Don't trip...or Maybe Do! The Efficacy of Shrooms for TRD

    Psilocybin, a naturally occurring psychedelic compound found in certain mushrooms, is gaining attention in the field of mental health, especially for its potential effects on treatment-resistant depression (TRD). Traditional antidepressants primarily target monoamine neurotransmitters like serotonin, norepinephrine, and dopamine. However, they often fall short for individuals with TRD, where typical therapies don’t produce meaningful improvement. Although non-FDA approved, psilocybin shows promising results for people who haven’t found relief with standard treatments. Understanding the physiological mechanisms behind psilocybin’s effects offers insights into its unique therapeutic potential. 

    At a cellular level, psilocybin acts as a partial agonist for serotonin (5-HT) receptors, particularly the 5-HT2A receptor, which is densely expressed in the prefrontal cortex, striatum, and areas of the limbic system. Activation of this receptor is thought to underlie the hallucinogenic and consciousness-altering effects of psilocybin, as well as its impact on mood and perception (Carhart-Harris et al., 2016). This receptor activation promotes the release of the serotonin neurotransmitter, strengthens communication between neurons, and triggers a cascade of cellular responses that contribute to "synaptic plasticity," or the brain's ability to rewire itself. Enhanced synaptic plasticity is crucial for individuals with TRD, as it helps in forming new pathways that may counteract the negative, rigid thought patterns often seen in depression.

    Research has also shown that psilocybin can reduce the activity of the brain's default mode network (DMN), a network active during self-referential thinking and rumination. Hyperactivity in the DMN is common in depression, leading to repetitive negative thinking. By reducing DMN activity, psilocybin allows the brain to "reset" and potentially disengage from these persistent negative thought loops. Studies using functional MRI show that psilocybin creates a highly interconnected brain state, fostering communication between regions that typically don’t interact. This effect appears to be associated with sustained relief from depressive symptoms, even after just one or two sessions. In fact, research shows that it relieves depressive symptoms in adolescents with MDD after a single therapeutic session (Goodwin et al., 2023). Psilocybin's impact on serotonin pathways, synaptic plasticity, and brain network dynamics provides a promising avenue for the treatment of TRD and a unique outlook on how altering neurochemistry with psilocybin can support recovery and remission in TRD.

Reference articles: 

Goodwin, G. M., Croal, M., Feifel, D., Kelly, J. R., Marwood, L., Mistry, S., O'Keane, V., Peck, S. K., Simmons, H., Sisa, C., Stansfield, S. C., Tsai, J., Williams, S., & Malievskaia, E. (2023). Psilocybin for treatment resistant depression in patients taking a concomitant SSRI medication. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 48(10), 1492–1499. https://doi.org/10.1038/s41386-023-01648-7. 

Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., Bloomfield, M., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Pilling, S., Curran, V. H., & Nutt, D. J. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The lancet. Psychiatry, 3(7), 619–627. https://doi.org/10.1016/S2215-0366(16)30065-7.