Psilocybin and Depression

Written by: Alexander Pralea '24
Edited by: Jason Johnston '23

​Psychiatric drug treatment for depression has been stagnating–until recently. For the past 70 years, the discussion about depression has been dominated by the monoamine hypothesis—that depression is associated with deficiencies of various neurotransmitters like serotonin, dopamine, and epinephrine—and therefore interventions should aim to selectively boost levels of these substances within the brain [1].

The first generation of antidepressant medications, tricyclic antidepressants and monoamine oxidase inhibitors, boosted levels of serotonin and norepinephrine. However, their broad mechanisms of action meant that patients were often subject to dangerous side effects, since these medications often affected other pathways in unwanted ways [2]. The next generation of antidepressants, the selective serotonin reuptake inhibitors (SSRIs), built on the monoamine hypothesis. These were created in an attempt to  more specifically target these neurotransmitters in their role in mood disorders without affecting their other roles in the body. These medications, of which fluoxetine (commonly known as Prozac) and sertraline (commonly known as Zoloft) are among the most well known, caused a commotion in the 1980’s when they first rose to immense popularity. For the millions of people for whom they were undoubtedly effective, they were quite literally a life-saver, revolutionary in expanding access to mental health treatment.

Nonetheless, the fixation on the monoamine hypothesis has caused psychiatry to remain somewhat static. Although boosting serotonin levels may be associated with increased mood levels in some patients, there is still no evidence proving a causal relationship. Monoamine levels increase rapidly, while the lag time for mood levels to increase, among the patients for whom antidepressants work, is within a two to four week span [3]. However, 10-30% of patients are deemed treatment-resistant, showing either no improvement or partial improvement with severe side effects [4]. Clearly, the monoamine hypothesis that seemed so elegant in the 1950’s is an oversimplification.

The field is desperately in need of new medications that work more effectively than the current iteration of what Dr. Friedman calls “me too” drugs in The New York Times [5]. Although new SSRIs have been developed, they still share, from Dr. Friedman’s perspective, the same fundamental formula as fluoxetine or sertraline, merely tinkered with slightly since they have the same overall mechanism. Thankfully, however, scientists have begun to research nontraditional methods of treating depression, in particular psilocybin.

Psilocybin was traditionally sidelined given concerns about its recreational use and safety, but modern research has shown that it is safe [7]. Moreover, compared to ketamine, a new antidepressant treatment modality that has been pioneered, psilocybin has lower capacity for abuse and toxicity and requires less medical monitoring, making it a better overall candidate for a new antidepressant [8]. Psilocybin also generally has no long-term consequences to cognitive or neurological function [8].

One major study focused on treatment-resistant patients with severe unipolar depression, or depression that does not alternate with mania as encapsulated by bipolar depression. The study was an open-label trial conducted on twenty patients, six of whom were female [9]. The patients tolerated the treatment, and had marked reductions in symptoms, scoring more than two standard deviations below their initial depressive baseline. A more granular analysis demonstrated that nine patients responded well (improved significantly) and four were in remission (absence of depression). Given that this study was open-label, the patients knew that they were receiving psychedelic treatment, and there was no control condition to contrast this with. However, this study demonstrated that psychedelics could offer relief to those for whom antidepressants have not been helpful. Notably, none of the study participants pursued other antidepressants within five weeks of receiving psilocybin.

The Center for Psychedelic and Consciousness Research at Johns Hopkins University, a mecca for psychedelic research, found through a randomized clinical trial published in 2020 that psilocybin is highly effective for treatment of major depressive disorder (MDD), even for those without treatment-resistant depression [8]. Their study randomized twenty-seven patients to either a treatment or a delayed treatment after eight weeks, in which they received two doses of psilocybin alongside supportive psychotherapy. The two groups differed by almost three standard deviations in the mean depression as quantified by the the GRID-Hamilton Depression Rating Scale (GRID-HAMD), an index of the severity of one’s depressive symptoms [8]. Of course, their study had limitations owing to the small sample size and limited racial diversity of their sample (their sample was predominantly non-Hispanic white). These factors make generalizability more difficult, but the importance of this study cannot be understated. Previous studies have focused on the use of psilocybin mainly for a small subset of the population, such as cancer patients or treatment-resistant depression. This study, however, demonstrated that psilocybin could also potentially work for a population which responds well to antidepressants. 

​According to a meta-analysis—which compiles data from multiple studies to reach a more nuanced conclusion—the current evidence is promising, although scientists and laypeople should be reluctant to make any sweeping generalizations [10]. However, the scientists emphasized the high potential for bias in their studies, meaning that more research is necessary. Even though many more, larger studies will be needed, the fact that scientists are willing to push the envelope to question the monoamine hypothesis illustrates innovation that has the potential to drastically improve the quality of life for some of the sickest Americans. 


References:

[1] Cosci F, Chouinard G. The monoamine hypothesis of Depression revisited: Could it mechanistically novel antidepressant strategies? Neurobiology of Depression. 2019; 63–73.

[2] Pacher P, Kecskemeti V. Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Current Medicinal Chemistry. 2008 Apr; 11(7): 925–43.  

[3] Boku S, Nakagawa S, Toda H, Hishimoto A. Neural basis of major depressive disorder: Beyond monoamine hypothesis. Psychiatry and Clinical Neurosciences. 2017 Sep 19; 72(1): 3–12.  

[4] S. Al-Harbi K. Treatment-resistant depression: Therapeutic trends, challenges, and Future Directions. Patient Preference and Adherence. 2012 May 1; 6: 369–88.  

[5] Friedman RA. A dry pipeline for psychiatric drugs [Internet]. The New York Times. The New York Times; 2013 [cited 2021 Nov 2]. Available from: https://www.nytimes.com/2013/08/20/health/a-dry-pipeline-for-psychiatric-drugs.html 

[6] Rizvi S, Khan AM. Use of transcranial magnetic stimulation for depression. Cureus. 2019 May 23; 11(5).  

[7] Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology. 2016 Nov 30; 30(12): 1181–97.  

[8] Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, et al. Effects of psilocybin-assisted therapy on major depressive disorder. JAMA Psychiatry. 2021; 78(5): 481-89.  

[9] Carhart-Harris RL, Bolstridge M, Day CM, Rucker J, Watts R, Erritzoe DE, et al. Psilocybin with psychological support for treatment-resistant depression: Six-month follow-up. Psychopharmacology. 2017 Nov 8; 235(2): 399–408.  
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[10] Goldberg SB, Pace BT, Nicholas CR, Raison CL, Hutson PR. The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis. Psychiatry Research. 2020; 284.   

Image link: https://commons.wikimedia.org/wiki/File:Mechanism_of_Prozac.jpg