Psychedelics experts across clinical trials, psychotherapy and regulation have been reflecting on the challenges facing the field since a webinar organised by the International Alliance of Mental Health Research Funders (IAMHRF) in late 2024. This commentary looks at the future of psychedelics as mental health treatment and provides recommendations for moving the field forward.
This blog has been co-authored by: Niall Boyce, Florence Butlen-Ducuing, Pim Cuijpers, Allan Young and Anna Zecharia.
After a period out in the cold, the so-called “psychedelic renaissance” built up hopes that psychedelics—usually in combination with psychotherapy—could offer a new treatment paradigm for mental health conditions. However, significant concerns about the quality of research, including issues of bias, led to the FDA declining to approve a therapy combining MDMA (which is not strictly a psychedelic) with psychotherapy. Yet, just months later, Compass Pathways announced that its first Phase 3 trial of COMP360 psilocybin met its primary endpoint—a statistically and clinically significant reduction in depression symptoms at six weeks—demonstrating that, where trial design meets regulatory standards, progress remains possible.
Hope, as ever, must be tempered by pragmatism. Whilst it’s tempting to talk about the heyday of psychedelics research in the 1950s and 60s—which made significant contributions to understanding of the states induced by these compounds—in fact, the issues the field now faces (e.g. small trials, inadequate controls, the need to protect vulnerable people) were problems then too (see section 3).
These challenges are well-known, they have persisted, and they will not solve themselves.
It’s possible for the field to take the same approach to these issues as Charles Dickens’s Mr Micawber took to his finances, and live in hope that “something will turn up”. However, this would be a missed opportunity and a disservice to the patients who might benefit from psychedelic therapies. Therefore, in this commentary, we argue that the field needs to be proactive in developing a consensus on the way forward, and we offer five key areas for action, with tangible suggestions that we hope will get this discussion started:
- Set a balanced tone
- Find consensus on methods
- Define smart research priorities
- Clarify the role of psychotherapy
- Prepare health systems
Are we really in the middle of a psychedelic renaissance for our mental health?
1. Set a balanced tone
Embrace the promise of psychedelics without overselling or losing sight of clinical reality.
Whilst the therapeutic potential is significant, psychedelics will never be a cure-all. The reality is that if treatments are shown to be safe and effective, they will most likely benefit a subgroup of people who are experiencing intractable symptoms in specific conditions, such as depression and PTSD. The way we talk about psychedelics matters.
However, discussions about psychedelics take on a different tone compared to other therapeutic modalities. A mixture of fascination, caution, and hyperbole surrounds the field – and we believe this is having an unhelpful impact on research and patients. The social context of their ‘heyday’, their essential disappearance from the research landscape, and their subsequent resurgence all seem to have shaped the way we see psychedelics.
The origin of psychedelics research in Western culture is traced to Arthur Heffter, who isolated mescaline from peyote cactus, itself brought back from Mexico by Carl Lumholz. Advances in organic chemistry and pharmacology at this time fueled wide exploration of psychoactive compounds, set against a background of so-called ethnology studies of indigenous rituals. The roots of the heyday (though of course this became overtaken by the synthesis of LSD) are set in a broader context of scientific fascination with human consciousness. Indeed, the roots of the word psychedelic are in the Greek for ‘psyche – or soul – manifesting’. The current interest in psychedelics seems to be coinciding with a resurgence in interest in spirituality, particularly in young people.
Two things happened in the 1960s to stem the tide of research into psychedelics: Schedule 1 classification (following a backlash against rising recreational use of psychedelics) and an increase in medicines regulation following the thalidomide scandal. Both led to practical restrictions on researchers’ ability to access and use psychedelics, alongside a loss of respectability of the research itself. Scientific activity dropped off a cliff.
Its resurgence has been linked to advocacy within the scientific community: a Swiss Academy of Medical Sciences Symposium that brought the small research community together, and the establishment of the Heffter Research Institute (HRI) with the goal of rebuilding the research base. It was not possible for governments to fund psychedelics research, so the landscape became dominated by HRI funding until psychedelics research again entered the mainstream. The legacy of advocacy-driven funding remains.
We would like to see the discussion of psychedelics retain its tone of fascination, but to balance this with clinical realism – and to recognise the sociocultural heritage of psychedelic compounds that play an important role in spiritual practices in indigenous cultures around the world. We should embrace our fascination with psychedelics in these research settings – but we should be explicit that this is part of a curiosity about human consciousness and the spiritual experience, not use psychedelics research as a proxy. Perhaps raising the respectability and acceptability of that kind of research in mental health and the neurosciences (respectfully, with partners in other fields and cultures) will help us separate this aspect of psychedelics research from investigations into therapeutic potential that must focus on the impartial establishment of safety and efficacy.
We would like to see the discussion of psychedelics retain its tone of fascination, but to balance this with clinical realism.
2. Find consensus on methods
Tackle the trial design issues that may compromise the safety and efficacy of psychedelics.
The multiple sources of variability in psychedelics trials muddy the interpretation of therapeutic effect in human trials. Regulators need the same level of robustness to demonstrate safety and efficacy as any other drug. Therefore, addressing study design issues is a priority to support development and approval.
The challenge is in how these variables can be controlled and isolated, whilst being pragmatic about the subjective nature of the psychedelic experience. Variables can be grouped into four main categories:
- safety and efficacy of the psychedelic;
- safety and efficacy of the associated psychotherapy;
- participant mindset and expectation; and
- therapist/trialist mindset and level of expertise, which can impact interactions with the participant.
A general challenge which further hampers discerning signal from noise is that trials tend to be small and underpowered.
Regarding establishing safety and efficacy of the drug, a conscious patient will be aware that they are taking a psychedelic. This means that the usual approach to placebo-controlled and double-blinded trials is not possible; or to put it another way, you might or might not know if you have taken an SSRI, but you will almost certainly know if you have taken a dose of LSD.
Further complications arise when it comes to understanding whether the psychotherapeutic component of psychedelic treatments is effective. First, the psychotherapeutic regimen used in psychedelic therapy (preparation – safety during experience – integration) evolved based on clinical observations during the 1950s and 1960s, and is only used in combination with psychedelics; it is not a validated standalone psychotherapeutic approach. Furthermore, there is considerable variability in how this psychotherapy is delivered within and across trials, including the level of expertise of the therapist. Finally, we just don’t know whether validated therapies such as CBT or short-term psychodynamic psychotherapy are appropriate, so it’s not possible to substitute in a form of therapy that is more easily controlled without further studies.
Then there is the important fact that participants who take part in psychedelics trials may start out with a preference or high expectation; this further complicates the difficulty with placebo control, as the patient who does not receive a drug with acute psychotropic effects will know it, and their outcome might reflect dissatisfaction with their allocation. This can be compounded by therapists who show a bias (conscious or unconscious) towards psychedelics if it influences their behaviour and approach to the participant.
Table 1. Potential solutions for addressing variability in psychedelic-assisted psychotherapy trials.
| Source of variability | Potential solutions for discussion and development with the field |
| Safety and efficacy of the psychedelic
|
Recognising that blinding is not possible for high doses of psychedelics:
Revisit low dose psycholytic approaches, that minimise the psychedelic effect to enable blinding through traditional placebo methods. Limit trial participants to the intended patient population – i.e. prioritise severe patients with intractable symptoms. The high clinical need would enable safety to be prioritised in a short-term study, with a lower threshold for efficacy. Longer term follow-up for both safety and efficacy should be built into study design to assess this patient population and support focused HTA decision-making. Ensure diversity in trial participants to improve real world validity. |
| Safety and efficacy of the psychotherapy
|
Design trials with a rationally designed therapy control. That is, use a standardised control psychotherapy protocol that ensures a safe experience, and compare this to ‘active’ protocols that are designed to support integration of the experience, or are already validated protocols (e.g. short-term psychodynamic therapy, CBT).
Ensure open manuals for psychotherapeutic protocols used in trials. Set a minimum experience level for therapist eligibility. Explore implications of separate regulatory pathways e.g. in the reporting of potential long-term adverse effects of psychotherapy. |
| Participant mindset
|
Index patients by ‘psychedelic preference/expectations’ to at least track this variable.
Exclude participants with previous experience of psychedelics. |
| Therapist/trialist mindset
|
Ensure all stakeholders in a psychedelic trial have a shared understanding of the importance of robust trial design and execution, including how sources of variability interact.
Ensure that psychotherapy protocols used in trials make ‘therapeutic sense’ to the therapist—including engaging psychotherapists in co-designing trials. Establish clear codes of conduct, including conflict of interest declarations. Introduce blinding for results analysis. |
Finally, variability in approaches to study design are a barrier to demonstrating safety and efficacy at scale: standardising design is a way to improve consistency. The European Medicines Agency (EMA) has also acknowledged the need for methodological innovation in this space. In their 2024 multi-stakeholder workshop, they emphasised the importance of adapting traditional trial frameworks to account for the unique characteristics of psychedelics, and highlighted the potential value of international collaboration to harmonise approaches across jurisdictions. The EMA also finalised a new Guideline on the Clinical Investigation of Medicinal Products for Depression, which includes for the first time a dedicated section on psychedelics—formalising best practices for their evaluation in depression trials. The COMP360 Phase 3 trial is an early indication that with rigorous trial design and defined patient populations, psychedelic compounds can meet conventional regulatory standards.
Unpicking these sources of variability is not easy, but we think it is possible—and there are clear examples of movement towards deliberation, decision and action in concert across the field, potentially including checkpoints at the level of funders and journals. In table 1 we have suggested some tangible approaches (that would need to be enacted in combination) in the hope that this will help guide scientific discussion.
Regulators need the same level of robustness in psychedelics research to demonstrate safety and efficacy as any other drug.
3. Define smart research priorities
Target the critical questions that will truly move the field forward.
High interest in psychedelics offers an opportunity for investment in research that has the potential to significantly advance the field if these questions can be identified and addressed with focused attention. These questions relate to safety and efficacy, mechanism of action, the broader application of psychedelics, the role of animal studies, and research on the psychedelic experience itself.
Recent public and institutional investment—including over USD $50 million from the State of Texas for ibogaine research, new U.S. Department of Defense and Veterans Affairs grants for MDMA-assisted therapy, a €6.5 million (equivalent to over USD $7.5 million) Horizon Europe award for the EU-wide PsyPal trial in palliative care, and Australia’s insurer-backed funding for psychedelic treatment—signals growing global commitment to psychedelic innovation, provided it is grounded in robust, high-quality evidence.
In table 2, we have highlighted what we believe to be the most pressing and promising avenues for research.
*Table 2. Priority research questions, by theme.
| Theme | Priority research questions, for discussion and development with the field |
| Safety & efficacy | What are the optimal treatment protocols? (dose, duration, frequency)
What is the duration of the therapeutic effect post treatment? Is psychotherapy an integral part of psychedelic treatment, and if so – what kind of psychotherapy? Can clinical features and/or biological biomarkers predict efficacy and/or safety? Can clinical features and/or biological biomarkers support personalisation of psychedelic therapy? Does the concomitant administration of other (commonly prescribed) psychiatric medications affect the safety and efficacy of psychedelics and vice versa? If so, what are the clinical implications (e.g. discontinuation, concomitant use) and how should this be reflected in the product information? |
| Mechanism of action in intractable depression and PTSD | How might neural pathways implicated in other pharmacological therapeutic strategies contribute to the clinical action of psychedelics? What are the neural mechanisms for psychedelic therapeutic effect at the cellular and network level?
Are the acute dissociative/hallucinogenic effects necessary for long-lasting therapeutic efficacy? And if not, would it be possible to develop psychedelics that would be effective without the potentially challenging ‘trip’ experience? How does the psychotherapy component of psychedelic assisted therapy work? However, we recognise that identifying the mechanism of action of psychotherapy (in any setting) is fraught with challenges, and would require significant research investment. |
| Potential application of psychedelics in other clinical indications.
|
What is the therapeutic potential of psychedelics in neurodegenerative conditions such as Alzheimer’s disease?
What is the therapeutic potential of psychedelics in palliative care, particularly when usual treatments do not help reducing symptoms of anxiety, depression, or existential distress What are the neural mechanisms for psychedelic therapeutic effect across a range of other potential clinical indications, at the cellular and network level? How can we ensure safety and efficacy in these settings, with learnings from trial design challenges to date? |
| Role of animal studies
|
Which animal models have predictive validity for human studies of psychedelics, and what aspects of the experience or therapeutic benefit are they a proxy for?
Which animal models can support investigation into neural mechanisms? Which animal studies lack validity and should no longer be acceptable in the field? Could this guidance be expanded to help shape psychedelics research? |
| The psychedelic experience | What are the best measurements (objective and subjective) to quantify and describe the psychedelic experience? What is the role of qualitative research in the field?
Recognising that the psychedelic experience has roots in indigenous spiritual practice, do we have the interdisciplinary expertise and collaborations (including partners such as from indigenous culture, philosophy, ethics, religion) to develop the fieldin investigating spiritual/religious experience as it relates to the human experience—to meaning, purpose, resilience and wellbeing? |
Research investment has the potential to significantly advance the field, but only if we prioritise the most important questions.
4. Clarify the role of psychotherapy
Resolve the regulatory grey zone.
High quality trials that enable confidence in safety and efficacy data should support the psychedelic journey through standard approval processes, and progress here will necessarily be linked to efforts to improve trial quality and consistency as we have outlined in section 2. However, an additional complicating factor is that applications are for psychedelic-assisted psychotherapy—and psychotherapy falls beyond the remit of regulatory agencies.
In principle, this is not a problem. If a psychotherapy is deemed to be an integral part of drug treatment, this could be represented on the drug label – this has been done previously. However, this has not yet been established for psychedelic treatment. Regulators need to know whether psychotherapy is integral, or whether it should be handled as a part of a more global safety support framework. To address this, a clinical trial with a factorial design would likely be needed to allow an accurate evaluation of the efficacy of both components based on respective relevant endpoints.
Is psychotherapy an integral part of psychedelic treatment?
5. Prepare health systems
Ensure readiness for implementation.
Much of the discussion in the field to date has been about everything up to the approval process, but not much beyond it. The therapeutic benefit of psychedelics will only be realised when they are used in the right patient populations in the real world. So even as we grapple with safety and efficacy, we must also think ahead to potential implementation in case they prove to be effective.
We know that lack of long-term data on safety and effectiveness has impacted HTA recommendations, so it is clearly necessary to integrate this kind of data collection (via phase 4 trials) into research programmes with the aim of supporting HTA organisations to make informed decisions. To be able to assess the potential added value of those treatments compared to our existing therapeutic arsenal, HTA bodies would need to know also how psychedelics would fit in current treatment paradigms and under which clinical setting. We are not aware whether HTA organisations have been engaged in stakeholder discussions about psychedelics, but there is an opportunity to ensure the research community understands their needs and how this might impact research design. As with regulators, early dialogue with HTA organisations is key to ensure that trials are aligned with requirements.
It is also not clear whether current clinical service models, facilities, training, and staffing levels in any geographical setting are ready to support implementation of psychedelics-assisted therapy in health care systems. Portugal has published its first multidisciplinary clinical guidance on psychedelic therapies, developed by professional associations across psychiatry, psychology, pharmacy, and ethics—a proactive step toward real-world readiness. There is a potential issue of equity of access, and the risk of wide variation both within and between countries in provision of treatment (including legislation to support access), and safe, ethical approaches to protection of individuals in acutely vulnerable states.
What needs to happen in the real world for us to start implementing psychedelic-assisted therapy in health care systems?
Closing thoughts
Investment in psychedelics research must be focused on the questions that will take the field forward – not on high volume, low return research.
As therapeutic agents, psychedelics offer hope to the sub-group of patients who find no relief through existing treatment strategies. It is our view that such studies should focus on these patients, embedding their needs into study design and long-term follow up to rigorously establish safety and efficacy of the drug and associated psychotherapy. This will allow regulators to accurately specify clinical particulars of psychotherapy – thus clearing the runway for regulatory approval. To do this, we need to prioritise large, high-quality trials that can establish safety and efficacy.
Approval and adoption are different challenges: we are not convinced that there has been sufficient HTA organisation involvement with this discussion to date, and would like to see this change. HTA organisations make decisions against the care currently available – however, the point is that the patients who stand to benefit from psychedelics do not respond to these options. Given the healthcare systems cost of psychedelic-assisted psychotherapy is likely to be greater than a drug-only approach, there is a risk that these treatments will be systematically disadvantaged unless the costing is tailored to the intended patient population.
Psychedelics can help us explore truly fascinating questions about human consciousness, and what it means to be human. These questions cannot be the domain of one field – be that neuroscience, philosophy or spiritual traditions from across the world – but perhaps working together we could establish a new field that balances experimental approaches with other forms of enquiry and evidence.
Psychedelic-assisted therapy should target people with difficult to treat conditions, who have not benefitted from other treatments.
Statement of interest
This blog has been co-authored by a group of experts who participated in a webinar organised by the International Alliance of Mental Health Research Funders (IAMHRF) in late 2024:
- Niall Boyce “I am Head of Knowledge and Measurement at Wellcome, and have no other interests to declare.”
- Florence Butlen-Ducuing “I am a psychiatrist working in the psycho-oncology Unit at Gustave Roussy Cancer Campus Grand Paris, and in the INSERM Moods research Unit, at Paris Saclay University. I have no interests to declare.”
- Pim Cuijpers “I am Professor Emeritus at the Vrije Universiteit Amsterdam, and I have no interests to declare.”
- Allan Young – Declaration of Interests (PDF)
- Anna Zecharia “I am Director, Programmes and Partnerships at IAMHRF and I have no interests to declare.”
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