The effect of psychedelics on associative learning: a systematic review

Abstract

IntroductionPsychedelics are emerging as potential treatments for neuropsychiatric conditions, with evidence suggesting a single administration can lead to enduring behavioural changes. While the underlying putative mechanism(s) remain unclear, there is evidence supporting altered learning as a key candidate. AimThis systematic review examined studies assessing the effects of psychedelics on associative learning in both humans and animals. MetodsElectronic databases were searched up until 13/01/2025 for studies investigating any difference in learning after psychedelic administration. Results31 studies were included (29 in animals, 2 in humans). Classical and operant conditioning paradigms were employed, including fear extinction, conditioned avoidance, and reversal learning. Studies assessed acute and post-acute effects, however repeated dosing paradigms often obscured this distinction. There was considerable heterogeneity in study designs, paradigms, drug administration timings and doses, and behavioural effects appeared to be influenced by dose, timing, training intensity, and sex. Due to between-study heterogeneity, a meta-analysis was not possible. Evidence suggests that psychedelic administration enhances associative learning in animals across paradigms, although findings were not entirely consistent. Possible mechanisms identified were increased prediction error sensitivity, serotonin receptor agonism, and structural plasticity. Learning enhancements may extend into the post-acute phase and appear to depend on active environmental engagement during this window. ConclusionStudies suggest that psychedelics enhance associative learning in animals; however, these findings are yet to be translated into humans. Understanding whether a period of enhanced learning follows the psychedelic experience may have important implications for psychedelic-assisted psychotherapy, where behavioural changes must generalise and persist beyond the drug-induced state.