Psilocybin, Depression, and Synaptogenesis: Insights into the Field’s Past, Present, and Future

Depression is one of the most common mental health disorders in the United States. Four years ago, the FDA granted psilocybin breakthrough therapy status as a possible treatment. Psilocybin and other hallucinogens have shown promise as alternatives to classical antidepressants. Research into the mechanistic action of 5-HT2A receptor agonists has increased. Hallucinogens produce different downstream effects than non-hallucinogenic 5-HT2A agonists, including forming a receptor complex with metabotropic glutamate receptors. Psilocybin's unique synaptogenic effect may contribute to its therapeutic effect for major depressive disorder, but the underlying mechanism has not been explored. Psilocybin's upregulation of transcription factors like egr-2, c-fos, and brain-derived neurotrophic factors, and its connection with the TrkB signaling pathway, may explain this mechanism.

Study at a glance

Abstract

Depression remains one the most commonly diagnosed mental health disorders in the United States. The Food and Drug Administration granted psilocybin breakthrough therapy status four years ago as a possible solution to this pervasive disorder. Since then, psilocybin, and hallucinogens in general, have produced promising results as alternatives to classical antidepressants. As more research confirms psilocybin’s potential therapeutic effect, research surrounding the mechanistic action of these 5-HT2A receptor agonists has increased as well. Hallucinogens have different downstream effects compared to non-hallucinogenic 5-HT2A receptor agonists, including the formation of a 5-HT2A receptor and metabotropic glutamate receptor complex. Psilocybin’s unique synaptogenic effect may play a role in its therapeutic effect for major depressive disorder; however, the underlying mechanism by which synaptogenesis is induced upon psilocybin administration has not been explored. Psilocybin’s distinctive upregulation of transcription factors, such as egr-2, c-fos, and brain-derived neurotrophic factors, and its connection with the TrkB signaling pathway, may be the answer to this unexplained mechanism.