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End-of-life distress

Research on easing psychological and existential suffering near the end of life, a landmark area for psilocybin therapy.

State of the evidence

Synthesized

Synthesized from 25 studies in the library · AI-generated, grounded in the abstracts below

Found by searching the library for End-of-life distress, existential distress, palliative, terminal illness anxiety, then ranked by relevance.

Psilocybin-assisted psychotherapy consistently produces large, sustained reductions in anxiety, depression, demoralization, loss of meaning, and death anxiety in patients with life-threatening cancer, with benefits persisting up to 4.5 years in open-label follow-ups. A network meta-analysis of nine RCTs confirms moderate-to-large effect sizes for depression and anxiety, though the certainty of evidence is low due to small samples, unblinding risk, and narrow demographics. Real-world implementation faces major barriers including regulatory hurdles, lack of trained providers, and logistical constraints, with one implementation study reporting zero patients treated after one year.

Confidence in the evidence

Low-Moderate
  • Multiple RCTs and a network meta-analysis (9 RCTs, 606 participants) show consistent positive effects, but sample sizes are small and most evidence comes from single-site trials.
  • Risk of unblinding is high because psychedelics produce subjective effects that are difficult to mask, and few studies adequately assessed expectancy or blinding.
  • Long-term follow-up data (3.2–4.5 years) are from open-label within-subject analyses with no control group, limiting causal inference.
  • Implementation studies reveal major real-world barriers (regulatory, logistical, training) that have not yet been overcome, and stakeholder surveys show knowledge gaps.
  • Qualitative evidence also documents that psychedelic experiences can trigger persistent existential distress in some individuals, indicating potential harms.
How we rate confidence

Confidence reflects the strength of the underlying evidence, not whether the result is favorable. It weighs the number and size of studies, their design (randomized trials count for more than observational or single-case work), how consistently they point the same way, and their risk of bias.

Tiers run from Insufficient to High. High is rare in this field: small, early, or open-label studies land lower even when their direction is encouraging.

Evidence by study

Direction is each study's finding relative to your question: Supports, Opposes, No effect, Mixed, or Unclear.

Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer 2020
Supports

Reductions in anxiety, depression, hopelessness, demoralization, and death anxiety were sustained at 3.2 and 4.5 years post-psilocybin, with 60–80% meeting criteria for clinically significant antidepressant or anxiolytic responses.

RCT with long-term within-subjects follow-up · Sample size: 15

Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer 2021
Supports

Psilocybin-assisted psychotherapy produced within-group reductions in suicidal ideation as early as 8 hours and persisting for 6.5 months, and large reductions in loss of meaning sustained at 4.5 years.

RCT secondary analysis

Psychedelic-assisted psychotherapy to treat psychiatric and existential distress in life-threatening medical illnesses and palliative care. 2022
Supports

Reviews efficacy data from first and second waves of psychedelic research and argues that psychedelic-assisted psychotherapy could address the high unmet need for psycho-spiritual interventions in palliative care.

commentary/review

Top Ten Tips Palliative Care Clinicians Should Know About Psychedelic-Assisted Therapy in the Context of Serious Illness. 2022
Supports

One-time PAT dosing may lead to sustained reductions in anxiety, depression, and demoralization in seriously ill and end-of-life patients.

narrative review/tips article

Psychedelic-assisted therapy for treating anxiety, depression, and existential distress in people with life-threatening diseases 2024
Supports

Psychedelic-assisted therapy may be effective for anxiety, depression, and possibly existential distress, but certainty of evidence is low to very low due to unblinding risk and small samples.

systematic review

The Potential of Psychedelics for End of Life and Palliative Care. 2022
Supports

Reviews recent research and proposes that psychedelics may provide an additional psychopharmacological treatment option for depression, existential distress, and well-being in end-of-life and palliative care.

narrative review

Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs 2023
Supports

Preliminary evidence suggests psychedelics may improve quality of life, functionality, and reduce disability and distress in chronic pain, possibly via increased tolerability and acceptance.

commentary

Navigating groundlessness: An interview study on dealing with ontological shock and existential distress following psychedelic experiences. 2025
Opposes

Psychedelic experiences can trigger long-lasting existential distress, ontological confusion, and meaning-making struggles; participants alleviated distress through grounding practices.

qualitative interview study · Sample size: 26

Palliative Nursing and Sacred Medicine: A Holistic Stance on Entheogens, Healing, and Spiritual Care. 2019
Supports

Clinical trials show impressive preliminary findings for entheogens (psychedelics) in promoting presence, introspection, decreased fear, and increased joy and acceptance in patients confronting advanced serious illness.

narrative review/case study

Psilocybin in Palliative Care: An Update. 2023
Supports

Psilocybin has significant and sustained anxiolytic, antidepressant, anti-inflammatory, and entheogenic effects with a favorable safety profile, but research is limited by selection bias and short follow-up.

narrative review

Social acceptability of psilocybin-assisted therapy for existential distress at the end of life: A population-based survey 2024
Supports

79.3% considered psilocybin-assisted therapy a reasonable medical choice for existential distress at end of life, and 84.8% agreed public health system should cover costs.

population-based survey · Sample size: 2800

Psychedelic medicines for end-of-life care: Pipeline clinical trial review 2022. 2023
Supports

Identified 25 eligible studies (13 RCTs, 12 open-label) of psychedelics for depression, anxiety, and existential distress at end of life, with investigational drugs including ketamine, psilocybin, MDMA, and LSD.

scoping review of pipeline trials

Exploring the Use of Psilocybin Therapy for Existential Distress: A Qualitative Study of Palliative Care Provider Perceptions 2021
Mixed

Providers identified multiple barriers to addressing existential distress and expressed uncertainty about the risks and benefits of psilocybin therapy.

qualitative interview study · Sample size: 5

Psychedelics and Dying Care: A Historical Look at the Relationship between Psychedelics and Palliative Care. 2019
Supports

Examines historical discussions about LSD's potential for easing anxiety associated with dying, noting that early conversations were lost after criminalization.

historical review

Psychedelics as an intervention for psychological, existential distress in terminally ill patients: A systematic review and network meta-analysis 2024
Supports

Meta-analysis supported efficacy of psychedelics on depression (SMD: -0.80) and anxiety (SMD: -0.84); network meta-analysis identified psilocybin as most effective for depression and LSD for anxiety.

systematic review and network meta-analysis · Sample size: 606

Intranasal Ketamine for Existential Distress in Advanced Cancer. 2026
Supports

Intranasal ketamine produced improvements in anxiety, death and dying distress, symptom burden, and quality of life, with large effect sizes (d = 0.91–1.53).

RCT secondary analysis · Sample size: 15

The need for another tool: Australian healthcare professionals on the use of psilocybin for existential distress in people with cancer 2026
Mixed

HCPs were interested in PAT but identified barriers, knowledge gaps, and desire for more research; they preferred multidisciplinary, culturally sensitive, and ethically rigorous delivery.

qualitative interview study · Sample size: 11

Reframing distress in oncology: the potential of psychedelic-assisted therapy. 2026
Supports

Recent trials in advanced cancer populations report improvements in anxiety, depression, pain-related distress, and quality of life following one or two dosing sessions, but evidence is limited by small samples and expectancy effects.

narrative review

Return of the sacred: Psychiatry's evolving relationship with spirituality. 2026
Supports

Psychedelic-assisted therapies highlight both therapeutic potential and ethical risks in addressing existential suffering, and psychiatry faces an opportunity to integrate spiritual dimensions of distress.

theoretical/review

Bringing Psilocybin-Assisted Therapy to Palliative Oncology: Early Lessons from Real-World Implementation. 2026
No effect

After one year, no patients had received PAT; key barriers included administrative/regulatory procedures and logistical constraints, while perceived clinical relevance and leadership were facilitators.

single-case implementation study · Sample size: 10

Psychedelic-Assisted Interventions in Palliative Care: A Narrative Overview and Critical Evaluation. 2026
Supports

Across 22 reviews, PAT was consistently associated with reductions in depression, anxiety, and existential distress, along with improvements in quality of life, but evidence is from early-phase trials and observational studies.

overview of reviews

Implementing psilocybin-assisted therapy in palliative care settings: A survey of stakeholders 2026
Supports

95% of physicians reported favorable attitudes toward psilocybin-assisted therapy; lack of trained providers was the primary barrier, and 68% endorsed introduction during early illness trajectory.

cross-sectional survey · Sample size: 121

Meaning and Psychedelics in Palliative Care: A Narrative Review. 2026
Supports

Loss of meaning is a hallmark of demoralization syndrome linked to diminished quality of life and increased suicide risk; early clinical trial data suggest psychedelic therapies may improve meaning and reduce demoralization.

narrative review

A Blueprint for Implementing Ketamine-Assisted Psychotherapy in Palliative Care: Design, Process, and Treatment Patterns of a Real-World Clinical Program. 2026
Supports

A real-world ketamine-assisted psychotherapy program in palliative care treated 30 patients (80% cancer) with a median of 1.5 medicine sessions, demonstrating feasibility and safety.

descriptive program report · Sample size: 30

Psilocybin-assisted psychotherapy for psycho-existential distress in advanced cancer: a narrative review 2026
Supports

Psilocybin-assisted psychotherapy is a compelling therapeutic option warranting further rigorous, interdisciplinary research for implementation in palliative settings.

narrative review

Points of agreement

  • Psilocybin-assisted psychotherapy consistently reduces anxiety, depression, and existential distress in patients with life-threatening cancer across multiple RCTs and long-term follow-ups.
  • Network meta-analysis and systematic reviews report moderate-to-large effect sizes for depression and anxiety outcomes.
  • Qualitative studies of palliative care providers and stakeholders show generally favorable attitudes but identify major implementation barriers.
  • Real-world implementation studies report significant regulatory, logistical, and training barriers that have prevented patient access in some settings.

Conflicts

  • One qualitative study found that psychedelic experiences can trigger persistent existential distress and ontological confusion in some individuals, contrasting with the predominantly positive outcomes in clinical trials.
  • Palliative care providers in a small qualitative study expressed uncertainty about risks and benefits, while larger stakeholder surveys showed strong favorable attitudes.
  • The network meta-analysis identified psilocybin as most effective for depression and LSD for anxiety, but head-to-head comparisons are lacking.

Gaps

  • Durability of effects beyond 4.5 years is unknown; most long-term data come from open-label follow-ups without control groups.
  • Research samples are predominantly white, healthy, and financially privileged, limiting generalizability.
  • Blinding and expectancy effects are poorly controlled; few studies assess blinding integrity or use active placebos.
  • Head-to-head comparisons of different psychedelics (psilocybin, LSD, ketamine, MDMA) are lacking.
  • Implementation research is scarce; only one study reported actual patient treatment in a real-world program, and another reported zero patients treated after one year.
  • Dosing protocols, psychotherapy integration models, and optimal timing of intervention in the illness trajectory are not standardized.
Browse these studies in the library
How we analyze this

This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is End-of-life distress, up to 25 in all. The most-cited set anchors the established evidence, and the recent set surfaces work that is too new to have gathered citations yet.

A study qualifies only when End-of-life distress or a known alias appears in its title or keywords, so broad reviews that mention it only in passing are left out. Each study is read from its abstract, strongest evidence first, and the summary reports the direction of the results along with any conflicts and gaps.

Ask your own question in the Research Synthesis Tool

228 articles · 115 from the last two years · 170,395 participants across 77 studies reporting sample size

Common study designs

review 54 narrative review 11 qualitative study 20 systematic review 18 theoretical or philosophical paper 17

Research

Synthesize the evidence → Search all →

Ketamine for Depression in Serious Illness: Evidence, Safety, and Practical Approaches.

Journal of pain and symptom management • August 1, 2026 • Paul Noufi, Joshua B Borris, Danielle Chammas et al.

Ketamine and esketamine offer rapid antidepressant effects, with intravenous ketamine producing moderate-to-large improvements within 1–24 hours that last one to two weeks, and a number needed to treat of three in the first week. Esketamine nasal spray shows similar early efficacy and is FDA-approved for treatment-resistant depression and major depression with suicidal ideation. Evidence specific to people with serious illnesses is limited to perioperative cancer trials and small open-label studies, showing short-term reductions in depressive symptoms and suicidal ideation but not addressing long-term management. Safety is generally favorable, with transient dissociation, hypertension, and somnolence as common adverse effects. Rigorous psychiatric trials in serious illness are lacking.

DOI: 10.1016/j.jpainsymman.2026.04.604 Full text Depression Ketamine Palliative care Psychopharmacology +1

Intranasal Ketamine for Existential Distress in Advanced Cancer.

Journal of pain and symptom management • August 1, 2026 • Stefan Aguiar, Mary Makarious, Orly Lipsitz et al.

In adults with advanced cancer receiving palliative care, intranasal ketamine was associated with clinically meaningful improvements in existential distress, anxiety, symptom burden, and quality of life. Fifteen participants who completed three doses of ketamine showed improvements exceeding established minimal clinically important differences on measures of anxiety, death and dying distress, overall symptoms, and quality of life. Improvements in existential well-being were larger than those in physical symptoms. Changes in depression did not significantly correlate with changes in existential distress outcomes, suggesting ketamine may have independent effects on multiple dimensions of distress in this population.

DOI: 10.1016/j.jpainsymman.2026.04.611 Full text Intranasal ketamine Cancer Existential distress Palliative care +2

The need for another tool: Australian healthcare professionals on the use of psilocybin for existential distress in people with cancer

BMC Medicine • July 6, 2026 • Hannah Adler, Rebecca Filipic, Dr Maria Gonzalez et al.

Healthcare professionals show interest in psychedelic-assisted therapy with psilocybin for existential distress in people with cancer, but face knowledge gaps, barriers, and a desire for more research. Interviews with 11 professionals from Australian cancer centers revealed four themes: varied knowledge about the therapy, conceptualizing its practical use, navigating complex provision and engagement, and envisioning future applications. Professionals preferred delivery by multidisciplinary teams that are culturally sensitive and ethically rigorous. Some saw it as a last resort, while others viewed it as another needed tool. The findings offer preliminary insights into implementation pathways for this therapy in oncology settings.

DOI: 10.1186/s12916-026-05024-2 Existentialism Distress Thematic analysis Psilocybin +13

Mind-Body Interventions for People With Cancer: Evidence, Innovation, and Implementation.

Seminars in radiation oncology • July 1, 2026 • Hanna S W Conradi, Jamie N Petersson, Julie M Deleemans et al. • 1 citation

Many people with cancer experience persistent psychological and physical challenges such as anxiety, depression, fatigue, pain, sleep problems, fear of recurrence, cognitive issues, and reduced quality of life. Mind-body interventions, which target the connection between mental and physical processes, are increasingly used alongside standard cancer care. This review examines evidence for interventions including mindfulness, yoga, tai chi, qigong, relaxation, hypnosis, music therapy, acupuncture, massage, and aromatherapy, as well as emerging approaches like psychedelic therapy and nature-based interventions. It summarizes target symptoms, treatment timing, and evidence quality, and calls for more rigorous research, understanding of mechanisms, and broader access across diverse populations and all stages of cancer care.

DOI: 10.1016/j.semradonc.2026.151009 Full text

Reframing distress in oncology: the potential of psychedelic-assisted therapy.

Current opinion in oncology • July 1, 2026 • Fatima Zohra Moujahid, Olivier Taymans

Psychedelic-assisted therapy (PAT) may offer a new approach to address the multidimensional nature of psychological and existential distress common across the cancer trajectory. PAT combines psychedelic compounds with structured psychotherapeutic support, including preparatory sessions, a supervised dosing experience, and post-session integration. Psychedelics are thought to enhance neuroplasticity and emotional flexibility, potentially supporting sustained psychological change. Recent trials in advanced cancer populations report improvements in anxiety, depression, pain-related distress, and quality of life following one or two dosing sessions. However, current evidence is limited by small and demographically narrow samples, variable treatment protocols, and potential expectancy effects, and implementation faces practical challenges such as training requirements and resource intensity.

DOI: 10.1097/cco.0000000000001242 Full text Cancer-related distress Existential distress Psychedelic-assisted therapy Psycho-oncology +1

Self‑transcendence and identity transformation in recovery from substance use disorder

American Journal of Medicine and Health Studies • June 26, 2026 • Mehrdad F. Falavarjani

A spiritually oriented intervention that emphasizes self-transcendence and identity transformation helped a person with substance use disorder move from an addiction-centered identity toward a more integrated spiritual self. Through narrative reconstruction and contemplative practices, the participant became better able to engage with everyday life, suggesting that reorganizing identity through spiritual approaches may be an important mechanism of change in treatment.

DOI: 10.32674/5p5crr47 Identity music Contemplation Existentialism Narrative identity +16

Association of Esketamine use with mortality and clinical outcomes in patients with cancer-related depression: A target trial emulation.

Progress in neuro-psychopharmacology & biological psychiatry • June 20, 2026 • Jen-ping Chen, Chih-Wei Hsu, Yi-ya Fang et al.

Esketamine initiation, compared with oral antidepressant monotherapy, was associated with a 26% lower risk of all-cause mortality over two years among adults aged 18–74 with cancer-related depression, according to a target trial emulation using electronic health records. After propensity score matching of 1,751 patients per group, esketamine also corresponded to lower risks of emergency room visits, intensive care unit visits, ischemic stroke, and psychotherapy utilization. Safety outcomes were generally comparable between groups. The associations were more pronounced in older patients. These real-world findings support esketamine as a potential therapeutic option for managing cancer-related depression.

DOI: 10.1016/j.pnpbp.2026.111764 Full text Cancer-related depression Esketamine Mortality Target trial emulation

Psilocybin and Mental Health Outcomes: Scoping Review with ☸SAIMSARA

SAIMSARA Journal • June 15, 2026

A scoping review of 216 original studies with over 271 million total participants indicates that the most consistent finding for psilocybin and health is a rapid, large, and sustained reduction of depressive symptoms in clinical populations. A randomized, waiting-list–controlled trial for major depressive disorder reported a Cohen's d of 2.5 at week 5, and benefits in treatment-resistant depression persisted up to 6 months. Converging evidence suggests broader therapeutic potential for anxiety, PTSD, and existential distress, along with preliminary signals for substance use disorders, though risks such as manic or psychotic episodes in vulnerable individuals warrant rigorous screening. Real-world benefits and access are moderated by race and ethnicity, with protective associations and program participation concentrated among White participants.

DOI: 10.62487/saimsara7a54f680 Psilocybin Mental health Major depressive disorder Psycinfo +11

Return of the sacred: Psychiatry's evolving relationship with spirituality.

Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists • June 5, 2026 • Osama Bhatti, Mohammad Qasim Latifi

Psychiatry has long held an ambivalent stance toward religion and spirituality, recognizing their importance but remaining cautious about integrating them into clinical practice. This article examines the historical, conceptual, and clinical tensions surrounding spirituality in psychiatry, particularly in light of renewed interest from contemporary psychedelic research. The authors discuss definitions, diagnostic categories, and evidence linking spirituality and meaning to mental health. They explore how psychedelic-assisted therapies highlight both therapeutic potential and ethical risks in addressing existential suffering. Psychiatry faces a challenging opportunity to incorporate spiritual dimensions of distress without undermining scientific integrity, which will shape its future relationship with the sacred.

DOI: 10.1177/10398562261457011 Full text Existential distress Meaning Mysticism Psychedelics +2

Bringing Psilocybin-Assisted Therapy to Palliative Oncology: Early Lessons from Real-World Implementation.

Healthcare (Basel, Switzerland) • June 3, 2026 • Michel Dorval, Virginie Audet-croteau, Sue-Ling Chang et al.

After one year of offering psilocybin-assisted therapy (PAT) at a Canadian university-affiliated tertiary care center, no patients had received the treatment despite clinicians and managers viewing it favorably. Interviews with ten professionals identified administrative and regulatory procedures, along with logistical constraints, as key barriers, while perceived clinical relevance and institutional leadership were facilitators. The estimated cost of delivering a complete PAT intervention ranged from 2,648 to 5,827 Canadian dollars per patient, excluding the cost of psilocybin itself. The gap between regulatory authorization and actual service uptake highlights the need for structured implementation strategies, sustained institutional support, and alignment between regulatory frameworks and clinical workflows.

DOI: 10.3390/healthcare14111559 Full text Cost analysis Existential distress Implementation Palliative care +2

Clinical trials

All End-of-life distress trials →