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.
A single dose of psilocybin (1.5 mg/kg) in female rats enhanced cognitive flexibility in several learning tasks by amplifying dopamine signals in the nucleus accumbens. The drug increased learning rates and reduced reliance on prior expectations, leading to faster reversal learning. However, calorie restriction and prior exposure to activity-based anorexia (ABA) reduced these benefits. Calorie restriction shifted the timing of psilocybin's effect on reversal learning and increased neural activity in the nucleus accumbens. Prior ABA exposure eliminated improvements in discrimination accuracy and trended toward worsening reversal learning, likely due to reduced cortical 5-HT2A receptor availability. The results show that nutritional state and history of anorexia-like behavior critically moderate psilocybin's cognitive effects.