The effect of psychedelics on associative learning: a systematic review

Psychedelics show potential for enhancing associative learning in animals, according to a systematic review of 31 studies (29 animal, 2 human). The review found that psychedelic administration improved learning across classical and operant conditioning paradigms, including fear extinction and reversal learning, though effects varied by dose, timing, training intensity, and sex. Possible mechanisms include increased prediction error sensitivity, serotonin receptor agonism, and structural plasticity. Learning enhancements may persist into the post-acute phase and depend on active environmental engagement. These findings have not yet been confirmed in humans, but suggest a window of enhanced learning that could inform psychedelic-assisted psychotherapy.

Study at a glance

Abstract

Introduction: Psychedelics 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. Aim: This systematic review examined studies assessing the effects of psychedelics on associative learning in both humans and animals. Methods: Electronic databases were searched up until 13/01/2025 for studies investigating any difference in learning after psychedelic administration. Results: 31 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. Conclusion: Studies 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.