Psilocybin-assisted therapy for anxiety and depression: implications for euthanasia

Contemporary research suggests potential benefits of psychedelic drugs in treatment-resistant depression and terminally ill patients

Despite their stigmatisation, psychedelic drugs are once again being clinically researched in Europe and North America. This long-awaited renaissance is showing very promising results and, unlike the pioneering research that occurred before these drugs were outlawed over 30 years ago, the current methodology is rigorous and of a very high standard.

The biggest progress so far has been with 3,4-methylenedioxymethamphetamine in the treatment of post-traumatic stress disorder,1 where phase 2 studies have yielded promising results and phase 3 studies have been recently approved by the United States Food and Drug Administration. A second psychedelic drug, psilocybin, has also been studied. In 2016, results from three trials using psilocybin in the treatment of psychiatric illness were published.

The first was an open label feasibility study published in Lancet Psychiatry.2 Twelve patients with chronic treatment-resistant depression were treated with two oral doses of psilocybin 7 days apart, and provided with psychological support before, during and after each session. All patients were found to have some reduction in depression severity. Eight patients (67%) achieved complete remission at 1 week, with five of these (42%) still in complete remission 3 months later. No serious or unexpected adverse events occurred. Reported reactions were all transient, including anxiety during drug onset (100%), confusion or thought disorder (75%), mild nausea (33%) and headache (33%). This may be encouraging news for the one-third of people with major depression who currently cannot achieve remission, even after trying multiple options.

The other two trials,3,4 which resulted from a collaboration between the Johns Hopkins University School of Medicine and New York University, were larger and focused specifically on the management of depression and anxiety in people with life-threatening cancer using psilocybin-assisted psychotherapy. Although physical treatments in palliative care are now highly effective, associated negative psychological syndromes such as depression and anxiety are often very difficult to treat, given that antidepressants have low efficacy in patients with terminal cancer.5 In these randomised, blinded, controlled, crossover studies, participants were supported with psychotherapy over several weeks, both before and after the psilocybin sessions.

In the first of these two studies,3 31 participants were randomised to receive a single dose of either psilocybin or niacin control, and then crossed over to receive the other treatment after 7 weeks. The authors found that before crossover, the 14 participants in the psilocybin-first arm had statistically significant improvements in anxiety and depression scores, which were sustained at 7 weeks, while only transient and non-significant responses were seen in the control group. More specifically, 83% of participants in the psilocybin group (compared with 14% in the niacin group) met the criteria for an antidepressant response, while 58% of participants in the psilocybin group met the criteria for the anxiolytic response (compared with 14% in the niacin-first group). Similar acute effects were observed among the crossover group when they received psilocybin, where the effects were maintained at the same level at a 26-week follow-up.

The second study4 in 51 patients with cancer used a very low placebo-like dose of psilocybin as a control. Results also showed significant reductions in several measures of anxiety and depression and improved quality of life in the high-dose psilocybin group compared with the control group. These effects were maintained at the same levels at a 6-month follow-up.

In both studies, cardiovascular effects were monitored along with other potentially harmful adverse events throughout the treatment sessions.3,4 No serious adverse events, either medical or psychiatric, were observed in any session. Moreover, consistent with previous psilocybin research in healthy volunteers and in people with terminal cancer, in both studies there were transient and non-clinically significant increases in systolic and diastolic blood pressure and heart rate that resolved by the end of each session. Other adverse events included headache, nausea and vomiting, anxiety and transient psychotic-like symptoms (such as paranoid ideation and thought disorder). None of the patients required hospitalisation and all resolved by the end of each session.

In light of the transient psychiatric adverse events observed in the two studies, all psychedelic research must carefully take into consideration both the subjects’ mental state or “set” (which refers to the personality, intention, mood and preparation of the individual ingesting a drug) and “setting” (ie, the environment in which the drug is taken, including physical, interpersonal and cultural aspects). The preparatory psychotherapy in these trials readies the participant for the drug experience and builds the therapeutic alliance between patient and treater, which facilitates and supports the psychedelic experience itself. The trials are carried out not in a clinical setting, but rather in a comfortable, aesthetically pleasing environment resembling a living room, which contains a couch for the participant to lie on and carefully selected music. Eye masks are worn as required. The two study therapists remain with the participant throughout the 8-hour sessions. Post-drug session follow-up and integration sessions over the next few weeks complete the program.

Overall, investigators have concluded that psilocybin is not hazardous to somatic health.6 Accepting that all current psychedelic research is medically monitored, and that “set” and “setting” are well understood and catered for throughout the trials, the adverse effects of these drugs which are seen when used recreationally, may be, and generally are, avoided or minimised.

Blinded studies with psychedelic drugs are potentially problematic because the psychedelic experience can be so profound that unblinding may easily occur, increasing the potential for a placebo effect among the treatment group. In spite of this limitation, and the small size of the studies to date, the promising research results so far ensure that more psychedelic research will be initiated in Europe and the US. It is unfortunate, however, that attempts to perform similar psychedelic drug research in Australia still meet significant opposition, particularly from universities, which remain fearful of potential controversy, and ethics committees, which have been very conservative in their responses despite proven safety and promising results in clinical trials overseas. It is not regulatory change that will facilitate psychedelic research in Australia, but rather an acceptance by the academic community that psychedelic drugs are medical agents — notwithstanding their recreational use — which were developed predominantly in laboratories by and for the medical research community.7

From a phenomenological perspective, the reported experiences of subjects who have ingested psychedelic drugs correspond to the “mystical experience” as measured by the Pahnke–Richards Mystical Experience Questionnaire.8 Although psychedelic drugs are not the only initiators of such an experience, which can indeed be spontaneous,9 the hypothesis is that this experience may be healing and transformative. It involves one or more of the following components:

• a sense of unity with all things, associated with ego dissolution;

• a sense of sacredness or reverence;

• a deep intellectual understanding of reality;

• a sense of joy or bliss;

• the experience of transcending time and space; and

• the experience of being at ease with ineffability and paradox.

It is not surprising that the possibility of the use of the mystical experience as a psychiatric therapeutic tool may unsettle established thinking and provoke resistance, but it also raises interesting challenges to the current psychiatric paradigm, which today is largely based on the organic biomedical model. This model predominantly deals with physiological and chemical imbalances in the brain and not with the facilitation of shifts in mind and meaning. This experiential mechanism is novel for a pharmacological agent, which may eventually contribute to a shift in the current paradigm. Psychedelic drugs appear to precipitate a significant alteration of the individual’s world view, and may even alter personality. For dying patients, psilocybin appears to provoke an adaptive reinterpretation of the existential threat of death, and allows a refocusing on the relationships and aspects of life that the individual values. For patients with depression, it similarly appears to facilitate an adaptive change in perspective that reverses the depressive illness. Drugs that operate this way may only need to be ingested once or twice,2 as opposed to conventional treatments like antidepressants, which may be long term and bring a range of side effects.

The social and monetary costs of mental illness continue to increase in Australia,10 and some have questioned the limitations of the current methods of treatment for conditions such as post-traumatic stress disorder and severe depression. The possibility of a new and effective meaning-focused pharmacological paradigm could bring large rewards. So far, the focus of psychedelic research on individuals with ailments that are untreatable or incurable and that bring intractable suffering invites comparison with the recent public discussion of euthanasia in Victoria. Although initial euthanasia legislation in countries such as Belgium and the Netherlands referred to suffering stemming from an illness or injury, euthanasia is increasingly approved for intractable psychiatric illness. A recent study11 involving 100 psychiatric patients who had requested euthanasia because of unbearable suffering unsurprisingly found that those with depression were most likely to request help to die. Moreover, an article recently published in the MJA further highlighted the importance of psychological suffering as patients’ rationale for requesting euthanasia and physician-assisted suicide.12

The question of psychiatric involvement in the euthanasia debate is complex. Euthanasia takes the focus away from medicine’s traditional role of improving health and saving lives, and puts the focus directly on the patients’ subjective experience in relation to both the quality and value of their lives. Psychedelic medicine, if it is to become a reality, will likely be used to directly modify and hopefully improve subjective experience. For patients struggling with severe depression related to loss of meaning or hope, or with the profound existential despair common in the process of dying, psychedelic drugs may in certain cases offer a less radical option in situations where euthanasia appears to be the only way out. As we grapple with the euthanasia debate, it is also time for Australia to seriously join the international conversation around psychedelic therapy.