Clay Dalton reports on the company Delix Therapeutics, which is trying to create a drug with the mental-health benefits of a psychedelic experience without the trip.
A chemical neuroscientist named David Olson, then a graduate student at Stanford, told me that he encountered these studies and was “struck by the ability of a substance, with a single dose, to have such long-lasting effects.
” He wanted to know how the drugs worked. He followed closely as researchers began investigating the effects of mind-altering substances on depression, anxiety, substance-use disorders, post-traumatic stress disorder, and other conditions. These studies often identified positive results, sometimes marked ones, and they sparked discussions about a new mental-health paradigm. Might we one day take psychedelics as a kind of therapy? How would clinicians safely prescribe substances that change our perceptions, thoughts, and moods? And perhaps the most perplexing question of all: Why would such drugs make us feel better in the first place? An important clue came in 2010, when another team at Yale published a study of how ketamine affected the brain cells of rats. In the prefrontal cortex, which regulates mood, the drug seemed to prompt brain cells to grow new branch-like projections that help neurons connect with one another. These projections, known as dendritic spines, typically develop as we learn, gain skills, and experience new things, and their growth contributes to what scientists call neuroplasticity—the brain’s ability to change structurally and functionally over time. Stress and depression, meanwhile, can make them wither like dying trees—especially in the prefrontal cortex. Before administering the ketamine to the rats, the Yale researchers induced symptoms of depression by subjecting the animals to grim protocols such as “learned helplessness” and a “forced swim test.” The drug not only bolstered dendrites but also improved the rats’ behaviors. Yet when the researchers blocked key proteins involved in dendritic growth, the improvements disappeared—a suggestion that the drug’s mental-health effects might depend on the growth. Olson designed similar experiments with several psychoactive drugs: psilocin , LSD, DMT, MDMA. In a 2018 paper, he and several colleagues reported that all of these substances spurred dendrite growth in isolated neurons in a dish. When they dosed fruit flies with LSD, they observed a similar neural response. The researchers then injected DMT into live rodents. Twenty-four hours later, changes were readily apparent in the prefrontal cortex. In several microscope images included in the paper, the rodent neurons look like newly fertilized trees. Advocates of psychedelic therapy have long argued that altered mental states help explain whatever therapeutic effects these drugs have. Roland Griffiths, who oversaw the Johns Hopkins study of psilocybin, believed that the drug helped people because it sparked mystical experiences. “Very often, people report these experiences to be the most personally meaningful, personally insightful, of their entire lifetime,” he told me before his death in 2023. Olson had a different hypothesis: What if the most important effect of these drugs is not on the mind but on the brain? Olson became convinced that scientists could take the psychedelic effects out of psychedelic drugs—without sacrificing many of the mental-health benefits. This is a provocative view. “I don’t really buy the basic argument that you can remove the trip entirely and get the therapeutic response,” Robin Carhart-Harris, a psychedelics researcher at the University of California, San Francisco, told me. Carhart-Harris has used fMRI scans to document changes in brain activity that occur during psychedelic experiences. “Imagine the brain’s activity patterns like a snow globe that has settled,” he has said. “Psychedelics shake the snow globe, disrupting these patterns and allowing for new ones to form.” In his telling, a trip is just what you feel when the globe shakes; skip the trip and your brain remains stuck in its patterns. In 2019, Olson co-founded a company called Delix Therapeutics, which says that its “singular focus is pushing the boundaries of neuroscience to treat conditions of the brain.” His academic research takes place at the University of California, Davis, where I went to visit him in his laboratory. He started to make his case by sketching the structure of serotonin, a neurotransmitter that regulates mood, on a piece of paper. He drew two geometric rings, with groups of atoms branching out. Then he pencilled in some methyl groups—CH3—and moved a single oxygen atom from one carbon to another. “That’s psilocin,” he said. Olson erased the oxygen. Now the molecule was DMT, which causes an extremely intense but relatively short trip. “Small structural changes make a huge difference,” he explained. Finally, he transposed the nitrogen and carbon rings from one position to another. In terms of the molecule’s over-all shape, it was nearly identical to DMT. “If you held models in your hands, you wouldn’t be able to tell them apart,” Olson said. “But they have very different effects.” In rodent experiments, both molecules promote dendritic growth in the prefrontal cortex. This last molecule, however, wasn’t hallucinogenic. Olson, who has a shaved head and piercing eyes, showed me how the scientists in his lab break psychedelic molecules into parts, as though they’re cars in a chop shop, and build new ones. There were beakers everywhere, full of chemical reagents such as sodium hydrosulfite and inorganic bases. We walked by liquid-chromatography machines and hulking specimen freezers. Graduate students in tie-dye shirts worked under fume hoods; on the glass that protected them from chemicals, synthesis reactions were scribbled in black marker. One researcher, Andrian Basargin, explained that he was making a substructure of LSD in an acetone and dry-ice bath. It would become a component in a new compound, which would then be taken for a test drive. Olson got hints on where to begin from an odd pair of books by Alexander and Ann Shulgin: “PiHKAL,” short for “Phenethylamines I Have Known and Loved,” and “TiHKAL: The Continuation,” short for “Tryptamines I Have Known and Loved.” Alexander was a chemist who, beginning in the nineteen-sixties, created nearly two hundred novel chemical compounds, many of them psychedelic, and tested some of them on himself. The books contain extensive notes on the drugs’ synthesis and effects. Olson tasked a grad student with reading the books and cross-referencing drug forums on Reddit—“kind of a weird thing,” he admitted. He wanted to know which of Shulgin’s concoctions didn’t produce much of a trip. “Some of the first molecules we made were informed by procedures from those books,” he told me. A long trial-and-error process gave Olson a sense of which molecular motifs seemed likely to cause mind-altering effects. “You make a change, you do a round of testing, then you see, Oh, this change takes us closer to where we want to be,” he said. He showed me a large black box about the size of an industrial printer. Inside were lab-grown cells studded with modified receptors. A new substance would be squirted over the cells, Olson explained. If the molecule was likely to have hallucinogenic properties, it would trigger a fluorescence reaction that sensors in the box would detect. This helped the team weed out trippy compounds. In this way, for example, the team discovered that flipping two atoms within the LSD molecule—Olson compared the change to a tire rotation—affected how hallucinogenic it was. To confirm these findings, this new compound was also tested on rodents. If a molecule passed these tests, the next step was to determine whether it stimulated the growth of dendrites. In another lab across Davis’s leafy campus, we met John Gray, a neuroscientist who tested experimental drugs on living neurons. Slices of mouse brain floated in dishes of synthetic cerebrospinal fluid; on a monitor, I could see a single teardrop-shaped neuron. I watched through a microscope as a postdoc, Raghava Jagadeesh Salaka, broke through the neuron’s cell membrane with a micropipette. It looked like a needle pricking a dollop of translucent jelly. The micropipette allowed the researchers to measure electrical activity in the neuron, Gray explained. Blue spikes, which suggested increased signalling and connectivity, soon appeared on another computer monitor. The team also looked for physical changes. After exposing neurons to a compound, they used a microscope to count any new dendritic spines that had popped up. Olson eventually found a substance that did not seem to be hallucinogenic but potently stimulated growth in the cortical neurons of rodents. He named the compound zalsupindole; it was similar to the variant of DMT that he’d sketched for me in his lab. He felt he needed a term for this new category of drug, so a classics professor at Davis helped him come up with “psychoplastogen,” from the Greek roots psych and plast . Delix, the company that he co-founded, tends to use the term “neuroplastogens,” which emphasizes the impact on the brain rather than on the mind. I asked Olson what he thought it might be like for a person to take it. “Well, we started clinical trials two weeks ago,” he told me. In December, Delix Therapeutics presented the results of what it called the first human clinical trial of a neuroplastogen. Eighteen patients with major depression were treated with zalsupindole for one week in a monitored setting. There were no significant safety concerns, and the team confirmed that the drug has no subjective effects. “Definitely, without a doubt, it is not hallucinogenic,” Olson said. Although the study was designed primarily to establish safety, almost all of the participants reported substantial improvements in their symptoms for at least a month. Two participants mentioned that their depression had abated completely. Edward Sellers, an emeritus professor at the University of Toronto and an expert on pharmacology who is not affiliated with Delix, told me that results were “encouraging but inconclusive.” He stressed that the trial was limited by its small size, its lack of a placebo control, and the fact that participants knew what they were taking. But it was enough to convince the Food and Drug Administration to approve a larger, placebo-controlled study in the coming years and to allow participants to take the drug at home. Carhart-Harris, at U.C.S.F., is skeptical that mystical experiences can fully explain why psychedelic drugs help people with depression. “If you look up mystical in the dictionary, you see supernatural, and that’s a problem in my view,” he told me. But his brain-imaging studies suggest that, during a psychedelic trip, communication between different regions of the brain becomes far less constrained than during normal consciousness, allowing new ways of thinking to emerge. Zalsupindole might not produce those effects. Other research has found that psychedelic trips elicit psychological insights and emotional breakthroughs, which are strong predictors of a therapeutic response. “It’s not magic,” Carhart-Harris said. “It’s psychology.” David Nichols, a neuroscientist who is an expert on psychedelics, told me about a woman with alcohol-use disorder who realized during a psilocybin trip that her drinking was harming her children and decided to stop. Another patient had a revelation about the origins of his severe obsessive-compulsive disorder, which significantly improved his symptoms. “There is something that happens that is transformative,” Nichols said. “It’s not just the physiological effect of making some dendrites grow.” Many pharmaceutical companies are betting on neuroplastogens, however. One 2024 analysis, published in the journal Nature Biotechnology, estimated that the field could be worth nearly seven billion dollars by 2030. That same year, AbbVie, one of the largest drug companies in the U.S., signed a deal with Gilgamesh Pharmaceuticals, worth roughly $1.95 billion, to develop “novel neuroplastogens.” Another biotech company, Enveric Biosciences, is preparing for human trials of its own non-hallucinogenic analogue of DMT. In September of 2025, the National Institute on Drug Abuse awarded a grant worth up to $11.4 million to atai Life Sciences to develop similar drugs. Neuroplastogens are “quietly redefining the psychedelic medicine narrative,” according to “Microdose,” an industry newsletter. “The result is a shift that feels less like a cultural movement and more like a return to classic pharmaceutical logic, just with radically new science underneath.” “If you absolutely need the hallucinogenic effects, then these new compounds are not going to be the revolution in psychiatry that people are hoping they will be,” Olson told me. Hallucinogens could trigger schizophrenia or a bipolar episode. A family history of these conditions can exclude patients from treatment. Psychedelic treatment protocols are also resource-intensive, and can involve multiple lengthy sessions with trained facilitators that may not be covered by insurance. In Oregon, where psilocybin therapy was legalized in 2023, a third of new clinics have already closed owing to high operating expenses and treatment costs. There have also been reports of facilitators taking advantage of patients while they were under the influence of mind-altering drugs. Neuroplastogens would fit much more comfortably in the existing apparatus for drug development, regulation, and distribution, without the cultural baggage. “I’ve faced significant criticism for creating non-hallucinogenic analogues of psychedelics,” Olson said. “But why wouldn’t you want to try this, to help as many people as possible?” Even the skeptics are paying close attention. David Yaden, a psychologist at Johns Hopkins whose official title is the Roland Griffiths Professor of Psychedelic Research, described the development of neuroplastogens as a grand experiment. “Scientifically, I’m interested in the question of whether the trip matters,” he told me. Non-psychedelic neuroplastogens may test that question with a new level of specificity. “If it was all just castles in the sky, and the acute subjective effects don’t matter, that would be really interesting,” Yaden went on. “It would undermine my entire perspective.” If that turns out to be the case, he’s open to changing his mind. ♦
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