Psilocybin and depression

Psilocybin and its active metabolite psilocin (4-OH-N,N-dimethyltryptamine) is a plant alkaloid derived from tryptamine precursors. Psilocin acts as a serotonin transporter inhibitor and 5-HT2A receptor partial agonist. It also binds to the 5-HT2C, 5-HT1A and 5-HT1B receptors. fMRI has shown psilocybin to cause heightened activity in the amygdala, which has been interpreted as evidence of an antidepressant mechanism. Psilocybin has also been shown in numerous studies to disrupt Default Mode Network (DMN) connectivity, inducing temporary neuroplasticity that increases receptivity to coadministered non directive support therapy (Raison et al., 2023). With regards to neuroplasticity, psilocybin promotes spine formation in the prefrontal cortex and also significantly increases spine density. It has been demonstrated to increase the head size of spines on cortical neurons and the AMPA/NMDA ratio at synapses of the hippocampal CA1 pyramidal neurons (Grieco et al., 2022). Neuroplasticity effects have been shown to perpetuate for up to 30 days post treatment (Shao et al., 2021). Psychedelics have been shown to increase suggestibility with context-dependent effects in the psychiatric space. 

In the paper “Trial of Psilocybin versus Escitalopram for Depression”, a phase II, double-blind, randomized, controlled trial for long standing, moderate-to-severe major depression disorder showed psilocybin to be equal in effectiveness to the SSRI Escitalopram. The trial comprised 59 participants split with 30 participants receiving psilocybin and 29 participants receiving the SSRI. The experiment took place over 6 weeks. Group 1 was given 25mg of psilocybin at week 1 and 3 with six weeks of placebo, while group 2 was administered the SSRI for six weeks, along with 1mg of psilocybin (considered an inconsequential dose) at weeks 1 and 3. All patients received psychiatric support. 

Men and women between the age of 18-80 were recruited via recruitment networks, social media and other sources. Participants were screened for personal and/or family history of psychosis, suicide risk, pregnancy, known reasons to not take SSRIs, previous use of the trial SSRI escitalopram, and preexisting psychiatric conditions including borderline personality disorder and others. Previous use of psilocybin was acceptable. 

Participants were initially screened with the 17-item Hamilton Depression Scale (HAM-D-17) to determine level of depression, with a minimum of 17 indicating moderate-to-severe depression. Primary trial outcome was measured by a change in baseline score with the 16-item Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR-16) with scores ranging from 0 to 27 with higher scores representing greater depression. Secondary outcomes were measured via ≥50% decrease on score in QIDS-SR-16, remission according QIDS-SR-16, change in score for the 14-item QIDS-SR before and after day 1 administering of dosage, and finally changes from day 1 to end via the Beck Depression Inventory 1A, the 17-item Hamilton Depression Rating Scale and the Montgomery and Asberg Depression Rating Scale. Other secondary measurements included the Flourishing Scale, The Spielberger’s Trait Anxiety Inventory, the Brief Experiential Avoidance Questionanaire, the Work and Social Adjustment Scale, the Snaith Hamilton Anhedonia Pleasure Scale, the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), the Suicidal Ideation Attributes Scale, the Psychotropic-Related Sexual Dysfunction Questionnaire, the Laukes Emotional Intensity Scale and the Emotional Breakthrough Inventory. fMRI scans and 6 month follow ups occurred but were not included in the paper.

In both trial groups, the concluding depression score scales were lower than baseline scores. For the QIDS-SR-16 primary assessment (ranging 0 to 27), both groups reported a decline in score (indicating lessening depression), with the SSRI group dropping -6.0±1.0 points and the psilocybin group dropping -8.0± points. For WEMWBS secondary assessment (ranging from 14-70), both groups showed an increase in mental well-being, with the SSRI group increasing approximately 7 points and the psilocybin group increasing approximately 15 points. Scores for psilocybin vs escitalopram treatment were regarded statistically similar, but psilocybin scored better on both counts. 

The lack of a placebo group complicated the significance of these findings for both treatments. Because psilocybin required patients to be screened for psychiatric conditions believed to be incompatible with psychedelic treatment, there is a possibility that results were biased. The duration of the experiment (6 weeks) might have also misrepresented the escitalopram treatment because SSRI treatments are known to have delayed efficacy, although SSRI’s are commonly understood to reach optimal effectiveness by 4 weeks. The unique quality of the psychedelic experience also made it impossible to effectively participants, allowing for biased expectations. The researchers concede that most of the participants of the trial were self-recruited and most expressed preference for the psilocybin group. 

Adverse effects such as anxiety, dry mouth, sexual dysfunction or reduced emotional responsiveness were higher among the SSRI group than the psilocybin group. While psilocybin scored better in secondary outcomes, the lack of confidence intervals for these differences prohibits conclusions to be drawn. SSRI and Psilocybin were shown to be equal in effectiveness by the end of the 6 week trial.

Conclusion:

Psilocybin is non-addictive and cheap. Two 2 psychedelic sessions find near equal results to 42 days of SSRI medication. Psilocybin risks include anxiety, headaches, stomach aches and vomiting, but these risks may be mitigated and controlled for. The researchers screened for numerous psychological factors such as risk of suicide, history of psychosis and psychiatric conditions such as borderline personality disorder and I believe this is wise by any measure.

Ultimately psilocybin is shown to be a low risk/high reward alternative to expensive, drawn-out regimens of SSRIs.

Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., & Nutt, D. J. (2021). Trial of Psilocybin versus Escitalopram for Depression. New England Journal of Medicine, 384(15), 1402–1411. https://doi.org/10.1056/NEJMoa2032994

Grieco, S. F., Castrén, E., Knudsen, G. M., Kwan, A. C., Olson, D. E., Zuo, Y., Holmes, T. C., & Xu, X. (2022). Psychedelics and Neural Plasticity: Therapeutic Implications. The Journal of Neuroscience, 42(45), 8439–8449. https://doi.org/10.1523/JNEUROSCI.1121-22.2022

Raison, C. L., Sanacora, G., Woolley, J., Heinzerling, K., Dunlop, B. W., Brown, R. T., Kakar, R., Hassman, M., Trivedi, R. P., Robison, R., Gukasyan, N., Nayak, S. M., Hu, X., O’Donnell, K. C., Kelmendi, B., Sloshower, J., Penn, A. D., Bradley, E., Kelly, D. F., … Griffiths, R. R. (2023). Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA, 330(9), 843–853. https://doi.org/10.1001/jama.2023.14530

Shao, L.-X., Liao, C., Gregg, I., Davoudian, P. A., Savalia, N. K., Delagarza, K., & Kwan, A. C. (2021). Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron, 109(16), 2535-2544.e4. https://doi.org/10.1016/j.neuron.2021.06.008