Using Psychedelic Treatments in End-of-Life Care: Summary and Critical Review

Palliative care emerged in response to the recognition that modern biomedicine, despite remarkable advances in disease-modifying treatments and life-prolonging technologies, has often struggled to adequately address the multidimensional suffering experienced by patients facing serious and life-limiting illness. Rooted in the modern hospice movement inspired by Dame Cicely Saunders, palliative care has emphasized a holistic, person-centered approach to care, encapsulated in the concept of total pain, which integrates physical, psychological, social, and spiritual dimensions of suffering [1,2]. This framework remains foundational to contemporary definitions of palliative care, including that of the World Health Organization, which explicitly recognizes spirituality and psychosocial well-being as integral components of quality end-of-life care [3].

Despite substantial progress in symptom control and supportive care, existential distress remains highly prevalent among patients with advanced illness. Manifestations such as demoralization, loss of meaning, death anxiety, spiritual anguish, and a desire for hastened death are commonly reported and are associated with diminished quality of life and increased psychological suffering [4,5]. Although several psychotherapeutic interventions—including dignity therapy, meaning-centered psychotherapy, CALM therapy, and supportive-expressive approaches—have demonstrated modest benefits, their effects are often limited in magnitude and duration, with inconsistent impact on depression and anxiety [5]. Pharmacological approaches, particularly antidepressants, have similarly shown limited efficacy in addressing existential distress per se, underscoring a persistent therapeutic gap in palliative care [4].

In this context, psychedelic-assisted interventions have re-emerged as a promising area of inquiry for addressing psychological and existential suffering associated with life-threatening illness. Psychedelics are “mind-manifesting” psychoactive substances capable of profoundly altering perception, affect, cognition, and sense of self [6]. When administered within structured psychotherapeutic frameworks emphasizing preparation, therapeutic support, and post-session integration, psychedelic-assisted therapy (PAT) may occasion experiences characterized by ego dissolution, enhanced meaning-making, emotional openness, and acceptance of mortality [7,8]. These experiential effects bear notable phenomenological similarities to states described in spiritual traditions and near-death experiences, positioning psychedelics as uniquely relevant to the existential challenges encountered at the end of life [8].

Historically, the intersection between psychedelics and palliative care is not novel. Early clinical studies conducted during the first wave of psychedelic research in the 1950s and 1960s—primarily involving lysergic acid diethylamide (LSD)—suggested reductions in pain, anxiety, and fear of death among patients with advanced cancer, alongside improvements in psychological well-being [4]. However, methodological limitations and the subsequent global prohibition of psychedelic substances in the late 1960s and early 1970s led to a prolonged interruption of this research. In recent years, a renewed “psychedelic renaissance” has produced a growing body of early-phase clinical trials investigating psilocybin-, LSD-, MDMA-, and ketamine-assisted interventions for depression, anxiety, and existential distress in patients with serious illness, particularly cancer [9,10].

Contemporary studies suggest that PAT may offer rapid and, in some cases, sustained reductions in anxiety, depressive symptoms, demoralization, and existential distress, along with improvements in quality of life and spiritual well-being [11,12]. Importantly, available data indicate a favorable safety profile in carefully selected patient populations, with no serious adverse events attributable to study drugs reported in recent trials [12]. Nonetheless, these findings must be interpreted cautiously. Existing trials have employed stringent inclusion and exclusion criteria, often enrolling highly motivated participants with relatively preserved prognoses, limited comorbidity, and, in some cases, prior psychedelic experience. Consequently, the generalizability of these results to patients with more advanced disease, complex medical conditions, or those receiving hospice care remains uncertain [9,12].

Beyond questions of efficacy and safety, psychedelic-assisted interventions raise broader ethical, epistemological, and clinical considerations. Similar to the historical development of hospice and palliative medicine itself, psychedelic therapy occupies a liminal space between biomedical treatment, psychotherapy, and spiritual care, drawing on humanistic psychology and experiential models of healing [13,14]. This convergence challenges conventional biomedical paradigms and invites renewed reflection on how medicine engages with meaning, suffering, and spirituality at the end of life.

In response to the rapid expansion of clinical interest and research activity in this field, an international interdisciplinary workshop recently convened clinicians, researchers, ethicists, and policymakers to formulate recommendations guiding best practice for psychedelic-assisted therapy (PAT) in the context of serious illness and palliative care [10]. These recommendations address key domains including patient selection, preparation and integration processes, safety and risk mitigation, therapeutic framing, clinician training and competencies, ethical governance, and alignment with core principles of palliative care. While this consensus effort represents an important step toward responsible clinical translation, it remains unclear to what extent these recommendations have been systematically incorporated into the secondary literature. Specifically, it is not yet known whether narrative, systematic, and scoping reviews that aim to synthesize the available evidence on psychedelic-assisted interventions in palliative care explicitly engage with or operationalize these best-practice recommendations.

The primary objective of this study is to provide a overview of reviews with framework-based narrative synthesis and critical evaluation of the existing secondary literature on psychedelic-assisted interventions in palliative care and serious illness. Specifically, this overview aimed to identify, synthesize, and appraise published narrative reviews, systematic reviews, and scoping reviews that summarize the current evidence on psychedelic-assisted therapy (PAT) for psychological, existential, and symptom-related outcomes in patients with life-limiting conditions.

A secondary objective is to examine the extent to which recently proposed best-practice recommendations for psychedelic-assisted therapy in palliative care—formulated through an international interdisciplinary workshop—are explicitly addressed, integrated, or operationalized within these reviews. By mapping the convergence and divergence between the synthesized evidence and emerging consensus-based guidance, this study sought to clarify how well current knowledge synthesis reflects evolving standards for ethical, clinical, and methodological best practice in this field.

A total of 22 studies were included in this overview, all of which were considered eligible according to the previously defined criteria. These studies comprised narrative reviews, systematic reviews, scoping reviews, and meta-analyses addressing psychedelic-assisted interventions in palliative care and in populations with serious and potentially life-limiting illnesses.

Table 1 presents a summary of the main characteristics of the included studies, including authors, year of publication, review type, psychedelics addressed, population or clinical context, number of included studies, and outcomes analyzed. Detailed information on additional variables, including main findings, safety, relevance to palliative care, and reported methodological limitations, is provided in the Supplementary Materials (Table S4).

Regarding the psychedelics addressed, most reviews focused on psilocybin, either alone or in combination with other classic psychedelics such as LSD and ayahuasca (DMT/MAOIs). A relevant subset of studies also included MDMA and ketamine or esketamine, either as atypical psychedelic interventions or within the context of dissociative-assisted psychotherapy. Several reviews adopted a cross-cutting approach, analyzing more than one substance, while others focused on a single compound or a specific therapeutic model.

The clinical outcomes most frequently examined included depression, anxiety, existential distress, quality of life, spiritual well-being, demoralization, and attitudes toward death. In many studies, these outcomes were discussed jointly, reflecting a multidimensional understanding of suffering in the context of serious illness. Issues related to safety and tolerability were also addressed in the majority of reviews, although generally in a descriptive manner, based on reports from the primary studies included.

When mapping the content of the reviews according to the analytical framework adopted in this study, the incorporation of the different domains proved to be heterogeneous. Domains such as clinical indications, psychological and existential outcomes, and general description of the intervention model were widely addressed in most reviews. Conversely, other core elements of the framework—such as length of therapy, preparation and integration processes, mystical-type experiences, integration with palliative care models, family and relational issues, clinical training and competencies, and ethical and organizational aspects—were addressed variably and, in many cases, only partially or were absent (Table 2). Table 2 presents the domain-level classification for each included study according to the extent of coverage, categorized as “Explicit”, “Partial”, or “Absent”. Detailed data extraction supporting these classifications is provided in the Supplementary Materials (Table S5).

Overall, relatively few reviews explicitly operationalized these domains as formal analytical criteria. Instead, many elements of the framework appeared vaguely throughout the narratives, without systematic structure or comparative evaluation across the reviewed studies. This variability limited direct comparison between reviews regarding the degree of adherence to emerging recommendations for the practice of psychedelic-assisted therapies in palliative care.

Figure 2 graphically illustrates the frequency with which the included studies addressed each of the framework domains, highlighting how many reviews explicitly, partially, or did not address each component. Accordingly, domains related to clinical indications and outcomes were the most frequently reported, whereas aspects such as integration within palliative care systems, professional training, biographical dynamics, and family issues were less consistently addressed.

Taken together, the results indicate that the 22 included reviews report preliminary evidence regarding psychedelic-assisted interventions in contexts of serious illness, with consistent signals of potential clinical benefit. Nevertheless, the framework-based analysis reveals a partial and uneven incorporation of components considered essential for responsible clinical practice, underscoring the importance of analyses that extend beyond efficacy and safety to also encompass processes, context, and integration with the principles of palliative care.

This overview of reviews with framework-based narrative synthesis sought to synthesize the current state of secondary evidence on psychedelic-assisted interventions in palliative care, while examining the extent to which this body of literature engages with emerging best-practice recommendations. Overall, the findings suggest a field characterized by promising but methodologically constrained evidence, alongside a partial and uneven incorporation of normative clinical frameworks.

Across the included reviews, there is a relatively consistent signal that psychedelic-assisted therapies—particularly those involving psilocybin—may contribute to meaningful reductions in depression, anxiety, and existential distress among patients with serious illness. Improvements in spiritual well-being, sense of meaning, and death acceptance were also frequently reported, often in association with the intensity or significance of subjective or “mystical-type” experiences. These findings align with earlier primary studies suggesting that the therapeutic effects of psychedelics may be mediated less by direct symptom suppression and more by transformative experiential processes [36,37,38,39,40,41].

Importantly, these benefits were not limited to narrowly defined psychiatric outcomes but extended to broader domains central to palliative care, including quality of life, psychosocial functioning, and relational dimensions of suffering. Such multidimensional effects resonate with the concept of “total pain” [42] and seem to support the hypothesis that psychedelic-assisted interventions may uniquely address the intertwined psychological, existential, and spiritual dimensions of serious illness [43,44].

However, it is equally important to emphasize that these findings derive largely from small, highly controlled clinical trials, often conducted in specialized research environments with carefully selected participants. As such, the observed therapeutic signal should be interpreted as preliminary and context-dependent, rather than definitive evidence of effectiveness in real-world palliative care settings.

The overview highlights several well-recognized but still unresolved methodological challenges in psychedelic research [9,45]. First, functional unblinding remains a pervasive issue, as the subjective effects of psychedelics make it difficult to maintain masking, potentially inflating expectancy effects and outcome estimates [46]. Second, the consistent use of multicomponent interventions—combining pharmacological administration with structured preparation, therapeutic support, and integration—renders it difficult to disentangle the specific contribution of the psychedelic compound from that of the surrounding psychotherapeutic and environmental context [47].

In addition, the evidence base is marked by substantial heterogeneity in dosing regimens, number of sessions, therapeutic models, and outcome measures, limiting comparability across studies and complicating efforts at synthesis. The absence of large-scale, multicenter phase III trials further constrains the robustness of current conclusions, while the lack of head-to-head comparisons between different compounds or active comparators leaves important clinical questions unanswered.

A particularly salient limitation concerns the limited representativeness of study populations. Most trials have been conducted in high-income countries, often with predominantly white, relatively well-resourced participants. This raises concerns regarding the generalizability and equity of findings, especially in the context of palliative care, where patients frequently present with multimorbidity, frailty, and complex psychosocial needs. Data on drug–drug interactions, long-term safety, and outcomes in more medically vulnerable populations remain notably scarce [48,49,50].

A central aim of this overview was to examine whether existing reviews engage with the emerging consensus on best practices for psychedelic-assisted therapy, as articulated in recent international workshop recommendations. The analysis suggests that while many reviews implicitly acknowledge key elements—such as the importance of preparation, therapeutic support, and integration—there is limited systematic engagement with these domains as structured evaluative frameworks [16,28,30,31,32,33,35].

Core components emphasized by the workshop, including patient selection criteria, clinician training and competencies, ethical safeguards, and integration within palliative care systems, are often addressed only superficially or inconsistently in the review literature [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. In particular, domains such as ethical governance, management of patient vulnerability, and alignment with palliative care principles remain underdeveloped in many syntheses, which tend to focus more narrowly on efficacy outcomes [16,28,32,33].

Moreover, few reviews explicitly conceptualize psychedelic-assisted therapy as a complex intervention embedded within a broader care model, as opposed to a discrete pharmacological treatment [19,20,21,32]. This conceptual gap may contribute to disproportionate emphasis on outcome metrics at the expense of process variables, such as therapeutic alliance, experiential depth, and integration practices, which are increasingly recognized as central to clinical effectiveness.

Taken together, these findings suggest that psychedelic-assisted interventions in palliative care should be understood not simply as novel therapeutics, but as multidimensional care processes that intersect with foundational questions of meaning, identity, and relationality at the end of life. This positions PAT within a domain that is both clinically promising and ethically complex, requiring careful integration into existing models of care.

From a clinical perspective, the preliminary evidence indicates a signal of benefit regarding the potential of these interventions to address otherwise refractory forms of suffering, particularly those related to existential distress. However, this potential must be balanced against the current limitations of the evidence base and the need for robust safeguards in vulnerable populations [9,23].

From a conceptual perspective, the field may benefit from moving beyond narrowly reductive efficacy paradigms toward frameworks that account for context, embodiment, and relational dynamics. Such an approach would be more consistent with both palliative care philosophy and contemporary models of psychedelic therapy, which emphasize the co-constitutive roles of drug, set, and setting [51].

Future research should prioritize: large, multicenter trials with more diverse and clinically representative populations; greater standardization of intervention protocols and outcome measures; explicit investigation of mechanisms of action, including the role of subjective experience and therapeutic context; systematic evaluation of safety, drug interactions, and long-term outcomes in palliative populations.

In parallel, there is a need for greater integration of normative frameworks, such as those proposed by international expert consensus, into both primary studies and evidence syntheses. This includes developing operational criteria for best practice, which can guide not only clinical implementation but also the design and evaluation of future research.

From an implementation science perspective, future research on psychedelic-assisted therapy (PAT) in palliative care may benefit from conceptualizing these interventions not merely as pharmacological treatments, but as complex, multicomponent models of care delivery. Similar to care bundles and structured clinical pathways developed in other high-risk healthcare settings, PAT involves the coordinated interaction of multiple interdependent elements, including therapeutic setting, preparatory and integration processes, multidisciplinary team coordination, clinician competencies, safety monitoring, and ethical governance structures [10]. Recent literature on care bundle development in clinical risk management has emphasized the importance of evidence-based pathway design, multidisciplinary consensus-building, implementation feasibility, fidelity monitoring, and continuous evaluation mechanisms as core dimensions of clinically governable interventions [52]. In this context, implementation science frameworks such as the Consolidated Framework for Implementation Research (CFIR) may offer useful conceptual tools for assessing implementation readiness, organizational preparedness, workforce training requirements, institutional culture, and barriers to sustainable integration of PAT within palliative care systems [53]. Such an approach may be particularly relevant given that psychedelic-assisted interventions require competency-based delivery models, interdisciplinary collaboration, integration of spiritual and psychosocial dimensions of care, continuity across preparation-treatment-integration phases, and clear referral and follow-up systems [10]. Accordingly, future translational research should move beyond efficacy-oriented paradigms alone and also investigate how PAT can be operationalized through reproducible, ethically accountable, and clinically monitorable models of care within real-world palliative care settings.

This overview is subject to limitations inherent to narrative syntheses of secondary literature. Although systematic search strategies were employed, the analysis remains dependent on the scope and quality of existing reviews, which themselves vary in methodological rigor. Furthermore, given the substantial overlap of primary studies across reviews, findings should not be interpreted as independent replication. In addition, the interpretation of alignment with workshop recommendations necessarily involves a degree of conceptual judgment, as these recommendations are not always operationalized in ways that lend themselves to straightforward comparison.

The current body of review literature on psychedelic-assisted interventions in palliative care provides encouraging but incomplete evidence of therapeutic potential. While clinical signals of efficacy seem to be supported across multiple domains of suffering, they are tempered by significant methodological and contextual limitations. At the same time, the partial incorporation of emerging best-practice recommendations highlights a gap between evidence synthesis and normative clinical guidance.

Although the literature reviewed suggests preliminary therapeutic potential under highly controlled research 22 conditions, current evidence remains insufficient to support broad clinical implementation. Bridging this gap will be essential for the responsible development of the field.