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

Objectives. People with terminal illnesses often experience psychological distress and associated disability. Recent clinical trial evidence has stimulated interest in the therapeutic use of psychedelics at end of life. Much uncertainty remains, however, mainly due to methodological difficulties that beset existing trials. We conducted a scoping review of pipeline clinical trials of psychedelic treatment for depression, anxiety, and existential distress at end of life. Methods. Proposed, registered, and ongoing trials were identified from 2 electronic databases (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform). Recent reviews and both commercial and non-profit organization websites were used to identify additional unregistered trials. Results. In total, 25 studies were eligible, including 13 randomized controlled trials and 12 open-label trials. Three trials made attempts beyond randomization to assess expectancy and blinding effectiveness. Investigational drugs included ketamine ( n = 11), psilocybin ( n = 10), 3,4-methylenedioxymethamphetamine ( n = 2), and lysergic acid diethylamide ( n = 2). Three trials involved microdosing, and fifteen trials incorporated psychotherapy. Significance of results. A variety of onging or upcoming clinical trials are expected to usefully extend evidence regarding psychedelic-assisted group therapy and microdosing in the end-of-life setting. Still needed are head-to-head comparisons of different psychedelics to identify those best suited to specific indications and clinical populations. More extensive and rigorous studies are also necessary to better control expectancy, confirm therapeutic findings and establish safety data to guide the clinical application of these novel therapies


Introduction
Life-threatening illnesses affect physical, emotional, social, and spiritual well-being (LeMay and Wilson 2008). Psychiatric disorders are common, with the prevalence of anxiety and depressive disorders estimated at around 10% and 15%, respectively, in patients with cancer (Mitchell et al. 2011). Additionally, this confronting experience can induce existential distress by challenging one's fundamental expectations about various aspects of life (Vehling and Kissane 2018). Individuals with progressive disorders may experience a demoralization syndrome, a welldefined state of existential distress characterized by feelings of hopelessness, meaninglessness, and a sense of failure. Demoralization syndrome is clinically significant in 13%-18% of this population (Robinson et al. 2015), associated with impaired quality of life, functional compromise, and suicidal ideation (Simard et al. 2013;Vehling et al. 2017).
The mitigation of clinically significant psycho-existential distress remains a challenging issue in palliative care (Blinderman 2016). The use of pharmacotherapy in cancerrelated psychiatric conditions is common, yet meta-analysis fails to show the superiority of antidepressants over placebo (Ostuzzi et al. 2015), and there is insufficient evidence to substantiate the effectiveness of anxiolytics (Salt et al. 2017). Psycho-oncologic interventions yield significant albeit time-limited effects on existential well-being, quality of life, and self-efficacy (Bauereiß et al. 2018). Nonetheless, the results on depression and anxiety are ambiguous (Bauereiß et al. 2018;Wang et al. 2017). The need for additional effective treatments stimulates interest in exploring the therapeutic potential of psychedelic medicines. Before global prohibition in 1971, there were promising findings from early-phase clinical trials in terminal illness of classic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), characterized by agonist activity at serotonin 5-HT 2A receptors and perception-altering properties (Petranker et al. 2020). Entering the 21st century, the revival of psychedelic research includes re-examination of the use of these drugs in terminal illness (Fig. 1) and extends to include other hallucinogens, namely ketamine and 3,4methylenedioxymethamphetamine (MDMA) (Reiff et al. 2020). The entactogen MDMA (mixed serotonin and dopamine reuptake inhibitor and releaser) and dissociative anesthetic ketamine 2 Xuepeng Jing et al. Figure 1. Trend of end-of-life-related psychedelic publications. Number of Web of Science publications where the title or abstract contains a psychedelic drug (classic psychedelics and related compounds) and the following terms: "dying"; "palliative"; "hospice"; "life-threatening"; "terminal"; "cancer"; "tumour," by year, from 1960 to 2021.
(N-methyl-D-aspartate receptor antagonist) share important similarities with serotonergic psychedelics in their ability to induce temporary but profound alterations of consciousness (Garcia-Romeu et al. 2016). Therefore, for the present article, the term "psychedelic" will be used to denote classic psychedelics and related compounds (i.e., ketamine and MDMA). Recent systematic reviews indicate the potential utility of these agents in terminal illness (Maia et al. 2022;Schimmel et al. 2022).
The accumulating evidence for psychedelic therapies at the end of life has been accompanied by growing commercial and public interest. The evolving social and legal landscape demands continuing critical appraisal of scientific evidence, particularly in light of methodological challenges and sources of bias that beset psychedelic trials (Muthukumaraswamy et al. 2022). This scoping review aims to shed light on the near future of this field by summarizing proposed, registered, and ongoing clinical trials of psychedelic treatments for end-of-life anxiety, depression, and existential distress. Scoping reviews are distinguished from systematic reviews by their broader inclusion of topics and the lack of need to address specific research questions or appraise study quality (Arksey and O'Malley 2005). They serve to map available evidence, clarify concepts, examine research conduct, highlight knowledge gaps, or inform systematic reviews (Munn et al. 2018). They are thus helpful for investigating emerging evidence and synthesizing an overview, appropriate for the objective of this article.

Method
We performed a scoping review of ongoing and upcoming trials of psychedelic medicines for end-of-life care.  Schimmel et al. (2022), we chose to include ketamine in the review because its psychotomimetic effects have been implicated in mediating depression and anxiety (Dore et al. 2019;Luckenbaugh et al. 2014;Sos et al. 2013). We acknowledge that ketamine may not necessarily be used for its psychedelic properties and the distinction will be highlighted later in the review. Synonym search was enabled. The final search results were exported to Microsoft Excel, and duplicates were removed. Our search also included unregistered projects identified in recent pertinent reviews, and the websites of relevant commercial and non-profit organizations, specifically atai Life Sciences, COMPASS Pathways, Multidisciplinary Association for Psychedelic Studies (MAPS), Beckley Foundation, Heffter Research Institute, and the Ketamine Research Foundation. Collateral information on studies was gathered from press releases and published protocols via PubMed.
Randomized and open clinical trials were included if they (1) test classic psychedelics and related substances (i.e., MDMA and ketamine), (2) include participants with life-threatening illnesses or in palliative/hospice care, and (3) include psychological outcomes. We excluded trials of patients with early-stage cancer and those conducted in a postoperative setting. We also excluded trials that had published results or had been withdrawn. Ketamine trials with analgesia as the primary outcome were excluded. Only trials with registry details in English were considered; no limit was placed on the year of registration. Data were extracted and screened by 1 author (XJ). Uncertainties were resolved through discussion and consensus. Trial investigators were contacted to request information for unregistered studies.

Psilocybin
In the largest trial identified (target n = 300), a team at New York University is planning a Phase 2b, double-blind, placebo-controlled multicenter RCT in advanced-stage cancer (NYU NCT05398484). The intervention consists of single doses of either 25 mg or 1 mg (active control) of psilocybin, both delivered in conjunction with psychotherapy. This study extends a previous, smaller crossover RCT undertaken by the same principal investigator (Ross et al. 2016) showing enduring antidepressant and anxiolytic effects in a similar population.
In addition to low-dose psilocybin, studies are using other active placebos. For example, another RCT (St. Vincent's Hospital 4 Xuepeng Jing et al.  ( [St. Vincent] ACTRN12619001225101) uses 100 mg niacin, which can induce a mild acute physiological reaction (e.g., flushing, lower blood pressure) (Bays and Rader 2009;Mills et al. 2003). Niacin has been used in doses up to 250 mg as placebo in previous psilocybin studies but, unfortunately, without assessment of the integrity of the blind (Grob et al. 2011;Ross et al. 2016). Owing to its psychoactive properties, the short-acting benzodiazepine midazolam has previously been used as an active comparator in psychedelic trials with partial success (Muthukumaraswamy et al. 2021 ) explores the therapeutic potential of psilocybin-assisted group treatment in cancer patients with major depression. This study has completed recruitment, with 30 participants divided into cohorts to receive simultaneous administration of 25 mg psilocybin in a cancer center setting, complemented by group preparatory and integration sessions. The pilot project developed by the University of Utah (Utah NCT04522804) echoes this concept, where 12 recruited participants will undergo 7 group therapy sessions (1 with psilocybin).

Ketamine
Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist with anesthetic, analgesic, dissociative, and hallucinogenic properties (Wolff and Winstock 2006). However, its dose-dependent psychotomimetic effects are generally considered undesirable in antidepressant research (Garcia-Romeu et al. 2016). The development of ketamine-assisted psychotherapy (KAP) in recent times has aimed to harness the psychedelic properties of ketamine at relatively higher doses to treat psychiatric illnesses and existential issues (Dore et al. 2019). Similarly, 2 pipeline trials in this review combine ketamine with psychotherapy. The same group of Dore et al. (2019) at Ketamine Research Foundation plans a Phase 2 pilot study (KRF NCT05214417) of intramuscular KAP in terminally ill patients. Two separate sessions with multiple doses of up to 100 mg per session will be administered to 18 subjects across 5 sites. The naturalistic control group will continue to receive pre-existing conventional treatment and complete the same assessments and will then be offered an optional crossover intervention. Another trial in the USA (Northwell Health [Northwell] NCT05344625) is an open-label study of repeated intramuscular KAP with individualized doses up to 60 mg or 1 mg/kg in a session. Both KAP studies will explore the impact of the intervention on existential distress, as assessed by the Death and Dying Distress Scale (DADDS).
Numerous routes of administration are examined by the other ketamine pipeline trials in the end-of-life setting, including intravenous (n = 2), intramuscular (n = 1), oral (n = 3), subcutaneous (n = 2), and intranasal (n = 1). The feasibility and efficacy of (S)-ketamine use (more potent than the racemic drug) in this population will also be investigated (White et al. 1985). One trial measures expectancy via the Credibility/Expectancy Questionnaire (Cedars-Sinai Medical Center [Cedars-Sinai] NCT02836288). However, it is worth noting that these trials are likely designed to minimize the psychotomimetic symptoms of ketamine due to the lower dose range employed (e.g., <0.5 mg/kg IV, <1 mg/kg oral) compared to the 2 KAP trials.

Lysergic acid diethylamide
Another RCT in development at New York University (Ross et al. 2022) focuses on LSD-assisted psychotherapy in patients with advanced cancer pain syndromes; existential and psychiatric distresses are important secondary outcomes. A similar trial in development at the University of Auckland (Health Research Council of New Zealand [HRCNZ] 2021) evaluates the feasibility of combining microdosed LSD with meaning-centered psychotherapy. This study will provide 40 advanced cancer patients with either a titrated dose of LSD (4-12 μg) or an inert placebo twice a week for 6 weeks, both in the clinic and at home (Lisa Reynolds 2022, personal communication). Blinding maintenance and treatment expectancy will be measured as secondary outcomes.

3,4-Methylenedioxymethamphetamine
A 2-center New Zealand Phase 2 trial (Universities of Otago and Auckland [Otago/Auckland] ACTRN12619001334190) aims to recruit 32 participants with advanced-stage cancer. It will assess the effect of psychotherapy with either 120 mg MDMA or 20 mg methylphenidate. Methylphenidate shares MDMA's stimulant properties and appears effective in blinding a prior psilocybin study (Griffiths et al. 2006). Finally, an open-label trial with a novel protocol in the USA, sponsored by MAPS (MAPS NCT05584826), will recruit 10 dyads of a patient with cancer and a significant other (n = 20). Each dyad will undergo 2 MDMA-assisted therapy sessions with 100 mg MDMA and 6 additional psychotherapy sessions over 8 weeks. The primary outcomes are the Adjustment Disorder New Module (ADNM-20) and Couples Satisfaction Index (CSI-16).

Discussion
Our review of pipeline trials of psychedelic medicines for end-oflife depression, anxiety, and existential distress demonstrates the continued momentum of research in this area. The 25 included studies were heterogenous and focused chiefly on psilocybin and ketamine. A striking observation is that drug treatment combined with psychotherapy is unusual (2/11) in ketamine trials and almost universal in current trials of the other 3 drugs (13/14). This may be a consequence of most ketamine trials using the drug for other than its psychedelic properties.
The findings expected from these trials will augment existing knowledge in several ways. So far, there is limited evidence on psychedelic assisted-group therapy in patients with a life-threatening illness. A pilot study by Anderson et al. (2020) demonstrated the efficacy of group psychotherapy with individual psilocybin administration in patients with chronic AIDS. More extensive evidence documents the feasibility of psychedelicassisted group therapy for treating mood, personality, and alcohol use disorders (Trope et al. 2019). Hence, the 2 psilocybin group intervention trials (Utah NCT04522804; Maryland NCT04593563) will set the stage for the next phase of group-focused research. Group interventions have the potential to increase the scalability and cost-effectiveness of psychedelic-assisted therapies.
Pipeline trials also explore the potential benefits of microdosing psychedelics in the end-of-life context. Although lowdose LSD and psilocybin had previously been used as short-term active placebos (Gasser et al. 2014;Griffiths et al. 2016), clinical trials are now set to evaluate the effects of repeated microdosing in patients with life-threatening illness (HRCNZ 2021; 6 Xuepeng Jing et al.

UCLA NCT05403086
). Unlike full-dose regimens, microdosing in a research context refers to the regular ingestion of subhallucinogenic amounts of psychedelics (10%-12% of a full dose by convention) (Polito and Liknaitzky 2022). Home dosing is possible with the less intense experience involved in this practice (Murphy et al. 2021). Additionally, results from the Griffiths et al. 's (2016) study highlighted that more of the participants receiving high-dose psilocybin reported psychological discomfort than those in the low-dose arm. Thus, microdosing may offer an alternative approach that is more acceptable to patients and (similar to group therapy) has the potential to reduce demand on clinician time.
The diversity of ketamine trials in progress will add to emerging evidence of its use in the end-of-life setting. Although most of the pipeline trials attempt to avoid the psychotomimetic effects of ketamine with lower doses, they can still provide valuable data on the feasibility and tolerability of ketamine use in the palliative care population, which is currently lacking in the literature (Lee et al. 2021). Concerns regarding durability of mood improvement appear more of an issue with ketamine than with classic psychedelics (Bahji et al. 2021). KAP trials (KRF NCT05214417; Northwell NCT05344625) are hence particularly awaited and expected to show the extent to which ketamine benefits can be augmented or extended by the presence of psychedelic experiences.
Despite the anticipated advances, as outlined above, expected from current pipeline trials, important methodological issues and research gaps will remain. Fundamentally, the psychoactive properties of psychedelics pose significant difficulties in blinding (Nichols and Barker 2016), while expectancy effects, both positive and negative (Aday et al. 2022) require rigorous control. Concerns have thus been raised about the possible overestimation of treatment effects in psychedelic studies (Butler et al. 2022;Muthukumaraswamy et al. 2021). The substantial proportion (13/27) of RCTs among identified trials is encouraging, as is the range of active placebos employed to enhance blinding.
Unfortunately, only 3 trials plan to assess the integrity of masking and expectancy (HRCNZ 2021; Cedars-Sinai, NCT02836288; UCLA, NCT05403086). Moreover, most ketamine trials lack active placebo control. Few published psychedelic studies assess expectancy and blinding (Muthukumaraswamy et al. 2021), emphasizing the importance of including such measures in future RCTs. Additionally, following the largest (n = 300) pipeline Phase 2 trial (NYU, NCT05398484), more extensive Phase 3 studies will be needed to confirm therapeutic findings and establish a safety profile in the long term. Lastly, further head-to-head comparisons between psychedelics as the 2 pipeline trials aimed at (NIMH, 2020-005037-32; UCLA, NCT05403086) are needed to identify optimal agents for the specific indications and clinical context. This would also require additional MDMA and LSD trials as they currently constitute a minority of the available evidence (Schimmel et al. 2022).
Our review highlights both the extent and challenges of research into the use of psychedelics in palliative care. The very nature of the target population poses barriers to conducting clinical trials. Recruitment can be hindered by various factors, including engagement-limiting anhedonia (Lee et al. 2022) and the often competing priorities of patients and families. There are also concerns about possible interactions of psychedelics when co-administered with medications commonly used at the end of life (Sarparast et al. 2022). Despite their promising potential, the prescription of psychedelics at the end of life also raises bioethical considerations, particularly regarding the possibility of interfering with one's pre-existing belief system and sense of identity (Smith and Sisti 2021). Modern palliative care calls for a multi-dimensional approach to improve quality of life, addressing physical, psychological, social, and spiritual or existential needs (Davies and Higginson 2004). Available evidence indicates that psychedelic-assisted therapies can decrease physical distress related to pain and also promote improved sleep in this patient population (Maia et al. 2022). More importantly, the import of mystical-type experience, defined by feelings of unity, interconnectedness, peace, and joy, as well as senses of sacredness, ineffability, and transcendence, may address elements at the core of psychoexistential suffering (MacLean et al. 2011). Preliminary evidence has demonstrated positive psychological effects and reduced psychiatric and existential distress following psychedelic treatments (Maia et al. 2022;Schimmel et al. 2022). Some also propose that psychedelic experiences extend beyond the alleviation of suffering and enhance social relationships that could be deeply meaningful for people approaching end of life (Earp 2018).
This review presents several limitations. The literature search was mainly based on data gleaned from clinical registries, which may not accurately or entirely reflect trial details in real time. One author (XJ) reviewed individual studies with active supervision, analysis, and critical input from the other authors.

Conclusion
Addressing the psychological and physical needs of patients approaching end of life is an enduring clinical priority. Existing studies support the potential role of psychedelic medicines in this area, but much uncertainty remains. Our scoping review highlights ongoing scientific interest internationally and identifies pipeline trials set to provide important additions to the evidence base. More extensive, methodologically stronger trials will be needed to address blinding and expectancy problems. There will also be a need for head-to-head comparisons of different psychedelics for particular indications.