What are the potential benefits of psilocybin in therapeutic use for TRD?

Trials of efficacy have generally been positive thus far. Phase 2 study results showed that a single dose of 25 mg of psilocybin reduced depression scores on the Montgomery–Åsberg Depression Rating Scale more than a comparison 1 mg at 3 weeks (mean difference −6.6, 95% CI: −10.2 to −2.9; P < 0.001). ^{Reference Goodwin, Aaronson, Alvarez, Arden, Baker and Bennett3} Recent initial phase 3 results have been published as press releases (peer reviewed study results to follow) and also showed a positive although relatively modest effect measured on the Montgomery–Åsberg Depression Rating Scale at 6 weeks (COMP005 press release: single dose 25 mg versus inactive placebo, mean difference −3.6, 95% CI: −5.7 to −1.5; P < 0.001). ⁷ A further large-scale international phase 3 trial is ongoing (https://clinicaltrials.gov/study/NCT05711940) and the initial results of the two acute doses also show similar results on the same scale at 6 weeks (COMP006 press release, two doses of 25 mg v 1 mg, mean difference −3.8, 95% CI −5.8 to −1.8; P < 0.001). ⁸

In clinical trials, psilocybin appears to be relatively safe and well tolerated in the short term, with the most common side-effects including transient headache, dizziness, nausea and fatigue. ^{Reference Hinkle, Graziosi, Nayak and Yaden9} However, possible lower-frequency delayed side-effects such as suicidal ideation and hallucinogen persisting perception disorder will need to continue to be actively monitored both in trials and post-licensing. ^{Reference McIntyre, Kwan, Mansur, Oliveira-Maia, Teopiz and Maletic10} Recreational use data also suggest that longer-term effects may occur in non-clinical settings. In a mixed methods study of individuals selected because they self-identified as having experienced difficulties after using a psychedelic drug (n = 608, >95% in a non-clinical setting), participants reported that some of these were extended or longer-term challenges, most commonly described as emotional difficulties, which lasted beyond 3 years in 103 responses. ^{Reference Evans, Robinson, Argyri, Suseelan, Murphy-Beiner and McAlpine11} Although these reported data are from a different setting, and one less controlled than that of clinical trials, they support the importance of careful monitoring and reporting of adverse events, including in longer-term follow-up.

In addition to evidence of their efficacy, the potential of psilocybin and psychedelics in general as therapeutic agents is strengthened by a number of factors.

1. (a) Limited numbers of new drugs have been developed in psychiatry (including for TRD) in recent years, and so a new approach with a possible novel and longer-lasting mechanism of action seems promising. For example, psilocybin, as well as its direct pharmacological action (particularly at 5HT-2A receptors), may also have long-lasting neural effects. Supporting this hypothesis, studies suggest that even a single psychedelic experience can lead to persistent changes in brain network dynamics. For example, acute psilocybin seems to be associated with reduced connectivity in the default mode network but increased functional connectivity with other brain networks, and these changes may persist after administration, potentially reflecting a more flexible and integrated brain state. ^{Reference Berkovitch, Fauvel, Preller and Gaillard12,Reference Drew13}

2. (b) Psychedelics are also appealing to the general population because of their long history of use as recreational drugs, which gives some limited real-world data on effects and side-effects. They are also similar to ‘natural’ substances such as so-called ‘magic mushrooms’ and ayahuasca.

3. (c) Their use has become part of a wider ‘psychedelic culture’, ^{Reference Newson, Haslam, Haslam, Cruwys and Roseman14} providing a sense of support and a social identity which may be important in both recreational and research settings.

4. (d) The use of oral psychedelics such as psilocybin is also appealing for some people with mental health problems, as their use can be seen as a unique combination of pharmacological and psychological treatment. It is often believed by patient groups that medications are overused at the expense of psychological therapies, including in the treatment of depression, and so the model of combined psychedelic drug administration with psychological support is appealing. However, there is significant debate in this area: some researchers argue that psychedelic treatment should be better understood as PAT, a combination of psychological and pharmacological approaches, and not merely as a drug treatment; ^{Reference Nutt, Crome and Young1,Reference Gründer, Brand, Mertens, Jungaberle, Kärtner and Scharf15} whereas others argue for a primary pharmacological action with psychological support in place to ensure safety. ^{Reference Goodwin, Malievskaia, Fonzo and Nemeroff16}

What are the challenges in therapeutic psilocybin use?

What further research is needed?

Although there has been a surge in psychedelic research in recent years, mechanistic studies are needed to investigate not only the underlying biological processes but also the psychotherapeutic elements responsible for the therapeutic effects of psychedelics. ^{Reference Yaden, Potash and Griffiths29}

This mechanistic work will be critical to enable us to understand the exact applications of psychedelics and how they can translate into real-world clinical services. Exploring mechanisms may involve synthesising a variety of different experimental approaches. Synthesis of multiple sources of evidence can be approached using the process of triangulation, which has been adopted in other areas in mental health. ^{Reference Smith, Downs, Robinson, Malhi, Potts and Tonia30}

For psychological support specifically, assessment of which components are essential to develop protocols for treatment and definition of the skills will be required. However, current data and reporting are not sufficient for this type of analysis, although frameworks (such as use of the TIDieR checklist and ReSPCT guidelines) have been suggested. ^{Reference Seybert, Schimmers, Silva, Breeksema, Veraart and Bessa23,Reference Pronovost-Morgan, Greenway and Roseman31} Future research (Box 1) could compare outcomes for participants randomised to, for example, protocolised psychotherapy/support alone, psychedelic treatment alone (with usual NHS safety support) and combination psychotherapy/support and psychedelic treatment, ^{Reference Drew13,Reference Dworkin, McDermott, Nayak and Strain32} with more detailed reporting to allow analysis of the components and their outcomes.

Our experience as an illustrative example

In the absence of these data, we took a pragmatic approach to model the implementation of therapeutic psychedelic use in the NHS, and we present our experience here as an illustrative example which may be a useful model in other settings. The Oxford Health Clinical Research Facility is one of several UK sites for a phase 3 study of the efficacy, safety and tolerability of two administrations of psilocybin in patients with TRD, comparing doses of 25 mg, 10 mg and 1 mg and including a longer-term follow-up (ClinicalTrials.gov ID: NCT05711940). In agreement with the sponsor of the study, we took a different approach to delivering the full model of therapeutic support. Instead of adhering to the use of professionally registered staff only, we prioritised training and clinical experience. We used experienced research assistants, who were all psychology graduates with significant in-patient and out-patient experience (and were therefore very similar to ‘mental health practitioners’ in the NHS). All completed the same rigorous training for psychedelic therapy support ^{Reference Lennard-Jones, Atli, Malievskaia, Modlin and Peck24} as therapists at the other sites in the trial. Following completion of training, they successfully delivered preparation sessions (1–2 h), support through the 6 h dosing sessions and then integration sessions, all delivered under close supervision by the clinical research team led by the principal investigator (K.A.S.), a consultant psychiatrist.

Our experience is of one model of therapeutic support in a psilocybin research programme which uses NHS mental health staff, who are relatively numerous and readily available. The focus is on safety and psychoeducation, which form the bedrock of good clinical care in the NHS. The exact role of psychological support in psychedelic treatment is still unclear, and further research is needed to determine whether there are a smaller number of essential components and whether a lower ‘dose’ is possible. In the absence of these studies, we will need to continue to deliver therapeutic support as described in the current trials of psilocybin; however, in the meantime, our experience suggests the potential of a model of safely administering psilocybin on the standard psychological support ‘dose’ but – crucially for real-world implementation – using a more numerous and readily available category of mental health staff.

Next steps

In this feature, we have identified a number of areas in which more research is needed (Box 1). These include:

1. (a) improved reporting of psychological support in psychedelic trials, perhaps using existing guidelines; ^{Reference Pronovost-Morgan, Greenway and Roseman31}

2. (b) investigating how different elements of the psychological support can affect the outcome of the psychedelic experience;

3. (c) standardising treatment across trials and creating evidence-based guidelines for clinical implementation;

4. (d) designing and implementing a training and/or experience requirement for mental health workers to qualify for providing psychedelic support (which could rely on milestones of training and clinical experience rather than general professional licensing).

However, we think that this will require joined-up and focused consideration rather than a piecemeal approach. This could take the form of a consensus process in which all stakeholders from a variety of backgrounds sit around the same table and define and agree on the criteria that should inform research prioritisation and unmet needs. Importantly, stakeholders should include not only clinicians but a wider spectrum of interested parties. A relevant model may be that of the Wellcome-funded GALENOS project (Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis; https://www.galenos.org.uk/). This is a structured methodological approach for assessing the evidence and identifying priorities for further research by incorporating existing types of evidence, including human and animal data, and different study designs with lived experience expertise throughout. ^{Reference Cipriani, Seedat, Milligan, Salanti, Macleod and Hastings33} This approach should be supported by independent funders and may help to inform clinical practice as it allows novel insights and collaborative research prioritisation focused on the areas of greatest need. ^{Reference Ostinelli, Salanti, Macleod, Chiocchia, Smith and Stringaris34}

Whatever the model adopted, now is the time to focus the research field for psychedelic drugs such as psilocybin and to join forces to more clearly understand the underlying mechanisms of action and the exact role of psychological support, and their impact on translation into existing clinical settings such as the NHS.