Comparison
Melatonin vs MOTS-c
Side-by-side of Melatonin and MOTS-c. Every row below is pulled from the compound schema and will update as our data grows. For deeper reads, follow through to each compound page.
Melatonin
Melatonin as a sleep supplement: 0.3-1 mg matches physiological output, 3-10 mg is pharmacological. Shifts circadian phase, shortens sleep latency.
MOTS-c
MOTS-c peptide is a 16-amino-acid mitochondrial-derived peptide. Preclinical signals for insulin sensitivity, exercise capacity, dosage notes.
Effects at a glance
Melatonin
- •Shortens sleep onset latency by ~7 to 12 minutes at physiological 0.3 to 1 mg doses
- •Advances circadian phase when taken 30 to 60 minutes before target bedtime, useful for jet lag and shift work
- •Does not meaningfully increase total sleep time in healthy adults without circadian misalignment
- •Endogenous nighttime production is not suppressed by short-term exogenous supplementation
- •Higher doses (3 to 10 mg) raise plasma levels above physiological range and often increase morning grogginess
- •Effective for delayed sleep-wake phase disorder and reducing jet-lag severity in eastward travel
MOTS-c
- •16-amino-acid peptide encoded in mitochondrial DNA (12S rRNA region); discovered 2015
- •Activates AMPK in skeletal muscle and liver; improves insulin sensitivity in rodent models
- •Circulating endogenous levels decline with age, motivating the longevity-restoration hypothesis
- •CohBar's MOTS-c analog CB4211 discontinued after phase 1b NASH readout did not meet endpoints
- •Anecdotal protocols use 5 to 10 mg subcutaneously 2 to 3 times weekly
- •Not on the WADA Prohibited List as of 2026; future scrutiny likely given exercise-mimetic mechanism
Side-by-side
| Attribute | Melatonin | MOTS-c |
|---|---|---|
| Category | supplement | peptide |
| Also known as | N-acetyl-5-methoxytryptamine | Mitochondrial Open Reading Frame of the Twelve S rRNA-c, MOTSc |
| Half-life (hr) ↗ | 0.75 | 0.5 |
| Typical dose (mg) ↗ | 0.5 | 5 |
| Dosing frequency | daily, 30 to 60 minutes before target sleep time | 2-3x weekly |
| Routes | oral, sublingual | subcutaneous |
| Onset (hr) | 0.5 | 1 |
| Peak (hr) | 1 | 4 |
| Molecular weight | 232.28 | 1880.18 |
| Molecular formula | C13H16N2O2 | C82H132N22O25S2 |
| Mechanism | Agonist at MT1 and MT2 receptors in the suprachiasmatic nucleus, signaling biological night and promoting sleep-onset gating plus circadian phase shifts. | Mitochondrial-derived peptide that activates AMPK in skeletal muscle and liver, improves insulin sensitivity, and translocates to the nucleus under metabolic stress to modulate nuclear gene expression in retrograde mitochondrial signaling. |
| Legal status | OTC in US; prescription in UK, EU, Japan | Not FDA approved; research-use-only grey market; not currently on WADA Prohibited List |
| WADA status | allowed | unknown |
| DEA / Rx | OTC supplement in US; Rx in UK, EU, Japan, Australia | Not scheduled (research chemical) |
| Pregnancy | Insufficient data; not routinely recommended | Insufficient data; not recommended |
| CAS | 73-31-4 | 1627580-64-6 |
| PubChem CID | 896 | 139599184 |
| Wikidata | Q179243 | Q24832108 |
Safety profile
Melatonin
Common side effects
- vivid dreams
- morning grogginess (higher doses)
- headache
- dizziness
Contraindications
- autoimmune disease (theoretical)
- concurrent anticoagulant therapy without monitoring
Interactions
- fluvoxamine: CYP1A2 inhibition raises melatonin levels substantially(major)
- warfarin: possible increased bleeding risk(moderate)
- benzodiazepines and alcohol: additive sedation(moderate)
- antihypertensives: may alter blood pressure response(minor)
MOTS-c
Common side effects
- injection-site irritation
- transient fatigue
- headache (anecdotal)
Contraindications
- pregnancy
- lactation
- active malignancy (theoretical)
- severe hypoglycemia risk on concurrent insulin or sulfonylurea
Interactions
- insulin: additive insulin sensitization may increase hypoglycemia risk(moderate)
- metformin: both activate AMPK; theoretical additive metabolic effect, no controlled data(minor)
- sulfonylureas: increased hypoglycemia risk via additive insulin sensitization(moderate)
Which Should You Take?
Melatonin comes out ahead for most readers on the criteria we weight: 2 catalogued goals, OTC, oral dosing, with a Tier-A outcome catalogued. MOTS-c is the right call when one of the conditionals below applies.
- → If your priority is sleep onset or sleep quality, pick Melatonin.
- → If your priority is circadian regulation, pick Melatonin.
- → If your priority is healthspan extension, pick MOTS-c.
- → If your priority is metabolic health and glucose control, pick MOTS-c.
Edge case: If you want to avoid research-only / gray-market sourcing, Melatonin is the more accessible choice.
Default choice: Melatonin. Wider use case, a Tier-A evidence outcome catalogued, and broader goal coverage. Reach for MOTS-c only if your priority sits squarely in the goals it owns above.
This verdict is generated from each compound's schema (goals, legal status, evidence outcomes, dosing route). It updates automatically as our compound data evolves; the deeper read sits on each individual compound page.
Common questions
What is the difference between Melatonin and MOTS-c?
Melatonin and MOTS-c differ in category (supplement vs peptide), mechanism, and typical dosing. See the side-by-side table for full details.
Which has a longer half-life, Melatonin or MOTS-c?
Melatonin half-life is 0.75 hours; MOTS-c half-life is 0.5 hours.
Can you stack Melatonin with MOTS-c?
Stack compatibility depends on mechanism overlap, legal status, and individual response. Check each compound page for specific interactions and contraindications before combining.
Go deeper