The down-scheduling of MDMA and psilocybin(e): Too fast and too soon

There has been recent interest in combining psychedelics and related compounds with psychotherapy for the treatment of mental, behavioural or developmental disorders including methylenedioxymethamphetamine (MDMA) and psilocybin(e). However, until recently, both these agents were classified by Australia’s Therapeutic Goods Administration (TGA) as Prohibited Substances (Schedule 9). This meant that they had no established therapeutic use and were only available for research, or for analytical, teaching or training purposes following approval from the Commonwealth and/or States or Territories. This was confirmed by an interim decision in February 2020 that rejected a proposal from the charity and lobby group, Mind Medicine Australia (MMA), to reclassify MDMA and psilocybin(e) from Schedule 9 to Schedule 8. This followed advice from the TGA’s expert committee, the Advisory Committee on Medicines Scheduling (ACMS), which includes pharmacists, clinicians, policy experts and community representatives. Down-scheduling would have meant that both agents had legitimate therapeutic uses and could be prescribed under strict legislative controls.

Following criticism, the TGA deferred making a final decision and commissioned an independent report into the risks and benefits of these agents, to which this author contributed (Kisely et al., 2021). This concluded that while MDMA and psilocybin(e) might show promise in highly selected populations in closely supervised settings, trial quality was variable with only small proportions of potential participants included in randomised comparisons. As a result, the certainty of evidence was rated as low or very low using the Cochrane Collaboration’s GRADE framework in a subsequently published peer-reviewed meta-analysis of the findings (Kisely et al., 2023). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach uses several domains to categorise levels of certainty. Evidence from randomised controlled trials is initially graded as high but can then be downgraded to lower levels depending on study limitations.

After consideration of the report, and other factors, the TGA confirmed its original decision and also rejected one further application from MMA. However, the TGA unexpectedly reversed this decision and announced it would down-schedule MDMA for posttraumatic stress disorder (PTSD) and psilocybin(e) for treatment-resistant depression (TRD) from July 2023 (Therapeutic Goods Administration, 2023). Australia is therefore one of the first countries to recognise these agents as medicines.

Importantly, this was a ‘delegate-only’ decision made without reference to the TGA’s own committee of experts, the ACMS, but influenced by approximately 3500 submissions, which on inspection seem to be largely individual opinion rather than expert advice. In the case of psilocybin(e), mention is made of a paper published at the end of 2022 on the treatment of TRD where a single dose of 25 mg reduced depression scores significantly more than a 1 mg dose over a period of 3 weeks (Goodwin et al., 2022). Although not published in a peer-reviewed journal at the time, these findings were available and considered in this author’s systematic review and meta-analysis, which noted that results were no longer significant at 12-week follow-up (Kisely et al., 2023). However, there was also a signal of increased suicidal ideation and behaviour at higher doses. Furthermore, psilocybin(e) was compared to a sub-therapeutic not an active dose. As also reported in the meta-analysis, psilocybin(e) was only equally as effective for long-standing depression in a head-to-head comparison with a therapeutic dose of escitalopram (Kisely et al., 2023). It was superior for secondary outcomes but these results were not adjusted for multiple comparisons (Kisely et al., 2023).

In the view of this author of the independent report to the TGA, the decision to down-schedule is ahead of the available scientific evidence especially as unresolved issues remain surrounding relapse, long-term safety and the challenges of conducting randomised controlled trials in this area. One issue is the ability to effectively blind participants and researchers to the study allocation. This is rarely considered but in a study of MDMA for alcohol use disorder, over 90% of participants and therapists correctly guessed allocation to the active or control arm (Bogenschutz et al., 2022). Another is the generalisability of findings where less than 10% of potential participants reach randomisation. Reasons for exclusion have included recent suicide attempts, aggression, comorbid substance use disorders and a personal or family history of psychosis or mania (Kisely et al., 2023).

The decision also seems particularly premature given results are awaited from the US$14.8 million awarded in 2021 by the Medical Research Futures Fund for clinical trials of hallucinogens and stimulant drugs when used in conjunction with psychological/psychiatric care.

The measures to regulate supply may also be insufficient. Both agents can only be prescribed by appropriately-trained psychiatrists in combination with psychotherapy in a controlled medical setting (Therapeutic Goods Administration, 2023). Prescribers first need to gain approval from a human research ethics committee (HREC) that is registered with the National Health & Medical Research Council before applying through the regulator’s Authorised Prescriber Scheme to initiate psychedelic-assisted therapy (Therapeutic Goods Administration, 2023). However, it is unclear if HRECs will have the necessary expertise and how the required psychotherapy monitored. Outside rigorously conducted trials, there are dangers of psychological harm if these agents are given to unsuitable patients, or by psychiatrists without the necessary training.

On the other hand, if the psychedelic-assisted psychotherapy is delivered as intended, there may be significant barriers to treatment in terms of both accessibility and cost. There are very few psychiatrists in Australia who have received the training to become accredited therapists and the intensity of this type of therapy means that it would be prohibitively expensive for all but the most affluent. In addition, trials have often been of proprietary agents that are covered by patent, and this is likely to be reflected in the subsequent price. For example, the recent study of psilocybin(e) used a synthetic version called COMP360 (Goodwin et al., 2022). There are also philosophical concerns that naturally occurring compounds are being exploited for profit and used in isolation from the knowledge and practice of the Indigenous cultures from which their use emerged (Devenot et al., 2022).

In conclusion, the TGA’s decision to down-schedule in the absence of advice from its own independent group of experts, or new scientific findings, seems premature especially given that Australian trials are underway that might better establish efficacy.