What FDA Approval of MDMA Could Mean for the Future of Psychedelic Therapy
Dr. Sam Clark discusses the potential impact of a psychedelic-based therapy for PTSD gaining FDA approval.
Complete the form below to unlock access to ALL audio articles.
Psychedelics have shown promise for the treatment of psychiatric conditions, with studies demonstrating the therapeutic potential of drugs derived from substances such as psilocybin, ketamine and MDMA.
Recently, a US Food and Drug Administration (FDA) advisory panel voted on whether current data shows that a New Drug Application (NDA) for MDMA-assisted therapy from Lykos Therapeutics is effective for patients with post-traumatic stress disorder (PTSD).
Australia’s drug regulator has already given its approval for doctors to use both MDMA and psilocybin to treat PTSD after a three-year review process and expert consultation. However, the PDAC voted nine to two in favor of “no”, citing factors such as a lack of safety data and concerns over placebo effects. The FDA is not obligated to directly follow PDAC guidance.
If the NDA is approved, it will mark the first-ever MDMA and psychedelic-assisted therapy to reach the US market, potentially breaking the stigma for psychedelics and paving the way for other psychedelic-based therapies.
To learn more about the pending decision and the outlook for psychedelics-assisted therapies, Technology Networks interviewed Dr. Sam Clark, CEO of Terran Biosciences, who leads one of the industry’s largest psychedelic development programs.
Molly Campbell (MC): Can you discuss the origins of the stigma that we see surrounding psychedelic drugs, and why it is problematic?
Sam Clark (SC): During the wave of legislation that accompanied Nixon’s “War on Drugs” in the 1960s and 70s, and due to their association with anti-war protestors, we saw these relatively safe psychedelic compounds be grouped with potentially lethal drugs such as heroin, and all were labeled as “Schedule I” controlled substances.
Schedule I is reserved for compounds that have “no currently accepted medical use and a high potential for abuse.” Unfortunately, this mischaracterization became the pervading public sentiment, and psychedelic compounds were perceived (without any factual basis) as dangerous “hard” drugs. The medical and scientific community has worked tirelessly to fix this over the years, and the remarkable data from compounds like MDMA, LSD, 5-MeO-DMT and psilocybin have shown that these compounds do indeed have medical value.1,2,3,4,5
However, we still face many challenges due to this 50-year-old policy. For example, the compounds are currently still listed as Schedule I, meaning they can only be researched under a special license, which greatly slows the pace of research in the United States. For this reason, many psychedelic companies have moved their labs to the UK and Europe, where the laws governing research on these compounds are more favorable.
Sarah Whelan (SW): Many psychiatric conditions, including PTSD, have FDA-approved treatments. What benefits might psychedelic-based treatments provide over these existing approaches?
SC: While there are indeed a couple of SSRIs approved for the treatment of PTSD (in addition to their use in depression), there are millions of people who still do not receive remission from their PTSD symptoms even after trying these options. Additionally, the current therapeutic options come with many undesirable side effects, such as weight gain and sexual dysfunction. So, there remains a large unmet need for patients with PTSD and other psychiatric conditions such as depression and anxiety.
I believe psychedelics could significantly improve this treatment landscape, as the data is now showing that they are powerful medicines with rapid efficacy and are largely free from the side effects that we see with current therapies.
MC: Can you provide an overview of the available clinical data supporting psychedelic-assisted therapies, such as MDMA for PTSD?
SC: The most robust and reliable clinical data for the use of MDMA in PTSD to date comes from two Phase 3 studies conducted by the Multidisciplinary Association for Psychedelic Studies (MAPS), now rebranded as “Lykos.” Over many years, MAPS conducted a full clinical development plan for MDMA-assisted therapy (“MDMA-AT”), which included the standard preclinical, Phase 1, Phase 2 and Phase 3 studies typically required by the FDA.
The two recent Phase 3 studies in adult patients with PTSD, called MAPP1 (90 patients randomized) and MAPP2 (104 patients randomized), were placebo-controlled and randomized 1:1 to placebo. In these studies, the research team measured response to therapy using the “gold standard” PTSD scale called CAPS-5, which measures several symptoms to determine the severity of the disease and response to therapy. In both studies, MDMA-AT was shown to be safe and effective, significantly improving patients’ scores on the CAPS-5 and functional impairment scale. For MAPP1, 67% of participants given MDMA-AT no longer met diagnostic criteria for PTSD. For MAPP2, 86.5% of participants treated with MDMA-AT achieved a clinically meaningful benefit and 71.2% of participants no longer met criteria for PTSD by the study end.
These results are promising, and MAPS had aligned with the FDA on these study designs and endpoints in a Special Protocol Assessment (SPA) prior to the study to give them the best chance at approval. Given the lack of treatment options for patients with PTSD, MDMA-AT could be a paradigm shift in the standard of care.
Other drug development companies and academic researchers have similarly shown that other psychedelic compounds, like psilocybin and 5-MeO-DMT, are safe and effective treatments for depression in multiple Phase 2 studies, and LSD has been shown to be a safe and effective treatment for anxiety in multiple Phase 2 studies as well.
We look forward to seeing the Phase 3 study data for these other compounds over the next couple of years and hope they can also provide compelling data that results in novel therapeutic options for patients in need.
SW: What do we know – and what do we not know – about the molecular mechanisms underpinning the effects of psychedelics on psychiatric disorders?
SC: We know that psychedelic compounds act on many targets in the brain, including serotonergic, dopaminergic, adrenergic and TrkB receptors, but exactly which of these receptors (or which combination of these receptors) is truly driving the efficacy we see in psychiatric disorders is still largely unknown.
Typically, after serotonin neurotransmission occurs in the brain, a serotonin reuptake transporter is responsible for the reabsorption of serotonin back into the neurons. Researchers have shown that MDMA binds to this transporter and causes it to work in reverse, flooding the neuronal synapse with serotonin and increasing serotonin signaling. For other psychedelics such as psilocybin, 5-MeO-DMT and LSD, we know that activity at the serotonin 2A receptor is linked to the hallucinations and the psychedelic “trip” that one experiences, but the emerging evidence suggests this trip may be independent of the anti-depressant effects of these compounds. In fact, we are working now on pharmacological strategies to block the effects at the 2A receptor in an attempt to create safe and effective “non-hallucinogenic” psychedelic compounds that could potentially be taken at home as antidepressants.
MC: What, in your opinion, are the main challenges that need to be overcome for these therapies to enter the clinical space?
SC: Over recent years, we’ve seen many of these compounds enter clinical trials, overcoming many bureaucratic challenges and red tape that had prevented sufficient research into these compounds for decades. With proper licenses in place and the generation of sufficient preclinical data, these compounds can now follow an FDA-sanctioned drug development pathway toward approval.
The remaining hurdles are in the logistics of the delivery itself. For compounds such as psilocybin, LSD or 5-MeO-DMT, which cause a hallucinogenic trip, regulators have required their administration to be within a clinic or hospital under the supervision of a physician or trained healthcare professional. These trips can often last many hours (up to 12 in the case of LSD) and so the logistics of this supervised care has become quickly problematic for clinical trials and even more problematic when it comes to commercial reimbursement and viability. MDMA is classified as an empathogen and doesn’t necessarily cause the full trip associated with other psychedelics, and while this means that it will likely be the least burdensome of the class to roll out logistically, it must still be given in the context of a supervised psychotherapy session.
The time and costs associated with rolling out physician-supervised multi-hour sessions for the other fully psychedelic compounds like psilocybin, LSD and 5-MeO-DMT will be a challenge, as physician time and resources are already stretched so thin in conventional care models. We need to continue to innovate with shorter-acting compounds and even look to those new therapeutics that may be able to deliver similar efficacy without the hallucinogenic experience entirely.
MC: Do you think that the potential approval of Lykos Therapeutics’ MDMA-assisted therapy will break down the many barriers that psychedelic therapy developers are facing? If so, can you discuss why?
SC: In many ways, Lykos (formerly MAPS) has already done an incredible amount of work over the past couple of decades to break down regulatory barriers to get this far and has significantly advanced the field of psychedelic medicine.
As the first to submit a New Drug Application to the FDA, Lykos has helped create a regulatory precedent for what the agency will require for the approval of future similar compounds. Additionally, by showing that MDMA, which is currently classified as a Schedule I compound, has such an immense therapeutic benefit, it opens the door to rescheduling the other psychedelics and improving access to researchers and clinics. We believe this is the first step in undoing the damage caused by the mistakes made when these compounds were incorrectly scheduled and preventing similarly harmful mistakes from being repeated in the future.
MC: What is your stance on the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) decision that the risks of MDMA treatment for PTSD outweigh the benefits?
SC: I would disagree with the FDA advisory committee recommendation and believe that the benefits of approval outweigh the risks. I commend Dr. Walter Dunn as the lone member of the committee who voted in favor of approval.
It is critical to look at all of this data and the issues presented in the full context of the disease and therapeutic landscape. PTSD is an illness that can cause severe impairment in a patient’s life, sometimes with grave consequences (e.g., increased risk of suicide). The currently approved treatment options are meager (only two SSRIs) and often have to be taken chronically. On average, the patients in the Phase 3 trials had severe PTSD for over a decade, and after only 3 MDMA treatment sessions, approximately 70% of them no longer met the diagnostic criteria for PTSD. So, despite the fact that the exact mechanism of the different factors that played into this remarkable improvement may not be fully understood, the outcome is remarkable.
I was also surprised to hear some of the committee members speaking about general and personal feelings about psychedelic compounds and their illicit use in society, and one member even went so far as to say that the use of clinical MDMA-AT in a therapeutic treatment setting would somehow lead to cocaine and alcohol abuse at home. This type of rhetoric is speculative, is not supported by either the data or the published literature and perpetuates the harmful and spurious stereotypes of psychedelics as gateway drugs.
While the committee did raise several important points of concern, given the huge unmet need and unprecedented effect size, I have no doubt these issues could be dealt with post-approval via a strict REMs program and vigorous post-marketing surveillance. Denying a potentially lifesaving treatment for patients who badly need it would be a tragic outcome, and I hope the FDA still grants approval in August, despite the AdComm feedback.
SW: Could the approval of MDMA-assisted therapy open the doors for similar psychedelic-based treatments?
SC: An MDMA approval would certainly set a valuable precedent for the psychedelic-assisted therapy model, would result in a rescheduling of this compound and would go a long way to demonstrate further the commitment of the regulators to deliver innovative, safe and effective therapies to patients in need. As the first mover in the space, Lykos is expected to be a trailblazer, and future drug developers have the advantage of learning from any successes or failures here to bring additional psychedelic-based therapies to market.
MC: What are your aspirations for the future of psychedelic-assisted therapies?
SC: I believe that, in the not-so-distant future, we will see a handful of these classic psychedelic therapies win FDA approval, e.g., compounds like MDMA, psilocybin, LSD and 5-MeO-DMT.
I also believe we will quickly see generic or generic-like compounds follow closely via 505(b)(2) pathways (including some of our own here at Terran) to expand therapeutic options and increase access and affordability. In the end, it’s a truly vast and exciting ecosystem, and I firmly believe in the power of psychedelic medicine to change the course of these diseases forever.
References:
1. Mitchell J, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. doi: 10.1038/s41591-021-01336-3
2. Mitchell J, Ot’alora M, van der Kolk, et al. MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial. Nat Med. doi: 10.1038/s41591-023-02565-4
3. Holze F, et al. Lysergic acid diethylamide–assisted therapy in patients with anxiety with and without a life-threatening illness: A randomized, double-blind, placebo-controlled phase II study." Biological Psychiatry. 2023. doi: 10.1016/j.biopsych.2022.08.025
4. Reckweg J, et al. A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N, N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression. Front Psychiatry. 2024. doi: 10.3389/fpsyt.2023.1133414
5. Raison C, Sanacora G, Woolley J, et al. Single-dose psilocybin treatment for major depressive disorder: A randomized clinical trial. JAMA. 2023. doi: 10.1001/jama.2023.14530
Dr. Sam Clark, CEO of Terran Biosciences, was speaking to Molly Campbell, Senior Science Writer for Technology Networks, and Dr. Sarah Whelan, Science Writer for Technology Networks.
About the interviewee
Dr. Sam Clark, CEO of Terran Biosciences, leads one of the largest psychedelic development programs in the industry, and is the co-inventor of more than 200 patent applications and the world’s first new forms of psilocybin and MDMA to treat psychiatric and neurodegenerative conditions.
