Human studies of silymarin have shown minimal adverse effects in multiple large, blinded, placebo-controlled, randomized studies. Silymarin is well tolerated, with only rare reports of a mild laxative effect. Mild allergic reactions have been seen at high doses (>1,500 mg /day), although the details of these allergic reactions were not reported. A recent case report from Australia described a reaction to a milk thistle extract that included intermittent episodes of sweating, abdominal cramping, nausea, vomiting, diarrhea, and weakness. All symptoms resolved when the silymarin was discontinued. The authors suggested that the capsules were contaminated; the type of contamination was unknown.
According to the German Commission E, there are no reported side effects with milk thistle within the recommended doses. Rare cases of milk thistle having a laxative effect have been reported. Human studies have reported stomach upset, heartburn, and transient headaches; however, none of these symptoms were attributed to supplementation with milk thistle, and supplementation was not discontinued. One human dosing study reported nausea, heartburn, and dyspepsia in patients treated with 160 mg/day, dyspepsia in patients treated with 240 mg/day, and postprandial nausea and meteorism in patients treated with 360 mg/day. None of these side effects were dose related.
Silymarin has been well tolerated in high doses. Silymarin has been used in pregnant women with intrahepatic cholestasis at doses of 560 mg/day for 16 days, with no toxicity to the patient or the fetus. The published data on silymarin use in children focuses on intravenous doses of 20 to 50 mg/kg body weight for mushroom poisoning. Silymarin has also proved nontoxic in rats and mice when administered in doses as high as 5,000 mg/kg body weight. Rats and dogs have received silymarin at doses of 50 to 2,500 mg/kg body weight for a 12-month period. Investigations, including postmortem analyses, showed no evidence of toxicity.
It is not known whether milk thistle may reduce, enhance, or have no effect on the effectiveness of chemotherapy. Silymarin decreases the activity of the cytochrome P450 enzyme system, which is involved in the clearance of certain chemotherapy drugs. However, the dose at which inhibition is observed is high and not achieved with oral intake of silymarin. One study investigated the effects of silymarin on the pharmacokinetics of irinotecan. Oral administration of milk thistle (200 mg, a clinically relevant dose, 3 times per day) had no significant effects on the pharmacokinetics of irinotecan. The authors concluded that the recommended doses of milk thistle are too low to affect activity of CYP3A4 or UGT1A1 enzyme pathways.
Theoretically, milk thistle may also interact adversely with chemotherapy drugs that exert their cytotoxic effects through the generation of free radicals. Silymarin and its metabolite inhibit P-glycoprotein–mediated cellular efflux, leading to the potentiation of doxorubicin cytotoxicity. No trials have been performed to support or negate these theoretical considerations. No effects on indinavir and alcohol pharmacokinetics have been observed. Enhancement of antiarrhythmic effects of amiodarone in rats has been observed.
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