Stakeholders Address Alleged Research Bias As Veterans Endorse MDMA-AT
As reactions to last month’s unexpected resistance to pending FDA approval of MDMA-assisted therapy continue to reverberate, observations about the clinical data and the need for effective treatments have led to sometimes bruising public discussions in advance of the August 11th decision.
In part one of our series, we looked at whether Lykos Therapeutics, which filed the New Drug Application (NDA) for MDMA-AT, can address safety concerns raised by FDA advisors during a June 4th public meeting to discuss the proposed therapy. In response to criticism from the FDA’s Psychopharmacologic Drugs Advisory Committee (AdComm) and the Institute for Clinical and Economic Review (ICER) that Lykos NDA data was insufficient to outweigh potential risks, the company says it is confident that it can work with the FDA to address safety concerns.
In this concluding story in our series, we will examine concerns about potential bias arising from pro-psychedelics advocacy and the functional unblinding of clinical trials, allegations about Lykos management, and the widely divergent perspectives of some stakeholders with PTSD, including veterans who are pressing for more effective treatments.
Did Pro-Psychedelics Advocacy Bias The Study?
In their separate evaluations of the Lykos NDA, both the AdComm and ICER, a nonprofit which advises the insurance industry, expressed multiple criticisms about the reliability of the application’s data. In its Final Evidence Report on the Lykos data, ICER identified potential “concerns about reporting bias,” arising from “very strong feelings” concerning “the value of psychedelics for management of serious mental health conditions” within “some number” of the MDMA-AT therapist and patient population. This is “unusual in most assessments of medical interventions,” the advisory group said, adding that this heightened the difficulty of “assessing the balance of benefits and harms.”
ICER “felt these concerns could potentially affect the interpretation of the evidence for MDMA-AT.” During their analysis, the organization says it “conducted a number of interviews with those with firsthand or secondhand knowledge of the trials and related events.” This included seeking more information about allegations of therapist misconduct at a Canadian clinical trial site documented in the podcast Cover Story: Power Trip, produced by New York Magazine and Psymposia in 2021. ICER investigators said they spoke with “people involved with the podcast, subjects in the trials, and a therapist who had been involved in one of the trials.”
Dr. David Rind, the chief medical officer for ICER, told NPR, “You have a group of people who are very upset about how these trials went. We couldn’t tell, even though we talked with people where this happened, whether that represents a tiny fraction of bad events or a number of bad events large enough to have rendered the trial just not believable.”
The organization said it “received relatively little input from Lykos” prior to June 26, the day before the publication of ICER’s Final Evidence Report. On that day Lykos requested a call with ICER advisors. In an April 22 letter submitted as a public comment to ICER’s Draft Report, Lykos CEO Amy Emerson said, “Unfortunately, the issues in the ICER report were not raised during the three meetings held between ICER and the Lykos management team prior to issuance of the draft report.”
ICER’s self-admittedly “(limited) investigation” documented in its Final Evidence Report found that “the pool of therapists and, in some cases, trial participants appears to have pulled heavily from the existing community of those interested and involved in the use of psychedelics for possible psychological benefits.” Some participants and therapists ICER talked with reported “feeling pressured to report good outcomes and suppress bad outcomes when they were in the MDMA arms of the trials.”
According to ICER, sources who identified as part of this community felt that reporting “bad outcomes” could lead to being “shunned” or contribute to “future patients being denied the benefits of MDMA-AT.” ICER also charges that “Patients in the trials included therapists who had worked in this space, including some with very close relations with those running the clinical trials.” The organization says this “is unusual and heightens concerns about pressures to tailor reported results.”
A letter released on April 22 by more than 70 clinical professionals who worked on the Phase 3 trials of MDMA-AT, submitted in response to ICER’s Draft Report, strongly rebutted this analysis. The signers, who included clinical investigators, clinicians, supervisors, trainers, and monitors, wrote that the underreporting of adverse effects “seems unlikely.” They argued that “another safeguard against intentional or unintentional bias in the Phase 3 trials was that the entire study team was trained in, and collectively responsible for, adverse event reporting. Clinically significant destabilization (e.g., worsening depression or anxiety) was always documented as an adverse event, either by the study therapists or other study staff.”
The ICER report further alleged that biases toward psychedelics were embraced not only by clinical trial investigators, but also by the subjects. The organization wrote in its report that sources told them that “feelings around psychedelics,” which were “common” among trial participants, “lead the community to engage with them more like a religious movement than like pharmaceutical products.” According to the report, “feelings were sometimes inculcated in patients participating in the trials.” ICER also asserted the need to balance the “strong beliefs” among those voicing critical concerns about the trials.
Many clinical professionals rejected ICER’s characterizations, including those who signed the April 22nd letter. The authors of the letter challenged ICER’s assertions about “inappropriate study design and conduct” as “hearsay,” stating that to their knowledge, none of the 109 therapists and principal/co-investigators who contributed to the Phase 3 trials were consulted to “address accusations.” The perspectives of the authors were not represented in ICER’s Final Report.
Speaking to NPR, Willa Hall, a clinical psychologist who worked in the Phase 3 trials said, “I didn’t recognize the study they were talking about. I think a lot of us felt quite insulted” by ICER’s characterizations.
Did Functional Unblinding Impact The Data?
Another concern about the validity of the NDA data shared by AdComm and ICER involved potential bias arising from functional unblinding. This occurs when study investigators or participants can correctly guess which treatment a study participant receives during the clinical trials.
In its June 4 briefing document, AdComm wrote that “the study was designed and conducted as a double-blind trial, but participants experienced functional unblinding due to the effects of the drug itself.” A post study survey cited by AdComm states that the percentage of participants correctly guessing which treatment they received was 90% for the MDMA group and 75% for the placebo group. AdComm also noted the potential presence of expectation bias. This occurs when participants who believe that they “received active treatment expected that they would experience a clinical benefit,” while placebo recipients “fared worse due to disappointment” from not experiencing “anticipated effects,“ or “some combination of both.”
A consensus statement, issued on July 7th by 23 prominent researchers and clinicians who work with psychedelics, addressed this concern arguing that functional unblinding and expectancy events “are common issues with testing psychoactive medications.” They do not believe these concerns “rise to a level that would call the main clinical trial findings into question.”
The April 22nd letter submitted by clinicians and researchers notes that functional unblinding is a common concern in conventional clinical research as well as psychedelic research. They cite “medication side effects” and “a comparative-efficacy psychotherapy trial (e.g., EMDR vs. CPT)” as examples.
According to the authors of the letter, “Study design should take measures to minimize the effect of functional unblinding.” They assert that the Phase 3 trials of MDMA-AT did so by using rigorously trained independent raters, blind to the participant’s treatment, to “rate therapists on their adherence to the MDMA-assisted therapy treatment manual.” In ICER’s Final Report, the organization argued that the raters only addressed portions of the data, stating, “The safety data collection relied on site therapists, unlike the primary and secondary study outcomes which were assessed by blinded and independent raters.”
ICER Calls on FDA To Investigate Lykos Conduct
In its analysis of the MDMA-AT study data, ICER also raised concerns about the management of Lykos, including “design choices that affected the interpretation of the results,” and “misconduct that could have influenced the validity of the trial outcomes.” In addition to concerns about the potential for therapist misconduct, the organization called on the FDA to investigate an email exchange it discovered “where it appears that the [principal investigator] excluded [a] patient from the long-term follow up study.” ICER wrote in its Final Evidence Report that it “heard that some patients were prevented” from entering the study. According to the report, sources “felt this was done to keep negative outcomes out of the data set.”
A clinical investigator involved with the Phase 3 trials disputed this claim in a public comment to ICER, stating, ”This is untrue. No participants were prevented from entering the Phase 3 long-term follow-up study (MPLong). Indeed, we went through great pains to locate and include all Phase 3 study participants in order to evaluate the durability of the study drug. Approximately 70% of Phase 3 participants contributed long-term follow-up data, the rest either declined to participate or never responded to our repeated requests for contact.”
In response, ICER said, “We had first-hand reports of such events. We cannot be certain that these reports were accurate, but we do wonder whether [the PI] is certain that this could not have occurred.”
In its Final Evidence Report, ICER described an event reported to them by a study participant who was “told to take their own supply of MDMA at home” when struggling “after the trial was completed.” The organization says it also heard “secondhand reports of similar events.” ICER asserted in its report that “Even if this was only a singular event, it shows the clear breakdown of blinding, the inclusion of participants who were anticipated to have access to their own supply of MDMA, and a disregard of good clinical trial practices.”
ICER also called on the FDA to investigate an article published in STAT+ that contains allegations from two former Lykos employees describing an “unprofessional approach to data, where nearly everyone in the company had access to results coming in from the trials.” ICER noted, “If this is correct, it would reflect a serious breach of data protection and would raise concerns about whether decisions were made during the trial based on knowledge of interim trial outcomes, as well as how to correctly interpret statistical tests of significance when data have been repeatedly examined. Additionally, this raises potential concerns about the integrity of collected data.”
Lykos Response to ICER Allegations
Lykos pushed back on ICER’s claims in a June 27 statement disputing the validity of the “contents and overall findings” in the organization’s Final Evidence Report. ICER’s analysis, the company said, “cast unfair doubt on the integrity of Lykos, dozens of dedicated clinicians and researchers, and data from hundreds of clinical trial participants.” It charges that ICER “does so without adequate regard for the high unmet need for new treatments for PTSD and the unique complexity of developing treatments for this patient population.”
Lykos said that in its report, ICER “goes beyond” its “traditional scope” of “value assessment and cost-effectiveness evaluation of potential new treatments.” The company asserts that ICER “cites trial design concerns that, while important, have been and are being extensively discussed with FDA” through the development and application process. Lykos further charges that the ICER report relies on “subjective analysis in a manner that seems misaligned to the data driven approach ICER is meant to provide,” creating “a concerning precedent that could negatively impact innovative treatments.”
Lykos specifically objected to the ICER report’s use of “select anonymous reports, without adequate and proper documentation.” The April 22nd letter issued by clinical professionals goes further, saying that none of the 109 therapists and principal/co-investigators who contributed to the Phase 3 trials were consulted for the ICER Draft Report. The letter argues that this group was in the strongest position to address concerns about study design and conduct. Instead, the authors wrote that “a number of assertions in the ICER report represent hearsay, and should be weighted accordingly.”
According to the letter’s authors, this is especially important because two of the sources referenced in the ICER report include a podcast and online article “written and produced by individuals who have repeatedly and publicly expressed strongly negative views about the medicalization of psychedelic substances, underscoring the high risk of bias in the preliminary report.”
The material linked in this observation included an opinion piece written by David Nickels, former managing editor of Psymposia who has been critical of MAPS, and a Substack post by Neşe Devenot, a senior lecturer in the University Writing Program at Johns Hopkins Krieger School of Arts & Sciences.
Devenot also offered public comments to ICER and AdComm, in part by co-authoring a citizen petition to extend the FDA public hearing on MDMA-AT. The petition focuses on disclosures from an anonymous former employee of MAPS PBC, the for-profit predecessor organization to Lykos Therapeutics.
The allegations contend that MAPS PBC fostered “an organizational culture that normalized violations” of Institutional Review Board (IRB), Health & Human Services (HHS), and FDA regulations. The petition includes a number of statements that challenge the credibility of MAPS PBC, Lykos, and its employees. As a result of the petition, the public comment period of the AdComm meeting was significantly extended.
Stakeholders With PTSD Speak Out
During a period for public comments during a May 30th ICER New England Comparative Effectiveness Public Advisory Council (CPAC) public meeting on PTSD, other stakeholders stated their objections to the Lykos NDA.
“I’m a woman with PTSD who understands clearly what is at stake here,“ said Meaghan Buisson, an MDMA-AT trial participant whose allegations of abuse against two former Canadian clinical trial investigators were detailed in the Cover Story: Power Trip podcast. During the meeting, Buisson asserted that “Even as [Lykos Therapeutics] promotes itself as a global healer for trauma, its response to patients harmed in their own trials highlights a relentless disregard for minimal standards of care, and or genuine interest or capacity for trauma-informed practices.”
Buisson told ICER during the public forum that she has been “repeatedly targeted and attacked” for speaking out, charging that “Lykos stakeholders relentlessly frame my assaults as a consensual relationship.” Buisson says the fact that her “personal abuse” and “name are public is very difficult for me, and a decision that came about as a direct result of Lykos’ effort to bury truth about the harms being done to me.”
“There is no consent in patient/therapist sexual abuse,” Buisson said. “Every single American and Canadian Medical and Psychological Association is explicit and clear on this. There is no consent. It is an exploitative, coercive, overwhelmingly abusive power dynamic. No diagnosis, ever, justifies the use of sexual assault as a therapeutic modality.”
MAPS PBC, which was then sponsoring the Phase 3 trials, addressed the allegations in 2019 and 2022, saying it reported the “ethical violation” to health officials in Canada where the conduct occurred and to the FDA. The organization said the co-therapists, Richard Yensen, Ph.D. and Dr. Donna Dryer, a married couple, “were barred from all MAPS-related activities and from becoming providers of MAPS-affiliated MDMA-assisted therapy if the treatment is approved.” On August 1, 2023, Dryer permanently relinquished her medical license and accepted a reprimand after an investigation by the College of Physicians and Surgeons of British Columbia determined she “committed unprofessional conduct.”
Lykos Therapeutics, which succeeded MAPS PBC, told Lucid News, “We regret what happened with these therapists in our study, and the safety of our participants is of utmost importance. Since then, we have carefully developed and implemented policies and practices aimed to prevent, reasonably detect, investigate, report and thoroughly respond to allegations of misconduct. Lykos continues to assess practices regarding the safety of patients through a code of ethics, compliance procedures, a robust quality system, ongoing reviews of clinical trial processes, and ongoing risk assessments.”
In the heated discussions about harm, bias, and ethics surrounding the FDA approval of MDMA-AT, critics continue to speak out. “Ours is a biased view,” said Lily Kay Ross during the May 30th CPAC public meeting. Ross worked with Nickels to develop the Cover Story podcast for Psymposia and New York Magazine. Ross asserts that she and Nickels “are in a position where we have heard, and continue to hear, stories about the horrible things people do involving psychedelics, and the silencing of harms by institutions leading the psychedelic renaissance.” She has been critical about what she views as boundary violations, sexual assault, and manipulation that she alleges “psychedelic therapy condones as normal behavior.”
Ross credits a 2013 MDMA session with an underground facilitator with helping her achieve remission from “severe and debilitating PTSD symptoms.” She called for “high quality research into MDMA-AT [to] be conducted by a CRO [Contract Research Organization],” and for the field to encourage “healthy debate in order to establish sound clinical and ethical norms.”
The allegations and safety concerns presented by Buisson, Devenot, and Ross were reflected in ICER’s Final Evidence Report and the AdComm criticisms of the Lykos NDA. The AdComm vote against approving MDMA-AT sent shockwaves through communities that were hopeful about FDA approval, especially veterans groups, including Healing Breakthrough and Heroic Hearts Project. On June 24th, those organizations circulated a statement by Heroic Hearts Project Founder and President Jesse Gould characterizing ICER’s report as an “anti-veteran campaign against” MDMA-AT.
On July 10, the veterans organizations organized a press conference to amplify the needs of service members seeking effective treatment for PTSD. The event was held outside the U.S. Capitol building, where a memorial constructed of 150,000 paired dog tags was created to represent the deaths of military personnel by suicide since 9/11. Gould placed 17 dog tags on the memorial, representing the average daily number of of veteran suicides, and called on the FDA to grant veterans access to MDMA-AT. “Enough is enough,” he said. “Approving this treatment is not just a formality. It is a lifeline for the nation’s veterans.”
“Psychedelic assisted therapies have the potential to be the first genuine advancement in the treatment of veterans mental health in decades,” said event sponsor Congressman Jack Bergman (R-MI), a retired Lt. General in the U.S. Marine Corps. “If psychedelic assisted therapy can help treat a service member or veteran’s PTSD or prevent them from taking their own life, we owe it to them to take an active role in advancing these potentially life-saving therapies,” said Bergman.
Congressman Lou Correa (D-CA), who chairs the Congressional Psychedelics Advancing Therapy (PATH) Caucus criticized the FDA for “essentially stalling.” Correa said, “I want to remind the FDA that every day you wait, another 17 to 40 veterans lose their lives. FDA, do your job. Save veterans from suicide.”
Amid Controversies MDMA-AT Efficacy Data Is Considered
Some critics of the Lykos NDA charge that the veterans press conference on July 10 was not a grassroots effort, but instead funded by backers of Lykos Therapeutics, which Psymposia characterizes as a “therapy cult.” “It’s unacceptable and dangerous to use veterans as guinea pigs for a big pharma profit grab without safety and efficacy concerns,” the media organization stated on its website.
Other analysts take a different view. Considering the scope of the MDMA-AT clinical trial data, including the concerns raised by ICER and AdComm, the consensus statement of psychedelics researchers issued on July 7 focused on “the very urgent and widespread unmet need for effective treatments for PTSD.” They maintain that MDMA-AT merits immediate regulatory approval contingent upon a Risk Evaluation and Mitigation Strategy and “suitable safeguards and post-approval monitoring.” According to the researchers, this “should include a [REMS] that can be adjusted as real-world safety and efficacy data emerge.”
ICER acknowledges that if the efficacy results in the clinical trials “are reflective of the expected outcomes if MDMA-AT is administered broadly to people with PTSD, it would be an important addition to treatment options for PTSD, an often severe and disabling condition.” The AdComm also noted that “Although this application presents a number of complex review issues, it does include two positive studies in which participants in the [MDMA] arm experienced statistically significant and clinically meaningful improvement in their PTSD symptoms, and that improvement appears to be durable for at least several months after the end of the acute treatment period despite no additional doses of [MDMA].”
Researchers note in their consensus statement that participants who received MDMA plus therapy achieved higher rates of improvement than those who received therapy alone. They argue that the trial data demonstrates “substantial evidence of efficacy with a consistency of results” across fifteen study sites and multiple patient subgroups, offering “confidence in the reliability of the primary finding.” According to the statement, “87% of participants in the [MDMA] group experienced a clinically meaningful response, 69% no longer met the diagnostic criteria for PTSD, and 40% achieved remission,” each measure performing at least 20% higher than therapy alone.
Long-term studies show that remission is durable, persisting “for at least 6 months after the treatment, with 39% of the [MDMA] group still in remission, compared to 11% of the placebo-plus-therapy group,” the statement says. The MDMA plus therapy group also “showed significantly greater reductions” in scores on the Sheehan Disability Scale and Beck Depression Inventory, markers of functional impairment associated with PTSD and depression symptoms measured in the study’s key secondary endpoint. Patients in both studies “suffered from PTSD for an average of 15 years.”
“The word psychedelic scares everyone,” said Congressman Morgan Lutrell (R-TX), who acknowledged receiving psychedelic-assisted therapy for his combat-related trauma.
“It terrified me when I first got into the research. We need tools to affect change, to decrease symptomatic issues, to increase the quality of life, and MDMA is so perfectly positioned to do that. In August, if the FDA comes back with a result we don’t care for, we will continue to conduct research, because our service members and their families deserve that,” Lutrell said.
“New treatments are urgently needed,” said signers of the April 22 public comment letter from clinical professionals. “Future research will help quantify whether the benefit-risk profile changes when studying different patient populations, treatment protocols, and/or models of care. But given the enormous unmet need, coupled with robust Phase 3 efficacy data and a favorable drug safety profile, the 13 million patients with PTSD have good reason to hope that access to the combination treatment of MDMA-AT could change their symptoms and their lives.”