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POSSIBLY INEFFECTIVE

• Night vision. Most research suggests that oral bilberry does not improve night vision in healthy individuals. Details: There is contradictory evidence about the effectiveness of bilberry for improving night vision; however, much of the research is of poor quality. In general, the most rigorous research shows that bilberry is not effective for improving night vision in healthy individuals (8139,9739,14280,35446). Whether bilberry can improve night vision in patients with night blindness is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of elderly Norwegian males with subjective cognitive impairment shows that drinking 330 mL of bilberry and red grape juice twice daily for 9 weeks does not improve measures of memory or motor skills when compared with placebo (110641).
• Age-related macular degeneration (AMD). Although there has been interest in using oral bilberry for AMD, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Asthenopia (eye strain). Small clinical studies suggest that oral bilberry fruit extract may improve objective measures of asthenopia, but it is unclear if oral bilberry improves subjective symptoms of asthenopia. Details: Two small clinical studies in adults who report general eye strain or those who look at computer or other display screens at work for long periods of time show that taking bilberry-derived anthocyanins 43.2 mg daily for 6 weeks or bilberry extract 240 mg daily for 12 weeks improves objective measures of eye strain after staring at computer screens when compared with placebo (103190,104195). However, bilberry extract did not improve subjective measures of eye strain in the study that evaluated these outcomes (104195). This study may have been underpowered to detect significant differences between groups. Bilberry has also been evaluated in combination with other ingredients for improving eye strain. A small clinical trial in patients with eye strain shows that a combination of fish oil, lutein, and bilberry extract containing bilberry anthocyanidins 59 mg, taken daily for 4 weeks, reduces dry eye, lower back pain, shoulder stiffness, and stuffy head when compared with placebo (35470). It is unclear if these effects are due to bilberry, other ingredients, or the combination.
• Atherosclerosis. Although there has been interest in using oral bilberry for atherosclerosis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Cataracts. Although there has been interest in using oral bilberry for cataracts, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Chronic venous insufficiency (CVI). It is unclear if oral bilberry is beneficial in patients with CVI. Details: One small clinical study in patients with CVI shows that taking bilberry extract containing anthocyanins 173 mg daily for 30 days reduces symptoms of CVI when compared with placebo (35510).
• Diabetes. It is unclear if oral bilberry is beneficial in patients with diabetes. Details: One small clinical trial in patients with type 2 diabetes shows that taking a specific extract of bilberry fruit (Mirtoselect, Indena S.p.A) 470 mg once, prior to taking an oral glucose tolerance test, lowers plasma glucose levels when compared with placebo (91507). However, a small crossover trial in Chinese patients with type 2 diabetes shows that taking bilberry fruit extract 700 mg twice daily for 4 weeks does not improve glycated hemoglobin (HbA1c), body weight, blood pressure, or lipid levels when compared with placebo (104194). The validity of the HbA1c-related findings is limited due to the short study duration.
• Diabetic retinopathy. It is unclear if oral bilberry is beneficial in patients with diabetic retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also reduced flow velocity in those with high-flow, diabetic retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Dry eye. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with severe dry eye symptoms suggests that taking bilberry extract 600 mg and docosahexaenoic fish oil 240 mg once daily for 3 months may modestly improve measures of tear quality and patient-reported scores for dry eye symptoms when compared with control (112415). However, the validity of these results is limited by the lack of a statistical comparison between groups. Additionally, it is unclear if these effects are due to bilberry, fish oil, or the combination.
• Dysmenorrhea. It is unclear if oral bilberry is beneficial in patients with dysmenorrhea. Details: One small clinical study in patients with dysmenorrhea shows that a specific bilberry product (Tegens) containing bilberry anthocyanoside 160 mg, taken twice daily beginning 3 days prior to menses and continuing for 8 days, reduces pelvic pain, lumbosacral pain, breast pain, nausea, vomiting, and headache when compared with placebo (35512).
• Exercise-induced muscle soreness. It is unclear if oral bilberry is beneficial for reducing exercise-induced muscle soreness. Details: A small clinical study in trained athletes shows that drinking 200 mL of bilberry juice, containing about 744 mg phenols and 80 mg anthocyanins, twice daily for 5 days prior to running a half-marathon modestly worsens muscle soreness immediately after the run when compared with placebo. There was no longer a difference in muscle soreness between groups within 1-2 days after the run (99540).
• Glaucoma. Small clinical studies suggest that oral bilberry fruit extract, when taken with maritime pine extract, may lower intraocular pressure in patients with glaucoma. It is unclear if oral bilberry alone is beneficial in patients with glaucoma. Details: One small, uncontrolled clinical trial in Japanese patients with open-angle glaucoma shows that taking a specific product (Sante Glagenox, Saten Pharmaceutical Co. Ltd.) containing bilberry fruit extract 90 mg and maritime pine extract 40 mg daily for 4 weeks reduces intraocular pressure by 8.7% when compared to baseline (104192). Another small clinical study in patients with high intraocular pressure shows that taking a specific product (Mirtogenol) containing bilberry fruit extract (Mirtoselect, Indena S.p.A.) 80 mg and maritime pine extract (Pycnogenol, Horphag Research) 40 mg twice daily for 6 months lowers intraocular pressure and improves intraocular blood flow when compared with no treatment (35456). It is unclear if these findings are due to bilberry, maritime pine, or the combination. A retrospective chart review of patients with normal tension glaucoma has found that taking bilberry anthocyanin 60 mg twice daily for at least 12 months is associated with improvements in visual function when compared to pretreatment (35472).
• Hemorrhoids. Although there has been interest in using oral bilberry for hemorrhoids, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Hyperlipidemia. It is unclear if oral bilberry is beneficial in patients with hyperlipidemia. Details: A small clinical study in adults with hyperlipidemia shows that taking bilberry-derived anthocyanins 320 mg daily for 4 weeks does not improve total cholesterol, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, or triglyceride levels. Further, no improvements in other biomarkers of cardiovascular disease were reported (110640). The validity of this study is limited by its short duration.
• Hypertension. Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with hypertension shows that consuming 500 mL of a juice containing bilberry, red grape, and chokeberry, with or without black currant (MANA Blue, TINE SA), daily for 12 weeks does not improve blood pressure when compared with placebo (92371).
• Hypertensive retinopathy. It is unclear if oral bilberry is beneficial in patients with hypertensive retinopathy. Details: One small clinical trial in adults with diabetic and hypertensive retinopathy shows that taking bilberry fruit extract 160 mg daily for 6 months, in addition to standard management, improves edema and measures of retinal circulatory health when compared with standard management alone. Bilberry in the form of a generic, commercially available product appears to produce less dramatic improvements than a branded formulation (Mirtoselect, Indena S.p.A.) containing matching anthocyanin content. This specific product also increased flow velocity for those with ischemic, hypertensive retinopathy when compared with either the generic bilberry extract or standard management alone (97032).
• Impaired glucose tolerance (prediabetes). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with impaired glucose tolerance and two markers of metabolic syndrome shows that consuming a diet high in whole grain products, fatty fish, and bilberries three times daily for 12 weeks reduces levels of plasma glucose when compared to baseline (35468). However, it is unclear if these findings are due to bilberry, another component of the diet, or the combination.
• Irritable bowel syndrome (IBS). Oral bilberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical trial in adults with IBS shows that consuming a formula containing powdered bilberry fruit, aerial agrimony parts, cinnamon quills, and slippery elm bark modestly improves bowel movement frequency and reduces symptoms such as abdominal pain, bloating, flatulence, and straining when compared to baseline (35462). It is unclear if these findings are due to bilberry, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral bilberry is beneficial in patients with metabolic syndrome. Details: One small clinical study in patients with metabolic syndrome shows that consuming a diet containing 400 grams of fresh bilberries daily does not affect body weight, glucose metabolism, or lipid metabolism when compared with a control diet (35473).
• Myopia. It is unclear if oral bilberry is beneficial in patients with myopia. Details: One small clinical trial in adults with myopia shows that a specific fermented bilberry fruit extract (Fermented Blueberry, Ajinomoto, Co., Inc.) 200 mg, taken twice daily for 4 weeks, improves night vision as well as the eye's ability to adjust focus when compared with placebo. The amplitude of accommodation was also significantly increased from 4.62 to 5.33 (91505).
• Obesity. It is unclear if oral bilberry is beneficial in patients with obesity. Details: One small clinical study in obese and overweight females shows that consuming 100 grams of frozen, whole bilberries daily for 33-35 days decreases weight and waist circumference when compared to baseline (35463). The validity of these findings is limited by the lack of a comparator group.
• Osteoarthritis. Although there has been interest in using oral bilberry for osteoarthritis, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Ulcerative colitis. It is unclear if oral bilberry is beneficial in patients with ulcerative colitis. Details: One small, open-label clinical study in adults with mild-to-moderate ulcerative colitis shows that consuming sieved bilberries and concentrated bilberry juice (Symrise GmbH & Co) 160 grams daily for 6 weeks induces remission in 46% of patients. Furthermore, 91% of patients achieved remission at the end of treatment, and 72% of patients achieved remission at the end of the study (91506). The validity of these findings is limited by the lack of a comparator group.
• Urinary tract infections (UTIs). Although there has been interest in using oral bilberry for UTIs, there is insufficient reliable information about the clinical effects of bilberry for this purpose.
• Varicose veins. Although there has been interest in using oral bilberry for varicose veins, there is insufficient reliable information about the clinical effects of bilberry for this purpose. More evidence is needed to rate bilberry for these uses.

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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.

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POSSIBLY INEFFECTIVE

• Head and neck cancer. Subcutaneous European mistletoe extract does not seem to improve survival in patients with head and neck cancer. Oral European mistletoe has not been evaluated for this use. Details: A large clinical trial in patients with head and neck squamous cell carcinoma shows that subcutaneous administration of European mistletoe extract before or after surgery or radiation does not improve overall survival or disease-free survival when compared with surgery or radiation alone (8842).
• Melanoma. Subcutaneous European mistletoe extract does not seem to improve long-term survival rates in patients undergoing surgery for stage II or III melanoma. Oral European mistletoe has not been evaluated for this use. Details: A phase III clinical trial in patients with stage II or III melanoma undergoing surgical removal of lesions and positive lymph nodes shows that subcutaneous administration of a specific European mistletoe extract (Iscador M) does not improve disease-free interval or overall survival over a period of 8 years when compared with observation alone (24780).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bladder cancer. It is unclear if subcutaneous or intravesical European mistletoe extract is beneficial in patients with bladder cancer. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in patients who have had transurethral resection for superficial urothelial bladder carcinoma shows that intravesical administration of a specific European mistletoe extract 50 mL, containing mistletoe lectin 10 ng/mL to 5000 ng/mL, weekly for 6 weeks might reduce bladder cancer recurrence rates at 12 months, with similar rates to those observed with bacillus Calmette-Guerin (BCG) therapy (15258). Also, a small retrospective chart review of patients with recurrent bladder cancer has found that subcutaneous administration of a specific European mistletoe extract (Iscucin Salicis, Wala Heilmittel GmbH) for several months might be associated with reduced tumor recurrence and an increased duration of tumor-free periods (93268).
• Breast cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with breast cancer. Oral European mistletoe has not been evaluated for this use. Details: Observational research in patients with solid tumors of the breast has found that subcutaneous administration of certain specific European mistletoe extracts (Iscador, Weleda; Helixor, Helixor Heilmittel GmbH & Co. KG) is associated with reduced tumor progression and improved survival when compared with a control (7045,15351,24798). However, these findings were not replicated in a randomized, controlled study. A small clinical trial in patients with breast cancer receiving chemotherapy shows that subcutaneous injection of European mistletoe extracts (Helixor A, Iscador M Spez) three times weekly for 18 weeks does not reduce the rate of relapse or metastasis or improve quality of life when compared with chemotherapy alone (99497).
• Cancer. A meta-analysis of several small, low-quality clinical studies suggests that subcutaneous European mistletoe extract might improve quality of life in some patients with cancer. Oral European mistletoe has not been evaluated for this use. Details: Several small clinical studies have assessed the impact of various European mistletoe extracts (PS76A2, Helixor, Isorel, Eurixor, and AbnobaViscum Quercus), given subcutaneously either alone or with chemotherapy, on quality of life in patients with various types of cancer (24777,24782,24786,24788,24803,24804,93259,93260,93262,93269). A meta-analysis of these and many other small clinical studies shows that subcutaneous administration of European mistletoe extract has a moderate effect on overall quality of life when compared with a control group, with significant improvements on various subdomains. A larger effect size is observed with more recent trials; however, this may be due to the inclusion of patients with less severe disease in more recent studies when compared with earlier studies (105839). The validity of these findings is limited by the high risk of bias of most of the included studies and the heterogeneity of the studies and patient populations.
• Cancer-related fatigue. A meta-analysis of several low-quality studies suggests that subcutaneous European mistletoe extract might improve fatigue in some patients with cancer. Oral European mistletoe has not been evaluated for this use. Details: A meta-analysis of 12 mostly small, unblinded randomized studies in 1525 patients with a variety of cancers shows that various European mistletoe extracts (e.g., Abnobaviscum, Eurixor, Helixor, Iscador, Lektinol) given subcutaneously at undefined doses modestly improves patient-reported fatigue scores when compared with placebo or usual care (110441). This report also describes a meta-analysis of 7 mostly large nonrandomized, retrospective studies in the same patient population. This analysis suggests that various European mistletoe extracts given subcutaneously may modestly improve clinician-reported fatigue when compared with usual care (110441). The validity of these findings is limited by the low quality and heterogeneity of the included studies.
• Chemotherapy-induced diarrhea. It is unclear if subcutaneous European mistletoe extract can reduce the rate of chemotherapy-induced diarrhea. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in patients with gastric cancer recovering from surgery and receiving chemotherapy with doxifluridine shows that subcutaneous administration of a specific European mistletoe extract (Abnobaviscum Quercus, Abnoba GmbH) three times weekly for 24 weeks reduces the risk of chemotherapy-induced diarrhea by 86% when compared with doxifluridine alone (93262).
• Colorectal cancer. Several small, low-quality clinical and observational studies suggest that subcutaneous administration of specific European mistletoe extracts may improve survival or tumor response in patients with colorectal cancer when used as adjunct therapy. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in patients with solid tumors of the colon shows that subcutaneous administration of a specific European mistletoe extract (Iscador, Weleda) increases survival time when compared with matched controls not receiving European mistletoe (7045). Another small clinical study in patients with advanced colorectal cancer shows that infusions of another specific European mistletoe extract (Isorel, Novipharm GmbH), in combination with chemotherapy and surgery, improves survival by at least 38% when compared with chemotherapy plus surgery or surgery alone (24783). Other small clinical studies in patients with colorectal cancer show that subcutaneous administration of another specific European mistletoe extract (Helixor, Helixor Heilmittel GmbH & Co. KG) 100-200 mg three times weekly, in addition to chemotherapy, nearly doubles survival over 2 years when compared with chemotherapy alone; however, between-group differences in tumor progression were not observed (24785,24789). Additionally, a small observational study in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy shows that subcutaneous administration of a specific European mistletoe extract (Abnobaviscum Quercus, Abnoba GmbH) 0.02 mg three times weekly for three weeks, and then slowly titrated up to 20 mg three times weekly for a total of 24 weeks, improves tumor response rates when compared with chemoradiotherapy alone (107285). Despite these promising results, much research in this field suffers from poor study design (10672).
• Common cold. It is unclear if subcutaneous European mistletoe extract can prevent the common cold. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in healthy individuals shows that subcutaneous administration of a specific European mistletoe extract (Iscador P or Iscador Qu, Weleda) twice weekly for 12 weeks does not reduce the frequency or duration of the common cold when compared with placebo (24806).
• Epilepsy. Although there has been interest in using oral European mistletoe for epilepsy, there is insufficient reliable information about the clinical effects of European mistletoe for this purpose.
• Gastric cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with gastric cancer. Oral European mistletoe has not been evaluated for this use. Details: One small clinical study in patients with solid tumors of the stomach shows that subcutaneous administration of a specific European mistletoe extract (Iscador, Weleda) improves survival when compared with matched controls not receiving European mistletoe (7045). Another small clinical study in patients with gastric cancer recovering from surgery shows that subcutaneous administration of a different European mistletoe extract (Abnobaviscum Quercus, Abnoba GmbH) three times weekly for 24 weeks plus chemotherapy improves quality of life, increases total white blood cell and eosinophil counts, and reduces the risk of chemotherapy-induced diarrhea by 86% when compared with chemotherapy alone. However, there is no effect on lymphocyte responses (93262). Much research in this field suffers from poor study design (10672).
• Hepatitis C. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with chronic hepatitis C. Oral European mistletoe has not been evaluated for this use. Details: While a small case series of patients with chronic hepatitis C has found that subcutaneous injection of a specific aqueous extract of European mistletoe (Iscador Qu, Weleda) may decrease viral load and improve quality of life (9770), a small observational study in patients with chronic hepatitis C has found that subcutaneous administration of a different European mistletoe product (Abnobaviscum Quercus, Abnoba GmbH) three times weekly for 6 months does not normalize viral load or liver enzymes, but is associated with improved disease-related symptoms, when compared to baseline (24805). The validity of the findings from these studies is limited by their retrospective nature and lack of a control group.
• Hypertension. Although there has been interest in using oral European mistletoe for hypertension, there is insufficient reliable information about the clinical effects of European mistletoe for this purpose.
• Kidney Transplant. It is unclear if retroperitoneal instillation of European mistletoe extract is beneficial in kidney transplant patients with significant postoperative lymphatic drainage. Oral European mistletoe has not been evaluated for this use. Details: A large retrospective chart review in hospitalized kidney transplant patients with a large amount of postoperative lymphatic drainage suggests that retroperitoneal instillation of European mistletoe extract (Helixor M) 100 mg via the drainage tube may reduce drainage by about 83 mL from postoperative days 7 to 14 and decrease the length of hospitalization when compared with usual care (110442) The validity of these findings is limited by the retrospective study design.
• Leukemia. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with leukemia. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in patients with chronic myeloid leukemia shows that subcutaneous administration of a specific European mistletoe extract (Helixor) at doses up to 350 mg increases survival by up to 25.7 months when compared with survival times previously published in the scientific literature (24781). The validity of this finding is limited by the lack of a randomized comparator group.
• Lung cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with lung cancer. Oral European mistletoe has not been evaluated for this use. Details: Observational research in patients with non-small cell lung cancer (NSCLC) has found that subcutaneous administration of European mistletoe extracts (Abnobaviscum, Helixor, and Iscador) along with chemotherapy is associated with increased survival in patients with stage IV NSCLC, but not stage I-IIIA NSCLC, when compared with chemotherapy alone (99498,105840). Additionally, a small, randomized clinical study in patients with NSCLC shows that treatment with a specific European mistletoe extract (Iscador) does not significantly increase median survival time or tumor response when compared with placebo (24784,24790).
• Malignant pleural effusions. It is unclear if intrapleural European mistletoe extract is beneficial in patients with malignant pleural effusions. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in patients with malignant pleural effusions shows that intrapleural administration of a specific European mistletoe extract (Helixor M; Helixor Heilmittel GmbH & Co. KG) 100 mg, repeated every other day up to 5 times with doses increased by 100 mg with each successive procedure, increases response rate when compared with doxycycline. The response rate, defined as the percentage of patients who achieved complete or partial response, was 91% with European mistletoe extract and 67% with doxycycline (24774). Another small clinical study in patients with lung cancer and malignant pleural effusions shows that intrapleural administration of this same European mistletoe extract and dosing regimen leads to a one-month pleural effusion recurrence rate of 48% (102547). The validity of this findings if limited by a lack of control group.
• Osteosarcoma. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with osteosarcoma. Oral European mistletoe has not been evaluated for this use. Details: A small, open-label clinical study in patients with complete surgical remission following a second osteosarcoma relapse shows that subcutaneous administration of a specific European mistletoe extract (Iscador P), 3 times weekly for 12 months, improves post-relapse disease-free survival when compared with oral etoposide 50 mg/m2 daily for 21 days of each 28-day cycle for 6 cycles. After one year, 5 of 9 patients who completed treatment with European mistletoe extract had not relapsed, compared with 3 of 10 patients who completed etoposide therapy (105854). In a follow-up report, after a median of 83 months, disease-free survival remained the same in those receiving European mistletoe extract, whereas 0 of 10 patients remained disease-free after completion of etoposide treatment (105837).
• Ovarian cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with ovarian cancer. Oral European mistletoe has not been evaluated for this use. Details: A small observational study in patients with ovarian cancer has found that subcutaneous administration of a specific European mistletoe extract (Iscador) along with conventional therapy is associated with improved survival by more than one year when compared with conventional therapy alone (93260).
• Pancreatic cancer. It is unclear if subcutaneous or intratumoral European mistletoe extract is beneficial in patients with pancreatic cancer. Oral European mistletoe has not been evaluated for this use. Details: Some observational research in patients with stage IV pancreatic cancer has found that subcutaneous administration of European mistletoe extract is not associated with improved rates of partial or complete remission (3707,8848). However, another observational study in patients with inoperable pancreatic cancer being treated with chemotherapy and palliative surgical interventions has found that intratumoral administration of European mistletoe (Helixor, AbnobaViscum, and/or Iscucin) is associated with improved survival when compared with historical survival rates in patients receiving chemotherapy alone (93264). Additionally, a small, open-label clinical study in patients with stage III or IV pancreatic cancer who are no longer eligible for chemotherapy shows that subcutaneous administration of a specific European mistletoe extract (Iscador Qu spezial) at doses starting at 0.01 mg and titrated up to 10 mg three times weekly for up to 12 months increases survival by about 2 months when compared with supportive care alone (93267).
• Radiation exposure. It is unclear if subcutaneous European mistletoe extract is beneficial in children with radiation exposure. Oral European mistletoe has not been evaluated for this use. Details: A small clinical study in children with recurrent respiratory infections due to exposure to ionizing radiation from the Chernobyl nuclear accident shows that subcutaneous administration of a specific European mistletoe extract (Iscador) at doses ranging from 0.001 mg twice weekly to 1 ng/kg twice weekly for 5 weeks reduces the frequency of recurrent respiratory infections by 73% to 78% and improves symptoms such as fatigue, sweating, headache, joint pain, emotional instability, and muscle pain when compared to baseline (24779). The validity of these findings is limited by the lack of a comparator group.
• Uterine cancer. It is unclear if subcutaneous European mistletoe extract is beneficial in patients with uterine cancer. Oral European mistletoe has not been evaluated for this use. Details: A small observational study in patients with uterine cancer has found that subcutaneous administration of a specific European mistletoe extract (Iscador) is associated with improved survival when compared with matched controls (24794). More evidence is needed to rate European mistletoe for these uses.

(Read more about EUROPEAN MISTLETOE)

POSSIBLY EFFECTIVE

• Atherosclerosis. When used alone or in combination with other ingredients, oral garlic seems to slow the progression of atherosclerosis. Details: Taking low doses of garlic powder (Kwai, Lichtwer Pharma) 300 mg, administered as a single dose or three times daily for up to 4 years, seems to lessen age-related decreases in aortic elasticity (4797,51595). Additionally, taking a specific time-released garlic powder supplement (Allicor, INAT-Farma) 150 mg twice daily for 24 months seems to reduce the rate of atherosclerosis progression, as measured by carotid intima-media thickness, when compared with placebo in males with early evidence of carotid atherosclerosis (88394). Higher doses of 900 mg daily seem to slow development of atherosclerosis in both aortic and femoral arteries when used over a four-year period in females, but not in males (3315,4798). In patients with evidence of coronary artery calcium and a Framingham risk score of greater than 10%, taking aged garlic extract (Kyolic Reserve, Wakunaga) 1200 mg twice daily for 12 months reduces coronary artery calcium progression by 29% when compared with placebo (102670). A meta-analysis also found that garlic powder tablets and aged garlic extract may reduce coronary artery calcium scores when compared with placebo (110721). Some clinical research has investigated the use of garlic in combination with other ingredients. Taking a specific supplement (Kyolic, Total Heart Health, Formula 108, Wakunaga) containing aged garlic extract 250 mg plus vitamin B12 100 mcg, folic acid 300 mcg, vitamin B6 12.5 mg, and L-arginine 100 mg daily for 12 months significantly reduces coronary artery calcium progression and improves vascular function in patients with a Framingham risk score of 10% to 20% without coronary artery disease (88385). In addition, taking a combination product containing aged garlic extract 1200 mg and coenzyme Q10 120 mg daily for one year significantly improves vascular elasticity endothelial function in firefighters facing high degrees of occupational stress (44225).
• Diabetes. Most clinical research suggests that oral garlic, taken alone or in combination with metformin for at least 12 weeks, modestly reduces fasting blood glucose levels in patients with diabetes. It is unclear if garlic improves postprandial glucose levels or glycated hemoglobin (HbA1c). Details: A meta-analysis of results from seven clinical studies in adults with type 2 diabetes shows that taking garlic powder 600-1500 mg daily, garlic oil 8.2 mg daily, or aged garlic extract 1000 mg daily reduces fasting blood glucose levels by about 2 mg/dL when compared with control. The greatest benefit is seen for patients with hyperglycemia at baseline, for interventions lasting at least 12 weeks, and for formulations consisting of garlic powder (96004). Specific garlic formulations used in the reviewed studies have included garlic powder 300 mg 2-3 times daily as tablets (Kwai, Lichtwer Pharmaceuticals) or time-released tablets (Allicor, INAT-Farma) for 4-24 weeks, sometimes in combination with metformin or a sulfonylurea (51396,51463,96004). In one study, when used in combination with metformin, garlic reduced fasting blood glucose levels 70% more than when metformin was used alone (51463). The findings from these studies are in contrast with the results from older meta-analyses, which showed that garlic does not improve glycemic indices or lipid levels in patients with diabetes. Reasons for these discrepancies may relate to the fact that the older analyses included lower quality research (6465,6897). There is insufficient reliable information available to determine if garlic significantly improves postprandial glucose levels or HbA1c (96004). A small clinical trial shows that taking aged garlic extract (Kyolic, Wakunaga) 2400 mg daily for 12 months does not reduce left ventricular myocardial mass, a marker of poor cardiac outcomes, in patients with diabetes. However, this study may have been inadequately powered to detect a difference between groups (102671).
• Endometriosis. Oral garlic seems to improve pain in people with endometriosis. Details: A clinical study in patients with endometriosis shows that taking a tablet containing garlic powder 400 mg, providing allicin 1.1 mg, daily for 3 months along with standard care reduces overall pain scores from baseline by 72%, compared with an increase of 4% from baseline in patients receiving placebo along with standard care (106615).
• Hyperlipidemia. Most research shows that taking oral garlic for at least 8 weeks seems to modestly reduce total and low-density lipoprotein (LDL) cholesterol levels in patients with hyperlipidemia. However, evidence is conflicting on whether garlic improves high-density lipoprotein (HDL) cholesterol or triglyceride levels. Details: A robust meta-analysis on this topic suggests that, on average, garlic preparations reduce total cholesterol by 15 mg/dL and LDL cholesterol by 6 mg/dL when compared with placebo in patients with hyperlipidemia. These improvements appear to be more pronounced when garlic is taken for more than 8 weeks and in patients with total and LDL cholesterol levels that are at least borderline high before treatment. This same analysis shows no reduction in triglycerides and only a slight increase in HDL of 1.5 mg/dL with garlic treatment (88399). A more recent meta-analysis supports prior findings that taking garlic improves HDL, LDL, and apolipoprotein-A levels while having no impact on triglycerides level. The meta-analysis found that while garlic does not appear to reduce cholesterol in the general population, it may reduce total cholesterol when taken by patients with cardiovascular risk factors (110721). Another partially conflicting meta-analysis found that garlic powder reduces total cholesterol, LDL, and triglyceride levels, but has no impact on HDL levels (110720). The majority of available research supports these findings, but conflicting results exist (279,731,732,1873,1875,4782,4783,4784,4785,4786)(4787,4788,4789,4792,4793,4794,4795,4807,6457,6897)(51343,15295,15296,51422,51429,51469,51590,88399,107238)(107352,110721). Whether garlic is beneficial for treating hyperlipidemia may also depend on the specific formulation or product taken. Mixed results have been reported for a variety of specific garlic products, including garlic powder tablets (Kwai, Lichtwer Pharma) 600-900 mg daily in two or more divided doses for 6-16 weeks (279,731,4782,4783,4784,4785,4787,4789,4792,4793)(4795,4807), aged garlic extract (Kyolic, Wakunaga) 1000-7200 mg daily in divided doses for 4-6 months (1873,1875,15295), a garlic powder product (Garlex, Bosch Pharmaceuticals) 300 mg twice daily for 12 weeks (51343), aged back garlic extract (ABG+; PharmActive Biotech Products) 250 mg daily for 6 weeks (108607), and others (732,15295). Subgroup analyses from the most robust meta-analysis to date suggest that products containing aged garlic extract may be more effective for lowering total cholesterol than garlic powder preparations. If garlic powder preparations are used, total cholesterol levels seem to be lowered to a greater degree in patients taking enteric-coated garlic powder tablets. The opposite trend may be true for reducing LDL cholesterol. Garlic powder tablets seem to reduce LDL cholesterol levels while aged garlic extract does not. However, the few studies that did evaluate the effect of aged garlic extract on LDL cholesterol did so in patients with low baseline LDL cholesterol levels. There is limited evidence on the use of raw garlic or garlic oil products for treating hyperlipidemia (88399). Taking garlic 1200 mg with fish oil 3 grams daily for 4 weeks or garlic oil 500 mg with fish oil 700 mg daily for 60 days also appears to improve lipid parameters in some patients (4789,4790,51669). Garlic alone may be more effective than garlic plus fish oil for improving LDL cholesterol levels, but the combination may be useful in patients with elevated levels of total cholesterol, LDL cholesterol, and triglycerides (4789).
• Hypertension. Some clinical research suggests that oral garlic seems to modestly reduce blood pressure in hypertensive and normotensive patients. Details: One meta-analysis of clinical studies show that taking garlic can reduce systolic and diastolic blood pressure by about 5 mmHg and 3 mmHg, respectively, in patients with or without hypertension (16605,51414,96007). However, another meta-analysis found that taking garlic may not impact systolic or diastolic blood pressure in patients with coronary artery disease when compared with placebo (110721). When only patients with hypertension are considered, taking garlic can decrease systolic blood pressure by about 7-9 mmHg and diastolic blood pressure by about 4-6 mmHg. These results are limited by the fact that many of the included studies were of low to moderate quality and short duration (96007,96008,96014). Most clinical research appears to support these findings (278,279,1873,51442,88398). However, conflicting results exist (107238,110721). Some garlic formulations evaluated for hypertension have included a specific garlic powder formulation (Kwai, Lichtwer Pharma) 2400 mg as a single dose or 600 mg daily for 12 weeks and a specific aged garlic extract (Garlic High Potency Everyday Formula 112, Wakunaga/Wagner) 960 mg to 7.2 grams daily in up to three divided doses for up to 6 months (278,279,1873,51442,88398). Other doses used in the available research have included garlic tablets 300-1500 mg in divided doses daily for 24 weeks (88386) and garlic oil 500 mg plus fish oil 600 mg daily for 60 days (51669). Hypotensive effects of garlic have also been examined in population research. A large population study found that eating raw garlic at least twice daily is associated with a reduced likelihood of having prehypertension when compared with eating raw garlic three or fewer times per week. However, any significant relationship was eliminated after adjusting for dietary salt, making conclusions difficult (102677).
• Nonalcoholic fatty liver disease (NAFLD). Oral garlic seems to reduce the severity of hepatic steatosis in patients with NAFLD. Details: A meta-analysis including 4 studies with 186 patients with NAFLD found that taking 800-1600 mg of garlic powder daily may reduce aspartate aminotransferase (AST) and alanine transaminase (ALT) and lower the probability of hepatic steatosis by 2.75 times when compared with placebo (110720). Clinical research in patients with NAFLD shows that taking garlic powder reduces the severity of steatosis in 51% to 62% of patients, compared to 16% to 26% of those taking placebo (102681,103470). Doses of garlic included a specific powder (Amin Pharmaceutical Company) 800 mg twice daily for 12 weeks or an enteric-coated powder 400 mg twice daily for 15 weeks (102681,103479). There was also an improvement in most liver enzymes, other than alkaline phosphatase, and the level of low-density lipoprotein (LDL) cholesterol when compared with placebo (102681). In addition, population research shows a 7% reduction in odds of developing NAFLD with each 1 gram of raw garlic per 1000 kcal consumed. However, this association was not observed in females (102673). NAFLD is strongly and independently associated with an increased risk for prehypertension and hypertension. A clinical study in adults with NAFLD and stable diet- or antihypertensive-controlled blood pressure shows that taking an enteric-coated tablet containing garlic powder 400 mg (Amin Pharmaceuticals), providing allicin 1.5 mg, twice daily for 15 weeks reduces systolic blood pressure, diastolic blood pressure, and mean arterial pressure by 8, 3, and 6 mmHg, respectively, when compared with placebo. High-sensitivity C-reactive protein is also reduced by 16% when compared with placebo (106614).
• Periodontitis. Oral aged garlic extract seems to improve some measures of gum health in people with mild to moderate periodontitis. Details: Clinical research in otherwise healthy patients with mild to moderate periodontitis shows that taking a specific aged garlic extract (Kyolic, Wakunaga) orally 1200 mg twice daily for 18 months improves probing pocket depth, but not gingival recession, when compared with placebo (105760). The validity of these findings is limited by the lack of an intention to treat analysis.

POSSIBLY INEFFECTIVE

• Gastric cancer. Oral garlic does not seem to prevent gastric cancer. Details: Clinical research evaluating the effects of taking aged garlic extract for 7 years failed to show a reduced risk of developing gastric cancer up to 22 years later (14447,51470,102016), although there was a reduction in mortality associated with gastric cancer in subjects followed for 12-22 years (5-15 years after stopping the garlic extract) (102016). Also, a prospective, case-control study of 123,484 adults over a 30-year review period suggests that garlic intake, whether obtained from the diet or via supplementation, is not associated with a reduction in the rate of gastric cancer occurrence (97034). However, some research disagrees. One prospective population study suggests that a 1 kg/year increased increment in garlic intake is associated with a 17% reduced risk in gastric cancer incidence over 22 years. Also, consuming at least 3.25 kg yearly is associated with at least a 12% reduced risk when compared with consuming less than 2 kg each year. A sub-analysis suggests that this potential benefit is associated with garlic stalks, rather than garlic bulbs (111764). Meta-analyses of population research, as well as small population studies, have suggested 23% to 51% lower odds of developing gastric cancer with increased dietary garlic intake when compared with never eating garlic (3320,4775,4776,51209,51460,96005,108604). However, these studies have limited external validity.
• Helicobacter pylori. Oral garlic does not seem to be beneficial for Helicobacter pylori eradication. Details: Despite some promising initial laboratory research suggesting activity against Helicobacter pylori, garlic cloves, powder, or oil does not seem to have any beneficial effect when used to treat patients infected with Helicobacter pylori (3322,4761,4762,4763,4765,4774,97034).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral garlic for allergic rhinitis (hay fever), there is insufficient reliable information about the clinical effects of garlic for this condition.
• Alopecia areata. Topical garlic may increase hair growth by a small amount. Details: Preliminary clinical research in adults with alopecia areata shows that applying garlic 5% gel four times daily for 3 months, in addition to topical corticosteroid use, increases hair growth by 18% when compared with placebo plus topical corticosteroid (51386).
• Asthma. Although there has been interest in using oral garlic for asthma, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Athletic performance. It is unclear if oral garlic is beneficial for athletic performance. Details: Preliminary clinical research shows that taking a single dose of garlic 900 mg prior to exercise increases endurance when compared with placebo in young athletes (51623). A small preliminary clinical trial shows that taking garlic extract 1000 mg daily for 4 weeks does not reduce the time to cycle 40 km when compared to placebo (111765).
• Benign prostatic hyperplasia (BPH). It is unclear if oral garlic is beneficial for BPH. Details: In patients with BPH, preliminary clinical research shows that taking aqueous garlic extract 1 mg/kg daily for one month decreases prostate mass and urinary frequency and improves symptom scores and urinary flow rates when compared to baseline (10374). The validity of these findings is limited by the lack of a comparator group.
• Bladder cancer. Although there has been interest in using oral garlic for bladder cancer, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Breast cancer. It is unclear if oral garlic prevents breast cancer. Details: The relationship between garlic intake and risk of breast cancer is unclear. Overall, population research suggests that taking garlic does not seem to decrease the risk of breast cancer. However, when garlic and onions are examined together, there is some evidence of an association with a decreased risk of breast cancer (4779,102674). More research is needed.
• Bronchitis. Although there has been interest in using oral garlic for bronchitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Cardiovascular disease (CVD). It is unclear if oral garlic is beneficial for reducing CVD risk factors in adults with hypercholesterolemia. Details: A clinical crossover study in adults with moderate hypercholesterolemia shows that taking a specific product (ABG+; PharmActive Biotech Products) containing aged black garlic extract 250 mg, standardized to provide S-allyl-L-cysteine 1.25 mg, daily for 6 weeks does not improve blood pressure, glucose or cholesterol levels, or anthropometric measures when compared with placebo. A subgroup analysis in males with elevated diastolic blood pressure at baseline shows that taking this product reduces diastolic blood pressure by 5-mmHg when compared with placebo (108607). It is unclear if garlic is beneficial in patients with existing CVD.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral garlic for CFS, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Colorectal cancer. It is unclear if oral garlic prevents colorectal cancer. Details: Several individual population studies have found that higher dietary intake of garlic is associated with a reduced risk of colorectal cancer (3320,4770,4771,4772). However, results from meta-analyses of population research are mixed (96003,102669). Reasons for the discrepancy seem to relate to the type of population study conducted. A meta-analysis of case-control studies supports a preventative effect of garlic. However, this is not supported when cohort studies are analyzed separately (102669). Case-control studies are prone to recall and selection bias, and some do not account for confounding factors associated with colorectal cancer (96003). Two separate meta-analyses of observational research conducted in various countries have found that consumption of garlic and other allium-containing vegetables (onions, leeks, chives and scallions) is associated with a reduced risk of colorectal cancer; however, subgroup analyses suggest improvement is greatest in studies conducted in Asian countries, modest in those conducted in North America, and absent in those conducted in Europe (108604,108605). The reasons for these differing findings are unclear but may be related to regional differences in dietary habits, such as the use of raw or cooked garlic. Few studies have examined the effects of garlic supplements. While a single preliminary clinical study in patients with confirmed colorectal adenomas shows that taking high-dose aged garlic extract 2.4 mL daily for 12 months reduces the risk of developing new adenomas by 29% when compared with a lower dose of 0.16 mL daily (51320), other studies do not support the use of garlic supplements for this purpose (4773,96003).
• Common cold. Oral garlic might reduce the frequency of the common cold when used prophylactically. Details: Preliminary clinical research shows that taking one capsule of garlic daily for 12 weeks during the winter months reduces the number of self-reported colds by approximately 63% when compared with placebo. The duration of symptoms was also reduced by approximately one day (10787). Also, a small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more common cold episodes compared with 45% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
• Corns. It is unclear if topical garlic is beneficial for corns. Details: Preliminary clinical research in a small number of patients with corns shows that applying a lipid soluble garlic extract topically to corns on the feet twice daily for 10-20 days results in improvement in most patients when compared with baseline (15030). The validity of this finding is limited by the lack of a comparator group.
• Coronary heart disease (CHD). It is unclear if oral garlic is beneficial for CHD. Details: A meta-analysis of preliminary clinical research in adults with CHD shows that taking garlic orally 800-2000 mg daily for 2-48 weeks reduces total cholesterol levels by an average of 16 mg/dL when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. The validity of this study is limited by inclusion of patients with and without dyslipidemia at baseline (107238).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral garlic is beneficial for COVID-19. Details: Clinical research in non-critically ill patients hospitalized with COVID-19 shows that taking garlic extract (Gallecina, Samisaz Pharmaceutical Company, Iran) 90 mg every 8 hours for 5 days or until discharge modestly reduces the proportion of patients requiring supplemental oxygen for at least 1 day when compared with placebo. However, there was no overall effect on clinical status, intensive care admission, or discharge prior to day 6. All patients also took remdesivir (111766). A small preliminary clinical study in patients hospitalized with mild to moderate symptoms of COVID-19 shows that taking garlic essential oil orally 50 mg twice daily before breakfast and dinner for 10 days, in addition to standard COVID-19 treatment, reduces the median duration of fever from 5 to 4 days, cough from 7 to 5 days, and weakness from 9 to 7 days when compared with standard treatment alone. The median time to a negative COVID-19 test decreased from 8 to 7 days (109530). The validity of this study is limited by incomplete randomization, the lack of a placebo comparator, and the exclusion of people with severe symptoms.
• Cystic fibrosis. It is unclear if oral garlic is beneficial for cystic fibrosis. Details: Preliminary clinical research shows that taking garlic oil macerate 625 mg daily for 8 weeks does not improve pulmonary function, symptom scores, or the need for antibiotic therapy when compared with placebo in children with cystic fibrosis and chronic pulmonary infection (51438).
• Dental hypersensitivity. Although there has been interest in using oral garlic for dental hypersensitivity, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Denture stomatitis. It is unclear if topical garlic as a mouthwash is beneficial for denture stomatitis. Details: Preliminary clinical research in patients with oral denture stomatitis shows that using a garlic mouthwash 40 mg/mL three times daily for 4 weeks improves redness when compared to baseline. When compared with nystatin, garlic has a lesser degree of recovery, but better patient satisfaction (51466).
• Diabetic retinopathy. It is unclear if oral garlic is beneficial for diabetic retinopathy. Details: Preliminary research in patients with diabetic retinopathy and macular edema, treated with intravitreal bevacizumab and laser photocoagulation, shows that taking garlic powder 1 gram orally daily for 4 weeks improves the best-corrected visual acuity by 0.18 logMAR (logarithm of the minimum angle of resolution), compared with 0.06 for placebo. It also decreases intraocular pressure by 1 mmHg, compared with 0.3 mmHg for placebo (109529).
• Diarrhea. Although there has been interest in using oral garlic for various types of diarrhea, including travelers' diarrhea and dysentery, there is insufficient reliable information about the clinical effects of garlic for these conditions.
• Dysmenorrhea. Although there has been interest in using oral garlic for dysmenorrhea, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Esophageal cancer. It is unclear if oral garlic prevents esophageal cancer. Details: Observational research regarding the use of garlic in preventing esophageal cancer is conflicting. Some evidence suggests that raw garlic consumption does not prevent the development of esophageal cancer (51508). However, other population research suggests that weekly garlic consumption decreases the risk of developing esophageal cancer (51209).
• Exercise-induced muscle soreness. It is unclear if oral garlic is beneficial for exercise-induced muscle soreness. Details: Preliminary clinical research shows that taking allicin, a constituent of garlic, 80 mg daily for 14 days can reduce subjective assessments of exercise-induced muscle soreness in athletes when compared with placebo (51404).
• Fatigue. Although there has been interest in using oral garlic for fatigue, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Familial hypercholesterolemia. Oral garlic does not seem to improve blood lipid levels in children with familial hypercholesterolemia. Details: In children with familial hypercholesterolemia, a small clinical trial shows that taking garlic powdered extract, standardized based on alliin content, does not improve levels of total cholesterol, low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein (a), apolipoprotein B-100, homocysteine, fibrinogen, or blood pressure (4796).
• Fibrocystic breast disease. Oral garlic 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 (Karinat, INAT-Farma), containing garlic powder 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months reduces the severity of breast pain, premenstrual syndrome, and menstruation pain, and can cause regression of palpable symptoms of breast fibromatosis (51317). It is unclear if these effects are due to garlic, other ingredients, or the combination.
• Gastritis. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with gastritis shows that taking a specific combination product (Karinat, INAT-Farma), containing garlic 150 mg, beta-carotene 2.5 mg, alpha-tocopherol 5 mg, and ascorbic acid 30 mg twice daily for 6 months improves digestion, inhibits H. pylori infection, and reduces the risk of precancerous lesion formation when compared with placebo (51308). It is unclear if these effects are due to garlic, other ingredients, or the combination.
• Gout. Although there has been interest in using oral garlic for gout, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Hepatitis. It is unclear if oral garlic is beneficial for hepatitis. Details: Preliminary clinical research shows that taking 3-6 capsules of a product containing garlic oil 50 mg and diphenyl-dimethyl-dicarboxylate 25 mg per capsule daily for 6 weeks improves liver function enzyme levels when compared with placebo in patients with chronic hepatitis (51478). The effects of garlic alone have not been determined.
• Hepatopulmonary syndrome. It is unclear if oral garlic is beneficial for hepatopulmonary syndrome. Details: Preliminary clinical research shows that garlic oil (Garlic Pearls, Ranbaxy, India) 1-2 grams/m² daily in two divided doses for 9-18 months may improve oxygen levels and remission rates when compared with placebo in patients with hepatopulmonary syndrome (51439).
• Influenza. Oral garlic has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in older patients living in residential care shows that 12% of those taking one capsule daily of a combination of garlic and onion powder (Aliocare, Domca Sau, Spain) for 36 weeks had one or more influenza-like episodes compared with 36% of those taking placebo. Each capsule provided 14 mg garlic powder (111768).
• Lead toxicity. It is unclear if oral garlic is beneficial for lead toxicity. Details: Preliminary clinical research shows that taking garlic powder 400 mg three times daily for 4 weeks reduces blood lead concentration when compared with baseline, but not when compared to treatment with D-penicillamine, in patients with mild to moderate lead poisoning (51467).
• Lung cancer. It is unclear if oral garlic prevents lung cancer. Details: Some population research suggests that eating raw garlic is associated with a reduced odds of developing lung cancer. However, other research suggests that eating garlic or taking garlic supplements is not associated with a reduced risk of lung cancer (4778,103482). Reasons for the discrepancy possibly relate to the type of garlic consumed.
• Metabolic syndrome. Meta-analyses of small studies suggest that oral garlic may improve some metabolic parameters in patients with metabolic syndrome and other metabolic disorders. Details: Two meta-analyses of several small clinical studies in adults with metabolic syndrome or metabolic disorders including hyperlipidemia, hypertension, nonalcoholic fatty liver disease, obesity, and type 2 diabetes show that taking various forms of garlic improves triglycerides, total cholesterol, low-density lipoprotein cholesterol, diastolic blood pressure , measures of insulin resistance, and waist circumference when compared with control. However, the meta-analyses reach conflicting conclusions on whether garlic is beneficial for body mass index, high-density lipoprotein cholesterol, fasting blood glucose, or systolic blood pressure when compared with control. Garlic forms studied in the meta-analyses include raw garlic 5000-20,000 mg, aged garlic extract 240-6000 mg, garlic powder tablets 188-6000 mg, and garlic derivative ajoene 2.34 mg, taken daily for 4 to 36 weeks (113617,113619).
• Mosquito repellent. It is unclear if oral garlic is beneficial as a mosquito repellent. Details: Preliminary clinical research shows that taking a single dose of garlic orally does not seem to effectively repel mosquitos (51322). The effect of long-term garlic administration is unclear.
• Multiple myeloma. It is unclear if oral garlic prevents multiple myeloma. Details: A case-control study comparing a small population of adults with and without multiple myeloma has found that increased intake of garlic in the diet may be associated with a decreased risk of developing multiple myeloma (51476).
• Muscle strength. It is unclear if oral garlic is beneficial for muscle strength. Details: Population research has found that increased consumption of raw garlic is associated with increased hand grip strength in healthy adults. Females consuming raw garlic 2-3 times per week were 23% less likely to have low handgrip strength, defined as being below the 20th percentile, when compared to those who almost never eat garlic. In males, the odds of having low handgrip strength were 34% lower. Eating any raw garlic, even less than once per week, was associated with an increased likelihood for having high grip strength (102678).
• Obesity. It is unclear if oral garlic is beneficial for obesity. Details: Clinical research shows that taking garlic powder (Amin Pharmaceutical Company) 1600 mg daily for 12 weeks does not reduce body weight or body mass index when compared with placebo in overweight or obese patients with nonalcoholic fatty liver disease (NAFLD), although there is a small effect on waist circumference (102681). One small clinical study evaluating garlic in combination with multiple other ingredients shows that the combination (Prograde Metabolism) modestly improves body weight, fat mass, and waist and hip circumference when compared with placebo. The other ingredients include raspberry ketone, caffeine, capsicum extract, ginger root extract, bitter orange fruit, L-theanine, and black pepper fruit (40802). However, it is unclear if this benefit is due to garlic, other ingredients, or the combination.
• Onychomycosis. Although there has been interest in using topical garlic for onychomycosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Oropharyngeal candidiasis. It is unclear if oral garlic is beneficial for oropharyngeal candidiasis. Details: Preliminary clinical research in patients with oral candidiasis shows that applying a topical garlic paste four times daily for 14 days to affected areas can increase the rate of complete eradication of oral lesions by 23% when compared with clotrimazole solution (51330).
• Osteoarthritis. It is unclear if oral garlic is beneficial for osteoarthritis. Details: Preliminary clinical research in overweight and obese females with knee osteoarthritis shows that taking garlic tablets (Nature Made) 500 mg twice daily for 12 weeks modestly reduces pain scores by an additional 15% when compared with placebo (98813).
• Otitis media. Although there has been interest in using topical garlic for otitis media, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Peripheral arterial disease (PAD). Oral garlic seems to improve pain-free walking distance by a small amount in patients with PAD. However, it does not seem to improve blood pressure. Details: In patients with stage II peripheral arterial occlusive disease, a small clinical trial shows that taking garlic (Kwai) 400 mg twice daily for 12 weeks improves pain-free walking distance by about 15 meters. There was no effect on blood pressure or ankle or brachial pressures (4801).
• Polycystic ovary syndrome (PCOS). It is unclear if oral garlic is beneficial for PCOS. Details: Preliminary clinical research in adults with PCOS shows that taking garlic orally 800 mg daily for 8 weeks reduces low-density lipoprotein (LDL) cholesterol levels by approximately 8% when compared with placebo. Taking garlic did not affect other cholesterol levels; however, the study may have been inadequately powered to detect a difference between groups. Garlic supplementation also modestly reduces body mass index (BMI) and waist circumference in this population. However, there was no change in hip circumference (107238,111763).
• Pre-eclampsia. It is unclear if oral garlic prevents pre-eclampsia during the third trimester. Details: Preliminary clinical research shows that taking a specific garlic extract (Garlet, Cosar Pharmaceutical Company) 800 mg daily during the third trimester of pregnancy does not reduce the risk of developing pre-eclampsia in high-risk patients with first-time pregnancies (9201,51626).
• Premenstrual syndrome (PMS). It is unclear if oral garlic is beneficial for PMS. Details: Preliminary clinical research in adult students with moderate to severe PMS shows that taking a specific garlic supplement (Allium-S, Dineh Pharmaceutical Company) orally 400 mg daily, standardized to contain 1.1 mg allicin, for 3 menstrual cycles improves PMS symptom scores 1.4 times more than placebo. After taking garlic for 3 cycles, 91% of students improved to mild PMS, compared with only 36% in the placebo group (107239).
• Prostate cancer. Observational research on the relationship between garlic intake and prostate cancer risk is conflicting. It is unclear if garlic supplements are beneficial in patients with prostate cancer. Details: Observational research in Chinese males shows that those who eat garlic 2.14 grams/day (about one clove) seem to have a 50% lower risk of developing prostate cancer (9876). Also, a pooled analysis of epidemiological research suggests that garlic consumption may be associated with a 23% decreased odds of developing prostate cancer (88410). A case-control study has also found that garlic, consumed at least twice weekly, may reduce the risk for prostate cancer when compared with lower consumption (4777). However, other population research suggests that garlic consumption has no effect on prostate cancer risk in Iranian males (51454). One very small clinical study in patients with prostate cancer shows that taking garlic extract 1 mg/kg daily for one month might improve prostate specific antigen (PSA) levels, urinary flow, and urinary frequency when compared with baseline (10374). The validity of these findings is limited by the small study size and lack of a comparator group.
• Rheumatoid arthritis (RA). Oral garlic seems to reduce pain by a small amount in patients with RA. Details: Clinical research in females with RA shows that taking dried garlic (Garcin; Goldaru Co.) 500 mg twice daily, providing allicin 5 mg, for 8 weeks reduces pain after activity and improves functional ability by a small amount when compared with placebo. Fatigue and pain were reduced by approximately 13% and tender joint count was reduced by 47% (102680,103481). The long-term effect of garlic supplementation is unclear.
• Scleroderma. It is unclear if oral garlic is beneficial for scleroderma. Details: Clinical research shows that taking garlic 900 mg daily for 7 days does not have an effect on vasomotor function when compared with placebo in females with scleroderma (51374).
• Stress. Although there has been interest in using oral garlic for stress, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tick repellent. It is unclear if oral garlic is beneficial as a tick repellent. Details: Preliminary clinical research shows that taking garlic 1200 mg daily for 8 weeks reduces the number of tick bites when compared with placebo (3318). However, the effect of garlic when compared with commercially available tick repellents is unknown (8027).
• Tinea capitis. Although there has been interest in using topical garlic for tinea capitis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tinea corporis. It is unclear if topical garlic is beneficial for tinea corporis. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea corporis (4767).
• Tinea cruris. It is unclear if topical garlic is beneficial for tinea cruris. Details: Applying a gel containing 0.6% ajoene, a constituent of garlic, twice daily for one week seems to be as effective as terbinafine 1% cream for tinea cruris (4767).
• Tinea pedis. It is unclear if topical garlic is beneficial for tinea pedis. Details: Applying a gel containing 1% ajoene, a constituent of garlic, twice daily seems to be more effective than 0.6% ajoene gel, and seems to be as effective as 1% terbinafine (Lamisil) for tinea pedis infections. Sixty days after completing one week of treatment, mycological cure occurred in 100% of patients using 1% ajoene, 72% of patients using 0.6% ajoene , and 94% of those using 1% terbinafine (8019). Additional research suggests that 0.4% ajoene gel twice daily has a 7-day cure rate of around 80% (4766).
• Trichomoniasis. Although there has been interest in using oral garlic for trichomoniasis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Tuberculosis. Although there has been interest in using oral garlic for tuberculosis, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Unstable angina. It is unclear if intravenous garlic is beneficial for unstable angina. Details: Preliminary clinical research in patients with unstable angina shows that giving garlicin, 60 mg by intravenous infusion daily for 10 days improves symptoms by 7% when compared with intravenous nitroglycerin (51244).
• Urinary tract infections (UTIs). Although there has been interest in using oral garlic for UTIs, there is insufficient reliable information about the clinical effects of garlic for this condition.
• Vaginal candidiasis. It is unclear if oral or topical garlic is beneficial for vaginal candidiasis. Details: One small clinical study in asymptomatic patients with culture-positive candida infections shows that taking garlic (Garlicin, Nature's Way) 1050 mg (3 tablets) twice daily for 14 days does not improve vaginal symptoms, candida colony counts, or cases of vaginal candidiasis when compared with placebo (88405). Another small clinical study shows that application of a vaginal cream containing garlic and thyme nightly for 7 nights is as effective as clotrimazole vaginal cream for treating vaginal candidiasis (88387). However, it is unclear if this effect is due to garlic, thyme, or the combination.
• Warts. It is unclear if topical garlic is beneficial for warts. Details: Preliminary clinical research shows that applying a specific lipid-soluble garlic extract topically to warts on the hands twice daily results in wart resolution within 1-2 weeks. An aqueous garlic extract applied twice daily also seems to provide modest improvement, but only after 30-40 days of treatment (15030). The validity of these findings is limited by the lack of a comparator group.
• Wound healing. It is unclear if topical garlic is beneficial for wound healing. Details: Based on patient and physician evaluations, preliminary clinical research shows that applying an ointment containing fresh garlic in petroleum jelly twice daily for 2 weeks results in 80% of surgical wounds healing at a faster rate than those treated with petroleum jelly. Most patients also indicated that the wound treated with garlic experienced less discomfort (102676). More evidence is needed to rate garlic for these uses.

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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)

LIKELY EFFECTIVE

• Irritable bowel syndrome (IBS). Oral enteric-coated peppermint oil is conditionally recommended by the American College of Gastroenterology (ACG) for the relief of global IBS symptoms, such as abdominal pain. Details: The ACG conditionally recommends the use of peppermint for the relief of global IBS symptoms. This recommendation is based on an available meta-analysis of generally low-quality clinical research (105124). Several clinical trials and meta-analyses show that taking enteric-coated peppermint oil 1-2 capsules orally two to four times daily reduces abdominal pain, distention, flatulence, and bowel movements in patients with IBS. Each capsule provides approximately 0.2 mL of peppermint oil or 180-225 mg peppermint oil. Most trials have used specific products (Colpermin, Tillotts Pharma; Mintoil, Cadigroup; Ibgard, IM HealthScience, Tempocol) (3802,3803,4469,11778,11779,17681,17682,68467,68515,68522)(68603,68604,68605,96360,99493,109980). The most recent meta-analysis to date shows that four patients would need to take peppermint oil to prevent one patient from having persistent IBS symptoms, and seven patients would need to take peppermint oil to prevent one patient from having abdominal pain. However, the individual studies included in the analysis lasted no more than 12 weeks (109980); any long-term effects are unclear. Although most studies have shown benefit for reducing symptoms, some older studies have found no significant effect (11777,11789) or only short-term benefits (68620). Also, a well-designed study shows that taking peppermint oil capsules designed for either small intestinal release (enteric-coated) or ileocolonic release does not increase the number of people with at least a 30% decrease in abdominal pain over a period of 4 weeks, although symptoms are modestly reduced when compared with placebo (102602). Another clinical trial in patients with moderate to severe IBS shows that taking a specific enteric-coated formulation of peppermint oil (Pepogest; Nature's Way) 180 mg three times daily for 6 weeks does not further improve symptom severity when compared with placebo. However, both groups experienced a large improvement on the IBS-Severity Scoring System (IBS-SSS) and the IBS Global Improvement Scale (107955). The validity of these findings is limited due to lost data and inconsistent follow-up; additionally, adverse effects occurred more frequently in the peppermint oil group. The reasons for these negative findings are unclear but may include short treatment durations and the use of different formulations; additionally, IBS is comprised of various subtypes and symptoms that can range in severity and presentation, which may alter treatment response. Some clinical research has also evaluated a specific combination product (Atrantil, KBS Research) containing peppermint leaf, red quebracho extract, and conker tree extract. Taking this product as needed for 2 weeks seems to reduce constipation and bloating when compared to baseline in patients with constipation-predominant IBS (95429,95430). It is unclear if the effects of this product are due to peppermint, the other ingredients, or the combination.

POSSIBLY EFFECTIVE

• Barium enema-related colonic spasm. Rectal peppermint, as part of barium enema preparations, seems to reduce colonic spasms during examination. Oral peppermint also seems to be beneficial. Details: Rectal use of peppermint oil, added as an ingredient in barium enema preparations, seems to relax the colon during barium enema examination and reduce the percentage of patients who experience colonic spasms by about 25% to 30% (6739,6749,12009). Adding peppermint oil to the barium enema seems to be at least as effective as using systemic scopolamine (Buscopan). Adding peppermint oil to the barium solution also does not seem to impair image quality (12009). Some clinical research also shows that taking peppermint oil orally before the start of a double-contrast barium enema examination decreases spasms and might also increase diagnostic quality (14467).
• Chemotherapy-induced nausea and vomiting (CINV). Oral and inhaled peppermint seem to reduce nausea and vomiting in patients with CINV. Details: Clinical research shows that adding peppermint oil, 40 drops in 20 mL water, every 8 hours following chemotherapy treatment to treatment with standard antiemetics reduces the severity of nausea, vomiting, and anorexia by moderate to large amounts over 48 hours when compared with a plain water placebo (105123). The use of peppermint oil aromatherapy has also been investigated. Clinical research shows that adding 2 drops of peppermint oil to a cool, damp washcloth for use on the neck as aromatherapy for about 30 minutes helps relieve chemotherapy-induced nausea by a small amount when compared with a washcloth without peppermint oil (102603). Additional clinical research in patients receiving standard antiemetics after chemotherapy shows that applying one drop of peppermint oil below the nose three times daily for 5 days reduces the severity of nausea and the frequency of nausea, vomiting, and retching by a moderate to large amount when compared with the antiemetics alone. These parameters were not improved following treatment with cisplatin (105122). A meta-analysis of 3 randomized controlled trials in adults receiving chemotherapy also shows that peppermint oil aromatherapy moderately improves nausea and vomiting when compared with control. However, the results of this analysis are limited by heterogenous application methods, doses, and durations of peppermint therapy (114761). In children with acute leukemia, a small clinical study shows that aromatherapy with 2 drops of peppermint oil and 3 drops of lemon oil in 80 mL of water diffused 30 minutes prior to and 2 and 4 hours after chemotherapy once weekly for 4 weeks decreases the severity of nausea, vomiting, and retching, and improves quality of life scores when compared with diffused water or no intervention (112015). The validity of these findings is limited by the use of patient-reported outcomes. Another small clinical trial in children receiving chemotherapy for acute leukemia shows that aromatherapy with peppermint oil 2%, 0.2 mL inhaled over 3 minutes immediately prior to 3 consecutive chemotherapy sessions, added to standard care (e.g. antiemetic medications), reduces overall incidence of nausea by 40%, and improves nausea and vomiting severity scores, when compared with no additional interventions. These results were similar to those receiving Swedish massage prior to chemotherapy sessions (114759).
• Dyspepsia. Oral peppermint, in combination with caraway and possibly other ingredients, seems to reduce symptoms of dyspepsia. It is unclear if oral peppermint alone is beneficial. Details: Some clinical research shows that taking specific products containing peppermint and caraway oil (Enteroplant, Dr Willmar Schwabe Pharmaceuticals; Menthacarin, Dr Willmar Schwabe GmbH & Co.) improves quality of life and reduces symptoms of dyspepsia, including feelings of fullness, pain, and mild gastrointestinal spasms (6740,6741,10075,96344,102600). A meta-analysis of three of these clinical studies shows that taking this combination product 2-3 times daily for 4 weeks modestly reduces abdominal pain when compared with placebo (110091). Taking this combination twice daily for 4 weeks also improves postprandial distress syndrome and epigastric pain syndrome, two subtypes of dyspepsia, when compared with placebo (96344). The combination of enteric-coated peppermint oil 90 mg and caraway oil 50 mg appears to be comparable to cisapride for relieving dyspepsia when taken 2-3 times daily for up to 4 weeks (6740,6741,10075). However, most trials investigating this combination are small and/or of overall low quality (102600). A specific combination product containing peppermint leaf (Iberogast, Steigerwald Arzneimittelwerk GmbH) also seems to improve symptoms of dyspepsia. The combination includes peppermint leaf plus clown's mustard plant, German chamomile, caraway, licorice, milk thistle, angelica, celandine, and lemon balm (7049). A meta-analysis of studies using this combination product shows that taking 1 mL orally three times daily over a period of 4 weeks reduces the severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo (13089). A similar combination product containing extracts from peppermint leaf, clown's mustard plant, German chamomile flower, caraway, licorice root, and lemon balm (STW 5-II, Steigerwald Arzneimittelwerk GmbH) 1 mL taken three times daily for up to 8 weeks eliminates gastrointestinal symptoms in 40% more dyspepsia patients when compared with placebo (12724).
• Endoscopy-associated adverse effects. Intraluminal peppermint seems to reduce spasticity during an endoscopy. It is unclear if oral peppermint is beneficial for reducing adverse effects related to endoscopy. Details: A meta-analysis of four clinical trials show that peppermint oil, administered orally or intraluminally, reduces the incidence of spasticity by about 41% when compared with placebo in patients undergoing endoscopy, with severe spasticity occurring at about 30% the rate of those taking placebo. However, there was no effect on subjective pain (102604). Individual clinical studies show that intraluminal peppermint oil can reduce both pain and spams in patients undergoing endoscopy (18220,68371,68395,68445,68532). However, there are limitations with this form of administration, including cost and practicality, which has led to interest in the use of oral formulations (104221). Studies evaluating oral extended-release peppermint have been conflicting. While one study shows that a specific extended-release peppermint oil product (Colpermin) 187 mg or 0.2 mL taken orally 4 hours prior to a colonoscopy reduces procedure time, pain, and spasticity (68532), a study using another specific extended-release peppermint oil (IBGard) did not show an effect on colonic spasms, procedure time, or adenoma detection rate when compared with placebo (104221). These differing outcomes may be due to timing of administration. The study that showed benefit administered the treatment 4 hours prior to endoscopy, whereas the study showing no benefit administered the treatment only 1 hour prior. This suggests that extended-release peppermint may need to be administered at least 4 hours prior to the procedure to allow for adequate colonic release (68532,102604,104221).
• Nipple fissures. Topical peppermint seems to reduce cracked skin and pain in the nipples due to breastfeeding. Details: Clinical research shows that topical application of peppermint oil in gel or water reduces cracked skin and pain in the nipple area from breastfeeding when compared with using placebo, lanolin, or the expressed breast milk technique (68454,68462). Other research shows that applying peppermint oil in cream immediately after breastfeeding for 2 weeks decreases pain and trauma in the nipple area similarly to the topical application of dexpanthenol or lanolin (96365).
• Pressure ulcers. Topical peppermint seems to reduce the risk of pressure ulcers. Details: Clinical research in bedridden patients shows that prophylactic application of a topical gel containing peppermint oil 0.2% three times daily for up to 14 days results in pressure injuries in about 23% of patients compared with 77% of those given a placebo gel (102605).
• Tension headache. Topical peppermint seems to relieve tension headaches. Details: Clinical research shows that topical application of peppermint oil 10% relieves tension headaches when compared with placebo (3801,6190).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Abdominal pain. Although there has been interest in using oral peppermint for abdominal pain, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Anxiety. It is unclear if inhaled peppermint oil is beneficial for reducing anxiety. Details: A clinical trial in patients presenting to the emergency department for an acute coronary syndrome event shows that placing 3 drops of peppermint oil on a cotton ball and inhaling for 1 hour improves anxiety and respiratory rate when compared with baseline or placebo (107958). Due to the single-dose nature of this study, the effects of repeated inhalation of peppermint oil are unclear.
• Athletic performance. It is unclear if oral peppermint oil is beneficial for athletic performance. Details: Preliminary clinical research in trained adult runners shows that taking peppermint essential oil, 0.05 mL diluted in 500 mL of water, orally once 30 minutes before exercise improves running time to exhaustion by 11% when compared with placebo (112742). Another very small clinical study in elite soccer athletes shows that use of a specific peppermint essential oil (doTERRA), 1 drop rubbed into hands and inhaled with 5 deep breaths, does not improve jump performance metrics when compared with placebo (114760).
• Breast cancer-related hot flashes. It is unclear if topical peppermint is beneficial for reducing hot flashes in patients with breast cancer. Details: Preliminary clinical research shows that using a spray containing a combination of peppermint and neroli hydrolat does not alleviate hot flashes in most patients receiving chemotherapy for breast cancer when compared with using a plain water spray (68481).
• Cognitive function. It is unclear if inhaled peppermint oil is beneficial for improving cognitive function. Details: Preliminary clinical research shows that inhalation of peppermint oil slightly improves memory and the performance of cognitive tasks such as typing, alphabetization, and ordering, but not attention and speed of task completion, when compared with control (56954,68416,68466).
• Common cold. Although there has been interest in using oral, topical, or inhaled peppermint for the common cold, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Dental plaque. Topical peppermint has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that rinsing the mouth for one minute with 10 mL of a specific combination product (HiOra, Himalaya Herbal Healthcare) containing peppermint oil and numerous other ingredients twice daily for two days reduces plaque index or plaque area when compared with placebo; however, it was not as effective as chlorhexidine 0.2% solution (68530). It is unclear if these effects are due to peppermint oil, other ingredients, or the combination.
• Diffuse esophageal spasm. It is unclear if oral peppermint oil is beneficial for diffuse esophageal spasm. Details: A small exploratory study in adults with diffuse esophageal spasm shows that drinking a solution of peppermint oil, 5 drops in 10 mL of water, can resolve esophageal contractions when compared with baseline (13415). The validity of this finding is limited by the lack of a comparator group.
• Dysmenorrhea. It is unclear if oral peppermint oil is beneficial for reducing menstrual pain. Details: Preliminary clinical research shows that taking three capsules of peppermint oil (Colpermin; Tillotts Company or Razak company) daily for 3 days, starting on the first day of menstruation, is as effective as mefenamic acid 250 mg three times daily for reducing pain, and more effective for reducing nausea and vomiting, associated with dysmenorrhea. However, mefenamic acid was more effective for reducing bleeding and analgesic use (105125).
• Fatigue. It is unclear if inhaled peppermint oil improves fatigue in patients with cardiac disease. Details: A clinical trial in hospitalized patients with various forms of cardiac disease shows that placing 3 drops of peppermint oil on a cotton ball and inhaling for 20 minutes nightly for 7 days improves fatigue scores when compared with placebo. These improvements were similar to those seen with lavender oil inhalation. Fatigue scores decreased by 24 and 21 points in the peppermint and lavender groups, respectively, compared with a 2-point reduction in the placebo group (107959). The validity of these findings is limited due to the short duration of treatment.
• Halitosis. Peppermint has only been evaluated in combination with other ingredients as a mouthwash; its effect when used alone is unclear. Details: Preliminary clinical research shows that rinsing the mouth with a specific combination of tea tree oil, peppermint, and lemon essential oil once for three minutes improves breath smell when compared with placebo or benzydamine hydrochloride (19177). Other preliminary clinical research in elderly adults with dementia who require oral care assistance shows that cleaning the mouth with a mixture of peppermint oil, tea tree oil, and lemon essential oils diluted to 0.5%, applied via gauze, twice daily for 7 days improves halitosis scores and oral condition scores when compared with placebo (112957).
• Insomnia. It is unclear if inhaled peppermint oil is beneficial for insomnia. Details: Preliminary clinical research in cancer patients shows that receiving aromatherapy as three drops of peppermint oil applied to a cotton ball and attached to the collar for 20 minutes at bedtime for one week improves sleep when compared with baseline. However, it seems to be no better than using lavender oil aromatherapy or using a control of lavender oil 1% (103063).
• Menopausal symptoms. It is unclear if inhaled peppermint oil is beneficial for menopausal symptoms. Details: Preliminary clinical research in adults with menopausal symptoms shows that receiving aromatherapy as 2 drops of peppermint oil with upper extremity massage and for 30 minutes twice weekly for 4 weeks moderately improves menopause symptom scores, including both somatic symptoms and urogenital symptoms, when compared with placebo (112745).
• Migraine headache. It is unclear if intranasal or inhaled peppermint oil is beneficial for migraine headache. Details: Preliminary clinical research shows that using 1-2 doses of intranasal peppermint oil 1.5% (Poursina Company) at the start of migraine pain is as effective as intranasal lidocaine 4%, and more effective than placebo, for reducing migraine headache intensity. Approximately 42% of those using peppermint oil indicated a high level of headache reduction, compared with 42% of those using lidocaine and 5% of those using placebo. Also, pain relief was felt within 5 minutes in more patients using peppermint than placebo (105126). However, it is unclear if participants were truly blinded to the use of peppermint oil. Other preliminary clinical research in pediatric patients with migraine or other chronic headaches shows that receiving aromatherapy with peppermint oil over 10 minutes during a footbath does not improve pain or anxiety scores when compared with control (112746).
• Mosquito repellent. Although there has been interest in using topical peppermint oil as a mosquito repellent, there is insufficient reliable information about the clinical effects of peppermint for this purpose.
• Myalgia. Although there has been interest in using topical peppermint oil for myalgia, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Oral mucositis. Topical peppermint has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults undergoing stem cell transplantation shows that using an oral rinse containing peppermint oil and German chamomile three times daily, in addition to standard treatment with sodium chloride and chlorhexidine, reduces the duration and severity of mucositis and the use of narcotic analgesics when compared with placebo and standard treatment. However, this oral rinse does not reduce or delay the occurrence of mucositis or affect the duration of hospitalization (96363). Another small clinical study in adults with head and neck cancers undergoing radiation shows that rinsing with 5 mL of a polyherbal mouthwash containing peppermint oil, German chamomile, aloe vera, and honey for 1 minute 3 times daily for 6 weeks reduces oral mucositis incidence, severity, and pain when compared with chlorhexidine 0.2% and placebo (111291). Clinical research in adults receiving treatment with 5-fluorouracil shows that using an oral rinse containing peppermint, sage tea, and thyme in addition to basic oral care, starting on the first day of chemotherapy and continuing for 14 days, delays the onset of mucositis, but not the rate or severity of mucositis, when compared with basic oral care alone (96364). It is unclear if these effects are due to peppermint oil, other ingredients, or the combinations.
• Osteoarthritis. Although there has been interest in using topical peppermint oil for osteoarthritis, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Pain (acute). It is unclear if inhaled or topical peppermint oil is beneficial for acute pain. Details: Preliminary clinical research in cardiac patients shows that peppermint oil aromatherapy reduces pain associated with intravenous catheterization by a small amount when compared with a distilled water control (102601). Another small open-label study in adults undergoing venipuncture for dialysis shows that topical application of peppermint gel 5 mL reduces pain scores by approximately 50% when compared with no intervention. These results were similar to using a cold compress (114758). Additionally, a small open-label study in children undergoing a dental procedure, shows that topical application of peppermint oil 0.2% , moderately improves pain scores after a buccal injection when compared with lidocaine spray 15% (114757).
• Postherpetic neuralgia. Although there has been interest in using topical peppermint oil for postherpetic neuralgia, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Postoperative ileus. It is unclear if oral peppermint oil is beneficial for the prevention of postoperative ileus. Details: Clinical research shows that taking a specific peppermint oil product (Colpermin, Tillotts Pharma) as two capsules three times daily for 5 days after routine gynecological surgery does not prevent postoperative abdominal distension and dyspepsia when compared with placebo (68602). Conversely, a small clinical study in patients undergoing elective cesarean section shows that taking 20 drops of peppermint oil 4 hours after surgery and then hourly for a total of three doses reduces the time to first bowel sounds by around 3.3 hours, first flatulence by 4.4 hours, and first stool by 5 hours when compared with placebo (110092).
• Postoperative nausea and vomiting (PONV). Some preliminary clinical studies suggest that inhaled peppermint may be beneficial for PONV. However, it is unclear if the benefit is due to aromatherapy or improved breathing patterns. Details: Some preliminary clinical research shows that using peppermint aromatherapy helps relieve postoperative nausea (3804,13415,68524,104219,104220). Inhaling peppermint oil 10% and 30% as aromatherapy reduces the severity of nausea when compared with placebo, with no significant difference between concentrations (104220). Small clinical trials show improvement in PONV within the first 4 hours after surgery. However, this effect diminishes beyond 4 hours (104219). Other preliminary clinical research shows that peppermint oil aromatherapy is no more effective for reducing postoperative nausea than inhaling isopropyl alcohol or saline (13416,68529). It is possible that any relief of postoperative nausea observed with peppermint aromatherapy results from improved breathing patterns after surgery rather than peppermint oil itself (13416,90512). One small study shows that inhaling peppermint oil while practicing controlled breathing does not appear to relieve PONV better than practicing controlled breathing alone (90512). Some preliminary clinical research shows that inhaling vapors from a mixture of peppermint, ginger, spearmint, and cardamom essential oils reduces symptoms of postoperative nausea in approximately 15% more patients when compared with inhaling ginger essential oils alone, and in approximately 43% more patients when compared with inhaling saline (89888). However, it is not clear if the effect is due to peppermint, the other oils, or the combination. In contrast, a small clinical trial in adults undergoing port catheter placement shows that application of a specific aromatherapy patch containing peppermint and lavender (Elequil Aromatabs, Beekley Medical) preoperatively does not reduce PONV rescue treatment when compared with placebo (114623). Another small clinical trial in adults with anxiety undergoing total hip or knee arthroplasty shows that application of the same patch containing peppermint and lavender every 12 hours for 6 doses does not reduce overall PONV when compared with placebo (114622).
• Postoperative pain. It is unclear if inhaled peppermint oil is beneficial for postoperative pain. Details: Preliminary clinical research in adults undergoing open heart cardiac surgery shows that receiving aromatherapy with peppermint oil 10%, 0.1 mL, three times daily for 7 doses moderately improves pain scores when compared with placebo (112747). Other preliminary clinical research in adults undergoing lumbar discectomy surgery shows that receiving aromatherapy with peppermint oil 5 drops once postoperatively modestly improves pain scores and anxiety scores when compared with no intervention (112744). A small clinical trial in adults undergoing port catheter placement shows that application of a specific aromatherapy patch containing peppermint and lavender (Elequil Aromatabs, Beekley Medical) preoperatively does not improve pain scores or reduce opioid rescue treatment in the immediate post-operative period when compared with placebo (114623). Another small clinical trial in adults with anxiety undergoing total hip or knee arthroplasty shows that application of the same patch containing peppermint and lavender every 12 hours for 6 doses modestly reduceses opioid consumption on postoperative day 2, but not day 1, 7, or 30, when compared with placebo (114622). However, these changes are unlikely to be clinically relevant. In addition, it is unclear if any potential effects are due to peppermint, lavender, or the combination.
• Postoperative recovery. Inhaled peppermint has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults undergoing port catheter placement shows that application of a specific aromatherapy patch containing peppermint and lavender (Elequil Aromatabs, Beekley Medical) preoperatively does not shorten postoperative length of stay when compared with placebo (114623).
• Postoperative sleep disturbance. It is unclear if inhaled peppermint oil is beneficial for postoperative sleep disturbance. Details: Preliminary clinical research in adults undergoing open heart cardiac surgery shows that receiving aromatherapy with peppermint oil 10%, 0.1 mL, three times daily for 7 doses modestly improves sleep scores when compared with placebo (112747).
• Pre-procedural anxiety. It is unclear if inhaled peppermint oil is beneficial for reducing anxiety prior to a medical procedure. Details: Preliminary clinical research in cardiac patients shows that peppermint oil aromatherapy does not reduce anxiety associated with intravenous catheterization when compared with a distilled water control (102601).
• Pregnancy-induced nausea and vomiting. Inhaled peppermint oil has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that aromatherapy with a mixture of 5% lemon and 5% peppermint essential oils modestly reduces the intensity of nausea and vomiting on days 2-4, but not day 1, when compared with placebo aromatherapy. When nauseated, patients placed three drops of the essential oil mixture (Barij Essence Co.) onto a cotton ball held 3 cm from the nose. This action could be repeated after 5 minutes if needed (105121).
• Pruritus. Some preliminary clinical studies suggest that topical peppermint oil improves itching of various etiologies. Details: Preliminary clinical research in adults with renal, hepatic, or diabetic pruritus shows that topical application of peppermint oil 5% in petrolatum twice daily for 2 weeks improves symptoms of pruritus when compared with petrolatum alone (96361). Preliminary clinical research in patients with severe or intractable pruritus secondary to burn scars shows that applying a specific product (Chongqing No.1, CQ-01, MJ Medical Gel Systems Ltd.) containing peppermint oil 3.6%, menthol 1.4%, and methyl salicylate 2.5%, covered with gauze for 24 hours, reduces the severity of pruritus for up to 7 days after application when compared with hydrogel covered with gauze or with gauze alone (96362). Preliminary clinical research in females experiencing itchy skin due to intrahepatic cholestasis of pregnancy also shows that applying peppermint oil 0.5% in sesame oil twice daily for 2 weeks reduces pruritus severity approximately 1.8-fold when compared with sesame oil alone (89478).
• Small intestinal bacterial overgrowth (SIBO). Although there has been interest in using oral peppermint for SIBO, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Stress. It is unclear if inhaled peppermint oil is beneficial for stress. Details: Clinical research shows that peppermint aromatherapy decreases physical and perceived levels of stress when compared with baseline (68422,68517). A small clinical study in adults undergoing a virtual reality (VR) driving scenario to test road rage shows that exposure to peppermint oil (Pure Essential Oil of Peppermint, Tisserand Aromatherapy) 5 drops via fan diffuser improves aggressive driving behavior scores but does not seem to improve self-reported stress, aggression, alertness, happiness, or calmness when compared with controls that did not receive aromatherapy during the VR session (112017).
• Toothache. Although there has been interest in using topical peppermint oil for toothache, there is insufficient reliable information about the clinical effects of peppermint for this condition.
• Urticaria. Although there has been interest in using topical peppermint oil for urticaria, there is insufficient reliable information about the clinical effects of peppermint for this condition. More evidence is needed to rate peppermint for these uses.

(Read more about PEPPERMINT)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there has been interest in using oral skullcap for allergic rhinitis (hay fever), there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Anxiety. It is unclear if oral skullcap is beneficial for reducing symptoms of anxiety. Details: Preliminary clinical research shows that healthy people who take a single dose of freeze-dried skullcap extract 100-350 mg feel more relaxed when compared to baseline. This effect appears to last for about 2 hours (12216). However, other preliminary clinical research in healthy patients shows that taking freeze-dried skullcap (Skullcap, Eclectic Institute) 350 mg three times daily for 2 weeks does not reduce anxiety scores when compared with placebo (91690). Because these were short-term studies in healthy patients, it's unclear if skullcap is beneficial in anxiety disorders or if extended use is beneficial.
• Atherosclerosis. Although there has been interest in using oral skullcap for atherosclerosis, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Contact dermatitis. Although there has been interest in using oral skullcap for contact dermatitis, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Epilepsy. Although there has been interest in using oral skullcap for epilepsy, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Hyperlipidemia. Although there has been interest in using oral skullcap for hyperlipidemia, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Insomnia. Although there has been interest in using oral skullcap for insomnia, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Premenstrual dysphoric disorder (PMDD). Although there has been interest in using oral skullcap for PMDD, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Spasticity. Although there has been interest in using oral skullcap for spasticity, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Stress. Although there has been interest in using oral skullcap for stress, there is insufficient reliable information about the clinical effects of skullcap for this purpose.
• Stroke. Although there has been interest in using oral skullcap for stroke, there is insufficient reliable information about the clinical effects of skullcap for this purpose. More evidence is needed to rate skullcap for this use.

(Read more about SKULLCAP)

POSSIBLY EFFECTIVE

• Back pain. Oral willow bark extract has been evaluated for the treatment of back pain, with promising results. Details: Clinical research in patients with chronic low back pain shows that taking a standardized willow bark extract providing salicin 120 mg or 240 mg daily for 4 weeks reduces lower back pain and decreases the need for rescue analgesia when compared with placebo. Salicin 240 mg appears to be more effective than salicin 120 mg, and significant pain relief may be observed after 1 week of high-dose use (6456). Additional research suggests that taking willow bark extract providing salicin 240 mg daily for 4 weeks is as effective as rofecoxib (Vioxx) for lower back pain (12804).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Ankylosing spondylitis. Although there has been interest in using oral willow bark for pain associated with ankylosing spondylitis, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Common cold. Although there has been interest in using oral willow bark for common cold symptoms, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Dysmenorrhea. Although there has been interest in using oral willow bark for dysmenorrhea, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Gout. Although there has been interest in using oral willow bark for gout, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Headache. Although there has been interest in using oral willow bark for headache, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Influenza. Although there has been interest in using oral willow bark for pain and fever associated with influenza, including swine flu, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Joint pain. Oral willow bark has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with joint pain shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 500 mg, methylsufonlylmethane 167 mg, white willow bark extract 83 mg, ginger root concentrate 17 mg, boswellia extract 42 mg, turmeric root extract 17 mg, cayenne 40 m H.U. 17 mg, and hyaluronic acid 1.3 mg three times daily for 8 weeks reduces joint pain severity by 37% compared to only 16% with placebo. However, the specific combination product does not appear to significantly improve joint stiffness or function when compared with placebo (89560). It is unclear if these findings are due to willow bark, other ingredients, or the combination.
• Myalgia. Although there has been interest in using oral willow bark for myalgia, there is insufficient reliable information about the clinical effects of willow bark for this purpose.
• Obesity. Oral willow bark has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests that willow bark in combination with ephedra and cola nut might cause modest weight loss in overweight and obese people. Willow bark 600 mg daily (containing 90 mg salicin) in divided doses given for 3 months in combination with these central nervous system stimulants might cause a 2 kg reduction in weight (12811). However, this combination may not be appropriate due to safety concerns associated with ephedra. Ephedra is banned in the US due to severe adverse effects (10055).
• Osteoarthritis. Small clinical studies suggest that oral willow bark extract may improve symptoms of osteoarthritis, although some conflicting evidence exists. Details: Some preliminary clinical research in patients with osteoarthritis shows that taking willow bark extract standardized to contain 240 mg of salicin daily for 2 weeks produces moderate analgesic activity when compared with placebo (12474,86490). Additional research shows that taking a specific willow bark extract (Optovit actiFLEX, Hermes Arzneimittel GmbH) standardized to contain salicin 120-240 mg daily for 6 weeks improves swelling, tenderness, and physical function similarly to conventional non-steroidal anti-inflammatory drugs (NSAIDs) (91406). However, other research shows that taking willow bark extract standardized to 240 mg of salicin daily for 6 weeks does not improve pain, stiffness, or physical function when compared with placebo (12475).
• Rheumatoid arthritis (RA). It is unclear if oral willow bark is beneficial in patients with RA. Details: Clinical research in a small number of patients with RA shows that willow bark extract standardized to 240 mg of salicin daily for 6 weeks does not improve pain when compared with placebo (12475). However, it is possible this study was underpowered to detect a significant difference in pain in these patients. More evidence is needed to rate willow bark for these uses.

(Read more about WILLOW BARK)

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

POSSIBLY SAFE ...when used orally and appropriately for medicinal purposes. Bilberry fruit extracts have been used with apparent safety in clinical trials at a dose of up to 160 mg daily for up to 6 months (39,40,8139,9739,14280,35472,35510,35512,103190,104192,104195). A higher bilberry extract dose of 1.4 grams daily has been used with apparent safety for up to 4 weeks (104194). Whole bilberries or bilberry juice have also been consumed with apparent safety in quantities of 100-160 grams daily for up to 35 days (35463,91506).

POSSIBLY UNSAFE ...when the leaves are used orally in high doses or for a prolonged period. Death can occur with chronic use of 1.5 gram/kg daily (2).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in the amounts commonly found in foods. However, there is insufficient reliable information available about the safety of bilberry when used in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about BILBERRY)

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)

POSSIBLY SAFE ...when used orally, subcutaneously, or intravenously and appropriately. There is some evidence that European mistletoe extracts can be used safely (7039,9769,15351,24773,24778,93261,93266,93267,96487,107285). However, they have a narrow therapeutic range; high doses are not safe. Tell patients not to consume more than three mistletoe berries or two leaves (12). Advise patients not to use European mistletoe for self-medication.

LIKELY UNSAFE ...when used orally in high doses. Ingestion of high doses of mistletoe berry or leaf can cause serious adverse reactions. More than three berries or two leaves can cause seizures, bradycardia, hypotension, and death (7039).

PREGNANCY: LIKELY UNSAFE
when used orally or subcutaneously. European mistletoe might have uterine stimulant and abortifacient activity (19).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about EUROPEAN MISTLETOE)

LIKELY SAFE ...when used orally and appropriately. Garlic has been used safely in clinical studies lasting up to 7 years without reports of significant toxicity (1873,4782,4783,4784,4785,4786,4787,4789,4790,4797)(4798,6457,6897,14447,96008,96009,96014,102016,102670,103479)(107238,107239,107352,108607,110722,111763).

POSSIBLY SAFE ...when used topically. Garlic-containing gels, lipid-soluble garlic extracts, garlic pastes, and garlic mouthwashes have been safely used in clinical research for up to 3 months (4766,4767,8019,15030,51330,51386). ...when used intravaginally. A vaginal cream containing garlic and thyme has been safely used nightly for 7 nights (88387).

POSSIBLY UNSAFE ...when raw garlic is used topically (585). Raw garlic might cause severe skin irritation when applied topically.

PREGNANCY: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Garlic is reported to have abortifacient activity (11020). One study also suggests that garlic constituents are distributed to the amniotic fluid after a single dose of garlic (4828). However, there are no published reports of garlic adversely affecting pregnancy. In clinical research, garlic 800 mg daily was used during the third trimester of pregnancy with no reported adverse outcomes (9201,51626). There is insufficient reliable information available about the safety of topical garlic during pregnancy.

LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (3319).

LACTATION: POSSIBLY UNSAFE
when used orally in amounts greater than those found in foods. Several small studies suggest that garlic constituents are secreted in breast milk, and that nursing infants of mothers consuming garlic are prone to extended nursing (3319,4829,4830). There is insufficient reliable information available about the safety of topical garlic during lactation.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately for up to 8 weeks. Garlic extract 300 mg three times daily has been used with apparent safety for up 8 weeks in children ages 8-18 years (4796). There is insufficient reliable information available about the safety of garlic when used over longer durations or in higher doses.

CHILDREN: POSSIBLY UNSAFE
when raw garlic is used topically. Raw garlic might cause severe skin irritation when applied topically (585,51210).

(Read more about GARLIC)

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)

LIKELY SAFE ...when peppermint oil is used orally, topically, or rectally in medicinal doses. Peppermint oil has been safely used in multiple clinical trials (3801,3804,6190,6740,6741,10075,12009,13413,14467,17681)(17682,68522,96344,96360,96361,96362,96363,96364,96365,99493).

POSSIBLY SAFE ...when peppermint leaf is used orally and appropriately, short-term. There is some clinical research showing that peppermint leaf can be used safely for up to 8 weeks (12724,13413). The long-term safety of peppermint leaf in medicinal doses is unknown. ...when peppermint oil is used by inhalation as aromatherapy (7107). There is insufficient reliable information available about the safety of using intranasal peppermint oil.

CHILDREN: POSSIBLY SAFE
when used orally for medicinal purposes. Enteric-coated peppermint oil capsules have been used with apparent safety under medical supervision in children 8 years of age and older (4469).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts commonly found in foods (96361). There is insufficient information available about the safety of using peppermint in medicinal amounts during pregnancy or lactation; avoid using.

(Read more about PEPPERMINT)

There is insufficient reliable information available about the safety of skullcap.

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

(Read more about SKULLCAP)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Willow bark has been used safely for up to 12 weeks (6456,12474,12475,12804,12811,86473,91406).

CHILDREN: POSSIBLY UNSAFE
when used orally for viral infections. Salicylic acid and aspirin are contraindicated in children with viral infections (12801). Although Reye's syndrome has not been reported, the salicin constituent in willow bark is similar to aspirin and might pose the same risk.

PREGNANCY:
Insufficient reliable information available; avoid using.

LACTATION: POSSIBLY UNSAFE
when used orally. Willow bark contains salicylates which are excreted in breast milk and have been linked to adverse effects in breast-fed infants (12802,12803).

(Read more about WILLOW BARK)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details In vitro, animal, and clinical research suggest that anthocyanidin extracts from bilberry can inhibit platelet aggregation (16631,35455,35503,35504,35505).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry leaf or fruit extract may increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Animal research suggests that bilberry leaf extract might have blood glucose-lowering activity (1264). Also, one small clinical trial in patients with type 2 diabetes shows that taking bilberry fruit extract 470 mg as a single dose prior to an oral glucose tolerance test lowers plasma glucose levels when compared with placebo (91507).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might decrease levels of drugs metabolized by CYP2E1.  Details Animal research shows that exposure to small concentrations of bilberry extract in drinking water for around one month increased CYP2E1 activity by 31%. However, exposure over a 2-month period did not increase CYP2E1 activity (103191). This effect has not been reported in humans.

ERLOTINIB (Tarceva) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, bilberry fruit extract might reduce the efficacy of erlotinib.  Details In vitro research suggests that bilberry fruit extract and its constituents, delphinidin and delphinidin-3-O-glucoside, inhibit the activity of erlotinib (97031). This interaction has not been reported in humans.

(Read more about BILBERRY)

ACE INHIBITORS (ACEIs) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, using topical capsaicin may increase the risk of ACE inhibitor-induced cough.  Details There is one case report of a topically applied capsaicin cream contributing to the cough reflex in a patient using an ACEI (12414). However, it is unclear if this interaction is clinically significant.

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, capsicum may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro research shows that capsicum might increase the effects of antiplatelet drugs (12406,12407). Also, population research shows that capsicum is associated with an increased risk of self-reported bleeding in patients taking warfarin (12405,20348). However, clinical research shows that taking a single dose of capsaicin (Asian Herbex Ltd.), the active ingredient in capsicum, 400-800 mcg orally in combination with aspirin 500 mg does not decrease platelet aggregation when compared with taking aspirin 500 mg alone. Also, there was no notable effect on measures of platelet aggregation with capsaicin (92990). It is unclear whether capsaicin must be used in more than a single dose to affect platelet aggregation.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking capsicum with antidiabetes drugs might increase the risk of hypoglycemia.  Details Preliminary clinical research shows that consuming capsicum 5 grams along with a glucose drink attenuates the rise in plasma glucose after 30 minutes by 21%, decreases the 2-hour postprandial area under the curve of plasma glucose by 11%, and increases the 2-hour postprandial area under the curve of plasma insulin by 58% in healthy individuals when compared with placebo (40453,40614). Other clinical research shows that taking capsicum 5 mg daily for 28 days significantly reduces postprandial blood glucose and insulin levels, but not fasting blood glucose and insulin levels, in patients with gestational diabetes (96457).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with aspirin might reduce the bioavailability of aspirin.  Details Animal research shows that acute or chronic intake of capsicum pepper reduces oral aspirin bioavailability (22617). This has not been shown in humans.

CIPROFLOXACIN (Cipro) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with ciprofloxacin might increase levels and adverse effects of ciprofloxacin.  Details Animal research shows that concomitant use of capsaicin, the active constituent of capsicum, and ciprofloxacin increases the bioavailability of ciprofloxacin by up to 70% (22613).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking capsicum with theophylline might increase the levels and adverse effects of theophylline.  Details In animal research, oral administration of capsicum reduced excretion of theophylline (12405). However, capsicum does not seem to affect the pharmacokinetics of theophylline when administered intravenously (22616).

(Read more about CAPSICUM)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, European mistletoe might increase the risk of hypotension when taken with antihypertensive drugs.  Details Animal research suggests that European mistletoe extracts have hypotensive effects (93270,96492).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, European mistletoe might decrease the effectiveness of immunosuppressants.  Details Clinical and in vitro studies suggest that European mistletoe might have immunostimulant effects (7039,8843,8844,24775,24779).

(Read more about EUROPEAN MISTLETOE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Garlic may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397,96013).

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking garlic with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research suggests that garlic and garlic extract lower blood glucose levels in healthy and diabetic individuals (51463,96004).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garlic with antihypertensive drugs might increase the risk of hypotension.  Details In human research, both garlic and garlic extracts have blood pressure-lowering effects (277,278,279,1873,4787,6897,16605,51414,51442,51669)(88386,88398,96007).

ATAZANAVIR (Reyataz) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might decrease levels and effects of atazanavir.  Details In a case report, a patient consuming six stir-fried garlic cloves three times weekly developed suboptimal atazanavir levels and increases in HIV viral load. While the exact cause of this interaction is unclear, there is speculation that garlic might decrease the intestinal absorption of atazanavir or increase its metabolism by inducing cytochrome P450 3A4 (CYP3A4) (88388). Until more is known, advise patients not to consume large amounts of garlic while taking atazanavir.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Garlic might increase levels of drugs metabolized by CYP2E1.  Details Clinical research suggests garlic oil can inhibit the activity of CYP2E1 by 39% (10847). Use garlic oil cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic products containing allicin might induce intestinal CYP3A4 and inhibit hepatic CYP3A4. This may increase or decrease levels of drugs metabolized by CYP3A4.  Details Some human research suggests that garlic may induce INTESTINAL CYP3A4, reducing levels of drugs metabolized by this enzyme. This is primarily based on a study showing that taking a specific allicin-containing garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induced CYP3A4 in the gut mucosa (7027,93578). Another study shows that giving docetaxel intravenously, bypassing the CYP3A4 enzymes in the gut mucosa, along with the same specific garlic product for 12 consecutive days, does not affect docetaxel levels (17221). Conversely, there is concern that garlic may inhibit HEPATIC CYP3A4. In a single case report, increased tacrolimus levels and liver injury occurred in a liver transplant patient after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days (96010). Several other studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

ISONIAZID Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might decrease levels of isoniazid.  Details Animal research suggests that an aqueous extract of garlic reduces isoniazid levels by about 65%. Garlic reduced the maximum concentration (Cmax) and area under the curve (AUC), but not the half-life, of isoniazid. This suggests that garlic extract might inhibit isoniazid absorption across the intestinal mucosa (15031); however, the exact mechanism of this potential interaction is not known.

PROTEASE INHIBITORS (PIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic products containing allicin might decrease levels of PIs.  Details Protease inhibitors are metabolized by cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4, reducing plasma levels of protease inhibitors. This is primarily based on a study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces levels of saquinavir, a PI, by approximately 50%. It is speculated that the allicin constituent induce CYP3A4 in the gut mucosa (7027,93578). Several studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506).

SAQUINAVIR (Fortovase, Invirase) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic containing allicin might decrease levels of saquinavir.  Details Saquinavir is a substrate of cytochrome P450 3A4 (CYP3A4) isoenzymes. There is concern that garlic products containing allicin might induce intestinal CYP3A4 and cause subtherapeutic levels of saquinavir. This is primarily based on a pharmacokinetic study showing that taking a specific garlic product (GarliPure Maximum Allicin Formula, Natrol Inc.) twice daily for 3 days reduces saquinavir levels by approximately 50%. It is speculated that the allicin constituent induces CYP3A4 in the gut mucosa (7027,93578). Several pharmacokinetic studies have evaluated the impact of other garlic formulations on CYP3A4 substrates and have found no effect. Most of the products in these studies provided little or no allicin (10335,10847,15031,94506). Until more is known about this potential interaction, use garlic containing allicin cautiously in patients taking saquinavir.

SOFOSBUVIR (Sovaldi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking garlic with sofosbuvir might decrease its effectiveness.  Details Animal research in rats shows that giving aged garlic extract 120 mg/kg orally daily for 14 days decreases the area under the concentration time curve (AUC) after a single sofosbuvir dose of 40 mg/kg by 36%, increases the clearance by 63%, and decreases the plasma concentrations at 1 and 8 hours by 35% and 58%, respectively. This interaction is hypothesized to be due to induction of intestinal P-glycoprotein expression by garlic (109524).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, garlic might increase levels of tacrolimus.  Details In one case report, a liver transplant patient taking tacrolimus experienced increased tacrolimus levels and liver injury after taking a specific garlic supplement (Garlicin Cardio, Nature's Way) at up to three times the manufacturer recommended dose for 7 days. It is speculated that garlic inhibited hepatic cytochrome P450 3A4 (CYP3A4), which increased plasma levels of tacrolimus (96010).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, garlic might increase the risk of bleeding with warfarin.  Details Raw garlic and a variety of garlic extracts have antiplatelet activity and can increase prothrombin time (586,616,1874,3234,4366,4802,4803,51397). In addition, there is a report of two patients who experienced an increase in a previously stabilized international normalized ratio (INR) with concomitant garlic and warfarin use (51228,51631). However, this report has been subsequently debated due to limited clinical information. Other clinical studies have not identified an effect of garlic on INR, warfarin pharmacokinetics, or bleeding risk (15032,16416). More evidence is needed to determine the safety of using garlic with warfarin.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal research shows that hawthorn can inhibit platelet aggregation (95528,95529,95530,95531). However, its effect in humans is unclear. One observational study shows that patients taking hawthorn shortly before undergoing coronary artery bypass graft (CABG) surgery or valve replacement surgery have a 10% incidence of postoperative bleeding, compared with 1% in those who never consumed hawthorn extract (95527). However, clinical research shows that taking a specific preparation of dried hawthorn leaves and flowers (Crataesor, Soria Natural Lab) 800 mg three times daily for 15 days does not affect platelet aggregation or levels of thromboxane B2, the metabolite of thromboxane A2, in healthy humans (54664).

BETA-BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive effects on blood pressure and heart rate.  Details Some evidence shows that hawthorn might lower blood pressure and heart rate (12595,19245,113112,113113).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilation and hypotensive effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn might potentiate the effects and adverse effects of digoxin.  Details Hawthorn appears to improve cardiac output (12595); however, hawthorn does not appear to affect digoxin pharmacokinetics (19249). Case reports suggest that at least one species of hawthorn root extract (Crataegus mexicana) may produce adverse effects similar to digoxin and can cross-react with digoxin assays, leading to falsely elevated plasma digoxin levels (113112,113113).

NITRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilatory effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

PHOSPHODIESTERASE-5 INHIBITORS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might result in additive vasodilation and hypotension.  Details Hawthorn might inhibit PDE-5 and cause vasodilation (12595).

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CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, peppermint oil might increase the levels and adverse effects of cyclosporine.  Details In animal research, peppermint oil inhibits cyclosporine metabolism and increases cyclosporine levels. Inhibition of cytochrome P450 3A4 (CYP3A4) may be partially responsible for this interaction (11784). An interaction between peppermint oil and cyclosporine has not been reported in humans.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, peppermint might increase the levels of CYP1A2 substrates.  Details In vitro and animal research shows that peppermint oil and peppermint leaf inhibit CYP1A2 (12479,12734). However, in clinical research, peppermint tea did not significantly affect the metabolism of caffeine, a CYP1A2 substrate. It is possible that the 6-day duration of treatment may have been too short to identify a difference (96359).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, peppermint might increase the levels of CYP2C19 substrates.  Details In vitro research shows that peppermint oil inhibits CYP2C19 (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, peppermint might increase the levels of CYP2C9 substrates.  Details In vitro research shows that peppermint oil inhibits CYP2C9 (12479). So far, this interaction has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, peppermint might increase the levels of CYP3A4 substrates.  Details Clinical research in healthy volunteers shows that a single dose of peppermint oil 600 mg inhibits CYP3A4 enzymes and increases the AUC of felodipine, a CYP3A4 substrate (11783). However, in vitro research suggests that peppermint oil only inhibits CYP3A4 at very high concentrations (12479).

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CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, skullcap can have additive effects when used with other CNS depressants.  Details Animal and clinical research suggests that skullcap can cause sedation and cognitive impairment (12216,74008).

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ACETAZOLAMIDE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, willow bark might result in additive adverse effects associated with acetazolamide.  Details Willow bark contains salicin, a plant salicylate. Human case reports suggests that a combination of acetazolamide and salicylate increases unbound plasma levels of acetazolamide, as well as adverse effects related to acetazolamide (86481).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the risk of bleeding when taken with anticoagulant/antiplatelet drugs.  Details Willow bark has antiplatelet effects, but less so than aspirin (12810).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of aspirin.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as aspirin (12808).

CHOLINE MAGNESIUM TRISALICYLATE (Trilisate) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of choline magnesium trisalicylate.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as choline magnesium trisalicylate (12808).

SALSALATE (Disalcid) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, willow bark might increase the effects and adverse effects of salsalate.  Details Willow bark contains salicin, a plant salicylate. It might have an additive effect when taken with other salicylate-containing drugs such as salsalate (12808).

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General ...Orally, bilberry fruit, juice, and extracts seem to be well tolerated.
Most Common Adverse Effects:
Orally: Dark-colored stools, flatulence, and gastrointestinal discomfort.

Gastrointestinal ...In one small clinical trial, mild-to-moderate flatulence was reported in 33% of patients taking sieved bilberries and concentrated bilberry juice (91506). However, the patients in this study had ulcerative colitis, and the study lacked a control group, limiting the validity of this finding. In another small clinical study of males with age-related cognitive impairment, temporary adverse gastrointestinal (GI) effects were reported in 13% of patients drinking a combination of bilberry and grape juice. However, the adverse GI effect rate was identical in patients drinking a placebo juice (110641). A post-marketing surveillance report of 2295 patients using bilberry extract (Tegens) found that 1% of patients complained of GI discomfort and less than 1% experienced nausea or heartburn (35500).
Theoretically, fresh bilberry fruit may have laxative effects. One clinical trial noted an increased frequency of bowel movements following the administration of a combination formulation containing aerial agrimony parts, cinnamon quills, powdered bilberry fruit, and slippery elm bark (35462). It is unclear if these effects were due to bilberry, other ingredients, or the combination.

Other ...Orally, bilberry may cause discoloration of feces and the tongue. In one study, a dark-bluish to black discoloration of both the feces and the tongue was observed following consumption of sieved bilberries and concentrated bilberry juice. In one patient, a slight discoloration of the teeth has also been observed (91506). In another study, 50% of patients reported dark green stools after taking bilberry extract 700 mg twice daily for 4 weeks (104194).

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General ...Orally, capsicum is generally well tolerated in amounts typically found in food or when the extract is used in doses of up to 200 mg daily. Topically and intranasally, capsaicin, a constituent of capsicum, is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, burning, diarrhea, dyspepsia, gas, headache, mild constipation, nausea, rhinorrhea, skin flushing, and sweating.
Serious Adverse Effects (Rare):
Orally: Cases of myocardial infarction and hypertensive crisis have been reported.

Cardiovascular ...Orally, palpitation was reported in one clinical trial (105196).
One case of myocardial infarction has been reported in a 41-year-old male without cardiovascular risk factors; the event was attributed to the use of an oral capsicum pepper pill that the patient had been taking for weight loss (40768). Another case of coronary vasospasm and acute myocardial infarction has been reported for a healthy 29-year-old male; the event was attributed to the use of a topical capsicum-containing patch that the patient had been applying to the middle of the back for 6 days (40658). Two cases of arterial hypertensive crisis have been reported for individuals who ingested a large amount of peppers and chili peppers the day before. One of the patients also had an acute myocardial infarction, and the other had high levels of thyroid stimulating hormone (40569,40606).

Dermatologic ...Orally, capsicum or its constituent capsaicin may cause urticaria and skin wheals in rare cases (96457,105203).
Topically, capsicum can cause a prickling sensation, itching, pain, burning, edema, stinging, irritation, rash, and erythema. About 1 in 10 patients who use capsaicin topically discontinue treatment because of adverse effects. These effects seem to occur more often with topical formulations containing higher concentrations of capsaicin, the active constituent of capsicum. Side effects tend to diminish with continued use (12401,15260,15261,40358,40439,40483,40547,40676,40682,40719)(40784,40847,92979,92983,92984,96453,105193,105197,105202,111514). In one case, application of a capsaicin 8% patch (Qutenza) for 60 minutes caused a second-degree burn, characterized by burning, erythema, severe pain, and blistering at the administration site. The burn was treated with topical corticosteroids, but 9 months later neuropathic pain persisted, resulting in limited mobility. It is unclear whether the mobility sequalae were caused by topical capsaicin or the patient's pre-existing neurological disorders (111514). Skin contact with fresh capsicum fruit can also cause irritation or contact dermatitis (12408).
Intranasally, capsaicin can cause nasal burning and pain in most patients. It also often causes lacrimation, sneezing, and excessive nasal secretion; however, these side effects appear to diminish with repeat applications (14323,14329,14358). In some cases, the burning sensation disappears after 5-8 applications (14351,14358). In some cases, patients are pretreated with intranasal lidocaine to decrease the pain of intranasal capsaicin treatment. However, even with lidocaine pretreatment, patients seem to experience significant pain (14324).

Gastrointestinal ...Orally, capsicum can cause upper abdominal discomfort, including irritation, fullness, dyspepsia, gas, bloating, nausea, epigastric pain and burning, anal burning, diarrhea, mild constipation, and belching (12403,12410,40338,40427,40456,40503,40560,40584,40605,40665)(40718,40725,40745,40808,40828,96456,96457,105194,105196). There is a case report of a 3-year-old female who experienced a burning and swollen mouth and lips after touching the arm of a parent that had been treated with a capsaicin patch and then placing the fingers in the mouth (105199). Excessive amounts of capsaicin can lead to gastroenteritis and hepatic necrosis (12404). In a case report, a 40-year-old male with diabetes consumed white wine daily and chewed cayenne which was thought to result in black teeth stains and loss of enamel (40809). Some preliminary research links ingestion of capsaicin with stomach and gallbladder cancer; however the link may be due to contamination of capsaicin products with carcinogens (40771).
Topically, capsaicin can cause diarrhea and vomiting (105202).

Immunologic ...In a case report, a 34-year-old female had anaphylaxis involving difficulty breathing and stupor and also urticaria after consuming a red bell pepper, which is in the capsicum genus. The causal chemical was theorized to be 1,3-beta-glucanase (92978). In another case report, a 33-year-old female experienced angioedema, difficulty breathing and swallowing, and urticaria after ingesting raw green and red peppers (92982).

Neurologic/CNS ...Orally, capsicum can cause sweating and flushing of the head and neck, lacrimation, headache, faintness, and rhinorrhea (7005,12410,105196,105203). Topically, applying capsaicin can cause headache (96450,105202). Injection of capsaicin into the intermetatarsal space has also been associated with headache (96454).

Ocular/Otic ...Topically, capsicum can be extremely irritating to the eyes and mucous membranes. Capsicum oleoresin, an oily extract in pepper self-defense sprays, causes intense eye pain. It can also cause erythema, blepharospasm, tearing, shortness of breath, and blurred vision. In rare cases, corneal abrasions have occurred (12408,12409,40345,40348,40383,40720,40857).
Inhalation of capsicum can cause eye irritation, and allergic alveolitis (5885). In a case report, a 38-year-old female had acute anterior uveitis that developed about 12 hours after using a specific patch (Isola Capsicum N Plus) that contained capsaicin 1.5 mg per patch and methyl salicylate 132 mg per patch for neck pain. The uveitis was controlled with topical steroids and did not recur (92977).

Oncologic ...Population research suggests that moderate to high intake of capsaicin, the active constituent of capsicum, is associated with an increased risk of gastric cancer, while low intake is associated with a decreased risk. It is not clear from the study what amount of capsaicin is considered high versus low intake (92988). Additionally, some research suggests that any link may be due to contamination of capsaicin products with carcinogens (40771).

Pulmonary/Respiratory ...Orally, difficulty breathing was reported in a clinical trial (105196).
Topically, nasopharyngitis related to the use of a cream containing capsaicin has been reported (105202).
Inhalation of capsicum and exposure to capsicum oleoresin spray can cause cough, dyspnea, pain in the nasal passages, sneezing, rhinitis, and nasal congestion (5885,15016,40522,40546,40647). In rare cases, inhalation of the capsicum oleoresin or pepper spray has caused cyanosis, apnea, respiratory arrest and death in people. Death was caused by asphyxiation probably due to acute laryngeal edema and bronchoconstriction from inhalation of the capsicum oleoresin spray (40546,40672,40837,40879).
In a case report, a 47-year-old female who was exposed to capsaicin gas for more than 20 minutes experienced acute cough, shortness of breath, short-term chest pain, wheezing, and difficulty breathing for months afterwards (92980). In rare cases, exposure to capsicum oleoresin spray resulted in apnea, pulmonary injury, cyanosis, and even respiratory arrest (40383,40546).

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General ...Orally, European mistletoe seems to be well tolerated when used in small amounts. However, a thorough evaluation of safety outcomes has not been conducted. Parenterally, European mistletoe may be safe when administered by a healthcare provider. High oral or parenteral doses may be unsafe.
Most Common Adverse Effects:
Orally: Diarrhea, intestinal cramps, and vomiting at high doses.
Parenterally: Chills, diarrhea, eosinophilia, fever, flatulence, headache, malaise, nausea, pruritus, vomiting, and pain and inflammation at the injection site.
Serious Adverse Effects (Rare):
Orally: Hepatitis, seizures, coma, and death at high doses.
Parenterally: Necrosis at injection site. Allergic reactions, including anaphylaxis, in sensitive individuals.

Cardiovascular ...Subcutaneously, European mistletoe may cause angina and orthostatic circulatory disturbances (7044,7045,9769).

Dermatologic ...Subcutaneously and intravenously, European mistletoe may cause pruritus, skin rash, and angioedema (93261,93265,93266,96476,107285,107286). When administered subcutaneously, the use of an extended dose-escalation regimen may limit the development of localized reactions in comparison to rapid dose escalation (96476).

Endocrine ...Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may cause hypokalemia (16385).

Gastrointestinal ...Orally, European mistletoe may cause vomiting, diarrhea, and intestinal cramps (18). Intraperitoneal and intratumoral injection may cause nausea, vomiting, and abdominal pain (7106,93264,96495). Subcutaneously, European mistletoe may cause flatulence, loose stools, diarrhea, nausea, and vomiting (93261,93265). Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may cause nausea and vomiting (16385,93261).

Genitourinary ...Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may change urinary frequency (16385,93261).

Hematologic ...Subcutaneously, intraperitoneally, or intratumorally, European mistletoe may cause eosinophilia (7044,7045,7106,9769).

Hepatic ...Orally, European mistletoe has been associated with two cases of hepatotoxicity when used in combination with other herbal ingredients. In one case, in which a patient took a combination herbal product, it was deemed unlikely that European mistletoe was the causative agent. It was determined to be most likely due to another ingredient or product contamination (3932). In another case, a previously healthy male presented to the hospital with mild fever, brownish urine, and elevated liver function enzymes after frequent use of European mistletoe extract for 1 month and kudzu root extract for 10 days. Upon discontinuation of the two extracts, liver function slowly returned to normal with no other symptoms (88777). It is unclear if European mistletoe, kudzu, or the combination was responsible for this adverse effect.
Intravenously, aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, may cause elevated liver enzymes (16385,93261).

Immunologic ...Subcutaneously, European mistletoe may cause allergic reactions (7044,7045,9769) or flu-like symptoms or mild infections (93261). Early research shows that European mistletoe is not associated with an increase in side effects when it is administered in conjunction with targeted cancer treatments such as monoclonal antibodies and immunotherapy regimens, including PD-1/PD-L1 or CTLA-4 inhibitors (96490,96489). There are two case reports of apparent immunologic response to the application of European mistletoe for pleurodesis, resulting in acute respiratory distress and pneumonitis (96488,96494).
There are at least 5 reports of anaphylactic reactions associated with subcutaneous European mistletoe extract (15352,107286). In one case, anaphylaxis did not occur until after 2 years of treatment with European mistletoe (15352). Aviscumine has also been associated with anaphylactic reactions in people who have previously used European mistletoe products (16385).

Musculoskeletal ...Subcutaneous, intratumoral, intraperitoneal, and intravenous administration of European mistletoe can cause pain at the injection site (7044,7045,9769,93264,93266,7106,93261,96495). There is one report of a benign abdominal wall mass developing at the European mistletoe injection site, which was likely the result of a local inflammatory response (15350). Necrosis can also occur at the site of injection (8).

Neurologic/CNS ...Orally, European mistletoe may cause seizures, coma, and death (18). Subcutaneously, European mistletoe can cause headaches (7044,7045,9769,93261,93265) or fatigue or malaise (93261,93265). When injected into the tumor, European mistletoe can cause headaches (93264,96495). Intravenous infusion of aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, can cause fatigue (16385,93261).

Ocular/Otic ...Orally, European mistletoe may cause contraction of the pupil and uncontrollable eye movement (18). Subcutaneously, European mistletoe may cause dry eyes (93261).

Pulmonary/Respiratory ...There are multiple reports of acute respiratory effects after application of European mistletoe for pleurodesis. In one case, a 52-year-old male presenting with pneumothorax received European mistletoe extract 40 mg (ABNOBAviscum F, ABNOBA Helmittel GmbH) with 50 mL of normal saline into the pleural space. After 3 days, the patient experienced worsening dyspnea with right pleural effusion and bilateral lung infiltration requiring intubation and mechanical ventilation (96488). In another case, a 58-year-old male presenting with postoperative pleural effusion received pleurodesis with European mistletoe extract 500 mg (ABNOBAviscum F) on days 6, 8, 12, and 16 after surgery. Imaging revealed apparent acute respiratory distress and pneumonitis, but without corresponding clinical symptoms, which improved after 5 days of supportive care (96494). In a small retrospective study, 28% of elderly patients with secondary spontaneous pneumothorax who underwent chemical pleurodesis with European mistletoe extract 60 mg (Abnova Viscum-F) in 50 mL of normal saline experienced dyspnea with associated desaturation. These adverse effects were attributed to pain caused by the induced pleural inflammation, and may have also been related to the patients' underlying impaired pulmonary function. Treatment with oxygen via nasal cannula resulted in improvement of symptoms in most patients within 24 hours (105838).

Other ...Subcutaneously, intravenously, and intratumorally, European mistletoe can cause malaise, chills, and high fever (7044,7045,9769,93261,93264,93265,93266,93268,96495,99499). Intravenous infusion of aviscumine, a pure form of mistletoe lectin I produced by recombinant DNA techniques, can cause fever (16385,93261).

(Read more about EUROPEAN MISTLETOE)

General ...Orally, garlic is generally well tolerated. Topically, garlic seems to be well tolerated. Intravenously, there is insufficient reliable information available about adverse effects.
Most Common Adverse Effects:
Orally: Abdominal pain, body odor, flatulence, malodorous breath, and nausea. Allergic reactions in sensitive individuals.
Topically: Burns and dermatitis with fresh garlic.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about increased risk of bleeding with garlic.

Dermatologic ...Orally, garlic may cause pruritus (51316,51474,107239), flushing, and acne (107239). Oral intake of a specific garlic product containing allicin (Allimax) has been associated with a case of pruritic rash (51474). Enteric-coated garlic tablets standardized to 1.5% allicin have also been associated with a case of pruritus (51316). Garlic has also been associated with a case of superficial pemphigus in a 49-year-old male with type 2 diabetes (51564). Garlic-induced oral ulcers have also been reported (51467).
Topically, garlic may cause contact dermatitis and urticaria (4833,5004,12635,51258,51265,51375,51403,51412,51459,51483)(51511,51512,51530,51616,51617,51618,111769), as well as contact cheilitis (51384). Fresh garlic may be more likely to elicit a reaction than garlic extract. Most reactions have resolved following withdrawal of garlic therapy. In one case report, applying crushed garlic on the neck to help ease a sore throat resulted in an itchy, burning, erythematous lesion in a young female patient. The lesion healed after one week of treatment with topical antibiotics, steroids, and antihistamine ointments (88390). Cases of occupational eczema or dermatitis have been reported in cooks (51303,51210), food handlers (51292), and caterers (51304). According to one case report, dermatitis appeared in chefs exposed to garlic (15033). Treatment with acitretin 25 mg daily or topical psoralen-ultraviolet A (PUVA) for 12 weeks proved effective in mitigating the symptoms. A 34-year-old female with a history of hand dermatitis and paronychia had a worsening of these conditions after peeling raw garlic. She had a positive skin patch test to fresh, raw garlic but not to any other tested allergens, and the conditions resolved when she avoided contact with garlic (105528). Topically, garlic may also cause chemical burns, usually within 12 hours of application. Second- and third-degree chemical burns have been reported in adults, children, and infants exposed to topical garlic, often as an unintended consequence of using garlic medicinally on the skin (585,4832,51226,51230,51252,51281,51377,51418,51468,51495,51536)(51558,51576,51577,88409,96006). A case of painful blisters on the soles of the feet of a 23-year-old Chinese female has been attributed to chemical burns caused by applying crushed raw garlic for 3 hours (51440). Topically, garlic may also cause hyperpigmentation, ulcers, necrotic lesions, facial flushing, and local irritation (4832,15030,51268,51269,108606). In one case report, applying crushed raw garlic to the palatal mucosa for several minutes to relieve mouth pain resulted in a chemical burn that produced a 3 cm necrotic ulcer in an adult female with trigeminal neuralgia (108606).

Gastrointestinal ...Orally, dehydrated garlic preparations or raw garlic may cause malodorous breath (51438,51444), body odor (732,1873,4784,4793,4795,4798,9201,10787,42692,49769)(51269,51316,51467,51602), abdominal pain or fullness, anorexia, diarrhea, constipation, flatulence, belching, heartburn, nausea, unpleasant taste, reflux, and bowel obstruction (1884,6457,6897,9201,49769,51269,51343,51380,51438,51442)(51450,51457,51466,51471,51474,51520,51593,51602,51623,88398)(88405,111766).
Large quantities of garlic may damage the gastrointestinal tract. In one case report, a patient taking garlic for hypertension reported odynophagia and retrosternal pain after taking garlic without any water the previous day. An esophageal lesion 3 cm in length was detected upon endoscopy. The symptoms resolved 3 days after starting a liquid diet and taking lansoprazole 30 mg twice daily and sucralfate four times daily (88389). One case of bowel obstruction was reported in a 66-year-old male who ingested an entire garlic bulb (51525). Esophageal perforation has been reported in at least 17 individuals who consumed entire garlic cloves. In one case the perforation led to mediastinitis and death (102672).
Garlic has also been associated with eosinophilic infiltration of the gastrointestinal tract. In one case report a 42-year-old female presented with symptoms of eosinophilic gastroenteritis, which included pollinosis, asthma, diarrhea, heart burn, peripheral eosinophilia, and urticaria. After stopping use of garlic and sesame, the patient improved (51441). In a case report of eosinophilic esophagitis, garlic was determined to be the causative agent in a patient with long-standing gastrointestinal symptoms. The patient had attempted to treat upper gastrointestinal symptoms as gastrointestinal reflux disease without success for many years. Skin prick testing showed a positive reaction to garlic, of which the patient noted frequent consumption. Marked symptom improvement was noted within 3 weeks of garlic avoidance (88393).
Intravenously, garlic 1 mg/kg of body weight daily diluted into 500 mL saline and administered over 4 hours has been reported to cause abdominal discomfort, vomiting, diarrhea, nausea, anorexia, flatulence, weight loss, and garlicky body odor (51462).
Clinical research suggests that patients with metabolic syndrome taking 1600 mg of powdered garlic by mouth daily for 3 months may experience improved intestinal transit time when compared with placebo, suggesting that garlic powder may reduce symptoms of constipation (110722).

Genitourinary ...Orally, garlic might cause dysuria, hematuria, or polyuria (51438,51450,51467,113618). In one case, an older male with high dietary and supplemental garlic intake at doses of 300-5400 mg daily for 3-4 years developed severe hematuria with clots after undergoing a minimally invasive prostate procedure (113618).

Hematologic ...Oral use of dietary garlic or supplements containing garlic has caused platelet dysfunction, increased fibrinolytic activity, prolonged bleeding time, retrobulbar hemorrhage (bleeding behind the eye) postoperative bleeding, and spinal epidural hematoma (586,587,4801,4802,11325,51397,51473,51491,51532,51534)(51570,51584,51593,51594,113618). Also, a case of kidney hematoma following extracorporeal shock-wave lithotripsy (SWL) has been reported in a patient with nephrolithiasis who took aged garlic (51630). A case of increased bleeding time that complicated epistaxis management has been reported in a patient taking garlic, aspirin, and milk thistle (51426).
Intravenously, garlic has been associated with the development of thrombophlebitis at the injection site (51462).

Immunologic ...There is a case report of an immediate sensitivity reaction to oral raw garlic, resulting in wheals, in a 31-year-old female. The patient did not react to cooked garlic, and skin prick tests showed allergy only to raw garlic (96015). Researchers note that at least some allergens in raw garlic are heat labile (88392,96012,96015). This suggests that consuming cooked rather than raw garlic may help avoid this reaction in patients allergic to raw garlic. However, different people react to different allergens in garlic. At least some of these allergens are heat stable (96012). While rare, garlic-induced anaphylaxis has been reported (88392,96012).
Topically, allergic contact dermatitis has been reported in case reports (51406,51498,51510,51519,51560).

Musculoskeletal ...Orally, garlic has been associated with individual cases of gout and low back pain (51474,51467), but it is not clear if these adverse events can be attributed to garlic.

Neurologic/CNS ...Orally, dizziness, insomnia, headaches, diaphoresis, fever, chills, somnolence, increased appetite, euphoria, and weight loss have been reported with garlic (15032,42692,51316,51467,51471,51520). In one case, the smell of garlic was identified as a trigger for migraines in a 32-year-old female. The subject reported fortification spectra along with visual spots for a few seconds followed by instantaneous biparietal, crushing level (10/10) headaches upon exposure to the scent of garlic or onion (88404).

Pulmonary/Respiratory ...Garlic exposure, most notably in occupational settings, may cause asthma and other symptoms such as sneezing, nasal obstruction, rhinorrhea, and sinusitis (40661,51218). A case of minor hemoptysis has been reported for one patient with cystic fibrosis following intake of garlic capsules orally once daily for 8 weeks (51438). A 77-year-old female developed pneumonia related to the intake of one whole black garlic clove daily. The cloves were prepared by heating a whole garlic bulb in a pot for one month. Symptoms included dyspnea and coughing, and test results were positive for lymphocyte-induced stimulation by black garlic and raw garlic. The patient required treatment with oral steroids and was told to avoid garlic (96011).

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General ...Orally, hawthorn seems to be well tolerated when used appropriately. Topically, no adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Multiorgan hypersensitivity reactions resulting in acute renal failure have been reported rarely.

Cardiovascular ...Orally, tachycardia (with facial pains) of uncertain relationship to hawthorn was reported in a multicenter clinical trial (54640). Palpitations (19244) were reported in three patients in a large surveillance trial of 3,664 patients with cardiac failure (54692) and in 11 patients with congestive heart failure (CHF) in a literature review of 5,577 patients (19247). Circulation failure has been reported in two patients with CHF in a literature review of 5,577 patients (19247). Incidences of hospitalization, hospitalization due to CHF, worsening of CHF, angina, and atrial fibrillation have also been reported with the use of hawthorn extract WS 1442 (Crataegutt forte), although it is unclear if these events are related to hawthorn supplementation or existing CHF (19222). In clinical trials, chest pain (8281), short-term increases in blood pressure (19240), and other non-specific heart problems (17203) have also been reported following the use of various hawthorn preparations (e.g. WS 1442, Korodin).
Orally, severe bradycardia, bradypnea, and Mobitz type 1 second degree heart block have been reported in a 16-year-old female who consumed Hawthorn root extract. Blood tests indicated plasma digoxin levels in the therapeutic range, despite no history of digoxin use. Medical treatment for digoxin cardiotoxicity did not improve symptoms. Symptoms gradually normalized over 3 days after discontinuation of the product (113112). Similarly, a 40-year-old female presented with bradycardia and elevated plasma digoxin levels after taking hawthorn root extract 196 mg daily for 2 days with no history of digoxin use. Symptoms resolved within 24 hours (113113).

Dermatologic ...Orally, erythematous rash has been reported in patients with CHF in a literature review of 5,577 patients (19247). Non-specific rashes and itching (19222,19243) as well as toxiderma from the fruits of hawthorn (54670) have also been reported.

Gastrointestinal ...Orally, rare abdominal discomfort of uncertain relationship to hawthorn has been reported in a large clinical trial, surveillance study, case reports, and a literature review (19247,54640,54692,113112). Digestive intolerance (19241), diarrhea (19243,113112), flatulence (8281), gastroenteritis (8281), increased bowel movements (19243), obstipation (8281), mild and rare nausea (10144,19247,19244), vomiting (113112), nutritional and metabolic problems (17203), and other non-specific gastrointestinal effects (19222), have also been reported. Furthermore, gastrointestinal hemorrhage has been reported in two patients with CHF in a literature review of 5,577 patients (19247).

Musculoskeletal ...In clinical trials, arthritis (8281), back pain (8281), weakness (19243), and other non-specific musculoskeletal effects (19222) have been reported following the use of various hawthorn preparations g. WS 1442, CKBM-A01). Additionally, in a case report, myalgia has been reported following use of hawthorn root extract (113113).

Neurologic/CNS ...Orally, headache and dizziness/vertigo were reported in 2 patients in a large surveillance trial of 3,664 patients with cardiac failure (54692), in 15 patients with CHF as reported in a literature review of 5,577 patients (19247), in a varying number of clinical trial participants (8281,19222,19244), and in case reports (113112,113113). Incidences of fainting (19222), fever (17203), and infrequent, mild and transient sleepiness have also been reported (19221,54692).

Psychiatric ...Orally, agitation was reported in a large surveillance trial of 3,664 patients with cardiac failure (54692).

Pulmonary/Respiratory ...Orally, bronchitis has been reported following the use of hawthorn extract WS 1442 (8281), and bradypnea has been reported following the use of hawthorn root extract (113112).

Renal ...A case of multiorgan hypersensitivity reaction and acute renal failure following the consumption of C. orientalis has been reported (54654).

Other ...Flu-like syndrome (8281) and other non-specific infections have been reported following the use of the hawthorn extract WS 1442 (17203,19222). Hawthorn has also been reported to cause nosebleeds (8281,10144).

(Read more about HAWTHORN)

General ...Orally, topically, or rectally, peppermint oil is generally well tolerated. Inhaled, peppermint oil seems to be well tolerated. Intranasally, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted. Orally, peppermint leaf seems to be well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, anal burning, belching, diarrhea, dry mouth, heartburn, nausea, and vomiting.
Topically: Burning, dermatitis, irritation, and redness.

Dermatologic ...Topically, peppermint oil can cause skin irritation, burning, erythema, and contact dermatitis (3802,11781,31528,43338,68473,68457,68509,96361,96362). Also, a case of severe mucosal injury has been reported for a patient who misused an undiluted over the counter mouthwash that contained peppermint and arnica oil in 70% alcohol (19106).
In large amounts, peppermint oil may cause chemical burns when used topically or orally. A case of multiple burns in the oral cavity and pharynx, along with edema of the lips, tongue, uvula, and soft palate, has been reported for a 49-year-old female who ingested 40 drops of pure peppermint oil. Following treatment with intravenous steroids and antibiotics, the patient's symptoms resolved over the course of 2 weeks (68432). Also, a case of chemical burns on the skin and skin necrosis has been reported for a 35-year-old male who spilled undiluted peppermint oil on a previous skin graft (68572). Oral peppermint oil has also been associated with burning mouth syndrome and chronic mouth ulceration in people with contact sensitivity to peppermint (6743). Also, excessive consumption of mint candies containing peppermint oil has been linked to cases of stomatitis (13114).

Gastrointestinal ...Orally, peppermint oil can cause heartburn, nausea and vomiting, anal or perianal burning, abdominal pain, belching, dry mouth, diarrhea, and increased appetite (3803,6740,6741,6742,10075,11779,11789,17682,68497,68514)(68532,68544,96344,96360,102602,104219,107955). Enteric-coated capsules might help to reduce the incidence of heartburn (3802,4469,6740,11777). However, in one clinical study, a specific enteric-coated formulation of peppermint oil (Pepogest; Nature's Way) taken as 180 mg three times daily was associated with a higher rate of adverse effects when compared with placebo (48% versus 31%, respectively). Specifically, of the patients consuming this product, 11% experienced belching and 26% experienced heartburn, compared to 2% and 12%, respectively, in the placebo group (107955). A meta-analysis of eight small clinical studies in patients with irritable bowel syndrome shows that taking enteric-coated formulations of peppermint oil increases the risk of gastroesophageal reflux symptoms by 67% when compared with a control group (109980). Enteric-coated capsules can also cause anal burning in people with reduced bowel transit time (11782,11789).

Genitourinary ...Orally, a sensitive urethra has been reported rarely (102602).

Hepatic ...One case of hepatocellular liver injury has been reported following the oral use of peppermint. Symptoms included elevated liver enzymes, fatigue, jaundice, dark urine, and signs of hypersensitivity. Details on the dosage and type of peppermint consumed were unavailable (96358).

Immunologic ...One case of IgE-mediated anaphylaxis, characterized by sudden onset of lip and tongue swelling, tightness of throat, and shortness of breath, has been reported in a 69-year-old male who consumed peppermint candy (89479). An allergic reaction after use of peppermint oil in combination with caraway oil has been reported in a patient with a history of bronchial asthma (96344). It is not clear if this reaction occurred in response to the peppermint or caraway components.

Neurologic/CNS ...Orally, headache has been reported rarely (102602).

Ocular/Otic ...Orally, peppermint has been reported to cause blurry vision (3803).

(Read more about PEPPERMINT)

General ...There is currently a limited amount of information available on the adverse effects of skullcap.
Most Common Adverse Effects:
Orally: Cognitive impairment, digestive disturbances, sedation.

Gastrointestinal ...Orally, mild digestive disturbances were reported in around 9% of patients taking skullcap 350 mg three times daily for 2 weeks (91690).

Hepatic ...There are four reports of hepatotoxicity associated with products thought to contain skullcap. However, it is uncertain whether the products actually contained skullcap. It is thought that the products might have been contaminated with an adulterant such as germander (515), which is known to cause liver damage.

Neurologic/CNS ...A single skullcap extract dose of 100 mg does not seem to have adverse CNS effects. However, a higher dose of 200 mg might cause sedation and cognitive impairment (12216). One patient taking skullcap 350 mg three times daily for 2 weeks reported vivid dreams (91690). It is unclear if this event was associated with skullcap.

(Read more about SKULLCAP)

General ...Orally, willow bark seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, dyspepsia, heartburn, and vomiting. May cause itching and rash in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal bleeding and renal impairment. May cause serious allergic reactions, including anaphylaxis, in people who are allergic to aspirin.

Cardiovascular ...In one clinical trial, a single patient withdrew from the study investigating oral willow bark due to blood pressure instability that the authors determined was 'possibly' related to treatment (12804).

Dermatologic ...Orally, willow bark may cause itching and rash in some people due to allergy (6456,12474,12475,12804,86459).

Gastrointestinal ...Orally, willow bark extract can cause gastrointestinal adverse effects, but these appear to be less frequent than those caused by NSAIDs. Examples include diarrhea, heartburn, vomiting, and dyspepsia (12474,12475,12804,86459). In a case report of a child, severe gastrointestinal bleeding occurred following use of a specific syrup (FreddoBaby), which contained ribwort plantain, licorice, willow bark, black elder, meadowsweet, and propolis. The adverse effect was attributed to salicylate content of the syrup. This product has since been withdrawn from the market (86477).

Immunologic ...Orally, willow bark may cause serious allergic reactions, including anaphylaxis, in people who are allergic to aspirin (10392)

Neurologic/CNS ...Orally, willow bark may cause headache and dizziness (12804). In a clinical trial evaluating a combination product containing willow bark, black cohosh, sarsaparilla, poplar bark, and guaiac wood (Reumalex), severe headaches occurred (35946).

Ocular/Otic ...Orally, symptoms of allergy to willow bark have included swollen eyes (6456).

Renal ...Salicylates can inhibit prostaglandins, which can reduce renal blood flow (12805). Salicin can cause renal papillary necrosis (12806). The risk for toxicity is greater with high acute doses or chronic use (12805).

(Read more about WILLOW BARK)