In a rat model of anorexia nervosa (activity-based anorexia), psilocybin improved body weight maintenance and facilitated cognitive flexibility, particularly by enhancing adaptation when reward contingencies were reversed. The cognitive benefits depended on signaling through the serotonin 5-HT1A receptor, as blocking that receptor negated the effects. Psilocybin also transiently altered cortical expression of serotonin receptor genes, increasing Htr2a and decreasing Htr1a transcripts, with a further reduction in Htr2a in anorexic-model rats. These findings suggest psilocybin could help break cognitive inflexibility in anorexia nervosa and indicate that therapeutic mechanisms may extend beyond 5-HT2A receptor binding.
Psilocybin, a serotonergic psychedelic, shows promise for treating anorexia nervosa by enhancing cognitive flexibility and modifying reward processing—two core processes disrupted in the disorder. Its effects are primarily mediated by the 5-HT2A receptor, but recent evidence indicates broader interactions with dopaminergic pathways in brain regions like the prefrontal cortex and nucleus accumbens. Rodent models demonstrate that psilocybin induces rapid and enduring neuroplastic changes, improving cognitive flexibility through complex neurochemical mechanisms. Advances in real-time neurochemical recording now allow simultaneous monitoring of serotonin and dopamine signaling, which will provide insights into their coordinated actions during cognitive performance. Further research into psilocybin's dual modulation of these systems is needed to optimize therapeutic applications for anorexia nervosa.