Systematic Review of the Effect of Psychedelic-Assisted Therapy on Attitudes Toward Death, Life, and Spirituality on Symptoms of Distress, Depression, and/or Anxiety in Patients with Life-Threatening Illness

Abstract

Background:

The underlying mechanism(s) of action of psychedelic-assisted therapy (PAT) to reduce distress, depression, and/or anxiety symptoms in life-threatening illness are poorly understood. It has been postulated that addressing death anxiety, and components of spiritual and existential distress, may be mediating factors.

Method:

This systematic review describes the current evidence base regarding the impact of PAT on attitudes toward life, death, and spirituality. MEDLINE, Embase, PsychINFO, and PubMed databases were systematically searched for original clinical research articles on PAT for distress, depression, and/or anxiety symptoms in life-threatening illness, with outcome measures related to attitudes toward life, death, and spirituality. The risk of bias was assessed using Joanna Briggs Institute critical appraisal checklists. A descriptive analysis was conducted.

Results:

A total of 14 articles met the inclusion criteria. Improvements in distress, depression, and/or anxiety symptoms were associated with reduced demoralization, reduced hopelessness, improvements in spirituality, greater death acceptance, a greater sense of optimism toward life, and a greater sense of meaningful existence. Mixed results were found in other attitudes toward life and death.

Conclusions:

This review identifies several mechanisms by which PAT may improve distress, depression, and/or anxiety symptoms in patients with life-threatening illness, via effects on a range of attitudes toward life, death, and spirituality. Results need to be considered with caution, given the paucity and quality of available data. This review also identifies gaps in the current evidence base for consideration in future research.

Introduction

After a period of global prohibition, 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin were designated as “breakthrough therapies” for post-traumatic stress disorder and treatment-resistant depression, respectively, by the U.S. Food and Drug Administration¹ and, in July 2023, were also approved by Australia’s Therapeutic Goods Administration for these indications.² Psychedelic-assisted therapy (PAT) is a re-emerging field with research being conducted for a number of indications including post-traumatic stress disorder, unipolar depression, and social anxiety in adults with autism spectrum disorder.³

There has been growing interest in use of PAT for the treatment of anxiety, depression, and distress in life-threatening illness, with numerous trials underway in an “end of life” context.⁴ This research has been driven by the limited effective evidence-based treatment options for depression and anxiety in cancer and palliative care contexts.^5–8

Preliminary research has been conducted into the pharmacological properties of psychedelics; however, our overall understanding of the mechanisms of action and processes underlying the combination of psychedelics with psychotherapy in this context is largely speculative with a limited evidence base.⁹ It has been postulated that addressing death anxiety and components of spiritual and existential distress may be mediating factors in PAT.^10,11 Looking more broadly at the mechanism of action of psychedelics in reducing fear of death, multiple relevant theories have been proposed including Carhart-Harris and Friston’s Relaxed Beliefs Under Psychedelics model, Letheby’s Metaphysical Belief Theory, Letheby’s “self-unbinding” theory, and Van Eyghen’s contextual belief recalibration.¹² The wider evidence base also includes healthy volunteer PAT and psychedelic studies which have shown sustained improvements in a range of spirituality measures and attitudes toward life and death transcendence-related measures with psychedelic treatment.^13–15 These types of measures of attitudes toward life, death, and spirituality help us gain an understanding of the potential mechanism of action and processes underlying PAT, including specifically in the context of life-threatening illness.

The evidence base for the use of PAT for depression, anxiety, and distress in life-threatening illness has been explored in recent systematic reviews.^16,17 However, to date, outcomes and mediating factors related to attitudes toward life, death, and spirituality in this context have not been evaluated in a systematic way. The objective of this review is to analyze the current evidence base in this regard.

Methods

A systematic review approach was chosen as it allows for identification, collation, and evaluation of the current evidence base. A literature search confirmed a systematic review had not already been published on the topic. A 2022 systematic review explored the therapeutic potential of PATs for symptom control in patients diagnosed with serious illness, however, did not focus on the spiritual domain as has been done in this systematic review.¹⁸ Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was used as a framework for this review.¹⁹

Search

A search was conducted to identify relevant studies in MEDLINE, Embase, PsychINFO, and PubMed published from 1950 to July 30, 2023. The earlier date was set in 1950 to reflect the year of publication of the first English language article on lysergic acid diethylamide (LSD)-assisted therapy.^16,20 The following terms were searched in each database: psychedelic, “psychedelic-assisted therapy,” “psychedelic-assisted psychotherapy,” “life-threatening illness,” “end of life,” cancer, “terminal illness,” and palliative. The Boolean operator OR was used within terms and the operator AND was used to combine terms to ensure articles would include at least one of the three former terms and at least one of the five latter terms.

Inclusion and exclusion criteria

Studies were included if (1) they were an original research article, published in English, in a peer-reviewed journal from 1950 onward; (2) the intervention studied was PAT; and (3) the participant population was individuals with a physical life-threatening illness with associated distress, depression, and/or anxiety symptoms. Studies were excluded if (1) there were no outcomes measured related to attitudes toward life, death, or spirituality or (2) there were no empirical data (such as reviews). “Attitudes toward life” was defined as broader attitudes related to the phenomenon of being alive such as meaning, purpose, and overarching positive or negative attitudes toward being alive. Measures regarding specific facets of life (such as relationships or attitudes toward illness) and overall quality of life were excluded. Measures of anxiety, depression, and distress were excluded as these have been reviewed in recent systematic reviews.^16,17

Screening procedure

Rayyan, a web-based screening tool for systematic reviews, was used for the screening of titles and abstracts.²¹ Duplicate articles were removed, and titles and abstracts were screened by one reviewer (T.T.) to identify relevant articles for full-text retrieval. Full-text review was conducted by T.T. In cases of ambiguity, articles were discussed with a second reviewer (P.G.) to reach consensus decisions regarding inclusion or exclusion. References of included articles were subsequently searched to identify any additional relevant studies.

Data collection and qualitative assessment

Relevant data were extracted by T.T. including main author, country and year of study, select inclusion criteria, participant characteristics, study design, and results of relevant outcome measures. Joanna Briggs Institute (JBI) critical appraisal checklists for qualitative research, quasi-experimental studies, and randomized controlled trials (RCTs) were used to assess the methodological quality and risk of bias in study design, conduct, and analysis.^22–24 JBI critical appraisal findings are available in Supplementary Tables S4–S6. One reviewer (T.T.) evaluated the studies. Areas of ambiguity were discussed with a second reviewer (P.G.) to reach consensus on decisions regarding individual checklist items and overall risk of bias.

Data synthesis

There was significant heterogeneity in study design including psychedelics used, therapy processes, and outcomes measured. The data collected were therefore not suitable for quantitative synthesis or qualitative meta-synthesis. Both quantitative and qualitative data were synthesized using descriptive methods. Descriptions of rating scales are listed in Supplementary Appendix SA1.

Results

Study selection

A total of 2,052 titles and abstracts were screened with 27 articles identified for full-text retrieval. Of the full-text articles reviewed, 13 were excluded. Reasons for exclusion are listed in Figure 1.

Fig. 1.

Flowchart outlining search strategy and selection process. ^*Of reports excluded as not from peer-reviewed publications: one report was also not a clinical trial, and full text for two reports was unavailable; however, information available suggested they were unlikely to be clinical trials. ^**Data from participants with a physical life-threatening illness and those without were not separately collected and analyzed. ^***Dissertation involving qualitative analysis of the same semi-structured interview data as in Barone et al.³⁹—not included given the significant overlap in scope and results. Barone et al.’s article³⁹ was preferentially included as its scope aligned better with the relevant outcome measures for this systematic review.

Study characteristics

A total of 14 studies met the inclusion criteria (Table 1). Study methodologies included four RCTs, four uncontrolled open-label trials, four qualitative studies, one quantitative long-term follow-up of a previously conducted trial, and one post hoc analysis of a subset of data from previously conducted trials. A total of 244 unique patients were included in the review.

Table 1.

Study Characteristics

Author, year	Select inclusion criteria	Participants: N; mean age (years); sex (% female); majority ethnicity/race (%); two main religious/spiritual orientations	Study design, original study or studies if applicablea	Intervention, comparison group if applicable	Risk of bias
Agin-Liebes, 202028	Participants from Ross et al. (201634)	N = 15; Mean age = 53; Female = 60%; Majority ethnicity/race = “White/Caucasian” (93.33%); Two main religious/spiritual orientations = atheist/agnostic (33.33%), Jewish (20%)	Prospective uncontrolled long-term follow-up; Original trial: Ross et al. (2016)	As per Ross et al. (201634)	High
Anderson, 202027	(1) Moderate-to-severe demoralization assessed by a Demoralization Scale-II score of ≥8/32; (2) Gay-identified, cisgender men ≥50 years old and living with HIV with self-report of HIV diagnosis prior to the clinical availability of protease inhibitors (∼1996)	N = 18; Mean age = 59.2; Female = 0%; Majority ethnicity/race = “White” (77.7%); No data on religious/spiritual orientation	Uncontrolled open-label trial	-0.3 mg/kg or 0.36 mg/kg (dependent on cohort) oral psilocybin -Preparation therapy sessions: 90-min individual session, four 90-min group sessions -Psychedelic-assisted therapy session: either an individual or with portions of both individual and group therapy (two participants per group) dependent on cohort -Integration therapy sessions: 2-h individual session and 4 or 6 group sessions (dependent on cohort) over 3 weeks Group therapy modeled on Brief Supportive Expressive Group Therapy	High
Barone, 202239	Participants from Wolfson et al. (2020)31	N = 6; Mean age = no data; Female = 100%; Majority ethnicity/race = “White/Caucasian” 83.3%; No data on religious/spiritual orientation	Interpretative phenomenological analysis of semi-structured interviews; Original trial: Wolfson et al. (2020)31	As per Wolfson et al. (2020)31	Low
Belser, 201736	Participants from Ross et al. (2016)34	N = 13b; Mean age = 50; Female = 46%; Majority ethnicity/race = “White” (92%); Two main religious/spiritual orientations = atheist/agnostic (38%), other Christian (15%), Jewish (15%)	Interpretative phenomenological analysis of semi-structured interviews	As per Ross et al. (2016)34	Low
Gasser, 201537	Participants from Gasser et al. (2014)38 Gasser et al. (2014)38: Anxiety associated with life-threatening illness (participants reported scores of >40 on either the state or the trait scale of the Spielberger State-Trait Anxiety Inventory)	N = 10; Mean age = 51.1; Female = 40% No data on ethnicity/race; No data on religious/spiritual orientations	Qualitative Content Analysis of semi-structured interviews; Original RCT with open-label crossover design: Gasser et al. (2014)38	-Gasser et al. (2014) protocol: 200 mcg oral LSD -Control: 20 mcg oral LSD -RCT: Two full-dose or two-low dose (active placebo) sessions. -Open-label crossover: control group offered two full-dose LSD-assisted therapy sessions -Preparation therapy sessions: three individual sessions -Psychedelic-assisted therapy sessions: 8-h long individual sessions -Integration therapy sessions: three 60–90-min individual sessions following each dosing session -Open-label preparation and integration sessions: five non-drug therapy sessions total	Low
Griffiths, 201633	(1) DSM-IV diagnosis that includes anxiety and/or depressive symptoms that is judged to have been precipitated by or exacerbated by the psychological stress of the cancer diagnosis; (2) Potentially life-threatening cancer diagnosis including active cancer, disease progression, recurrence, or if not active cancer, disease progression or disease recurrence then at least 1 year has elapsed since their diagnosis.	N = 51; Mean age = 56.3; Female = 49%; Majority ethnicity/race = “White” (94%); No data on religious/spiritual orientation	RCT with crossover design	-22mg/70 kg or 30 mg/70 kg oral psilocybin -Control: 1 mg/70 kg or 3 mg/70 kg oral psilocybin -Crossover trial with psychedelic-assisted therapy sessions ∼5 weeks apart -Preparation therapy sessions: minimum of two individual sessions (mean three sessions with a mean total of 7.9 h) -Psychedelic-assisted therapy sessions: individual session with participants encouraged to focus their attention on their inner experiences throughout the session -Therapy sessions between dosing sessions: minimum of two individual sessions (mean 2.7 sessions with a mean total of 3.4 h) -Therapy sessions between second psychedelic dose and 6-month follow-up: minimum of two individual sessions (mean of 2.5 sessions with a mean total of 2.4 h)	Medium
Grof, 197329	“The presence of some degree of physical pain, depression, anxiety and psychological isolation associated with malignancy”	N = 31; Mean age = 54; Female = 74.1%; Majority ethnicity/race = Caucasian (83.9%); Two main religious/spiritual orientations = Jewish (51.6%), Protestant (45.2%)	Uncontrolled open-label trial	-200–500 mcg oral LSD -Preparation therapy sessions: series of individual sessions lasting on average 9.75 h (6–12 h) over 2–3 weeks. Families were also seen with and without the patient -Psychedelic-assisted therapy session: individual session of average duration of 11.15 h with family joining for termination period -Integration therapy sessions: several individual sessions (not quantified further)	High
Lewis, 202326	(1) DSM-5 depressive disorder (including major depressive disorder and adjustment disorder with depressed mood); (2) Cancer of any type, stage, grade, or prognosis.	N = 12; Mean age = 48.2; Female = 66.7% Majority ethnicity/race = “White race” (91.6%); No data on religious/spiritual orientation	Uncontrolled open-label trial (feasibility and safety)	-25 mg oral psilocybin -Preparation therapy sessions: three 90-min group sessions and three 30-min individual sessions -Psychedelic-assisted therapy session: group session with a non-directive, supportive therapeutic approach -Integration therapy sessions: three 90-min group sessions and three 30-min individual sessions over 2 weeks -Groups consisted of four participants. A non-manualized supportive-expressive group therapeutic approach was used.	High
Richards, 197532	(1) Suffering from some degree of depression, anxiety, and/or psychological isolation; (2) Cancer	N = 45; Mean age = 53.5; Female = 62%; Main ethnicity/race = Caucasian (56%); Religion = protestant (58%), Catholic (27%)	RCT	-75–127.5 mg (mean 101.7 mg) intravenous DPT. -Control: no placebo medication and no counseling -Preparation therapy sessions: 2–5 reviews per week over 2–3 weeks (5.75–16 h, mean 10 h). Counselor also met with family either with or without the patient. -Psychedelic-assisted therapy sessions: 4–10.25 h (mean 6.75 h). Family involved in latter part of session. -Integration therapy sessions: 0–7.5 h (mean 2.25 h) over 1 week	High
Ross, 201634	(1) Primary diagnosis of Acute Stress Disorder, Generalized Anxiety Disorder, anxiety disorder due to cancer, or adjustment disorder with anxiety ± depression, as assessed by the Structural Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Version; (2) Life-threatening cancer (included patients who were in “remission” from their cancer)	N = 29; Mean age = 56.28; Female = 62%; Majority ethnicity/race = “White/Caucasian” (90%); Two main religious/spiritual orientations = atheist/agnostic (48%), Jewish (17%)	RCT with crossover design	-0.3 mg/kg oral psilocybin -Control: 250 mg oral niacin -Crossover at 7 weeks -Preparation therapy sessions: three individual sessions (6 h total) -Medication-assisted therapy sessions: 8-h long individual session -Therapy sessions between dosing sessions: three individual sessions (6 h total) -Integration therapy sessions: three individual sessions (6 h total) over 6 weeks followed by unquantified “ongoing support and integration with study therapist”	Medium
Ross, 202130	Subset of participants from Ross et al. (2016) trial with suicidal ideation at baseline. Suicidal ideation measured using composite score consisting of item 9 from the Beck Depression Inventory-II and item 9 from Brief Symptom Inventory.	N = 11; Mean age = 60.3; Female = 63.6%; Majority ethnicity/race = “White/Caucasian” (90.9%); Two main religious/spiritual orientations = atheist/agnostic (45.5%), Catholic (18.2%), other faith/tradition (18.2%)	Post hoc analysis Original trials: Ross et al. (2016)34 and Agin-Liebes et al. (2020)	As per Ross et al. (2016)34	High
Shnayder, 202325	(1) Major depressive disorder single episode or recurrent without psychotic features according to the DSM-5 and Hamilton Depression Rating Scale score ≥18; (2) M alignant neoplasm based on ICD-10 codes C00-C97	N = 30; Mean age = 56; Female = 70%; Majority ethnicity/race = Caucasian (80%); No data on religious/spiritual orientation	Uncontrolled open-label trial	-25 mg oral psilocybin -Preparation therapy sessions: 2-h individual session, 75-min group session, and 45-min individual session -Psychedelic-assisted therapy session: simultaneous psilocybin treatment administered in adjacent rooms with 6–7 h non-directive therapy -Integration therapy sessions: two 75-min group sessions and two 45-min individual sessions over 1 week. -Groups consisted of three to four participants.	High
Swift, 201735	Participants from Ross et al. (2016)34	-N = 13b; -Mean age = 50; -Female = 46%; -Majority ethnicity/race = “White” (92%); -Two main religious/spiritual orientations = atheist/agnostic (38%), other Christian (31%)	Interpretative phenomenological analysis of semi-structured interviews	As per Ross et al. (2016)34	Medium
Wolfson, 202031	(1) Anxiety primarily related to life-threatening illness as determined by SCID-I/P (all participants reported scores on State-Trait Anxiety Inventory Trait subscale of 45 or higher); (2) Diagnosed with life-threatening cancer or non-dementing neurological illness that was ongoing or in remission with a risk of recurrence	N = 18; Mean age = 54.9; Female = 77.8%; Majority ethnicity/race = “White/Caucasian” (83.3%); No data on religious/spiritual orientation	RCT with open-label crossover design	-For each MDMA dosing session: 125 mg oral MDMA followed by an optional supplemental dose of 62.5 mg after 90–150 min -Control: placebo -RCT: two psychedelic- or placebo-assisted therapy sessions 2–4 weeks apart. MDMA (n = 13) and placebo (n = 5) -Open-label crossover: single MDMA session for participants in MDMA group and three MDMA sessions for participants in placebo group -Preparation therapy sessions: three 60–90 min individual sessions -Psychedelic-assisted therapy sessions: 8-h long individual sessions (non-directive therapy) -Integration therapy sessions: Three 60–90 min individual sessions following each dosing session	High

^a Original study or studies for long-term follow-up studies, post hoc analysis studies, and qualitative studies with participants recruited from another study.

^b Identical participants, studies used the same set of semi-structured interview data.

DPT, dipropyltryptamine; LSD, lysergic acid diethylamide; MDMA, 3,4-methylenedioxymethamphetamine; RCT, randomized controlled trial.

All studies used convenience sampling including self-referrals and referrals by health care professionals. All studies were conducted in the United States. Nine studies used psilocybin, two studies used MDMA, two studies used LSD, and one study used dipropyltryptamine (DPT). Nine studies used individual psychotherapy only, three studies included group therapy, and two studies included family in some sessions.

A total of 10 studies exclusively included participants with cancer, and one study exclusively included older long-term AIDS survivors. Nine studies had predominantly female participants with one study having only female participants and one study including only male participants. In the 13 studies providing data on race/ethnicity, participants were predominantly “White”/Caucasian. In the seven studies providing data on religious/spiritual affiliation, common affiliations included atheist/agnostic, Christian, and Jewish. A wide range of primarily self-report quantitative measures were used (Supplementary Table S1).

Quality assessment

Evaluation of risk of bias identified eight high-risk, four medium-risk, and two low-risk studies (Table 1). Five high-risk studies lacked a control group.^25–29 Three high-risk studies were underpowered.^26,30,31 In one high-risk RCT control group, participants did not receive any therapy and were unaware of their participation in the study, and there were high rates of attrition from both experimental and control groups.³² Five high- and medium-risk studies did not account for loss to follow-up in analysis beyond providing numbers and reasons for loss to follow-up.^{28,30,32–34} Three high- and medium-risk RCTs had a crossover design with no control group for medium- and long-term timepoints.^31,33,34 All studies with medium- and long-term timepoints, falling under medium- and high-risk categories, noted participants either received multiple other interventions (mental health and cancer treatments) over the follow-up period or did not collect data regarding this.^{28,30,31,33,34} One medium-risk qualitative study did not explicitly discuss ethical approval.³¹ Two medium-risk qualitative studies combined interview data from participants interviewed 1 week after the final dosing with participants interviewed 1 year after the final dosing.^35,36 None of the qualitative studies, under both medium- and low-risk categories, discussed the influence of the researcher on the research and vice versa as outlined in the JBI checklist for qualitative research.^{22,35–37,39}

Outcomes

Several measures related to attitudes toward death, life, and spirituality were assessed at a range of timepoints. Supplementary Tables S2 and S3 include a more detailed summary of relevant results from both quantitative and qualitative studies. For this review, short term was defined as <6 months, medium term was defined as 6–12 months, and long term was defined as over 1 year.

Attitudes toward death (quantitative measures)

Nine studies quantitatively assessed changes in attitudes toward death with PAT.^26–34 Six of these studies used psilocybin-assisted therapy.^{26–28,30,33,34} The psilocybin-assisted therapy short-term results were mixed, with results showing an impact of psilocybin-assisted therapy on Life Attitude Profile-Revised (LAP-R) death acceptance but not on Death Transcendence Scale (DTS), Death Anxiety Scale (DAS), or Schedule of Attitudes toward Hastened Death (SAHD) ratings.^26,27,33,34 Medium-term psilocybin-assisted therapy results showed significant improvements in LAP-R death acceptance and mixed results in DAS and DTS.^28,31,34 Long-term psilocybin-assisted therapy results showed significant improvements in DAS.²⁸

DTS ratings were measured in three psilocybin-assisted therapy trials with participants with cancer: two RCTs with a crossover design and an uncontrolled open-label trial.^26,33,34 Both RCTs found no significant short-term between-group difference.^33,34 The uncontrolled open-label trial found no significant short-term changes in overall DTS; however, it did show significant improvements in the mysticism subscale (Cohen’s d = 1.08).²⁶ Of the two studies with uncontrolled medium-term data, one showed no significant within-group change and one showed significant improvement in DTS at 6 months (Cohen’s d = 0.58).^33,34

DAS ratings were measured in one psilocybin-assisted therapy RCT with crossover design and an uncontrolled long-term follow-up of this study.^28,34 The RCT showed no significant short-term between-group difference and medium-term uncontrolled data showed no significant within-group differences (post-first dose to 6 months).³⁴ The follow-up study with uncontrolled data showed significant reductions in DAS from baseline to 6.5–8 months (Cohen’s d >0.88), 3.2 years (Cohen’s d >0.8), and 4.5 years (Cohen’s d >1).²⁸ This study also noted that cancer remission status did not significantly interact with DAS scores.²⁸

LAP-R death acceptance was measured in one psilocybin-assisted therapy RCT with crossover design, which found significant results that met conservative criteria for concluding the effect of psilocybin-assisted therapy on LAP-R death acceptance.³³ There was a significant short-term between-group difference prior to crossover (Cohen’s d = 0.97) and significant improvements within groups for pre-post intervention dose data.³³ There was also a significant improvement in LAP-R death acceptance from baseline to 6 months with uncontrolled data collapsed across both groups (Cohen’s d = 0.84).³³

SAHD ratings were measured in an uncontrolled open-label psilocybin-assisted therapy trial in older long-term AIDS survivor men; this showed no meaningful change in SAHD from baseline to 3 months.²⁷

A “Suicidal Ideation” composite score (Supplementary Table S1) was measured in a post hoc analysis of a psilocybin-assisted therapy RCT with crossover design and the associated uncontrolled long-term follow-up study looked at the subset of participants with suicidal ideation.^28,30,34 Results showed significant short-term within-group differences only in the intervention group with improvement relative to baseline (Cohen’s d >1.2).³⁰ There was no significant short-term between-group difference.³⁰ After crossover, within-subject reductions relative to baseline remained significant at 6.5 months (Cohen’s d >1.51).³⁰

Columbia-Suicide Severity Rating Scale (C-SSRS) ratings were measured in two uncontrolled open-label psilocybin-assisted therapy trials and one MDMA-assisted therapy RCT with results showing no significant change.^26,27,31 Of note, one of these psilocybin studies excluded patients with suicidal ideation in the last month and the other excluded patients with suicidal intent in the last 3 months or a suicide attempt in the last 2 years.^26,27

Death Attitude Profile (DAP) subscales were measured in an MDMA-assisted therapy RCT with a crossover design; this showed no significant short-term between-group differences for any DAP subscales.³¹ Medium- and long-term results were mixed for different subscales. When groups were collapsed for one-way repeated measures ANOVA across the timepoints of baseline, treatment exit, and 6- and 12-month follow-up, significant improvements were found in DAP subscales of fear of death, neutral acceptance, and approach acceptance.³¹ There were no significant changes in death avoidance or escape acceptance subscales.³¹

Emotional Condition Rating Scale (ECRS) ratings were measured in an uncontrolled open-label LSD-assisted therapy trial which found significant short-term improvements in the ECRS “fear/calm acceptance of death” continuum for ratings by the therapist, co-therapist, physician, nurse, and independent raters, but not family member raters.²⁹ Collapsed data from all raters showed a significant mean improvement of 3.27.²⁹

The single DPT-assisted therapy study, an RCT, found no significant short-term changes in ECRS “denial/acknowledgment of the imminence of physical death” and “fear/calm acceptance of death” continua.³²

Spirituality (quantitative measures)

Five psilocybin-assisted therapy studies, all with participants with cancer, quantitatively assessed spirituality. Short—and medium-term results were all positive with mixed results in one long-term study.^{25,26,28,33,34}

National Institute of Health measure of Healing Experiences in All Life Stressors (NIH-HEALS) was measured in an uncontrolled open-label trial, which found significant improvements in all three factors of NIH-HEALS at multiple short-term timepoints.²⁵ Overall from baseline to week 8, connection, reflection and introspection, and trust and acceptance improved by 12.7%, 7.7%, and 22.4%, respectively.²⁵

Functional Assessment of Chronic Illness Therapy—Spiritual Wellbeing Scale (FACIT-Sp-12) ratings were measured in four studies.^26,28,33,34 An uncontrolled open-label trial showed a significant main effect of time between baseline and 2 weeks post-dosing for overall spiritual well-being and all subscales of spiritual meaning (Cohen’s d = 0.76), spiritual peace (Cohen’s d = 0.85), and spiritual faith (Cohen’s d = 0.73).²⁶ Uncontrolled data collapsed across groups in an RCT with crossover design showed significant improvements in FACIT-Sp-12 from baseline to 5 weeks post-crossover dose (Cohen’s d = 1.03) and 6 months (Cohen’s d = 1.28).³³ Another RCT with crossover design found significant short-term between-group differences in overall spiritual well-being and subscales of meaning/peace and faith.³⁴ This study also found positive medium-term results with uncontrolled within-group data.³⁴ The control-first group showed a significant improvement from pre-crossover to 6 months post-crossover in all subscales.³⁴ The intervention-first group’s improvements were maintained with no significant change from 2 weeks post-intervention dose to 6 months post-crossover in any subscale.³⁴ An uncontrolled long-term follow-up of this study using collapsed data from both groups showed mixed results across subscales.²⁸ Overall spiritual well-being showed significant improvements relative to baseline at 6.5–8 months and 4.5 years, but not 3.2 years.²⁸ The faith subscale showed significant improvements relative to baseline at 6.5–8 months, 3.2 years, and 4.5 years.²⁸ The meaning/peace subscale showed a significant improvement relative to baseline at 6.5–8 months but not the long-term timepoints.²⁸

Faith Maturity Scale ratings were measured in an RCT.³³ Uncontrolled collapsed data from this RCT with crossover design demonstrated significant improvements in Faith Maturity Scale ratings from baseline to 5 weeks post-crossover (Cohen’s d = 0.2) and 6 months (Cohen’s d = 0.28), and significant improvements in Spiritual/Religious Outcome Scale ratings from baseline to 5 weeks post-crossover (Cohen’s d = 0.61) and 6 months (Cohen’s d = 0.55).³³

Persisting Effects Questionnaire (PEQ) results from two RCTs with crossover design had significant findings with participants attributing greater changes in “increased spirituality” to their intervention session than their control session.^33,34 Attributions of “increased spirituality” to psilocybin-assisted therapy were maintained in the medium term in both studies.^33,34 There were no significant findings in the “decreased spirituality” subscale in either study.^33,34

Attitudes toward life (quantitative measures)

Two psilocybin-assisted therapy studies quantitatively assessed attitudes toward life, demonstrating positive effects on McGill Quality of Life Questionnaire (MQOL) meaningful existence and Life Orientation Test-Revised (LOT-R), improvements in Purpose in Life Test and LAP-R coherence measures, which did not correlate with psilocybin-assisted therapy, and significant improvements in PEQ “positive attitudes toward life” attributed to psilocybin-assisted therapy.^33,34

MQOL meaningful existence subscale and LOT-R ratings were measured in an RCT with crossover design. This showed significant improvements in both MQOL meaningful existence subscale and LOT-R ratings with results meeting conservative criteria for demonstrating an effect of psilocybin-assisted therapy.³³ MQOL meaningful existence data showed a significant short-term between-group difference (Cohen’s d = 0.65) and significant improvements within groups for pre-post intervention dose data.³³ LOT-R data showed a significant short-term between-group difference (Cohen’s d = 0.75) and significant improvements within groups for pre-post intervention dose results.³³ There were also significant improvements in MQOL meaningful existence and LOT-R from baseline to 6 months with uncontrolled data collapsed across both groups (respectively, Cohen’s d = 1.12 and 0.66).³³

Purpose in Life Test and LAP-R coherence ratings were also measured in this RCT with results not fulfilling conservative criteria for demonstrating an effect of psilocybin-assisted therapy.³³ Both Purpose in Life Test and LAP-R coherence ratings showed significant short-term within-group improvements for both intervention and control groups, and there was no short-term between-group difference for either measure.³³ However there were significant improvements within the control-first group from pre- to post-crossover in both Purpose in Life and LAP-R coherence (respectively, Cohen’s d = 0.28 and 0.49).³³ There were also significant improvements in Purpose in Life and LAP-R coherence from baseline to 6 months with uncontrolled data collapsed across both groups (respectively, Cohen’s d = 0.85 and 0.90).³³

PEQ results from two RCTs with crossover design had significant findings with participants attributing greater changes in “positive attitudes about life” to their intervention session than their control session.^33,34 Attributions of “positive attitudes about life” to psilocybin-assisted therapy were maintained in the medium term in both studies.^33,34 There were no significant findings in the “negative attitudes about life” subscale in either study.^33,34

Demoralization (quantitative measures)

Four psilocybin-assisted therapy studies, including one follow-up study and one post hoc analysis, measured quantitative outcomes regarding the related concepts of demoralization, hopelessness, and loss of meaning with consistently positive results across all measures.^27,28,30,34

Demoralization Scale-II (DS-II) ratings were measured in an uncontrolled open-label trial in older long-term AIDS survivor men with results showing significant improvements in DS-II ratings.²⁷ At end-of-treatment and 3-month follow-up, respectively, 88.9% and 66.7% of participants demonstrated at least a 2-point reduction in demoralization compared with baseline, and 50% and 33.3% demonstrated an over 50% reduction in demoralization compared with baseline.²⁷

Demoralization Scale (DS) and Hopelessness Assessment in Illness Questionnaire (HAI) ratings were measured in an RCT with a crossover design, which showed significant short-term between-group differences in both the DS and HAI measures.³⁴ This study also found positive medium-term results for these measures with uncontrolled within-group data. The control-first group showed significant improvements from pre-crossover to 6 months post-crossover in both measures.³⁴ The intervention-first group’s improvements were maintained with no significant change from 2 weeks post-intervention to 6 months post-crossover in either measure.³⁴ A long-term follow-up of this study using uncontrolled collapsed data showed significant reductions in both DS and HAI from baseline to 6.5–8 month follow-up (Cohen’s d >0.88), 3.2 year follow-up (Cohen’s d >0.8), and 4.5 year follow-up (Cohen’s d >1).²⁸ This study also noted that cancer remission status did not significantly interact with DS or HAI scores.²⁸

A “Suicidal Ideation”’ composite score (Supplementary Table S1) was measured in a post hoc analysis of a psilocybin-assisted therapy RCT with crossover design and the associated uncontrolled long-term follow-up study looked at the subset of participants with suicidal ideation.^28,30,34 A significant improvement in the “loss of meaning” factor of DS over short term was noted in only the intervention group prior to crossover (Cohen’s d >1.2).³⁰ A significant between-group difference was also noted at this timepoint (Cohen’s d >1.2).³⁰ After crossover, within-subject reductions in “loss of meaning” relative to baseline remained significant at 6.5 months, 3.2 years, and 4.5 years (Cohen’s d >1.51).³⁰

Qualitative measures

Of the four qualitative studies, three identified themes related to greater acceptance and reduced fear of death with spiritual themes also prominent in the two psilocybin-assisted therapy studies (Supplementary Table S3).^35–37,39 An LSD-assisted therapy study using semi-structured interviews and qualitative content analysis noted that seven of nine participants mentioned experiencing less fear of death.³⁷ An MDMA-assisted therapy study using semi-structured interviews and interpretative phenomenological analysis noted a shared theme of “reconciliation with life and death” across all participants.³⁹

Two studies used the same set of psilocybin-assisted therapy semi-structured interview data with separate interpretative phenomenological analyses and different scopes.^35,36 Relevant themes included “wisdom lessons,” “revised life priorities,” “ineffability,” “from separateness to interconnectedness,” “loved ones as guiding spirits,” “reconciliation with death,” “spiritual or religious interpretations,” and “reconnection to life.”^35,36

Discussion

This is the first systematic review to examine the impact of PAT on attitudes toward death, life, and spirituality for symptoms of distress, depression, and/or anxiety in patients with life-threatening illness. Overall results were mixed with different findings for different outcome measures and timeframes. Psilocybin-assisted therapy is associated with short- and medium-term improvements in spirituality.^{25,27,28,33,34} This encompasses spirituality more broadly and the narrower concept of religious faith. Long-term findings with uncontrolled data suggest sustained improvements in faith but not in sense of peace/meaning or overall spirituality.²⁸ Quantitative results also show that individuals attribute improvements in spirituality to their PAT experience.^33,34 It was noted that qualitative research themes related to spirituality were more prominent in psilocybin-assisted therapy studies than MDMA- and LSD-assisted therapy studies; this may reflect variations in study scope or differences in mechanism of action with different psychedelics.^9,35,36

A heterogeneous range of measures was used to assess attitudes toward death, encompassing different conceptual approaches and facets. Findings suggest that both LSD- and psilocybin-assisted therapies are associated with greater acceptance of death in the short-term data with medium-term data also available for psilocybin-assisted therapy.^29,33 Qualitative data suggest this finding may potentially also be applicable to MDMA-assisted therapy.⁹ DPT-assisted therapy was not found to be associated with greater acceptance of death; this finding may reflect differences in mechanism of action with different psychedelics; however, it needs to be interpreted with significant caution, given the notable methodological limitations of the single DPT study.³² Death anxiety measures did not show significant improvements with psilocybin-assisted therapy compared with control in the short term; however, improvements over the medium and long term were found with uncontrolled data.^28,34 Multiple potential scenarios could account for these results including delayed onset of improvements in death anxiety following PAT, or improvements in death anxiety occurring with time as part of the natural progression of life-threatening illness and standard treatments for this. Findings suggest that overall psilocybin-assisted therapy does not appear to impact death transcendence.^26,33,34 Included studies also suggest that PAT does not impact desire to die (C-SSRS, SAHD) with the caveat that most studies investigating these measures had explicit exclusion criteria regarding recent suicidality.^26,27,31 Findings suggest this may also be applicable in the subgroup of individuals with suicidality; however, this result needs to be viewed with caution given the underpowered nature of the single post hoc analysis exploring this subgroup.³⁰

Findings related to attitudes toward life suggest improvements in optimism and a sense of meaningful existence attributable to psilocybin-assisted therapy, with the limitation that these findings are from a single study.³³ Results also show that individuals attribute improvements in positive attitudes toward life to their psilocybin-assisted therapy experience.^33,34 Improvements in measures related to sense of purpose in life as per a logotherapy approach and coherence (having an integrated and consistent understanding of self, others, and life) were found in both intervention and control groups in the short term and across both groups collapsed in the medium term.³³ This suggests that improvements in these domains may be attributable to therapy (without psychedelic component) or may be a reflection of improvements with time as part of the natural progression of life-threatening illness and standard treatments for this.

Results also suggest that psilocybin-assisted therapy is associated with consistent and sustained improvements across the related concepts of demoralization, hopelessness, and, within a subgroup with suicidal ideation, loss of meaning.^27,28,30,34 RCT findings suggest that the improvements, at least in the short term, are likely attributable to psilocybin-assisted therapy.^28,30,34 No deterioration was reported in any measures of attitudes toward life, death, and spirituality, supporting the psychological safety of this intervention.^25–28

This review included predominantly modern studies published in the last 8 years, with only two older studies which were published in the 1970s.^29,32 The older trials had notably a greater risk of bias and involved family members in therapy sessions, unlike modern trials.^29,32

Strengths and limitations

There are a number of limitations to this review. There were only a small number of studies included with overlap in participants between studies, including a long-term follow-up study, a post hoc analysis, three qualitative studies with participants recruited from included quantitative studies, and two qualitative studies based on the same set of semi-structured interviews data.^{9,28,30,35,36} Most studies were of medium or high risk of bias, with the single quantitative MDMA-, LSD- and DPT-assisted therapy studies all being at high risk of bias.^29,31,32 It is unclear whether psilocybin-assisted therapy results can be extrapolated to all PATs, given the different mechanisms of action and paucity of data for non-psilocybin PATs.⁹ Generalizability is also limited by the largely female, “White”/Caucasian, and Judeo-Christian or atheist/agnostic participant group, and all studies being conducted in the United States.

With regard to study design, all original studies used convenience sampling, which increases the risk of sampling biases. There was also heterogeneity in the quantity and nature of psychotherapy, which may account for some of the variation in findings between different studies. There were only four RCTs and randomized controlled data was short term in duration, given the crossover design of the psilocybin-assisted therapy RCTs, and the short follow-up period of the DPT RCT.^31–34 Risk of confounding with uncontrolled data limits confidence in conclusions drawn regarding the medium- and long-term effects attributable to PAT. It is also notable that some studies used outcome measures, which have not been demonstrated to be reliable and/or valid (Supplementary Table S1). It is also of questionable face validity that outcome measures with Christian and Protestant frameworks were used in a participant group of unknown religious affiliations.³³

Given the heterogeneity of measures used, quantitative synthesis was not possible for this review. It is also noted that division into categories of attitudes toward death, spirituality, attitudes toward life, and demoralization is largely arbitrary with significant overlap between these concepts. These also overlap with other concepts that have been explored in psychedelic research; however, these were not included in this review including self-actualization and domains of personality such as openness.^9,40

In considering these as potential mediating factors, it is also notable that apart from a single study finding a correlation between suicidal ideation and other depressive symptoms, there are no data available regarding the correlation between changes in these measures and changes in anxiety, depression, and distress symptomology.³⁰

Clinical and research implications

The World Health Organization has identified spiritual problems as one of the central domains that need to be addressed to improve quality of life in a palliative care context.⁴¹ However, relative to other bio-psycho-socio-spiritual domains, treatment of spiritual problems and existential distress in life-threatening illness is an area with a less developed evidence base.⁴² Demoralization is a pertinent related concept with emerging evidence suggesting it is a distinct entity from depression with limited current evidence-based treatment options.²⁷ This review suggests that PAT may have a role as an effective treatment option for spiritual well-being, including treatment of demoralization, in the life-threatening illness context.

It has been postulated that spiritual and existential changes may be a mediator for psychedelic-assisted therapy.¹⁰ While this review cannot draw any conclusions regarding mediating factors, it does show that improvements in various spirituality measures occur with PAT. This highlights the need for further research regarding the types of spiritual changes found with PAT, a correlation between mystical experiences during the psychedelic sessions and spirituality measures, a correlation between changes in spirituality and changes in psychiatric symptomology, and whether the use of more spirituality-focused psychotherapeutic approaches impacts outcomes.

Addressing death anxiety has also been suggested as a potential mediator for the efficacy of psychedelics.¹¹ This review did not show clear improvements in death anxiety that can be attributed to PAT and more broadly showed significant variations in different death-related outcome measures using different underlying theoretical frameworks. This highlights the need for further research and specific consideration around the measures used in this research—the DTS was the most commonly used death-related measure; however, results suggest that beliefs around transcendence do not change with psilocybin-assisted therapy.

The evidence base for PAT in palliative care is growing with numerous clinical trials currently underway.⁴ This review highlights gaps in the evidence base that need to be considered in future research to expand our understanding of the mechanistic processes underlying PAT. This includes the need for large, adequately powered, long-term RCTs to clarify which changes can be attributed to psychedelic treatment rather than natural progression of illness and/or psychotherapy. Further development of reliable and valid measures of outcomes related to attitudes toward life, death, and spirituality also needs to occur. This study also highlights the need for further research with non-psilocybin PATs in this context to determine the generalizability of results across different psychedelics.

Conclusion

This systematic review is a comprehensive analysis of the impact of PAT on attitudes toward death, life, and spirituality on symptoms of distress, depression, and/or anxiety in patients with life-threatening illness. This review highlights the reduced demoralization, reduced hopelessness, improvements in spirituality, greater death acceptance, a greater sense of optimism toward life, and a greater sense of meaningful existence attributable to PAT in this context. Mixed findings were identified for a range of other measures associated with attitudes toward life and death. Results need to be interpreted with significant caution given the overlap of participants between trials, paucity of trials, and risk of bias, especially with regard to non-psilocybin PATs. Recommendations to address this in future research include the development of reliable and valid outcome measures, further research into a range of psychedelics, and conducting large high-quality RCTs over longer time periods and with rigorous statistical power.

Authors’ Contributions

T.T.: Conceptualization, methodology, analysis, writing, and original draft preparation. P.G.: Conceptualization, writing, reviewing, and editing.

Author Disclosure Statement

T.T. has no disclosures. P.G. is named on a patent for a slow-release ketamine tablet formulation.

Funding Information

This work received no specific funding.