Facilitation 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, andEnglish speaking.

• Meet criteria for chronic PTSD (i.e., CAPS-5 determined PTSD duration more than 3months).

• Generally healthy and not on any prohibited medications (that could affect studyoutcomes).

• Willing to abstain from alcohol for 2 weeks and from nicotine, marijuana or illicitdrugs 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 effectivebirth control (except for hormonal contraceptives, unless IUD or a device likeNuvaring) for a week before the IV Allo or placebo infusion, and for one monthafter.

Exclusion Criteria:

• Present an imminent risk to self or others or require clinical intervention tomaintain safety

• Diagnosis of moderate or severe substance use disorder within three months ofscreening per administration of the DIAMOND substance abuse evaluation. Diagnosis ofa mild substance use disorder within three months of screening will be allowed ifthe participant agrees to abstain from illicit drugs for one month and/or alcoholfor 2 weeks prior to the experimental procedures, has a negative screening orfollow-up urine toxicology and/or saliva alcohol test (if the screening test ispositive), and tests negative for these substances on the morning of theexperimental procedures.

• Bipolar I disorder, schizophreniform disorders, or clinically significant psychoticsymptoms apart from the presence of trauma-related sensory hallucinations ornegative 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 ofmoderate 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 beexclusionary under the following conditions:

1. During screening for eligibility:

2. Use of illicit substances, as well as prescribed opiates orbenzodiazepines (either reported or detected on urine toxicology testing)will be exclusionary.

3. Reported non-dependent use of cannabinoids or nicotine (indicated by apositive urine toxicology or cotinine test at screening) will not beexclusionary if the individual agrees to abstain from cannabinoids andnicotine for one month prior to the experimental procedures, has afollow-up negative screening test, and tests negative for these substanceson the mornings of experimental procedures.

4. A positive urine alcohol test at medical screening (which indicatesuncontrolled alcohol use and likely moderate to severe alcohol dependence)will be exclusionary.

5. A high serum gamma-glutamyl-transferase (GGT) test at screening (indicative of more remote recent drinking but not necessarily moderate tosevere alcohol use or dependence) will not be exclusionary if theindividual does not meet criteria for a moderate or severe alcohol usedisorder within three months of screening, agrees to abstain from drinkingfor 2 weeks prior to the experimental procedures, and has normal follow-upurine alcohol and serum GGT tests.

6. Use of non-illicit over the counter or prescribed medications that mayincrease the risk of IV Allo side effects or adversely affect theexperimental results is exclusionary. Participants may agree to stopnon-psychotropic medications used on a prn basis, such as acetaminophen,ibuprofen, or loratadine (a CYP3A inhibitor) for 5 half-lives of theparent drug or active metabolite (whichever is longer) before theexperimental procedures. Regular psychotropic medications (including thoseused to treat non-psychiatric conditions, such as alpha1-antagonistsprescribed for hypertension or urinary hesitancy) may be discontinuedunder the management of the potential participant's non-study prescriberfor 3 months before evaluation for eligibility and participation insubsequent experimental procedures.

7. On the mornings of the PK-1, PK-2, Expt. 1 or Expt. 2 experimental procedures:

8. Use of any medications or substances that may increase the risk of IV Alloside effects or adversely affect the experimental results (indicated byreport, urine toxicology, urine nicotine/cotinine testing, or urinealcohol testing) will be exclusionary.

9. Systemic hormone therapy or contraception will be exclusionary [Exception:Hormonal IUDs (e.g., Mirena, Kyleena, Liletta, and Skyla) or othercontraceptive devices (e.g., Nuvaring)] will be allowed if the participantstill has normal menstrual periods and is found to ovulate usingcommercial 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).