PSilocybin for psYCHological and Existential Distress in PALliative Care (PSYCHED-PAL): A Multi-site, Open-label, Single Arm Phase I/II Proof-of-concept, Dose-finding, and Feasibility Clinical Trial

Patients with advanced illness report feeling a sense of hopelessness, loss of autonomy and relationships, and a lack of purpose in life. These feelings of psychological suffering have been described as "existential distress" and are associated with poor outcomes, including decreased medication adherence and quality of life, increased desire for hastened death and rates of suicide, and has been identified as a primary reason why individuals pursue medical assistance in dying (MAiD).

Current treatments for psychological and existential suffering have low efficacy and are challenging to use in a palliative context. Pharmacological approaches for treating psychological suffering may reduce symptoms of depression and anxiety, but evidence to support their efficacy in palliative care (PC) is underwhelming. Antidepressant and anxiolytic medications also take time to work and can cause serious side effects such as falls and confusion, which can be substantial deterrents for patients. Similarly, results from randomized controlled trials (RCTs) and meta-analyses have demonstrated psychotherapeutic interventions show limited benefit in a PC population. Further, psychotherapy can be time consuming and slow to work, which is not ideal for patients with limited life expectancy. Given the burden of psychological and existential distress among patients followed by PC providers, there is a need to develop scalable, brief, and rapidly effective therapeutic approaches to reduce this distress.

Psychedelic medications offer an innovative, safe, complementary approach to address psychological and existential suffering in patients receiving PC. Studies from the 1950's showed serotonergic hallucinogens ("psychedelics") improved depression and anxiety symptoms in cancer patients. However, legislative changes restricted the use of these medications in clinical care and research. Interest in psychedelic medications has been rekindled by two recently published RCTs that studied the use of psilocybin (a mushroom-derived 5HT2A agonist) during a single psychotherapeutic session in cancer patients with anxiety and/or depression. These trials demonstrated rapid, clinically meaningful, and long-lasting reductions in depressed mood and/or anxiety symptoms and improvements in quality of life and death acceptance. There is also evidence suggesting psilocybin microdosing - taking sub-hallucinogenic doses continuously over longer time periods, rather than a one-time hallucinogenic dose - can improve mood and anxiety. The effects of microdosing, however, have not been rigorously evaluated, particularly in patients with life limiting illness.

Results from recent trials are encouraging but knowledge gaps remain. First, studies to date primarily enrolled patients with localized disease who experience different distress than that of patients with advanced disease who are near the end of life. Second, it is unclear if Canadians would find psilocybin an attractive option in the context of MAiD legalization, which provides an alternative option for patients with severe psychological suffering. Third, there is no empirical research on the therapeutic effects of psilocybin microdosing, as most studies have followed macrodosing protocols. While preliminary efficacy of macrodosing has been demonstrated, there are important barriers to administering this therapy in a PC context. Previous trials had slow recruitment rates, suggesting there may be barriers related to the acceptability of psilocybin macrodosing from the perspectives of patients and families. Macrodosing requires the patient to dedicate an entire day to participating in a guided hallucinogenic experience and remain in an acute care setting where they can be closely monitored. It also requires patients to engage in preparatory sessions with monitors and a post-therapy session. In a PC context, this time commitment may not be acceptable or feasible for patients who are nearing the end of life. Additionally, macrodosing requires at least two trained moderators to guide the patient through their psychedelic experience and facilitate the pre- and post-dosing sessions. In most PC settings, it is not feasible to have clinicians dedicate two days to a single patient, thus limiting the scalability of this intervention.

Psilocybin microdosing has the potential to overcome barriers to the feasibility and acceptability of macrodosing. By removing the requirement for trained moderators, minimizing the time commitment required of patients, eliminating the hallucinogenic effects of the therapy, and allowing patients to receive treatment either as an inpatient or in the community, microdosing may be a more acceptable option to patients and families and allow psychedelic therapy to be scalable across various PC settings. Psilocybin microdosing is a novel, complementary therapy that, while still unproven for patients near the end of life, has the potential to fundamentally change the way psychological and existential distress is responded to in PC, improving the lives of the 30% of patients who experience this suffering at the end of life.