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  • Writer's pictureAlaina M. Jaster

FDA Meeting of the Psychopharmacologic Drugs Advisory Committee for MDMA-AT: An Overview

Background

The FDA Ad-Comm meeting convened starting at 8:30am ET on June 4th, 2024. The FDA novel drug application (NDA) for MDMA (MDMA) assisted psychotherapy for treatment of post traumatic stress disorder (PTSD)  by Lykos was accepted for review in February of this year. The application was given priority status, meaning its processing will be expedited. The final decision target action date set by the FDA is August 11, 2024.


A few months after the acceptance of the NDA, no public advisory meeting was announced. In April 2024, advocates and researchers submitted a citizen petition to the FDA requesting a public advisory meeting with extended time and prioritization of stakeholders who have potential critiques on the current application methodology. The FDA had informed Lykos Therapeutics of the advisory meeting before informing the public or those undersigned and in response. The petition was altered to state: 


“We are aware that the FDA informed Lykos (formerly MAPS Public Benefit Corporation) of a planned meeting in June 2024, but this meeting was not publicly announced by the time of posting this petition. This advance notice allows Lykos to organize advocates in preparation for the meeting. Although the FDA stipulates that meetings must be publicly advertised at least 15 calendar days before the meeting date, other stakeholders should also be afforded the opportunity to prepare for this meeting. Additionally, given that some former clinical trial participants are disabled, advance notice is a reasonable accommodation for their full participation in the OPH. In light of strong public interest in FDA’s decision, this meeting should also be made available by webcast.”


The FDA announced the June 4 advisory committee meeting in an official notice published on May 8, with all oral presentation requests to be filed by May 21, 2024 (an extension from the original deadline May 17, 2024). The original time slot for public comment was extended by 45 minutes to accommodate the number of oral presentations.


Representatives from Lykos presented first followed by a Q&A and break, then the FDA presented their analysis and concerns, also followed by a Q&A. The committee broke for lunch before hearing the public comments. After public commentary, the FDA panel discussed the various questions put forth:


  1. Discuss the evidence of effectiveness for MDMA for the treatment of post-traumatic stress disorder (PTSD). Consider the following:

    1. The potential impact of functional unblinding on interpretability of efficacy results

    2. The durability effect

    3. The role of psychological intervention in the treatment paradigm

  2. Discuss whether the available data are adequate to characterize the safety of MDMA for the treatment of PTSD.

    1. Consider the limited data collected on events deemed positive, favorable, or neutral that would inform abuse potential for this program and the lack of data from some clinical laboratory tests.

    2. Comment on whether you have concerns about other safety issues and what additional data would be useful to characterize the safety of MDMA.

  3. Discuss the potential for patient impairment to occur with MDMA and the potential for serious harm that may result due to the impairment.

  4. Discuss whether the proposed risk mitigation is sufficient to mitigate serious harm resulting from patient impairment. Include any additional safety monitoring conditions needed for the safe administration and monitoring of MDMA if approved for PTSD.


Following this discussion they voted on two questions:

  1. Do the available data show that the drug is effective in patients with posttraumatic stress disorder?

  2. Do the benefits of MDMA with FDA's proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD?


In terms of the questions, there was a lot of confusion on whether the discussion and voting should take place around the drug itself, or take into account the psychotherapy component. Considering the contribution of psychotherapy has not been characterized, nor have they compared their therapy component with other types of therapy the FDA found it difficult to separate the two components. There were concerns about the 21 CFR 201.57(c)(i)(A) in which the FDA cannot regulate therapy and is only able to approve drug on its own. This alone highlights a major issue present throughout the advisory meeting.


This overview will highlight key elements from the meeting organized by topic not chronologically.


FDA Timeline

2001
Investigational New Drug (IND) submitted and approved to proceed
Applicant conducted multiple phase 1 pharmacokinetic (PK) and safety studies and multiple phase 2 proof-of-concept studies 
2016
End of Phase 2 Meeting 
Agency expressed concerns of possible functional unblinding and expectation bias, suggested active comparators - no agreement met
01/2017
MAPP1 protocol submitted as special protocol assessment (SPA)

03/2017
No Agreement Letter on SPA
Noted issues with blinding and inadvertent bias but agreed to primary and secondary endpoints, as well as safety endpoints including special AEs related to cardiac events. Advised “For all Phase 1, 2 and 3 studies, [adverse events] associated with potential abuse or overdose must be documented.”
05/2017
Type A Meeting to Discuss No Agreement Letter
Agreements were reached that two phase 3 trials with identical designs would be conducted to support the NDA. A thorough QT study would be conducted prior to submission of the NDA. No new animal and human studies of the abuse potential of midomafetamine needed.
06/2017
SPA request was resubmitted

07/2017
Special Protocol – Agreement Letter
FDA states the design and planned analysis of the study adequately address the objectives necessary to support a regulatory submission. SPA agreement does not indicate FDA concurrence on every protocol detail. The existence of an SPA agreement does not guarantee that FDA will accept an NDA for filing or that the trial results will be adequate to support approval.
08/2017
Breakthrough Therapy Designation for midomafetamine for the treatment of PTSD was granted

03/2018
MAPP1 Protocol Amendment 1 re: overnight stay
Introduced a sub-study to assess the feasibility of medication sessions without an overnight stay.
09/2019
MAPP1 Protocol Amendment 2 re: Adverse Events of Special Interest (AESI)
Addition of nonpostural syncope as an AESI
as this could potentially indicate QT interval prolongation. Additionally, the Applicant clarified that all events related to drug abuse, intentional misuse, dependence, overdose, or diversion would be captured as AEs, but only those AEs related to midomafetamine or ecstasy would be classified as AESIs.
11/2019
MAPP1 Protocol Amendment 3 re: Suicidal Ideation/Behavior
Clarified AESI of suicide risk to include AEs recorded under the terms suicide, suicide attempt, self-injurious behavior associated with suicidal ideation, and suicidal ideation judged to be serious or severe in the opinion of the investigator. Additionally, occurrences of scores of 4 or 5 on the C-SSRS were counted as AESIs.
10/2020
Agency suggests a Participant Blinding Survey in response to a MAPP2 Amendment submission
Applicant agreed to submit the results in the NDA submission.
09/2022
Type B Breakthrough Therapy Designation advice meeting
Agency shared concerns about the adequacy of the safety database to support an NDA, the need for further data on durability, as well as the adequacy of MPLONG study for supporting the durability of their existing paradigm but agreed it could be submitted.
05/2023
Pre-NDA meeting
Agency noted that the specific risks to be addressed through the REMS would be a matter of review
12/2023
Applicant submitted an NDA

02/2024
NDA Accepted for Review

04/2024
Petition for Public Advisory Meeting Submitted

05/2024
Public Advisory Meeting Announced
With extensions to submission deadlines for written and oral comments, as well as extensions for oral presentations.
06/2024
FDA Advisory Meeting Convenes
FDA Ad-Comm votes No on efficacy and safety, highlights concerns with safety data, AE reporting, unblinding/expectancy, misconduct and unclear psychotherapy component.


The Application

As many are probably aware, the application included three sessions of MDMA administration with psychological interventions over the course of four months. These included:

  • Preparatory sessions: 3 sessions of psychotherapy to prepare and taper off any medications. 

  • Medication administration session with psychological support: 3 sessions with psychological support as needed

  • Integrative sessions with psychological support: occur after medication sessions 


MAPP1 and MAPP2 Clinical Design from Lykos Briefing Document Figure 3.










There would be three medication sessions, with at least 21 days between each session. The FDA and Lykos presented different dosing regimens which is due to the formulation of the compound. The Lykos Presentation references the MDMA Hydrochloride formulation (top) and The FDA Presentation references the freebase formulation (bottom).














The Psychotherapy Component

The FDA ad-comm panel was perplexed by the inclusion of a psychotherapy component and was even told to focus on the drug-application and not the therapy component or allegations of misconduct within this component. Many sought to clarify how they should be basing their vote since the application is not just for MDMA, but MDMA-AT. 


Per the Lykos briefing documents, they perform psychological intervention based on their own MDMA-assisted Psychotherapy Treatment Manual, which was developed over the years as these trials progressed. In their presentation they highlighted that the use of psychotherapy is to provide a safe environment that fosters healing without directing the patient.


It was somewhat surprising to many that Lykos representatives did not address their founder Rick Doblin’s beliefs of an “inner healing intelligence” through MDMA-AT, nor did they share with the FDA the core of their treatment manual comes from ideals from Stan Grof, a psychiatrist who is responsible for the “Basic Perinatal Matrices” and how the fetus’ experience in the birth canal predicts trauma and resilience. The concept of inner healing intelligence is widely debated and has been adapted by several underground psychedelic treatments that encourage patients to “let go” and “surrender,” which may amplify the risk of harm associated with increased openness and vulnerability from the effects of MDMA.


The Lykos briefing document shares their psychological intervention is:

  • Largely non-directive; inviting inquiry and providing suggestion rather than directing the patient.

  • Relied on active or engaged listening and responding and support for approaching difficult material.

  • Included periods of introspection alternating with periods of communication between therapists and the patient.

  • Required cultural sensitivity in support of effective, sensitive communication with patients from different cultures.


If the application is approved, Lykos plans to provide the training used in the clinical trials to therapists in post-marketing. This was something that was concerning to many of the panelists, 


One panelist brought up that while the specific modalities of psychotherapy are undefined and largely non-directive, the treatment manual still follows general principles of therapeutics such as “empathy, support, fostering openness to inner experiences that may emerge, and providing a comfortable physical environment.”


During the Q&A session following the Lykos presentation, a representative explained one of the reasons they chose “psychological intervention” as a term was to allow broader uses of MDMA-AT outside of their manual. This was reassuring to some panelists, including consumer representative Kim Witczak, who was concerned that their manual would be required moving forward. Despite Lykos' statement, they still would train the initial wave of therapists post-approval.


About 50% of the discussion surrounded the psychotherapy component, which is completely out of the FDA’s wheelhouse. A couple of committee members even asked if it was possible to consult with other experts regarding the psychotherapy component or if there was a way for the FDA to form a subcommittee to deal with these types of applications.


A significant portion of the discussion concerned therapist misconduct and how the FDA could possibly comment on this application because of the psychotherapy intervention. Many noted that the way it is presented in the application “makes it impossible to disentangle” the MDMA component from the psychotherapy component. No MDMA administration was done without psychotherapy, and with no standardized therapy it is difficult to determine how effective and safe it is for patients who are under the influence of MDMA to undergo the types of therapies present. Another major concern around the psychological intervention was that due to the fast and loose definitions given by Lykos, the therapy may differ across treatment arms and between sites, making it extremely confounding to whether or not the MDMA is what is driving these effects at primary and secondary endpoints. 


What is MDMA and how does it work? 

MDMA stands for 3,4-Methyl​enedioxy​methamphetamine but is called by many names and has been given many classifications. Structurally it is a substituted amphetamine with serotonergic properties, which account for some of its psychedelic-like effects including changes in perception, sensory processing and increased feelings of euphoria. It’s commonly referred to as an empathogen or entactogen due to its ability to increase feelings of empathy towards oneself or others, which is one reason for its use as an adjunct to psychotherapy. Onset of subjective effects following oral administration of MDMA typically begins within 30 to 60 minutes and reaches peak effect at 75 to 120 minutes, which then plateaus for about 3.5 hours. MDMA is a commonly used recreational drug in the music scene with some abuse potential, due to it causing physical dependence in some individuals and withdrawal symptoms if frequent use is suddenly stopped.


The main way MDMA alters signaling in the brain is through its effects on monoamine release. Monoamines are neurotransmitters such as dopamine and serotonin, for example, which are released from specific neuron populations in various brain regions. MDMA enters these neurons through monoamine transporters, and has high affinity for transporters of dopamine, norepinephrine and serotonin.


The methylenedioxy- substitution (see structure right) provides the serotonergic activity, as most other substituted amphetamines show negligible affinity for the serotonin transporter.


It is important to note that MDMA has two structural isomers called enantiomers: S)-MDMA and (R)-MDMA. Typically the racemic mixture of both isomers is used recreationally, but through pharmacological research it’s been evidenced that (S)-MDMA causes the entactogenic effects through its affinity for the transporters, whereas (R)-MDMA has notable agonism towards 5-HT2AR which is thought to contribute to the mild psychedelic-like effects induced by high doses of MDMA. Lykos' studies used racemic MDMA which contains both enantiomers.


As for the way MDMA works in the context of PTSD and psychotherapy, the research is still ongoing. Lykos' presentation included a slide that highlights how MDMA assists psychotherapy which included:

  • May increase patients sense of empathy and connectedness

  • May foster patient’s sense of safety and trust

  • May increase recall of affectively charged memories

  • Serotonergic effects of MDMA often translate to transiently reduced anxiety


While MDMA has been evidenced to foster a sense of empathy and trust, and/or reduce anxiety in some patients, some patients may respond differently. MDMA administration can also put patients in a vulnerable or susceptible state. Further, the effects of MDMA on memory is still a highly debated field with some studies showing the opposite of Lykos’ claims (Bershad et al., 2016; Kuypers and Ramaekers 2005; Doss et al., 2018). 


In one of the highlighted studies, Doss and colleagues found MDMA given at either the encoding or retrieval phase did not affect overall memory accuracy, but when given at the encoding phase, “MDMA reduced recollection estimates for negative and positive pictures but had little to no effect on neutral items or familiarity estimates.” It’s not to be remiss that there is evidence for MDMA to positively affect memory recall (Carhart-Harris et al. 2014; Ballard et al., 2014), but it's important to remember these studies are still ongoing.


Despite this, the idea is that MDMA administered with psychological support will allow patients to revisit their trauma without negative feelings and in a more open state of mind. It’s important to note these experiences are often difficult, emotional and overwhelming. Despite this, many participants completed the MAPP1 and MAPP2 trials with positive results as shown by Lykos’ presentation and in their briefing documents.


The Data (Lykos and FDA Presentations)

The primary endpoint for both MAPP1 and MAPP2 was a change from baseline to week 18 in the clinician administered PTSD scale (CAPS-5), specifically 10-point or greater change in treatment arms was considered clinically meaningful. The CAPS-5 is based on DSM-5 criteria and is the industry standard for PTSD trials. The secondary endpoint was a change from baseline to week 18 on clinician-rated functional impairment using the Sheehan Disability Scale or SDS across domains. 


The only differences between MAPP1 and MAPP2 that was highlighted was that MAPP1 included participants with severe PTSD, whereas MAPP2 included participants with moderate to severe PTSD, and MAPP2 incorporated an unblinding survey.


Both studies had a clinically meaningful and statistically significant difference in reduction of CAPS-5 at week 18 after MDMA sessions. 

  • Approximately a -24-point mean change in MDMA arm

  • Mean change in both MDMA and placebo arms were clinically meaningful

  • Difference between MDMA and plaebo arms was approximately 12 points


Both studies had a clinically meaningful and statistically significant difference in reductions of SDS disability scale at week 18 after MDMA sessions.

  • Approximately a -3-point mean change in MDMA arm

  • Mean change in both arms was considered clinically meaningful

  • Difference between MDMA and placebo arms was approximately 1.3 points


The unblinding data for MAPP2 revealed that study participants were able to guess their treatment with a high degree of accuracy, moreso in the MDMA arm, which is unsurprising given the strong subjective effects with MDMA and other psychedelic-related compounds. This was a large problem for the FDA but there was little solution offered and no computational approaches to account for unblinding.


In attempts to mitigate this blinding issue, efficacy assessments were conducted by a

pool of mental health professionals with graduate-level training in psychology, social

work, or counseling and at least 1 year of experience working with a trauma-exposed population. Reviewers were blinded to study design, assessment timepoint (except baseline), and safety data collected by sites, and no reviewer was to assess the same patient more than once. These folks were not onsite and conducted assessments over live video conferences.


In addition to adding the independent reviews, Lykos also tried a string of studies to use low doses of MDMA, but ultimately decided these doses worsened patients, although sample sizes were relatively small.


An exploratory observational study, MPLONG, was also included to explore the durability of treatment effect after 6 months in participants who chose to enroll after completing the parent study. Data from this study suggest that MDMA effects on PTSD symptom severity persist after 6 months and up to two years in some patients.


The FDA noted caveats in MPLONG, which included:

  • On average, participants who enrolled for MPLONG had less severe PTSD symptoms compared to those who did not enroll.

  • MAPP1 participants who enrolled were already formally unblinded to treatment

  • Time for long-term follow-up varied considerably among participants, some from MAPP1 were up to two years post-completion.

  • Interim drug use of psychedelic-related compounds between parent study and MPLONG

  • Including MDMA, ketamine and 5-MeO-DMT

  • Unsure about other compounds


To attempt to get at some of these issues, the FDA did its own exploratory analysis, treating any data collected after interim use of non-study drug considered as missing. The purpose of this is to determine if other drugs impacted prolonged durability of MDMA’s efficacy. They found that removing data varied by parent study and arm. In MAPP2, results were less favorable in the MDMA arm but better in the placebo arm. In MAPP1, results varied depending on the analysis methodology for the MDMA arm, but remained stable in the placebo arm.


Safety (Lykos and FDA Presentations)

The overall safety profile observed in the program aligned closely with what has been previously described about safety issues associated with MDMA in the literature. The drug was well-tolerated with mostly transient mild to moderate adverse events (AE). Only one patient discontinued due to an AE.


Most common AEs occurring in at least 15% of patients were within expectation and consistent with the known mechanism of actions for MDMA (see below):


One large flaw the FDA noted was the lack of AEs collected if the sponsor deemed them to be “positive, favorable or neutral,” which includes several subjective effects. As shown in the timeline, the FDA provided clear guidelines for collecting AE data in 2017 and voiced concerns of AE and safety data again in 2022.


The sponsor stated in their presentation that “Acute [subjective] effects are thought to be a central component of long-term treatment benefit, and this altered mental state may result in patient impairment as an effect of MDMA… as noted in the briefing document we did not collect positive or neutral [subjective] effects of treatment in our trials as we interpreted adverse to be negative.”  They also noted they are prepared to collect this data in a post-approval context to further the safety profile of MDMA-AT.


Suicidal ideation (SI) and behavior was another large concern, especially in this patient population. Only a small number of severe adverse events (SAE) were reported related to SI/behavior and only occurred in the placebo arm in MAPP1. Of these cases, one participant dropped out of the study and another remained in the study following suicide attempts until day 132 of the treatment.  No SI related SAEs were reported in MAPP2, as reflected by the FDA and Lykos briefing documents.. AEs related to SI that were assessed as mild or moderate were around 40% for both arms, with no immediate behaviors post-drug administration. Other psychiatric symptoms were consistent with PTSD itself, or can be related to serotonergic or stimulant properties.


It’s important to note that issue has been raised with Lykos' inclusion of suicide-related SAEs in the final dataset, as well as them dissuading people from participating in the follow-up study if they had worsening symptoms or did not respond to MDMA treatment. The FDA stated that these, along with other allegations of misconduct and criminal behavior across the clinical trials including sexual assault, are being investigated by the agency.


Further safety assessments on blood pressure and cardiac events were presented, as they were noted to be AESIs due to MDMA’s effects on heart rate. Patients with moderate cardiovascular risk underwent additional screening measures, including stress testing. Patients were excluded if they had relevant conditions such as uncontrolled hypertension, significant cardiovascular or cerebrovascular disease, and/or atrial and ventricular tachyarrhythmias. All vital signs measured pre-dose, interim, and at the end of medication sessions. When the agency asked why blood pressure and heart rate were not measured throughout the study the sponsor said that equipment and consistent monitoring would’ve interfered with the MDMA-AT process by being intrusive.


Some other questions for the Lykos team included:

  • How participants were recruited and whether recruitment through referral or certain internet forums “stacked the deck” for people with experience with MDMA and other psychedelics. Specifically noting that 40% of participants had prior MDMA experience.

    • Lykos responded by showing data that evidenced there was no difference between primary outcomes for those who had an MDMA experience and those who did not

  • How interim therapy before the follow-up influenced MPLONG results.

    • Over 70% of patients in either arm had received any psychotherapy in between the parent study and MPLONG, with the majority being in the undefined category

    • Several in the placebo group had a form of cognitive behavioral therapy, EMDR and psychodynamic therapy which are commonly used for PTSD treatment

  • How could concomitant medication potentially confound results?

    • Approximately 90% of both treatment arms reported concurrent use of at least one medication

    • 20% of patients in the MDMA-arm were using psychostimulants for ADHD and nootropics, which given their similarity in pharmacological profile or physiological properties to MDMA, could be confounding.

  • How would the therapist team look in post-approval, whether relationships between therapists should be assessed including financial or mentorship relationships that may compromise ability or willingness to intervene.

    • Lykos CSO stated that guardrails should be considered when developing the post-approval therapy team

  • How would MDMA be kept from diversion outside of its approved indication?

    • Lykos noted that they would begin with a limited roll out that was only available in specific healthcare settings, mandatory enrollment in a registry monitoring the drug, and use single-dose packaging.


Proposed REMS (Lykos and FDA Presentations)

A large discussion focused on proposed Risk Evaluation and Mitigation Strategies (REMS). The FDA stated, “REMS must be determined due to potential for harm associated with impairment after exposure to MDMA,” but they are not sure what these REMS would be at this time given the lack of AE and other safety data. A large issue noted by the panel was the lack of laboratory assessments post-MDMA, which is included in every NDA application, but due to some poor oversight the reviewer for the agency did not notice this data was missing. One of the committee members stated: “both the applicant and we have to take responsibility…”.


Ignoring this huge issue (which is apparently what the agency and Lykos did), REMS were proposed by both groups. The Lykos proposed REMS was limited and focused on supporting safe use through patient monitoring and provider training as they do a limited roll-out. 


The FDA spent a lot more time focusing on proposed REMS, of which some of the suggestions overlapped with those proposed by Lykos. They noted the following:

  • The drug be dispensed only in certain healthcare settings, which include

    • a prescriber is available during midomafetamine administration and monitoring

    • at least two healthcare providers are onsite (one of which must be a licensed healthcare provider) to monitor the patient’s medical (including vital signs) and psychological status for at least eight hours or until the patient is stable to be discharged

    • emergency action plans are in place to escalate care if needed based on the patient’s medical or psychological status

    • plans are in place in case the patient requires longer monitoring

    • the patient is stable to be discharged from the healthcare setting

    • the patient is released to an accompanying adult after each medication session

  • The drug must be dispensed to patients with documentation of safe-use conditions and patients must enroll in REMS, which include education on:

    • potential effects and risks of midomafetamine

    • need to be monitored for at least eight hours

    • need to leave the medication session with an accompanying adult

    • not to drive or operate machinery until at least the next day

    • need to follow up with the healthcare setting after medication sessions

  • Each patient using the drug be subject to monitoring

  • Each patient using the drug be enrolled in a registry, of which data collected will include but not be limited to:

    • signs and symptoms of mental or physical distress experienced by the patient

    • onset and duration of short-term effects

    • monitoring duration

    • if care needed to be escalated

    • safety after medication sessions including the occurrence of events indicative of serious harm from patient impairment from midomafetamine administration

  • Implementation system to assist with operationalization of the REMS

  • Timetable for submission of assessments


FDA also noted other issues that need to be addressed separate from REMS, which included:

  • Return of blood pressure and heart rate to safe level prior to discharge

  • Addressing risk of adverse cardiovascular sequelae in patients with preexisting cardiac disease

  • Focus on mitigating events resulting in hospitalization or death, events that could put someone in the hospital or death (driving, walking into traffic, etc.)

  • Negative consequences like sexual assault or financial coercion

  • Worsening psychological disorders that cause disability

  • Suicidal ideation and behavior


Most importantly, the panel stated many times throughout the meeting that proper REMS could not fully be determined at this time due to a lack of safety data surrounding cardiac events, AEs, and laboratory assessments.


Public Commentary

This was perhaps the most awaited part of the ad-comm meeting, given they had to extend time to accommodate all the speakers. There were 32 oral presentations, approximately 20 that were in full support of the application, 10 that were against the application but in support of MDMA-AT as a concept, and 2 that were neutral. One oral presenter was not present, bringing the original count of 33 down to 32. Each speaker had 3 minutes and were promptly cut off if they went over. While I will not be recounting every comment, I will highlight some that moved me.


If you are interested in reading the written comments, please check out that coverage from my colleagues at Psychedelic Alpha: Patients, Practitioners, Researchers and Public Submit Comments Ahead of FDA Advisory Committee on MDMA, May 29.)


Russell Hausfeld, an investigative journalist and writer at Psymposia, shared his research and reporting from the last eight years on the developments of Lykos Therapeutics. He noted when he began covering this topic and organization, he had aligned with “the goals to legalize and destigmatize psychedelics,” but after years of reporting felt “it would be irresponsible to endorse this company…” After discussing some of the misconduct he had heard through his reporting, he highlighted the words of some of the veterans who volunteered their stories of mistreatment in 2022. Hausfeld quoted one such story, “I [the veteran] watched as they used veterans and discarded them as soon as they no longer served the useful purpose, regardless of mental health consequences or social implications.” Another veteran quote included, “If this treatment by Lykos is happening to me, it concerns me about the population that Lykos will be working with moving forward.”


Jonathan Alpert, Chair of the Council On Research for the American Psychiatric Association, shared his thoughts on the efficacy of the trials. He stated that while decreasing symptom ratings represent promising treatment for a devastating illness, there are significant limitations to the current evidence based on MDMA for PTSD. He highlighted bias and functional unblinding of participants, as well as the participants in the phase 3 trials prior exposure to MDMA. He said, “ [prior use] …is unusual for drug treatment studies. That means that people who presumably had positive or neutral effects from MDMA in the past might be more likely to have participated…,” highlighting the threat to the generalizability of the studies. He concluded by noting the APA supports research and therapeutic discovery of psychedelic agents that are pursued with the same scientific integrity, rigger and regulatory standards applied to other promising therapy. This includes future research with head-to-head comparison with other FDA approved medication.


Kayla Greenstein, a psychology candidate at the University of Sydney with experience in sexual assault response shared her thoughts despite it being 4am her time. She shared how she wanted to conduct a psychedelic clinical trial for PTSD, but as she looked at the psychotherapy component, she quickly realized there were serious issues in the research protocol. “I read the therapeutic manual very closely, and I’ve read all of the references in the manual,” Greenstein said. “The core of the therapy is that we all have an inner healing intelligence that can be accessed through MDMA and other non-ordinary states of consciousness. Given the centrality of the inner healing intelligence in their therapy manual and mechanism of action, I was really surprised we didn’t hear more about it today from the sponsor.”  She further shared that through her research she discovered the manual is rooted in ideas that trauma originates in the birth canal, which includes homosexuality.  She urges, “this is not a safe therapy model,” highlighting the lack of recognition of the role of coercive control and increased vulnerability. She ends by saying, “I am still hopeful about MDMA therapy and I look forward to seeing the research from labs that are not associated with Lykos. I wish I could support this application however, I believe approving this model of MDMA therapy would result in substantial further harm.”


In the same vein, Dr. Neşe Devenot, researcher at Johns Hopkins University with expertise in psychedelic bioethics, shared their concerns with the Lykos protocol. They open by stating, “This committee has been misled by Lykos to believe this intervention was nondirective and empathetic.” Devenot continued, “The therapeutic approach is based on spiritual teaching, and the essence of that treatment approach is a death-rebirth process. Although this specific intervention isn’t in any of the briefing documents that were submitted to the committee, it is associated with identifiable patterns of harm across like clinical trials.” They then went on to highlight an excerpt from Integral Psychedelic Therapy, where Lykos supervisor and therapist, Veronika Gold, touted consent violations and use of physical force as a part of the therapeutic process, dismissing the distress of her patient. Devenot urges the agency to take her comments into consideration and think about what other instances of misconduct Lykos is not sharing.


Ifetayo Harvey, Executive Director of the People of Color Psychedelic Collective, began her comment by sharing that she had previously worked as an assistant at the Multidisciplinary Association for Psychedelic Studies (Lykos previously was MAPS Public Benefit Corporation) for eight months in 2015. “Despite my poor treatment as an employee,” Harvey said. “I am grateful to MAPS for starting a movement around psychedelic healing in clinical settings.” She went on to state, “this is the first time, in my opinion, that advocates have had the space to share and have others engage with our concerns. There’s a tendency in the psychedelic community to shy away from critiques or confrontations.” Her main critique was that the field and MAPS regularly dismiss valid concerns from other critics and refuse to engage. There needs to be an effort to improve and ensure consumer safety, especially after seeing the evidence of abuse, crossing of boundaries and discrepancies in data. Harvey states, “I’ve concluded that there needs to be more rigorous research on MDMA psychotherapy before it’s brought to the public.”


MDMA researcher and CEO of Tactogen, Matthew Baggott, sought to provide comment on risks associated with the application. Importantly, he highlights NIDA has funded 460 million dollars of

projects involving MDMA. In which, over 1,500 participants have been given MDMA in studies not sponsored by Lykos. Baggott says that “controlled MDMA-administration studies document manageable physiological risks such as time-limited cardiovascular changes and, when fluid intake is unrestricted, hyponatremia.” He also spoke on potential harms related to vulnerability. “Controlled MDMA-administration studies also confirm acute self-report changes in mood and social feelings. These changes, combined with MDMA’s history, raise reasonable concerns that MDMA might increase patient vulnerability to boundary violations or other harms.” Ultimately, and despite being CEO of a company that is a direct competitor with Lykos, Baggot states “It is clear that MDMA can be used with acceptable safety under medical supervision. Additional data will help quantify likelihoods and time courses of specific risks in patients, but the balance of apparent benefits and risks appears to be favorable.”


Veteran organizations such as the Wounded Warrior Project, Veterans of Foreign Wars and Disabled American Veterans spoke on behalf of their members, pointing out the large need for novel treatments for veterans with PTSD. Many highlighted the overwhelming statistics of veteran suicide and comorbid disorders. Several participants, of which many were veterans, provided public comments with extremely positive things to say about their participation in the clinical trials, some of which I will quote below (and regret that my AI voice-to-text did not capture the names of the speakers):


“...I couldn’t imagine a world where there was a solution, now I get to fully live my life. My perspective on the world has changed because my perspective of my experience changed…I learned that I was living in survival mode, and once I was able to process my grief and trauma I felt self-empathy and self-love for the first time in decades and my trust in this world grew again. I started looking at the glass full instead of being stuck in this endless victim narrative.”


“...I kept searching for new treatments and found this trial. Within the very first hour of the MDMA session. I felt an intense sense of repair and spontaneous rewiring of my body. The effects were immediate, the emotional flooding banished what used to feel like a tsunami of overwhelming panic to now merely a puddle at my feet. A change of perspective is everything and MDMA is a reset button… This was hard work, but the results were life-changing. None of my previous therapies came close to unraveling all of my trauma. The best aspect of this medicine is that I no longer need it. My MDMA training wheels are off and I remain resilient after those three sessions.”


“I was very fortunate to be accepted into a trial after reading about social media and applying. I was entering the trial with a healthy dose of skepticism, having numerous treatments in the past without success and hearing about this treatment…These sessions became a pathway to explore a new outlook through this love and appreciation, transforming my relationship with others. But, also, I wouldn’t claim that MDMA eradicated my PTSD upon completing the trial…but also, I no longer have the symptoms that tormented me for years. I am experiencing a newfound ease and laughter, and a profound sense of lightness and calmness…This transformation has made me a more effective partner, parent and most significant to me, is granting me the enjoyment of motherhood.”


“I’ve lost count of all the people who reached out to me to say ‘I was going to kill myself, but I saw you so I’m going to wait…’ For the last decade, I had to tell hundreds of people who have reached out to me that help is coming, but we have to wait for the proper approval process… I fear what will happen to them if this therapy is not approved.”


Despite the many raves for MDMA-AT, some people shared negative experiences. Beau Witka described a guided therapy session from someone who received training from the California Institute of Integral Studies - which provides training for Lykos studies – that made his PTSD worse. He shared that following this experience he experienced symptoms that completely “derailed his life” which include “extreme exhaustion, brain fog, and severe cognitive impairment.” He also shared that he had a positive experience after, which is helping him recover from the devastating first guided experience. He fully supports MDMA-AT as an option, but cannot support MDMA therapy being available to the mainstream without additional focus on training and helping those with extended difficulties.


In one of the most moving presentations, was a statement read on behalf of trial participant Meaghan Buisson, who was specifically recruited to the study by Lykos. The letter stated that the trial sponsor failed to consent the day before her first session and they found something in her screening, which qualified her for exclusion criteria and was ignored to keep her in the study. Her letter reads in regards to the harms suffered in the trial, “I will not be going into detail. There is a video available online. The fact that it and my name are public is extremely difficult. It should never have been necessary.” Buisson shares that she now suffers new symptoms of PTSD, including a distrust of medical providers, and urges “the panel to reconsider the veracity of Lykos’ claims.”


Misconduct Concerns

To many peoples’ surprise Lykos did mention the case of misconduct that took place in the Phase 2 Clinical trial, which resulted in some changes to their protocol and an internal investigation. Despite their attempts to circumvent this discussion by mentioning it in their presentation, this was something that was discussed throughout the 9 hour long advisory meeting. Information on this specific issue can be found here and here.


In the Q&A portion following Lykos’s presentation, patient representative, sociologist and qualitative research consultant at the Injury Prevention Research at University of North Carolina Chapel Hill, Elizabeth Joniak-Grant, said “let’s try not to gloss over this misconduct; it was sexual misconduct”. This is especially important when discussing treatment for PTSD, where several folks have sexual violence related traumas. Joniak-Grant later voiced several points on the lack of data and inability of Lykos to provide more information before the voting. These included concerns over misconduct and the ongoing investigations, stating “I can’t in good conscience support something where these many harms are being reported.”


Another panelist referenced the misconduct and ‘probably criminal violations’ in his question about therapists and relationships, asking Lykos how that would be addressed moving forward. Their response that there should be consideration on this topic. In the discussion prior to voting, this same panelist again raised some serious questions about the sponsor being able to educate and deliver psychological intervention in a responsible way. They stated, “Unfortunately there has been misconduct that has occurred, which really polluted our ability to interpret the data.”


Consumer representative, Kim Witczak, brought up the misconduct from a different perspective. They noted that while they are pleased to see this treatment as something that is being discussed today, they are concerned with the misconduct allegations. “Usually this happens when something is on the market already,” highlighting that this typically comes with lawsuits, pricey litigation, and public concern. “We have an advantage to investigate before that.”


Summary of Discussion and Major Review Issues


“We are creating a new field of medicine…and we don’t take this lightly.”


“Amidst the complication of all of this, the patients deserve the opportunity for us to move forward and this regulated way is the only way to do this.”

These are just a few of the statements before the discussion and review after all the presentations. Below I will highlight the major points discussed by the panel as it relates to each question and their final votes.


Question 1. Discuss the evidence of effectiveness for MDMA for the treatment of post-traumatic stress disorder (PTSD). Consider the following:
  • The potential impact of functional unblinding on interpretability of efficacy results

  • The durability effect

  • The role or psychological intervention in the treatment paradigm


Major Issues: 
  • Functional unblinding degrades confidence in efficacy

    • Only attempt for comparator was smaller doses MDMA, rejected other suggestions

    • Blinding not tested in MAPP1

    • Unblinding of therapists during sessions

    • Expectancy bias within sample

  • Issues with recruitment and recruitment methods

    • Confounding variables in the long-term durability data

    • Unblinding of MAPP1 before follow-up

    • Length of follow up differs between participants

    • Confounding substance use and intermittent therapy

  • Generalizability

    • Prior exposure to MDMA vs prior exposure to standardized therapy

    • Lack of diversity in race/ethnicity

    • Lack of diversity in PTSD severity

  • Disentangling of the psychotherapy component and MDMA treatment

    • No non-therapy arm or drug-only arm, lacking 2 x 2 design to determine MDMA effectiveness of the drug alone

    • No standardized therapy approach across arms and sites


One of the panelists stated the results are “really promising and it's obvious this treatment has impacted a number of people in positive ways, but there are problems with the data.” She continued by pointing out, “One or two [data issues] may be okay and addressable, but when you pile them on top of each other there isn’t enough convincing evidence.” 


One comment was quite interesting, as it caught on to the uniqueness of the psychedelic field and this application. ‘The language use is unlike most things that we see,” They said, highlighting several public commenters referring to these studies as being part of a larger “movement”. The panelist points out this so-called movement has a large following which could influence expectancy and explain why there is such high background use of MDMA and low drop-out rates. They further state these points all may be “suggestive of a high level of interest in engagement and allegiance.”


Question 2. Discuss whether the available data are adequate to characterize the safety of MDMA for the treatment of PTSD.
  • Consider the limited data collected on events deemed positive, favorable, or neutral that would inform abuse potential for this program and the lack of data from some clinical laboratory tests.

  • Comment on whether you have concerns about other safety issues and what additional data would be useful to characterize the safety of MDMA.


Major Issues:
  • Missing data

    • Lack of collection of laboratory assessments (which the FDA admitted is the fault of both parties)

    • Hepatotoxicity, hyponatremia, drug-drug interaction data

    • Safe medication titration data

  • Lack of AEs collected despite FDA asking specifically for them

    • AEs that sponsor deemed positive, favorable or neutral

    • Concerns over omissions of other data that they didn’t consider AEs (i.e. distress)

  • Specifics on Dropouts and withdrawn consent

    • Never received information from Lykos


One panelist noted that while they are less concerned with things like euphoria and blissfulness as it relates to “abuse potential,” they are more concerned about how these positive feelings may “make it easier for clinicians to prey on vulnerable patients.” 


Despite missing data a few panelists including Walter Dunn, were confident that many of these could be addressed post-approval. Some panelists noted that phase 4 trials would be necessary to assess some of the potentially safety concerns, specifically with cardiac events. Phase 4 trials are typically to assess side effects that are not seen in earlier trials and can also be used to assess how well a novel treatment is working in the general population over a long period of time. 


Others were not so convinced. While excited about the potential of MDMA-AT, one panelist stated:

"We're building the airplane as we're flying it, and while that’s ok with something like blinding, that is not okay with safety concerns."

Another commented on the fact that there are already evidence based treatments, of which many of the participants did not attempt before the trials. While these other treatments have dropout rates, the panelist pointed out they have strong outcomes and take around 12 h of therapy, whereas the Lykos treatment has 40+ hours of treatment and potential lifestyle changes that put a burden on access for patients and on the providers.


This discussion took a turn to discuss diversion of MDMA from its indicated use, and was spearheaded by the Committee Chair, Rajesh Narendran. He voiced several concerns that “illicit MDA is going to soar.” He further went on to say, “I would not be surprised if people go home and use cocaine, you know, use alcohol I mean with their partner who is supposed to be responsible, you’re going to have left and right issues, that’s my personal feelings on it.” Many people watching were confused by this rant, especially since diversion would be addressed in REMS and through the Drug Enforcement Agency.


As a pharmacologist, substance use researcher and psychedelic researcher I have to comment that these personal insights by Narendran were not based on evidence or fact. The present application does not have anything to do with cocaine or alcohol use and the data presented to him do not suggest any use of these substances after sessions. This attitude is wholly inappropriate and further stigmatizes drug use, especially in vulnerable populations like those with PTSD.


Question 3. Discuss the potential for patient impairment to occur with MDMA and the potential for serious harm that may result due to the impairment.

Major Issues:
  • Staffing Needs and avoidance of power dynamics

    • Trainees should not be used as core staff

    • Two licensed therapists of similar standing should be present

    • Need for ancillary staff like nurses and technicians to mitigate potential emergencies (attempts to harm self or others, elopement)

  • Titration off other medications like SSRIs

    • Lack of data on titration and potential withdrawal from medications before and during study influencing drug effects

  • Discharge Guidelines

    • Adult should have to accompany the patient home

    • Overnight stays might be necessary


For the third question, the panel was advised by an FDA Representative that the discussion and voting should be based on what was contained in the briefing documents and open public hearing not  “unfounded complaints of misconduct.”


Some panelists were concerned over the lack of diversity in the trials and how that might cause issues in a general roll-out, stating that cultural differences may influence response to the drug. Others rebutted, suggesting that diversity only is an issue in drug approval if there is a physiological reason for the drug to produce different results due to race/ethnicity/sex/gender.


Question 4. Discuss whether the proposed risk mitigation is sufficient to mitigate serious harm resulting from patient impairment. Include any additional safety monitoring conditions needed for the safe administration and monitoring of MDMA if approved for PTSD.

Major Issues:
  • Not enough information to inform REMS properly

    • Lack of safety data including characterization of subjective effects

    • Necessity for labs to be done before, during and after treatment 

  • Outside accreditation and training for personnel

    • Including medical training to respond to physiological events

    • Training and accreditation outside of Lykos Therapy Manual 

  • A way to ensure safety of patients from misconduct

    • Registry and independent entity to report AEs 

    • Potential surveillance with explicit direction about review


Surveillance was a large topic in this discussion question. Many noted that having surveillance may be beneficial to review sessions and ensure patient safety, but others noted that many PTSD patients may not consent to surveillance due to issues with trusting others, including healthcare professionals. One panelist said, “surveillance rarely ever gets looked at” and there needs to be “very explicit directions in terms of what we are going to do with that surveilled information.”


The Vote & Final Thoughts

  1. Do the available data show that the drug is effective in patients with posttraumatic stress disorder? 

2 YES // 9 NO
  1. Do the benefits of midomafetamine with FDA’s proposed risk evaluation and mitigation strategy (REMS) outweigh its risks for the treatment of patients with PTSD?

1 YES // 10 NO

Many committee members note the decision was difficult given the promise of data and significant p-values, but were overall concerned with recruitment, durability and unblinding ultimately led them to vote no. Many echoed the same sentiments,


“too many missing parameters”
“we're still trying to understand the risks''
“its new territory”

For the one person who voted yes to both, Dunn explained why. “REMs are still in conversation between sponsor and agency, but I think it's 75% of the way there and small tweaks would be fine to address these.”  “I ultimately voted yes because we are in dire need of new treatments for PTSD… and this has potential to make a difference.” 


Although this is an advisory committee, the FDA does not officially decide on approval of Lykos’ application for MDMA-AT for PTSD until August 11, 2024. In the meantime, they may do more data analysis or come up with REMS that both parties agree to. It is unclear whether the investigation of the FDA into the misconduct and data omission claims will be complete before August 11 and whether or not this investigation will prevent approval.


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