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Introduction: Psilocybin-assisted therapy (PAT) has gained traction in palliative care as a treatment for existential distress in the last decade. Patients with brain cancer have been excluded from studies, yet they stand to benefit as much as other patients with cancer-related psychological distress. Case description: In this report, we discuss the case of a patient with end-of-life distress secondary to stage 4 astrocytoma that received PAT through Health Canada's Special Access Program. The patient had a positive response to PAT without adverse events. Discussion: Standard treatment for existential distress is often inefficacious and PAT is rarely available, especially for patients with brain cancer. We highlight the importance of making PAT more available as many patients with unresolved existential distress resort to medical assistance in dying without ever knowing of the existence of PAT. Conclusion: PAT was effective in partially alleviating the patient's existential distress. Access to PAT needs to be expanded urgently.

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CONTEXT: Death anxiety is associated with fears of suffering and uncertainty at the end of life. It is also relevant to patients' family caregivers, who can experience fears about the patients' death and dying. OBJECTIVES: This study investigates the prevalence of death anxiety in advanced cancer patients and their family caregivers and its association with sociodemographic and medical characteristics. METHODS: We recruited patients with UICC stage IV solid tumors from in- and outpatient oncology and palliative care settings. We administered the Death and Dying Distress Scale to assess clinically significant death anxiety. We analyzed its association with sociodemographic and medical characteristics using simultaneous multiple linear regression analyses. RESULTS: Death anxiety was prevalent in 37% of patients (N = 481) and 75% of family caregivers (N = 140). Most frequent death anxiety concerns were "feeling distressed about the impact of one's own death on loved ones" (52% of patients) and "feeling distressed about running out of time with their loved one" (69% of family caregivers). Patients who experienced high death anxiety were more likely to be younger (standardized ß = -0.1; P=0.005) and have known about their diagnosis for less time (standardized ß = -0.1; P=0.046). Being female predicted higher death anxiety in patients (ß = 0.12; P=0.041) and family caregivers (ß = 0.32; P=0.002). CONCLUSION: The results indicate that death anxiety is a common, clinically significant problem in patients with advanced cancer and their family caregivers, emphasizing the need for targeted psychological support.

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Existential distress is commonly experienced by patients diagnosed with a life-threatening illness. This condition has been shown to adversely impact quality of life and is correlated with increased suicidal ideation and requests for hastened death. While palliative care teams are experienced in treating depression and anxiety, existential distress is a distinct clinical condition for which traditional medications and psychotherapy approaches demonstrate limited efficacy or duration of effect. Psychedelic drugs, including psilocybin and lysergic acid diethylamide (LSD), in conjunction with psychotherapy have been shown to produce rapid and sustained reductions in existential and psychiatric distress and may be a promising treatment for patients facing existential distress in palliative care settings. In this narrative review article, we describe the history of psychedelic medicine including early studies and the modern wave of research over the past 20 years, which includes high quality clinical trial data. This review outlines specific considerations for therapeutic application of psilocybin including pharmacokinetics, patient selection, dosing, protocol designs, and safeguards to reduce potential adverse effects to help guide future psychedelic practitioners. With growing public interest and evolving state level policy reforms allowing access to psychedelic treatments, it is critical for palliative care providers to gain familiarity with the current state of science and the potential of psilocybin assisted psychotherapy in the treatment of existential distress.

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Introduction: Patients with incurable illnesses often experience existential distress, profoundly impacting their well-being. Current medical approaches have limitations in addressing these burdens. Psilocybin, a promising psychedelic compound, may offer therapeutic benefits. This pilot survey study aimed to investigate the attitudes and openness toward psilocybin-assisted psychotherapy (PAT) among patients with incurable illnesses. The objective is to assess patients' attitudes toward PAT and identify potential barriers and concerns, including exploring the association between beliefs in psilocybin's therapeutic benefits and interest in receiving this treatment. Methods: The survey study was conducted at the Tampa General Hospital Palliative Care Outpatient office in the United States. Participants were 32 English-fluent patients, aged 18 or older, with incurable illnesses. The survey included demographic questions, a validated tool to measure existential distress, and questions about knowledge and concerns regarding psilocybin. Attitudes toward PAT and interest in its future use were assessed using Likert scale responses. Results: Among the 31 analyzed participants, 51.6% expressed interest in future psilocybin treatment, while 32.3% did not indicate interest. Belief in the psilocybin's therapeutic benefits for stress and anxiety significantly correlated with interest in use. Concerns included risk of psychosis, lack of trained providers, and potential for exploitation. No demographic factors were associated with interest or levels of distress. Conclusions: This pilot study provides insights into the attitudes and concerns toward PAT among patients with incurable illnesses. Over half of participants expressed interest. However, concerns regarding its use were identified, with patients' concern for the risk of exploitation associated with PAT as an especially novel concern documented in this patient population. This highlighted the need for further education of risks and benefits or PAT by trained clinicians and rigorous training of clinicians with the establishment of safeguards against exploitation. Further research is necessary to explore the potential benefits of PAT and related non-psilocybin psychedelic compounds in addressing existential distress among patients with incurable illnesses.

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BACKGROUND: Psychological and existential suffering affects many people with advanced illness, and current therapeutic options have limited effectiveness. Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective therapy for refractory depression, but no previous study has used rTMS to treat psychological or existential distress in the palliative setting. AIM: To determine whether a 5-day course of "accelerated" rTMS is feasible and can improve psychological and/or existential distress in a palliative care setting. DESIGN: Open-label, single arm, feasibility, and preliminary efficacy study of intermittent theta-burst stimulation to the left dorsolateral prefrontal cortex, 600 pulses/session, 8 sessions/day (once per hour) for 5 days. The outcomes were the rates of recruitment, completion of intervention, and follow-up (Feasibility); and the proportion of participants achieving 50% improvement on the Hamilton Depression Rating Scale (HDRS) or Hospital Anxiety and Depression Scale (HADS) 2 weeks post-treatment (Preliminary Efficacy). SETTING/PARTICIPANTS: Adults admitted to our academic Palliative Care Unit with advanced illness, life expectancy >1 month and psychological distress. RESULTS: Due to COVID-19 pandemic-related interruptions, a total of nine participants were enrolled between August 2021 and April 2023. Two withdrew before starting rTMS, one stopped due to clinical deterioration unrelated to rTMS, and six completed the rTMS treatment. Five of six participants had a >50% improvement in HDRS, HADS-Anxiety, or both between baseline and the 2 week follow up; the sixth died prior to the 2-week follow-up. In this small sample, mean depression scores decreased from baseline to 2 weeks post-treatment (HDRS 18 vs 7, p = 0.03). Side effects of rTMS included transient mild scalp discomfort. CONCLUSIONS: Accelerated rTMS improved symptoms of depression, anxiety, or both in this small feasibility and preliminary efficacy study. A larger, sham-controlled study is warranted to determine whether rTMS could be an effective, acceptable, and scalable treatment in the palliative setting. TRIAL REGISTRATION: NCT04257227.

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BACKGROUND: Advanced cancer patients often experience existential distress (ED). However, the factors associated with ED remain unclear. This study investigated the current state of ED and identified the associated factors in Chinese patients with advanced cancer. METHODS: A cross-sectional study was conducted among 352 advanced cancer patients from 3 tertiary hospitals in Fujian, China. Participants were invited to complete the Existential Distress Scale, Number Rating Scale, Self-Perceived Burden Scale, Quality of Life Concerns in the End-of-Life Questionnaire, and Hospital Anxiety and Depression Scale. OBJECTIVES: This study aimed to investigate the level of existential distress among advanced cancer patients in China and identify the associated factors. RESULTS: A total of 352 advanced cancer patients were recruited for this study. The average score for ED was 8.48 ± 7.12 among the advanced cancer patients. Multiple regression showed that the associated factors included depression (ß = 0.32, p = 0.000), self-perceived burden (SPB) (ß = 0.18, p = 0.001), the presence of a spouse (ß = -0.10, p = 0.050), and reception of government subsidies (ß = 0.17, p = 0.001). The factors accounted for 30.1% of the total variance in ED (F = 8.472, p < 0.001). SIGNIFICANCE OF RESULTS: Among the advanced cancer patients queried, ED was found to be positively influenced by depression, SPB, and reception of government subsidies and negatively influenced by the presence of a spouse. Depression was the most important risk factor, and thus future ED interventions should target depression.

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OBJECTIVES: Existential guilt is a deep and multidimensional concept that is correlated with concepts, such as in/authenticity, existential anxiety, decisiveness, and personal and social responsibility. The aim of the present study is to investigate the experience of existential guilt among cancer patients. METHODS: The present research was conducted with a qualitative method with a content analysis design. A purposeful sampling method was used to select the participants and the sampling procedure went on until we reached data saturation. Data were obtained using semi-structured interviews with the participants. RESULTS: From a total of 18 interviews, 94 codes related to existential guilt were obtained. After the analysis, three main concepts were extracted: (1) incompleteness, (2) passivity, and (3) feelings of harm to self and others. Each of these had a number of subcategories. SIGNIFICANCE OF RESULTS: The participants of the present research were found to experience existential guilt in different ways. The research showed that it is necessary to find the sources of existential guilt in order that effective therapeutic attention can be given cancer patients.

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Psychological distress at the end of life is a common experience that lacks effective treatments. This is in part due to the multidimensional nature of psychological distress at the end of life, encompassing an interplay between psychosocial and existential distress as well as physical symptom burden. Research shows that psychedelic-assisted therapy is an effective treatment of end of life distress. Ketamine and cannabis may help with quick and effective treatment of symptom burden at the end of life. Although these novel interventions show promise, further data is needed, particularly in elderly populations.

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Background: There is ongoing debate on whether continuous deep sedation (CDS) for psycho-existential suffering is appropriate. Objective: We aimed to (1) clarify clinical practice of CDS for psycho-existential suffering and (2) assess its impact on patients' survival. Methods: Advanced cancer patients admitted to 23 palliative care units in 2017 were consecutively enrolled. We compared patients' characteristics, CDS practices, and survival between those receiving CDS for psycho-existential suffering ± physical symptoms and only for physical symptoms. Results: Of 164 patients analyzed, 14 (8.5%) received CDS for psycho-existential suffering ± physical symptoms and only one of them (0.6%) solely for psycho-existential suffering. Patients receiving CDS for psycho-existential suffering, compared with those only for physical symptoms, were likely to have no specific religion (p = 0.025), and desired (78.6% vs. 22.0%, respectively; p < 0.001) and requested a hastened death more frequently (57.1% vs. 10.0%, respectively; p < 0.001). All of them had a poor physical condition with limited estimated survival, and mostly (71%) received intermittent sedation before CDS. CDS for psycho-existential suffering caused greater physicians' discomfort (p = 0.037), and lasted for longer (p = 0.029). Dependency, loss of autonomy, and hopelessness were common reasons for psycho-existential suffering that required CDS. The survival time after CDS initiation was longer in patients receiving it for psycho-existential suffering (log-rank, p = 0.021). Conclusion: CDS was applied to patients who suffered from psycho-existential suffering, which often associated with desire or request for a hastened death. Further studies and debate are warranted to develop feasible treatment strategies for psycho-existential suffering.

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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.

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The author, an internist and psychiatrist who works with intensive care unit (ICU) patients, offers reflections and clinical insights on implementing a psychodynamic framework when treating survivors of critical illness. In this short essay, contributions from the critical care and psychoanalytic literature are included to highlight the significance of post-intensive care syndrome (PICS) and the psychodynamic considerations that might enhance the treatment of this patient population.

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OBJECTIVE: To synthesize the scientific findings on demoralization and spirituality in the oncology context. METHODS: This is an integrative systematic review, in line with the PRISMA 2020 guidelines, as proposed by Whittemore and Knalf (2005). The MEDLINE via PubMed, Scopus, Web of Science, APA PsycNet, CINAHL, Cochrane Library, EMBASE, and LILACS databases were searched without limitations regarding language or year of publication. The studies were screened for inclusion according to the predefined eligibility criteria. Data extraction and evidence quality assessment were performed. RESULTS: Out of the 1587 articles evaluated, 10 studies were included in this review. In general, it was found that demoralization tends to increase with the proximity of death and seems to be inversely related to spirituality, with spiritual well-being being a protective factor against demoralization, while the non-fulfillment of spiritual needs is related to increased demoralization in people with cancer. Furthermore, even among caregivers of people with advanced cancer, demoralization seems to be associated, among other factors, with spiritual suffering. These results should be analyzed with caution, considering that the studies included in this review are all observational studies, which prevents establishing cause and effect relationships. CONCLUSIONS: Demoralization tends to increase with growing frailty and the proximity of death in people with cancer, and it seems to be inversely related to spirituality, both in these patients and in their caregivers.

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Chronic pain is a leading cause of disability, reduced productivity, healthcare seeking behavior, and a contributor to opioid overdose in the United States. For many people, pain can be satisfactorily managed by existing medicines and comprehensive psychosocial treatments. For others, available treatments are either ineffective or not acceptable, due to side effects and concerns about risks. Preliminary evidence suggests that some psychedelics may be effective for certain types of pain and/or improved quality of life with increased functionality and reduced disability and distress in people whose pain may never be completely relieved. Efficacy in these quality-of-life related outcomes would be consistent with the 'reset in thinking' about chronic pain management being increasingly called for as a more realistic goal for some people as compared to complete elimination of pain. This commentary summarizes the rationale for conducting more basic research and clinical trials to further explore the potential for psychedelics in chronic pain management. Additionally, if shown to be effective, to then determine whether the effects of psychedelics are primarily due to direct antinociceptive or anti-inflammatory mechanisms, or via increased tolerability, acceptance, and sense of spirituality, that appear to at least partially mediate the therapeutic effects of psychedelics observed in psychiatric disorders such as major depression. This commentary represents a collaboration of clinical and more basic scientists examining these issues and developing recommendations for research ranging from neuropharmacology to the biopsychosocial treatment factors that appear to be as important in pain management as in depression and other disorders in which psychedelic medicines are under development. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".

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In the setting of major disease progression coupled with active pain, hospitalized patients may become disconnected from their metanarratives and personal grounding. Transdisciplinary palliative care teams are poised to foster patients' connection with their metanarratives by collaborating across areas of expertise to establish goals of care and manage total pain. This case study demonstrates: (1) the unique value of the palliative Chaplain in journeying with the patient through existential distress towards self-discovery, and (2) the role of the palliative chaplain in encouraging a transdisciplinary approach to total pain within a palliative care team.

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OBJECTIVES: The current study explored the impact of cancer-related fertility concerns on existential distress and meaning making among female breast cancer (BC) patients of childbearing age and assessed support needs. METHODS: The current study was embedded within a larger study. A seven-question online survey was administered to female BC participants to explore meaning and identity in their lives. Applied thematic analysis was used to analyze participants' written responses. RESULTS: A total of 98 participants completed the survey, the majority of whom identified as white, married or partnered, and employed full time and with stage I or II BC. More than 50% of the participants expressed a need for support from a counselor or support group during their cancer experience. Three subthemes emerged related to existential distress and cancer-related fertility concerns: (1) loss of womanhood: treatment-related physical changes impact on gender identity; (2) existential distress due to treatment decisions impacting fertility; and (3) shattered vision: cancer-related infertility impact on meaning and purpose. Four subthemes emerged related to meaning making with fertility-related existential concerns: (1) coping with loss of meaning, (2) re-evaluating priorities in life; (3) resilience to loss, and (4) persistent loss of meaning. SIGNIFICANCE OF RESULTS: Study results offer valuable insights into the experiences of female BC survivors' cancer-related fertility on existential distress and meaning making. Development of psychological interventions targeted to support this population to cope with existential distress due to cancer-related fertility concerns and meaning making are needed to improve the quality of life of this population.

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OBJECTIVES: A resurgence of research investigating the administration of psychedelic compounds alongside psychotherapy suggests that this treatment is a promising intervention for anxiety, depression, and existential distress in people with cancer. However, psychedelic treatment that induces a mind-altering experience potentially poses barriers to vulnerable cancer patients, and health-care practitioners may have concerns about referring their patients to trials investigating this approach. The aim of the current study was to investigate the perceptions of cancer health-care practitioners based in New Zealand and the USA related to psychedelic-assisted therapy. METHODS: This study utilized a cross-sectional survey of cancer health-care practitioners in New Zealand and the USA via convenience sampling to identify their perceptions about the concept of conducting psychedelic-assisted therapy with cancer patients. RESULTS: Participants perceived that (1) psychedelic-assisted therapy has the potential to provide benefit for cancer patients, (2) research in this area across a variety of domains is important, (3) work should consider spiritual and indigenous perspectives of health, and (4) there was willingness to refer patients to trials in this area, especially patients with advanced disease who were no longer going through curative treatment. Participants in the USA had greater awareness of psychedelics than the New Zealand sample; however, New Zealand participants more strongly believed that spiritual/indigenous factors should be considered in psychedelic-assisted therapy. SIGNIFICANCE OF RESULTS: Cancer health-care practitioners in our sample considered research investigating the potential for psychedelic-assisted therapies to be important and may be more open to studies that start in palliative and end-of-life contexts.

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Anxiety associated with life-threatening illness (LTI) is a pervasive mental health issue with a wide impact. A spectrum of traditional pharmacotherapies and psychotherapies are available, but offer varying success in reducing symptoms and improving quality of life. We explore a novel therapy for this condition by assessing prominent thematic elements from participant narrative accounts of a pilot phase 2 clinical trial of 3,4 Methylenedioxymethamphetamine-Assisted Therapy (MDMA-AT) for treating anxiety associated with LTI. Semi-structured qualitative interviews were conducted with a subset of adult participants 3 months following completion of this trial. This qualitative analysis sought to complement, clarify, and expand upon the quantitative findings obtained from the clinical trial to further understand the process and outcomes of the treatment. Interviews were coded and analyzed using an Interpretative Phenomenological Analysis (IPA) methodological framework. Participants described in detail their experiences from before, during and after the trial, which were analyzed and categorized into thematic clusters. Specifically, participants explored what they felt were important elements of the therapeutic process including processing trauma and grief, exploring mystical and existential experiences, engaging with the present moment with reduced physiological activation, and facing illness and existential fears. Outcomes of the treatment included increased ability to cope with LTI, reduced psychological symptoms, improved vitality and quality of life, and feeling more resourced. Participant narratives also showed a reconnection to life and greater emotional resilience in response to trauma and medical relapse. These findings are compared to similar treatments for the same indication. Limitations and challenges encountered in conducting this study are discussed along with implications for theory and clinical treatment.

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BACKGROUND: Self-perceived burden (SPB) is an important predictor of quality of life (QoL) in patients with advanced cancer. However, the mechanism how SPB affects patients' QoL remains unclear. This study aimed to examine the potential mediating roles of existential distress (ED) and anxiety in the relationship between SPB and QoL. METHODS: A multicenter cross-sectional study was conducted. 352 advanced cancer patients were recruited from three hospitals in southeast of China. The Self-perceived Burden Scale, the Existential Distress Scale, the Hospital Anxiety and Depression Scale, and the Quality-of-Life Concerns in the End of Life Questionnaire were adopted to collect data. Hayes's bootstrapping method was used to analyze the data. RESULTS: SPB was negatively associated with QoL (P < 0.01). ED and anxiety partially mediated the relationship between SPB and QoL (P < 0.01). Moreover, ED had direct effects on anxiety, and sequentially QoL (P < 0.01). The serial multiple mediation model of SPB accounted for 73.25% of the variance in QoL in advanced cancer patients. CONCLUSIONS: ED and anxiety are important mediating factors between SPB and QoL in advanced cancer patients. To improve patients' QoL, comprehensive interventions for reducing anxiety and ED are highly recommended in clinical practices.

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Psychiatric and existential distress commonly occur in advanced cancer and other serious, life-threatening or end-of-life medical illnesses and are associated with poor medical and psychiatric outcomes. Currently available treatment modalities in this patient population, including medication and psychotherapy, are limited in effectiveness, especially regarding existential distress. The lack of effective psycho-spiritual interventions is a critical shortcoming in palliative care and represents a high unmet need in medicine. In this commentary, we review the rationale of researching and developing psychedelic-assisted psychotherapy as a novel pharmacologic-psychotherapeutic intervention to treat psychiatric and existential distress in life-threatening medical conditions and palliative care. This paper reviews efficacy data from first and second waves of psychedelic research, and future directions for research and implementation science. More rigorous research, especially funded by governments, is needed to assess effectiveness and mechanisms of action of psychedelic therapies to treat psychiatric and existential distress in life-threatening medical illnesses and palliative care. If psychedelic-assisted treatments were made available as approved and prescribable medications in people with serious medical illnesses, it could be a significant development that opens up a pathway for clinical dissemination and public health impact internationally.

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