Moving Forward From FDA-Rejection

A call for better, more rigorous research in psychedelics

Original publication on Medium September, 2024. It is unknown as of 2025 how these programs and progresses will be hindered by budget and personnel cuts to the various government institutions mentioned in this article.

Its been a month since the United States Federal Drug Administration (FDA) rejected Lykos Therapeutics novel drug application for MDMA-assisted therapy as a treatment for post traumatic stress disorder (PTSD) on August 11, 2024.

Between the FDA public advisory meeting and this decision, Lykos and MAPS hired public relations firms and partnered with Heroic Hearts Project, among other organizations, to launch a large campaign in attempts to push forward FDA approval. This campaign included highlighting that many veterans will commit suicide while the FDA Ad-Comm rejected safety and efficacy of MDMA-AT, as well as calling for more donations to MAPS. Part of this campaign also included hateful speech from the Heroic Hearts Project singling out a specific member of Psymposia who chose to speak out against Lykos protocols. This post has since been taken down, but a response by Dr. Peter H. Addy, former VA research psychologist, still is available and highlights some of this response.

Lykos and MAPS also issued their own petition, calling for experts to endorse MDMA-AT, which gained 26 signatories. Of these 26 signatories, 12 are involved with the sponsor or MAPS. This is a contrast to the petition that was filed to the FDA calling for the public ad-comm meeting and encouraging the FDA to pay attention to misconduct of the sponsor organization. This petition received over 80 signatures, of which 50% were experts in trauma-related disorders, psychology, psychedelic and/or patient advocates. Under 10 of these signatories were involved in other groups such as Psymposia.

In August, despite the PR campaign and a bi-partisan political effort, the FDA officially rejected Lykos’ application with a call for more rigorous Phase 3 Clinical Trials. This was a large surprise to almost everyone, as polls suggested that many thought FDA would approve with post-approval monitoring.

Adding accidental fuel only 24 h following the decision, the official journal of the European Behavioral Pharmacology Society, Psychopharmacology, retracted three articles related to Lykos clinical trials, including data from four phase two trials (Feduccia et al, 2021). This came after multiple efforts and letters by independent journalist Sasha Sisko. In the aftermath, Lykos has undergone a complete personnel reorganization, including the resignation founder Rick Doblin from the Board, resignation of their CEO Amy Emerson, and layoff of over 75% of staff. They also have brought on David Hough, former Janssen executive, as senior medical advisor.

There is no need to dive deeper into the explosive aftermath from the FDA decision, as it has been extensively reported and all over the internet. The rest of this article will focus primarily on how to move forward, highlighting the other opportunities to further psychedelic medicine.

There are several other groups working to further psychedelic science and psychedelic-assisted therapy (including MDMA). Lykos Therapeutics is not the only organization seeking FDA approval for MDMA-AT or developing MDMA and related compounds for mental health. Tactogen, Arcadia, Terran, Mindmed and others are actively working towards this as well. Just this week, Clearmind Medicine — a clinical-stage psychedelic pharmaceutical biotech out of Vancouver, Canada — recently announced an international patent application for its combination of MDMA with N-Acylethanolamines (NAEs). This is the thirteenth patent application associated with this line of work, but as we know, patent applications don’t necessarily mean progress on clinical use and accessibility of these compounds.

Outside of these companies, many publicly funded universities and organizations without pharmaceutical interests are also progressing on understanding psychedelics and other pharmacological interventions and how they can be useful for treatment of trauma-related disorders. This includes work at University of Calgary, Johns Hopkins University, Emory University, and more. According to clinicaltrials.gov, there are currently 477 studies recruiting/not yet recruiting related to studying PTSD.

Regulatory Agency Interest

Regulatory agencies have not stopped conversations about next steps regarding novel therapeutics for PTSD. Just this past week, the Reagan-Udall Foundation for the Food and Drug Administration, an independent 501(c)(3) organization created by Congress, hosted a hybrid event titled, “Advancing Treatments for Post-Traumatic Stress Disorder.”

This event had opening remarks by Dr. Bernard A. Fischer, Deputy Director of Office of New Drugs Center for Drug Evaluation and Research, FDA, which featured a brief history of PTSD and symptomatology, as well as where we are in terms of current research and drug development. He highlighted there are currently two approved pharmacotherapies for PTSD, sertraline and paroxetine, both of which are selective serotonin reuptake inhibitors (SSRIs). Dr. Fischer also shared information about an approved medical device, Nightware, which is used to temporarily reduce sleep disturbance related to nightmares in adults 22 years or older who have been diagnosed with nightmare disorder or have nightmares from PTSD.

In the end of his introduction, he gave some advice from the FDA. First, he emphasized the need to have a representative sample in research. This was not only about demographics, but also of the disease itself, including a range of times since the traumatic event, variety of events, and single vs. repeated events. Dr. Fischer then went on to discuss how the field is actually quite well-suited to understand PTSD from a neuroscience point-of-view, and that future studies should build from what we know, instead of trying to reinvent the wheel.

“There are not a lot of good animal models to understand mental health conditions, but this response to threat circuit [related to PTSD] that I’ve talked about can be modeled in animals.”

Given the uniqueness of neuropsychiatric symptoms across individuals, a lot of research is also being done with genetic biomarkers. These may be able to help determine who is at risk for developing PTSD and maybe in the future used to help diagnose PTSD or determine whether people with PTSD will respond to a certain treatment.

Finally, he discussed how looking at resilience studies of people without PTSD may be able to better inform development of novel therapeutics. Specifically, focusing on what can be taught from people who experience traumatic events and don’t end up developing PTSD.

In addition to these remarks, this event featured a panel of prominent voices in the regulatory space including: Dr. Elyse Katz of the Department of Defense, Dr. Leith J. States of the Office of the Assistant Secretary for Health within HHS, Dr. Neeraj ‘Jim’ Gandotra of the Substance Abuse and Mental Health Services Administration (SAMHSA) within HHS, Dr. Marta Sokolowska of the FDA within HHS, and Dr. Paula P. Schnurr and Dr. Miriam J. Smyth of the US Department of Veterans Affairs. There comments will be summarized below.

SAMHSA

Dr. Gandotra discussed some important work going on at SAMHSA as it relates to PTSD. The overall goal of this organization is to be able to provide resources for evidence-based interventions that balance the therapeutic efficacy but also the risks associated with interventions.

“Our strategic plan is underpinned by the principles of equity, trauma-informed approaches and committment to data and recovery. We feel that all of those cross-cutting principles must be addressed in everything we do.” -Dr. Gandotra

The projects that SAMHSA has been working on related to PTSD include projects focused on suicide prevention. First being the 988 crisis lifeline, which is a number that can be dialed or texted for immediate intervention for someone with suicidal ideation or plan. Dr. Gandotra praised this line, which has been “a tremendous resource for under-resourced communities” and has been very useful in linking people to care.

Another program Dr. Gandotra highlighted is their technical service program, ReCAST: Resiliency in Communities After Stress and Trauma. This program has trained over 100,000 mental health workers and community members, as well over 950 partner organizations. He also discussed that PTSD can be initiated and emerge in childhood and as such, they have a program specifically for children, National Child Traumatic Stress Initiative. The initiative has served over 1 million people and includes resources for collaboration among the community.

“While we can sit in DC and come up with policies, its the programs out in the communities that implement these policies and we don’t know what we don’t know. We have to get feedback from those grantees, from those individuals who are serving the communities that we hope benefit from our resources.” — Dr. Gandorta

Department Of Defense

Dr. Katz, contractor supporting the DOD Health Agencies PTSD Program, discussed a clinical trial happening through the DOD. She shares the objective of their PTSD drug treatment program is to develop drugs that effectively treat PTSD, taking into account high quality evidence for or against use of existing drugs and by partnering or supporting industry development programs to increase chances of approval of novel drugs.

Dr. Katz shared her thoughts on the recent developments in novel treatment for PTSD,

“We believe much of the failure in this area is due to the lack of fully understanding the clinical and biological differences between individuals with PTSD, as well as due to a siloed research approach in the area that includes the conduct of small one-off studies from individual investigators or companies with unique testing procedures and endpoints. — Dr. Katz

She went on to share how the DOD program aims to address these issues. This program has partnered with organizations across disciplines and industries to create a PTSD Adaptive Platform Trial, which is the first of its kind in psychiatry. This study design is unique in that it allows sharing of placebo data across arms, as well as testing multiple drugs at the same time. The idea is that the drugs being tested will cycle off the platform based on evidence for their probability of success or failure for decreasing PTSD symptoms. This trial is currently testing two drugs in the FDA-regulated Phase 2 Master Protocol and 4 other drugs, including an intranasal racemic ketamine formulation.

Dr. Katz also discussed the collection of biomarker data and several clinical assessments, hoping to tease apart the heterogeneity of individuals with PTSD. The goal of this research is to lead to a precision medicine approach where drugs are prescribed based on what would be most effective for the individual. The website for this study will be live in the coming weeks: ptsdclinicaltrial.org

Veteran Affairs

To begin, Dr. Schnurr shared the top priority of the VA is providing the safest, most effective care available for the nations veterans. The VA approach prioritizes recovery through evidence based treatment across continuum of care , which includes access to everything from self help apps to acute care to residential treatment. The VA also collaborates with with the DOD to determine appropriate clinical practice guidelines for both mental and physical conditions relevant to population.

As the executive director of National Centers for PTSD, Dr. Schnurr shared advancements in groundbreaking research related to intervention, medication, psychotherapy and even integrative practices (e.g yoga) that have led to creating gold standards in assessments, questionnaires and interviews for PTSD.

The VA has also sponsored a large practitioner training program for providers that teaches evidence based psychotherapy for PTSD using two of the most effective treatments: prolonged exposure therapy and cognitive processing therapy. All VA medical centers offer these treatments and have trained professionals in other evidence based treatments to encourage folks to seek treatment. Dr. Katz promoted that the VA is also preparing to implement psychedelic-assisted therapy for PTSD when the evidence is enough for FDA approval.

“First of all PTSD is treatable condition, I think that sometimes we don’t hear that. PTSD is a treatable condition. There are effective treatments that work well for a lot of people, although not everyone has a satisfactory response for improvement. This isn’t just a PTSD problem, its a mental health disorder problem. This is why at the VA is committed to supporting innovations for PTSD and other mental disorders, which includes psychedelic medicine. At VA, we are preparing for future potential clinical implementation of psychedelic treatment, primarily by supporting and conducting research on medications such as MDMA and psilocybin for treating PTSD and depression.” -Dr. Katz

Dr. Smyth of the VA built on the comments related to innovative research, sharing how the VA is involved in over 140 active research projects and have 230 million dollars invested in this research. She highlighted three programs:

1. The PTSD Psychopharmacology Initiative. Active since 2017, the goal of this initiative is to provide better treatments for veterans by broadening psychopharmacology clinical trials workforce. The first trial under this intiative is ending in 2024 and results will be published accordingly.

2. The Million Veteran Program. This is a novel national research program looking at how genes, lifestyle, military experiences and exposures effect health and wellness of veterans. There are 1.5 million participants enrolled in this program. To date, studies have found genes related to re-experiencing traumatic memories and advanced understanding the relationship between PTSD, TBI and dementia. Specifically, they have found evidence of PTSD and TBI as risk factors for developing dementia in this population.

3. Psychedelic Medicine. The VA shared their first request for applications related to psychedelic research in 2024. They are primarily interested in testing MDMA and psilocybin in combination with psychotherapy for PTSD and depression in veterans.

   
   

Dr. Smyth shared that while some studies related to psychedelics have occurred at VA sites across the country these were funded by external organization with overall small veteran enrollment. She shared decisions related to VA funding will be made this fall. “In the meantime,” she said, “We remind veterans for their safety, they should not use psychedelics as part of a self-treatment program.”

FDA

Dr. Sokolowska discussed the role of the FDA in reviewing applications related to novel treatments and medical devices. The main responsibility of the FDA is to ensure a drug is both safe and effective, which is done by reviewing the data and information provided in the application of the sponsors.

The FDA has approved two medications for PTSD, but they understand the great need for better treatments. With that, Dr. Sokolowska added, the FDA has the breakthrough status program in which they have granted breakthrough status for MDMA for treatment of PTSD. She also highlighted the FDA has done a lot in terms of approving marketing authorization of medical devices related to PTSD. This includes the approval of Nightware in 2020, as mentioned above. Recently, Prism Technology was approved to be marketed as adjunct treatment for PTSD to help patients self-regulate symptoms.

HHS

Dr. States, who works within the Office of the Assistant Secretary for Health of Human Health and Services, opened by acknowledging that PTSD doesn’t happen in isolation and there are many factors that won’t be solved by a seminar or single drug-application.

He discussed the importance of remembering there are co-morbid mental health and behavioral considerations, but also impacts of generational trauma, food insecurity, and issues in accessibility to treatments that contribute to baseline individual level of distress and inability to comply to a treatment regime. The available treatments, and even novel treatments, very well may be founded on good sound base of evidence, but because of those other considerations they’re not going to get the full effectiveness in the entire population.

He had a unique response to what comes next for innovative treatments, speaking to the “relative lack of innovation in the space”,

“…its not just that we need to get more tools, but we need to learn how to use adequately and respond to the environment were currently operating in. There is no silver bullet. The hard work of getting to change is what is taking place here today….We all feel some type of way about the decision that came out sometime ago, and that’s alright. We’re all big kids in the room, thats okay. For me, its indicative of a fact that were pushing forward and were stressing the system in a way that marches us forward in an incremental way. Now, granted, there might be some dissonance about what we thought was appropriate levels of evidence of this or that, but regardless of this, at the end of the day I see opportunity.” — Dr. States

Dr. States went on to say he believes the opportunity is in understanding that solution is not just in NDAs and the FDA sharing the burden alone, its about collaboration and developments across the various regulatory agencies and the increased opportunities for representative data, novel trial design and time needed to adjust to the rapidly evolving changes in approach to randomized clinical trial design.

He ended with suggesting a shift in focus to pivot beyond clinical trials and NDAs, to acknowledge the landscape in which were operating in, which includes looking toward state, local, tribal and territorial governments. By interacting and embracing these places and programs that are moving forward, there is an opportunity to collect data that could be informative to the health and safety of the American people.

Stakeholder Interest

In a similar vein to the FDA Ad-Comm meeting, this sponsored event also included a public stakeholder comment section. The comment period consisted of 75 minutes of public commentary, which each commenter was given 3 minutes to share their thoughts. Considering the overlap in the commentary of this event and the FDA Ad-Comm meeting, this section will highlight a select number of commentary from several viewpoints and from those with organizations that are moving forward with psychedelic-assisted therapy based approaches.

Dr. Michael Abrams, representative of a consumer advocacy organization.

He began with a brief overview of the adequacy of various therapies, including psychedelic-AT. Dr. Abrams stated that while these psychedelic substances have profound brain-based effects, the evidence surrounding their use for treatment for neuropsychiatric disorders like PTSD is not sufficient, as reflected by the FDA decision. He stated that he and his organization agree with the FDA decision, highlighting the need for addressing unblinding bias, proper collection of toxicological and abuse-potential related data, and standardized therapeutic approaches. He ends by highlighting that within the sponsors studies, drug vs. non drug comparison in these trials had evidence that intensive talk therapies alone are effective in some patients in the placebo group.

Mary Armstrong, who shared their experiences with generational, sexual and physical traumas throughout her life.

She described how standard forms of treatment, both therapy and medication, were unhelpful for her conditions. She shared how without Rick Doblin and MAPS, despite their flaws, she would have ended up in the bottom of a bay. She stated, “MDMA, psilocybin and ketamine…they work. Fibromyalgia will be held at bay after six doses of ketamine using the Imperial College London Method. MDMA will give you an open mind to hold your own memories in your head and reframe a lifetime of trauma. I know this as fact, because I am sitting here today.”

Dr. Neşe Devenot, researcher at Johns Hopkins University with expertise in psychedelic bioethics and well-known critic of Lykos Therapeutics.

Similar to her commentary in the FDA Ad-Comm meeting, she shared her own background with complex PTSD and how she understands the need for novel medications, but that doesn’t mean the field should sacrifice safety and ethics. Dr. Devenot then when on to discuss the issues in the psychotherapy protocol in the Lykos application, “Due to the stigma associated with former underground practices descriptions of this therapy have employed euphemistic language that presented an inaccurate picture of the intervention. This has led to significant misunderstandings among researchers, which explains why the bioethics literature has not yet engaged with the highest risk applications of touch in this therapy. At its core, MDMA-AT taught that therapists can telepathically attune to their patients needs including when the patient needs to suffer for their healing. This is a scientifically discredited premise that increases the risk of boundary violations.”

Dr. Robert M. Grant, practicing physician and Professor of Medicine at UCSF.

He has sat on multiple FDA advisory committees for new drug applications and has researched groundbreaking research on an HIV drug that became FDA approved. He said, “I consider myself a friend of the FDA and as a friend of the FDA, it is my opinon that their recent review of MDMA failed.” Dr. Grant highlights many issues in the overall guidance provided by the FDA during the decision and how the FDA did not stand by guidance that was given to the sponsor during the application process. In addition, the FDA “failed to provide context” for their decision, specifically how the methods of blinding used in the Lykos application were not rigorous. He shared his experience as an intensive care doctor and how many of these patients likely have untreated or poorly treated PTSD, which drove him to become trained in MDMA-AT in hopes to combat the disease.

David Heldreth Jr. of Panacea Plant Sciences, a biotech company developing psychedelic medicines, provided a unique perspective regarding his work with tribal nations.

He used his time to bring up generational and communal traumas of Indigenous tribes but their lack of representation in these conversations. “There are 574 recognized tribes, yet on this panel there is a variety of government agencies but there is no one from the Bureau of Indian Affairs or from the Indian Health Services. Why weren’t they invited?” Heldreth went on to provide potential ways to include these voices, such as providing more time to apply for public comments, outreach to these specific communities with limited access, and supporting these communities as much financially as veteran populations. “These things would go a long way for healing generational trauma and reducing conflict and mistrust of the government by Native communities. In that vein, many of these items being researched for PTSD actually come from Indigenous medicines, including psilocybin.” said David. “We need to honor these people and give benefits and honoring to them because this is where these medicines come from.”

Vanessa Joy Walker, representative of the Depression Bipolar Support Alliance, shared her experiences with cancer, family trauma, emotional abuse and suicidal thoughts.

She shared, “Surviving survivorship is exhausting and often death feels easier than living. I had no idea that these crises and trauma could lead to PTSD, I thought that was only for war veterans and violent attack survivors. I didn’t want people to think I was broken or less than.” Walker continued to discuss in her experience, sharing that treatment is complicated and finding combinations of medication and therapy is difficult and takes time, but for some trauma survivors there is not time. She ends by highlighting the need for trauma informed care and acceleration of advancing treatments, which includes the exploration of psychedelic therapies.

Major Aaron Wolfgang, US Army psychiatrist and Assistant Professor Adjunct at Yale.

He shared statistics surrounding PTSD in service members and how there is a need to address PTSD to increase operational readiness. He stated, “PTSD is the most common psychiatric diagnosis for disability discharge across all branches of US military. Depending on the service, 14–27% of all disability discharged service members have service-related PTSD. The US military is currently losing thousands of service members a year to PTSD related PTSD disability discharge. Each one of these service members, is someone who may otherwise have contributed their invaluable military experience…, instead we are prematurely losing the most casualties to PTSD before the next conflict has even occurred.” He ends his comment period by sharing the need for improving the golden standards of treatment and embracing cutting edge research, which includes DOD and VA programs and clinical trials with psychedelics, as mentioned above.

Deran Young, a retired captain of US Air Force, licensed therapist and founder of Black Therapists Rock, an organization dedicated to training black therapists and heal racial trauma and other cultural burdens.

Young shared how their organization has trained several black therapists in psychedelic-assisted therapy included MDMA-AT. Young describes how MDMA can provide a way for those with medical mistrust can seek healing of their trauma, highlighting the intersections that influence complex trauma. She ended her commentary by stating, “I believe the FDA can do a lot to change the legacy of institutional betrayal stemming for incidences such as the Tuskeegee experiments and more. We want to trust healthcare and medicine but that will only happen when voices of the people are prioritized over the stigma and politics.”

Virna Little, behavioral health clinician and national advocate,

shared the Collaborative Care Model, an evidence based model to identify and treat behavioral health conditions in primary care settings. She expressed that many people go to primary care first to seek treatment, especially in areas without access to mental health resources, and therefore more clinicians should be trained to better understand mental health conditions such as PTSD. She shared that this model is in existence in 34 states, with insurance codes, and clinical trials are continuing to evidence the efficacy of these programs, thanks in part to funding by SAMSHA.

Sonja Patrick, retired veteran

shared her experience with pain treatment using hydrocodone through the VA and how sudden discontinuation following the opioid epidemic caused significant physical and mental health issues. She shared concerns that something similar may happen after psychedelic approval, where its deemed a miracle drug but all of a sudden, if problems arise, it will be taken away from those who found it helpful. “It’s great that everyone is learning, but in the end its the veterans are the ones who are suffering when you just yank it from them like that,” Patrick said. She ended by urging people doing the research and making these decisions to consider the outcome in the event that medications must be further regulated or taken out of circulation.

Conclusions

Given the sentiments shared by the panelists, public stakeholders, veterans and researchers that have been involved in this ongoing conversation, it’s obvious there is a great complexity to furthering psychedelic medicine.

While many disagreements arise from hot topics such as these, the largest take away is the need for cross-discipline collaboration to promote rigorous research and evidence-based treatments. There are so many organizations across the regulatory, industry and academic spaces that have growing interest in advancing research and medicine related to psychedelics, which is one of the reasons its so difficult to collaborate. The psychedelic field is unique in that it has individuals who are so passionate about their cause that the judgement becomes clouded, which ultimately fails the patients who need advancements in treatment.

It is important that we listen to those with PTSD, but this includes those with PTSD who have also been harmed by psychedelic therapies or by the organizations who claim to want to help those with this debiliating disorder. As mentioned and highlighted throughout this article, there are people and organizations beyond Lykos Therapeutics that want to see psychedelics through. The more these productive discussions are had, the better the outcomes for those suffering become.