Interactions: when grapefruit, coffee or St John's wort affects your medication

Interactions don't only occur between pills. Grapefruit juice, your morning coffee, a calcium supplement, or a herbal remedy can change how much of a drug actually reaches your bloodstream. Here are the examples that are well documented and how to protect yourself.

Saturday morning, brunch at a friend's place. On the table there's freshly squeezed grapefruit juice, coffee, and a basket of rolls. You've brought your tablets along because you take them with breakfast, and you wash them down with a glass of juice. Back home in the bathroom cabinet, there's been a pack of St. John's wort for a few weeks now — autumn has been getting you down. And since your last blood test you've been taking some iron, so that's on hand too. All purely herbal or just normal food, you think.

That's exactly what this article addresses. Most people know that two tablets can interfere with each other. Less well known is that foods, drinks, and dietary supplements can also change how much of an active ingredient reaches your bloodstream and how long it stays there. Sometimes a medication then works more weakly, sometimes noticeably more strongly than expected.

We have limited ourselves to examples that have been measured in studies: grapefruit, St. John's wort, calcium and iron with thyroid hormone, coffee, dairy products with an antibiotic, vitamin K with certain blood thinners, and caffeine and quitting smoking. No article can replace a complete list. Whether something applies to your medication is always something you check with your pharmacist, doctor, or specialist.

What is a drug interaction?

An interaction occurs when a substance changes how a medication works. That substance can be another medication, but also a food or a dietary supplement. In a US study, around 15 percent of people aged 62 to 85 were at risk of a serious interaction in 2010/2011, mostly from medications taken together with supplements.

There are two main pathways. In the first, absorption in the gut is disrupted: a substance binds the active ingredient, so less of it reaches the bloodstream. In the second, the breakdown is altered. Many medications are broken down in the gut wall and liver by enzymes that specialists call cytochrome P450 enzymes, referred to by abbreviations like CYP3A4 or CYP1A2. If a substance slows these enzymes, the drug level rises. If it drives them harder, the level falls.

How widespread this is was shown in a study by Qato and colleagues in JAMA Internal Medicine in 2016. They visited people in the US between the ages of 62 and 85 at home and looked at all their medication packages — once in 2005/2006 with 2,351 participants and once in 2010/2011 with 2,206. The share taking dietary supplements rose during this period from 51.8 to 63.7 percent, and the share with a possible serious interaction from 8.4 to 15.1 percent.

Most of these risky combinations involved medications and supplements that had become more popular during that time. The study is from the US, but the principle applies everywhere: the more products are combined, the more important it is for someone to keep track. You can read more in the article on multiple medications and the medication plan.

Multiple medications and the medication plan

Why is grapefruit dangerous with medications?

Grapefruit contains compounds that permanently inhibit an important breakdown enzyme in the gut. This can cause the levels of certain medications to rise sharply. According to a review in the Canadian Medical Association Journal, grapefruit can interact with more than 85 medications, with 43 of them carrying the risk of serious consequences. In 2008, the number of such drugs was only 17.

The review was written by David Bailey, George Dresser, and Malcolm Arnold from London, Canada, and was published online in November 2012. The responsible compounds are called furanocoumarins. They permanently disable the enzyme CYP3A4 in the gut wall until the body has produced new enzyme.

That's why it doesn't matter whether you drink the juice at the same time as the tablet. According to the Western University press release, the interaction can also occur if the grapefruit was eaten many hours before the medication. As an example, the researchers mention a glass of 200 millilitres of grapefruit juice: drunk once a day for three days, the level of the cholesterol-lowering drug simvastatin rose to 330 percent of the level measured with water.

According to the researchers, the same compounds are also found in bitter oranges, limes, and pomelos. People over 45 are particularly affected, according to the researchers, because they buy the most grapefruit and are prescribed the most medications. Older people also tolerate excessively high drug levels less well.

Whether your medication is affected is stated in the package insert, or you can find out at the pharmacy. The list changes with each new active ingredient, so a current answer is better than an old table from the internet.

How does St. John's wort affect the way medications work?

St. John's wort ramps up the breakdown of many medications, causing their levels to fall. A 2020 review lists, among others, digoxin, tacrolimus, warfarin, alprazolam, simvastatin, and the pill. In 2000, two people with donor hearts experienced acute rejection after taking St. John's wort because the level of their medication ciclosporin dropped.

St. John's wort is used as a herbal remedy for low mood and is available without a prescription in many places. Precisely because it is herbal, it is often not perceived as a medication and not mentioned at a doctor's appointment. The research group led by Simona Nicolussi from Basel summarised in 2020 in the British Journal of Pharmacology what 20 years of research on its interactions had revealed.

The mechanism: active ingredients in St. John's wort activate a switch in the body called the pregnane X receptor. This drives the breakdown enzyme CYP3A4 as well as a kind of pump called P-glycoprotein, which moves active ingredients out of cells. Both effects lower the levels of many medications. How strongly this occurs is related to the content of hyperforin, an ingredient that varies in concentration depending on the product.

The affected drugs include the heart medication digoxin, tacrolimus and ciclosporin — used after organ transplants to suppress the immune system — the blood thinner warfarin, the sedative alprazolam, the cholesterol-lowering drug simvastatin, the HIV medication indinavir, and hormonal contraceptives. For some of these medications, an excessively low level can have serious consequences.

If you are taking or want to take St. John's wort, tell your doctor and your pharmacist before you start and also before you stop taking it.

Does the pill still work if you're taking St. John's wort?

Its effectiveness may be reduced. In a study with twelve women, St. John's wort reduced the half-life of the oestrogen in the pill from 23.4 to 12.2 hours. Breakthrough bleeding occurred in seven of the twelve women; without St. John's wort it occurred in only two. The researchers advised considering an additional barrier method. Talk about this with your gynaecologist.

Hall and colleagues from Indianapolis published this study in 2003 in Clinical Pharmacology and Therapeutics. Twelve healthy women who had been using the pill for some time took it for three cycles. In the second and third cycles, they additionally took St. John's wort three times a day.

While taking St. John's wort, the progestogen in the pill was removed from the body more quickly, and the half-life of the oestrogen approximately halved. The half-life is the time after which only half of an active ingredient remains in the blood. However, the hormones that indicate whether ovulation is taking place did not change measurably in this small study.

The study cannot therefore prove that the pill fails when taken with St. John's wort. But the more frequent breakthrough bleeding is a warning sign. Whether additional contraception makes sense for you, or whether a different remedy for low mood would be a better fit, is something to discuss with your gynaecologist or at the pharmacy.

Can you take calcium or iron together with thyroid hormone?

If taken at the same time, both can reduce the effectiveness of thyroid hormone. In a study with 20 people, the TSH value rose on average from 1.6 to 2.7 milli-units per litre while taking calcium. In a study with 14 people, it rose from 1.6 to 5.4 while taking iron. The right interval for you is something to clarify with your pharmacist or doctor.

Thyroid hormone in tablet form is called levothyroxine or L-thyroxine. Whether the dose is right is shown mainly by the TSH value in the blood. TSH is the hormone the pituitary gland uses to stimulate the thyroid. If it rises, that's a sign that too little thyroid hormone is reaching the body. You can read more in the article on thyroid diagnostics.

Singh and colleagues had 20 people in JAMA in 2000 — who had been stably dosed on levothyroxine for a long time — take 1,200 milligrams of calcium as calcium carbonate per day together with their tablet for three months. The level of free thyroid hormone fell, the TSH value rose, and in 20 percent of participants it was above the normal range. Two months after stopping the calcium, the values were back to where they had been. In the test tube, it was shown that the hormone binds to calcium in an acidic environment.

Campbell and colleagues gave 14 people with hypothyroidism in the Annals of Internal Medicine in 1992 a daily iron tablet with 300 milligrams of ferrous sulphate at the same time as their hormone for twelve weeks. The TSH value rose on average from 1.6 to 5.4, and nine of the 14 had more signs of underactive thyroid. In the test tube, iron and the hormone formed a poorly soluble violet complex.

Both studies were small and had no comparison group. But they clearly show that minerals taken at the same time can interfere. This also applies to multivitamin and mineral supplements. If you're taking calcium or iron, ask your pharmacist how long to wait between these and your thyroid hormone, and have your TSH checked after any change.

Testing your thyroid properly · Ferritin and iron status

Can you take thyroid tablets with coffee?

Better not at the same time. In an Italian study, coffee taken to swallow the tablet reduced the amount of thyroid hormone absorbed by 27 to 36 percent. When the tablet was taken with water and coffee was not drunk until 60 minutes later, absorption was similar to water alone.

Benvenga and colleagues from the University of Messina described in 2008 in the journal Thyroid eight women whose TSH level remained too high as long as they swallowed their levothyroxine with coffee or espresso. Six of them and nine healthy volunteers then took part in an absorption test: they swallowed the hormone once with coffee, once with water, and once with water and coffee an hour later. The amount of hormone entering the bloodstream was measured over four hours.

With coffee, the patients absorbed 36 percent less hormone; the healthy volunteers absorbed 27 percent less, and the peak level was reached later. With water and coffee an hour later, the results did not differ from water alone. Dietary fibre from bran interfered with absorption even more strongly than coffee in the study.

This doesn't mean you have to give up your morning coffee. It's about timing. How long to wait before taking your particular product is stated in the package insert, or you can ask at the pharmacy. You can read more about caffeine in the article on caffeine.

Caffeine

Can you take antibiotics with milk or yogurt?

Not with some antibiotics. In a study with seven healthy volunteers, the absorption of the antibiotic ciprofloxacin dropped by 30 to 36 percent when it was taken with milk or yogurt instead of water. The peak level in the blood was 36 percent lower with milk and 47 percent lower with yogurt. Whether your antibiotic is affected is stated in the package insert.

In 1991, Neuvonen and colleagues gave seven fasting volunteers 500 milligrams of ciprofloxacin in Clinical Pharmacology and Therapeutics — once with 300 milliliters of water, once with milk, and once with yogurt. Half an hour after taking it, the level was 70 percent lower with milk and 92 percent lower with yogurt compared to water.

The researchers warned that this could make it harder to treat infections caused by pathogens that respond only moderately to the drug. They advised against taking ciprofloxacin together with larger amounts of liquid dairy products.

This does not apply equally to all antibiotics. Some are barely affected by dairy products, others are. That's why it's worth checking the package insert for every new antibiotic, or asking a quick question at the pharmacy when you pick it up: What should I take it with, and what is better to avoid?

Do you have to avoid vitamin K when taking blood thinners?

Based on current evidence, no. A 2016 review found no evidence that people taking vitamin K antagonists such as warfarin or phenprocoumon need to change their diet or avoid vitamin K-rich vegetables. What matters more is avoiding large fluctuations. If something different applies to your blood thinner, your doctor will let you know.

Vitamin K antagonists are an older group of anticoagulants. They work by blocking vitamin K in the liver, which the body needs for blood clotting. For a long time, people were advised to avoid green leafy vegetables such as spinach or kale. How well blood clotting is controlled is measured with the INR value.

In 2016, Violi and colleagues from Rome and Birmingham summarized two dietary studies and nine observational studies in the journal Medicine. The results were mixed: in some, the INR value fell with more vitamin K; others suggested that a minimum amount of vitamin K may actually be necessary for stable control. Participants consumed an average of between 76 and 217 micrograms of vitamin K per day. An effect on clotting was most likely to appear above 150 micrograms.

The authors' conclusion: restricting dietary vitamin K does not appear to be a suitable way to improve control. It makes more sense to keep eating habits stable and avoid large swings. So if you significantly change your diet — for example with a new diet or a supplement containing vitamin K — tell your doctor beforehand. This review only covers vitamin K antagonists. Your pharmacy can explain what applies to your specific anticoagulant.

How do caffeine and quitting smoking affect the breakdown of medications?

Both involve the same enzyme, CYP1A2. In one study, the antidepressant fluvoxamine extended the half-life of caffeine from 4.9 to 56 hours. Conversely, when heavy smokers quit, the activity of this enzyme dropped and caffeine breakdown slowed by 36 percent. Some medications can then reach higher levels in the blood.

In 2005, Culm-Merdek and colleagues from Boston gave seven healthy volunteers fluvoxamine or a placebo for two days, together with a single dose of caffeine. With fluvoxamine, the body broke down caffeine so much more slowly that the half-life rose from 4.9 to 56 hours. The caffeine did not make people feel more alert. However, the researchers did not rule out that caffeine could build up in the body with daily coffee intake and trigger side effects.

Cigarette smoke works in the opposite direction: it drives CYP1A2 activity up. In 2004, Faber and Fuhr from Cologne studied twelve people who smoked 20 or more cigarettes a day and then stopped from one day to the next. Enzyme activity, measured by caffeine breakdown, fell by 36.1 percent — half of this decline was already reached after about 39 hours. Medications broken down by this enzyme, such as theophylline for respiratory conditions or the psychiatric drug clozapine, can then reach higher levels in the blood.

Quitting smoking is one of the best decisions you can make for your health. If you take medications, tell your doctor that you are quitting — ideally before you do. Only they can decide whether one of your medications needs to be adjusted or your levels monitored. Do not change the dose yourself.

How do you find out whether a supplement is compatible with your medications?

Ask at the pharmacy before starting any new product, including herbal preparations and dietary supplements. In Switzerland, the pharmacy team checks every prescription for interactions as part of the so-called Medikamenten-Check. For this to work, the pharmacy needs to know everything else you are taking. A complete list is therefore your best protection.

According to the Swiss Pharmacists Association pharmaSuisse, during the Medikamenten-Check two members of the pharmacy team review the prescription for risks, contraindications, dosing, and possible interactions, and consult the prescribing doctor if needed. During the so-called Bezugs-Check, the pharmacy creates a dossier so it can detect incompatibilities even if you are being treated by several different doctors.

Such a check can only find what it knows about. Supplements ordered online, teas from a drugstore, or products from abroad do not appear in any pharmacy system. So bring a list to your next visit that includes everything: prescription medications, over-the-counter products, herbal preparations, and dietary supplements.

Good questions to ask with any new product are: Does it interact with what I am already taking? Do I need to take it at a certain time apart from specific foods or drinks? And what should I do if I notice something unusual? You can read about what a complete list looks like and which checks are available in Germany, Austria, and Switzerland in the article on multiple medications.

Multiple medications and the medication plan

How the YUTHI app helps you

When you enter medications in the YUTHI app, your Coach knows about them and can point out possible interactions. But he is not allowed to evaluate them. The app therefore checks each of his responses itself: if he assesses an interaction or advises leaving out a medication, the response is corrected. If he mentions a supplement without referring you to a doctor, the reminder is added.

Some well-documented connections from this article are shown directly in the app's sections. If L-thyroxine is on your list and you log coffee, the Drinking section reminds you of the Benvenga study. If you take fluvoxamine and drink caffeinated beverages, it points out the slower caffeine breakdown. And if you have set your quit date in the Smoking cessation section, the app advises you to let your doctor know. Every note cites its source, and you receive at most one per section per day.

The Compatibility page explains what is documented about St. John's wort, with the clear statement that YUTHI does not check whether your medications are compatible with each other. That is in the hands of your pharmacy, doctor, or specialist. So you can show them everything, your medications and your supplements are all in one place, and for your next appointment you can generate a report as a PDF.

And what about you — does your pharmacy actually know what's sitting in your bathroom cabinet next to your prescription tablets?

YUTHI app

Frequently asked questions

How long before or after taking medication can I eat grapefruit?

No safe time window can be given as a general rule. According to Bailey and colleagues, the interaction can occur even if grapefruit was eaten many hours before the medication, because the enzyme is permanently inhibited. Whether your medication is affected, ask at the pharmacy.

Are herbal products safer when it comes to interactions?

No. St. John's wort is a herbal product and is one of the most thoroughly studied triggers of drug interactions. It can lower the levels of anticoagulants, transplant medications, cholesterol-lowering drugs, and the contraceptive pill.

Can I take magnesium or zinc alongside my medications?

It depends on your medications. Minerals can bind certain active substances in the gut, as the studies on calcium and iron with thyroid hormone show. So ask at the pharmacy before you start, whether you can take them and if so, how much time to leave in between.

Does the grapefruit warning also apply to regular oranges?

According to Bailey and colleagues, bitter oranges, limes, and pomelos contain the same compounds as grapefruit. Sweet oranges are not mentioned in this list. If in doubt, ask at the pharmacy.

As a smoker, do I need to think about my medications when I quit?

Yes. After quitting, the body breaks down some medications more slowly and their levels can rise. Tell your doctor in advance, if possible, that you are quitting, and do not change the dose yourself.

How do I find out whether a food interacts with my medication?

A good first step is the package insert, in the section on taking the medication together with food and drinks. For reliable advice specific to your situation, ask your pharmacy, doctor, or specialist.

Sources

• Qato DM, Wilder J, Schumm LP, et al. Changes in Prescription and Over-the-Counter Medication and Dietary Supplement Use Among Older Adults in the United States, 2005 vs 2011. JAMA Intern Med. 2016;176(4):473–482.
• Bailey DG, Dresser G, Arnold JMO. Grapefruit–medication interactions: forbidden fruit or avoidable consequences? CMAJ. 2013;185(4):309–316.
• Western University, Schulich School of Medicine & Dentistry. Grapefruit-medication interactions increasing. Press release, 26 November 2012.
• Nicolussi S, Drewe J, Butterweck V, Meyer zu Schwabedissen HE. Clinical relevance of St. John's wort drug interactions revisited. Br J Pharmacol. 2020;177(6):1212–1226.
• Hall SD, Wang Z, Huang SM, et al. The interaction between St John's wort and an oral contraceptive. Clin Pharmacol Ther. 2003;74(6):525–535.
• Singh N, Singh PN, Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. JAMA. 2000;283(21):2822–2825.
• Campbell NR, Hasinoff BB, Stalts H, et al. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Ann Intern Med. 1992;117(12):1010–1013.
• Benvenga S, Bartolone L, Pappalardo MA, et al. Altered intestinal absorption of L-thyroxine caused by coffee. Thyroid. 2008;18(3):293–301.
• Neuvonen PJ, Kivistö KT, Lehto P. Interference of dairy products with the absorption of ciprofloxacin. Clin Pharmacol Ther. 1991;50(5 Pt 1):498–502.
• Violi F, Lip GY, Pignatelli P, Pastori D. Interaction Between Dietary Vitamin K Intake and Anticoagulation by Vitamin K Antagonists: Is It Really True? A Systematic Review. Medicine (Baltimore). 2016;95(10):e2895.
• Culm-Merdek KE, von Moltke LL, Harmatz JS, Greenblatt DJ. Fluvoxamine impairs single-dose caffeine clearance without altering caffeine pharmacodynamics. Br J Clin Pharmacol. 2005;60(5):486–493.
• Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther. 2004;76(2):178–184.
• pharmaSuisse. Checks für Ihre Sicherheit: Medikamenten-Check, Bezugs-Check. Patient leaflet, May 2018.