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Pn8.5
Pregnenolone Research
Likely helpsModerate safety
23 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 60 participants.
Based on 23 studies · 3 meta-analyses · 15 RCTs · 5,127 total participants
Confidence
High
What the studies found
6helped1unclear· 16 more without graded effect data
By outcome
Therapeutic & clinical
Likely helps23 studies
Cognitive functionNeurosteroid enhances memory consolidation and recall · 2-4 weeks
Likely helps9 studies
Anxiety & stressNeurosteroid with GABAergic anxiolytic properties · 2-4 weeks · Support for upstream steroid-hormone balance under stress · 4-8 weeks
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.
8Cocaine 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.
10Negative 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).
11Alcohol 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.
12Negative 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.
13PANSS 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.
14Visual 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.
16Chronic 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).
17Stress-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.
19Microtubule associated protein 2 levelsRCTCited 14×n=11 · very small study2017
These findings suggest possible differences in serum MAP-2 levels between bipolar depressed persons and controls and a relationship between changes in depressive symptoms and MAP-2 levels during pregnenolone therapy.
Daftary S et al. · Journal of affective disorders (2017)
MAP2 levels in the bipolar depressed patients (n=11) tended to be higher than in controls (n=4) (p=0.062).
MAP2 level changes correlated positively with change in self-reported depressive symptom scores in the pregnenolone group (r=0.771, p=0.072) but not in the placebo group (r=0.000, p=1.000).
These findings suggest possible differences in serum MAP-2 levels between bipolar depressed persons and controls and a relationship between changes in depressive symptoms and MAP-2 levels during pregnenolone therapy.
20Positive symptoms and cognitive performanceRCTCited 73×n=44 · small study2010
Low-dose PREG augmentation demonstrated significant amelioration of positive symptoms and EPS and improvement in attention and working memory performance of schizophrenia and schizoaffective disorder patients.
Ritsner MS et al. · The Journal of clinical psychiatry (2010)
Low-dose PREG augmentation demonstrated significant amelioration of positive symptoms and EPS and improvement in attention and working memory performance of schizophrenia and schizoaffective disorder patients.
Further double-blind controlled studies are needed to investigate the clinical benefit of pregnenolone augmentation.