Resetting the hippocampal buffer: a neurocognitive account of psychedelic therapy for anxiety-related psychopathology

Abstract Psychedelics (hallucinogenic 5-HT 2A agonists such as psilocybin) are being investigated for their potential to treat a range of conditions, including anxiety-related psychopathology. Despite promising results, the mechanisms by which psychedelic therapy may alleviate anxiety are not well understood. Here, we review neural and cognitive mechanisms underlying anxiety-related psychopathology and how psychedelics may impact these mechanisms. This review culminates in a tentative neurocognitive account of how psychedelics may promote long-term anxiolysis. We propose a model of anxiety related psychopathology wherein anxiety-related contextual information from the hippocampus may influence amygdala and salience network activity, biasing information processing toward anxiety-related content that thereby is encoded by the hippocampus and perpetuates this cycle. We posit that psychedelic may acutely free cortical networks from hippocampal-dependent contextual constraints in part through 5-HT 2A expression on excitatory and inhibitory neurons in the cortex and hippocampus, respectively, while the intrinsic plasticity of the hippocampus and/or psychedelic-mediated plasticity allows for a “resetting of the hippocampal buffer.” Following acute effects, increased cortical plasticity may enable the hippocampus to adaptively integrate novel information into a contextual frame less biased or constrained by prior aversive conditioning, promoting an overall reduction in anxious thoughts and appraisals. We end by discussing potential challenges of psychedelic therapy for anxiety, and suggest directions for future research to determine the optimal treatment paths informed by cognitive neuroscience.