Melatonin
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Melatonin: From No EU-Approved Indication to Migraine with Brainstem Aura
One-Sentence Summary
Melatonin currently has no EU marketing authorization on record in this evidence pack (0 licenses; market status: Not Marketed), so its original approved indication cannot be characterized from the available data. The TxGNN model predicts it may be effective for Migraine with Brainstem Aura, but this specific subtype is currently supported only by 20 publications and no dedicated clinical trials — the evidence is extrapolated from broader migraine research rather than subtype-specific studies.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not available — no EU marketing authorization on record in this evidence pack |
| Predicted New Indication | Migraine with Brainstem Aura |
| TxGNN Prediction Score | 87.90% |
| Evidence Level | L3 |
| EU Market Status | Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data for melatonin is not available in this evidence pack, and no EU-approved indication is on record to compare against. Based on the general pharmacology reflected in the supporting literature, melatonin acts as an MT1/MT2 receptor agonist with anti-inflammatory and circadian-regulatory properties.
The repurposing rationale for this specific prediction notes that migraine (in general) is associated with reduced nocturnal melatonin excretion and interacts with the serotonergic system, which modulates both pain transmission and the circadian timing of headache attacks — providing biological plausibility for melatonin as a migraine-related intervention. However, “migraine with brainstem aura” is a distinct, rarer subtype, and none of the identified clinical trials or literature specifically isolate this subtype. Existing RCT evidence (e.g., NCT01357031, a completed Phase 3 trial) does not stratify by aura subtype, so the mechanistic link here is extrapolated from general migraine biology rather than subtype-specific data.
Notably, a closely related but broader predicted indication in this evidence pack — “migraine disorder” (unstratified) — is supported by considerably stronger evidence (Evidence Level L1, including a completed Phase 3 RCT with n=192 and a published meta-analysis). This suggests melatonin’s therapeutic signal is real for migraine generally, but the brainstem-aura-specific claim should be treated as a lower-confidence extrapolation until subtype-specific data becomes available.
Clinical Trial Evidence
Currently no related clinical trials registered specifically for migraine with brainstem aura.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 27165014 | 2016 | RCT | J Neurol Neurosurg Psychiatry | Randomized trial comparing melatonin 3mg, amitriptyline 25mg, and placebo for migraine prevention (general migraine, not aura-stratified) |
| 24909684 | 2015 | RCT/Safety-Efficacy | Current Drug Safety | Safety and efficacy of melatonin in pediatric migraine prophylaxis |
| 38166859 | 2024 | RCT | BMC Neurology | Agomelatine (melatonin receptor agonist) vs placebo for headache severity/frequency in episodic migraine without aura |
| 18810607 | 2008 | Open-label trial | Neurol Sci | 3-month melatonin (3mg) prophylaxis trial in children with migraine and tension-type headache; ~67% reported improvement |
| 9595871 | 1998 | Case series | Headache | Melatonin 5mg resolved headache in patients with delayed sleep phase syndrome, including one with disabling migraine attacks |
| 30906963 | 2019 | Review | Neurol Sci | Reviews the bidirectional relationship between sleep disorders and migraine subtypes, including those with aura |
| 22644189 | 2012 | Review | Neurol Sci | Reviews future migraine prophylaxis drugs, including circadian/melatonergic mechanisms |
| 31054199 | 2019 | Biomarker study | Headache | Found melatonin metabolite levels are not a reliable biomarker for predicting pediatric episodic migraine |
| 7641249 | 1995 | Observational | Cephalalgia | Nocturnal melatonin excretion significantly decreased in women with menstrually-associated migraine without aura |
| 7954740 | 1994 | Observational | Cephalalgia | Urinary melatonin excretion reduced throughout ovarian cycle in menstrually-related migraine patients |
EU Market Information
No EU marketing authorizations are on record for melatonin in this evidence pack (0 licenses; market status: Not Marketed).
Safety Considerations
Please refer to the SmPC for safety information.
(Note: safety.key_warnings, safety.contraindications, and safety.ddi are all marked as Data Gaps in this evidence pack — DG001 flags this as a Blocking gap that prevents a full S1 safety initial assessment.)
Conclusion and Next Steps
Decision: Hold
Rationale: The predicted indication (migraine with brainstem aura) has no dedicated clinical trials and relies on evidence extrapolated from general migraine research; combined with a Blocking data gap on TFDA/EMA warnings and contraindications (DG001), a safety-informed decision cannot yet be made.
To proceed, the following is needed:
- Resolve DG001 (Blocking): obtain SmPC/label warnings and contraindications for melatonin
- Resolve DG002 (High): obtain detailed mechanism of action data from DrugBank
- Subtype-stratified clinical evidence specifically for migraine with (vs. without) brainstem aura
- Clarification of melatonin’s EU regulatory/marketing status, since 0 licenses are currently on record
- Consider evaluating the broader “migraine disorder” indication in parallel, which has substantially stronger evidence (L1, Phase 3 RCT, meta-analysis) and may be a more defensible near-term repurposing candidate
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.