Psilocybin & Depression: Psychedelic effects optional yet we still don’t have the full picture

Whether more people are becoming depressed or access to accurate diagnosis is increasing, the prevalence of depression is increasing. As a greater portion of our population becomes affected by depression, the demand for effective treatment grows. The drugs that were first developed to treat depression are not working with the same efficacy for a subsect of our population therefore researchers have begun to look at other pharmacological treatments such as psilocybin. 

Psilocybin is the psychedelic compound found in certain mushrooms that are also called magic mushrooms. The effects caused by psilocybin are said to be mind-altering, euphoric, and hallucinogenic are the attributes people often cite as to why it effectively treats depression. In modern history, psilocybin was used for psycholytic therapy, which is therapy that involves controlled use of psychedelic drugs, until legal restrictions of the drug were put in place in the mid 1960’s. These restrictions labeled psilocybin as an illicit drug with no known benefits.

While these legal restrictions are still in place, current research efforts are electing to change that by showcasing how effective the use of psilocybin can alleviate depressive symptoms and in one particular case, alleviate depression without the psychedelic effects. 

According to researchers from Maryland, utilizing an anti-hallucinogen alongside psilocybin treatment for depressive-like symptoms in male mice was effective (Hesselgrave et al., 2021). To discover this, researchers induced depressive symptoms, then treated mice with psilocybin, psilocybin and the anti-hallucinogen, or no treatment at all and discovered that the mice treated with psilocybin and the anti-hallucinogen had similar decreases as the mice treated with just psilocybin, thereby showcasing that the hallucinogen effects of psilocybin are not necessary for alleviating depression (Hesselgrave et al., 2021). 

Despite these findings, researchers are still aiming to develop a broad understanding of the efficacy of psilocybin as a treatment for depression. In a recent longitudinal study, researchers found that when patients were provided two doses of psilocybin and supportive therapy, at the 12-month follow up they had large and significant decreases in depressive symptoms (Gukasyan et al., 2022) (Figure 1). 

Decrease in GRID-HAMD depression scores over time from baseline through the 12-month follow-up (N = 24).

With these results, psilocybin is being shown to have long-term positive outcomes for people with depression. 

Additional research has found that the positive effects of psilocybin therapy may be linked to increased brain connectivity. Utilizing fMRI data, researchers discovered that psilocybin treatment was correlated with decreases in brain modularity which implied that the antidepressant action of psilocybin may be due to an overall increase in brain network integration (Daws et al., 2022). Simply, brain imaging showed significant changes in how the certain regions of the brain connect and communicate with other regions. A decrease in brain modularity signifies that within a particular region there are less connections which in turn implies greater connections between different regions, or an increase in region-to-region communication. To further affirm these findings, researchers conducted a second trial where the anti-depressant escitalopram was prescribed and the brain were observed, yet researchers did not observe any changes in brain network organization. The results of the second trial indicate that brain network integration may be a component of psilocybin’s unique mechanism of action to produce anti-depressant effects. 

As depression continues to affect people and increase the demand for treatment, researchers must continue the search and development of a variety of treatment modalities. If the continued promising research of psilocybin is any indicator, we may have a new treatment in the coming decades and the relabeling of psilocybin altogether. 


Daws, R.E., Timmermann, C., Giribaldi, B. et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med 28, 844–851 (2022).

Gukasyan, N., Davis, A. K., Barrett, F. S., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., & Griffiths, R. R. (2022). Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up. Journal of Psychopharmacology36(2), 151–158.

Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B., & Thompson, S. M. (2021). Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences118(17).

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