The Defense Advanced Research Project Agency (DARPA) is funding a four-year $27 million research project to develop new medicines that replicate the effectiveness of psychedelic substances for treating mental health conditions without the psychoactive effects.
A team of researchers led by Dr. Bryan Roth, a professor of pharmacology at the University of North Carolina School of Medicine, will combine large-scale computational modelling with cutting-edge technologies to understand how drugs bind to various receptors.
The project is part of the Focused Pharma program, announced by DARPA last September, which aims to develop a new class of psychotherapeutic drugs for treating a range of neuropsychiatric conditions.
DARPA develops emerging technologies for use by the U.S. military. Some of its projects, such as the ARPANET, which laid the technical foundation for the Internet, have a wide impact beyond military use.
In its drug development program, DARPA is focusing on addressing the mental health crisis among U.S. military veterans suffering from PTSD, chronic depression, and substance abuse.
Roth, who directs the National Institute of Mental Health Psychoactive Drug Screening Program, believes that while ketamine and potentially psilocybin are effective antidepressants, their “hallucinogenic, addictive, and disorienting side effects make their clinical use limited.”
Roth and his research team aim to develop medications that retain the fast-acting mental health benefits of psychedelic substances while removing their psychoactive effects.
Roth’s interest in researching psychedelic compounds stems from promising research showing psilocybin as an effective medication for treatment-resistant depression. Reviewing findings from the Phase II clinical trial data, Roth was intrigued by the “large magnitude and duration of therapeutic effect” of psilocybin.
“Such an approach could be a potential game-changer in terms of treating mental illness,” said Roth. “If we succeed in creating drugs which rapidly diminish the symptoms of depression, anxiety, and substance abuse without the hallucinatory actions of drugs like psilocybin, that would be revolutionary.”
Some researchers believe that drugs which replicate the mental health benefits of psychedelics without psychoactivity will be more scalable, marketable, and profitable than the current paradigm of psychedelic-assisted therapy. Others assert that the visionary altered states brought on by psychedelic substances are central to the process of healing depression and other illnesses.
Asked to comment on this view, Roth argues that research has not confirmed the benefits of the psychedelic experience.
“Right now there is no real evidence that the psychedelic effect per se is essential or even necessary for the potential antidepressant effects of drugs like psilocybin,” says Roth.
Roth further suggests that the “only evidence at present is based on studies which rate the intensity of the experience with the therapeutic actions.” He adds “that this correlation is pharmacodynamic in nature and is a proxy for receptor occupancy by the drug.”
Psychiatrist and ayahuasca researcher Dr. Simon Ruffell shares the view that trip-free psychedelics are more accessible.
“One benefit that may come of these types of drugs is increased access, where those uncomfortable with the psychedelic “side effects” may be more open to receiving treatment,” says Ruffell.
Ruffell also expressed uncertainty, however, that such medications may not be as effective as active psychedelics.
“The current understanding of the psychological therapeutic mechanisms of classic psychedelics is that aspects of the subjective experiences facilitate improvement,” says Ruffell.
For example, the so-called “mystical experience” associated with psychedelics has been shown to generate personal meaning and spiritual significance that could potentially impact therapeutic outcomes.
Roth and his colleagues are using new technologies to determine how drugs bind to and affect the activity of cells called G protein-coupled receptors or GPCRs. They use lipidic cubic-phase x-ray crystallography, cryo-electron microscopy, and ultra-large-scale computation chemistry to examine how drugs impact the signal processes inside these cells.
“Designing drugs to stabilize these specific cell-signaling complexes represents a ‘grand challenge’ for neuropsychiatric drug discovery, as there are currently no FDA-approved medications with the desired signaling profiles,” says Roth.
“We will take advantage of our recent innovations in GPCR structural determination to stabilize specific serotonin receptors and identify tens to hundreds of thousands of new candidates for developing better medications.”
These studies will not include human clinical trials. At the end of the four-year research agreement, Roth and his fellow investigators are expected to submit an Investigational New Drug application to the U.S. Food and Drug Administration.
Roth says this research is currently solely funded by the U.S. government. “There are no commercial entities involved,” says Roth. “And at present, patenting small molecules is not something we’ve decided upon.”
Image: Bryan L. Roth, MD, PhD