Major depressive disorder (MDD) is one of the leading causes of disability worldwide, affecting over 250 million people. But despite decades of research and the availability of numerous antidepressants, these conventional treatments are ineffective in approximately 30 percent of patients. Traditional therapies often require daily administration and can take weeks to show benefits, leaving patients vulnerable to persistent symptoms, decreased quality of life, and increased risk of suicide.
In recent years, psychedelic compounds have received a huge surge of interest as promising new treatments for mental health disorders. Classic psychedelics, such as lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and psilocybin, have been shown to catalyze long-lasting improvements in mental health after a small number of doses, especially when combined with psychotherapy. It’s theorized that this is due to their ability to promote neural plasticity, encouraging the growth of new connections between neurons, which may help “reset” dysfunctional brain circuits implicated in depression.
However, early psychedelic therapies have faced practical and scientific barriers including long psychoactive sessions lasting several hours, intensive clinical supervision, and the need for psychological support before, during, and after dosing. Beyond this, there is also controversy over how much to trust trial results in the first place.
Psychedelic trials are often complicated by functional unblinding, where the noticeable psychoactive effects make it obvious to both patients and clinicians who received the drug versus the placebo, undermining the gold standard of blinded studies. This issue was central to the FDA’s rejection of Lykos Therapeutics’ MDMA therapy. Collectively, these challenges have limited broad clinical adoption and scalability — but a new therapy could change this.
A short-acting psychedelic therapy
Gilgamesh Pharmaceuticals’ lead asset, bretisilocin, is a next generation, short-acting psychedelic therapy designed to deliver rapid antidepressant effects while minimizing the duration of psychoactive experiences. Much of the current clinical pipeline is dominated by psilocybin-based programs, where treatment sessions often last six to eight hours and require all-day clinical supervision. Bretisilocin’s psychoactive effects last just 60 to 90 minutes, aligning with the existing two-hour monitoring period already required for esketamine, the only FDA-approved hallucinogenic antidepressant.
Bretisilocin acts as both a 5-HT2A (5-hydroxytryptamine 2A) receptor agonist and 5-HT (serotonin) releaser — mechanisms which are directly linked to neuroplasticity and profound changes in perception, cognition, and mood. This was reflected in the results from the Phase 2a trial. A single 10mg dose resulted in a -18.5 point change within 24 hours on the Montgomery-Åsberg Depression Rating Scale (MADRS). Remarkably, by day 29 the reduction reached -28.0 points, with 94 percent of patients in remission, and these effects were sustained through to day 74 without further treatment. Equally important, bretisilocin was well tolerated: Most adverse events were mild and resolved within two hours, highlighting its potential as a safe, rapid-acting antidepressant.
Notably, the trial also addressed the broader methodological hurdle of functional unblinding by using a low-dose psychoactive comparator as the control. This innovative approach strengthened the validity of the results and represents a meaningful advance for the field, potentially setting a new standard for future psychedelic trials.
Committing billions to novel drug research
AbbVie has since announced the acquisition of bretisilocin for up to $1.2 billion. Under the deal, AbbVie will acquire bretisilocin while Gilgamesh spins out a new entity to continue advancing its broader pipeline, including an oral NMDA (N-Methyl-D-aspartate) receptor antagonist, a cardio-safe analogue of ibogaine, and an M1/M4 (muscarinic acetylcholine 1/4) receptor program.
The psychedelic therapeutics market is poised for rapid growth, with projections expecting it to surpass $10 billion by 2032. This expansion is driven by an increase in clinical research, growing recognition of mental health as a public health priority, and regulatory frameworks that support controlled medical use. This is reflected in the number of clinical trials currently listed on ClinicalTrials.gov:
These trials target not only depression but also post-traumatic stress disorder, addiction, alcohol-use disorder, and social anxiety.
"The field of psychiatry represents one of the most challenging areas in medicine, with a significant need for innovative solutions," said Roopal Thakkar, Executive Vice President at AbbVie. "This acquisition underscores our commitment to broadening and enhancing psychiatric care by investing in novel treatment approaches with the potential to reach patients for whom other treatments have been ineffective. We look forward to advancing bretisilocin to late-stage clinical development."
With bretisilocin, AbbVie is not just entering the psychedelic space, it’s aiming to lead it, targeting a class of compounds that could redefine mental health treatment for millions.
Frequently asked questions (FAQ):
What is bretisilocin?
Bretisilocin is a next-generation, short-acting psychedelic therapy developed by Gilgamesh Pharmaceuticals. It is designed to provide rapid antidepressant effects while minimizing the duration of psychoactive experiences.
How does bretisilocin work?
Bretisilocin acts as both a 5-HT2A receptor agonist and a 5-HT (serotonin) releaser. Serotonin is a key neurotransmitter involved in regulating mood, emotion, and cognition. By increasing serotonin activity and stimulating 5-HT2A receptors, bretisilocin can enhance neural plasticity, which is the brain’s ability to form new connections between neurons. This process may help “reset” dysfunctional brain circuits that contribute to depression, allowing for rapid and sustained improvements in mood and emotional regulation.
How is bretisilocin different from traditional psychedelics?
Unlike psilocybin-based therapies that require six-eight hour sessions with intensive supervision, bretisilocin’s psychoactive effects last just 60-90 minutes.
What clinical evidence supports bretisilocin’s effectiveness?
In a Phase 2a trial, a single 10mg dose of bretisilocin resulted in:
- -18.5 point change in MADRS scores within 24 hours
- -21.6 points by day 14, with 70 percent of patients in remission
- -28.0 points by day 29, with 94 percent of patients in remission
These effects were sustained through day 74 without further treatment. Most adverse events were mild and resolved within two hours.
What is functional unblinding?
Functional unblinding happens when the noticeable effects of a drug make it obvious who received the active treatment versus placebo. In psychedelic trials, this can bias results because patients and clinicians may subconsciously influence outcomes based on expectations.
How did the bretisilocin trial address the issue of functional unblinding?
The study used a low-dose psychoactive comparator as the control. This approach made it harder to tell who received the full therapeutic dose, helping preserve blinding and ensuring the results more accurately reflect the drug’s true effects.
Why is there growing interest in psychedelic therapies?
Only around 50 percent of people with depression and 60 percent of people with post traumatic stress disorder respond to current antidepressants. Recent trials suggest psychedelics like psilocybin, DMT and MDMA could provide rapid, lasting alternatives.
How large is the psychedelic therapeutics market?
The market is projected to surpass $10 billion by 2032, driven by increasing clinical research, greater recognition of mental health as a public health priority, and regulatory frameworks that support controlled medical use.
