by Helena Da Costa, Dr Matt Hayler, and Professor Muireann Quigley
Since their emergence into western consciousness in the 1950s, integrating psychedelics into clinical, social, and legal frameworks has been a persistent challenge. For decades, sceptical perspectives resulted in regulatory frameworks that stifled research and clinical application. More recently, psychedelics have been under reconsideration for their potential to revolutionise treatments for post-traumatic stress disorder (PTSD), depression, anxiety, and a variety of addictions. Despite the optimism generated by clinical trials, however, the path to approval remains fraught with legal, regulatory, and ethical hurdles that need to be addressed if the psychedelic promissory is to be fully realised.
A Promising New Frontier for Mental Health?
Mental health disorders impose immense personal, social and economic costs. Yet, conventional treatments, including antidepressants and anxiolytics, commonly fail to deliver effective, long-term relief. Despite this, innovation remains underdeveloped in these areas, with very few new and effective treatments coming to market. Psychedelics and psychedelic-assisted psychotherapies offer innovative and potentially efficacious alternatives. Clinical studies have shown that, by inducing changes in a person’s neural pathways, both classical (e.g. psilocybin from magic mushrooms) and non-classical (e.g. MDMA/ecstasy) psychedelics can exert long-lasting therapeutic effects and often require only two to three dosing sessions.
The positive therapeutic potential of these substances – such as the use of psilocybin for major depressive disorder and treatment resistant depression, and MDMA for PTSD – is such that between 2017 and 2024, the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) granted expediated statuses to five companies for psilocybin-supported and MDMA-assisted psychotherapy trials. Meanwhile in 2023, Australia rescheduled both for therapeutic use, an act many saw as the mainstreaming of psychedelics.
However, in August 2024, the FDA’s rejection of Lykos Therapeutics’ New Drug Application (NDA) for MDMA-assisted psychotherapy (MDMA-AT) for PTSD caused a setback for psychedelic medicine. Although some have accused the FDA of holding psychedelics to a different standard in comparison to other psychiatric drugs, there were a number of methodological and ethical concerns articulated, which are indicative of some of the many of the challenges facing psychedelics’ journey into more mainstream clinical use.
Issues of Evidence & Ethics
A number of concerns, discussed during the meeting of the FDA’s advisory panel preceding the FDA decision, were likely pivotal in the ultimate rejection of the NDA. First, due to MDMA’s pronounced psychoactive effects, there was in effect no blinding in the active treatment arms of Lykos’ clinical trials (so-called ‘functional unblinding’). Second, there was a pronounced selection bias. Many participants had prior (positive) experiences with psychedelics, including MDMA. Third, and relatedly, this likely introduced expectation bias, where participants had pre-existing beliefs about the efficacy of the treatment going into the trials. These may, therefore, have combined to undermine data reliability in respect of both safety and efficacy.
Additionally, there were concerns that the trial did not adequately distinguish between MDMA’s pharmacological effects and the contribution of the psychotherapeutic component. Thus, it was unclear which of these was doing the therapeutic work (or which proportion of each was contributing). Unease here was compounded by the fact that an assessment of the efficacy of psychotherapies falls outside the FDA’s regulatory remit.
Finally, ethical concerns with the conduct of the trials and triallists were raised. These included pressure on participants to emphasise positive, and downplay negative outcomes, as well as an allegation of sexual misconduct by a therapist and concern around the subsequent handling of this by Lykos.
Resolving Challenges
The difficulties encountered in the trial reflect broader systemic issues that hinder progress in psychedelic medicine. Overhyped claims of miracle cures have led to unrealistic expectations, arguably overshadowing patient safety and scientific rigour. As the credibility of prior data is questioned, many are championing the design of more robust trials to ensure that methodological concerns are adequately addressed.
However, the extent to which psychedelic-assisted therapies ought to be altered to better fit current clinical trial design and evidence-based medicine (EBM) paradigms is a live debate. For example, regulators, such as the European Medicines Agency, continue to attach a high degree of importance to blinding and the RCT trial design (e.g. in the EMA’s recent Guideline on the Clinical Investigation of Medicinal Products in the Treatment of Depression[1]). However, not only is it often difficult to (fully) blind certain psychiatric drugs, due to their side effect profile, it is unclear whether and how psychedelics specifically could be effectively blinded. In addition, it is not uncommon for regulators in different jurisdictions, including the EMA and the UK’s MHRA, to approve such drugs, leading some to question whether psychedelics are being held to a different standard than other psychiatric medicines.[2]
Similarly, the EMA’s Guidelines makes clear that “[t]rials need to be able to demonstrate that the effect of the psychedelic assisted therapy is not due to the psychological intervention alone.”[1] However, it is not altogether clear how psychedelic therapies with genuine psychotherapeutic components might be made to fit. In short, it is as yet undetermined whether therapists are assisting the effects of the psychedelic, or the psychedelic is assisting the work of the therapists, a complexity that isn’t reflected in the terminology of “psychedelic-assisted therapy.” Moreover, given the fact that psychotherapies (of whatever flavour) are dependent on therapist-patient interactions, how could the many subjective elements be controlled? And what kind of outcomes or endpoints ought to be measured?
Whatever the solution, however, what is clear is that ultimately these issues will need to be resolved to the satisfaction of the regulators if psychedelics are to gain approvals – whether as standalone medicines or as a new class of adjuncts to talking therapies – and become integrated into more mainstream clinical practice.
Towards & Beyond Medicines Authorisation
Whilst it is clear that regulators want more and better evidence, the law as it stands represents a significant hurdle to generating this. Psychedelics are currently Schedule 1 substances, meaning that, as far as the law is concerned, they have no therapeutic benefit and pose a high risk to public health. Practically, this means that their import, cultivation, sale, possession, prescription, and use are illegal. Whilst research can be done on psychedelics with appropriate Home Office licences, their Schedule 1 status severely hinders this research, as obtaining the mandatory licences, and complying with their requirements, is expensive and time intensive. In 2023, a report from the UK’s Advisory Council on the Misuse of Drugs recommended treating psychedelics ‘as if’ they were on Schedule 2 for certain research purposes. However, as yet, there have been no moves from the Government to act on this.
Nevertheless, if and when psychedelics gain medicines authorisation, arguably this represents only the start of the journey towards more mainstream clinical use. Again, scheduling will represent a barrier, with decisions needing to be made regarding exactly how and to what extent they might be rescheduled, something which would be necessary in order for these new medicines to be legally manufactured/imported, prescribed, and used. This will likely not be as straightforward as it ought to be, however.
In the European Union, whilst medicines authorisations are centralised and the purview of the EMA, national drugs control laws are not harmonised. Meanwhile, in the UK, the post-Brexit landscape means that there is the potential for regulatory divergence between Northern Ireland (NI) and Great Britain (GB). This could lead to difficulties, for instance, where the EMA approves a particular psychedelic, making it available in principle in NI, but the MHRA has not, meaning it isn’t available in GB. The complexities here would also be compounded by the UK-wide Schedule 1 status of these substances.
Beyond this, rolling-out psychedelics, in particular psychedelic-assisted psychotherapies, into mainstream healthcare systems presents further obstacles. Psychedelic-assisted therapies are resource-intensive treatments, requiring extensive training and funding, and so guaranteeing personalised, yet scalable therapies would likely be a substantial burden for an already overstretched NHS.
Future Trajectories
The ongoing quest for psychedelic legitimacy is complex and can only be realised when multidisciplinary collaboration addresses hurdles at scientific, regulatory, clinical, and cultural levels. Attention should focus towards understanding methodological and practical challenges such as unblinding, expectancies, and establishing efficacies, as well as exploring rescheduling alternatives, evaluating public and practitioner needs, and identifying resource bottlenecks. This is necessary if the psychedelic promissory is to become a safe, equitable, and feasible reality.
[1] European Medicines Agency,‘Guideline on Clinical Investigation of Medicinal Products in the Treatment of Depression’, EMA/CHMP/185423/2010 Rev.3, 20 January 2025. Due to come into effect on 30 September 2025.
[2] Nuwer, R. (2024) ‘FDA’s Rejection of MDMA Psychotherapy for Trauma Draws Criticism from Psychedelic Experts’, Scientific American, (13 August). Available at: https://www.scientificamerican.com/article/fdas-rejection-of-mdma-psychotherapy-for-trauma-draws-criticism-from/
This post is based on a forthcoming chapter by Muireann Quigley and Matt Hayler, ‘A Psychedelic Research Agenda? The Quest for Therapeutic and Legal Legitimacy’ in Faulkner, A. (ed.), A Research Agenda in Biomedicine and Society (Edward Elgar, 2025).