Liver Support by AOR Advanced Orthomolecular Research Advanced

Colorectal cancer. Consumption of cruciferous vegetables, including broccoli, seems to reduce the risk of developing colorectal cancer. Details: Epidemiological research has found that the highest intakes of cruciferous vegetables, including broccoli, are associated with an 18% to 20% reduced risk of developing colorectal neoplasms when compared with the lowest intakes (14148,96187,96189).

Bladder cancer. It is unclear if consumption of broccoli reduces the risk of developing bladder cancer. Details: Epidemiologic research has found that eating about 1.75 cups daily of cruciferous vegetables, such as broccoli or cabbage, is associated with a 30% reduced risk of developing bladder cancer (14864).
Breast cancer. It is unclear if consumption of broccoli reduces the risk of developing breast cancer. Details: Epidemiological research has found that consumption of broccoli is associated with a modestly reduced risk of developing breast cancer in premenopausal adults. However, broccoli consumption does not seem to be associated with breast cancer risk in postmenopausal adults (14146).
Fibromyalgia. Broccoli has only been evaluated in combination with ascorbigen; its effect when used alone is unclear. Details: A small clinical study in females with fibromyalgia shows that taking one capsule containing ascorbigen 100 mg and broccoli powder 400 mg once daily for one month improves pain by 18% and reduces physical impairment by 20% when compared with baseline (19605). It is unclear if this effect is due to broccoli, ascorbigen, or the combination. The validity of these findings is limited by the lack of a comparator group.
Gastric cancer. It is unclear if consumption of broccoli reduces the risk of developing gastric cancer. Details: A small epidemiological study has found that higher consumption of broccoli is associated with a reduced risk of developing gastric cancer when compared with lower consumption (14148).
Hypercholesterolemia. Broccoli has only been evaluated in combination with cabbage; its effect when used alone is unclear. Details: A small clinical study in patients with mild to moderate hypercholesterolemia shows that consuming 160 grams of a beverage containing broccoli, cabbage, and fruit twice daily for 12 weeks reduces levels of low-density lipoprotein (LDL) cholesterol by 8.5% when compared with baseline. It is unclear if the improvement from baseline differed when compared with those consuming a similar beverage without broccoli and cabbage (19607). It is unclear if this effect is due to broccoli, cabbage, or the combination.
Prostate cancer. It is unclear if consumption of broccoli reduces the risk of developing prostate cancer; the available research is conflicting. In patients with prostate cancer, broccoli has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some epidemiological research has found that consumption of Brassica vegetables, such as broccoli, Brussels sprouts, cauliflower, and cabbage, is associated with a reduced risk of developing prostate cancer (14145). However, other epidemiological research has found no association (14147,15172). Clinical research in adults with prostate cancer shows that taking a whole food formulation containing broccoli powder 100 mg, turmeric powder 100 mg, pomegranate whole fruit powder 100 mg, and green tea extract 20 mg three times daily for 6 months prevents an increase in prostate specific antigen (PSA) levels. Mean PSA levels increased by 15% in the whole food formulation group, compared with 79% in the placebo group. Also, 46% of those taking the whole food formulation showed final PSA levels that were the same or lower than initial PSA levels, compared with 14% of those in the placebo group (89730). However, it is not yet known whether the whole food formulation reduces the risk of prostate cancer progression or recurrence. It is unclear if these effects are due to broccoli, other ingredients, or the combination. More evidence is needed to rate broccoli for these uses.

CHANCA PIEDRA (Chanca Piedra (Phyllanthus amarus) leaf extract)

Kidney stones (nephrolithiasis). Although some research disagrees, most clinical research shows that taking chanca piedra might improve clearance and decrease the size of kidney stones. However, it seems that disease severity, stone location, and chanca piedra dose and/or formulation may alter the likelihood of benefit. Details: Preliminary clinical research in adults with kidney stones shows that taking a specific chanca piedra product (Uriston) 2 grams orally daily for up to 3 months after undergoing 1-3 extracorporeal shock wave lithotripsy sessions increases clearance of kidney stones within 30-60 days by 1-2 times that of control (41224). Other preliminary clinical research in patients with kidney stones smaller than 10 mm also shows that drinking a chanca piedra tea, prepared with 4.5 grams of dried extract in 250 mL boiled water, twice daily for 12 weeks decreases the number of kidney stones by 38% and kidney stone size by 40% when compared with baseline (99849). However, a small clinical trial in adults with kidney stones failed to demonstrate beneficial effects from chanca piedra extract 450 mg three times daily orally for 3 months (41202). Some subgroup and other analyses also suggest that chanca piedra may be more effective in patients with hyperoxaluria or hyperuricosuria at baseline or those with smaller kidney stones of less than 6 mm or 10 mm (41224,99849,102692). Preliminary clinical research also shows that, in patients taking chanca piedra leaf extract 225 mg with magnesium stearate 152 mg and vitamin B6 2 mg twice daily for 3 months, stone-free status occurs in about 55% of patients with middle or upper kidney stones and about 14% of those with lower stones when compared with baseline (102692).

LIKELY INEFFECTIVE

Hepatitis B. Most clinical research shows that oral chanca piedra is not effective for treating hepatitis B. Details: Despite preliminary clinical research suggesting that chanca piedra may be beneficial in patients with hepatitis B (41287), multiple follow-up clinical trials show that taking chanca piedra 200-900 mg three times daily for 1-6 weeks is not effective for treating hepatitis B, decreasing the duration of acute hepatitis B, or decreasing levels of hepatitis B surface antigen (HBsAg) (3924,3925,41180,41242,41255,41259,41294,41318).

Abdominal pain. Although there has been interest in using oral chanca piedra for abdominal pain, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Anemia of chronic disease. Although there has been interest in using oral chanca piedra for anemia of chronic disease, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Asthma. Although there has been interest in using oral chanca piedra for asthma, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Benign prostatic hyperplasia (BPH). Oral chanca piedra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with BPH, some of whom were already receiving treatment for their symptoms, shows that taking a specific product containing water-soluble extracts of chanca piedra, boldo, goldenrod, fireweed, and spiny restharrow (Fluxonorm, Omega Pharma) for 30 days improves lower urinary tract symptom scores by about 50% when compared with baseline. Maximum urinary flow rate and quality of life were also improved when compared with baseline (106432). The validity of these findings is limited by the lack of a comparator group.
Colic. Although there has been interest in using oral chanca piedra for colic, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Diabetes. It is unclear if oral chanca piedra is beneficial in patients with diabetes. Details: Preliminary clinical research in patients with types 2 diabetes shows that taking chanca piedra extract 12.5 grams orally twice daily for 7 days does not affect fasting or postprandial blood glucose levels when compared with baseline. The extract was prepared as 25 grams boiled in 200 mL of water (41186). The validity of this study is limited by the lack of a comparator group.
Gallbladder disease. Although there has been interest in using oral chanca piedra for gallbladder disease, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Gastric cancer. Although there has been interest in using oral chanca piedra for gastric cancer, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Gonorrhea. Although there has been interest in using oral chanca piedra for gonorrhea, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Hangover. It is unclear if oral chanca piedra is beneficial in patients with hangover. Details: Preliminary clinical research in a small number of healthy adults shows that taking a standardized extract of chanca piedra (PHYLLPRO, Biotropics Malaysia Berhad) 375 mg orally twice daily for 10 days prior to heavy alcohol consumption may improve alcohol clearance, but does not improve hangover symptom scores or mood scores, when compared with placebo (99846). However, the study may have been inadequately powered to detect a difference between groups.
Hypertension. It is unclear if oral chanca piedra is beneficial in patients with hypertension. Details: Preliminary clinical research in patients with hypertension shows that taking chanca piedra 1.6 grams orally three times daily for 10 days does not reduce systolic or diastolic blood pressure when compared with baseline (3928). The validity of this study is limited by the lack of a comparator group.
Intestinal parasite infection. Although there has been interest in using oral chanca piedra for intestinal parasite infection, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Lymphedema. Although there has been interest in using oral chanca piedra for lymphedema, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Malaria. Although there has been interest in using oral chanca piedra for malaria, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Miscarriage. Although there has been interest in using oral chanca piedra for miscarriage, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Osteoarthritis. It is unclear if topical chanca piedra is beneficial in patients with osteoarthritis. Details: Preliminary clinical research in patients with knee osteoarthritis shows that topical application of a chanca piedra gel with phonophoresis once daily for 10 days reduces pain and improves function when compared with placebo gel. Pain was reduced by 78%, compared with a reduction of 44% in those using the placebo gel, and patients using chanca piedra were able to walk 62 meters farther in 6 minutes when compared with placebo gel (102691).
Premature ejaculation. Oral chanca piedra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in adults with premature ejaculation shows that taking a specific combination product containing chanca piedra, cardamom, vitamin B6, tribulus, tryptophan, thiamine, and winter savory (Eiacumev, Farmaceutica MEV) orally once daily for 3 months improves premature ejaculation severity scores and increases time to ejaculation when compared with sexual counseling. Time to ejaculation increased by around 30 seconds when compared with control (97016). The validity of this study is limited by the lack of randomization and placebo-control.
Pruritus. Although there has been interest in using oral chanca piedra for pruritus, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Respiratory tract infections. Although there has been interest in using oral chanca piedra for respiratory tract infections, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Sexual dysfunction. Although there has been interest in using oral chanca piedra for sexual dysfunction, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Solid tumors. Although there has been interest in using oral chanca piedra for solid tumors, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Tonsillopharyngitis. Oral chanca piedra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients with tonsillopharyngitis shows that taking chanca piedra 50 mg and black seed 360 mg orally three times daily for 7 days moderately relieves pain when compared with placebo (36199).
Urinary tract infections (UTIs). Although there has been interest in using oral chanca piedra for UTIs, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Vaginitis. Although there has been interest in using oral chanca piedra for vaginitis, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose.
Vertigo. Although there has been interest in using oral chanca piedra for vertigo, there is insufficient reliable information about the clinical effects of chanca piedra for this purpose. More evidence is needed to rate chanca piedra for these uses.

MILK THISTLE (Milk Thistle (Silybum marianum) dry seed extract, Silymarin)

Diabetes. Oral milk thistle extracts of silymarin seem to improve glycemic control in diabetic patients. 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). 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).

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 clinical study 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). Additionally, 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 has found 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 moderately improves 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.
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. 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 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). 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 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). 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 (AST), alanine aminotransferase (ALT), and bilirubin levels, but does not improve alkaline phosphatase or albumin levels (113144). Similarly, 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).
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).
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).
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).
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.
Hypercholesterolemia. 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 low-density lipoprotein (LDL) cholesterol by an average of 34 mg/dL when compared with diet and exercise alone. There was no effect on high-density lipoprotein (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). It is unclear if the effects of this product are due to milk thistle extract, tree turmeric extract, or the combination. 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.
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 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: Two meta-analyses of 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 IU/L and alanine aminotransferase (ALT) by 9-15 IU/L, but does not affect weight or lipid levels, when compared with control (97622,105051). 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). Preliminary clinical research 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). 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).
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).
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).
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).
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). More evidence is needed to rate milk thistle for these uses.

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).

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).

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.

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).

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: 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). Another 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. 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.

Safety view details

Below is general information about the safety of the known ingredients contained in the product Liver Support. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROCCOLI (Broccoli (Brassica oleracea) seed extract)

LIKELY SAFE ...when used orally in food amounts (14145). There is insufficient reliable information available about the safety of broccoli when used in medicinal amounts.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in food amounts (14145). There is insufficient reliable information available about the safety of broccoli when used in medicinal amounts during pregnancy and lactation; avoid using.

CHANCA PIEDRA (Chanca Piedra (Phyllanthus amarus) leaf extract)

POSSIBLY SAFE ...when taken orally in doses of up to 2 grams daily for up to 3 months (3924,3928,41180,41186,41224,41287,41294,41318,98846,107946). There is insufficient reliable information available about the safety of chanca piedra when used topically.

PREGNANCY: POSSIBLY UNSAFE
when used during pregnancy or in those trying to become pregnant. Animal research shows that chanca piedra, particularly at high doses, may have contraceptive effects or may increase the risk of low birth weight or birth defects (41183,41316,41317); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

MILK THISTLE (Milk Thistle (Silybum marianum) dry seed extract, Silymarin)

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 of 140 mg daily for up to 6 months and doses of 420 mg daily for up to 6 weeks (95021,95029,102851,102852,105793,105794,105795). 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).

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.

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.

Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product Liver Support. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROCCOLI (Broccoli (Brassica oleracea) seed extract)

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, broccoli might reduce the levels and effects of drugs metabolized by CYP1A2.

Details

Pharmacokinetic research in humans shows that eating 500 grams of fresh broccoli daily for 6-12 days can increase CYP1A2 activity by 10% to 200% (19608,95722). Induction of CYP1A2 activity by broccoli is attributed to its glucosinolate constituents (19608).

CYTOCHROME P450 2A6 (CYP2A6) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Theoretically, broccoli might reduce the levels and effects of drugs metabolized by CYP2A6.

Details

Pharmacokinetic research in humans shows that eating 500 grams of broccoli daily for 6 days increases CYP2A6 activity by 135% to 550%. Induction of CYP2A6 activity is attributed to its glucosinolate constituents (19608).

CHANCA PIEDRA (Chanca Piedra (Phyllanthus amarus) leaf extract)

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, chanca piedra might increase the risk of bleeding when used concomitantly with anticoagulant/antiplatelet drugs.

Details

In vitro research suggests that methyl brevifolincarboxylate, a constituent isolated from chanca piedra, can inhibit platelet aggregation (41234). This effect has not been reported in humans.

ANTIDIABETES DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Theoretically, concomitant use with antidiabetes drugs might affect glucose control and increase the risk of hypoglycemia.

Details

Animal research suggests that chanca piedra can have hypoglycemic effects (19,41226,41280,41305,41306,41307). However, a small clinical study in adults with diabetes shows that chanca piedra extract 25 grams orally daily for 1 week does not lower fasting or postprandial blood glucose levels (41186).

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Theoretically, concomitant use of chanca piedra with antihypertensive drugs might have additive blood pressure lowering effects.

Details

Animal research suggests that chanca piedra can decrease blood pressure (41245). However, this effect was not observed in most hypertensive patients treated with chanca piedra for 10 days (3928).

DIURETIC DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, concomitant use of chanca piedra with diuretics might increase diuresis.

Details

Some preliminary clinical research in adults with hypertension shows that chanca piedra has diuretic properties (3928). However, higher quality research in adults with kidney stones shows taking chanca piedra does not increase urine volume when compared with placebo (41202). Until more is known, use cautiously in patients taking diuretic drugs.

LITHIUM

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, chanca piedra might reduce excretion and increase levels of lithium.

Details

Some preliminary clinical research in adults with hypertension shows that chanca piedra has diuretic properties (3928). However, higher quality research in adults with kidney stones shows that taking chanca piedra does not increase urine volume when compared with placebo (41202). Until more is known, use cautiously in patients taking lithium. The dose of lithium might need to be decreased.

NOREPINEPHRINE (Levophed)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, chanca piedra may reduce the effects of norepinephrine.

Details

Animal research suggests that methyl brevifolincarboxylate, a constituent isolated from chanca piedra, can reverse blood vessel contraction caused by norepinephrine (41215).

MILK THISTLE (Milk Thistle (Silybum marianum) dry seed extract, Silymarin)

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).

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). 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).

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. 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.

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

Although in vitro research shows that milk thistle can inhibit P-glycoprotein activity (95019), clinical research does not agree. 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 probe 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).

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).

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.

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Adverse Effects view details

Below is general information about the adverse effects of the known ingredients contained in the product Liver Support. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROCCOLI (Broccoli (Brassica oleracea) seed extract)

General ...Broccoli is well tolerated when consumed as food. A thorough evaluation of safety outcomes when broccoli is taken as medicine has not been conducted.

Dermatologic ...Topically, allergic reactions to broccoli have caused contact dermatitis (14158).

Hepatic ...In one case report, a 56-year-old adult developed elevated transaminases, with alanine aminotransferase (ALT) 5. 8 times above normal, aspartate aminotransferase (AST) 2.4 times above normal, and gamma-glutamyl transpeptidase (GGT) 5.1 times above normal. This was thought to be related to the consumption of 800 mL of broccoli juice daily over a 4-week period. Values returned to normal 15 days after cessation of juice consumption (96191).

Immunologic ...Topically, allergic reactions to broccoli have caused contact dermatitis (14158).

CHANCA PIEDRA (Chanca Piedra (Phyllanthus amarus) leaf extract)

General ...Orally, chanca piedra seems to be well tolerated. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Abdominal pain, nausea, vomiting.

Gastrointestinal ...Orally, use of chanca piedra can cause abdominal pain, nausea, and vomiting (99849,107946).

Ocular/Otic ...Orally, chanca piedra was associated with cases of visual impairment in one clinical trial (107946).

Other ...Orally, chanca piedra was associated with cases of fatigue in one clinical trial (107946).

MILK THISTLE (Milk Thistle (Silybum marianum) dry seed extract, Silymarin)

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). 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).

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).

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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