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One of my chronically depressed patients recently found a psychoactive drug that works for him after decades of searching. He took some psilocybin from a friend and experienced what he deemed a miraculous improvement in his mood. “It was like taking off a dark pair of sunglasses,” he told me in a therapy session. “Everything suddenly seemed brighter.” The trip, he said, gave him new insight into his troubled relationships with his grown children and even made him feel connected to strangers.
I don’t doubt my patient’s improvement—his anxiety, world-weariness, and self-doubt seemed to have evaporated within hours of taking psilocybin, an effect that has continued for at least three months. But I’m not convinced that his brief, oceanic experience was the source of the magic. In fact, some neuroscientists now believe that the transcendent, reality-warping trip is just a side effect of psychedelics—one that isn’t sufficient or even necessary to produce the mental-health benefits the drugs seem to provide.
For several years, researchers have understood that the hallucinatory effects of psychedelics can, in theory, be separated from the other ways the drugs affect our mental state and brain structure. But until recently, they have not been able to design a psychedelic that reliably produces only the neurocognitive effects and not the hallucinatory ones. That may soon change. A new generation of nonhallucinogenic psychedelics, at least one of which is currently being tested in humans, aims to provide all of the mental-health benefits of LSD, psilocybin, or Ecstasy without the trip. Trip-free psychedelics would be a great therapeutic boon, dramatically expanding the number of people who can experience the benefits of these drugs. They might also shed new light on how much psychedelics can alleviate psychic distress—and why they do so at all.
Over the past five years, studies have demonstrated that psilocybin has powerful antidepressant effects, and that MDMA (a.k.a. Ecstasy), in conjunction with psychotherapy, can relieve the symptoms of PTSD. Remarkably, just a few doses of either psilocybin or MDMA can produce a rapid, lasting improvement in depression and anxiety symptoms, meaning symptom relief within minutes or hours that lasts up to 12 weeks. (MDMA is what psychiatrists call an “atypical psychedelic”; it has a mix of psychedelic-like and amphetamine-like effects, producing a feeling of bliss rather than a transcendent or mystical state.) The FDA is widely expected to approve MDMA for supervised use sometime in 2024—an extraordinary turnabout for drugs that have long been stigmatized for their potential (if rare) serious harms.
From a clinical perspective, this psychedelic revolution is potentially miraculous. An estimated 23 percent of Americans have a mental illness, and a considerable number of them, like my patient, don’t get sufficient relief from therapy or existing medications. Drugs like psilocybin, ayahuasca, and LSD could help many of these patients—but others won’t be able to tolerate the trip. (By “trip,” I mean the variety of altered mental states that psychedelic drugs can cause, such as the transcendence and mystical experience of LSD and psilocybin, and the bliss and social openness of MDMA.) Drug-induced hallucinations are known to give certain people—like those with psychotic disorders or severe personality disorders—extreme anxiety or even lead to a psychotic break. That’s why clinical trials of psychedelics typically exclude those patients.
I don’t mean to discount the delight and power of a transcendent hallucination. Many people who’ve tripped on psychedelics describe the experience as among the most meaningful of their life. And in several studies of psilocybin for depression, the intensity of the trip correlates with the magnitude of the therapeutic effect. A trip is an extraordinary, consciousness-expanding experience that can offer the tripper new insight into her life and emotions. It also feels pretty damn good. But it’s far from the only effect the drugs have on the human brain.
During a trip, psychedelics are silently doing something even more remarkable than warping reality: They are rapidly inducing a state of neuroplasticity, in which the brain can more easily reorganize its structure and function. (Microdosing enthusiasts, who take subtherapeutic doses of drugs like psilocybin, claim to experience enhanced creativity. They may be getting neuroplastic effects without a trip, but as yet, little scientific evidence backs up that idea.) Neuroplasticity enhances learning, memory, and our ability to respond and adapt to our environment—and could be central to the therapeutic effects of psychedelics. In depression, for example, the prefrontal cortex (the brain’s reasoner in chief) loses some of its executive control over the limbic system (the brain’s emotional center). Drugs that enhance neuroplasticity allow new connections to be formed between the regions, which can help reset the relationship and put the prefrontal cortex back in control of emotion.
Like MDMA, ketamine—the animal tranquilizer, surgical anesthetic, and dissociative party drug that was also approved as a rapidly acting antidepressant in 2019—typically doesn’t produce hallucinations. But it does create a dissociative mental state, and it’s known to make neurons sprout new spines within hours of administration, a structural change that’s been linked with a reduction in depression-related behavior in animals. In humans, ketamine has been shown to boost mood—even if it’s administered when patients are unconscious. Several studies show that patients who receive ketamine during surgery wake up happier than they were before the operation. This suggests that you don’t need to consciously experience the dissociative effects in order to get the antidepressant benefits.
Scientists are on their way to finding out for sure. For the first time, researchers have purposively developed psychedelic drugs that appear to bring about the neuroplastic effects without producing a trip. These drugs stimulate the same serotonin receptor as traditional psychedelics: 5-HT2A, which, when triggered, causes the brain to produce more of a compound called BDNF, a kind of brain fertilizer that promotes neuronal growth and connectivity. But the nonhallucinogenic versions activate 5-HT2A without leading to a trip. (Binding and activating receptors isn’t an all-or-nothing phenomenon; different drugs can bind the same receptor in different ways, producing very different effects.)
Some of these trip-free psychedelics are new inventions. Last year, for example, scientists synthesized a new nonhallucinogenic psychedelic by imitating lisuride, an analog of LSD. (An analog is a chemical that is structurally very similar to the original compound, but has been modified to have a different function.) It doesn’t have a name yet—just a serial number, IHCH-7113—but it’s being studied in animals.
Other trip-free psychedelics have been around for decades, if not recognized as such: 2-Br-LSD, another nonhallucinogenic analog of LSD, was first synthesized in 1957 by the same chemist who created LSD. (It was meant to treat migraine.) Recent experiments show that 2-Br-LSD, like LSD, relieves depressive behavior in mice. But unlike LSD, it doesn’t make the mice twitch their heads—a sign that a substance will give humans hallucinations and other psychotic symptoms. More than 60 years after 2-Br-LSD’s invention, the Canadian company BetterLife Pharma is planning to study it as a treatment for major depression and anxiety.
LSD isn’t the only psychedelic inspiring imitators. Delix Therapeutics, a biotech company based in Boston, is using animal models to study tabernanthalog, which is an analog of the active psychedelic in ibogaine. Tabernanthalog has acute antidepressant and neuroplastic effects in animal models, and, like 2-Br-LSD, it doesn’t cause head twitching. Delix is also testing a drug that it’s calling DLX-1, which David Olson, one of Delix’s co-founders, told me is the first nonhallucinogenic psychedelic to be tested in humans; Phase 1 studies, he said, are nearly completed. Olson, who is also the director of the Institute for Psychedelics and Neurotherapeutics at UC Davis, calls the drugs he works on “psychoplastogens,” for their rapid neuroplasticity-inducing effects. He said that other nonhallucinogenic psychoplastogens that the company is working on are “close to entering clinical trials,” though how soon any of them might reach the market is unclear.
As of yet, the federal government has provided little funding for nonhallucinogenic-psychedelics research. Delix and other makers of these new psychedelics will have to submit an application to the FDA to get their drug approved, which generally requires that the new drug beats a placebo control in two randomized clinical trials. This can be a slow process, but the FDA can expedite it by designating the drug a “breakthrough therapy,” which is exactly what it did in 2018 with psilocybin.
In clinical trials, nontrip psychedelics will have at least one major advantage over their trip-inducing analogs: They can more easily be placebo-tested. Classic psychedelic research has been bedeviled by the simple fact that it is virtually impossible not to know that you are taking a classic psychedelic. Indeed, in clinical trials of MDMA and psilocybin, more than 90 percent of subjects who received the treatment correctly guessed that the drug they were given was real. This sort of defeats the purpose of placebo-testing psychedelics at all, because participants who receive the real drugs will expect to feel better. But the new nontrip psychedelics don’t produce the transcendent mental states that tend to “unblind” research subjects. They might produce more typical drug side effects, such as dry mouth or sedation, but that’s a far cry from a mystical experience.
Nontrip psychedelics may also have it easier with respect to regulation. If they don’t make you high or produce a transcendent state, they’ll likely have little appeal as recreational drugs. The Drug Enforcement Administration classifies LSD and psilocybin as Schedule I drugs, which makes them difficult for researchers to study and doctors to prescribe. Even ketamine is Schedule III and must be administered in a medical setting, which may be inconvenient for patients. Perhaps the DEA will take more kindly to nontrip psychedelics; if so, they’d be easier to access for patients and researchers alike. Plus, nonhallucinogenic psychedelics would not require the time and expense of a guide to monitor the experience. All said, the nontrip psychedelics might end up being a more popular, better-researched choice than traditional ones.
If the FDA really does approve MDMA next year, psychiatrists will have plenty of reason to celebrate. But I suspect that the future of psychedelic medicine will lean toward the wonder of pure neuroplastic potential and away from transcendence. Psychedelic trips will probably never disappear from society—for one thing, they are viewed as essential to some religious and cultural rituals. But perhaps they’ll come to be seen as less like therapy, and more like good old-fashioned fun.
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Richard A. Friedman
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