Side-by-side comparison of mechanisms, dosing, interactions, and stacking potential.
| Melatonin | Pregnenolone | |
|---|---|---|
| Category | Supplements | Supplements |
| Standard Dose | 0.3-1mg for sleep onset (physiological); 3-5mg for jet lag; 10-20mg for oncological adjunct (under supervision) | Research indicates 10-50 mg daily orally for neurosteroid and cognitive support. Clinical trials in schizophrenia used up to 500 mg/day. |
| Timing | 30-60 minutes before desired sleep onset. For circadian phase advance: 4-6 hours before desired bedtime. Sublingual for faster onset. Dim lights 1-2 hours before taking. | Morning dosing preferred (aligns with diurnal cortisol rhythm). Sublingual may provide faster onset and better bioavailability. Take with or without food. |
| Cycle Duration | Short-term for jet lag (3-5 days); ongoing at low dose for circadian support if needed; extended for oncological use under supervision | Ongoing with periodic reassessment. Cycle 5 days on / 2 days off, or 3-4 weeks on / 1 week off to prevent downstream hormone accumulation. |
| Evidence Level | strong_human | moderate_human |
Melatonin (N-acetyl-5-methoxytryptamine) is synthesized from serotonin in the pineal gland, regulated by the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract. It binds MT1 and MT2 G-protein coupled receptors: MT1 activation suppresses neuronal firing in the SCN (sleep onset), while MT2 modulates circadian phase shifting. Beyond sleep, melatonin is a potent antioxidant that scavenges hydroxyl radicals, peroxynitrite, and singlet oxygen, and upregulates antioxidant enzymes (GPx, SOD, catalase) via Nrf2. It has anti-inflammatory properties (NF-kB suppression), immunomodulatory effects, oncostatic activity (anti-proliferative in several cancer types), and mitochondrial protective functions.
0.3-1mg for sleep onset (physiological); 3-5mg for jet lag; 10-20mg for oncological adjunct (under supervision)
30-60 minutes before desired sleep onset. For circadian phase advance: 4-6 hours before desired bedtime. Sublingual for faster onset. Dim lights 1-2 hours before taking.
Short-term for jet lag (3-5 days); ongoing at low dose for circadian support if needed; extended for oncological use under supervision
Pregnenolone is the 'master steroid' synthesized from cholesterol via CYP11A1 (side-chain cleavage enzyme) in adrenal glands, gonads, and brain. It serves as the biosynthetic precursor to all steroid hormones (progesterone, DHEA, cortisol, testosterone, estradiol, aldosterone). In the CNS, pregnenolone and its sulfated derivative (pregnenolone sulfate) function as potent neurosteroids: pregnenolone sulfate is a positive allosteric modulator of NMDA receptors enhancing glutamatergic neurotransmission, a negative modulator of GABA-A receptors (increasing neural excitability), and an activator of TRPM3 calcium channels. It also modulates sigma-1 receptors involved in neuroplasticity.
Research indicates 10-50 mg daily orally for neurosteroid and cognitive support. Clinical trials in schizophrenia used up to 500 mg/day.
Morning dosing preferred (aligns with diurnal cortisol rhythm). Sublingual may provide faster onset and better bioavailability. Take with or without food.
Ongoing with periodic reassessment. Cycle 5 days on / 2 days off, or 3-4 weeks on / 1 week off to prevent downstream hormone accumulation.
Take our free assessment to get personalized recommendations based on your health goals, current stack, and biomarkers.
Get Your Free Protocol →or take the assessment →