atai Life Sciences (NASDAQ:ATAI, ETR:9VC) chief scientific officer Glenn Short spoke with Proactive about the company’s recent NIH grant and its innovative discovery program targeting opioid use disorder (OUD).
Short explained that the NIH grant review process is “highly competitive,” with independent experts assessing the novelty and potential impact of atai’s work.
He said this was the first time external reviewers had a chance to examine the company’s serotonergic 2A/2C agonists, compounds with non-hallucinogenic potential designed to address the challenges of OUD.
The program began in 2019, when atai set out to develop novel compounds using artificial intelligence.
Through its partnership with Cyclica (now part of Recursion Pharma), the company used AI-driven proteome scanning to design molecules with the desired pharmacology while avoiding adverse effects.
Short noted that the approach led to the discovery of promising compounds that do not appear to have hallucinogenic properties yet may reduce craving and relapse risk by targeting serotonergic pathways.
He emphasized the urgent need for new OUD treatments, given that the condition affects about 16 million people worldwide and leads to more than 120,000 deaths annually.
Current therapies remain limited, but atai believes its compounds could address multiple dimensions of addiction, from trauma processing to drug-seeking behaviors.
Short also underlined the importance of public-private partnerships, highlighting how collaboration with the National Institute on Drug Abuse could accelerate development.
Proactive: Hello you're watching Proactive, joining me is atai Life Sciences chief scientific officer, Glenn Short. Congratulations on the NIH grant. How does receiving this grant validate atai’s discovery program?
Glenn Short: It's quite shocking to say that there's really a very pressing unmet medical need and challenges in the mental health spaces associated with opioid use disorder. OUD affects approximately 16 million people globally, that's greater than 120,000 opioid associated deaths annually. And there just needs to be a better way.
Just to let the audience know, the NIH grant process, of course, is a highly competitive review process, and the process is made up of independent scientific grant reviewers that have expertise in opioid use disorder, or OUD, overall pharmacology and drug development.
This was really the first time that external parties were able to get a so-called look under the hood at the atai discovery story, which is really focused on the serotonergic 2A/2C agonists that we discovered have non hallucinogenic potential. Overall, the reviewers thought that this polypharmacy approach could have a significant impact, that our scientific approach was innovative, and that we would serve as a good development partner for the National Institute on Drug Abuse as these agonists progress through development.
So I think that overall, the review process validated the novelty of our approach, the utility of the 2A/2C agonists with non hallucinogenic potential in OUD, and the promise of our current lead compounds.
Many people are familiar with atai’s psychedelic-based therapies. How is the discovery program different? Can you provide background on the discovery program, especially since this program focuses on non hallucinogenic compounds as well as AI?
Yeah, this is a really interesting story. It all started back in 2019 with our desire to come up with novel psychedelic compounds that maintained a hallucinogenic potential but had a shorter duration of effect compared to typical psychedelics. We wanted to emulate the desirable pharmacology of psychedelics but remove the undesirable elements.
So we started a collaboration with a company called Cyclica, out of Toronto, Canada, which has since been purchased by Recursion Pharma. Their technology allowed us to scan the entire proteome for our specific drug and understand interactions with various proteomic targets.
This AI-based machine learning approach enabled us to identify compounds with the target polypharmacology we wanted — namely 2A/2C agonism — while avoiding undesirable pharmacology such as 5-HT2B, dopamine, or histamine receptor engagement.
We then created and tested these AI-identified molecules. A handful had the pharmacology we wanted. Initially I was dubious, but it turned out to be a real discovery. From there, we embarked on a medicinal chemistry campaign to optimize compounds. We discovered that a subset of molecules did not show hallucinogenic properties when tested in animal models.
These 5-HT2A/2C agonists with non-hallucinogenic potential are the basis of the NIH grant. We now have two molecular classes as leads going forward.
What does this NIH grant mean for atai and the work you're doing in mental health?
First off, it’s a source of non-dilutive, milestone-based funding. It keeps us disciplined and focused on OUD. The discovery process was initially tuned for depression, so this allows us to expand into OUD as a second indication.
It will also accelerate our lead optimization process in OUD and provide funding to advance candidates into pre-clinical testing and CMC-based activities.
Why is it so important to find new treatments for OUD and how could your approach make a difference?
OUD affects around 16 million people globally, with more than 120,000 opioid-related deaths annually. Current therapies like methadone and buprenorphine are effective but limited, as they target the mu opioid receptor to block opioid binding.
Our approach is different. By driving 2A/2C agonism, we aim to reduce craving and relapse through serotonergic pathways. Traditional treatments don’t adequately address trauma or compulsive drug seeking caused by dysregulated reward circuitry. Our agonists could address both.
Activation of 5-HT2A may help with trauma processing, memory consolidation, and neuroplasticity, supporting healthier brain networks. Meanwhile, 2C activation can modulate dopamine levels and potentially reduce drug seeking and relapse.
Finally, can public-private partnerships like this one with the NIH help move science forward faster?
Absolutely. These partnerships are force multipliers in translational science. The UG3/UH3 Grant is a true partnership with the NIH and the National Institute on Drug Abuse. We will have access to their expertise, combined with our discovery capabilities, to move much faster and smarter.