MDMA alters fear extinction, and reduces alcohol consumption in inbred alcohol preferring iP rats but not outbred Wistar rats.
Kade L Huckstep, Billi Newton, Grace Bailey, Annai Charlton, Amy J Pearl, Xavier J Maddern, Robyn M. Brown, Gavan P Mcnally, Dan I Lubman, Shalini Arunogiri, Kirsten Morley, Erin J Campbell, Andrew J Lawrence, Leigh C. Walker
Neuropsychopharmacology March 27, 2026 DOI: 10.1038/s41386-026-02394-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Inbred alcohol-preferring (iP) and outbred Wistar rats of both sexes |
| Intervention | MDMA |
| Topics | MDMA |
| Key findings | MDMA prevented the shock-related increase in alcohol consumption only in genetically vulnerable (iP) rats, without improving long-term fear extinction. |
Abstract
Comorbidity between post-traumatic stress disorder (PTSD) and alcohol use is common and mutually-reinforcing, yet there are no pharmacological strategies that specifically target trauma-linked escalation of alcohol intake. We evaluated whether 3,4-methylenedioxymethamphetamine (MDMA), given in a therapy-adjunctive fashion (30 min before fear extinction), could facilitate extinction of conditioned fear and reduce alcohol consumption in a rat model that combines fear conditioning, binge-like alcohol access, abstinence, and re-exposure. Inbred alcohol-preferring (iP) and outbred Wistar rats of both sexes underwent auditory fear conditioning, voluntary ethanol drinking, and subsequently fear extinction after MDMA or vehicle administration, with drug-free extinction recall and alcohol consumption assessed thereafter. Fear conditioning increased voluntary alcohol intake only in iP rats, suggesting a genotype-related fear-alcohol contingency. MDMA acutely reduced freezing during extinction, but ultimately reshaped across-session freezing patterns in a strain- and sex-dependent manner. There were no lasting MDMA treatment effects on next-day drug-free recall. MDMA also altered on-drug fear-expression during extinction without affecting later recall in an iP rat cohort without prior alcohol exposure, indicating the effect is not secondary to drinking history. Critically, MDMA prevented the shock-related increase in alcohol consumption but only in iP rats. These data suggest MDMA's most reliable action in this model is to disrupt trauma-linked escalation of alcohol intake in genetically- and experientially- vulnerable rats, rather than to globally enhance fear extinction.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cites 22
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- 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The Lancet Psychiatry May 1, 2018
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- MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms? Progress in Neuro-Psychopharmacology and Biological Psychiatry June 8, 2018
- 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning Translational Psychiatry September 15, 2015
and 17 more in the library