# Neuroactive Steroid Potentiation to Decrease Alcohol Craving, Normalize HPA axis function and Prevent Alcohol Relapse

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $696,371

## Abstract

PROJECT SUMMARY/ABSTRACT
Alcohol Use Disorder (AUD) is a chronic relapsing illness associated with high rates of relapse and in which
there is great need to develop and evaluate novel treatments to decrease relapse rates and the associated
burden of AUD. This application proposes a novel, mechanistic combined laboratory and clinical outcome
study to examine whether the neuroactive steroid precursor Pregnenolone (PREG) via its conversion to the
potent GABAergic neuroactive steroid Allopregnanolone (ALLO) decreases provoked alcohol craving and
anxiety, normalizes stress dysregulation, and improves cognitive flexibility and alcohol use outcomes in
treatment seeking individuals with AUD. Previous research by our group and others has shown that chronic
alcohol abuse dysregulates brain stress pathways including the hypothalamic pituitary adrenal (HPA) axis
responses and is associated high provoked alcohol craving, anxiety, and cognitive flexibility, which in turn, are
predictive of subsequent alcohol relapse and clinical outcomes. Promising new preliminary findings from our
laboratory indicate that potentiating ALLO via administration of its precursors, including PREG, may reverse
such stress-related disruptions and decrease alcohol craving and relapse risk. However, the mechanism by
which PREG, and the specific doses at which it may potentially decrease alcohol craving and relapse risk is
not known. On the basis of these findings, we propose a proof-of-concept 4-year, randomized, double-blind, dose
dependent laboratory and clinical study to evaluate the preliminary efficacy of PREG treatment (200/400
mg/day for 8 weeks) versus placebo (PBO) in 90 AUD men and women. The following specific aims will be
addressed: Aim 1: To evaluate the safety/tolerability of 200mg and 400mg/daily of PREG in AUD individuals.
Aim 2a: To evaluate the effects of PREG doses (PBO, 200 and 400 mg/day) on ALLO levels and on
experimentally provoked craving, HPA dysregulation, anxiety, mood and cognitive flexibility in AUD patients.
Aim 2b: To assess whether PREG-stimulated ALLO levels mediate its effects on provoked craving, HPA
dysregulation, anxiety, mood and cognitive flexibility in the laboratory component. Aim 3a: To assess the
preliminary efficacy of 8-week PREG doses versus PBO treatment on primary alcohol use outcomes and
secondary outcomes of alcohol craving, anxiety and negative mood. Aim 3b: To assess whether PREG-
stimulated ALLO levels mediate its effects on primary alcohol use outcomes and on secondary clinical
outcomes during the 8-week treatment phase. Exploratory Aim: To explore whether pre-treatment patient
characteristics (gender, family history of alcoholism (FH), trauma history and co-morbid drug use) influence
PREG-potentiated ALLO levels and primary and secondary alcohol use outcomes. Successful completion of
the proposed aims has the potential to support further development of novel neuroactive steroid targets such
as PREG and ALLO in the treatment of AUD...

## Key facts

- **NIH application ID:** 9948548
- **Project number:** 5R01AA026514-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Rajita Sinha
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $696,371
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948548

## Citation

> US National Institutes of Health, RePORTER application 9948548, Neuroactive Steroid Potentiation to Decrease Alcohol Craving, Normalize HPA axis function and Prevent Alcohol Relapse (5R01AA026514-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948548. Licensed CC0.

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