| Ingredients | Amount Per Serving |
|---|---|
|
(Silybum marianum )
(seeds)
(80% Silymarin)
(Milk Thistle extract (Form: 80% Silymarin) PlantPart: seeds Genus: Silybum Species: marianum )
|
250 mg |
| 150 mg | |
| 150 mg | |
|
(Trimethylglycine)
|
150 mg |
| 75 mg |
HPMC Note: capsule, Ascorbyl Palmitate, Medium-Chain Triglyceride Oil, L-Leucine, Silica
Below is general information about the effectiveness of the known ingredients contained in the product Liver Nutrients. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product Liver Nutrients. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
POSSIBLY SAFE ...when used orally and appropriately. Alpha-lipoic acid has been used with apparent safety in doses of up to 2 grams daily for 3 months to 2 years. Lower doses of 600 mg daily have been used with apparent safety for up to 4 years (3540,3541,3542,20479,96449,97630,101867,101869,103327,103333)(103335,104651,104660,113892,113897). ...when used topically and appropriately. A cream containing alpha-lipoic acid 5% has been used with apparent safety in clinical trials lasting up to 12 weeks (12021). ...when given intravenously and appropriately. Intravenous alpha-lipoic acid has been used safely in doses of up to 6000 mg weekly in clinical trials lasting up to 3 weeks (3540,3557,10148,12106).
CHILDREN: POSSIBLY SAFE
when used orally and appropriately.
Alpha-lipoic acid has been used with apparent safety in doses of up to 600 mg daily for 3 months in children aged 10-17 years (103330).
CHILDREN: POSSIBLY UNSAFE
when used orally in amounts over 600 mg daily.
At least five cases of alpha-lipoic acid intoxication have been reported for children aged 14 months to 16 years who consumed alpha-lipoic acid at doses up to 226 mg/kg (approximately 2400 mg). Symptoms of alpha-lipoic acid-induced intoxication included seizures, acidosis, vomiting, and unconsciousness (90444,96227,96234,104653).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term.
Alpha-lipoic acid has been used safely during pregnancy at doses up to 600 mg daily for up to 4 weeks (96222).
LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately in doses of up to 6 grams daily (698,10631). However, some patients have used up to 20 grams daily with apparent safety (698). Betaine anhydrous is available as an FDA-approved prescription product (Cystadane) (698), and also as a supplement. The European Food Safety Authority states that betaine anhydrous is safe to use in doses up to 6 mg/kg daily, in addition to usual dietary intake (105548). There is insufficient reliable information available about the safety of topical betaine anhydrous.
CHILDREN: LIKELY SAFE
when used orally and appropriately in doses up to 150 mg/kg daily (698).
However, some patients have used up to 20 grams daily with apparent safety (698). Prescription betaine anhydrous (Cystadane) is approved by the US FDA for use in infants and children (698).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
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 (95021,95029,102851,102852,105793,105794,105795,113979). 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 in amounts found in foods. Typical daily intakes for adults range from 40-400 mg (101471).
POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Taurine 2-4 grams daily in two or three divided doses has been used safely in studies lasting up to 3 months (5248,5271,8217,8221,10454,77147,95612,98337,104165,104167). Higher doses of taurine 6 grams daily have been used safely in studies lasting up to 4 weeks (98336,98337). A risk assessment of orally administered taurine has identified an Observed Safe Level (OSL) of up to 3 grams daily for healthy adults (31996).
CHILDREN: LIKELY SAFE
when used in amounts found in foods.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately in medicinal amounts.
Taurine 2.4-4.8 grams daily in three divided doses has been safely used in children 6-16 years of age for up to 12 weeks (103210).
PREGNANCY AND LACTATION: LIKELY SAFE
when used in amounts found in foods.
There is insufficient reliable information available about the safety of taurine when used in medicinal amounts during pregnancy and lactation; avoid using.
Below is general information about the interactions of the known ingredients contained in the product Liver Nutrients. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
Theoretically, the antioxidant effects of alpha-lipoic acid might alter the effectiveness of alkylating agents.
 Details
The use of antioxidants like alpha-lipoic acid during chemotherapy is controversial. There are concerns that antioxidants could reduce the activity of chemotherapy drugs that generate free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as alpha-lipoic acid have on chemotherapy. Advise patients to consult their oncologist before using alpha-lipoic acid.
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Theoretically, alpha-lipoic acid may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
Details
In vitro, alpha-lipoic acid inhibits platelet aggregation (98682).
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Theoretically, taking alpha-lipoic acid with antidiabetes drugs might increase the risk of hypoglycemia.
Details
Although some small clinical studies have suggested that alpha-lipoic acid can lower blood glucose levels (3545,3874,3875,3876,20490,20493,104650), larger clinical studies in patients with diabetes have shown no clinically meaningful effect (20494,20495,20496,90443,90445,110118). Additionally, co-administration of single doses of alpha-lipoic acid and glyburide or acarbose did not cause detectable drug interactions in healthy volunteers (3870).
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Theoretically, the antioxidant effects of alpha-lipoic acid might alter the effectiveness of antitumor antibiotics.
Details
The use of antioxidants like alpha-lipoic acid during chemotherapy is controversial. There are concerns that antioxidants could reduce the activity of antitumor antibiotic drugs, which work by generating free radicals (391). However, some researchers theorize that antioxidants might make chemotherapy more effective by reducing oxidative stress that might interfere with apoptosis (cell death) of cancer cells (14012,14013). More evidence is needed to determine what effect, if any, antioxidants such as alpha-lipoic acid have on chemotherapy involving antitumor antibiotics. Advise patients to consult their oncologist before using alpha-lipoic acid.
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Theoretically, alpha-lipoic acid might decrease the effects of thyroid hormone drugs.
Details
Animal research suggests that co-administration of thyroxine with alpha-lipoic acid reduces conversion into the active T3 form (8946).
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Taking milk thistle with antidiabetes drugs may increase the risk of hypoglycemia.
Details
Clinical research shows that milk thistle extract, alone or along with tree turmeric extract, can lower blood glucose levels and glycated hemoglobin (HbA1c) in patients with type 2 diabetes, including those already taking antidiabetes drugs (15102,63190,63314,63318,95019,96140,96141,97624,97626,113987).
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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).
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It is unclear if milk thistle inhibits CYP2C9; research is conflicting.
Details
In vitro research suggests that milk thistle might inhibit CYP2C9 (7089,17973,17976). Additionally, 3 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are CYP2C9 substrates, including imatinib and capecitabine (111644). However, contradictory clinical research shows that milk thistle extract does not inhibit CYP2C9 or significantly affect levels of the CYP2C9 substrate tolbutamide (13712,95026). Differences in results could be due to differences in dosages or formulations utilized (95026).
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It is unclear if milk thistle inhibits CYP3A4; research is conflicting.
Details
While laboratory research shows conflicting results (7318,17973,17975,17976), pharmacokinetic research shows that taking milk thistle extract 420-1350 mg daily does not significantly affect the metabolism of the CYP3A4 substrates irinotecan, midazolam, or indinavir (8234,17974,93578,95026). However, 8 case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are CYP3A4 substrates, including gefitinib, sorafenib, doxorubicin, and vincristine (111644).
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Theoretically, milk thistle might interfere with estrogen therapy through competition for estrogen receptors.
Details
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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.
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Theoretically, milk thistle might interfere with statin therapy by decreasing the activity of organic anion transporting polypeptide 1B1 (OATB1B1) and inhibiting breast cancer resistance protein (BCRP).
Details
Preliminary evidence suggests that a milk thistle extract of silymarin can decrease the activity of the OATP1B1, which transports HMG-CoA reductase inhibitors into the liver to their site of action, and animal research shows this increases the maximum plasma concentration of pitavastatin and pravastatin (113975). The silibinin component also inhibits BCRP, which transports statins from the liver into the bile for excretion. However, in a preliminary study in healthy males, silymarin 140 mg three times daily had no effect on the pharmacokinetics of a single 10 mg dose of rosuvastatin (16408).
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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).
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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).
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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.
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Milk thistle may inhibit one form of OATP, OATP-B1, which could reduce the bioavailability and clinical effects of OATP-B1 substrates.
Details
In vitro research shows that milk thistle inhibits OATP-B1. Two case reports from the World Health Organization (WHO) adverse drug reaction database describe increased toxicity in patients taking milk thistle and cancer medications that are OATP substrates, including sorafenib and methotrexate (111644). OATPs are expressed in the small intestine and liver and are responsible for the uptake of drugs and other compounds into the body. Inhibition of OATP may reduce the bioavailability of oral drugs that are substrates of OATP.
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Theoretically, milk thistle might increase the absorption of P-glycoprotein substrates. However, this effect does not seem to be clinically significant.
Details
In vitro research shows that milk thistle can inhibit P-glycoprotein activity (95019,111644) and 1 case report from the World Health Organization (WHO) adverse drug reaction database describes increased abdominal pain in a patient taking milk thistle and the cancer medication vincristine, a P-glycoprotein substrate, though this patient was also taking methotrexate (111644). However, a small pharmacokinetic study in healthy volunteers shows that taking milk thistle (Enzymatic Therapy Inc.) 900 mg, standardized to 80% silymarin, in 3 divided doses daily for 14 days does not affect absorption of digoxin, a P-glycoprotein substrate (35825).
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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).
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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.
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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).
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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.
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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).
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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).
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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).
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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.
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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).
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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).
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Theoretically, taurine might increase the risk of hypotension when taken with antihypertensive drugs.
Details
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Theoretically, taurine might reduce excretion and increase plasma levels of lithium.
Details
Taurine is thought to have diuretic properties (3647), which might reduce the excretion of lithium.
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Below is general information about the adverse effects of the known ingredients contained in the product Liver Nutrients. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Alpha-lipoic acid appears to be generally well tolerated when used orally, intravenously, or topically.
Most Common Adverse Effects:
Orally: Headache, heartburn, nausea, and vomiting.
Topically: Irritation and rash.
Intravenously: Nausea and vomiting.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about insulin autoimmune syndrome (IAS).
Cardiovascular ...Orally, hypotension has been reported rarely in a clinical trial (104650).
Dermatologic ...Orally, skin rash and itching have been reported after use of alpha-lipoic acid (16391,20490,21674,96233,104650). Topically, alpha-lipoic acid can cause local irritation, including burning, stinging, mild rash, or contact dermatitis (12021,30836,111701). In one case, an 86-year-old female developed allergic contact dermatitis with severe itching and oozing after applying alpha-lipoic acid 5% cream to her lower extremities. The patient had a positive skin patch test for alpha-lipoic acid, confirming the causative agent (111701). In another case, a 47-year-old female developed contact dermatitis characterized by a pruritic rash and labial adhesions hours after applying a 5% vulvar serum containing lipoic acid 0.9 grams, vitamin E, vitamin C, hyaluronic acid, and retinol palmitate to the vulva to treat vulvar lichen sclerosis. Testing confirmed that the causative agent was alpha-lipoic acid (111704). Intravenously, local allergic reactions have occurred at the injection site (1547).
Endocrine ...Orally, at least 50 published cases of insulin autoimmune syndrome (IAS) thought to be associated with use of alpha-lipoic acid have been reported (16392,104656,104657,104658,104659,107893,112941). Most reported cases have been associated with alpha-lipoic acid supplements or enriched foods; IAS has not been reported with intake of alpha-lipoic acid in food. IAS has been linked to compounds, such as alpha-lipoic acid, that contain sulfhydryl groups, but it is unclear if taking alpha-lipoic acid with other drugs known to trigger IAS increases the risk (107893,112941). IAS is characterized by very high serum insulin levels and high titers of autoantibodies against endogenous insulin. Sulfhydryl groups interact with disulfide bonds of insulin, increasing its immunogenicity (112941). Symptoms include severe spontaneous hypoglycemic episodes, as well as hunger and neuroglycopenic symptoms such as blurred vision, weakness, confusion, dizziness, sweating, and palpitations (104656,104657,107893,112941). Time to onset of IAS ranges from 1 week to 4 months (107893). Most cases of IAS have been reported in Japan and have occurred in individuals with the human leucocyte antigen (HLA)-DRB1*04:06 allele (16392,104656,107893). For patients of European decent, cases of IAS have mainly occurred in individuals with the HLA-DRB1*04:03 allele (104656,104658,104659,107893). This suggests that either of these alleles might produce a genetic predisposition to alpha-lipoic acid-associated IAS. Reported doses of alpha-lipoic acid have ranged from 200-800 mg daily, most commonly 600 mg daily (104656,104658,104659,107893). IAS-related hypoglycemic episodes have been treated with oral or intravenous glucose or sucrose, as well as prednisone. Episodes decline following discontinuation of alpha-lipoic acid, and insulin values normalize within 3-9 months (104656,104658,104659,107893).
Gastrointestinal ...Orally, heartburn, nausea, and vomiting have been reported after use of alpha-lipoic acid (3557,12106,16391,20475,30844,96225,101868,103327,103328,103333)(103335,104650,104654,104655). Higher doses (1200-1800 mg daily) seem to cause more severe effects than lower doses (600 mg daily) (3557,20475,30844,96225). Alpha-lipoic acid may also cause a burning sensation from the throat to the stomach, abdominal discomfort, or bitter taste when used orally (20478,20490,21664,96225). Intravenously, alpha-lipoic acid can cause gastrointestinal upset, including nausea and vomiting. Adverse effects are more common in patients receiving higher intravenous doses (3557) and may be more common in the elderly (96225).
Genitourinary ...Orally, alpha-lipoic acid may cause urinary disorders (20479). Oral alpha-lipoic acid has also been associated with a change in urine odor (96225,103327).
Neurologic/CNS
...Orally, alpha-lipoic acid may cause headache (21664,103328,104655) or dizziness (104650).
Intravenously, paresthesias have been reported to worsen temporarily at the beginning of therapy. Also, intravenous alpha-lipoic acid can cause headache. Adverse effects are more common in patients receiving higher intravenous doses (3557).
General
...Orally, betaine anhydrous is generally well tolerated.
Most Common Adverse Effects:
Orally: Body odor, diarrhea, elevated cholesterol levels, GI distress, nausea, vomiting.
Serious Adverse Effects (Rare):
Orally: Cerebral edema.
Cardiovascular ...Betaine anhydrous might have adverse effects on the plasma lipid profile. Some studies have reported a 3% to 4% increase in total and low-density lipoprotein (LDL) cholesterol levels with betaine anhydrous 6 grams daily (16452,16455,16456,34904). A meta-analysis of 6 studies in adults, some with obesity and/or prediabetes, shows that taking betaine anhydrous 4-6 grams daily for 6-24 weeks is associated with a mean increase in total cholesterol of 4 mg/dL, with no significant change in LDL cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels (105814). Another meta-analysis of 12 studies, some in healthy adults and others in adults with various disease states, shows that taking betaine anhydrous 1.5-20 grams daily for 2-52 weeks is associated with a mean increase in total cholesterol of 14 mg/dL, and a mean increase in LDL cholesterol of 10 mg/dL, with no change in triglyceride or HDL cholesterol levels (105813).
Gastrointestinal ...Orally, betaine anhydrous can cause vomiting, nausea, GI distress, and diarrhea (698,10631,34888,34928,111374).
Neurologic/CNS ...When used orally to treat homocystinuria due to cystathionine beta-synthase deficiency, elevated plasma methionine concentrations can occur following use of betaine anhydrous, which might lead to cerebral edema (698,111374).
Other ...Orally, betaine anhydrous can cause body odor (698,10631).
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, taurine is generally well-tolerated when used in typical doses for up to one year.
Most Common Adverse Effects:
Orally: Constipation, diarrhea, and dyspepsia.
Serious Adverse Effects (Rare):
Orally: Hypersensitivity reactions in sensitive individuals. Case reports raise concerns for serious cardiovascular adverse effects, but these reports have involved energy drinks containing taurine and other ingredients. It is unclear if these adverse effects are due to taurine, other ingredients, or the combination.
Cardiovascular ...Changes in heart rate and increased blood pressure have been reported following the co-administration of taurine and caffeine, although the effects of taurine alone are unclear (77088). In healthy individuals, consumption of energy drinks containing taurine increased platelet aggregation and decreased endothelial function (77151,112268,112741). A case of cardiac arrest following strenuous exercise and an excessive intake of energy drinks containing caffeine and taurine has been reported (77136). In another case report, a 28-year-old male without cardiovascular risk factors presented to the hospital with radiating chest pain, shortness of breath, and diaphoresis after excessive intake of an energy drink containing taurine, caffeine, sugar, and glucuronolactone. Electrocardiogram findings confirmed myocardial infarction, and subsequent catheterization confirmed thrombotic occlusion (112741).
Endocrine ...Orally, taurine has been reported to cause hypoglycemia (77153).
Gastrointestinal ...Orally, constipation has been reported following the administration of taurine (77231). Dyspepsia has also been reported after oral taurine use (104165).
Hematologic ...In clinical research, taurine reduced platelet aggregation (77245). A case of massive intravascular hemolysis, presenting with confusion, dark urine, dyspnea, emesis, and fever, has been reported following the administration of a naturopathic vitamin infusion containing taurine, free amino acids, magnesium, and a vitamin B and D complex (77177). However, the effects of taurine alone are unclear.
Immunologic ...A case report describes a hypersensitivity reaction in a female patient with a history of allergies to sulfonamides, sulfites, and various foods, after ingestion of taurine and other sulfur-containing supplements. The amount of taurine in the products ranged from 50-500 mg per dose. The allergic reaction recurred upon rechallenge with taurine 250-300 mg (91514).
Neurologic/CNS
...In a case study, encephalopathy occurred in a body-builder who took approximately 14 grams of taurine in combination with insulin and anabolic steroids.
It is not known if this was due to the taurine or the other drugs taken (15536).
Cases of seizures following the consumption of energy drinks containing taurine have been reported (77105,77196). In clinical research, taurine has been reported to cause drowsiness and ataxia in epileptic children (77241).
Psychiatric ...In a case report, a 36-year-old male with adequately controlled bipolar disorder was hospitalized with symptoms of mania after consuming several cans of an energy drink containing taurine, caffeine, glucuronolactone, B vitamins, and other ingredients (Red Bull Energy Drink) over a period of four days (14302). It is unknown if this effect was related to taurine.
Pulmonary/Respiratory ...In human research, an exacerbation of pulmonary symptoms of cystic fibrosis has been associated with taurine supplementation, although this could also be caused by progression of the disease (77231).
Renal ...A case of acute kidney failure has been reported following the concomitant intake of 1 liter of vodka and 3 liters of an energy drink providing taurine 4. 6 grams, caffeine 780 mg, and alcohol 380 grams (77185).
