Reappraisal of the hype and hope offered by psilocybin treatment of depression

The recent announcement by Associate Health Minister David Seymour that Medsafe has approved the prescription of psilocybin by a highly experienced psychiatrist for patients with treatment-resistant depression (TRD) has placed psychedelic treatments in the spotlight.¹ A flurry of related media activity suggests that there is an appetite for this form of treatment alongside the need for more effective antidepressants. We are concerned that the use of psychedelic treatments (of which psilocybin is one) is not yet matched by their evidence base and write this article to offer a message of caution.

Psychedelic substances temporarily induce altered states of consciousness. Typical experiences include hallucinations and distortions of mood, time and thought. Some psychedelics (peyote, psilocybin, ayahuasca) are present in the natural environment and are known to Indigenous peoples. Others were created in laboratories as medical models of psychosis and to explore other benefits. The psychedelics all have agonist or partial agonist effects at brain serotonin 5-HT2A receptors.²

The first phase of research into the therapeutic benefits of psychedelics began in the 1940s.² LSD was used to potentiate psychotherapy by allowing repressed material to be more easily passed into consciousness.² It was also used in patients with schizophrenia to generate insights into psychosis and in the treatment of alcoholism and addiction.² However, these avenues of research ended abruptly in the late 1960s due to the widespread uptake of LSD for recreational purposes and subsequent backlash leading to the so-called war on drugs.

There has been renewed research into the therapeutic benefits of psychedelics for the past decade, but randomised controlled trials (RCTs) have only been reported more recently. The first two RCTs evaluating psilocybin for major depressive disorder (MDD) were published in 2021.^3,4 Davis et al. reported large mood improvements with psilocybin compared to a wait list control group 5 and 8 weeks after dosing.³ However, Carhart-Harris et al. did not report significant antidepressant benefits from psilocybin compared to escitalopram, although secondary outcome measures assessing mood and functioning favoured psilocybin.⁴ A follow-up study comparing outcomes at 6 months reported sustained improvements for psilocybin and escitalopram, but differences between groups for the primary outcome were non-significant.⁵

A recent systematic review of the efficacy of psilocybin for depression identified nine RCTs evaluating 602 participants. It concluded that psilocybin demonstrated significant depression reduction compared to controls, but this was to a moderate degree.⁶ The control treatments were: being placed on a wait list, a low dose of psilocybin and escitalopram, placebo, niacin, and a low dose of psilocybin alone. The review suggested that interpretation of benefits associated with psilocybin should factor in the risk of bias due to blinding concerns, the lack of formal evaluation of adverse events, financial conflicts and lack of consideration of mechanisms of action.

A key issue in psilocybin research is the issue of expectation and blinding.⁷ Given the hype with psilocybin, participants are likely to enter studies with hope and beliefs that psilocybin will be beneficial. The psychedelic experience associated with psilocybin is typically 4 to 6 hours duration. For participants allocated psilocybin, the belief in improvement will be preserved by the presence of the psychedelic experience whereas the opposite is likely for those that are allocated to the wait list or receive a control treatment without any psychedelic effects.

Clinical trials are often criticised for their participants not being representative of the wider patient pool. This is the nature of efficacy trials that seek to define tight inclusion and exclusion criteria to increase validity. For Carhart-Harris et al. approximately 1000 patients were screened for 59 patients to be enrolled,⁴ and for Davis et al. 870 individuals were screened and 27 were enrolled to enter the study.³

To date, adverse events in psychedelic trials are not uniformly monitored and reported. A systematic review and meta‑analysis of adverse events reported that psychedelics were generally well tolerated with serious adverse events occurring in four percent of participants with preexisting psychiatric conditions.⁸ However, fewer than a quarter of studies systematically assessed adverse events.⁸ We also note the intensive nature of psychedelic-assisted psychotherapy may increase the risk of boundary violations. This is mitigated by the presence of two therapists, but sexual misconduct was reported and acknowledged in an MDMA (commonly known as ecstasy) study of post-traumatic stress disorder (PTSD).⁹ In population samples, there are also reports of persisting hallucinations and flashbacks to earlier trips following psychedelic experiences.¹⁰ This suggests that harm may occur following psychedelic experiences for some vulnerable individuals.

Regulators have taken note of developments in this area. The United States Food and Drug Administration (FDA) granted psilocybin “breakthrough” status for its potential benefits for TRD in 2018 and MDD in 2019. MDMA was granted breakthrough status for PTSD in 2017. Following these announcements, the Therapeutic Goods Administration (TGA) of Australia approved the clinical use of psilocybin for TRD and MDMA for PTSD in 2023. This occurred despite misgivings from experts in the field and concerns that approval was provided ahead of evidence for efficacy.¹¹ More recently, the FDA declined to approve MDMA-assisted psychotherapy for clinical use due to concerns about functional unblinding and bias in clinical trials.¹²

Psilocybin treatment is resource intensive. Typically, two therapists are provided for participants. Following hours of preparatory sessions, one or two dosing sessions are provided weeks apart, and then post-treatment integration meetings take place. The therapists attend to “set” and “setting”. Set refers to the person’s internal mindset and emotional state, and setting is the physical and social environment in which the experience takes place. Participants are advised to surrender to the experience and to have trust in the process. The preparation is intended to reduce the risk of the person having a “bad trip” but sets expectations that the experience will be beneficial. This framing is thought to influence longer term outcomes.¹³ The intensive nature of treatment and amount of staff input means it is unlikely that public mental health providers will offer psilocybin treatment (particularly when the evidence base is questioned). When offered privately, the costs are substantial and likely to be outside of the reach of many with MDD.

We are involved in research using ketamine for the treatment of TRD. Ketamine is classified as a dissociative anaesthetic but has some psychedelic effects. Ketamine has also been promoted widely in non-research settings, but it is interesting to compare the scientific literature for ketamine with psilocybin. The body of ketamine related research is oriented towards those with TRD as opposed to MDD (a much more difficult group to help). Despite this, the evidence base supporting the benefits of ketamine as a short-term treatment of depression is substantial. A 2023 Lancet systematic review identified 49 RCTs evaluating ketamine for depression (n=3299 participants) with moderate to large effect size improvements with ketamine compared to the control depending on dose and formulation.¹⁴

Many of the methodological challenges with psilocybin treatment are also present for ketamine. For example, the dissociative effects are marked with parenteral dosing. This means preservation of blinding is difficult. However, we see more opportunities with ketamine to provide treatment in publicly funded mental health services.¹⁵ For example, oral dosing of ketamine offers a low-intensity option that minimises the dissociative experience. This raises the possibility of community dosing and addresses equity and access concerns that are present with psilocybin treatment.

To date, many of the ketamine studies are short-term with high relapse rates following dosing ending. If ketamine is to become an established treatment, further research is required to address areas of concern including the role of longer ketamine courses, its safety profile with extended treatment, and the role of adjunctive psychotherapy. We have also previously expressed caution about ketamine as a solution to the psychosocial drivers of depression.¹⁶

In conclusion, we are concerned that recent announcements and desire for new antidepressant treatments is outpacing the evidence and fuels expectation bias. The literature supporting psilocybin treatment is early, and methodological challenges suggest non-specific factors play a large role in its benefits. Although MDD is burdensome, psilocybin treatment does not present a scalable intervention that can address its impacts. In private settings, care is required to ensure individuals are well-informed before embarking on costly treatments with uncertain evidence for efficacy. Perhaps repeated low-dose studies or studies with lower intensity psychotherapeutic components will provide a pathway forwards. For the foreseeable future, we expect that psilocybin treatment of MDD will be a niche treatment in New Zealand. Until then, a cautionary note is required about the excitement offered by psilocybin treatment of MDD.