In the second part of this series of articles focused on plant-based medicines, DDW’s Megan Thomas evaluates the use of psilocybin in drug discovery. The first part explored medical cannabis.
What is the regulatory landscape of psilocybin?
Psilocybin is a naturally occurring psychedelic compound that is produced by more than 200 species of fungi. Despite psilocybin’s presence in many mushrooms, by and large they are considered ‘controlled substances’, or a Schedule I drug, and as such a drug or chemical whose manufacture, possession and use is illegal. However, the substance has shown promise in the field of medicine for a range of diseases and conditions, making its legality a debating point within the drug discovery industry internationally.
On February 2023, Australian regulators announced that medicines containing the psychedelic substances psilocybin and MDMA (3,4-methylenedioxy-methamphetamine) can be prescribed by specifically authorised psychiatrists for the treatment of certain mental health conditions, making it the first country in the world to formally recognise the therapeutic use of psychedelics1. This looks to be a significant milestone which will ideally propel other regulatory agencies forward in this field.
Where the US stands on the issue is also influential, though as is often the case, varies significantly between states. The movement to decriminalise psilocybin started with Denver, Colorado, in 2019, which became the first US city to decriminalise psilocybin, which led to Colorado voters approving access to natural medicine with Proposition 122. Proposition 122 decriminalises personal use, possession growth, and transport of natural medicines for people who are 21 years and older and legalises multiple natural medicines.
Another US milestone took place in November 2020, when Oregon became the first US state to legalise the use of psilocybin under Measure 1092. Of course, while the regulation remains a continuous battle, this does not hinder the research being undertaken. For instance, though psilocybin remains illegal in Maryland, The Johns Hopkins Center for Psychedelic and Consciousness Research continues to explore innovative treatments using psilocybin and its potential for mental illnesses3. Moreover, the US Food and Drug Administration (FDA) granted breakthrough therapy status to psilocybin in 2018 for treatment-resistant depression, and in 2019 for major depressive disorder4. As reported by DDW, the FDA also published new draft guidance in June 2023 to highlight fundamental considerations to researchers investigating the use of psychedelic drugs for the potential treatment of medical conditions, including psychiatric or substance use disorders. Guidelines like these are sure to strengthen the quality of research and in turn the likelihood of regulatory approval.
As of February 2023, there are no approved therapeutic products containing psilocybin in Canada. However, in June 2023, the Government of Canada invested nearly $3 million to study the potential benefits of psilocybin-assisted psychotherapy4, indicating the country’s journey towards an end-goal of safe, legalised psilocybin use in the country. Dr Samuel Weiss, Scientific Director of the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction, says: “We are beginning to see a resurgence of research on psychedelics as a potential therapeutic aid for a range of mental health and substance use conditions. Despite this, there are still many unknowns as to the safety and efficacy of psilocybin-assisted psychotherapy. These three newly funded clinical trials represent the careful research that is urgently needed to build upon preliminary findings, and guide clinical practice in Canada5.”
In the UK, psilocybin is a Schedule I drug and therefore illegal, but there are growing calls for its reclassification to allow for therapeutic use. To this end, a debate took place in parliament in May 2023 regarding access to psilocybin treatments6. Within the debate, an e-petition was presented, which closed in February 2023 and received 11,824 signatures, and called on the government to reschedule psilocybin for medical research on untreatable conditions to Schedule II of the Misuse of Drugs Regulations 2001. This will be a particularly interesting area of regulation to watch as the MHRA finds its feet post-Brexit, especially considering how much dedicated research is going into this field at centres such as Imperial College London’s Centre for Psychedelic Research.
Like the UK, many other countries – ones that are widely considered epicentres for drug discovery – draw a hard line on the regulation of psilocybin such as China, Japan, Germany and Singapore.
What research is being done into medical psilocybin?
The next question of interest is where the potential is for psilocybin, and what research is being undertaken to advance it? The strongest use case for psilocybin is from clinical trials in cancer-related depression and anxiety and treatment-resistant depression, as well moderate-level evidence from several clinical trials for alcohol use disorder and tobacco addiction4. Other applications include a range of neuroscience research outcomes, end-of-life distress, cognitive enhancement and creativity, as well as anorexia nervosa.
Major depressive disorder
In July 2023, DDW reported on a milestone in a major depressive disorder trial. Cybin, a clinical-stage biopharmaceutical company developing psychedelic-based treatment options for mental health, completed dosing in Cohort 5 of a Phase II trial evaluating CYB003, an investigational proprietary deuterated analog of psilocybin for the potential treatment of major depressive disorder (MDD). To date, CYB003 has demonstrated a favourable safety and tolerability profile with no serious adverse events reported at the doses evaluated (1mg, 3mg, 8mg, 10mg, and 12 mg). Interim findings from the Phase I/IIa study have also demonstrated positive observations, showing that CYB003 dosing led to a rapid and robust psychedelic response in participants at low doses, while maintaining a safe and well-tolerated therapeutic profile.
The Usona Institute is a research facility exploring ‘consciousness-expanding’ medicines to address some of society’s most challenging mental health problems. One such focus is psilocybin. The insititute’s current clinical trials include PSIL201, PSIL201 LTFU, PSIL102 TQT, and PSIL102 – Food Effect (Part 2). PSIL201 is a Phase II, randomised, double-blind, placebo-controlled study of single-dose psilocybin to treat major depressive disorder. PSIL201 is a Long Term Follow Up (LTFU) study, a one year observational follow up study of participants to assess symptoms of major depressive disorder at six months post intervention in participants treated with a single-dose of either psilocybin or niacin (active-controlled) in the PSIL201 study. PSIL102 TQT is a safety study evaluating a supratherapeutic dose of psilocybin on cardiac repolarisation in healthy volunteers. Finally, the Food Effect study is an open-label safety study evaluating the effect of food on the PK of a single 25mg dose of psilocybin in healthy volunteers.
Treatment-resistant depression
In November 2022, DDW also reported on the results of the COMPASS Pathways’ Phase IIb trial, which were published in The New England Journal of Medicine (NEJM). In the study – the largest of its kind – psilocybin proved effective as a therapy for treatment-resistant depression (TRD). The data showed that after a single 25mg dose of COMP360 psilocybin, combined with psychological support, 29.1% of participants were in remission by week three. Scott Aaronson, Chief Science Officer of the Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt Health System, and a Principal Investigator on the trial, says: “Over 100 million people around the world suffer with treatment-resistant depression, and haven’t found relief from existing therapies. Yet in this study, a substantial number of patients in the 25mg group experienced improvement in their symptoms of depression, with the effects lasting for up to three months.”
Alcohol use disorder
Over a year ago now, Origin Therapeutics, an investment company focused on psychedelic therapies, added Canadian biotech Clairvoyant to its portfolio. DDW reported that Clairvoyant is developing psychedelic drug therapy focused on addiction and is targeting the clinical validation of psilocybin in the EU, the UK, and Canada. The company is currently proceeding with a Phase II clinical trial in Canada for the clinical validation of psilocybin for the treatment of alcohol use disorder (AUD). The trial will evaluate the safety and efficacy of a 25mg synthetic psilocybin capsule versus placebo, delivered in conjunction with Motivational Enhancement Therapy (MET). Are these details up to date is this was reported a year ago?
Similarly, Cybin, a biotechnology company focused on progressing psychedelic therapeutics, is developing CYB003, a proprietary molecule derived from psilocybin, which is part of a family of molecules called indolamines that includes more common neurotransmitters like serotonin. CYB003 is being evaluated for the potential treatment of both Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD). “We are optimistic that CYB003 could have the potential to improve the lives of AUD sufferers and their loved ones by providing a durable respite from alcohol dependence and the potential to overcome this often-crippling disease,” states Doug Drysdale, Chief Executive Officer of Cybin.
Anorexia nervosa
Previously mentioned COMPASS Pathways’ most recent clinical success is the publication of a paper in Nature Medicine that demonstrates the potential for COMP360 psilocybin treatment in anorexia nervosa. The investigator-initiated open-label study was conducted by Dr Walter Kaye and Dr Stephanie Knatz Peck at the University of California San Diego School of Medicine and is believed to be the first clinical research study to report the effects of psilocybin treatment in anorexia nervosa8.
Business: Where is the money?
When it comes to something as volatile and irregular in terms of regulation as psilocybin, funding is a key component if the field is to expand and progress. Investment is needed to ensure companies and biotechs have the resources required to take this extremely promising therapeutic opportunity to the next level. So, where is the money?
In October 2022, clinical stage company Beckley Psytech entered into an agreement to acquire clinical-stage life science company, Eleusis Therapeutics. As reported by DDW, under the terms of the agreement, Beckley Psytech has acquired 100% of Eleusis, receiving full developmental and commercial rights for the company’s assets which will further enhance Beckley Psytech’s innovative and differentiated pipeline of psychedelic compounds. The acquisition adds ELE-101, an intravenous (IV) formulation of psilocin, the active metabolite of psilocybin, to Beckley Psytech’s pipeline.
Also in October 2022, Clerkenwell Health, a psychedelic-specialist clinical research organisation, raised £2.1 million in seed funding, bringing the total to date up to £2.5 million, which the company planned to use to get the London-based startup fully operational. Since then, Toronto-based life sciences company Psyence started its first trials at Clerkenwell’s London site, following its approval from the MHRA, which will assess the efficacy and safety of psilocybin-assisted psychotherapy versus psychotherapy alone for the treatment of adjustment disorder due to an incurable cancer diagnosis9.
Earlier in 2023, the UK government announced a life sciences investment package which Psychedellic Spotlight believe will positively impact the psychedelic sector on account of the fact that £42.7 million of the investment is dedicated to mental health research7. Commenting on the money and its relevance to psychedelics, Professor Peter Jones, Trustee of Mental Health Research UK, said: “Recently we have seen some novel treatments showing significant promise, such as [NMDA] antagonists and psilocybin for depression, and the use of virtual reality headsets for PTSD and psychosis. The focus on a new ‘Mental Health Mission’ and significant injection of funding for mental health research will raise all our efforts to improve the lives of people living with mental ill-health in the future.”
Prior to the previously mentioned FDA issuance of the draft guidance for clinical trials with psychedelics, Blake Mycoskie, founder of Toms Shoes, pledged $100 million, 25% of his stated net worth, on psychedelic therapies for the treatment of mental health conditions, according to MarketWatch10. According to the capital market company, the donations will be paid over the next decade, beginning with $5-7 million donations by the end of 202310.
What does the future look like for psilocybin?
Between plentiful investment and dedicated scientists, it goes without saying that the scale of this research area will continue to expand in the future. However, in order for this to be effective, the public perception of psilocybin as a ‘party’ drug needs to subside. Even with regulation in check and successful clinical trials, ultimately people who need psilocybin need to be willing to take it without stigma. Ideally, the results will speak for themselves, but advocacy groups also play an important role. This was evident with the Psychedelic Access and Research European Alliance (PAREA) and Psychedelics EUROPE, whose two years of advocating culminated in the launch of a cross-party MEP Action Group for the Medical Use of Psychedelics in European parliament in May 2023. In Australia, the previously mentioned TGA approval was in part a result of an application submitted in March 2022 by Mind Medicine Australia (MMA), a non-profit working to alleviate the suffering caused by mental illness in Australia, focused on the development of safe and effective psychedelic-assisted therapies to cure a range of mental illnesses1.
Microdosing is an interesting concept which will require further investigation in the future. Microdosing is defined as taking very small amounts of psilocybin to benefit from its physiological action while minimising undesirable side effects like a ‘trip’. In a Harvard Medical School article on the popularity of microdosing of psychedelics, author Peter Grinspoon says11: “There is no definitive evidence yet that microdosing with psychedelics is either effective or safe.” He provides to contrasting examples of the current landscape. First, A systematic study of microdosing psychedelics, a paper published in PLos One, which indicated significant benefit from microdosing, including positive impacts on improved mental health, attentional capabilities, and neuroticism12. On the other hand, a study published in Translational Psychiatry, Microdosing with psilocybin mushrooms: a double-blind placebo-controlled study, the researchers found that even though there were cases where people felt happier, the low dose of psilocybin did not show objective evidence of improvements in creativity, well-being, and cognitive function. By and large, the evidence at present is anecodotal, and a more concentrated scientific effort is required if microdosing is to be taken seriously as a medical treatment in the future.
Justin Brandt, Founding Partner, Bianchi & Brandt, says that mainstream medicine’s embrace of psilocybin is inevitable as ongoing clinical research expands our understanding of its therapeutic benefits for various mental health conditions like PTSD, depression and addiction. He told DDW: “Meanwhile, the regulatory landscape for psilocybin and other psychedelics is rapidly evolving around the globe, with Australia leading the way by formally recognising psilocybin as medication. But other countries, including the US, Canada, and Israel, are also progressing in this regard. The overall shift in public perception, coupled with a growing body of clinical data, is driving further research aimed at addressing safety and efficacy. In the context of drug discovery, we’re navigating what is a perfect storm for expediting the formulation and standardisation of psilocybin for mainstream prescription therapies.”
References
- https://www.tga.gov.au/news/media-releases/change-classification-psilocybin-and-mdma-enable-prescribing-authorised-psychiatrists
- https://www.oregon.gov/oha/ph/preventionwellness/pages/oregon-psilocybin-services.aspx
- https://www.hopkinsmedicine.org/psychiatry/research/psychedelics-research
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9751063/
- https://www.canada.ca/en/institutes-health-research/news/2023/06/government-of-canada-invests-nearly-3-million-to-study-the-potential-benefits-of-psilocybin-assisted-psychotherapy.html
- https://researchbriefings.files.parliament.uk/documents/CDP-2023-0108/CDP-2023-0108.pdf
- https://psychedelicspotlight.com/will-the-uks-ambitious-life-sciences-investment-power-up-the-psychedelic-sector/
- https://techcrunch.com/2022/10/10/clerkenwell-health-raises-2-1m-to-test-the-new-wave-of-psychedelics-treatments/?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAANv3ZgToU3KwBFcieuRhk52PHXWB-oYLFyq3sS1e5kh2TAQXlTZfqUzffFJKgrO4954swBFa1g_i3CdPaKMN28gXVxBjMrS1Z5R_TEcZeK3cx7kyc1crz4QG7CbSW0QyxAWV1-edsuiYGcIGDoUJZA6caxth9lDjohrhD-PuVe8Q
- https://ir.compasspathways.com/news-releases/news-release-details/first-clinical-study-results-psilocybin-treatment-anorexia
- https://www.marketwatch.com/story/toms-shoes-founder-is-pledging-100-million-for-psychedelic-research-heres-why-hes-doing-it-cdbf0b0e
- https://www.health.harvard.edu/blog/the-popularity-of-microdosing-of-psychedelics-what-does-the-science-say-202209192819
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364961/
