Psilocybin in end of life care: Implications for further research

This issue of the Journal of Psychopharmacology contains two important randomized controlled studies on the use of psilocybin to treat mood and anxiety (including adjustment disorders) in carefully selected and supervised patients with later stage malignancies. Ross et al. (2016) studied 29 cancer patients using a twosession, double-blind, crossover (seven weeks after administration of dose 1) design employing psilocybin first then niacin second, or niacin first and psilocybin second. Both groups had extensive orientation to the trial and psychotherapy with supportive, psychodynamic, and existential elements. They found that psilocybin produced an immediate and ongoing anxiolytic and antidepressant response, with 83% in the psilocybin-first group (vs. 14% in the niacin-first group) meeting criteria for antidepressant response seven weeks after dose 1. Pre-crossover results were significant post initial drug administration, although Beck Depression Inventory between groups was significant at the p<0.05 level one day prior to initial drug administration but not at baseline. At follow-up at six and a half months (after both groups received psilocybin), antidepressant or anxiolytic response rates were in the 60–80% range depending upon measure. Subjects’ mystical or spiritual experiences were highly correlated with clinical response and mediated four out of six primary outcome measures. Griffiths et al. (2016) studied 51 cancer patients using a twosession, double-blind, crossover (five weeks after administration of dose 1) design employing high-dose psilocybin first then very low-dose (placebo-like) psilocybin second, or very low-dose (placebo-like) psilocybin first and high-dose psilocybin second. The use of low-dose psilocybin as its own control, instructional language to subjects and that which aimed to minimize the placebo response, and extensive supportive meetings with study personnel (but not formalized psychotherapy) were distinctive element of the study design. It was found that high-dose psilocybin produced large decreases in clinicianand self-rated measures of depressed mood and anxiety. Five weeks after session 1, 92% in the high-dose psilocybin-first group (vs. 32% in the lowdose-first group) showed a clinically significant response and 60% versus 16% symptom remission. At follow-up at six months (after both groups received high-dose psilocybin), these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Subjects’ mystical or spiritual experiences were highly correlated with clinical response and mediated seven of the primary outcome measures. In both studies, adverse events were limited and included expected increases in blood pressure, pulse, nausea and vomiting, and transient anxiety or occasional psychotic symptoms, which remitted rapidly. Improvements in attitudes toward death and the experience of deeply meaningful spiritual experience were likewise reported in both studies. These studies build on prior smaller studies, including a psilocybin study that found a trend to decreased psychological distress in people with life-threatening illness (Grob et al., 2011). While there are several methodological issues in the Ross et al. (2016) study, including changes in cancer severity, recruitment criteria, and a larger number of agnostic/atheist subjects in the niacin-first group, and changes in the highand low-dose regimens shortly after initiation in the Griffiths et al. (2016) study, analyses showed these did not contribute to the outcomes. More substantial is the difficulty of blinding subjects or study personnel to the effects of a drug with such dramatic effects as psilocybin. The study instructions and use of low-dose psilocybin as the control drug in the Griffiths et al. (2016) study was a creative way to address these issues. It is, however, unclear how effective blinding procedures were. Placebo responsiveness and expectations are of course complex issues to isolate. This is especially true in studies that included a significant percentage of participants with prior psychedelic use and who were facing serious medical and existential issues. Nevertheless, the rate and speed of response to an active drug, its intensity and duration, is decidedly more substantial than one sees in placebo responses in moderately depressed patients, even with highly committed and engaged research groups. What are the implications of these studies for ongoing research and clinical care with psychedelic agents? If the agents used in these studies were new investigational compounds, given the paucity of agents that have rapid effects on depressed mood, there would likely be rapid dissemination of the results, expansion of trials to larger and other clinical populations, and attempts to develop additional compounds with similar mechanisms of action. If, after further study, initial findings were confirmed, discussions of compassionate use Psilocybin in end of life care: Implications for further research