*This article was originally published in DoubleBlind Magazine Issue 7 in June 2022.
It’s been more than two years since the Defense Advanced Research Projects Agency (DARPA), the US military’s research-and-development arm, unveiled an ambitious effort to scrub the mystical journey out of psychedelics. Persuaded by emerging research indicating that psilocybin and other federally illegal drugs can treat anxiety, depression, and PTSD, the Defense Department announced a plan to design and produce an entirely new class of pharmaceuticals offering similar mental health benefits to entheogens—but without the consciousness-altering trip.
Mental health conditions are common in the US, with nearly one in five people suffering from a mental illness, according to the National Institute of Mental Health. Anxiety and severe depression top the list. Veterans and active-
duty military have even higher rates of severe mental illness, which is one of DARPA’s stated reasons behind the research. A Veterans Administration report from 2019 found that veterans have a suicide rate 1.5 times that of the general adult population.
With the program set to expire in mid-2023, a research team funded by a $27 million DARPA grant is now readying revisions to a forthcoming paper detailing its latest findings. Although the data has yet to be published, scientists involved in the work say they’re cautiously optimistic.
“We haven’t published the data yet, so I can’t tell you what the results are,” Bryan Roth, the University of North Carolina pharmacologist who leads the project, said in a recent interview, “but I’ll just say we’re very encouraged by the results.”
If Roth and his team succeed in creating compounds that disentangle psychedelics’ therapeutic benefits from their acute subjective effects, the discoveries could help usher in the next wave of mental health medications. Though the annual global market for antidepressants alone is nearly $20 billion, an estimated ten to thirty percent of the 16.1 million Americans with major depression do not respond to them, according to a 2012 study published in Patient Preference and Adherence. Clinical evidence suggests that just a few facilitated sessions with substances like psilocybin, MDMA, or ketamine may provide relief for months or even years.
DARPA’s aim, however, isn’t to produce more psychedelics, emphasized Roth. “The goal of the project, actually, is to make drugs that are not psychedelic, but are therapeutic instead.”
The distinction implicit in the pharmacologist’s statement—that the new drugs will not be psychedelic but therapeutic instead—stirs complicated feelings in the psychedelic community. For one thing, researchers are still unclear on the causal relationship between the subjective effects of a psychedelic journey and the associated mental health benefits. What parts of a trip exactly—the journey itself, or the change in brain chemistry—allow someone to more easily process past trauma, quiet anxiety, or see beauty in the connectedness of things? How necessary is it to alter your consciousness in order to change your mind? Others worry that progress toward DARPA’s imagined drugs could slow or stifle wider access to psychedelics themselves, which have been used by humans for thousands of years not only for therapeutic purposes, but also for spiritual and ceremonial use or personal development.
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David B. Yaden, an assistant professor at Johns Hopkins University School of Medicine in The Center for Psychedelic and Consciousness Research, is skeptical that any new drugs produced through DARPA’s research will ultimately show the “full and enduring therapeutic effects” of true psychedelic therapies, but nevertheless says he “cheers on” the government effort. “In a lot of cases, it will be absolutely the correct thing to do to withhold the acute subjective effects,” said Yaden, noting that the new pharmaceuticals could be useful for treating patients with certain risk factors that might prevent them from taking psychedelics. On the other hand, Yaden noted that many people who use psychedelics describe the experience as “highly positive” and deeply profound.
“I think it would be scientifically and clinically valuable to have a non-subjective psychedelic,” he said, referring to a drug that would affect the same receptors as psychedelics but not otherwise change a user’s consciousness. “I just think that it’s important to bear in mind that ethical issues do arise from withholding the acute subjective effects of psychedelics, given that they’re so often rated as one of life’s most meaningful moments.”
Not long ago, the discovery of new pharmaceuticals regularly entailed journeys into the depths of jungles and oceans. A decade ago, for example, the majority of anti-cancer drugs were either harvested from other lifeforms or otherwise derived from natural substances. Today, researchers look increasingly to AI and computer-aided modeling to design chemicals that have never before existed.
Roth, the UNC pharmacologist, has spent much of his career studying how drugs interact with receptors in the brain. For the DARPA project, he and the research team—which includes about 30 scientists in labs at Stanford, University of California, San Francisco, Duke, and others—use computers to design substances that will tickle the serotonin 5-HT2A receptor, which is also activated by psychedelics.
“We have the ability now to basically test billions of compounds that don’t exist in the physical universe, but could be made,” Roth said. The project lead has authored papers in the prestigious journal Nature about the technology and said that in recent years the process has been “robustified to a really astounding degree.”
After promising drug models are synthesized, they’re looked at in test tubes of cells that allow researchers to gauge the new substances’ activation of target receptors in the brain. Partners then test the drugs in mouse models, looking for indications of both psychedelic and therapeutic effects. Roth finds those results encouraging, though he acknowledges the project might ultimately lead to nowhere. It’s worth noting that, in addition to DARPA, there are more than a dozen pharmaceutical companies engaging in this same process of trying to find new compounds or refine existing ones, inspired by psychedelics, and many pharmaceutical companies never actually get the drugs that they’re investigating into humans and on the market.
“What I tell people is that I’m agnostic about whether the psychedelic experience is essential for the therapeutic action of any of these drugs,” said Roth. “It’s possible that it is and our attempts will fail. It’s also possible that the
psychedelic experience is not essential to the therapeutic action of the drugs…I’m just hoping that we get a clear answer.”
Tristan McClure-Begley, the program director at DARPA overseeing the $27 million project, agreed that the work was exploratory and not designed to yield a market-ready product immediately. “Why do I think therapeutic activity can be uncoupled from psychedelic activity with these drugs? I always answer the same way,” said McClure-Begley, who was a research professor at the University of Colorado Boulder before joining DARPA in 2017. “It’s not that I think they can. I’m asking if they can.”
“To be brutally honest,” he added, “coming up with novel chemical matter that has demonstrable therapeutic activity for any mental condition is already a monumental lift.”
Both Roth and McClure-Begley said they were persuaded by preliminary findings that psychedelics have the potential to treat certain mental health conditions far more effectively than existing treatments. That’s despite nearly all such drugs being categorized as Schedule I substances under federal law, meaning by definition that they have no accepted medical use. Psilocybin, the main psychoactive ingredient in psychedelic mushrooms, “looks to be astoundingly effective in treating depression,” said Roth.
McClure-Begley, at DARPA, called it “factually accurate to say that psilocybin—or psilocin, the active metabolite—which is a classical psychedelic, is observed to produce therapeutic effects when delivered with a therapist and evaluated in certain patient populations.”
It’s precisely those effects that caught the attention of the federal government. Separate studies from Johns Hopkins and New York University, for example, have shown psilocybin to be associated with significant decreases in depression and anxiety that, in nearly eight in ten patients, lasted at least six months. Though it remains unclear how long exactly the effects persist, an Imperial College London report found that twice as many patients with major
depression who took two doses of psilocybin were in remission after six weeks compared to patients who took the antidepressant escitalopram. Additionally, MDMA has been given “breakthrough therapy” status by the Food and Drug Administration for post-traumatic stress disorder, fast tracking it for approval.
So why bother making new drugs at all?
When DARPA first announced its Focused Pharma project, it noted that existing “Schedule I controlled drugs that engage serotonin receptors” have “significant side effects, including hallucination.” An early UNC press release about the $27 million grant said the goal was to design fast-acting treatments resembling psilocybin and ketamine, but free from what were described as “disabling side effects.”
“If we produce molecules that do have some form of antidepressant, et cetera, effect without inducing a psychedelic state, then that opens the aperture of potential beneficiaries,” McClure-Begley said. “I always tend to think that diversity of therapeutic options is key to health in the public sense…We should have as many options available to us as possible.”
Roth added another argument in favor of nixing the psychedelic trip: cheaper, more efficient alternatives to psychedelic treatment, which sometimes entails hours of intensive, in-person therapy with one or more facilitators, usually during a few sessions spread across several months.
“That’s going to be a lot of money right there,” he said. “If nothing else, it would be more cost-effective if we had a drug that didn’t require that degree of supervision and management and all that stuff. It’s just so much easier for the patients.”
Roth used meditation as a comparison, noting that he’s practiced Zen Buddhism for many years and tries to meditate at least three hours a day. “It’s been extraordinarily helpful in my life, but it’s not for everybody,” he said. “Not everybody can carve out two, three, four hours a day to sit in silent meditation.”
DARPA researchers also cautioned that studies highlighting psychedelics’ therapeutic successes often exclude people with family histories of schizophrenia, bipolar disorder, or psychotic illness because researchers were concerned about the potential for adverse side effects.
The agency’s experiments with novel drugs aren’t unprecedented, McClure-Begley noted, pointing to similar DARPA projects such as the so-called Panacea program, which is designed to investigate multi-target therapeutics that
treat everything from metabolic stress caused by high-altitude exertion to soft-tissue injury and accompanying pain and inflammation. Another, the Accelerated Molecular Discovery program, is even more fundamental and focuses on the efficient discovery and production of “high-performance molecules,” including stimulants, dyes, and specialty fuels.
Beyond promoting military readiness, McClure-Begley added, the program’s goal is to support America’s technological capabilities more broadly. “The program is supporting the development and application of advanced
structural biology techniques, such as high-resolution cryo-electron microscopy and molecular dynamics simulations,” he said. “DARPA places no restrictions on the publication or dissemination of results from any of its fundamental research, and all of the research supported by Focused Pharma is being conducted at academic institutions.”
In 2020, Canada’s health ministry granted a handful of cancer patients permission to use psilocybin legally as part of their end-of-life care. According to the nonprofit TheraPsil, which assisted the patients with their applications, the patients were the first people to legally use psilocybin in Canada since the compound was outlawed in 1974, as the global Drug War ramped up.
Sean O’Sullivan, a physician in Canada, was TheraPsil’s medical director when Canada granted the psilocybin exemptions. He now advocates for broader patient access to psychedelics and educates other doctors on psychedelic therapy. Despite his deep belief in the potency of psilocybin and other natural psychedelics, O’Sullivan is sympathetic to clinicians’ desire to work with a single compound rather than the cocktail of molecules in a plant or fungus.
“We ask two things of any medication. We ask that it be efficacious, and we ask that it be safe,” O’Sullivan said. A single molecule, whether extracted from an existing psychedelic or created afresh, may not be any safer than psychedelics themselves, “but at least you’ll get to drill down and learn what the side effects are likely to be, as opposed to having 20 alkaloids that could each be contributing unique sets of side effects.”
Isolated compounds generally also tend to be easier to study than whole-plant therapies, which are more prone to variance in potency and overall chemical makeup, he said. “There’s value in having a precise dose of a clean formulation that is reproducible from patient to patient.” It’s why we take aspirin instead of chewing on a slab of willow bark.
But O’Sullivan dismissed Roth’s claim that non-psychedelic drugs would be cheaper and more efficient than traditional psychedelic therapy as “nonsense.” “The whole point about psychedelics is you’re doing them once, twice, or three times,” he said. The amount of time and money most people would spend on traditional medications “is actually a lot more over the course of their lifetime.”
Any new drug may also not be the convenient fix that DARPA hopes it will be. Even if the team successfully identifies and creates psychedelic-inspired drugs, said Yaden at Johns Hopkins, those substances may require just as much
therapeutic support as actual psychedelics, regardless of whether or not patients hallucinate. “If you’re putting people into highly neuroplastic physical states and just allowing them to go about their daily life, that may be very risky,” he said. “We just don’t know.”
Yaden is also convinced that at least some of the consciousness-altering experience of a trip is essential to the healing power of psychedelics. Treatment involving drugs like psilocybin or MDMA, for example, typically involve shifts in cognition and personal meaning-making. Those processes are often guided by trained counselors or clinicians. “If you’re not engaging those higher-order mental processes, I just doubt that you would get full and enduring therapeutic effects,” Yaden said. The therapeutic impacts of psilocybin, he added, appear to persist far longer than the drug itself. And psychedelics typically activate multiple receptors in the brain, not just one.
Both Yaden and O’Sullivan warned against seeing DARPA’s project as an endpoint in the exploration of psychedelics. The investigation into human consciousness is at the forefront of psychiatry and neuroscience, and psychedelics offer a way to explore the frontier, O’Sullivan said. “To try and reduce that to a single receptor, with a single molecule that acts on it, to treat a single symptom? This is an absolutely ridiculous reductionism.”
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