Melatonin : Interactions

by MedlinePlus

(Page 6 of 6)

Interactions with Drugs

Fluvoxamine and other P450 1A2 drugs: Melatonin is broken down (metabolized) in the body by the liver enzyme cytochrome P450 1A2 (with a small contribution from P450 2C19). As a result, drugs that alter the activity of these enzymes may increase or decrease the effects of melatonin supplements. For example, the drug fluvoxamine, when given with melatonin, reduces the activity of P450 1A2, thereby increasing blood levels of melatonin and theoretically increasing the effects or side effects of melatonin. Other drugs that may increase melatonin levels (by inhibiting P450 1A2) include: amiodarone, anastrozole, cimetidine, ciprofloxacin, citalopram, clarithromycin, diethyl-dithiocarbamate, diltiazem, enoxacin, erythromycin, ethinyl estradiol, fluoroquinolones, fluoxetine (high dose), furafylline, interferon, isoniazid, ketoconazole, levofloxacin, methoxsalen, mexiletine, mibefradil, norfloxacin, paroxetine (high dose), ritonavir, sertraline (mild), tacrine, tricyclic antidepressants (tertiary), ticlodipine, and zileuton. There is a case of psychotic symptoms in a patient taking both melatonin and the antidepressant drug fluoxetine, which may be due to this interaction. Drugs that may reduce melatonin levels (by inducing P450 1A2) include: carbamazepine, insulin, 3-methyl cholanthrene, modafinil, nafcillin, nicotine, omeprazole, phenobarbital, phenytoin, primidone, rifampin, ritonavir.

Zolpidem and other sedative drugs: Increased daytime drowsiness is reported when melatonin is used at the same time as the prescription sleep-aid zolpidem (Ambien®), although it is not clear that effects are greater than with the use of zolpidem alone. In theory, based on possible risk of daytime sleepiness, melatonin may increase the amount of drowsiness caused by some other drugs, for example benzodiazepines such as lorazepam (Ativan®) or diazepam (Valium®), barbiturates such as phenobarbital, narcotics such as codeine, some antidepressants, and alcohol. Caution is advised while driving or operating machinery.

Warfarin and other blood-thinners: Based on preliminary evidence, melatonin should be avoided in patients taking the blood-thinning medication warfarin (Coumadin®), and possibly in patients using other blood-thinners (anticoagulants) such as aspirin or heparin. There are at least six reported cases of alterations in prothrombin time (a measurement of blood clotting ability) in patients taking both melatonin and warfarin. These cases have noted decreases in prothrombin time (PT), which would tend to decrease the effects of warfarin and increase the risk of blood clots. However, blood clots have not been noted in these patients. Rather, minor bleeding was noted in two of these cases (nosebleed and internal eye bleed), which may have been due to the blood-thinning effects of warfarin alone without a relationship to use of melatonin, or possibly to an interaction between melatonin and warfarin.

Natural melatonin levels: Multiple drugs are reported to lower natural levels of melatonin in the body. It is not clear that there are any health hazards of lowered melatonin levels, or if replacing melatonin with supplements is beneficial. Examples of drugs that may reduce production or secretion of melatonin include non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®); beta-blocker blood pressure medications such as atenolol (Tenormin®) or metoprolol (Lopressor®, Toprol®); and medications that reduce levels of vitamin B6 in the body (such as oral contraceptives, hormone replacement therapy, loop diuretics, hydralazine, theophylline). Other agents that may alter synthesis or release of melatonin include diazepam, vitamin B12, verapamil, temazepam, and somatostatin.

Anti-seizure drugs: Based on preliminary evidence, melatonin should be avoided in patients taking anti-seizure medications. It has been suggested that melatonin may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders, as reported in 4 out of 6 children in one study, and in an adult in whom symptoms recurred when melatonin was given a second time. However, multiple other studies actually report reduced incidence of seizure with regular melatonin use. This remains an area of controversy. Patients with seizure disorder taking melatonin should be monitored closely by a healthcare professional.

Blood pressure medications (antihypertensives): Melatonin may cause drops in blood pressure, as observed in animals and in preliminary human research. It is not known if melatonin causes further drops in blood pressure when taken with antihypertensive drugs. In animals, melatonin reduces the effects of the alpha-blocker drugs clonidine and methoxamine. In contrast, in humans, blood pressure increases have been observed when melatonin 5 milligrams is taken at the same time as the calcium-channel blocker nifedipine.

Diabetes medications : Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) and low doses of melatonin have reduced glucose tolerance and insulin sensitivity. Caution is advised in patients taking drugs for diabetes by mouth or insulin. Serum glucose levels may need to be monitored by a healthcare provider, and medication adjustments may be necessary.

Caffeine: It is not clear if caffeine alters the effects of melatonin supplements in humans. Caffeine is reported to raise natural melatonin levels in the body, possibly due to effects on the liver enzyme cytochrome P450 1A2. However, caffeine may also alter circadian rhythms in the body, with effects on melatonin secretion.

Succinylcholine: Based on laboratory study, melatonin may increase the neuromuscular blocking effect of the muscle relaxant succinylcholine, but not vecuronium.

Methamphetamine: Based on animal research, melatonin may increase the adverse effects of methamphetamine on the nervous system.

Haloperidol (Haldol®)(positive interaction): Preliminary reports suggest that melatonin may aid in reversing symptoms of tardive dyskinesia associated with haloperidol use.

Isoniazid (positive interaction): Based on preliminary evidence, melatonin may increase the effects of isoniazid against Mycobacterium tuberculosis.

Ethanol (alcohol): Alcohol consumption seems to affect nocturnal melatonin secretion

Interactions with Herbs and Dietary Supplements

Sedative herbs: Melatonin may increase daytime sleepiness or sedation when taken with herbs or supplements that may cause sedation. Examples of such agents include 5-HTP, ashwagandha root, calamus, calendula, California poppy, capsicum, celery, cough elecampane, German chamomile, goldenseal, hops, kava, lemon balm, sage, sassafras, shepherd's purse, Siberian ginseng, skullcap, stinging nettle, valerian, wild carrot, wild lettuce, and yerba manse.

Herbs that affect blood sugar: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) and low doses of melatonin have reduced glucose tolerance and insulin sensitivity. Caution is advised when using herbs or supplements that may also raise blood sugar levels, such as arginine, cocoa, DHEA, and ephedra (when combined with caffeine).

Blood-thinning herbs/supplements: Based on preliminary evidence of an interaction with the blood thinning drug warfarin, and isolated reports of minor bleeding, melatonin may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding. Multiple cases of bleeding have been reported with the use of Ginkgo biloba , and fewer cases with garlic and saw palmetto. Numerous other agents may theoretically increase the risk of bleeding, although this has not been proven in most cases. Some examples include: alfalfa, American ginseng, angelica, anise, Arnica montana , asafetida, aspen bark, bilberry, birch, black cohosh, bladderwrack, bogbean, boldo, borage seed oil, bromelain, capsicum, cat's claw, celery, chamomile, chaparral, clove, coleus, cordyceps, danshen, devil's claw, dong quai, EPA (eicosapentaenoic acid, found in fish oils), evening primrose oil, fenugreek, feverfew, fish oil, flaxseed/flax powder (not a concern with flaxseed oil), ginger, grapefruit juice, grapeseed, green tea, guggul, gymnestra, horse chestnut, horseradish, licorice root, lovage root, male fern, meadowsweet, nordihydroguairetic acid (NDGA), omega-3 fatty acids, onion, papain, panax ginseng, parsley, passionflower, poplar, prickly Ash, propolis, quassia, red clover, reishi, Siberian ginseng, sweet clover, rue, sweet birch, sweet clover, turmeric , vitamin E, white willow, wild carrot, wild lettuce, willow, wintergreen, and yucca.

Chasteberry (Vitex agnus-castus): Chasteberry may increase natural secretion of melatonin in the body, based on preliminary research.

Folate: Severe folate deficiency may reduce the body's natural levels of melatonin, based on preliminary study.

DHEA (Dehydroepiandrosterone): In mice, DHEA and melatonin have been noted to stimulate immune function, with slight additive effects when used together. Effects of this combination in humans are not clear.

Echinacea purpurea : In mice, a combination of echinacea and melatonin has been noted to slow the maturation of some types of immune cells, which may reduce immune function. Effects of this combination in humans are not clear.

Caffeine: It is not clear if caffeine alters the effects of melatonin supplements in humans. Caffeine is reported to raise natural melatonin levels in the body, possibly due to effects on the liver enzyme cytochrome P450 1A2. However, caffeine may also alter circadian rhythms in the body, with effects on melatonin secretion.

Other Interactions

It has been theorized that chronic exposure to magnetic fields or recurrent cellular telephone use may alter melatonin levels and circadian rhythms. However, several studies suggest that this is not the case.

Body Mass Index (BMI) and gender seem to affect nocturnal melatonin secretion. Also, nocturnal production of melatonin is reduced in autism.

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