Speaker Bio
Dr. Cody J. Wenthur is an innovative, translational investigator in psychopharmacology who has been on the UW–Madison faculty since 2018. His work is focused on improving our understanding of the basis for beneficial and detrimental effects of psychedelics, opioids, cannabinoids, and other neuroplasticity-inducing approaches in the context of novel therapeutic approaches for promoting and maintaining mental health. His research program has received grant and fellowship support from NIGMS, NIDA, NIMH, independent foundations, and philanthropic funds. The resulting findings have been published in leading journals such as Nature and PNAS and have yielded the development of first-in-class tool compounds and generated new pharmacologic techniques for the investigation of complex psychoactive mixtures. He also supports novel graduate education opportunities in neuropharmacology, including active service as the founding director of the Psychedelic Pharmaceutical Investigation Master’s program, and mentorship of PharmD and PhD students in Pharmaceutical Sciences, Molecular and Cellular Pharmacology, and Neuroscience.
ICPR 2024 Abstract
Transient elevation of plasma glucocorticoids supports psilocybin-induced anxiolysis in mice
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.
Our major research question is whether psychedelic-induced elevations in systemic glucocorticoid concentrations are supportive of long-term reductions in anxiety-like behaviors. Our hypothesis is that psilocybin-induced release of corticosterone is necessary for anxiolytic-like effects in the novelty suppressed feeding assay (NSF) and open field test (OFT) in mice up to 7 days later.
Intraperitoneal psilocybin was administered to C57BL/6 male mice following exposure to chronic oral corticosterone or vehicle. Psilocybin administration was preceded by pretreatment with mifepristone, ketanserin, or vehicle. Changes in plasma corticosterone concentrations were assessed using ELISA. Behavioral changes were assessed at 15 min, 4 h, and 7 days after psilocybin, and quantified using time in center for OFT and latency to feed for NSF.
Psilocybin had anxiolytic-like effects at 4 h after treatment. This was not altered by pretreatment with a serotonin 2A receptor antagonist but was blunted by pretreatment with a glucocorticoid receptor antagonist or suppression of psilocybin-induced corticosterone elevations. Psilocybin's anxiolytic-like effects persisted at 7 days following administration only in animals without chronically elevated plasma corticosterone.
Psilocybin-induced corticosterone release is a critical factor driving reductions in anxiety-like behavior in mice in the hours following drug clearance. Ongoing, unresolved glucocorticoid elevations can invert the long-term outcome of psilocybin administration on anxiety-like behavior up to seven days later.