IV allopregnanolone to improve extinction retention and block reconsolidation in PTSD.

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

This study will test whether a single IV dose of allopregnanolone helps adults with chronic PTSD better retain extinction learning or block reconsolidation of traumatic responses.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 96 (estimated)
• Ages: 18 Years to 55 Years
• Sex: All
• Sponsor: Massachusetts General Hospital (Academic / other)
• Locations: 1 site (Boston, Massachusetts)
• Trial ID: NCT07079761 on ClinicalTrials.gov

What this trial studies

This Phase 2 interventional study gives a single intravenous dose of allopregnanolone or matching placebo to adults with chronic PTSD and uses three-day laboratory paradigms to measure aversive conditioning, extinction, and either extinction retention or reconsolidation blockade. Participants undergo controlled conditioning and extinction sessions with physiological and behavioral measurements to determine whether the drug enhances consolidation of extinction or interferes with reconsolidation of trauma responses. Women are studied in two distinct menstrual phases to account for hormonal effects on neurosteroid levels. The protocol excludes people with imminent safety risks, recent moderate-to-severe substance use disorders, or prohibited medications and requires abstinence from alcohol and certain substances before and during participation.

Who should consider this trial

Good fit: Adults aged 18–55 with chronic PTSD who are generally healthy, willing to abstain from alcohol and drugs as required, and who meet the study's menstrual and contraception criteria for women.

Not a fit: People with imminent self-harm risk, recent moderate or severe substance use disorder, prohibited medications, or who fall outside the age or health requirements are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, a single IV dose could strengthen psychotherapy by improving extinction learning and reducing the return of traumatic responses.

How similar studies have performed: Preclinical work and small human studies indicate neurosteroids can influence fear learning, but using IV allopregnanolone specifically to boost extinction or block reconsolidation in PTSD remains largely experimental.

Eligibility criteria

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).

Where this trial is running

Boston, Massachusetts

• Massachusetts General Hospital — Boston, Massachusetts, United States (Recruiting)

Study contacts

• Study coordinator: Kristen Curran

Conditions Post Traumatic Stress Disorder; Trauma; Allopregnanolone; Neurosteroid