Milk thistle and medication: interactions

The shortest answer sits in the EU monograph of the EMA, section 4.5: “none reported”. The 78-page assessment report behind it puts it at greater length — milk thistle extract does inhibit CYP3A4 in the test tube, but in clinical investigations no influence on the pharmacokinetics of concomitant medicines appeared, which is why “the risk of clinically relevant drug interactions is considered low”.

That does not settle the question, it only frames it properly. Two investigations in people did find something after all — one of them in the direction hardly anyone expects. And milk thistle is bought precisely by people who often already take tablets. One thing at a time.

Where the warning lists come from: enzymes in the test tube

Drug substances are converted in the liver and the intestinal wall by enzymes so that the body can excrete them. The most important ones are called cytochrome P450 — CYP for short, with numbers after it — and, at the second stage, the UDP-glucuronosyltransferases (UGT). If one of these enzymes is inhibited, more of the drug stays in the blood. If it is induced, the drug disappears faster and the medicine works less well. Either can be unwanted.

This is where silibinin comes in, the main component of the silymarin mixture. The EMA assessment report (EMA/HMPC/294188/2013, ema.europa.eu) records: silibinin inhibits phase I and phase II enzymes and inactivates the cytochromes CYP3A4 and CYP2C9; it is also a strong inhibitor of UGT1A1, the enzyme that glucuronidates naltrexone, buprenorphine, estradiol and irinotecan among others. In the same breath the report adds that the clinical significance of these findings is “not well defined or unknown” — and that the enzyme inhibition does not correlate with interactions in humans.

These laboratory findings are the source of practically every warning list about milk thistle circulating online. They come from cell experiments in which the substance is present at concentrations a tablet never produces in the blood. That is no criticism of the laboratories — this is how interactions are first traced. It only means: the list is a suspicion, not a finding.

What was actually measured in people

There is a standard procedure for testing the suspicion: volunteers are given a medicine whose blood profile is precisely known, then the plant preparation for several days, and the measurement is repeated. Those studies exist.

Investigation	Medicine	Silymarin amount and duration	Result
Gurley et al. 2004 (12 healthy)	probe substances for CYP1A2, 2D6, 2E1, 3A4	28 days	no significant effect on any of the four enzymes
Mills et al. 2005 (16 healthy, randomised)	indinavir (HIV)	3 × 456 mg	differences in AUC, Cmax and half-life below 10 %
Rao et al. 2007 (12 healthy)	ranitidine	3 × 140 mg over 7 days	no change in AUC, Cmax or urinary excretion
van Erp et al. 2005 (6 cancer patients)	irinotecan	3 × 200 mg over 4 and 12 days	clearance unchanged (31.2 vs 25.4 vs 25.6 l/h; p = 0.16)
Rajnarayana et al. 2004 (12 healthy)	metronidazole (antibiotic)	140 mg daily, 9 days	clearance +29.5 %, half-life, Cmax and AUC lower
Han et al. 2009 (12 healthy)	losartan (blood pressure)	3 × 140 mg over 14 days	AUC raised in CYP2C9*1/*1, unchanged in *1/*3

Four of six investigations found nothing — and precisely where the laboratory data suggested something was most likely. Irinotecan is a substrate of both CYP3A4 and UGT1A1, that is, exactly the two enzymes silibinin inhibits in the test tube. The authors supplied the explanation themselves: the highest silibinin concentrations measured in blood lay between 0.025 and 0.257 µmol/l — too little to affect CYP3A4 or UGT1A1 in the body to any meaningful degree.

The pharmacokinetics in the same EMA report fit this: silymarin is poorly water-soluble, around 75 % of the silibinin reaching the plasma is already conjugated, the half-life is about six hours, and 20–40 % of the dose leaves again via the bile. What barely enters the blood and vanishes quickly cannot block much there either.

The two investigations that did find something

Metronidazole. In 2004 Rajnarayana and colleagues gave twelve volunteers the antibiotic alone and, after a week's break, together with silymarin. Under silymarin the clearance of metronidazole rose by 29.5 % and that of its main metabolite by 31.9 %; peak level, half-life and total amount in the blood fell accordingly. The authors read this as induction of intestinal P-glycoprotein and CYP3A4 — the opposite direction to the feared inhibition. In practice that would mean: not too much antibiotic in the blood, but possibly too little. It is a single small study that nobody has repeated so far; as a pointer it still counts for more than any test-tube figure.

Losartan. In 2009 Han and colleagues selected twelve men with a known CYP2C9 genotype. In carriers of the common *1/*1 variant the blood level of the blood pressure medicine rose significantly after 14 days of silymarin, in carriers of *1/*3 it did not; the amount of the active metabolite E-3174 fell in both groups. The effect therefore depends on which enzyme variant someone carries — something nobody can be seen to have.

Both investigations worked with 140 to 420 mg of silymarin a day, that is, with medicinal amounts.

How much silymarin is in a food supplement?

This question decides more than any list. Our own milk thistle preparation contains 100 mg of silymarin per tablet, one tablet a day — roughly a quarter of the 420 mg the losartan and ranitidine studies worked with, and about a seventh of the indinavir study. Where the higher amounts already moved nothing, even less is to be expected from the smaller one.

One caveat belongs with it: milligram figures for silymarin are only comparable if you know the measuring method. The same extract carries either 140 mg (photometric) or 108.2 mg (HPLC) depending on the method — the two numbers stand side by side in the EMA assessment report. How extract ratio, percentage and milligrams relate to one another is explained in Milk thistle 20:1 or 80 %.

Where caution still belongs

The evidence takes the pressure off milk thistle — but it does not replace a conversation. With some medicines the gap between “it works” and “it no longer works properly” is so narrow that even a shift of a few per cent matters. That includes coumarin-type anticoagulants (broken down via CYP2C9), immunosuppressants after a transplant, cancer medicines, HIV and hepatitis therapies and epilepsy medication. For none of these groups is an interaction with milk thistle established; for most it has not been studied either, and that is the reason to raise it — with the doctor or at the pharmacy, before the first tablet is taken.

Two practical points come with that. First: anyone taking a prescribed medicine does not stop it because of a food supplement and does not change the dose on their own. Second: milk thistle is often bought by people who are thinking about their liver for a concrete reason — and who are therefore more likely than average to be under treatment already. For that group the question is not a formality.

What is not an interaction but belongs here anyway

The EU monograph (EMA/HMPC/294187/2013) names a single contraindication: hypersensitivity to Asteraceae, the plant family that also includes mugwort, chamomile and marigold. For children and adolescents under 18 there is insufficient data; the same holds for pregnancy and breastfeeding, which is why use is not recommended there. Among undesirable effects the monograph lists mild gastrointestinal complaints, headache and allergic reactions, each with unknown frequency. And it names a limit that is not an amount: if complaints last longer than two weeks, or if skin, urine or stool takes on an unusual colour, that belongs with a doctor.

The second ingredient of our tablets, inulin from chicory root, is a dietary fibre and plays no part in this question; why it is in the preparation at all is explained in Milk thistle with inulin. Food supplements are not a substitute for a balanced and varied diet and a healthy lifestyle. The preparations themselves are in the Liver category.

Frequently asked questions

Do I have to leave a gap between the tablet and my medicine? For silymarin this has not been studied, and it would be the wrong lever anyway: enzymes are influenced over days, not over minutes. With minerals such as iron or zinc a gap helps because they compete for absorption in the gut — here it is about the metabolism that follows. Anyone looking for the right time of day for other reasons will find the evidence in Taking milk thistle.

Milk thistle during a course of antibiotics? The only investigation on this (Rajnarayana et al. 2004, metronidazole) found the antibiotic being excreted about 30 % faster. Whether that impairs its effect was not tested. Anyone taking an antibiotic for a few days can leave the milk thistle out during that time without losing anything — nothing accumulates in the body in any case.

And with the pill or other hormonal preparations? There is no solid human data on this. From the laboratory it is known that silibinin inhibits UGT1A1, an enzyme that also breaks down estradiol. That is not proof of an effect in the body, but it is the right question for the consultation — unlike St John's wort, where the weakening of hormonal contraception is well documented.

Why is milk thistle on every interaction list, then? Because such lists are compiled from enzyme data and not from studies in people. A substance that inhibits CYP3A4 in the test tube automatically lands next to every medicine broken down via CYP3A4 — several hundred of them. That the measurement in people subsequently failed to confirm the suspicion no longer corrects the list.