Melatonin Superior To Toxic Drug In Migraine Prevention Study

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A substance secreted by your own brain was found superior to a commonly prescribed toxic pharmaceutical at significantly reducing migraine headache frequency. 

At we have a special research section titled, “Superiority of Natural Substances versus Drugs,” which catalogs research from the National Library of Medicine ( that clearly demonstrates the superiority of foods, herbs, and even therapeutic interventions like acupuncture and yoga, versus conventional, drug-based interventions. Thus far, we have indexed compelling complementary and alternative medicine (CAM) solutions demonstrated to be superior to drugs for 175 ailments, and the research keeps coming in.

The newest addition to this special catalog of studies, which includes over 7,600 topics you can peruse on our newly re-designed Research Dashboard (.7 beta version), is a powerful new study published in the Journal of Neurology, Neurosurgery & Psychiatry, which compared melatonin, a hormone like substance first discovered in the pineal gland, to the commonly prescribed drug amitriptyline, for the prevention of migraine attacks.

Titled, "Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention,” the new study sought to investigate whether melatonin could provide an alternative to a commonly prescribed drug amitriptyline, which has an unfavorable side effect profile that limits its use.

The study pointed out that migraine disorder is a debilitating and chronic neurological condition that affects between 12-20% of the world’s population. Presently, about half of those who seek medical help for their migraines stop seeking care for their headaches, because of the side effects associated with conventional, drug-based treatment, which for amitriplyine run the gamut from physical to psychiatric disorders; some of which can be more debilitating than the migraines themselves, such as:

  • unusual thoughts or behavior;

  • a light-headed feeling, like you might pass out;

  • chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating;

  • pounding heartbeats or fluttering in your chest;

  • confusion, hallucinations;

  • a seizure (convulsions);

  • painful or difficult urination;

  • severe constipation;

  • easy bruising, unusual bleeding; or

  • sudden weakness or ill feeling, fever, chills, sore throat, mouth sores, red or swollen gums, trouble swallowing.

  • constipation, diarrhea;

  • nausea, vomiting, upset stomach;

  • mouth pain, unusual taste, black tongue;

  • appetite or weight changes;

  • urinating less than usual;

  • itching or rash;

  • breast swelling (in men or women); or

  • decreased sex drive, impotence, or difficulty having an orgasm.


The new study was conducted using a randomized, double-blind, placebo-controlled protocol, as follows:

Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups."

The results were summarized as follows:

Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users."

The authors concluded:  

Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg."


Amazingly, not only was melatonin found to be equipotent to the drug amitriptyline in reducing headache frequency, and at a much lower dose (3 mg versus 25 mg), but as stated above, “Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency.” This is all the more powerful when you consider that melatonin is a natural compound produced by the human body (pineal gland), and is perhaps several of orders of magnitude safer than the synthetic, xenobiotic chemical amitriptyline.

Considering that neuropsychiatric and physiological side effects commonly occur while on the drug, and that these “side effects” are the primary reason why those who are seeking help for their headaches end up discontinuing its use, melatonin appears to represent an ideal natural alternative.

Notably, the melatonin group experienced significant weight loss; an effect opposite to the weight-promoting effects commonly observed with amitriptyline. The study expanded on these findings:

Melatonin was more tolerable than amitriptyline and as tolerable as placebo. Weight loss was found in the melatonin group as opposed to a slight weight gain in placebo and a significant one in amitriptyline group. This is a very important and original finding that deserves special discussion. There is substantial experimental evidence in the literature indicating the role of melatonin in the control of food intake, energy balance and body weight. An inhibitory action of melatonin in preadipocytes differentiation into adipocytes, reducing the number of cells in the visceral adipose tissue has been demonstrated.15 Melatonin treatment reduced body weight gain, visceral adiposity, blood triglycerides and insulin resistance in a model of high-calorie diet-induced metabolic syndrome.16 Likewise, a single daily administration of melatonin decreased visceral fat in middle-aged mice,17 and after melatonin treatment aged rats showed weight reduction, preceded by an increase in insulin signalling in the central nervous system (CNS) and peripheral tissues.18 In addition, melatonin might have a direct anorexigenic action regulating hypothalamic pro-opiomelanocortin (POMC) gene expression.19 In ageing animals, melatonin and moderate exercise training induced a reduction in food intake associated with a reduction in body weight and amount of visceral adipose tissue depot.20 Melatonin should be considered as regulating the other side of energy balance increasing the energy expenditure by its ability to convert white adipose tissue into brown adipose tissue increasing its metabolic rate.21 The reduction in body weight of patients in the melatonin treated group is, to the best of our knowledge, the first demonstration of the putative effect of melatonin in body weight reduction in humans."

Lower levels of melatonin have been measured in those suffering from migraine attacks, which may explain why correcting this deficiency with supplemental melatonin may have an ameliorative effect. The study discussed additional possible mechanisms through which melatonin exerts its therapeutic effects:

Melatonin mechanism of action in migraine prevention could be due to one of its several effects, including: membrane stabilisation, anti-inflammatory properties, inhibition of dopamine release, modulation of serotonin, gamma amino butyric acid (GAMA) and glutamate neurotransmission, scavenging toxic-free radicals and cerebrovascular regulation.22

The study, however, cautions that melatonin could have contraindications in certain patients:

Melatonin also potentiates opioid analgesia; therefore, it should be used with caution in patients taking and/or overusing opioids.23 Patients with diabetes and hypertensive patients should be monitored since melatonin may decrease blood pressure24 and glucose levels.25

That said, melatonin is clearly safer than conventional drugs in its interaction/contradiction profiles, which the authors reiterate in the concluding remarks:

Owing to its favourable side effect profile and efficacy, melatonin could be an option for patients sensitive to other drugs or with a preference for natural products. With the same efficacy level compared with other treatments and a low cost, melatonin should be a cost-effective treatment.

They also point out the need for further research to clarify the correct doses and applications of melatonin for migraines and related conditions (comorbidities):

Different melatonin doses (lower and higher) should be studied, as well as its effect in other migraine types and comorbidities. The use of other chronobiotic agents, including melatonin analogues, could be tested in migraine prevention. Other trials in different populations and other latitudes should be conducted in the future.

For additional research both on the therapeutic properties of melatonin, and the wide range of factors involved in migraine attacks, and their resolution naturally, use our new research sections on the topic:






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