Migraine Prevention Study - Melatonin vs. Amitriptyline

Patient Expert
Medically Reviewed

In 2016, there was an interesting study about melatonin for migraine prevention.

The Study:

Study introduction: "Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use."

Study methods:

This was a randomized, double-blind, placebo-controlled trial. That means:

  • Participants were randomly assigned to the different study groups,
  • Neither the participants nor the researchers knew which group was getting which treatment group, and
  • The study was controlled by one group getting placebo rather than active medication.

A total of 438 patients were recruited and assessed for eligibility with 196 of them randomized into the study. Study participants were:

  • Male and female;
  • Aged 18 -65 years;
  • Had migraine with or without aura as defined by the International Headache Society's International Classification of Headache Disorders, 3rd edition (ICHD-3); and
  • Were experiencing two to eight migraine attacks per month when they enrolled in the study.

The study began with a four-week period to establish baseline measurements for the participants.

The opening four-week period was followed by a 12-week treatment period with patients randomized into one of three groups with the medications taken at bedtime:

  1. Placebo.
  2. 3 mg melatonin, or
  3. 25 mg amitriptyline.

The primary efficacy outcome measure was the number of migraine days per month, comparing the initial four-week baseline period with the final four weeks of treatment.

Secondary endpoints included:

  • Migraine intensity,
  • Length of migraine attacks,
  • Acute medication usage, and
  • Achieving greater than 50% reduction in migraine days.

Study results:

Mean migraine frequency reduction was

  • 2.7 migraine days in the melatonin group,
  • 2.2 migraine days in the amitriptyline group, and
  • 1.1 migraine days in the placebo group.

Melatonin significantly reduced migraine frequency compared with placebo, but not to amitriptyline.

Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50 percent reduction in migraine frequency.

Melatonin was better tolerated than amitriptyline.

Some patients in the melatonin group experienced weight losss.

A slight weight gain was experienced by some patients in the placebo group.

Significant weight gain was experienced by some patients in the amitriptyline group.

Study conclusions:

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

Summary and Implications for Patients:

Amitriptyline has long been prescribed for migraine prevention, but many patients have been unhappy with its side effects, especially weight gain. This study was well designed, but the sample size was small, with only 196 participants. With small studies such as this one, it's customary for larger studies to be conducted as well in order to replicate the results before the conclusions are fully accepted.

This small study indicates that melatonin may be a viable substitute for amitriptyline, but melatonin also has contraindications and potential side effects, and it's recommended for short-term use only, i.e., no longer than two months. Care must be exercised when choosing a melatonin supplement. Those that are lab-created are considered safer than those made from animal sources, which might contain contaminants. Patients considering taking melatonin should discuss it with their doctors first.


Gonçalves, Andre Leite' Ferreira, Adriana Martini; Ribero, Reinaldo Teixeira; Zukerman, Eliova; Cipolla-Neto, José; Peres, Mario Fernaando Prieto. "Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention (http://jnnp.bmj.com/content/early/2016/05/10/)." J Neurol Neurosurg Psychiatry. Published Online First. May 10, 2016.

Bauer, Brent A. MD. "Melatonin side effects: What are the risks?" The Mayo Clinic. November 11, 2014.

Answered by David Watson, MD