COMPOUND

Compounds / Supplements

Pregnenolone

Supplements Oral · Sublingual OTC supplement

Endogenous neurosteroid and the upstream precursor for ALL steroid hormones (progesterone, DHEA, cortisol, aldosterone, testosterone, estradiol). Synthesized in the adrenal cortex, gonads, and CNS from cholesterol via CYP11A1. Used as an OTC supplement for cognitive function, mood, GABAergic effects (via allopregnanolone metabolite), and hormonal foundation support. Allowed under DSHEA in the US; positioned as a nootropic and adrenal/HPA support agent. Decline with age is well documented and is the basis for the replacement hypothesis.

At a glance

Half-life
~7 h CLINICAL ESTIMATE ONLY. There is NO published human oral PK study that formally measures the elimination half-life of oral pregnenolone. PMID 39598281 (Nguyen 2024) explicitly states that clinical utility is questioned due to limited bioavailability and stability data, and is the closest study, finding stable serum levels across a 2-8h window. The 7h figure shown here is derived from that 4-8h serum-doubling window and should not be read as a measured elimination half-life.
Routes
Oral · Sublingual
Evidence base
3 studies 3 human

Mechanism

Acts via two distinct pathways: (1) Steroid precursor: converted to progesterone (3β-HSD), DHEA (CYP17A1 17α-hydroxylase + lyase), and downstream sex steroids. (2) Direct neurosteroid signaling: modulates GABA-A (via metabolite allopregnanolone), NMDA, sigma-1, and pregnane X receptors in the CNS. Independently affects memory consolidation, mood, and sleep architecture even without conversion to other hormones. PK data gap: serum stable 2-8h on twice-daily dosing; elimination half-life not formally characterized.

Dosing

Any amounts shown here are reported from published studies only. 3 of 3 catalogued studies involved human subjects. COMPOUND does not publish its own dosing guidance.

Where a study reports an amount, it appears in that study's entry below, attributed to the source.

Published evidence

  1. Human RCT 2024

    Pharmacokinetics and safety of pregnenolone in healthy adults

    Nguyen TVL, Stoops WW, Lile JA, et al. Drug Alcohol Depend

    Twice-daily oral pregnenolone (300/500mg) in cocaine use disorder cohort; serum stable 2-8h. Explicitly CONFIRMS data gap for absorption rate and elimination half-life: 'clinical utility questioned due to limited data on bioavailability and stability of blood levels in humans.'

    PMID 39598281

  2. Human RCT 2010

    Pregnenolone for cognition and mood in dual diagnosis patients

    Osuji IJ, Vera-Bolanos E, Carmody TJ, Brown ES Psychiatry Res

    Pregnenolone in bipolar depression: modest cognitive endpoint signal; supports neurosteroid hypothesis.

    PMID 20493557

  3. Human RCT 2009

    Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia

    Marx CE, Keefe RS, Buchanan RW, et al. Neuropsychopharmacology

    500mg/day pregnenolone improved cognition and negative symptoms vs placebo in schizophrenia. Established high-dose tolerability and CNS effect.

    PMID 19339966

Reported side effects

Sedation / drowsiness
Common Mild · Allopregnanolone GABAergic effect via 5α-reductase metabolism. Dose-dependent: minimal at lower supplemental amounts, pronounced at higher ones.
Vivid dreams
Common Mild · Common anecdotal report, likely mediated by progesterone/allopregnanolone effects on REM architecture.
Headache
Occasional Mild · Reported in clinical trials; usually transient.
Mild estrogen-related symptoms (high doses)
Occasional Moderate · Downstream conversion via DHEA → estradiol pathway. Breast tenderness possible at >100mg/day chronic.
Elevated DHEA, cortisol, or progesterone
Common Mild · Expected pharmacology: pregnenolone is upstream of all steroidogenesis. Monitor if symptomatic.
Paradoxical anxiety (subset)
Occasional Moderate · Subset of users report agitation rather than calming effect; mechanism unclear, possibly individual variation in 5α-reductase vs other metabolic pathways.

Interactions

  • Benzodiazepines Caution

    Allopregnanolone metabolite is a positive allosteric modulator at GABA-A: additive sedation, respiratory depression risk with benzodiazepines or alcohol.

  • DHEA Synergy

    Both feed the same steroidogenic pathway (pregnenolone → DHEA → androgens/estrogens). Stacking elevates downstream DHEA, T, and E2 additively.

  • Finasteride Caution

    5α-reductase inhibition blocks the 5α-DHP → allopregnanolone conversion that drives pregnenolone's GABAergic effect. Users report dramatically reduced calming/sedating effect on finasteride.

  • Anastrozole Synergy

    AI limits downstream estrogen conversion of pregnenolone-derived androgens: useful in men prone to E2 elevation on chronic supplementation.

Storage

Room temperature, dry, original container.