FDA blocks MDMA therapy for PTSD—What’s next for mental health breakthroughs?

Inside the FDA’s recent decision and what it means for the future of psychedelic medicine

The field of psychedelic therapies has captured widespread attention as a potential breakthrough in mental health treatment. However, recent developments, including the FDA’s rejection of Lykos Therapeutics’ application for MDMA-assisted therapy to treat PTSD on August 9 highlight the complex regulatory and clinical challenges. Read this week’s deep dive about the current landscape of psychedelic drugs and candidates in clinical trials.

Current research into psychedelic treatments

Psychedelic therapies are being researched as potential treatments for a variety of mental health conditions, particularly those that are treatment-resistant. The main applications so far include:

• PTSD: MDMA-assisted therapy is being investigated as a treatment for PTSD, particularly for individuals who do not respond to traditional treatments such as selective serotonin reuptake inhibitors. About 50% of people with PTSD fall into this category. A large phase 3 clinical trial conducted by researchers at UCSF found that MDMA combined with psychotherapy significantly reduced PTSD symptoms compared to a placebo. However, on August 9, 2024, the FDA rejected Lykos Therapeutics’ application for MDMA-assisted therapy for PTSD, which would have been the first psychedelic-based therapy approved in the United States.

  
  The FDA’s rejection of Lykos Therapeutics’ application for MDMA-assisted therapy for PTSD was primarily influenced by ethical concerns surrounding the company’s clinical trials. Notably, an unlicensed therapist was accused of sexually assaulting a participant at a Canadian trial site, and this ethical breach was not disclosed to regulatory agencies or journals by the authors of related research papers. Additionally, potential conflicts of interest arose due to affiliations between the authors and organizations involved in the trials. The lack of adequate oversight and monitoring further raised questions about the integrity of the research. These ethical lapses ultimately undermined the reliability of Lykos’ data, prompting the FDA to call for an additional phase 3 trial before reconsidering approval, highlighting the critical need for rigorous ethical standards in psychedelic research.

• Treatment-Resistant Depression: Psilocybin (the psychoactive compound in “magic” mushrooms) has shown promise in treating depression, particularly in patients who have not responded to traditional antidepressants. A phase 2 trial led by researchers at Columbia University found psilocybin therapy led to rapid and sustained antidepressant effects in patients with treatment-resistant depression.

• Anxiety: LSD-assisted psychotherapy has been studied as a treatment for anxiety associated with terminal illness. A small trial in Canada found LSD reduced state anxiety in patients with life-threatening diseases. Psilocybin has also demonstrated potential in reducing end-of-life anxiety in patients with terminal cancer.

• Substance use disorder: Psychedelic therapies are being investigated for treating alcohol and substance use disorders. The proposed mechanisms include reducing cravings and breaking addictive thought patterns.

• Postpartum depression (PPD): In 2023, zuranolone was approved by the FDA for the treatment of PPD. Zuranolone is a neuroactive steroid that mimics the effects of allopregnanolone, a naturally occurring hormone in the body. It enhances the activity of GABA, a neurotransmitter that helps reduce anxiety and improve mood. While no psychedelics have yet been approved specifically for PPD, there is growing interest in their potential therapeutic effects. Research is exploring the use of psychedelics, such as psilocybin, in treating PPD. Some studies suggest that psychedelics could enhance maternal sensitivity and positively impact the mother-infant relationship. Reunion Neuroscience is developing a psychedelic prodrug called RE104, which is currently in phase 2 clinical trials. This compound is designed to provide a rapid effect on depressive symptoms with a shorter duration of psychoactive effects compared to traditional psychedelics, potentially making it more suitable for therapeutic use in postpartum settings.

There are many companies currently investigating these compounds in clinical trials. However, the recent rejection by the FDA of MDMA as a treatment for PTSD has raised significant concerns within the field of psychedelic therapies.

This decision surprised many researchers and advocates who had hoped for a breakthrough in the use of psychedelics for mental health treatment. The FDA’s advisory committee had previously expressed concerns about the validity of the clinical trials, particularly regarding the integration of MDMA with psychotherapy and the challenges of conducting placebo-controlled studies with hallucinogens.

In the wake of the FDA’s decision, the journal Psychopharmacology retracted three studies related to MDMA-assisted therapy due to unethical conduct at a Canadian trial site, further complicating Lykos’s and other efforts and highlighting ongoing ethical issues in psychedelic research.

The rejection of MDMA not only affects its potential as a PTSD treatment but also casts a shadow over the future of other psychedelic therapies currently in development, such as psilocybin and LSD. Some companies are already shifting their approaches by excluding psychotherapy from their clinical trials to streamline the FDA review process, which may alter the traditional understanding of these treatments.

Despite the setbacks, there is ongoing research in academia and the pharmaceutical industry. Numerous clinical trials focused on various psychedelics are underway, exploring their efficacy in treating conditions like depression, anxiety, and chronic pain.

The landscape of psychedelic therapy remains dynamic, with researchers emphasizing the importance of rigorous scientific scrutiny and ethical conduct to build trust and advance the field. The path forward may be challenging, but the commitment to exploring the therapeutic potential of psychedelics continues, underscoring the need for patience and further investigation.

Regulatory stance on psychedelics

In June 2023, the FDA has released draft guidance to support the development of psychedelic drugs, signaling a shift in regulatory attitudes towards these substances. Historically associated with both cultural rituals and controversial experiments, psychedelics such as LSD and psilocybin were classified as schedule I substances, which halted research for decades.

However, recent studies have shown promising results, particularly with psilocybin, which has demonstrated significant potential in treating major depression and other mental health conditions. Research into other psychedelic is increasing in popularity as can be seen in the graph below published by Drug discovery trends last year.

The FDA’s document from last year outlined key considerations across several areas regarding psychedelics research. It highlighted the need for careful planning and rigorous study design to ensure the safety, efficacy, and regulatory compliance of psychedelic drugs in clinical research.

The FDA’s draft guidance provided considerations for sponsors developing psychedelic drugs for treating medical conditions like psychiatric disorders. It highlights the need for proper chemistry, manufacturing, and controls, especially given the unique challenges posed by the intense perceptual effects of these drugs.

The guidance also emphasizes the need for abuse potential assessments due to the psychoactive nature of psychedelics, which are often schedule I substances. Clinical trial designs must address issues like functional unblinding and the role of psychotherapy in treatment.

Companies leading the charge in psychedelic therapies

The psychedelic sector has seen a surge in investment, with billions of dollars funneled into research and development. This interest is driven by a growing recognition of the therapeutic potential of psychedelics, particularly in treating conditions like depression, anxiety, and PTSD.

🔹 On August 9, Lykos Therapeutics issued a statement where they outlined their plan to engage with the FDA and pursue all available regulatory pathways to bring this treatment to people suffering from PTSD. The company expressed disappointment but remains committed to addressing the FDA’s concerns and advancing the therapy. The company focuses on MDMA and plans further research into MDMA’s potential for other mental health conditions.

🔹 Compass Pathways is investigating the effect of psilocybin compound COMP360 for treatment-resistant depression. The successful phase 2b trial that involved 233 patients across 10 countries and found that a single 25mg dose, combined with psychological support, significantly reduced depressive symptoms after three weeks, with effects lasting up to 12 weeks. The results were published in the New England Journal of Medicine. Phase 3 clinical trials ongoing.

🔹 Reunion Neuroscience’s lead treatment RE104, similar to psilocybin, is investigated for treatment of postpartum depression. The company recently announced first patient dosed in its phase 2 RECONNECT clinical trial. RE104 is designed as a fast-acting, single-dose therapy to address unmet needs in mental health. The trial is a multicenter, randomized, double-blind study focused on the safety and efficacy of RE104 in women with moderate-to-severe PPD, with the primary outcome measured by changes in depression severity.

🔹 Beckley Psytech has BPL-003 in an ongoing phase 2b clinical trials for treatment-resistant depression. Beckley Psytech’s phase 2a study showed promising results. BPL-003 is synthetic benzoate salt formulation of the psychedelic compound 5-MeO-DMT (also known as mebufotenin) which is administered intranasally. A single 10mg dose led to a rapid antidepressant response in 55% of patients by the next day, with 55% in remission at day 29 and 45% at day 85. The treatment was well-tolerated with no serious adverse events, and patients were dischargeable within two hours, indicating the potential for a scalable treatment model. In April 2024, Beckley Psytech published results from a phase 1 study of BPL-003 for treatment of alcohol use disorder, in The Journal of Psychopharmacology. The study, which involved 44 healthy volunteers, showed that BPL-003 was safe, well-tolerated, and rapidly effective, with psychedelic effects resolving within two hours.

🔹 Gilgamesh Pharmaceuticals is collaborating with AbbVie for development of GM-1020 and GM-2505 for major depressive disorder. As of May 2024, phase 2a trials are currently ongoing. This trial aims to evaluate GM-1020’s safety, tolerability, and effectiveness. GM-1020 is a novel NMDAR antagonist that was developed to address limitations of ketamine. Also, unlike traditional antidepressants that can take weeks to show effects and often have significant side effects, GM-1020 is intended to provide faster relief with fewer adverse effects.

🔹 Sunstone Therapies has many psychedelics in their pipeline, including MDMA, psilocybin, 5-MeO-DMT, LSD and methylone for the treatment of PTSD, major depressive disorder, anxiety disorders, postpartum depression, and palliative care, many of which are in ongoing clinical trials. In light of recent MDMA rejections by the FDA, Sunstone’s CEO, Manish Agrawal, issued a statement where he mentioned that Sunstone is actively expanding its research and will conduct 11 trials in 2024, focusing on various psychedelic compounds and patient groups. He emphasized the complexity of MDMA-assisted therapy, stressing the need for skilled mental health professionals and rigorous safety protocols. Agrawal noted that while MDMA is not a universal cure, it holds promise for many suffering from PTSD and is a potential breakthrough treatment after decades.

🔹 GH Research has their lead candidate, GH001 (5-MeO-DMT), in phase 2b trial for treatment-resistant depression and phase 2 open-label trials in patients with bipolar II disorder and postpartum depression. The phase 1/2 results were published in Frontiers in Psychiatry in 2023 and reported that administration of GH001 was well tolerated and provided potent and rapid antidepressant effects.

🔹 MindMed is investigating MM-120 (LSD) for generalized anxiety disorder. In March 2024, the FDA granted Breakthrough Therapy Designation to MM-120. This designation followed positive 12-week topline results from a phase 2b study, which demonstrated that a single 100 µg dose of MM-120 significantly reduced anxiety symptoms and maintained its effects through 12 weeks. The study showed a 65% clinical response rate and a 48% remission rate. The company is on track to initiate the phase 3 program in the second half of 2024.

🔹 Cybin’s lead drug CYB003 (psilocybin analog) has received FDA Breakthrough Therapy Designation for use in treating major depressive disorder. After successfully completing a phase 2 trial in participants with moderate to severe major depressive disorder, the next step is to launch a phase 3 pivotal, multinational trial in the summer of 2024.

🔹 Delix Therapeutics has several drugs in preclinical and early phase trials. In May, they announced promising results from an ongoing phase 1 trial of DLX-001, a novel neuroplastogen being developed for treating major depressive disorder and related neuropsychiatric conditions. The trial showed that DLX-001 penetrates the brain and promotes significant neuroplasticity without causing psychotomimetic, dissociative, or hallucinogenic effects. The drug was well-tolerated with no serious adverse events reported. Preclinical data also highlighted DLX-001’s rapid and enduring antidepressant effects, comparable to those of ketamine and psilocybin, but without the hallucinogenic side effects.

🔹 Academic institutions like UCSF are conducting studies on psilocybin for chronic low back pain and depression in Parkinson’s disease.

As the psychedelic sector navigates regulatory hurdles, the commitment to uncovering novel therapeutic avenues remains unwavering. While the path forward is complex, the ongoing research and evolving strategies in this field continue to inspire hope for a revolution in mental health treatment.

The future of psychedelic research is promising, supported by a growing body of evidence that highlights their transformative potential. As more compounds progress through clinical trials and regulatory frameworks adapt, there is optimism that psychedelics will offer effective solutions for those suffering from mental health disorders, especially where traditional treatments have fallen short. This evolving landscape not only marks significant advancements in research but also signals a potential paradigm shift in mental health care, offering new hope for countless individuals.

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DISCLAIMER: This content is for informational purposes only. It should not be taken as legal, tax, investment, financial, or other advice. The views expressed here are my own and do not reflect the opinions of any company or institution.

DISCLOSURE: I have no business relationships with any company mentioned in this article.