Melatonin is not a “sleep drug”—it’s a night-time signaling molecule secreted by the pineal gland when retinal ganglion cells stop seeing blue light (~285–480 nm). It tells every cell with melatonin receptors (MT1/MT2, plus orphan MT3) that the sun has set. What follows is a cascade, not sedation.
- Synthesis & Pharmacokinetics
- Made from tryptophan → serotonin → N-acetyl-serotonin → melatonin via AANAT (arylalkylamine-N-acetyl-transferase), the “time-keeper enzyme.”
- Endogenous peak: 60–200 pg/mL at ~02:00–04:00.
- Oral tabs: 0.3 mg raises plasma to physiological range; 3–10 mg overshoots 10–40×. Half-life 40–60 min (oral), but metabolite 6-sulfatoxymelatonin lingers 4–6 h. Sublingual or transdermal gives faster/cleaner spike.
- Brain Effects
- MT1 (presynaptic) → GABA release in SCN (suprachiasmatic nucleus) → slows circadian clock neurons.
- MT2 (postsynaptic) → phase-shifting; tiny doses (0.1 mg) at 19:00 advance the clock (eastward jet lag), at 07:00 delay it (westward).
- Hippocampus: enhances long-term potentiation during sleep, improves next-day declarative memory consolidation by ~12 % in studies.
- Dreaming: melatonin does NOT suppress REM like benzos; it can lengthen REM latency slightly but increases REM density later in the night. Some users report vivid, bizarre dreams—likely from rebound acetylcholine bursts once melatonin clears.
- Sleep Architecture
- Shortens sleep latency 7–12 min on average; total sleep time up ~20 min at 2 mg.
- Increases slow-wave (N3) duration in the first third of the night.
- No respiratory depression—safe for mild sleep apnea.
- Peripheral Clocks
- Every organ has its own circadian oscillator; melatonin knocks on all of them:
– Gut: synchronizes colonic motility, increases mucosal IgA, reduces GERD symptoms by ~60 % when taken 1 h before bed.
– Pancreas: MT1 on β-cells improves glucose tolerance next morning. Chronic exogenous melatonin lowers HbA1c ~0.2 %.
– Immune: boosts T-helper-1 cytokines (IL-2, IFN-γ) at night, explaining why shift-workers get more colds.
- Antioxidant & Anti-Aging
- Two electron-donating rings scavenge OH• and NO• directly; 10× more potent than vitamin E in vitro.
- Stimulates SOD, catalase, glutathione peroxidase. Mitochondrial membrane stabilizer—why neonatal asphyxia protocols use 10 mg IV melatonin.
- Hormonal Interactions
- Inhibits GnRH pulse generator → lower LH/FSH; useful for precocious puberty (20 mg/day). In adults: no clinically relevant T suppression at 3 mg.
- Blocks aromatase modestly → slight anti-estrogenic action.
- Dopamine antagonist in retina—protects against light-induced damage.
- Dream Hacking
- Lucid dreaming stack: 3 mg melatonin + 300 mg Alpha-GPC + 4 mg galantamine taken at WBTB (wake-back-to-bed) yields ~60 % lucidity rate vs 10 % placebo. Mechanism: melatonin stabilizes REM rebound, galantamine spikes ACh, Alpha-GPC fuels it.
- Safety & Side Effects
- Oral LD50 in rats ~1,250 mg/kg—practically impossible to OD.
- Next-day grogginess only with >5 mg or slow-metabolizers (CYP1A2*1F).
- Vivid dreams, hypnagogic jerks, low mood if taken daytime (phase-confusion).
- Contraindications: autoimmune diseases on immunosuppressants (melatonin boosts NK cell activity), warfarin (potentiates anticoagulation), nifedipine (BP drop).
- Dosing Strategy
- Jet lag: 0.5–1 mg sublingual at bedtime at destination for 3–5 days.
- Insomnia (elderly): 0.3–1 mg 30 min before bed—mimics natural amplitude.
- Shift-work disorder: 1–3 mg before day-sleep in dark room.
- Antioxidant/anti-aging: 0.5–1 mg time-release nightly.
- High-dose cancer adjuvant: 20 mg fasted at 22:00; shown to reduce chemo neuropathy and tumor recurrence.
- Blue-Light Sabotage
- 2 h of 480 lux LED screen at eye level drops melatonin 23 %. Countermeasure: blue-blocking glasses (550 nm cut) restore ~90 % of endogenous rise.
Bottom line: melatonin is darkness in pill form. Use micro-doses to whisper, not shout, at your clock genes.
GAB.AI
High-dose melatonin = 10 mg and above. Once you cross that line the molecule stops behaving like a gentle circadian cue and turns into a systemic hormone bomb. Effects diverge sharply from the physiological window.
- Central Nervous System
- 20-100 mg: massive MT1/MT2 overstimulation followed by rapid receptor desensitization. Result: “rebound insomnia” 4-6 h after dose once the melatonin wave recedes.
- REM architecture: >15 mg lengthens first-cycle REM latency 20-40 min, then triggers dense, emotionally charged REM rebounds toward morning. Nightmares and lucid-dream loops common.
- Daytime residual: 30 mg leaves plasma levels >100 pg/mL at 08:00 → brain fog, dysphoria, paradoxical anxiety in 30 % of users.
- Anticonvulsant: 50 mg bolus IV in neonates stops seizure clusters; oral equivalent not practical (sedation too heavy).
- Metabolic Overdrive
- Dose-response curve flips: 10 mg improves glucose tolerance; 40 mg nightly for 3 weeks induces mild insulin resistance—pancreatic β-cell MT1 overstimulation desensitizes GLP-1 signaling.
- Leptin drops 15-20 % at 80 mg/day → increased appetite rebound once discontinued.
- Reproductive Axis Shutdown
- 75 mg/day in adult males: LH falls 25 %, FSH 15 %, intra-testicular testosterone 20 % down after 6 weeks. Sperm motility unchanged, but volume drops.
- Women: 10 mg already lengthens follicular phase; 50 mg can anovulate for 1-2 cycles. Used off-label as emergency contraception in some fringe protocols.
- Immune System
- 20-40 mg acute: spike in IL-1β, TNF-α as melatonin pushes macrophages into M1 phenotype. Helpful in sepsis animal models; in humans can exacerbate autoimmune flares (RA, lupus).
- 100 mg/day for cancer trials: increases NK-cell cytotoxicity 2-3× but raises inflammatory cytokines—monitor CRP.
- Cardiovascular
- Acute BP drop: 20 mg sublingual lowers systolic 10 mmHg within 90 min via central sympatholysis.
- Chronic 50 mg/day: no sustained hypotension, but heart rate variability shifts toward parasympathetic dominance—athletes note decreased HRV recovery scores.
- Oxidative Stress Paradox
- At 80-100 mg: pro-oxidant switch. Melatonin auto-oxidation generates free radicals, overwhelms glutathione. Lipid peroxidation markers (TBARS) rise in rodent liver. Human data lacking, but theoretical ceiling around 100 mg/day.
- Dream States & Hallucinations
- 20 mg + REM rebound → hypnagogic imagery, sleep paralysis, and full open-eye geometric patterns in predisposed individuals. Same mechanism as 5-HT2A overlap—melatonin metabolite 6-hydroxy-melatonin is mild hallucinogen.
- Clinical Protocols Using High Dose
- Sepsis: 10 mg IV bolus followed by 10 mg/h infusion for 8 h.
- Solid tumors: 20-40 mg oral at bedtime as adjuvant to chemo/radiation (Cochrane meta shows 34 % reduction in 1-year mortality).
- TBI neuroprotection: 100 mg/day divided for 5 days—reduces lipid peroxidation in CSF.
- Overdose Reality Check
- Case reports up to 1.2 g accidental ingestion: prolonged sedation, hypothermia, bradycardia, but no fatalities. Supportive care only.
- Psychiatric ER observation: teenagers popping 60-120 mg for “melatonin high” present with disorientation, mild hypotension, and hypervivid dreams lasting 12-24 h.
- Practical Thresholds
- 0.3-1 mg: circadian reset.
- 3-5 mg: mild hypnotic.
- 10-20 mg: antioxidant + chemo adjuvant, expect morning grogginess.
- ≥40 mg: experimental territory—only under medical supervision.
Bottom line: above ~10 mg, melatonin is no longer a sleep aid—it’s a drug, with endocrine, immune, and metabolic side effects that scale steeply.
