Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer

This follow-up study (n=11) of psilocybin-assisted therapy for anxiety and depression, found that it also significantly reduced suicidal ideation (SI) and loss of meaning (LoM) up to the 4.5 years follow-up.

Abstract

“People with advanced cancer are at heightened risk of desire for hastened death (DHD), suicidal ideation (SI), and completed suicide. Loss of Meaning (LoM), a component of demoralization, can be elevated by a cancer diagnosis and predicts DHD and SI in this population. We completed a randomized controlled trial in which psilocybin-assisted psychotherapy (PAP) produced rapid and sustained improvements in depression, demoralization, and hopelessness in people with cancer. Converging epidemiologic and clinical trial findings suggests a potential antisuicidal effect of this treatment. To probe our hypothesis that PAP relieves SI through its beneficial impacts on depression and demoralization (LoM in particular), we performed secondary analyses assessing within- and between-group differences with regard to LoM and an SI composite score. Among participants with elevated SI at baseline, PAP was associated with within-group reductions in SI that were apparent as early as 8 h and persisted for 6.5 months postdosing. PAP also produced large reductions in LoM from baseline that were apparent 2 weeks after treatment and remained significant and robust at the 6.5 month and 3.2 and 4.5 year follow-ups. Exploratory analyses support our hypothesis and suggest that PAP may be an effective antisuicidal intervention following a cancer diagnosis due to its positive impact on hopelessness and demoralization and its effects on meaning-making in particular. These preliminary results implicate psilocybin treatment as a potentially effective alternative to existing antidepressant medications in patients with cancer that are also suicidal, and warrant further investigation in participants with elevated levels of depression and suicidality.”

Authors: Stephen Ross, Gabrielle Agin-Liebes, Sharon Lo, Richard J. Zeifman, Leila Ghazal, Julia Benville, Silvia Franco Corso, Christian Bjerre Real, Jeffrey Guss, Anthony Bossis & Sarah E. Mennenga

Notes

This paper is a further analysis of data from Ross and colleagues (2016) and the follow-up from Agin-Liebes and colleagues (2020) which studied psilocybin-assisted therapy for anxiety and depression in patients with life-threatening cancer.

Summary

■ INTRODUCTION

Suicide is a leading cause of death in the United States and worldwide, and is increased by advanced illness, uncontrolled pain, psychiatric distress, and existential distress. There is little evidence for current pharmacologic interventions effectively targeting suicidal ideation and behavior among individuals with life-threatening cancer. Patients with advanced cancer who desire for hastened death have been shown to have higher rates of existential distress and a higher rate of suicide attempts. Demoralization syndrome, a manifestation of existential distress, is positively correlated with desire for hastened death.

Psilocybin-assisted psychotherapy for cancer-related anxiety, depression, and existential distress has been investigated in several RCTs, and has been associated with rapid analgesic effects, improvements in psychiatric distress, and improved psychiatric outcomes associated with mystical experiences. Three RCTs have shown that psilocybin, delivered in conjunction with psychotherapy, produces rapid, substantial, and sustained reductions in anxiety and depressive symptoms, as well as sustained reductions in existential distress, and improved quality-of-life.

Psilocybin-Assisted Psychotherapy for Cancer-Related SI: Converging evidence suggests that psilocybin may also have antisuicidal effects. In particular, single-dose ayahuasca administration is associated with rapid and sustained decreases in suicidality in patients with major depressive disorder.

The NYULH/Bellevue Hospital trial and its ancillary long-term follow-up study did not explore suicidality as a primary or secondary outcome, but found that psilocybin-assisted psychotherapy improved several constructs related to suicide and demoralization syndrome, including depression, cancer-related hopelessness and demoralization, and spiritual well-being.

To assess the efficacy of a single dose of psilocybin administered in conjunction with psychotherapy in treating clinically significant anxiety and/or depression as well as existential distress in patients with advanced cancer, we performed post hoc analyses of relevant data from our completed NYULH/ Bellevue Hospital trial. A subsample of participants from the parent trial participated in two additional long-term follow-up assessments. The studies were approved by the NYULH Perlmutter Cancer Protocol Review and Monitoring Committee and the NYU School of Medicine IRB.

A total of 108 participants were screened, 42 provided informed consent, 31 were randomized into the experimental or control group, and 29 received study medication. 11 were included in this secondary analysis due to detectable baseline levels of SI.

We created a composite score for suicidal ideation using scores on two items from the Beck Depression Inventory-II and the Brief Symptom Inventory, and transformed the summed Z-scores into standardized T-scores with a range of 0100, with higher scores indicating a higher risk of suicide.

Higher SI was assessed at baseline, 8 h after dose 1, 2 weeks after dose 1, 7 weeks after dose 1, and 6.5 months after dose 2.

The Demoralization Scale, a 24-item questionnaire with Likert scale response categories ranging from 0 to 4, was used to assess Loss of Meaning (LoM) in patients with advanced cancer. The LoM factor positively correlates with scores on a validated measure of DHD.

The remaining items from the BDI-II were scored to represent other depressive symptoms. Change in other depressive symptoms was assessed from baseline to 2 weeks after dose 1.

Hopelessness is assessed using an 8 item existential distress scale that ranges from 0 to 16, with higher scores indicating greater levels of hopelessness.

The FACIT-Sp-12 is a 12 item measure of spiritual well-being in patients with cancer and other forms of chronic illness. It shows strong internal consistency and is a well-validated scale.

Data from the original parent investigation and the ancillary long-term follow-up study were combined for posthoc analyses. Power analyses indicated that analyses with four repeated measures were sufficiently powered to detect large effect sizes.

Mixed effect models with repeated measures were constructed in SPSS (version 25) to assess the impact of psilocybin treatment on SI and LoM. Effect sizes were tentatively estimated as Cohen’s d, although deviations from normality and small sample size were expected to introduce bias into these estimates.

The majority of participants were non-Hispanic White, and most had advanced gynecological cancers. Approximately one-third of participants reported one or more occasions of prior psychedelic use, and most met DSM-IV criteria for cancer-related adjustment disorder with anxious and depressed features or adjustment disorder with anxious only features.

Psilocybin-Assisted Psychotherapy improved scores on SI and LoM at all post dose 1 administration session time points relative to baseline. There was no effect of group on SI or LoM, and there was no interaction between group and time on LoM.

After crossover, Psilocybin-Assisted Psychotherapy remained effective in reducing SIG and LoM. The effects persisted for 3.2 year and 4.5 year follow-ups.

The reductions in self-injury scores were positively and strongly correlated with reductions in other depressive symptoms, but the correlation between reductions in spiritual well-being did not approach significance.

Psilocybin, in combination with psychotherapy, can reduce suicidality in patients with life-threatening cancer. This effect is sustained even after a single moderate-to-high dose, suggesting that psilocybin may be protective against progression to more serious forms of suicidality. We found a positive relationship between a decrease in meaning-making and a decrease in suicide risk in patients with advanced cancer. This finding is consistent with a growing literature on the efficacy of existential psychotherapies in decreasing depressive symptoms in advanced cancer.

Psilocybin is associated with antisuicidal effects in patients with treatment-resistant depression, and the risks are minimal as long as it is delivered in carefully controlled clinical settings.

Psilocybin could be a novel avenue for treatment of major depressive disorder in people that are suicidal, as it has been shown to reduce suicide risk in people with higher baseline SI levels.

Ketamine, a N-methyl-D-aspartate receptor antagonist and dissociative anesthetic, has been shown to rapidly reduce suicidal thoughts in patients with major depressive disorder and suicidality, and psilocybin has similar potential for rapid and sustained antisuicidal effects.

■ DISCUSSION

If the above findings can be replicated in future trials, psilocybin-assisted psychotherapy may be a potentially novel paradigm in psychiatry and psycho-oncology that could target patients with advanced or terminal forms of cancer who are experiencing elevated rates of depression, existential distress, or pain, and associated DHD, SI, and suicidal behaviors.

Psilocybin treatment may reduce suicidality in advanced cancer patients by reducing depression, demoralization, hopelessness, and chronic pain. Further research is needed to explore the mechanisms of action of psilocybin, including a parallel design without crossover, and recruitment of participants with clinically relevant suicidality and DHD.

We included measures to assess for the various psychological change mechanisms, a sufficient sample size, and techniques to assess potential neurobiological mechanisms of action in accounting for improvement in long-term clinical outcomes.

The parent trial was not designed to assess the antisuicidal effects of psilocybin in patients with advanced cancer, and the crossover design limits the ability to assess long-term clinical benefits relative to a control condition.

Psilocybin, in conjunction with psychotherapy, was associated with acute and enduring anti-SI and anti-LoM effects in patients with psychiatric and existential distress related to life-threatening cancer.