diarrhea in children. Details: In children aged 6-30 months at risk of malnourishment, clinical research shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of diarrhea when compared with placebo. Enrichment with folic acid, with or without vitamin B12, actually seems to increase the likelihood of having more episodes of both persistent diarrhea and diarrhea lasting over 3 days (90391).
• Fall prevention. Oral folic acid does not seem to reduce the risk of falls. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily, for 2 years, does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Fetal and premature infant mortality. Oral vitamin B12 does not seem prevent mortality in premature infants. Details: Clinical research shows that supplementation with folic acid during pregnancy does not decrease the risk of miscarriage, stillbirth, or neonatal death (91307,96156).
• Leukemia. Oral vitamin B12 does not seem to reduce the risk for pediatric acute lymphoblastic leukemia. Details: A meta-analysis of results from two case-control studies has found that increased folate intake during pregnancy is not associated with a reduced risk of childhood acute lymphoblastic leukemia (50247).
• Male infertility. Oral folic acid does not seem to improve sperm parameters or pregnancy rates in males with infertility. Details: Some small clinical studies show that taking folic acid, alone or with zinc, increases sperm count in males with idiopathic infertility or in males with a grade III varicocele (9334,90194). However, another small study in males with asthenozoospermia shows that taking folic acid 5 mg, selenium 200 mcg, and vitamin E 400 IU daily for 3 months does not improve sperm parameters when compared with placebo (104907). Furthermore, there seems to be no improvement in clinical outcomes. One large, high-quality clinical study in males with idiopathic infertility shows that taking folic acid 5 mg with zinc 30 mg daily for 6 months does not improve sperm morphology, pregnancy rate, or live birth rate when compared with placebo (102085). Folic acid has also been evaluated in combination with other ingredients. A retrospective study in males with or without varicocele-related infertility suggests that taking a specific combination product containing folic acid 0.2 mg, vitamin C, zinc, L-carnitine fumarate, acetyl-L-carnitine, coenzyme Q10, selenium, and vitamin B12 (Proxeed Plus, Sigma-Tau) twice daily for 6 months is associated with improvements in sperm count, sperm concentration, and sperm motility when compared to baseline. Improvement in semen parameters were greatest in subjects with more severe varicoceles (111296). The validity of this study is limited by the lack of a comparator group.
• Osteoporosis. Oral folic acid does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly adults or adults with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral folic acid does not seem to improve physical performance in older adults. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg daily for 2 years, does not improve hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).
• Pre-eclampsia. Oral folic acid does not seem to prevent pre-eclampsia in pregnant patients. Details: While the effect of low-dose prenatal folic acid is unclear, high-dose folic acid does not seem to reduce the risk of pre-eclampsia. Some population research has found that low-dose folic acid is associated with a 22% reduced odds of pre-eclampsia, while other research has found no association (91308,99370,99372,110447). A large clinical trial evaluating high-dose folic acid in pregnancies at risk for pre-eclampsia shows that taking 4 mg daily, starting at 8-16 weeks of gestation and continuing until delivery, does not reduce the risk of pre-eclampsia when compared with placebo (103929). A secondary analysis of this study in twin pregnancies has also found no benefit with high-dose folic acid supplementation (103977).
• Respiratory tract infections. Oral folic acid does not seem to prevent respiratory tract infections. Details: Clinical research in children aged 6-30 months at risk of malnourishment shows that taking a nutritional supplement (Nutriset Ltd) enriched in folic acid 75-150 mcg, with or without vitamin B12 0.9-1.8 mcg, daily for 6 months does not reduce the incidence of lower respiratory infections when compared with a supplement not enriched with folic acid and vitamin B12 (90391).

LIKELY INEFFECTIVE

• Colorectal adenoma. Oral folic acid does not prevent colorectal adenomas. Details: Although some population research and one clinical study has found that high folate intake is associated with reduced colorectal adenoma risk (2142,2143,91303), most clinical research does not support this finding. Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily for up to 9.2 years, does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389). Other clinical research suggests that taking folic acid does not reduce the occurrence or recurrence of adenomas or incidence of advanced adenomas (34596,50241,50265,50369,50394,50449,50522). Furthermore, treatment with folic acid for more than 3 years seems to be associated with an increased risk of advanced adenomatous lesions (50378).
• Fragile X syndrome. Oral folic acid does not improve symptoms in children with fragile X syndrome. Details: Clinical research shows that taking folic acid orally does not improve symptoms of fragile X syndrome (2155,2156,2157,2158,2159,2160,50575).
• Preterm labor. Oral folic acid does not seem to reduce the risk of preterm birth. Details: Meta-analyses of clinical research show that supplementation with folic acid 200 mcg to 5 mg during pregnancy does not decrease the risk of preterm birth (91307,96155). An observational study in patients with and without epilepsy found that folic acid supplementation during pregnancy was associated with a lower odds of preterm birth in patients receiving antiseizure medications; however, no link between folic acid and preterm labor was reported in patients without epilepsy or in those with epilepsy not receiving antiseizure medications (110447).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abdominal wall defects. It is unclear if oral folic acid helps to prevent abdominal wall defects in newborns. Details: Observational research in a population in northern China has found that taking folic acid supplements until the end of the first trimester modestly reduces the risk of abdominal wall defects and the risk of omphalocele, specifically, in the newborn when compared with not taking folic acid. However, this association was not found in a population in southern China (109191). These differing outcomes may be related to the lower dietary folate intakes in northern China.
• Acne. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing folic acid, vitamin B6, nicotinamide, azelaic acid, zinc, and copper for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared with baseline (90800).
• Age-related macular degeneration (AMD). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg daily reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to folic acid, other ingredients, or the combination.
• Age-related testosterone deficiency. Folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with overweight or obesity, mild erectile dysfunction, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte) increases testosterone, luteinizing hormone, and measures of erectile dysfunction but not follicle-stimulating hormone or sperm parameters when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Alzheimer disease. It is unclear if oral folic acid reduces the risk of developing this condition. Details: Low levels of folate and high levels of homocysteine have been linked to a greater risk of Alzheimer disease (50094). Also, some observational studies have found that higher intake of folate from the diet and supplements in elderly adults is associated with a reduced risk of developing Alzheimer disease when compared with lower intake (13165,15270). One small clinical trial in patients with Alzheimer disease who are taking cholinesterase inhibitors shows that taking folic acid 1 mg daily for 6 months increases the likelihood of treatment response, classified as global improvement in behavioral and/or functional status with no decline in mental status scores, by 78% to 87% when compared with placebo (50246). Also, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). However, not all research agrees. Clinical research in patients with probable Alzheimer disease using routine medications shows that taking folic acid 5 mg, vitamin B12 1 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo (50319). However, all patients in this study were also consuming a folate-fortified diet.
• Angioplasty. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that folic acid 1 mg, vitamin B12 400 mcg, and pyridoxine 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6, and vitamin B12 followed by oral administration of folic acid 1.2 mg, vitamin B6 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151).
• Atopic dermatitis (eczema). It is unclear if oral folic acid during pregnancy reduces the risk of eczema in the child. Details: Observational research has found that consuming both iron and folic acid supplements during pregnancy is associated with a four-fold reduced risk for developing atopic dermatitis in the child. However, use of either iron or folic acid supplementation alone is not associated with an effect on the child's risk for atopic dermatitis (102387).
• Autism spectrum disorder. It is unclear if oral folic acid intake during pregnancy reduces the risk of autism spectrum disorder in the child. Details: A meta-analysis of population research has found that consumption of folic acid of at least 400 mcg daily from both diet and supplements during pregnancy is associated with a 45% reduced risk of autism in the child at 2-15 years of age. Also, supplementation with folic acid during the prenatal to early period of pregnancy is associated with an approximate 43% reduced risk of autism in the child. This association did not differ between countries with or without a folate fortification program (109198). An individual population study has also found that prenatal folic acid supplementation initiated the first day of the last menstrual period before conception is associated with a 39% reduced odds of autism in the child at age 3.3-10.2 years when compared to pregnancies without folic acid supplementation (91324).
• Beta-thalassemia. There is limited evidence on the oral use of folic acid for beta-thalassemia minor. Details: Patients with beta-thalassemia minor may experience decreased muscle strength and increased bone or muscle pain. A small clinical study in children with this condition shows that taking folic acid 1 mg, with or without L-carnitine 50 mg/kg, daily for 3 months reduces bone pain by 64% to 84% and increases the number of stairs climbed by 2- to 5-fold when compared with baseline (90631). The validity of this finding is limited by the lack of a control group.
• Bipolar disorder. It is unclear if adding oral folic acid to conventional bipolar therapy further improves symptoms. Details: Some clinical evidence suggests that folic acid does not improve the antidepressant effects of lithium in patients with bipolar disorder (50566). However, other clinical evidence suggests that taking folic acid in combination with valproate during the acute phase of mania improves the effects of valproate (50357).
• Breast cancer. It is unclear if oral folic acid reduces breast cancer risk. Details: Some older population research suggests that increased intake or levels of folic acid alone does not affect the risk of breast cancer or breast cancer-related mortality (50218,50224). However, in a specific group of women who also consume high amounts of dietary methionine, cyanocobalamin (vitamin B12), or pyridoxine (vitamin B6), dietary intake of folate is associated with a reduced risk of breast cancer (9328,50224). Also, more recent population research has found that folic acid plus folate dietary intakes between 153-400 mcg are associated with a reduced risk of breast cancer. This risk is further reduced in those who drink relatively large amounts of alcohol (90794). Folate intakes greater than 400 mcg daily do not appear to be protective against breast cancer (90794).
• Cancer. It is unclear if oral folic acid prevents cancer. Details: A large cohort study of children born to mothers with epilepsy on antiseizure medications suggests that prenatal folic acid exposure of 1 mg daily or more, at an average of 4.3 mg daily, is associated with a 2.7-fold greater risk of pediatric cancer when compared with children born to mothers with epilepsy but without prenatal exposure to high-dose folic acid. Additionally, this risk is not present in children of mothers without epilepsy taking high-dose folate (112103). It is unclear how maternal epilepsy, antiseizure medications, and folate interact to increase the risk of pediatric cancers. However, in the absence of clear guidelines, mothers with epilepsy should take no more than 4 mg of folic acid daily (112101,112102).
• Cardiovascular disease (CVD). Although oral folic acid does not seem to prevent most CVD events, some research suggests that increased dietary folic acid might lower the risk of stroke and CVD-related mortality in patients at high risk for CVD. Details: In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Meta-analyses of available research show that folic acid might lower the risk of stroke in patients with CVD (97619,102386,107136). Some clinical research shows that taking folic acid reduces the risk of CVD by 15% in patients with kidney failure or chronic kidney disease (50444,91311). However, most research shows that folic acid supplementation, alone or in combination with vitamin B6 and vitamin B12, does not improve endothelial function or reduce the risk of death or CVD events in patients with existing hyperhomocysteinemia, coronary heart disease, CVD, kidney disease, or prior stroke, despite having a homocysteine-lowering effect (9313,9322,11337,11387,13482,50437) (50512,50527,96154,96147,97619,102386). Some population research has evaluated adults at high risk for CVD. This research has found that dietary folate intake of at least 382 mcg daily is associated with a modest reduction in CVD-related mortality and possibly all-cause mortality. Consuming folic acid as a component of fortified food in doses of more than 251 mcg daily is associated with a modest reduction in CVD-related mortality. Conversely, folic acid supplementation is associated with a higher risk of CVD and overall mortality, and there is a J-shaped association between folate intake, serum folate levels, and red blood cell folate levels, with both CVD-related and all-cause mortality (109199).
• Cervical cancer. It is unclear if oral folic acid prevents cervical cancer. Details: Epidemiological evidence has found that increasing folate intake from dietary and supplement sources, along with thiamine, riboflavin, and vitamin B12, might decrease the risk of precancerous cervical lesions (11074).
• Child development. It is unclear if oral folic acid supplementation during pregnancy improves child development. Details: Clinical research in Northern Ireland shows that taking folic acid 400 mcg daily starting in the 14th week of gestation and continuing until the end of pregnancy improves word reasoning in the child at 7 years of age when compared with placebo. When compared with a historical cohort from Britain, folic acid supplementation was associated with an increase in full scale IQ, verbal IQ, performance IQ, and general language at 7 years of age (102385). At age 11, benefits in word reasoning were no longer significant. However, there were modest benefits in some measures of processing speed when compared with placebo. Verbal comprehension was modestly improved in females, but not males (109192). Observational research in pregnant individuals and their children in Spain has found that taking less than 400 mcg of folic acid daily during pregnancy is associated with lower mental alertness scores in children at ages 7-9 years when compared with folic acid 400-999 mcg daily, while taking folic acid 1000 mcg or more daily during pregnancy was associated with improvements in some measures of working memory in the children. However, no relationship between folic acid dosing and most other measures of cognitive function was identified (110449).
• Chronic fatigue syndrome (CFS). Although there is interest in using oral or injectable folic acid for CFS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Chronic kidney disease (CKD). While adding oral folic acid to enalapril might slow CKD progression, adding folic acid to high-dose vitamin B12 does not seem to be beneficial. Details: Clinical research in adults with hypertension and CKD shows that taking enalapril with folic acid 800 mcg for a median of 4.4 years reduces the risk of worsening kidney function by 21% and slows the rate of kidney function decline by 44% when compared with enalapril alone (96153). However, clinical research does not support the use of folic acid in patients with CKD when used in combination with high-dose vitamin B12 (cyanocobalamin). Vitamin B12 might increase the risk of negative outcomes (50253,50409,96150). More research is needed to determine the benefits of folic acid when used alone.
• Colorectal cancer. It is unclear if oral folic acid prevents colorectal cancer. Details: Although the majority of population research suggests that taking folic acid orally from dietary and supplemental sources reduces the risk of colorectal cancer (505,2140,2144,2145,2250,6271,9325,9326,50109,50427,50450)(91306,91323,96160,109188,110450), clinical evidence in general is not supportive. Most clinical research and meta-analyses of clinical trials suggest that taking folic acid from dietary or supplemental sources does not reduce the risk of colorectal cancer (2141,34596,50394). The reason for this discrepancy is unclear. Some observational research suggests that an inverse association between folate intake and risk of colorectal cancer was not apparent until at least 12 years after baseline folate intake was determined (109188). A meta-analysis of observational studies suggests that the benefits of folic acid supplementation on colorectal cancer risk might be limited to patients with moderate to high alcohol consumption (110450). Other clinical evidence suggests that the beneficial effect of folic acid may be limited to colon, but not rectal, cancer (21501). Furthermore, the beneficial effect for colon cancer may be limited to only certain subtypes. For instance, females with folate intake of at least 400 mcg daily seem to have a 46% reduction in the risk of p53-overexpressing colon cancer, but not p53-negative tumors, when compared with those who consume less than 200 mcg daily (21300). Also, the source of folic acid may influence its effects. Some observational research suggests that dietary folate, but not folic acid supplementation, reduces the risk of colon cancer (21501).
• Congenital heart disease. It is unclear if oral folic acid prevents congenital heart disease. Details: The exact cause of congenital heart disease is unknown but is thought to be a combination of genetic and environmental factors. Population research has found that supplementation with folic acid or folic acid-containing prenatal vitamins during pregnancy is associated with up to a 40% lower risk of congenital heart defects in newborns (99373).
• Dementia. It is unclear if oral folic acid is beneficial for the prevention or treatment of dementia. Details: While some preliminary research shows that folic acid might aid in the prevention and treatment of Alzheimer disease (13165,15270,50246,90374), two small clinical trials show that taking folic acid 15-20 mg daily for 10-12 weeks does not seem to improve cognitive function or the severity of dementia in patients with various forms of dementia, including vascular dementia, Lewy body dementia, probable Alzheimer disease, or dementia due to other causes (50062,50597).
• Diabetes. Small clinical studies suggest that oral folic acid does not improve glycemic control. Details: Meta-analyses of small clinical trials in patients with type 2 diabetes show that folic acid does not reduce glycated hemoglobin (HbA1C) when compared with placebo (50528,109197). Another small clinical study in patients with diabetes who are stabilized on metformin and/or a sulfonylurea shows that taking folic acid 5 mg daily for 8 weeks does not affect HbA1C when compared with placebo (104917). The validity of this study is limited by its small size and lack of blinding. Conversely, a meta-analysis of clinical research shows that taking folate modestly reduces fasting blood glucose and insulin levels, as well as measures of insulin resistance, when compared with placebo or no intervention (109197). There was no clear relationship between these changes and the dose or duration of folate. However, the studies included in this analysis evaluated multiple patient populations; the effect of folate in patients with diabetes, specifically, is unclear. Beyond glycemic control, some research has assessed the impact of dietary folate intake on cardiovascular risk in patients with diabetes. An observational study in Chinese adults with type 2 diabetes has found that dietary intake of folate in the highest quartile is associated with 68% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with folate intake in the lowest quartile (110452). Folic acid has also been evaluated in gestational diabetes. A meta-analysis of 20 studies shows that serum and red blood cell (RBC) folate levels are higher in patients with gestational diabetes than without gestational diabetes. Subgroup analysis suggests that patients with gestational diabetes have higher serum and RBC folate levels in the second trimester than in those without gestational diabetes, while RBC folate levels in patients with gestational diabetes were higher in the first trimester than those without gestational diabetes. Overall, higher serum folate levels are associated with a slight increase in the odds of gestational diabetes when compared with lower serum folate levels (112107).
• Diabetic neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with diabetic neuropathy shows that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate), for 24 weeks does not improve neural dysfunction based on vibration perception, but does seem to improve total neuropathy symptoms, when compared with placebo. These symptoms, which include both sensation and pain, decreased by 25% with the B vitamin combination, compared with only 15% in those taking placebo (90375).
• Epilepsy. It is unclear if oral folic acid reduces seizure frequency. Details: A meta-analysis of preliminary clinical research shows that taking folic acid does not reduce seizure frequency in patients with epilepsy (50124). However, there is some speculation that folate deficiency might be linked to increased seizure frequency. A preliminary clinical study in folate-deficient children with epilepsy shows that taking folic acid 5 mg daily for 3 months reduces seizure frequency when compared to baseline, but not when compared with a control group that is not deficient in folate (99371).
• Erectile dysfunction (ED). Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in males with mild erectile dysfunction, overweight or obesity, and normal to low androgen levels shows that taking a combination product containing folic acid 400 mcg, alpha-lipoic acid, myo-inositol, and apple (Sinopol Forte, Laborest) improves measures of erectile dysfunction when compared to baseline (111674). The validity of these effects is limited by the small sample size and the lack of a comparator group, and it is unclear if these effects are due to folic acid, other ingredients, or the combination.
• Esophageal cancer. Higher dietary folate intake is associated with a lower risk of esophageal cancer. Details: One meta-analysis of observational research has found that higher levels of dietary folate are associated with a 34% lower risk of esophageal squamous cell carcinoma and a 50% lower risk of esophageal adenocarcinoma when compared with low levels of dietary folate (50208). Another meta-analysis of observational research has found that consuming high amounts of folate is associated with a 36% decrease in the odds of esophageal cancer when compared with lower dietary folate intake (100950).
• Fenofibrate (Tricor)-induced hyperhomocysteinemia. Folic acid seems to attenuate increases in homocysteine in people taking fenofibrate. Details: A small open-label clinical trial in patients taking fenofibrate shows that adding folic acid 10 mg every other day might reduce elevated plasma homocysteine levels by up to 59% when compared with taking fenofibrate alone (9321).
• Gastric cancer. It is unclear if oral folic acid reduces gastric cancer risk. Details: Observational research has found that taking folic acid reduces the risk of gastric cardia adenocarcinoma by 17% and the risk of noncardia gastric cancer by 33%, but does not reduce the risk of gastric cancer overall (50208). Also, a meta-analysis of 13 small clinical studies in patients with gastric precancerous conditions shows that taking folic acid 20-30 mg daily for 3-6 months improves gastric mucosal atrophy and intestinal metaplasia but does not seem to improve symptoms when compared with a control (110448). Whether these findings are associated with a lower risk of gastric cancer is unclear.
• Gout. It is unclear if oral folic acid reduces the risk for gout. Details: An observational study has found that increased dietary folate intake is associated with a lower incidence of gout (50454).
• Head and neck cancer. It is unclear if oral folic acid is beneficial for head and neck cancer prevention. Details: Population research has found that the highest intake of dietary folate is associated with a 50% reduced risk of head and neck cancer when compared with the lowest intake of folate. Each 100 mcg increase per day seems to reduce the risk by about 4% (96151).
• Hearing loss. It is unclear if oral folic acid prevents hearing loss. Details: Low levels of serum folate seem to be a risk factor for sudden sensorineural hearing loss in adults (21283). Observational research in females has found that serum folate levels in the lowest quintile are associated with a 19% increased risk for hearing loss when compared with levels in the second quintile. Also, folate levels in the highest quintile are associated with a 12% lower risk of hearing loss when compared with the second quintile (109807). A clinical study in older adults from the Netherlands shows that taking folic acid 800 mcg daily for 3 years slows the decline of age-related low-threshold hearing loss when compared with placebo (15163). However, at the time of this study, folate enrichment of foods was not allowed in the Netherlands. As a result, baseline folate levels in this study population were about 50% lower than in the US population. The effect of folic acid supplementation in people with higher baseline folate levels is unclear.
• Infertility. It is unclear if oral 5-methyltetrahydrofolate (5-MTHF) in combination with vitamin B6 and vitamin B12 is more beneficial than folic acid alone for increasing pregnancy rate in females undergoing assisted reproductive technology (ART). Details: Retrospective research from Italy suggests that taking 5-MTHF 400 mcg, vitamin B12 5 mcg, and vitamin B6 3 mg daily results in clinical pregnancy and live birth rates of approximately 60% and 49%, respectively, compared with 45% and 35% of those taking folic acid 400 mcg daily. A sub-analysis suggests that beneficial effects on pregnancy rates are limited to individuals aged less than 40 years (109189). The findings from this study are limited by its retrospective design. Also, it is unclear if these findings are generalizable to countries with folate fortification.
• Kidney failure. It is unclear if oral folic acid is beneficial in patients with kidney failure. Details: Because hemodialysis removes folate from the body, there is concern that folate deficiency may cause complications in patients with kidney failure receiving hemodialysis. Observational research in Taiwanese patients with kidney failure undergoing hemodialysis has found that taking folic acid 5 mg daily for an average of 5.8 years is associated with a 31% lower risk of arteriovenous access thrombosis when compared with folic acid 5 mg weekly. However, daily folic acid supplementation was not linked to a lower risk of cardiovascular events, cancer, or mortality when compared with weekly folic acid (110120). Oral folic acid has also been evaluated in combination with other ingredients. A small, low-quality clinical study in adults with kidney failure undergoing regular hemodialysis shows that taking oral folic acid 30 mg daily with thiamine 90 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if these findings are due to folic acid, thiamine, or the combination.
• Lometrexol toxicity. While oral folic acid might reduce lometrexol toxicity, intravenous folic acid does not seem to help. Details: In a phase I trial, intravenous folic acid 5-25 mg administered 1 hour or 3 hours prior to lometrexol 15-30 mg/m2 every 3 weeks does not seem to reduce cumulative lometrexol toxicity (2161). However, in a phase II study, taking oral folic acid 3 mg/m2 daily in addition to lometrexol 10 mg/m2 weekly seems to attenuate cumulative toxicity and improve its tolerability in cancer patients (104948).
• Low birth weight. It is unclear if oral folic acid supplementation during pregnancy reduces the risk of a low birth weight. Details: Clinical research shows that supplementation with folic acid 200 mcg to 5 mg daily during pregnancy increases mean birth weight when compared with placebo (91307). Furthermore, some population research has found that pre- or peri-conception folic acid supplementation, usually 400 mcg daily, is associated with a reduced risk of a child born small-for-gestational age. However post-conception folic acid supplementation is not associated with reduced risk (91304,103983). An observational study in pregnant Chinese patients found that supplementation with folic acid is associated with a 20% lower odds of low birth weight when compared with no supplementation. This association was observed when folic acid was used both before conception and during pregnancy for at least 24 weeks or during pregnancy only for at least 12 weeks. Increased dietary folate intake was not linked to a lower risk of low-birth-weight infants (110446). However, other observational research has found no association between folic acid supplementation during pregnancy and the risk for small-for-gestational age births (110447).
• Lung cancer. It is unclear if oral folic acid reduces lung cancer risk. Details: There does not appear to be a relationship between deficiency of folate and lung cancer (9454). However, consuming at least 130.4 mcg of folate per 1000 kcal daily seems to reduce the risk of lung cancer by 40% in former smokers when compared to those with lower dietary folate intake (50065).
• Melanoma. It is unclear if oral folic acid reduces melanoma risk. Details: Population research has found that folic acid supplementation of 2-2.5 mg daily in combination with vitamin B6 and vitamin B12 is linked with a 53% reduced risk of melanoma (91312).
• Metabolic syndrome. Although there is interest in using oral folic acid for metabolic syndrome, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Nitrate tolerance. It is unclear if oral folic acid helps to prevent the development of tolerance to treatment with nitroglycerin. Details: Some clinical evidence suggests that taking folic acid 1 mg daily for 1 week does not prevent the development of nitroglycerin-induced endothelial dysfunction or tolerance in healthy individuals (50442). However, other research suggests that taking folic acid 10 mg daily for 1 week prevents nitric oxide synthase dysfunction caused by continuous nitroglycerin (9316).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral folic acid is beneficial for NAFLD. Details: A cross-sectional analysis suggests that adults with NAFLD have lower levels of serum folate and its major component 5-MTHF when compared with healthy controls. Additionally, adults with NAFLD seem to consume less supplementary and dietary folate when compared with healthy controls. Overall, serum folate levels are negatively associated with the risk of NAFLD, and inadequate folate intake is associated with an increased risk of NAFLD (112104).
• Oral clefts. It is unclear if oral folic acid reduces the risk of oral clefts in infants. Details: Observational research has found that maternal folic acid supplementation is associated with an up to 49% reduced risk of cleft lip with or without cleft palate (50220,104921). Furthermore, a large clinical trial in pregnancies at-risk for oral cleft suggests that taking a higher dose of folic acid 4 mg from pre-conception until the end of the first trimester results in a similar oral cleft recurrence rate of 2.5%, compared with a 2.9% recurrence with a lower dose of folic acid (400 mcg). Both doses demonstrate a lower incidence of oral clefts when compared with historical rates of 6.3% (91322). Although there is speculation that genetic markers of folate status impact the effect of folic acid on orofacial cleft incidence, the current data do not show a relationship (104921).
• Overall mortality. It is unclear if oral folic acid reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of folic acid in the highest quintile is associated with a 14% to 23% lower risk of all-cause mortality and a 41% to 47% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary folic acid intake (110451).
• Pancreatic cancer. It is unclear if oral folic acid reduces pancreatic cancer risk. Details: Consuming greater than 280 mcg daily of dietary folate is associated with a decreased risk of exocrine pancreatic cancer (9327). A meta-analysis of case-control and cohort studies suggests that consuming higher amounts of dietary folate reduces the risk of pancreatic cancer by 51% compared to low levels of dietary folate (50208). However, another meta-analysis of prospective cohort studies suggests that folate/folic acid intake does not significantly affect the overall risk of pancreatic cancer (50499). The contradictory results may be associated with the form of intake or may be related to the gender of the participants. A meta-analysis of clinical research shows that dietary folate, but not folic acid, significantly reduces the risk of pancreatic cancer (50387). Also, one meta-analysis of observational studies has found that high dietary folate decreases the risk of pancreatic cancer in females, but not males (50387).
• Peripheral neuropathy. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows taking a combination of folic acid 400 mcg, vitamin B12 3 mcg, and uridine monophosphate 50 mg daily (Keltican) for 60 days reduces pain associated with peripheral neuropathy. Use of this product reduces pain intensity by approximately 44%, with loss of burning pain in approximately 50% of patients, strong tingling or pricking in approximately 57% of patients, strong pain attacks in 92% of patients, and numbness in 90% of patients when compared with baseline. Radiating pain and the use of concomitant medications are also reduced (90384). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefits are due to folic acid, other ingredients, or the combination.
• Pharyngeal cancer. It is unclear if oral folic acid reduces pharyngeal cancer risk. Details: Population research has found that intake of folic acid and folate from natural, fortified, and supplemented sources, may protect against oropharyngeal cancer. Intake of at least 258-816 mcg total folate/folic acid reduces the odds by 35% when compared with intakes of less than 344 mcg. Furthermore, folate/folic acid may be more beneficial for oral cancer versus pharyngeal cancer and in heavy alcohol users versus non users or light users (91302).
• Polycystic ovary syndrome (PCOS). It is unclear if oral folic acid is beneficial for PCOS. Details: One clinical study in overweight or obese patients with PCOS shows that taking folate 1 mg or 5 mg daily for 8 weeks modestly reduces levels of homocysteine, as well as insulin resistance, when compared with placebo. However, only the 5 mg dose modestly reduces insulin, total cholesterol, and low-density lipoprotein (LDL) cholesterol levels. Neither dose appears to affect fasting plasma glucose, high-density lipoprotein (HDL) cholesterol, or triglyceride levels when compared with placebo (109200). Other clinical research in patients with PCOS taking metformin shows that taking folate 400 mcg daily for 6 months does not affect glycemic parameters, plasma lipid levels, or hormone levels when compared with placebo (109194). The reasons for discrepancies between studies are unclear but may relate to patient characteristics. One study included only overweight or obese individuals with at least two of the three PCOS criteria, whereas the other study limited enrollment to patients in any weight category but with all three PCOS criteria (109194,109200).
• Pregnancy-induced hypertension. It is unclear if oral folic acid reduces the risk of hypertension during pregnancy. Details: Population research has found that taking folic acid during pregnancy is not associated with a reduced risk of gestational hypertension (91308,99370,99372).
• Restless legs syndrome (RLS). Although there is interest in using oral folic acid for RLS, there is insufficient reliable information about the clinical effects of folic acid for this condition.
• Schizophrenia. Oral folic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of folic acid 2 mg and vitamin B12 400 mcg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral folic acid has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Suicidal ideation. It is unclear if oral folic acid reduces the risk of suicidal ideation or suicide attempts. Details: One observational study has evaluated the association between folic acid supplementation and suicidal events in patients with various underlying conditions, including 12% with depression, 15% with anxiety, and 46% with pain. This within-person cohort study found that filling a prescription for folic acid 0.4-5 mg daily, either alone or as part of a multivitamin, is associated with a 44% reduced rate of suicidal events during the months after the prescription when compared with the months without the prescription. For the 48% of patients who received folic acid 1 mg daily, each additional month of taking the prescription was associated with a 5% decrease in suicidal events (109201). Prospective clinical research is needed to confirm any benefits of folic acid and to determine whether baseline folate deficiency plays a role in these outcomes. More evidence is needed to rate folic acid for these uses.

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POSSIBLY EFFECTIVE

• Burns. Topical gotu kola seems to improve the rate of burn healing. Details: Clinical research shows that applying a cream containing gotu kola 3% once daily to second degree burns increases the rate of re-epithelialization and complete healing by about 7 days when compared with silver sulfadiazine (SSD) 1% cream. Gotu kola cream also seems to reduce dryness, itching, irritation, and scar severity when compared with SSD (97027). Other research in adults with second degree burns shows that applying a gauze dressing containing gotu kola 5% and aloe 2.5%, covered with absorbent cotton wool and changed every 3 days, reduces time to healing by 1.5 days and length of hospital stay by 1.7 days when compared with the use of a gauze dressing containing chlorhexidine acetate 0.5% (97028).
• Venous insufficiency. Oral gotu kola seems to improve symptoms of venous insufficiency. Details: Clinical research shows that taking gotu kola or a specific extract of gotu kola (Centellase) 60-180 mg daily orally for 4-8 weeks seems to improve measures of circulation and decrease symptoms such as edema in patients with venous insufficiency (6887,9786,11063,11064,11066,11070,52894,52909).

POSSIBLY INEFFECTIVE

• Cognitive function. Oral gotu kola does not seem to be beneficial for cognitive function. Details: A meta-analysis of a small number of generally moderate quality clinical trials shows that taking a single dose of gotu kola, alone or in combination with other ingredients, does not improve cognitive function when compared with placebo (105334). In one study, gotu kola was taken in combination with ginkgo and docosahexaenoic acid (DHA) for 4 months by healthy, cognitively intact older adults (52880).
• Radiation dermatitis. Topical gotu kola does not seem to reduce symptoms of radiation dermatitis. Details: Clinical research in females undergoing radiotherapy for breast cancer shows that applying a cream containing gotu kola extract 7% once daily during and up to 4 weeks following radiotherapy does not reduce the severity of dermatitis when compared with no treatment or applying a moisturizing cream (102792).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy, middle-aged females shows that applying a topical emulsion containing extracts of gotu kola 3% and Indian gooseberry 3% twice daily for 60 days improves skin hydration, some measures of skin wrinkles, and elasticity of the cheek (but not the eye) when compared with placebo (111571). It is unclear if these effects are due to gotu kola, Indian gooseberry, or the combination.
• Alzheimer disease. Although there is interest in using oral gotu kola for Alzheimer disease, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Anal fissures. It is unclear if topical gotu kola is beneficial for anal fissures. Details: In patients with chronic anal fissures who are using standard dietary and hygiene treatments, preliminary clinical research shows that taking gotu kola extract 60 mg twice daily for 8 weeks and locally applying an ointment containing gotu kola does not reduce the mean time to bleeding cessation when compared with standard treatments alone. However, pain may be modestly improved. Also, gotu kola was less effective than an unspecified flavonoid mixture used both orally and topically (105332).
• Atherosclerosis. It is unclear if oral gotu kola is beneficial for slowing the progression of atherosclerotic plaques. Details: Some preliminary clinical research shows that taking gotu kola extract 60 mg orally three times daily for 12 months helps stabilize low-density atherosclerotic plaques when compared with placebo (11062,11069). Gotu kola has also been evaluated in combination with a specific maritime pine bark product (Pycnogenol, Horphag Research). A non-randomized clinical trial shows that taking gotu kola 225 mg and Pycnogenol 150 mg in two divided doses daily for 3 months reduces plaque height and length and increases plaque echogenicity and stability when compared to control (97030). Another non-randomized clinical study in adults with atherosclerotic plaques and no other cardiovascular risk factors shows that taking gotu kola extract 100 mg and Pycnogenol 100 mg daily for up to 4 years reduces plaque progression and increases plaque echogenicity when compared with Pycnogenol alone or no treatment at all. Taking gotu kola and Pycnogenol is also associated with a reduced rate of clinical vascular events, including angina, myocardial infarction, minor transient ischemic attacks (TIAs), and minor strokes when compared with taking Pycnogenol alone or receiving no treatment at all (97029). It is unclear how these outcomes would compare to the use of gotu kola alone.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral gotu kola for ADHD, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Atopic dermatitis (eczema). Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying an ointment containing 5% each of the extracts of heart's ease, gotu kola, and Oregon grape twice daily for 4 weeks does not improve eczema when compared with a base cream. However, patients with eczema on skin exposed to cold weather might experience some improvement (67372).
• Depression. Although there is interest in using oral gotu kola for depression, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Diabetic foot ulcers. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with deep diabetic foot ulcers, preliminary clinical research shows that applying a cream (WH-1 cream) containing 1.25% of gotu kola and Plectranthus amboinicus extracts in a 4:1 ratio twice daily for 2 weeks after surgical debridement is as effective as the use of a standard hydrocolloid fiber wound dressing for improving wound size. However, when compared with baseline, changes in wound size were not statistically significant (105335).
• Diabetic microangiopathy. It is unclear if oral gotu kola is beneficial for diabetic microangiopathy. Details: Preliminary clinical research shows that taking gotu kola extract 60 mg orally twice daily for 6-12 months helps increase measures of circulation and decrease edema in patients with diabetic microangiopathy (11065,11068,52917).
• Dry skin. It is unclear if topical gotu kola is beneficial for dry skin. Details: In patients with dry skin associated with type 2 diabetes, clinical research shows that topical application with 0.25 grams of a gotu kola 1% ointment twice daily, either alone or with oral gotu kola 1100 mg twice daily, for 28 days does not improve dry skin when compared with placebo. However, in a sub-group of patients with well-controlled diabetes, the combination of oral and topical gotu kola modestly improved dry skin (105329). Additionally, a small clinical study in individuals with dry skin due to working with synthetic and natural dyes shows that application of a gotu kola 2% ceramide-based cream to the hands and arms twice daily for 4 weeks improves skin barrier hydration, as measured by hydration of the stratum corneum and skin acidity, when compared to baseline. These improvements were similar to those seen with a ceramide 5% cream (109554). As the gotu kola cream was formulated with ceramide, it is unclear if these findings are due to gotu kola, ceramide, or the combination.
• Epilepsy. Although there is interest in using oral gotu kola for epilepsy, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Generalized anxiety disorder (GAD). It is unclear if oral gotu kola is beneficial for GAD. Details: In patients with GAD, preliminary clinical research shows that taking gotu kola extract 500 mg twice daily for 60 days reduces symptoms of anxiety, depression, and stress by 22% to 26% when compared with baseline (105333). The validity of these findings is limited by the lack of a comparator group.
• Hemorrhoids. It is unclear if topical gotu kola is beneficial for hemorrhoids. Details: Preliminary clinical research in patients with chronic hemorrhoids, as well as patients with acute symptoms following a hemorrhoidectomy or surgical treatment for hemorrhoidal thrombosis, shows that taking gotu kola extract (Centella complex) 60 mg twice daily for 15 weeks and locally applying an ointment (Proctocella) containing gotu kola, arnica, and aloe, in conjunction with standard treatments, does not reduce the mean time to bleeding cessation when compared with standard treatments alone. Anal irritation was modestly improved in the patients with chronic hemorrhoids and in those undergoing treatment for hemorrhoidal thrombosis, but not in those that had undergone a hemorrhoidectomy (105336).
• Herpes zoster (shingles). Although there is interest in using oral gotu kola for shingles, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Hypertension. It is unclear if oral gotu kola is beneficial for hypertension. Details: Preliminary clinical research in patients with hypertension shows that drinking a tea made by boiling gotu kola 4 grams in 250 mL water three times daily for 3 days modestly reduces systolic and diastolic blood pressure when compared with baseline. After consuming the tea, about 40% of patients had normal or high-normal systolic blood pressure and 77% had optimal or normal diastolic blood pressure, compared with 0% and 45%, respectively, prior to consumption (105330). The validity of these findings is limited by the lack of a comparator group.
• Hypertrophic scars. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that topical use of a specific silicone gel (Bangkok Botanica) containing 15% extracts of gotu kola, onion, aloe, and paper mulberry, starting 2 weeks after surgery and continuing for 6 months, moderately improves the height and pliability of the post-surgical hypertrophic scar when compared with a silicone placebo gel. There was no effect on pigmentation or vascularity (102793). It is unknown whether any benefit is related to gotu kola, other ingredients, or their combination.
• Idiopathic interstitial pneumonia. Oral gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational registry study in males less than 65 years old with idiopathic interstitial pneumonia has found that taking a specific gotu kola extract (Centellicum; Horphag Research) 225 mg three times daily in combination with a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 8 months is associated with a modest improvement in Karnofsky Performance Scale scores and a reduction in fatigue when compared with pirfenidone (108862). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Keloids. It is unclear if oral or topical gotu kola are beneficial for keloids. Details: There is some early evidence that applying a specific extract of gotu kola (Madecassol) topically might help reduce keloids and hypertrophic scarring (13558). Gotu kola has also been taken orally for keloids. Preliminary clinical research in patients at high risk for keloids shows that taking a specific extract of gotu kola (Centellicum, Horphag Research Ltd) 450 mg daily for 4 weeks starting on the second week after surgery seems to improve scar homogeneity and regularity (99756). However, the reliability of these results is limited because patients in this study were not randomized or blinded to different interventions.
• Laser skin resurfacing. It is unclear if topical gotu kola is beneficial for recovery from laser skin resurfacing. Details: A small clinical trial shows that applying a gel containing gotu kola extract (ECa 233) 0.05% four times daily for 7 days, then twice daily for 3 months, improves wound healing following laser resurfacing for facial acne. Redness returned to baseline levels by day 7, in contrast to day 28 on the side treated with a placebo gel. The general wound appearance and crusting were also improved on the side on which the gotu kola extract gel was applied (102794).
• Osteoarthritis. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large, single-blind clinical study in adults with knee osteoarthritis causing moderate pain shows that applying a specific cream (TMP-4) containing extracts of gotu kola leaf, sesame seed, soybean, and mangosteen peel four times daily for 4 weeks provides similar improvement in pain scores when compared with diclofenac 1% gel. Topical TMP-4 cream also seems to improve knee stiffness, stair climbing, and mobility similarly to diclofenac gel. However, patient impression of overall improvement was higher with diclofenac (110128). The validity of this study is limited by inadequate blinding.
• Scarring. It is unclear if topical gotu kola is beneficial for scarring or tenderness from scarring. Details: Preliminary clinical research in patients without a history of keloid formation suggests that applying a specific cream (Alpha Centella, not available in the US) containing gotu kola and Bulbine frutescens extracts twice daily for 6-8 weeks following suture removal might help to reduce scarring (11072). Also, a large clinical study in adults who underwent carpal tunnel release surgery shows that applying gotu kola cream 1% three times daily for 6 months after suture removal marginally improves self-reported scar tenderness pain when compared with control, and modestly improves scarring scores when compared to baseline (112425). However, the interpretation of these findings is limited by patient-reported outcomes and insufficient validity of the scar scoring tool in this population.
• Skin grafts. Although there is interest in using topical gotu kola for skin graft recovery, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Stretch marks (striae distensae). It is unclear if oral gotu kola is beneficial for stretch marks; topical gotu kola has only been evaluated in combination with other ingredients. Details: Preliminary clinical research in females with stretch marks shows that taking a specific extract of gotu kola (Centellicum, Horphag Research Ltd) 225 mg three times daily for 6 weeks increases skin thickness, elasticity, and perfusion when compared with a stretch mark minimizer cream (Clarins) and regular control cream (99757). The validity of these results is limited by the fact that patients were not randomized or blinded to the different interventions. Gotu kola has also been evaluated topically in combination with other ingredients. Preliminary clinical research shows that applying a specific mixture of gotu kola, vitamin E, and collagen-elastin hydrolysates in a cream (Trofolastin, not available in the US) daily during the second and third trimesters reduces stretch marks when compared with a placebo cream (13559). Another small clinical study shows that applying a specific mixture of gotu kola, vitamin E, essential fatty acids, hyaluronic acid, elastin, and menthol in an ointment (Verum, not available in the US) helps decrease the formation of stretch marks during pregnancy when compared with placebo (11073). Other preliminary clinical research in patients without previous striae shows that applying a specific formula containing hydroxyprolisilane C, rosehip oil, gotu kola triterpenes, and vitamin E (Velastisa Antiestrías, ISDIN) twice daily, beginning at week 10-14 and continuing throughout pregnancy, decreases the severity of both new and old stretch marks and the incidence of stretch marks when compared with placebo (92507). It is unclear if the effects seen in these studies are due to gotu kola, other ingredients, or the combinations.
• Systemic lupus erythematosus (SLE). Although there is interest in using oral gotu kola for SLE, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Tonsillitis. Although there is interest in using oral gotu kola for tonsillitis, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Venous thromboembolism (VTE). It is unclear if oral gotu kola is beneficial for VTE prevention. Details: Preliminary clinical research shows that gotu kola decreases edema and improves measures of circulation in patients traveling on airplanes for more than 3 hours when compared to a control group receiving no treatment (11067). However, it is unknown if these changes reduce the incidence of clots.
• Wound healing. Although there is interest in using topical gotu kola for wound healing, there is insufficient reliable information about the clinical effects of gotu kola for this purpose.
• Wrinkled skin. It is unclear if topical gotu kola is beneficial for wrinkled skin. Details: Small, low-quality studies in healthy adults suggest that topical formulations of gotu kola extract or the constituent asiaticoside 0.1% or 0.2% applied 1-3 times daily have shown modest benefit for wrinkled skin. Cream or gel formulations were used for 12 weeks for periorbital wrinkles and a lipstick was used for 8 weeks for lip wrinkles. However, the extent of benefit is not clear and meta-analyses are limited to a very small number of studies with varied comparator groups, including placebo, vehicle, tretinoin 0.02%, and Pueraria mirifica extract (106639). More evidence is needed to rate gotu kola for these uses.

(Read more about GOTU KOLA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral hawthorn is beneficial in patients with angina. Details: Preliminary clinical research in patients with angina taking chronic beta-adrenergic receptor blockers or ACE inhibitor therapy shows that taking a hawthorn (Crataegus pinnatifada) extract 100 mg orally three times daily for four weeks improves angina and electrocardiogram (ECG) findings and reduces nitroglycerin intake when compared with placebo (19242). Other preliminary clinical research in patients with unstable angina shows that taking hawthorn 10 grams and hu zang 15 grams orally daily for 4 weeks does not reduce the frequency of angina pectoris attacks when compared with control. However, taking hawthorn and hu zang improved some subjective symptom scores and quality of life scores (109610).
• Anxiety. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate generalized anxiety shows that taking a specific product (Sympathyl, not available in the US) containing hawthorn, magnesium, and California poppy for 90 days modestly improves anxiety scores when compared with placebo (12583). Also, a clinical study in adults with adjustment disorder and anxious mood shows that hawthorn, in combination with black horehound, passion flower, valerian, kola nut, and guarana, modestly improves anxiety scores when compared with placebo (6250). It is unclear if these effects are due to hawthorn, other ingredients, or the combination. Another small clinical study in healthy adults shows that taking a combination of herbal extracts containing hawthorn, passionflower, ballota, and valerian root daily for 14 days reduces subjective anxiety and objective sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to hawthorn, other ingredients, or the combination.
• Arrhythmia. Although there has been interest in using oral hawthorn for arrhythmia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Atherosclerosis. Although there has been interest in using oral hawthorn for atherosclerosis, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral hawthorn for CVD, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cognitive function. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, a single dose of 25 drops of a combination product of D-camphor and hawthorn berry extract (Korodin) was superior to placebo for increasing cognitive performance in elderly female patients as measured by visuomotor speed and information processing capacity. The active treatment group showed an improvement in attentional and mental performance (19240,91504).
• Congestive heart failure (CHF). The evidence on the effects of oral hawthorn in patients with CHF is conflicting. Although some older research suggests it may be beneficial, more recent, larger studies suggest it may actually increase the risk for complications. Details: There is contradictory evidence about the effects of hawthorn extract in heart failure patients. Several clinical studies show that taking specific hawthorn leaf and flower extracts (LI 132, Faros 300, Lichtwer Pharma; WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; or HeartCare, Nature's Way) 240-600 mg daily improves ejection fraction and exercise tolerance, reduces subjective symptoms, and decreases the risk of death in patients with New York Heart Association (NYHA) stage II heart failure. In these studies, the maximum effect was usually seen after 6-12 weeks of treatment (8279,8280,11449,19221,19223,19225,19226,19227,19228). Another clinical trial shows that hawthorn extract (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals or HeartCare, Nature's Way) 1800 mg daily, combined with diuretic therapy, improves exercise tolerance and reduces subjective symptoms in NYHA stage III heart failure. In this study, maximum effect was usually seen after 16 weeks of treatment (8281). In another trial, patients with NYHA II heart failure taking either hawthorn (LI 132, Faros) 300 mg three times daily or captopril 12.5 mg three times daily experienced similar improvements in cardiac performance and symptoms (19230). However, other clinical research suggests no benefit and possible harm with hawthorn. A large-scale clinical trial (SPICE) in patients with NYHA stage II or III heart failure shows that taking specific hawthorn extracts (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; HeartCare, Nature's Way) 900 mg daily for 24 months, in combination with conventional treatment, does not decrease hospitalization due to progressive heart failure, non-fatal myocardial infarction, or cardiac death (17203). Another clinical trial in patients with NYHA stage II or III heart failure shows that taking these same specific hawthorn extracts at the same dose for up to 6 months does not slow the progression of heart failure when compared with placebo (19222). In a retrospective analysis of this study, it was shown that heart failure progression was significantly increased in patients taking hawthorn when compared with placebo. The rate of death was also increased by 1.7% over placebo, and heart failure-related hospitalizations increased by 8% over placebo in patients treated with hawthorn (16824).
• Hyperlipidemia. Although there has been interest in using oral hawthorn for hyperlipidemia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Hypertension. It is unclear if oral hawthorn is beneficial for lowering blood pressure. Details: One preliminary clinical trial showed that taking hawthorn standardized extract 1,000-2,500 mg daily for three days does not significantly reduce blood pressure in hypertensive or prehypertensive patients when compared with placebo (19244). However, another study in patients with diabetes and hypertension shows that taking a specific hawthorn extract (LI 132) 1,200mg daily for 16 weeks significantly decreased diastolic, but not systolic, blood pressure when compared with placebo (19245).
• Obesity. Although there has been interest in using oral hawthorn for obesity, there is insufficient reliable information about the clinical effects of hawthorn for this condition.
• Orthostatic hypotension. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in older adults with orthostatic hypotension shows that taking a specific combination product containing hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen) 25 drops orally three times daily for 7 days attenuates the blood pressure reduction upon standing when compared with placebo. Signs and symptoms of orthostatic hypotension such as dizziness, blurry vision, and falls also seem to be reduced when compared with baseline (39614,39617). A meta-analysis of 4 studies shows that giving single doses of 20-25 drops of the same combination product increases systolic and diastolic blood pressure when compared with placebo (103620). However, the studies have methodologic problems and, while 2 were conducted in females with orthostatic hypotension, the others involved health young adults or normotensive elderly subjects. The effect of hawthorn alone for treatment of orthostatic hypotension has not been determined. The combination product used in these studies is not available in the US. More evidence is needed to rate hawthorn for these uses.

(Read more about HAWTHORN)

POSSIBLY EFFECTIVE

• Angina. Oral L-arginine seems to improve symptoms and exercise tolerance in patients with angina. Details: Clinical research shows that taking L-arginine orally seems to decrease symptoms and improve exercise tolerance and quality of life in patients with mild to severe angina (3593,7815,7816,31866,31923). Some patients with severe angina who have frequent attacks at rest despite treatment with standard antianginal agents might also benefit from L-arginine (3593). However, L-arginine does not seem to improve objective measures of blood vessel dilation or increase circulating concentrations of nitric oxide (7817,99262). Also, when used in combination with ten 200 mcg injections of vascular endothelial growth factor (VEGF)-165 plasmid DNA, L-arginine 6 grams daily orally for 3 months does not improve angina severity in patients with coronary artery disease who underwent surgical angiogenesis compared to patients who did not receive this combination (32001). In addition, intravenous infusion of arginine 10% solution does not improve exercise capacity in patients with stable angina when compared with placebo (31843,32293).
• Erectile dysfunction (ED). Oral L-arginine might improve symptoms of ED. When taken with phosphodiesterase type 5 (PDE5) inhibitors, L-arginine seems to provide a small additional benefit. Details: Taking L-arginine orally in high doses, 5 grams daily, improves subjective assessment of sexual function in males with organic ED when compared with placebo (222,102586). Additionally, a meta-analysis of 4 small clinical studies in patients with ED, including those with diabetes and/or cardiovascular disease risk factors, shows that although PDE5 inhibitors improve sexual function better than L-arginine, the combination of PDE5 inhibitors and L-arginine may be more effective than either treatment alone (105065). In most clinical trials, doses of L-arginine 2.5-5 mg daily for 6-12 weeks were used alone or in addition to PDE5 inhibitors such as sildenafil 50 mg or tadalafil 5-10 mg daily (102586,102587,102592,104222). Higher doses have also been investigated. One clinical trial shows that taking L-arginine (Bioarginina, Farmaceutici Damor S.p.A., Napoli, Italy), 2 grams three times daily for 3 months improves sexual function compared with placebo (110387). However, taking lower doses, 1.5 grams daily, might not be effective in patients with mixed-type ED (2038). L-arginine has also been examined in combination with other ingredients. A meta-analysis of 2 small clinical studies in males with mild-to-moderate ED shows that taking L- arginine, up to 3 grams daily, in combination with maritime pine for 1-6 months improves a subjective assessment of sexual function when compared with control (112715). Some preliminary clinical evidence suggests that taking L-arginine orally in low doses, 1.7 grams daily in combination with maritime pine bark extract (Pycnogenol) or taking 0.69 grams daily along with maritime pine bark extract and aspartic acid (Edicare, Kobayashi Pharmaceutical Co. Ltd.) modestly improves symptoms of ED (10416,50924). Another preliminary clinical trial has investigated the effects of a combination of L-arginine 2.5 grams daily for 6 months and tadalafil 5 mg daily for 3 months, both starting with the initiation of weekly extracorporeal shock wave (ESW) therapy. When compared with ESW alone, this combination modestly improves sexual function for up to 12 months (110388). The effect of L-arginine alone is not clear from these studies.
• Hypertension. Oral L-arginine can modestly reduce systolic and diastolic blood pressure. Details: Oral L-arginine seems to have additive vasodilating effects when used with angiotensin converting enzyme (ACE) inhibitors or nitrate vasodilators such as isosorbide mononitrate (7822,20192,31916). A meta-analysis of clinical research in a variety of populations shows that taking L-arginine reduces systolic and diastolic blood pressure (SBP; DPB) by an average of 6.40 mmHg and 2.64 mmHg, respectively. Sub-analyses show that these reductions occur in both normotensive and hypertensive individuals. Beneficial effects were limited to adults with a body mass index (BMI) of 18.5 to 19.9 kg/m² (110384). The effect of L-arginine on blood pressure levels in adults exposed to traffic-related air pollution (TRAP) has also been investigated. Clinical research in adults with hypertension shows that taking L-arginine 3 grams three times daily for 2 weeks modestly reduces SBP and DBP elevations following a 2-hour exposure to TRAP during an outdoor walk compared with taking placebo (110383). Doses have included 4-24 grams daily, with the best evidence of benefit for doses of less than 9 grams daily, for 2-24 weeks (7818,10636,31871,31923,32167,32201,110383,110384).
• Necrotizing enterocolitis (NEC). Oral L-arginine may help prevent NEC in premature infants. Details: In a meta-analysis of 3 clinical trials, L-arginine 260 mg/kg orally in a single dose or two divided doses daily reduces the absolute risk of NEC in premature infants by about 62% when compared with placebo. To prevent one case of NEC, 6 infants would need to be treated with L-arginine (8474,91194,96803).
• Peripheral arterial disease (PAD). Short-term use of intravenous or oral L-arginine may improve symptoms of PAD, but long-term use does not seem to be beneficial. Details: Clinical research shows that using L-arginine intravenously or orally for up to 8 weeks increases flow-mediated dilation and improves symptoms of intermittent claudication associated with PAD (3465,31857,31905). However, long-term administration of L-arginine orally for up to 6 months does not improve walking speed, walking distance, or absolute claudication distance in patients with PAD and intermittent claudication (31957,31985).
• Pre-eclampsia. Intravenous L-arginine may have beneficial effects in pre-eclampsia. However, it is unclear if oral L-arginine is effective. Details: One small clinical study shows that intravenous L-arginine 30 grams as a one-time dose decreases systolic blood pressure (SBP) by 5 mmHg and diastolic blood pressure by 11 mmHg when compared to baseline in pregnant patients with hypertension or pre-eclampsia (31847), while intravenous L-arginine 20 grams daily for 5 days decreases SBP and DBP by about 2% when compared with placebo (31978). Another small clinical study shows that oral use of L-arginine 3 grams daily for 3 weeks reduces SBP and DBP by around 7 and 5 mmHg, respectively, when compared with placebo (31938); however, taking L-arginine 12 grams daily by mouth for 5 days does not seem to improve blood pressure in these patients (11828). Another preliminary clinical trial allowing for both oral and intravenous dosing shows that taking L-arginine 3.5 grams by mouth every 6 hours or 10 grams via intravenous infusion every 8 hours shortly before or immediately after delivery and continuing until postpartum day 3 does not improve blood pressure when compared with placebo (31959). The reasons for the disparate findings are unclear, but the small study sizes, as well as variations in the dose, duration, and timing of therapy before and/or after delivery, may explain some of the differences. Oral L-arginine has also been evaluated for the prevention of pre-eclampsia. One clinical study in patients at high risk for pre-eclampsia shows that taking L-arginine 3 grams daily starting the 20th week of gestation reduces the risk of pre-eclampsia by about 74% when compared with placebo (96811). Based on these results, one case of pre-eclampsia is prevented for every 6 high-risk pregnant patients treated with L-arginine 3 grams daily. Another clinical study also shows that taking two bars of a specific medical food (Heart Bars, Nellson Nutraceutical) containing L-arginine 6.6 grams and antioxidant vitamins daily starting at 14-32 weeks gestation and continuing until delivery reduces the risk of pre-eclampsia by 44% when compared with a bar containing antioxidant vitamins alone in patients at high risk of pre-eclampsia (91197). Based on these results, one case of pre-eclampsia is prevented for every 11 high risk patients treated with this L-arginine-containing medical food.
• Pregnancy-induced hypertension. Intravenous L-arginine may have beneficial effects in pregnancy-induced hypertension. Details: Some clinical research in patients with pregnancy-induced hypertension shows that intravenous infusion of L-arginine 20 grams daily for up to 5 days decreases systolic blood pressure by 2% to 3% and diastolic blood pressure by about 3% when compared with placebo (31933,31961,31978). Clinical research in patients with pre-existing hypertension has also been conducted. One clinical trial shows that taking L-arginine 4 grams by mouth daily for 10-12 weeks does not seem to reduce blood pressure in those with pre-existing hypertension or mild gestational hypertension. However, these results are confounded by the fact that more patients taking placebo needed to be placed on antihypertensive therapy during the study. L-arginine reduced the risk of being placed on antihypertensive drug therapy during the pregnancy by 47% when compared with placebo (32191). Based on this study, for every 5 patients with pregnancy-induced hypertension treated with L-arginine over placebo, antihypertensive drug therapy is avoided in one additional patient. L-arginine has also been investigated in combination with other ingredients in patients with pre-existing hypertension. Preliminary clinical research in patients with pre-existing hypertension and a previous history of pre-eclampsia, stillbirth, intrauterine growth restriction (IUGR), or other placenta vascular disorder shows that taking L-arginine and other ingredients starting at 14 weeks gestation prevents an increase in blood pressure and reduces the percentage of patients requiring new antihypertensive medication by about 73% compared with 24.5% of those not taking this combination. In this study, L-arginine 3 grams daily was taken with magnesium 350 mg and salicylate 100 mg. Therefore, the effect of L-arginine alone is unclear. All patients in the study were taking low dose aspirin 100 mg daily (110382).

POSSIBLY INEFFECTIVE

• Chronic kidney disease (CKD). Oral or intravenous L-arginine does not seem to improve CKD. Details: Most preliminary clinical research shows that taking L-arginine, either orally for up to 6 months or intravenously short-term, does not improve kidney function, glomerular filtration rate, or renal plasma flow in patients with CKD, although proteinuria may be reduced in some patients (31844,31904,32235,32303).
• Hypercholesterolemia. Oral L-arginine does not seem to reduce cholesterol levels. Details: Preliminary clinical research in patients with hypercholesterolemia shows that taking L-arginine 21 grams daily for 4 weeks does not reduce plasma lipids (1363). Furthermore, meta-analyses of clinical research show that taking L-arginine for up to about 6 months does not reduce total or low-density lipoprotein (LDL) cholesterol levels in populations of healthy individuals or those with cardiovascular disease risk factors. However, there was a very small effect on fasting triglyceride levels (102590,102591).
• Myocardial infarction (MI). Oral L-arginine does not seem to improve outcomes after MI. Details: Patients who have had an ST-segment MI who take L-arginine within 24 hours to 21 days, titrated up to a dose of 3 grams three times a day for up to 6 months, do not seem to have reduced vascular stiffness or increased ejection fraction (13221,32137). Also, there is some concern that long-term use of L-arginine might actually worsen outcomes and increase mortality in these patients (13221). Population studies also suggest that intake of L-arginine does not reduce the risk of experiencing an acute coronary event such as MI or coronary heart disease-related mortality (3332,6896,7821,10637).
• Tuberculosis. Oral L-arginine does not seem to improve symptoms or the clearance of tuberculosis infection. Details: Clinical research shows that taking L-arginine (ArgimaxH) 6 grams daily orally for 8 weeks, with or without vitamin D, does not improve symptoms of tuberculosis or the clearance of tuberculosis infection when used with standard treatment (91196).
• Wound healing. Oral L-arginine does not seem to improve wound healing. Details: Clinical research shows that taking L-arginine (as arginine aspartate) 17 grams orally in three divided doses daily for 2 weeks does not improve epithelialization in healthy, elderly patients with catheter wounds, although it may improve collagen deposition (32247). Also, taking L-arginine (as L-arginine hydrochloride) 26 grams daily for 5 days perioperatively does not improve angiogenesis, re-epithelialization, or neutrophil count in patients undergoing skin graft donation when compared with placebo (20692). In addition, taking a wound-specific oral nutrition supplement containing L-arginine 4.5 grams, zinc, and vitamin C twice daily for 4 weeks, along with standard wound care for 8 weeks, is no more effective for wound healing than a standard oral nutrition supplement along with standard wound care (90198). L-arginine has also been studied in combination with other ingredients. Taking L-arginine enterally or orally, before or after surgery, in combination with ribonucleic acid (RNA) and either eicosapentaenoic acid (EPA) or fish oil, seems to improve wound healing when compared with a control group (5531,32174). Another observational study conducted in Italy in newborns shows that applying a specific topical powder containing L-arginine, arnica extract, zinc oxide, and other ingredients (Cicaben, Orsana Italia S.r.l.) to the newborn's umbilical cord stump 3 to 4 times daily until stump detachment reduces the rates of mild complications 48 hours after discharge such as a wet cord stump but does not change the time to cord stump detachment or the rates of purulent secretions or umbilical granulomas when compared with standard dry care. However, no differences were noted between the groups one week after discharge (113662). The validity of these results is limited by the observational nature of the study and the ability of the parents to select a treatment group. It is unclear if the effects in these studies are due to L-arginine, other ingredients, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). Small clinical studies suggest that oral L-arginine may prevent ARDS. Details: A meta-analysis of three small studies shows that taking L-arginine 3 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of ARDS in the infant by about 54% when compared to control, including placebo or no treatment (110379).
• Altitude sickness. It is unclear if oral L-arginine is beneficial in patients with altitude sickness. Details: Preliminary clinical research shows that taking L-arginine 4 grams orally three times daily for 2 days while ascending to a high altitude and for 24 hours while at high altitude does not reduce altitude sickness when compared with placebo (31955).
• Anthracycline cardiotoxicity. Although there is interest in using oral L-arginine for anthracycline cardiotoxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose.
• Anemia of chronic disease. It is unclear if oral L-arginine is beneficial for anemia in patients with chronic kidney disease. Details: One very small clinical study in elderly adults with chronic kidney disease and anemia shows that taking L-arginine orally 1.3 grams daily might increase hemoglobin and erythropoietin levels in some patients when compared to baseline (31988). The validity of these findings is limited by the small study size and the lack of a comparator group.
• Asthma. It is unclear if oral L-arginine is beneficial in patients with asthma. Details: Preliminary clinical research in adults with severe asthma shows that taking L-arginine 0.05 gram/kg ideal body weight twice daily does not reduce asthma exacerbations when compared with placebo (104223). This study may have been inadequately powered to detect a difference in exacerbation rates between groups. While other studies have shown adverse airway effects in patients with asthma (121,31849), this study demonstrated no change in exacerbations and reported no adverse airway effects.
• Athletic performance. Small clinical studies suggest that oral L-arginine may improve measures of athletic performance. Details: A meta-analysis of 5 small clinical trials shows that taking L-arginine seems to modestly improve measures of cardiorespiratory fitness, as measured by a 0.07 L/minute increase in maximal oxygen uptake, when compared with control (105064). L-arginine has also been examined for its effects on athletic performance. Most research suggests that taking L-arginine does not improve athletic performance. However, clinical trials are small and may not be adequately powered to detect a difference in these outcomes Taking L-arginine as a single dose of 5 or 6 grams or as 5-10 grams daily for 2-4 weeks does not improve grip strength, strength during resistance exercise, power output during cycling, or muscle function during recovery from intense resistance exercise in healthy adults (91190,97393,99265,110381,110389). Also, taking L-arginine 5 grams daily for 4 weeks (Bioarginina Farmaceutici Damor) or 8 grams daily for 8 days does not increase swim speed (110381,110386). In contrast, some research suggests that drinking a single beverage containing the same dose of L-arginine 6 grams increases the time to exhaustion during high-intensity exercise when compared with placebo (32180). Also, a meta-analysis of small clinical trials shows that supplementation with L-arginine has a large beneficial effect on aerobic performance and a small beneficial effect on anaerobic performance. However, publication bias was evident in the aerobic performance data, limiting these conclusions. Doses found to be beneficial in this analysis included an acute dose of L-arginine 0.15 gram/kg 60-90 minutes before performance or chronic dosing of 1.5 grams to 2 grams daily for 4-7 weeks for aerobic performance. The chronic dose of L-arginine most likely to be beneficial for anaerobic performance is unclear from this analysis due to inclusion of studies using arginine alpha-ketoglutarate (110395). With the exception of a few studies which include a very small number of healthy females (99265,110395,110386), research on the use of L-arginine for athletic performance has focused almost exclusively on healthy males. Also, studies are heterogeneous with respect to sport and endpoints. Therefore, whether results can be applied to females or specific athletes is unclear. L-arginine has also been evaluated in overweight males. One small clinical study shows that taking a single dose of L-arginine 6 grams 90 minutes prior to high-intensity interval training seems to improve exercise tolerance by improving ventilation, heart rate, and oxygen uptake when compared with placebo (105060). L-arginine has also been evaluated in combination with other ingredients. Research in male soccer players shows that taking L-arginine 1.2 grams and L-citrulline 1.2 grams daily for 7 days increases total power output over a 10-minute cycling test and improves subjective perceptions of exertion when compared with placebo (100956). Another study shows that taking L-arginine 1.5 or 3 grams daily, in combination with grape seed extract, increases physical working capacity at fatigue threshold when compared with pretreatment in untrained, college-aged males (32164).
• Beta-thalassemia. It is unclear if oral L-arginine is beneficial in children with beta-thalassemia. Details:Preliminary clinical research in children aged 6-18 years treated conventionally for pulmonary hypertension related to beta-thalassemia shows that taking L-arginine 0.1 mg/kg daily for 60 days reduces Doppler echocardiography pulmonary arterial pressure by 35% compared with baseline. This measurement was increased by up to 15% in children given conventional treatments only; however, a statistical comparison between these treatment groups was lacking (110391).
• Breast cancer. It is unclear if oral L-arginine is beneficial in patients with breast cancer. Details: Preliminary clinical research shows that taking L-arginine 30 grams daily for 3 days prior to chemotherapy does not improve the clinical response rate in breast cancer patients when compared with placebo (32282).
• Cognitive impairment. It is unclear if oral L-arginine is beneficial in patients with cognitive impairment. Details: A small clinical trial in frail adults aged 65 years of age and up with hypertension shows that taking L-arginine (Bioarginina) 1.66 grams twice daily for 4 weeks modestly improves cognitive function when compared to placebo (110385).
• Congestive heart failure (CHF). It is unclear if oral L-arginine is beneficial in patients with CHF. Details: One small clinical study in patients with CHF stage 2-3 shows that taking L-arginine 15 grams daily for 5 days, in combination with conventional treatment, seems to improve glomerular filtration rate (GFR), creatinine clearance, and sodium and water elimination after saline loading, indicating an improvement in kidney function (3596).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral L-arginine is beneficial in patients with severe COVID-19 infection. Details: A small clinical trial in patients with severe COVID-19 shows that receiving oral L-arginine (Argin, Nutrigrow, India) 3 grams daily for a maximum of 10 days while on oxygen support does not affect the percentage of patients weaned off oxygen support after 10 days, the length of time requiring oxygen support, the duration of hospitalization, or the incidence of adverse thrombotic events, compared with placebo (110392). This study may not have been adequately powered to detect differences between groups. An interim analysis of a small clinical trial in patients hospitalized with severe COVID-19 shows that adding oral L-arginine (Bioarginina, Farmaceutici Damor) 1.66 grams twice daily to standard therapy throughout hospitalization increases the rate of respiratory support reduction by 60% after 10 days of therapy, but not after 20 days of therapy, when compared with placebo. L-arginine also significantly reduced the length of hospital stay. The median hospital stay was 25 days and 46 days, respectively, for L-arginine and placebo (106500). L-arginine has also been investigated in combination with other ingredients for post-acute COVID symptoms. Preliminary clinical research in adults with persistent fatigue following a COVID infection shows that taking L-arginine 1.66 grams plus vitamin C 500 mg (Bioarginina C, Farmaceutici Damor) twice daily for 28 days increases the distance walked in 6 minutes by 30 meters and reduces the percentage of patients with fatigue by about 89%, when compared with placebo. Grip strength was also increased (110390).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral L-arginine is beneficial for preventing complications after CABG surgery. Details: Preliminary clinical research shows that venous infusion of L-arginine hydrochloride 30 grams as a 10% solution over 15 minutes helps maintain mean arterial pressure, coronary vascular resistance, and graft blood flow when compared with a placebo infusion in patients that have undergone CABG (31840). Administering L-arginine 7.5 grams in 500 mL of cardioplegic solution also seems to reduce wedge pressure and intensive care unit stay in patients undergoing CABG; however, it does not reduce hospital stay duration or postoperative complications when compared with cardioplegic solution alone (31958,31886).
• Critical illness (trauma). Oral L-arginine has only been evaluated in combination with other ingredients; its effects when used alone are unclear. Details: A meta-analysis of clinical research shows that taking L-arginine orally with glutamine, nucleotides, and omega-3 fatty acids reduces the recovery time, the need for ventilation, and infection rates in critically ill patients, but does not reduce the risk of mortality (31853).
• Cyclosporine-induced nephrotoxicity. Although there is interest in using oral L-arginine for cyclosporine-induced nephrotoxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose.
• Cystic fibrosis. It is unclear if oral L-arginine is beneficial in patients with cystic fibrosis. Details: Preliminary clinical research in teens and adults with cystic fibrosis shows that twice daily inhalation with L-arginine 500 mg for 2 weeks does not improve lung function when compared with inhaling 2.6% hypertonic saline twice daily (96807).
• Dental caries. Small clinical studies suggest that using a dentifrice containing L-arginine might prevent dental caries. Details: A meta-analysis of small studies shows that use of a dentifrice containing L-arginine 1.5% w/w in combination with calcium base (Dical or calcium carbonate) and fluoride 1450 ppm 2-3 times daily for up to 2 years reduces the risk of developing dental caries by a small to moderate amount when compared with a dentifrice containing only fluoride in children and adults (96806). Also, preliminary clinical research shows that using a confection containing an L-arginine complex (CaviStat) for one year reduces the number of dental caries in molars of children when compared with a sugarless mint control (32011). L-arginine has also been investigated as a prebiotic in combination with probiotics. In 5- to 9-year-old children with low caries risk, clinical research shows that taking one lozenge daily for 10-12 months containing arginine 20 mg along with Lacticaseibacillus paracasei and Lacticaseibacillus rhamnosus, modestly reduces caries severity, but does not reduce caries progression, active caries lesions, plaque, or gingivitis, when compared with placebo (113241,113242).
• Dental hypersensitivity. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a toothpaste containing L-arginine, calcium, and fluoride twice daily reduces dentin hypersensitivity when compared with pretreatment or control (32130,32131,32132,32177). Another moderate-sized clinical study in adults shows that applying a topical combination of L-arginine 10% and ibuprofen to tooth enamel surfaces for 10 minutes prior to in-office tooth bleaching reduces the risk and intensity of tooth sensitivity when compared with placebo (115354). It is unclear whether the effects are due to L-arginine, other ingredients, or the combination.
• Diabetes. Small, low-quality studies suggest that oral L-arginine does not improve glycemic control in people with type 2 diabetes. Details: A meta-analysis of small, low-quality studies shows that taking L-arginine 2-20 grams daily for up to 77 weeks decreases fasting blood glucose and serum insulin levels in adults without diabetes. However, no improvements occurred in adults WITH type 2 diabetes. This may be explained by previous studies which suggest L-arginine affects glucose control only in the early steps of beta-cell dysfunction. L-arginine did not improve insulin resistance or glycated hemoglobin (HbA1c) in patients with or without diabetes (104225). Also, a prospective observational study in patients with type 1 or type 2 diabetes has found that taking a specific product (Flebotrofine, AMNOL Chimica Biologica) containing L-arginine for 3 months is not associated with improvements in HbA1c, cholesterol, or triglyceride levels when compared with baseline. Other ingredients in this product included diosmin, troxerutin, hesperidin, black currant extract, and gotu kola extract (108151). The validity of these findings is limited by the lack of a comparator group.
• Diabetic foot ulcers. It is unclear if oral or subcutaneous L-arginine is beneficial in patients with diabetic foot ulcers. Details: A very small clinical study shows that administering L-arginine subcutaneously at the site of diabetic foot ulcers does not decrease healing time or rate of amputation when combined with conventional therapies (14914). Also, taking a specific drink containing L-arginine 7 grams, L-glutamine 7 grams, and calcium hydroxymethylbutyrate (HMB) 1.5 grams (Juven/Abound, Abbott Nutrition) orally twice daily for 16 weeks does not improve diabetic foot ulcer healing when compared with a control drink in non-ischemic patients or those with normal albumin levels. However, in specific populations with low albumin and/or poor limb perfusion, up to 74% more patients had total wound healing when compared with the control drink (96637).
• Diabetic neuropathy. It is unclear if oral L-arginine is beneficial in patients with diabetic neuropathy. Details: Preliminary clinical research shows that taking L-arginine 3 grams daily for 3 months does not improve circulation, disability, or nerve function in patients with diabetic neuropathy when compared with placebo (32145).
• Head and neck cancer. It is unclear if oral L-arginine is beneficial in patients with head and neck cancer. Details: Small clinical studies suggest that enteral nutrition supplemented with L-arginine does not seem to have any beneficial effects on markers of immune function such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), length of postoperative hospital stay, or fistula rates; however, it seems to reduce wounds and general infections after surgery in patients with head and neck cancer when compared with control (10160,32008).
• Heart failure. It is unclear if oral L-arginine is beneficial in patients with heart failure. Details: Preliminary clinical research in adults with heart failure shows that taking L-arginine 3.0-12.6 grams orally daily for 6-12 weeks does not consistently improve exercise tolerance or peripheral vascular resistance (3595,6028,32138). However, some research shows that taking L-arginine 1000 mg three times daily for 10 weeks modestly improves measures of cardiac function compared with placebo (110380). Although some research disagrees (32138), most research shows that taking L-arginine modestly improves quality of life (3595,110380).
• Heart transplant complications. It is unclear if oral L-arginine is beneficial in patients that have received a heart transplant. Details: Preliminary clinical research shows that taking L-arginine 6 grams orally twice daily for 6 weeks increases walking distance and oxygen uptake and delays the ventilatory threshold in heart transplant patients when compared with baseline (32150).
• HIV/AIDS-related wasting. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study in patients with HIV/AIDS shows that taking L-arginine orally, in combination with hydroxymethylbutyrate (HMB) and glutamine for 8 weeks, increases body weight, particularly lean body mass, and positively affects immune status when compared with placebo (1909). However, other clinical research in HIV-positive patients shows that taking L-arginine 7.4 grams daily orally, in combination with omega-3 fatty acids and a balanced oral nutritional supplement for 6 months, does not improve body weight or fat mass, total energy intake, or immune status when compared to taking the nutritional supplement alone (113).
• Impaired glucose tolerance (prediabetes). It is unclear if oral L-arginine can prevent the development of type 2 diabetes in adults with prediabetes. Details: Clinical research shows that taking L-arginine (Bioarginine, Farmaceutici Damor) 3.2 grams orally twice daily for 18 months does not reduce the incidence of diabetes in patients with impaired glucose tolerance (prediabetes). However, when assessed one year after treatment discontinuation, patients who took L-arginine had a 58% lower risk of developing diabetes when compared with placebo (91195).
• Infertility. It is unclear if oral L-arginine improves outcomes in people undergoing an assisted reproductive technology (ART) program. Details: Some preliminary clinical research shows that taking L-arginine 16 grams daily decreases the cancellation rate of in vitro fertilization (IVF) and increases the number of oocytes collected in females undergoing an ART program when compared with control. However, taking L-arginine does not seem to improve the number of viable pregnancies (31842). A small clinical study of females undergoing an ART program shows that taking a combination product containing L-arginine 1 gram with folate 200 mcg or L-arginine 2 grams, folate 400 mcg, and vitamin E 10 mg daily for 12 weeks does not affect the hCG-positive rate or clinical pregnancy rate when compared with placebo. A subgroup analysis suggests that taking these combination products might improve HCG-positive and clinical pregnancy rates in females who are undergoing ART due to male infertility (104224). However, this small study was not adequately powered to detect a difference in these outcomes, limiting the validity of these findings.
• Interstitial cystitis. Small clinical studies suggest that oral L-arginine may improve pain in interstitial cystitis. Details: Taking L-arginine orally seems to reduce some symptoms, especially pain, that are associated with interstitial cystitis (107,114,3460,31855,32267). Research shows that patients with interstitial cystitis having a bladder capacity greater than 800 mL and/or a history of recurrent genitourinary infections might respond more favorably to L-arginine than patients with bladder capacity less than 800 mL and/or no history of recurrent genitourinary infections. Three months of treatment may be necessary before significant symptom improvement occurs (3460). However, L-arginine does not seem to reduce the need to urinate at night or improve urgency or frequency of urination (3460,31855).
• Intrauterine growth restriction (IUGR). Small clinical studies suggest that oral or intravenous L-arginine may increase birthweight in IUGR. Details: A meta-analysis of mainly small studies shows that L-arginine given orally or intravenously in the third trimester for a time period of 7 days or until delivery increases the birthweight by up to 650 grams in patients with an IUGR pregnancy. Furthermore, there is evidence from a small number of these studies that L-arginine supplementation decreases the risk of neonatal respiratory distress syndrome and fetal intracranial hemorrhage (96804). A more recent meta-analysis of small studies also shows that taking L-arginine 3 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of an IUGR infant by about 32% when compared to control, including placebo or no treatment (110379). Doses used in clinical research have usually been 3 grams daily orally, although some studies have used up to 20 grams intravenously (31930,31937,96804,110379). However, supplementation with L-arginine does not seem to increase birthweight or reduce neonatal mortality or morbidity when compared with placebo in patients with severe IUGR (32083).
• Kidney transplant. Small clinical studies suggest that oral L-arginine may not improve kidney function in patients after kidney transplantation. Details: Although preliminary clinical research showed some benefit, evidence from other clinical research shows that infusion with L-arginine does not increase renal plasma flow or glomerular filtration rate in kidney transplant patients treated with cyclosporine, including those experiencing transplant dysfunction (112,31876,32229). Other evidence suggests that intravenous L-arginine improves kidney function only in transplant patients receiving organs with a short cold ischemia time or those receiving kidneys from young donors (31887).
• Male infertility. It is unclear if oral L-arginine is beneficial in males with infertility. Details: Preliminary clinical research shows that taking L-arginine 4 grams daily for 12 weeks does not improve semen quality in males with oligospermia when compared with placebo (32209). However, one small clinical study shows that a specific formulation of L-arginine aspartate and maritime pine bark extract (Prelox), taken for 6 months, improves sperm quality in males with idiopathic male infertility when compared to baseline (32061). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to L-arginine, maritime pine bark, or the combination.
• Mitochondrial myopathies. Small clinical studies suggest that intravenous L-arginine may modestly improve symptoms in patients with MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome). Details: Preliminary clinical research shows that infusions of L-arginine, 0.5 grams/kg administered within one hour of stroke-like symptoms, improves headaches, nausea, vomiting, transient blindness, and the appearance of bright spots when compared to pretreatment in patients with MELAS (31943,99263). Also, taking oral L-arginine 4-24 grams daily for 18 months seems to reduce the frequency and severity of stroke-like symptoms associated with MELAS when compared to baseline (31943). However, other preliminary clinical research shows that taking oral L-arginine 0.3-0.5 grams/kg daily in three divided doses for 2 years does not reduce the severity of MELAS symptoms, including migraine and stroke-like episodes. If a stroke-like episode did occur, administration of intravenous L-arginine 0.5 grams/kg improved headache, nausea, vomiting, and visual disturbance (99263). The validity of this research is limited by the small study sizes and the absence of comparator groups.
• Migraine headache. Although there is interest in using oral L-arginine for migraine, there is insufficient reliable information about the clinical effects of L-arginine for this condition.
• Muscular dystrophy. There is limited evidence on the oral use of L-arginine in patients with Duchenne muscular dystrophy. Details: A very small study in five children with Duchenne muscular dystrophy, shows that drinking a beverage containing L-arginine hydrochloride (L-Arginine Hydrochloride, Selectchemie) 2.5 grams three times daily, in addition to metformin 250 mg twice daily, for 16 weeks improves motor function by 4% and increases distance walked in two minutes by 9.6 meters when compared to baseline (96805). The validity of these findings is limited by the very small study size and lack of a comparator group.
• Nitrate tolerance. It is unclear if oral L-arginine is beneficial for nitrate tolerance. Details: A very small crossover study in adults with stable angina shows that taking L-arginine orally 700 mg four times daily for up to 10 days seems to prevent tolerance to transdermal nitrate when compared with placebo (8475).
• Obesity. Small clinical studies suggest that oral L-arginine may be beneficial for weight loss. Details: A meta-analysis of mainly small clinical trials shows that taking L-arginine daily for at least 8 weeks modestly reduces body weight, body mass index (BMI), and waist circumference when compared with placebo. However, when taking L-arginine for less than 8 weeks, BMI and body weight were not affected. The optimal dose of L-arginine was 2-6 grams (110398). An additional small clinical study suggests that taking a specific arginine supplement (NOW Foods) 3 grams by mouth three times daily for 12 weeks, in addition to receiving dietary counseling, reduces waist circumference by 4-6 cm and reduces body weight by 1.8-2.9 kg when compared to baseline in obese females 18-40 years of age (91193). The validity of these findings is limited by the lack of a comparator group.
• Oral mucositis. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study shows that taking a specific combination of L-arginine 7 grams, L-glutamine 7 grams, and hydroxymethylbutyrate (HMB) 1.2 grams (Abound; Abbott) in water twice daily during chemoradiotherapy treatment for head and neck cancer does not reduce the incidence of severe oral mucositis when compared with a historical control (99243). The validity of this finding is limited by the lack of a placebo control. Additionally, a small open-label study in patients undergoing chemoradiation for head and neck cancer shows that taking a specific combination product (Abound, Abbot) containing L-arginine, glutamine, and HMB twice daily throughout chemoradiation treatments decreases the incidence of grade 3 or higher oral mucositis and ameliorates body weight loss when compared with no intervention (113726). However, the incidence of grade 2 or higher oral mucositis was not reduced. It is unclear if this effect is due to L-arginine, other ingredients, or the combination. Additionally, the validity of the study is limited by the lack of blinding.
• Periodontitis. It is unclear if oral L-arginine is beneficial in patients with periodontitis. Details: Preliminary clinical research in patients with chronic periodontitis shows that using L-arginine aspartate (Yuria-Pharm, Ukraine) 1 gram three times daily orally for 10 days after scaling and root planing, modestly reduces bleeding on probing but not periodontal pocket depth, when compared with untreated controls (108926).
• Physical performance. It is unclear if oral L-arginine is beneficial for improving physical performance in older adults. Details: A small study in physically active females 65 years of age and older shows that taking L-arginine 8 grams as a single dose does not improve lower body strength, measured by knee flexion and extension tests, or functional performance, measured by sit-stand, tandem gait, and timed up-and-go tests, when compared with placebo (96812).
• Polycystic ovary syndrome (PCOS). Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of N-acetylcysteine 1200 mg daily plus L-arginine 1600 mg daily for 6 months modestly improves menstrual function and decreases insulin resistance in patients with PCOS when compared to baseline (32094). The validity of these findings is limited by the lack of a comparator group.
• Postoperative infection. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies show that taking L-arginine, enterally or orally, either before or after surgery, in combination with fish oil, or with ribonucleic acid (RNA) and eicosapentaenoic acid (EPA), seems to reduce the rate of perioperative infection when compared with a control group. The risk of infection was 41% lower when compared to taking no arginine-based formulations. However, there is no good evidence to support the use of L-arginine alone for this purpose, and it is possible that this effect is due to the other ingredients or the combination of ingredients (5531,32174,32196).
• Postoperative recovery. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies show that taking L-arginine, enterally or orally, either before or after surgery, in combination with fish oil, or with ribonucleic acid (RNA) and eicosapentaenoic acid (EPA), seems to reduce the recovery time after surgery or serious illness when compared with a control group. This seems to be related to a reduced number of perioperative infections and improved wound healing. However, there is no good evidence to support the use of L-arginine alone for this purpose, and it is possible that this effect is due to the other ingredients or the combination of ingredients (5531,32174,32196). The effect of another combination product containing L-arginine is unclear. In one clinical study, taking a combination product (Abound, Abbott) containing L-arginine 7 grams, glutamine 7 grams, and hydroxymethylbutyrate 1.2 grams orally daily for 3 days before and 7 days after abdominal surgery did not reduce the incidence of wound infection or other complications when compared with placebo (99413). However, when a similar combination of L-arginine 14 grams, glutamine 14 grams, and hydroxymethylbutyrate 3 grams (Heallagen) was taken orally daily for one month before heart surgery, the length of hospital and ICU stay were reduced by about one day. Recovery, based on some but not all biochemical or other measurements, was also improved. However, there was no difference in risk of overall postoperative complications (110394). The discrepancies between these two studies may be related to differences in the dose or duration of the combination product and/or the type of surgery.
• Pressure ulcers. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Oral L-arginine has been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients show that administering an oral nutritional supplement enriched with L-arginine, zinc, and vitamin C improves ulcer healing when compared with a standard diet (31953,87173). A small preliminary clinical study in sedentary older adults in care facilities shows that giving an oral or enteral combination of L-arginine 7.4 grams, L-glutamine 7.4 grams, and hydroxymethylbutyrate (HMB) 1.3 grams (Abound, Abbott) daily for 20 weeks reduces median time to healing by 48 days when compared with standard care only (110396). Also, preliminary clinical research in patients living in long-term care facilities with grade II-IV pressure ulcers shows that taking an oral nutritional supplement enriched in protein, energy, L-arginine, vitamin C, and zinc daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Preterm labor. Small clinical studies suggest that oral L-arginine may prevent preterm labor. Details: A meta-analysis of three small studies shows that taking L-arginine 3-6.6 grams daily, starting in the second or third trimester usually until delivery, reduces the risk of preterm labor by about 50% when compared to control, usually placebo (110379).
• Pulmonary hypertension. It is unclear if oral L-arginine is beneficial in children with pulmonary hypertension related to beta-thalassemia. Details: Preliminary clinical research in children aged 6-18 years treated conventionally for pulmonary hypertension related to beta-thalassemia shows that taking L-arginine 0.1 mg/kg daily for 60 days reduces Doppler echocardiography pulmonary arterial pressure by 35% compared with baseline. This measurement was increased by up to 15% in children given conventional treatments only; however, a statistical comparison between these treatment groups was lacking (110391).
• Radiation dermatitis. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with head and neck cancer shows that taking a combination of L-arginine 7 grams, L-glutamine 7 grams, and hydroxymethylbutyrate (HMB) 1.2 grams (Abound, Abbott) in water twice daily from the first day of radiation to approximately 1 week after completion does not reduce the number of patients with severe dermatitis when compared with taking no supplement. However, there was a 34% reduction in the incidence of moderate dermatitis and the overall duration of dermatitis was reduced (96639).
• Restenosis. It is unclear if intravenous L-arginine helps to prevent restenosis after stent implantation. Details: Some clinical research suggests that intravenous and intracoronary infusion of L-arginine during stent implantation followed by oral L-arginine for 2 weeks does not reduce the risk of restenosis when compared with placebo (31925). However, local delivery of 6 mL of L-arginine 100 mg/mL for 15 minutes after stent deployment seems to reduce neointimal formation at 6 months after stent placement when compared with placebo (31883).
• Respiratory tract infections. Although there is interest in using oral L-arginine for respiratory tract infections, there is insufficient reliable information about the clinical effects of L-arginine for these conditions.
• Schizophrenia. It is unclear if oral L-arginine is beneficial in patients with schizophrenia. Details: A small clinical study shows that taking L-arginine 3 grams twice daily for 3 weeks, in conjunction with an individualized medication regimen, does not improve positive, negative, or depressive symptoms associated with schizophrenia when compared with taking the medication regimen alone (99264).
• Sexual dysfunction. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with sexual dysfunction who are taking oral contraceptives shows that taking a specific combination product (Lady Prelox, Horphag Research) containing L-arginine, maritime pine bark extract, L-citrulline, and rose hip extract daily for 8 weeks improves symptoms of sexual dysfunction by 18% when compared with a control group (91963). Taking the same product in a dose of 2 tablets twice daily for 8 weeks, in addition to the lifestyle management program, improves vaginal dryness in pre- and post-menopausal patients when compared with lifestyle management alone (103611). It is unclear if this effect is due to L-arginine, the other ingredients, or the combination.
• Sickle cell disease. Small clinical studies suggest that oral or intravenous L-arginine may modestly improve complications in patients with sickle cell disease. Details: Two small clinical studies in hospitalized children aged 3-19 years with sickle cell disease-related veno-occlusive crisis shows that administering L-arginine intravenously or orally 100 mg/kg three times daily for 5 days or until discharge reduces total opioid use by 26% to 54%, pain scores at discharge by 23%, and median length of hospital stay by about 36 hours when compared with placebo (97392,105063). Another very small clinical study in patients aged 13-63 years with sickle cell disease shows that taking L-arginine 0.1 grams/kg orally three times daily for 5 days reduces pulmonary hypertension when compared to baseline (11428).
• Stress. Oral L-arginine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults shows that taking a single dose of L-arginine 50 mg plus L-theanine 200 mg modestly reduces stress associated with a stress-loading test when compared with placebo, but was no more effective than taking L-theanine alone (110393).
• Valproic acid-induced toxicities. Although there is interest in using intravenous L-arginine for valproic acid toxicity, there is insufficient reliable information about the clinical effects of L-arginine for this purpose. More evidence is needed to rate L-arginine for these uses.

(Read more about L-ARGININE)

LIKELY EFFECTIVE

• Pellagra. Oral niacinamide is approved for the treatment of pellagra and niacin deficiency. Details: Niacinamide is FDA-approved for the prevention and treatment of niacin deficiency and pellagra. Niacinamide is sometimes preferred over niacin for this indication because it lacks the vasodilating and flushing effects of niacin (15,6243).

POSSIBLY EFFECTIVE

• Acne. Topical niacinamide seems to improve acne symptoms in some patients. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One clinical study shows that applying niacinamide 4% gel twice daily for 8 weeks is as effective as clindamycin 1% gel for reducing the number and severity of acne lesions. The niacinamide gel appears to be more effective in patients with oily skin than those with non-oily skin (93360). Other preliminary clinical research in adults with mild to moderate acne vulgaris shows that applying niacinamide 5% cream twice daily, 10 minutes after applying benzoyl peroxide 2.5% gel, for 12 weeks reduces the number of acne lesions, but not erythema or inflammation, when compared with benzoyl peroxide alone (107711). Niacinamide has also been studied in combination with other ingredients. In preliminary clinical research, oral niacinamide has been reported to improve acne when used in combination with zinc, copper, and folic acid (Nicomide) (25557), or in combination with azelaic acid, zinc, pyridoxine, copper, and folic acid (NicAzel, Elorac Inc.) (90800). In a small observational study, topical niacinamide 4% combined with gallic acid 1% and lauric acid 1% was associated with some improvement in acne (104931). It is unclear if the effects in these studies are due to niacinamide, other ingredients, or the combinations.
• Diabetes. Oral niacinamide does not seem to prevent the onset of type 1 diabetes, although it might slow its progression. Details: Although some older research has suggested that taking high-dose niacinamide can reduce the risk of type 1 diabetes in high-risk children (4874), results from higher quality, more rigorous clinical trials show that taking niacinamide up to 3 grams daily for 5 years does not prevent the onset of type 1 diabetes in first-degree relatives of patients with type 1 diabetes (4875,25553,25554). However, taking niacinamide 1.2 grams/m2 daily for 5 years may prevent the loss of beta-cell function in these patients (25555). Also, there is evidence showing that niacinamide can preserve residual beta-cell function in patients with newly diagnosed type 1 diabetes (4877,4878,4879,4880,25556). Clinical trials, including one placebo-controlled trial and one vitamin E-comparison study, show niacinamide can prolong the "honeymoon period" in those newly diagnosed with type 1 diabetes, when the pancreas is still capable of producing some insulin (4877,4878,4879,4880,25556). However, some scientists have raised concerns about potential induction of insulin resistance with short-term use of niacinamide 2 grams daily for 2 weeks (4881). Niacinamide has also been evaluated in adults with type 2 diabetes. A small clinical study in lean patients with type 2 diabetes who failed sulfonylurea therapy shows that taking niacinamide 500 mg three times daily for 6 months in addition to continuing insulin or a sulfonylurea increases C-peptide release and improves insulin secretion when compared with insulin alone (4882).
• Hyperphosphatemia. Adding oral niacinamide to standard treatment with phosphate binders further lowers blood levels of phosphorus in patients on hemodialysis. Details: A meta-analysis of nine small clinical trials in patients on hemodialysis with hyperphosphatemia who are using a phosphate binder shows that taking niacinamide 250-1500 mg daily for 2-6 months lowers serum phosphorus and parathyroid hormone levels when compared with placebo (98940) Another meta-analysis of two small clinical trials in the same patient population also shows that taking niacinamide, titrated from 500 mg to 1500 mg daily over 8 weeks, reduces serum phosphorus levels by about 0.9 mg/dL when compared with placebo (94188). Other clinical research in this population shows that taking modified-release niacinamide 250-1500 mg orally daily for 12-24 weeks also lowers serum phosphate and parathyroid levels when compared with placebo. However, these effects were not maintained at 40-52 weeks follow-up (107709,110499). In addition, this product was not compared with immediate-release niacinamide. Niacinamide has also been studied in place of phosphate binders. One small clinical study in patients on hemodialysis with hyperphosphatemia shows that taking niacinamide 500-1750 mg daily for 12 weeks, beginning 2 weeks after discontinuation of phosphate binders, decreases serum phosphorus levels by 1.5 mg/dL and intact parathyroid hormone levels by 50 pg/mL, without affecting calcium levels, when compared to baseline (25561).The validity of these findings is limited due to the lack of a control group.
• Osteoarthritis. Oral high-dose niacinamide might be beneficial for improving osteoarthritis symptoms. Details: Clinical research in patients with osteoarthritis shows that taking niacinamide 3 grams daily in six divided doses for 12 weeks improves joint flexibility, reduces inflammation, and modestly decreases use of nonsteroidal anti-inflammatory drugs (NSAIDs) when compared with placebo (4883).

POSSIBLY INEFFECTIVE

• Brain tumor. Adding high-dose oral niacinamide to chemotherapy does not seem to improve survival in patients with brain tumors. Details: Preliminary clinical research in patients with surgically resected brain tumors shows that treatment with radiotherapy, niacinamide, and carbogen does not improve survival when compared with radiotherapy alone or radiotherapy plus carbogen (11695,11696).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Actinic keratoses. It is unclear if oral or topical niacinamide is beneficial for reducing actinic keratoses. Research results are conflicting. Details: A large clinical trial in healthy Australian adults with actinic keratoses shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the number of actinic keratoses by 13% when compared with placebo. The difference between the 2 groups was observed as early as 3 months after starting niacinamide (93362). Additionally, a small clinical study in healthy, older Australian adults with actinic keratoses shows that taking niacinamide (Nature's Own, Virginia) 500 mg once or twice daily for 4 months reduces the total number of actinic keratoses by 29% and 35%, respectively, when compared with placebo (93365). However, a large clinical trial in solid organ transplant recipients in Australia shows that taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 6 months does not reduce the number of actinic keratoses when compared with placebo (113559). Also, a small clinical trial in kidney transplant recipients with actinic keratoses and a history of nonmelanoma skin cancer shows that taking niacinamide 500 mg twice daily for 12 months does not decrease the number of actinic keratoses when compared with placebo (113682). The study may have been inadequately powered to detect a difference between groups. Two small clinical studies conducted in Brazil in elderly adults with actinic keratoses shows that taking niacinamide 500 mg twice daily for 120 days or applying a cream containing niacinamide 5% twice daily for 56 days does not reduce the number of actinic keratoses when compared with placebo (107714,113684). Most studies were conducted in countries with high year-round ultraviolet radiation exposure, such as Australia and Brazil; results may not be readily extrapolated to populations in other geographic regions.
• Age-related cognitive decline. Although there is interest in using oral niacinamide for age-related cognitive decline, there is insufficient reliable information about the clinical effects of niacinamide for this purpose.
• Age-related macular degeneration (AMD). Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with early-stage age-related maculopathy shows that taking a combination of niacinamide 18 mg, vitamin E 20 mg, and lutein 15 mg daily for nearly a year improves retinal function when compared with no treatment (60134). It is unclear if this effect is due to niacinamide, other ingredients, or the combination.
• Aging skin. It is unclear if topical niacinamide improves symptoms of aging skin. Details: A small study in females with signs of facial photo-aging shows that applying niacinamide 5% cream to half of the face twice daily for 12 weeks improves blotchiness, the appearance of wrinkles, skin elasticity, and skin pigmentation when compared with applying placebo cream to the other half of the face (25551).
• Atopic dermatitis (eczema). It is unclear if topical niacinamide improves eczema symptoms. Details: A small clinical study in patients with atopic dermatitis and dry skin shows that applying niacinamide 2% cream twice daily for 8 weeks decreases skin water loss and improves skin hydration when compared with using a white petrolatum moisturizer (25560). A moderate-sized clinical study in adults with mild atopic dermatitis (AD) shows that applying a specific niacinamide containing body emollient (Bioderma Atoderm PP Baume, Bioderma Cosmetics Trading Co., Ltd.) 250 grams weekly, applied twice daily for 28 days with or without pre-cleansing with a specific niacinamide containing gel wash (Atoderm Intensive Gel Moussant, Bioderma Cosmetics Trading Co., Ltd.), improves AD severity, itching, trans-epidermal water loss, skin water content, and dermatological quality of life when compared with a control emollient and water-only skin cleansing. Additionally, using both the niacinamide containing emollient and cleansing gel improves trans-epidermal water loss and skin water content sooner when compared with niacin containing emollient only (113681). However, the study may have been inadequately powered and too short in duration to detect additional differences between the 2 niacinamide groups.
• Attention deficit-hyperactivity disorder (ADHD). Oral niacinamide has only been evaluated in combination with other vitamins; its effect when used alone is unclear. Details: A small clinical study in children with ADHD shows that taking a maximum of niacinamide 3 grams, ascorbic acid 3 grams, calcium pantothenate 1.2 grams, and pyridoxine 600 mg daily for 3 months seems to improve behavior in 29% of participants when compared with baseline (9957). The validity of this finding is limited by the lack of a comparator group.
• Bladder cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in advanced bladder cancer; its effect when used alone is unclear. Details: A phase II clinical study in patients with locally advanced bladder cancer shows that adding inhaled carbogen and oral niacinamide 40-60 mg/kg about 2 hours before radiotherapy shows a trend to improved survival at 3 years when compared with inhaled carbogen and radiotherapy (25558), and a larger phase III study shows that carbogen and oral niacinamide improves 3-year survival by about 13% when compared with radiotherapy alone (93366). An observational follow-up of the phase III study found a trend to increased survival at 5 years in the carbogen and niacinamide group when compared with radiotherapy alone. And in a subgroup of patients with tumor necrosis, the 5-year survival was significantly greater with carbogen and niacinamide when compared with radiotherapy alone (93356). It is unclear if these effects are due to niacinamide, carbogen, or the combination.
• Child growth. It is unclear if oral niacinamide improves child growth. Details: Preliminary clinical research in children in rural Tanzania shows that supplementing niacinamide orally from birth to 18 months of age does not improve length-for-age, weight-for-age, or head circumference when compared with control. Niacinamide was initially supplemented to breast-feeding mothers, 250 mg daily, until 6 months of age, followed by 100 mg daily taken by the child until 18 months of age (107713).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral niacinamide is beneficial for COVID-19. Details: Observational research in adults with acute kidney injury secondary to coronavirus disease-19 infection has found that taking niacinamide 1000 mg orally daily for 7 days is associated with a 55% lower risk of mortality when compared with control. However, taking niacinamide was not associated with a lower risk of renal replacement therapy (110500).
• Cutaneous lupus erythematosus (CLE). It is unclear if topical niacinamide is beneficial for CLE. Details: Preliminary clinical research in adults with discoid lupus erythematosus, a type of CLE, shows that applying topical niacinamide 2% to 4% twice daily for 12 weeks modestly improves lesion scores, but not quality of life scores, when compared with placebo. However, the study may have been inadequately powered to detect a difference between groups (110498).
• Depression. Although there is interest in using oral niacinamide for depression, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Diabetic neuropathy. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with diabetic polyneuropathy shows that taking a specific combination product (Cytoflavin, Polysan) containing niacinamide, inosine, riboflavin, and succinate daily for 12 weeks improves symptom scores, including paresthesia and numbness scores, when compared with placebo. The therapy was first administered intravenously, providing niacinamide 200 mg, inosine 400 mg, riboflavin 40 mg, and succinate 2000 mg daily for 10 days, followed by an oral formulation providing niacinamide 100 mg, inosine 200 mg, riboflavin 20 mg, and succinate 1200 mg daily for the remainder of the study (110503).
• Erythema. Topical niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: There is interest in using niacinamide to reduce the side effects of topical tretinoin, including erythema. A small preliminary clinical study in patients using isotretinoin for acne shows that applying a specific cream (Sebiaclear Hydra, SVr Laboratoire Dermatologique) containing niacinamide 5% and omega-ceramides 8% twice daily for 6 months reduces isotretinoin-induced erythema, dryness, and itching of the skin when compared with a glycerin placebo (98938). It is not clear if this effect is due to niacinamide, omega-ceramides, or the combination.
• Head and neck cancer. Oral niacinamide has only been evaluated in combination with carbogen for improving survival in laryngeal cancer; its effect when used alone is unclear. Details: A phase III clinical trial in patients with laryngeal cancer shows that treatment with accelerated radiotherapy plus carbogen and niacinamide 60 mg/kg taken orally 1-1.5 hours prior to each fraction of radiation improves local tumor control, but does not improve overall survival or 5-year disease-free survival, when compared with accelerated radiotherapy alone. In a subgroup of patients with hypoxic tumors, anemia, or high expression of epidermal growth factor receptor, receiving niacinamide and carbogen seems to improve both survival and tumor control when compared with radiotherapy alone (93358,93359,93363).
• Melasma. It is unclear if topical niacinamide improves melasma. Details: A small clinical study in female adults with melasma shows that applying a specific niacinamide 10% serum (Bo leda, Shanghai Ruizhi Medical Technology Co., Ltd) twice daily after skin cleansing for 16 weeks improves melasma area and severity, pigmented spots, and skin texture when compared with control. Both groups were also treated with salicylic acid 30% throughout the study (113683). Topical niacinamide has also been studied in patients with hyperpigmentation. A small clinical study in Japanese females with uneven facial hyperpigmentation shows that applying niacinamide 5% moisturizer to the face twice daily reduces hyperpigmentation and increases skin lightness after 4 weeks when compared with placebo moisturizer. However, further improvements are not observed after another 4 weeks of treatment (25552). Another small clinical study in Korean females with uneven facial hyperpigmentation shows that applying a moisturizer containing niacinamide 2% plus tranexamic acid 2% (Regederm RX White Project, Aestura) twice daily for 8 weeks reduces skin pigmentation by about 9% when compared with a placebo cream (93361).
• Non-Hodgkin lymphoma. It is unclear if adding oral niacinamide to chemotherapy reduces relapses of refractory lymphoma. Details: One small clinical study in patients with relapsed or refractory lymphoma shows that 24% of patients achieve complete or partial remission and 57% achieve disease stabilization when compared with baseline, following treatment with vorinostat 400 mg daily and niacinamide titrated from 20 mg/kg to 100 mg/kg over the first 14 days of a 21-day cycle for up to 18 cycles (93355). It is unclear how these outcomes compare to using vorinostat alone, or to other control treatments.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral niacinamide is beneficial for NAFLD. Details: Preliminary clinical research in adults with NAFLD and diabetes shows that taking a specific niacinamide product (Nature's Life) 1000 mg orally daily for 12 weeks does not improve liver function tests, liver steatosis, or liver fibrosis when compared with no intervention. However, some quality of life domain scores were moderately improved. However, the study may have been inadequately powered to detect a difference between groups (110502).
• Nonmelanoma skin cancer. It is unclear if oral or topical niacinamide reduces the risk of nonmelanoma skin cancer. Details: A meta-analysis of 4 clinical trials in adults shows that taking niacinamide 500 mg twice daily for 4-12 months does not reduce the risk of nonmelanoma skin cancer when compared with placebo. This analysis also shows no effect of niacinamide on the risk of basal cell carcinoma and squamous cell carcinoma (113560). However, there was high heterogeneity across the studies due to differences in patient populations and mixed results overall. Two studies included in the analysis show that niacinamide, including a specific niacinamide product (Nature's Own, Virginia), reduces the risk of nonmelanoma skin cancer in immunocompetent adults when compared with placebo (93362,93365). One was a large clinical trial that shows taking a specific niacinamide product (Insolar, Blackmores) 500 mg twice daily for 12 months reduces the rate of new nonmelanoma skin cancer by 23%, but it does not reduce the risk of not recurrent nonmelanoma skin cancers, when compared with placebo. However, this reduced risk appears to be transient. Follow up 6 months after niacinamide was discontinued showed no difference between groups (93362). The 2 other studies analyzed, including a large trial using a specific niacinamide product (Insolar, Blackmores), were conducted in transplant recipients showed no reduced risk of nonmelanoma skin cancer when compared with placebo (113560,113559). All studies were conducted in Australia; it is unclear if these results can be extrapolated to other geographical regions with different background ultraviolet radiation exposure and skin cancer rates. A previous meta-analysis of 5 clinical studies shows taking niacinamide 500-1000 mg daily for 6-12 months or applying niacinamide 1% twice daily for 6 months decreases the rate of basal cell and cutaneous squamous cell carcinomas by 54% and 52%, respectively when compared with control. Niacinamide was only administered topically in 1 of the 5 studies and only reduced risk of cutaneous squamous cell carcinoma (110497).
• Premenstrual syndrome (PMS). Although there is interest in using oral niacinamide for PMS, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Pruritus. It is unclear if oral niacinamide reduces pruritus in patients with kidney failure. Details: A small clinical study in patients with pruritus due to kidney failure shows that taking niacinamide sodium 500 mg twice daily for 4 weeks does not reduce pruritus severity when compared with placebo (93364). This study is limited due to small size and short study duration.
• Psoriasis. It is unclear if oral niacinamide is beneficial for psoriasis. Details: Preliminary clinical research in adults with mild to moderate psoriasis shows that applying niacinamide 4% cream topically twice daily for 12 weeks improves psoriasis scores by 31% when compared with baseline. The validity of these results is limited by the lack of a comparator group (110501).
• Rosacea. Oral niacinamide has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that 71% of adult and adolescent patients with rosacea who take a combination product (Nicomide) containing niacinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 mcg once or twice daily report improvement in appearance after 4 weeks when compared to baseline (25557). The validity of these findings is limited by the lack of a control group.
• Schizophrenia. Although there is interest in using oral niacinamide for schizophrenia, there is insufficient reliable information about the clinical effects of niacinamide for this condition.
• Seborrheic dermatitis. It is unclear if topical niacinamide is beneficial for reducing seborrheic dermatitis symptoms. Details: One small clinical study in patients with seborrheic dermatitis shows that applying niacinamide 4% cream once daily for 12 weeks reduces the severity of symptoms such as redness and scaling by 75%, compared with a 35% reduction when using a placebo cream (93357). More evidence is needed to rate niacinamide for these uses.

(Read more about NIACINAMIDE)

POSSIBLY EFFECTIVE

• Cognitive function. In middle-aged individuals, but not young adults, oral Panax ginseng seems to improve abstract thinking, attention, arithmetic skills, and reaction time. Any benefit to memory seems to be dependent on the inclusion of ginkgo. Details: Some clinical evidence shows that taking Panax ginseng orally can improve abstract thinking, attention, mental arithmetic skills, and reaction times in healthy, middle-aged people; however, Panax ginseng does not seem to improve these outcomes in young adults (2064,23596,23599,23608,23609,54374). While Panax ginseng alone does not seem to improve memory (2064), there is some evidence that a combination of Panax ginseng (G115) and ginkgo leaf (GK501) extract 80-320 mg daily for 12 weeks can improve memory in otherwise healthy people or people with neurasthenia 38-66 years of age (8591,9759,87984,88046). In clinical trials, various doses have been used. These include a specific Panax ginseng extract (G115, Pharmaton SA, Lugano) 200-400 mg once daily or in two divided doses for up to 12 weeks, or 200-960 mg administered as a single dose (8591,23596,23599,23608,23609,54374,88046). Another extract (Gerimax Ginseng Extract; Dansk Droge A/S Ishoj) 400 mg daily for 8 weeks has also been used (2064).
• Erectile dysfunction (ED). Oral Panax ginseng seems to improve sexual function in people with ED. Details: Taking Panax ginseng orally for 8 weeks seems to improve sexual function in adults with ED (8813,23637,23638,89747). Doses used in clinical research have included extract from the juice and pulp of 4 year-old Panax ginseng berry 700 mg twice daily (89747), tissue-cultured mountain ginseng extract 1000 mg twice daily (23638), and Korean red ginseng, a type of Panax ginseng, 1000-2700 mg daily (8813,112840). Panax ginseng has also been studied in adults with symptoms of ED that are associated with an enlarged prostate. A small clinical study in adult males with moderate lower urinary tract symptoms shows that taking a specific extract of Korean red ginseng (RXGIN, Jung Kwan Jang), a type of Panax ginseng, 1000 mg daily for 12 weeks improves symptoms of sexual dysfunction including erectile function, sexual desire, orgasmic function, and intercourse satisfaction when compared with placebo. However, there was no improvement reported in overall satisfaction. Most symptoms of ED except sexual desire had not significantly improved by 6 weeks, suggesting that longer durations of at least 12 weeks may be needed for Panax ginseng to significantly improve ED symptoms (112840). Additionally, Panax ginseng has been evaluated in combination with other ingredients. A moderate-sized, open-label clinical study in adults with mild-to-moderate ED shows that taking a specific combination supplement (Icarifil, Anvest Health S.p.A) containing Panax ginseng 150 mg, L-carnitine, L-citrulline, tribulus, and other ingredients daily for 3 months improves patient-reported erectile function when compared to baseline. Additionally, taking the supplement with tadalafil improves some, but not all, patient-reported assessments of erectile function when compared with taking tadalafil alone (114989). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination. Additionally, the interpretation of these results is limited by poor methodology, including the use of per-protocol analysis and lack of a placebo group.
• Influenza. Oral Panax ginseng seems to modestly reduce the risk of developing influenza. However, it might not reduce the severity or duration of symptoms. Details: Some preliminary clinical research shows that taking a specific Panax ginseng extract (G115) 200 mg daily, beginning 4 weeks prior to influenza vaccination and continuing for 8 weeks thereafter, can decrease the relative risk of getting the flu or common cold by 65% when compared with placebo (589). Also, clinical research in healthy adults shows that taking Panax ginseng extract 1 gram three times daily for 12 weeks reduces the relative risk of developing an acute influenza infection by 45% when compared with placebo. However, taking Panax ginseng does not seem to affect symptom duration or severity (89746).
• Multiple sclerosis-related fatigue. Oral Panax ginseng seems to reduce fatigue and improve quality of life in patients with multiple sclerosis. Details: Clinical research shows that taking Panax ginseng 250 mg twice daily for 3 months improves symptoms of fatigue and quality of life when compared with placebo in female patients with relapsing-remitting multiple sclerosis (RRMS). Females taking Panax ginseng experienced a 75% reduction in fatigue, compared with no change in the placebo group; quality of life was increased by 19.9 points in the Panax ginseng group, compared with only 4.2 in the placebo group (89745).
• Sexual arousal. Oral Panax ginseng, alone or in combination with other ingredients, seems to improve sexual arousal in postmenopausal adults or females with sexual dysfunction. Details: Taking Korean red ginseng, a specific form of Panax ginseng, 3 grams daily for 8 weeks seems to improve sexual arousal and satisfaction when compared with placebo in postmenopausal adults (23630). Also, other preliminary clinical research shows that taking a specific combination product (ArginMax for Women, Daily Wellness Company) containing ginkgo leaf extract, Panax ginseng root extract, damiana leaf extract, L-arginine, multivitamins, and minerals for 4 weeks can improve sexual satisfaction when compared with placebo in females who are self-reported to have sexual dysfunction (23635,46933). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Athletic performance. Most research shows that oral Panax ginseng does not improve athletic performance. Details: Taking Panax ginseng 0.4 to 3 grams daily orally for up to 8 weeks, or as a single dose 200 mg one hour prior to exercise, does not improve aerobic exercise capacity (1427,4230,4231,23646,23647,89737,114981). Higher doses of Panax ginseng also do not seem to improve athletic performance. A small study in young athletes shows that taking Panax ginseng 100 mg/kg (about 5-7 grams, standardized to 10% ginsenosides) daily in three divided doses for 8 days does not improve squat exercise performance, although it might modestly improve perceived exertion, when compared with placebo (103045). Similarly, a small clinical study in adult male recreational athletes shows that taking Panax ginseng extract 500 mg daily for 14 days does not improve 10-kilometer running times when compared with placebo (114981).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral Panax ginseng for aging, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Anthracycline cardiotoxicity. It is unclear if oral Panax ginseng protects against anthracycline cardiotoxicity. Details: A very small clinical study in adults with non-metastatic HER-2 negative breast cancer being treated with anthracycline-based chemotherapy in Iran shows that taking Panax ginseng rhizome powder 1000 mg daily starting on the first day of doxorubicin administration until one week after completion of the eighth doxorubicin cycle improves left ventricular ejection fraction (LVEF) by 1% when compared with placebo, which was associated with a 7% reduction in LVEF. Treatment with Panax ginseng also reduces the incidence of chemotherapy-related cardiac dysfunction when compared with placebo, an effect that endured over a 6-month follow up period. However, Panax ginseng did not improve the cardiac biomarker high-sensitive cardiac troponin I or transthoracic echocardiographic measurements of left atrium diameter, left ventricular end-systolic diameter, or left ventricular end-diastolic diameter when compared with placebo (112817).
• Attention deficit-hyperactivity disorder (ADHD). Oral Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small low-quality study in children with ADHD aged 6-12 years shows that taking Panax ginseng extract 3 mg with omega-3 fatty acids 500 mg daily for 12 weeks improves overall symptoms, reduces errors of commission, and improves reaction time when compared with baseline (103049). The validity of this study was limited by the lack of a comparator group. Also, it is unclear if these changes are due to Panax ginseng, omega-3 fatty acids, or the combination.
• Age-related cognitive decline. It is unclear if oral Panax ginseng is beneficial in age-related cognitive decline. Details: Clinical research in patients over 50 years of age with memory impairments shows that taking standardized ginseng extract (G115) in combination with vitamins, minerals, and dimethylaminoethanol bitartrate may improve memory when compared to baseline (23600). The validity of this finding is limited by the lack of a comparator group. Also, it is unclear if these changes are due to Panax ginseng, other ingredients, or the combination.
• Allergic rhinitis (hay fever). It is unclear if oral Panax ginseng is beneficial in allergic rhinitis. Details: A small clinical study in adults with allergic rhinitis shows that taking Panax ginseng (Korean Ginseng Corporation) 3 mg/kg daily for 4 weeks improves rhinorrhea, nasal itch, and eye itch when compared to baseline (103047). The validity of this study is limited because it did not report statistical comparisons between the treatment and control groups.
• Alzheimer disease. Some preliminary clinical studies suggest that oral Panax ginseng might improve cognitive performance in patients with this condition. Details: Clinical research shows that taking Panax ginseng root 4.5 to 9 grams daily for 12 weeks can improve cognitive performance in patients with Alzheimer disease when compared with control (23611,23612). The validity of this finding is limited by the lack of patient and caregiver blinding.
• Androgenic alopecia. Topical Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with androgenic alopecia shows that applying 1 mL of a topical combination product (Hirsuit hair tonic, Dermcor Pharmaceutical) containing Panax ginseng extract, biochanin A (from red clover), acetyl tetrapeptide-3, Salvia officinalis oil, and other ingredients, twice daily for 24 weeks, is similarly effective to minoxidil 3% solution for increasing hair count and mass (105672). It is unclear if the benefit is due to Panax ginseng, other ingredients, or the combination.
• Anxiety. Although there has been interest in using oral Panax ginseng for anxiety, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Aplastic anemia. Although there has been interest in using oral Panax ginseng for aplastic anemia, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Asthma. Although there has been interest in using oral Panax ginseng for asthma, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Benign prostatic hyperplasia (BPH). It is unclear if oral Panax ginseng is beneficial for treating lower urinary tract symptoms. Details: A small clinical study in adults with moderate lower urinary tract symptoms shows that taking a specific extract of Korean red ginseng (RXGIN, Jung Kwan Jang), a type of Panax ginseng, 1000 mg daily for 12 weeks reduces serum prostate-specific antigen (PSA) and improves most prostate symptoms including residual urine sensation, frequency, intermittency, urgency, weak stream, straining, and nocturia after 6 and 12 weeks when compared with placebo. However, there was no improvement in maximum urinary flow rate or post-void residual volume when compared with placebo (112840).
• Breast cancer. It is unclear if oral Panax ginseng is beneficial in breast cancer. Details: Observational research in Chinese patients with breast cancer suggests that regular use of ginseng, including either Panax ginseng or American ginseng, is associated with higher quality of life scores and a lower risk of overall mortality, breast cancer-related mortality, and breast cancer recurrence when compared with patients who do not take ginseng (14466). However, ginseng users were also significantly more likely to have been treated with tamoxifen. Another small clinical study in adults with non-metastatic breast cancer undergoing anthracycline-based chemotherapy in Iran shows that taking Panax ginseng 1 gram daily starting on the first day of chemotherapy until 1 week after completion of the final cycle at 7 or 10 weeks improves social, emotional, and functional measures of health-related quality of life but does not improve physical well-being when compared with placebo (112823).
• Bronchitis. It is unclear if oral Panax ginseng is beneficial in bronchitis. Details: One small clinical study shows that taking a specific Panax ginseng extract (G115) 100 mg twice daily for 9 days might be beneficial when used adjunctively for treating acute exacerbations of chronic bronchitis. Panax ginseng, combined with antibiotic therapy, might reduce bronchial bacterial counts more than antibiotic therapy alone (8814).
• Cancer. It is unclear if oral Panax ginseng is beneficial in preventing cancer. However, it might increase quality of life in some cancer patients. Details: Observational research has found that taking ginseng orally might decrease the incidence of cancer, specifically breast, stomach, lung, liver, ovarian, and skin cancer (2063,3122). But evidence from large-scale clinical research shows that taking Panax ginseng 1 gram once weekly for 3 years does not reduce the risk of cancer development (23622). However, some clinical research suggests that Panax ginseng may slow cancer progression or improve quality of life in patients already diagnosed with cancer. One clinical study shows that taking sun ginseng, a form of Panax ginseng that has been heat treated, 3000 mg daily orally for 12 weeks can improve quality of life for cancer patients (23643). Evidence from a case series suggests that giving Panax ginseng (also called Cultivated Wild Ginseng Pharmacopuncture) 20 mL daily by intravenous infusion for up to 13 cycles lasting 2-4 weeks each may attenuate the progression of advanced non-small cell lung cancer in some patients (23619,23620).
• Cancer-related fatigue. It is unclear if oral Panax ginseng is beneficial in cancer-related fatigue. Details: Preliminary clinical research shows that taking Panax ginseng 400 mg twice daily for 4 weeks reduces fatigue in 63% of adults with cancer-related fatigue when compared to baseline. Panax ginseng also reduces pain and improves appetite and overall quality of life when compared to baseline. The lack of a control group limits the validity of these findings (96217). Another clinical study in patients with colorectal cancer receiving the mFOLFOX-6 chemotherapy regimen shows that taking Panax ginseng 2000 mg daily for 16 weeks improves fatigue as measured on the brief fatigue inventory (BFI) when compared with placebo. However, when evaluated on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, no benefit was seen (103048).
• Chronic fatigue syndrome (CFS). It is unclear if oral Panax ginseng is beneficial in patients with severe CFS. Details: A nonblinded, observational study in patients with severe CFS, most of whom also have fibromyalgia, shows that taking Panax ginseng daily for one month improves patient reports of energy, overall wellbeing, mental clarity, sleep, pain, and stamina when compared with baseline. Patients took Panax ginseng either as capsules (Terry Naturally HRG80 Red Ginseng Energy capsules; EuroPharma, Inc) 200-400 mg daily or chewable tablets (Terry Naturally HRG80 Red Ginseng Energy chewable tablets; EuroPharma, Inc) 100-200 mg daily. There were no dose- or formulation-dependent differences between groups (107746). The validity of these findings is limited by the lack of randomization and placebo-control; additionally, the majority (89%) of patients included in this study were female.
• Chronic kidney disease (CKD). It is unclear if oral Panax ginseng prevents CKD. Details: A cross-sectional study in Korea suggests that supplemental Panax ginseng or American ginseng use is associated with a higher prevalence of CKD when compared with no supplemental ginseng use. However, no association was found when adjusting the results for potential confounders (112810). The applicability of these results is limited by a lack of subgroup analysis on the type of supplemental ginseng.
• Cognitive impairment. It is unclear if oral Panax ginseng is beneficial for the prevention or treatment of cognitive impairment. Most research has evaluated Panax ginseng in combination with other ingredients. Details: Preliminary clinical research in elderly patients with mild cognitive impairment shows that taking a specific combination product (Memo, Pharco Pharmaceuticals), which contains natural lyophilized royal jelly 750 mg, standardized ginkgo leaf extract 120 mg, and standardized Panax ginseng root extract 150 mg, orally for 4 weeks improves memory when compared with placebo (89712). It is unclear if these benefits are due to Panax ginseng, other ingredients, or the combination. A moderate-sized clinical study in older adults with subjective memory impairment shows that taking a specific Panax ginseng sprout extract (ThinkGIN, BTC Corporation) 450 mg daily for 12 weeks improves performance on some verbal and visual memory tests and cognitive function as measured with MoCA-Korean version when compared with placebo (114983).
• Common cold. It is unclear if oral Panax ginseng is beneficial in preventing the common cold. Details: Preliminary clinical research shows that taking a specific Panax ginseng extract (G115) 200 mg daily orally beginning 4 weeks prior to influenza vaccination and continuing for 8 weeks thereafter can decrease the relative risk of getting the flu or common cold by 65% when compared with placebo (589).
• Congestive heart failure (CHF). It is unclear if oral Panax ginseng is beneficial in CHF. Details: A small clinical study in adults with CHF shows that Panax ginseng 2 grams daily, with or without digoxin 0.25 mg once daily for 15 days, seems to improve heart function according to New York Heart Association (NYHA) classification when compared to baseline. Ginseng might also improve hemodynamics and may work synergistically with digoxin (4243). The validity of these findings is limited by the lack of a comparator group.
• Constipation. It is unclear if oral fermented Panax ginseng is beneficial for constipation. Details: An observational study in healthy postmenopausal adults aged 50 years and older in Korea suggests that taking fermented red ginseng 20 mL before meals daily for 3 weeks normalizes stool consistency and increases the frequency of bowel movements when compared to baseline (112837). The validity of these effects is limited by the observational study design, lack of a comparator group, and insufficient blinding.
• Chronic obstructive pulmonary disease (COPD). Oral Panax ginseng has primarily been evaluated in combination with other ingredients for improving symptoms of COPD; its effect when used alone is unclear. Taking Panax ginseng doesn't seem to prevent exacerbations. Details: A meta-analysis of clinical trials in patients with stable COPD shows that taking Panax ginseng, usually in combination with other ingredients as part of TCM formulations, significantly improves pulmonary function tests and quality of life when compared with placebo after 3-6 months of treatment. These formulations improve COPD symptoms by approximately 53% when compared with placebo. However, they only modestly improve forced expiratory volume in one second (FEV1) (17736). In contrast, Panax ginseng might not reduce the risk of COPD exacerbations. A clinical study in patients with moderate to very severe COPD shows that taking Panax ginseng 200 mg does not reduce the rate of acute COPD exacerbations over 12 months (103044).
• Depression. It is unclear if Panax ginseng is beneficial in depression. Details: In adults with treatment-resistant major depressive disorder, a small clinical study shows that taking Panax ginseng 2 grams daily in addition to current antidepressant medications for 6 weeks produces remission in 39% of patients and decreases scores on the Montgomery-Asberg Depression Rating Scale by a mean of 44% when compared with baseline (104954). The reliability of these findings is limited by the lack of a control group, randomization, blinding, and an intention-to-treat analysis, as well as a high drop-out rate.
• Diabetes. Research on the use of oral Panax ginseng for improving glycemic control in patients with diabetes is inconclusive and conflicting. Details: A meta-analysis of 6 small clinical trials in patients with type 2 diabetes using Panax ginseng for 4-24 weeks and 3 small trials using American or unidentified ginseng for 4-8 weeks, shows that taking these ingredients modestly reduces fasting blood glucose, but does not affect glycated hemoglobin (HbA1c) or insulin levels, when compared with control (105689). This analysis is limited by publication bias, as well as the heterogeneity and imprecision of the included trials. Another meta-analysis of 5 clinical studies in healthy adults and adults with a variety of metabolic disorders including diabetes and prediabetes shows that taking Panax ginseng 200 mg up to 8 grams daily for 4 to 24 weeks does not improve fasting blood glucose, 2-hour postprandial blood glucose, HbA1c, or insulin levels when compared with placebo. However, Panax ginseng might improve glucose AUC in these individuals. Subgroup analysis further suggests that the beneficial effect of Panax ginseng on glucose AUC is greater in adults with diabetes than those with prediabetes (112838). Individual small studies have shown modest glycemic benefit with fermented Panax ginseng 2.7 grams daily for 4 weeks or non-fermented Panax ginseng 6 grams daily for 8-12 weeks (23627,89740), and other studies have shown no benefit with Korean red ginseng extract or Korean black ginseng 2-8 grams daily for 4-6 weeks (17734,112839). It is unclear if the effects of Panax ginseng may be dose- or product-dependent. Panax ginseng has also shown some glycemic benefit when used in combination with other ingredients. Panax ginseng extract 750 mg (standardized to 30% ginsenosides) has been used in combination with American ginseng extract 1500 mg (standardized to 10% ginsenosides), viscous fiber 10 grams, and ground white chia seeds 60 grams daily for 24 weeks (105673). It is unclear if this benefit is due to Panax ginseng, other ingredients, or the combination.
• Diabetic neuropathy. It is unclear if oral Panax ginseng is beneficial in diabetic neuropathy. Details: A small clinical study in patients with diabetic neuropathy shows that taking Panax ginseng extract powder 1 gram daily for 24 weeks seems to improve sensory perception of electric currents, a marker for severity of diabetic neuropathy, when compared with baseline (103051). The validity of this study was limited by the lack of statistical comparison between treatment and placebo groups.
• Exercise-induced muscle damage. Although there has been interest in using oral Panax ginseng for exercise-induced muscle damage, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Fatigue. Most clinical research shows that oral Panax ginseng can reduce fatigue in adults with idiopathic chronic fatigue. However, not all research agrees. Details: Some clinical research in patients with idiopathic chronic fatigue or self-reported fatigue shows that taking Panax ginseng improves self-reported fatigue when compared with baseline or placebo (89743,23623,106665). A small clinical study in patients with idiopathic chronic fatigue shows that taking an ethanolic extract of Panax ginseng 1 gram twice daily for 4 weeks reduces self-reported fatigue by 66% and mental fatigue by 50% when compared with placebo (89743). Another clinical study in adults with chronic fatigue also shows that taking a specific combination product containing Panax ginseng (G115) 80 mg, vitamins, and minerals daily for 7 weeks alleviates fatigue symptoms in 20% more patients when compared with placebo (23623). However, not all research has been positive. A small clinical study in middle-aged patients with idiopathic chronic fatigue shows that taking Panax ginseng, steamed and aged for six years, 3 grams daily for 6 weeks is no different than placebo for reducing fatigue (103052). Notably, this clinical trial had a robust placebo effect.
• Fibromyalgia. It is unclear if oral Panax ginseng is beneficial for fibromyalgia. Details: Clinical research shows that taking Panax ginseng root extract 100 mg daily orally for 12 weeks does not improve pain, fatigue, sleep quality, anxiety, tender point count, or quality of life when compared with placebo in patients with fibromyalgia (89744). A nonblinded, observational study in patients with fibromyalgia, most of whom also have severe chronic fatigue syndrome (CFS), shows that taking Panax ginseng daily for one month improves patient reports of energy, overall wellbeing, mental clarity, sleep, pain, and stamina when compared with baseline. Patients took Panax ginseng, either as a capsule (Terry Naturally HRG80 Red Ginseng Energy capsules; EuroPharma, Inc) 200-400 mg daily, or chewable tablet (Terry Naturally HRG80 Red Ginseng Energy chewable tablets; EuroPharma, Inc) 100-200 mg daily. There were no dose- or formulation-dependent differences between groups (107746). The validity of these findings is limited by the lack of randomization and placebo-control; additionally, the majority (89%) of patients included in this study were female.
• Gallbladder disease. It is unclear if oral Panax ginseng is beneficial for gallbladder disease. Details: Clinical research shows that taking Panax ginseng 7.5 grams as an adjuvant to the bile acids chenodeoxycholic acid (CDCA) 500 mg daily plus ursodeoxycholic acid (UDCA) 500 mg daily, divided into three doses daily for 24 weeks, does not decrease the total volume of gallstones or increase gallstone dissolution when compared to use of bile acids alone (89748).
• Gastritis. Although there has been interest in using oral Panax ginseng for gastritis, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Glaucoma. It is unclear if oral Panax ginseng is beneficial for glaucoma. Details: A clinical crossover study in patients with glaucoma shows that taking oral Panax ginseng 1 gram three times daily for 4 weeks improves dry eye severity, daytime visual function, and eye pain when compared with placebo. In a sub-group of patients with early or moderate glaucoma, nighttime visual function was also improved (107744). The validity of this study is limited due to short duration of treatment.
• Halitosis. It is unclear if oral Panax ginseng is beneficial for halitosis. Details: Preliminary clinical research shows that taking Korean red ginseng, a type of Panax ginseng, 2.7 grams daily for 10 weeks helps reduce bad breath when compared with baseline, particularly in patients with bad breath caused by Helicobacter pylori (H. pylori) infection (23624). The validity of this finding is limited by the lack of a comparator group.
• Hangover. It is unclear if oral Panax ginseng is beneficial for hangover. Details: One small clinical study shows that drinking 100 mL of a drink containing Panax ginseng extract 0.321 mg/mL within 5 minutes of drinking 100 mL blended Scotch whiskey with 40% alcohol and eating a piece of cheese may reduce hangover symptoms by approximately 66% when compared with placebo in healthy males. Levels of alcohol in the blood also appear to be reduced (89742).
• Hearing loss. It is unclear if oral Panax ginseng is beneficial for hearing loss. Details: Preliminary clinical research in male textile workers exposed to continuous noise shows that taking Korean red ginseng, a type of Panax ginseng, 200 mg daily for 14 days reduces temporary hearing loss caused by noises at frequencies of 4, 6, or 16 kHz when compared with control. However, Panax ginseng may be slightly less effective than N-acetyl cysteine at preventing temporary hearing loss caused by noise at 4 kHz frequency (89739).
• HIV/AIDS. It is unclear if oral Panax ginseng is beneficial for this condition. Details: Preliminary clinical research in adults with HIV shows that taking Korean red ginseng, a particular form of Panax ginseng, along with highly active antiretroviral therapy (HAART) modestly increases CD4 count, but does not affect viral load, when compared with HAART alone (23625).
• Hyperlipidemia. It is unclear if oral Panax ginseng is beneficial for hyperlipidemia. Details: A meta-analysis of clinical studies in healthy adults and adults with a variety of metabolic disorders shows that taking Panax ginseng 200 mg to 8 grams daily for 4 to 24 weeks reduces total cholesterol by 7 mg/dL and low-density lipoprotein (LDL) cholesterol by 9 mg/dL but does not reduce triglycerides or increase high-density lipoprotein (HDL) cholesterol when compared with placebo (112838). However, a meta-analysis of up to 28 clinical studies in healthy adults and adults with a variety of metabolic disorders shows that taking Panax ginseng 300 mg to 6 grams daily for 3 to 32 weeks does not reduce total or LDL cholesterol or triglycerides or increase HDL cholesterol when compared with placebo (114985).
• Hypertension. It is unclear if oral Panax ginseng is beneficial for hypertension. Details: A meta-analysis of clinical studies in healthy adults and adults with a variety of metabolic disorders shows that taking Panax ginseng 200 mg to 8 grams daily for 4 to 24 weeks does not reduce systolic (SBP) or diastolic (DBP) blood pressure when compared with placebo. However, subgroup analysis suggests that Panax ginseng might modestly reduce SBP in people with prehypertension, hypertension, or metabolic syndrome (112838). Smaller individual studies of various forms of Panax ginseng have been evaluated in patients with mild to severe hypertension with conflicting results. Some preliminary clinical research in patients with essential hypertension shows that taking Panax ginseng 4.5 grams daily in three divided doses, alone or with a beta-blocker or calcium channel blocker for 8 weeks, moderately decreases 24-hour SBP (23632). However, in patients with prehypertension or mild hypertension, taking protopanaxatriol-enriched Panax ginseng (Ginseol K-g1) 100 mg or 300 mg daily for 8 weeks does not reduce seated SBP or DBP when compared with placebo (89741). Panax ginseng has also been evaluated in combination with American ginseng. Clinical studies in patients with hypertension with or without type 2 diabetes show that taking Panax ginseng 0.75 grams and American ginseng 1.5-2.25 grams enriched to contain 30% total ginsenosides daily for 12 weeks reduces central SBP by about 5 mmHg and 24-hour SBP by about 4 mmHg, but does not impact DBP, when compared with placebo or a control of wheat-bran (103046,107745). Patients receiving this combination also have greater reductions in daytime SBP, glycated hemoglobin, total cholesterol levels, and triglyceride levels when compared with control (107745). It is unclear if these effects are due to Panax ginseng, American ginseng, or the combination; additionally, it is unclear if enrichment with ginsenosides alters clinical effects.
• Impaired glucose tolerance (prediabetes). It is unclear if oral Panax ginseng is beneficial for impaired glucose tolerance. Details: In overweight adults with prediabetes, a small clinical study shows that taking hydrolyzed Panax ginseng extract, 320 mg three times daily before meals for 6 months, does not improve fasting blood glucose levels. However, compliance in this study was only 49% (104953). Additionally, a large, cross-over, clinical study in patients with prediabetes initiating a lifestyle intervention shows that taking a Chinese herbal medicine preparation containing Panax ginseng providing ginseng berry saponins 50 mg three times daily for 4 weeks improves 2-hour post-prandial glucose, but not fasting blood glucose, when compared with placebo (114980). Panax ginseng has also been studied in combination with other ingredients. One clinical study shows that taking a combination of Korean red ginseng, a type of Panax ginseng, and cheonggukjang, a type of fermented soybean paste, 20 grams daily for 8 weeks can decrease fasting blood glucose levels by 17% in patients with prediabetes (23640). Also, taking fermented Panax ginseng 2.7 grams daily for 4 weeks reduces 2-hour postprandial glucose by about 17% and increases 2-hour postprandial insulin levels by about 44% when compared to baseline; when compared with placebo, these changes are significant (89740). It is unclear if these effects are due to Panax ginseng, other ingredients, or the combinations.
• Inflammatory bowel disease (IBD). Although there has been interest in using oral Panax ginseng for Crohn disease and ulcerative colitis, there is insufficient reliable information about the clinical effects of Panax ginseng for these conditions.
• Insomnia. Although there has been interest in using oral Panax ginseng for insomnia, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Liver disease. Although there has been interest in using oral Panax ginseng for liver diseases, there is insufficient reliable information about the clinical effects of Panax ginseng for these conditions.
• Male infertility. It is unclear if oral Panax ginseng is beneficial for male infertility. Details: Chronic prostatitis due to Chlamydia trachomatis infection is associated with reduced male fertility due to decreased sperm concentration and motility. Preliminary clinical research in adults with this condition shows that taking 25 mL of a specific product containing L-arginine 1660 mg, L-carnitine 150 mg, acetyl-L-carnitine 50 mg, and Panax ginseng 200 mg (Fertimev) along with prulifloxacin 600 mg daily for 6 months improves sperm concentration and sperm motility when compared to treatment with prulifloxacin alone (59006). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination.
• Menopausal symptoms. Research on oral Panax ginseng for menopausal symptoms has yielded conflicting results. Details: One clinical study in postmenopausal adults shows that taking Panax ginseng extract (G115) 200 mg daily orally for 16 weeks does not improve psychological well-being or reduce vasomotor symptoms such as hot flashes when compared with placebo (10981). However, several smaller clinical studies in postmenopausal adults demonstrate beneficial effects with higher doses of Panax ginseng. One study shows that taking Panax ginseng 1 gram (containing 30 mg ginsenosides) three times daily for 12 weeks reduces hot flashes and other symptoms, as measured by the Kupperman index and the Menopause Rating Scale (MRS), when compared with placebo (89749). Another study shows that taking an extract of Korean red ginseng, a specific form of Panax ginseng, 500 mg 4 times daily for 8 weeks improves fatigue severity scores by 21%, compared with 3% in those receiving placebo (106666). In premenopausal adults with menopausal symptoms following surgery for gynecologic cancer, taking Panax ginseng 1 gram three times daily for 12 weeks reduces the total symptom score on the MRS when compared with baseline. However, there was also a robust response in the placebo group, with no significant difference in symptom reduction between groups (104596). Panax ginseng has also been evaluated for improving genitourinary syndrome and cognition after menopause. A small clinical trial in postmenopausal adults with genitourinary syndrome shows that taking a specific Panax ginseng supplement (Ruginseng, Ghaem Daru Pharmaceutical) 500 mg twice daily for 4 weeks does not affect vaginal maturation index or pH, but seems to improve patient-rated symptoms such as vaginal itching and burning, when compared with a lactose placebo (105670). This study was funded by the supplement manufacturer. In another clinical study, taking a specific combination product (Gincosan) containing Panax ginseng 200 mg and ginkgo 120 mg daily for 6-12 weeks does not improve cognition, memory, mood, anxiety, or sleep when compared with placebo (87767).
• Metabolic syndrome. It is unclear if oral Panax ginseng is beneficial for metabolic syndrome. Details: A meta-analysis of 23 clinical studies in healthy adults, menopausal adults, and adults with a variety of metabolic disorders shows that taking Panax ginseng 200 mg to 8 grams daily for 4 to 24 weeks reduces glucose area under the plasma concentration-time curve (AUC), total cholesterol, and high-density lipoprotein cholesterol, but does not improve other measures of blood glucose, insulin resistance, blood pressure, lipids, or anthropometric measures when compared with placebo (112838). Additionally, a small clinical study in adults with metabolic syndrome shows that taking Korean red ginseng, a specific form of Panax ginseng, 6 grams daily for 8 weeks modestly reduces systolic blood pressure from baseline, but not when compared with placebo. Additionally, Panax ginseng has no effect on anthropometric measurements, biochemical markers, or other vital signs when compared with placebo (106667).
• Nausea and vomiting. Although there has been interest in using oral Panax ginseng for nausea and vomiting, there is insufficient reliable information about the clinical effects of Panax ginseng for these conditions.
• Neuropathic pain. Although there has been interest in using oral Panax ginseng for neuropathic pain, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral Panax ginseng is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking Panax ginseng 2 grams (containing ginsenosides 4.5 mg/gram) daily for 30 days modestly reduces fatigue and plasma levels of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) when compared with placebo. All patients were also given milk thistle dried extract 450 mg (Legalon, Bukwang Pharmaceutical) daily and asked to exercise daily for at least 30 minutes (105671).
• Oral cancer. It is unclear if topical Panax ginseng is beneficial for oral health in patients with oral cancer. Details: A small clinical study in patients with oral cancer and poor oral hygiene shows that rinsing with a specific herbal mouthwash (Dr. Dental care liquid, Jangin Pharm Co., Ltd.) containing Panax ginseng 8 mL for 1 minute twice daily for 14 days reduces oral bacterial load and improves oral hygiene and gingival indices when compared with chlorhexidine or saline rinses (114987).
• Osteoarthritis. It is unclear if oral Panax ginseng is beneficial for osteoarthritis of the hand. Details: A small clinical study in postmenopausal adults with degenerative osteoarthritis of the hand shows that taking oral Korean red ginseng, a type of Panax ginseng, 1 gram three times daily for 12 weeks improves pain scores at rest, during daily activity, and at work or sport, and also improves disabilities of the arm, shoulder, and hand (DASH) score when compared with placebo (107747). The validity of this trial is limited due to the lack of objective outcome measures.
• Pneumonia. Injectable Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Oral Panax ginseng has not been evaluated for this use. Details: A meta-analysis of 20 small, low-quality randomized and non-randomized studies in older Chinese adults with severe pneumonia shows that administering an injection containing Panax ginseng extract 0.8 mg/mL and aconite extract 0.1 mg/mL in addition to standard treatment leads to improvement in symptoms such as fever, cough, and chest tightness in 77% of patients as compared with 61% of those who received standard treatment alone. This combination injection may also modestly reduce disease severity and the risk of mortality when compared with standard treatment alone. However, these outcomes were not evaluated in all studies, and dosing regimens were heterogenous (110472). Additionally, it is unclear whether these effects are due to Panax ginseng, aconite, or the combination.
• Premature ejaculation. Oral Panax ginseng has primarily been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Applying a multi-ingredient cream preparation containing Panax ginseng, angelica root, Cistanches deserticola, Zanthoxyl species, torlidis seed, clove flower, asiasari root, cinnamon bark, and toad venom (SS Cream) to the glans penis one hour prior to intercourse and washing off immediately before intercourse seems to improve ejaculatory latency in adults with premature ejaculation when compared with placebo (2537). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination.
• Quality of life. It is unclear if oral Panax ginseng is beneficial for quality of life. Details: While some research suggests that Panax ginseng might improve self-rated quality of life (6254,23644), other studies show no benefit (8601,10314). In studies showing benefit for quality of life, doses have included one capsule daily of a specific Panax ginseng extract (Pharmaton Capsules, Pharmaton Natural Health Products) for 12 weeks (6254) and Panax ginseng extract (G115) 40 mg twice daily for 12 weeks (23644).
• Rheumatoid arthritis (RA). It is unclear if oral Panax ginseng is beneficial for improving symptoms of RA. Details: A moderate-sized clinical study in patients with RA, Sjogren syndrome, or both shows that taking Panax ginseng 2000 mg daily for 3 months does not improve fatigue scores when compared with placebo (114984).
• Sjogren syndrome. It is unclear if oral Panax ginseng is beneficial in patients with Sjogren syndrome. Details: A moderate-sized clinical study in patients with RA, Sjogren syndrome, or both shows that taking Panax ginseng 2000 mg daily for 3 months does not improve fatigue scores when compared with placebo (114984).
• Stress. It is unclear if oral Panax ginseng is beneficial for stress. Details: A small clinical study in healthy patients with occupational stress shows that taking a specific Panax ginseng root preparation (HRG80) high in ginsenosides daily for 14 days modestly reduces perceived stress and improves attention and memory when compared with placebo. However, taking a standard Panax ginseng preparation with a lower quantity of ginsenosides was no better than placebo (103050). However, a moderate-sized clinical study in adult males shows that taking Panax ginseng 2000 mg daily for 8 weeks does not improve self-reported stress response when compared with placebo (114988).
• Stroke. It is unclear if oral Panax ginseng prevents stroke. Details: A small clinical study in adults with severe atherosclerosis in major intracranial arteries or extracranial carotid arteries at high risk for ischemic stroke shows that taking an extract of Korean red ginseng, a type of Panax ginseng, 1000 mg twice daily for 12 months does not prevent transient ischemic attack or ischemic stroke and does not improve neurological disability, cerebral blood flow, or the incidence of new ischemic brain lesions when compared with placebo (112835).
• Traumatic brain injury (TBI). It is unclear if oral Panax ginseng is beneficial for asthenic syndrome due to TBI. Details: A small study in adults with asthenic syndrome secondary to mild combat TBI shows that taking Panax ginseng improves autonomic nervous system functioning and asthenic symptoms when compared to baseline (112834). The validity of these effects is limited by a lack of a comparator group.
• Vascular dementia. Oral Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients aged 60 years or older with vascular dementia shows that taking a supplement containing extracts of Panax ginseng, ginkgo, and saffron three times daily for 16 weeks modestly improves some cognitive function scores, caregiver assessed activities of daily living, and patient-reported quality of life when compared with placebo. However, these effects were not maintained after patients stopped taking the supplement (111336). Additionally, it is unclear if these effects are due to Panax ginseng, other ingredients, or the combination.
• Wrinkled skin. It is unclear if oral Panax ginseng is beneficial for wrinkled skin. Details: Preliminary clinical research shows that taking 3 grams of a combination of Korean red ginseng root with Torilus fructus and Corni fructus daily for 24 weeks may reduce wrinkles when compared with placebo. However, it does not seem to affect skin elasticity, moisture, thickness, or color (23645). It is unclear if this benefit is due to Panax ginseng, other ingredients, or the combination. More evidence is needed to rate Panax ginseng for these uses.

(Read more about PANAX GINSENG)

EFFECTIVE

• Ariboflavinosis. Oral riboflavin can treat and prevent low riboflavin levels.

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral riboflavin reduces homocysteine levels in individuals with the MTHFR 677 TT genotype. It does not seem to provide benefit in individuals with other genotypes. Details: Population research has found that poor riboflavin status is associated with high homocysteine levels in individuals with the 677 TT genotype for the MTHFR enzyme (71386,71403,71409). Taking riboflavin 1.6 mg daily for 12 weeks reduces homocysteine levels by 22% to 40% in individuals with the 677 TT genotype of MTHFR when compared with pretreatment. However, riboflavin supplementation does not seem to reduce homocysteine levels in individuals with the 677 CC or CT genotypes (71443).
• Migraine headache. Oral riboflavin modestly reduces migraine attack frequency and severity in adults. The benefits of oral riboflavin in children are unclear. Details: A meta-analysis of 5 small clinical trials in adults with migraine shows that taking riboflavin 100-400 mg daily, alone or in combination with other natural ingredients, for three months modestly reduces migraine duration, frequency, and pain scores when compared with control (105480). These findings are limited by significant heterogeneity. Most clinical studies compared riboflavin 400 mg daily with placebo, no treatment, or an active control (1396,1397,1398,12387,105480). Limited evidence also suggests that taking riboflavin 400 mg daily might be no different for migraine prevention than certain conventional treatments such as bisoprolol 10 mg, metoprolol 200 mg, propranolol 80 mg, or valproate 500 mg (1396,105480). These findings are limited due to small study size and a lack of power to detect a difference between groups. Limited research has also evaluated riboflavin in children. A network meta-analysis of 3 small clinical trials in children with migraine shows that taking oral riboflavin 100-200 mg daily for 4-12 months does not significantly reduce incidence of migraine when compared with placebo. However, there was a non-significant trend towards reduced migraine frequency. Furthermore, conventional treatments such as propranolol, pregabalin, valproate, and topiramate were not shown to be significantly better than riboflavin for migraine prevention (105484). These findings are limited by small population sizes and insufficient power to detect differences between groups. Although riboflavin 100-200 mg has been used in prospective clinical studies, small observational studies have found some benefit in children taking riboflavin doses as low as 10-40 mg daily and as high as 400 mg daily for 3-4 months (105481,105485). Riboflavin has also been studied in combination with other ingredients, with research suggesting potential benefit. Specifically, riboflavin 400 mg has been combined with magnesium 600 mg and coenzyme Q10 150 mg daily (Dolovent; Linpharma Inc.) (92101), and also with magnesium 300 mg and feverfew 100 mg daily (12389).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral riboflavin for acne, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Alzheimer disease. Although there is interest in using oral riboflavin for Alzheimer disease, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Anxiety. It is unclear if oral riboflavin is beneficial for anxiety. Details: A large observational cohort study in adults suggests that a dietary riboflavin intake above 2.1 mg daily is associated with a 5% lower prevalence of anxiety when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Cardiovascular disease (CVD). It is unclear if oral riboflavin can prevent mortality due to CVD. Details: Epidemiological research has found that dietary and supplemental riboflavin intake in the highest quartile, around 3.4 mg daily, is associated with a 47% lower risk of CVD mortality when compared with riboflavin intake in the lowest quartile, around 1 mg daily. The reduction in CVD mortality with riboflavin was enhanced by higher folate intake (110727). The validity of this finding is limited by the fact that dietary riboflavin intake was based on 2-day dietary recall.
• Carpal tunnel syndrome. Although there is interest in using oral riboflavin for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Cataracts. It is unclear if oral riboflavin is beneficial in patients with cataracts. Details: Observational research has found that high dietary intake of riboflavin is associated with a reduced risk of nuclear cataracts and age-related lens opacification (6378,14301). Furthermore, a clinical study in Chinese patients with nutrient deficiencies shows that taking a combination of riboflavin 3 mg plus niacin 40 mg daily also seems to reduce the risk of developing nuclear cataracts when compared with no supplementation (4885). It is unclear if the benefit is due to riboflavin, niacin, or the combination.
• Cervical cancer. It is unclear if oral riboflavin helps to prevent cervical cancer. Details: Epidemiological evidence has found that increased riboflavin intake from dietary and supplement sources, along with other B vitamins, is associated with a reduced risk of precancerous cervical lesions (11074).
• Cognitive function. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a combination supplement containing riboflavin 70 mg, other group B vitamins, ginkgo leaf, and bacopa daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Epidemiological evidence in a Chinese population suggests that increased dietary intake of riboflavin is associated with a reduced risk of developing colorectal cancer (105482).
• Depression. It is unclear if oral riboflavin is beneficial for depression. Details: A large cross-sectional study in middle-aged adults suggests that dietary riboflavin intake above 2.1 mg daily is associated with an 8% lower prevalence of depression when compared with a riboflavin intake less than 1.6 mg daily. Subgroup analysis suggests that this association is especially strong in males (111209).
• Diabetes. It is unclear if oral riboflavin reduces the risk of developing gestational diabetes. Details: A large prospective cohort study in pregnant adults shows that supplementation with riboflavin at doses over 2.5 mg daily during the first trimester and 2.1 mg daily in the second trimester is associated with a lower risk of developing gestational diabetes when compared with riboflavin doses under 1.1 mg daily. However, this effect was not found for dietary intake of riboflavin, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic neuropathy. Intravenous and oral riboflavin have only been evaluated in combination with other ingredients; riboflavin's effect when used alone is unclear. Details: Clinical research in patients with type 2 diabetes shows that intravenous administration of a specific combination product containing succinic acid, inosine, nicotinamide, and riboflavin (Cytoflavin, Polysan) daily for 10 days followed by an oral formulation of the same product, taken daily for 76 days, reduces symptoms of diabetic neuropathy including paresthesia, numbness, and burning when compared with placebo (110503). It is unclear if these findings are due to riboflavin, other ingredients, or the combination.
• Esophageal cancer. It is unclear if oral riboflavin reduces esophageal cancer risk. Details: Population research in Iranian patients has found that low riboflavin status is associated with a two-fold increase in the risk of esophageal cancer (71439). However, not all evidence agrees. Preliminary clinical studies in Chinese individuals with esophageal dysplasia shows that taking riboflavin, alone or in combination with calcium or niacin, for 3-5 years does not seem to reduce the risk of esophageal cancer in patients when compared with baseline or control (4679,63576,71488). Taking riboflavin 200 mg weekly, in combination with retinol 15 mg and zinc 50 mg, also does not seem to be beneficial in this patient population (71501). It is unclear if these findings are generalizable to geographic locations other than China and Iran.
• Gastric cancer. It is unclear if oral riboflavin reduces colorectal cancer risk. Details: Low quality clinical research in a Chinese population shows that taking riboflavin in combination with niacin does not reduce the risk of gastric cancer when compared with control (4679).
• Hypertension. There is limited evidence on the oral use of riboflavin for reducing blood pressure in patients with the MTHFR 677 TT genotype. Details: A 677 C to T polymorphism on the MTHFR gene has been associated with hypertension. In patients with a confirmed MTHFR 677 TT genotype and premature cardiovascular disease, preliminary clinical research suggests that taking riboflavin 1.6 mg daily for 16 weeks reduces systolic blood pressure (SBP) by 9 mmHg and diastolic blood pressure (DBP) by 6 mmHg when compared with placebo. This decrease in blood pressure is larger than that reported in other trials, which may be due to the fact that only patients with the 677 TT genotype were included. These patients seem to respond to riboflavin therapy more so than patients with 677 CC or 677 CT genotype (92102). Additional clinical research in patients with the 677 TT genotype but without cardiovascular disease shows that taking riboflavin 1.6 mg daily for 16 weeks reduces SBP by 5.6 mmHg but does not reduce DBP (92103). There is also interest in using dietary riboflavin for reducing the onset of hypertension. Some epidemiological evidence in a Chinese population has found that increased dietary intake of riboflavin is associated with a reduced risk of developing hypertension (105483).
• Liver cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals older than 55 years shows that taking riboflavin in combination with niacin does not seem to prevent liver cancer mortality when compared with control. However, there was a reduced risk of liver cancer mortality in people aged less than 55 years when compared with control (63470).
• Lung cancer. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals shows that taking riboflavin in combination with niacin does not appear to reduce the risk of lung cancer when compared with control (34539).
• Malaria. Oral riboflavin has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children ages 5-14 years living in Gambia and at high risk for malaria exposure suggests that taking riboflavin, in combination with iron, thiamine, and vitamin C, for 3 months does not reduce the frequency or severity of malaria infections when compared with placebo (56730).
• Malnutrition. There is limited evidence on the oral use of riboflavin with other ingredients in children at risk for kwashiorkor. Details: A clinical study in Malawian children at risk for kwashiorkor, a severe form of malnutrition, suggests that taking riboflavin, vitamin E, selenium, and N-acetyl cysteine at a dose of three times the recommended dietary allowance does not prevent kwashiorkor, reduce edema, increase physical growth, or reduce infection when compared with placebo (71433).
• Mitochondrial myopathies. Although there is interest in using oral riboflavin for mitochondrial myopathies, there is insufficient reliable information about the clinical effects of riboflavin for this condition.
• Multiple sclerosis (MS). It is unclear if oral riboflavin slows the progression of MS-related disability. Details: A small clinical study in patients with relapsing-remitting MS or secondary progressive MS who are undergoing treatment with disease-modifying therapies suggests that taking oral riboflavin 10 mg daily for six months is no more effective for improving disability than placebo (91752). The validity of this finding is limited by the small study sample size.
• Oral leukoplakia. It is unclear if oral riboflavin prevents or slows progression of oral leukoplakia. Details: Population research in people living in Uzbekistan suggests that low blood levels of riboflavin are associated with an increased prevalence of oral leukoplakia (71502). However, clinical evidence in patients with a high occurrence of oral and esophageal cancer who are living in Uzbekistan suggests that taking riboflavin 80 mg weekly for 20 months does not improve the prevalence or progression of oral leukoplakia when compared to baseline (71565). The validity of this finding is limited by the lack of a placebo group and unusual once weekly dosing. Furthermore, it is unclear if these results are generalizable to other geographic locations.
• Pre-eclampsia. Although there is interest in using oral riboflavin for pre-eclampsia, there is insufficient reliable information about the clinical effects of riboflavin for this purpose.
• Pregnancy-related iron deficiency. It is unclear if oral riboflavin is beneficial in patients with iron deficiency due to pregnancy. Details: Preliminary clinical research in pregnant patients in China suggests that adding riboflavin 1 mg daily to supplemental iron and folic acid does not improve iron status when compared with taking iron and folic acid alone (71480).
• Sickle cell disease. It is unclear if oral riboflavin is beneficial in patients with sickle cell disease. Details: One small clinical study in patients with sickle cell disease suggests that taking riboflavin 5 mg twice daily for 8 weeks increases serum iron and transferrin saturation when compared to baseline; however, riboflavin does not seem to improve serum ferritin or circulating hemoglobin levels (71566).
• Stroke. Oral riboflavin has only been evaluated in combination with niacin; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese individuals with poor nutritional status who are at risk for stroke suggests that taking riboflavin 5.2 mg daily in combination with niacin 40 mg daily does not reduce the risk of stroke-related mortality (2673). More evidence is needed to rate riboflavin for these uses.

(Read more about RIBOFLAVIN)

POSSIBLY EFFECTIVE

• Cognitive function. Oral L-theanine may improve some aspects of cognitive function. It is unclear if using L-theanine in conjunction with caffeine can enhance the effects of either ingredient. Details: A single dose of L-theanine 100 mg seems to improve vigilant attention, reducing error rates in cognitive tests when compared with placebo (91747). However, taking L-theanine (Suntheanine, Taiyo Kagaku) 200 mg daily for 4 weeks does not improve verbal fluency, memory, motor speed, or executive function in an adult population, although it may moderately improve verbal fluency in a subgroup of people with lower cognitive function at baseline (101986). When L-theanine is combined with caffeine, a meta-analysis and multiple individual clinical studies show that the combination improves alertness, as well as accuracy during a test that requires switching attention between different tasks, but does not improve reaction time (38116,91750,96335,96336). Some research also shows that L-theanine plus caffeine improves cognitive performance and reduces task-induced fatigue when compared with baseline and placebo. However, it is unclear if this is due to the individual ingredients or the combination (38116,96335,96336). Some research suggests that the combination is no better than either individual ingredient alone (91747,96335,96336).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral L-theanine, taken continuously or as a single dose, improves cognition in older adults. Details: A small clinical study in healthy, Japanese adults aged 50-69 years shows that taking a specific product (Suntheanine; Taiyo International.) containing L-theanine 101 mg daily after breakfast for 12 weeks does not improve mini-mental state exam (MMSE) scores when compared with placebo. However, a single-dose analysis from this study shows that administration of L-theanine 101 mg may improve the quality of working memory and reaction times during a cognitive function test when compared with placebo (108553). Patients were permitted to consume polyphenol-rich beverages during the study period; however, consumption was not documented, limiting the validity of this finding.
• Alzheimer disease. Although there is interest in using oral theanine for Alzheimer disease, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Anxiety. It is unclear if oral L-theanine is beneficial in patients with anxiety. Results of clinical research are conflicting. Details: A preliminary clinical study shows that taking a single dose of a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg does not reduce experimentally-induced anticipatory anxiety when compared with placebo (12188). However, another preliminary clinical study in healthy adults with stress-related anxiety shows that taking L-theanine 200 mg daily for 4 weeks reduces anxiety scale scores and sleep disturbance when compared with placebo (101986).
• Attention. It is unclear if oral theanine improves attention. Details: A small clinical study in healthy males shows that taking a single dose of L-theanine 200 mg improves selective attention similar to a single dose of caffeine 160 mg (96337). However, other small clinical studies in adults show that taking L-theanine 100-400 mg does not improve most measures of attention, especially sustained attention or attention in executive control tasks, but doses of 100-200 mg may improve performance in simple attentional tasks when compared with placebo (96338,111396). Some of these studies suggest that taking L-theanine with caffeine appears to provide more benefit than either individual ingredient alone (96337,96338).
• Attention deficit-hyperactivity disorder (ADHD). Oral L-theanine seems to improve some aspects of ADHD, including cognition and sleep. Details: Some preliminary clinical research in children with ADHD shows that taking a one-time dose of L-theanine 2.5 mg/kg increases cognition scores, but does not improve results on sustained attention or inhibitory control tests, when compared with placebo. Taking L-theanine with caffeine 2 mg/kg also increases cognition scores and improves performance on a sustained attention test, but does not improve inhibitory control, when compared with placebo (104141). Other preliminary clinical research in males aged 8-12 years with ADHD shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg orally twice daily for 6 weeks increases the percent of time spent in restful sleep by about 5% and decreases the number of bouts of nocturnal activity by about 6 when compared with placebo (91744).
• Cancer. Although there is interest in using oral theanine for cancer, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Chemotherapy-induced diarrhea. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with colon cancer shows that taking L-cystine 700 mg and L-theanine 280 mg (Ajinomoto Co. Inc.) orally once daily, starting one week before chemotherapy with TS-1 (Taiho Pharmaceutical) and continuing for 28 days, increases the rate of therapy completion by 49%, reduces the incidence of diarrhea by 37%, reduces appetite loss by 33%, and improves the reported tolerability of chemotherapy when compared with chemotherapy alone (96334). However, this combination does not appear to be beneficial in patients with gastric cancer, or in those with colorectal cancer receiving 4 courses of capecitabine-based adjuvant chemotherapy. (96334,101985).
• Cognitive impairment. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One very small clinical study in adults with mild cognitive impairment shows that taking a product containing L-theanine 120 mg and green tea extract 720 mg (LGNC-07, LG Household & Health Care, Ltd) orally twice daily after meals for 16 weeks modestly improves memory and attention when compared with baseline. However, taking this product does not appear to improve memory and attention when patients with self-reported memory problems, but without mild cognitive impairment, are also considered (96339).
• Depression. It is unclear if oral L-theanine is beneficial in patients with depression. Details: A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku Co. Ltd.) 250 mg at bedtime for 8 weeks reduces symptoms and improves sleep quality when compared to baseline in individuals with mild major depressive disorder (MDD) (96331). The validity of these findings is limited by the lack of a comparator group. Another small clinical study in adults with MDD shows that taking L-theanine 200 mg daily with sertraline for 6 weeks reduces depression symptoms and increases remission rates but does not improve treatment response rates when compared with sertraline and placebo (112278). The validity of these effects is limited by the small sample size and short study duration. Additionally, it is unclear if the reduction in depressive symptoms is clinically significant.
• Erythema. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy females with self-perceived skin sensitivity shows that taking a specific supplement containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne) daily for 8 weeks reduces facial pigmentation when compared to baseline (111399). The validity of this finding is limited by a lack of a placebo group. It is unclear if these effects are due to L-theanine, other ingredients, or the combination.
• Generalized anxiety disorder (GAD). It is unclear if oral L-theanine is beneficial for reducing anxiety in people with GAD. Details: One small clinical study in adults with GAD shows that taking L-theanine 225 mg twice daily for 4 weeks, then 450 mg twice daily for 4 weeks, in conjunction with prescribed antidepressants, does not reduce anxiety scores when compared with antidepressants and placebo (104976).
• Hypertension. Although there is interest in using oral theanine for hypertension, there is insufficient reliable information about the clinical effects of theanine for this condition.
• Influenza. Oral L-theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of green tea catechins (THEA-FLAN 90S, Ito-en Co.) 378 mg, standardized to contain epigallocatechin gallate 270 mg and L-theanine (Suntheanine, Taiyo Kagaku) 210 mg daily for 5 months reduces the risk of developing clinically diagnosed influenza when compared with placebo. However, the combination does not seem to prevent laboratory-confirmed influenza infection (54021).
• Insomnia. It is unclear if oral L-theanine is beneficial for insomnia. Details: A very small clinical study in young healthy adults with sleep quality worsened by caffeine intake shows that taking L-theanine 50 mg (Suntheanine, Taiyo Kagaku Co. Ltd) once 10 minutes before bedtime suppresses caffeine-induced elevations in wake after sleep onset time but does not improve parameters of sleep quality including sleep onset latency, sleep time, or number of times waking after sleep onset when compared with placebo (112275). L-theanine has also been studied in combination with other ingredients. A small clinical study in adults with insomnia or disturbed sleep patterns shows that a specific product (RLX2; LiveLife Biosciences AG) containing L-theanine 50 mg and a specific casein peptide, alpha-s1-casein tryptic hydrolysate, 150 mg, taken one hour before bedtime for 4 weeks, increases sleep duration by 45 minutes and improves habitual sleep efficiency and daytime dysfunction when compared with baseline (108556). Another very small clinical study in healthy adults shows that taking a combination product containing tryptophan, glycine, magnesium, tart cherry powder, and L-theanine 2 hours before bedtime decreases sleep onset latency and increases total sleep duration, leading to better sleep efficiency and reduced morning sleepiness, when compared with placebo (111184). Another combination product containing L-theanine, ashwagandha, and saffron (InnerCalm, Arbonne), taken daily for 8 weeks, seems to improve sleep quality when compared to baseline (111399). However, the validity of this finding is limited by a lack of a control group. It is unclear if the effects described above are due to L-theanine, other ingredients, or the combination.
• Obsessive-compulsive disorder (OCD). It is unclear if oral L-theanine is beneficial for OCD. Details: A small clinical study in adults with OCD shows that taking L-theanine 100 mg twice daily for 10 weeks with fluvoxamine reduces OCD symptoms, particularly obsessive symptoms, and increases the proportion of patients with a complete response to treatment but does not improve compulsive symptoms, partial response rates, or remission rates when compared with placebo and fluvoxamine (112276).
• Postoperative recovery. Oral theanine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of adults with esophageal cancer undergoing esophagectomy shows that taking theanine 280 mg and cystine 700 mg daily, staring 4 days before surgery and continued for 13 days after surgery, does not improve measures of physical activity but does improve exercise tolerance and some measures of quality of life when compared with placebo (111400). It is unclear if these findings are due to theanine, cystine, or the combination.
• Schizophrenia. It is unclear if oral L-theanine is beneficial in patients with schizophrenia; the available evidence is limited and conflicting. Details: One small preliminary clinical study in adults with schizophrenia or schizoaffective disorder shows that taking L-theanine (Biosynergy) 200 mg orally twice daily for 8 weeks along with antipsychotic medications improves positive symptoms, anxiety, and general psychopathology symptoms, such as poor impulse control and disorientation, when compared with placebo. However, theanine does not improve general disease severity, negative symptoms, depression, cognitive function, extrapyramidal side effects, or quality of life (96341). In contrast, two small clinical studies show that taking L-theanine 400 mg (Suntheanine, BioSynergy Health Alternatives) with antipsychotics and with or without pregnenolone 50 mg daily for 8 weeks reduces negative symptoms, general psychopathology symptoms, and anxiety when compared with placebo in patients with schizophrenia or schizoaffective disorder. However, there were no improvements in positive schizophrenia symptoms, extrapyramidal side effects, or symptoms of depression (97923,112277). The inconsistency of results might be due to the small study sizes and the subjectivity of the outcomes measured.
• Stress. It is unclear if oral L-theanine is beneficial in patients with stress. Details: One very small clinical study shows that taking L-theanine 200 mg prior to a stress-inducing exam reduces tension-anxiety and may prevent blood pressure increases caused by psychological stress when compared with placebo (91746). Other preliminary clinical research in pharmacy students shows that taking theanine 200 mg twice daily for one week prior, and then for the first 10 days of a pharmacy practice period, decreases subjective stress scores when compared with placebo (91745). Another small clinical study in healthy young adults shows that drinking a beverage containing L-theanine 200 mg alone or combined with L-arginine 50 mg after a psychological stressor reduces stress, as measured by salivary alpha-amylase activity, when compared with placebo. The combination of L-arginine and L-theanine did not differ from L-theanine alone, suggesting that the combination does not act synergistically to reduce markers of stress (110393). However, not all research has been positive. A small clinical study shows that taking a specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg induces subjective feelings of tranquility in relaxed people, but not those with experimentally-induced anticipatory anxiety, when compared with placebo (12188). Also, a small, clinical crossover study in healthy, moderately stressed adults shows that taking a single dose of a specific product (Alphawave; Ethical Naturals) containing L-theanine 200 mg prior to a stress-inducing exam does not improve anxiety at any time point when compared with placebo (108554). Due to the single-dose nature of this study, the effects of continued administration of this product are unclear. L-theanine has also been evaluated in combination with other ingredients. A small clinical study in adults with stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis Group), containing green tea extract 125 mg (providing 50 mg L-theanine), magnesium 150 mg, vitamin B6 0.2 mg, vitamin B9 0.1 mg, vitamin B12 1.25 mcg, and rhodiola 222 mg, orally once daily for 28 days modestly improves stress and anxiety scores when compared with placebo. Improvements in stress scores, but not anxiety scores, appear to persist at 28 days after treatment completion (108672). It is unclear if any effects are due to L-theanine, other ingredients, or the combination.
• Tourette syndrome. It is unclear if oral L-theanine is beneficial in children with Tourette syndrome. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing L-theanine 200 mg and vitamin B6 2.8 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups. More evidence is needed to rate theanine for these uses.

(Read more about THEANINE)

EFFECTIVE

• Thiamine deficiency. Oral thiamine prevents and treats thiamine deficiency syndromes. Details: Thiamine deficiency is treated with oral thiamine 5-30 mg daily as a single dose or in divided daily doses for one month. For severe deficiency, thiamine up to 300 mg daily can be used (15).Thiamine deficiency can occur in people with malabsorption conditions such as alcohol use disorder, cirrhosis, and gastrointestinal diseases; in those with inadequate intake due to anorexia, nausea, and vomiting; and in those with increased requirements, including pregnancy, increased carbohydrate intake, increased physical activity, hyperthyroidism, infection, and liver disease. However, deficiency is rare with these conditions (15). The elderly might also be at increased risk for subclinical thiamine deficiency (11076).
• Wernicke-Korsakoff syndrome (WKS). Parenteral thiamine is effective for treating symptoms of WKS. Details: Parenteral administration of thiamine 5-200 mg daily for 2 days decreases the risk of developing WKS and decreases symptoms of WKS in acute alcohol withdrawal. Between 30% and 80% of alcoholics are suspected to have thiamine deficiency (11075). An optimal dose for treating WKS has not been established; however, early research suggests that a 200 mg intramuscular dose may be more effective than lower doses (11075). In contrast, a moderate-sized clinical trial in adults with a history of heavy alcohol use who were asymptomatic or symptomatic for WKS shows that there is no benefit to administering high doses (300 mg 3 times daily) compared with medium (100 mg 3 times daily) or low (100 mg daily) doses of parenteral thiamine on cognitive or neurological functioning (111690). The study may have been inadequately powered to detect a difference between groups.

POSSIBLY EFFECTIVE

• Dysmenorrhea. Oral thiamine might reduce pain in some patients with dysmenorrhea. Details: A clinical study in adolescent Iranian females with dysmenorrhea shows that taking thiamine 100 mg alone or along with fish oil 500 mg daily for 2 months moderately reduces pain intensity and duration when compared with placebo (89341). Another preliminary clinical study in Indian females 12-21 years of age with moderate to severe primary dysmenorrhea shows that taking thiamine 100 mg daily for 90 days eliminates pain in 87% of participants when compared to baseline (77820). The validity of this finding is limited by the lack of a placebo group. Furthermore, available research was conducted in India and Iran, so it is unclear if these findings are generalizable to other geographic locations.

POSSIBLY INEFFECTIVE

• Coronary artery bypass graft (CABG) surgery. Intravenous thiamine does not seem to improve outcomes after CABG surgery. Details: A small clinical study in adults undergoing CABG surgery with cardiopulmonary bypass shows that giving intravenous thiamine 200 mg immediately prior to surgery and immediately after surgery does not improve clinical outcomes or lactate levels when compared with placebo (97010). Larger doses of thiamine also don't seem to be beneficial. Another small clinical study in patients receiving CABG with cardiopulmonary bypass shows that giving thiamine 600 mg intravenously on the day of surgery, and 400 mg daily for three postoperative days, does not improve postoperative outcomes when compared with placebo (103000).
• Heart failure. Most research suggests that oral or intravenous thiamine does not improve outcomes in patients with heart failure. Details: Observational research suggests that having heart failure is associated with 2.5-fold increased odds of having thiamine deficiency, possibly because of diuretic use, intestinal malabsorption, and metabolism changes. However, it is unclear if thiamine supplementation is beneficial. A meta-analysis of 2 small clinical trials in adults with systolic heart failure and unclear thiamine status shows that thiamine 200-300 mg given orally or by IV for 7-28 days improves left ventricular ejection fraction (LVEF) by 3% when compared with control (97012). However, other meta-analyses and clinical studies in adults with heart failure with or without thiamine deficiency show that taking intravenous, intramuscular, or oral thiamine 100-500 mg daily does not improve LVEF fraction, left ventricular end-diastolic volume, dyspnea, mortality, hospitalization, or exercise tolerance when compared with placebo or control (103002,111682,111686,111688).
• Mosquito repellent. Oral thiamine does not seem to repel mosquitos. Details: Clinical research in healthy volunteers shows that taking thiamine does not improve mosquito repellency when compared with taking vitamin C as a control (18016).
• Sepsis. Intravenous or oral thiamine, alone or in combination with vitamin C and hydrocortisone, does not seem to reduce mortality or prevent organ failure in sepsis or septic shock. Details: Multiple meta-analyses of small clinical studies in patients with septic shock show that intravenous or oral thiamine 100-500 mg 2-3 times daily for 3-7 days is no better than placebo for improving mortality, end-organ damage, number of ventilator-free days, and duration of intensive care unit (ICU) stay (105443,107717,107727,111689). One meta-analysis suggests that administration of thiamine alone increases the risk of mortality in these patients (111689). Subgroup analyses including only higher quality studies also fail to show a benefit of thiamine (107717). Another recent small clinical trial in patients with septic shock shows that receiving the same dose of intravenous thiamine does not increase vasopressor-free days when compared with placebo (105441). Intravenous thiamine 200 mg every 12 hours has also been evaluated in combination with intravenous vitamin C 1.5-2 grams and hydrocortisone 50-200 mg every 6-12 hours for 4-10 days (HAT therapy). While some retrospective research found HAT therapy to be beneficial (100315,102980,111689), high-quality, prospective clinical research has shown no benefit (105447,109956,111689). Meta-analyses in patients with sepsis and septic shock shows that receiving HAT therapy does not improve mortality, kidney injury, number of ventilator-free days, or ICU length of stay when compared with control (102129,104027,104028,104032,102998,105447,109956,111642,111689). Additionally, the meta-analyses suggest that HAT therapy does not reverse shock or improve sequential organ failure assessment (SOFA) scores (109556,111642). However, one meta-analysis found that HAT therapy shortened the duration of vasopressor use when compared with placebo (111642). Long-term follow up from a study in patients with sepsis-induced respiratory and/or cardiovascular dysfunction shows that receiving HAT therapy does not improve cognitive, psychological, or functional status after 6 months and, for immediate memory scores and development of posttraumatic stress disorder, HAT therapy was less beneficial when compared with placebo (111299).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute kidney injury (AKI). It is unclear if oral or intravenous thiamine is beneficial for treating or preventing AKI. Details: Observational research in adults admitted to the intensive care unit (ICU) with AKI has found that treatment with thiamine (dose unspecified) within the first 48 hours of admission is associated with 39% lower odds of in-hospital mortality and 28% higher odds of kidney function recovery when compared with patients that did not receive thiamine. Receiving thiamine was also associated with a 0.5-day reduction in ICU length of stay (107719).
• Anxiety. Although there is interest in using oral thiamine for anxiety, there is insufficient reliable information about the clinical effects of thiamine for this purpose.
• Cardiac arrest. It is unclear if intravenous thiamine reduces the risk of death after resuscitation from cardiac arrest. Details: A small clinical study in adults resuscitated from cardiac arrest shows that receiving intravenous thiamine 100 mg every 8 hours for 7 days does not reduce 28-day mortality when compare with a normal saline placebo (105442).
• Cardiovascular disease (CVD). It is unclear if oral thiamine is beneficial for treating or preventing CVD. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 16% increased odds of developing angina or myocardial infarction when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on CVD have not been studied (107725).
• Cataracts. Small studies suggest that increased dietary thiamine might help prevent cataracts. Details: Observational research has found that a high dietary intake of thiamine 10 mg daily is associated with 40% lower odds of nuclear cataracts (6378). Other population research has found that higher dietary intake of thiamine is associated with a modestly reduced risk of age-related lens opacification (14301).
• Cervical cancer. It is unclear if oral thiamine reduces the risk of developing cervical cancer. Details: Epidemiological research has found that increasing intake of thiamine from dietary and supplemental sources, along with folic acid, riboflavin, and vitamin B12, is associated with a lower odds of precancerous cervical lesions (11074).
• Child development. It is unclear if supplementing breastfeeding females with oral thiamine improves infant neurocognitive development. Details: Preliminary clinical research shows that supplementing breastfeeding females with oral thiamine, 1.2-10 mg daily for 22 weeks, starting at 2 weeks postpartum, does not improve most cognitive or neurodevelopmental scores in the child when compared with placebo. However, one subgroup analysis suggests that thiamine supplementation may improve language scores (107726).
• Cognitive function. Oral thiamine has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing thiamine hydrochloride 50 mg, other group B vitamins, bacopa, and ginkgo daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo. Subgroup analysis shows a possible benefit of the combination supplementation on measures of attention in those with an optimal diet at baseline (111334). It is unclear if these findings are due to thiamine, other ingredients, or the combination.
• Coronavirus disease 2019 (COVID-19). It is unclear if intravenous or oral thiamine improves clinical outcomes in patients hospitalized with COVID-19. Details: A small observational study of adults admitted to the intensive care unit with COVID-19 has found that treatment with intravenous or oral thiamine 100 mg daily for an average of 7 days is associated with a 63% reduction in the odds of death within 30 days when compared with control. However, there was no associated reduction in duration of hospitalization or mechanical ventilation (107721). In addition, a small observational study of adults with encephalopathy that were mechanically ventilated secondary to COVID-19 has found that taking thiamine 500 mg three times daily orally for 5 days improves neurological manifestations, including ophthalmoparesis and ataxia, when compared with baseline. The validity of this study is limited by the lack of a comparator group (107722).
• Critical illness (trauma). It is unclear if oral or intravenous thiamine is beneficial in patients with critical illness. Details: A meta-analysis of critically ill patients shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days does not affect the need for mechanical ventilation, duration of hospital stay, or mortality when compared with control (107727).
• Delirium. It is unclear if oral or intravenous thiamine helps to prevent or treat delirium. Details: In critically ill patients, a meta-analysis of clinical research shows that treatment with oral or intravenous thiamine 100-600 mg daily for up to 7 days reduces the odds of developing delirium by 42% when compared with control (107727). However, some observational research in adults with septic shock has found that receiving intravenous thiamine 400 mg daily with vitamin C 6 grams daily, both in divided doses, is not associated with reduced delirium when compared with control (103001). In non-critically ill, hospitalized adults with altered mental status, retrospective, observational research has also found that administration of oral or intravenous thiamine is not associated with improved cognitive function or reduced in-hospital mortality when compared with control (107723). Preliminary clinical research in adults undergoing an allogeneic hematopoietic stem cell transplant also shows that administering thiamine 200 mg three times a day intravenously for 7 days does not prevent delirium or shorten duration of delirium when compared with placebo (107718).
• Dementia. It is unclear if oral thiamine is beneficial for the prevention of dementia. Details: Observational research in patients with alcohol use disorder has found that taking thiamine is associated with a 24% to 46% lower risk of developing dementia when compared with not taking thiamine (102999).
• Depression. It is unclear if oral thiamine is beneficial in patients with depression. Details: Meta-analyses of population research in adults has found that high dietary consumption of thiamine is associated with a 10% to 31% lower risk of having depression when compared with low dietary consumption of thiamine. However, this research did not evaluate the effects of thiamine supplementation on depression (107133,107725). One small clinical study in adults with major depressive disorder shows that taking thiamine 300 mg daily in conjunction with fluoxetine 20 mg daily leads to greater improvements in depressive symptoms at 6 weeks when compared to fluoxetine with placebo. This benefit was no longer present at 12 weeks. This suggests that thiamine may accelerate improvement in symptoms during initiation of fluoxetine therapy (97013).
• Diabetes. It is unclear if oral thiamine is beneficial for type 2 diabetes or gestational diabetes. Details: A meta-analysis of 6 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not reduce glycated hemoglobin (HbA1c), fasting blood glucose, or postprandial blood glucose when compared with placebo (111681). A large, prospective cohort study in adults without type 2 diabetes suggests that the risk of new-onset diabetes is minimized in adults consuming thiamine 0.75-1.10 mg daily from the diet, while lower and higher thiamine intake levels are associated with an increased risk of new-onset diabetes (111685). Thiamine has also been studied for preventing gestational diabetes. A large, prospective cohort study in pregnant adults suggests that higher supplementation with thiamine during the first and second trimesters is associated with a lower risk of gestational diabetes when compared with lower levels of total thiamine intake. However, this effect was not found for dietary intake of thiamine, only supplementation. Additionally, the participants were mostly Han Chinese adults, limiting the generalizability of the findings to other populations (111680).
• Diabetic nephropathy. It is unclear if oral thiamine is beneficial for diabetic nephropathy. Details: A small clinical study in patients with early-stage diabetic nephropathy and microalbuminuria shows that taking thiamine 100 mg three times daily for 3 months decreases urinary albumin excretion, but does not affect glomerular filtration rate (GFR), when compared with placebo (16556).
• Diabetic neuropathy. Although there is interest in using oral thiamine for diabetic neuropathy, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Dry eye. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with dry eye suggests that adding unspecified doses of thiamine and mecobalamin to treatment with daily artificial tears and corticosteroid drops might slightly improve overall symptoms when compared with only artificial tears and corticosteroid drops for 1 month. There were no differences between groups at 2 months (105444). This finding is limited due to incomplete reporting and a lack of adjustment for multiple hypothesis testing.
• Dyslipidemia. It is unclear if oral thiamine is beneficial for treating or preventing dyslipidemia. Details: A meta-analysis of 3 clinical studies in adults with type 2 diabetes shows that taking thiamine 100-300 mg or its derivative benfotiamine 120-900 mg daily for 1-3 months does not improve low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or triglycerides when compared with placebo (111681). Observational research in Korea suggests that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with 10% higher odds of developing dyslipidemia when compared with sufficient dietary thiamine intake. However, the effects of thiamine supplementation on dyslipidemia have not been studied (107725).
• Emergence delirium. It is unclear if intravenous thiamine helps to prevent emergence delirium in patients after surgery. Details: One clinical study in adults in the intensive care unit (ICU) after gastrointestinal surgery shows that receiving intravenous thiamine 200 mg daily for 3 days is associated with up to 84% lower odds of emergence delirium on the first two days, but not on the third day, when compared with a normal saline control (105440).
• Fatigue. It is unclear if oral thiamine is beneficial in patients with fatigue. Details: A small clinical crossover study in patients with chronic fatigue and inflammatory bowel disease (IBD) shows that taking thiamine 600-1800 mg daily for 20 days reduces fatigue scores when compared with placebo (105438). Taking oral thiamine 300 mg daily for an additional 12 weeks did not seem to affect fatigue scores when compared with placebo. However, an observational follow-up study found that those who self-continued thiamine for an additional 24 weeks after the study ended reported lower fatigue scores when compared with those who did not self-continue thiamine (107720).
• Glaucoma. Although there is interest in using oral thiamine for glaucoma, there is insufficient reliable information about the clinical effects of thiamine for this condition.
• Herpes zoster (shingles). It is unclear if subcutaneous thiamine is beneficial in patients with shingles. Details: A small clinical trial shows that receiving subcutaneous thiamine 100 mg injections six times weekly for 4 weeks reduces itching by at least 30% in 67% of patients with herpes zoster. However, thiamine does not appear to significantly reduce pain in most patients (90396).
• Hypertension. It is unclear if oral thiamine is beneficial in treating or preventing hypertension. Details: Population research in Korea has found that insufficient dietary thiamine intake (daily intake of less than 1.22 mg in males or 1.03 mg in females) is associated with a 5% increased odds of developing hypertension when compared with sufficient dietary thiamine. However, the effects of thiamine supplementation on hypertension have not been studied (107725).
• Impaired glucose tolerance (prediabetes). It is unclear if oral thiamine is beneficial in patients with prediabetes. Details: A very small clinical trial in patients with prediabetes shows that taking thiamine 100 mg by mouth three times daily for 6 weeks modestly decreases 2-hour postprandial plasma glucose levels when compared to baseline and decreases fasting blood glucose levels when compared with placebo (91168).
• Kidney failure. Oral thiamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary, low-quality, clinical research in adults with kidney failure undergoing regular hemodialysis shows that taking oral thiamine 90 mg daily with folic acid 30 mg daily for 96 weeks reduces overall mortality by 67% and improves cognitive scores by 31% when compared with no intervention (107724). It is unclear if this effect is due to thiamine, folic acid, or the combination.
• Migraine headache. It is unclear if dietary thiamine is beneficial for the prevention or treatment of migraine headache. Details: A large, retrospective, cross-sectional study suggests that higher dietary intake of thiamine is associated with lower odds of severe headache or migraine, especially in females (111684). The validity of these effects is limited by the subjective outcome measures and retrospective study design.
• Pneumonia. It is unclear if thiamine is beneficial for patients with pneumonia. Details: A large retrospective cohort study in adults hospitalized with pneumonia and active alcohol use disorder suggests that parenteral administration of thiamine is associated with reduced 14-day mortality and more frequent discharges home, but not a shorter length of stay or fewer ICU transfers, when compared with no thiamine use. Furthermore, parenteral thiamine doses above 200 mg do not appear to improve mortality but may be associated with longer length of stay and less frequent discharges home when compared with low oral doses of thiamine or parenteral thiamine at doses under 200 mg (111679). The validity of these effects is limited by the retrospective study design.
• Ventilator-associated pneumonia (VAP). It is unclear if oral or parenteral thiamine is beneficial for patients with VAP. Details: A retrospective study in adults with VAP in the intensive care unit (ICU) suggests that supplementation with intravenous or oral thiamine may be associated with reduced ICU and in-hospital mortality (111683). The validity of these effects is limited by the retrospective study design. More evidence is needed to rate thiamine for these uses.

(Read more about THIAMINE)

POSSIBLY EFFECTIVE

• Dementia. Oral vinpocetine, taken for up to 1 year, might improve cognitive function to a small degree in patients with dementia. Details: While some conflicting evidence exists (1784), several small clinical studies in patients with cognitive impairment due to various causes including dementia, Alzheimer disease, and vascular disease show that taking vinpocetine 5-20 mg three times daily for up to 1 year slightly to modestly improves cognitive function when compared with baseline scores or placebo (1787,1789,82151,82152,82153,82154,82179,82180)(82182,82183,92934,111333). However, most of these studies were published prior to 1990 and used diagnostic and evaluative criteria that limit the applicability of these results to current clinical practice (10221,10827,111333).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Although there has been interest in using oral vinpocetine for age-related cognitive decline, there is insufficient reliable information about the clinical effects of vinpocetine for this purpose.
• Age-related macular degeneration (AMD). It is unclear if oral vinpocetine is beneficial in patients with AMD. Details: One small clinical study in patients with AMD shows that taking vinpocetine 10 mg daily for 2 months, in conjunction with conventional therapy, improves visual acuity and retinal function when compared with conventional therapy alone (82089).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral vinpocetine for CFS, there is insufficient reliable information about the clinical effects of vinpocetine for this purpose.
• Epilepsy. Although there has been interest in using oral and intravenous vinpocetine for epilepsy, there is insufficient reliable information about the clinical effects of vinpocetine for this purpose.
• Hearing loss. It is unclear if oral or intravenous vinpocetine is beneficial in patients with hearing loss. Details: One small clinical study in patients with acoustic trauma shows that intravenous administration of vinpocetine 10 mg twice daily for 10 days is less effective than nicergoline, an ergot derivative, for improving hearing loss (82147). Another small, open-label clinical study in patients with sensorineural hearing loss shows that taking vinpocetine 10 mg three times daily for 12 months improves some measures of hearing capacity, particularly in months 6-12, when compared to baseline (106845). The validity of these findings is limited by a lack of control group.
• Memory. Small clinical studies suggest that oral vinpocetine might slightly improve memory in healthy individuals. Details: Two very small clinical studies in healthy individuals show that taking vinpocetine 40 mg as a single dose or vinpocetine 10-40 mg three times daily for 2 days enhances some measures of memory when compared with placebo (1796,1797). Additionally, one small clinical study in healthy adults shows that taking a combination product containing vinpocetine 10 mg, ginkgo extract 40 mg, and other ingredients three times daily for 2 weeks improves short-term memory when compared with placebo (8544). It is unclear if these findings are due to vinpocetine, other ingredients, or the combination.
• Menopausal symptoms. Although there has been interest in using oral vinpocetine for menopausal symptoms, there is insufficient reliable information about the clinical effects of vinpocetine for this purpose.
• Motion sickness. Although there has been interest in using oral vinpocetine for motion sickness, there is insufficient reliable information about the clinical effects of vinpocetine for this purpose.
• Stroke. Research on the use of intravenous vinpocetine to improve outcomes in patients recovering from ischemic stroke is mixed. It is unclear if oral vinpocetine is beneficial in these patients. Details: Some small clinical studies show that vinpocetine modestly reduces the residual effects of acute ischemic stroke (1785,10222,82087,82091,82120,82158,82159,82186). However, most clinical studies investigating the use of vinpocetine for stroke have been published in languages other than English and assessed intravenous formulations of vinpocetine not available in the US. One large clinical study shows that intravenous administration of vinpocetine 30 mg once daily for 7 days after an acute stroke, in addition to oral citicoline and aspirin or clopidogrel, seems to improve cerebral blood flow and measures of cognition, neurological function, and quality of life when compared with citicoline plus aspirin or clopidogrel (98226). A meta-analysis of 4 moderate-to-good quality clinical studies that included 837 adults with acute ischemic stroke, some of which are described above, shows that intravenous administration of vinpocetine in addition to standard care, followed by oral administration in some studies, reduces significant disability when compared with standard care. Vinpocetine also seems to improve cognition scores but does not reduce mortality (110744). The included studies used widely heterogeneous dosing regimens and excluded patients with severe strokes. However, a small clinical study not included in the meta-analysis shows that intravenous vinpocetine 20 mg followed by oral vinpocetine 10 mg three times daily for 3 months does not significantly improve neurophysical functioning post-stroke when compared with placebo (82074).
• Tinnitus. It is unclear if oral or intravenous vinpocetine is beneficial in patients with tinnitus. Details: A small observational study in patients with chronic unilateral or bilateral tinnitus has found that intravenous infusion of a specific vinpocetine product (Cavinton) 20 mg plus oral vinpocetine (Cavinton) 10 mg twice daily along with physiotherapy is associated with improved symptoms when compared to baseline (82099). However, a small clinical study in patients with tinnitus due to acoustic trauma shows that intravenous administration of vinpocetine (Cavinton) 10 mg twice daily appears to be less effective than nicergoline, an ergot derivative, for reducing tinnitus (82147).
• Urinary incontinence. It is unclear if oral vinpocetine is beneficial in patients with urinary incontinence. Details: One small, uncontrolled clinical study in patients with urinary incontinence shows that taking vinpocetine 10 mg three times daily for 2 weeks reduces daytime and nighttime frequency of urination when compared to baseline (82041). The validity of these findings is limited by a lack of control group. More evidence is needed to rate vinpocetine for these uses.

(Read more about VINPOCETINE)

EFFECTIVE

• Imerslund-Grasbeck disease. Intramuscular vitamin B12 is effective for patients with this condition. Details: Administering intramuscular vitamin B12 (hydroxocobalamin) 1 mg daily for 10 days, followed by monthly injections for the remainder of a patient's life, is effective for treating familial selective vitamin B12 malabsorption (Imerslund-Grasbeck disease) (15,82862).
• Vitamin B12 deficiency. Administering vitamin B12 orally, intramuscularly, or intranasally is effective for preventing and treating vitamin B12 deficiency. Details: Vitamin B12 deficiency has varying definitions but is often defined as vitamin B12 (cobalamin) levels less than 180-200 pmol/L (or 240 pg/mL). Some believe that only intramuscular vitamin B12 is effective for treating vitamin B12 deficiency. However, clinical research shows that oral therapy increases cobalamin levels similarly to intramuscular administration, even in patients with pernicious anemia or malabsorption, if a high enough dose is given (2909,2911,2915,9335,82832) (82836,82949,82860,103976,103972,107141,107144). Some evidence suggests that the most effective oral dose is between 647-1032 mcg daily (13106). However, in certain situations, intramuscular treatment might be more appropriate. Guidelines by the British Committee for Standards in Hematology recommend only intramuscular vitamin B12 for initial treatment of severe vitamin B12 deficiency in patients with pernicious anemia, malabsorption disorders, or neurological involvement (94722). Intramuscular vitamin B12 is also appropriate in patients with diarrhea or vomiting and those likely to be nonadherent (103972). Vitamin B12 deficiency is especially common in older adults, primarily due to lack of intrinsic factor and malabsorption (2915,2919,9335). Daily supplementation with vitamin B12 50-100 mcg might be needed to correct deficiency (10126), while daily doses of 25-37.5 mcg help to maintain normal levels over time (9335). In addition to supplements, foods such as milk and bread fortified with vitamin B12 can be used and are approximately 55% to 60% absorbed by people over 60 years of age (10124). Vitamin B12 deficiency is also common in patients that have had gastric surgery, including gastrectomy and bariatric surgery (107144,107145). Taking vitamin B12 in the doses found in multivitamins or generic vitamin B supplements does not seem to prevent vitamin B12 deficiency following bariatric surgery (107145). However, taking methylcobalamin 500 mcg daily is beneficial for treating vitamin B12 deficiency associated with a total gastrectomy and taking cyanocobalamin 5000 mcg daily is beneficial for preventing vitamin B12 deficiency following gastric bypass (107144). Other people at risk for vitamin B12 deficiency include strict vegetarians who eat no animal products (vegans) and people with increased vitamin B12 requirements associated with pregnancy, thyrotoxicosis, hemolytic anemia, hemorrhage, malignancy, and hepatic and kidney disease. Moderate consumption of animal products may not be sufficient to restore and maintain vitamin B12 levels, especially in adolescents who had consumed macrobiotic (vegan type) diets for the first 6 years of life. High dietary intake of vitamin B12 or supplements is usually needed in order to restore and maintain optimal vitamin B12 levels in these adolescents (10125).

LIKELY EFFECTIVE

• Cyanide poisoning. Intravenous hydroxocobalamin (Cyanokit) is likely effective as an antidote for patients with suspected or known cyanide toxicity due to inhalation, ingestion, or skin exposure. Details: Treatment of cyanide poisoning with hydroxocobalamin (Cyanokit) up to 10 grams has been approved by the US Food and Drug Administration (FDA) and recommended by the Australian Resuscitation Council (82870,82905,82906). Hydroxocobalamin is also FDA-approved for treating cyanide toxicity during pregnancy (82904).

POSSIBLY EFFECTIVE

• Canker sores. Sublingual or topical vitamin B12 seems to reduce canker sore symptoms. Details: Clinical research in patients with canker sores shows that applying a topical ointment containing vitamin B12 500 mcg in four divided doses daily for 2 days reduces pain levels by 80% when compared with a control ointment not containing vitamin B12 (96176). Other preliminary clinical research shows that taking vitamin B12 1000 mcg sublingually daily for 6 months reduces the duration of canker sore outbreaks, the number of ulcers, and level of pain when compared with placebo in patients with normal vitamin B12 levels (17242).
• Hyperhomocysteinemia. Oral vitamin B12 in combination with folic acid, and sometimes with vitamin B6, reduces homocysteine levels. Details: While folic acid 0.5-5 mg daily lowers fasting homocysteine levels by an average of 25%, adding vitamin B12 0.5 mg daily produces an additional decrease of about 7% on average (6883,9400,9401,9405,9409,50145,107136). Vitamin B12 in combination with folic acid and other vitamins also reduces homocysteine levels in patients with kidney failure, sickle cell disease, and those receiving nitrous oxide general anesthesia (1489,6883,6884,7289,7881,9324,9414,9415,9416,9481,82941). Some researchers recommend routine use of vitamin B12 with homocysteine-lowering regimens to avoid the risk of neuropathy in people with undetected vitamin B12 deficiency (9405). Using vitamin B12 alone has a limited effect on homocysteine levels, and probably only in those people with vitamin B12 deficiency (2147,9410,9512). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,2147,3323,9402,9405,9408,9409). Clinical research suggests that supplementation with folic acid, pyridoxine, and vitamin B12 decreases homocysteine levels and reduces the atherosclerosis progression in patients at risk for atherosclerosis when compared with placebo (50133,50056,82806). However, other research suggests that elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50%, and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9400,9405,9409,96417). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem improve endothelial function or help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50373,50314,97619). There is also some debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136).
• Postherpetic neuralgia. Subcutaneous injections of vitamin B12 seem to reduce postherpetic neuralgia symptoms. Details: Clinical research in patients with subacute herpetic neuralgia shows that subcutaneous injection of vitamin B12 (methylcobalamin) 1000 mcg six times weekly for 4 weeks reduces pain when compared with oral vitamin B12 or subcutaneous lidocaine (90394). Another clinical study shows that administering local subcutaneous injections of methylcobalamin 1000 mcg plus lidocaine up to 20 mg daily for 12 injections over 14 days, starting within 7 days of the onset of subacute ophthalmic herpetic neuralgia, decreases the mean pain score by 63% to 79% when compared with intravenous lidocaine and intramuscular methylcobalamin. Less than 2 patients need to be treated to achieve a pain reduction to ≤3 out of 10. Healing of rash, itching, numbness, and tingling were also improved (96175). Additional clinical research in patients with postherpetic pain and itching shows that this same dosing regimen of subcutaneous vitamin B12 reduces pain and analgesic requirements when compared to baseline (90396).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B12 does not seem to improve cognitive function in older adults when used alone or in combination with other B vitamins. Details: Taking vitamin B12 100-1000 mcg plus folic acid 400-2000 mcg, with or without vitamin B6 3-50 mg, daily for up to about 2 years does not seem to improve tests of cognitive function in adults aged 65 or older, most of whom do not report cognitive impairment at baseline (14392,50225,50510,90392,107140). Also, supplementation with vitamin B12 does not seem to improve cognitive function in elderly individuals with low vitamin B12 levels (12305).
• Alzheimer disease. Oral vitamin B12, when used in combination with other B vitamins, does not seem to improve cognitive function in patients with Alzheimer disease. Details: Clinical research in patients with probable Alzheimer disease using routine medication shows that taking vitamin B12 1 mg, folic acid 5 mg, and vitamin B6 25 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, a meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). Observational research has also found that higher vitamin B12 intake over 3 years in a population consuming a folate-fortified diet is not associated with a decreased risk of developing Alzheimer disease (15270). In contrast, preliminary clinical research in patients with probable Alzheimer disease who are not consuming a folate-fortified diet shows that taking vitamin B12 50 mcg daily plus folic acid 1.2 mg daily for 6 months modestly improves some measures of cognitive performance and decreases levels of homocysteine when compared with placebo (107150). More research is needed to determine if any changes in this latter study are clinically relevant.
• Cataracts. Oral vitamin B12 does not seem to reduce cataract development. Details: Clinical research in women with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts and seems to increase the risk of cataract extraction by 28% when compared with placebo (96149).
• Circadian rhythm sleep disorders. Oral vitamin B12 does not seem to improve sleep disorders. Details: Oral vitamin B12 (methylcobalamin) does not seem to be effective for treating delayed sleep phase syndrome. Methylcobalamin 0.5-1 mg three times daily, with or without bright light therapy, also does not seem to help people with primary circadian rhythm sleep disorders (1344,1345,1346,1347,1348).
• Cognitive impairment. Oral vitamin B12 does not seem to be beneficial for older adults with cognitive impairment. Details: A meta-analysis of clinical research in elderly adults with mild cognitive impairment or dementia shows that taking vitamin B12, usually with other B vitamins, does not improve cognitive function (50510). One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374).
• Fall prevention. Oral vitamin B12 does not seem to reduce the risk of falls. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not prevent falls when compared with placebo in elderly individuals also taking vitamin D (96148).
• Osteoporosis. Oral vitamin B12 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in elderly patients or patients with a history of cerebrovascular disease shows that taking vitamin B12 500 mcg and folic acid 0.4-2 mg, with or without vitamin B6 25 mg, daily for 2-3 years does not seem to reduce the risk for osteoporotic fractures when compared with placebo (90377,90393). A 5-7 year follow-up of this research has also found no benefit (103981).
• Physical performance. Oral vitamin B12 does not seem to improve physical performance in older adults. Details: Clinical research shows that taking B vitamins, including folic acid 400 mcg and vitamin B12 500 mcg, daily for 2 years does not increase hand strength or improve performance such as walking when compared with placebo in elderly individuals also taking vitamin D (96148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related macular degeneration (AMD). Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B12 1000 mcg, folic acid 2.5 mg, and vitamin B6 50 mg daily, reduces the risk of developing AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or at least three risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). It is unclear if high-dose intramuscular vitamin B12 improves the prognosis of ALS. Details: A clinical study in patients with ALS symptoms for 3 years or less shows that intramuscular vitamin B12 (methylcobalamin) 25-50 mg twice weekly for 3.5 years does not slow functional decline or increase the time until ventilation or death when compared with placebo. However, other clinical research in patients with early-stage ALS shows that intramuscular methylcobalamin 50 mg twice weekly for 16 weeks is associated with slower functional decline and a longer period of time until death or full ventilation when compared with placebo (104947,111556). These effects seem to be particularly notable in fine and gross motor skills, but not bulbar or respiratory functions. Furthermore, vitamin B12 and riluzole slowed clinical progression of ALS more than riluzole alone (111556).
• Angioplasty. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B12 400 mcg, folic acid 1 mg, and vitamin B6 10 mg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412,34540). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, pyridoxine, and vitamin B12 followed by oral administration of folic acid 1.2 mg, pyridoxine 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151,34540). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B12, other ingredients, or the combination.
• Anxiety. Although there is interest in using oral vitamin B12 for anxiety and panic attacks, there is insufficient reliable information about the clinical effects of vitamin B12 for these uses.
• Asthma. Although there is interest in using oral vitamin B12 for asthma, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Atherosclerosis. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in patients with intermediate risk for coronary heart disease shows that taking vitamin B12 100 mcg, aged garlic extract 250 mg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B12, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if topical vitamin B12 reduces the severity of eczema. Details: Preliminary clinical research shows that applying a specific topical vitamin B12 0.07% cream (Regividerm) twice daily reduces the extent and severity of atopic dermatitis when compared with placebo (15765).
• Attention. Although there is interest in using oral vitamin B12 for improving attention and focus, there is insufficient reliable information about the clinical effects of vitamin B12 for this use.
• Cancer. It is unclear if oral vitamin B12 reduces overall cancer risk when used in combination with other B vitamins. Details: An ancillary clinical study in middle-aged and elderly adults with cardiovascular disease shows that taking a combination of vitamin B12 (cyanocobalamin) 0.02 mg, folic acid 0.56 mg, and vitamin B6 3 mg, with or without eicosapentaenoic acid (EPA) 400 mg plus docosahexaenoic acid (DHA) 200 mg, for a median of 4.7 years does not reduce the risk of cancer when compared with placebo (90666). An additional secondary analysis of clinical research in patients recovering from stroke or transient ischemic attack shows that taking vitamin B12 500 mcg, folic acid 2 mg, and vitamin B6 25 mg daily for around 3.4 years does not reduce the risk of cancer when compared with placebo (90378). The validity of these findings is limited because the studies were not designed nor adequately powered to test for cancer risk.
• Cardiovascular disease (CVD). Oral vitamin B12, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly reduce the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B12 in combination with folic acid and/or vitamin B6 does not seem to reduce the risk for secondary death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, other research shows that taking vitamin B12 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). It is unclear which specific combination of B vitamins, if any, might be optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cervical cancer. It is unclear if oral vitamin B12 reduces cervical cancer risk. Details: Some epidemiological evidence has found that increasing vitamin B12 intake from dietary and supplement sources, along with folic acid, thiamine, and riboflavin, might decrease the risk of precancerous cervical lesions (11074). Also, an analysis of two case control studies has found that increased intake of vitamin B12 is associated with a 75% reduced odds of cervical cancer (34609).
• Chemotherapy-induced peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients receiving chemotherapy shows that a combination of B vitamins that includes vitamin B12 (cyanocobalamin) 1000 mcg, taken daily starting one week prior to treatment and finishing 12 weeks after treatment is completed, does not prevent peripheral neuropathy when compared with placebo (96173).
• Child development. It is unclear if oral vitamin B12 is beneficial for child development. Details: Population research has found that daily dietary intake of less than 2.26 mcg vitamin B12 in the third trimester of pregnancy is associated with an increased risk of poorer outcomes in the offspring for some measures of speech and mathematics ability, including vocabulary at 24 months, combining words at 38 months, speech intelligibility at 6 years, and math comprehension between ages 8-11 years, when compared with dietary intakes of at least 2.26 mcg daily. There was no association between prenatal vitamin B12 intake and reading or spelling abilities, vocabulary at other ages, or full-scale Intelligence Quotient (IQ) at ages 8 or 15 (107143). Furthermore, a very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve neurodevelopment as measured by language, motor, socioemotional, or cognitive scores at 12 months old and may worsen early motor performance at 8-12 weeks when compared with placebo. However, the negative effects on motor performance resolved by 6 and 12 months of age (112431).
• Child growth. Oral vitamin B12 taken by pregnant adults does not seem to be beneficial for infant growth. Details: A very large clinical study in infants of pregnant adults, 71% of whom were deficient in vitamin B12 at baseline, shows that taking vitamin B12 50 mcg daily starting in early pregnancy (<15 weeks gestation) until 6 months postpartum does not improve the infant's linear growth, length, or weight at 12 months of age (112431).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral vitamin B12 reduces the risk of COPD. Details: Clinical research in patients with COPD shows that taking vitamin B12 500 mg daily for 8 weeks modestly improves endurance on the cycle ergometer, but does not improve oxygen consumption, when compared with placebo (96172).
• Cognitive function. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy, middle-aged adults shows that taking a combination product containing vitamin B12, other B vitamins, bacopa, and gingko biloba twice daily for 12 weeks does not improve measures of memory, attention, cognition, mood, or stress reactivity when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B12 reduces colorectal cancer risk. Details: Some epidemiological evidence has found that increased dietary intake of vitamin B12 is associated with a reduced risk of developing colorectal cancer (90383). However, preliminary clinical research shows that taking vitamin B12 1 mg, folic acid 2.5 mg, and vitamin B6 50 mg daily for up to 7.3 years does not reduce the risk of colorectal adenoma in females at high risk for cardiovascular disease (90389). Furthermore, a secondary analysis of clinical research in elderly patients suggests that taking vitamin B12 500 mcg and folic acid 400 mcg daily for 2 years might increase the risk of colorectal cancer when compared with placebo (90393).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral vitamin B12 is beneficial for patients with COVID-19. Details: A small observational study in hospitalized patients with COVID-19 pneumonia has found that higher plasma vitamin B12 levels may be associated with an increased risk of transfer to intensive care or death than lower plasma levels. However, when multivariate regression was conducted, only patient age was associated with worsened outcomes. Additionally, the total study population was small, with only nine of 49 patients experiencing the worsened outcomes (107138).
• Dementia. It is unclear if oral vitamin B12 reduces the risk of developing dementia. Details: A large cohort of Danish adults has found that vitamin B12 levels or intake does not seem to impact the risk of developing Alzheimer disease or other dementias (104922). However, vitamin B12 might be beneficial in specific patient populations. A small observational study in patients with Parkinson disease has found that higher vitamin B12 levels (648.5 ng/L) are associated with a lower risk of developing dementia when compared with lower vitamin B12 levels (452 ng/L) (103975). It is not yet known if supplementation with vitamin B12 reduces the risk for dementia in these patients.
• Depression. It is unclear if oral vitamin B12 is beneficial for reducing depression risk. Details: A meta-analysis of epidemiological research has found that the highest dietary intake of vitamin B12 is associated with a 14% reduced risk of depression. However, in a sub-analysis, this association was not significant in males (107133). In contrast, one epidemiological study in older males included in the analysis has found that daily dietary intake of at least 4.79 mcg vitamin B12 is linked with a 58% lower risk of depression when compared with daily intake of less than 3.16 mcg. In this study, this inverse association was not observed in females (96168). Other observational research has found that low-normal serum vitamin B12 levels are associated with a 3.8 times increased risk for depression during pregnancy when compared with normal vitamin B12 levels (102384). It is unclear if increased intake of vitamin B12 through the diet or supplements reduces the risk for depression or is beneficial for treating symptoms of depression in any population. However, a meta-analysis of clinical research in elderly populations shows that supplementation with vitamin B12 100-1000 mcg daily, usually in combination with folic acid 400-2000 mcg daily, does not reduce symptoms of depression. Most individuals in these studies were not specifically diagnosed with depression (107140).
• Diabetes. It is unclear if oral vitamin B12 improves glycemic indices or prevents loss of skeletal muscle in patients with diabetes. Details: A small clinical study in patients with diabetes in India who are stabilized on metformin and/or a sulfonylurea shows that taking vitamin B12 (methylcobalamin) 500 mcg with or without folic acid 5 mg daily for 8 weeks seems to reduce glycated hemoglobin (HbA1C) by 1.3% to 1.5%, compared with a 0.3% increase with placebo (104917). This study is limited due its small sample size and lack of blinding. In elderly adults with type 2 diabetes, population research has found a lower dietary intake of vitamin B12 (average of 11.2 mcg daily) in individuals with a loss of skeletal muscle mass of at least 1.2%, compared with an average intake of 13.4 mcg daily in those with a skeletal muscle mass loss of less than 1.2%. However, further analysis determined that any relationship between vitamin B12 intake and loss of skeletal muscle mass was only significant in individuals with insufficient energy intake overall (107151).
• Diabetic neuropathy. Small clinical studies suggest that oral vitamin B12 may modestly improve pain in patients with diabetic neuropathy. Details: Two small clinical studies in patients with diabetic peripheral neuropathy show that taking vitamin B12 (methylcobalamin) 1-1.5 mg for 4-12 months modestly improves pain when compared with baseline or placebo (82841,104923). Some research also shows that vitamin B12 may be beneficial in combination with other ingredients. Studies have evaluated products containing vitamin B12 (methylcobalamin or cyanocobalamin), benfotiamine, and vitamin B6 daily for 9-12 weeks (82931,82939); and vitamin B12 (methylcobalamin) 2 mg, folic acid (L-methylfolate) 3 mg, and vitamin B6 (pyridoxal-5'-phosphate) 35 mg (Metanx; Pamlab) daily for 24 weeks (90375).
• Diarrhea. It is unclear if oral vitamin B12 is beneficial for reducing diarrhea in children. Details: Preliminary clinical research in children aged 6-30 months from low- and middle-income countries shows that taking vitamin B12 at twice the recommended dietary allowance, with or without folic acid, does not reduce the risk for diarrhea when compared with placebo (90391).
• Fatigue. It is unclear if intramuscular vitamin B12 is beneficial for improving well-being in those with fatigue or tiredness. Details: A small crossover trial in patients complaining of tiredness or fatigue shows that receiving intramuscular injections of vitamin B12 (hydroxocobalamin) 5 mg twice weekly for 2 weeks seems to improve general well-being and happiness, and has a trend toward improving fatigue, when compared with placebo (10127). The validity of this study is limited by a large drop-out rate and unstandardized outcome measures.
• Hearing loss. Oral vitamin B12 has only been evaluated in combination with adenosine triphosphate; its effect when used alone is unclear. Details: A small observational study in adults with idiopathic sudden sensorineural hearing loss has found that taking vitamin B12 1.5 mg with adenosine triphosphate 300 mg daily for 8-16 weeks is associated with modestly reduced hearing loss at 4-6 months after starting treatment when compared with taking the combination for less than 8 weeks (104924). This finding is limited due to its observational nature and lack of a control group.
• Hepatitis C. It is unclear if intramuscular vitamin B12 is beneficial for sustaining viral response in patients with chronic hepatitis C infection. Details: A small clinical study in patients with chronic hepatitis C infection shows that intramuscular vitamin B12 (cyanocobalamin) 5000 mcg every 4 weeks along with standard care improves sustained viral response when compared with standard of care alone (90386).
• Hypertriglyceridemia. It is unclear if oral vitamin B12 is beneficial for reducing triglyceride levels. Details: Some evidence shows that taking vitamin B12 7.5 mcg with fish oil 5 grams might be superior to fish oil alone when used daily to reduce total serum cholesterol and triglycerides. This suggests vitamin B12 might have an independent effect in lowering serum cholesterol and triglycerides, but further investigation is needed to confirm this effect (8694).
• Hypotension. It is unclear if oral vitamin B12 is beneficial for treating hypotension. Details: A meta-analysis of 3 observational studies in patients hospitalized with hypotension secondary to cardiac surgery vasoplegia suggests that administration of intravenous vitamin B12 (hydroxocobalamin) is associated with an 8 mmHg higher mean arterial pressure (MAP) at 1 hour but no change in vasopressor dosage at 1 hour or mortality rate when compared with methylene blue (112264). The validity of these findings is limited by the inclusion of only retrospective studies.
• Infant development. It is unclear if taking oral vitamin B12 during pregnancy is beneficial for improving infant development. Giving oral vitamin B12 to infants does not seem to be beneficial. Details: Clinical research shows that supplementation with vitamin B12 50 mcg daily from less than 14 weeks gestation until 6 weeks postpartum does not improve cognitive development in infants by 9 months of age when compared with placebo (96174). When these children were evaluated at 30 months of age, a very small benefit of vitamin B12 on expressive language was identified; however, there was no effect on cognition, receptive language, fine motor skills, or gross motor skills (100169). It is unknown whether a longer duration of postpartum supplementation or supplementation in specific populations might be beneficial. Vitamin B12 supplementation in infants has also been evaluated. A large clinical trial in marginally stunted Nepalese infants aged 6-11 months shows that giving vitamin B12 (cyanocobalamin) 2 mcg daily for 12 months reduces homocysteine levels, but does not improve motor or cognitive development, when compared with placebo (104926).
• Inflammatory bowel disease (IBD). Although there is interest in using oral vitamin B12 for IBD, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Lung cancer. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: The association between vitamin B12 and lung cancer is unclear. Some population research found no relationship between blood levels of vitamin B12 and lung cancer (9454). However, other observational research involving over 5,000 case-control pairs found that higher vitamin B12 levels are linked with an increased risk for lung cancer (102383). It is unclear if increased intake of vitamin B12, either through the diet or supplementation, directly affects the risk of lung cancer.
• Male infertility. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A retrospective study in adult males with idiopathic and varicocele-related infertility suggests that taking a combination product containing vitamin B12 1.5 mcg, L-carnitine, acetyl L-carnitine, citric acid, selenium, coenzyme Q10, vitamin C, zinc, and folic acid (Proxeed Plus) twice daily for 6 months is associated with improvements in ejaculate volume, sperm count, sperm concentration, total motility, and progressive motility in patients with idiopathic infertility when compared to baseline. However, improvement in sperm morphology was lacking. Furthermore, patients with more severe varicocele seem to benefit most, especially with regard to progressive motility (111296). The validity of these findings is limited by a lack of comparator group. Further, it is unclear if these effects are due to vitamin B12, other ingredients, or the combination.
• Mastalgia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in patients with mastalgia shows that taking a combination of vitamin B12 as methylcobalamin 100 mg, gamma-linolenic acid, and vitamin C daily for 12 weeks does not improve the proportion of patients with minimal or no pain when compared with placebo (111059).
• Multiple sclerosis (MS). Although there is interest in using oral vitamin B12 for MS, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B12 is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking vitamin B12 1000 mcg daily for 12 weeks reduces serum levels of homocysteine but has no effect on serum aminotransferases, measures of steatosis, fibrosis scores, fasting blood glucose, serum insulin, measures of insulin resistance, triglycerides, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol when compared with placebo (111555).
• Pancreatic cancer. It is unclear if oral vitamin B12 is beneficial for reducing the risk of pancreatic cancer. Details: Most population research has found that increased intake of vitamin B12, as a supplement or in the diet, is not associated with a reduced risk of pancreatic cancer (9327,104927). However, a small, retrospective population study in which smoking and non-smoking adults recalled past eating habits found that increased dietary intake of vitamin B12 is associated with a 33% reduction in pancreatic cancer risk (97976). These conflicting findings may be related to study methodology, as well as the age, gender, or smoking status of the included patients.
• Periodontitis. Although there is interest in using oral vitamin B12 for periodontitis, there is insufficient reliable information about the clinical effects of vitamin B12 for this condition.
• Peripheral neuropathy. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific product containing vitamin B12 3 mcg, folic acid 400 mcg, and uridine monophosphate 50 mg (Keltican) daily for 60 days reduces pain by 44% and decreases analgesic use by over 75% when compared to baseline in patients with peripheral neuropathy, including those with lumbar/lumbosacral radiculopathy, sciatic pain, and cervical radiculopathy (90384). The validity of this finding is limited by the lack of a control group. Furthermore, it is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Psoriasis. Topical vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a specific cream containing vitamin B12 and avocado oil (Regividerm, Regeneratio Pharma AG) reduces symptoms of psoriasis as effectively as calcipotriol ointment (Psorcutan) after 12 weeks of therapy. The vitamin B12 combination cream also causes less irritation than calcipotriol (14909). It is unclear if the benefits are due to vitamin B12, other ingredients, or the combination.
• Respiratory tract infections. A small study suggests that oral vitamin B12 does not reduce the rate of respiratory tract infections in children. Details: Preliminary clinical research in children aged 6-30 months from low-and middle-income countries suggests that taking vitamin B12 at twice the recommended dietary allowance with or without folic acid does not reduce the risk for lower respiratory tract infections when compared with placebo (90391).
• Schizophrenia. Oral vitamin B12 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking a combination of vitamin B12 400 mcg and folic acid 2 mg daily for 16 weeks improves negative symptoms when compared with placebo in patients with schizophrenia who have persistent symptoms and a specific genetic variant of the folate transporter gene FOLHI. This variant normally results in reduced folate absorption. However, in patients without this genetic variant, folate is not beneficial with respect to negative symptom improvement (90387).
• Sickle cell disease. Oral vitamin B12 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B12 4.2-6 mcg, folic acid 700 mcg, and vitamin B6 4.2-6 mg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B12, either alone or with other B vitamins, is beneficial for stroke prevention. Details: Epidemiological research has found that people with a higher intake of vitamin B12 from dietary sources do not have a reduced risk of ischemic or hemorrhagic stroke (14316). A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50420,50423,83050,90379,90380,96150). However, a more recent meta-analysis of 10 clinical trials including over 44,000 patients shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk or with a history of CVD (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, a meta-analysis in adults with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and vascular death by 11% when compared with placebo (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis suggests that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Another meta-analysis suggests that exposure to low, but not high, amounts of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tinnitus. It is unclear if intramuscular vitamin B12 is beneficial in patients with tinnitus. Details: A small clinical study shows that intramuscular vitamin B12 2500 mcg weekly for 6 weeks reduces tinnitus severity by 22% when compared to baseline in patients with chronic tinnitus and vitamin B12 deficiency, but not in patients with normal levels of vitamin B12. Vitamin B12 does not improve pitch or volume in either group of patients (96170). The validity of this finding is limited by the lack of a control group.
• Venous thromboembolism (VTE). It is unclear if oral vitamin B12 is beneficial for preventing VTE. Details: Epidemiological research has found that low levels of vitamin B12 are associated with an increased risk for VTE. However, clinical trials evaluating the use of B vitamins for prevention of VTE have shown conflicting results (90398). More evidence is needed to rate vitamin B12 for these uses.

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EFFECTIVE

• Pyridoxine-dependent epilepsy. Intravenous vitamin B6 is effective for controlling pyridoxine-dependent seizures. Details: Pyridoxine-dependent seizures are a rare type of refractory seizures in neonates that do not respond to anticonvulsant drugs. These seizures are typically controlled within minutes of intravenous administration of pyridoxine, a form of vitamin B6. Pyridoxine-dependent seizures can be due to genetic (autosomal recessive) pyridoxine dependency, or more commonly, a result of the use of high-dose pyridoxine during pregnancy (8197,8198).
• Sideroblastic anemia. Oral vitamin B6 is effective for treating hereditary sideroblastic anemia. Details: Taking vitamin B6 (pyridoxine) orally is effective for treating hereditary sideroblastic anemia (15,9518). Taking the active form of vitamin B6 (pyridoxal-5'-phosphate) also seems to be effective in cases in which the patient does not respond to pyridoxine (93049).
• Vitamin B6 deficiency. Oral vitamin B6 is effective for preventing and treating vitamin B6 deficiency. Details: Taking oral vitamin B6 can prevent and treat vitamin B6 deficiency (15).

LIKELY EFFECTIVE

• Hyperhomocysteinemia. Taking vitamin B6 orally, alone or in combination with folic acid, is effective for reducing hyperhomocysteinemia. Details: Vitamin B6 (pyridoxine) seems to lower homocysteine concentrations when folic acid and vitamin B12 are at physiologic levels or when given with folic acid and vitamin B12 supplements (9451,83042,107136). A combination of vitamin B6 100 mg and folic acid 0.5 mg daily seems to lower homocysteine levels by about 35% and is recommended for people with postprandial hyperhomocysteinemia (1489,9406). Other research shows that taking pyridoxine 50-200 mg daily reduces postprandial homocysteine levels by 32% to 35% (9406,10350). Pyridoxine also seems to reduce homocysteine levels in patients with kidney failure, kidney transplant patients (1489,6884,9414,9415), or patients who receive general anesthesia with nitrous oxide (9481). However, some research in healthy adults suggests that adding pyridoxine to folic acid might not provide any additional benefit over folic acid alone (9400,9405,9409,50145). Hyperhomocysteinemia is considered by some to be an independent risk factor for atherosclerosis, recurrent thromboembolism, deep vein thrombosis, myocardial infarction, and ischemic stroke (1899,3323,9402,9405,9408,9409). However, elevated homocysteine levels may be a marker, as opposed to a cause, of vascular disease (11387,11388). A 5 µmol/L increase in plasma homocysteine increases the risk of cerebrovascular disease by 50% and the odds of coronary heart disease by 60% and 80% in males and females, respectively (9407,9411). However, it is not clear if reducing homocysteine levels results in reduced cardiovascular morbidity and mortality (1489,6883,6884,9308,9400,9405,9409). Folic acid, vitamin B6, and vitamin B12 supplementation can reduce total homocysteine from 13.4 to 11 µmol/L. However, this reduction does not seem to help with secondary prevention of death or myocardial infarction, and some research even suggests an increase in cardiovascular disease (CVD) risk (11387,13482,50423,83050,97619). There is also debate about whether supplementation with homocysteine-lowering B vitamins can reduce the risk of stroke. A number of large clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with CVD or impaired renal function (11387,13482,50423,83050,96150). However, a more recent meta-analysis shows that B vitamin supplementation modestly reduces the relative risk of stroke by 10% when compared with placebo in patients at risk for or with a history of CVD (97619). Also, a meta-analysis in patients with a history of stroke shows that B vitamin supplementation modestly reduces the relative risk of stroke recurrence by 13% and the risk of vascular death by 11% when compared with placebo (107136).

POSSIBLY EFFECTIVE

• Antipsychotic-induced hyperprolactinemia. It is unclear if oral vitamin B6 is beneficial for patients with antipsychotic-induced hyperprolactinemia. Details: Clinical research in male patients with hyperprolactinemia who are on a consistent antipsychotic dose shows that taking vitamin B6 300 mg twice daily for 16 weeks reduces serum prolactin levels by 68%, compared with 37% in patients taking aripiprazole 5 mg twice daily. Also, 67% of patients taking vitamin B6 had prolactin levels less than 40 mcg/mL versus 2% of those taking aripiprazole (107128).
• Kidney stones (nephrolithiasis). Oral vitamin B6 seems to decrease urinary oxalate levels and decrease the risk of kidney stone formation in some patients. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally, alone or in combination with magnesium, can decrease urinary oxalate levels in people with type I primary hyperoxaluria, a hereditary disorder (1201,6437,6438,6439,6440,8548,8549,8550). Additionally, a small clinical study in this population suggests that intravenous pyridoxine hydrochloride can reduce urinary oxalate by 25.5% when compared to baseline (90796). In patients with idiopathic hyperoxaluria, taking a combination of pyridoxine 25mg and magnesium oxide 400 mg for 3 months decreases urinary oxalate by approximately 16%, with 68% of patients experiencing a reduction. However, supplementation is less effective than following a low-oxalate diet, which reduces urinary oxalate in 91% of patients by an average of 31% (107127). There is also preliminary evidence that higher pyridoxine intake in females with no history of kidney stones is associated with decreased risk of kidney stone formation (6441), but this association has not been found in males (6442).
• Pregnancy-induced nausea and vomiting. Oral vitamin B6 may reduce nausea and vomiting in some pregnant patients and is sometimes used in combination with doxylamine. Details: While some conflicting evidence exists, most small clinical studies suggest that oral vitamin B6 is effective for improving nausea and vomiting associated with pregnancy when compared with baseline or placebo. However, vitamin B6 may not be as effective as ginger (110459). Two small clinical studies show that taking vitamin B6 (pyridoxine) 25 mg every 8 hours for 3-4 days decreases pregnancy-induced nausea severity and vomiting incidence when compared with placebo (6168,16306). A larger clinical trial shows that taking lower doses of vitamin B6, 10 mg every 8 hours over 5 days, improves pregnancy-induced nausea, but not vomiting, when compared with placebo (6167). A small clinical study in patients with mild to moderate nausea and vomiting shows that taking a higher dose of 40 mg twice daily for 4 days is more effective than placebo, but no better than ginger 500 mg twice daily (99404). The American College of Obstetrics and Gynecology (ACOG) considers vitamin B6 at a dose of 10-25 mg 3 to 4 times daily a first-line treatment for pregnancy-induced nausea and vomiting due to its benign safety profile (111601). However, it is not effective for all patients, such as those with hyperemesis gravidarum, a severe form of pregnancy-induced nausea and vomiting. Adding vitamin B6 20 mg three times daily for 2 weeks to intravenous rehydration, metoclopramide, and thiamine seems to be no more effective than placebo for reducing vomiting in hyperemesis gravidarum (99405). Vitamin B6 is also sometimes used in combination with doxylamine. In fact, a combination of vitamin B6 plus doxylamine (Diclegis or Bonjesta, Duchesnay Inc., and various generics) has been approved by the US Food and Drug Administration (FDA) as a prescription product111601). ACOG recommends vitamin B6 in combination with doxylamine as another first-line treatment option (111601). However, the clinical trial used to obtain FDA approval has some methodological problems, and the significance of the results has been questioned. The improvement in symptom scores seen with Diclegis was less than one point on a 13-point scale, which is unlikely to be clinically significant (97998). Also, some clinical research shows that taking pyridoxine 25 mg and doxylamine 12.5 mg is less effective than ondansetron 4 mg when taken every 8 hours for 5 days. Only 41% of the patients using pyridoxine and doxylamine had a clinically significant reduction in nausea, compared to 92% of patients using ondansetron (90797). The combination of vitamin B6 and doxylamine is also studied with acupuncture. A large clinical study in patients with moderate to severe pregnancy-induced nausea and vomiting conducted in China shows that taking vitamin B6-doxylamine (Diclegis, Duchesnay, Inc) 20 to 40 mg each at bedtime for 14 days in combination with daily acupuncture modestly improves patient-reported nausea and vomiting scores when compared with either intervention alone (111820). However, it is unclear whether this improvement is clinically significant.
• Premenstrual syndrome (PMS). Oral vitamin B6 seems to reduce PMS symptoms. Details: There is some evidence that taking vitamin B6 (pyridoxine) orally can improve symptoms of PMS such as breast pain or tenderness (mastalgia) and depression in some patients. Pyridoxine in doses of at least 50 mg daily, plus magnesium oxide 200 mg daily, seems to relieve PMS-related anxiety and other symptoms (8555,39007,82962). Although some clinicians advocate doses of pyridoxine 200-500 mg daily for PMS, doses of 50-100 mg daily seem to work just as well. There is no apparent dose-response curve for PMS, so the lowest effective dose should be used. Higher doses might increase the risk of side effects (3093).

POSSIBLY INEFFECTIVE

• Age-related cognitive decline. Oral vitamin B6 does not seem to slow age-related cognitive decline. Details: One clinical trial in elderly people with memory complaints shows that taking a combination of B vitamins, including folic acid 0.8 mg, vitamin B12 0.5 mg, and vitamin B6 (form not specified) 20 mg daily for 24 months reduces cerebral atrophy in the gray matter regions associated with Alzheimer disease by up to seven-fold when compared with placebo. However, this protection does not occur in patients with the lowest average blood levels of homocysteine (90374). Furthermore, other clinical research shows that taking vitamin B6 (pyridoxine) 3-75 mg daily in combination with folic acid and vitamin B12 does not improve cognitive function in elderly adults (14392,50225,50510).
• Alzheimer disease. Oral vitamin B6 does not seem to improve cognitive function in patients with Alzheimer disease when used in combination with other B vitamins. Also, oral vitamin B6 does not seem to reduce the risk of developing this condition. Details: Clinical research in patients with probable Alzheimer disease taking routine medications shows that taking vitamin B6 25 mg with folic acid 5 mg and vitamin B12 1 mg daily for 18 months does not have a beneficial effect on cognitive function or the severity of disease when compared with placebo. In this study, all patients were consuming a folate-fortified diet (50319). Also, population research in elderly adults has found that a high intake of vitamin B6 from dietary or supplemental sources is not associated with a decreased risk of Alzheimer disease when compared to lower vitamin B6 intake (13165,15270).
• Carpal tunnel syndrome. Oral vitamin B6 does not seem to reduce symptoms of carpal tunnel syndrome. Details: Most research shows that people with carpal tunnel syndrome are not generally deficient in vitamin B6 and do not benefit from taking vitamin B6 supplements (8203,8937,9448,9450,9478,9482). Although early studies by a single group of researchers, as well as anecdotal reports, suggest that taking vitamin B6 may relieve carpal tunnel symptoms, more reliable research has not supported these findings (8202,9445,9447,9449,9483,15955,83086). Vitamin B6 has also been evaluated in combination with other ingredients. A moderate-sized clinical study in adults with mild to moderate carpal tunnel syndrome shows that taking a combination product containing vitamin B6, alpha-lipoic acid, acetyl-L-carnitine, phosphatidylserine, turmeric, and vitamins C, E, B1, B2, and B12 twice daily for 60 days reduces symptom severity and pain but does not improve measures of hand and wrist function when compared with a control (111702). The dose of vitamin B6 was not provided. The validity of this study is limited by the lack of blinding and placebo. Additionally, it is unclear if the effects are due to vitamin B6, other ingredients, or the combination.
• Cataracts. Oral vitamin B6 does not seem to slow cataract development. Details: Clinical research in females with existing cardiovascular disease (CVD) or at increased risk of CVD shows that taking a combination of folic acid 2.5 mg, vitamin B6 (form not specified) 50 mg, and vitamin B12 1 mg daily for an average of 7.3 years does not reduce the risk of cataracts when compared with placebo. Furthermore, the risk of cataract extraction was increased by 28% (96149).
• Chemotherapy-induced acral erythema. While some conflicting evidence exists, most research suggests that oral or topical vitamin B6 does not seem to prevent or reduce the severity of acral erythema induced by chemotherapy. Details: A meta-analysis of 10 clinical trials and 4 observational studies shows that taking vitamin B6 60-500 mg daily for up to 8 chemotherapy cycles does not prevent chemotherapy-induced acral erythema or reduce the incidence of severe cases when compared with control. Most studies used capecitabine chemotherapy alone or in combination, and one study used pegylated liposomal doxorubicin; however, no subgroup analysis was conducted to differentiate chemotherapy regimens. Results did not seem to vary based on study location, study design, or vitamin B6 dose (104930). However, a more recent preliminary clinical study in patients receiving doxorubicin for multiple myeloma shows that taking vitamin B6 100 mg on the first day of chemotherapy then twice daily for 7 days with each cycle reduces the risk of developing acral erythema by 72%, but does not improve the severity of acral erythema, when compared with no vitamin B6 supplementation (110458). Also, one small, low-quality clinical study suggests that taking vitamin B6 400 mg daily reduces the risk of moderate or severe chemotherapy-induced acral erythema when compared with vitamin B6 200 mg daily; however, the higher dose also seems to be associated with worsened tumor response and increased treatment failure (97620). Topical vitamin B6 has also failed to show benefit. A small clinical study in patients with acral erythema from capecitabine or pegylated liposomal doxorubicin shows that applying vitamin B6 1% cream to affected areas three times daily for 6 weeks does not improve symptoms when compared with placebo (104929).
• Colorectal adenoma. Oral vitamin B6 does not seem to reduce the risk of developing colorectal adenomas. Details: Clinical research shows that taking a combination of B vitamins, including folic acid 2.5 mg, vitamin B6 (pyridoxine) 50 mg, and vitamin B12 1 mg, daily for up to 9.2 years does not reduce the risk of colorectal adenoma in females at high risk of cardiovascular disease when compared with placebo (90389).
• Eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of eclampsia when compared with control (83046,96166).
• Osteoporosis. Oral vitamin B6 does not seem to reduce the risk of osteoporotic fractures. Details: Clinical research in patients with cerebrovascular disease shows that taking a combination of B vitamins, including folic acid 2 mg, vitamin B6 (form not specified) 25 mg, and vitamin B12 500 mcg daily for up to 10.5 years does not prevent osteoporotic fractures when compared with placebo (90377). Furthermore, a secondary analysis of two large studies in patients with cardiovascular disease has found that taking vitamin B6 (pyridoxine) 40 mg daily in addition to folic acid and vitamin B12 for 1-3 years is associated with a 42% increased risk of hip fracture over an 11-year period when compared with only folic acid and vitamin B12 (96163). This finding is limited because these studies were not designed to assess the effects of vitamin B6 on fracture risk and the analyses were not adjusted for baseline bone health or fall risk.
• Pre-eclampsia. Oral or intramuscular vitamin B6 does not seem to reduce the risk of pre-eclampsia. Details: Meta-analyses of limited clinical research in pregnant patients show that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of pre-eclampsia when compared with placebo (83046,96166).
• Preterm labor. Oral or intramuscular vitamin B6 does not seem to reduce the risk of preterm labor. Details: Meta-analyses of limited clinical research in pregnant patients shows that taking vitamin B6 (pyridoxine), either as 25 mg daily or a single dose of 100 mg orally or intramuscularly, does not reduce the risk of preterm labor when compared with placebo (83046,96166).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults and children with inflammatory acne shows that taking 1-4 tablets of a specific product (NicAzel, Elorac Inc.) containing vitamin B6 (pyridoxine), nicotinamide, azelaic acid, zinc, copper, and folic acid for 8 weeks reduces inflammatory lesions and improves appearance in 88% and 81% of patients, respectively, when compared to baseline (90800). The validity of these findings is limited by the lack of a comparator group.
• Age-related macular degeneration (AMD). Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large-scale clinical study shows that taking vitamin B6 (pyridoxine) 50 mg, vitamin B12 1000 mcg, and folic acid 2.5 mg daily reduces the risk for AMD in females over 40 years of age with a history of cardiovascular disease (CVD) or with risk factors for CVD. Those who took this combination for an average of 7.3 years had a 34% reduced risk of developing AMD and a 41% reduced risk of visually significant AMD when compared with placebo (14620). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Angioplasty. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some evidence suggests that vitamin B6 (pyridoxine) 10 mg, folic acid 1 mg, and vitamin B12 400 mcg daily can decrease the rate of restenosis in patients treated with balloon angioplasty (8009,9412). However, this combination does not seem to be as effective for reducing restenosis in patients after coronary stenting (8009). An intravenous loading dose of folic acid, vitamin B6 (pyridoxine), and vitamin B12 followed by oral administration of folic acid 1.2 mcg, vitamin B6 (pyridoxine) 48 mg, and vitamin B12 60 mcg daily after bare metal coronary stenting also does not seem to reduce restenosis and might actually increase restenosis (12150,12151). Due to the lack of evidence of benefit and potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents (12151). It is unclear if any effects are due to vitamin B6, other ingredients, or the combination.
• Antipsychotic-induced metabolic side effects. It is unclear if oral vitamin B6, as an adjunct to progesterone, is beneficial in patients with antipsychotic-induced amenorrhea. Details: A small clinical study in females with antipsychotic-induced amenorrhea shows that taking vitamin B6 80 mg three times daily for 1 month plus intramuscular progesterone daily for 5 days increases levels of estradiol and follicle stimulating hormone, reduces prolactin levels, and increases the rate of clinical efficacy, defined as the normalization of menstruation and improvement in endocrine indicators, by 14% when compared with progesterone alone (110457).
• Anxiety. It is unclear if oral vitamin B6 is beneficial in patients with anxiety. Details: Clinical research in college students shows that taking vitamin B6 100 mg daily for one month does not reduce anxiety scores when compared with placebo (110453). However, because a diagnosis of anxiety was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with anxiety.
• Asthma. It is unclear if oral vitamin B6 is beneficial in patients with asthma. Details: Preliminary clinical studies show that taking vitamin B6 (pyridoxine) 200-300 mg daily may improve symptoms of asthma in some patients, but not others, when compared with placebo (7064,7065). Studies have yielded conflicting results, with some research suggesting that it may only be beneficial in children with severe asthma (7065). Additionally, some research suggests that theophylline may lower vitamin B6 levels, although it is unclear if vitamin B6 supplementation is beneficial (4522,7066,9503).
• Atherosclerosis. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with intermediate risk for coronary heart disease shows that taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunga) containing vitamin B6 12.5 mg, aged garlic extract 250 mg, vitamin B12 100 mcg, folic acid 300 mcg, and L-arginine 100 mg daily for 12 months reduces coronary artery calcium progression when compared with placebo (88385). It is unclear if this effect is due to vitamin B6, other ingredients, or the combination.
• Atopic dermatitis (eczema). It is unclear if oral vitamin B6 is beneficial in patients with eczema. Details: A small clinical study in children with eczema shows that taking vitamin B6 (pyridoxine hydrochloride) 50 mg daily for 4 weeks does not reduce symptoms such as redness and itchiness when compared with placebo (83090).
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral vitamin B6 is beneficial for ADHD. Details: A small crossover study in children with ADHD shows that taking vitamin B6 600 mg, niacinamide and ascorbic acid 3 grams, and calcium pantothenate 1.2 grams daily for 6 weeks does not improve behavior scores when compared with placebo (9957).
• Autism spectrum disorder. Although there is interest in using oral vitamin B6 for autism, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Bipolar disorder. It is unclear if oral vitamin B6 is beneficial in patients with bipolar disorder. Details: A small clinical trial in patients with type 1 bipolar disorder who are taking lithium and experiencing an acute episode of mania shows that taking vitamin B6 80 mg daily for 8 weeks does not improve cognitive function or the severity of mania when compared with placebo. Cognitive function was reduced in patients taking vitamin B6; any effect on sleep was unclear (107132).
• Cancer. It is unclear if oral vitamin B6 reduces overall cancer risk. Details: Population research has found that higher dietary intake of vitamin B6 is associated with a 22% reduced risk of cancer, including esophageal, pancreatic, gastric, colorectal, and breast cancer. However, when dietary and supplemental vitamin B6 intake is considered, the inverse association between vitamin B6 and cancer risk is weaker and limited to fewer tumor sites. Furthermore, a meta-analysis of 9 clinical studies shows that taking vitamin B6 3-100 mg orally daily for 2-7.3 years, in combination with vitamin B12 and folate, does not reduce the risk of cancer in patients with cardiovascular disease or kidney failure (96164).
• Cardiovascular disease (CVD). Oral vitamin B6, taken along with other B vitamins, does not seem to improve secondary prevention of death or myocardial infarction in patients with CVD. However, it might slightly lower the risk of stroke. Details: Overall evidence from clinical research and meta-analyses shows that taking vitamin B6 in combination with folic acid and/or vitamin B12 does not seem to help with secondary prevention of death or myocardial infarction in patients with or at risk for CVD (11387,13482,34540,50423,83050,90379,97619). In fact, some research suggests that long-term supplementation with vitamin B6, folic acid, and vitamin B12 for secondary prevention increases the risk of CVD by 20% despite lowering homocysteine levels by 30% (13482). However, some research shows that taking vitamin B6 in combination with other B vitamins modestly reduces the risk of stroke, although results are conflicting (11387,13482,50423,83050,96150,96165,97619,107136). Additionally, it is unclear which specific combination of B vitamins is optimal for reducing stroke risk and which patients are most likely to benefit. In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) approved a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368).
• Cognitive function. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in healthy adults aged 40-65 years shows that taking a supplement containing vitamin B6, ginkgo leaf, bacopa, and other B vitamins twice daily for 12 weeks does not improve memory or attention when compared with placebo (111334).
• Colorectal cancer. It is unclear if oral vitamin B6 reduces the risk of colorectal cancer. Details: A meta-analysis of observational studies suggests that the highest dietary intake of vitamin B6 is associated with a 20% reduced risk of colorectal cancer when compared with the lowest dietary intake. However, this association was not shown in subgroup analyses of studies conducted in Australia, Europe, or North America (111600). The validity of this analysis is limited by the heterogeneity of the included studies.
• Dental caries. There is limited evidence on the oral use of vitamin B6 for dental decay during pregnancy. Details: Meta-analyses of limited clinical research show that taking vitamin B6 (pyridoxine), 25 mg daily or a single dose of 100 mg orally or intramuscularly, may reduce the risk of dental decay during pregnancy when compared with placebo (83046,96166).
• Depression. It is unclear if oral vitamin B6 reduces the risk of developing depression or improves symptoms of depression. Details: Clinical research in healthy college students shows that taking vitamin B6 100 mg daily for one month does not reduce depression scores when compared with placebo (1104453). However, because a diagnosis of depression was not a requirement for study participation, it is unclear if these findings can be generalized to patients diagnosed with depression. Whether vitamin B6 reduces the risk of developing depression is also unclear. A meta-analysis of population research has found that the highest dietary intake of vitamin B6 is associated with a 19% lower risk of depression when compared with the lowest intake. However, sub-analyses suggest that this association is only relevant in females and not males (107133). In one individual population study in community dwelling older adults included in the analysis, the consumption of at least 1.71 mg of vitamin B6 daily from food was associated with a 43% reduction in the likelihood of becoming depressed when compared with the consumption of 1.33 mg or less daily in females. However, there was no association between vitamin B6 levels and risk of depression in males, and the finding in females was no longer significant when adjusted for total energy intake, since foods rich in vitamin B6 are energy-dense (96168). Another observational longitudinal study in healthy adults starting oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 40% lower risk of depression when compared with no supplementation (90789). Most available studies are cross-sectional in nature, making any conclusions related to causation difficult.
• Diabetes. It is unclear if oral vitamin B6 is beneficial in patients with type 2 diabetes or gestational diabetes. Details: Observational research in Chinese adults with type 2 diabetes has found that dietary intake of vitamin B6 in the highest quartile is associated with 53% lower odds of developing cardiovascular disease, defined as a non-fatal myocardial infarction, non-fatal stroke, or hospitalization for unstable angina, when compared with vitamin B6 intake in the lowest quartile (110452). Small clinical studies in patients with gestational diabetes and vitamin B6 deficiency shows that taking vitamin B6 (pyridoxine) 100 mg daily for 2 weeks improves glucose tolerance and blood glucose levels when compared with baseline (82967,83088). However, there is concern that these findings were confounded by dietary alterations. This benefit was not observed in a subsequent small case series in patients with gestational diabetes (22380).
• Diabetic neuropathy. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research suggests that taking a combination of B vitamins, including folic acid (L-methylfolate), vitamin B12 (methylcobalamin), and vitamin B6 (pyridoxal-5'-phosphate) for 24 weeks does not improve neural dysfunction based on vibration perception when compared with placebo in patients with diabetic neuropathy. However, taking this combination appears to modestly improve neuropathy symptoms and quality of life related to mental functioning when compared with placebo (90375).
• Dysmenorrhea. It is unclear if oral vitamin B6 is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research shows that taking vitamin B6 (form not specified) 200 mg daily reduces pain associated with dysmenorrhea when compared with placebo. However, taking vitamin B6 in combination with magnesium does not reduce pain when compared with placebo (77388).
• Fibromyalgia. It is unclear if oral vitamin B6 is beneficial in patients with fibromyalgia. Details: A small clinical study in patients with fibromyalgia shows that taking vitamin B6 80 mg daily for 8 weeks does not improve pain, disease severity, anxiety, depression, or quality of life when compared with placebo (110454).
• Gastroenteritis-associated nausea and vomiting. It is unclear if oral vitamin B6 is beneficial in children with gastroenteritis. Details: A small clinical study in children aged 6 months to 12 years with acute viral gastroenteritis shows that taking vitamin B6 (form not specified) does not improve symptoms of dehydration or the frequency of vomiting when compared with placebo (90793).
• Helicobacter pylori. It is unclear if oral vitamin B6 is beneficial for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy does not improve eradication rates when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Hypertension. It is unclear if oral vitamin B6 reduces blood pressure. Details: One small clinical study in patients with essential hypertension shows that taking vitamin B6 (pyridoxine hydrochloride) 5 mg/kg daily for 4 weeks can reduce systolic and diastolic blood pressure when compared with baseline (83091). The validity of this finding is limited by the lack of a control group.
• Hypertriglyceridemia. It is unclear if oral vitamin B6 reduces triglyceride levels. Details: Preliminary clinical research shows that vitamin B6 (form not specified) 50 mg daily for 12 weeks does not reduce triglyceride levels in people with hypertriglyceridemia when compared with placebo. However, vitamin B6 appears to decrease total cholesterol and high-density lipoprotein (HDL) cholesterol by approximately 9% in these patients (59028).
• Infertility. Although there is interest in using oral vitamin B6 for infertility, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Insomnia. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in healthy adults with self-reported sleep difficulty shows that taking a specific product (LZ Complex3, Sanofi Consumer Healthcare Pty Ltd.) containing vitamin B6, zizyphus extract, hops extract, hydrolyzed milk protein (Lactium), and magnesium oxide nightly, 30 minutes before bed, for 2 weeks does not improve sleep quality, daytime functioning, or physical fatigue when compared with placebo. However, due to the large improvement seen in both the treatment and placebo groups, the effectiveness of this product is unclear (95971).
• Isoniazid-induced neuropathy. It is unclear if oral vitamin B6 prevents the development of neuropathy in patients taking isoniazid. Details: Preliminary clinical research in patients taking isoniazid for tuberculosis shows that taking vitamin B6 (pyridoxine) 6 mg daily reduces the development of neuropathy when compared with control (83068).
• Lactation. It is unclear if oral vitamin B6 helps to suppress postpartum lactation. Details: A meta-analysis of two small clinical trials shows that taking vitamin B6 (pyridoxine) 400-600 mg daily for 6-7 days postpartum does not suppress lactation when compared with no treatment (83047).
• Levetiracetam-induced side effects. While some conflicting evidence exists, several small, low-quality studies suggest that oral vitamin B6 (pyridoxine) may reduce some neuropsychiatric adverse effects related to the use of levetiracetam. Details: In an analysis of case reports, retrospective studies, and a single low-quality prospective study, improvement in levetiracetam-associated neuropsychiatric symptoms occurred in approximately 73% of patients taking pyridoxine (107137). A more recent preliminary clinical trial in children ages 1-17 years shows that taking pyridoxine 10 or 15 mg/kg daily as needed based on symptoms improves behavioral side effects associated with levetiracetam by a small amount when compared with low-dose pyridoxine 0.5 mg/kg daily used as placebo (107124). Also, observational research in children ages 9 months to 14 years has found that taking vitamin B6 is associated with improved behavior and a 44% lower risk of levetiracetam discontinuation when compared with no vitamin B6 supplementation (110455). Some observational research in adults with levetiracetam-associated irritability has found that taking vitamin B6 is associated with an improvement in irritability in 45% of patients when compared to baseline (107129). However, a small clinical trial in adults with epilepsy shows that taking pyridoxine 40 mg daily for 3 weeks does not improve levetiracetam-related psychiatric adverse effects when compared with placebo (110456). This study may have been underpowered to detect differences between groups. Pyridoxine doses used in the studies above have ranged from 50-400 mg daily in children and 40-600 mg daily in adults (107124,107129,107137,110456).
• Lung cancer. It is unclear if dietary or oral vitamin B6 reduces lung cancer risk. Details: Epidemiological research has found that higher serum levels of vitamin B6 in male smokers is associated with a lower risk of lung cancer (9454). Also, people with blood levels of vitamin B6 in the top quartile have a modestly lower risk of lung cancer when compared with those whose levels are in the lowest quartile. The association is stronger for males and for people who have smoked (97999). However, other epidemiological research found that increased dietary intake of vitamin B6 is not associated with a reduced risk of lung cancer (96164).
• Menopausal symptoms. Although there is interest in using oral vitamin B6 for menopausal symptoms, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Motion sickness. Although there is interest in using oral vitamin B6 for motion sickness, there is insufficient reliable information about the clinical effects of vitamin B6 for this condition.
• Nausea and vomiting. It is unclear if oral vitamin B6 is beneficial for nausea and vomiting in patients taking oral contraceptives or antibiotics for Helicobacter pylori. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding. An observational longitudinal study in healthy females taking oral contraceptives containing ethinyl estradiol and levonorgestrel has found that taking vitamin B6 25 mg daily for 6-12 months is associated with a 43% reduced risk of nausea when compared with no supplementation (90789).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral vitamin B6 for patients with NAFLD. Details: A small clinical trial in patients with NAFLD shows that taking vitamin B6 (pyridoxine) 30 mg three times daily for 12 weeks does not reduce levels of liver transaminases or plasma lipids when compared with baseline. However, hepatic fat accumulation was modestly reduced (107130). The validity of this study is limited by the lack of a comparator group.
• Obesity. It is unclear if oral vitamin B6 in beneficial in overweight or obese individuals. Details: A small clinical trial in females with a body mass index (BMI) of at least 25 kg/m² shows that taking vitamin B6 as pyridoxine 80 mg daily for 8 weeks reduces fat mass and improves insulin resistance and triglyceride levels by a small amount when compared with placebo. Although some other anthropometric and metabolic indices were improved when compared with baseline, there was no effect of pyridoxine on body weight, visceral adiposity, or other endpoints when compared with placebo (107131).
• Overall mortality. It is unclear if oral vitamin B6 reduces the risk of overall mortality. Details: Observational research in US adults has found that dietary intake of vitamin B6 in the highest quintile is associated with a 12% to 21% lower risk of all-cause mortality and a 31% to 44% lower risk of cardiovascular mortality when compared with the lowest quintile of dietary vitamin B6 intake (110451).
• Pancreatic cancer. It is unclear if oral vitamin B6 reduces the risk of pancreatic cancer. Details: Observational research has found that higher dietary intake of vitamin B6 is associated with a 37% lower risk of developing pancreatic cancer when compared with lower intake (104927).
• Postpartum depression. It is unclear if oral vitamin B6 is beneficial in patients with postpartum depression. Details: Preliminary clinical research in individuals considered at increased risk for postpartum depression, but without clinical depression, shows that taking vitamin B6 80 mg daily from the 28th week of pregnancy until birth, and then 40 mg daily for one month, reduces symptoms of depression 1.5 months after birth when compared with baseline (measured during the third trimester) and when compared with placebo. However, it is unclear if any of the patients included in the study developed postpartum depression, as there were no changes in overall symptoms in patients taking placebo (107126).
• Proton pump inhibitor-induced gastrointestinal (GI) symptoms. It is unclear if oral vitamin B6 is beneficial for proton pump inhibitor-induced GI symptoms. Details: A large clinical study in adults with Helicobacter pylori infection shows that taking vitamin B6 20 mg twice daily for 2 weeks alongside conventional quadruple therapy reduces the incidence and severity of gastrointestinal adverse effects when compared with a control group not receiving vitamin B6 (113551). Conventional therapy consisted of a proton pump inhibitor, bismuth, minocycline, and metronidazole. The validity of this study is limited by the lack of placebo and inadequate blinding.
• Restless legs syndrome (RLS). It is unclear if oral vitamin B6 is beneficial in patients with RLS. Details: A small clinical study in adults with RLS who are beginning treatment with pramipexole shows that also taking vitamin B6 40 mg daily for 2 months moderately improves RLS scores and sleep quality scores when compared with pramipexole and placebo (110052).
• Schizophrenia. It is unclear if oral vitamin B6 is beneficial for patients with treatment-resistant schizophrenia. Details: Clinical research in male patients with treatment-resistant schizophrenia who are on a consistent antipsychotic dose shows that adding vitamin B6 300 mg twice daily for 16 weeks modestly improves psychotic symptoms and some measures of cognitive performance when compared with adding aripiprazole 5 mg twice daily (107128). More research is needed to determine if these benefits are clinically relevant.
• Seizures. It is unclear if oral vitamin B6 is beneficial for preventing seizures in patients with glycosylphosphatidylinositol (GPI) deficiency. Details: Observational case series in a small number of children and young adults with GPI deficiency has found that taking vitamin B6 20-30 mg/kg daily for 3-12 months is associated with some reduction in seizure frequency in 9 of 13 patients. However, no patient reached seizure freedom (107125,107135). In one case series, treatment for 12 months was associated with modest developmental improvements in almost all patients (107135). The study patient populations were slightly different in terms of age and underlying genetic causes for GPI deficiency.
• Sickle cell disease. Oral vitamin B6 has only been evaluated in combination with other B vitamins; its effect when used alone is unclear. Details: Preliminary clinical research in adults with sickle cell disease shows that taking vitamin B6 4.2-6 mg, vitamin B12 4.2-6 mcg, and folic acid 700 mcg daily might lower homocysteine levels. However, it is unknown if this will reduce the risk of endothelial damage in these patients (9324).
• Stroke. It is unclear if oral vitamin B6, either alone or with other B vitamins, is beneficial for stroke prevention. Details: There is some debate about whether supplementation with homocysteine-lowering B vitamins, including vitamin B6, can reduce the risk of stroke. A number of clinical studies and meta-analyses show that supplementation with folic acid, vitamin B6, and vitamin B12, alone or in combination, does not reduce the risk of stroke in patients with cardiovascular disease (CVD) or impaired kidney function (11387,13482,50423,83050,96150). However, a more recent meta-analysis of 10 clinical trials, including over 44,000 patients at risk for or with a history of CVD, shows that B vitamin supplementation reduces the relative risk of stroke by 10% when compared with placebo (97619). This meta-analysis differed from some of the earlier analyses due to the inclusion of several additional clinical trials. Also, another meta-analysis of three clinical trials including 9900 patients with a history of stroke shows that B vitamin supplementation reduces the relative risk of stroke recurrence by 13% when compared with placebo, although this finding was determined to have a low level of certainty. Based on two clinical trials, there was also a 17% reduced risk of vascular death and an 11% reduction in the combined risk of stroke, myocardial infarction, and vascular death (107136). In 2001, prior to the publication of the highest quality research on this topic, the US Food and Drug Administration (FDA) allowed a qualified health claim stating that, as part of a well-balanced diet that is low in saturated fat and cholesterol, folic acid, vitamin B6, and vitamin B12 may reduce the risk of vascular disease (102368). Unfortunately, even after the publication of higher quality research, it is still unclear which specific combination of B vitamins is optimal and which patients are most likely to benefit. One network meta-analysis shows that a combination of folic acid and vitamin B6 lowers the risk of stroke more effectively than B vitamin mixtures that include vitamin B12 (96165). However, this analysis is limited because it didn't account for dosing. Exposure to low, but not high amounts, of vitamin B12 (cyanocobalamin) seems to reduce stroke risk (96150).
• Tardive dyskinesia. It is unclear if oral vitamin B6 prevents tardive dyskinesia in patients taking neuroleptic drugs. Details: A small clinical study in patients taking neuroleptic drugs for schizophrenia shows that taking vitamin B6 (form not specified) 400 mg daily seems to improve Parkinsonian, dystonic, and dyskinetic symptoms when compared with placebo (8558).
• Tourette syndrome. Oral vitamin B6 has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, nonblinded clinical study in children aged 4-17 years with untreated Tourette syndrome or with chronic tic disorder and associated symptoms of anxiety shows that taking a liquid nutritional supplement providing vitamin B6 2.8 mg and L-theanine 200 mg daily for 2 months improves scores on the Yale Global Tic Severity Scale, but does not reduce anxiety, when compared with patients receiving psychoeducation (108555). This study may have been inadequately powered to detect a difference between groups.
• Vincristine-induced neuropathy. Oral vitamin B6 has only been evaluated in combination with pyridostigmine; its effect when used alone is unclear. Details: A small clinical study in children ages 11 months to 13 years with neuropathy due to vincristine treatment for acute lymphoblastic leukemia, shows that taking vitamin B6 150 mg/m2 and pyridostigmine 3 mg/kg twice daily for 3 months is associated with reduced severity of sensory and motor neuropathy when compared with baseline (104928). The validity of this finding is limited by the lack of a control group. More evidence is needed to rate vitamin B6 for these uses.

(Read more about VITAMIN B6)

POSSIBLY EFFECTIVE

• Mastalgia. Meta-analyses of small clinical studies show that vitex agnus-castus moderately reduces breast pain due to cyclic mastalgia. Details: Two small meta-analyses of low-to-moderate quality clinical studies in patients with cyclic mastalgia show that taking vitex agnus-castus moderately reduces breast pain when compared with placebo (101981,111753). The validity of these findings is limited by the heterogeneity of the included studies. Doses of vitex agnus-castus dried fruit extract range from 3.2-40 mg daily, for 2-6 months (90617,96250,101981,111753). Vitex agnus-castus is commonly used in proprietary products, alone or in combination with other herbs (Agnucaston/Cyclodynon, Bionorica AG, Femicur, Mastodynon, Bionorica AG, Monoselect Agnus, ZE 440) (13395).
• Premenstrual syndrome (PMS). Clinical research shows that vitex agnus-castus produces modest improvements in PMS symptoms. Details: Clinical research shows that taking vitex agnus-castus fruit extract orally for 2-6 menstrual cycles seems to reduce symptoms of PMS, especially breast pain or tenderness (mastalgia), edema, constipation, irritability, depressed mood, anxiety, anger, and headache (7055,7076,7078,7079,13394,15065,41483,41489,41490,41494,90619,101981). Doses of fruit extracts have varied from 3.5-40 mg daily, usually for 2-3 menstrual cycles (7055,7076,7078,7079,15065,41483,41489,41490,90619,96435). A meta-analysis of the available clinical research, including 17 studies involving 2,401 patients, shows that taking vitex agnus-castus is comparable to fluoxetine or oral contraceptives, and modestly more effective than placebo, for reducing the symptoms of PMS. A sub-group analysis indicates that efficacy is not impacted by the dose or form used, although the dried powdered berries appear to be ineffective. The low quality of the included studies and the high level of bias and heterogeneity limit the validity of these findings (96435). Another meta-analysis limited to three randomized controlled trials shows that taking vitex agnus-castus increases the likelihood of PMS symptom remission by 2.6-fold over placebo (101979). Some clinical studies have used a specific dried extract of vitex agnus-castus fruit (Agnolyt, Madaus AG) (7076). Other studies used a specific fruit extract known as Ze 440 (Prefemin, Zeller AG), which is standardized to casticin content (7078,90619). Additional studies have used the fruit extract BNO 1095 (Agnucaston/Cyclodynon, Bionorica AG) (15065,41483,41489,41490).

POSSIBLY INEFFECTIVE

• Fractures. Limited evidence suggests that vitex agnus-castus does not improve fracture healing rates. Details: Clinical research shows that taking a specific vitex agnus-castus dried fruit extract (Agnugol, Goldaru Pharmacy Company) 4 mg, alone or in combination with magnesium oxide (Nature Made Company) 250 mg, daily for 8 weeks does not improve long bone fracture healing when compared with placebo (90618).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Although there is interest in using oral vitex agnus-castus for acne, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Aging skin. Vitex agnus-castus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical trial in postmenopausal adults with wrinkles shows that taking one capsule orally daily of a combination of vitex agnus-castus 400 mg, evening primrose oil 500 mg, soy isoflavones 100 mg, and black cohosh 520 mg (Estosalus, Max Biocare Pty Ltd) for 12 weeks improves skin elasticity, skin smoothness, and wrinkle density scores when compared with placebo (109440).
• Amenorrhea. Although there is interest in using oral vitex agnus-castus for amenorrhea, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Anxiety. Although there is interest in using oral vitex agnus-castus for anxiety, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral vitex agnus-castus for BPH, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Dementia. Although there is interest in using oral vitex agnus-castus for dementia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Dysmenorrhea. It is unclear if oral vitex agnus-castus is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research in patients with primary dysmenorrhea shows that taking a specific vitex agnus-castus extract (Agnucaston, Bionorica AG) daily for 3 months reduces pain, as measured on a visual analog scale, similarly to ethinyl estradiol 0.03 mg / drospirenone 3 mg (Yasmin) taken daily (104975).
• Fibrocystic breast disease. Although there is interest in using oral vitex agnus-castus for fibrocystic breast disease, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Hyperprolactinemia. Although there is interest in using oral vitex agnus-castus for hyperprolactinemia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Infertility. It is unclear if oral vitex agnus-castus is beneficial for female infertility. Details: Preliminary clinical research in infertile females with oligomenorrhea or amenorrhea shows that taking homeopathic vitex agnus-castus (Phyto Hypophyson L, Steierl-Pharma GmbH) 50 drops orally three times daily for 3 months does not increase the chance of getting pregnant (41470). Also, one small clinical study in those with infertility due to secondary amenorrhea or luteal insufficiency shows that taking a vitex agnus-castus preparation (Mastodynon, Bionorica GmbH, Neumarkt/Opf.) 30 drops twice daily for at least 3 months does not increase the chance of pregnancy when compared with placebo, although the study was likely inadequately powered to detect a difference (7077).
• Insect repellent. Limited research suggests that topical vitex agnus-castus has insect repellent activity. Details: Preliminary clinical research shows that applying a carbon dioxide extract of vitex agnus-castus seeds seems to repel ticks and fleas for 6 hours, mosquitoes for 3-8 hours, and biting flies for 3 hours (13396). It is unclear how this compares with commonly used insect repellants.
• Insomnia. Although there is interest in using oral vitex agnus-castus for insomnia, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Lactation. Although there is interest in using oral vitex agnus-castus for stimulating lactation, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Menopausal symptoms. Clinical research suggests that vitex agnus-castus can relieve some menopausal symptoms; however, most research uses vitex agnus-castus in combination with other treatments. Details: Clinical research shows that taking vitex agnus-castus extract 15 mg twice daily for 8 weeks improves some menopausal symptoms, including anxiety and vasomotor dysfunction, by 76% and 88%, respectively, when compared with baseline. However, there was no effect on depression or sexual dysfunction (101980). Vitex agnus-castus has also been studied as a component of combination products. Preliminary clinical research shows that taking a combination of vitex agnus-castus, equivalent to 1000 mg dried fruit, black seed powder 500 mg, and citalopram 20 mg daily for 8 weeks reduces vasomotor, psychosocial, and physical symptoms of menopause when compared with citalopram alone (100325). Other preliminary clinical research shows that taking one capsule orally daily of a combination of vitex agnus-castus 400 mg, evening primrose oil 500 mg, soy isoflavones 100 mg, and black cohosh 520 mg (Estosalus, Max Biocare Pty Ltd) for 12 weeks moderately reduces the severity of hot flashes, sweating, sleep problems, depressed mood, and irritability when compared with placebo. There was no effect on plasma lipids, joint discomfort, anxiety, exhaustion, or sexual problems (105102). It is unclear if these effects are due to vitex agnus-castus, other ingredients, or the combination.
• Menorrhagia. It is unclear if oral vitex agnus-castus is beneficial in patients with menorrhagia. Details: A meta-analysis of two moderate quality clinical trials in patients who had heavy menstrual periods shows that taking vitex agnus-castus does not reduce menstrual bleeding over the next 1-2 menstrual cycles when compared with placebo (101982). However, preliminary clinical research in patients using an intrauterine device (IUD) shows that taking vitex agnus-castus three times daily for 8 days, starting on the first day of menstruation, and repeated for four consecutive menstrual cycles, reduces the amount of bleeding by approximately 48% when compared with baseline. This reduction was similar to the effects of mefenamic acid 250 mg daily after 4 months, although treatment with mefenamic acid was superior during the first three months (90620).
• Migraine headache. Although there is interest in using oral vitex agnus-castus for migraine headache, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Polycystic ovary syndrome (PCOS). Vitex agnus-castus has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with oligomenorrhea due to PCOS shows that taking a traditional combination product (Aslagh) containing equivalent amounts of essential oils of vitex agnus-castus fruit, fennel, and wild carrot seeds orally daily for 3 months, either alone or in combination with metformin, improves rates of menstrual bleeding and menstrual cyclicity similarly to metformin alone. All three groups experienced a significant improvement from baseline. Aslagh was taken as two, 500-mg capsules twice daily, except during menses; metformin was titrated over one week to a dose of 500 mg three times daily (108974).
• Premenstrual dysphoric disorder (PMDD). Limited evidence suggests that vitex agnus-castus might improve symptoms of PMDD. Details: In a clinical trial, vitex agnus-castus 20-40 mg daily for 8 weeks was similar to fluoxetine 20-40 mg daily for relieving symptoms of PMDD. About 58% of patients responded to vitex agnus-castus, compared to about 68% of patients taking fluoxetine. Vitex agnus-castus was more effective for physical symptoms such as breast tenderness, swelling, cramps, and food cravings (12207,41493).
• Rheumatoid arthritis (RA). Although there is interest in using oral vitex agnus-castus for RA, there is insufficient reliable information available about the clinical effects of vitex agnus-castus for this condition.
• Sexual dysfunction. It is unclear if oral vitex agnus-castus is beneficial in patients with sexual dysfunction. Details: Preliminary clinical research in healthy females under 44 years of age with sexual dissatisfaction shows that taking a specific vitex agnus-castus product (Agnugol, Goldaru Herbal Pharmaceutical Company) 3.2-4.8 mg orally once daily for 16 weeks modestly improves scores of sexual satisfaction, function, arousal, and desire when compared with placebo (109437). Additionally, a moderate-sized clinical study in females 50-69 years old with sexual dysfunction conducted in Iran shows that taking vitex agnus-castus 40 drops daily for 8 weeks improves sexual dysfunction scores from mild dysfunction to no dysfunction at 6 and 8 weeks when compared with placebo but does not improve scores at 4 weeks (112361). More evidence is needed to rate the effectiveness of vitex agnus-castus for these uses.

(Read more about VITEX AGNUS-CASTUS)

EFFECTIVE

• Zinc deficiency. Orally or intravenously, zinc is effective for treating and preventing zinc deficiency. Details: Taking zinc orally or intravenously prevents and treats zinc deficiency (2619). However, routine zinc supplementation is not recommended (403). Zinc deficiency requiring supplementation may occur in patients with severe diarrhea, malabsorption syndromes, liver cirrhosis, and alcoholism; after major surgery, renal failure, and dialysis; or during long-term administration of total parenteral nutrition (3900,24321). Zinc supplementation (136 mg of elemental zinc per day) in patients with cirrhosis and zinc deficiency seems to improve liver function and glucose tolerance, possibly by increasing insulin-like growth factor (8624,87520).

LIKELY EFFECTIVE

• Diarrhea. Oral zinc reduces duration and severity of acute diarrhea in malnourished children. Doses of 5-20 mg seem to be effective, while 5-10 mg daily is less likely to cause vomiting. Details: Most research, including meta-analyses and over 30 clinical trials, show that taking zinc orally reduces the duration and severity of acute and persistent diarrhea in malnourished or zinc-deficient children, but not in well-nourished children (87236,96074). Most studies have been conducted in Bangladesh and India, so it is unclear if these findings are generalizable to other geographic locations. The most comprehensive meta-analysis of clinical studies in children older than 6 months shows that zinc supplementation reduces the duration of acute diarrhea by about 11 hours and the duration of persistent diarrhea by about 16 hours when compared with placebo. However, zinc does not seem to reduce the duration of acute diarrhea in children younger than 6 months. Zinc supplementation seems to have the greatest benefit in children with clear malnutrition and diarrhea. In these children, zinc reduces diarrhea duration by about 26 hours and reduces the risk of diarrhea persisting through days 3, 5, and 7 by 18% to 24% when compared with placebo. There was no clear benefit of using zinc in a specific dose or salt form. The most common dose of zinc was 20 mg daily and salt forms included zinc sulfate, gluconate, and acetate (96074). Also, a large clinical trial in children with acute diarrhea shows that taking zinc 5 or 10 mg daily for 14 days is non-inferior to taking 20 mg. Furthermore, zinc 5 or 10 mg results in a respective 29% and 19% lower risk of vomiting within the first 30 minutes when compared with zinc 20 mg (104045). It's unclear whether zinc supplementation reduces mortality in children with diarrhea. A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of mortality from diarrhea by 15% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). However, many studies were conducted in hospitals where rates of mortality are low and were not adequately powered to determine whether zinc has an effect on mortality in children with acute diarrhea (87210,96074,106239).
• Wilson disease. Taking zinc orally improves symptoms of this condition. Details: Zinc acetate (Galzin) is an FDA-approved orphan drug for treating this condition. Zinc blocks copper absorption and increases copper elimination in the stool of people with Wilson disease (2692,2693,87327). Small clinical studies suggest that taking zinc after 8 weeks of treatment with tetrathiomolybdate alone can improve Kayser-Fleischer rings, urine copper levels, and neurological symptoms for up to 6 years post-treatment (63588,87491).

POSSIBLY EFFECTIVE

• Acne. Orally, zinc might help to reduce symptoms of acne. However, it's unclear how oral zinc compares to conventional acne treatments. Topical zinc doesn't seem to be beneficial if used alone. Details: Observational research has found that people with acne seem to have lower zinc levels in the serum and skin (104056). A meta-analysis of small, low quality clinical trials suggests that taking zinc sulfate or zinc gluconate 137-300 mg 2-3 times daily by mouth can modestly improve acne when compared with placebo (104056). However, not all individual trials show benefit (87002,104056). So far, it is not clear how oral zinc compares to other treatments. Trials comparing zinc sulfate with various tetracyclines have yielded conflicting results (6505,6506,86946,106233). One large open-label clinical trial shows that taking zinc sulfate 200 mg twice daily for 12 weeks is at least as effective as lymecycline 300 mg daily for reducing acne severity. Quality of life related to acne was modestly improved in the patients using zinc sulfate (106233). However, in another clinical trial, a 3-month treatment of oral zinc gluconate 30 mg daily reduced the number of acne lesions from baseline, but was not as effective as minocycline (86946). When applied topically, clinical research shows that zinc does not help treat acne when compared with placebo (87297,104056). However, when used in combination with erythromycin, topical zinc seems to result in improvement (819,820,2687,2688).
• Acrodermatitis enteropathica. Oral zinc seems to improve symptoms of this rare genetic disorder. Details: Multiple case reports have found that taking oral zinc seems to help improve symptoms of acrodermatitis enteropathica, a rare disorder (821,2689,2690,2691). One case report in a female with necrolytic acral erythema and hepatitis C suggests that adding oral zinc sulfate 225 mg twice daily to interferon alfa-2b for 6 months contributed to resolving all lesions. Necrolytic acral erythema is categorized in the family of necrolytic erythemas that includes acrodermatitis enteropathica (6192).
• Age-related macular degeneration (AMD). Oral zinc, especially in combination with antioxidant vitamins, seems to slow the progression of AMD. Details: Clinical research shows that taking elemental zinc 80 mg plus vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily reduces the odds of progression to advanced AMD by 28%. In patients with more severe AMD, this combination reduced the odds of progression to advanced AMD by 34%. This combination also reduced the odds of visual acuity loss by 27% in patients with severe AMD (7303,11326). However, there is contradictory evidence about the effects of zinc plus antioxidants on visual acuity loss or the progression to advanced AMD in low-risk patients with AMD (6583,6584,7303). Some clinical evidence shows that, when taken without antioxidant vitamins, zinc supplementation does not slow the progression of existing AMD (6580,90069). However, a subgroup analysis of results from a large clinical trial that included patients with intermediate or advanced AMD suggests that the effect of zinc on AMD progression might vary depending on a patient's genetic predisposition. Complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) are two genes for which specific variations (i.e., risk alleles) have been associated with an increased risk of AMD. Results from the retrospective subgroup analysis suggest that zinc supplementation may DECREASE the progression of AMD in patients with ARMS2 risk alleles and INCREASE the progression of AMD in patients with CFH risk alleles (90193). However, some experts question the results from this analysis due to the retrospective nature of the study (93045). Another retrospective analysis of similar data found that only zinc plus antioxidants, but not zinc alone, was beneficial for slowing the progression of AMD, regardless of the patient's genotype (93046). Consequently, the American Academy of Ophthalmology does not currently recommend routine genetic screening to determine which patients would benefit from zinc, antioxidants, or the combination. Instead, patients with intermediate or advanced AMD are recommended to take an antioxidant and zinc supplement similar to those used in the Age-Related Eye Disease Study (AREDS) and the Age-Related Eye Disease Study 2 (AREDS2) (93047). Large scale population studies suggest that increasing dietary intake of zinc might reduce the risk of developing AMD (6579,14257).
• Child growth. Oral zinc seems to increase growth when taken by children and improve infant growth in the first year of life when taken by pregnant adults. Details: A meta-analysis of 8 clinical studies in healthy children over 2 years old shows that taking supplemental zinc 5-15 mg daily for 6-56 weeks modestly increases height and weight when compared with placebo. This analysis also shows that taking zinc may improve height for age, but not weight for age when compared with placebo (112474). Most of these studies were conducted in developing countries; results may not apply elsewhere. Another clinical study in pregnant adults in Peru shows that taking zinc 15 mg daily in addition to iron and folic acid, starting during the first or second trimester and continuing up to one month after delivery, modestly improves growth measures of infants at one year when compared with taking iron and folic acid alone. Improved growth measures include body weight, calf and chest circumference, and calf muscle area (87130).
• Common cold. Oral zinc seems to help treat cold symptoms in adults. However, it is unclear if zinc is beneficial for common cold prevention. Details: Using zinc oral lozenges seems to be beneficial in helping TREAT the common cold in adults. The majority of clinical trials and analyses of clinical research show a significant decrease in the duration of symptoms of the common cold when adults take zinc gluconate or zinc acetate lozenges providing 9-24 mg of elemental zinc per dose. It is recommended that lozenges be taken every 2 hours while awake, starting within 48 hours of symptom onset for a total daily dose of at least 75 mg in order to attain a mean cold duration reduction of 3 days (333,334,335,337,6703,6705,87501,92212,106902). However, not all studies have been positive (333,338,339,6522,6700,87512). The reasons for these different findings are not clear, but might be due to differences in zinc formulations and doses and study methodologies. In some cases, flavoring agents such as citric acid, mannitol, and sorbitol might chelate zinc and decrease zinc ionization. Since ionization is thought to be necessary for zinc activity, a decrease in zinc ionization could decrease effectiveness (300,340,6522). Some of the positive studies have also been criticized for inadequately blinding the unpleasant, distinctive taste of zinc (6522,6706). Allergy and smoking status do not appear to impact the efficacy of zinc acetate lozenges (92212). Overall, zinc products may be beneficial for modestly reducing the duration of symptoms of the common cold in adults, but adverse effects such as bad taste and nausea may limit their usefulness (18216). There is conflicting evidence for the use of oral zinc products to PREVENT colds. Some clinical research suggests that taking zinc prophylactically does not prevent the common cold in adults (10780,10784) or children (341). However, other clinical research suggests that administering zinc gluconate lozenges can reduce the incidence of colds in children and adolescents (10803,86972). In a meta-analysis of 28 randomized controlled trials with a total of 5446 participants, oral zinc prevented 5 viral upper respiratory tract infections per 100 person months of zinc use when compared with placebo, with a number needed to treat (NNT) of 20 (106902). Intranasal zinc is not recommended for the prevention or treatment of the common cold due to the risk for anosmia. See the Adverse Effects section for more information. Some research shows that zinc nasal spray (as a sulfate, gluconate emulsion, or gluconium gel) reduces the severity and duration of cold symptoms; however, other research has found no effect (6471,8628,8629,10247,87035). Zinc nasal spray does not seem to prevent experimentally-induced colds (8628).
• Coronavirus disease 2019 (COVID-19). While oral zinc does not seem to speed recovery from COVID-19 in non-hospitalized patients, an analysis of a small number of studies suggests that oral or intravenous zinc might reduce the risk of death in hospitalized patients with COVID-19. Details: A small observational study in patients with COVID-19 has found that lower serum zinc levels are associated with worse clinical outcomes, such as admission to the intensive care unit (ICU) and death, when compared with higher zinc levels (105681). Another small observational study has found that 96% of patients with confirmed COVID-19 were zinc-deficient based on plasma levels of zinc, and that these patients had lower plasma zinc levels than a group of individuals without COVID-19. However, plasma zinc concentrations were only weakly correlated with length of hospital stay and there was no correlation with morbidity or mortality (106236). One clinical study in adult outpatients with COVID-19 shows that taking zinc gluconate 50 mg daily at bedtime, alone or with vitamin C (ascorbic acid) 8000 mg daily, for 10 days does not reduce symptom severity when compared with standard care (104450). This study was terminated prior to complete enrollment due to a lack of effect with zinc and/or vitamin C supplementation. Limitations of this study include a lack of placebo control and blinding. Zinc supplementation also does not appear to enhance the clinical efficacy of hydroxychloroquine in patients with confirmed COVID-19 infection. Taking zinc sulfate 220 mg twice daily during a 6-day course of hydroxychloroquine does not improve the clinical recovery rate, reduce the mortality rate, or reduce the need for mechanical ventilation when compared with hydroxychloroquine alone (104818). Other research has evaluated zinc in hospitalized patients. Multiple meta-analyses of small and low-quality clinical studies, including randomized controlled trials and retrospective studies, involving hospitalized patients with COVID-19 shows that supplementation with oral or intravenous zinc is associated with a 29% to 43% reduction in the odds of in-hospital mortality when compared with control (109451,110631). However, in one meta-analysis, the odds of 30-day mortality were not different between groups (110631). These meta-analyses did not elevate the most effective form, dose, frequency, or duration of zinc supplementation (109451,110631). Additionally, a retrospective study in adults admitted to the ICU with COVID-19 has found that those who received oral zinc sulfate, 220 mg daily for a median of 11 days, had a lower 30-day mortality rate when compared with those who did not receive zinc. However, there was no difference in hospital length of stay or in-hospital mortality (106903).
• Depression. Oral zinc seems to be beneficial when used in combination with antidepressant treatments. Details: Population research has found that higher zinc levels and higher dietary intake of zinc are associated with a 28% lower incidence of depression (90227,97139,104057). Oral zinc seems to be beneficial as an adjunct therapy in depression. A meta-analysis of small, low-quality studies in patients with major depression shows that taking zinc in addition to antidepressant therapy is associated with modestly improved depression symptoms when compared with antidepressant therapy alone (104044). Clinical studies used zinc doses of 7-25 mg daily for up to 12 weeks (86985,90221,104044). One small clinical study also shows that adding zinc to imipramine therapy might improve depression that was previously resistant to antidepressant treatment (87158). One clinical guideline also provisionally recommends use of zinc 25 mg elemental orally daily to treat patients with depression based on low-quality evidence. This guideline recommends use of chelated or picolinate zinc products over other forms of zinc (110318).
• Diabetes. Oral zinc might modestly improve glycemic control in some patients. Details: A meta-analysis of 12 clinical studies in patients with diabetes shows that taking zinc supplements reduces fasting blood glucose by up to 20 mg/dL and glycated hemoglobin (HbA1c) by 0.35% when compared with control. However, when only high quality studies were included, the reduction in fasting blood glucose dropped to 12 mg/dL. Zinc seems to only have glycemic benefit in patients living in the Eastern hemisphere, and not the Western hemisphere. Also, glucose reduction seems to be higher with inorganic zinc formulations at doses of at least 30 mg daily taken for at least one month (104080). Zinc has also been evaluated for improving lipid parameters in patients with diabetes. A meta-analysis of nine studies in patients with diabetes shows that taking zinc reduces triglycerides by 17 mg/dL, but does not seem to affect low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol levels, when compared with placebo (104041). The findings from these meta-analyses are limited by the high heterogeneity and small size of the included studies. Zinc has also been studied for gestational diabetes. Some clinical research in patients with gestational diabetes shows that taking zinc gluconate for 6 weeks, starting at 24-28 weeks' gestation, reduces fasting plasma glucose levels by about 10% and improves insulin resistance by 14% when compared to baseline (96072). However, taking zinc gluconate does not reduce the need for caesarean section or insulin therapy, or improve infant outcomes, such as size or health at birth, in these patients (96073).
• Diaper rash. Topical and oral zinc seem to reduce the incidence and severity of diaper rash in infants. Details: Clinical research shows that administering oral zinc gluconate 10 mg daily for 4 months can reduce the incidence of diaper rash in infants when compared with placebo (87281). Other clinical research shows that applying 47% zinc oxide paste to affected areas for 5 days can improve the healing of diaper rash. However, the effect of zinc oxide paste is inferior to eosin 2% solution (86918).
• Gingivitis. Topical zinc seems to reduce the development of gingivitis. Details: While some clinical research shows that zinc, in combination with triclosan, does not prevent plaque and gingivitis (24093,87020), most clinical research shows that using zinc toothpaste or mouthwash, alone or in combination with triclosan, can prevent plaque accumulation, gingivitis, or the formation of calculus (6523,6524,6525,6526,6527,6528,6529,87418,87507). However, most studies used zinc citrate in combination with triclosan, which is not available in the US (6523). For treating existing plaque, calculus, and gingivitis, some clinical research suggests that using zinc citrate 0.5% toothpaste three times daily for 3 months reduces calculus scores by 14% when compared with placebo (87205). However, other evidence suggests that stannous fluoride 0.454% toothpaste is more effective than zinc citrate 0.75% toothpaste for reducing plaque levels (87136).
• Halitosis. Oral zinc seems to reduce halitosis when taken as a gum, mouth rinse, or candy. Details: Clinical research shows that chewing zinc-containing gum reduces volatile sulfur compounds and related odor levels when compared with placebo gum in patients with moderate to severe halitosis (87538). Clinical research also shows that using one of two mouth rinses (Halita, which contains 0.05% chlorhexidine and 0.14% zinc lactate, or Meridol, which contains 0.025% fluoride plus 0.2% zinc lactate) improves breath odor and volatile sulfur compounds by approximately two-fold when compared with mouth rinse containing only 0.05% fluoride or chlorhexidine 0.12% (90206). Additional clinical research shows that sucking a candy containing abrasive substances and zinc gluconate 0.5% or candy containing abrasive substances plus zinc 0.25% and propolis 1% improves breath malodor two- to three-fold when compared with sucking placebo candy (90196).
• Herpes labialis (cold sores). Topical zinc seems to reduce the severity and duration of cold sores. Details: Applying zinc topically seems to help treat herpes simplex infection (6538,6539,8623,11051). Zinc sulfate seems to reduce the severity and duration of symptoms in both orolabial and genital herpes (6538,6539). Zinc oxide (0.3%) in combination with glycine cream applied topically every 2 hours to facial and circumoral herpes seems to reduce symptoms such as blistering, soreness, itching, and tingling. It can also reduce the duration of lesions from 6.5 days to 5 days when treatment is begun within 24 hours of onset of symptoms (8623). A specific combination product containing zinc oxide and L-lysine plus 14 other ingredients (Super Lysine Plus +) also seems to help decrease symptoms and duration of herpes lesions when applied topically every 2 hours (11051). However, zinc may not be effective for recurrent herpes simplex infections. In one clinical study, applying zinc sulfate 0.0025% or 0.05% solution to affected areas did not reduce the frequency, severity, or duration of herpes episodes when compared with a placebo solution in patients experiencing more than five episodes per year (87330).
• Hypogeusia. Oral zinc might improve taste disturbance and taste acuity in people with hypogeusia of various etiologies. Details: A meta-analysis of low-quality studies in patients with taste disorders that are idiopathic or due to zinc deficiency shows that taking oral zinc modestly improves taste acuity when compared with placebo (104055). Studies tested zinc gluconate, zinc sulfate, zinc acetate, and zinc-carnosine as Polaprezinc (Promac, Zeria Pharmaceutical Co., Ltd.), containing 17-68 mg elemental zinc, daily for up to 12 weeks (104055). Zinc also might improve hypogeusia conditions unrelated to zinc deficiency, such as gustin/carbonic anhydrase VI deficiency, captopril-induced taste disturbances, hypogeusia due to chronic renal failure, and post-traumatic olfactory disorder (6543,6544,104055). It also seems be beneficial in radiation-induced dysgeusia. A meta-analysis of three small clinical trials shows that oral zinc reduces the risk of radiation-induced dysgeusia by 28%, but does not improve taste acuity when compared with placebo (104043). However, patients with hypogeusia from other causes may not benefit. Zinc supplementation does not seem to improve taste perception when compared with placebo in patients with acetazolamide-induced taste dysfunction or chemotherapy-induced taste dysfunction (87388,90214).
• Leishmania lesions. Oral zinc and intralesional injections of zinc might improve healing of these lesions. Details: Clinical research shows that taking zinc sulfate 2.5-10 mg/kg orally in three divided doses daily, improves the cure rate of cutaneous leishmania lesions after 45 days when compared with no treatment (86935). Other clinical research shows that intralesional injections of zinc sulfate 2% solution for 6 weeks improves cure rates of cutaneous leishmania lesions when compared with no treatment (6587). However, intralesional injections with zinc sulfate solution does not appear to be more effective than intralesional injections of meglumine antimoniate (Glucantime), hypertonic saline, or sodium stibogluconate (6587,86996,87008).
• Leprosy. Oral zinc seems to be beneficial when used in combination with anti-leprosy drugs. Details: Zinc levels appear to be reduced in people with leprosy. Early clinical research suggests that the addition of zinc improves tolerance of the anti-leprosy drug regimen and might allow for lowering or eliminating steroid doses in erythema nodosum leprosum, a severe form of leprosy (6534,6535,6536,6537).
• Low birth weight. Oral zinc supplementation seems to improve growth in low birth weight infants. Whether oral zinc can improve other outcomes, including mortality, is unclear. Taking oral zinc during pregnancy does not seem to reduce the risk of having a low birth weight infant. Details: While there is some mixed evidence regarding the effects of zinc supplementation on weight gain and length in infants born with low birth weight (87172,87452,90229), a meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, increases weight by around 380 grams, length by around 3 cm, and head circumference by around 0.6 cm when compared with control (109455). There is also mixed evidence regarding the effect of zinc supplementation on other outcomes in low birth weight infants. A large clinical trial in full-term, underweight infants aged 1-6 months in developing countries shows that adding zinc to nutritional supplementation reduces the risk of mortality by about 68% when compared with nutritional supplementation not containing zinc (8920). A small clinical trial in very low birth weight preterm infants born in an industrialized country shows that adding zinc to multivitamin supplementation appears to reduce the occurrence of necrotizing enterocolitis and mortality. However, adding zinc does not appear to prevent late-onset sepsis, bronchopulmonary dysplasia, or retinopathy of prematurity (90229). A meta-analysis of these trials and two other studies in low birth weight infants shows that supplementation with zinc reduces the risk of all-cause mortality by 52% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). Another small clinical study in low birth weight and preterm infants born in a developing country shows that zinc supplementation seems to improve alertness and attention when compared with placebo (97140). However, a meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, does not improve mental or psychomotor development or reduce the risk of mortality, hospitalization, acute respiratory infection, or sepsis when compared with control (109455). Some of these discrepant findings may be due to differences in patient populations (hospitalized, non-hospitalized), milk sources (breastfed, formula-fed, or both), and duration of follow-up. The effect of zinc intake or supplementation during pregnancy has also been evaluated. Population research has found that low dietary intake of zinc during pregnancy is associated with low birth weight in infants; similarly, zinc supplementation is associated with increased infant weight at birth (87471,105678). However, a meta-analysis and a large clinical study show that zinc supplementation during pregnancy does not reduce the risk of having a low birth weight infant (97142,105679). Reasons for the discrepancies may be due to differing zinc status prior to supplementation. Also, numerous factors contribute to the risk of low birth weight, which may confound research on the use of zinc supplementation alone.
• Peptic ulcers. Oral zinc seems to treat and prevent peptic ulcers. Details: Taking zinc orally seems to help treat and prevent peptic ulcers (6588,6589,6591). Some clinical research shows that zinc acexamate improves peptic ulcers when compared with placebo (6589,87285), and seems to be as effective as H2-receptor antagonist drugs (6589,87533). It is not known if other zinc salts are effective.
• Pneumonia. Oral zinc might reduce the risk for pneumonia in children, but it doesn't seem to improve symptoms in children that already have pneumonia. Details: A meta-analysis of four clinical studies shows that giving zinc supplements to children, ages 3 months to 5 years living in developing countries, some of whom were undernourished, reduces the risk of pneumonia incidence by 21% when compared with placebo (104047). Another meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of pneumonia mortality by 21% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). The research on TREATING existing pneumonia in children is inconsistent. Most meta-analyses and clinical studies in children ages 2 months to 5 years with severe pneumonia show that taking elemental zinc in addition to antibiotic therapy does not improve symptom resolution or the time to recovery when compared with antibiotic therapy alone. Zinc also does not seem to reduce mortality in these patients (87248,90197,96080,98131,104042). However, two clinical studies in children in the same age group with pneumonia suggest that adding zinc to standard antibiotic therapy improves symptom resolution and decreases hospital stay when compared with placebo (11052,87242). Reasons for these discrepancies are not clear, but may be related to zinc status prior to treatment.
• Prematurity. Analyses of clinical studies suggest that oral zinc improves growth in premature infants. Whether zinc improves development or reduces the risk of mortality in these patients is unclear. Details: A meta-analysis of small clinical trials in hospitalized infants born prematurely suggests that receiving enteral zinc supplementation at a dose of up to 10 mg daily reduces mortality and might improve short-term weight gain when compared with placebo (105687). Another meta-analysis of small clinical studies in preterm infants shows that adding zinc to formula or to a multivitamin seems to modestly increase infant weight and height and improve motor development when compared with control (105676). A larger meta-analysis of 14 clinical trials in preterm or low birth weight infants receiving breastmilk shows that zinc supplementation, typically 5-7 mg daily started at birth and continued for up to 12 months with or without other micronutrients, increases weight by around 380 grams, length by around 3 cm, and head circumference by around 0.6 cm when compared with control. However, zinc supplementation did not improve mental or psychomotor development or reduce the risk of mortality, hospitalization, acute respiratory infection, or sepsis when compared with control (109455). These analyses are limited by imprecision as well as a high risk of bias in some of the included studies. Some of the discrepant findings may be due to differences in patient populations (hospitalized, non-hospitalized), milk sources (breastfed, formula-fed, or both), and duration of follow-up.
• Pressure ulcers. Topical zinc paste seems to work as a skin barrier and improve pressure ulcer healing. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that applying zinc oxide paste to pressure ulcers daily for 8 weeks reduces necrotic tissue and decreases the surface area of skin pressure ulcers similarly to using a topical streptokinase-streptodornase product (Varidase) (87331). Other small clinical studies show that applying zinc oxide paste to pressure ulcers daily for 8-12 weeks improves healing similarly to a hydrocolloid dressing (Duoderm) (87181) or a specific barrier film product (Cavilon No Sting Barrier Film) (87017). Oral zinc has been evaluated in combination with other ingredients for the treatment of grade II-IV pressure ulcers. Two small clinical studies in hospitalized patients shows that administering an oral nutritional supplement enriched with zinc, L-arginine, and vitamin C improves ulcer healing when compared with a standard diet (31953,87173). Also, clinical research in patients living in long-term care facilities shows that taking an oral nutritional supplement enriched in protein, zinc, L-arginine, and vitamin C daily for 9 weeks reduces ulcer area and decreases oozing when compared to baseline (32045). The validity of this finding is limited by the lack of a comparator group.
• Sickle cell disease. Oral zinc seems to improve symptoms of sickle cell disease in patients with zinc deficiency. Details: Taking zinc orally seems to help reduce symptoms of sickle cell disease in people with zinc deficiency (6594,6595,6596,8626,87343). Taking zinc supplements also seems to decrease the occurrence rate of sickle-cell crises and infections (6594,6596,90228). Additionally, zinc might reduce the number of hospitalizations for sickle cell crises, although the severity of the crises that do develop is not necessarily decreased by taking zinc supplements (6594,6596). In prepubertal children and adolescents with homozygous sickle cell disease, taking zinc seems to improve growth, height, and weight gain (8626,87403).
• Warts. Oral and topical zinc seem to improve the cure rate of cutaneous warts. Details: A small clinical study suggests that applying zinc sulfate 10% solution three times daily for 4 weeks improves plane warts, but not common warts, when compared with distilled water (87094). Another small clinical study suggests that applying topical zinc oxide 20% ointment twice daily for up to 3 months seems to have a similar cure rate as ointment containing salicylic acid 15% with lactic acid 15% (87082). Taking zinc orally may also be effective in treating warts (87227). A meta-analysis of low quality clinical studies shows that taking zinc sulfate orally improves the odds of curing cutaneous warts nearly 17-fold when compared with respective controls (87227). Preliminary clinical research in adults treated with cryotherapy for anogenital warts shows that taking zinc gluconate 30 mg orally three times daily for 2 months does not reduce the number of warts when compared with placebo (111445).

POSSIBLY INEFFECTIVE

• Alopecia areata. Oral zinc does not seem to improve symptoms of this condition. Details: Although there is preliminary evidence that suggests zinc in combination with biotin might be helpful for alopecia areata (6932), most studies indicate that zinc is not effective for alopecia areata, alopecia totalis, or alopecia universalis (6931,6932).
• Cystic fibrosis. Oral zinc does not improve cystic fibrosis symptoms or progression. Details: Clinical research shows that taking supplements providing 30-90 mg of elemental zinc for 6 weeks to one year does not improve lung function when compared with placebo in children and adolescents with cystic fibrosis (87066,87113,96079). One clinical study also shows that taking elemental zinc for one year does not reduce the number of days requiring oral or intravenous antibiotics for pulmonary infections (96079). However, one study shows that taking zinc can reduce the number of days of oral antibiotic use when compared with placebo (87113).
• HIV/AIDS. Oral zinc does not seem to improve outcomes in patients with HIV. Details: Clinical research in adult HIV patients with normal or low zinc levels shows that taking elemental zinc 12-15 mg daily orally for 18 months along with antiretroviral therapy does not improve viral load, CD4/8 counts, or mortality when compared with placebo (87036,87216,105686). In children with HIV-1, clinical research shows that administering zinc sulfate, providing 10 mg elemental zinc, daily for 6 months does not improve mortality, viral load, or CD4 counts when compared with placebo (82377).
• HIV/AIDS-related pregnancy complications. Oral zinc does not prevent pregnancy complications related to HIV infection. Details: Adding zinc 25 mg orally during pregnancy does not seem to reduce parent-to-child vertical transmission of HIV, infant mortality, birth weight, or gestational period in HIV-infected females with low zinc levels (11054,87034). Also, one clinical study in HIV-1-infected pregnant patients suggests that supplemental zinc can increase the risk of wasting, as assessed by weight and mid-upper arm circumference, by 170% when compared with placebo (87034).
• HIV/AIDS-related wasting. Oral zinc does not seem to improve HIV-related wasting syndrome. Details: A clinical study in patients with HIV-related wasting syndrome shows that taking zinc orally in combination with vitamins and albendazole does not seem to improve diarrhea or mortality when compared with taking albendazole alone (6564).
• Infant development. Oral zinc does not seem to improve infant mental and psychomotor development. Details: Clinical research, including a meta-analysis of eight studies, shows that giving zinc to infants or children at high risk for zinc deficiency does not improve mental and psychomotor development when compared with placebo (87013,90209). In another meta-analysis of studies in children whose baseline zinc status was not specified, there was no beneficial effect of zinc supplementation on mental or psychomotor development at 6 or 12 months of age (104817).
• Inflammatory bowel disease (IBD). Oral zinc does not improve symptoms of IBD. Details: Some clinical research shows that taking zinc orally does not seem to help treat IBD (6913,6915,6916).
• Influenza. Oral zinc does not seem to reduce the risk for influenza. Details: Supplemental zinc seems to improve cell-mediated immune response in elderly people (824), but it does not seem to have a significant effect on antibody response and incidence of influenza infection after the vaccine (6553,6563). Additionally, zinc supplementation in patients on hemodialysis, who have a high risk of zinc deficiency, does not seem to improve response to influenza vaccine (10809). Taking zinc supplements orally is unlikely to improve immune function in people without risk factors for zinc deficiency (10789). However, there is preliminary evidence that suggests zinc along with selenium might reduce the incidence of infections in institutionalized older patients (8921).
• Otitis media. Oral zinc does not prevent otitis media in children. Details: A meta-analysis of clinical research shows that taking elemental zinc 3-70 mg daily for up to 24 months does not prevent the occurrence of ear infections in children from low- or middle-income countries (87258).
• Pre-eclampsia. Oral zinc taken prenatally does not seem to be beneficial for pre-eclampsia prevention. Details: A meta-analysis and a large clinical study show that zinc supplementation during pregnancy does not reduce the risk of pre-eclampsia when compared with placebo (97142,105679).
• Prostate cancer. Oral zinc does not reduce the risk for prostate cancer or prostate cancer-related mortality. Details: Some epidemiological research has found an inverse relationship between dietary zinc intake and prostate cancer (96075). Also some clinical research shows that taking zinc 20 mg in combination with vitamin C 120 mg, vitamin E (alpha-tocopherol) 30 mg, beta-carotene 6 mg, and selenium 100 mcg daily for an average of 8 years might reduce the risk of prostate cancer in men with normal PSA levels; however, it does not seem to be beneficial for reducing the risk of prostate cancer in patients with PSA levels above 3 mcg/L (14135). However, some evidence raises concern that zinc might actually INCREASE the risk of prostate cancer. A large-scale population study found that taking more than 100 mg of supplemental zinc daily or taking supplemental zinc for 10 or more years doubles the risk of developing prostate cancer (10306). Another large-scale population study shows that men who take a multivitamin more than seven times per week and who also take a separate zinc supplement have a significantly increased risk of prostate cancer-related mortality (15607). Despite these studies suggesting the potential for adverse effects of zinc, a meta-analysis of mainly population research has found that there is no association between zinc intake and the risk of prostate cancer (96075).
• Psoriasis. Oral zinc does not reduce the severity of psoriasis symptoms. Details: Zinc epidermal levels are reportedly lower in people with psoriasis (6509). However, taking zinc orally does not seem to help treat psoriasis (6513,6514,6912,87363). Zinc supplementation has no effect on the psoriasis area and severity index (6513,6514).
• Rheumatoid arthritis (RA). Oral zinc does not treat symptoms of RA. Details: Multiple clinical studies in patients with RA show that taking zinc orally does not improve function or symptoms when compared with baseline or control (6517,6518,6519,87406).
• Sexual dysfunction. Oral zinc does not improve sexual function in males with chronic kidney disease (CKD). Details: Clinical research shows that zinc supplementation does not improve sexual activity or libido when compared with placebo in males with sexual dysfunction secondary to CKD (6708,6568,87220,87386,87416). In fact, one clinical study shows that taking zinc can decrease the frequency of intercourse by 76% when compared with placebo in patients with CKD-related sexual dysfunction (87220).
• Tinnitus. Oral zinc does not improve severity of tinnitus or reduce tinnitus-related disability. Details: A meta-analysis of three small clinical trials in adults with tinnitus shows that taking elemental zinc 50 mg daily for up to 16 weeks does not improve tinnitus severity, or disability from tinnitus when compared with placebo (104051).

LIKELY INEFFECTIVE

• Malaria. Oral zinc does not prevent or treat malaria in undernourished children or pregnant adults in developing countries. Details: A meta-analysis of clinical research in children or pregnant adults shows that taking zinc orally, alone or in combination with other supplements, for does not reduce the risk of malaria parasitemia (111444). A large multi-country study in zinc-deficient preschool children with acute malaria shows that taking zinc supplements does not affect fever, parasitemia, or hemoglobin when compared with placebo (10246). An even larger clinical study of over 40,000 children with malaria aged 1-36 months shows that taking zinc 5-10 mg daily orally for approximately 17 months does not reduce mortality when compared with placebo (87078). Zinc supplements also do not appear to protect against infection by Plasmodium falciparum (8638,87235,86937). However, one small study in children with low and high levels of parasitemia shows that taking zinc 10 mg daily for 46 weeks may lower the incidence of fever episodes by 38% and 69%, respectively, when compared with placebo (86937).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral zinc is beneficial in patients with age-related cognitive decline. Details: An epidemiological study based on elderly adults enrolled in the National Health and Nutrition Examination Survey (NHANES) has found that taking zinc may improve cognition in a non-linear manner. Daily doses below 9 mg and 8 mg in males and females, respectively, showed a positive association with cognitive function, but doses above that level showed no association. Additionally, high intake of both zinc and selenium was associated with improved cognition in females, but not in males (108446). Dietary intake was collected from two patient-reported 24-hour recalls and cognition was only measured once, limiting the validity of these findings.
• Alcohol-related liver disease. It is unclear if oral zinc is beneficial in patients with alcoholic-related liver cirrhosis. Details: A small clinical study in patients with alcoholic liver cirrhosis shows that taking zinc sulfate 600 mg daily for 6 weeks improves liver function, based on increased alkaline phosphatase activity and reduced serum bilirubin, when compared to baseline (87325).
• Anorexia nervosa. Oral zinc seems to improve weight gain in people with anorexia nervosa. Details: Anorexia nervosa might be linked with zinc deficiency. Small clinical trials in adolescents and adults with anorexia nervosa show that oral zinc supplements might help increase weight gain and improve depressive symptoms when compared with placebo (6905,6906).
• Arsenic poisoning. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study shows that taking zinc 4 mg in combination with spirulina extract 500 mg daily for 16 weeks can decrease skin manifestations and reduce arsenic levels in the urine and in hair of patients with chronic arsenic poisoning (18301).
• Asthenopia (eye strain). Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults without dry eye disease shows that taking a specific combination product containing zinc 10 mg, L-carnitine 50 mg, elderberry fruit extract 300 mg, currant 100 mg, and Eleutherococcus root 50 mg (Meramirt CM) orally once daily for 1 month improves measures of eye strain and contrast sensitivity when compared to baseline. Improvements in these measures were lacking in the control group (111295). Statistical comparison between the two groups was not reported. It is unclear if these effects are due to zinc, other ingredients, or the combination.
• Athletic performance. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in sleep-deprived recreational athletes shows that taking a combination of zinc 90 mg, magnesium 1350 mg, and vitamin B6 31.5 mg orally for 3 nights at bedtime does not improve grip strength, squat, or bench press performance when compared with placebo (113655).
• Atopic dermatitis (eczema). It is unclear if oral zinc is beneficial for alleviating eczema in children. Details: A small clinical study in children with eczema shows that taking zinc sulfate 185.4 mg orally daily for 8 weeks does not appear to improve the surface area affected and degree of erythema, symptom scores of itch and sleep disturbance, or topical steroid use when compared with placebo. Also, plasma zinc levels appear to be normal in children with eczema (6911).
• Attention deficit-hyperactivity disorder (ADHD). Oral zinc might improve certain symptoms in children with ADHD. Details: Observational research has found that lower serum zinc levels are both more prevalent in children with ADHD and are linked to worsened response to stimulant therapy (9965,9966,9967). Based on this evidence, there is some interest in using zinc to improve symptoms in children with ADHD. A meta-analysis of six small clinical trials shows that although taking zinc modestly improves overall symptoms of ADHD when compared with placebo, there is no effect on hyperactivity or inattention when these outcomes are examined separately. The sub-analyses conducted for these two separate outcomes included only 3 studies. Most, but not all, of the included studies were conducted in children also receiving methylphenidate treatment (106240). Elemental zinc, usually as sulfate, was typically used in doses of 10-40 mg daily for 6-12 weeks (11350,12060,106240). There is some evidence that zinc could be most helpful in children with a high body mass index (BMI), low zinc levels, and low free fatty acid levels (11350). It is unclear if zinc is beneficial in children who are not already taking stimulant medications. One clinical guideline also provisionally recommends against use of oral zinc to treat patient with ADHD based on low-quality evidence (110318).
• Autism spectrum disorder. It is unclear if oral zinc is beneficial in children with autism spectrum disorder. Details: One small clinical study conducted in children with autism spectrum disorder shows that taking zinc 15-30 mg orally, alone or as add-on therapy to amphetamine, does not improve attention deficit hyperactivity disorder (ADHD) symptoms when compared with placebo (98711). However, the optimal mg/kg dose of amphetamine was shown to be 37% lower for those children also taking zinc 15 mg twice daily when compared with those taking placebo (98711).
• Autoimmune thyroiditis. It is unclear if oral zinc is beneficial in children with autoimmune thyroiditis. Details: A small clinical study in children aged 3-18 years with autoimmune thyroiditis shows that taking zinc acetate 25 mg daily in addition to standard therapy for 12 weeks does not change thyroid auto-antibody levels, thyroid function tests, or oxidative stress markers when compared with standard therapy alone. However, subjects taking zinc did not require escalation in levothyroxine doses when compared with the control group control group, which did require levothyroxine dose escalation (113661).
• Behcet disease. It is unclear if oral zinc is beneficial in patients with Behcet disease. Details: A small clinical trial in patients with Behcet disease shows that taking zinc gluconate 30 mg daily for 12 weeks does not improve disease activity scores, quality of life, or measures of inflammation when compared with placebo (109453).
• Benign prostatic hyperplasia (BPH). Although there is interest in using oral zinc for BPH, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Beta-thalassemia. It is unclear if oral zinc is beneficial in patients with beta-thalassemia major. Details: A small clinical study in children recently diagnosed with beta-thalassemia major shows that initiating zinc sulfate in addition to standard blood transfusions increases linear growth rate when compared with transfusions alone (87329). Another small clinical study in adult and pediatric patients with thalassemia major and low bone mass shows that taking zinc 25 mg daily (as zinc sulfate) for 18 months improves whole-body bone mineral content, as well as hip and spine bone mineral density, by small amounts when compared with placebo (90208).
• Brain tumor. It is unclear if dietary zinc is beneficial for reducing the risk for brain cancer. Details: Population research has found that zinc intake is not associated with a reduced risk of developing brain cancer (87098).
• Breast cancer. It is unclear if increased dietary zinc intake is beneficial for reducing the risk for breast cancer. Details: Population research has found that neither zinc intake nor blood levels of zinc are associated with a reduced risk of breast cancer (106229).
• Bronchiolitis. It is unclear if oral zinc is beneficial for viral bronchiolitis in infants and children. Details: A small clinical study in children 2 years or younger with acute viral bronchiolitis shows that taking elemental zinc 10-20 mg as zinc sulfate for 5 days improves clinical recovery and reduces the duration of hospital stay by almost one day when compared with placebo. After 72 hours, 98% of infants and children taking zinc were considered fully recovered, compared to only 52% of infants taking placebo (96076).
• Burning mouth syndrome. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with burning mouth syndrome shows that taking zinc 15 mg and vitamin C 35 mg once daily, along with a vitamin B complex twice daily, for 30 days modestly decreases pain and burning when compared to baseline (105195). The validity of this finding is limited by the lack of a comparator group. Furthermore, it is unclear if the benefit is due to zinc, other vitamins, or the combination.
• Burns. Intravenous zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. The effects of oral zinc for burn healing are unclear. Details: Administering zinc intravenously in combination with other minerals seems to improve the outcomes of burn patients. Supplementation with zinc, copper, and selenium appears to improve wound healing, reduce pulmonary infections, and shorten intensive care unit stay in patients with serious burns (6520,87085). The effect of supplementation with zinc alone is unclear.
• Canker sores. It is unclear if oral zinc is beneficial in patients with canker sores. Details: Evidence for the use of zinc in canker sores is conflicting. A small clinical crossover study in patients with recurrent canker sores shows that taking zinc sulfate 660 mg daily for 3 months does not improve the size or frequency of canker sore ulcers when compared with control (6592). However, another clinical study in patients with recurrent sores and low or normal zinc levels shows that taking zinc sulfate 220 mg daily for 1 month reduces recurrence of sores when compared with placebo (86964). Reasons for conflicting results are unclear. Zinc might be beneficial when used in a muco-adhesive formulation. A small clinical study in patients with canker sores shows that taking a muco-adhesive zinc sulfate 5 mg tablet three times daily for 7 days reduces pain and speeds up healing when compared with placebo (104048).
• Cataracts. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking zinc orally in combination with antioxidant vitamins does not seem to help treat or prevent cataracts. Taking elemental zinc 80 mg plus vitamin C 500 mg, vitamin E 400 IU, and beta-carotene 15 mg daily does not seem to have any effect on the development or progression of age-related lens opacities (cataracts) or the need for cataract surgery in well-nourished people 55-80 years of age. However, it is unknown whether earlier intervention and/or a longer period of treatment with supplements would have any effect on cataracts (7304).
• Chemotherapy-induced acral erythema. It is unclear if oral zinc reduces the severity of acral erythema induced in patients treated with the vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) treatment regorafenib. Details: A small study in patients with metastatic colorectal cancer undergoing treatment with regorafenib shows that taking zinc gluconate 78 mg twice daily reduces the proportion of patients with more severe acral erythema when compared with control. Though there is no association in the zinc treatment group, lower serum zinc levels seem to correlate with more severe acral erythema in the control group, suggesting a possible role of zinc deficiency in the pathogenesis of acral erythema (112472). The validity of this study is limited by the lack of blinding.
• Chemotherapy-related fatigue. It is unclear if oral zinc improves symptoms in patients with fatigue due to chemotherapy. Details: A small clinical study in patients undergoing 4 or more cycles of chemotherapy for colorectal cancer shows that taking zinc 70 mg daily for 16 weeks does not improve fatigue or quality of life when compared with placebo (97141).
• Chronic fatigue syndrome (CFS). Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in females with CFS shows that taking zinc 10 mg as zinc sulfate plus melatonin 1 mg daily for 16 weeks modestly reduces self-reported symptoms of physical fatigue when compared with placebo. However, there was no effect on cognitive or psychological symptoms, sleep, or symptoms of anxiety or depression (106241). This study may not have been adequately powered to detect differences between groups.
• Cirrhosis. It is unclear if zinc is beneficial for reducing cirrhosis-related mortality. Details: A meta-analysis of four small clinical trials shows that zinc supplementation does not seem to reduce mortality in patients with cirrhosis when compared with control (104054). This finding is limited due to the heterogeneity and small size of the available studies.
• Cognitive function. It is unclear if zinc is beneficial for cognitive function. Details: A very small clinical study in adults with overweight and obesity shows that taking supplemental zinc 30 mg daily for 12 weeks improves some measures of cognitive function and executive processing but does not improve verbal fluency when compared with placebo (112471). Zinc has also been evaluated in combination with other ingredients. A small clinical trial in healthy adults shows that taking a specific product containing a combination of zinc 9 mg, Lactobacillus helveticus, Lactiplantibacillus plantarum, Bifidobacterium longum, and other ingredients (Puraflor, GSK Consumer Healthcare, Milano, Italy) orally daily for 4 weeks does not affect cognitive performance during acute stress when compared with placebo (110923).
• Colorectal adenoma. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large clinical study shows that taking a combination supplement containing zinc 30 mg, selenium 200 mcg (as l-selenomethionine), vitamin A 2 mg (as retinol), vitamin C 180 mg, and vitamin E 30 mg (as D-a-tocopherol acetate) by mouth daily for 5 years or until the recurrence of an adenoma reduces the risk of recurrent large-bowel adenomas by approximately 40% when compared with placebo (92903). It is not clear if the benefit is due to zinc, other supplements, or the combination.
• Colorectal cancer. It is unclear if oral zinc is beneficial for reducing colorectal cancer risk. Details: Population research has found that increased intake of zinc is associated with a 17% to 20% reduced risk of colorectal cancer (90213,90220).
• Congenital heart disease. It is unclear if oral zinc is beneficial for reducing the risk of congenital heart defects. Details: An observational study in pregnant adults has found that consuming the recommended nutritional intake of zinc may be associated with a lower risk of total congenital heart defects in infants, including atrial and ventricular septal defects, when compared with low zinc intake. This association appears to persist despite copper or selenium intake (108445).
• Critical illness (trauma). It is unclear if oral zinc is beneficial for critically ill patients. Details: A meta-analysis of two small randomized clinical trials in adults with head trauma shows that supplementing zinc, given as 120 mg elemental zinc orally daily or 12 mg elemental zinc intravenously daily for 15 days to 3 months, regardless of serum zinc levels, does not improve the risk of 30-day mortality when compared with control (111290). However, the study may have been inadequately powered to detect a difference between groups.
• Dementia. Although there is interest in using oral zinc for dementia, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Diabetic foot ulcers. Although there is interest in using oral zinc for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of zinc for this condition.
• Diabetic neuropathy. It is unclear if oral zinc is beneficial in patients with diabetic neuropathy. Details: A small clinical study in patients with poorly-controlled diabetic neuropathy shows that taking zinc sulfate 660 mg daily for 6 weeks improves motor nerve conduction velocity and reduces fasting and postprandial blood sugar when compared to baseline (86933). The validity of this finding is limited by the lack of statistical comparison to the control group.
• Down syndrome. It is unclear if oral zinc is beneficial for improving immune function in people with this condition. Details: A very small clinical study in Down syndrome patients with zinc deficiency shows that taking zinc sulfate 1 mg/kg daily for 2 months seems to improve immune function and reduce recurrent infections when compared with baseline (87289). The validity of this finding is limited by the lack of a control group. Another small clinical study in children with Down syndrome shows that zinc 25-50 mg daily for 6 months does not improve immune function when compared with placebo (87278). Reasons for the discrepancies may be related to the dose of zinc or zinc status at baseline.
• Dysmenorrhea. It is unclear if oral zinc is beneficial in patients with dysmenorrhea. Details: Preliminary clinical research in females aged 13 to 21 years with primary dysmenorrhea shows that taking zinc sulfate 40 mg orally daily for the first 3 days of menstruation for three cycles reduces mean pain scores by 51% when compared with placebo (111446).
• Epilepsy. There is limited evidence on the oral use of zinc in children with intractable seizures. Details: A small clinical study in children with intractable epilepsy shows that taking elemental zinc 1 mg/kg daily as zinc sulfate heptahydrate for 6 months reduces seizures when compared with placebo. About 31% of children taking zinc experienced a 50% decrease in seizure frequency, compared to only 5% of children taking placebo (96078).
• Erectile dysfunction (ED). It is unclear if oral zinc is beneficial in patients with erectile dysfunction. Details: A moderate-sized, open-label clinical study in adults with mild-to-moderate ED shows that taking a specific combination supplement (Icarifil, Anvest Health S.p.A) containing zinc 15 mg, L-carnitine, L-citrulline, tribulus, and other ingredients daily for 3 months improves patient-reported erectile function when compared to baseline. Additionally, taking the supplement with tadalafil improves some, but not all, patient-reported assessments of erectile function when compared with taking tadalafil alone (114989). It is unclear if this effect is due to zinc, other ingredients, or the combination. Additionally, the interpretation of these results is limited by poor methodology, including the use of per-protocol analysis and lack of a placebo group.
• Esophageal cancer. It is unclear if oral zinc is beneficial for esophageal cancer prevention. Details: Population research in Chinese and Iranian patients has found that low intake of zinc is associated with an increased risk of esophageal squamous cell cancer (17205,87059). However, other population research in patients from America, Europe, or Asia has found that dietary zinc intake is not associated with esophageal cancer risk (90213).
• Fatigue. It is unclear if oral zinc is beneficial for reducing fatigue in older individuals. Details: A clinical study in adults 50 years and older, some with below-normal levels of zinc at baseline, shows that taking zinc 30 mg daily for 70 days improves subjective fatigue when compared with no intervention (105675). The validity of this finding is limited due to a lack of placebo control and potential performance bias. Additionally, it is unclear whether baseline zinc status alters the benefits of zinc supplementation.
• Fecal incontinence. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with fecal incontinence shows that topically applying an ointment containing zinc sulfate 1% and aluminum sulfate 5% to the anal canal mucosa three times daily for 4 weeks improves symptoms approximately twice as much as a placebo ointment. Quality of life related to the incontinence also improved (90219).
• Gastric cancer. It is unclear if dietary zinc is beneficial for gastric cancer prevention. Details: Population research has found that increased dietary zinc intake is not associated with a decreased risk of gastric cancer (90213).
• Head and neck cancer. It is unclear if oral zinc improves survival in patients with head and neck cancers. Details: Preliminary clinical research in patients with head and neck cancers shows that zinc supplementation does not improve disease-free or metastasis-free survival rates after 3 years when compared with placebo (87103).
• Hepatic encephalopathy. It is unclear if oral zinc is beneficial for reducing the severity of hepatic encephalopathy or preventing recurrence. Details: A meta-analysis of small clinical studies, as well as some individual clinical studies, show that short-term zinc supplementation improves cognitive function and possibly quality of life in patients with hepatic encephalopathy. These findings are based on results from the number connection test and other tests (87377,90202,106227). One study in patients with minimal hepatic encephalopathy used zinc bisglycinate 75 mg three times daily, providing elemental zinc 45 mg daily for 12 weeks (106227). However, other preliminary clinical research shows that short-term zinc supplementation does not improve hepatic encephalopathy severity when compared with placebo when assessed using Conn's index, which includes evaluation of mental state, asterixis (flapping tremor), number connection test, electroencephalogram (EEG) record, and plasma ammonia (87144). Also, a meta-analysis of clinical research shows that zinc sulfate supplementation does not reduce encephalopathy recurrence (90202). Based on these results, zinc supplementation may marginally improve cognitive function in hepatic encephalopathy patients, but it does not appear to improve disease severity or reduce the risk of recurrence.
• HIV/AIDS-related diarrhea. It is unclear if oral zinc is beneficial for preventing diarrhea in adult HIV patients. Details: Short-term zinc supplementation does not appear to TREAT diarrhea in adult HIV patients with persistent diarrhea. Clinical research shows that taking zinc 50 mg twice daily for 7 days does not reduce the duration of HIV-related diarrhea when compared with placebo (87055). However, zinc supplementation may help PREVENT HIV-related diarrhea when administered long-term. Clinical research shows that taking elemental zinc 12-15 mg daily for 18 months reduces the rate of diarrhea by about half when compared with placebo in adult HIV patients with zinc deficiency (87216). In HIV-infected children, clinical research shows that taking elemental zinc 10 mg daily for 6 months can reduce the occurrence of diarrhea by 49% when compared with placebo (82377). However, administering zinc in combination with vitamin A until 2 years of age does not reduce the occurrence of diarrhea when compared with vitamin A alone in HIV-infected children (82417).
• HIV/AIDS-related opportunistic infections. It is unclear if oral zinc is beneficial in opportunistic infections in patients with HIV/AIDs. Details: A small clinical study in patients with AIDS shows that taking zinc supplements orally in combination with zidovudine (AZT, Retrovir) might reduce opportunistic infections of Pneumocystis carinii and Candida when compared with taking zidovudine without zinc (6566).
• Human papillomavirus (HPV). It is unclear if oral zinc is beneficial for preventing relapse in patients with vulvar warts or for treating HPV infections and cervical lesions in patients with abnormal cervical cytology. Details: One small clinical study in patients with vulvar warts shows that taking zinc sulfate 400 mg daily for 8 weeks in addition to topical treatments including podophyllin 20%, imiquimod 5%, or cryotherapy, does not affect the duration of response, but does reduce the relapse rate by approximately 66% after 6 months, when compared with topical treatments alone (90190). Additionally, a small, open-label study in zinc-sufficient females with HPV shows that taking zinc sulfate 220 mg twice daily for 3 months reduces the odds of persistent HPV infection by 87% and improves the resolution of pre-existing cervical lesions when compared with no treatment (109456).
• Hypertension. It is unclear if oral zinc reduces blood pressure in normotensive or hypertensive patients. Details: A meta-analysis of small clinical trials shows that taking zinc reduces systolic blood pressure by about 1.5 mmHg, but does not reduce diastolic blood pressure, when compared with placebo. Response did not differ with the dosage of zinc or duration of supplementation. Only one study evaluated patients with hypertension; other patient populations included those with type 2 diabetes, diabetic retinopathy, pre-diabetes, obesity, polycystic ovary syndrome (PCOS), and patients on dialysis (104052). More research in patients with hypertension is needed to determine if zinc is beneficial in this population.
• Impaired glucose tolerance (prediabetes). While some conflicting evidence exists, several small clinical studies suggest that oral zinc may improve glycemic control in patients with prediabetes. Details: A meta-analysis of three low-quality studies in patients with prediabetes suggests that taking zinc sulfate 20-30 mg, alone or in combination with lysine and vitamin C, for 6-12 months reduces fasting blood glucose and postprandial glucose when compared with control (105682). Furthermore, a small clinical study in patients with prediabetes shows that taking zinc gluconate 30 mg daily for 90 days improves glycemic parameters when compared with placebo. All study participants were also instructed to increase physical activity and start a calorie-restricted diet (105391). However, another small clinical study in patients with prediabetes shows that taking zinc gluconate 30 mg daily for 12 months does not improve glycemic parameters when compared with placebo (109454). The available research has been conducted in Sri Lanka, Bangladesh, Iran, and Australia; it is unclear if these findings are generalizable to other geographic locations.
• Intestinal parasite infection. It is unclear if oral zinc is beneficial in patients with intestinal parasitic infections. Details: Zinc supplementation may help TREAT infection from Schistosoma mansoniin, but not other parasites, in children in developing countries. Results from one clinical study show that taking oral zinc sulfate 30-50 mg for 12 months reduces the intensity of Schistosoma mansoniin infection in children, as measured by number of eggs per gram in feces, when compared with placebo (87495). However, supplementation with zinc does not appear to reduce the intensity of Ascaris lumbricoides, Trichiuris trichura, nor Giardia lamblia infection in children (6586). Furthermore, preliminary clinical research suggests that supplementation with zinc may increase the duration of Entamoeba histolytica infection in children (87099). There are also inconsistent results regarding the effects of zinc in PREVENTING intestinal parasite infections. Some clinical research shows that taking zinc in combination with vitamin A reduces the incidence of Giardia lamblia infections when compared with placebo (87099). However, zinc supplementation does not appear to prevent intestinal infections by Ascaris lumbricoides, Schistosoma haematobium, nor Schistosoma mansoniin (87099,87495).
• Kidney failure. It is unclear if oral zinc is beneficial for patients on hemodialysis who have resistance to erythropoiesis-stimulating agents (ESAs). Details: Zinc deficiency is thought to play a role in ESA-resistant anemia in patients with kidney failure. A small clinical trial in patients on hemodialysis with low zinc levels shows that taking zinc acetate hydrate, usually 25mg or 50 mg daily, for 12 months increases plasma levels of zinc and modestly reduces the required weekly dose of ESAs when compared with placebo. However, there was no effect on hemoglobin levels (109781).
• Leukemia. It is unclear if oral zinc is beneficial for improving weight maintenance in children and adolescents with leukemia. Details: A small clinical study in children and adolescents with acute leukemia shows that taking zinc 2 mg/kg (as an amino acid salt) in two divided doses daily for 60 days doubles weight gain and reduces infection rate by approximately 60% when compared with placebo. However, zinc supplementation does not appear to improve nutritional status (90204).
• Liver cancer. It is unclear if oral zinc is beneficial for preventing hepatocellular carcinoma (HCC). Details: In patients treated for hepatitis C, the presence of hepatic fibrosis increases the risk for development of HCC, and is also associated with low plasma zinc levels. In a retrospective analysis of patients with a sustained virological response to hepatitis C therapy, those taking oral zinc supplements for at least 6 months had approximately half the risk of developing HCC when compared with those not taking zinc. Maintaining a serum zinc level above 90 mcg/dL seems to reduce the risk for HCC (106904).
• Lung cancer. It is unclear if increased dietary zinc intake is beneficial for reducing the risk of lung cancer. Details: Population research suggests that the highest dietary intake of zinc is associated with a 32% reduced risk of lung cancer when compared with the lowest intake (106235). Additionally, another large epidemiological cancer screening trial with a mean follow-up of 12.2 years suggests that dietary intake of zinc is protective against lung cancer, with the highest quartile of dietary intake showing the greatest benefit. However, this protective effect was not found for supplemental intake of zinc (112096).
• Male infertility. It is unclear if oral zinc is beneficial for infertility in males. Details: Some preliminary clinical research shows that taking zinc sulfate 66 mg daily increases sperm count, testosterone levels, and the incidence of pregnancy in idiopathic infertile men with low testosterone levels (9334,87430). Another clinical study shows that taking zinc sulfate 66 mg daily can improve sperm morphology by approximately 33% when compared to baseline in men with a grade III varicocele (90194). However, not all research agrees. One clinical study shows that taking elemental zinc 30 mg with folic acid 5 mg daily for 6 months does not improve sperm morphology or pregnancy rates when compared with placebo in infertile men (102085). It is possible the lower dose used in this study was insufficient to produce the beneficial effects observed in earlier research. Zinc supplementation has also been studied as part of combination therapy. A retrospective study in males with or without varicocele-related infertility has found that taking a specific combination product containing zinc 10 mg, L-carnitine fumarate 1725 mg, acetyl-L-carnitine 500 mg, vitamin C 90 mg, coenzyme Q10 20 mg, folic acid 0.2 mg, selenium 0.05 mg, and vitamin B12 0.015 mg (Proxeed Plus, Sigma-Tau) orally twice daily for 6 months improves sperm count, sperm concentration, and sperm motility when compared with baseline. Improvements in semen parameters were greatest in subjects with more severe varicoceles. The validity of this study is limited by the lack of a comparator group (111296). There is also interest in using zinc to improve results of in vitro fertilization (IVF). A small clinical study in couples undergoing IVF suggests that infertile male partners who take a specific combination product (Menevit) containing zinc and other antioxidants seem to have an increased rate of viable pregnancies when compared with placebo (87087). However, it's unclear if the benefit can be attributed to zinc, other antioxidants, or the combination.
• Melasma. It is unclear if topical zinc reduces melasma severity. Details: A small clinical study shows that applying a topical solution containing zinc sulfate 10% once daily for 2 months is less effective at reducing melasma severity when compared with hydroquinone 4% (90232).
• Menopausal symptoms. It is unclear if oral zinc improves sexual function after menopause. Details: A single clinical trial shows that taking zinc sulfate 110 mg daily for 6 weeks modestly improves testosterone levels and sexual function, including desire, arousal, satisfaction, and pain, after menopause when compared with placebo (106228).
• Migraine headache. It is unclear if oral zinc is beneficial in patients with migraine. Details: Two small clinical studies in patients with migraine show that taking zinc sulfate 200 mg or zinc gluconate 15 mg daily for 8-12 weeks modestly reduces migraine severity and frequency when compared with placebo (104040,105684). Both studies were conducted in Iran; it is unclear if these findings are generalizable to other geographic locations.
• Nasopharyngeal cancer. It is unclear if oral zinc is beneficial in patients with this type of cancer. Details: A small clinical study in patients with locally advanced nasopharyngeal cancer shows that zinc supplementation 75 mg daily for 2 months may improve disease-free survival rates after 5 years when compared with placebo (87163).
• Neonatal jaundice. It is unclear if oral zinc is beneficial for neonatal jaundice. Details: There is contradictory evidence about the effects of oral zinc in infants with hyperbilirubinemia. Two small clinical studies in infants with idiopathic neonatal hyperbilirubinemia show that receiving oral zinc sulfate 5 mg twice daily for 5-7 days does not affect levels of total bilirubin, the required duration of phototherapy, or the duration of hospitalization, when compared with placebo (90212,104814). However, a larger clinical trial in preterm infants receiving phototherapy and zinc 1.2 mg/kg daily as zinc sulfate heptahydrate, via either orogastric or nasogastric tube for 10 days, serum bilirubin levels were modestly decreased only on days 8-10 when compared with phototherapy alone (106242). Additionally, a second larger clinical trial in infants with idiopathic hyperbilirubinemia shows that receiving oral zinc sulfate (Zinc sulfate, Ramofarmin Company) 1 mg/kg daily for 3 days reduces total bilirubin levels and duration of phototherapy when compared with placebo; additionally length of hospitalization is reduced by less than 1 day (115631). The reason for these discrepant findings is unclear but may be attributed to variations in baseline characteristics, treatment duration, and dose.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral zinc is beneficial in patients with NAFLD. Details: A small clinical study in patients with NAFLD shows that following a calorie-restricted diet and taking zinc 30 mg daily for 12 weeks reduces certain liver enzymes, but does not improve steatosis or reduce weight, when compared with taking placebo and following a calorie-restricted diet (104046).
• Non-Hodgkin lymphoma. It is unclear if oral zinc is beneficial for non-Hodgkin lymphoma prevention. Details: Population research has found that higher dietary intake of zinc is associated with a 42% decreased odds of developing non-Hodgkin lymphoma (87048).
• Obesity. Small studies suggest that oral zinc does not reduce weight or calorie intake in people with overweight or obesity. Details: A very small clinical study in adults with overweight or obesity shows that taking supplemental zinc 30 mg daily for 12 weeks does not reduce body weight, body mass index (BMI), calorie intake, or macronutrient intake when compared with placebo (112471). Additionally, clinical research in adults with overweight or obesity shows that taking zinc gluconate 25 mg and L-selenomethionine 200 mcg once daily for 8 weeks does not improve BMI, total body fat, or fat free mass when compared with placebo (111448).
• Obsessive-compulsive disorder (OCD). It is unclear if oral zinc reduces symptoms in patients with OCD. Details: A small clinical study in patients with OCD shows that taking zinc sulfate 200 mg twice daily with fluoxetine 20 mg daily for 8 weeks modestly reduces the severity of OCD symptoms when compared with taking placebo with fluoxetine (90223).
• Oral mucositis. It is unclear if oral or topical zinc prevents oral mucositis due to chemotherapy. Some small clinical studies suggest that oral zinc might prevent mucositis due to radiotherapy. Details: Two small clinical studies in adults with leukemia and other cancers shows that taking zinc sulfate 220 mg three times daily for 14 days or until the end of chemotherapy treatment reduces oral mucositis and pain intensity when compared with placebo (90191,98132). However, smaller doses have not shown benefit. A small clinical study in children and adolescents with leukemia shows that taking zinc 2 mg/kg daily (up to 60 mg daily) in two divided doses does not affect chemotherapy-induced mucositis when compared with placebo (90204). An unblinded clinical study in children and adolescents aged 8-16 years with recently diagnosed leukemia shows that taking zinc gluconate 50 mg (7 mg elemental zinc) daily does not significantly reduce the incidence or duration of oral mucositis when compared with a control group not receiving zinc (104816). Zinc also doesn't seem to be beneficial with high-dose chemotherapy. A small clinical study in adolescents and adults receiving high-dose chemotherapy prior to undergoing hematopoietic stem cell transplantation (HSCT) suggests that taking zinc sulfate 220 mg (50 mg elemental zinc) twice daily, beginning one day prior to the chemotherapy regimen and continuing for 3 weeks, does not affect the severity, duration, or onset of mucositis when compared with placebo (90215). Other preliminary clinical research in children aged 3-18 years receiving chemotherapy for leukemia or other cancer also shows that taking zinc 1 mg/kg orally daily for 14 days, beginning on the first day of chemotherapy, does not reduce the incidence or severity of mucositis when compared with placebo (111447). Topical zinc has also been investigated for radiation-induced or chemotherapy-induced oral mucositis. In two clinical studies, using 7.5 mL of a mouthwash containing zinc chloride 0.2% twice for 2 minutes every 8 hours for 3 weeks modestly reduces the incidence and severity of oral mucositis, and improves quality of life, when compared with a placebo mouthwash (106232,109690). In one study, the average patient weight was higher in the group using the mouthwash containing zinc (106232). Other preliminary clinical research in adults with head and neck cancer undergoing radiotherapy treatment, consisting of at least 30 Gy radiation exposure shows that using zinc sulfate 1% mouthwash, 5 mL three times daily for 6 weeks, beginning on the first day of radiation therapy, moderately improves oral mucositis severity and pain scores when compared with chlorhexidine 0.2% or placebo mouthwash (111291). Taking zinc orally might be beneficial in radiation-induced oral mucositis. A small clinical study in patients with head and neck tumors shows that taking zinc sulfate, providing 150 mg elemental zinc, daily starting at the first day of radiation therapy and ending at 6 weeks, reduces the severity of mucositis and prolongs the onset of mucositis when compared with placebo (86981). Another clinical study in patients with head and neck cancer shows that taking zinc sulfate 150 mg daily during and after chemoradiotherapy treatment, consisting of a total 69.5 Gy radiation exposure and cisplatin 40 mg/m2 weekly, is associated with less severe mucositis when compared with placebo (105677).
• Osteoporosis. It is unclear if oral zinc improves bone density in patients with osteoporosis. Details: Population research has found that reduced zinc intake and lower zinc serum levels seem to be associated with lower bone mineral density (BMD) (6920,14410). In elderly patients with at least marginal zinc deficiency who are taking standard therapy for osteoporosis, preliminary clinical research shows that taking zinc acetate dihydrate (Nobelzin, Nobelpharma) providing elemental zinc 25 mg twice daily for 12 months increases BMD when compared with baseline. Increases in serum zinc were associated with improvements in BMD. However, it is unclear if increases in BMD were significant when compared with placebo (106230). It is also unclear if zinc improves BMD in patients without zinc deficiency. A small clinical study in healthy postmenopausal adults suggests that taking zinc in combination with copper, manganese, and calcium might slow bone loss when compared with placebo (1994). It is not clear if this effect is due to zinc, other ingredients, or the combination.
• Overall mortality. It is unclear if oral zinc reduces overall mortality in young children. Details: A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc in daily doses of at least 10 mg reduces the risk of all-cause mortality by 16% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation. The risk of mortality was reduced by 54% when children took zinc for up to one year, but overall mortality was not reduced in studies lasting at least one year (106239).
• Periodontitis. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with moderate or advanced periodontitis shows that taking a combination supplement containing zinc 3.75 mg, alpha-lipoic acid, coenzyme Q10, cranberry extract, grapeseed extract, selenium, vitamin C, and vitamin E twice daily for 8 weeks in addition to standard nonsurgical therapy does not reduce periodontal indices including bleeding on probing, gingival recession, plaque index, or inflammation when compared with placebo (111708).
• Polycystic ovary syndrome (PCOS). It is unclear if oral zinc is beneficial in patients with PCOS. Details: A small clinical study in adults taking metformin for PCOS shows that also taking zinc sulfate 220 mg (50 mg elemental zinc) daily for 8 weeks improves hair loss and facial growth, but not acne, when compared with placebo (96071).
• Postoperative sore throat. It is unclear if oral zinc is beneficial for postoperative sore throat. Details: Clinical research shows that dissolving a lozenge containing zinc 40 mg as zinc sulfate in the mouth in the 30 minutes before surgery involving endotracheal intubation reduces the incidence of postoperative sore throat by 58% when compared with placebo lozenges. It also seems to reduce the severity of postoperative sore throat that does occur (97138). Other clinical research in adults undergoing a procedure that required endotracheal intubation shows that using a preoperative 30-mL gargle containing zinc 40 mg does not affect sore throat scores when compared with magnesium sulphate 250 mg or budesonide 200 mcg gargles (114763).
• Postpartum depression. It is unclear if oral zinc prevents postpartum depression after a Cesarean section (C-section). Details: A small observational study in pregnant patients with anemia who underwent C-section has found that taking zinc sulfate 100 mg daily for 4 days after surgery is associated with a 75% reduction in the odds of developing postpartum depression when compared with no supplementation (109452).
• Premenstrual syndrome (PMS). It is unclear if oral zinc improves symptoms in patients with PMS. Details: A small clinical study in female college students shows that taking elemental zinc 30 mg daily for 3 months improves quality of life, but not quality of sleep, when compared with placebo (104049).
• Preterm labor. It is unclear if oral zinc reduces the risk of preterm labor. Details: Observational research has found that low dietary intake of zinc during pregnancy is associated with an increased likelihood of preterm deliveries (87471). Also, most meta-analyses of clinical research show that taking zinc supplements during pregnancy modestly reduces the risk of preterm birth (106231). However, one large meta-analysis of 22 clinical studies shows that zinc supplementation during pregnancy seems to have little or no benefit for reducing the risk of preterm birth when compared with control (105679). Zinc supplementation also does not seem to reduce the risk of stillbirth, neonatal death, spontaneous abortion, or premature rupture of membranes (97142,105679,106231).
• Prostatitis. It is unclear if oral zinc improves symptoms in men with chronic prostatitis. Details: A clinical study in men with chronic prostatitis shows that taking zinc sulfate 220 mg daily along with prazosin 2 mg daily for 12 weeks does not improve difficulty urinating or quality of life, but does seem to improve pain, when compared with prazosin alone (90210). The validity of this study was limited by a significant dropout rate.
• Pruritus. There is limited evidence on the oral use of zinc for reducing pruritis in hemodialysis patients. Details: A small clinical study in end-stage renal disease patients with hemodialysis-associated pruritus shows that taking zinc sulfate 220 mg twice daily for 2 months reduces pruritus severity when compared with placebo (90218).
• Psoriatic arthritis. It is unclear if oral zinc improves psoriatic arthritis symptoms. Details: Two small clinical trials in patients with psoriatic arthritis show that taking zinc orally, alone or in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), does not seem to reduce pain or improve function when compared with control (6514,6515).
• Respiratory tract infections. It is unclear if oral zinc reduces respiratory tract infections in children. Details: An open-label study in children aged 6 months to 5 years with zinc deficiency shows that taking zinc sulfate 20 mg orally once daily for 2 weeks reduces the number of episodes and the mean duration of upper and lower respiratory tract infections over 6 months of follow-up when compared with the 6 months prior to zinc supplementation (104815). The validity of this finding is limited by the lack of a comparator group.
• Rosacea. It is unclear of oral zinc improves symptoms of rosacea or quality of life. Details: A small clinical trial shows that taking zinc sulfate 440 mg in two divided doses daily for 90 days does not improve quality of life or symptoms associated with rosacea when compared with placebo (90195).
• Seizures. It is unclear if oral zinc reduces recurrent febrile seizures in children. Details: Although some individual preliminary clinical research disagrees (96069), a meta-analysis of generally low-quality research in children under 5 years of age with a previous febrile seizure shows that taking zinc sulfate 1-2 mg/kg or 20 mg daily for 6-12 months does not reduce febrile seizure recurrence when compared with placebo (106237). Also, a small clinical study shows that taking zinc does not increase the time to first febrile seizure recurrence (96069).
• Sepsis. It is unclear if oral zinc is beneficial in pediatric or adult patients with sepsis. Details: A meta-analysis of clinical research in children under the age of five years shows that supplementation with zinc reduces the risk of sepsis mortality by 57% when compared with either placebo, other vitamin and/or mineral supplementation, or no supplementation (106239). Also, a small clinical study in newborns with sepsis shows that giving zinc sulfate monohydrate 3 mg/kg twice daily for 10 days along with antibiotics reduces the likelihood of neurological abnormalities, such as those related to posture, behavior, and reflexes, by 70% when compared with antibiotics alone. Mortality and length of hospital stay were not improved, but the study may have been inadequately powered to detect a difference in these parameters (96077). Another study in preterm infants with late-onset sepsis (developing at least 72 hours after birth), shows that giving 1.4 mg/kg elemental zinc daily orally for 10 days in addition to antibiotics reduces the number of infants with unresolved sepsis at 10 days, and reduces C-reactive protein and procalcitonin levels, when compared with giving antibiotics alone (104819). A meta-analysis of small clinical studies in infants less than 4 months old shows that administering zinc 1-3 mg/kg daily for 1-18 weeks may reduce the rate of infant mortality and treatment failure when compared with placebo or control, but does not seem to prevent sepsis or improve sepsis-related mortality (108444). Additionally, zinc has been evaluated in adults. A single-center observational study in adults with sepsis found that administering zinc orally or enterally in various doses, ranging from less than 15 mg to greater than 50 mg daily, does not improve survival rates or reduce the length of stay in the intensive care unit (115630).
• Shigellosis. It is unclear if oral zinc is beneficial in patients with acute shigellosis from food poisoning. Details: A small clinical study in malnourished children with acute shigellosis (food poisoning) shows that administering a multivitamin syrup containing elemental zinc 20 mg daily for 2 weeks, in addition to standard treatment, can improve recovery time and reduce the number of diarrhea episodes when compared with multivitamin syrup without elemental zinc (87088).
• Sleep deprivation. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in sleep-deprived recreational athletes shows that taking a combination of zinc 90 mg, magnesium 1350 mg, and vitamin B6 31.5 mg orally for 3 nights at bedtime does not change sleep quality, subjective sleepiness, mood, or fatigue when compared with placebo (113655).
• Substance use disorder. It is unclear if oral zinc is beneficial for substance use disorder. Details: Preliminary clinical research in adults with opioid use disorder that were being treated with methadone shows that taking zinc sulfate, containing 12 mg zinc, orally daily for 3 months moderately improves relapse prevention scores, including drug use and drug craving scores, when compared with control. Taking zinc also modestly improved stress and anxiety scores (111293).
• Tonsillopharyngitis. It is unclear if oral zinc is beneficial in patients with tonsillopharyngitis. Details: A moderate-sized, open-label clinical study in pediatric patients aged 3 to 10 years with acute tonsillopharyngitis shows that taking a specific combination solution (PediaFlù, Pediatrica S.r.l.) containing zinc (age dependent doses ranging from 2 to 4 mg), honey, propolis, and pelargonium sidoides daily for 6 days along with standard of care reduces tonsilitis severity scores when compared with standard care alone; however, this improvement is not clinically significant. (115632). It is not clear if these effects are due to zinc, other ingredients, or the combination.
• Traumatic brain injury (TBI). There is limited evidence on the parenteral use of zinc for closed head injury. Details: A small clinical study shows that administering zinc parenterally immediately following severe closed head injury seems to improve the rate of neurological recovery when compared with standard therapy (2696).
• Tuberculosis. It is unclear if oral zinc can improve outcomes in patients receiving tuberculosis treatment. Details: Low levels of zinc are common in patients with tuberculosis. In patients newly diagnosed with tuberculosis and using anti-tuberculosis treatment, some clinical research shows that taking zinc 50 mg daily as zinc sulfate for 6 months increases the number of patients with negative sputum smears by 50% to 80% within the first 6 weeks of treatment when compared with placebo. However, there were no differences in the number of patients with negative smears after this time point. There were also improvements in some liver function enzyme levels after 2 months, but not 6 months, when compared with placebo (106238). However, other clinical research shows that taking zinc 15-90 mg daily for 2-6 months does not improve cure rates or sputum smear conversions when compared with placebo. However, when combined with vitamin A, serum levels of vitamin A, zinc, and hemoglobin were modestly improved and there was a modest increase in sputum smear conversions (109754).
• Urinary tract infections (UTIs). It is unclear if oral zinc is beneficial in children with UTI. Details: A low-quality, clinical study in children aged 3-12 years hospitalized for a UTI and receiving intravenous antibiotic treatment shows that taking zinc 1 mg/kg daily for 14 days reduces the duration of dysuria, urinary frequency, and urgency when compared with intravenous antibiotics alone. Zinc does not improve fever or the time to negative urine culture (96081). However, this study did not demonstrate that treatment groups were equal at baseline.
• Venous leg ulcers. It is unclear if oral or topical zinc is beneficial for leg ulcer healing. Details: Two small studies in elderly patients with leg ulcers suggest that using a zinc saline solution on a wound dressing or applying zinc oxide to a dressing might improve healing of leg ulcers (2694,6901). However, oral zinc supplementation does not seem to be beneficial. A meta-analysis of four small clinical trials in patients with venous leg ulcers shows that taking zinc orally does not improve healing when compared with placebo (104079).
• Vertigo. Oral zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with benign paroxysmal positional vertigo with serum 25-hydroxyvitamin D levels less than 20 ng/mL shows that taking a specific combination product containing zinc 7.5 mg, alpha-lipoic acid 600 mg, L-carnosine 165 mg, curcumin 100 mg, piperine 1 mg, cholecalciferol 800 units, vitamin B2 0.8 mg, and vitamin B6 1 mg (Vertistop D, Difass) orally daily for 6 months moderately reduces the number of vertigo relapse episodes when compared with control. However, in patients with serum 25-hydroxyvitamin D levels greater than 20 ng/mL that took a specific combination product containing zinc 7.5 mg, alanine 600 mg, L-carnosine 165 mg, curcumin 100 mg and piperine 1 mg (Vertistop L, Difass) orally daily for 6 months there was no difference in relapse episodes when compared with control (111294). It is unclear if this effect is due to zinc, other ingredients, or the combination.
• Water warts. It is unclear if oral zinc is beneficial for the treatment of water warts in children. Details: In children with water warts, preliminary clinical research shows that taking zinc sulfate heptahydrate (as Zinco syrup) for 2 months results in lesion resolution in 70% of patients when compared with baseline. Lesion resolution occurred in an additional 13% of patients in the month after treatment completion, with no recurrence in any of these children over the next 9 months. Zinc 3 mg daily was used in children up to 3 years of age, and 5 mg daily was used in older children (106234). Due to the lack of a comparator group, it is unclear if these outcomes are due to zinc or the natural resolution of the condition.
• Wound healing. Topical zinc might be beneficial for the healing of uncomplicated wounds. Details: A small clinical study shows that applying zinc chloride solution, standardized to contain zinc 20 mcg/mL, twice daily improves wound healing when compared with saline solution in patients with uncomplicated, skin wounds. However, when zinc is administered as a component of an insulin product (Humulin, Eli Lilly and Company), it seems to be more effective than zinc chloride alone (90192).
• Wrinkled skin. Topical zinc has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A topical preparation containing 10% vitamin C as L-ascorbic acid and acetyl tyrosine, zinc sulfate, sodium hyaluronate, and bioflavonoids (Cellex-C High Potency Serum) applied to photo-aged facial skin for 3 months seems to improve fine and coarse wrinkling, yellowing and sallowness, roughness, and skin tone when compared with placebo (6155). More evidence is needed to rate zinc for these uses.

(Read more about ZINC)

LIKELY SAFE ...when used orally and appropriately. Biotin has been safely used in doses up to 300 mg daily for up to 6 months. A tolerable upper intake level (UL) has not been established (1900,6243,95662,102965). ...when applied topically as cosmetic products at concentrations of 0.0001% to 0.6% biotin (19344).

POSSIBLY SAFE ...when used intramuscularly and appropriately (8468,111366).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Biotin has been safely used at adequate intake doses of 5-25 mcg daily for up to 6 months (173,6243,19347,19348,111365). A tolerable upper intake level (UL) has not been established.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Biotin has been safely used at the adequate intake (AI) dose of 30 mcg daily during pregnancy and 35 mcg daily during lactation. It has also been used in supplemental doses of up to 300 mcg daily (6243,7878). A tolerable upper intake level (UL) has not been established.

(Read more about BIOTIN)

POSSIBLY SAFE ...when used orally and appropriately short-term. A specific butcher's broom rhizome extract (Fagorutin Ruscus Kapseln, GlaxoSmithKline Consumer Healthcare) has been used with apparent safety at a dose of 75 mg daily for up to 3 months (9932,37502). A specific combination product (Cyclo 3 Fort, Pierre Fabre Medicament) containing butcher's broom root extract, hesperidin methyl chalcone, and vitamin C has been used with apparent safety in doses providing butcher's broom root extract 150 mg twice daily for up to 3 months or 300 mg three times daily for up to 1 month (10068,37494,94779). There is insufficient reliable information available about the safety of butcher's broom when used topically.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about BUTCHER'S BROOM)

LIKELY SAFE ...when used orally in amounts typically found in food. Capsicum has Generally Recognized as Safe (GRAS) status in the US (4912). ...when used topically and appropriately (7038,10650,105345). The active capsicum constituent capsaicin is an FDA-approved ingredient used in certain over-the-counter, topical preparations (272).

POSSIBLY SAFE ...when used orally and appropriately, short-term in medicinal amounts. A specific sustained-release chili extract (Capsifen) has been used safely in doses of up to 200 mg daily, for up to 28 days (105196). ...when used intranasally and appropriately, short-term. Capsicum-containing nasal sprays, suspensions, and swabs seem to be safe when applied multiple times over 24 hours or when applied daily or every other day for up to 14 days. Although no serious side effects have been reported in clinical trials, intranasal application of capsicum-containing products can be very painful (14322,14324,14328,14329,14351,14352,14353,14356,14357) (14358,14359,14360,15016,105204). POSSIBLY UNSAFE when used orally, long-term or in high doses. There is concern that long-term use or use of excessive doses might be linked to hepatic or kidney damage, as well as hypertensive crisis (12404,40569,40606). There is insufficient reliable information available about the safety of capsicum when injected.

CHILDREN: POSSIBLY UNSAFE
when used topically in children under 2 years old (272). There is insufficient reliable information available about the safety of capsicum when used orally in children.

PREGNANCY: LIKELY SAFE
when used topically and appropriately (272).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. Capsicum 5 mg daily has been used for up to 28 days during the latter half of the second trimester and the third trimester (96457).

LACTATION: LIKELY SAFE
when used topically and appropriately (272).

LACTATION: POSSIBLY UNSAFE
when used orally. Dermatitis can sometimes occur in infants when foods heavily spiced with capsicum peppers are ingested during lactation (739). Also, observational research suggests that intake of raw capsicum peppers during pregnancy is associated with an increased risk of sensitization to inhalant allergens in children by the age of 2 years (41021).

(Read more about CAPSICUM)

LIKELY SAFE ...when used orally and appropriately (13161,14306,14307,14308,15655,15752,17187,92271,92274,103247)(103250,108898). However, cocoa naturally contains caffeine, and caffeine may be unsafe when used orally in doses of more than 400 mg daily (11733,98806). While most cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), one cup of unsweetened, dry cocoa powder can contain up to 198 mg of caffeine (100515). To be on the safe side, cocoa should be used in amounts that provide less than 400 mg of caffeine daily. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine naturally found in ingredients such as cocoa does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Advise patients to consume cocoa in moderation. ...when used topically. Cocoa butter is used extensively as a base for ointments and suppositories and is generally considered safe (11).

CHILDREN: POSSIBLY UNSAFE
when dark chocolate is used orally. Cocoa and dark chocolate products worldwide contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Children are at increased risk of adverse effects from intake of lead and/or cadmium. There is insufficient reliable information available about the safety of other chocolate-based products that typically contain smaller quantities of cocoa.

PREGNANCY: POSSIBLY SAFE
when used orally in moderate amounts. However, due to the caffeine content of cocoa preparations, intake should be closely monitored during pregnancy to ensure moderate consumption. Fetal blood concentrations of caffeine approximate maternal concentrations (4260). Some research has found that intrauterine exposure to even modest amounts of caffeine, based on maternal blood levels during the first trimester, is associated with a shorter stature in children ages 4-8 years (109846). While many cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), unsweetened, dry cocoa powder can contain up to 198 mg of caffeine per cup (100515). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, doses of up to 300 mg daily can be consumed during pregnancy without an increased risk of spontaneous abortion, still birth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). To be on the safe side, cocoa should be used in amounts that provide less than 300 mg of caffeine daily. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cocoa, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

PREGNANCY: POSSIBLY UNSAFE
when used orally in large amounts. Caffeine found in cocoa crosses the placenta producing fetal blood concentrations similar to maternal levels (4260). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Additionally, high intake of caffeine during pregnancy have been associated with premature delivery, low birth weight, and loss of the fetus (6). While many cocoa products contain only small amounts of caffeine (about 2-35 mg per serving) (2708,3900), unsweetened, dry cocoa powder can contain up to 198 mg of caffeine per cup (100515). To be on the safe side, cocoa should be used in amounts that provide less than 300 mg of caffeine daily (2708). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cocoa, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Large doses or excessive intake of cocoa should be avoided during pregnancy.

LACTATION: POSSIBLY SAFE
when used in moderate amounts or in amounts commonly found in foods. Due to the caffeine content of cocoa preparations, intake should be closely monitored while breastfeeding. During lactation, breast milk concentrations of caffeine are thought to be approximately 50% of serum concentrations. Moderate consumption of cocoa would likely result in very small amounts of caffeine exposure to a nursing infant (6). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cocoa, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Consumption of excess chocolate (16 oz per day) may cause irritability and increased bowel activity in the infant (6026). Cocoa and dark chocolate products worldwide also contain heavy metals such as lead and cadmium. In the US, one ounce (approximately 28 grams) of most commercially available dark chocolate products tested contained levels of lead and/or cadmium above the maximum allowable dose level for California, with cadmium levels generally increasing with the percentage of cocoa (109847,109848,109849). Large doses or excessive intake of cocoa should be avoided during lactation.

(Read more about COCOA)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Damiana has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (12,46933,11866).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about DAMIANA)

POSSIBLY SAFE ...when used orally and appropriately. Dong quai has been used with apparent safety in a dose of 4.5 grams daily for 24 weeks, or in combination with other ingredients in doses of up to 150 mg daily for up to 6 months (19552,35797). ...when used intravenously as a 25% solution, in a dose of 200-250 mL daily for up to 20 days (48438,48442,48443,48483).

POSSIBLY UNSAFE ...when used orally in large amounts, long-term. Theoretically, long-term use of large amounts of dong quai could be harmful. Dong quai contains several constituents such as bergapten, safrole, and isosafrole that are considered carcinogenic (7162). There is insufficient reliable information available about the safety of dong quai when used topically.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Dong quai has uterine stimulant and relaxant effects (8142); theoretically, it could adversely affect pregnancy. Observational research has found that intake of An-Tai-Yin, an herbal combination product containing dong quai and parsley, during the first trimester is associated with an increased risk of congenital malformations of the musculoskeletal system, connective tissue, and eyes (15129).

LACTATION:
Insufficient reliable information available; avoid use.

(Read more about DONG QUAI)

LIKELY SAFE ...when used orally or parenterally and appropriately. Folic acid has been safely used in amounts below the tolerable upper intake level (UL). The UL for folic acid is based only on supplemental folic acid and is expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for folic acid in adults is 1000 mcg (6241). In cases of megaloblastic anemia resulting from folate deficiency or malabsorption disorders such as sprue, oral doses of 1-5 mg per day can also be used safely until hematologic recovery is documented, as long as vitamin B12 levels are routinely measured (6241,7725,8739).

POSSIBLY SAFE ...when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term. L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks (104913,104914) and a dose of 113 mcg daily for 24 weeks (104920). A specific L-5-MTHF product (Metafolin, Eprova) has been used with apparent safety at a dose of 1.3 mg daily for 12 weeks (104912).

POSSIBLY UNSAFE ...when used orally in large doses, long-term. Clinical research shows that taking folic acid daily in doses of 800 mcg to 1200 mcg for 3-10 years significantly increases the risk of developing cancer and adverse cardiovascular effects compared to placebo (12150,13482,16822,17041). Doses above 1 mg per day should also be avoided if possible to prevent precipitation or exacerbation of neuropathy related to vitamin B12 deficiency (6241,6242,6245). However, there is contradictory evidence suggesting that higher doses may not be harmful. There is some evidence that doses of 5 mg per day orally for up to 4 months can be used safely if vitamin B12 levels are routinely measured (7725). Also, other clinical research suggests that folic acid supplementation at doses up to 5 mg, usually in combination with vitamin B12, does not increase the risk of cancer when taken for 2-7 years (91312). Very high doses of 15 mg per day can cause significant central nervous system (CNS) and gastrointestinal side effects (505).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Folic acid has been safely used in children in amounts below the tolerable upper intake level (UL). The ULs for folic acid are based only on supplemental folic acid and are expressed in mcg folic acid. Dietary folate is not included in UL calculations, as dietary folate consumption has not been associated with adverse effects. The UL for children is: 1-3 years of age, 300 mcg; 4-8 years of age, 400 mcg; 9-13 years of age, 600 mcg; 14-18 years of age, 800 mcg (6241).

CHILDREN: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately. One clinical study in infants aged 27 days and younger shows that consuming a formula containing L-5-MTHF (Metafolin, Merck & Cie) 10.4 mcg/100 mL daily has been used with apparent safety for up to 12 weeks (104918).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Folic acid 300-400 mcg is commonly used during pregnancy for prevention of neural tube defects (8739). Miscarriage rates and negative impacts on fetal growth have not been shown to increase with peri-conception supplemental folic acid intakes of 4 mg per day (91320,91322). However, other research shows that taking more than 5 mg per day during pregnancy may reduce development of cognitive, emotional, and motor skills in infants (91318). Also, the tolerable upper intake level (UL) of folic acid for pregnant or lactating women is 800 mcg daily for those 14-18 years of age and 1000 mcg daily for those 19 years and older (6241).

PREGNANCY AND LACTATION: POSSIBLY SAFE
when L-5-methyltetrahydrofolate (L-5-MTHF), the reduced form of folate, is used orally and appropriately, short-term. L-5-MTHF has been used with apparent safety at a dose of 416 mcg daily for 16 weeks during lactation. Compared to folic acid, this form seems to further increase the folate concentration of red blood cells, but not breast milk (104913,104914).

(Read more about FOLIC ACID)

POSSIBLY SAFE ...when used topically and appropriately. Gotu kola has been used safely in a cream or ointment for up to 10 weeks (11072,11073,67372,102792,105329,105335). An emulsion containing gotu kola extract 3% and other ingredients has been applied safely to the skin twice daily for up to 60 days (111571). ...when used orally and appropriately. Gotu kola extract has been used with apparent safety in doses of up to 180 mg daily for up to 12 months or 1000 mg daily for 60 days. Dried gotu kola has been used with apparent safety in doses of up to 2200 mg daily for 4 weeks (6887,11062,11063,11064,11065,11066,11067,11068,11069,11070)(11071,99756,99757,99758,105329,105332,105333). A specific gotu kola extract (Centellicum, Horphag Research Ltd) 450-675 mg daily has been used with apparent safety for up to 6 weeks (99756,99757).

PREGNANCY: POSSIBLY SAFE
when used topically and appropriately (11073,13559). There is insufficient reliable information available about the safety gotu kola when used orally during pregnancy; avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about GOTU KOLA)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Hawthorn preparations in doses of up to 1800 mg daily seem to be safe when used for up to 16 weeks. Although hawthorn might be safe for long-term use, current studies have not evaluated safety past 16 weeks (8279,8280,8281,10144,17203,104689). There is insufficient reliable information available about the safety of hawthorn when used topically.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about HAWTHORN)

POSSIBLY SAFE ...when used orally and appropriately. L-arginine has been used safely in clinical studies at doses of up to 24 grams daily for up to 18 months (3331,3460,3595,3596,5531,5532,5533,6028,7815,7816)(8014,8473,13709,31943,91195,91196,91963,99264,99267,110380)(110387). A tolerable upper intake level (UL) for arginine has not been established, but the observed safe level (OSL) of arginine intake established in clinical research is 20 grams (31996). ...when used intravenously and appropriately. Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically and appropriately. L-arginine appears to be safe when 5 grams is applied as a topical cream twice daily for 2 weeks or when a dentifrice is used at a dose of 1.5% w/w for up to 2 years (14913,96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks (96807).

CHILDREN: POSSIBLY SAFE
when used orally in premature infants and children (8474,32286,96803,97392,110391). ...when used intravenously and appropriately (97392). Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically, short-term. A dentifrice containing L-arginine appears to be safe when used at a dose of 1.5% w/w for up to 2 years in children at least 3.7 years of age (96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks in children at least 13 years of age (96807).

CHILDREN: POSSIBLY UNSAFE
when used intravenously in high doses. Parenteral L-arginine is an FDA-approved prescription product (15). However, when higher than recommended doses are used, injection site reactions, hypersensitivity reactions, hematuria, and death have occurred in children (16817).

PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term. L-arginine 12 grams daily for 2 days has been used with apparent safety in pregnancy during the third trimester (11828). L-arginine 3 grams daily has been taken safely during the second and/or third trimesters (31938,110379,110382). ...when used intravenously and appropriately, short-term. Intravenous L-arginine 20-30 grams daily has been used safely in pregnancy for up to 5 days (31847,31933,31961,31978).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about L-ARGININE)

LIKELY SAFE ...when prescription products are used orally and appropriately (12033). ...when niacinamide supplements are taken orally in doses below the tolerable upper intake level (UL) set by the Institute of Medicine (IOM). The UL of niacinamide is 30 mg daily for adults 18 years of age and 35 mg daily for adults 19 years and older (6243).

POSSIBLY SAFE ...when used orally in doses greater than 30 mg but less than 900 mg daily. The European Food Safety Authority has set the tolerable upper intake level (UL) of niacinamide at 900 mg daily (104937). However, oral niacinamide has been safely used in doses up to 1500 mg daily for 12 weeks in some clinical trials (25561,94188,98940,107709,110502) and up to 1000 mg daily for 12 months in other trials (93362,113559,113560). ...when used topically and appropriately for up to 16 weeks (5940,93360,110497,110498,110501,113681,113683,113684).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Niacinamide has been safely used in children for up to 7 years in doses below the tolerable upper intake level (UL) (4874,9957). The UL of niacinamide for children by age is: 1-3 years, 10 mg daily; 4-8 years, 15 mg daily; 9-13 years, 20 mg daily; 14-18 years, 30 mg daily (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the tolerable upper intake level (UL) for niacinamide. The UL of niacinamide during pregnancy and lactation is 30 mg daily for those 14-18 years of age and 35 mg daily for those 19 years and older (6243). There is insufficient reliable information available about the safety of larger oral doses of niacinamide or topical niacinamide; avoid using.

(Read more about NIACINAMIDE)

LIKELY SAFE ...when used orally and appropriately, short-term. Panax ginseng seems to be safe when used for up to 6 months (8813,8814,17736,89741,89743,89745,89746,89747,89748,103044)(103477,114980,114981,114984,114985). Panax ginseng sprout extract has also been used with apparent safety in doses up to 450 mg daily for up to 12 weeks (114983).

POSSIBLY UNSAFE ...when used orally, long-term. There is some concern about the long-term safety due to potential hormone-like effects, which might cause adverse effects with prolonged use (12537). Tell patients to limit continuous use to less than 6 months. There is insufficient reliable information available about the safety of Panax ginseng when used topically.

CHILDREN: LIKELY UNSAFE
when used orally in infants. Use of Panax ginseng in newborns is associated with intoxication that can lead to death (12). There is limited reliable information available about use in older children (24109,103049); avoid using.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Ginsenoside Rb1, an active constituent of Panax ginseng, has teratogenic effects in animal models (10447,24106,24107); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about PANAX GINSENG)

LIKELY SAFE ...when used orally and appropriately. Riboflavin 400 mg daily has been taken for up to 3 months, and 10 mg daily has been taken safely for up to 6 months (4912,91752,105480). A tolerable upper intake level (UL) has not been established (3094,91752,94089).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089). ...when used orally in higher doses for up to 1 year. Doses of 100-200 mg daily have been used safely for 4-12 months in children ages 9-13 years (71483,105484).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established (3094,94089).

(Read more about RIBOFLAVIN)

POSSIBLY SAFE ...when used orally and appropriately, short-term. L-theanine has been used safely in clinical research in doses of up to 900 mg daily for 8 weeks (12188,36439,96331,96332,96334,96341,97923,101986,104976). There is insufficient reliable information available about the safety of L-theanine when used long-term.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A specific L-theanine product (Suntheanine, Taiyo Kagaku) 200 mg twice daily has been used safely in males aged 8-12 years for up to 6 weeks (91744).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

(Read more about THEANINE)

LIKELY SAFE ...when used orally and appropriately. A tolerable upper intake level (UL) has not been established for thiamine, and doses up to 50 mg daily have been used without adverse effects (15,6243). ...when used intravenously or intramuscularly and appropriately. Injectable thiamine is an FDA-approved prescription product (15,105445).

CHILDREN: LIKELY SAFE
when used orally and appropriately in dietary amounts. A tolerable upper intake level (UL) has not been established for healthy individuals (6243).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in dietary amounts of 1. 4 mg daily. A tolerable upper intake level (UL) has not been established for healthy individuals (3094,6243).

(Read more about THIAMINE)

POSSIBLY SAFE ...when used orally and appropriately for up to 12 months (1784,1788,82041,82074,82089,82091,82120,82121,82151,82152)(82153,82154,82179,82180,82182,82183,104522,106845,110744). ...when used intravenously and appropriately, short-term (82074,82099,82147,82158,82159,82186,110744).

PREGNANCY: POSSIBLY UNSAFE
when used orally. In June 2019, the US Food and Drug Administration (FDA) issued a statement of warning that those who are pregnant or who could become pregnant should avoid vinpocetine (95751). In rats, vinpocetine has been associated with an increased risk of miscarriage at a dose of 60 mg/kg daily and with reduced fetal weight and increased incidence of birth defects at a dose of 5-20 mg/kg. Based on pharmacokinetic analyses, a daily vinpocetine dose of 10 mg in humans is comparable to a daily dose of 5 mg/kg in rats (99701).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about VINPOCETINE)

LIKELY SAFE ...when used orally, topically, intravenously, intramuscularly, or intranasally and appropriately. Vitamin B12 is generally considered safe, even in large doses (15,1344,1345,1346,1347,1348,2909,6243,7289,7881)(9414,9416,10126,14392,15765,82832,82949,82860,82864,90386)(111334,111551).

PREGNANCY: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B12 during pregnancy is 2.6 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA of vitamin B12 during lactation is 2.8 mcg daily (6243). There is insufficient reliable information available about the safety of larger amounts of vitamin B12 while breastfeeding.

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LIKELY SAFE ...when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of 100 mg daily in the form of pyridoxine for adults (15,6243). ...when used parenterally and appropriately. Injectable vitamin B6 (pyridoxine) is an FDA-approved prescription product (15).

POSSIBLY SAFE ...when used orally and appropriately in doses of 101-200 mg daily (6243,8558).

POSSIBLY UNSAFE ...when used orally in doses at or above 500 mg daily. High doses, especially those exceeding 1000 mg daily or total doses of 1000 grams or more, pose the most risk. However, neuropathy can occur with lower daily or total doses (6243,8195). ...when used intramuscularly in high doses and frequency due to potential for rhabdomyolysis (90795).

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses that do not exceed the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 30 mg daily for children aged 1-3 years, 40 mg daily for 4-8 years, 60 mg daily for 9-13 years, and 80 mg daily for 14-18 years (6243).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately in amounts exceeding the recommended dietary allowance (5049,8579,107124,107125,107135).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses, long-term (6243).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. A special sustained-release product providing vitamin B6 (pyridoxine) 75 mg daily is FDA-approved for use in pregnancy. Vitamin B6 (pyridoxine) is also considered a first-line treatment for nausea and vomiting in pregnancy by the American College of Obstetrics and Gynecology (111601). However, it should not be used long-term or without medical supervision and close monitoring. The tolerable upper intake level (UL) refers to vitamin B6 in the form of pyridoxine and is 80 mg daily for those aged 14-18 years and 100 mg daily for 19 years and older (6243).

PREGNANCY: POSSIBLY UNSAFE
when used orally in excessive doses. There is some concern that high-dose maternal vitamin B6 (pyridoxine) can cause neonatal seizures (4609,6397,8197).

LACTATION: LIKELY SAFE
when used orally in doses not exceeding the tolerable upper intake level (UL) of vitamin B6 in the form of pyridoxine 80 mg daily for those aged 14-18 years and 100 mg daily for those 19 years and older. The recommended dietary allowance (RDA) in lactating women is 2 mg daily (6243). There is insufficient reliable information available about the safety of vitamin B6 when used in higher doses in breast-feeding women.

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LIKELY SAFE ...when the fruit extract is used orally and appropriately, short-term. Vitex agnus-castus fruit extract has been used safely in studies at doses up to 40 mg daily, for up to 3 months (7055,7076,7077,7078,7079,12207,13393,15065,90617,90618,96435). There is insufficient reliable information available about the safety of vitex agnus-castus seeds when used orally or topically.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally. Theoretically, the hormonal effects of vitex agnus-castus might adversely affect pregnancy or lactation (10979,11456,13393,109439). Animal research shows that taking vitex agnus-castus fruit extract when planning to become pregnant or during pregnancy may increase the risk of infertility, low fetal body weight, abortion, and stillbirth (109439); avoid using.

(Read more about VITEX AGNUS-CASTUS)

LIKELY SAFE ...when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 40 mg daily (7135). ...when used topically and appropriately (2688,6538,6539,7135,8623,11051,111291).

POSSIBLY SAFE ...when used orally and appropriately in doses higher than the tolerable upper intake level (UL). Because the UL of zinc is based on regular daily intake, short-term excursions above 40 mg daily are not likely to be harmful. In fact, there is some evidence that doses of elemental zinc as high as 80 mg daily in combination with copper 2 mg can be used safely for approximately 6 years without significant adverse effects (7303,8622,92212). However, there is some concern that doses higher than the UL of 40 mg daily might decrease copper absorption and result in anemia (7135).

POSSIBLY UNSAFE ...when used intranasally. Case reports and animal research suggest that intranasal zinc might cause permanent anosmia or loss of sense of smell (11155,11156,11703,11704,11705,11706,11707,16800,16801,17083). Several hundred reports of anosmia have been submitted to the US Food and Drug Administration (FDA) and the manufacturer of some intranasal zinc products (Zicam) (16800,16801). Advise patients not to use intranasal zinc products.

LIKELY UNSAFE ...when taken orally in excessive amounts. Ingestion of 10-30 grams of zinc sulfate can be lethal in adults (7135). Chronic intake of 450-1600 mg daily can cause multiple forms of anemia, copper deficiency, and myeloneuropathies (7135,17092,17093,112473). This has been reported with use of zinc-containing denture adhesives in amounts exceeding the labeled directions, such as several times a day for several years (17092,17093). Advise patients to follow the label directions on denture adhesives that contain zinc.

CHILDREN: LIKELY SAFE
when used orally and appropriately (7135). Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL for children is based on age: 4 mg daily for 0-6 months, 5 mg daily for 7-12 months, 7 mg daily for 1-3 years, 12 mg daily for 4-8 years, 23 mg daily for 9-13 years, and 34 mg daily for 14-18 years (7135,97140).

CHILDREN: POSSIBLY UNSAFE
when used orally in high doses. Taking amounts greater than the UL can cause sideroblastic anemia and copper deficiency (7135). ...when used topically on damaged skin. An infant treated with 10% zinc oxide ointment for severe diaper rash with perianal erosions developed hyperzincemia. Absorption seemed to occur mainly via the erosions; plasma levels dropped after the erosions healed despite continued use of the ointment (106905).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during pregnancy in those 14-18 years of age and 40 mg daily in those 19-50 years of age (7135).

PREGNANCY: LIKELY UNSAFE
when used orally in doses exceeding the UL (7135).

LACTATION: LIKELY SAFE
when used orally and appropriately. Zinc is safe in amounts that do not exceed the tolerable upper intake level (UL) of 34 mg daily during lactation in those 14-18 years of age, and 40 mg daily for those 19-50 years of age (7135).

LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher doses can cause zinc-induced copper deficiency in nursing infants (7135).

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(Read more about BIOTIN)

ALPHA-ADRENERGIC AGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, butcher's broom might increase the effects and adverse effects of alpha-adrenergic agonists.  Details Animal and in vitro studies show that butcher's broom has alpha-adrenergic agonist effects (10069,94784).

ALPHA-ADRENERGIC ANTAGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, butcher's broom might reduce the effects of alpha-adrenergic antagonists.  Details Animal and in vitro studies show that butcher's broom has alpha-adrenergic agonist effects (10069,94784).

(Read more about BUTCHER'S BROOM)