Mindstate Uses AI to Design “Next-Gen” Psychedelics Combined With 5-MeO-MiPT 

Mindstate Design Labs says it has received approval from both the FDA and its European equivalent, the European Medicines Agency, for a Phase 1 clinical trial of the psychedelic compound MSD-001 in human subjects. The drug is the company’s formulation of 5-MeO-MiPT, which was created by the late chemist Sasha Shulgin. 

Dillan DiNardo, the co-founder and CEO of Mindstate describes MSD-001 as a base substance which can be combined with other drugs to target precise serotonin receptors in the brain and create a new class of psychedelic medicines. Due to its ability to select receptors with high specificity, DiNardo says MSD-001 can minimize wider psychoactive effects and create customized states of consciousness.   

“Our first line of psychotropic effects is built on the single base formula of the Shulgin psychedelic 5-MeO-MiPT, commonly called moxy – a ‘psychedelic tofu,’” wrote DiNardo in an announcement on X. “At normalized clinical doses there are some basic psychedelic effects but no mystical experiences or entities or blissful formless voids or immersive memory replays. 5-MeO-MiPT is a blank canvas on which to paint infinite possibilities.”

According to DiNardo, Mindstate is using AI tools to develop combinations of known drugs that reach specific areas of the brain combined with 5-MeO-MiPT which engages the serotonergic pathways. He says that this approach will allow the company’s scientists to design compounds that generate precise moods, cognitions and perceptions and produce a new class of psychedelic medicines that are selective and designable.

“So we’re kind of going beyond 5-HT2A and thinking in this multi-target, systems-level manner,” says DiNardo, noting the receptor identified as a target of serotonergic psychedelic drugs such as LSD and psilocybin mushrooms. “This isn’t just one drug that we’re going to develop as a mental health therapeutic. This is the base component for a long range of drugs we are designing to induce different states of consciousness.”

In its approach to drug development, Mindstate is responding to challenges encountered by researchers who study psychedelics for therapeutic outcomes and often find that psychedelic experiences are highly variable. Mindstate is exploring if there is a way to generate states associated with positive outcomes, such as mystical experiences, more reliably through drug design.

Mindstate publicly launched in January 2022 and raised $11.5M for psychedelic research and drug development from a collection of investors including Y Combinator, Negev Capital, Day One Ventures, Initialized, Max Hodak, one of the co-founders of Neuralink, Instacart founder Apoorva Mehta, and the founders of OpenAI.  

The company has attracted seasoned pharma professionals. Dr. David Hough, a board member of Mindstate, was vice-president of research and development at J&J Innovative Medicine, where he led the Spravato esketamine nasal spray program. Dr. Hough recently became chief medical officer of Lykos Therapeutics after the company’s unsuccessful effort to gain FDA approval for MDMA-assisted therapy for PTSD.

Combining Drugs to Create a Therapeutic Match

Mindstate refers to 5-MeO-MiPT as a psychedelic primer and the non-psychedelic combination substances as probes. Reflecting on why Mindstate is attempting to create precisely designed states of consciousness, DiNardo notes that while psychedelics can be highly effective therapies, they can also produce unexpected experiences. 

“They’re unpredictable, they’re unreliable, they’re scary,” says DiNardo. “We’re basically saying, ‘Hey, here’s some psilocybin. Here are the contents of your subconscious, good luck, right?’ But if we can instead say you are going to experience X, Y and Z, and that effect profile is the optimized effect profile for your specific cluster of symptoms in your specific diagnosis, we’re not just doing a coin flip and saying, good luck. We are, to a very high degree, guaranteeing you a specific set of subjective effects.”

DiNardo emphasizes that Mindstate is not seeking a synergy between drugs; say, taking an antidepressant like Lexapro and adding a psychedelic to improve its effectiveness. Instead, the company’s scientists are combining 5-MeO-MiPT with an already-approved generic or new drug that has no psychedelic effect on its own, such as a heart disease medication, to selectively target and change the receptors in the brain that the psychedelic acts on to create a unique altered state of consciousness. 

DiNardo observes that current development of new psychedelic compounds tends to tweak existing drugs or create analogs that modify the experience, such as lowering the duration of the trip, or removing hallucinogenic effects. He says Mindstate seeks to go beyond this by targeting areas of the brain no other psychedelic has accessed, creating as-of-yet unseen consciousness-altering experiences and developing medicines for disease indications that psychedelics are not yet addressing. 

According to DiNardo, Mindstate is “generating mechanistic insights into the biological basis of different psychedelic effects.” He believes this will allow the company’s products to produce “valuable altered states that already exist but can’t be reliably induced or yet-unseen psychoactive effects which may help with indications that psychedelics are not yet addressing.” 

While classic psychedelics such as LSD, DMT, MDMA, psilocybin and others collectively target 30-50 sites in the brain, DiNardo says his team is casting a wider net by focusing on roughly 300 potential sites that drug combinations could act on. He says this allows them to design new experiences in consciousness that are targeted to a therapeutic outcome rather than “just accepting whatever effects happen to come from the drugs that nature or the vicissitudes of history gave us, like LSD and psilocybin and so forth.”

According to DiNardo, MSD-001 is part of a next-gen category of psychedelics which will allow Mindstate to design “specific altered states of consciousness for a limitless range of future psychotropic therapies.” He says the company’s scientists are seeking to reliably activate cognitive states such as mystical experiences, which are associated with better outcomes in clinical trials for treatments addressing death anxiety, depression, addiction and other mental health issues. 

Mining Trip Reports For Drug Development

Mindstate selected 5-MeO-MiPT as its base molecule using its neurotech Osmanthus platform AI tool which includes large language and natural language processing models. The company is using Osmanthus to examine trip reports, analyzing the chemistry of a drug in relation to the experiences they create. DiNardo asserts that Mindstate is the first to take this approach to psychedelic drug development. “I have not been able to find any kind of precedent in psychiatry or elsewhere,” says DiNardo.

For every trip report out there, there’s a good chance Osmanthus has read it. The platform was trained on datasets that describe the biochemistry of psychedelic drugs sourced from books, direct submissions, and blogs, as well as 70,000 trip reports from publicly accessible websites. DiNardo says Osmanthus can review a personal description of someone’s psychedelic experience and pinpoint the drug they took.

According to DiNardo, Mindstate’s suite of AI models allows an individual’s perspective and use of metaphor in trip reports to be transformed into mathematical relationships. “These relationships between phenomenology and underlying pharmacology are way stronger than you might expect,” says DiNardo. “Historically, it’s been very difficult to quantify the subjective, to do phenomenology in a quantitative way, and that’s where the large language models come in.”

DiNardo says Mindstate has assembled multiple AI systems to create these predictive models overlaying phenomenology in a quantitative manner with pharmacology, looking for the differences in the impact of different compounds. “Why does [N,N-]DMT give you entities, but 5-MeO[-DMT] gives you ego loss, but 2C-B mostly enhances sensory inputs and amplifies sensory information, and DiPT doesn’t have any visual impact, but it affects your auditory system? Where are those differences?” asks DiNardo. He says that Mindstate is discovering these connections and making predictive models about how consciousness changes when altering neurotransmitter systems in the brain. 

“Sometimes you don’t need any AI, sometimes it’s super obvious — the patterns when you compare the wide scale biochemical data to the phenomenological data — but sometimes it’s in the math,” says DiNardo. “It’s in using these various AI systems to connect the pharmacology to the phenomenology. And that’s what’s really innovative here.”

Aamina Bawany, a neuroscientist and doctoral student at New York University who researches psychedelics and AI thinks that the Mindstate strategy for drug development moves the field forward. “This opens up an entire new approach to the way we look at therapeutics and pharmaceuticals in general,” says Bawany. She adds that human clinical trial data generated by Mindstate and other research groups “is going to be what really determines whether institutions adopt psychedelics as a therapeutic approach.”  

Columbia University postdoctoral research scientist Hannah Goodman, who studies iboga alkaloids to treat substance use disorders, praises the team’s use of AI to improve the efficiency of the translational research pipeline. Drug development heavily relies on animal models, she says, but researchers who study psychedelics in animals can only speculate on their subjective experience and therefore therapeutic value. 

Goodman believes that, “the models that are available for drug development do not necessarily apply to developing psychedelics.” She particularly notes the challenges of the placebo effect in clinical trials with psychedelic compounds and patient access which may contribute to the challenges of approving psychedelics as medicines. “Hopefully this platform will help us to get out of this rut,” says Goodman.

Phase 1 Trials

DiNardo points out that poly-drug use with 5-MeO-MiPT is not new to psychonauts in the underground. With hundreds of trip reports attesting to the safety of 5-MeO-MiPT, as well as such combinations, DiNardo expects that MSD-001, Mindstate’s proprietary formulation of the Shulgin compound, will be proven safe for participants in the Phase 1 trial. If proven safe and effective, Mindstate says it will enact a long-term plan to test other drugs in combination with MSD-001. The company says it has already taken their compound through all the required animal studies.

The upcoming human Phase 1 clinical trials will be conducted at the Centre for Human Drug Research (CHDR) in Leiden, Netherlands. The research will involve 52 healthy participants in a double-blind, placebo-controlled study, focusing on the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MSD-001. According to the company, advanced diagnostic tools such as qEEG and fMRI will be utilized to further understand the neural impacts of the drug.

Simultaneous FDA approval for Phase 1 clinical trials in the U.S. lays the groundwork for Mindstate to expand their research. Examining the drug combinations by pairing MSD-001 with medications that are already approved could speed up the process of polydrug research for human subjects. DiNardo says that Mindstate’s goals are to expand to multiple clinical sites with numerous combinations of MSD-001 and other compounds. 

DiNardo believes the company’s use of their AI platform and MSD-001 as a base component will improve the efficacy and safety of psychedelic therapies. “It changes our ability to democratize access to psychedelics in a way that is safer, that is more effective, and just more accessible for people,” says DiNardo. 

He believes that new possible states of consciousness could expand exponentially through the Mindstate polydrug approach. “This thing we think of as the world of psychedelics,” says DiNardo, “is probably only the tip of the iceberg.”