Psilocybin Microdose for Psychological and Existential Distress in Palliative Care (PSYCHED-PAL-RCT)

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. Although the exact mechanism by which psilocybin affects mood symptoms is unclear, functional MRI studies of the brain show psilocybin disrupts the functional connectivity between anterior hippocampus (involved in memory and anticipation of future events) and the default mode network (associated with anhedonia and rumination on negative themes). 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. 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. Anecdotally, concerns about the safety of high-dose psilocybin in the terminally ill, as well as access to psychotherapy, may also be substantial barriers in this population. Moreover, randomized trials of psychedelic medications are methodologically challenging because patients cannot be blinded to having a psychedelic experience. This "functional unblinding" was one major reason why the US FDA chose not to approve psychedelic medication for the treatment of post-traumatic stress disorder in August 2024, despite strongly positive trial results.

Psilocybin microdosing may be safer and more feasible than psilocybin macrodosing in palliative setting. Psychedelic microdosing involves taking 5-10% of a psychedelic dose of a substance such as psilocybin on a regular basis (daily or several times per week). It does not produce a psychedelic experience, nor does it involve psychotherapy, but large surveys and anecdotal reports suggest that microdosing produces substantial and sustained improvements in mood and anxiety symptoms without any important side effects. 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.

We have completed a phase 2 dose-finding and proof of concept study for microdosing psilocybin in people with advanced illness receiving PC. Using progressively increasing microdoses of psilocybin over a 3-week period (from 1 mg to 3 mg daily), we found that a large proportion of participants experienced dramatic improvements in their psychological distress, with minimal side effects. This effect was durable after stopping the medication but diminished after 4 weeks. Given the encouraging findings from our phase 2 study, and the potential feasibility, scalability, and safety of psilocybin microdosing for a population with few effective options, proceeding to a phase 3 placebo-controlled trial is warranted.

Objectives

Primary Objectives:

To determine the efficacy of microdose psilocybin for improving psychological distress among patients with advanced illness followed by a palliative care provider.

Secondary Objectives:

1. Assess whether microdose psilocybin improves quality of life and desire to die among patients with advanced illness followed by a palliative care provider.
2. Determine the safety of long-term (up to 1 year) use of psilocybin microdose to treat psychological distress among patients with advanced illness followed by a palliative care provider.

Open-Label Access and Extension Phase

Following the primary study 2-week follow-up completion, all participants will have the option to participate in an open-label access phase. In this phase, participants will be offered open-label psilocybin for two consecutive weeks (same dosing and schedule as the primary study). Two weeks after the access phase has been completed, all participants will have the option to participate in the open-label extension period for up to 1 year. The open-label extension will follow a three-week dosing cycle, where all participants will take psilocybin microdoses for two consecutive weeks, and then no doses on the third week, before starting the cycle again.

The open-label and open-label extension phase include safety and primary and secondary outcomes (see Outcome Measures), in line with the primary study protocol.

Sample Size

We require a sample size of 60 patients per arm (120 patients in total). This assumes a 20% loss to attrition/deterioration and 10% withdrawal (based on our phase 2 study). This sample would have 80% power to detect a change of 0.30 from 30% PGIC response (control) to 60% PGIC response (intervention) at last treatment day, corresponding to an effect size (Cohen's d) of 0.61.

Statistical Analysis

We will follow an intent-to-treat approach. We will use chi-square tests to compare the proportion of participants in the microdose psilocybin vs. placebo arm with a PGIC score of ≥5 at the last day of treatment and at 2-week follow-up, and to compare the proportion of participants who demonstrate a minimal clinically important difference (MCID) in secondary efficacy outcomes. To minimize type I error, a correction will be performed on the multiple secondary endpoint analyses.

Safety and feasibility outcomes will be analyzed using descriptive statistics with 95% confidence intervals.