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Migraines and Headaches


Migraines have a solid correlation to altered gut microbiota involving amines and indoles. Depleted gut melatonin may be involved in migraine occurrence because of the relative increase in N-acetylserotonin to melatonin ratios, resulting in hyperactive glutamatergic excitatory transmission in migraines. Migraines can also be correlated with many autoimmune disorders tied to melatonin regulation failure. These conditions include Hashimoto’s thyroiditis with associated hypothyroidism, rheumatic diseases, and antiphospholipid syndrome (1). Ultimately, the gut microbiota may influence CNS function and, over time, could cause neurological diseases, including Alzheimer’s disease, mood and anxiety disorders, multiple sclerosis (MS), Parkinson’s disease, and migraines.


Migraine headaches are comorbid with several health conditions, including neurological, psychiatric, cardiovascular, cerebrovascular, GI, metaboloendocrine, and immunological disorders. It is suspected that the gut-brain axis is a network of complex interactions between the nervous and GI systems with significant contributions from intestinal microbiota. Many neurological disorders feature elements of the kynurenine pathway of tryptophan, specifically the dysregulation of tryptophan metabolism and subsequent melatonin production (1).


A randomized, multi-center, parallel-group design was conducted in which melatonin was compared with amitriptyline and placebo for twelve weeks. A 3 mg dose of melatonin reduced migraine frequency, demonstrating the same effectiveness as amitriptyline in the primary endpoint of the frequency of migraine headaches per month (1). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency, and melatonin was better tolerated than amitriptyline. It has also been reported as an effective treatment for primary headache disorders (1).


An additional surveillance study observed sixty-one patients diagnosed with chronic tension headaches (2,3). Patients were given 3 mg of melatonin for thirty days following a baseline period and followed up after sixty days. Quality scores were obtained using VAS pain intensity, Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D) at the study’s inception, post-thirty days of treatment, and post-sixty days of treatments. Overall, significant decreases in pain and tension headache-associated symptoms were observed after melatonin use. Sleep quality was also significantly improved during and after the study (2,3).


Authors: Deanna Minich, Ph.D., Melanie Henning, ND, Catherine Darley, ND, Mona Fahoum, ND, Corey B. Schuler, DC, James Frame

Reviewer: Peer-review in Nutrients Journal

Last updated: September 22, 2022



1. Gonçalves AL, Ferreira AM, Ribeiro RT, Zukerman E, Cipolla-Neto J, Peres MFP. Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry. 2016;87(10).

2. Gelfand AA, Goadsby PJ. The Role of Melatonin in the Treatment of Primary Headache Disorders. Vol. 56, Headache. 2016.

3. Danilov AB, Danilov AB, Kurushina O v., Shestel EA, Zhivolupov SA, Latysheva N v. Safety and Efficacy of Melatonin in Chronic Tension-Type Headache: A Post-Marketing Real-World Surveillance Program. Pain Ther. 2020;9(2).

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