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Pn4.5
Pregnenolone Research
Likely helps
32 peer-reviewed studies
What the evidence says
Likely helps
Pregnenolone appears to help in 6 of 7 studies with measurable effects — the evidence leans clearly favourable.
Most evidence is from high-quality meta-analyses and randomised trials published 1992–2025 with a typical study size of 52 participants.
Based on 32 studies · 3 meta-analyses · 16 RCTs · 5,079 total participants
Confidence
High confidence
What the studies found
6helped1unclear· 25 more without graded effect data
By outcome
Therapeutic & clinical
Likely helps31 studies
Cognitive functionNeurosteroid studied for cognition; memory benefit unproven in healthy people · 2-8 weeks
Likely helps9 studies
Anxiety & stressGABAergic mechanism; anxiolytic benefit not established in healthy people · 2-4 weeks · Plausible role in stress-hormone balance, but unproven in healthy adults · 4-8 weeks
Mostly mechanism / observational7 studies
Substance-use & cravings
Mostly mechanism / observational7 studies
Depression & moodModest, mixed mood effects in small psychiatric trials; unproven for general mood · 2-4 weeks
Mostly mechanism / observational5 studies
Women's healthUpstream hormone precursor; effects on hormonal balance are unpredictable and unproven · 4-8 weeks
Mostly mechanism / observational4 studies
Men's vitalityUpstream hormone precursor; downstream effects are unpredictable and benefit is unproven · 4-8 weeks
Mostly mechanism / observational3 studies
Safety profile
Too few graded studies2 studies
Pain & analgesia
Too few graded studies1 study
By the numbers
Pulled from 25 studies with measurable effects
Likely real effects
71%
across studies
People studied
5,079
typical study: 52 people
Strongest designs
19
3 pooled, 16 randomised
Showed benefit
86%
6/7 studies
How long studies ran
1–3 months
5
Populations Studied
Patients with schizophrenia5
Women with schizophrenia2
Patients with schizophrenia and schizoaffective disorder2
Bipolar disorder patients1
Active research area
13 studies in the last 5 years · Latest meta-analysis: 2019
199220082025
1Anti-inflammatory adjuvant therapy efficacy vs antipsychotics aloneMeta-AnalysisCited 100×n=2,914 · very large study2019
The comparative evaluation of efficacy and safety supported the use of anti-inflammatory adjuvant therapy over the use of antipsychotics alone.
Cho M et al. · The Australian and New Zealand journal of psychiatry (2019)
The comparative evaluation of efficacy and safety supported the use of anti-inflammatory adjuvant therapy over the use of antipsychotics alone.
However, future studies could focus on patients with homogeneous clinical profile to figure out more detailed effects of anti-inflammatory therapy.
2Total symptoms improvement with estrogen actionMeta-AnalysisCited 65×n=1,149 · large study2015
Estrogens and SERMs could be effective augmentation strategies in the treatment of women with schizophrenia, although potential side effects, partially associated with longer duration use, should be taken into account.
Heringa SM et al. · Schizophrenia research (2015)
Large benefit
← WorseNo effectBetter →
Likely real
Significant effects were found for estrogen action (k=10), regarding total symptoms (Hedges' g=0.63, p=0.001), positive (Hedges' g=0.42, p<0.001), and negative symptoms (Hedges' g=0.35, p=0.001).
Testosterone augmentation in males (k=1) was beneficial only for negative symptoms (Hedges' g=0.82, p=0.027).
Estrogens and SERMs could be effective augmentation strategies in the treatment of women with schizophrenia, although potential side effects, partially associated with longer duration use, should be taken into account.
3Schizophrenia symptom severityMeta-AnalysisCited 163×n=270 · medium study2019
Some, but not all agents with anti-inflammatory properties showed efficacy.
Çakici N et al. · Psychological medicine (2019)
Noticeable benefit
← WorseNo effectBetter →
The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies.
Some, but not all agents with anti-inflammatory properties showed efficacy.
Effective agents were aspirin, estrogens, minocycline, and NAC.
4Non-dopaminergic treatment efficacy for schizophrenia symptomsSystematic ReviewCited 5×2024
Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function.
6Cognitive improvement in major mood disorders and schizophreniaSystematic ReviewCited 55×n=12 · very small study2018
Positive trials were found for BD (mifepristone), MDD (dehydroepiandrosterone and fludrocortisone) and schizophrenia (dehydroepiandrosterone, raloxifene and pregnenolone).
Soria V et al. · Psychoneuroendocrinology (2018)
Positive trials were found for BD (mifepristone), MDD (dehydroepiandrosterone and fludrocortisone) and schizophrenia (dehydroepiandrosterone, raloxifene and pregnenolone).
The use of drugs targeting hormones related to the HPA axis and sex steroids is a promising field of research that might help to improve the cognitive outcome of patients with schizophrenia, bipolar disorder and major depressive disorder in the near future.
This review uniquely highlights the paradigm shift offered by neurosteroids, moving beyond the traditional monoamine hypothesis, and positions them as novel, multi-target therapeutics capable of addressing the complex neurobiology of TRD.
Nagpurkar K, Ghive P, Kale M, Nistane N, Taksande B, Umekar M, Trivedi R. · Neuroscience (2025)
However, challenges such as limited bioavailability, long-term safety concerns, and regulatory hurdles must be addressed to optimize their clinical application.
This review explores the therapeutic potential of neurosteroids in TRD, discussing their mechanisms, clinical evidence, and future directions.
The findings support the integration of neurosteroid-based treatments into TRD management, offering new hope for patients unresponsive to conventional antidepressants.
Additionally, we discuss the impact of pharmacological interventions targeting 5α reductase activity in neuropsychiatric conditions characterized by excessive activation of the dopaminergic system, ranging from psychotic (endo)phenotypes and motor complications to decision-making problems and addiction.
Scheggi S, Concas L, Corsi S, Carta M, Melis M, Frau R. · Neuroscience and biobehavioral reviews (2024)
Specifically, subclasses of Neuro(active)steroids belonging to the 5α reductase pathway are prominently involved in brain disorders characterized by dopaminergic signaling imbalances.
This review highlights the neuromodulatory effects of Neuro(active)steroids on the dopamine system and related aberrant behavioral phenotypes.
We critically appraise the role of pregnenolone, progesterone, and allopregnanolone on dopamine signaling.
9neuroactive steroid effects in Parkinson's diseaseReview2024
Thus it might be useful to target different cellular mechanisms that contribute to neuronal loss and neuroactive steroids provide therapeutics options as they have multiple mechanisms of action.
Bourque M, Morissette M, Di Paolo T. · Neuroscience and biobehavioral reviews (2024)
Here, we review the effect on sex hormones (estrogen, androgen, progesterone and its metabolites) as well as androstenediol, pregnenolone and dehydroepiandrosterone) in human studies and in animal models of PD.
The effect of neuroactive steroids is reviewed by considering sex and hormonal status to help identify specifically for women and men with PD what might be a preventive approach or a symptomatic treatment.
PD is a complex disease and the pathogenesis likely involves multiple cellular processes.
10Emotion regulation neurocircuit activation after pregnenolone administrationRCTn=31 · small study2013
During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety.
Sripada RK et al. · Biological Psychiatry (2013)
Compared with placebo, allopregnanolone was associated with reduced activity in the amygdala and insula across all conditions.
During the appraisal condition, allopregnanolone increased activity in the dorsal medial prefrontal cortex and enhanced connectivity between the amygdala and dorsal medial prefrontal cortex, an effect that was associated with reduced self-reported anxiety.
These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacologic intervention in the treatment of anxiety disorders.
11Cocaine craving and use reductionRCTn=55 · small study2025
These pilot findings suggest that PREG reduces cocaine craving and improves cocaine use outcomes in treatment seeking individuals with CUD, supporting further assessment of PREG in the treatment of CUD.
Sakmar E et al. · Drug and alcohol dependence (2025)
Could be chance
A non-significant reduction was observed for % days of cocaine used (p = .122).
These pilot findings suggest that PREG reduces cocaine craving and improves cocaine use outcomes in treatment seeking individuals with CUD, supporting further assessment of PREG in the treatment of CUD.
The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.
Brown ES et al. · Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology (2014)
In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed.
Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ(2)(1)=3.99, p=0.046), but not the HRSD.
In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=-0.43, p=0.036) and pregNANolone (r(22)=-0.48, p=0.019) levels.
13Negative symptom severity in recent-onset schizophreniaRCTCited 46×n=52 · small study2014
Thus, add-on pregnenolone reduces the severity of negative symptoms in recent-onset schizophrenia and schizoaffective disorder, especially among patients who are not treated with concomitant mood stabilizers.
Ritsner MS et al. · Psychiatry and clinical neurosciences (2014)
Large benefit
← WorseNo effectBetter →
Fifty-two participants (86.7%) completed the trial.
Compared to placebo, adjunctive pregnenolone significantly reduced Positive and Negative Symptoms Scale negative symptom scores with moderate effect sizes (d = 0.79).
Significant improvement was observed in weeks 6 and 8 of pregnenolone therapy among patients who were not treated with concomitant mood stabilizers (arms × visit × mood stabilizers; P = 0.010).
14Alcohol craving and HPA axis normalizationRCTCited 28×n=43 · small study2023
Findings indicate that pregnenolone decreases stress- and alcohol cue-provoked craving and normalizes HPA axis and autonomic arousal in individuals with AUD, thereby supporting the need for further assessment of pregnenolone in the treatment of AUD.
Milivojevic V et al. · Psychopharmacology (2023)
Pregnenolone levels were significantly increased in the PREG groups versus PBO.
Findings indicate that pregnenolone decreases stress- and alcohol cue-provoked craving and normalizes HPA axis and autonomic arousal in individuals with AUD, thereby supporting the need for further assessment of pregnenolone in the treatment of AUD.
15Negative and anxiety symptoms of schizophreniaRCTCited 16×n=40 · small study2018
Pregnenolone with L-theanine augmentation may offer a new therapeutic strategy for treatment of negative and anxiety symptoms in schizophrenia and schizoaffective disorder.
Kardashev A et al. · Clinical schizophrenia & related psychoses (2018)
Negative symptoms such as blunted affect, alogia, and anhedonia (SANS) were found to be significantly improved with moderate effect sizes among patients who received PREG-LT, in comparison with the placebo group.
Pregnenolone with L-theanine augmentation may offer a new therapeutic strategy for treatment of negative and anxiety symptoms in schizophrenia and schizoaffective disorder.
16PANSS total score changesRCTCited 7×n=82 · small study2017
No significant difference was found in the PANSS total score changes between the two arms (mean difference (CI 95%) = -9.41 (-20.24 to 1.41); p = 0.087).
Kashani L et al. · Journal of psychiatric research (2017)
No clear effect
← WorseNo effectBetter →
Borderline
No significant difference was found in the PANSS total score changes between the two arms (mean difference (CI 95%) = -9.41 (-20.24 to 1.41); p = 0.087).
Significant differences were initially found for PANSS negative change scores (mean difference (CI 95%) = -2.61 (-5.03 to -0.19); p = 0.035) and general psychopathology change scores (mean difference (CI 95%) = -5.93 (-11.37 to -0.48); p = 0.033).
However, these findings did not survive Bonferroni correction for multiple testing.
17Visual attention deficitRCTCited 37×n=60 · small study2017
Pregnenolone augmentation demonstrated significant amelioration of the visual attention deficit in recent-onset SZ/SA.
Kreinin A et al. · Clinical schizophrenia & related psychoses (2017)
Noticeable benefit
← WorseNo effectBetter →
Likely real
Compared to placebo, adjunctive PREG significantly reduced the deficits in visual attention measured with the Matching to Sample Visual Search task (p=0.002), with moderate effect sizes (d=0.42).
Pregnenolone augmentation demonstrated significant amelioration of the visual attention deficit in recent-onset SZ/SA.
Long-term, large-scale studies are required to obtain greater statistical significance and more confident clinical generalization.
However, a further amelioration of symptoms by additional drugs that enhance extinction learning is desirable.
An interesting candidate is pregnenolone, which positively modulates NMDA and GABAA receptors in preclinical studies and influences amygdala and prefrontal activity in humans.
19Chronic low back pain reductionRCTCited 19×n=94 · small study2020
Participants receiving pregnenolone reported a clinically meaningful reduction in low back pain and 2 pain interference domains compared with those receiving placebo.
Naylor JC et al. · JAMA network open (2020)
Noticeable benefit
← WorseNo effectBetter →
Likely real
A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included.
Veterans randomized to pregnenolone reported significant reductions in low back pain relative to those randomized to placebo.
Least-square mean (LSM) analysis showed that pain scores significantly improved in the pregnenolone-treated group compared with placebo (LSM [SE] change in pain diary rating, -0.56 [0.25]; P = .02; LSM [SE] change in pain recall, -0.70 [0.27]; P = .01).
20Stress-induced craving and autonomic arousal in cocaine use disorderRCTCited 14×n=30 · small study2022
Findings indicate that pregnenolone decreases stress- and cocaine cue-provoked craving and anxiety and reduces stress-induced autonomic arousal in individuals with CUD.
Milivojevic V et al. · Biomolecules (2022)
PREG significantly increased pregnenolone levels compared to PBO.
Both PREG doses decreased stress- and cocaine cue-induced craving and reduced both stress- and cue-induced anxiety only in the 500 mg/day group.
The 500 mg/day PREG group also displayed decreased stress-induced HR, SBP and DBP.