Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((±)-DOI) on cognitive flexibility

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine ((+/-)-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2 mgkg-1 (+/-)-DOI. We then demonstrate lasting effects of (+/-)-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2 mgkg-1 (+/-)-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, (+/-)-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that (+/-)-DOI's effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. (+/-)-DOI's facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.