Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models

Abstract

Anorexia nervosa (AN) has the highest mortality rate of any psychiatric disease, yet available pharmacological treatments are largely ineffective due, in part, to an inadequate understanding of the neurobiological drivers that underpin the condition. The recent resurgence of research into the clinical applications of psychedelic medicine for a range of mental disorders has highlighted the potential for classical psychedelics, including psilocybin, to alleviate symptoms of AN that relate to serotonergic signaling and cognitive inflexibility. Clinical trials using psychedelics in treatment-resistant depression have shown promising outcomes, although these studies are unable to circumvent some methodological biases. The first clinical trial to use psilocybin in patients with AN commenced in 2019, necessitating a better understanding of the neurobiological mechanisms through which psychedelics act. Animal models are beneficial in this respect, allowing for detailed scrutiny of brain function and behavior and the potential to study pharmacology without the confounds of expectancy and bias that are impossible to control for in patient populations. We argue that studies investigating the neurobiological effects of psychedelics in animal models, including the activity-based anorexia (ABA) rodent model, are particularly important to inform clinical applications, including the subpopulations of patients that may benefit most from psychedelic medicine.

Keywords: 5-HT2A; activity-based anorexia; animal models; anorexia nervosa; cognitive flexibility; psilocybin; psychedelic medicine; serotonin.

FIGURE 1

Serotonergic (5-HT) pathways within the brain and the considerable overlap between brain regions implicated in anorexia nervosa (AN), the task-positive executive control network (ECN) and the task-negative default mode network (DMN). These networks are highly interactive and are modulated by activity in the insula (Ins). Changes in functional connectivity within and between these networks are proposed to underlie the impact of psilocybin on cognitive flexibility in AN. dlPFC = dorsolateral prefrontal cortex; vmPFC = ventromedial prefrontal cortex; vStr = ventral striatum; pACC = perigenual anterior cingulate cortex; PCC = posterior cingulate cortex; PPC = posterior parietal cortex.