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

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 hippocampaldependent 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. Anxiety-related psychopathology is one of the most prevalent classes of mental health conditions (Remes et al., 2016) and medical conditions more generally (Vos et al., 2020). Anxiety-related psychopathology within the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American Psychiatric Association, 2013) are represented by disorders characterized by excessive fear or anxiety responses, with the primary differentiation between disorders being the particular focus of the fear or anxiety and the breadth of the stimuli that provoke it. For example, although a relatively wide breadth of stimuli could be the focus of social anxiety disorder and panic disorder, both have relatively circumscribed areas of primary focus (social stimuli and panic-related sensations/situations, respectively). In contrast, generalized anxiety disorder (GAD) is characterized by a broad, pervasive, and difficult-tocontrol chronic apprehension, which is generally less specific in focus than social anxiety disorder or panic disorder. More broadly, pathological anxiety can also be considered a heightened intolerance to uncertainty that results in disproportionate learning to expect threat (Brown et al., 2023; McGovern et al., 2022) and increased distress and dysfunction (Watson et al., 2022). Here, we consider anxiety-related psychopathology as the overall category of interest and target for treatment, and our proposed model and related conclusions apply broadly to this category. Furthermore, we avoid referencing work strictly on posttraumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD), which are no longer grouped with anxiety disorders in DSM-5 due to diagnostic differences and unique presentations that differentiate them from anxiety disorders such as GAD, panic disorder, and social anxiety disorder (for reviews on psychedelic therapy for PTSD and OCD, see Ehrmann et al., 2021; Graziosi et al., 2024; Henner et al., 2022; Krediet et al., 2020). 4 Pharmacological treatments for anxiety-related psychopathology include drugs that modulate the serotonergic system, such as selective serotonin reuptake inhibitors (SSRIs), which increase the availability of synaptic serotonin (5-HT) by block the serotonin transporter, and other drugs that modulate various 5-HT receptors, especially 5-HT1A receptors (5-HT1AR). The anxiolytic effects of these drugs tend to be modest or even ineffective in a large proportion of patients, and their side effects can make long-term maintenance difficult (Cassano et al., 2002; Graziosi et al., 2024). GABAA positive allosteric modulators (i.e., benzodiazepines) are also common treatments, though their sedating effects and abuse potential make them less ideal longterm solutions. Increasing attention has recently been devoted to psychedelics, hallucinogenic 5-HT2A receptor (5-HT2AR) agonists, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), for their rapid amelioration of anxiety related to a lifethreatening terminal diagnosis (Gasser et al., 2014; Griffiths et al., 2016; Holze et al., 2023; Ross et al., 2016). More recently, LSD received breakthrough therapy designation from the U.S. Food and Drug Administration specifically for the treatment of GAD due to robust anxiolysis after a single dose in a to-be published phase III clinical trial. While promising, the mechanisms by which one or doses of a psychedelic ameliorate anxiety-related psychopathology remain poorly understood. A better understanding of these therapeutic mechanisms may aid in the development and optimization of psychedelic treatments for anxiety-related psychopathology. Here, we briefly review key molecular mechanisms, subcortical structures, and cortical networks underlying anxiety-related psychopathology and the impact of psychedelics on these neural substrates. This review culminates in a model of how psychedelics may specifically improve anxiety-related psychopathology (rather than a range of mental illnesses) in a fashion that defines them from other treatments. We conclude by outlining considerations for the 5 therapeutic application of psychedelics for anxiety-related psychopathology and discuss potential challenges for successful integration of psychedelics into modern clinical practice. Neural Mechanisms of Anxiety-Related Psychopathology Molecular Mechanisms 5-HT has been a focal point in the treatment and conceptualization of the pathophysiology of anxiety (Baldwin & Rudge, 1995; Gordon & Hen, 2004; Stein & Stahl, 2000). Consistent with SSRI treatment, anxiety-related psychopathology is associated with decreased 5-HT concentrations in cerebrospinal fluid (Brewerton et al., 1995). However, lower 5-HT transporter availability may also be associated with elevated anxiety (Reimold et al., 2008; Wu et al., 1999), suggesting a complex relationship potentially owing to dysregulation of specific serotonin receptors. The 5-HT1A receptor (5-HT1AR) is one of the most widely expressed 5-HT receptors that has been implicated in anxiety-related psychopathology (Celada et al., 2013; Garcia-Garcia et al., 2014). 5-HT1ARs are inhibitory and notably expressed on presynaptic autoreceptors in the dorsal raphe nucleus that inhibit 5-HT release (Tiwari et al., 2023). 5-HT1AR knockout mice exhibit increased anxiety-like behavior (Toth, 2003), and the anxiolytic effects of the medication buspirone are thought to be mediated by its activation of 5-HT1ARs, particularly those in the hippocampus (Inoue et al., 2011) where 5-HT1ARs are densely distributed postsynaptically on pyramidal and granule cells (Beliveau et al., 2017; Lanfumey & Hamon, 2000). Although 5-HT1AR agonists acutely impair the formation of hippocampal-dependent memory (Ögren et al., 2008) including human episodic memory (i.e., memories for where or when one experienced an event, Tulving, 2002), 5-HT1ARs are implicated in the upregulation of hippocampal neurogenesis (Gould, 1999; Grabiec et al., 2009). 6 In contrast to 5-HT1ARs, activation of the 5-HT2AR tends to be excitatory, and 5-HT2ARs are highly expressed in the cortex on pyramidal cells (Aghajanian & Marek, 1997; Beliveau et al., 2017; Jakab & Goldman-Rakic, 1998; Martin & Nichols, 2016). Interestingly, compounds that activate 5-HT2ARs (indirectly via SSRIs and directly via psychedelics) and block 5-HT2ARs (e.g., trazodone and atypical antipsychotics) both downregulate 5-HT2A receptors (Van Oekelen et al., 2003). Stress appears to upregulate 5-HT2ARs particularly in frontal regions that are thought to facilitate learning about threats (Murnane, 2019) and could minimize uncertainty (Brown et al., 2023), and 5-HT2AR knockout mice exhibit less anxiety-like behavior (Weisstaub et al., 2006). Consistent with these findings, patients with GAD, but not depression (Anand et al., 1994), exhibit a larger anxiety response than healthy participants in response to mchlorophenylpiperazine (Germine et al., 1992), a hallucinogenic 5-HT2AR agonist with additional activity at other 5-HT receptors. Nevertheless, stress may also decrease 5-HT2AR expression and function in the hippocampus and amygdala (Jiang et al., 2009; Wu et al., 1999), regions where 5-HT2ARs are notably expressed on inhibitory neurons (Bombardi, 2012; Bombardi & Di