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Pregnenolone

Emerging

P5 | 3β-hydroxypregn-5-en-20-one | "mother of all steroids" — endogenous neurosteroid + master steroid precursor

Aliases (5)
P5 · mother of all steroids · 3β-hydroxypregn-5-en-20-one · pregn-5-en-3β-ol-20-one · PREGNENOLONE
TYPICAL DOSE
5-50 mg/day
Daily (AM default; PM for sleep variant)
ROUTE
Oral (capsule, sublingual, micronized)
Oral capsule with food
CYCLE
Continuous with periodic bloodwork; cycle 8-12 …
8-12 weeks with bloodwork checkpoint
STORAGE
Room temp; cool dry place; protect from light
Room temp; protect from light

Overview

What is Pregnenolone?

Pregnenolone (P5) is the master endogenous steroid precursor — cholesterol → P5 via P450scc (CYP11A1), and from P5 the body builds cortisol, aldosterone, DHEA, testosterone, estradiol, and progesterone. It is also a direct CNS neurosteroid: pregnenolone sulfate negatively modulates GABA-A and positively modulates NMDA receptors. Sold OTC as a supplement in the US; not WADA-banned by name (but downstream metabolites are); not DEA-scheduled.

Key Benefits

Plausible signal in schizophrenia (negative symptoms + cognition, Marx 2009), PTSD (Brown 2018), and bipolar depression (Brown 2014) — all in clinical populations at 100-500 mg/day. OTC supplement claims for cognition, mood, stress resilience, and sleep are mostly extrapolated from older studies and rodent work; modern healthy-adult RCT evidence is thin. Most realistic use: hormone-deficient older adult or specific psychiatric adjunct under clinician supervision.

Mechanism of Action

Two-arm action: (1) substrate for steroidogenesis — converts to progesterone, cortisol, DHEA, testosterone, estradiol via tissue-specific enzymes; conversion direction is highly individual; (2) direct neurosteroid — P5 sulfate is a negative allosteric modulator at GABA-A and positive at NMDA, producing a pro-arousal/pro-cognitive profile, while downstream allopregnanolone gives the opposite (positive GABA-A, sedating/anxiolytic) profile.

Pharmacokinetics

—·—
PeakHalf-life
Approximate curve — visual aid only, not data-precise PK

Research Indications

Most Effective

The steroidogenesis tree

1. Cholesterol → pregnenolone via P450scc (CYP11A1) at the inner mitochondrial membrane — rate-limiting step in *all* steroidogenesis. Re…

Effective

Pharmacokinetics + the first-pass problem

- Oral absorption: 40-80% of dose, food-dependent (fatty meal +30-50% absorption). - First-pass: Heavy. Oral P5 is rapidly converted in l…

Investigational

Endogenous lifecycle

P5 peaks in young adulthood (age 18-30), declines steadily thereafter. By age 70, CSF P5 is ~50% of young-adult levels; serum DHEA-S drop…

Peptide Interactions

Magnesium (glycinate, threonate, malate)
Synergistic

modest GABAergic allopregnanolone-arm potentiation. Already in most canonical stacks.

DHEA in older deficient adults (50+)
Synergistic

paired in post-menopause / late-andropause replacement. Not for users under 35.

Progesterone in women (clinician-coordinated)
Synergistic

perimenopausal HRT protocols.

Vitamin D3+K2, B-complex
Synergistic

substrate/clearance support; indirect.

Psychiatric protocols (clinician-supervised)
Synergistic

combined with SSRIs, 2nd-gen antipsychotics, lithium, valproate, lamotrigine in Marx 2009 / Brown 2014.

TRT / exogenous androgens
Avoid

exogenous T saturates AR + shuts endogenous output; added P5 aromatizes to E2 with no androgenic upside. Counterproductive.

DHEA in young users (<35)
Avoid

both upstream sex-steroid precursors; amplifies conversion-direction problem.

Aromatase inhibitors without bloodwork
Avoid

supraphysiological androgen load + E2 rebound risk on cessation.

SERMs (enclomiphene/clomiphene)
Avoid

without coordination — combined estrogenic load via P5 → E2 layered on SERM-driven endogenous T rise.

Exogenous progesterone in young men
Avoid

duplicative; sedation, libido suppression.

5α-reductase inhibitors (finasteride, dutasteride)
Avoid

block P5 → allopregnanolone conversion. Men on finasteride lose the calming arm entirely; relevant for post-finasteride syndrome users who try P5 expecting r…

Phenibut, alcohol, benzos, GHB, baclofen, gabapentin/pregabalin
Avoid

additive GABAergic depressant load via allopregnanolone arm.

Quality Indicators

✓

Third-party COA + micronized form

Reputable brands publish a Certificate of Analysis for identity, potency, and contaminant testing. Micronized pregnenolone is preferred for consistent absorption.

✓

GMP-certified manufacturing

Look for cGMP / NSF / USP certifications on the label. Pure Encapsulations, Life Extension, Thorne, Designs for Health are commonly trusted brands.

!

Sublingual / lozenge formats

Sublingual claims higher bioavailability but with steroid kinetics is largely marketing. Stick to oral with food unless brand has data.

✗

Proprietary blends or no COA

Avoid products that hide pregnenolone amounts inside a proprietary blend. Anonymous-seller capsules carry quality and adulteration risk.

What to Expect

  • Week 1
    Tolerability and dose-response.
  • Week 2-4
    Early effect window.
  • Week 4-8
    Peak benefit assessment.
  • Week 8+
    Cycle decision point.

Side Effects & Safety 11

Side Effects

  1. 1Headache — first 1-2 weeks; usually fades. Hydration, magnesium, dose reduction.
  2. 2Irritability, mild anxiety, agitation — PregS arm dominant ("alerting" phenotype).
  3. 3Vivid/disturbing dreams — sleep architecture shift; pronounced first 1-2 weeks.
  4. 4Acne, oily skin, body-odor change — androgenic Δ5 arm; most visible early conversion-drift sign.
  5. 5Fatigue/sedation — paradoxical; allopregnanolone arm dominant. Community data: 27/309 users.
  6. 6Water retention, gynecomastia signal, nipple sensitivity — estrogenic conversion; more common in higher body fat.
  7. 7Libido changes (either direction, conversion-dependent).
  8. 8Brain fog / cognitive blunting — paradoxical; often isopregnanolone (counteracts allopregnanolone) or estrogenic drift.
  9. 9Mild HPG axis suppression at sustained >50 mg/day; reversible within weeks of cessation.
  10. 10Mood destabilization — irritability, dysphoria; can be PregS-arousal unopposed by allopregnanolone.
  11. 11Sleep disruption — particularly AM-dosed alerting phenotype.

When to Stop

  • Hormone-sensitive cancer concern (theoretical, no causal data). Same concern as DHEA. HARD BLOCK with personal or 1st-degree family history of breast/prostate/ovarian/endometrial/testicular cancers — worst case is irreversible.
  • Bipolar mood destabilization. Brown 2014 didn't show manic switching but used active mood-stabilizer background. Use with caution in bipolar history; HARD BLOCK in active mania.
  • PCOS — may worsen androgenic phenotype. CAUTION, endocrinologist coordination.
  • Pregnancy/lactation — HARD BLOCK.
  • Hepatotoxicity — rare/theoretical at >300 mg/day chronic; LFTs in monitoring.
  • Acute psychosis — case reports; relevant for schizophrenia-spectrum history.
  • Week 1-2: sleep, dreams, headache, irritability. Stop if sleep significantly disrupted.
  • Week 2-4: skin (androgenic), gyno signal (estrogenic), libido drift. Photo baseline + week-4 recheck useful.
  • Week 4-8: mood/cognitive effects stabilize; re-test bloodwork.
  • Quarterly on chronic use: full hormone panel + LFTs.

References

Marx CE et al. "Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia." Neuropsychopharmacology 2009. **PMID: 19129526**

pubmed.ncbi.nlm.nih.gov · 2009

8-week double-blind RCT, n=21, pregnenolone 100-500 mg/day adjunct to antipsychotics. Significant SANS (negative symptoms, mean change 10.38 vs 2.33 placebo) and BACS (cognition) improvement vs pla…

View Study

Kreinin A et al. "Adjunctive pregnenolone ameliorates the cognitive deficits in recent-onset schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial." Clin Schizophr Relat Psychoses 2014. **PMID: 25030803**

pubmed.ncbi.nlm.nih.gov · 2014

Replication attempt; mixed result. 120 participants randomized to pregnenolone or placebo; improved functional capacity but did not replicate cognitive-symptom benefit over 8 weeks.

View Study

Brown ES et al. "A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression." Neuropsychopharmacology 2014. **PMID: 24917198**

pubmed.ncbi.nlm.nih.gov · 2014

12-week RCT, n=80, pregnenolone titrated to 500 mg/day. Depression remission 61% (pregnenolone) vs 37% (placebo) on IDS-SR (p=0.046). No manic switching, well-tolerated. Strongest bipolar-depressio…

View Study

Naylor JC, Kilts JD, Bradford DW, ... Marx CE. "Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial." JAMA Network Open 2020. **PMID: 32119096**

pubmed.ncbi.nlm.nih.gov · 2020

Most recent definitive trial. Pregnenolone vs placebo for chronic low back pain in Iraq/Afghanistan-era veterans. Clinically meaningful pain reduction and 2 pain-interference domains improved vs pl…

View Study

Majewska MD. "Neurosteroids: endogenous bimodal modulators of the GABA-A receptor. Mechanism of action and physiological significance." Prog Neurobiol 1992. **PMID: 1409647**

pubmed.ncbi.nlm.nih.gov · 1992

Foundational paper establishing pregnenolone sulfate as GABA-A negative modulator and the bimodal allopregnanolone-positive / P5-sulfate-negative neurosteroid framework. Most-cited mechanistic refe…

View Study
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