Resetting the Hippocampal Buffer: A Neurocognitive Account of Psychedelic Therapy for Anxiety-Related Psychopathology

Psychedelics such as psilocybin show promise for treating anxiety, but how they work is unclear. This review proposes a model where anxiety disorders involve the hippocampus biasing the amygdala and salience network toward anxiety-related information, creating a self-perpetuating cycle. Psychedelics temporarily free cortical networks from this hippocampal constraint, and increased plasticity afterward allows the hippocampus to integrate new information into a less biased contextual frame, reducing anxious thoughts. The model highlights that psychedelics can acutely increase anxiety, and future research should determine optimal treatment approaches informed by cognitive neuroscience.

Study at a glance

Abstract

Psychedelics (hallucinogenic 5-HT2A agonists such as psilocybin) are gaining recognition for their potential to treat a range of conditions, including anxiety-related psychopathology. Despite early promising results, the mechanisms by which psychedelic therapy alleviates anxiety are not well understood. Here, we review neural and cognitive mechanisms underlying anxiety-related psychopathology and the impact of psychedelics on these mechanisms. This review culminates in a novel neurocognitive model of how psychedelics promote long-term anxiolysis. We conceptualize anxiety-related psychopathology as a case in which anxiety-related contextual information provided by the hippocampus entrains the amygdala and salience network to bias processing toward anxiety-related information that “refills” the hippocampus and perpetuates this cycle, due to 5-HT2A expression on excitatory and inhibitory neurons in the cortex and hippocampus, respectively. Psychedelics acutely free cortical networks from hippocampal-dependent contextual constraints in part through 5-HT2A 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.” As the acute effects wane, increased cortical plasticity may enable the hippocampus to adaptively integrate novel information into a contextual frame that is less biased or constrained by prior aversive conditioning, thus promoting an overall reduction in anxious thoughts and appraisals. We end by discussing potential challenges of psychedelic therapy for anxiety, including that psychedelics can acutely increase anxiety, and suggest directions for future research to determine the optimal treatment paths informed by cognitive neuroscience.