Mind your M’s: Migraine and Melatonin

Dr. Weeks’ Comment: Melatonin is far more than sleep aid.  It is a brain aid in that it protects as a powerful anti-oxidant but recent research is promising as regards support for people suffering from migraines. So read the research below and mind your M’s – for migraine, think melatonin!


Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial

Mohsen Ebrahimi-Monfared 1Mojtaba Sharafkhah 2Ali Abdolrazaghnejad 3Abolfazl Mohammadbeigi 4Fardin Faraji 1

Restor Neurol Neurosci. 2017;35(4):385-393. doi: 10.3233/RNN-160704.


Background: Melatonin is known to be effective in curing migraine.

Objective: This study aimed to investigate the therapeutic effect of melatonin versus sodium valproate in the prophylaxis of chronic migraine.

Methods: This randomized, double-blind, placebo-controlled clinical trial included patients with chronic migraine who were divided into three equal sized groups, and baseline therapy with nortriptyline (10-25 mg) and propranolol (20-40 mg) was used. Patients in groups A, B, and C were adjunctively treated daily with 3 mg melatonin, 200 mg sodium valproate, and a placebo, respectively. The patients underwent treatment for 2 months and follow-up was done at baseline (baseline), first (I) and second month (II). Attack frequency (AF), attack duration, attack severity, Migraine Disability Assessment (MIDAS) score (within 3 months in two steps), analgesic intake, and drug side effects between the groups and during follow-up were compared.

Results: The mean of monthly AF (melatonin: baseline: 4.2, I: 3.1, II: 2.5, p = 0.018; valproate: baseline: 4.3, I: 3.1, II: 2.3, p = 0.001; placebo: baseline: 4.1, I: 3.8, II: 3.8 p = 0.211), attack duration (hr) (melatonin: baseline: 19.8, I: 10.1, II: 8.7, p < 0.001; valproate: baseline: 19.5, I: 10.2, II: 8.8, p < 0.001; placebo: baseline: 19.6, I: 15.4, II: 14.1, p = 0.271), attack severity (melatonin: baseline: 7.3, I: 5.4, II: 3.5, p < 0.001; valproate: baseline: 7.4, I: 5.3, II: 3.4, p = 0.000; placebo: baseline: 7.3, I: 6.4, II: 6, p = 0.321), and MIDAS score (melatonin: baseline: 15.2, II: 8.9, p = 0.005; valproate: baseline: 16.1, II: 8.3, p = 0.001; placebo: baseline: 16, II: 12.1, p = 0.44), were significantly reduced in the melatonin and sodium valproate groups, but not in the placebo groups. Adverse events were reported in 11 patients (10.47%): 2 (5.71%) during melatonin treatment, 8 (22.85%) during valproate, and 1 (2.85%) during placebo.

Conclusion: The adjuvant treatment with melatonin was found to be superior to the placebo and had the same clinical efficacy as sodium valproate, but with higher tolerability. Melatonin may prove to be an efficient substitute for sodium valproate, as a chronic migraine prophylaxis.


Therapeutic role of melatonin in migraine prophylaxis: Is there a link between sleep and migraine?

Tae-Jin Song 1Byung-Su Kim 2Min Kyung Chu 3

Prog Brain Res. 2020;255:343-369.

doi: 10.1016/bs.pbr.2020.05.014. Epub 2020 Jun 10.



Melatonin is a ubiquitously distributed molecule that possesses diverse functions. Melatonin plays a key role in the endogenous circadian rhythms of humans via light stimulation in the hypothalamus. In addition, melatonin has roles in the opioid system, the nitric oxide pathway, free radical scavenging, inflammation, and antinociception. Melatonin is nontoxic and relatively safe. Recently, exogenous melatonin has been shown to have significant effects in the treatment of migraine. Further, it has demonstrated efficacy in the treatment of sleep disorders, including insomnia, circadian rhythm sleep-wake disorders, parasomnias, and sleep breathing disorders. Sleep disorders are commonly reported by those who experience migraine, and migraine and sleep disorders have been reported to be closely associated in cross-sectional studies. Longitudinal studies have shown that some sleep disorders and migraine show bidirectional comorbidities. Therefore, the identification and treatment of sleep disorders is important when treating migraine. Melatonin represents a promising treatment strategy for both disorders, especially when these conditions are combined.


Medicine (Baltimore). 2019 Jan;98(3):e14099.

doi: 10.1097/MD.0000000000014099.

Therapeutic role of melatonin in migraine prophylaxis: A systematic review

Rujin Long 1Yousheng ZhuShusheng Zhou

Medicine (Baltimore). 2019 Jan;98(3):e14099.

doi: 10.1097/MD.0000000000014099.


Background: Melatonin is the “clock factor” generated from pineal gland dominating regular circadian rhythm in humans. Migraine is one of the most severe and debilitating primary headache disorders. Thus far, many diseases have been found to associate with melatonin, including the migraine. Therefore, melatonin’s therapeutic potential for migraine is drawing attention.

Objectives: The aim of this study is to offer a systematic review of extant data of melatonin in migraine prophylaxis and to provide clinical implications and specific recommendations for future studies.

Data sources and study methods: A systematic research was conducted in September 2018 by using PubMed and Google Scholar databases to search for science literature published after 1988.

Results: In all, 7 eligible articles were identified, including 4 randomized controlled studies and 3 observational studies. Due to high heterogeneities and limited number of studies, meta-analysis was not feasible, and only systematic review was performed. The results show that present evidence cannot claim melatonin’s effectiveness according to the conflicting outcomes; however, the two negative outcomes of melatonin not different from placebo and melatonin inferior to amitriptyline are possible under-powering because of methodological, pharmacological, and therapeutic shortcomings. Observational studies also support melatonin’s efficacy in migraine. As a result, melatonin is very likely to benefit migraine in prophylaxis and may have a similar effectiveness to other main preventive medications. Immediate-release melatonin 3 mg was established as effective, melatonin receptor agonist (Agomelatine) 25 mg and prolonged-release melatonin 4 mg were observed efficacious in observational studies. Melatonin displayed ineffective in the 2-month trial; thus, 3 months or more may be an enough duration for migraine therapy. Despite melatonin being generally safe, emerging literature is illustrating that a few severe adverse effects can be caused by melatonin, for example, liver injuries, reproductive system dysfunctions, and detrimental immunostimulation.

Conclusions: Melatonin is very likely to be a promising alternative for migraine prophylaxis. Current literature examining melatonin’s efficacy in migraine prevention is growing, but still limited. Future studies of perfect design in methodology, pharmacology, and therapeutics are needed to achieve a deeper awareness of melatonin’s role in migraine as well as more studies to explore the safety issues of melatonin medicine.




Integrating Pathophysiology in Migraine: Role of the Gut Microbiome and Melatonin

George Anderson 1

Curr Pharm Des. 2019;25(33):3550-3562.

doi: 10.2174/1381612825666190920114611.



Background: The pathoetiology and pathophysiology of migraine are widely accepted as unknown.

Methods: The current article reviews the wide array of data associated with the biological underpinnings of migraine and provides a framework that integrates previously disparate bodies of data.

Results: The importance of alterations in stress- and pro-inflammatory cytokine- induced gut dysbiosis, especially butyrate production, are highlighted. This is linked to a decrease in the availability of melatonin,and a relative increase in the N-acetylserotonin/melatonin ratio, which has consequences for the heightened glutamatergic excitatory transmission in migraine. It is proposed that suboptimal mitochondria functioning and metabolic regulation drive alterations in astrocytes and satellite glial cells that underpin the vasoregulatory and nociceptive changes in migraine.

Conclusion: This provides a framework not only for classical migraine associated factors, such as calcitonin-gene related peptide and serotonin, but also for wider factors in the developmental pathoetiology of migraine. A number of future research and treatment implications arise, including the clinical utilization of sodium butyrate and melatonin in the management of migraine.


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