PROJECT SUMMARY ABSTRACT Plants and fungi have a long history of medicinal use yet, modern medicine has turned away from plant-based medicinals due to heterogeneity that results in inconsistent and unpredictable dosing. In 2018, psilocybin was granted Breakthrough Therapy Designation for the therapy of treatment-resistant depression. Initial results of psychedelic-assisted psychotherapy using the psilocybin molecule to treat major depressive disorder report sustained relief from chronic conditions after just one treatment—a breakthrough treatment indeed. In our understanding, these studies—and many others investigating psilocybin’s effect on a range of conditions—rely on the psilocybin molecule as the active compound, not Psilocybin Sp.. As this treatment gains support, it’s important to consider the differences between the molecule psilocybin and various Psilocybin species. In 2019 Blei et. al. published an unexpected paper revealing that β- carbolines—monoamine oxidase inhibitors (MAOIs)—are also found in five common Psilocybin sp.. Generally, MAOIs are considered to be counter indicated with Selective Serotonin Reuptake Inhibitors (SSRIs)—common treatments for psychiatric disorders, migraine headaches and neuropathic pain. In fact, patients taking SSRIs have developed serotonin syndrome after ingesting mixtures of serotonergic psychedelics and MAOIs—overwhelming the serotonin system and resulting in death. These counter indications are absent in research that relies exclusively on the psilocybin molecule. It is therefore of critical importance that we understand the chemistry of various psilocybin- containing mushrooms so that clinicians, researchers, policymakers, and the public can make informed decisions. To this end, we propose investigating the β-carboline content in 13 different psilocybin-containing species. (Aim 1), the growth conditions that may vary this content (Aim 2), and their effects on the serotonin system (Aim 3). As city and state legislatures are now legalizing and/or decriminalizing Psilocybin sp., these potential drug interactions represent a high-risk to current SSRI patients. With over 100 different species of psilocybin-containing mushrooms spanning at least six genera, there is a lot to learn as legalization proceeds.

PROJECT NARRATIVE Combining Selective-Serotonin Reuptake Inhibitors (SSRIs)—the standard for treating depression and other psychiatric disorders—with serotonergic psychedelics can result in the potentially lethal serotonin syndrome. We believe that a greater understanding of the chemistry of psilocybin-containing mushrooms and the development of a serotonin syndrome model of disease will lead to better and safer clinical treatment options. This project aims to increase our understanding of A) the chemical constituents of two psilocybin containing genera—psilocybe and panaeolus and B) the growth conditions that effect ß-carboline content and C) screen psilocybe-derived compounds against a serotonin syndrome model of disease for both toxicological and therapeutic effects.