Placebo-controlled randomised clinical trials (RCTs) are considered the gold standard, but they present significant challenges in the rapidly expanding field of psychedelic therapy. Unblinding and expectancy bias have raised significant questions about the validity of outcomes in psychedelic trials. ^{Reference Muthukumaraswamy, Forsyth and Lumley1} However, these concerns obscure more fundamental methodological problems facing complex psychedelic treatments that integrate pharmacologic and psychological interventions. To bring appropriate rigour to the primary questions of safety and efficacy that guide regulatory decisions, we must approach the challenges of studying psychedelic treatments as a methodological opportunity instead of an insufficiency.

The most obvious challenge is the widely acknowledged fact that there are no true placebos for psychedelics. The profound and unmistakable changes in mood, perception and consciousness they create result in near-universal functional unblinding (when blinding is assessed at all). ^{Reference Nayak, Bradley, Kleykamp, Strain, Dworkin and Johnson2} Active placebos such as low-dose psychedelics or stimulants have been promoted as a solution but rarely succeed in masking treatment allocation. ^{Reference Nayak, Bradley, Kleykamp, Strain, Dworkin and Johnson2,Reference Szigeti and Heifets3} There are also no placebos for psychotherapy, which depends on active collaboration between patient and clinician and cannot be ‘inert’ or blinded. ^{Reference O’Leary and Borkovec4} When patients in the placebo arm experience disappointment, demoralisation or frustration, and those in the active treatment arm potentially experience heightened expectancy effects, ^{Reference Szigeti and Heifets3} two different psychotherapy conditions are created. Thus, placebo-controlled psychedelic psychotherapy trials do not blind participants or clinicians, control expectancy effects or test comparable psychotherapy conditions.

Most critical, however, is the integrative and synergistic nature of psychedelic therapies, in which psychedelics are theorised to catalyse an unfolding psychotherapeutic process. This is explicit for MDMA (3,4-methylenedioxymethamphetamine)-assisted therapy and implicit in psilocybin trials, which describe their treatment models as ‘psychological support’ rather than ‘psychotherapy’ but are also deeply contextual. Importantly, the power of the treatment is understood to be more than the sum of its parts, which cannot be separated and isolated. Even proponents of placebo-controlled studies acknowledge that the ‘active component’ of the treatment may be ‘an emergent property of a complex system comprising expectations, drug effects, setting, and therapeutic alliance… [and thus it] may be impossible to isolate an individual component of this complex package in an RCT’. ^{Reference Aday, Heifets, Pratscher, Bradley, Rosen and Woolley5} Attempting to study psychedelics as though they function like serotonergic antidepressants misidentifies the object of study, and this in turn undermines the validity of trial outcomes.

Placebo-controlled trials for psychedelic therapies also raise significant ethical concerns, including withholding treatments from patients in need by assigning them to a placebo condition, violating clinical equipoise when alternative therapies are available, and exposing participants to potential harm. ^{Reference Freedman, Glass and Weijer6} These issues are particularly acute for psychiatric patients, who have significant unmet needs. Regulatory bodies have acknowledged such challenges in other fields and recommend alternative trial designs when blinding is infeasible or unethical. ⁷

To advance psychedelic therapies, stakeholders must prioritise clinically relevant data that address real-world needs, while maintaining a high degree of scientific rigor. ^{Reference Carhart-Harris, Wagner, Agrawal, Kettner, Rosenbaum and Gazzaley8} Researchers must generate evidence that answers critical questions for clinical and policy-level decisions: are these treatments safe; and how do they compare with existing standards of care? Placebo-controlled trials often fail to reflect the realities of clinical practice, in which the key questions are about a treatment’s relative effectiveness, safety and suitability for different patient populations.

Data-driven medical science can answer these questions with respect to psychedelic therapies, but not necessarily with placebo-controlled trials. Advances in clinical trial methodologies available for use in psychedelic clinical trials include Bayesian designs that include historical data or other methods using historical controls to supplement or replace a control arm; benchmarking studies that set expectations for risk, adverse events etc., ahead of time; use of master protocols such as basket or platform trials; registry-based studies; adaptive dose-finding trials; and wearable technologies, data science and machine learning. ^{Reference Carhart-Harris, Wagner, Agrawal, Kettner, Rosenbaum and Gazzaley8} For example, pragmatic clinical trials have been successfully implemented in cardiovascular medicine, paediatric oncology, bipolar disorder, schizophrenia and depression. ^{Reference March, Silva, Compton, Shapiro, Califf and Krishnan9} Innovation will require collaboration with interdisciplinary methodologists, potentially with expertise in statistics, epidemiology, computer science, behavioural science and public policy. Alternative study designs that could easily be implemented include:

1. (a) active comparator (superiority or non-inferiority) trials that compare investigative treatments against an established treatment;

2. (b) adaptive trial designs that allow for modifications (e.g. in dosing regimen) on the basis of interim data to improve efficiency and personalisation;

3. (c) leveraging of expectancy effects by incorporating them into treatment and study designs as independent variables, which could identify moderators or mediators and help optimise outcomes. ^{Reference Szigeti and Heifets3}

The challenges of placebo-controlled designs for studying psychedelic therapy highlight an urgent need for innovation. The default faith in placebo control is a doomed attempt to reduce a complex treatment and mislabel that reduction as rigour. Chaining the future of complex treatments to traditional placebo-controlled trials will not only lead to irrelevant information but will also impede the application of methodological rigour required to determine whether these interventions are safe and effective enough for therapeutic application. Funders, regulators and policy makers must embrace alternative trial methodologies that rigorously prioritise ecological validity, patient safety and clinical relevance. Investigators must also ensure adherence to ethical standards and good clinical practice guidelines.Footnote ^a By supporting novel approaches, the field could generate credible, meaningful data to advance both science and patient care.