Drug Science and University College London (UCL) are joining forces in a new collaboration that seeks to address concerns over the therapy component of MDMA-assisted psychotherapy in light of the recent U.S. Food and Drug Administration (FDA) rejection.

After 30 years of research and eight clinical trials by the Multidisciplinary Association for Psychedelic Studies (MAPS [now Lykos Therapeutics]), MDMA therapy for PTSD was granted Breakthrough Therapy Status due to positive results.

However, in June, the FDA rejected the treatment, citing concerns about blinding, potential misuse, risk of unethical conduct, long-term benefits, training challenges, and an unfavourable benefit-risk ratio. Another major issue is the regulation of combination therapy, as the FDA does not have jurisdiction over psychotherapy, making regulation a considerable challenge.

Experts argue that this therapy component is essential for the long-term success of MDMA-assisted psychotherapy.

In a recent position statement published by Drug Science, a UK non-profit advocating for evidence-based drug policy, Mind Medicine Australia, a psychedelic therapy organisation, and PAREA, a European advocacy group, the organisations highlight that: “The Lykos submission is the first instance where a combination of drug plus psychotherapy has been submitted to the FDA for regulatory approval…

“This scenario creates uncertainty for regulators as they have no direct precedent and lack the authority to adjudicate on the psychotherapy component.”

Similarly, Drug Science emphasises that the interaction between MDMA treatment and its therapeutic component is poorly understood.

They suggest that a “refined understanding of this interaction may require a shift away from the traditional methods of evaluation typically used in neuroscience and psychopharmacology.”

To address these concerns over MDMA’s therapy component, Drug Science’s new collaboration with UCL aims to explore different therapeutic modalities to assess their compatibility with MDMA and to identify the key features of the psychotherapeutic model that are crucial to its effectiveness.

Professor David Nutt, Founder of Drug Science, commented in a press statement: “MDMA-assisted therapy has shown great promise, but the recent decision by the FDA highlights the necessity for further research.

“Our collaboration with UCL aims to address the specific concerns raised, particularly around the regulation of combination therapy and therapist training.

“This partnership is crucial for developing a more refined and evidence-based understanding of MDMA’s therapeutic potential.”

Drug Science and UCL say they will be taking a bold and alternative approach to understanding how MDMA works.

In the press statement, Prof Sunjeev Kamboj, Professor of Translational Clinical Psychology at UCL stated: “Modern neuroscience and pharmacological experiments have been pivotal in driving our understanding of MDMA and psychedelics. But we’re now at an impasse in understanding of how these drugs work at a high level.

“This is why we are taking an unusual, more qualitative approach to tackling this issue by testing the effects of MDMA in psychotherapists who have a strong foundation in theories of psychopathology.

“We think this will be a critical step in advancing our understanding of the psychological, rather than neurobiological, mechanisms of action of MDMA”.

The collaboration aims to produce a set of practical understandings that can be directly implemented in a standardised way to help advance the treatment’s safety and efficacy. Recruitment for study participants will begin in 2025.

A new study from MedUni Vienna has identified three new variants of MDMA as promising alternatives for safer use in a controlled psychotherapeutic setting.

The recent blow to MDMA therapy from the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) has put a dampener on many people’s hopes that the treatment would be approved this August.

While that still may happen, one of the major concerns of the advisory body was the compound’s safety data, and the PDAC has advised that Lykos has not collected enough safety data on the molecule in its trials so far.

Despite this setback in the US, countries such as Canada and Australia have increased legal access to MDMA-assisted psychotherapy for PTSD in recent years.

However, there are concerns about the safety profile of the drug due to its side effects such as tachycardia, high blood pressure, and liver and nerve damage despite promising studies.

Safer alternatives

Now, published in the Journal of Neurochemistry, an international research team led by Harald Sitte at MedUni Vienna’s Center for Physiology and Pharmacology has identified three new variants of MDMA as promising alternatives for safer use.

According to the team, the variants – ODMA, TDMA and SeDMA – have been developed to retain the positive effects of MDMA while reducing negative effects.

The studies suggest that the variants impact structures in the brain such as serotonin and dopamine in a similar way to MDMA, but unlike MDMA, they have lower activity at certain serotonin receptors.

Study lead Harald Sitte stated: “This allows the conclusion that both the acute and long-term side effects of ODMA, TDMA and SeDMA may be lower than those of the conventional substance.”

“Since the MDMA analogues also have a weaker interaction with certain transport proteins in the body that are responsible for the absorption and excretion of drugs, the risk of interactions with other drugs could also be reduced,” added first author, Ana Sofia Alberto-Silva.

Sitte continued: “Our experimental results showed that the new variants can retain the therapeutic potential of the conventional substance, but are likely to cause fewer side effects.

“This could advance the controlled use of psychoactive substances in neuropsychiatric illness.”

The authors wrote: “Our findings suggest that these new MDMA bioisosteres might constitute appealing therapeutic alternatives to MDMA, sparing the primary pharmacological activity at hSERT, hDAT, and hNET, but displaying a reduced activity at 5-HT2A/2B/2C receptors and alternative hepatic metabolism. Whether these MDMA bioisosteres may pose lower risk alternatives to the clinically re-emerging MDMA warrants further studies.”

A wealth of research is showing how psychedelic-assisted therapy holds promise for the treatment of mental health conditions such as depression, but what role does the therapist play in a patient’s outcome? A new study has suggested it may be a big one.

Psychedelics have piqued huge interest due to their effects on the brain. Research points to their ability to induce neuroplasticity in the brain as one of the key reasons they may help with conditions such as depression and anxiety.

However, set – the individual’s (or patient’s) mental state – and setting – the individual’s environment during a psychedelic experience – are hugely impactful on the outcome of these experiences.

In the traditional use of psychedelic medicines, shamans help to guide set and setting throughout the experience with singing, drumming and ritual. Today, in scientific research, trials, and in clinics, the clinician is essentially playing this role.

Senior author of a new study, Alan Davis, associate professor and director of the Center for Psychedelic Drug Research and Education in The Ohio State University College of Social Work, has highlighted that the impact of clinicians on patient outcomes is not new, with research consistently showing that a trusting relationship between patients and clinicians has been key to better outcomes. This concept is known as a “therapeutic alliance”.

Understanding the therapeutic alliance

To find out more about the impact of this therapeutic alliance in psychedelic therapy, researchers from Ohio State University College of Medicine analysed data from a clinical trial that investigated psilocybin-assisted psychotherapy for the treatment of major depressive disorder (MDD).

In the trial, participants received two doses of psilocybin and 11 hours of psychotherapy, completing a therapeutic alliance questionnaire afterward, which assessed the strength of the therapist-participant relationship.

Participants also completed questionnaires about any mystical and psychologically insightful experiences they had during the drug treatment sessions. In psychedelic research, the mystical experience has often been shown to be related to the continuing positive effects of this therapy.

The Ohio team looked at the depression outcomes alongside patient reports about their experiences with the medicines as well as their connection with their therapists.

They found that a stronger relationship between patient and clinician led to a better clinical outcome for the patient – with improved depression scores up to 12 months following the experience.

Lead author Adam Levin, a psychiatry and behavioral health resident at Ohio State University College of Medicine, stated: “What persisted the most was the connection between the therapeutic alliance and long-term outcomes, which indicates the importance of a strong relationship.”

Analysis results revealed that over time, the alliance score increased, and in fact demonstrated more acute mystical experiences for the patient. The team also found that acute effects were linked to lower depression four weeks following treatment, but were not associated with better depression outcomes a year after the trial.

“The mystical experience, which is something that is most often reported as related to outcome, was not related to the depression scores at 12 months,” Davis stated.

“We’re not saying this means acute effects aren’t important – psychological insight was still predictive of improvement in the long term. But this does start to situate the importance and meaning of the therapeutic alliance alongside these more well-established effects that people talk about.”

According to the team, the analysis showed that a stronger relationship during the final therapy preparation session predicted a more mystical and psychologically insightful experience – which in turn was linked to further strengthening the therapeutic alliance.

“That’s why I think the relationship has been shown to be impactful in this analysis – because, really, the whole intervention is designed for us to establish the trust and rapport that’s needed for someone to go into an alternative consciousness safely,” Davis stated.

“This isn’t a case where we should try to fit psychedelics into the existing psychiatric paradigm – I think the paradigm should expand to include what we’re learning from psychedelics,” Levin added.

“Our concern is that any effort to minimise therapeutic support could lead to safety concerns or adverse events. And what we showed in this study is evidence for the importance of the alliance in not just preventing those types of events, but also in optimizing therapeutic outcomes.”

The authors emphasised that efforts to minimise negative experiences in future studies of psychedelics is vital, and that therapy is critical to creating a supportive environment for patients.