Developing Next-Generation Psychedelic Treatments: Insights on Bretisilocin From AJ Cannon, MD

CLINICAL CONVERSATIONS

In 2025, AbbVie acquired Gilgamesh Pharmaceuticals’ lead asset, bretisilocin (GM-2505), a potential best-in-class compound for the treatment of major depressive disorder (MDD).¹ Positive topline results from a phase 2a study showed that bretisilocin led to a clinically impactful and statistically significant reduction in severity of depressive symptoms when compared with a low dose active comparator, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) total score.²

Psychiatric Times sat down with AJ Cannon, the senior medical director in Neuroscience Clinical Development at AbbVie, to learn more about this novel treatment and the evolving psychedelic landscape.

Psychiatric Times: What do you see as the largest hurdles facing psychedelic development for serious mental illness?

AJ Cannon, MD: There are 2 core challenges shaping the future of psychedelic development in serious mental illness, both of which reflect broader themes we see across neuroscience innovation.

The first is a long-standing challenge: the need to continue to evolve perceptions and reduce stigma around mental health disorders and psychedelic compounds. Both have long been burdened by misunderstanding, and psychedelics in particular have faced significant regulatory constraints. Still, there has been meaningful progress in recent years, driven by greater recognition of unmet clinical need, improved research methods, and a deeper understanding of the science underlying psychiatric disease, including how effective treatments may support clinical recovery by reshaping brain networks.

The other key hurdle is ensuring that psychedelic therapies are not only scientifically compelling, but clinically practical. Beyond demonstrating durable efficacy and safety, there is a need to establish care models that can support appropriate patient selection, supervised administration, and follow-up necessary to ensure adequate patient support and benefit. Infrastructure and clinician training will be critical, particularly as health care systems evaluate how these therapies can be responsibly integrated into real-world psychiatric care.

In my work, for example, we are focused on developing novel solutions for complex psychiatric disorders, which requires new ways of thinking, grounded in advanced understanding of disease biology. Ultimately, progress will depend on bridging innovation with implementation, ensuring advances translate into real-world, patient-centered care.

PT: President Donald Trump recently signed an executive order titled “Accelerating Medical Treatments for Serious Mental Illness,” directing the FDA to issue National Priority Vouchers for Breakthrough Therapy-designated psychedelics. How could this impact access to and research on psychedelics?

Cannon: Once limited by policy, stigma, and public perception, the therapeutic benefits of psychedelics are now being examined through a more rigorous scientific lens. The recent US Executive Order on psychedelics is a constructive development for the broader field of psychedelic research, underscoring its positive momentum and unique potential to enhance the treatment of mental illness. If implemented as written, the order may accelerate review timelines for assets that already have Breakthrough Therapy Designation, while encouraging stronger collaboration among government bodies, such as the Department of Health and Human Services and Food and Drug Administration, with elements of the private sector.

It is important to note that the order does not guarantee approval or access, but it does encourage wider data sharing and real-world evidence generation that could ultimately help expedite bringing these therapies to the patients who most need them.

PT: What does the executive order mean for the biopharmaceutical industry, and how is AbbVie responding to this evolving landscape?

Cannon: It is incumbent on us as an industry to ensure we are bringing the most rigorous scientific approaches forward in this time of heightened attention and accelerated momentum, providing clear objective evidence of a treatment’s efficacy and safety profile.

For AbbVie, this means a continued commitment to advancing bretisilocin, a next-generation psychedelic compound that is currently in phase 2 development for the treatment of major depressive disorder (MDD), through a rigorous, science-based clinical program. There remains significant unmet need in MDD, particularly for patients who need symptom relief more quickly than current treatment options may provide. We believe it is important to explore innovative approaches that have the potential to address these gaps, and we will continue working closely with regulatory authorities as bretisilocin progresses through development.

PT: Talk to us about bretisilocin. Would you qualify this as a “next-generation” psychedelic? How does it differ from other psychedelics in the pipeline?

Cannon: Bretisilocin is a next-generation psychedelic compound in clinical development for the treatment of MDD. It is a novel, short-acting serotonin 5-HT2A receptor agonist designed to address development challenges associated with this class of compounds, including long duration psychoactive experience.

Preliminary phase 2a findings have demonstrated that the compound exerts a shorter duration of psychoactive experience while retaining an extended therapeutic benefit, which may help support a more practical treatment experience in real-world clinical settings.

PT: Is there a specific data point or finding from the research on bretisilocin thus far that has really stood out to you?

Cannon: What has stood out to date is the strength and rapidity of the early signal in depressive symptom improvement following a single dose of bretisilocin. In a phase 2a study presented in May 2025, bretisilocin demonstrated a clinically meaningful and statistically significant reduction in depressive symptom severity, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), compared with a low-dose (1 mg) of bretisilocin as an active comparator. Notably, a rapid antidepressant effect was observed within 24 hours, with an 18.5-point reduction from baseline in MADRS score. By day 14, a single 10 mg dose of bretisilocin produced a 21.6-point reduction from baseline vs 12.1 points for the low dose comparator. These efficacy findings, together with an encouraging preliminary safety and tolerability profile, highlight the potential for a differentiated treatment approach in patients with MDD.

PT: What is on the horizon for bretisilocin?

Cannon: Looking ahead, the program continues to advance, with data expected from 2 additional phase 2a cohorts this year. These readouts will further characterize the efficacy and safety profiles of bretisilocin and help inform potential advancement to phase 3 development.

While our current focus is MDD, where significant unmet need remains, we are also encouraged by the broader potential of psychoplastogen-based approaches across other serious psychiatric disorders. As our understanding of neuroplasticity continues to evolve, we believe these mechanisms may have relevance beyond depression, including conditions such as posttraumatic stress disorder (PTSD). Continued research will be important in determining in which conditions these therapies may ultimately have the greatest impact for patients.

PT: How could a shorter psychedelic treatment experience affect patient access and clinical implementation?

Cannon: This ties directly back to how we are thinking about the clinical profile of compounds like bretisilocin at AbbVie.

As previously mentioned, one of the key limitations of existing psychedelic approaches has been the duration of the psychoactive experience, which may impact patient willingness to participate and limit broader use in practice. For clinicians treating patients, longer treatment experiences will likely mean extended monitoring and observation, creating additional logistical complexity for patients and care providers.

A shorter duration of effect may help address some of these challenges. A more manageable treatment window has the potential to improve feasibility in care settings and simplify delivery, which will be important if these medicines are to reach patients at scale.

PT: What do you wish psychiatrists and mental health clinicians knew about this potential treatment?

Cannon: I think one of the biggest hurdles we have in this space is overcoming existing stigmas related to psychedelics and skepticism around their potential therapeutic use and benefit. It is important for clinicians and psychiatrists to recognize this as an evidence-driven effort to address a critical unmet need, rather than a novelty. Therapeutic psychedelics will not replace good psychiatric care but may expand the toolkit for patients who have not found enough relief through currently available options.

What makes this area particularly exciting is that these compounds appear to produce measurable changes in brain circuitry and neuroplasticity that are accompanied by meaningful changes in conscious experience. Historically, psychiatry has often approached treatment through either a biological lens or a psychological one. Psychedelics may represent a unique opportunity to bridge those perspectives, linking changes in brain function with profound subjective experiences that may contribute to therapeutic benefit. That combination has the potential to deepen our understanding of mental illness and the brain’s ability to adapt, and inform more personalized approaches to treatment.

PT: We have heard some hesitancy on the part of clinicians about psychedelics. What would you say to those with doubts?

Cannon: To those with doubts or hesitations, I would say: your caution is an appropriate response in responsible medicine. But it is important to note that we are not exploring psychedelics for therapeutic use as a novelty. Our research is grounded in the systematic collection of clinically relevant data through rigorous study design and execution, including prespecified endpoints and statistical analytic approaches, careful patient screening, and thoughtful implementation.

At the same time, the burden of serious mental illnesses such as MDD and PTSD remains substantial, and many patients do not achieve adequate relief with existing standards of care. Given that reality and based on the early data emerging from psychedelic research, we believe these therapies warrant rigorous scientific investigation. Like any serious therapy, compounds like bretisilocin need to be judged by evidence of their efficacy, safety, durability, and ability to be delivered responsibly to patients.

PT: Anything else you would like to share?

Cannon: The energy we are seeing around psychedelic research reflects a broader shift in how we are approaching mental health. Importantly, that enthusiasm is not limited to clinicians and researchers. We are seeing growing interest from patients, payers, regulators, clinicians, and politicians, who recognize this as a serious area of biomedical research and whose collaboration will be required for these treatments to reshape psychiatric care.

While important questions remain around safety, scalability, and implementation, it is encouraging to see so many stakeholders engaged in advancing the science underlying clinical benefits of psychedelics.

At AbbVie, we are focused on advancing bretisilocin through a rigorous, science-based clinical program for patients living with serious mental health conditions and are committed to keeping patients at the center as we work to advance investigations of bretisilocin with the seriousness and care this area deserves. We believe this progress matters for patients who have not found adequate symptom relief through existing treatments. Ultimately, better treatments that work more rapidly and effectively have the potential not only to improve outcomes, but also to help reduce stigma by encouraging more people to seek care.

Dr Cannon is a board-certified psychiatrist, physician-neuroscientist, and senior medical director in Neuroscience Clinical Development at AbbVie, where he designs and leads clinical trials evaluating novel treatments for serious mental illnesses.

References

1. AbbVie to acquire Gilgamesh Pharmaceuticals' bretisilocin, a novel, investigational therapy for major depressive disorder, expanding psychiatry pipeline. News released. August 25, 2025. Accessed June 10, 2026. https://news.abbvie.com/2025-08-25-AbbVie-to-Acquire-Gilgamesh-Pharmaceuticals-Bretisilocin,-a-Novel,-Investigational-Therapy-for-Major-Depressive-Disorder,-Expanding-Psychiatry-Pipeline

2. Gilgamesh Pharmaceuticals announces positive topline phase 2a results for GM-2505 in major depressive disorder (MDD). News release. May 27, 2025. Accessed June 10, 2026. https://www.prnewswire.com/news-releases/gilgamesh-pharmaceuticals-announces-positive-topline-phase-2a-results-for-gm-2505-in-major-depressive-disorder-mdd-302465404.html