By Sunaina Borkar
Over the past few decades, depression has become increasingly prevalent around the world. Although ongoing scientific research has made great strides in the development of effective and accessible mental health treatments, tackling a specific type of depression known as treatment-resistant depression has been a challenge. Treatment-resistant depression currently affects 100 million people, and it prevents patients from experiencing any therapeutic effect from standard treatments such as the administration of antidepressants or psychotherapy (i.e., verbal communication).4 In response, the condition is usually tended to via alternative treatments like esketamine prescriptions and electroconvulsive therapy (ECT), however the search for additional treatment options is still ongoing.4
Fortunately, a recent Phase 2 double-blind trial conducted by the organization Compass Pathways has shown that psilocybin, a psychedelic compound found in magic mushrooms, produced significant outcomes in patients with treatment-resistant depression when followed by psychotherapy.2,5 This trial involved 233 patients randomly assigned to 1 mg, 10 mg, or 25 mg synthetic psilocybin treatment groups.2,5 The patients then spoke to a licensed therapist the next day and the following week.5
The results showed that patients from all 3 treatment groups experienced reductions in their depression scores, which were measured using the Montgomary-Åsberg Depression Rating Scale.2,5 This indicated a decrease in the severity of their depression. However, the patients who took the highest dose (25 mg) of psilocybin experienced the most significant reduction in their scores compared to the lower doses.2,5 This also correlated with how, after 3 weeks of intake, 29% of patients in the 25 mg group were in remission compared to only 8-9% of patients in the 10 mg and 1 mg groups.5 As agreed upon by various neuropharmacologists and psychiatrists, these results point towards psilocybin’s clinical effectiveness.3,5
Psilocybin, like most other psychedelics, acts on subtype 2A serotonin receptors; the 5-HT2A serotonin receptor, specifically.1 By doing so, it dysregulates neuronal activity at a population level, consequently decreasing brain network modulation.1 This implies that brain networks are less segregated into sub-networks and are instead more interconnected than previously believed.1 The increased integration and connection within the brain is one of the most significant contributors of therapeutic relief in depressed patients.1,5
In depression, numerous high-order brain networks are impaired, such as the default mode network (DMN), the salience network (SN) and the executive network (EN).1 This impairment manifests itself as problems related to decision-making and the ability to focus, alongside other behavioral malfunctions.1 The 5-HT2A serotonin receptor is highly expressed in these networks. It is only natural, then, that the addition of psilocybin has been shown to greatly interact with receptors associated with such systems.1 Psilocybin-receptor binding results in a notable increase in brain integration within the DMN network, as well as between the DMN, SN and EN networks, all of which ultimately show tangible improvements in patients’ previously impaired cognitive functions.1
Another effect of psilocybin involves an increase in psychological and cognitive flexibility, which contributes to a liberating feeling in patients.1 Here, psilocybin poses again as an agonist for the 5-HT2A receptor, with their binding deregulating the neural activity in 5-HT2A receptor-rich areas of the brain.1 This has shown to positively impact patients by increasing their responsiveness to emotion and their psychological flexibility, as well as augmenting their behavioral optimism.1,6
Psilocybin is also known for its ability to induce a hyperplastic state within the brain.1,5 Along with its direct interaction with serotonin receptors, psilocybin produces anti-depressant effects by being processed in our metabolism to form psilocin.5 In turn, psilocin production leads to the release of various neurotransmitters in the brain, which further contributes to the formation of the connections discussed earlier.5 This increased connectivity results in greater plasticity and has additionally been termed a “therapeutic window of opportunity”, as it makes the brain more susceptible to therapy.5 The hyperplasticity has also been seen to make patients more inclined towards learning, change and emotional responses.1,5,6 Altogether, these features demonstrate that psilocybin does induce a plethora of therapeutic effects that effectively help to combat depression.
Alas, based on current findings, the effects from psilocybin do not seem to be long-lasting.3 According to the results from the recent Phase 2 trial mentioned earlier, the amount of sustained positive response to depression after 12 weeks was significantly lower for all dose groups.3 The therapeutic effects patients were receiving after this time period even stopped depicting statistically significant improvements in their symptoms.3 Most likely, further research on psilocybin could help generate a way to prolong all the benefits it has to offer in patients.
It should be noted that psilocybin does produce a few side-effects, including dizziness, headaches, fatigue, and nausea.5,6 These effects were observed in patients from the recent Phase 2 trial. Furthermore, 3 patients from the trial (ranging from all dose groups) experienced severe side-effects that involved suicidal thoughts and self-harm.5,6 Therefore, although psilocybin appears to possess many therapeutic benefits against treatment-resistant depression, additional clinical trials need to be conducted to further evaluate its safety profile.
Despite these drawbacks, psilocybin’s anti-depressant effects have been highly regarded by specialists in the field and further experimentation is already in the works. Legal constraints in countries like the UK – involving psychedelic drug licensing and funding – could potentially limit the extent of research that can be done to demonstrate psilocybin’s key role as a psychedelic drug for depression.5 Nevertheless, both the recent Phase 2 trial and previous research have clearly illustrated that psilocybin offers a plethora of therapeutic benefits, including increased brain integration, hyperplasticity and cognitive flexibility – all of which have improved depression outcomes in patients.1,5,6 Conducting larger and more extensive clinical trials will help further demonstrate its efficacy and safety compared to existing anti-depressants, in turn allowing us to provide a safe and effective alternative therapy for treatment-resistant depression.
- Daws, R.E., Timmermann, C., Giribaldi, B. et al. Increased global integration in the brain after psilocybin therapy for depression. Nat Med. 2022;28(4): 844–851. Doi: 10.1038/s41591-022-01744-z.
- Goodwin G, Sci F, Aaronson T, Alvarez MD, Psych MRC, Arden P et al. Single-Dose Psilocybin for a Treatment Resistant Episode of Major Depression. New England Journal of Medicine. 2022;387(19): 1637-1648. Doi: 10.1056/NEJMoa2206443.
(3) LaMotte S. Severe depression eased by single dose of synthetic ‘magic mushroom’. https://edition.cnn.com/2022/11/02/health/psilocybin-magic-mushroom-depression-wellness/index.html [Accessed 13th November 2022].
- Mayo Clinic. Treatment Resistant Depression. https://www.mayoclinic.org/diseases-conditions/depression/in-depth/treatment-resistant-depression/art-20044324 [Accessed 12th November 2022].
- Sample I. Magic mushrooms’ psilocybin can alleviate severe depression when used with therapy. https://www.theguardian.com/science/2022/nov/02/magic-mushrooms-psilocybin-alleviate-severe-depression-alongside-therapy [Accessed 12th November 2022].
- Watts, R., Day, C., Krzanowski, J., Nutt, D., & Carhart-Harris, R. Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for Treatment-Resistant Depression. Journal of Humanistic Psychology. 2017;57(5), 520–564. doi:10.1177/0022167817709585.