Current research

Serious illness represents a significant psychological burden

Feelings of hopelessness, loss of will to live, loss of meaning and sense of dignity, feeling like a burden to others. Sadness and fear. These are symptoms of existential distress (Reiche et al., 2018), which significantly reduces the quality of life of patients and their loved ones. Depression, anxiety, or adjustment disorder occurs in 29% of patients in palliative care and in 38% of patients in cancer and haematology care (Mitchell et al., 2011).

Current treatment options for existential distress are limited

A review and meta-analysis of the efficacy of standard antidepressant pharmacological treatment in early and advanced cancer patients (10 trials, 885 patients) showed no difference between antidepressants of two different classes (SSRIs and TCAs) and placebo (Ostuzzi, Matcham, Dauchy, Barbui, & Hotopf, 2018).

While the authors of an earlier meta-analysis (Rayner et al., 2011) focusing on palliative care (25 studies, 1197 patients with different diagnoses) confirmed a difference in effect between antidepressants and placebo, they add that the result may be overestimated by selective publication bias.

Psychooncological interventions (psychotherapy, counselling, relaxation, and others) have a small to moderate effect on alleviating psychological distress and improving quality of life in cancer patients (198 studies, 22,238 patients) (Faller et al., 2013), but are time-consuming and not widely available.

Research on psychedelic-assisted psychotherapy is yielding promising results

Current research confirms the safety of psychedelics and suggests unprecedented efficacy of psychedelic-assisted psychotherapy in alleviating anxiety and depression in patients in advanced stages of predominantly cancer-related diseases (Reiche et al., 2018).

Three completed studies (double-blind, placebo-controlled) evaluated the effect of a single administration of psilocybin at a dose of 0.2-0.3 mg/kg. The actual administration of the substance was always preceded by 4-6 hours of preparatory sessions and followed by 8-10 hours of so-called integration sessions.

The first study (n=12) was conducted by Charles Grob's team at the University of California Los Angeles (Grob et al., 1999), the next (n=51) was conducted by Roland Griffiths at Johns Hopkins University, Maryland (Griffiths et al., 2016), and the third study (n=29) was conducted by Stephen Ross at New York University (Ross et al., 2016). These studies described a rapid, substantial, and long-lasting effect accompanied by an improvement in quality of life in 60-80% of participating patients even after 6 months of therapy.

Lasting relief of anxiety and depression was evident in 60-80% of surviving patients in the third study even after 4.5 years (n=14). The majority (71-100%) attributed positive changes in quality of life to psilocybin-assisted psychotherapy and ranked it among the most essential and meaningful life experiences (Agin-Liebes et al., 2020).

Additional data analysis (Ross et al., 2021) of this study also found a strong and long-lasting reduction in suicidality lasting six and a half months. Significant was also the reduction in feelings of loss of life meaning, which maintained robustness at the 4.5-year follow-up.

The first modern study evaluating the effect of LSD-assisted psychotherapy on anxiety associated with a life-threatening illness was conducted by Peter Gasser in Switzerland. It confirmed the safety of the method and the long-term reduction of anxiety in 12 participants (Gasser et al., 2014). It was followed by a larger double-blind placebo-controlled clinical trial (Holze et al., 2023). Half of the 42 study participants had cancer or another life-threatening illness. Results showed significant reductions in anxiety, depression and other psychiatric symptoms even after 16 weeks. As part of the specific study design, all participants completed two sessions of LSD and two sessions of placebo, each led by a single therapist.

A pilot open-label study confirmed the feasibility of psilocybin-assisted psychotherapy, its relative safety, and its effect on reducing symptoms of demoralization in 18 patients with long-term AIDS. Here, Brian Anderson's team at UCSF newly tested a group training and integration model (Anderson et al. 2020).

The first double-blind, placebo-controlled trial evaluating the effect of MDMA-assisted psychotherapy on anxiety in seriously ill patients (n=18) was conducted in California, led by Philip Wolfson. The results suggest an alleviation of anxiety and other symptoms associated with life-threatening illness (Wolfson et al., 2020).

Critical evaluation of clinical trials

The authors of a recent detailed review of the use of classical psychedelics, ketamine and MDMA in palliative care (Schimmel et al., 2022) conclude that classical psychedelics such as LSD or psilocybin are well tolerated by patients, typically have only insignificant side effects and show positive effects on depression, anxiety and existential distress and other areas in the short and long term. The evidence for ketamine's efficacy in this type of patient is comparable to the relatively robust evidence for its efficacy against resistant depression. However, the authors also stress the need for larger studies with more advanced methodology.

A second similar review was published around the same time (Maia, Beaussant & Mesquita Garcia, 2022) with virtually identical conclusions. Its authors also stress the need for future research with better methodology to compensate for the methodological shortcomings of past research. They also mention the interconnection between patients' psychological health and the experience of physical pain and the possible potential of psychedelic therapy in this area.

According to Anthony Bossis (Bossis, 2021), a psychologist and professor of psychiatry at New York University, a number of participants describe a reduction in anxiety. Conversely, they experienced more compassion and love for themselves and others after they emotionally turned toward their fears and feelings they harbored about death. Study participants also mentioned gaining new insights. Although the psychedelic experience can be difficult, according to participants' accounts, it led to a greater fullness of living in the present moment.

It is also not entirely clear what context of administration is best for the use of psychedelics in palliative care. Much of the research cited above supports the usefulness of standard practices, but there is some evidence that the administration of psychedelics, specifically ayahuasca, in a ritual context may be also helpful (Maia, Daldegan-Bueno & Tófoli, 2021).

Research on psychedelic-assisted psychotherapy in patients with advanced cancer builds on the findings of studies from the 1950s-1970s that do not meet the requirements of current rigorous methodology. However, we appreciate well-designed case reports and valuable guidelines for therapeutic practice (Kast, 1966; Kast & Collins, 1964; Pahnke et al., 1969; Grof, Goodman, Richards & Kurland, 1973; Richards et al., 1980).

Attitudes towards psychedelics in palliative care vary

The views of those caring for patients with life-threatening illness on the use of psychedelics are complex. According to a recent small study on the topic (Niles, Fogg, Kelmendi, & Lazenby, 2021), four main themes emerge in their views. They consider existential distress to be a serious problem and difficult to manage within the current prevailing framework. At the same time, they find it difficult to apply a medicalisation approach to it; rather, in their view, it is a psychosocial-spiritual problem. They believe that the use of psychedelics is promising, but more research and better data are needed. Moreover, as they do not fit into current models of care, barriers to their application remain, interviewees claim. Workers' views on the position and potential of psychedelics in treatment also vary according to their specialization (Mayer, LeBaron & Acquaviva, 2022).

In a similar study (Beaussant et al., 2020) focusing on the views of palliative care experts, similar results emerged, with attitudes varying significantly between workers, from very open to very cautious. However, this study also seems to suggest that at least part of the negative views of experts stem from a lack of information regarding the safety and potential benefits of using psychedelics in palliative care. This is also why research needs to continue.

References

Agin-Liebes, G. I., Malone, T., Yalch, M. M., Mennenga, S. E., Ponté, K. L., Guss, J., ... & Ross, S. (2020). Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer. Journal of Psychopharmacology, 34(2), 155-166.

Anderson, B. T., Danforth, A., Daroff, R., Stauffer, C., Ekman, E., Agin-Liebes, G., ... & Woolley, J. (2020). Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine, 27, 100538.

Beaussant, Y., Sanders, J., Sager, Z., Tulsky, J. A., Braun, I. M., Blinderman, C. D., ... & Byock, I. (2020). Defining the roles and research priorities for psychedelic-assisted therapies in patients with serious illness: Expert clinicians' and investigators' perspectives. Journal of palliative medicine, 23(10), 1323-1334.

Bossis, A. P. (2021). Psilocybin, spirituality, and palliative care: Research and implications. Alternative and Complementary Therapies, 27(1), 14-17. Citováno podle: Garcia, A. C. M., & Maia, L. D. O. (2022). The therapeutic potential of psychedelic substances in Hospice and Palliative Care. Progress in Palliative Care, 30(1), 1-3.

Faller, H., Schuler, M., Richard, M., Heckl, U., Weis, J., & Küffner, R. (2013). Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis. Journal of clinical oncology, 31(6), 782-793.

Gasser, P., Holstein, D., Michel, Y., Doblin, R., Yazar-Klosinski, B., Passie, T., & Brenneisen, R. (2014). Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. The Journal of nervous and mental disease, 202(7), 513.

Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., ... & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of psychopharmacology, 30(12), 1181-1197.

Grob, C. S., Danforth, A. L., Chopra, G. S., Hagerty, M., McKay, C. R., Halberstadt, A. L., & Greer, G. R. (2011). Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Archives of general psychiatry, 68(1), 71-78.

Grof, S., Goodman, L. E., Richards, W. A., & Kurland, A. A. (1973). LSD-assisted psychotherapy in patients with terminal cancer. International pharmacopsychiatry, 8, 129-144.

Holze, F., Gasser, P., Müller, F., Dolder, P. C., & Liechti, M. E. (2023). Lysergic acid diethylamide-assisted therapy in patients with anxiety with and without a life-threatening illness: a randomized, double-blind, placebo-controlled phase II study. Biological Psychiatry, 93(3), 215-223.

Kast, E. (1966) LSD and the dying patient. The Chicago Medical School quarterly 26: 80-7.

Kast, E. C., Collins, V. J. (1964) Study of lysergic acid diethylamide as an analgesic agent. Anesthesia and analgesia 43: 285-91

Mayer, C. E., LeBaron, V. T., & Acquaviva, K. D. (2022). Exploring the use of psilocybin therapy for existential distress: a qualitative study of palliative care provider perceptions. Journal of Psychoactive Drugs, 54(1), 81-92.

Mitchell, A. J., Chan, M., Bhatti, H., Halton, M., Grassi, L., Johansen, C., & Meader, N. (2011). Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview-based studies. The lancet oncology, 12(2), 160-174.

Niles, H., Fogg, C., Kelmendi, B., & Lazenby, M. (2021). Palliative care provider attitudes toward existential distress and treatment with psychedelic-assisted therapies. BMC Palliative Care, 20(1), 1-14.

Maia, L. O., Daldegan-Bueno, D., & Tófoli, L. F. (2021). The ritual use of ayahuasca during treatment of severe physical illnesses: a qualitative study. Journal of Psychoactive Drugs, 53(3), 272-282.

Maia, L. O., Beaussant, Y., & Garcia, A. C. M. (2022). The therapeutic potential of psychedelic-assisted therapies for symptom control in patients diagnosed with serious illness: a systematic review. Journal of Pain and Symptom Management.

Ostuzzi, G., Matcham, F., Dauchy, S., Barbui, C., & Hotopf, M. (2018). Antidepressants for the treatment of depression in people with cancer. Cochrane Database of Systematic Reviews, (4).

Pahnke, W. N., Kurland, A. A., Unger, S., Savage, C., Wolf, S., & Goodman, L. E. (1970). Psychedelic therapy (utilizing LSD) with cancer patients. Journal of Psychedelic Drugs, 3(1), 63-75.

Rayner, L., Price, A., Evans, A., Valsraj, K., Hotopf, M., & Higginson, I. J. (2011). Antidepressants for the treatment of depression in palliative care: systematic review and meta-analysis. Palliative Medicine, 25(1), 36-51.

Reiche, S., Hermle, L., Gutwinski, S., Jungaberle, H., Gasser, P., & Majić, T. (2018). Serotonergic hallucinogens in the treatment of anxiety and depression in patients suffering from a life-threatening disease: A systematic review. Progress in neuro-psychopharmacology and biological psychiatry, 81, 1-10.

Richards, W. A., Rhead, J. C., Grof, S., Goodman, L. E., Di Leo, F., & Rush, L. (1980). DPT as an adjunct in brief psychotherapy with cancer patients. OMEGA-Journal of Death and Dying, 10(1), 9-26.

Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., ... & Schmidt, B. L. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of psychopharmacology, 30(12), 1165-1180.

Ross, S., Agin-Liebes, G., Lo, S., Zeifman, R. J., Ghazal, L., Benville, J., ... & Mennenga, S. E. (2021). Acute and sustained reductions in loss of meaning and suicidal ideation following psilocybin-assisted psychotherapy for psychiatric and existential distress in life-threatening cancer. ACS pharmacology & translational science, 4(2), 553-562.

Schimmel, N., Breeksema, J. J., Smith-Apeldoorn, S. Y., Veraart, J., van den Brink, W., & Schoevers, R. A. (2021). Psychedelics for the treatment of depression, anxiety, and existential distress in patients with a terminal illness: a systematic review. Psychopharmacology, 1-19.

Wolfson, P. E., Andries, J., Feduccia, A. A., Jerome, L., Wang, J. B., Williams, E., ... & Doblin, R. (2020). MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study. Scientific reports, 10(1), 1-15.