Intranasal Ketamine Reduces Existential Distress in Advanced Cancer Patients

Addressing Existential Suffering in Advanced Malignancy

Patients with advanced cancer frequently experience a complex interplay of depression, anxiety, and existential suffering that significantly impairs their remaining quality of life [1]. While traditional antidepressants remain the standard of care, their therapeutic lag of several weeks often exceeds the life expectancy of patients in palliative settings [2, 3]. This clinical gap has spurred interest in rapidly acting agents that might address the spiritual and existential dimensions of end-of-life distress [4, 5]. Recent systematic reviews suggest these compounds can modulate the psychological response to terminal illness by facilitating shifts in perspective, though evidence in specific palliative populations remains limited [6, 7]. A new study evaluates whether a common anesthetic, delivered intranasally, can specifically alleviate the existential burden associated with advanced malignancy.

Secondary Analysis of the INKeD-PC Trial

Depression and existential distress are highly prevalent among patients with advanced cancer, often complicating end-of-life care and reducing functional status. While there is growing evidence for ketamine as a rapidly acting antidepressant in this population, few studies have specifically examined existential distress outcomes following treatment. The Intranasal Ketamine for Depression in Palliative Care (INKeD-PC) trial previously demonstrated the efficacy of intranasal racemic ketamine, a formulation containing equal parts of the R and S enantiomers of the molecule, for depression in patients receiving palliative care. This current analysis reports on secondary trial outcomes from that study, focusing specifically on measures of existential distress and quality of life. The analysis included 15 trial participants who received three doses of intranasal racemic ketamine and completed all primary and secondary endpoint assessments. The researchers utilized the Montgomery-Åsberg Depression Rating Scale (MADRS) as the primary endpoint measure to track depressive symptom severity. To capture a multidimensional view of patient suffering, the study employed a comprehensive battery of secondary measures. These included the Patient Health Questionnaire-9 (PHQ-9) for depression and the Generalized Anxiety Disorders-7 (GAD-7) for anxiety. Physical and psychological symptom burdens were tracked using the Edmonton Symptom Assessment System-revised (ESAS-r), a tool that allows patients to self-report the intensity of nine common symptoms such as pain, nausea, and fatigue. Broader quality of life was measured via the McGill Quality of Life Questionnaire (MQOL), which includes a specific subscale for existential well-being. To specifically address the burden of terminal illness, the researchers used the Death and Dying Distress Scale (DADDS), a validated instrument designed to quantify concerns regarding the process of dying and the end of life. Qualitative comments from participants were also integrated into the analysis to provide context and support for the quantitative findings across these various clinical scales.

Quantifying Improvements in Death-Related Anxiety

The researchers observed that improvements across all secondary outcome measures exceeded established minimal clinically important differences (MCIDs), which represent the smallest change in a treatment outcome that a patient identifies as meaningful. This finding suggests that the statistical shifts observed in the study correspond to perceptible relief for patients facing terminal illness. Specifically, the Generalized Anxiety Disorders-7 (GAD-7) scores showed a substantial reduction in anxiety symptoms with a large effect size of d = 1.22 (p = 0.004). Similarly, the Edmonton Symptom Assessment System-revised (ESAS-r) demonstrated a significant improvement with an effect size of d = 1.21 (p = 0.003). The impact of the three doses of intranasal ketamine on death-related distress and overall quality of life was equally pronounced. Scores on the Death and Dying Distress Scale (DADDS) improved with an effect size of d = 0.91 (p = 0.003), indicating a significant reduction in the specific anxieties associated with the process of dying. The McGill Quality of Life Questionnaire (MQOL) showed the largest overall improvement in the study with an effect size of d = 1.53 (p = 0.004). Within this broader quality of life assessment, the MQOL Existential Well-Being factor specifically improved with an effect size of d = 1.02 (p = 0.015). This subscale measures a patient's sense of purpose and meaning, suggesting that the intervention addressed the core components of existential suffering in the context of advanced cancer.

Independence from Antidepressant Effects

A critical finding of the analysis was the statistical independence of existential relief from changes in depressive symptom severity. The researchers found that correlations between changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) and secondary outcomes were not significant. This lack of correlation suggests that the observed reductions in death-related anxiety and improvements in quality of life were not merely secondary effects of a lifting mood. Instead, the data indicate that intranasal ketamine may exert a direct effect on existential suffering that is distinct from its known antidepressant mechanisms. For the clinician, this implies that even patients who do not meet the full criteria for a clinical response to depression may still derive significant benefit regarding their existential distress. The study further delineated the impact of the intervention by comparing different symptom domains. The researchers observed that subscales related to psychological symptoms improved more than physical symptoms across the various assessment tools. This was particularly evident in the McGill Quality of Life Questionnaire (MQOL), where the psychological and existential domains showed more robust shifts than the physical subscale. These findings suggest that the three doses of intranasal racemic ketamine specifically target the cognitive and emotional burden of terminal illness. Consequently, intranasal ketamine was associated with clinically meaningful improvements in existential distress in individuals with advanced cancer being treated for depression, providing a measurable reduction in the psychological morbidity often seen in the final stages of life. Given the broad efficacy observed across multiple scales, including the Generalized Anxiety Disorders-7 (effect size d = 1.22, p = 0.004) and the Death and Dying Distress Scale (effect size d = 0.91, p = 0.003), the researchers conclude that ketamine may have relevance as a single agent for multidimensional distress in palliative care. In a clinical setting where patients often face a complex cluster of symptoms including anxiety, depression, and loss of meaning, the ability of a single medication to address these diverse facets of suffering offers a highly practical tool for palliative care physicians.

References

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