Therapeutic Mechanisms of Psilocybin in Psychiatric Disorders

Posted on:August 28, 2020
Last Updated: December 3, 2020
Time to read: 4 minutes

This article is based on the talk by Dr Robin Carhart-Harris at RCPsych IC 2019. Dr Carhart-Harris is Head of the Centre for Psychedelic Research, Division of Brain Sciences, Faculty of Medicine, Imperial College London.

Psilocybin is the prodrug of psilocin (4-OH-dimethyltryptamine), a non-selective serotonin 2A receptor (5-HT2A) agonist and classic ‘psychedelic’ drug. (See mechanisms of action here)

Both compounds occur naturally in the ‘psilocybe’ genus of mushrooms and are structurally related to the endogenous neurotransmitter serotonin.

1. An interesting question is how psychedelics differ from conventional antidepressants that also work on the serotonin system. A trial currently underway will investigate a 6-week escitalopram treatment arm vs two psilocybin therapy sessions with completion of the study by 2020. 

2. Principal findings from modern clinical trials include the rapid pharmaceutical action of psychedelics, e.g. the effect of ketamine in reducing acute suicidality, and how the therapeutic effects of psilocybin are similar but appear to be more enduring.[Rucker et al. 2018]

Evidence for psilocybin in depression. 

3. Reductions in OCD,[Moreno et al. 2006]; addiction[Johnson et al. 2014] and depression [Carhart-Harris et al. 2018], [Osório Fde et al. 2015] are also evident. 

4. Context and experience are also vital, and a naturalistic study of approximately 200 people showed that having an experience of an emotional breakthrough was a significant predictor of positive therapeutic outcomes.[Roseman et al. 2018]  

5. The emphasis is that this current research is very much a hybrid model of drug treatment with psychotherapy. To address the apparent transdiagnostic potential of psychedelic therapy, it might be considered that the space of overlap between different psychiatric disorders may be related to unusual habits, or of thought/behaviour biases, e.g. negative cognitive biases in depression, negative body image in eating disorders, and habits and behaviour associated with addiction. 

Psychedelic Therapy – A Beginner’s Guide. 

6. A logical treatment for such an overlap would be to relax these habits, to open a window of opportunity for some revision to those biases, and is described by a proposed new unified model (REBUS) of the brain activity of psychedelics.[Carhart-Harris et al. 2019]

7. REBUS: RElaxed Beliefs Under pSychedelics

Psychedelics appear to relax the weighting of internal models, particularly at a high hierarchical level in the mind and brain. Some phenomenology of the psychedelic experience, such as ego disintegration and insight reported by people, is consistent with this model.

Via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system.

The acute brain conditions induced by the pharmacological action of psychedelics, increasing brain entropy and relaxing the precision weighting on priors, are ideal for working on the revision of high-level priors or beliefs.

Consistent with recent work on the mechanics of insight, an entropic brain with relaxed high-level priors will be more amenable to curious behavior and Bayesian model optimization processes that can aid the occurrence of insight and perspective change. [Carhart-Harris et al., 2019]

8. Results of a recent trial for treatment-resistant depression revealed a revision of aberrant beliefs in participants when treated with psilocybin. Baseline pessimism levels were corrected post-treatment with no worrying shift into excessive optimism.[Lyons et al. 2018] 

9. The long-term brain effects are unknown, but a reliable biomarker of depression and effective response to an antidepressant treatment – the amygdala response to emotional faces – shows an augmented amygdala response to emotional stimuli with psilocybin therapy, particularly to negative stimuli, the effect of which correlates to treatment response.[Roseman et al. 2018, Carhart-Harris et al. 2017, Desbordes et al. 2012] 

Psilocybin increased emotional responsiveness to which was linked to positive outcomes which is a finding opposite to SSRIs.

Read a comprehensive review of psychedelics and hallucinogens in psychiatry.