Psilocybin therapy: a way out of the mental health crisis? In conversation with COMPASS Pathways

Written by Ryan Khan, edited by Daniele Guido and Swathi Kumar.

The human race has utilised psychedelic drugs to explore realms of expanded consciousness for many millennia. However, as 21st century societies enter a growing mental health crisis, could mushrooms containing psilocybin supplement pre-existing therapies and provide new treatments for the mental health conditions so many of us battle with?

The mechanism of the ‘mind-manifesting’ mushroom

The term ‘psychedelic’ was coined in 1956 and, based on a Greek etymology, (psychḗ, ‘soul, mind’ and dēleín, ‘to manifest’), implies a ‘mind-manifesting’ substance. Psilocybin, the psychoactive chemical found in over 200 species of fungi, including ‘magic mushrooms’, is a classic psychedelic and hallucinogen that directly stimulates a subtype of serotonin receptors called 5-HT2A.

Neuroimaging studies have revealed that, by binding to 5-HT2A receptors across the cortex, psilocybin has the ability to disrupt activity in brain regions such as the default mode network (DMN), medial prefrontal cortex (mPFC) and amygdala. The DMN and mPFC help integrate feelings, emotions and memories, and modulate different forms of sensory inputs; while, the amygdala is involved in stress and fear responses. Collectively, these brain regions form a major seat of consciousness, facilitate introspection and help develop a person's inner sense of self as distinct from the outer world. The psychedelic state, in which the normal functioning of these cerebral components is interrupted, and thus the sense of self diminished, is known in clinical terms as “ego-dissolution”.

Depression is characterised by hyperactivity in parts of the brain, including the DMN, mPFC and amygdala, that drives a state of consciousness dominated by pessimistic rumination with thinking clouded by persistent sensations of fear and anxiety. Thoughts and memories are perpetually re-analysed in a path of recurrent negativity, shame and guilt from which the patient cannot escape. In his autobiography, Professor David Nutt explains “This negative thinking develops an autonomy of its own that immerses the person deeper and deeper in their depressive ruminations, preventing them from being able to think about anything other than their depression”.

By modulating activity in the DMN, mPFC and amygdala, psilocybin can break down ego boundaries and induce alternate states of consciousness, reduce excessive rumination and mitigate chronic fear responses. In addition, psilocybin temporarily increases connectivity between brain regions that don't usually communicate and facilitates the formation of new distant neurological pathways that would rarely emerge in the non-psychedelic state, see Figure 2.

Figure 2: Simplified illustration of global brain connectivity while receiving a placebo (a) and psilocybin (b). Source: The Royal Society of Publishing — Figure 2: Simplified illustration of global brain connectivity while receiving a placebo (a) and psilocybin (b). Source: *The Royal Society of Publishing*

By binding to serotonin receptors in the mood centres, disrupting and quietining activity in the aforementioned brain regions, increasing cognitive flexibility and interconnectedness, psilocybin profoundly alters the nature and content of thinking. The subjective experience of ‘ego-dissolution’ can enable patients suffering from depression to break out of ruminating negative thought patterns and experience another way of reasoning outside depression's bleak veil.

In this psilocybin-induced psychedelic state, patients are able to gain insights and take new perspectives on previous experiences, developing a novel understanding of their problems. When administered in a supportive environment with psychological support, psilocybin can thereby enable patients to experience emotional breakthroughs, instigate immediate and enduring elevations in mood and, for many patients, kickstart the journey to overcoming their depression.

The urgent clinical need for new treatments for depression

Mental health illness is now the largest contributor to disability in the UK, and costs the British economy more than £100 billion per year. Depression is the most common mental illness, affecting 1 in 5 individuals in the UK and over 300 million worldwide. The condition poses widespread social and economic burdens but ultimately, depression can destroy an individual's wellbeing, lead to extreme suffering and is now the largest contributing factor to sucide in the UK.

Unfortunately, around 30% of patients suffering depression do not benefit from current treatment paradigms, including pharmaceutical antidepressants, cognitive behavioural therapy and counselling. For the 1.2 million patients in the UK suffering this form of treatment-resistant depression (TRD), their therapeutic options have been exhausted and their quality of life is extremely poor. Progress in the treatment of depression has been slow for some time and apart from the approval of esketamine by the European Commission in 2019, there have been no advancements in therapy since the licensing of selective serotonin reuptake inhibitors (SSRIs) more than 30 years ago. Unfortunately, SSRIs have a slow onset of action, unpleasant side effects and high levels of incomplete or non-response which collectively reduces adherence for much of the patient population.

Figure 3: COMPASS Pathways. Source: Meta News — Figure 3: COMPASS Pathways. Source: *Meta News*

COMPASS Pathways and psilocybin for treatment resistant depression

COMPASS Pathways, a pioneering mental health care company founded in 2016, is dedicated to exploring novel treatments for patients suffering from mental illnesses who do not respond to conventional therapies. Since developing COMP360, a proprietary and synthetic formulation of psilocybin, COMPASS Pathways have partnered with a number of prestigious academic institutions and provided the drug free of charge in exchange for the rights to use safety data collected in psychedelic research trials.

In an interview with Lars Wilde, the President, Chief Business Officer and Co-founder of COMPASS Pathways, he stated: “Our vision is a world of mental wellbeing, and we believe this will partially be achieved by the integration of psychedelic therapies for people with mental illnesses. We are all about accelerating patient access to evidence based innovation in mental health.”

Figure 4: Therapists at Imperial College London conducting psilocybin therapy. Source: Reuters — Figure 4: Therapists at Imperial College London conducting psilocybin therapy. Source: *Reuters*

In 2019, King's College London conducted a phase I, double-blind placebo-controlled study in healthy volunteers and revealed COMP360 psilocybin was well tolerated by participants, with no serious adverse events, and no clinically-relevant negative effect on cognitive functioning. COMPASS Pathways, and other institutions, are now developing models of psilocybin therapy, which combine the psychoactive substance with psychological support, to treat mental illnesses such as TRD. Recently, Imperial College London completed a phase II double-blind, randomised, controlled trial comparing COMP360 psilocybin with a six-week course of escitalopram - one of the most commonly prescribed SSRI antidepressants - for the treatment of major depressive disorder. Both treatment groups received equivalent psychological support, and although the study’s primary outcome (a change from baseline in the score of a 16-item Quick Inventory of Depressive Symptomatology–Self-Report at week 6) was not met, participants receiving COMP360 psilocybin exhibited quicker and more favourable responses in a variety of secondary outcomes. This included reduced depression on a number of rating scales, higher remission rates, lower suicidality and anxiety levels, increased social functioning and generally better wellbeing when compared to patients receiving escitalopram. A BBC 2 documentary about the study can be watched here.

COMPASS Pathways are currently running an international, randomised, controlled phase IIb study investigating COMP360 psilocybin therapy for patients with TRD. The trial, which is the largest psilocybin study to date, is investigating the safety profile and efficacy of COMP360 psilocybin therapy in TRD, and aims to determine an optimal therapeutic dose when combined with preparatory and integrational psychological support. Over 216 patients with TRD have now been treated in the study and results are expected to be released in late 2021. If positive, this data will enable COMPASS Pathways to begin Phase III clinical trials that will generate further information on the efficacy of COMP360 psilocybin and create an evidence base to support a proposed reimbursement scheme for the therapy.

Figure 5: Clinical Trial Phases. Source: ILD Collaborative — Figure 5: Clinical Trial Phases. Source: *ILD Collaborative*

Although COMPASS Pathways’s clinical development program is currently focused on exploring COMP360 psilocybin therapy for TRD - as this mental illness carries the biggest need in terms of patient numbers - there is growing evidence to suggest psilocybin could also hold promise for a variety of other conditions with currently unmet clinical need. This list includes, but is not limited to, anorexia nervosa, type II bipolar disorder, post traumatic stress disorder, chronic cluster headaches, obsessive compulsive disorder, end of life depression and anxiety, and substance use disorders.

As part of their Discovery Programme, COMPASS Pathways, and leading partners, are also exploring a large number of psychedelic compounds that target the intriguing 5-HT2A receptor. Their goal: to identify lead candidates and progress them into clinical research over the next 24 months. The Discovery Programme is also set to explore shorter duration psychedelics that may pose solutions to the problem of the scalability of psilocybin-assisted psychotherapy; most psilocybin sessions are between 4–8 hours long and usually require the presence of two trained therapists, incurring a high cost and unfortunately limiting the number of treatments that can be conducted in a given day.

The future of psilocybin therapy and psychedelic research

For psilocybin, as COMP360 or other formulations, to be licensed as a medicine, a greater evidence base needs to be collected to exemplify its efficacy for treating mental health disorders. For this to happen, larger scale clinical trials need to be conducted and more data needs to be gathered. However, the current status of psilocybin as a ‘Schedule 1’ drug, which characterises it as having ‘no therapeutic value’, largely impedes scientific exploration into the compound. Researching Schedule 1 drugs requires multiple Home Office licenses and creates bureaucratic barriers such as security and licensing obligations, which can collectively increase study fees by up to 10-fold. Additionally, research timelines are often delayed by several years when compared to non-Schedule 1 drugs - even those in Schedule 2, like heroin and cocaine, get an easier ride.

There are now increasing calls from the academic, political and commercial (including COMPASS Pathways) communities to reschedule psilocybin to a Schedule 2 drug. This would acknowledge psilocybin’s therapeutic value, reduce administrative and logistical burdens and consequently cut the prohibitive costs of this currently hamstrung research. Such a move would also attenuate stigma associated with psychedelic research, enabling scientists to work more efficiently, and expedite access to psilocybin based treatments and therapies for patients across the UK. A recent YouGov poll conducted by psilonautica and DrugScience, shown in Figure 6, revealed widespread support for the relaxation of government restrictions on research into the medical use of psilocybin, with 55% of British voters supporting reform.

Figure 6: YouGov Results - Is the UK Ready to Reschedule psilocybin? Source: DrugScience — Figure 6: YouGov Results - Is the UK Ready to Reschedule psilocybin? Source: *DrugScience*

A comprehensive report, produced by the Conservative Drug Policy Reform Group argues that rescheduling psilocybin would “permit the UK to develop world-leading mental health treatments that could be more effective and more cost-efficient than current options, enabling the UK to fulfil its potential as a global centre of excellence in mental health research.” Rescheduling psilocybin would enable Britain's pioneering academic establishments and biotech companies such as Albert Labs, Beckley Psytech, Eleuisis, ATAI LifeSciences and COMPASS Pathways to flourish. This would also stand the UK economy in a strong position to benefit from the growing psychedelic space and the medical research entrepreneurs it attracts - the sector is touted to grow to over £8 billion by 2027.

As the COVID-19 pandemic and resulting economic recession has led to a two-fold increase in the number of adults suffering depression, while conditions including PTSD, OCD and anxiety disorders are expected to increase in precedence over the coming decades, the need for novel mental health treatments is more salient than ever. While psilocybin-assisted therapy has not yet reached fruition, and is almost certainly not a panacea for all mental health conditions, the prospects of this psychedelic medicine are increasingly promising!

DISCLAIMER: The possession and consumption of psilocybin for recreational purposes is currently illegal in the UK. The author would like to stress that patients with depression or other mental health illnesses should not attempt to self-medicate with psilocybin, as this may lead to negative outcomes and could be dangerous.

If you are interested in finding clinical trials involving psychedelic therapy visit the following websites for more information:

https://www.kcl.ac.uk/research/psilocybin-trials

https://www.imperial.ac.uk/psychedelic-research-centre/trials/

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References:

https://www.ageuk.org.uk/information-advice/health-wellbeing/conditions-illnesses/depression-anxiety/

https://albertlabs.com/research/

https://www.atai.life/

https://www.beckleypsytech.com/

https://www.cdprg.co.uk/

https://www.cdprg.co.uk/psilocybin

https://clinicaltrials.gov/ct2/show/NCT04433845