The resurgence of interest in the therapeutic potential of psychedelics for treating psychiatric disorders has rekindled efforts to elucidate their mechanism of action. In this Perspective, we focus on the ability of psychedelics to promote neural plasticity, postulated to be central to their therapeutic activity. We begin with a brief overview of the history and behavioral effects of the classical psychedelics. We then summarize our current understanding of the cellular and subcellular mechanisms underlying these drugs’ behavioral effects, their effects on neural plasticity, and the roles of stress and inflammation in the acute and long-term effects of psychedelics. The signaling pathways activated by psychedelics couple to numerous potential mechanisms for producing long-term structural changes in the brain, a complexity that has barely begun to be disentangled. This complexity is mirrored by that of the neural mechanisms underlying psychiatric disorders and the transformations of consciousness, mood, and behavior that psychedelics promote in health and disease. Thus, beyond changes in the brain, psychedelics catalyze changes in our understanding of the neural basis of psychiatric disorders, as well as consciousness and human behavior.

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Psilocybin has shown positive preliminary signals in small-scale clinical trials for psychiatric disorders that exhibit maladaptive stress responses as a major component of their presentation. However, there are relatively few assessments of whether an acute administration of psilocybin exhibits reproducible effects in rodent models useful for the study of stress-associated psychiatric disorders. Here, we measured the responses of male C57BL/6J mice to this compound in a battery of relevant behavioral tests. These tests included the open-field test, forced swim test, sucrose preference test, and novelty suppressed feeding test. Furthermore, these tests were presented in either the absence or presence of chronic corticosterone administration, as a chemically induced model of ongoing stress burden. Our results indicate that the effects of psilocybin within these tests are dependent on the chronic hormonal stress burden of the mice: psilocybin alone promotes anxiolytic and hedonic responses, but promotes anxiogenic and anhedonic responses when pre-treated with chronic corticosterone. This identified interaction between stress hormone burden and psilocybin behavioral effects in mice suggests the possibility of further developing rodent behavioral models that can assess additional context-dependent effects of psychedelic administration that are deemed clinically-relevant, but are otherwise difficult to control for, in human studies.

While correlations between drug-induced cortisol elevation, self-reported anxiety, and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy, the mechanistic relationship between psychedelic-associated alterations in plasma glucocorticoid responses and the time course of anxious responsiveness remains unclear. Using rodents, both time-bound manipulation of glucocorticoid concentrations and assessment of anxiety-like behaviors can be achieved. Here, 3 mg/kg IP psilocybin was found to have anxiolytic-like effects in C57BL/6 male mice at 4 h after treatment. These effects were not altered by pretreatment with a 5-HT 2A antagonist but were blunted by pretreatment with a glucocorticoid receptor antagonist or suppression of psilocybin-induced corticosterone elevations. Anxiolytic-like effects were also observed at 4 h following treatment with the nonpsychedelic 5-HT 2A agonist lisuride at a dose causing a similar increase in plasma glucocorticoids as that seen with psilocybin, as well as following stress-induced (via repeated injection) glucocorticoid release alone. Psilocybin's anxiolytic-like effects persisted at 7 days following administration. The long-term anxiolytic effects of psilocybin were lost when psilocybin was administered to animals with ongoing chronic elevations in plasma corticosterone concentrations. Overall, these experiments indicate that acute, resolvable psilocybin-induced glucocorticoid release drives the postacute anxiolytic-like effects of psilocybin in mice and that its long-term anxiolytic-like effects can be abolished in the presence of chronically elevated plasma glucocorticoid elevations.