Can you take melatonin with a beta blocker? Dose, timing, interactions

A randomised trial tested melatonin in patients on beta blockers without recording any side effects, but the combination has never been studied on a large scale. The summary of product characteristics for Circadin, a melatonin-based medicine, notes that adrenergic antagonists, which include beta blockers, alter the natural secretion of melatonin, and states that no study has checked whether they interfere with melatonin taken as a tablet¹. For people on medication, the French Agency for Food, Environmental and Occupational Health & Safety (Anses) recommends not taking a melatonin supplement without a doctor’s advice².

This trial was conducted in Boston and published in 2012. It included 16 hypertensive patients aged 45 to 64, 9 of them women, who had been treated with atenolol or metoprolol for at least six months. Sleep problems were not among the inclusion criteria. After an initial laboratory assessment, the patients took every evening for three weeks 2.5 mg of melatonin or a placebo, an hour before bed. In the 15 patients analysed, melatonin lengthened total sleep time by 36 minutes compared with placebo, improved sleep efficiency by 7.6% and shortened sleep onset latency, measured by polysomnography, by 14 minutes. The patients did not, however, rate their sleep as better in the questionnaire completed on waking³.

A questionnaire covering around fifteen common symptoms recorded no side effects, and stopping melatonin caused no rebound effect. On the night after stopping, sleep onset latency was even 25 minutes shorter. The authors themselves highlight two limitations: the sample is small, and the trial cannot show whether the benefit is due to the fall in melatonin caused by the beta blocker, since their earlier work showed a comparable effect in hypertensive patients not taking beta blockers³.

Trials in people on beta blockers used 2.5 to 5 mg of melatonin, taken in the evening. In Europe, the authorised claim for food supplements is based on 1 mg taken close to bedtime, and Anses recommends not exceeding 2 mg a day, as certain risks have been identified at high doses⁴².

In the Boston trial, the dose was 2.5 mg an hour before bed³. An Australian study in young volunteers on atenolol used 3 mg, then 5 mg in total, in a single night⁵. All these doses exceed the ceiling of 2 mg a day that Anses recommends not crossing with a food supplement². Regulation (EU) No 432/2012 allows the claim that melatonin contributes to the reduction of time taken to fall asleep, provided the product supplies 1 mg per serving and the consumer is informed that the beneficial effect is obtained by taking 1 mg close to bedtime. A second claim, on jet lag, is based on at least 0.5 mg⁴.

Circadin, authorised at European level, contains 2 mg in prolonged-release form. It is taken once a day, one to two hours before bedtime and after food, as short-term treatment of insomnia in people aged 55 and over, for up to 13 weeks¹. In adults and children with primary sleep disorders, a meta-analysis of 19 trials (1,683 participants) found that, on average, melatonin shortened the time taken to fall asleep by 7 minutes and lengthened sleep by 8 minutes. The authors describe these effects as modest, and they were more marked in trials with higher doses and longer duration⁶. In the absence of sufficient long-term data, Anses recommends reserving melatonin food supplements for occasional use².

Some trials have measured a fall in night-time blood pressure with melatonin, others a rise in patients on another antihypertensive: the results vary with the form used and the current treatment.

In 16 men with untreated hypertension, 2.5 mg of melatonin taken an hour before bed for three weeks lowered blood pressure during sleep by 6 mmHg systolic and 4 mmHg diastolic, without changing heart rate. A single dose had no effect⁷. A meta-analysis of 7 trials (221 participants) found no overall effect, but a fall with prolonged-release forms (−6.1 mmHg systolic) and none with immediate-release forms⁸.

Conversely, in 47 patients well controlled on nifedipine, a calcium channel blocker, 5 mg of melatonin in the evening for four weeks raised blood pressure by 6.5 mmHg systolic and 4.9 mmHg diastolic, and heart rate by 3.9 beats per minute. The authors call for caution in people with hypertension⁹. Anses also notes that melatonin could, depending on the case, reduce or enhance the effect of antihypertensive drugs². None of the studies cited here reports blood pressure measurements specific to the combination with a beta blocker, and the question is worth raising with the doctor, who may suggest monitoring blood pressure when starting.

The best-documented interactions involve the liver, which clears melatonin via the enzyme CYP1A2, and medicines that act on alertness or on blood clotting.

The Circadin summary of product characteristics advises avoiding the combination with fluvoxamine, an antidepressant that increases exposure to melatonin seventeenfold. It calls for caution with cimetidine, quinolones and oestrogen-based treatments, including contraception, which raise blood melatonin levels, whereas carbamazepine, rifampicin and smoking lower them. Alcohol reduces its effectiveness on sleep, and melatonin can enhance the sedative effect of sleeping pills such as zolpidem or zopiclone¹.

Anses adds that melatonin can alter blood levels of drugs cleared by certain liver enzymes (CYP1A1, CYP1A2, CYP1B1, and possibly CYP2C19), and that it slows platelet aggregation and could enhance the effect of aspirin or of anticoagulants such as warfarin, treatments often combined with a beta blocker². The agency also recommends choosing simple formulations, which do not combine melatonin with other ingredients, and avoiding taking several food supplements at the same time, to limit the risk of interactions². Before taking anything, the doctor or pharmacist needs to know the full list of treatments, supplements included.

In Europe, melatonin exists both as a medicine and as an ingredient in food supplements, and its use as a supplement is subject to specific recommendations in France.

Circadin, the 2 mg prolonged-release medicine, holds a European authorisation for insomnia in people aged 55 and over¹. As a food supplement, the only authorised claims concern the time taken to fall asleep, at 1 mg close to bedtime, and jet lag⁴. Permitted doses vary from country to country: according to the survey published by Anses in 2018, melatonin was banned in supplements in Denmark and the Czech Republic, considered a medicine from 0.3 mg a day in Belgium and Germany, allowed up to 1 mg a day in Spain and Italy, and below 2 mg a day in France².

In 2018, Anses analysed 90 reports of adverse effects received through its nutrivigilance scheme between 2009 and May 2017. It advises against melatonin supplements for pregnant or breastfeeding women, children and adolescents, people with inflammatory or autoimmune diseases, and before any activity requiring sustained alertness. It makes them subject to medical advice for people with epilepsy, asthma, or mood, behavioural or personality disorders. Finally, the agency notes that few data exist on the safety of doses below 2 mg, that pharmacological activity cannot be ruled out at these doses, and calls for a harmonised regulatory framework at European level².

Fatigue is among the common side effects of beta blockers, especially at the start of treatment, but the excess fatigue attributed to them in placebo-controlled trials remains small.

A meta-analysis of 15 randomised trials, with more than 35,000 participants, measured an excess of 18 reports of fatigue per 1,000 patients treated per year (95% confidence interval: 5 to 30), that is one extra report for every 57 patients treated for a year. The risk was higher with first-generation beta blockers than with newer ones, and it did not vary with the molecule’s fat solubility¹⁰. The bisoprolol leaflet lists fatigue among common effects and states that it occurs mainly at the start of treatment and usually disappears within one to two weeks¹¹.

The EU regulation allows the statement that magnesium and vitamin B6 contribute to the reduction of tiredness and fatigue⁴. These claims apply to the general population and do not target the fatigue specific to beta blockers. Fatigue that persists beyond the first few weeks, or that comes with breathlessness, dizziness or a very slow pulse, should be reported to the doctor. Treatment is not stopped without medical advice: the leaflet points out that a beta blocker must not be stopped abruptly and that its dose is reduced gradually¹¹.