As of October 2018, psilocybin, the psychedelic, active ingredient of ‘magic mushrooms’ is now a breakthrough therapy, as designated by the U.S. Food and Drug Administration (FDA). This compound has shown marked potential as a therapeutic for depression, particularly treatment-resistant depression.

Psilocybin, known more for its hallucinogenic properties, has a history of use in spiritual rituals by ancient groups across the world, and more recently, for its recreational use in eliciting psychedelic ‘trips’ characterized by altered perception, introspection, and synesthesia (such as ‘hearing colors.’)

However, in recent years, psilocybin’s alteration of perception has been targeted as a means of addressing clinical depression. In fact, analyses of data from the National Survey on Drug Use and Health exploring psychological distress, suicidal thinking, suicidal planning, and suicide attempts indicated a negative correlation on all four outcomes for psilocybin users when compared to those who did not consume psychedelic drugs (Hendricks, Johnson, & Griffiths, 2015).

Such findings have been corroborated by a 2011 pilot study evaluating psilocybin in alleviating end-of-life anxiety and depression in terminally-ill, advanced-stage cancer patients. Here, patients reported significant improvements in depression measures after administration of psilocybin, an effect that continued up to half a year after the termination of the trial (Grob et al., 2011).

Neural Underpinnings of Psilocybin in Depression

Psilocybin, when in the body, is converted to psilocin, which acts as a partial agonist for serotonin (5-HT) receptors, particularly, the 5-HT2A receptor. Serotonin has been, and continues to be a major source of interest regarding depression, particularly given that selective serotonin reuptake inhibitors (SSRIs) are one of the major psychopharmacological treatments for depression.

However, psilocybin seems to elicit improvements in depression in different ways than typical SSRIs.

Recent experimentation has demonstrated that psilocybin may actually contribute in reviving emotional responsiveness in treatment-resistant depression. This has manifested through elevated amygdala responses to emotional stimuli, both fearful and happy, evaluated on functional magnetic resonance imaging (fMRI).

This reaction is in contrast with typical antidepressants and SSRIs, which appear to attenuate the amygdala response to fearful stimuli, and elicit a mixed response to happy stimuli. This observation with psilocybin suggests a different mechanism from SSRIs. Rather than stymie the negative emotions, psilocybin seems to allow for patients to reconnect with their emotions, confront, and work through them.

In the end, this observed increase in amygdala response with psilocybin correlated with substantially improved outcomes for treatment-resistant depression (Roseman et al., 2017).

Additionally, psilocybin has also been found to act on the coupled activities of the rostral anterior cingulate cortex (ACC) and the medial prefrontal cortex (mPFC). Individuals with major and treatment-resistant depression have demonstrated hyperactivity in the ACC/mPFC, with effective treatments for depression appearing to lower this hyperactivity (Holtzheimer & Mayberg, 2011).

In congruence with this notion, the administration of psilocybin has been found to deactivate the ACC/mPFC (Carhart-Harris et al., 2012). Hence, here lies another potential mechanism as to how psilocybin can ameliorate depression.

The next step is to pinpoint the exact mechanisms as to why psilocybin can elicit anti-depressant properties, and find a way to optimize and modify the compound to amplify these therapeutic properties. More empirical research, neuroimaging, and clinical trials will go a long way in really testing this potential ‘wonder’ drug.

The Growth of ‘Psychedelic Medicine’

In recent years, there has been such a shift in exploring previously contraband, taboo drugs as therapeutic for a myriad of mental health conditions. We see this with these psilocybin mushrooms, as well as with a ketamine nasal spray for depression, and the plethora of uses for medical marijuana (Johnson & Johnson, 2016; Whiting, Wolff, & Deshpande, 2015).

While there always remains an ever-present apprehension towards administering such compounds to a demographic suffering from psychiatric conditions, at this stage, given that mental health conditions generally have poor prognoses, with treatments often proving to be ineffective in the long-term, psychedelic medicine is an avenue worth pursuing even more.

If we can continue to conduct substantive research into the therapeutic effects of substances like psilocybin, we will be well positioned to generate a number of potentially life-saving therapeutics. Then, just maybe, victims of all forms of depression can finally have a drug that is safe and effective in the long-term.

Lastly, let us not lose sight of a crucial tenet of clinical psychology and psychiatry: that pharmacological interventions are to serve as adjuncts to actual psychotherapy, not as sole lines of treatment. Psilocybin, should it live up to its promise as a clinical therapeutic, should be used in conjunction with regular therapy and monitoring by a mental health professional.

References

Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., & Nutt, D. J. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences, 109(6), 2138-2143. doi:10.1073/pnas.1119598109

Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L., & Greer, G. R. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of General Psychiatry, 68(1), 71–78.

Hendricks, P. S., Johnson, M. W., & Griffiths, R. R. (2015). Psilocybin, psychological distress, and suicidality. Journal of Psychopharmacology, 29(9), 1041-1043. doi:10.1177/0269881115598338

Holtzheimer, P. E., & Mayberg, H. S. (2011). Stuck in a rut: Rethinking depression and its treatment. Trends in Neurosciences, 34(1), 1-9. doi:10.1016/j.tins.2010.10.004

Johnson & Johnson, Janssen Pharmaceutical Companies. (2016, August 16). Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for Suicide [Press release]. Retrieved from https://www.jnj.com/media-center/press-releases/esketamine-recieves-breakthrough-therapy-designation-from-us-food-and-drug-administration-for-major-depressive-disorder-with-imminent-risk-of-suicide

Roseman, L., Demetriou, L., Wall, M. B., Nutt, D. J., & Carhart-Harris, R. L. (2017). Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression. Neuropharmacology. doi:10.1016/j.neuropharm.2017.12.041

Whiting P.F., Wolff R.F., Deshpande S. Cannabinoids for Medical Use. A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456–2473. doi:10.1001/jama.2015.6358

Magic Mushrooms: Now an FDA-Approved Breakthrough Therapy for Depression