Where is the sweet spot for psychedelic-enhanced fear extinction? An integrative quantitative synthesis of...

Individuals with anxiety and stress-related disorders frequently demonstrate impaired threat extinction. Although psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), 3,4-methylenedioxymethamphetamine (MDMA), and ketamine can facilitate fear extinction in rodent models, comprehensive integrative analyses remain limited.

Regression-based approaches were employed to estimate cross-study trends to assess whether the dose-effect relationships of these compounds are linear, bell-shaped, or follow alternative patterns. The potential moderating effects of specific biological or procedural factors on extinction learning and recall were also assessed. Effect sizes from 177 experiments in mice and rats were analyzed by compound and pooled across classical psychedelics, with doses normalized using allometric scaling and serotonin 5-HT2A or 5-HT1A receptor-adjusted relative potency.

The available data for LSD were insufficient for evaluating the hypothesized relationships. For the other psychedelics, linear models provided the best relative fit for extinction learning and recall. Within the tested ranges, lower doses, except for MDMA, were frequently associated with larger positive effect sizes. Pooled analyses indicated that the interval between treatment administration and extinction recall testing may influence the effects of classical psychedelics on fear extinction. In contrast, sex, age, preconditioning stress/high-intensity conditioning, and the treatment-extinction learning interval did not affect the observed dose-effect relationships. These pooled associations were sensitive to high-leverage observations.

Psychedelics appear to enhance fear extinction across a broad range of doses. The timing of administration relative to memory extinction retrieval may contribute to variability in these effects. Evidence supporting nonlinear dose-effect relationships remains limited.