Melatonin

By Marcello Cherchi, MD PhD

For patients

Most people have heard of melatonin as a “sleeping pill,” but it has other uses as well. Some researchers believe that melatonin may help patients who have migraines. Melatonin is usually easy to take and has low risk.

For clinicians

Practical summary

Melatonin is produced primarily by the pineal gland, and is minimally available from dietary sources. It is widely known that melatonin plays a role in sleep-wake cycles, but it has numerous other biochemical effects as well, including as an analgesic. It has been observed that circulating melatonin levels are sometimes abnormal in patients with migraine. Emerging evidence suggests that melatonin may play a role in the management of migraine, though this needs to be verified by additional studies. Overall, melatonin appears safe and well-tolerated. Melatonin is available over-the-counter in the United States.

Introduction

The molecule N-acetyl-5-methoxytryptamine, an indoleamine more commonly known as melatonin, is synthesized primarily in the pituitary gland (Ahmad et al. 2023; Zhao et al. 2019). Melatonin serves multiple biological functions, including regulation of sleep-wake cycles. Minimal amounts are available from dietary sources (Ahmad et al. 2023).

Pharmacology

Melatonin binds to several receptors (MT1, MT2, MT3) (Ahmad et al. 2023; Zhao et al. 2019), but also appears to have effects independent of its activity at receptors (Ahmad et al. 2023). Melatonin is hepatically catabolized.

Serum levels of melatonin may be altered in migraine patients (Zielonka 2021), though the reason for this is unclear (Peres 2005; Toglia 1986, 2001; Tseng et al. 2020; Vogler et al. 2006). Melatonin appears to have some analgesic properties (Wilhelmsen et al. 2011). Taking these observations together suggests that exogenous administration may have some role in the management of migraine (Gagnier 2001; Gelfand and Goadsby 2016; Lyon and Langner 2017; Peres 2011; Peres et al. 2006), though the mechanism by which this may help remains to be elucidated (Song et al. 2020; Wilhelmsen et al. 2011; Zielonka 2021).

Adverse effects

Although melatonin is an endogenously-produced hormone and is thus frequently viewed by patients as “natural” and “safe,” exogenously administered melatonin is not risk-free (Tuft et al. 2023). A meta-analysis of placebo-controlled trials of melatonin (when used in the management of sleep disorders) reported that daytime sleepiness occurred in 1.66% of patients, headache occurred in 0.74% of patients, and dizziness occurred in 0.74% of patients (Besag et al. 2019). Overall the rate of adverse effects is low, and the risk also appears low. Generally, melatonin is well-tolerated (Rosenberg 2016).

Cautions and contraindications

Melatonin appears to be safe in pregnancy and lactation (Vine et al. 2022).

Relevance in otoneurology

The main relevance of melatonin in otoneurology is probably in the management of migraine associated vertigo, extrapolating from the literature regarding melatonin for migraine headaches.  Melatonin has been studied in randomized controlled trials versus placebo (Alstadhaug et al. 2010; Ebrahimi-Monfared et al. 2017) and versus other medications (Gonçalves et al. 2016).  While some reviews describe these trials as demonstrating a “positive trend” (Moreno-Ajona et al. 2021), earlier systematic reviews and meta-analyses conclude that the evidence is still emerging (Leite Pacheco et al. 2018; Liampas et al. 2020; Long et al. 2019; Puliappadamb et al. 2022; Yamanaka et al. 2021).  A more recent meta-analysis of 9 randomized controlled trials (788 patients) concluded that melatonin is superior to placebo in terms of reducing migraine attack duration, reducing the number of headache days, reducing headache severity, and reducing the need for analgesics; furthermore, melatonin was generally well-tolerated (Abouelmagd et al. 2026).

Other notes

Melatonin is currently available over-the-counter in the United States. The most commonly used dose for migraine prophylaxis is 3 mg per night (Peres et al. 2004).

References

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