Desynchronized brain activity may be the key to Psilocybin-assisted treatment of Depression

In 1957, TIME magazine shocked readers with the cover story “Seeing the Magic Mushroom,” introducing most Americans, for the first time, to psychedelics [1]. The Controlled Substances Act, denoting psilocybin a Schedule 1 drug, halted the first wave of western psychedelic research in 1970, until Johns Hopkins University published a study on psilocybin’s potential to treat the existential distress experienced by some patients with terminal cancer, thirty years later [2]. In 2019, the FDA granted “Breakthrough Therapy” designation for studies investigating treatment of Major Depressive Disorder (MDD) with psilocybin. Twenty-one million adults in the US have had at least one major depressive episode, defined as a period of at least two weeks of loss of pleasure, depressed mood, and diminished self-worth [3]. 

A phase two clinical trial by researchers at Washington University School of Medicine aimed to investigate how psilocybin impacts our brains to understand its demonstrated therapeutic benefits [4]. Seven healthy adults were administered a high dose (25 mg) of psilocybin, which acts as an agonist of serotonin (5-HT2A) receptors, meaning it increases serotonin activity in the brain. Two weeks before or after the psilocybin session, each participant was also given 40 mg of a comparison drug, methylphenidate (MTP), commonly prescribed for ADHD, as it works on the central nervous system. Using fMRI to track blood flow in the brain, researchers were able to track functional connectivity (FC), meaning how often regions of the brain work together, despite not being connected by physical pathways. Each participant completed fMRI scans several times throughout the study, including before drug administration, in order to account for individual differences in brain activity. The anterior hippocampus is a brain region closely involved in one’s self-perception and self-esteem, and is known to be functionally connected with the Default Mode Network (DMN), a brain region thought to create our sense of self, time, and space. Both regions have been linked to psychiatric disorders and show activity change under psilocybin.

After assessing the fMRI results of psilocybin intake, researchers found decreased FC between the hippocampus and DMN, while activity within each region was relatively less affected. This shift demonstrates a randomness of brain activity during the psychedelic state, supporting the hypothesis that these changes underpin the cognitive and perceptual changes associated with psychedelics. Furthermore, this randomness of brain activity induces a rapid increase in the expression of neuroplasticity-related genes (BDNF, MTOR, and EEF2) that underlie the brain’s ability to adapt and are thought to have a role in antidepressant response, making patients more receptive during psychotherapy. Neural flexibility can be potentially beneficial by allowing patients with MDD to escape maladaptive behaviors like rumination.

The results of psilocybin on FC were more than threefold larger than the effects of the comparison, indicating that the changes can be confidently attributed to psilocybin. Significant FC change in the brain persisted 3 weeks post-drug period; however, values returned to baseline 6-12 months later, suggesting the necessity of multiple rounds of treatment, if psilocybin were to be approved [4]. 

Unlike most drugs, context is a huge part of the experience of taking psychedelics. Both the mindset of the patient, as well as the setting the drug is taken in, heavily influence how one feels and what they perceive [4]. When participants were assigned a simple auditory-visual matching task, fMRI showed a significant decrease in psilocybin-associated network disruption. The researchers indicate this as strong evidence for context-dependent effects of psilocybin on brain activity.

In a clinical trial at King’s College London aimed to identify a safe and effective dose of psilocybin in patients diagnosed with Treatment Resistant Depression (TRD), a persistence of depressive symptoms following two courses of antidepressant treatments. Patients were assigned either a 25-mg, 10-mg, or 1-mg dose of psilocybin paired with psychotherapy [5]. The 25-mg group showed the greatest reduction in the depression score, and surprisingly, the 10-mg group demonstrated only marginally better improvements in depression score than the 1-mg group, providing insight on the threshold dose required to see results. Although the 25-mg dose was the most efficacious, severe adverse events occurred more frequently in the high dose groups than the 1-mg group. The researchers recommended that future psilocybin trials implement serious clinical vigilance, especially regarding suicidality, which can be a risk with certain antidepressants as well. The study found that psilocybin had a lower efficacy in comparison with trials of first-line treatments of MDD, but a much higher incidence of response compared with second-line treatments and beyond, suggesting that psilocybin therapy has potential applications specifically for TRD [5].

Despite these promising findings, unique challenges continue to elude researchers. Animal research has indicated that psilocybin can promote formation of new synapses in the anterior hippocampus of pigs and rats, but current imaging or microscopy technology cannot track these changes in human subjects [4]. While further trials to determine dosage, procedure, safety, and risks are required before psilocybin is ready for FDA approval, current research indicates exciting possibilities for patients with resistant depression who may benefit from a mental reset. 

References:

[1] Goodwin, G. M., Aaronson, S.T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J C., Bird, C., … Malievskaia, E. (2022) Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med, 18(387), 1637-1648. DOI: 10.1056/NEJMoa2206443

[2] Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., Cosimano, M. P., & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12), 1181–1197. https://doi.org/10.1177/0269881116675513 

[3] Maurer, L. (2023, May 7). History of psychedelics: Why are psychedelics schedule 1 drugs. Psilolab. https://psilolab.co/articles/why-psychedelics-are-schedule-one-history/ 

[4] Siegel, J. S., Subramanian, S., Perry, D., Kay, B. P., Gordon, E. M., Laumann, T. O., Reneau, T.  R., Metcalf, N. V., Chacko, R. V., Gratton, C., Horan, C., Krimmel, S. R., Shimony, J. S., Schweiger, J. A., Wong, D. F., Bender, D. A., Scheidter, K. M., Whiting, F. I., Padawer-Curry, J. A., … Dosenbach, N. U. (2024). Psilocybin desynchronizes the human brain. Nature, 632(8023), 131–138. https://doi.org/10.1038/s41586-024-07624-5 

[5] U.S. Department of Health and Human Services. (n.d.). Major depression. National Institute of Mental Health. https://www.nimh.nih.gov/health/statistics/major-depression