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

Summary

Purpose: About 6.4% of the U.S. population suffers from posttraumatic stress disorder (PTSD). Trauma-focused psychotherapies are generally effective in PTSD, but responses vary greatly across individuals and PTSD subpopulations. Neurobiological factors impacted by life experiences, stress, and genetics can affect treatment responses. These factors can alter brain capacities needed to reprocess traumatic memories prevent them from triggering intensely distressing, disruptive, out-of-place responses.

For example, during psychotherapy for PTSD, trauma memory activation engages two competing brain processes that affect recovery: "extinction" versus "reconsolidation" of trauma-related emotional, physiological, and behavioral responses. This study tests whether a single intravenous (IV) dose of allopregnanolone (Allo) compared to placebo (which is non-active): promotes consolidation of extinction learning (sub-study 1) or blocks reconsolidation of physiological responses triggered by aversive memories (sub-study 2). The study also tests whether Allo compared to placebo affects retention of non-aversive memories.

Conditions

• Post Traumatic Stress Disorder

Interventions

BEHAVIORAL

Experiment 1: Three-day aversive conditioning, extinction, and extinction retention testing paradigm

Day 1: Aversive conditioning will involve the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a colored shape appearing on a computer monitor (conditioned stimulus). An auditory stimulus will serve as the startle probe. Day 2: Extinction training will occur followed by IV Allo administration. Day 3: The effects of IV Allo (administered on Day 2) on extinction retention as well as reinstatement of conditioned psychophysiological reactions will be assessed.

DRUG

Allopregnanolone (Allo) with 6% USP Dexolve (sulfobutyl ether-beta-cyclodextrin sodium salt) in 0.9% saline for IV infusion will be provided by the University of California, Davis, GMP manufacturer.

On Day 2 of Experiment 1, a 1.7 mcg/kg dose of IV Allo will be administered over 5 minutes at the completion of extinction training to raise resting plasma Allo plus pregnanolone (PA) levels by 1500 pg/ml. This will be followed by a 4-5-hour continuous infusion of IV Allo at 2.6 mcg/kg/hr to maintain resting plasma Allo levels at the target level.

BEHAVIORAL

Experiment 1. Three-day aversive conditioning, extinction, and extinction retention testing paradigm

Day 1: Aversive conditioning will involve the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a colored shape appearing on a computer monitor (conditioned stimulus). An auditory stimulus will serve as the startle probe. Day 2: Extinction training will occur followed by IV Allo administration. Day 3: The effects of IV Allo (administered on Day 2) on extinction retention as well as reinstatement of conditioned psychophysiological reactions will be assessed.

OTHER

Matching IV Placebo

On Day 2 of Experiment 1, participants randomized to placebo will receive IV matching placebo over 5 minutes at the completion of extinction training followed by a continuous infusion of matching placebo over the next 4-5 hours. The matching IV placebo will be administered according to the same per kg dosing regimen as that for active drug.

BEHAVIORAL

Experiment 2. Three-day aversive conditioning, reconsolidation blockade, and testing paradigm

Day 1: Aversive conditioning will involve the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a colored shape appearing on a computer monitor (conditioned stimulus). An auditory stimulus will serve as the startle probe. Day 2: Brief exposure to the conditioned stimulus will be followed by IV Allo administration. Day 3: The effects of IV Allo (administered on Day 2) on reconsolidation blockade and reinstatement of conditioned psychophysiological reactions will be assessed.

DRUG

Allopregnanolone (Allo) with 6% USP Dexolve (sulfobutyl ether-beta-cyclodextrin sodium salt) in 0.9% saline for IV infusion will be provided by the University of California, Davis, GMP manufacturer.

On Day 2 of Experiment 2, a 28 mcg/kg dose of IV Allo will be infused over 30 minutes following brief reactivation of aversively conditioned psychophysiological reactions, after which IV fluid only (0.9% normal saline) will be administered over 4-5 hours.

BEHAVIORAL

Experiment 2. Three-day aversive conditioning, reconsolidation blockade, and testing paradigm

Day 1: Aversive conditioning will involve the pairing of a brief, noxious but not painful air blast to the neck (unconditioned stimulus; US) to a colored shape appearing on a computer monitor (conditioned stimulus). An auditory stimulus will serve as the startle probe. Day 2: Brief exposure to the conditioned stimulus will be followed by IV Allo administration. Day 3: The effects of IV Allo (administered on Day 2) on reconsolidation blockade and reinstatement of conditioned psychophysiological reactions will be assessed.

OTHER

Matching IV Placebo

On Day 2 of Experiment 2, matching IV placebo will be infused over 30 minutes following brief reactivation of aversively conditioned psychophysiological reactions, after which IV fluid only (0.9% normal saline) will be administered over the 4-5 hours. The matching IV placebo will be administered according to the same per kg dosing regimen as that for active drug.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH)

  collaborator NIH

• Massachusetts General Hospital

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

55 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2025-08-04

Primary Completion

2027-04-30

Completion

2027-04-30

FDA Drug

Yes

Countries

• United States

Study Locations