Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer, Stephen Ross et al., 2021

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

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

ACS Pharmacology & Translational Science, 2021, 4, 553−562.

doi : 10.1021/acsptsci.1c00020



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.

KEYWORDS : psilocybin, psychedelic, cancer, depression, suicidal ideation, demoralization, loss of meaning



There are approximately 48 000 and 804 000 deaths by suicide each year in the United States1 and worldwide,2 respectively, making suicide a leading cause of death. A diagnosis of cancer is a known risk factor for increased suicidal ideation (SI) and behavior and studies of completed suicide in cancer patients have reported prevalence rates up to 4 times greater than that in the general population.3−10 A systematic review and metaanalysis (k = 22 studies) of cancer diagnosis and suicide mortality reported a pooled standardized mortality ratio (SMR) of 1.55 (95% CI = 1.37−1.74).10 However, a retrospective, population-based study of a nationally representative sample including 8 651 569 patients with cancer reported a SMR = 4.44, indicating that risk of completed suicide might increase 4-fold following a cancer diagnosis.9 The association between cancer and increased suicide risk is predominantly mediated by advanced illness (i.e., poor prognosis and disease progression), uncontrolled pain, psychiatric distress (major depression in particular), and existential distress (hopelessness and helplessness).11−18 Importantly, within the context of cancer-related psychiatric and existential distress, there is little evidence for current pharmacologic interventions effectively targeting SI [for a review, see ref 19]. There is, therefore, a need for exploring innovative treatment strategies for reducing SI among individuals with life-threatening cancer, especially interventions that can work rapidly.

A more subtle manifestation of SI in patients with advanced cancer is the desire for hastened death (DHD), that is, the wish for a more rapid death than would naturally occur. DHD has been reported in 9−22% of patients with advanced or terminal cancer, is more common in palliative care settings,20−24 and has similarly been shown to be associated with physical distress, low social support, depression, demoralization, hopelessness, and lack of spiritual wellbeing.25,26 Among these, depression and hopelessness appear to predominantly mediate DHD in advanced cancer,21,27−31 and improving spiritual well-being in advanced cancer is associated with decreased hopelessness, depression, and desired for hastened death.32 In a study of HIV/AIDS patients, a population with similar rates of existential distress,33 DHD was significantly elevated among patients with past histories of suicide attempts,34 suggesting a bridge between DHD and SI. Demoralization syndrome, a manifestation of existential distress in patients with advanced cancer, consists of hopelessness and helplessness caused by lack of purpose and meaning related to confronting death, and occurs in up to onethird of patients with advanced cancer.35 Loss of meaning (LoM) associated with demoralization syndrome has been shown to be positively correlated with DHD.36

Psilocybin-Assisted Psychotherapy for Cancer-Related Anxiety, Depression, and Existential Distress.

Among the numerous clinical indications for which treatment with classic hallucinogens, such as psilocybin, have been investigated, psychiatric and existential disorders related to lifethreatening cancer emerge as front-runners in terms of the published evidence from modern RCTs.37,38 Two recently published review articles39,40 identified several published clinical trials in which subjects with advanced- or terminalcancer-related psychiatric and existential distress were treated with a serotonergic psychedelic [i.e., psilocybin, LSD, and dipropyltryptamine (DPT)], including four open-label trials of LSD therapy (N = 244) published between 1964 and 198041−44 and four RCTs (N = 104) published between 2011 and 2016.45−48 The historical open-label trials suggested that LSD-assisted psychotherapy was associated with rapid analgesic effects that endured for several weeks, improvements in psychiatric distress (depression, anxiety, insomnia) and existential distress (death anxiety), and improved psychiatric outcomes associated with mystical experiences.41−44 Three RCTs completed within the past decade (UCLA-Harbor, NYU Langone Health (NYULH)/Bellevue Hospital, and Johns Hopkins) assessed the efficacy of single-dose psilocybinassisted psychotherapy in patients with advanced-cancerrelated psychiatric and existential distress (N = 92).45,47−49 Results from these trials indicate that a single moderate to high dose of psilocybin, delivered in conjunction with psychotherapy, produces rapid, substantial (i.e., large effect sizes and high rates of psychiatric illness remission), and sustained (i.e., months to years) reductions in anxiety and depressive symptoms, as well as sustained reductions in existential distress, and improved quality-of-life. In addition, psilocybin occasioned mystical-type experiences, experienced as highly meaningful and spiritual, partially mediated anxiolytic and antidepressant effects assessed longitudinally (i.e., 5−7 weeks) postadministration of psilocybin.47,48

Psilocybin-Assisted Psychotherapy for Cancer-Related SI: Converging evidence.

There is indirect evidence from epidemiologic studies that psilocybin may also have antisuicidal effects. Population-level analysis of data from the National Survey on Drug Use and Health found that lifetime classic psychedelic use was associated with 14% reduced likelihood of past-year suicidal thinking, 29% reduced likelihood of past year suicidal planning, and 36% reduced likelihood of past year suicide attempts.50 An epidemiologic study of marginalized women (i.e., street-involved sex workers, unhoused, and drug users) in Canada found that lifetime psychedelic use was associated with a 60% reduced suicidality hazard (adjusted hazard ratio: 0.40; 95% CI 0.17−0.94).51 An open-label trial in which individuals with treatment-resistant major depressive disorder received two doses of psilocybin along with supportive psychotherapy reported decreases in SI up to 2 weeks after the intervention.52 Additional evidence from an open-label53 and a RCT54 suggest that single-dose ayahuasca administration is associated with rapid (i.e., within 40 min) and sustained (i.e., 1−3 weeks) decreases in suicidality in patients with major depressive disorder. Interestingly, among the classic psychedelics, psilocybin in particular may be protective against SI and behaviors.55

The NYULH/Bellevue Hospital trial and its ancillary longterm follow-up study did not explore suicidality as primary or secondary outcomes, and excluded participants with active SI or suicidal behaviors at screening. However, findings indicate that psilocybin-assisted psychotherapy improves several constructs related to SI and DHD, including depression, cancer-related hopelessness and demoralization, and spiritual well-being.47,49 Meaning-making was a key existentially oriented component of the psychotherapeutic platform within which psilocybin treatment was delivered,47 and several themes have emerged from qualitative analyses that implicate LoM specifically as a likely symptom of demoralization syndrome that psilocybin-assisted psychotherapy might target reduction of SI.56 Suicidality and symptoms of depression often change independently of one another,57 and not all interventions for depression are effective for relieving suicidality. For instance, SSRIs, a first-line intervention for depression, show limited efficacy for suicidality in particular,58 and may even increase suicidality within certain populations.59 Thus, determining whether and how psilocybin-assisted psychotherapy reduces SI in addition to its established antidepressive effects in people with cancer has emerged as an important question.

Rationale for Present Analyses.

To assess whether a single dose of psilocybin, administered in conjunction with psychotherapy, produces acute and sustained antisuicidal effects in patients with advanced cancer, we performed post hoc analyses of relevant data from our completed NYULH/Bellevue Hospital trial.47 Our aims were to (1) determine whether single-dose psilocybin-assisted psychotherapy acutely relieves SI and LoM; (2) evaluate the longevity of reductions in SI and LoM; and (3) examine relationships between SI, other (non-SI-related) depressive symptoms, and potential mediators of psilocybin’s antisuicidal effects, including demoralization, hopelessness, and spiritual well-being within people that have been given a cancer diagnoses. We hypothesized that psilocybin treatment would be associated with significant acute and sustained reductions in SI and LoM and that reductions in SI would be positively associated with improvements in other depressive symptoms, LoM, demoralization, hopelessness, and spiritual well being.