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.

On August 9 the U.S Food and Drug Administration rejected Lykos Therapeutics’ New Drug Application (NDA) for MDMA-assisted psychotherapy. However, the journey to approval is not over yet, and Lykos is now working to address the issues that led to the rejection.

While the news is a devastating blow to the 13 million in the U.S. living with PTSD, it comes as no surprise as the decision follows the recommendation of an independent advisory committee not to approve the therapy in June.

Rejecting the NDA, the FDA issued a complete response letter (CRL) citing concerns over blinding, expectancy bias, and insufficient data to demonstrate durability. The authority has now requested a further Phase 3 trial which will take years and cost millions to complete.

Lykos Therapeutics (Formerly MAPS PBC) has requested a meeting with the FDA to discuss its resubmission.

Since the decision, three studies from Lykos have been retracted from the academic journal Psychopharmacology due to “protocol violations amounting to unethical conduct”, the organisation has laid off 75% of its staff, and Founder and President of MAPS Rick Doblin has stepped down from the board of directors. 

Doblin responded to the FDA decision stating: “MAPS and our supporters have been advocating for the development and supporting the FDA-approved research of MDMA-assisted therapy for more than 38 years; MAPS will continue working towards safe, legal access to this therapy for the more than 350 million people living with PTSD worldwide.

“Our collective commitment to MDMA-assisted therapy remains unwavering. MAPS remains fully focused on supporting culturally appropriate research, rigorous science, and drug policy reform that empowers citizen advocacy in all areas of the world including those with high incidences of trauma and limited resources.”

The road to approval

While the contents of the CRL letter are not available to the public, it might be assumed that the issues laid out in the letter lay the groundwork for a successful second Phase 3 trial.

Chief Executive Officer of Lykos Therapeutics, Amy Emerson, has shared disappointment at the request for this second trial, stating that: “The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades.

“While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature.”

CRL’s are not unusual following Phase 3 trials, and Pink Sheet has highlighted how the use of CRL’s by the FDA hit an all time high in 2022, with 31% of decisions on novel agents resulting in a CRL and almost half of those needing further clinical trials. 

Pink Sheet further details that CRLs with clinical concerns generally had negative outcomes, with nine needing new trials and three programmes discontinuing following receipt of a CRL.

Dr Ingmar Gorman, co-founder and CEO of Fluence, however, believes the current circumstances are promising, highlighting that: “This perspective helps us frame the current situation not as a setback, but as a natural step in the rigorous process of bringing new treatments to those who need them.

“The extensive feedback typically offered in a CRL provides a clear roadmap for approval — something that would have been unimaginable four decades ago when MDMA was first banned. 

“This marks important progress in the field of psychedelic research and mental health treatment. We’ve come a long way, and that’s worth celebrating.”

Some of the main concerns from the FDA were expectancy bias and functional unblinding in the trials, as 90% of participants in the MDMA group guessed that they had received the medicine and not a placebo. Equally, 40% of participants had tried MDMA before participating in the trial. 

Bliding is a core issue for psychedelic research as the effectiveness of current methods is limited when using compounds that have a very noticeable effect. Research suggests the need for new methods for improving psychedelic trials in order to maintain their scientific integrity if these therapies are to make it to approval, such as utilising biomarkers or real-world data.

Additionally, combining a drug with psychotherapy as a protocol is novel, and the FDA does not regulate psychotherapy, making the approval process all the more complicated. 

However, concerning MAPS’ MDMA trials, the FDA agreed to the protocols early on, and Doblin has said the authority is “moving the goalposts” now the trials are completed.

PAREA, Drug Science and Mind Medicine Australia recently published a position statement addressing the issue of blinding and expectation, as well as the issues of combining a drug with psychotherapy, the misuse risks of MDMA, training of therapists, risks of therapist misconduct and boundary violations, uncertain long-term benefits, and the negative benefit-risk ratio.

The statement suggests potential routes forward for the therapy such as basing its advancement on a model created for cannabis by the US Department of Health and Human Services (DHHS).

The statement reads: “We have previous experience with similar challenges with new medicines. The most famous is that of the first drugs for HIV, the access to which was too slow for patients who were dying, prompting the creation of the accelerated approvals process by lobbying the FDA for faster regulatory process and the NIH for more research.  

 “If MDMA does not get marketing authorisation, a model might be based on the August 2023 decision of the US Department of Health and Human Services (DHHS) to move cannabis down from Schedule I to Schedule III alongside ketamine and buprenorphine. The decision was based on an eight-factor analysis of abuse related harms and an overview of clinical use. 

“This review was led by DHHS with input from various agencies including the FDA who agreed that cannabis met the criteria of commonly accepted medical use (CAMU) so was de-facto a medicine hence could not stay in Schedule I.  

“Schedule III was seen as commensurate with its low abuse potential. Current research data for MDMA in PTSD are almost certainly stronger than any medical cannabis product so the same decision could be reached, as was done by the TGA in Australia.”

It’s not over

While the decision marks a major setback for Lykos, MDMA therapy may still one day reach the millions of PTSD patients in need of innovative treatments if Lykos can address the issues raised in the CRL in the new Phase 3 trial. Additionally, it may be that emerging New Chemical Entities with improved profiles to MDMA may pip MDMA to the approval post elsewhere.

Political pressure is also on to get access to MDMA therapy for patients, with over 80 US lawmakers urging Biden to allow approval of the therapy for US veterans and advocacy organisations supporting the advancement of MDMA therapy for this patient population. 

Non-profit organisation, VETS: Veterans Exploring Treatment Solutions, commented on the development to say: “Roughly 20 veterans die by suicide every day. A recent study estimates the number could be as high as 44. This is unacceptable. 

“The potential of MDMA-assisted therapy to help veterans heal from post-traumatic stress disorder (PTSD) remains paramount. We will not allow bureaucratic processes to deter us from advocating for approval of this transformative treatment.

“While we understand and respect the FDA’s commitment to safety, we urge careful consideration of the cost of inaction. 

“The fight for safe, legal access to MDMA-assisted therapy may have hit a roadblock, but VETS stands resolute. We wholeheartedly believe that every veteran deserves access to the most effective forms of healthcare available. We are never out of the fight.”

Heroic Hearts, a non-profit organisation supporting veterans into legal psychedelic therapies, stated: “As leading federal advocates for Veterans’ access to MDMA-AT, Healing Breakthrough & Heroic Hearts are deeply concerned by the FDA’s denial of Lykos’ NDA for MDMA-AT. This is the epitome of bureaucratic red tape – and the result is people will keep dying. MDMA-AT is the most effective treatment ever developed for PTSD, a condition at the core of the Veteran suicide crisis that claims over 17 lives each day.

“The FDA’s decision is a missed opportunity to embrace groundbreaking science, save countless Veteran lives, and honor the sacrifices made by those who served our country. If this critical treatment remains inaccessible, we face losing an additional 6,000 Veterans to suicide this year alone—and every year thereafter.

“Healing Breakthrough and Heroic Hearts Project will not relent. Our commitment to advocating for this life-saving treatment is unequivocal. We will continue to push for progress, collaborate with stakeholders, and fight persistently until MDMA-AT is available to every Veteran who desperately needs and deserves it.”

Elsewhere in the world, Canada and Australia have already begun allowing access to MDMA-assisted therapy in specific circumstances for select, authorised patients, and the Dutch State Commission on MDMA recently released its report advising the Government to allow access to MDMA therapy for people living with PTSD. Equally, other companies are developing treatments with psychedelics such as psilocybin for mental health conditions including anxiety and depression, some of which are now in Phase 3 trials. 

Rivki Stern Youdkevich, Co-Founder and CEO of Shortwave Life Sciences, which is developing psychedelic treatments for anorexia nervosa, commented: “PTSD is associated with an increased risk of mortality due to comorbid conditions such as substance abuse, depression, physical health issues, as well as a higher risk of suicide.

“Risk of a new medicine or treatment versus the risk to the lives of the patient population existing without that treatment is a key consideration in the regulator’s assessment of new drugs. In the case of PTSD, the equation is very clearly positive, and even more so in the case of anorexia nervosa, which is the deadliest mental health disorder of all, with no currently approved FDA medication, and a 50% chronicity rate.

“We believe that this underlying high and positive benefit-to-risk ratio will ultimately guide the regulator to approve innovative and inherently safe psychedelic components in the treatment of life-threatening disorders. At Shortwave we are already proving the safety of our psilocybin-based combination drug and will be able to demonstrate its efficacy according to FDA regulations as we progress in our clinical trials.”

PAREA, a European advocacy organisation for access to psychedelic therapies stated: “People living with PTSD and other mental health conditions, as well as their families, had high hopes and expectations for the introduction of this new treatment option. 

“Although this decision pertains to the US and there is no current market application for this treatment in Europe, we are concerned that the regulatory expectations could set a precedent that might slow down progress in mental health innovation worldwide.”

Awakn Life Sciences has entered into a new collaboration with Graft Polymer to advance its New Chemical Entity (NCE) programme, developing novel molecules for innovative addiction and mental health treatments. 

Both MDMA and ketamine have been showing promise as innovative mental health treatments for conditions such as depression, anxiety, and PTSD. However, these treatments can take hours to administer and use up high amounts of staff resources.

Awakn’s new collaboration with biopolymer drug delivery systems company Graft Polymer (LON: GPL) will be harnessing Graft Polymer’s expertise to develop Awakn’s Aminoindane NCE programme.

LSE-listed Graft Polymer develops biopolymer drug delivery systems and has a proprietary patented platform – a bioabsorbable self-nanoemulsifying drug delivery system (SNEDDS), which represents a cutting-edge solution in drug delivery technology. 

The NCE programme aims to reduce the time the therapies last, improve accessibility and reduce strains on healthcare resources. 

Professor David Nutt, Chief Research Officer at Awakn Life Sciences and Senior Scientific Advisor for Graft Polymer, sat down with Psychedelic Health to tell us more. 

Helping transformative mental health therapies reach patients

The new collaboration will see an initial phase focused on completing pre-clinical research activities, and Graft Polymer will contribute £300,000 along with its expertise in novel drug delivery systems in a bid to enhance bioavailability and improve the pharmacokinetics of the Aminoindane NCEs. 

“We’ve been working on programmes to try to see if we can improve acute, rapid-acting treatments with ketamine and with MDMA,” explained Professor Nutt.

“There are two ways to do that. One is to develop new molecules, which is complex and expensive and needs a lot of investment. The other is to see if we can improve on the kinetics, and there are different ways of doing that. 

“You can get different routes – you can go through sublingually, you can go through buccally, you could go through the skin. But those different approaches need different formulations. Graph Polymer has a nanosphere formulation that they develop, which might begin to minimize some of the peripheral metabolism of both currently existing molecules, and you could potentially reformulate MDMA or ketamine. 

“If you develop new molecules, you want to optimize the kinetics, and that technology can be very helpful.”

“Optimising ketamine to make sure you get the optimal duration, speed of onset, speed of offset, and functional occupation of the brain, that’s never been done before.”

“MDMA is less challenging because currently, the MDMA treatment takes all day.

“If you’re giving someone MDMA therapy for PTSD, they come in at nine, they get the medicine at 10, and they don’t leave till five or six. That’s hugely tiring for the patient. It’s stressful for the therapists, because you have got to have someone present all the time, and no one knows whether that’s optimal.”

Reducing the time these treatments take will enable the scale-up of psychedelic therapy, allowing more patients to be treated, as well as improving the therapy’s safety due to less exposure time to the compounds.

Using Graft Polymer’s technology, which integrates active pharmaceutical ingredients into novel, patented delivery systems, the collaboration aims to to improve the bioavailability, pharmacokinetics, and stability of MDMA and ketamine. 

“We’re certainly going to be aiming to improve tolerability as well as the kinetics gap, but the scalability of MDMA therapy is the biggest challenge,” added Professor Nutt. 

“The other way is to look at therapies which can be given in groups. You can do four or five people at the time, so you might get it down from 10 hours with one person, to to three hours with 10 people. 

“Then we can begin to see how to approach the public health issue of trauma.”

Accelerating psychedelic therapies in the UK

The UK is currently facing a mental health crisis with one in six people in the UK living with some form of mental health condition, and with suicide being the leading cause of death in men under 50.

Equally, with unprecedented waiting times for therapy and no innovation in mental health treatments since the advent of SSRIs, there is a desperate need for new and effective mental health therapies.

Historically, the UK has been a leader in psychedelic research and remains so today, with multiple research institutions and companies developing cutting-edge treatments. However, current regulatory barriers are making it difficult to bring psychedelic therapies to UK patients.

“The problem we have in the UK is that we’ve got great science, but in terms of rolling it from the research lab into clinical treatment is proving quite difficult. However, we now have a new government, so there’s a chance for things to change,” commented Professor Nutt.

“Up to now, the decision-making about so-called “illegal” drugs has been driven almost completely by the Home Office which has wanted to stop people using these drugs recreationally. That has impeded research. 

“I hope the new government will be much more open-minded because there is very little evidence that current drug laws stop use. However, they certainly stop research. There are around six universities that have got a license to work with these drugs clinically and we’ve got to change that.”

Nutt highlights that the compounds in Awakn’s NCE programme are not controlled drugs, providing huge advantages in terms of both the costs of development and the costs of rolling the therapies out, as well as making it easier for hospitals to pharmacies to hold the compounds. 

“There’s a huge amount of pressure developing now to, at the very least, get the scheduling altered so that researchers can really go ahead and find out the real potential of these therapies,” added Professor Nutt.

“We have a crisis but people are not looking at solutions to the crisis. Psychedelics, entactogens, they are much more powerful treatments for trauma disorders than anything we’ve ever had, and we should be investing heavily in them and facilitating the research.”

“At Awakn, we are hoping that the governments will see the light. If you look back 20 years, there were no companies in this space. Now, there are probably worldwide, 40 to 50 companies. 

“The door is open for the UK if we want to walk through it. We could be innovative. We should. Whether we will, that’s a political, not a scientific decision.”

With the upcoming decision on Lykos Therapeutics (formerly MAPS Public Benefit Corporation) MDMA therapy from the US FDA later this month, the outcome may hugely influence decisions by policymakers elsewhere in the world, including the UK.

“I think the MHRA would be reluctant to be the first in the world to fully approve. If the FDA supports it, that will give the whole field an enormous boost, because the current MAPS therapy works. Now all we have got to do is optimize it.”