Liver Optimizer [Discontinued] by Jarrow Formulas

LIKELY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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POSSIBLY EFFECTIVE

• Diabetes. Oral milk thistle extracts of silymarin seem to improve glycemic control in patients with diabetes. Details: A meta-analysis of 7 small heterogeneous clinical trials in patients with type 2 diabetes shows that taking milk thistle containing silymarin 210-600 mg alone or with other ingredients daily for up to 6 months reduces fasting blood glucose and glycated hemoglobin when compared with control. Sub-group analyses suggest that studies conducted for less than 3 months seem to have a greater glycemic benefit than those lasting 3 months or longer. Furthermore, there was a greater glycemic benefit when milk thistle was used in combination with other natural ingredients (105054). Most studies in the analysis used silymarin in divided doses of 420-600 mg daily, while only one study used 200 mg daily (15102,63190,97626,105054). Additionally, a meta-analysis of 22 clinical studies in healthy adults and adults with diabetes or other medical conditions shows that taking milk thistle reduces fasting blood glucose by around 22 mg/dL, reduces glycated hemoglobin by 0.85%, and reduces fasting insulin by 3.8 mU/mL when compared with placebo or control (113987). The validity of this analysis is limited by heterogeneity between clinical trials, including population, background treatments, and outcomes. Most of these studies were conducted in the Middle East, so it is unclear whether these results are generalizable to other geographic locations. Most studies of combination products have been conducted in Italy and involve a specific product (Berberol, PharmExtracta) containing milk thistle standardized to silymarin 105-210 mg with tree turmeric standardized to berberine 500-1000 mg (96141,105054). In addition to improving glycemic indices in patients with type 2 diabetes (105054), this product has shown glycemic benefit in patients with concomitant obesity and metabolic syndrome (97624) and in patients with type 1 diabetes (96142).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. It is unclear if oral or topical milk thistle is beneficial in patients with acne when used alone or in combination with other treatments. Details: A small clinical trial in patients with acne vulgaris shows that taking a milk thistle extract standardized to silymarin 140 mg daily for 2 months does not improve acne severity based on the Global Acne Grading system scale when compared with doxycycline 100 mg daily, and silymarin is less effective than doxycycline when evaluated using the Acne Severity Index (ASI) scale. In addition, using silymarin in combination with doxycycline does not appear to be more effective than doxycycline alone (101160). There is also interest in using milk thistle topically for acne. A small quasi-experimental study in adults with mild to moderate acne suggests that applying silymarin 1.4% cream twice daily for 3 months improves global acne scores and appearance of acne when compared to baseline, but not when compared with biweekly salicylic acid chemical peels (113143). However, the interpretation of these results is limited by the use of subjective outcomes. Similarly, observational research in patients aged 12-25 years with mild-to-moderate acne suggests that applying a specific cream (Cleanance Comedomed, Pierre Fabre Dermo-Cosmetique) containing milk thistle fruit extract 25% twice daily for 8-12 weeks as initial or add-on therapy is associated with moderate improvements in acne scores when compared to baseline (111175). The interpretation of these results is limited by the lack of a comparator group. Further, most patients were also prescribed other skincare products or treatments. Topical milk thistle has also been evaluated in combination with other ingredients. A small open-label study conducted in Korea in adults with acne vulgaris shows that applying a specific topical product (Silymarin CF, Skinceuticals) containing silymarin 0.5%, vitamin C 15%, salicylic acid 0.5% and ferulic acid 0.5%, twice daily for 3 months moderately improves acne scores when compared to baseline (110488). A similar open-label study conducted in Brazil in adults with acne shows that applying a serum with this same combination and concentration of ingredients once daily for 12 weeks improves investigator's global assessment of acne severity, global lesion count, inflammatory and non-inflammatory lesions, post-inflammatory hyperpigmentation, skin clarity, skin tone evenness, and overall skin appearance and reduces skin surface oil when compared to baseline. Additionally, an open-label study conducted in the US and Germany in adults with acne shows that applying this same serum daily for 4 weeks in addition to prescription topical acne medications reduces investigator-assessed erythema, dryness, and scaling when compared to baseline (113985). In the aforementioned studies, it is unclear if these effects are due to milk thistle, other ingredients, or the combination. The validity of the studies is also limited by the lack of a comparator group.
• Acute kidney injury (AKI). It is unclear if oral milk thistle extract reduces the incidence of vancomycin-induced acute kidney injury. Details: A moderate-sized clinical study in hospitalized patients in Iran shows that taking a specific milk thistle extract (Livergol, Goldaru Herbal Products Pharmaceutical Company) 140 mg three times daily for the duration of vancomycin treatment, ranging from 7 to 14 days, reduces the incidence of acute kidney injury, but not hospital length of stay or need for kidney replacement therapy, compared with placebo (114909). The validity of these results is limited by the use of a per-protocol analysis.
• Alcohol-related liver disease. It is unclear if oral milk thistle is beneficial in patients with alcohol-related liver disease, as evidence is conflicting. Details: Some preliminary research shows that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 420 mg orally daily for one month to 4 years improves some liver function tests (2613,2618,17228,63260,63339). Some studies also report improvements in liver histology and survival (2616,17228,63278). However, in other studies, taking a similar dose of the same product for 3 months to 2 years is not associated with any benefit over placebo (7321,7322,7355,63158). A meta-analysis of clinical research also shows that milk thistle extract does not reduce mortality or complications related to liver disease in patients with alcohol-related liver disease (63192). Reasons for the conflicting findings are unclear but might relate to the low methodological quality of many of these studies.
• Allergic rhinitis (hay fever). It is unclear if oral milk thistle is beneficial in patients with allergic rhinitis. Details: One preliminary clinical trial shows that taking a milk thistle extract of silymarin 140 mg orally three times a day plus cetirizine (Zyrtec) 10 mg daily for one month decreases the severity of allergic rhinitis symptoms when compared with placebo plus cetirizine (18105).
• Alzheimer disease. It is unclear if oral milk thistle is beneficial in patients with Alzheimer disease. Details: A small, single-blind clinical study in patients with Alzheimer disease shows that taking milk thistle 450 mg daily for 3 months improves scores on the Mini Mental State Exam (MMSE) when compared with placebo (113978). However, another small clinical study in patients with Alzheimer disease shows that taking milk thistle extract (Livergol, Goldaru Herbal Products Pharmaceutical Company) 140 mg three times daily for 6 months does not improve MMSE or Clinical Dementia Rating scores when compared with placebo (114913). Other preliminary clinical research shows that taking a supplement containing a milk thistle extract of silymarin 150 mg in combination with ferulic acid, gamma-oryzanol, and apigenin orally twice daily for 3 months to 2 years may stabilize mental functioning in patients with Alzheimer disease when compared to baseline (63223). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Amanita mushroom poisoning. While an intravenous milk thistle constituent, silibinin, has been studied for treating Amanita mushroom poisoning, this product is not readily available in the U.S. Details: Preliminary evidence from uncontrolled studies shows that administering silibinin, a constituent of milk thistle, intravenously (IV) within 48 hours of Amanita phalloides (death cap) mushroom poisoning, followed by oral therapy, may lessen liver damage (2615,63293). However, silibinin is not readily available in the US.
• Benign prostatic hyperplasia (BPH). It is unclear if oral milk thistle is beneficial for benign prostatic hyperplasia. Details: A small clinical study in patients with benign prostatic hyperplasia shows that adding milk thistle extract (Liversil, Rose Pharmed Pharmaceutical Company) 240 mg twice daily for 3 months to tamsulosin improves prostate symptom scores, irritation, obstruction, prostate volume, and post-void residuals, but not serum prostate specific antigen levels, when compared with placebo plus tamsulosin (114910). However, it is unclear whether the noted improvements are clinically significant. Milk thistle has also been studied in combination with other ingredients. Preliminary clinical research shows that taking a milk thistle extract of silymarin 190 mg along with selenium 80 mcg orally three times daily for 6 months may improve lower urinary tract symptoms, urinary flow rates, and residual volumes in adults aged 45-70 years with BPH when compared with placebo (88155). It is unclear if these effects are due to milk thistle, selenium, or the combination.
• Beta-thalassemia. Meta-analyses of clinical studies in patients with beta-thalassemia suggest that oral silymarin, a constituent of milk thistle, reduces serum ferritin levels. Details: Most small clinical studies and meta-analyses of these studies show that taking silymarin in conjunction with conventional iron chelation medications such as deferiprone, deferasirox, or deferoxamine, is more effective for reducing serum ferritin levels than taking a conventional medication alone (88154,98452,107375). In one meta-analysis, the combination of silymarin and deferasirox appeared to be more effective than combinations with other iron chelation medications (107375). However, one preliminary clinical study in patients 12 years of age and older with beta-thalassemia shows that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 3 months, in conjunction with deferoxamine, does not improve serum ferritin when compared with deferoxamine alone (63212). This difference in outcome is likely due to the shorter duration of therapy. Silymarin also does not seem to affect total iron binding capacity or liver iron concentration in patients with beta-thalassemia (107375).
• Chemotherapy-induced acral erythema. It is unclear if topical milk thistle is beneficial in patients with acral erythema due to capecitabine. Details: Preliminary clinical research shows that applying a gel containing a milk thistle extract of silymarin 1% twice daily to the hands and feet, starting from the first day of chemotherapy and continuing for 9 weeks thereafter, prolongs the time to onset of acral erythema and decreases its severity when compared with placebo in patients with gastrointestinal cancer who are receiving capecitabine for the first time (95022).
• Chemotherapy-induced hepatotoxicity. Results of clinical studies are mixed over whether oral milk thistle prevents or improves chemotherapy-induced hepatotoxicity. Details: One small clinical study in children and adults up to age 21 with acute lymphoblastic leukemia (ALL) and elevated liver function tests (LFTs) shows that taking a specific product containing the milk thistle constituent silibinin (Siliphos, Thorne Research, Inc.) 80-320 mg (depending on patient weight) daily for 28 days concurrently with chemotherapy does not improve LFTs or bilirubin levels when compared with placebo (63218). Another small clinical study in patients with non-metastatic breast cancer receiving doxorubicin, cyclophosphamide, and paclitaxel shows that taking a specific milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg three times daily with meals for 4 weeks does not improve fatty liver grading or LFTs when compared with placebo (105795). A similar small clinical study in patients with non-metastatic breast cancer receiving doxorubicin and cyclophosphamide, with or without paclitaxel shows that taking this same milk thistle extract 140 mg three times daily for 9 weeks attenuates an increase in fatty liver grade liver grade but does not consistently improve LFTs after each course of chemotherapy (114914). Conversely, a large clinical study in children aged 5-14 with elevated liver enzymes and receiving chemotherapy for ALL shows that taking silymarin 70 mg capsules twice daily or 50 mg syrup three times daily for 9 months modestly improves aspartate aminotransferase, alanine aminotransferase, and bilirubin levels, but does not improve alkaline phosphatase or albumin levels (113144). Observational research in patients with a variety of solid tumors and elevated LFTs due to chemotherapy or targeted therapy suggests that taking silymarin 150-900 mg daily is associated with reduced or stabilized LFTs in over half of patients; however, doses above 300-450 mg daily don't seem to have much more benefit (111176). The interpretation of these results is limited by the lack of a comparator group.
• Chemotherapy-induced nephrotoxicity. It is unclear if oral milk thistle is beneficial for the prevention of cisplatin-induced nephrotoxicity. Details: A small clinical study shows that taking a milk thistle extract standardized to 70% to 80% silymarin (Liverherb, Amin Pharmaceutical Company) 140 mg orally three times daily with meals, starting 24-48 hours before cisplatin and continuing until the end of three 21-day cycles, does not prevent cisplatin-induced nephrotoxicity when compared with placebo (95025).
• Chemotherapy-induced peripheral neuropathy. It is unclear if oral milk thistle is beneficial for chemotherapy-induced peripheral neuropathy. Details: A small clinical study in adults with cancer receiving cisplatin chemotherapy shows that taking a specific product (Livergol, Goldaru) containing milk thistle 140 mg three times daily for 3 months improves overall symptoms of chemotherapy-induced peripheral neuropathy when compared to baseline, but not when compared with placebo, with the possible exception of hyposthesia to touch and pins and needles sensation which had worsened only in the placebo group (113979).
• Cirrhosis. It is unclear if oral milk thistle extracts of silymarin are beneficial for cirrhosis from various causes. Details: Preliminary clinical research shows that taking a milk thistle extract of silymarin 420 mg orally daily for up to 4 years might improve liver function tests and decrease mortality in people with cirrhosis due to a variety of causes (2616,63145,63278,63340). However, a meta-analysis of clinical research evaluating milk thistle studies for the treatment of various liver diseases shows that effect sizes are generally small or lack statistical significance (63161). An observational study in adults with hepatitis B virus-related liver cirrhosis suggests that taking milk thistle 150 mg 2-3 times daily for at least 30 days in combination with anti-viral therapy is associated with lower mortality and liver transplantation rates at 1- and 2-year follow up and greater improvement in international normalized ratio, model for end-stage liver disease score, and the Charlson comorbidity index at 1-year follow-up when compared with anti-viral therapy alone (113986).
• Contrast induced nephropathy. It is unclear if oral milk thistle is beneficial for reducing the risk of nephropathy from contrast agents. Details: Population research in Taiwanese patients with liver cirrhosis has found that taking silymarin daily for at least 90 days during a one-year period does not reduce the risk of contrast-induced nephropathy during the following four or more years (98453).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral milk thistle is beneficial for COVID-19. Details: Preliminary clinical research in adults hospitalized with COVID-19 requiring non-invasive oxygen support shows that taking a specific milk thistle product (SinaLive, Exir Nano Sina Company), 70 mg orally three times daily for 2 weeks, does not improve time to symptom resolution, lung scores, or length of stay when compared with placebo (109504).
• Critical illness (trauma). It is unclear if oral milk thistle is beneficial in critically ill patients with trauma-induced liver injury. Details: One small clinical study in patients admitted to the intensive care unit (ICU) due to trauma-induced liver injury shows that taking a specific milk thistle extract (Livergol, Goldaru Pharmaceutical Company) containing silymarin 140 mg three times daily for 14 days reduces markers of liver injury, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), when compared with placebo (105793). Whether this milk thistle extract improves morbidity, mortality, or length of ICU stay in these patients is unclear.
• Diabetic nephropathy. It is unclear if oral milk thistle is beneficial for improving kidney function in patients with this condition. Details: Preliminary clinical research in type 2 diabetic patients with diabetic nephropathy shows that taking a milk thistle extract of silymarin 140 mg orally three times daily for 3 months, in combination with conventional treatment decreases the urine albumin to creatinine ratio when compared with placebo. However, serum creatinine and estimated glomerular filtration rate are not improved (63250).
• Dyslipidemia. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of three clinical trials in adults with hypercholesterolemia shows that taking a specific combination product (Berberol, PharmExtracta) containing milk thistle extract 105 mg and tree turmeric extract 588 mg twice daily for 3 months, along with diet and exercise, reduces levels of LDL cholesterol by an average of 34 mg/dL when compared with diet and exercise alone. There was no effect on HDL cholesterol or triglyceride levels (101158). The studies included in this meta-analysis are generally of low quality, lasted for no more than 12 months, and sometimes include patients with statin intolerance (95019,96140,101158). Other clinical research shows that taking a similar product (Berberol K, PharmExtracta) containing milk thistle extract 105 mg, tree turmeric extract of berberine 500 mg, and monacolin K and KA 10 mg, taken once daily for 3 months along with diet and exercise, reduces levels of LDL cholesterol by about 28% when compared with diet and exercise alone in patients with hypercholesterolemia (97625). It is possible that any benefit of this product is due to the monacolin content. It is unclear if these effects are due to milk thistle, other ingredients, or the combination.
• Dyspepsia. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A specific combination product containing milk thistle (Iberogast, Medical Futures, Inc.) seems to improve symptoms of dyspepsia. The combination includes milk thistle plus peppermint leaf, German chamomile, caraway, licorice, clown's mustard plant, celandine, angelica, and lemon balm (19532). A meta-analysis of clinical research using this combination product shows that taking 1 mL orally three times daily over a period of 4 weeks reduces severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo (13089).
• Endometriosis. It is unclear if oral milk thistle is beneficial in patients with endometriosis. Details: Preliminary clinical research in females with ovarian endometrioma shows that taking a specific silymarin product (Goldaru Pharma) 140 mg twice daily for 12 weeks moderately improves pain scores, but not other sexual function scores, when compared with placebo (110486). However, some researchers have also recommended to avoid using milk thistle in estrogen-sensitive conditions, such as endometriosis, due to its estrogenic effects (93025,93026).
• Gambling disorder. It is unclear if oral milk thistle is beneficial for gambling disorder. Details: A small clinical study in adults with gambling disorder shows that taking milk thistle 150 mg twice daily for 2 weeks and then 300 mg daily for the next 6 weeks does not improve symptoms associated with gambling disorder, including gambling urges, thoughts, and behaviors, or improve symptoms of anxiety and depression when compared with placebo (113974). The interpretation of these results is limited by the small sample size and a strong placebo effect.
• Hepatitis. Small clinical studies suggest that oral milk thistle extracts of silymarin may improve hepatitis symptoms. It is unclear whether these products can improve liver function in these patients. Details: In people with hepatitis due to a variety of causes, taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 4 weeks reduces symptoms such as jaundice, dark urine, and scleral icterus, but does not improve liver function tests (LFTs) (63210,63317). However, some improvements in LFTs are seen with a silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) taken as 160-360 mg orally daily for 2 weeks to 3 months (63320,63321). However, there are methodological problems with these latter studies.
• Hepatitis B. Small clinical studies suggest that oral milk thistle extracts may improve liver function in people with hepatitis B, although it is unclear if these products can improve disease-related complications. Details: Preliminary clinical studies suggest that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 28 days to one year, or a silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) 240 mg orally twice daily for 7 days, improves liver function tests (LFTs) and liver histology (7356,63263,63299). However, another study shows that taking a milk thistle extract of silymarin 140 mg orally three times daily for 5-25 days has no effect of LFTs (63288). A meta-analysis of clinical research and a review conclude that any clinical effect of milk thistle in people with viral hepatitis is very limited and results suggest that it lacks a significant effect on mortality, liver disease complications, or liver histology (17228,63192).
• Hepatitis C. Small clinical studies suggest that oral milk thistle extracts may improve liver function but do not seem to reduce hepatitis C virus (HCV) RNA levels. Details: Preliminary clinical studies show that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 140 mg orally three times daily for 3-12 months, or a silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) 240 mg orally twice daily for 7 days, improves liver function tests (LFTs) and liver histology (7356,63299). However, other studies report that taking silymarin 125-140 mg three times daily for up to one year, 166 mg twice daily for 3 months, or 400 mg daily for 8 weeks does not improve serum HCV RNA levels, anti-HCV antibody levels, LFTs, or hepatomegaly (13170,63208,63247,63288,108658). Also, taking higher doses of silymarin, up to 700 mg three times daily for 6 months, does not have a significant effect on serum HCV RNA levels or LFTs when compared with placebo (63251). A meta-analysis of clinical research and a review conclude that any clinical effect of milk thistle in people with viral hepatitis is limited and most results show that milk thistle lacks a significant effect on mortality, liver disease complications, or liver histology (17228,63192,88156). Preliminary clinical research in adults with HCV-related advanced chronic liver disease shows that taking a specific milk thistle combination product containing silybinphospholipid complex 303 mg, vitamin D 10 mcg, and vitamin E 15 mg (Realsil 100 D, Ibi Lorenzini), twice daily for 12 months, improves liver stiffness scores, but not liver fibrosis scores, when compared with control (108659). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Hyperlipoproteinemia. It is unclear if oral milk thistle is beneficial in patients with hyperlipoproteinemia secondary to liver disease. Details: One very small crossover study shows that taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 420 mg orally daily for 7 months does not significantly improve cholesterol levels in patients with hyperlipoproteinemia secondary to liver disease when compared with placebo (63255).
• Hypoxic liver injury. It is unclear if oral milk thistle is beneficial for reducing liver injury in patients with hypoxia. Details: Preliminary clinical research in patients presenting to the emergency department with hypoxia shows that taking a milk thistle extract of silymarin 280 mg every 8 hours for 3 days reduces markers of liver injury, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT), when compared with placebo (103871).
• Infertility. It is unclear if oral milk thistle is beneficial for patients undergoing in vitro fertilization. Details: Preliminary clinical research shows that taking a milk thistle extract of silymarin 70 mg orally three times daily in combination with human chorionic gonadotropin (HCG) lowers the proportion of early and total apoptosis of follicle cells during in vitro fertilization due to male infertility. However, it does not have an effect on the number of oocytes retrieved or the thickness of the endometrium when compared with HCG plus placebo (63227).
• Lactation. It is unclear if oral milk thistle is beneficial for increasing milk production. Details: A small clinical study shows that taking a milk thistle extract standardized to 60% silymarin (BIO-C, Milte Italia S.r.l.) 240 mg twice daily for 4 weeks does not increase milk production when compared with placebo in mothers of preterm newborns (95027).
• Melasma. It is unclear if topical milk thistle is beneficial in patients with melasma. Details: Preliminary clinical research in adults with melasma shows that applying silymarin 1.4% cream twice daily for 3 months moderately improves melasma appearance scores when compared to baseline. These improvements were similar to hydroquinone cream 2% (110489). One small clinical trial in females with melasma shows that application of silymarin 1.4% cream twice daily to the affected area for 3 months is as effective for improving melasma area and severity as a specific type of laser therapy (low fluence Q switched ND:YAG 1064 nm) (105791).
• Menopausal symptoms. It is unclear if oral milk thistle reduces menopausal symptoms such as hot flashes. Details: One small clinical study in postmenopausal patients shows that taking milk thistle fruit extract 200 mg, containing 80% silymarin, twice daily for 8 weeks seems to reduce the number and severity of daily hot flashes and overall climacteric symptoms when compared with taking placebo (105053). This finding is limited by incomplete reporting and potentially inadequate blinding. Other preliminary clinical research has evaluated milk thistle in combination with black cohosh, dong quai, red clover, American ginseng, and chasteberry (Phyto-Female, SupHerb), with some evidence of benefit for reducing hot flashes and night sweats. (19552).
• Metabolic dysfunction-associated steatotic liver disease (MASLD). It is unclear if oral milk thistle is beneficial for MASLD. Details: A moderate-sized clinical study in patients with MASLD shows that taking milk thistle extract equivalent to 51.6 mg of silybin twice daily for 6 months reduces liver stiffness, but not levels of alanine transaminase, aspartate transaminase, or bilirubin when compared with placebo (114918). A moderate-sized, open-label, non-controlled study in patients with MASLD shows that taking milk thistle standardized to silymarin 150 mg twice daily for 6 months does not improve liver stiffness or liver enzymes when compared with essential phospholipids. It is unclear if any changes in these outcomes are statistically significant when compared to baseline (114462). The validity of these findings is limited by the lack of a placebo group. Also review milk thistle's effectiveness in nonalcoholic fatty liver disease (NAFLD), a similar condition.
• Metabolic syndrome. Oral silymarin, a constituent of milk thistle, seems to improve some of the laboratory abnormalities associated with metabolic syndrome. Details: A meta-analysis of 11 low-quality clinical trials in adults with metabolic syndrome, conducted in Asia and Africa, shows that silymarin, 140-2100 mg daily for 45 days to 12 months, modestly reduces fasting blood glucose, glycated hemoglobin, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels, and increases high-density lipoprotein cholesterol levels, when compared with placebo (107374).
• Multiple sclerosis (MS). Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with MS shows that taking a supplement containing a milk thistle extract of silymarin 150 mg in combination with ferulic acid, gamma-oryzanol, and apigenin twice daily for 3-24 months may stabilize clinical symptoms of MS when compared to baseline (63223). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Nonalcoholic fatty liver disease (NAFLD). Small clinical studies suggest that oral milk thistle extracts of silymarin may slightly improve markers of liver function patients with NAFLD. Details: Four meta-analyses of up to 23 mostly small clinical trials in patients with NAFLD show that taking milk thistle products containing a total of silymarin 140-2100 mg daily, either alone or in combination with other ingredients, for 8-48 weeks reduces aspartate aminotransferase (AST) by 7-13 IU/L and alanine aminotransferase (ALT) by 9-17 IU/L when compared with control (97622,105051,113976,113982). However, these changes in liver enzymes may not be clinically impactful and some experts note that serum AST levels do not reliably reflect the spectrum of liver histology in patients with NAFLD (98130). Metabolic indices have also been evaluated. A meta-analysis of up to 20 mostly small clinical studies in patients with NAFLD shows that taking milk thistle for up to 48 weeks slightly improves serum lipids when compared with control (113976). A small clinical study in adults with NAFLD and a body-mass index (BMI) of at least 35 kg/m² shows that taking milk thistle extract 140 mg 4 times daily for 8 weeks, in addition to lifestyle modifications, reduces BMI by approximately 1 kg/m² when compared with placebo with lifestyle modifications (108657). However, another small clinical trial in adults with NAFLD and a BMI of at least 40 kg/m² shows that taking a specific silymarin product (Livergol, Goldaru Pharmaceuticals) 140 mg three times daily for 4 weeks did not reduce BMI or improve liver enzymes, such as AST and ALT, when compared with placebo (110484). A meta-analysis of 7 small clinical trials also shows there is little to no change in BMI associated with silymarin use in these patients (113976). One small clinical study in patients with NAFLD shows that taking a specific combination product (Eurosil 85, MEDAS SL) containing milk thistle extract standardized to silymarin 540 mg and vitamin E 36 mg daily for 3 months, in addition to following a low-calorie diet, does not appear to improve NAFLD-Fibrosis score or fatty liver index (FLI) when compared with following a low-calorie diet alone (96261), though a meta-analysis of 2 small clinical studies in patients with NAFLD shows that taking milk thistle for 12-24 weeks does reduce FLI when compared with control (113976). Also review milk thistle's effectiveness in metabolic dysfunction-associated steatotic liver disease (MASLD), a similar condition.
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral milk thistle is beneficial in patients with NASH. Details: Clinical research in patients with NASH shows that taking a milk thistle extract of silymarin 700 mg three times daily for 48 weeks improves fibrosis in more patients when compared with placebo (96107). However, there is no significant between-group difference in global histological improvement with this product (96107) or with a specific silymarin product (Legalon, Rottapharm Madaus, Mylan) 420 or 700 mg three times daily for 48-50 weeks (101150). Pooling 1 of these clinical studies (96107) into a meta-analysis with another clinical trial that evaluated milk thistle in combination with phosphatidylcholine and vitamin E suggests an improvement in fibrosis by at least one stage when compared with placebo (113984). However, it is unclear if this effect is due to milk thistle, other ingredients, or the combination. Metabolic indices have also been evaluated. A meta-analysis of small clinical studies in patients with NASH or nonalcoholic fatty liver disease (NAFLD) shows that taking milk thistle reduces aspartate aminotransferase (AST) by about 13 IU/L, alanine aminotransferase (ALT) by about 17 IU/L, serum triglycerides by about 23 mg/dL and increases high-density lipoprotein cholesterol by about 2 mg/dL, but does not alter gamma-glutamyl transferase, total cholesterol, low-density lipoprotein cholesterol, body mass index, or insulin resistance when compared with control (113982). However, trials on NAFLD and NASH were not analyzed separately which limits the generalizability of these findings to patients with NASH specifically. The dose and duration of milk thistle treatment was also not described.
• Obesity. It is unclear if oral milk thistle is beneficial in patients with obesity. Details: A meta-analysis of 11 clinical studies in healthy adults and adults with various medical conditions shows that taking milk thistle does not reduce body weight or body mass index when compared with placebo or control (113987). A very small open-label study in adult females with obesity suggests that taking a specific milk thistle extract product (Neocholal-S, Italmex) 151.5 mg, containing silybin 45 mg, twice daily for 12 weeks does not reduce body weight but may reduce fasting blood glucose levels and insulin resistance when compared to baseline (113980). The validity of this study is limited by the lack of a comparator group and very small sample size.
• Obsessive-compulsive disorder (OCD). It is unclear if oral milk thistle is beneficial in patients with OCD. Details: Preliminary clinical research shows that taking milk thistle leaf extract 200 mg orally three times daily for 8 weeks has a limited effect on OCD symptom scores when compared to baseline, but does not provide any benefit over fluoxetine 10 mg three times daily (63219).
• Parkinson disease. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a supplement containing a milk thistle extract of silymarin 150 mg in combination with ferulic acid, gamma-oryzanol, and apigenin orally twice daily for 3 months to 24 months may stabilize clinical symptoms in patients with Parkinson disease when compared to baseline (63223). It is unclear if this effect is due to milk thistle, other ingredients, or the combination.
• Postpartum complications. It is unclear if topical milk thistle is beneficial in postpartum patients with an episiotomy. Details: Preliminary clinical research in postpartum patients shows that applying milk thistle 3% in Eucerin ointment twice daily to the suture site for 10 days reduces episiotomy pain and improves the healing rate when compared with placebo. The milk thistle product was prepared with an ethanolic extract of the seeds to provide 1.53% silybin (107373).
• Prostate cancer. Oral milk thistle has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with a history of prostate cancer who have had radiotherapy or radical prostatectomy shows that taking a dietary supplement containing a milk thistle extract of silymarin 160 mg, soy isoflavones (Novasoy, ADM) 62.5 mg, lycopene (Lyc-O-Mato, LycoRed Natural Products Industries, Ltd.) 15 mg, vitamins, minerals, and antioxidants orally daily for 10 weeks increases the time it takes for prostate-specific antigen (PSA) levels to double by 2.6-fold when compared with placebo (60361).
• Radiation dermatitis. It is unclear if topical milk thistle is beneficial in patients with dermatitis due to radiation. Details: Preliminary clinical research in females with breast cancer undergoing radiotherapy shows that applying a specific topical product containing a milk thistle extract of silymarin (Leviaderm, Madaus GmbH) significantly reduces the incidence of radiation dermatitis and prolongs the time to the onset of radiation dermatitis when compared with applying a panthenol-containing cream (63239). Additionally, meta-analysis pooling this study (63239) with one other small clinical study also shows that applying a cream or gel containing milk thistle extract reduces the incidence radiation dermatitis when compared with control (113674).
• Radiation mucositis. It is unclear if oral milk thistle is beneficial for preventing or treating mucositis due to radiation. Details: One small clinical study in patients with head and neck cancer receiving radiotherapy for the first time shows that taking a specific product containing a milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company), 140 mg three times daily starting from the first day of radiotherapy and continuing for 6 weeks thereafter, reduces the severity and prolongs the time to onset of radiation-induced mucositis when compared with placebo (95021).
• Rheumatoid arthritis (RA). It is unclear if oral milk thistle is beneficial for rheumatoid arthritis. Details: A moderate-sized clinical study in patients with rheumatoid arthritis (RA) on conventional RA medications shows that taking milk thistle (Silymarin Forte, Zenyth Pharmaceuticals SRL) 300 mg, in addition to standard RA medications, daily for 8 weeks reduces the number of tender and swollen joints, the duration of morning stiffness, severity of disease activity, and fatigue, depression and anxiety scores when compared with standard RA medicationsl (114915). The validity of this study is limited by the lack of blinding and lack of a placebo control.
• Toxin-induced liver damage. Most small clinical studies suggest that oral milk thistle extracts or constituents may reduce liver injury in people exposed to some, but not all, toxins and medications known to cause liver damage. Details: Taking a milk thistle extract containing 70% to 80% silymarin (Legalon, Madaus GmbH) 420 mg orally daily for up to one month improves liver function tests (LFTs) in people with abnormal LFTs due to chronic occupational exposure to paints or organic solvents such as toluene or xylene (2614,63280). Milk thistle extract has also shown some benefit for reducing drug-induced liver injury (DILI). In patients on isotretinoin therapy for acne, taking a specific milk thistle extract containing silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg daily for 30 days improves LFTs when compared with placebo (102852). A small clinical study in patients with relapsing-remitting multiple sclerosis who were initiating therapy with fingolimod shows that taking a specific milk thistle extract (Livergol, Goldaru Pharmaceutical Company) containing silymarin 140 mg daily for 6 months prevents fingolimod-induced LFT elevations when compared with placebo (105794). In patients receiving treatment for tuberculosis with rifampin, isoniazid, pyrazinamide, ethambutol, and streptomycin, taking the milk thistle constituent silibinin 70 mg orally three times daily for 6-12 months reduces the rate of liver toxicity to 14% compared with 53% in patients taking glucuronolactone 200 mg orally three times daily (63224). Additionally, in patients receiving standard treatment for tuberculosis with isoniazid, rifampicin, pyrazinamide, and ethambutol, taking a milk thistle extract of silymarin 140 mg orally three times daily for 4 weeks decreases the risk of DILI by 28% when compared with placebo. About 1 in every 4 patients who take silymarin for 4 weeks would avoid DILI (95024). A small clinical study in Iran, also in adults receiving standard treatment for tuberculosis, shows that taking a milk thistle extract of silymarin 150 mg twice daily for 2 weeks modestly improves LFTs when compared with control. None of the 16 patients in the silymarin group developed DILI compared with 2 of 21 patients in the control group; however, this finding was not statistically significant (112230). The interpretation of these findings is limited by the short study duration. However, taking a milk thistle extract of silymarin 420 mg orally daily for 3 months does not seem to prevent liver toxicity associated with tacrine (Cognex) therapy in people with Alzheimer disease (63140). Other research in people with elevated LFTs due to long-term therapy with phenothiazine or butyrophenone antipsychotic medications shows that taking silymarin 800 mg orally daily for 3 months also does not improve LFTs when compared with placebo (63344). A retrospective study in patients with DILI of various offending agents has also found that taking a milk thistle extract, containing a median of 450 mg silybin daily for 24 days is associated with 1.7-2.8 times higher likelihood of LFT normalization when compared with control (110485).
• Trichotillomania. It is unclear if oral milk thistle is beneficial in patients with this condition. Details: Preliminary clinical research in patients 12-65 years of age shows that taking milk thistle 150 mg twice daily for 2 weeks, and then 300 mg twice daily for 4 weeks, does not improve symptoms of trichotillomania when compared with placebo (99426).
• Ulcerative colitis. It is unclear if oral milk thistle is beneficial in patients with this condition. Details: Preliminary clinical research in patients 16-75 years of age shows that taking a specific milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg daily for 6 months, in conjunction with standard medications, decreases disease activity and helps maintain remission when compared with placebo in patients with ulcerative colitis (95029).
• Vitiligo. It is unclear if oral milk thistle reduces the severity of this condition. Details: Preliminary clinical research in a small number of patients with vitiligo shows that taking a specific milk thistle extract containing silymarin (Livergol, Goldaru Pharmaceutical Company) 140 mg twice daily along with phototherapy for 3 months does not improve the severity of vitiligo when compared with phototherapy plus placebo (102851). However, a small clinical study in patients with vitiligo undergoing hair follicle transplantation and phototherapy shows that taking this same milk thistle extract 70 mg twice daily for 3 months increases perifollicular re-pigmentation when compared with hair follicle transplantation plus phototherapy (114912). The validity of this study is limited by the lack of a placebo. More evidence is needed to rate milk thistle for these uses.

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EFFECTIVE

• Acetaminophen poisoning. Oral and intravenous N-acetyl cysteine, as prescription drug products, are effective for treating acetaminophen poisoning. Details: Administering prescription N-acetyl cysteine orally or intravenously is effective in decreasing mortality rate and preventing the permanent sequelae of acetaminophen poisoning (17,64513,64745,64746). N-acetyl cysteine injection and oral effervescent tablets are approved by the US FDA for this use (102147,104164).
• Atelectasis. When inhaled, N-acetyl cysteine is effective for treating atelectasis. Details: N-acetyl cysteine solution for inhalation is effective for atelectasis caused by mucus obstruction (15,91650) and is approved by the US FDA for this use (102147).
• Bronchial diagnostic studies. When inhaled, N-acetyl cysteine is effective for bronchial diagnostic study preparation. Details: N-acetyl cysteine solution for inhalation is helpful when used to prepare people for bronchial diagnostic studies (15,91650), and is approved by the US FDA for this use (102147).
• Tracheostomy care. When inhaled and used as adjunct therapy, N-acetyl cysteine is effective for preventing endotracheal crusting in patients with a tracheostomy. Details: N-acetyl cysteine solution for inhalation is effective when used as an adjunct for preventing endotracheal crusting in tracheostomy care (15), and is approved by the US FDA for this use (102147).

POSSIBLY EFFECTIVE

• Angina. Oral or intravenous N-acetyl cysteine may reduce nitroglycerin tolerance in patients with angina. However, some studies suggest that N-acetyl cysteine might increase the risk for severe headaches and hypotension when used with intravenous or transdermal nitroglycerin. Details: Administering N-acetyl cysteine orally or intravenously, in combination with nitroglycerin, seems to improve unstable angina pectoris (2245,2246). There is also some clinical research showing that concurrent intravenous or oral administration of N-acetyl cysteine reduces the development of nitroglycerin tolerance (832,2245,64546). However, other research shows that taking N-acetyl cysteine orally does not reduce the development of nitroglycerin tolerance in angina patients (2281,2282). Additionally, severe headache and hypotension can occur when oral N-acetyl cysteine and nitroglycerin are administered together, which may limit the feasibility of concomitant use (2245).
• Autism spectrum disorder. Oral N-acetyl cysteine may improve irritability, but not other symptoms, associated with autism spectrum disorder. Details: One small clinical study in children with autism shows that taking N-acetyl cysteine 900 mg daily for 4 weeks followed by 900 mg twice daily for 4 weeks and then 900 mg three times daily for 4 weeks improves symptoms of irritability when compared with placebo (91241). Another small clinical study in children and adolescents with autism shows that taking N-acetyl cysteine 1200 mg daily plus risperidone for 8 weeks is more effective than risperidone alone for reducing irritability (91239). However, it does not seem to improve other symptoms, such as hyperactivity, social withdrawal, lethargy, repetitive behaviors, and inappropriate speech (91239,91241,97047).
• Bronchitis. Via inhalation, N-acetyl cysteine is FDA-approved for managing acute episodes of bronchitis. Oral N-acetyl cysteine may help to reduce the occurrence of acute exacerbations of chronic bronchitis when used for 3-36 months. Details: N-acetyl cysteine solution for inhalation is FDA-approved for the management of acute bronchopulmonary disease, including bronchitis (102147). Taking N-acetyl cysteine 1200-1500 mg daily orally for 4 months seems to reduce shortness of breath and coughing, and improve lung capacity, in patients with sulfur mustard-induced bronchitis (64586,64614). Also, taking N-acetyl cysteine orally, usually 400-600 mg daily, seems to reduce the risk of acute exacerbations of chronic bronchitis by a moderate amount when used for 3-36 months (6176,64419,102660). Symptom improvement has been shown to occur in 61% of patients taking N-acetyl cysteine, compared with 34% of those taking placebo (102660). However, oral N-acetyl cysteine does not seem to have a beneficial effect on chronic bronchitis when administered for shorter durations (64685,64696,64737,64818).
• Chronic obstructive pulmonary disease (COPD). Taking N-acetyl cysteine orally seems to decrease the exacerbation rate and improve symptoms in patients with moderate to severe COPD, particularly those who are not taking inhaled corticosteroids. Also, taking N-acetyl cysteine along with standard therapy appears to improve recovery in patients hospitalized due to an acute exacerbation. Details: N-acetyl cysteine solution for inhalation is FDA-approved for the management of chronic bronchopulmonary disease, such as COPD (102147). A meta-analysis of 12 clinical studies involving 2,691 patients shows that N-acetyl cysteine, given as 257-1800 mg daily for at least 6 months, decreases the number of patients experiencing at least one COPD exacerbation by 15% when compared with placebo; however, it is not associated with a reduction in COPD exacerbation rate or improvement in measures of lung function (97046). Some smaller studies have shown a higher improvement rate of 23% to 40%, with the greatest efficacy seen in patients who are not already taking inhaled corticosteroids (10429,64552). While some studies have failed to show any benefit of N-acetyl cysteine, the lack of benefit appears to correlate with a treatment duration of less than 6 months (64704,97039,97046). The 2015 guidelines from the American College of Chest Physicians and Canadian Thoracic Society (AECOPD) recommend that N-acetyl cysteine be considered as an adjunctive treatment option for patients with moderate to severe COPD and a history of 2 or more exacerbations in the previous 2 years (97043). The 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline also states that N-acetyl cysteine may be an appropriate treatment option for patients who are not able to use inhaled corticosteroids (97050). In hospitalized patients with an acute exacerbation of COPD, preliminary clinical research shows that adding N-acetyl cysteine 1200 mg daily to regular treatment has a moderate effect on wheeze and the need for oxygen over a 7-day period when compared with regular treatment alone (102653).
• Contrast induced nephropathy. Oral or intravenous administration of N-acetyl cysteine seems to prevent contrast induced nephropathy in patients with kidney dysfunction. However, it is not beneficial in those with normal kidney function or diabetes. Details: Large meta-analyses of over 150 clinical studies in patients with reduced kidney function (serum creatinine of 1.2-2.4 mg/dL) show that oral N-acetyl cysteine is more effective than either sodium bicarbonate or saline hydration alone in preventing contrast agent-induced kidney damage after coronary angiography, computed tomography, left heart catheterization, and/or percutaneous coronary intervention. N-acetyl cysteine in combination with sodium bicarbonate appears to have similar efficacy to N-acetyl cysteine monotherapy, with an odds ratio of 0.62-0.67, when compared with hydration alone. Pretreatment with high-dose statin, prostaglandin, or theophylline appears to be more effective than N-acetyl cysteine, with odds ratios of 0.37, 0.37, and 0.48, respectively, when compared with hydration alone. However, combination treatment with N-acetyl cysteine and a high-dose statin appears to provide the greatest benefit of all treatments studied, with an odds ratio of 0.31, when compared with hydration alone. No treatments demonstrate significant efficacy in reducing the risk of contrast induced nephropathy in patients with diabetes (97036,97038). Some evidence also suggests that N-acetyl cysteine may have similar effects to fenoldopam in reducing the risk of contrast induced nephropathy in patients with reduced kidney function (64489,97036,97038). N-acetyl cysteine does not reduce the risk of contrast induced nephropathy in patients with normal kidney function (mean serum creatinine less than 1.2 mg/dL) when compared with control (64538,64573,64617). Although many individual studies have failed to show a significant benefit (11430,64514,64543,64561,64581,64623,64639,91232,91236,106884), pooled evidence from these and many additional studies provide a benchmark for the place for N-acetyl cysteine in reducing the risk of contrast induced kidney damage in people with reduced kidney function.
• Hyperhomocysteinemia. Oral N-acetyl cysteine seems to reduce homocysteine levels. Details: Taking N-acetyl cysteine orally seems to reduce homocysteine levels in patients with elevated homocysteine levels, including those with kidney failure requiring dialysis (2258,64542,64596).
• Hyperlipidemia. Oral N-acetyl cysteine seems to reduce lipoprotein(a) levels. Details: Taking N-acetyl cysteine orally seems to modestly reduce lipoprotein(a) levels in patients with hyperlipidemia (2256,2257,64516).
• Ifosfamide (Ifex) toxicity. Oral N-acetyl cysteine may be beneficial for reducing ifosfamide toxicity, although it does not appear to be as effective as mesna. Details: Taking N-acetyl cysteine orally seems to reduce ifosfamide-induced bladder toxicity (5808,10270,64730). However, mesna seems to be more effective for preventing ifosfamide toxicity than N-acetyl cysteine (10748).
• Influenza. Oral N-acetyl cysteine may reduce the risk for symptomatic influenza. Details: One multi-center clinical trial conducted in Italy shows that taking N-acetyl cysteine 600 mg twice daily for 6 months does not prevent influenza infection, but reduces the risk for clinically apparent disease by 68%, when compared with placebo (2260).
• Kidney failure. Oral N-acetyl cysteine may reduce the risk for cardiovascular events in patients with kidney failure. Details: One clinical study in adults with kidney failure who have been on dialysis for at least 3 months shows that taking N-acetyl cysteine 600 mg twice daily reduces the incidence of cardiovascular events, such as ischemic stroke and myocardial infarction, by about 40% when compared with placebo. There was no effect on total mortality or mortality from cardiovascular causes, although the study may have been inadequately powered to detect a difference in these outcomes (10430).
• Myocardial infarction (MI). Intravenous N-acetyl cysteine, along with standard therapy, seems to improve outcomes in patients with MI. Oral N-acetyl cysteine has not been evaluated for this use. Details: Clinical research in adults undergoing percutaneous coronary intervention (PCI) for ST-segment elevation MI shows that administering N-acetyl cysteine with nitroglycerin as a continuous intravenous infusion for 48 hours reduces myocardial infarct size by 5.5%, doubles the extent of myocardial salvage, and shortens the time to chest pain resolution when compared with nitroglycerin plus placebo (97044). Additional preliminary clinical research shows that intravenous N-acetyl cysteine, when given with nitroglycerin and streptokinase in patients with evolving MI, may preserve left ventricular function and reduce oxidative stress (7872,64502,64778).

POSSIBLY INEFFECTIVE

• Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Subcutaneous administration of N-acetyl cysteine does not seem to improve survival or disease progression in patients with ALS. Details: One clinical trial in patients with ALS shows that administering N-acetyl cysteine 50 mg/kg daily for 12 months via subcutaneous injection does not improve survival or slow disease progression when compared with placebo (2254).
• Anthracycline cardiotoxicity. Oral N-acetyl cysteine does not seem to prevent or treat doxorubicin-induced cardiac toxicity. Details: Small clinical studies show that taking N-acetyl cysteine orally does not seem to prevent or reverse doxorubicin-induced cardiac toxicity when compared with placebo or a control group (2252,2253,64712).
• Bronchopulmonary dysplasia. Intratracheal N-acetyl cysteine does not seem to prevent bronchopulmonary dysplasia in premature infants. Details: Clinical research in premature infants shows that intratracheal N-acetyl cysteine does not seem to improve symptoms, hasten recovery of chronic lung disease, or reduce the risk of bronchopulmonary dysplasia when compared with placebo (64460,64490).
• Cannabis use disorder. Oral N-acetyl cysteine does not seem to improve abstinence rates in patients with cannabis use disorder. Details: Most clinical research in adolescents and adults with cannabis use disorder shows that taking N-acetyl cysteine 1200 mg twice daily for 8-12 weeks as an adjunct to counseling and other interventions does not reduce symptoms of depression or help with cannabis abstinence (99531,102663,102666,102668). Although a single study shows that taking N-acetyl cysteine more than doubles the odds of a negative urine cannabinoid test over an 8-week period in adolescents aged 15-21 when compared with placebo, there was no significant difference in the time to first negative urine cannabinoid test or end of treatment abstinence (102666).
• Cystic fibrosis. Oral or inhaled N-acetyl cysteine does not seem to improve lung function in patients with cystic fibrosis. Details: Most clinical research shows that taking oral or nebulized N-acetyl cysteine does not significantly improve lung function or lung capacity in patients with cystic fibrosis when compared with a control (22735,64406,64671,64743). However, one preliminary clinical study shows that high-dose oral N-acetyl cysteine reduces the number and activity of airway neutrophils in these patients when compared with placebo (64510).
• Erythropoietic protoporphyria (EPP). Oral N-acetyl cysteine does not seem to improve photosensitivity in patients with EPP. Details: Small clinical studies show that taking N-acetyl cysteine 1800 mg daily orally for 4 weeks does not improve photosensitivity in patients with EPP when compared with placebo or baseline (64448,64756).
• Helicobacter pylori. Adding oral N-acetyl cysteine to conventional Helicobacter pylori (H. pylori) eradication regimens does not seem to increase eradication rates. Details: Despite conflicting findings from individual, small clinical studies (64497,97042), meta-analyses of clinical research show that adding N-acetyl cysteine to a standard antibiotic eradication regimen does not improve eradication when compared with standard eradication therapy alone (99530,106901). N-acetyl cysteine has also been evaluated in combination with other ingredients. Preliminary clinical research shows that taking N-acetyl cysteine 600 mg orally twice daily in combination with curcumin 30 mg, bovine lactoferrin 100 mg, and pantoprazole 20 mg, all taken twice daily for one week, without antibiotic therapy does not eradicate H. pylori infection, although it might improve dyspeptic symptoms and gastrointestinal inflammation (64559).
• Hepatitis. Oral N-acetyl cysteine does not appear to improve treatment response in patients with hepatitis. However, when taken with interferon, it might lengthen the time to relapse. Details: Taking N-acetyl cysteine orally does not seem to benefit patients with acute viral hepatitis (64462). Also, adding N-acetyl cysteine to conventional interferon therapy does not seem to improve treatment response in patients with hepatitis C when compared with interferon therapy alone (64418,64799,64825). However, some clinical research shows that adding N-acetyl cysteine to interferon therapy delays relapse in hepatitis C patients when compared with interferon treatment alone (64424).
• HIV/AIDS. Oral N-acetyl cysteine does not seem to increase CD4+ cell count in patients with HIV. Details: Small clinical studies show that taking N-acetyl cysteine 400 mg orally twice daily or 600 mg once daily for 4-6 months does not improve CD4+ cell counts or viral load in patients with HIV when compared with placebo (64482,64779). In addition, taking N-acetyl cysteine 600 mg orally three times daily in combination with sodium selenite 500 mcg daily for up to 24 weeks does not affect the percentage of CD4+ lymphocytes or viral load in HIV patients when compared with a control (64798).
• Hypotension. Oral N-acetyl cysteine does not seem to improve renal outcomes in patients with prolonged hypotension. Details: One clinical trial in patients with prolonged hypotension shows that taking N-acetyl cysteine orally for 7 days does not reduce the risk of acute kidney failure when compared with placebo (64545).
• Infertility. Oral N-acetyl cysteine does not seem to improve fertility in females with unexplained infertility. Details: One clinical trial in females with unexplained infertility shows that taking oral N-acetyl cysteine 1200 mg daily in addition to clomiphene citrate 50 mg twice daily for 5 days, beginning on the second day of the cycle, does not improve pregnancy rate or reduce miscarriage rate when compared with clomiphene citrate alone (64528).
• Liver transplant. Intravenous N-acetyl cysteine during liver donor operation does not seem to improve liver transplant outcomes. Oral N-acetyl cysteine has not been evaluated for this use. Details: One clinical trial shows that administering N-acetyl cysteine intravenously during a liver donor operation and preserving the liver in cold solution containing N-acetyl cysteine does not reduce the risk of ischemia reperfusion injury or acute cellular rejection in liver transplant recipients when compared with control (64486).
• Pancreatitis. Oral N-acetyl cysteine does not seem to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Additionally, intravenous N-acetyl cysteine does not seem to reduce the risk of organ dysfunction in patients being treated for severe acute pancreatitis. Details: Two clinical trials show that taking oral N-acetyl cysteine 1200 mg once before undergoing ERCP does not reduce the risk of post-ERCP pancreatitis when compared with placebo (64522,109939). One of these trials also evaluated oral N-acetyl cysteine in combination with rectal indomethacin, but the incidence of post-ERCP pancreatitis did not appear to be lower when compared with taking indomethacin alone. However, the study may have been inadequately powered to detect a difference between those groups (109939). In patients with severe acute pancreatitis, intravenous N-acetyl cysteine, in combination with selenium and vitamin C, also does not seem to reduce the risk of organ dysfunction (64551).
• Postoperative recovery. Oral or intravenous N-acetyl cysteine does not seem to improve survival, prevent complications, or reduce length of hospital stay in patients undergoing cardiac or liver surgery. Details: N-acetyl cysteine, taken orally or intravenously, does not seem to reduce the risk of myocardial infarction, stroke, kidney injury, or mortality or reduce the length of hospital stay following cardiac surgery (64610,64624,64628,64635,91233,91240). While some meta-analyses of clinical research show that taking N-acetyl cysteine orally or intravenously reduces the odds of postoperative atrial fibrillation by 36% to 44% when compared with placebo in patients undergoing cardiac surgery (64635,91233,91240), conflicting results exist (64624). In patients undergoing liver resection, intravenous N-acetyl cysteine does not reduce complication rate, risk of liver failure, length of hospital stay, or mortality when compared with a control group. In fact, patients receiving N-acetyl cysteine were more likely to experience delirium and its associated complications (99532).

LIKELY INEFFECTIVE

• Head and neck cancer. Oral N-acetyl cysteine does not seem to reduce mortality, improve event-free survival, or prevent additional tumors in patients with head and neck cancer. Details: Taking N-acetyl cysteine orally does not prevent second primary tumors in patients with head and neck cancer (1710). Also, N-acetyl cysteine alone, or in combination with retinyl palmitate, has no effect on mortality or event-free survival in these patients (1710).
• Lung cancer. Oral N-acetyl cysteine does not seem to reduce mortality, improve event-free survival, or prevent additional tumors in patients with lung cancer. Details: Taking N-acetyl cysteine orally does not prevent second primary tumors in patients with lung cancer (1710). Also, N-acetyl cysteine alone, or in combination with retinyl palmitate, has no effect on mortality or event-free survival in these patients (1705,1710).
• Multisystem organ failure. Administering intravenous N-acetyl cysteine might increase the risk of mortality due to multisystem organ failure. Oral N-acetyl cysteine has not been evaluated for this use. Details: Administering N-acetyl cysteine intravenously, greater than 24 hours after hospital admission, might increase mortality rate due to multisystem organ failure. The effect of N-acetyl cysteine given within 24 hours of hospital admission requires further study (7871).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute respiratory distress syndrome (ARDS). Research on the use of intravenous N-acetyl cysteine in patients with ARDS is conflicting. Oral N-acetyl cysteine has not been evaluated for this purpose. Details: Some clinical research shows that N-acetyl cysteine might reduce mortality and improve oxygenation in patients with acute lung injury/ARDS when compared with a control (64619). These patients were administered intravenous N-acetyl cysteine 150 mg/kg on the first day followed by 50 mg/kg for 3 more days. However, other clinical research shows that administering intravenous N-acetyl cysteine 40 mg/kg daily for 3 days does not reduce the risk of ARDS development in patients with acute lung injury (64771). Also, some clinical research shows that intravenous N-acetyl cysteine for up to 6 days does not reduce the time for improvement in patients with ARDS (64492). These discrepancies may be due to variations in genes involved in glutathione-S-transferase (GST) expression (64619).
• Adrenoleukodystrophy (ALD). It is unclear if oral or intravenous N-acetyl cysteine is beneficial in patients with ALD. Details: A case series of three male children with this rare condition suggests that administering N-acetyl cysteine orally and intravenously might improve overall survival and stabilize neurologic status after hematopoietic stem cell transplantation when compared with historical controls (64547).
• Aging. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in older adults shows that taking a combination product containing N-acetyl cysteine 100 mg/kg, glycerine 100 mg/kg, and alanine 200 mg/kg orally daily for 16 weeks modestly improved waist circumference, systolic blood pressure, and some serum markers of oxidative stress, but not body-mass index or diastolic blood pressure, when compared with placebo (110624). It is unclear if this effect is due to N-acetyl cysteine, other ingredients, or the combination.
• Alcohol-related liver disease. Although there has been interest in using oral N-acetyl cysteine for preventing alcohol-related liver damage, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral N-acetyl cysteine for allergic rhinitis, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this condition.
• Altitude sickness. It is unclear if oral N-acetyl cysteine can treat or prevent altitude sickness. Details: One very small clinical trial shows that taking N-acetyl cysteine 400 mg daily does not reduce altitude-associated anorexia or improve food intake in individuals exposed to high altitudes when compared with either placebo or vitamin E 400 mg daily (64599).
• Alzheimer disease. It is unclear if oral N-acetyl cysteine is beneficial for Alzheimer disease. Details: One clinical trial in a small number of patients with Alzheimer disease shows that taking N-acetyl cysteine 50 mg/kg daily for 6 months does not improve most cognitive symptoms of Alzheimer disease when compared with placebo (7870). However, preliminary clinical research in adults with mild to moderate Alzheimer disease also shows that taking a combination product containing N-acetyl cysteine 2.55 grams, L-serine 12.35 grams, nicotinamide riboside 1 gram, and L-carnitine tartrate 3.73 grams orally once daily for 28 days followed by twice daily for 56 more days improves cognitive functioning scores by 14% to 29% when compared with placebo (110623). It is unclear if this effect is due to N-acetyl cysteine, other ingredients, or the combination.
• Aminoglycoside ototoxicity. Small clinical studies suggest that oral N-acetyl cysteine may modestly reduce the risk of ototoxicity caused by aminoglycoside therapy. Details: A meta-analysis of available clinical research in adults with kidney failure receiving aminoglycosides for bloodstream infections shows that taking N-acetyl cysteine 600 mg twice daily for a total of 14 days, or for up to 7 days after completion of aminoglycoside therapy, reduces the risk of hearing loss by 33% when compared with placebo. The findings of this analysis are limited by the small sample sizes and high risk of bias of the included studies (97049).
• Asthma. It is unclear if inhaling N-acetyl cysteine is beneficial in patients with asthma. Details: Preliminary clinical research shows that, when administered as an aerosol daily for one week in combination with isoproterenol, N-acetyl cysteine 10% improves lung capacity and decreases sputum viscosity when compared with placebo in patients with asthma (64674).
• Athletic performance. It is unclear if oral N-acetyl cysteine can improve athletic performance. Details: Some small clinical studies shows that N-acetyl cysteine might be beneficial if taken orally at a dose of 1200 mg daily for 9 days leading up to exercise or when administered intravenously both before and during exercise (64529,91248), but that it might not improve performance when taken as a single 20 mg/kg oral dose 60 minutes prior to exercise (102028).
• Biliary disorders. It is unclear if intravenous N-acetyl cysteine is beneficial in patients with biliary disorders. Oral N-acetyl cysteine has not been evaluated for this use. Details: Preliminary clinical research in patients undergoing surgical bypass for obstructive jaundice shows that postoperative intravenous N-acetyl cysteine for 48 hours reduces levels of some liver enzymes, but not bilirubin levels or mean hospital stay, when compared with a control group. Although all liver enzyme levels had not returned to normal by 30 days after surgery, they were more improved in the group using N-acetylcysteine (102654).
• Bipolar disorder. The effects of oral N-acetyl cysteine in patients with bipolar disorder are conflicting. Oral N-acetyl cysteine might reduce symptoms of depression and increase remission rates, but it does not appear to be beneficial for reducing symptoms of mania or for maintaining remission. Details: One clinical study in patients with bipolar disorder shows that taking N-acetyl cysteine 1000 mg twice daily as adjunct to usual therapy for 24 weeks reduces symptoms of depression when compared with placebo (64608). A subgroup analysis of patients from this study who were diagnosed with bipolar II disorder shows that this dose of N-acetyl cysteine can increase the number of patients who achieve remission of both depression and mania, but not the number achieving remission of only one of these, when compared with placebo (91243). However, other research shows that taking N-acetyl cysteine 3 grams daily in addition to standard therapy for 20 weeks does not improve depression when compared with placebo in patients with bipolar depression experiencing a depressive episode for at least 4 weeks. A limitation of this study is the high (56%) placebo response rate, which might have limited the ability to detect between-group differences in symptoms improvements (99529). Taking N-acetyl cysteine as an adjunct to usual therapy does not appear to be beneficial for maintaining remission. A clinical study in patients with bipolar disorder shows that, although taking N-acetyl cysteine 1000 mg twice daily for 8 weeks improves symptoms of bipolar disorder when compared to baseline, maintenance therapy with N-acetyl cysteine for an additional 6 months does not improve depression symptoms or prevent recurrence when compared with placebo (91234).
• Bronchiectasis. Oral N-acetyl cysteine has been evaluated in patients with bronchiectasis, with promising results. Details: Preliminary clinical research in Chinese adults with bronchiectasis shows that taking N-acetyl cysteine 600 mg twice daily for 12 months reduces the risk of exacerbation by 59% when compared with a control group receiving on-demand treatment only. For every eight patients treated with N-acetyl cysteine, one additional patient was free of exacerbations at 12 months when compared with on-demand treatment only (102027).
• Canker sores. It is unclear if rinsing the mouth with N-acetyl cysteine solution is beneficial in patients with canker sores. Details: Preliminary clinical research in patients with recurrent canker sores shows that rinsing the mouth with N-acetyl cysteine (ACC, HEXAL AG) 200 mg dissolved in water for 30 seconds is no more effective than 0.12% chlorhexidine digluconate for canker sore healing time or level of pain. However, pain was reduced by 50% to 90% more over baseline 2-4 days after use of N-acetyl cysteine when compared with 0.12% chlorhexidine digluconate (102659).
• Chemotherapy-induced hepatotoxicity. It is unclear if intravenous N-acetyl cysteine is beneficial in patients with chemotherapy-induced hepatotoxicity. Oral N-acetyl cysteine has not been evaluated for this use. Details: Some observational research in children aged 2-17 years with chemotherapy-induced hepatotoxicity has found that intravenous N-acetyl cysteine 3 mcg/kg over 24 hours is associated with day-to-day improvement in liver injury, based on liver function enzyme levels, when compared with no N-acetyl cysteine therapy. Decreases in liver enzymes also occurred earlier in patients using N-acetyl cysteine (102664).
• Chemotherapy-induced peripheral neuropathy. Small clinical studies suggest that oral N-acetyl cysteine may reduce the risk for peripheral neuropathy in patients receiving oxaliplatin. Details: One preliminary clinical study in patients with colon cancer shows that taking N-acetyl cysteine 1200 mg orally at 1.5 hours prior to oxaliplatin therapy reduces the incidence of oxaliplatin-induced neuropathy when compared with placebo (64505). Another small clinical trial in patients with gastric or colorectal cancers shows that taking N-acetyl cysteine (Osveh Pharmaceutical Company) 1200 mg one hour before receiving oxaliplatin during eight courses of chemotherapy reduces the incidence and severity of neurotoxicity symptoms when compared with placebo. In patients taking N-acetyl cysteine, 31% had no signs of neurotoxicity after oxaliplatin chemotherapy, compared with 0% of those taking placebo. Also, 44% had mild symptoms, compared with 6% of those taking placebo. However, there were no significant differences in electrophysiological sensory results (102665).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral N-acetyl cysteine for CFS, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Chronic kidney disease (CKD). Oral N-acetyl cysteine does not seem to improve kidney function in patients with CKD or reduce the risk of kidney injury or other complications after cardiac surgery in patients with CKD. However, intravenous N-acetyl cysteine might offer some benefit in patients with CKD undergoing cardiac surgery. Details: Clinical research shows that taking N-acetyl cysteine 1200 mg orally daily in combination with standard antihypertensive drugs does not reduce proteinuria or other markers of kidney injury in patients with CKD (64627). N-acetyl cysteine has also been evaluated for the prevention of acute kidney injury following cardiac surgery in patients with CKD, with conflicting results. Several meta-analyses have shown that N-acetyl cysteine does not reduce the incidence of acute kidney injury, postoperative complications, postoperative interventions, length of hospitalization, or mortality after cardiac surgery in adults with CKD (95766,95767,95768). However, these meta-analyses found that intravenous, but not oral, N-acetyl cysteine might be beneficial (95767,95768). A more recent meta-analysis shows that intravenous N-acetyl cysteine reduces the risk of postoperative acute kidney injury by 23% and reduces the risk of cardiac adverse events by 17% (99533). However, most of the studies included in this latter meta-analysis were small and the definition of cardiac events varied among the included studies. Higher quality research is needed to determine the benefit, if any, of N-acetyl cysteine in reducing acute kidney injury after cardiac surgery in patients with CKD.
• Cocaine dependence. It is unclear if oral N-acetyl cysteine is effective for reducing cravings or withdrawal symptoms in people trying to stop cocaine use. Details: Some preliminary clinical research shows that taking N-acetyl cysteine 600 mg twice daily for 2 days reduces the desire to use cocaine when compared with placebo in individuals with cocaine dependence (64563). However, other preliminary clinical research shows that taking oral N-acetyl cysteine 600 mg twice daily for 2 days does not reduce cravings or withdrawal symptoms when compared with placebo in patients hospitalized for cocaine dependency (64504).
• Colorectal cancer. It is unclear if oral N-acetyl cysteine is effective for preventing colorectal cancer. Details: Clinical research in a small group of patients with a history of adenomatous colonic polyps shows that taking N-acetyl cysteine 800 mg daily for 12 weeks reduces the proliferative index of colonic crypts, suggesting that N-acetyl cysteine might decrease the likelihood of colorectal cancer (7873).
• Coronary artery bypass graft (CABG) surgery. It is unclear if oral or intravenous N-acetyl cysteine is beneficial in patients undergoing CABG surgery. Details: A small clinical study shows that taking N-acetyl cysteine 300 mg orally in addition to intermittent blood cardioplegia does not affect postoperative outcomes or the risk of mortality when compared with control in patients undergoing elective CABG surgery (64638). Another small clinical study shows that giving N-acetyl cysteine 100 mg/kg by intravenous infusion, for two doses during CABG surgery and one postoperative dose, seems to reduce serum creatinine levels at 4 and 48 hours after surgery and reduce the incidence of acute kidney injury when compared with placebo. However, serum creatinine levels were within the normal range in all patients (106886).
• Coronavirus disease 2019 (COVID-19). Small clinical trials suggest that intravenous N-acetyl cysteine is not beneficial in patients at risk for respiratory failure from severe COVID-19. It is unclear if oral use is beneficial. Details: A small single-center clinical trial of patients presenting to the emergency room with COVID-19 pneumonia in Brazil shows that receiving intravenous N-acetyl cysteine 21 grams in dextrose 5% over 20 hours in conjunction with institutional standard care, including empiric antibiotics, does not reduce the need for mechanical ventilation, length of intensive care unit (ICU) stay, or mortality when compared with dextrose 5% (105560). Another small single-center clinical trial in patients with COVID-19 and acute respiratory distress syndrome (ARDS) in Iran shows that receiving a continuous intravenous infusion of N-acetyl cysteine 40 mg/kg in dextrose 5% daily for 3 days in conjunction with institutional standard care, including corticosteroids, vitamin C, vitamin D, and zinc, also does not reduce the need for mechanical ventilation, length of ICU stay, or mortality when compared with dextrose 5% (105561). Similarly, a retrospective study of patients hospitalized in Italy for COVID-19 pneumonia shows that receiving intravenous N-acetyl cysteine 300 mg three times daily, switched to 600 mg twice daily if the patient was clinically stable, for a duration of least 5 days, does not improve inpatient mortality, ICU admission, length of ICU stay, or the incidence of atelectasis, when compared with no supplementation. At a 6-month follow-up, treatment with N-acetyl cysteine also did not appear to impact long-term outcomes in these patients (108449). In contrast, a small, retrospective study in hospitalized patients with moderate to severe COVID-19 pneumonia shows that taking oral N-acetyl cysteine, 600 mg twice daily for 10 days in addition to standard care, including empiric antibiotics, corticosteroids, and remdesivir, reduces the risk for severe respiratory failure requiring ventilator support and reduces mortality at 14 days in those with severe pneumonia when compared with standard care alone (106885). Prospective, randomized, double-blind trials are needed to confirm these findings.
• Dental plaque. It is unclear if mouthwash solutions containing N-acetyl cysteine can reduce dental plaque; higher concentrations may be more effective than lower concentrations. Details: Preliminary clinical research shows that using a mouthwash solution containing N-acetyl cysteine 10% four times daily for 7 days reduces dental plaque (64687). However, other clinical research shows that rinsing twice daily for 3 weeks with N-acetyl cysteine 1.25% does not reduce the development of plaque. In addition, N-acetyl cysteine 1.25% was not beneficial when used for 2 weeks as a treatment for experimental plaque (102662).
• Dry eye. Small clinical studies suggest that eye drops containing N-acetyl cysteine, with or without chitosan, might improve objective measures of dry eye. Details: Preliminary clinical research in patients with dry eye shows that using tear solution containing 20% N-acetyl cysteine every two hours for 2 months improves objective, but not subjective, symptoms of dry eye syndrome when compared with artificial tears (64705). A small clinical study in patients with moderate to severe dry eye disease shows that applying a specific product (Lacrimera) containing chitosan-N-acetyl cysteine as one drop once or twice daily improves tear film thickness (TFT) after 10 minutes of application, and is maintained for 24 hours, when compared with placebo. Once or twice daily application does not seem to alter the level of benefit (97710). It is unclear if the benefit of this combination product is due to N-acetyl cysteine, chitosan, or the combination.
• Endometriosis. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with endometriosis-associated pelvic pain shows that taking a combination product containing N-acetyl cysteine 1200 mg, alpha lipoic acid 400 mg, bromelain 50 mg, and zinc 20 mg daily for 6 months improves pain and reduces analgesic intake when compared to baseline (99535). This study was limited by a lack of comparator group.
• Esophagogastroduodenoscopy (EGD). It is unclear if N-acetyl cysteine (NAC) can improve visualization when used as a premedication for EGD. Details: Clinical research shows that giving NAC orally, 600 mg in 90 mL of an emulsion formulation, 20 minutes prior to EGD reduces foaming and mucus, allowing better visualization of the mucosa. The percentage of patients with no bubbles affecting visualization is about 51% with NAC, compared with 34% with placebo. The percentage not requiring suction or endoscopic flushes is 50% with NAC and 27% with placebo. Giving simethicone 150 mg in combination with NAC further improves visualization (108941).
• Exercise-induced muscle damage. It is unclear if oral N-acetyl cysteine is effective for preventing or treating exercise-induced muscle damage. Details: One small clinical study shows that taking N-acetyl cysteine 20 mg/kg daily in three divided doses after muscle-damaging exercise does not improve muscle repair or inflammatory response in healthy patients taking part in a specific resistance training program (91244).
• Fibrocystic breast disease. It is unclear if oral N-acetyl cysteine is effective for fibrocystic beast disease. Details: Preliminary clinical research in adult females with fibrocystic breast disease and cyclical mastalgia shows that taking N-acetyl cysteine (Osvah Pharmaceutical Company) 600 mg orally once daily for 12 weeks modestly improves pain scores when compared with placebo (109938).
• Gingivitis. It is unclear if mouthwash containing N-acetyl cysteine is effective for the prevention or treatment of gingivitis. Details: Clinical research shows that rinsing twice daily for 3 weeks with N-acetyl cysteine 1.25% is slightly more effective than placebo for reducing the development of gingivitis. However, there was no effect on plaque. In addition, N-acetyl cysteine is not as effective as chlorhexidine 0.2% and had no benefit when used for 2 weeks as a treatment for experimental gingivitis (102662).
• Hangover. Although there has been interest in using oral N-acetyl cysteine for treating hangovers, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Hearing loss. It is unclear if oral N-acetyl cysteine is effective for preventing or treating hearing loss. Details: A meta-analysis of clinical trials in adults shows that taking N-acetyl cysteine 900-2700 mg orally daily for up to 42 days modestly protects against noise-induced hearing loss in middle to high hearing thresholds (0 to 4 kHz and 0 to 6 kHz), but not low hearing thresholds (0 to 2 kHz), when compared with control. However, the validity of this study is limited by high heterogeneity (109937). Another meta-analysis of 2 clinical trials in adults with sudden hearing loss shows that taking N-acetyl cysteine 1200 mg orally daily for 2 weeks to 3 months moderately improves pure tone threshold hearing when compared with control (109940).
• Hepatorenal syndrome. It is unclear if intravenous N-acetyl cysteine is beneficial in patients with hepatorenal syndrome. Oral N-acetyl cysteine has not been evaluated for this use. Details: A case series of 12 patients with hepatorenal syndrome reported that intravenous N-acetyl cysteine, starting with a 150 mg/kg loading dose over 2 hours, followed by a continuous infusion of 100 mg/kg daily for 5 days, modestly improved kidney function, but not liver function or blood pressure. When compared with historical controls, N-acetyl cysteine administration was also associated with an improvement in total survival time (1752). Prospective clinical studies are needed to confirm these findings.
• Hereditary hemorrhagic telangiectasia (HHT). It is unclear if oral N-acetyl cysteine is beneficial in patients with HHT. Details: One small clinical study shows that taking N-acetyl cysteine 600 mg three times daily orally for 12 weeks decreases the frequency and severity of daytime nosebleeds, but not nighttime nosebleeds, when compared to baseline in individuals with HHT (64643). The validity of these findings is limited by the lack of a comparator group.
• Idiopathic interstitial pneumonia. It is unclear if oral or inhaled N-acetyl cysteine is beneficial for the management of various forms of interstitial pneumonia. Details: A very small clinical study in patients with idiopathic interstitial pneumonia shows that taking N-acetyl cysteine 600 mg three times daily for 12 weeks seems to improve pulmonary function tests and decrease biochemical markers of disease when compared with baseline (7868). However, a meta-analysis of clinical research in patients with idiopathic pulmonary fibrosis, a specific type of interstitial pneumonia, shows that oral or inhaled N-acetyl cysteine does not reduce the risk of acute exacerbations or attenuate decline of lung function as measured by forced vital capacity (FVC), when compared with placebo (99538).
• Lead toxicity. Although there has been interest in using oral N-acetyl cysteine for lead toxicity, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Malaria. It is unclear if intravenous N-acetyl cysteine is beneficial as an adjunct in treating malaria. Oral N-acetyl cysteine has not been evaluated for this use. Details: One small clinical study shows that intravenous N-acetyl cysteine, in combination with intravenous artesunate, does not reduce symptoms or the risk of mortality in patients with severe malaria when compared with artesunate alone (64630).
• Male infertility. It is unclear of oral N-acetyl cysteine is beneficial for male infertility. Details: Clinical research in adults with idiopathic oligoasthenoteratospermia shows that taking N-acetyl cysteine 600 mg orally daily for 26 weeks improves sperm concentration, but not sperm motility, when compared with placebo (64626). Additionally, a preliminary clinical study in adults with asthenoteratozoospermia shows that taking N-acetyl cysteine 600 mg daily for 3 months improves sperm motility and concentration, increases protamine, and improves hormone levels and sperm morphology when compared to baseline (99534). The validity of this study is limited by the lack of a comparator group. There is also interest in using N-acetyl cysteine to attenuate the infertility effects observed after COVID-19 infection. A large clinical study in males who had normal sperm analysis prior to COVID-19, but with significantly lower sperm parameters within 6 weeks after infection, shows that taking oral N-acetyl cysteine 600 mg daily for 3 months improves sperm volume, concentration, morphology, and total motility when compared with baseline post-COVID-19 levels (108447). Although the study enrolled a control group, the investigators did not provide a statistical comparison of outcomes between groups, limiting the validity of this finding.
• Mercury toxicity. Although there has been interest in using oral N-acetyl cysteine for mercury toxicity, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Miscarriage. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its benefit when used alone is unclear. Details: One small clinical trial shows that taking oral N-acetyl cysteine 600 mg daily with folic acid 500 mcg daily improves the likelihood of maintaining pregnancy past 20 weeks when compared with folic acid alone in adults with a history of recurrent pregnancy loss (64616).
• Multiple sclerosis (MS). It is unclear if oral and intravenous N-acetyl cysteine are beneficial in patients with MS. Details: One clinical trial in a small group of patients with MS shows that intravenous and oral N-acetyl cysteine in addition to standard care for 2 months improves self-reported cognition by a moderate amount when compared with standard care alone. Self-reported attention also seems to improve (102657).
• Nitrate tolerance. Intravenous N-acetyl cysteine seems to reduce the development of nitrate tolerance. Oral N-acetyl cysteine has shown mixed results for this use. Details: Some clinical research shows that concurrent intravenous or oral administration of N-acetyl cysteine reduces the development of nitroglycerin tolerance (832,2245,64546). However, other research suggests that oral N-acetyl cysteine does not reduce the development of nitroglycerin tolerance in patients with angina (2281,2282).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral N-acetyl cysteine is beneficial in patients with NASH. Details: One small clinical study in patients with NASH shows that taking N-acetyl cysteine 1.2 grams with metformin 850-1500 mg daily for 48 weeks reduces NASH activity scores and measures of steatosis and hepatocellular ballooning, but not inflammation or fibrosis, when compared to baseline. However, taking the same dose of N-acetyl cysteine and metformin along with ursodeoxycholic acid 15 mg/kg daily does not improve these outcomes, or improve liver enzyme levels, when compared with baseline (102026). The reasons for these disparate findings are unclear. Inadequate statistical power and the lack of a comparator group limit the validity of these findings.
• Obsessive-compulsive disorder (OCD). Oral N-acetyl cysteine might improve some symptoms of OCD when used with fluvoxamine in adults. Its effects when used in combination with other psychiatric medications or as monotherapy in children and adults is unclear. Details: Preliminary clinical research in adults shows that taking N-acetyl cysteine 1000 mg twice daily along with fluvoxamine 200 mg daily for 10 weeks modestly reduces overall symptoms of OCD and symptoms of obsession when compared with fluvoxamine alone. However, the addition of N-acetyl cysteine is not associated with an improvement in symptoms of compulsion, nor with a statistically significant increase in partial or complete responders, when compared with fluvoxamine alone (97048). A clinical trial in adults with OCD who are taking various psychiatric medications shows that adding oral N-acetyl cysteine 2000-4000 mg daily for 20 weeks does not reduce symptoms of OCD, or improve secondary outcomes such as anxiety, mood, functioning, or quality of life, when compared with placebo (108450). Over half (63%) of patients had a comorbid psychiatric diagnosis, limiting the applicability of these findings. Other preliminary clinical research in adults with moderate to severe OCD who are taking various psychiatric medications shows that taking N-acetyl cysteine 3000 mg daily for 16 weeks does not improve OCD symptoms when compared with placebo (97045). A very small preliminary clinical trial in children aged 8-17 years, most of whom are not taking psychiatric medications, shows some benefit for symptom reduction when N-acetyl cysteine 2700 mg daily for 12 weeks is compared with placebo (102656).
• Otitis media. Although there has been interest in using ear drops containing N-acetyl cysteine for otitis media, there is insufficient reliable information about the clinical effects of N-acetyl cysteine for this purpose.
• Polycystic ovary syndrome (PCOS). Oral N-acetyl cysteine might improve pregnancy-related outcomes in PCOS, although it appears to be less effective than metformin. Evidence on its benefits for other symptoms of PCOS is conflicting. Details: Some research in patients with PCOS shows that N-acetyl cysteine can increase insulin sensitivity, improve hirsutism, and improve menstrual irregularity (64435,64550,91245,102121). It may also improve fasting insulin levels, but results are conflicting (64435,64550,91245). Other research shows that N-acetyl cysteine, alone or as a specific combination product (Ovaric HP, Just Pharma), increases ovulation rates in some, but not all, patients with PCOS (64480,64550,64553,91246,91247,102121). A meta-analysis of clinical research suggests that N-acetyl cysteine increases the odds of having a live birth, getting pregnant, and/or ovulating by about 3-fold when compared with placebo. Its effects on the odds of pregnancy and ovulation appear to be greater in those resistant to clomiphene citrate. However, when compared with metformin, N-acetyl cysteine appears to decrease the odds of getting pregnant by about 60% and decrease the odds of ovulation by about 87%. N-acetyl cysteine also does not appear to reduce the rate of miscarriage, menstrual irregularity, or the severity of acne or hirsutism in people with PCOS (93057). Another meta-analysis shows that N-acetyl cysteine in various doses is associated with an insignificant improvement in ovulation and pregnancy rate, multiple pregnancy rate, and miscarriage rate, and is less efficacious than metformin for all of these outcomes (106888).
• Post-traumatic stress disorder (PTSD). It is unclear if oral N-acetyl cysteine is beneficial in veterans with PTSD. Details: A small clinical study in veterans with PTSD and a history of substance use disorders shows that taking N-acetyl cysteine 1200 mg orally twice daily for 8 weeks while receiving cognitive behavioral therapy reduces depressive symptoms and the rate of self-reported PTSD symptoms when compared with cognitive behavioral therapy plus placebo. Additionally, receiving N-acetyl cysteine reduces the amount and frequency of cravings by 81% and 72%, respectively, compared to a reduction of 32% and 29% for those receiving cognitive behavioral therapy with placebo. The use of N-acetyl cysteine did not impact the intensity of cravings or the actual rate of substance use during the study, which was low for all patients (97037).
• Postmenopausal conditions. It is unclear if oral N-acetyl cysteine is beneficial for preventing postmenopausal bone loss. Details: One small clinical trial shows that taking N-acetyl cysteine 2 grams daily for 3 months does not reduce postmenopausal bone loss when compared with placebo (64576).
• Preterm labor. It is unclear if oral N-acetyl cysteine is beneficial for reducing the risk for preterm labor. Details: Some clinical research shows that taking N-acetyl cysteine 0.6 grams daily orally in combination with 17-hydroxyprogesterone caproate (17-OHPC), beginning at 16 to 18 weeks gestation and continuing until active labor, increases the likelihood of reaching 36 weeks gestation and increases gestational age at delivery in adults with previous preterm labor and bacterial vaginosis when compared with 17-OHPC alone (64615). However, taking oral N-acetyl cysteine 0.6 grams every 8 hours, beginning at 25 to 33 weeks gestation and continuing until delivery, does not improve the treatment-to-delivery interval when compared with placebo in adults with early onset severe pre-eclampsia and/or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome (64493).
• Radiation-induced sialadenitis. It is unclear if mouthwash containing N-acetyl cysteine is beneficial for reducing dry mouth during chemoradiotherapy. Details: One clinical trial in a small group of patients undergoing chemoradiotherapy for head and neck cancer shows that using a mouth rinse containing N-acetyl cysteine 500 mg five times daily during radiotherapy and 2 weeks postradiotherapy improves daytime and total sticky saliva and feelings of dry mouth by up to 38% when compared with placebo. However, N-acetyl cysteine does not seem to improve nighttime symptoms (102661).
• Schizophrenia. Oral N-acetyl cysteine seems to improve negative symptoms of schizophrenia. The benefits of N-acetyl cysteine on positive symptoms of schizophrenia are less clear. Details: A meta-analysis of clinical research shows that taking N-acetyl cysteine for at least 6 months has a small to moderate effect on negative symptoms when compared with placebo. However, taking N-acetyl cysteine for only 8 weeks does not reduce negative symptoms, suggesting that a longer duration of treatment may be necessary (102658). Individual clinical studies show that N-acetyl cysteine does not improve positive symptoms, social function, cognition, and clinical global impression when compared with placebo (64605,99528). However, a meta-analysis of available research shows that taking N-acetyl cysteine for any duration has a small effect on positive symptoms, a moderate effect on working memory, and a large effect on overall symptoms (102658). It is possible that many individual studies were underpowered to detect a difference.
• Sepsis. Small clinical studies suggest that intravenous N-acetyl cysteine may improve respiratory function and tissue oxygenation, but not mortality, in patients with septic shock. Details: Two small clinical studies show that intravenous N-acetyl cysteine might improve respiratory function and tissue oxygenation, but not mortality, in some patients with recently diagnosed septic shock when compared with placebo (64760,64797).
• Sjogren syndrome. Small clinical studies suggest that oral N-acetyl cysteine may improve ocular and oral manifestations of this condition. Details: Two small clinical studies in adults with Sjogren syndrome show that taking oral N-acetyl cysteine 200 mg three times daily for 4 weeks reduces eye soreness and irritability, bad breath, and daytime thirst when compared with a control group; however, objective signs of dry eye were not improved (64673,64812).
• Systemic lupus erythematosus (SLE). It is unclear if oral N-acetyl cysteine is beneficial in patients with SLE. Details: One small clinical trial shows that taking N-acetyl cysteine orally 2.4-4.8 grams daily for 3 months significantly reduces disease activity and fatigue when compared with placebo in patients with SLE (91242).
• Thrombocytopenia. Oral N-acetyl cysteine has only been evaluated in combination with other ingredients, its effect when used alone is unclear. Details: A very small clinical study in adults with primary immune thrombocytopenia resistant or refractory to steroid therapy shows taking N-acetyl cysteine 400 mg every 8 hours with atorvastatin daily for at least one month at least doubles platelet count or increases it above 30 × 109/L compared to baseline in 60% of participants. However, 40% of participants did not respond to treatment (111572). It is unclear if this effect is due to N-acetyl cysteine, atorvastatin, or the combination. The validity of these findings is limited by the very small sample size, insufficient randomization, lack of a comparator group, and low retention rate, especially in the non-responder group.
• Tourette syndrome. It is unclear if oral N-acetyl cysteine is beneficial in patients with this condition. Details: One small clinical trial in children 8-17 years of age with Tourette syndrome shows that taking N-acetyl cysteine 600 mg twice daily for 2 weeks, followed by 1200 mg twice daily for the next 10 weeks, does not improve tic symptoms, premonitory urges, or the comorbid symptoms of obsessive-compulsive disorder (OCD), attention deficit-hyperactivity disorder (ADHD), anxiety, or depression when compared with placebo (97040).
• Trichotillomania. Oral N-acetyl cysteine might offer some benefit to adults, but not children, with trichotillomania. Details: One small clinical trial in adults shows that taking N-acetyl cysteine orally, in doses up to 2400 mg daily, significantly decreases the urge to pull hair, the amount of hair pulled, and patients' perception of their control over hair pulling as measured by a self-rating scale. After 12 weeks of treatment, scores decreased by 40% (16840). However, in children, taking N-acetyl cysteine in doses up to 2400 mg daily for 12 weeks does not seem to improve hair pulling when compared with placebo (91235).
• Ulcerative colitis. It is unclear if oral N-acetyl cysteine is beneficial in patients with ulcerative colitis. Details: One small clinical trial shows that oral N-acetyl cysteine 0.8 grams daily in combination with mesalamine 2.4 grams daily for 4 weeks does not improve the rate of clinical remission in individuals with ulcerative colitis when compared with mesalamine alone (64606).
• Urinary tract infections (UTIs). Oral N-acetyl cysteine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in female breast cancer survivors has found that taking the combination of D-mannose 500 mg, N-acetyl cysteine 100 mg, and Morinda citrifolia fruit extract 200 mg daily for 2 months in addition to antibiotic therapy is associated with reduced recurrence of UTIs and urinary discomfort when compared with antibiotics alone (97360).
• Uterine fibroids. It is unclear if oral N-acetyl cysteine is beneficial in patients with uterine fibroids. Details: Preliminary clinical research shows that taking N-acetyl cysteine 600 mg daily for 12 weeks reduces the volume of uterine fibroids by about 25%, compared with a reduction of about 1% with placebo. N-acetyl cysteine also reduces painful and heavy menstrual bleeding when compared with placebo (106889).
• Wound healing. It is unclear if postoperative intravenous N-acetyl cysteine is beneficial in patients undergoing lower extremity amputation. Details: A clinical study in patients undergoing lower extremity amputation due to critical limb-threatening ischemia shows that receiving postoperative intravenous N-acetyl cysteine 1200 mg twice daily for 5 days, beginning within 3 hours after surgery, improves tissue perfusion from days 3 to 5 and amputation stump healing at day 30 in patients that are defined as high-risk, but not in the intent-to-treat population, when compared with placebo (108448). The validity of these findings is limited due to the short duration of treatment and the inclusion of both above-the-knee and below-the-knee amputations. More evidence is needed to rate N-acetyl cysteine for these uses.

(Read more about N-ACETYL CYSTEINE (NAC))

POSSIBLY EFFECTIVE

• Prostate cancer. Oral sulforaphane seems to delay increases in levels of prostate specific antigen (PSA) in patients with prostate cancer. Details: One clinical study in adults who have undergone radical prostatectomy shows that taking a specific sulforaphane product (Prostaphane, Nutrinov) 20 mg three times daily for 6 months attenuates a rise in PSA levels after 3 months, with an 86% increase in the time needed for PSA levels to double when compared with placebo (95251). A small clinical study in adults with recurrent prostate cancer shows that taking a sulforaphane-rich broccoli sprout extract 35.2 mg daily for up to 20 weeks increases the time needed for PSA levels to double by 57% when compared to pre-treatment changes in PSA levels (95260).

POSSIBLY INEFFECTIVE

• Helicobacter pylori. Oral sulforaphane does not seem to improve the H. pylori eradication rate when used in combination with triple therapy treatment. Details: Clinical research shows that taking one capsule of broccoli sprout extract 250 mg, providing sulforaphane 1 mg, three times daily for 4 weeks in combination with clarithromycin-based triple-therapy treatment does not increase H. pylori eradication rate when compared with triple therapy alone or in combination with Saccharomyces boulardii (108138).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral sulforaphane is beneficial for improving cognitive function in older adults. Details: Clinical research in older adults shows that taking the sulforaphane precursor glucoraphanin (Kagome Co., Ltd.) 30 mg daily for 12 weeks modestly improves some measures of cognitive function, specifically working memory and processing speed, when compared with placebo. Half of all patients also underwent brain-training by playing a specific game (Brain Age) 15 minutes daily and the other half played an active control game (Tetris). However, the combination of brain-training and glucoraphanin does not seem to be more beneficial than either intervention alone (108133).
• Allergic rhinitis (hay fever). It is unclear if oral sulforaphane is beneficial for allergic rhinitis. Details: Clinical research in patients with grass-induced allergic rhinitis shows that using a daily steroid nasal spray in conjunction with an oral broccoli seed and sprout extract (Avmacol, Nutramax) 1500 mg daily, providing sulforaphane 60-70 micromoles, for 3 weeks improves nasal flow and symptom severity for up to about 30 minutes when compared with using a saline spray and oral placebo. However, use of either intervention alone did not improve nasal flow or symptoms when compared with placebo (108132). This study was small and may not have been adequately powered to detect beneficial effects of sulforaphane alone.
• Asthma. It is unclear if oral sulforaphane is beneficial for asthma. Details: Preliminary clinical research in adults with asthma shows that taking broccoli sprout extract containing sulforaphane 17.6 mg daily for 14 days attenuates the bronchoconstriction effects of methacholine by approximately 21% when compared to baseline. However, after taking sulforaphane, 20% of patients experienced a worsening of bronchoconstriction and 20% experienced no change. Taking sulforaphane did not improve most measures of pulmonary function, including forced expiratory volume, forced vital capacity, lung capacity, and residual capacity (95262).
• Autism spectrum disorder. It is unclear if oral sulforaphane is beneficial in children or adults with autism spectrum disorder; any benefits seen in clinical studies may not be considered clinically significant. Details: Research is conflicting on whether sulforaphane improves symptoms of autism. One small clinical study in children 4-12 years old with moderate to severe autism symptoms shows that taking sulforaphane 10-20 mg daily in combination with risperidone for 10 weeks improves irritability scores by 14% and hyperactivity scores by 12% when compared with placebo and risperidone. However, it is unclear if these improvements are clinically meaningful. Taking sulforaphane did not improve stereotypic, social/lethargy, or speech scores when compared with placebo. Children weighing up to 45 kg took approximately 10 mg daily and children weighing at least 45 kg took approximately 20 mg daily (104537). In contrast, a small clinical study in children 3-12 years old with moderate to severe autism symptoms shows that taking sulforaphane as a specific broccoli seed and sprout extract blend (Avmacol, Nutramax) daily for 15 weeks does not improve clinical impressions or most symptoms of autism when compared with placebo. The extract blend was dosed to provide approximately 1 mcmol sulforaphane per pound or 2.2 mcmol per kg body weight (108131). This study was small and may not have been adequately powered to detect differences between groups. Another very small clinical study in children aged 3-7 years old with autism spectrum disorder shows that taking a specific product containing broccoli sprout powder standardized for sulforaphane (BroccoPhane, Bioriginal) with red radish sprout daily for 36 weeks does not improve measures of aberrant behavior, communication, play and imagination, restricted interests, or social responsiveness and interaction when compared with placebo (112450). Sulforaphane has also been evaluated in older children or young adults. A small study in males 13-27 years of age with autism shows that taking sulforaphane daily for 18 weeks improves behavior scores by 33% and social scores by 17% when compared with placebo. After treatment discontinuation, behavior and social scores returned to baseline levels. Dosing was weight-based as follows: sulforaphane 26.6 mg daily in those weighing at least 91 kg, 17.6 mg daily in those weighing 45-91 kg, and 8.8 mg daily in those weighing up to 45 kg (95267). A small study in males and females 7-21 years of age with autism shows that taking sulforaphane as a specific broccoli seed and sprout blend (Avmacol, Nutramax Laboratories Consumer Care, Inc.) daily for 12 weeks improves social scores by 6%, but does not affect behavior scores, when compared with baseline. It is unclear if this improvement is clinically meaningful. The product used in this study contains glucoraphanin and myrosinase and was dosed to provide approximately 2.5 mcmol of glucoraphanin per pound of body weight (98501). The validity of these findings is limited by the lack of a comparator group.
• Cancer. Although there is interest in using oral sulforaphane for cancer, there is insufficient reliable information about the clinical effects of sulforaphane for this condition.
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral sulforaphane is beneficial for COPD. Details: Preliminary clinical research shows that taking sulforaphane 4.4 mg or 26.6 mg daily for 4 weeks does not improve symptoms of COPD when compared with placebo (95268).
• Depression. It is unclear if oral sulforaphane is beneficial for depression. Details: A small clinical trial in patients with mild to moderate depression related to cardiac interventions shows that taking sulforaphane (Acer) 30 mg daily for 6 weeks reduces depression score by at least 50% in 30% of patients, compared with only 7% of those taking placebo. However, there was no significant difference in remission rate between groups (108136).
• Exercise-induced muscle damage. It is unclear if oral sulforaphane is beneficial for exercise-induced muscle damage. Details: A small clinical trial in adult males shows that taking sulforaphane 30 mg daily for 4 weeks attenuates an increase in creatine kinase levels at 24 hours following heavy resistance exercise when compared with placebo. This suggests that sulforaphane may reduce muscle damage associated with exercise (108135). However, another small preliminary clinical trial in young adult males shows that taking the sulforaphane precursor glucoraphanin (Kagome Co., Ltd.) 30 mg daily, starting 2 weeks before exercise and continuing until 4 days after, does not reduce markers of muscle damage, including aldolase, aspartate aminotransferase, lactate dehydrogenase, or creatine kinase, when compared with not taking sulforaphane (108134).
• Exercise-induced muscle soreness. It is unclear if oral sulforaphane is beneficial for exercise-induced muscle soreness. Details: A small preliminary clinical trial in young adult males shows that taking the sulforaphane precursor glucoraphanin (Kagome Co., Ltd.) 30 mg daily, starting 2 weeks before exercise and continuing until 4 days after, reduces palpation-related muscle soreness and improves range of motion two days after exercise when compared with not taking sulforaphane. However, there was no difference between groups on days 1, 3, or 4 and there was no difference in pain related to extension (108134).
• Liver disease. Although there is interest in using oral sulforaphane to improve liver health, there is insufficient reliable information about the clinical effects of sulforaphane for this use.
• Pregnancy-induced hypertension. It is unclear if oral sulforaphane is beneficial for hypertension during pregnancy. Details: A small nonrandomized clinical trial in patients with pregnancy-induced hypertension or pre-eclampsia shows that taking broccoli extract modestly decreases diastolic, but not systolic, blood pressure, when compared with baseline. Patients took a single dose of either four or eight tablets of a myrosinase-activated broccoli seed extract (BroccoMax, Jarrow Formulas) providing an unknown dose sulforaphane (108130). This study was small and may not have been adequately powered to detect differences in blood pressure.
• Schizophrenia. It is unclear if oral sulforaphane is beneficial for schizophrenia. Details: Preliminary clinical research in patients with schizophrenia shows that taking sulforaphane as a specific broccoli seed and sprout blend (Avmacol, Nutramax) daily for 16 weeks does not improve positive or negative symptoms when compared with taking placebo (108137).
• Sickle cell disease. Although there is interest in using oral sulforaphane for sickle cell disease, there is insufficient reliable information about the clinical effects of sulforaphane for this condition.
• Sunburn. Although there is interest in using topical sulforaphane for sunburn prevention, there is insufficient reliable information about the clinical effects of sulforaphane for this use. More evidence is needed to rate sulforaphane for these uses.

(Read more about SULFORAPHANE)

EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about THIAMINE)

EFFECTIVE

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

LIKELY EFFECTIVE

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

POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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

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

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

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

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LIKELY SAFE ...when used orally and appropriately. A specific milk thistle extract standardized to contain 70% to 80% silymarin (Legalon, Madaus GmbH) has been safely used in doses up to 420 mg daily for up to 4 years (2613,2614,2616,7355,63210,63212,63278,63280,63299,63340)(88154,97626,105792). Higher doses of up to 2100 mg daily have been safely used for up to 48 weeks (63251,96107,101150). Another specific milk thistle extract of silymarin (Livergol, Goldaru Pharmaceutical Company) has been safely used at doses up to 420 mg daily for up to 6 months (95021,95029,102851,102852,105793,105794,105795,113979,114909,114913)(114914). Some isolated milk thistle constituents also appear to be safe. Silibinin (Siliphos, Thorne Research) has been used safely in doses up to 320 mg daily for 28 days (63218). Some combination products containing milk thistle and other ingredients also appear to be safe. A silybin-phosphatidylcholine complex (Silipide, Inverni della Beffa Research and Development Laboratories) has been safely used in doses of 480 mg daily for 7 days (7356) and 240 mg daily for 3 months (63320). Tree turmeric and milk thistle capsules (Berberol, PharmExtracta) standardized to contain 60% to 80% silybin have been safely used twice daily for up to 12 months (95019,96140,96141,96142,97624,101158).

POSSIBLY SAFE ...when used topically and appropriately, short-term. A milk thistle extract cream standardized to silymarin 0.25% (Leviaderm, Madaus GmbH) has been used safely throughout a course of radiotherapy (63239). Another milk thistle extract cream containing silymarin 1.4% has been used with apparent safety twice daily for 3 months (105791,110489). A cream containing milk thistle fruit extract 25% has been used with apparent safety twice daily for up to 12 weeks (111175). A milk thistle extract gel containing silymarin 1% has been used with apparent safety twice daily for 9 weeks (95022). There is insufficient reliable information available about the safety of intravenous formulations of milk thistle or its constituents.

PREGNANCY AND LACTATION:
While research in an animal model shows that taking milk thistle during pregnancy and lactation does not adversely impact infant development (102850), there is insufficient reliable information available about its safety during pregnancy or lactation in humans; avoid using.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A milk thistle extract 140 mg three times daily has been used with apparent safety for up to 9 months (88154,98452). A specific product containing the milk thistle constituent silybin (Siliphos, Thorne Research Inc.) has been used with apparent safety in doses up to 320 mg daily for up to 4 weeks in children one year of age and older (63218).

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LIKELY SAFE ...when used orally, intravenously, intratracheally, or by inhalation and appropriately. N-acetyl cysteine is an FDA-approved prescription drug (832,1539,1705,1710,2245,2246,2252,2253,2254,2256)(2258,2259,2260,5808,6176,6611,7868,10270,10271,16840)(91243,91247,102027,102660,102666,99531).

CHILDREN: LIKELY SAFE
when used orally and appropriately. N-acetyl cysteine has been safely used at doses of 900-2700 mg daily for 8-12 weeks (91235,91239,91241,102666). ...when used intravenously and appropriately. Intravenous N-acetyl cysteine 140 mg/kg/day plus oral N-acetyl cysteine 70 mg/kg four times daily for up to 10 months has been safely used (64547).

PREGNANCY: POSSIBLY SAFE
when used orally, intratracheally, intravenously, or by inhalation. N-acetyl cysteine crosses the placenta, but has not been associated with adverse effects to the fetus (1711,64615,64493,97041). However, N-acetyl cysteine should only be used in pregnancy when clearly indicated, such as in cases of acetaminophen toxicity.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about N-ACETYL CYSTEINE (NAC))

LIKELY SAFE ...when used orally in amounts found in foods (10264).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Sulforaphane-rich broccoli sprout extract has been used with apparent safety in clinical studies at a sulforaphane dose of up to 35.2 mg daily for up to 20 weeks (95260,95262,95265,95267,95268,104537,108136,108137,108138). A specific brand of sulforaphane (Prostaphane, Nutrinov) has been used with apparent safety in clinical research at a dose of up to 60 mg daily for up to 6 months (95251). A specific broccoli seed extract (BroccoMax, Jarrow Formulas) containing glucoraphanin 180 mg daily has been used with apparent safety in clinical research for up to 8 weeks (95269).

CHILDREN: LIKELY SAFE
when used orally in amounts found in foods (10264). There is insufficient reliable information available about the safety of sulforaphane in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (10264). There is insufficient reliable information available about the safety of sulforaphane in medicinal amounts.

(Read more about SULFORAPHANE)

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

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

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

(Read more about THIAMINE)

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

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

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

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

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

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

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

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

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

(Read more about VITAMIN B6)

(Read more about BIOTIN)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking milk thistle with antidiabetes drugs may increase the risk of hypoglycemia.  Details Clinical research shows that milk thistle extract, alone or along with tree turmeric extract, can lower blood glucose levels and glycated hemoglobin (HbA1c) in patients with type 2 diabetes, including those already taking antidiabetes drugs (15102,63190,63314,63318,95019,96140,96141,97624,97626,113987). Additionally, animal research shows that milk thistle extract increases the metformin maximum plasma concentration and area under the curve and decreases the renal clearance of metformin, due to inhibition of the multi-drug and toxin extrusion protein 1 (MATE1) renal tubular transport protein (114919).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might inhibit CYP2B6.  Details An in vitro study shows that silybin, a constituent of milk thistle, binds to and noncompetitively inhibits CYP2B6. Additionally, silybin might downregulate the expression of CYP2B6 by decreasing mRNA and protein levels (112229).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B It is unclear if milk thistle inhibits CYP2C9; research is conflicting.  Details In vitro research suggests that milk thistle might inhibit CYP2C9 (7089,17973,17976). Additionally, 3 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are CYP2C9 substrates, including imatinib and capecitabine (111644). However, contradictory clinical research shows that milk thistle extract does not inhibit CYP2C9 or significantly affect levels of the CYP2C9 substrate tolbutamide (13712,95026). Differences in results could be due to differences in dosages or formulations utilized (95026).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D It is unclear if milk thistle inhibits CYP3A4; research is conflicting.  Details While laboratory research shows conflicting results (7318,17973,17975,17976), pharmacokinetic research shows that taking milk thistle extract 420-1350 mg daily does not significantly affect the metabolism of the CYP3A4 substrates irinotecan, midazolam, or indinavir (8234,17974,93578,95026). However, 8 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are CYP3A4 substrates, including gefitinib, sorafenib, doxorubicin, and vincristine (111644).

ESTROGENS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might interfere with estrogen therapy through competition for estrogen receptors.  Details Animal research suggests that a milk thistle extract of silymarin binds to estrogen receptor beta (93025,93026).

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might affect the clearance of drugs that undergo glucuronidation.  Details Laboratory research shows that milk thistle constituents inhibit uridine diphosphoglucuronosyl transferase (UGT), the major phase 2 enzyme that is responsible for glucuronidation (7318,17973). Theoretically, this could decrease the clearance and increase levels of glucuronidated drugs. Other laboratory research suggests that a milk thistle extract of silymarin might inhibit beta-glucuronidase (7354), although the significance of this effect is unclear.

HMG-CoA REDUCTASE INHIBITORS ("Statins") Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, milk thistle might interfere with statin therapy by decreasing the activity of organic anion transporting polypeptide 1B1 (OATB1B1) and inhibiting breast cancer resistance protein (BCRP).  Details Preliminary evidence suggests that a milk thistle extract of silymarin can decrease the activity of the OATP1B1, which transports HMG-CoA reductase inhibitors into the liver to their site of action, and animal research shows this increases the maximum plasma concentration of pitavastatin and pravastatin (113975). The silibinin component also inhibits BCRP, which transports statins from the liver into the bile for excretion. However, in a preliminary study in healthy males, silymarin 140 mg three times daily had no effect on the pharmacokinetics of a single 10 mg dose of rosuvastatin (16408).

INDINAVIR (Crixivan) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, milk thistle may induce cytochrome P450 3A4 (CYP3A4) enzymes and increase the metabolism of indinavir; however, results are conflicting.  Details One pharmacokinetic study shows that taking milk thistle (Standardized Milk Thistle, General Nutrition Corp.) 175 mg three times daily in combination with multiple doses of indinavir 800 mg every 8 hours decreases the mean trough levels of indinavir by 25% (8234). However, results from the same pharmacokinetic study show that milk thistle does not affect the overall exposure to indinavir (8234). Furthermore, two other pharmacokinetic studies show that taking specific milk thistle extract (Legalon, Rottapharm Madaus; Thisilyn, Nature's Way) 160-450 mg every 8 hours in combination with multiple doses of indinavir 800 mg every 8 hours does not reduce levels of indinavir (93578).

LEDIPASVIR Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might increase the levels and clinical effects of ledipasvir.  Details Animal research in rats shows that milk thistle increases the area under the curve (AUC) for ledipasvir and slows its elimination (109505).

MORPHINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of milk thistle with morphine might affect serum levels of morphine and either increase or decrease its effects.  Details Animal research shows that milk thistle reduces serum levels of morphine by up to 66% (101161). In contrast, laboratory research shows that milk thistle constituents inhibit uridine diphosphoglucuronosyl transferase (UGT), the major phase 2 enzyme that is responsible for glucuronidation (7318,17973). Theoretically, this could decrease the clearance and increase morphine levels. The effect of taking milk thistle on morphine metabolism in humans is not known.

ORGANIC ANION-TRANSPORTING POLYPEPTIDE SUBSTRATES (OATP) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Milk thistle may inhibit one form of OATP, OATP-B1, which could reduce the bioavailability and clinical effects of OATP-B1 substrates.  Details In vitro research shows that milk thistle inhibits OATP-B1. Two case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are OATP substrates, including sorafenib and methotrexate (111644). OATPs are expressed in the small intestine and liver and are responsible for the uptake of drugs and other compounds into the body. Inhibition of OATP may reduce the bioavailability of oral drugs that are substrates of OATP.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, milk thistle might increase the absorption of P-glycoprotein substrates. However, this effect does not seem to be clinically significant.  Details In vitro research shows that milk thistle can inhibit P-glycoprotein activity (95019,111644) and 1 case report from the World Health Organization (WHO) adverse drug reaction database describes increased abdominal pain in a patient taking milk thistle and the cancer medication vincristine, a P-glycoprotein substrate, though this patient was also taking methotrexate (111644). However, a small pharmacokinetic study in healthy volunteers shows that taking milk thistle (Enzymatic Therapy Inc.) 900 mg, standardized to 80% silymarin, in 3 divided doses daily for 14 days does not affect absorption of digoxin, a P-glycoprotein substrate (35825).

RALOXIFENE (Evista) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might decrease the clearance and increase levels of raloxifene.  Details Laboratory research suggests that the milk thistle constituents silibinin and silymarin inhibit the glucuronidation of raloxifene in the intestines (93024).

SIROLIMUS (Rapamune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Milk thistle might decrease the clearance of sirolimus.  Details Pharmacokinetic research shows that a milk thistle extract of silymarin decreases the apparent clearance of sirolimus in hepatically impaired renal transplant patients (19876). It is unclear if this interaction occurs in patients without hepatic impairment.

SOFOSBUVIR (Solvaldi) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might decrease the levels and clinical effects of sofosbuvir.  Details Animal research in rats shows that milk thistle reduces the metabolism of sofosbuvir, as well as the hepatic uptake of its active metabolite (109505).

TAMOXIFEN (Nolvadex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, the milk thistle constituent silibinin might increase tamoxifen levels and interfere with its conversion to an active metabolite.  Details Animal research suggests that the milk thistle constituent silibinin might increase plasma levels of tamoxifen and alter its conversion to an active metabolite. The mechanism appears to involve inhibition of pre-systemic metabolism of tamoxifen by cytochrome P450 (CYP) 2C9 and CYP3A4, and inhibition of P-glycoprotein-mediated efflux of tamoxifen into the intestine for excretion (17101). Whether this interaction occurs in humans is not known.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, milk thistle might increase the effects of warfarin.  Details In one case report, a man stabilized on warfarin experienced an increase in INR from 2.64 to 4.12 after taking a combination product containing milk thistle 200 mg daily, as well as dandelion, wild yam, niacinamide, and vitamin B12. Levels returned to normal after stopping the supplement (101159). Although a direct correlation between milk thistle and the change in INR cannot be confirmed, some in vitro research suggests that milk thistle might inhibit cytochrome P450 2C9 (CYP2C9), an enzyme involved in the metabolism of various drugs, including warfarin (7089,17973,17976).

(Read more about MILK THISTLE)

ACTIVATED CHARCOAL Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D N-acetyl cysteine might reduce the effects of activated charcoal, while activated charcoal might reduce the absorption of N-acetyl cysteine.  Details N-acetyl cysteine appears to reduce the capacity of activated charcoal to adsorb acetaminophen and salicylic acid (7869). Conversely, although clinical research suggests that although activated charcoal can reduce the absorption of N-acetyl cysteine by up to 40%, it does not seem to reduce its clinical effects (1755,22774,22775,64501,64647). Other clinical evidence suggests that activated charcoal does not affect the absorption of N-acetyl cysteine (22776,22777).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, N-acetyl cysteine might increase the risk of bleeding when taken with anticoagulant or antiplatelet drugs.  Details Clinical research suggests that intravenous N-acetyl cysteine decreases prothrombin time, prolongs coagulation time, decreases platelet aggregation, and increases blood loss in surgical patients (64511,64644). Furthermore, in vitro research suggests that N-acetyl cysteine increases the anticoagulant activity of nitroglycerin (22780,64780).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, N-acetyl cysteine might increase the risk of hypotension when taken with antihypertensive drugs.  Details Animal research suggests that N-acetyl cysteine potentiates the hypotensive effects of the angiotensin-converting enzyme inhibitors (ACEIs) captopril and enalaprilat (22785). Theoretically, combining N-acetyl cysteine with other antihypertensive drugs might increase the risk of hypotension.

CHLOROQUINE (Aralen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, N-acetyl cysteine might interfere with the antimalarial effects of chloroquine.  Details Animal research suggests that N-acetyl cysteine might reduce the antimalarial effects of chloroquine by increasing cellular levels of glutathione (22786).

NITROGLYCERIN Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B N-acetyl cysteine can increase the risk for hypotension and headaches when taken with intravenous or transdermal nitroglycerin.  Details Clinical research shows that concomitant administration of N-acetyl cysteine and intravenous or transdermal nitroglycerin can cause severe hypotension (2246) and intolerable headaches (2245,2280). Furthermore, in vitro research suggests that N-acetyl cysteine increases the anticoagulant activity of nitroglycerin (22780,64780).

(Read more about N-ACETYL CYSTEINE (NAC))

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sulforaphane might alter the levels and clinical effects of CYP1A2 substrates.  Details Animal and in vitro research shows that sulforaphane inhibits CYP1A2 enzyme activity. However, its precursor glucoraphanin also appears to increase the expression of the CYP1A2 enzyme, which could lead to increased metabolism of CYP1A2 substrates (12701,105083,105085). These effects have not been reported in humans.

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sulforaphane might increase the levels and effects of CYP2E1 substrates.  Details In vitro evidence shows that sulforaphane inhibits CYP2E1 enzymes (105083). 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 = D Theoretically, sulforaphane might increase the levels and effects of CYP3A4 substrates.  Details Animal and in vitro research shows that sulforaphane inhibits CYP3A4 enzyme activity and downregulates its expression (105083,105434,105435). This interaction has not been reported in humans.

(Read more about SULFORAPHANE)

TRIMETHOPRIM (Proloprim) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Probable •  Level of Evidence = B Trimethoprim might increase blood levels of thiamine.  Details In vitro, animal, and clinical research suggest that trimethoprim inhibits intestinal thiamine transporter ThTR-2, hepatic transporter OCT1, and renal transporters OCT2, MATE1, and MATE2, resulting in paradoxically increased thiamine plasma concentrations (111678).

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AMIODARONE (Cordarone) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 might increase the photosensitivity caused by amiodarone.  Details Despite initial case reports suggesting that pyridoxine may have a protective effect against amiodarone-induced photosensitivity, preliminary clinical research suggests that pyridoxine may actually exacerbate this adverse effect (8892,8893).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.  Details Research in hypertensive rats shows that vitamin B6 can decrease systolic blood pressure (30859,82959,83093). Similarly, clinical research in patients with hypertension shows that taking high doses of vitamin B6 may reduce systolic and diastolic blood pressure, possibly by reducing plasma levels of epinephrine and norepinephrine (83091).

LEVODOPA Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Vitamin B6 may increase the metabolism of levodopa when taken alone, but not when taken in conjunction with carbidopa.  Details Vitamin B6 (pyridoxine) enhances the metabolism of levodopa, reducing its clinical effects. However, this interaction does not occur when carbidopa is used concurrently with levodopa (Sinemet). Therefore, it is not likely to be a problem in most people (3046).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenobarbital.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenobarbital, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenobarbital to avoid high doses of vitamin B6 (3046,10801).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D High doses of vitamin B6 may reduce the levels and clinical effects of phenytoin.  Details Preliminary clinical evidence suggests that vitamin B6 200 mg daily can reduce plasma levels of phenytoin, possibly by increasing metabolism. It is not known whether lower doses have any effect. Advise people taking phenytoin to avoid high doses of vitamin B6 (3046,10801).

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General ...Orally and topically, biotin is generally well tolerated.
Most Common Adverse Effects: None.

Gastrointestinal ...Orally, high-dose biotin has been rarely associated with mild diarrhea. Transient mild diarrhea was reported by 2 patients taking biotin 300 mg daily (95662).

Pulmonary/Respiratory ...In one case report in France, a 76-year-old female frequent traveler developed eosinophilic pleuropericarditis after taking biotin 10 mg and pantothenic acid 300 mg daily for 2 months. She had also been taking trimetazidine for 6 years (3914). Whether eosinophilia in this case was related to biotin, pantothenic acid, other substances, or patient-specific conditions is unknown. There have been no other similar reports.

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General ...Orally, milk thistle is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal bloating, diarrhea, dyspepsia, flatulence, and nausea. However, these adverse effects do not typically occur at a greater frequency than with placebo.
Serious Adverse Effects (Rare):
Orally: Allergic reactions, including anaphylaxis, have been reported.

Dermatologic ...Orally, milk thistle may cause allergic reactions including urticaria, eczema, skin rash, and anaphylaxis in some people (6879,7355,8956,63210,63212,63238,63251,63315,63325,95029). Allergic reactions may be more likely to occur in patients sensitive to the Asteraceae/Compositae family (6879,8956). A case report describes a 49-year-old female who developed clinical, serologic, and immunopathologic features of bullous pemphigoid after taking milk thistle orally for 6 weeks. Symptoms resolved after treatment with prednisone and methotrexate (107376). Topically, milk thistle can cause erythema (110489).

Gastrointestinal ...Mild gastrointestinal symptoms have been reported, including nausea, vomiting, bloating, diarrhea, epigastric pain, abdominal colic or discomfort, dyspepsia, dysgeusia, flatulence, constipation, and loss of appetite (2616,6879,8956,13170,63140,63146,63160,63210,63218,63219)(63221,63244,63247,63250,63251,63320,63321,63323,63324,63325)(63327,63328,95024,95029,107374,114914). There is one report of a 57-year-old female with sweating, nausea, colicky abdominal pain, diarrhea, vomiting, weakness, and collapse after ingesting milk thistle; symptoms subsided after 24-48 hours without medical treatment and recurred with re-challenge (63329).

Musculoskeletal ...In one clinical study three patients taking milk thistle 200 mg orally three times daily experienced tremor; the incidence of this adverse effect was similar for patients treated with fluoxetine 10 mg three times daily (63219).

Neurologic/CNS ...With oral milk thistle use, CNS symptoms have been reported, including headache, dizziness, and sleep disturbances (114913,114914).

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General ...Orally, intravenously, and as an inhalation, N-acetyl cysteine is generally well-tolerated when used in typical doses. Most adverse effects to N-acetyl cysteine occur when single doses of greater than 9 grams are used or when a regimen of greater than 30 grams daily is followed.
Most Common Adverse Effects:
Orally: Diarrhea, dry mouth, dyspepsia, heartburn, loss of appetite, nausea, and vomiting.
Intravenously: Skin rash and hypersensitivity reactions.
Inhaled: Bronchospasm, cough, epigastric pain, throat irritation, and wheezing.
Serious Adverse Effects (Rare):
Orally: Chest tightness, hemoptysis, and palpitations have been reported.
Intravenously: Anaphylaxis, angina, dystonic reactions, tachycardia, and transient sinus bradycardia have been reported.

Cardiovascular ...Intravenously, N-acetyl cysteine has been reported to significantly increase systolic and diastolic blood pressure after exposure to nitroglycerin when compared with placebo (2280). Tachycardia, chest pain, angina, and transient sinus bradycardia have been rarely reported after administration of intravenous N-acetyl cysteine (2280,7872,64658).
Intratracheally, infants receiving 5% N-acetyl cysteine every four hours for chronic lung disease have developed bradycardia (64490).
Orally, palpitations and chest tightness have been reported rarely in clinical research evaluating oral N-acetyl cysteine at doses up to 600 mg twice daily (64675,64717,64762).

Dermatologic ...Orally, N-acetyl cysteine may cause hives (64713,64739,64813), flushing (2260,64715), and edema (64714). Rash has also been reported (64510,64715,64717,102656). In one study, flushing was reported in 2% of patients receiving 600 mg of N-acetyl cysteine orally twice daily for six months (2260).
Intravenously, N-acetyl cysteine may cause rash, and the occurrence seems to be more common than with oral use (2254,64492,64562,64658,64759,64794). Hives (2280,64794), facial edema (2280), flushing (64412), and pruritus (64658,64763) have also been reported. In a small case series of 10 healthy male patients receiving 150 mg/kg of intravenous N-acetyl cysteine for muscle fatigue, erythema was experienced 30 minutes after infusion. Other side effects reported by these patients include facial erythema, palmar erythema, and sweating (64763). In other clinical research, three patients developed an erythematous flare at the sites of previous venipunctures after receiving 5.5 gm/m2 of N-acetyl cysteine with doxorubicin therapy (64712). Pain, inflammation, and excoriation of the skin have been reported after a 20% N-acetyl cysteine solution leaked from the catheter in one patient (64726).

Gastrointestinal ...Orally, gastrointestinal complaints are the most common adverse effects reported with N-acetyl cysteine. These include heartburn (64608,64715,64717,64738,64739,102666), dyspepsia (1710,64715,64717,64724,64738), and epigastric pain (2260,10429,64715,64717). In one case report, esophagitis related to ulcerations occurred following intake of N-acetyl cysteine while in the supine position with inadequate water (102655). Other common side effects include loss of appetite (64715,64812), flatulence (2256,64510), diarrhea (64713,64715,97049), constipation (64715), dry mouth (64715,64724), nausea (7868,11430,64715,64724,64738,64812,97049), vomiting (64717,64724,64715,97049), gastric upset (64510,64545,97045,97049), acid reflux (108450), changes in bowel habits (108450), and intolerance to taste and odor (64510,64545). N-acetyl cysteine's unpleasant odor makes it difficult for some patients to take orally. Using a straw to drink N-acetyl cysteine solutions can improve tolerability. Additionally, placement of a nasogastric or duodenal tube and administration of metoclopramide or ondansetron can be helpful for patients unable to tolerate oral N-acetyl cysteine (17).
Intravenously, N-acetyl cysteine may cause diarrhea (64712), dyspepsia, nausea, vomiting (64763), mild gastrointestinal upset (102657), and metallic taste (64763).
When inhaled, N-acetyl cysteine may cause epigastric pain and throat irritation (64703,64707,64674).

Genitourinary ...Orally, dysuria was reported in 2% of patients receiving 600 mg of N-acetyl cysteine twice daily for 6 months in one clinical trial (2260).

Hematologic ...In general, hematologic adverse reactions are reported more frequently with intravenous N-acetyl cysteine compared with oral use. In surgical patients, decreased prothrombin time (1341,64511), prolonged coagulation time (64511), increased blood loss (64511,64644), and decreased platelet aggregation (64511) have been reported after administration of IV N-acetyl cysteine. In one clinical trial, six healthy patients were administered a loading dose of IV N-acetyl cysteine 10 mg/kg followed by 10 mg/kg per hour for 32 hours. All patients experienced a decrease in prothrombin time by 30% to 40%. The decrease prothrombin time (25.4 sec to 20.6 sec) reached a steady state after 16 hours (1341). In a clinical trial evaluating patients with acute myocardial infarction, hemorrhage occurred in three patients taking intravenous N-acetyl cysteine 10 mg/min, heparin (per study protocol), and aspirin (7872). Two pediatric patients receiving intravenous N-acetyl cysteine (loading dose: 140 mg/kg followed by 70 mg/kg) experienced episodes of coagulopathy; however, patients were being treated for acetaminophen overdose (64794).
Hemoptysis was reported in six patients receiving 200 mg of N-acetyl cysteine orally twice daily for 6 months for treatment of chronic bronchitis (64739).

Immunologic ...Orally, anaphylaxis to N-acetyl cysteine has been rarely reported (64794). However, anaphylactic reactions to intravenous N-acetyl cysteine appear to be more common (1716,64412,64449,64628,64710,64711,64721,64786,64789).
Anaphylactic reactions to N-acetyl cysteine have involved rash, angioedema, hypotension, and bronchospasm (64449,64711,64720). The mechanism of this reaction is unclear, but some data suggest it is not an immunologic hypersensitivity reaction but rather an acute toxic effect of N-acetyl cysteine (64786,64641,64720). Management guidelines for the treatment of anaphylactoid reactions to intravenous N-acetyl cysteine have been published. In most cases, treatment is not required or treatment with diphenhydramine or salbutamol is sufficient to continue or restart N-acetyl cysteine infusion. Antihistamines are useful in controlling and preventing recurrence of anaphylactoid symptoms (1716).

Musculoskeletal ...In one clinical trial, joint pain was reported in more than 15% of patients receiving oral N-acetyl cysteine (64608). In other research, one patient experienced pain in the legs while taking 600 mg of N-acetyl cysteine twice daily for the treatment of chronic bronchitis (64762).

Neurologic/CNS ...Orally, headache has been frequently reported with N-acetyl cysteine in clinical research (7873,11430,64510,64608,64672,64713,64715,64724,64762). Other less common adverse effects reported in patients taking oral N-acetyl cysteine at a total daily dose of 600-1200 mg include dizziness (64715,64717,64724,64762), tiredness (64675,64717), vivid dreams (102666), disorientation, and inability to concentrate (64673). One pediatric patient receiving oral N-acetyl cysteine (loading dose: 140 mg/kg followed by 70 mg/kg) experienced encephalopathy (64794).
Intravenously, N-acetyl cysteine has been associated with rare neurologic adverse reactions , including headache (7872), lightheadedness (64763), and dystonic reactions (64794). In a previously healthy 2-year-old female, status epilepticus occurred during intravenous N-acetyl cysteine therapy for paracetamol ingestion (64781). Increased deterioration in bulbar function in patients with amyotrophic lateral sclerosis has also been reported with IV N-acetyl cysteine (2254).

Ocular/Otic ...While rare, blurred vision has been reported in research on oral N-acetyl cysteine (64715). Additionally, in a previously healthy 2-year-old female, status epilepticus followed by cortical blindness occurred during intravenous N-acetyl cysteine therapy for paracetamol ingestion. In this case, vision was almost completely recovered 18-months later (64781).

Psychiatric ...Intravenously, dysphoria was experienced 30 minutes after infusion of N-acetyl cysteine in 8 of 10 healthy males assessed in one clinical study (64763).

Pulmonary/Respiratory ...Respiratory adverse reactions to N-acetyl cysteine are most commonly reported with inhalable dosage forms. These include wheezing (64455,64707), bronchospasm (64455,64699), and cough (64455,64456,64703,64811). While less frequent, wheezing (64675), bronchospasm (64675), increased sputum production (7868), cough (7868,64510), decreased peak flow (64510), dyspnea (64714), and cold symptoms (64510) have been reported with oral N-acetyl cysteine in clinical research. A few cases of wheezing (64718,64719), cough (64763), and bronchospasm (64658) have also been reported with intravenous N-acetyl cysteine. Additionally, respiratory arrest has been reported in one case where a 16 year-old female was being treated for acetaminophen toxicity with intravenous N-acetyl cysteine (64450).
Two premature infants receiving 5% N-acetyl cysteine via intratracheal instillation for the treatment of chronic lung disease had an increased frequency of cyanotic spells (64490).

Other ...Injection site reactions, including burning and phlebitis, have been reported in patients receiving IV N-acetyl cysteine (1341,64763). Fever associated with IV N-acetyl cysteine was reported in one patient during clinical research (64759).

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General ...Orally, sulforaphane seems to be well tolerated.
Most Common Adverse Effects:
Orally: Bowel discomfort, heartburn, stomach upset, and vomiting.

Gastrointestinal ...Orally, sulforaphane and sulforaphane-rich extracts can cause bowel discomfort, stomach upset, heartburn, and vomiting (95251,95252,95260,95265,95267,95268,98501,104537,108132). A specific stabilized form of sulforaphane (Cavamax W6) caused mild stomach upset in 60% of subjects in a small study (95252). However, in some clinical studies, the gastrointestinal side effects reported with sulforaphane did not occur more frequently than with placebo (95268).

Hepatic ...Orally, sulforaphane has been associated with one case of elevated liver enzyme levels. However, the patient ran a marathon the day before testing, and levels returned to normal within one week (95262).

Neurologic/CNS ...Orally, sulforaphane has been reported to cause headache in one clinical study (104537). In another clinical trial, insomnia and irritability were reported (108131). Sulforaphane has also been associated with two cases of seizure in males with autism. In one case, a patient with a recent history of seizure experienced a seizure after taking sulforaphane for 3 weeks. In another case, a patient with seizures which had been well-controlled with antiepileptic drugs for more than 1 year experienced a seizure 3 weeks after discontinuing sulforaphane. It is unclear if sulforaphane precipitated seizures in these patients (95267).

Other ...Orally, sulforaphane has been reported to cause increased weight gain. In one clinical study in males 13-27 years of age with autism, patients taking sulforaphane gained an additional 4 pounds on average over 18 weeks when compared with those taking placebo (95267).

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General ...Orally and parenterally, thiamine is generally well tolerated.
Serious Adverse Effects (Rare):
Parenterally: Hypersensitivity reactions including angioedema and anaphylaxis.

Immunologic ...Orally, thiamine might rarely cause dermatitis and other allergic reactions. Parenterally, thiamine can cause anaphylactoid and hypersensitivity reactions, but this is also rare (<0.1%). Reported symptoms and events include feelings of warmth, tingling, pruritus, urticaria, tightness of the throat, cyanosis, respiratory distress, gastrointestinal bleeding, pulmonary edema, angioedema, hypotension, and death (15,35585,105445).
In one case report, a 46-year-old female presented with systemic allergic dermatitis after applying a specific product (Inzitan, containing lidocaine, dexamethasone, cyanocobalamin and thiamine) topically by iontophoresis; the allergic reaction was attributed to thiamine (91170).

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General ...Orally or by injection, vitamin B6 is well tolerated in doses less than 100 mg daily.
Most Common Adverse Effects:
Orally or by injection: Abdominal pain, allergic reactions, headache, heartburn, loss of appetite, nausea, somnolence, vomiting.
Serious Adverse Effects (Rare):
Orally or by injection: Sensory neuropathy (high doses).

Dermatologic ...Orally, vitamin B6 (pyridoxine) has been linked to reports of skin and other allergic reactions and photosensitivity (8195,9479,90375). High-dose vitamin B6 (80 mg daily as pyridoxine) and vitamin B12 (20 mcg daily) have been associated with cases of rosacea fulminans characterized by intense erythema with nodules, papules, and pustules. Symptoms may persist for up to 4 months after the supplement is stopped, and may require treatment with systemic corticosteroids and topical therapy (10998).

Gastrointestinal ...Orally or by injection, vitamin B6 (pyridoxine) can cause nausea, vomiting, heartburn, abdominal pain, mild diarrhea, and loss of appetite (8195,9479,16306,83064,83103,107124,107127,107135). In a clinical trial, one patient experienced infectious gastroenteritis that was deemed possibly related to taking vitamin B6 (pyridoxine) orally up to 20 mg/kg daily (90796). One small case-control study has raised concern that long-term dietary vitamin B6 intake in amounts ranging from 3.56-6.59 mg daily can increase the risk of ulcerative colitis (3350).

Hematologic ...Orally or by injection, vitamin B6 (pyridoxine) can cause decreased serum folic acid concentrations (8195,9479). One case of persistent bleeding of unknown origin has been reported in a clinical trial for a patient who used vitamin B6 (pyridoxine) 100 mg twice daily on days 16 to 35 of the menstrual cycle (83103). It is unclear if this effect was due to vitamin B6 intake.

Musculoskeletal ...Orally or by injection, vitamin B6 (pyridoxine) can cause breast soreness or enlargement (8195).

Neurologic/CNS ...Orally or by injection, vitamin B6 (pyridoxine) can cause headache, paresthesia, and somnolence (8195,9479,16306). Vitamin B6 (pyridoxine) can also cause sensory neuropathy, which is related to daily dose and duration of intake. Doses exceeding 1000 mg daily or total doses of 1000 grams or more pose the most risk, although neuropathy can occur with lower daily or total doses as well (8195). The mechanism of the neurotoxicity is unknown, but is thought to occur when the liver's capacity to phosphorylate pyridoxine via the active coenzyme pyridoxal phosphate is exceeded (8204). Some researchers recommend taking vitamin B6 as pyridoxal phosphate to avoid pyridoxine neuropathy, but its safety is unknown (8204). Vitamin B6 (pyridoxine) neuropathy is characterized by numbness and impairment of the sense of position and vibration of the distal limbs, and a gradual progressive sensory ataxia (8196,10439). The syndrome is usually reversible with discontinuation of pyridoxine at the first appearance of neurologic symptoms. Residual symptoms have been reported in patients taking more than 2 grams daily for extended periods (8195,8196). Daily doses of 100 mg or less are unlikely to cause these problems (3094).

Oncologic ...In females, population research has found that a median intake of vitamin B6 1. 63 mg daily is associated with a 3.6-fold increased risk of rectal cancer when compared with a median intake of 1.05 mg daily (83024). A post-hoc subgroup analysis of results from clinical research in adults with a history of recent stroke or ischemic attack suggests that taking folic acid, vitamin B12, and vitamin B6 does not increase cancer risk overall, although it was associated with an increased risk of cancer in patients who also had diabetes (90378). Also, in patients with nasopharyngeal carcinoma, population research has found that consuming at least 8.6 mg daily of supplemental vitamin B6 during treatment was associated with a lower overall survival rate over 5 years, as well as a reduced progression-free survival, when compared with non-users and those with intakes of up to 8.6 mg daily (107134).

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