Although the current model of palliative care has significantly improved the quality of life in patients with serious illness, pharmacologic interventions for psychological distress at the end of life remain limited despite it being among the most debilitating symptoms in palliative patients. This is largely due to the multidimensional nature of psychological distress in this population, encompassing both physical symptom burden and existential distress. Data surrounding the approved pharmacotherapies used to treat end-of-life distress has shown mixed efficacy.8,9 Therapeutic interven-tions such as meaning-centered psychotherapy and dignity therapy have been found to be effective in addressing psychological distress at the end of life, centered around evidence supporting the notion that existential distress is grounded in loss of meaning in one's life; however, manualized therapies often take time, and there remains a need for quick and effective pharmacologic interventions.12,38 PAT offers a novel tool to accentuate the therapeutic process of creating meaning amid the loss of self (functionality, relationships, identity, and so forth) that inevitably occurs at the end of life.11 Research indicates that existential distress is rooted in is-sues with meaning, purpose, and connection that "lie at the very center of the existen-tial crisis that is terminal illness."6 Current models of palliative care address these needs through a generalist/specialist model that ideally integrates mental health and spiritual care professionals. Yet, in many patients, psychosocial and/or spiritual needs remain under-addressed, and novel therapeutic tools are needed.39 Although the mechanism of action of PAT has yet to be clearly elucidated, data suggests their effi-cacy to be rooted in the cultivation of an altered state of consciousness that may help facilitate the therapeutic process of meaning-making through situational acceptance, reprioritization of values, and recontextualization of the self in light of functional losses.11 As opposed to PAT, the use of ketamine in palliative care has focused on the medi-cation itself, without paired psychotherapeutic processes. The available data supports ketamine as an intervention for quick and effective psychiatric symptom management in a frequently treatment-resistant population, arguably providing the fastest psycho-logical symptom relief as compared with all current interventions. However, the sus-tainability of its effect remains in question. It also remains unclear if and how ketamine's psychoactive properties relate to its therapeutic efficacy and how its pain management abilities play a role in alleviating psychological distress in patients with a high symptom burden. Similarly, some evidence supports a possible role for cannabis as an intervention for quick and effective symptom relief with a favorable side effect profile as compared with the current standard of treatment. However, the current cannabis studies are inconsistent, suggesting mixed efficacy. As such, more rigorous evidence is needed on both ketamine and cannabis in elderly patients in palliative care before supporting adoption into clinical practice. Of note, similar to ketamine, there is emerging discussion of cannabis-assisted psychotherapy within community treatment practices, suggesting a possible role for cannabis augmenting therapy in a manner like PAT. However, there is currently no scientific evidence inves-tigating this model of therapeutic cannabis use as an intervention for psychological distress at the end of life. It is important to note the current contraindications to these therapies despite their promise. All interventions that produce an acute change in consciousness carry a risk of psychosis, and as such, having a personal or family history of schizophrenia -spectrum disorders is a contraindication to use. For PAT and ketamine, a majority of research studies include bipolar in the list of contraindicated diagnoses; however, data is emerging that shows the risk of PAT exacerbating psychosis in patients with a personal or family history of bipolar disorder may be lower than expected.40 Simi-larly, data is also emerging supporting the safety and efficacy of ketamine in treating bipolar depression.41 Conversely, data shows that the use of cannabis with high-THC content may exacerbate the risk of psychosis in predisposed individuals and thus should be avoided in all patients with a personal or family history of psychosis.42 From a medical standpoint, all of the aforementioned pharmacotherapies cause acute increases in blood pressure and heart rate, and as such, careful cardiovascular screening (history, electrocardiogram, stress test) is necessary for individuals with car-diovascular disease.43 Although data surrounding the safety and tolerability of cannabis in the elderly is growing with legalization, there remains a scarcity of data on the safety, acceptability, and tolerability of psychedelics in patients aged older than 65 years, with only a small minority of participants in psychedelic research trials within this age range.44 Given that a majority of serious illness patients fall within this age range, more research is needed before psychedelic-based therapies can be implemented in palliative care. As data continues to emerge, the utility of these novel psychoactive treatment modal-ities for older adults in palliative care will continue to be evaluated; however, the cur-rent data support the potential use of PAT and ketamine as safe and effective interventions in addressing the multidimensional nature of end-of-life distress in elderly patients in palliative care. Although some data supports the potential use of cannabis for symptom relief, the data is mixed, and as such, further research is needed before conclusions can be drawn on its utility in this population.
