OPEN Foundation

On behalf of the OPEN Foundation.

10 min reading time

The recent decision by the US Food and Drug Administration (FDA) to withhold approval for MDMA-assisted psychotherapy (MDMA-AT) has sent ripples of disappointment and frustration throughout the scientific, psychedelic and therapeutic communities. This decision, issued via a Complete Response Letter to Lykos Therapeutics, effectively delays access to a promising treatment for millions of patients suffering from Post-Traumatic Stress Disorder (PTSD) by years. At OPEN, we feel compelled to express our concerns, while also proposing a path forward: one that emphasizes both rigorous scientific validation and compassionate pragmatism.

Disappointment in the FDA’s Decision to Restrict Access to Mdma-at

The FDA’s decision represents a significant setback for those advocating innovative approaches in mental healthcare. MDMA-AT has shown remarkable potential in treating PTSD, a condition that remains notoriously difficult to treat with existing therapies. The evidence presented by MAPS (Multidisciplinary Association for Psychedelic Studies) and Lykos Therapeutics (formerly MAPS PBC) demonstrates substantial improvements in PTSD symptoms among patients treated with MDMA-AT. These findings are not only statistically significant but also clinically meaningful, offering hope to those for whom traditional therapies have failed.

The FDA’s decision, while ostensibly rooted in a commitment to safety and efficacy, ultimately restricts access to a treatment that could transform and even save lives. For patients who have exhausted all other options, this decision feels like a denial of hope. 

Surprise at the Divergence from the Dutch State Committee Report “Beyond Ecstasy”

What is particularly surprising is the stark contrast between the FDA’s decision and the conclusions reached by the Dutch State Committee on MDMA. Based on the same body of evidence, the Dutch committee (consisting of scientists, psychiatrists, legal experts, drug prevention and harm reduction specialists) arrived at a radically different conclusion: MDMA-AT is promising, effective, relatively safe and warrants more scientific research to further explore its therapeutic potential.

The committee even concluded that based on the relatively low potential for harm, MDMA could be down-scheduled: moving the compound from List 1 to List 2 of the Opium Act. Finally, the Committee advised the Dutch government to start a naturalistic study to allow patients access to this new therapy form, while also allowing scientists to collect more data on an ongoing basis, all the while gaining important clinical experience in delivering this novel treatment form. These diverging perspectives raise important questions about the interpretation of scientific data and the role of cultural and institutional factors in regulating novel therapeutic approaches. 

The Dutch committee’s recommendation reflects a nuanced understanding of both the risks and benefits associated with MDMA-AT. They recognize that while methodological and ethical concerns remain, the potential therapeutic benefits of MDMA-AT cannot be ignored. This discrepancy between the FDA and the Dutch committee highlights the need for international dialogue and collaboration in the evaluation of novel therapies.

Want to learn more about the Dutch State Committee Report? Click here.

Acknowledging Methodological Concerns In MDMA Assisted Psychotherapy

At the moment, the specific reasons why the FDA rejected the approval of MDMA-AT are not yet publicly available, but we presume these concerns are likely based on the report from the FDA’s scientific advisory panel. These concerns are not without merit. The methodological issues raised, particularly those related to expectancy and placebo effects, are valid and warrant careful consideration. In randomized controlled trials (RCTs), both the MDMA and control groups have shown dramatic improvements, raising the possibility that nonspecific factors may be contributing to the observed outcomes. The contribution of these nonspecific factors to treatment outcomes is not unique to MDMA-AT, but is of concern in the evaluation of any psychoactive medicine. It is also crucial to note that the magnitude of improvement in the MDMA group far exceeds that of the control group, suggesting that the effects of MDMA-AT are not merely due to placebo or breaking blind. Placebo effects, while powerful, tend to diminish over time, whereas the benefits of MDMA-AT have been sustained in many cases. This durability is a critical factor in assessing the therapeutic potential of MDMA and underscores the need for further research to refine our understanding of its mechanisms of action.

Questions that need to be addressed

In our view, specific open questions that need to be addressed in future research include:

1. Role of Expectations: What is the role of patient expectations in the therapeutic benefits associated with MDMA-AT?
2. Blinding Integrity: How many participants are able to accurately guess their treatment assignment, and how does this impact the study outcomes?
3. Prior Experience with MDMA: Does the therapy work equally well for patients with and without prior experience with MDMA?
4. Control Conditions: Could alternative control conditions with experiential components, such as breathwork, be equally effective as MDMA in improving PTSD symptoms?
5. Non-Responders: What are the characteristics of patients who do not respond well to MDMA-AT, and how can their outcomes be improved?
6. Therapist-Client Interactions: What checks and balances are necessary to ensure the standardization and careful conduct of therapist-client interactions in MDMA-AT? 
7. Proper aftercare: How can we ensure appropriate, sensitive, and durable aftercare for patients who may struggle for a substantial period after having undergone MDMA-AT (or placebo-assisted therapy)? 

These questions highlight the need for further evaluating the efficacy of MDMA-AT and underscore the need for open science practices, including transparent reporting and rigorous study designs, to address these issues.

Addressing Ethical Concerns

Ethical concerns surrounding MDMA-AT are significant and need to be taken very seriously,  particularly regarding the risks related to boundary violations. We are acutely aware of the need for rigorous training, careful monitoring and adequate supervision of both therapists and patients involved in MDMA-AT. This is particularly true when these therapies do become approved, and will be rolled out at a large scale, to more diverse groups of patients. The therapy should only be conducted in controlled environments by qualified professionals who adhere to the highest standards of care. This includes official oversight of relevant professional associations, ideally with a thorough understanding of the nature of – and specific risk factors related to – psychedelic-assisted therapies.

A more difficult issue revolves around the standardization of the psychotherapeutic component of MDMA-AT. While some argue that standardized psychotherapy is essential to ensure consistent and safe treatment across different settings, others propose getting rid of psychotherapy altogether, while a third group suggests that common factors – like therapeutic alliance – are the defining feature, and that the specific form of psychotherapy is less important. 

What we can be sure of, is that as the demand for MDMA-AT grows, there will be an increasing need for well-trained therapists who can deliver this therapy responsibly. The establishment of clear guidelines and protocols is imperative to mitigate risks and protect patient safety.

The Impact of the FDA’s Decision on the Legal Landscape & Future Research on MDMA-aT

The FDA’s likely requirement for a third phase-3 trial presents a serious hurdle to the timely approval of MDMA-AT. The time and costs involved in conducting such a study are substantial, and will require additional fundraising. It is likely that this will postpone the availability of MDMA-AT in the USA by years. This delay is particularly concerning given the urgent need for effective treatments for PTSD, a condition that affects millions of people worldwide.

The implications for Europe are uncertain. It remains unclear whether the results of a future phase-3 trial in the USA will be leveraged to apply for marketing authorisation from the European Medicines Agency (EMA) as well. Theoretically, another phase 3 trial could also partially take place in Europe (there are trained and experienced MDMA-AT therapists sites in multiple European countries), thereby overcoming the EMA’s wish to have studies conducted in Europe. If Europe is not included, and the EMA does require additional data, this will further delay the availability of MDMA-AT in Europe, leaving many patients without access to this potentially life-changing treatment.

A Pragmatic Approach: Naturalistic Studies and Early Access

In light of these challenges, we propose a pragmatic approach that balances the need for rigorous science with the urgent need for patient access to MDMA-AT. Specifically, we support the recommendation of the Dutch State Committee on MDMA to initiate a naturalistic study in which patients are given MDMA-AT by qualified therapists in specialized treatment settings.

Such a study would provide valuable data on the real-world effects and risks associated with MDMA-AT, while also offering patients access to a therapy that they might otherwise seek in the so-called ‘underground’ or ‘grey’ circuit. A naturalistic study has the dual benefit of providing potential relief to suffering patients while advancing our understanding of the roll out of MDMA-AT in a controlled and ethical manner.

Furthermore, implementing this approach in the Netherlands could position the country as a leader in psychedelic science and innovative mental healthcare. It would enable us to gather valuable real world data, understand the complexities of offering such a therapeutic innovation in the real world, and, importantly, ensure that an increasing  number of qualified therapists can gain experience conducting MDMA-AT, putting in place structures, protocols, and guidelines to enable a smooth rollout when MDMA-AT eventually becomes a mainstream therapy.

Conclusion: Balancing Rigor with Compassion In Psychedelic Science

In sum, the OPEN Foundation believes that the FDA’s decision overlooks the immediate needs of patients who stand to benefit from MDMA-AT. We recognize the importance of rigorous science in establishing the safety and efficacy of this therapy, but we also advocate a pragmatic approach that allows for early access through naturalistic studies. Only by adopting this dual strategy can we ensure that MDMA-AT is administered safely and responsibly, while also collecting the data necessary to satisfy regulatory requirements. Ultimately, the goal of such an approach would be to minimize harm, maximize patient benefit, and pave the way for MDMA-AT to become a valuable tool in the treatment of PTSD.

We call on regulatory agencies, researchers, and clinicians to work together in the spirit of collaboration and innovation, to bring this promising therapy to those who need it most.