AllopregnanoloneFacilitation of Extinction Retention and Reconsolidation Blockade by IV Allopregnanolone in PTSD.

Inclusion Criteria:

• Between the ages of 18 and 55 (at time of enrollment), reproductively mature, and English speaking.
• Meet criteria for chronic PTSD (i.e., CAPS-5 determined PTSD duration more than 3 months).
• Generally healthy and not on any prohibited medications (that could affect study outcomes).
• Willing to abstain from alcohol for 2 weeks and from nicotine, marijuana or illicit drugs for 4 weeks before experimental procedures and throughout the study.
• For biological females:

• Natural menstrual cycle.
• If of childbearing potential, female and partner must use 2 types of effective birth control (except for hormonal contraceptives, unless IUD or a device like Nuvaring) for a week before the IV Allo or placebo infusion, and for one month after.

Exclusion Criteria:

• Present an imminent risk to self or others or require clinical intervention to maintain safety
• Diagnosis of moderate or severe substance use disorder within three months of screening per administration of the DIAMOND substance abuse evaluation. Diagnosis of a mild substance use disorder within three months of screening will be allowed if the participant agrees to abstain from illicit drugs for one month and/or alcohol for 2 weeks prior to the experimental procedures, has a negative screening or follow-up urine toxicology and/or saliva alcohol test (if the screening test is positive), and tests negative for these substances on the morning of the experimental procedures.
• Bipolar I disorder, schizophreniform disorders, or clinically significant psychotic symptoms apart from the presence of trauma-related sensory hallucinations or negative beliefs.
• History of a suicide attempt within 1 year of enrolling.
• A history of severe TBI is exclusionary for the PK-1 and PK-2 studies. A history of moderate or severe TBI is exclusionary for the main studies (i.e., Expt. 1 and Expt. 2).
• Diagnosis of sleep apnea
• Awake resting O2 saturation < 96%
• Severe renal failure with an eGFR <30 ml/min
• Use of medications or substances (by report or toxicology testing) will be exclusionary under the following conditions:

1. During screening for eligibility:

1. Use of illicit substances, as well as prescribed opiates or benzodiazepines (either reported or detected on urine toxicology testing) will be exclusionary.
2. Reported non-dependent use of cannabinoids or nicotine (indicated by a positive urine toxicology or cotinine test at screening) will not be exclusionary if the individual agrees to abstain from cannabinoids and nicotine for one month prior to the experimental procedures, has a follow-up negative screening test, and tests negative for these substances on the mornings of experimental procedures.
3. A positive urine alcohol test at medical screening (which indicates uncontrolled alcohol use and likely moderate to severe alcohol dependence) will be exclusionary.
4. A high serum gamma-glutamyl-transferase (GGT) test at screening (indicative of more remote recent drinking but not necessarily moderate to severe alcohol use or dependence) will not be exclusionary if the individual does not meet criteria for a moderate or severe alcohol use disorder within three months of screening, agrees to abstain from drinking for 2 weeks prior to the experimental procedures, and has normal follow-up urine alcohol and serum GGT tests.
5. Use of non-illicit over the counter or prescribed medications that may increase the risk of IV Allo side effects or adversely affect the experimental results is exclusionary. Participants may agree to stop non-psychotropic medications used on a prn basis, such as acetaminophen, ibuprofen, or loratadine (a CYP3A inhibitor) for 5 half-lives of the parent drug or active metabolite (whichever is longer) before the experimental procedures. Regular psychotropic medications (including those used to treat non-psychiatric conditions, such as alpha1-antagonists prescribed for hypertension or urinary hesitancy) may be discontinued under the management of the potential participant's non-study prescriber for 3 months before evaluation for eligibility and participation in subsequent experimental procedures.
2. On the mornings of the PK-1, PK-2, Expt. 1 or Expt. 2 experimental procedures:

1. Use of any medications or substances that may increase the risk of IV Allo side effects or adversely affect the experimental results (indicated by report, urine toxicology, urine nicotine/cotinine testing, or urine alcohol testing) will be exclusionary.
2. Systemic hormone therapy or contraception will be exclusionary \[Exception: Hormonal IUDs (e.g., Mirena, Kyleena, Liletta, and Skyla) or other contraceptive devices (e.g., Nuvaring)\] will be allowed if the participant still has normal menstrual periods and is found to ovulate using commercial urine test kits provided by study).

• Pregnancy (urine pregnancy tests given at each in-person session).
• Breast-feeding.
• Unable to tolerate IV placement or blood drawing by needle stick.
• Wear hearing aid(s) (For Expt. 1 and 2, not PK studies).
• Fail hearing test (For Expt. 1 and 2, not PK studies).