Anorexia nervosa has the highest mortality rate of any psychiatric disease, and current medications are largely ineffective partly because the neurobiological drivers are poorly understood. Recent research into psychedelic medicine suggests psilocybin may alleviate symptoms related to serotonin signaling and cognitive inflexibility. Clinical trials for treatment-resistant depression show promise but have methodological biases. The first clinical trial using psilocybin for anorexia nervosa began in 2019, highlighting the need to understand the neurobiological mechanisms. Animal models, such as the activity-based anorexia rodent model, allow detailed study of brain function and behavior without the confounds of expectancy and bias, and are argued to be crucial for informing which patient subpopulations may benefit most from psychedelic medicine.
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.