Pregnenolone is the first steroid the body makes from cholesterol. Every other steroid hormone, including progesterone, cortisol, DHEA, testosterone and estradiol, is built from it further down the pathway. The brain also makes it, and researchers class it as a “neurosteroid” because it and its metabolites act on brain receptors.
In the US it is sold over the counter as a dietary supplement, promoted for brain and immune health (Schleiff et al., J Pharm Biomed Anal 2023). Because it sits upstream of testosterone, it is also assumed to support male hormones, and anti-doping researchers have noted it could be misused alongside anabolic steroids (Saudan et al., Steroids 2005). There is no FDA-approved pregnenolone drug. The controlled human trials are small and almost all come from psychiatry and pain research, at doses of 30–500 mg/day. In the best-measured of these trials, 500 mg/day for 8 weeks raised progesterone more than fourfold but did not raise testosterone, DHEA, estradiol or cortisol. No trial has tested it for muscle, strength or body composition.
This page summarizes what the clinical trials, FDA documents and anti-doping research report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Endogenous C21 (pregnane) steroid; precursor of all steroid hormones; neurosteroid |
| Chemistry | 3β-hydroxypregn-5-en-20-one, C₂₁H₃₂O₂, 316.5 g/mol |
| Made by | Cholesterol side-chain cleavage enzyme P450scc (CYP11A1), in mitochondria |
| Approval status | No FDA-approved drug; sold as a dietary supplement; compounded products exist |
| Route studied | Oral capsules or tablets |
| Doses in cited trials | 15–30 mg/day in healthy volunteers; 30–500 mg/day in psychiatric and pain trials, for 4–12 weeks |
| Half-life | No published human half-life; with twice-daily dosing, plasma levels stayed raised across each 12-hour interval |
| Effect on testosterone | No rise in total or free testosterone at 500 mg/day for 8 weeks (small trial) |
| US schedule | Not a controlled substance; not listed in Schedule III |
| WADA status | Not named on the 2026 Prohibited List |
What it is
Pregnenolone is a 21-carbon steroid. Its chemical name is 3β-hydroxypregn-5-en-20-one (PubChem CID 8955). Its sulfated form, pregnenolone sulfate, circulates in the blood and is studied separately for its actions in the brain.
Where it sits in the hormone pathway
A cell counts as steroid-producing if it expresses P450scc, the enzyme that cuts the side chain off cholesterol. That conversion of cholesterol to pregnenolone, inside mitochondria, is the first, rate-limiting and hormonally regulated step in making all steroid hormones (Miller and Auchus, Endocr Rev 2011). From there, pregnenolone can go several ways:
| Next step | Enzyme | Leads toward |
|---|---|---|
| Pregnenolone → progesterone | 3β-hydroxysteroid dehydrogenase (3βHSD) | Progesterone, aldosterone, cortisol |
| Pregnenolone → 17α-hydroxypregnenolone | P450c17 (17α-hydroxylase) | Cortisol, or DHEA |
| 17α-hydroxypregnenolone → DHEA | P450c17 (17,20-lyase activity) | Androstenedione, testosterone, estrogens |
| Pregnenolone → pregnenolone sulfate | Sulfotransferases (SULT2A1, SULT2B1a) | Pregnenolone sulfate |
Pathway from Miller and Auchus, 2011. Which route dominates depends on the tissue. In the adrenal cortex, for example, the outer zona glomerulosa lacks P450c17 and makes aldosterone, the zona fasciculata makes cortisol, and the inner zona reticularis turns pregnenolone into DHEA.
DHEA, in turn, is the parent of 7-keto-DHEA. Being upstream in a pathway does not mean that swallowing it raises everything downstream, and the human data below show that it mainly does not.
A neurosteroid
Pregnenolone and pregnenolone sulfate can accumulate in the brain independently of what the adrenal glands and gonads make (Steiger et al., Brain Res 1993). Two pathways are of research interest:
- Pregnenolone sulfate behaves in lab studies as a GABA-A receptor antagonist and a positive modulator of NMDA (glutamate) receptors (Steiger et al., 1993; Marx et al., Psychopharmacology 2014).
- Allopregnanolone, made from pregnenolone via progesterone (Miller and Auchus, 2011), enhances GABA-A receptor responses, the same receptor that benzodiazepines act on (Marx et al., 2014).
Most of the trials below were designed around raising allopregnanolone and pregnenolone sulfate, not sex hormones.
History
Pregnenolone was tried as a drug in the 1940s and 1950s at 25–500 mg/day, including in rheumatoid arthritis and other inflammatory conditions. Several of those early reports described symptom improvements and good tolerability (as reviewed by Marx et al., Neuropsychopharmacology 2009). They were not placebo-controlled trials by modern standards.
How it behaves in the body
There is no formal human pharmacokinetic study of oral pregnenolone, and no published half-life. Trials have instead measured blood steroid levels before and after dosing.
| Study | Population | Dose | Serum pregnenolone | Allopregnanolone |
|---|---|---|---|---|
| Sripada et al., Biol Psychiatry 2013 | 31 healthy men aged 18–32 | 400 mg, single dose | About 3× baseline at 3 h | About 7× baseline |
| Naylor et al., JAMA Netw Open 2020 | 94 veterans with low back pain | 100 → 300 → 500 mg/day over 4 weeks | 1,353, 2,444 and 2,786 pg/mL vs about 600–680 pg/mL on placebo | 6.5×, 14.3× and 17.6× placebo |
| Marx et al., 2009 | Schizophrenia, pregnenolone arm n = 8–9 | Up to 500 mg/day for 8 weeks | About 4× baseline | About 5× baseline |
Naylor values are the pregnenolone-group means after each dose step (1 week of 100 mg, 1 week of 300 mg, 2 weeks of 500 mg).
A Yale pilot study sampled blood repeatedly over 32.5 hours in 7 people with cocaine use disorder, 5 of whom took 300 or 500 mg/day as two doses 12 hours apart and 2 placebo. Plasma pregnenolone stayed higher than placebo throughout, with no significant difference between the two doses. The investigators could not calculate a half-life, but concluded that twice-daily dosing gave stable raised levels (Gao et al., Life 2024).
Effects on other hormones
The most complete hormone panel comes from the 2009 schizophrenia trial. Patients took up to 500 mg/day for 8 weeks, and paired before-and-after levels were compared (Marx et al., 2009):
| Hormone | Change on pregnenolone |
|---|---|
| Pregnenolone sulfate | About 3× higher |
| Progesterone | 0.38 → 2.17 ng/mL (more than 4× higher) |
| DHEA sulfate (DHEAS) | About 16% higher |
| DHEA | No significant change |
| Total testosterone | No significant change |
| Free testosterone | No significant change |
| Estradiol | No significant change |
| Androstenedione | No significant change |
| Cortisol | No significant change |
The pregnenolone arm had only 8–9 patients, so small changes could have been missed. Later trials did not report sex hormones, but two measured androsterone (an androgen metabolite). In the back-pain trial, androsterone fell slightly on pregnenolone compared with placebo (Naylor et al., 2020), and the bipolar depression trial reported a modest fall in androsterone as well (Brown et al., Neuropsychopharmacology 2014).
About pregnenolone as a testosterone booster. Because it sits at the top of the pathway, pregnenolone is often assumed to raise testosterone. In the only trial with a full hormone panel, 500 mg/day for 8 weeks did not raise total or free testosterone, while progesterone rose more than fourfold. In 5 men given a single 50 mg dose, the testosterone/epitestosterone and testosterone/LH ratios did not change (Saudan et al., 2005). We found no controlled trial of pregnenolone in men on testosterone therapy.
Regulatory status
- Supplement, not an approved drug. FDA scientists have noted that pregnenolone is frequently sold as an over-the-counter dietary supplement, that there are no FDA-approved pregnenolone drugs, and that compounded pregnenolone products are available to US patients (Schleiff et al., 2023).
- Compounding review. FDA’s Pharmacy Compounding Advisory Committee discussed pregnenolone on November 20–21, 2017, as a substance nominated for the list of bulk drug substances that pharmacies may use under section 503A. FDA reviewed it for rheumatoid arthritis, high cholesterol, bipolar disorder (including with substance abuse) and schizophrenia (82 FR 49632). It has also been nominated for the 503B list used by outsourcing facilities (Schleiff et al., 2023).
- Controlled substance status. Pregnenolone is not named among the anabolic steroids in Schedule III (21 CFR 1308.13).
- Sport. Pregnenolone is not named on the WADA 2026 Prohibited List (WADA 2026 Prohibited List). Anti-doping researchers found that it shifts the carbon-isotope signature of pregnanediol, a reference steroid used in tests for testosterone misuse. They proposed that it be considered for the list as a masking agent and suggested alternative reference steroids for testing (Piper et al., Drug Test Anal 2011). DHEA, which is downstream of pregnenolone, is a separate matter: it is prohibited by name under S1.1.
What the research shows
All of the trials below used oral pregnenolone as an add-on to usual treatment unless stated otherwise. Most were small, short and run by a few research groups, and several report multiple outcomes with only some reaching significance.
Schizophrenia
Schizophrenia is the most-studied use. Results have been mixed:
| Trial | n | Daily dose, duration | Main finding vs placebo |
|---|---|---|---|
| Marx et al., 2009 | 21 randomized (18 completed ≥4 weeks) | Up to 500 mg, 8 weeks | Greater fall in negative symptoms (SANS change 10.38 vs 2.33, p = 0.048); no difference in cognitive composite scores |
| Ritsner et al., J Clin Psychiatry 2010 | 58 | 30 mg or 200 mg (also a DHEA 400 mg arm), 8 weeks | 30 mg reduced positive symptoms and movement side effects and improved attention and working memory; 200 mg did not differ from placebo |
| Ritsner et al., Psychiatry Clin Neurosci 2014 | 60 (recent-onset) | 50 mg, 8 weeks | Reduced negative symptom scores (effect size d = 0.79); other symptoms and functioning unchanged |
| Marx et al., 2014 | 120 | 100 → 300 → 500 mg, 8 weeks (NCT00894842) | No effect on cognition (primary); better functional capacity scores (p = 0.03) |
| Kashani et al., J Psychiatr Res 2017 | 82 women | 50 mg with risperidone, 8 weeks | No significant difference in total symptoms (mean difference −9.41, 95% CI −20.24 to 1.41) |
A 2015 meta-analysis of hormone add-on treatments in schizophrenia pooled 4 pregnenolone trials and found no overall effect on symptoms (Heringa et al., Schizophr Res 2015). Pregnenolone was well tolerated across these trials.
Bipolar depression
In a 12-week trial, 80 adults with bipolar disorder in a depressed phase took pregnenolone titrated to 500 mg/day, or placebo, alongside their usual medicines (Brown et al., 2014):
- The clinician-rated depression scale (HRSD) showed a significant treatment-by-week effect, but the self-rated scale (IDS-SR) did not.
- Remission on the self-rated scale was 61% vs 37% (p = 0.046), but remission on the clinician-rated scale did not differ.
- Changes in depression did not correlate with changes in neurosteroid levels.
Chronic low back pain
The largest pain trial randomized 100 Iraq- and Afghanistan-era US veterans to pregnenolone or placebo for 4 weeks, at 100 mg/day for 1 week, 300 mg/day for 1 week and 500 mg/day for 2 weeks (Naylor et al., 2020). Results, on a 0–10 pain scale:
| Measure | Placebo | Pregnenolone |
|---|---|---|
| Pain diary rating, baseline | 4.83 | 5.24 |
| Pain diary rating, end of treatment | 4.74 | 4.19 |
| Adjusted difference vs placebo | — | −0.56 (p = 0.02) |
Pain interference with work and activity also improved. The pregnenolone group started with pain ratings about 8% higher than placebo, and the trial was not designed to find an effective dose. It has not been replicated.
Alcohol and cocaine use disorders
A Yale group has run pilot trials of 300 and 500 mg/day for 8 weeks:
- Alcohol. In 43 people with alcohol use disorder, both doses reduced stress- and cue-provoked alcohol craving in laboratory sessions, and 300 mg/day reduced stress-induced anxiety (Milivojevic et al., Psychopharmacology 2023).
- Cocaine. In 55 people with cocaine use disorder, provoked craving rose on placebo but not on pregnenolone. The 300 mg group used lower amounts of cocaine than placebo (p = 0.047), but the 500 mg group did not, and the reduction in days of use was not significant (Sakmar et al., Drug Alcohol Depend 2025).
These are pilot results with laboratory craving as the main outcome, not trials of relapse or long-term abstinence.
Mood, memory and sleep in healthy people
- Low doses. In a crossover trial, 17 healthy volunteers took 15 mg/day for 2 weeks and then 30 mg/day for 2 weeks. Pregnenolone had no significant effect on mood, memory, sleep quality or well-being. In a small follow-up, people pre-treated with pregnenolone (n = 5) were less sedated by a dose of diazepam than those on placebo (n = 6) (Meieran et al., Psychoneuroendocrinology 2004).
- Single 400 mg dose. In 31 healthy young men, a single dose changed brain activity on functional MRI during an emotion task, but it did not reduce overall self-reported anxiety (Sripada et al., 2013).
- Sleep. A single dose in healthy men increased slow-wave sleep and did not change nighttime cortisol or growth hormone secretion (Steiger et al., 1993).
Muscle, strength and body composition
We found no controlled human trial of pregnenolone for muscle, strength, athletic performance or body composition. Given that 500 mg/day did not raise testosterone in the trial that measured it, there is no hormonal basis in the human data for an anabolic effect.
Side effects and risks
Tolerability in trials
Across trials of up to 500 mg/day for up to 12 weeks, pregnenolone was reported as well tolerated:
- Schizophrenia, 500 mg/day. Side effects more frequent than on placebo were two cases of mild restlessness, one of mild cold extremities and one of mild muscle pain or stiffness. There were no significant changes in weight, blood pressure, pulse, glucose, electrolytes, TSH or HDL (Marx et al., 2009).
- Bipolar depression, 500 mg/day. Overall side-effect burden did not differ from placebo. Adverse events on pregnenolone were a corneal ulcer from a contact lens, a skin abscess with an allergic reaction to the antibiotic, a skin rash and sinusitis (Brown et al., 2014).
- Low back pain, up to 500 mg/day. No serious adverse events, and few adverse events overall, evenly distributed between groups (Naylor et al., 2020).
- Cocaine use disorder, 300–500 mg/day. The share of people reporting at least one non-serious adverse event did not differ from placebo (Sakmar et al., 2025).
These trials were small and lasted 4–12 weeks. No long-term safety data exist.
Hormonal effects
Pregnenolone is a hormone precursor, and the progesterone rise seen at 500 mg/day is a real hormonal effect. Trial investigators have treated this as a reason for caution:
- The 2009 schizophrenia trial excluded people using oral contraceptives or estrogen, noting that changes in downstream steroids could in theory affect those treatments (Marx et al., 2009).
- The bipolar trial excluded people using systemic corticosteroids, hormone replacement, oral contraceptives or warfarin, and those who were pregnant (Brown et al., 2014).
- The bipolar investigators noted that because pregnenolone raises progesterone, it might affect women more than men.
There are no data on pregnenolone in pregnancy or breastfeeding, in hormone-sensitive cancers, or in children outside one autism trial in adolescents (Ayatollahi et al., Clin Neuropharmacol 2020).
Interaction with sedatives
In the small healthy-volunteer study, 4 weeks of pregnenolone reduced the sedation produced by diazepam (Meieran et al., 2004). The study was too small to draw conclusions, but it suggests pregnenolone can change how people respond to benzodiazepines.
Quality and standardization
No US Pharmacopeia (USP) monograph exists for pregnenolone, so there is no official quality standard for the substance or its products. FDA scientists noted that a lack of standardization in compounded hormone products may increase the chance of underdosing, overdosing or contamination. When they developed a testing method, the seven bulk samples and five supplements (three tablets, two capsules) they analyzed met the expected identity and assay criteria (Schleiff et al., 2023). That small sample says little about the wider market.
Key takeaways
- The first steroid in the pathway. The body makes pregnenolone from cholesterol, and every other steroid hormone is built from it. Being upstream does not mean that taking it raises the hormones downstream.
- It does not raise testosterone in the available data. At 500 mg/day for 8 weeks, testosterone, free testosterone, DHEA, estradiol and cortisol did not change, while progesterone rose more than fourfold.
- The research is about the brain, not muscle. Small trials in schizophrenia, bipolar depression, low back pain and addiction show mixed or preliminary results. A 2015 meta-analysis found no overall benefit in schizophrenia, and no trial has studied muscle or strength.
- Well tolerated in short trials. Doses up to 500 mg/day for 4–12 weeks caused few side effects, but no long-term safety data exist.
- Unregulated as a drug. It is a US dietary supplement with no FDA-approved form and no USP quality standard, is not a controlled substance, and is not named on the WADA list.
Sources
- National Center for Biotechnology Information. Pregnenolone, PubChem CID 8955. PubChem.
- Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81–151. PubMed; PMC.
- Steiger A, Trachsel L, Guldner J, et al. Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation. Brain Res. 1993;615(2):267–274. PubMed.
- Marx CE, Keefe RS, Buchanan RW, et al. Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia. Neuropsychopharmacology. 2009;34(8):1885–1903. PubMed; PMC.
- Marx CE, Lee J, Subramaniam M, et al. Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. Psychopharmacology (Berl). 2014;231(17):3647–3662. PubMed; trial registration NCT00894842.
- Sripada RK, Marx CE, King AP, et al. Allopregnanolone elevations following pregnenolone administration are associated with enhanced activation of emotion regulation neurocircuits. Biol Psychiatry. 2013;73(11):1045–1053. PubMed.
- Naylor JC, Kilts JD, Shampine LJ, et al. Effect of pregnenolone vs placebo on self-reported chronic low back pain among US military veterans: a randomized clinical trial. JAMA Netw Open. 2020;3(3):e200287. PubMed; PMC.
- Gao H, Magin Z, Fogelman N, et al. Stability and reliability of repeated plasma pregnenolone levels after oral pregnenolone dosing in individuals with cocaine use disorder: pilot findings. Life (Basel). 2024;14(11):1483. PubMed.
- Brown ES, Park J, Marx CE, et al. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014;39(12):2867–2873. PubMed; PMC.
- Saudan C, Desmarchelier A, Sottas PE, et al. Urinary marker of oral pregnenolone administration. Steroids. 2005;70(3):179–183. PubMed.
- Schleiff M, Sommers C, Yang J, et al. Development and validation of a quantitative proton NMR method for the analysis of pregnenolone. J Pharm Biomed Anal. 2023;222:115073. PubMed.
- Food and Drug Administration. Pharmacy Compounding Advisory Committee; notice of meeting; establishment of a public docket; request for comments. Federal Register. October 26, 2017;82:49632 (FR Doc 2017-23223). govinfo.
- 21 CFR 1308.13, Schedule III. eCFR.
- World Anti-Doping Agency. 2026 Prohibited List. WADA 2026 Prohibited List.
- Piper T, Schlug C, Mareck U, Schänzer W. Investigations on changes in ¹³C/¹²C ratios of endogenous urinary steroids after pregnenolone administration. Drug Test Anal. 2011;3(5):283–290. PubMed.
- Ritsner MS, Gibel A, Shleifer T, et al. Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomized, controlled, 2-center, parallel-group trial. J Clin Psychiatry. 2010;71(10):1351–1362. PubMed.
- Ritsner MS, Bawakny H, Kreinin A. Pregnenolone treatment reduces severity of negative symptoms in recent-onset schizophrenia: an 8-week, double-blind, randomized add-on two-center trial. Psychiatry Clin Neurosci. 2014;68(6):432–440. PubMed.
- Kashani L, Shams N, Moazen-Zadeh E, et al. Pregnenolone as an adjunct to risperidone for treatment of women with schizophrenia: a randomized double-blind placebo-controlled clinical trial. J Psychiatr Res. 2017;94:70–77. PubMed.
- Heringa SM, Begemann MJ, Goverde AJ, Sommer IE. Sex hormones and oxytocin augmentation strategies in schizophrenia: a quantitative review. Schizophr Res. 2015;168(3):603–613. PubMed.
- Milivojevic V, Sullivan L, Tiber J, et al. Pregnenolone effects on provoked alcohol craving, anxiety, HPA axis, and autonomic arousal in individuals with alcohol use disorder. Psychopharmacology (Berl). 2023;240(1):101–114. PubMed.
- Sakmar E, Wemm S, Fogelman N, et al. Pregnenolone reduces provoked craving and cocaine use in men and women with cocaine use disorder: a pilot trial. Drug Alcohol Depend. 2025;274:112765. PubMed.
- Meieran SE, Reus VI, Webster R, et al. Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation. Psychoneuroendocrinology. 2004;29(4):486–500. PubMed.
- Ayatollahi A, Bagheri S, Ashraf-Ganjouei A, et al. Does pregnenolone adjunct to risperidone ameliorate irritable behavior in adolescents with autism spectrum disorder: a randomized, double-blind, placebo-controlled clinical trial? Clin Neuropharmacol. 2020;43(5):139–145. PubMed.