Neurosteroids for Treatment of PTSD in Veterans

This study seeks to determine if pregnenolone can improve symptoms of PTSD and other symptoms that commonly occur with PTSD in Iraq/Afghanistan-era Veterans. The total study duration for each participant is 10 weeks. Eligible Veterans with PTSD will receive either pregnenolone or placebo throughout the study duration and will complete mental and physical health assessments at each study visit. Eligible participants will attend 6 in-person study visits and receive several short "check-in" phone calls.

Inclusion Criteria: * At study outset: DSM-5 diagnosis of PTSD with CAPS-5 Total Score \>=30. Following protocol amendment effective 4/13/2023: criterion modified to require diagnosis of PTSD using the CAPS-5 definition, defined by the following: at least one Criterion B symptom, at least one Criterion C symptom, at least 2 Criterion D symptoms and at least 2 Criterion E symptoms. This thus replaced the firm cutoff of CAPS-5 Total Score \>=30. * Females will be required to use a medically and study approved contraceptive or otherwise not be of child-bearing potential * Birth control methods must be non-hormonal * No anticipated need to alter psychiatric medications for duration of study involvement * Ability to participate fully in the informed consent process Exclusion Criteria: * History of allergy to pregnenolone * Medical disorders that may preclude safe administration of pregnenolone or exacerbate PTSD symptoms * Current suicidal or homicidal ideation necessitating clinical intervention or representing an imminent concern * Prior suicide attempt history or suicidal ideation that does not require clinical intervention or represent an imminent concern is permitted * Serious unstable medical illness, such as: * history of cerebrovascular accident * prostate, uterine, or breast cancer * others (at the discretion of the PI and medical oversight team) * Medical conditions not well controlled will be excluded, at the discretion of the PI and Medical Team * Standard pharmacological interventions for PTSD will not be exclusionary, including, but not limited to: * antidepressant medications such as SSRIs, SNRIs, tricyclics, bupropion, mirtazapine, venlafaxine, and nefazodone * mood stabilizers such as carbamazepine, divalproex, lamotrigine, topiramate * atypical antipsychotics, and other agents including prazosin * However, there may be no changes in psychotropic medications for PTSD 4 weeks prior to study randomization * Benzodiazepine use * Current diagnosis of bipolar disorder, schizophrenia or other psychotic disorder, or cognitive disorder due to a general medical condition other than mild TBI (assessed at screening) * Initiation or change in psychotherapy within 3 months of randomization, i.e. psychotherapy must be stable for 3 months prior to study start * Participants on hormonal therapies such as finasteride or hormonal birth control * Female participants who are pregnant or breast-feeding * As indicated by the DSM-5, moderate or severe Substance Use Disorders (excluding caffeine and tobacco) within 1 month of study entry * Mild Alcohol Use Disorder is not exclusionary, at the judgment of the PI and her medical team