Review of drugs that alter fear memory in healthy people, including MDMA

The question

Which drugs change the way people form, recall or update unpleasant (fear-related) memories? The authors set out to map the whole field in healthy human volunteers.

What they did

The researchers followed a standard review method (PRISMA-2020) and searched three research databases up to 14 June 2024. They started with a list of 215 candidate compounds acting on 17 biological signalling systems. They found 100 published studies covering 36 compounds across 13 systems, and grouped the findings by which stage of memory was targeted: forming a memory, storing it, recalling it, or learning that a feared cue is now safe (extinction).

What they found

Three drugs accounted for most of the research: hydrocortisone (25 studies), propranolol (19 studies) and D-cycloserine (8 studies). The strongest signal was for propranolol affecting reconsolidation, the process in which a recalled memory is re-stored. Weaker evidence was reported for propranolol, MDMA, benzodiazepines, yohimbine, reboxetine and D-cycloserine affecting the initial forming and storing of an unpleasant memory, and for valproic acid affecting extinction learning. Fifteen compounds showed significant effects in single studies that no one has yet tried to replicate.

The fine print

This is a descriptive review, not a statistical pooling of results, so the findings cannot be expressed as a single effect size. Most compounds, including MDMA, were tested in very few studies, and the authors themselves call that evidence weak and often unreplicated. All studies were in healthy volunteers using laboratory fear tasks, not in people with post-traumatic stress disorder, so the clinical meaning is unclear. This summary is based on the abstract only.

What it means

Laboratory research on drugs that alter fear memory is heavily concentrated on a few compounds, and the evidence for MDMA in this specific role is thin and largely unreplicated.

Evidence grade: Low. A systematic review that summarizes many small laboratory studies in healthy volunteers without pooling results statistically, and most compounds were tested only once.

This summary is based on the study’s published abstract.