Melatonin
The only drug in this catalog where the pharmacology argues for less, not more. The sleep dose-response curve is flat from 0.3 mg; timing predicts response almost perfectly; and the megadose tier — 20 mg and up — is oncology dosing with its own safety paper trail.
The short version
- 0.1, 0.3, 1, 10 mg: all equally effective for sleep induction — the curve is flat from physiological doses on up. DATA
- 0.3 mg reproduces normal nocturnal blood levels; 3 mg causes hypothermia and daytime spillover. DATA
- Timing explains 94% of the variance in response (r²=0.94) — dose explains almost none. DATA
- 20 mg/day is an oncology dose with a real trial record — and 300 mg/day was stopped early for liver-enzyme elevations in 3 of 4 patients. DATA
The flat curve
| Trial | Doses compared | Finding |
|---|---|---|
| Dollins 1994, PNAS | 0.1 / 0.3 / 1 / 10 mg | all equally effective; 0.1 and 0.3 mg reproduce peak nocturnal plasma levels |
| Zhdanova 1995 | 0.3 vs 1 mg | equivalent sleep promotion; no REM suppression, no hangover |
| Zhdanova 2001, elderly | 0.1 / 0.3 / 3 mg | 0.3 mg restored sleep efficiency (P<0.0001); 3 mg caused hypothermia + next-day spill-over |
| Mundey 2005, insomniacs | 0.3 vs 3 mg | equivalent efficacy; response driven by dosing time, r²=0.94 |
PMID 8127888 · Dollins 1994
PMID 7768078 · Zhdanova 1995
PMID 11600532 · Zhdanova 2001
PMID 16295212 · Mundey 2005
How big is the effect at all
Meta-analysis: latency −7 min, total sleep +8 min DATA
19 RCTs, n=1,683 (Ferracioli 2013): sleep latency −7.06 min, total sleep time +8.25 min. Melatonin is a phase-setting hormone with a modest direct hypnotic effect — the people who benefit most are those whose internal clock is misaligned (delayed phase, shift, jet lag), which is exactly what the r²=0.94 timing result reflects.
Pharmacokinetics — why formulation changes the question
IR: t½ 1 hour. SR: t½ 5 hours, half the peak DATA
Direct comparison (Thanawala 2024): immediate-release half-life 1.01 h, Tmax 0.87 h; sustained-release half-life 5.10 h with Cmax roughly halved. A 10× dose taken as IR is a spike; the same taken as SR is a long exposure — spillover into the daylight window is a formulation-and-dose problem, and only the low doses avoid it by construction.
The megadose tier — what is actually known
| Exposure | Dose | Outcome |
|---|---|---|
| Dollins 1993, daytime dosing | 10–80 mg | impaired, not improved performance — high daytime levels are a sedation-impairment state |
| Oncology RCT (Messina 2010) | 20 mg/d | tumor-response benefit signal — the setting 20 mg actually comes from |
| Ninomiya 2026 | 30 mg/d × 49 d | clean safety panel, n=12, short duration |
| MELATOMS-1, Bejarano 2026 | 300 mg/d | stopped after 8 enrollments — 3 of 4 melatonin patients developed hypertransaminasemia (reversible) |
Interactions and endocrine notes
Cleared by CYP1A2 — check co-medication DATA
Melatonin is a CYP1A2 substrate; fluvoxamine inhibits its clearance with Ki ≈ 0.02 µM — an order-of-magnitude interaction that turns an ordinary dose into a long exposure. Any 1A2 inhibitor or SSRI co-medication changes the effective dose.
Growth-hormone interaction: real but pathway-specific DATA
Classic endocrinology (Valcavi): melatonin roughly doubles GHRH-stimulated GH release — via somatostatin-pathway modulation — while having no direct effect on pituitary GH secretion in vitro. Relevant to anyone stacking it with GH: the interaction is documented at physiological melatonin levels, not studied at 20 mg.
Reproductive axis: rodent suppression, human male adolescent null DATA
In female rodents, 1 mg/kg suppresses the HPG axis. In human male adolescents, no suppression signal was found. No tolerance/desensitization study with chronic dosing exists — receptor downregulation under months of supraphysiologic exposure remains uncharacterized.
What does not exist
No chronic high-dose trial · no desensitization data · no adolescent megadose safety study DATA
Verified by search (2026-08-31): no trial of melatonin above 10 mg/day running longer than 8 weeks, no receptor-desensitization study under chronic dosing of any strength, and no safety study of high-dose melatonin in adolescents. The 20 mg tier's chronic safety case rests on oncology cohorts of sick adults and one 49-day n=12 panel — plus the flat sleep curve that gives no compensating benefit for the exposure.