Major depressive disorder (MDD) is a leading cause of mental illness world-wide. Economists estimate MDD to be one of the leading causes of disability worldwide. The cost is not just due to treatment, but comorbidities, lost work and suicide, too. However, treatments are available and range from psychotherapy, pharmacotherapy or more invasive treatments like electroconvulsive therapy or deep brain stimulation. For decades, the standard of pharmacotherapy care has been selective serotonin reuptake inhibitors (SSRIs). Yet, SSRIs are only effective in 60% of MDD patients and require weeks of treatment before reaching therapeutic efficacy. Thus, a large proportion of individuals experiencing MDD endure symptoms for weeks without guaranteed relief. In 2000, low doses of ketamine, a dissociative anesthetic, was found to have rapid acting antidepressant effects. Prior to this, electroconvulsive therapy was the only treatment known to induce rapid antidepressant effects. The use of ketamine as an antidepressant has been met with resistance since it is a known drug of abuse, has an addictive potential and psychotomimetic side effects. Findings from recent human studies suggest a single oral administration of psilocybin has antidepressant effects within 7 days. However, the hallucinatory effects of psilocybin, like ketamine, severely limit its clinical use. Currently, psilocybin is administered in a controlled environment with psychological support, which greatly increases the cost of care and patient burden. Administration of ketanserin, a serotonin 2 receptor (5HT2R) antagonist, prior to psilocybin attenuates the psychedelic side effects. But whether ketanserin would also block the antidepressant effect is unknown. I sought to test the hypothesis that psilocybin has an antidepressant-like effect in rodents independent of the 5HT2R. To this end, I have demonstrated that psilocybin has a rapid antidepressant effect in anhedonic mice and increases synaptic strength in hippocampus following chronic stress. Prior administration of ketanserin blocks neither psilocybin’s antidepressant-like effect nor the increase in synaptic strength. In vitro electrophysiology experiments failed to show acute effects of psilocin, possibly due to psilocin’s rapid oxidation. While the antidepressant mechanism of action of psilocybin remains unknown, my data suggest the 5HT2R may not be necessary for the antidepressant effects.