Recently, the FDA notified Lykos Therapeutics that its MDMA-assisted therapy would not be approved at this time and requested an additional Phase 3 trial “to further study the safety and efficacy of midomafetamine” (MDMA). The fallout led to MAPS founder Rick Doblin resigning from the Lykos Board, the layoff of 75% of its workforce, and Amy Emerson the CEO of Lykos stepping down. Michael Mullette will be the interim CEO and Dr. David Hough was named the Chief Medical Officer. Nevertheless, the VA is funding a study on whether MDMA-assisted therapy is an effective to treat Veterans for PTSD and alcohol-use disorder.
Rick Doblin will remain as the president of MAPS, Multidisciplinary Association for Psychedelic Studies. And Amy Emerson will transition to the role of an Observer on the Lykos Board. David Hough spent 17 years with Johnson & Johnson and oversaw the approval of Spravato (esketamine) by the FDA. He is also a West Point graduate and served as an Army psychiatrist for 10 years. Michael Mullette has worked more than twenty years in the pharmaceutical industry, and most recently oversaw the commercialization of Moderna’s COVID-19 vaccine during the pandemic.
Despite the reorganization of Lykos’ senior management, the company remains committed to its attempts to bring MDMA-assisted therapy to market, not only to treat PTSD, but also other mental health disorders. The Chairman of the Lykos Board, Jeff George, said: “Lykos is deeply dedicated to bringing midomafetamine to those suffering from PTSD and remains highly committed to this goal.” As a company, Lykos is dedicated to “transforming mental healthcare” and is committed to address the resubmission of MDMA capsules to the FDA to treat PTSD in adults. The VA is willing to also pursue Lykos’ goal, and Shereef Elnahal, the VA Under Secretary for Health, announced on LinkedIn the VA will help fund a study investigating the effectiveness of MDMA-assisted therapy for Veterans with PTSD and alcohol-use disorder.
In January of 2024, Politico said the VA announced it would fund psychedelic research for PTSD and depression for the first time since the 1960s. “In addition to being the largest health system in the country, the VA serves a population with disproportionately high PTSD rates.” The VA research will be done at the Providence VA Medical Center, and researchers plans to administer low-dose MDMA to the placebo group, hoping to better conceal which group study participants are in. The “functionally unblinded” previous studies had resulted in up to 90% of participants successfully guessing whether they were in the experimental or placebo groups.
Psychedelic-Assisted Therapy for Veterans
This is not just a whim of the VA Under Secretary for Health. The VA has an article, “Psychedelic-Assisted Therapy for PTSD,” that not only reviews the potential for MDMA-Assisted Therapy (MDMA-AT), but also looks at Psilocybin-Assisted Therapy (P-AT). It begins by noting while there are effective, evidence-based treatments for PTSD and depression, many people do not benefit enough from them. An exciting area of research is psychotherapy augmentation approaches with psychedelic drugs such as MDMA and psilocybin. “The Veterans Health Administration’s (VHA) Office of Research Development (ORD) is funding research on psychedelic compounds in Veterans.”
The effects of MDMA include reduced fear, increased social engagement, increased openness, increased receptiveness to positive affect, increased empathy and compassion, increased feelings of closeness, and increased disclosure of emotional content. MDMA targets memory reconsolidation and fear extinction processes, allowing for expanded perspectives and positive, affirming experiences. These effects are primarily attributed to MDMA’s activation of the 5-HT, or serotonin system.
The VA article noted that MDMA-AT is currently being investigated as a potential treatment for eating disorders, anxiety, alcohol and substance abuse, and PTSD. “The premise for MDMA-AT is that the therapeutic effects of MDMA are the result of an interaction between the medicine, the psychotherapy component, and the mindset of the participant and the therapists involved.” The rationale to look at MDMA to address PTSD is that it is an empathogen-enactogen drug. This means it causes the release of serotonin and dopamine, and elevates hormones and neurotransmitters that will help individuals with PTSD to overcome avoidance and better address their PTSD symptoms. MDMA is said to:
- Lead to greater social engagement, openness, empathy, receptiveness to positive affect, and disclosure of emotional content;
- Facilitate the release of oxytocin, which increases levels of empathy and closeness while also lowering stress responses;
- Increase self-compassion and prosocial feelings, both of which can assist with perspective taking when recalling a traumatic experience;
- Reopen the social reward learning critical period, creating cognitive flexibility that may support unlearning of distorted beliefs developed through traumatic experiences and the relearning of more helpful beliefs;
- Allow people to have higher tolerance when remembering unpleasant memories—a finding corroborated in humans following animal studies that showed that MDMA assists with improving fear extinction learning due to reducing amygdala activity, thus allowing for easier recall of traumatic memories for PTSD patients who may otherwise become overwhelmed by emotions; and
- Bolster fear extinction through improved hippocampal and ventral/medial prefrontal cortex activity, both of which show deficits in people with PTSD.
Historically, MDMA-AT had been used with a nondirective therapeutic approach. But now there are several studies underway to explore whether MDMA-AT can be used with established evidence-based trauma-focused therapies that have been used within the VA. These studies will inform next steps for larger clinical trials and implementation of the various therapies in conjunction with MDMA. “There is also a pilot trial of MDMA-AT with Veterans who have co-occurring PTSD and alcohol use disorder, evaluating both changes in alcohol use and PTSD over time.”
Psilocybin is the active ingredient found in certain types of psilcybe mushrooms. When they are ingested, they are converted to psilocibin, which then “act as an agonist at several serotonergic and non-serotonergic receptors.” When orally ingested, psilocybin has been shown to have low potential for abuse. Depending upon the dose, individuals report various experiences, including visual imagery, synesthesia (experiencing multiple unrelated senses together, such as tasting color), feeling of bliss and connectedness, the dissolution of self or ego (i.e., loss of a sense of self or the first-person experience), and mystical experiences that can create lasting changes in a person’s worldview.
Of note, psilocybin remains a Schedule I drug, although as of February 2024, Australia, the states of Oregon and Colorado, and the Canadian state of Alberta have legalized psilocybin for medicinal purposes in supervised settings. Similar bills are currently underway in the states of California, Washington, New Jersey, and Massachusetts. The FDA has been reviewing the evidence for P-AT for mental health treatment, which may lead to legalization of P-AT for this purpose.
P-AT is showing promise as a treatment for various mental health conditions, including treatment-resistant depression, substance use disorders and depression and anxiety from serious medical illnesses like cancer. Protocols usually last about 60 to 90-minute therapy sessions and one to two 6/8-hour administration sessions. Typically, P-AT sessions include a nondirective psychotherapy focused on preparation and integration of the psychedelic experience. For example, cognitive behavioral modalities or Acceptance and Commitment Therapy.
There are ongoing trials of P-AT for alcohol use disorder, depression, and obsessive-compulsive disorder, among others. Because of the significant theoretical potential for psilocybin to support PTSD treatment, there are also ongoing uncontrolled trials of P-AT for PTSD underway with U.S. Veterans and UK Veterans, with the latter study testing P-AT with Cognitive Processing Therapy. Although these studies are oriented toward preliminary evaluation and establishing feasibility and thus have small sample sizes, the results of this research will inform future research studies in P-AT for PTSD, which may include larger-scale trials.
The Challenges with Psychedelic Research
While the findings for MDMA-AT and P-AT are promising, there are several challenges with the trial design of psychedelic research, including the inability to effectively blind the experimental group for a double-blind randomized control trial (RTC). The strong physical and psychological effects of the psychedelics fail to keep patients, as well as researchers and staff, uncertain of the participants assigned treatment condition. The placebo effect occurs when participants know they have received the psychedelic treatment and believe it will improve their symptoms. Conversely, if participants believe they received an inert placebo that is unlikely to improve their symptoms, this can worsen the outcomes.
Active placebos that mimic aspects of the psychedelic experience and the use of masked assessors is necessary. To the extent possible, study staff should be masked; and the adequacy of the masking for both patients and providers should be assessed. “Despite the large effects of expectancies on treatment outcomes in psychedelic RCTs, baseline treatment expectancies and masking efficacy typically go unmeasured.” Many researchers will report that their psychedelic studies were “double-masked” without testing their claims.
Studies on both MDMA-AT and P-AT in Veterans are limited. There have been no clinical trials conducted on P-AT for PTSD. Despite being lauded as a treatment for the PTSD of Veterans, only around 19% of each sample of the Lykos MDMA-AT treatment model included Veterans. One phase 2 clinical trial looked at firefighters, police officers, and military Veterans, where Veterans made up 84% of the sample (n=22). “Additional research with a larger Veteran sample is needed to improve generalizability to the Veteran population.” There are additional challenges discussed in the VA article, including eligibility and safety criteria, and the time requirements involved in current MDMA-AT and P-AT models.
Conclusion
The rhetoric of news articles on psychedelic research is consistently promising. However, there are difficult and perhaps insurmountable obstacles to getting psychedelic approaches approved by the FDA as medical treatments. Rick Doblin strategically chose PTSD in Veterans as the disorder to target in his quest to overcome the government restrictions on psychedelics. He said: “We wanted to help a population that would automatically win public sympathy. . . No one’s going to argue against the need to help them.”
The research the VA is doing at the Providence VA Medical Center and the other clinical trials, not that done by Lykos Therapeutics, should be where the public and FDA focuses their hope for future research on psychedelics to treat PTSD. The FDA’s request that Lykos do an additional Phase 3 clinical trial as noted above for its MDMA-AT model should also lead the FDA to re-examine the existing data submitted by Lykos to the agency. The journal Psychopharmacology announced on August 11, 2024 that it was retracting three MDMA-AT papers submitted to it by Lykos. To what extent were there additional undetected protocol violations amounting to ethical violations in that data?
Rick Doblin had a vision to “develop investigational psychedelics to catalyze therapeutic approaches for mental health conditions.” But it seems Lykos cut some research corners it shouldn’t have, which raises serious questions about its research methods. We should do solid research and patiently wait to resolve all the safety and efficacy issues, before bringing MDMA-AT or P-AT to market. Our Veterans are worth the effort.
For more information on Lykos Therapeutics and Rick Doblin, see “The Long Strange Trip of MDMA-Assisted Therapy.”
