Herb-Drug Interactions: Melatonin

2011

Contents

N-(2-(5-Methoxyindol-3-yl)ethyl)acetamide

Types, sources and related compounds

N- Acetyl-5-methoxytryptamine.

Use and indications

Melatonin is a hormone that is produced in the pineal gland of the brain and influences the circadian rhythm. Supplements are therefore principally used for treating sleep disturbances and disorders such as jet lag, insomnia, sleep walking, and shift-work sleep disorder. It is also believed to have anticancer and antihypertensive properties, and has been used to treat cluster headaches. Melatonin has also been detected in a large number of plant species, including those used as foods. Concentrations detected have been very variable, the reasons for which are currently uncertain. In addition, the importance of dietary melatonin is unclear.

Pharmacokinetics

When an oral melatonin supplement 3mg was given to 17 healthy subjects the AUC and maximum serum levels of melatonin were about 18-fold and 100-fold greater, respectively, than overnight endogenous melatonin secretion, although there was a wide variation between individuals.The oral bioavailability was approximately 15% after oral doses of 2 or 4mg, possibly due to significant first-pass metabolism. The half-life has been found to be about 1 hour.Melatonin has been found to be extensively metabolised by the cytochrome P450 isoenzymes CYP1A1 and CYP1A2 in vitro. This has been supported by in vivo studies, see fluvoxamine and caffeine. In vitro, melatonin had no inhibitory effect on CYP3A4, CYP2D6, CYP2C9 and CYP2C19 and a modest inhibitory effect on CYP1A2.3.4

Interactions overview

Fluvoxamine markedly increases melatonin levels and increases its effects (drowsiness). Similarly, combined oral contraceptives modestly increase melatonin levels, and other oestrogens are predicted to interact similarly. Other drugs that inhibit CYP1A2 are predicted to similarly interact with melatonin. These include some quinolone antibacterials such as ciprofloxacin, the oral psoralens and, to a lesser extent, cimetidine. Caffeine also modestly increases melatonin levels. Increased cognitive impairment or similar has been seen when melatonin was used with zolpidem, imipramine and thioridazine, and might be expected with any CNS depressant drug. Alcohol is expected to decrease the efficacy of melatonin on sleep. Tobacco smoking reduces melatonin levels, and carbamazepine might be expected to have the same effect, but melatonin had no effect on carbamazepine levels. A few cases of increased or decreased effects of warfarin have been noted, but the relevance of this is uncertain. Melatonin slightly increased mean 24-hour blood pressure when given to patients taking nifedipine.

Melatonin + Alcohol

Alcohol may reduce the effects of melatonin on sleep.

Evidence, mechanism, importance and management

The manufacturer briefly notes that alcohol reduces the effectiveness of melatonin on sleep, and that it should not be taken with melatonin. Given the known effects of alcohol on sleep, if melatonin is being taken to improve quality of sleep then this is sensible advice.

Melatonin + Benzodiazepines and related drugs

The CNS effects of benzodiazepines and related hypnotics, such as zolpidem, may be additive to those of melatonin.

Clinical evidence

In a well-controlled single-dose study in 16 healthy subjects aged 55 years and older, giving prolonged-release melatonin 2 mg with zolpidem 10 mg at bedtime enhanced the impairment of cognitive function seen with zolpidem alone at 1 hour and 4 hours post-dose, but not the next morning. Melatonin alone had no effect on cognitive function. No pharmacokinetic interaction was found.

Experimental evidence

In three experiments in hamsters and mice, melatonin at doses of 300 micrograms/kg, 20mg/kg and 50mg/kg given intraperitoneally was found to significantly reduce locomotor activity, increase pain thresholds when placed on hot plates and prolong the onset of seizures when convulsions were induced, respectively. The benzo-diazepine antagonist, flumazenil 5mg/kg, 10 mg/kg and 50mg/kg given intraperitoneally, respectively, reduced the activity of melatonin back to approximately normal levels.

Mechanism

The activity of melatonin is thought to involve similar interactions at the GABA (y-amninobutyric acid) receptors in the brain to benzodiazepines. It may therefore enhance the activity of benzodiazepines and related drugs. Flumazenil is a benzodiazepine antagonist and may have blocked the direct effect of the melatonin, thus causing the GABA activity to fall below the level required to have the effects seen in the experimental study.

Importance and management

The evidence available suggests that melatonin might enhance the sedative properties of benzodiazepines and related hypnotics such as zolpidem. Although in the study of zolpidem, the enhanced effect was not apparent the morning after dosing, it would be wise to be aware that increased drowsiness is a possibility if melatonin is also given, especially with longer-acting hypnotics.

Melatonin + Buspirone

For a case report describing anxiety, with episodes of over-sleeping and memory deficits in a woman taking fluoxetine and buspirone with St John’s wort, ginkgo and melatonin, see St John’s wort + Buspirone.

Melatonin + Caffeine

Caffeine may moderately raise melatonin levels.

Clinical evidence

A crossover study in 12 healthy subjects found that a single 200-mg dose of caffeine (equivalent to one large or two small cups of coffee), taken 1 hour before and 1 and 3 hours after a single 6-mg oral dose of melatonin, increased the average AUC and maximum levels of melatonin by 120% and 137%, respectively, although the half-life of melatonin was not significantly affected. The interaction was less pronounced in smokers (6 subjects) than in non-smokers (6 subjects). In a similar study, taking caffeine 12 or 24 hours before melatonin did not affect the melatonin levels, although 2 subjects had raised melatonin levels when caffeine was taken 12 hours, but not 24 hours, before melatonin.

In 12 healthy subjects given a single 200-mg dose of caffeine, taken in the evening, endogenous, nocturnal melatonin levels were found to be increased, and the AUC of melatonin was increased by 32%.

Experimental evidence

No relevant data found.

Mechanism

Caffeine is thought to reduce the metabolism of melatonin by competing for metabolism by the cytochrome P450 isoenzyme CYP1A2.

Importance and management

It appears that caffeine significantly increases the levels of single doses of supplementary melatonin; however, the long-term effects of caffeine and concurrent multiple dosing of melatonin do not appear to have been studied. Melatonin can cause drowsiness when taken on its own, so patients who take melatonin should be advised that this effect may be increased (because of increased melatonin levels) if they also take caffeine, including that from beverages. This increased drowsiness may oppose the stimulating effect of caffeine, or alternatively caffeine may diminish the sedating effects of melatonin; the outcome of concurrent use does not appear to have been studied.

Melatonin + Carbamazepine

Carbamazepine levels are not affected by melatonin. Melatonin levels are predicted to be reduced by carbamazepine.

Evidence, mechanism, importance and management

In a placebo-controlled study on the effects of melatonin on antioxidant enzymes, melatonin 6 to 9mg/kg daily for 14 days was given to children with epilepsy taking carbamazepine monotherapy Serum levels of carbamazepine and its metabolite carbamazepine-10,11-epoxide were not affected by melatonin. Melatonin appeared to antagonise the accumulation of reactive oxygen species caused by carbamazepine.

One manufacturer predicts that carbamazepine may increase the metabolism of melatonin (by induction of the cytochrome P450 isoenzyme CYP1A2), decreasing its levels (magnitude unknown). However, note that carbamazepine is not a particularly potent inducer of this isoenzyme.

It appears that carbamazepine dose adjustments are unlikely to be needed when melatonin is taken. Nevertheless, be aware that melatonin may be less effective.

Melatonin + Cimetidine

Cimetidine slightly increases melatonin levels.

Evidence, mechanism, importance and management

In a single-dose controlled study, cimetidine 800 mg increased the plasma concentration of melatonin after a 2-mg oral dose (magnitude not stated), whereas the plasma levels of cimetidine were unaffected. The pharmacodynamics of melatonin were not affected. Cimetidine is a weak inhibitor of the cytochrome P450 isoenzyme CYP1A2 by which melatonin is principally metabolised. The pharmacokinetic interaction would be unlikely to be clinically relevant. Nevertheless, the manufacturer recommends caution. Be aware of a possible interaction if there is an increase in adverse effects of melatonin (e.g. irritability, dry mouth, dizziness) on concurrent use. Other H2-receptor antagonists are unlikely to interact as they are not known to have enzyme-inhibiting effects.
Melatonin + Food

No interactions found, but caffeine-containing beverages might increase melatonin levels, see Melatonin + Caffeine.

Melatonin + Herbal medicines

No interactions found, but note that caffeine from caffeine-containing herbs might increase melatonin levels, see Melatonin + Caffeine.

Melatonin + Imipramine

The concurrent use of imipramine and melatonin may lead to increased CNS effects.

Evidence, mechanism, importance and management

In a single-dose controlled study, there was no pharmacokinetic interaction between melatonin 2mg and imipramine 75 mg. However, there was a possible pharmacodynamic interaction, with increased feelings of tranquillity and difficulty in performing tasks (undefined) when compared with imipramine alone. Patients should be warned of a possible additive effect.

Melatonin + Nifedipine

Melatonin may have some modest effects on blood pressure in patients taking nifedipine.

Clinical evidence

Forty-seven subjects with mild-to-moderate hypertension well controlled on nifedipine GITS 30 mg or 60 mg daily for the past 3 months were given melatonin immediate-release capsules 5mg each evening for 4 weeks. At the end of the 4 weeks, there was a modest increase in mean 24-hour systolic and diastolic blood pressure of 6.5mmHg and 4.9mmHg, respectively, and an increase in heart rate of 3.9 bpm. However, there was no difference in single-time point ‘clinic’ blood pressure (136/85 mmHg versus 138/87 mmHg) and heart rate. While taking melatonin, there was a greater incidence of drowsiness, during the morning, and weakness. One subject dropped out of the study complaining of marked weakness.

Experimental evidence

No relevant data found.

Mechanism

Unknown. Melatonin has been reported to possess blood pressure-lowering properties when used alone and was expected to have additive effects to nifedipine.

Importance and management

Chronic use of melatonin appears to modestly impair the hypotensive effects of nifedipine and increase the blood pressure and heart rates of patients. However, this was only detected on 24-hour blood pressure monitoring, and was not apparent with single measures of blood pressure at the clinic. Therefore, the clinical relevance of the effect is probably minor. The mechanism is not clear and, until more is known, bear in mind the possibility of an interaction if patients taking calcium-channel blockers have increased blood pressure while also taking melatonin supplements.

Melatonin + Oestrogens

Oestrogens, from combined hormonal contraceptives, appear to increase melatonin levels.

Clinical evidence

In a clinical study, the AUC and maximum level of a single 6-mg dose of melatonin was about 4 times higher in subjects taking a combined oral contraceptive than those not. Melatonin alone did not significantly affect alertness in this study, and no reduced alertness was noted in those taking oral contraceptives. Oral contraceptives being used by the women included ethinylestradiol with cyproterone acetate, desogestrel, drospirenone or gestodene. There did not appear to be any obvious differences between these contraceptives, but the numbers of women taking each were too small for this to be conclusive.

Experimental evidence

No relevant data found.

Mechanism

Ethinylestradiol is a moderate inhibitor of the cytochrome P450 isoenzyme CYP1A2, by which melatonin is principally metabolised.

Importance and management

Women taking combined oral contraceptives may have higher levels of melatonin after using supplements. Although in the study cited this did not decrease alertness, it would be prudent to bear in mind the possibility of increased drowsiness. One UK manufacturer extends this caution to hormone replacement therapy, although it is unclear whether the oestrogens used for HRT will have the same effect as ethinylestradiol.

Melatonin + Propofol

Melatonin slightly reduces the dose of propofol needed for the induction of anaesthesia.

Clinical evidence

A study in 45 adult patients found that the induction dose of intravenous propofol, as measured by bispectral index and loss of eyelash reflex, was 15% lower in patients who had received a single 3- or 5-mg oral dose of melatonin 100 minutes preoperatively, compared with patients who had received placebo. The time to recover from the anaesthetic was not affected by premedication with melatonin. Propofol was given in an incremental dose fashion in this study so that any difference could be assessed, but is usually given as a bolus dose.

Experimental evidence

No relevant data found.

Mechanism

Melatonin appears to have anxiolytic and sedative effects, which might reduce the required induction dose of propofol.

Importance and management

This study was conducted to assess the clinical value of using melatonin premedication, which is not an established use. The reduction in required dose of propofol was small and, on the basis of these data, it is unlikely that any untoward effects would be seen in the situation where a patient who had recently taken a melatonin supplement was anaesthetised with propofol.

Melatonin + Psoralens

Psoralens are predicted to increase melatonin levels.

Evidence, mechanism, importance and management

The manufacturer briefly notes that methoxsalen and 5-methoxypsoralen inhibit the metabolism of melatonin and increase its levels (magnitude not stated). Note that 5-methoxypsoralen has been shown to increase endogenous melatonin levels (one study is cited as an example).

Psoralens are potent inhibitors of the cytochrome P450 isoenzyme

CYP1A2 by which melatonin is principally metabolised, and the manufacturer recommends caution on concurrent use, which seems prudent as the adverse effects of melatonin may be increased. Any interaction would apply only to these psoralens used orally, and not when they are used topically. Be aware of a possible interaction if there is an increase in adverse effects of melatonin (e.g. irritability, dry mouth, dizziness) in patients also taking psoralens.

Melatonin + SSRIs

Fluvoxamine raises melatonin levels. Limited evidence suggests that citalopram does not affect melatonin levels, and no effect would be expected with other SSRIs.

Clinical evidence

(a) Citalopram

In a study in 7 healthy subjects, citalopram 40 mg had no effect on the levels of endogenous melatonin or its excretion from the body. Extrapolating these findings to an instance where melatonin is given exogenously as a supplement is difficult, but they suggest that citalopram does not inhibit melatonin metabolism.

(b) Fluvoxamine

In a study in 5 healthy subjects, a single 50-mg dose of fluvoxamine taken 3 hours before a single 5-mg oral dose of melatonin markedly increased the AUC and maximum levels of melatonin by 17-fold and 12-fold respectively, although the half-life of melatonin was not significantly affected. The interaction was more pronounced in the one subject who was of a CYP2D6-poor metaboliser phenotype (meaning that this patient was lacking or deficient in this isoenzyme). All subjects reported marked drowsiness after melatonin intake, and this was even more pronounced after fluvoxamine was also given.

Similarly, fluvoxamine 75 mg raised the levels of oral melatonin 5mg by about 20-fold and significantly improved the sleep behaviour of a 51-year-old insomniac.

In another study in 7 healthy subjexcts, fluvoxamine 50 mg doubled the maximum serum levels and excretion of endogenous melatonin and increased the AUC by about threefold.

Experimental evidence

No relevant data found.

Mechanism

Fluvoxamine is a potent inhibitor of the cytochrome P450 isoenzyme CYP1A2, which is the principal isoenzyme involved in the metabolism of melatonin.

Importance and management

Fluvoxamine markedly increases the bioavailability of endogenous melatonin and melatonin given as a supplement. However, the long-term effects of fluvoxamine and concurrent multiple dosing of melatonin do not appear to have been studied. Be aware that excessive drowsiness and related adverse effects may occur on concurrent use. Note that one UK manufacturer advises that the combination should be avoided. Other inhibitors of CYP1A2 may interact similarly (although to a lesser extent as fluvoxamine is currently the most potent CYP1A2 inhibitor in clinical use). The UK manufacturer specifically mentions the quinolones. Of the quino-lones in common usage, ciprofloxacin is an example of a clinically important CYP1A2 inhibitor.

Note that this effect would not be expected with other SSRIs, as these are not CYP1A2 inhibitors, and the study looking at the effects of citalopram on endogenous melatonin somewhat supports this suggestion.

For a case report describing anxiety, with episodes of oversleeping and memory deficits in a woman taking fluoxetine and buspirone with St John’s wort, ginkgo and melatonin, see St John’s wort + Buspirone.

Melatonin + Thioridazine

The concurrent use of thioridazine and melatonin may lead to increased CNS effects.

Evidence, mechanism, importance and management

In a single-dose controlled study, there was no pharmacokinetic interaction between thioridazine 50 mg and melatonin 2 mg. However, there was a possible pharmacodynamic interaction, with increased feelings of ‘muzzy-headedness’ when compared with thioridazine alone. Patients should be warned of a possible additive effect.

Melatonin + Tobacco

Tobacco smoking reduces melatonin levels.

Evidence, mechanism, importance and management

In a study in 8 tobacco smokers, the AUC of a single 25-mg dose of melatonin was almost threefold higher when the melatonin was taken after 7 days of smoking abstinence than when taken while smoking.

Constituents of tobacco smoke are minor to moderate inducers of the cytochrome P450 isoenzyme CYP1A2, by which melatonin is principally metabolised.

The finding of this study suggests that melatonin might not be as effective in smokers. Be aware of this possibility, and consider trying an increased melatonin dose if it is not effective in a smoker.

Melatonin + Warfarin

Case reports suggest that melatonin may raise or lower the INR in response to warfarin.

Clinical evidence

Six case reports of a suspected interaction between melatonin and warfarin have been documented by the WHO Uppsala Monitoring Centre, and have been briefly summarised in a review of melatonin.In three cases, the prothrombin time was increased, with bleeding events in two (nosebleed, eye haemorrhage, bruising) occurring up to 8 days after starting to take melatonin. The other three cases reports describe a prothrombin time decrease.

Experimental evidence

See Mechanism, below.

Mechanism

Unknown. Melatonin did not inhibit the cytochrome P450 isoenzyme CYP2C9 in vitro, and would not therefore be expected to alter warfarin metabolism via this mechanism.

Importance and management

These appear to be the only reports in the literature of a possible interaction between melatonin and warfarin. They are difficult to interpret, since they include both increased and decreased warfarin effects, and it is possible that they are just idiosyncratic cases. Because of these cases, a study designed to exclude a pharmacokinetic/pharmacodynamic interaction would be useful. Until more is known, bear these cases in mind in the event of an unexpected change in coagulation status in patients also taking melatonin supplements.