Psilocybin for End-Of-Life Distress: Literature Review & Canadian Regulatory Context

KYDDER GROUP INC.

17 min readDec 10, 2020

Ron Shore, PhD (A.B.D.), M.P.A., Queen’s University/University of Ottawa, Keren Gottfried, MA, University of Ottawa

Contact: RS, 31rjs7@queensu.ca / rshore@uottawa.ca

October 25, 2020

Prepared for the Standing Committee on Justice and Human Rights and the Senate of Canada

Submitted by Field Trip Health Inc. and Kydder Management Group Inc.

Ronan Levy, Founder & Executive Chairman, Field Trip Health Inc.

Michael Kydder, Founder, Kydder Management Group Inc.

michael@kyddergroup.com 902.880.6121

Introduction

The following literature review was prepared at the request of Field Trip Health Inc. and Kydder Management Group Inc.

Its purpose is to inject an academic perspective from leading Canadian psychedelics researchers on the current Canadian regulatory environment as it relates to psilocybin-assisted therapy and end-of-life distress, particularly Bill C-7: Medical Assistance in Dying (MAiD).

We believe, as do many Canadians, that the palliative process is as much about the journey and spiritual awareness as it is the end. Of the roughly 270,000 Canadians who die each year, 90 per cent die of chronic illness, such as cancer, heart disease, organ failure, dementia, or frailty. Bill C-7 is an opportunity to discuss and legally integrate psilocybin-assisted therapy as a dignified, quality of life treatment option for palliative Canadians suffering mental distress from onset of diagnosis to the last stage of life.

The current ad hoc exemptions granted to palliative Canadians under Section 56(1) of the Controlled Drugs and Substances Act are unsustainable and could potentially lead to further complications without a well-informed policy. It is our position that the understanding of the end-of-life process, and the inclusion of psychedelics as a non-stigmatized therapeutic intervention, should be recognized and acknowledged before the Standing Committee on Justice and Human Rights, and subsequently the Bill C-7 Statutory Review.

We hope the information provided will lead to further dialogue and a broader understanding of the mental anguish associated with the end-of-life process.

Background

Psilocybin is a naturally occurring indole alkaloid tryptamine and serotonergic agonist found in hundreds of species of fungi, including Psilcoybe mushrooms (Guzman, 2008). Sacramental use of the Psilocybe genus of gilled fungi in Mesoamerica has been documented to 500 BC (Guerra-Doce, 2015). In combination with psychotherapy, psilocybin has emerged as novel and promising therapy for a range of treatment-resistant mental health conditions including obsessive-compulsive disorder, substance use disorder, unipolar depression, anxiety or depression in patients with life-threatening cancer, and demoralization due to long-term AIDS survival (Shore, 2019). Safety, tolerability and efficacy have been established; phase 2b/3 randomized controlled trials are now underway to establish treatment effectiveness in a range of patient populations (Rucker 2018, Shore 2019) and psilocybin has been granted breakthrough therapy status in the United States[1].

Canadian Regulatory Status

Psilocybin is a pro-drug to psilocyn, the psychoactive compound found in psycho-active mushrooms. Under Schedule 3 of the Controlled Drugs and Substances Act (CDSA), both are illegal to possess, obtain or produce unless authorized for clinical trial or research purposes. There are no currently approved therapeutic products approved for use though a tolerated grey-market has emerged in Canada, with multiple companies selling and distributing Psilocybe mushrooms online in Canada[2].

Authorization for manufacturing or other private work can be requested under the Food and Drug Regulations through a Dealer’s License from Health Canada. Numinus, a private firm in British Columbia, has obtained a Dealer’s License from Health Canada and is authorized to cultivate magic mushrooms and extract its psychoactive alkaloids; Numinus has recently completed the first flush of legal magic mushrooms production in Canada[3]; Calgary-based PsyGen Labs Inc. is similarly in application for a Dealer’s License and is scheduled to supply domestic researchers with synthetic psychedelics, including psilocybin[4].

Exemptions to the prohibition of controlled substances may be requested under subsection 56(1) of the CDSA, if the Minister of Health believes the exemption is “necessary for a medical or scientific purpose or is otherwise in the public interest.”[5] To date 11 Canadians with terminal illness have been approved to date for Schedule 56(1) access (exemption from narcotics legislation for compassionate reasons) in partnership with TheraPsil, the Canadian non-profit initiative that originally filed an application with Health Canada seeking a section 56(1) exemption to allow therapists to legally practice psilocybin-assisted psychotherapy in the compassionate treatment of certain cancer patients suffering from end-of-life distress (EOLD)[6].

Multiple jurisdictions in the United States have decriminalized magic mushroom use, including Denver, Oakland and Santa Cruz[7]. The state of Oregon will soon vote on regulatory changes to allow for the therapeutic use of psilocybin[8].

Precedents for Reclassification

In Canada, the previous medical cannabis regulatory framework may prove a good fit for therapeutic access to psilocybin as decided between a medical practitioner and patient.[9]

Legal access to cannabis began with section 56(1) exemptions in 1999, followed later by appellate courts ruling affirming the right to possess marijuana for medical purposes[10] and the subsequent creation of Marihuana for Medical Purposes Regulations.[11] Charter challenges argued the limits on those regulations contravened constitutionally-protected rights, and the Government of Canada legalized cannabis before those challenges were escalated to the Supreme Court. Health Canada can — and has recently — reclassify drugs from prohibition to regulatory approval for medical or other use.

Dronabinol (synthetic delta-9- tetrahydrocannabinol) is one such example, initially approved as an orphan drug for AIDS- related anorexia in 1985 and now approved for cancer chemotherapy related nausea and vomiting. Xyrem (sodium g-hydroxybutyrate) was approved for the treatment of cataplexy associated with narcolepsy in 2004 , and an extract of cannabis sativa has been licensed for medical application even in regimes of cannabis prohibition (Rucker et al., 2018)

Clinical Research

A review of seven systematic reviews of classical psychedelics demonstrates significant positive results in using reducing end of life depression and anxiety in the following cases: ayahuasca for major depressive disorder, psilocybin for treatment-resistant depression, psilocybin for anxiety and depression associated with life-threatening cancer, and LSD for anxiety associated with life-threatening disease (Muttoni, 2019). Psilocybin-assisted therapy has been documented in several clinical trials over the past ten years, indicating strong suggestions of efficacy for reducing anxiety and depression for patients facing cancer or terminal illness (Carhart-Harris et al, 2018, Griffiths et al. 2016, Ross et al, 2016, Grob et al, 2011). Psilocybin-assisted therapy may also be of support through its other psychiatric purposes (Shore 2020a). Encouraging results suggest its efficacy towards supporting patients with symptoms of treatment-resistant depression (Carhart-Harris et al, 2016) and depression (Carhart-Harris et al, 2016, Carhart-Harris et al, 2018, Ross et al, 2016), anxiety (Griffiths et al, 2016, Grob et al, 2011), substance use (Bogenschutz et al, 2015, Johnson et al, 2014), and obsessive-compulsive disorder (Moreno et al, 2006). 54 additional clinical trials using psilocybin are registered[12], a stage 3 randomized controlled trial, psilocybin for major depression, is currently underway.[13]

Mechanism of Action

Psilocybin’s efficacy may lie in its promotion of structural and functional neuroplasticity (Ly et al, 2018). It enables the creation of new neurological pathways that, when combined with other interventions like psychotherapy, can “re-wire” pathological patterns to adaptive ones (Shore et al, 2019). Stimulation of the 5-HT2A receptor has been shown to increase mental flexibility (James, 2020) and soften previously-held beliefs, so psilocybin is considered to encourage the cognitive conditions for behaviour change (Carhart‐Harris, 2018) and even personality change (Bouso et al, 2018, Aixalà, 2018). This “re-booting” of the brain to a changed state can last for some time after the drug has left the system (Spiegel, 2016). Combined with psychotherapeutic approaches, then, psilocybin’s role is understood as the catalytic component of the “total drug effect,” which includes the substance, the individual’s mindset, and the setting in which the substance is ingested (Hartogsohn, 2016). It is widely held that psilocin’s serotonin receptor agonism encourages cognitive flexibility and meaning-attribution (Muttoni, 2019) while resulting in psychological improvements in openness, acceptance and forgiveness (Shore, 2019, Watts, 2017, Carhart-Harris, 2018, Griffiths, 2016).

Safety Considerations

Serotonergic psychedelics possess relatively low physiological toxicity and have not been shown to lead to neurological deficits, organ damage or to cause genetic damage or birth defects (Gable, 2004; M. W. Johnson et al., 2008a; Strassman, 1984). Psychedelics have a low potential for abuse or dependence and have not been found to lead to compulsive drug seeking (Carbonaro et al., 2016; Johansen & Krebs, 2015; Krebs & Johansen, 2013a; Rucker et al., 2018)

Non-toxicity and safety of serotonergic psychedelics have been well established, though there are documented adverse experiences to mitigate, including increased blood pressure and heart rate, transient anxiety and post-session headaches (Shore, 2020).

The safety profile for psilocybin mushrooms — including established safety levels, that it is well tolerated, and that it has a low risk profile — has been well documented in the clinical trial literature over several decades (Shore, 2020, Aday et al, 2020, Ross, 2016, Barceloux, 2012). Various reviews have found no serious lasting negative side effects among participants in clinical trials (Aday, 2020, Shore, 2020), covering over n=2,000 participants who participated in trials since 2016 (Ross, 2016). Reports of long-term reactions, such as Hallucinogen Persisting Perception Disorder are negligible (Barceloux, 2012) and empirical evidence to support the existence of such a disorder is scant (Krebs & Johnson, 2015). Generally, these risks can be managed through appropriate management of set, setting, support, and participant selection, and no psilocybin clinical trial documented medically serious adverse effects (Shore, 2020).

Psilocybin-assisted Therapy for End-of-Life Distress

Of the nine completed clinical trials investigating psilocybin for clinical application, three are specific to cancer-related anxiety and distress and total 97 participants, representing 57% of the total (n=169) of all psilocybin clinical trial participants. Of all completed psilocybin clinical trials, the EOLD trials are characterized by the most robust methodology and demonstrated the clearest, measured positive treatment outcomes, most specifically reductions in depression and anxiety, and positive attitudes and beliefs towards mortality and life purpose (Shore, 2019, Rucker 2018, Grob et al, 2011, Griffiths et al., 2016, Ross et al., 2016.). A multi-site psilocybin clinical trial proposal co-sponsored by the University of Ottawa, McGill University, University of Toronto, McMaster University and Queen’s University has been developed and awaiting funding (Psilocybin for Psychological and Existential Distress in Palliative Care (PI.: Dr. James Downer, University of Ottawa)[14].

End-of-Life Distress

EOLD is identified as a primary reason why individuals pursue medical assistance in dying (Watt et al., 2017, Salt et al, 2017, Hendry et al., 2018) Psychological suffering and existential distress are common among cancer patients approaching end of life as well as others experiencing terminal illness. Patients report feelings hopelessness, loss of autonomy, poor relationships, and general lack of purpose. (Kissane, 2000, Bauereiss et al., 2018). End-of-life distress is associated with poor treatment and psychological outcomes, including decreased medication adherence (Colleoni et al, 2000, Skarstein et al., 2000), diminished quality of life (Colleoni et al, 2000, Oregon Health Authority, 2016), an increased desire for hastened death and higher rates of suicide. identified as a primary reason why individuals pursue medical assistance in dying (Watt et al., 2017, Salt et al., 2017).

Public Health Gap in Palliative Care

Up to 80% of patients with advanced cancer are likely to suffer distressing thoughts around death (Grossman et al, 2017) and up to 50% of patients with generally incurable conditions are likely to have psychiatric diagnoses (Asghar-Ali et al, 2013). Symptoms include depression, anger, hopelessness, fear of suffering and loneliness (Swift et al, 2017, Grossman et al, 2017). Death anxiety may be a normal part of the human life cycle, but the current medicalized model (Dyck, 2019) can make it difficult for palliative patients to focus on their holistic and spiritual well-being, which palliative nurses consider to be of top concern (Rosa, 2019). The literature suggests a gap between current palliative care offerings and the current and expected future demand; the literature suggests this gap is driven by a lack of reliable pharmacological interventions for palliative dread (Bernstein, 2020, Rosenbaum et al, 2019) and an ageing population (Dyck, 2019). If left unaddressed, death anxiety may lead to more palliative patients seeking medical assistance in dying (MAID) (Grossman, 2017).

Psychedelics may be effective supportive agents for patients experiencing end of life distress and considering medical assistance in dying. While medical assistance in dying is a protected right in Canada, patients approaching death may be underserved if promising therapies are withheld. Psychedelic-assisted therapy can promote patients to safely surface concerns about mortality and face death, our “primordial fear” (Dutta, 2012) while simultaneously enabling resolution of those these concerns (Moreton et al, 2019). They can also help patients find meaning in death, embrace mortality, and appreciate their lives (James, 2020, Swift, 2017, Ross, 2016, Grob, 2013).

Modelling the Need

Combining prevalence data, Canadian demographics, selection criteria for psilocybin for EOLD and estimation methodology, TheraPsil forecasts 2800 new Canadians each year may benefit from access to psilocybin-assisted therapy (TheraPsil, 2020). The estimate range is 1200–5900, with a projection that ~80% of this population experiencing clinically meaningful improvements in EOLD, with ~60% in full remission even 6 months after treatment. Inclusion criteria establish medical necessity and include: a) patients facing serious and life-threatening illness, cancer; b) patients suffering from serious end-of-life psychological distress, and c) other treatment options have proven unsuccessful. (TheraPsil, 2020). TheraPsil further estimates that 25 hours of therapist time accompany each psilocybin dosing session, in preparation, support and integration[15].

Conclusion

Clinical research has established the safety, tolerability and efficacy of psilocybin in the treatment of End-of-Life Distress. Regulatory channels are currently providing legal access on compassionate, humanitarian grounds while jurisdictions consider broader regulatory changes. Precedents exist for reclassification of Schedule 3 drugs in Canada. Previous regulations allowing medical access to cannabis offer a regulatory model to expand access. 2800 Canadians with terminal illness per annum could potential benefit from expanded access. Expanded regulatory access is justifiable given the established safety of psilocybin, it’s putative therapeutic benefits, Canada’s aging population and the prevalence of EOLD.

Appendices:

1. Review of the literature supporting the use of psilocybin at end of life.

2. Mapping Psilocybin Therapy: A Scoping Review, Shore, et al., 2019.

3. Estimating Eligible Candidates for Compassionate Treatment Using Psilocybin, TheraPsil.

4. References

References:

Psilocybin for End-of-Life Distress: Literature Review & Canadian Regulatory Context

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[1] https://compasspathways.com/compass-pathways-receives-fda-breakthrough-therapy-designation-for-psilocybin-therapy-for-treatment-resistant-depression/

[2] https://doubleblindmag.com/canada-psilocybin-dispensaries-dana-larsen/

[3] https://www.truffle.report/numinus-landmark-psilocybin-announcement/

[4] https://www.greenmarketreport.com/psygen-labs-to-supply-neonmind-with-psilocybin-for-weight-loss-study/

[5] https://www.canada.ca/en/health-canada/services/health-concerns/controlled-substances-precursor-chemicals/exemptions.html

[6] https://www.thestar.com/news/canada/2020/10/25/mental-illness-is-on-the-rise-due-to-covid-19-could-psychedelic-drugs-be-the-game-changer.html

[7] https://www.forbes.com/sites/davidcarpenter/2020/02/01/santa-cruz-is-third-us-city-to-decriminalize-psilocybin-plant-medicine-as-advocacy-expands/#45dd58805d0d

[8] https://www.kgw.com/article/news/politics/elections/oregon-measure-109-psilocybin-therapy-election/283-8805ddb6-7a61-4182-95ae-640fda00235f

[9] personal communication, Dr. B. Tobin, TheraPsil, October 2020.

[10] https://www.canlii.org/en/on/onca/doc/2000/2000canlii5762/2000canlii5762.html

[11] https://medicalmarijuana.ca/patients/marijuana-laws/