Nature is always performing chemistry experiments, and in the dark and sticky corners of its forests and jungles, it creates compounds that have hyper-specific effects on the human mind. In China’s Yunnan province, a yellow mushroom with a droopy cap sprouts up in the mountains, usually in the shade of long-needled pines. Many people of different ages and cultural backgrounds have eaten this mushroom and experienced the same hallucination. They report seeing elf-like figures that parkour around on clothes, on furniture, and on walls. These little people seem to like dancing and performing acrobatics. Large groups of them will march in formation. This “lilliputian hallucination” can last for a day, and closing your eyes is no escape. The tiny humans sometimes linger in the blank space of your mind, staring back at you in a teasing way.
For thousands of years, humans have searched nature for mind-altering substances through a process of trial and (sometimes fatal) error. People have choked down foul roots, boiled woody vines, and scraped bitter bark off of tree trunks. They’ve milked toad glands and chugged the urine of reindeer that were themselves tripping on fungi. These experiments have revealed hundreds of plants and fungi that contain psychedelic compounds.
Now that psychedelic research has been legitimized, scientists at university labs and biotech start-ups are wondering whether they can create a better one. It’s a seductive idea, that some new and perfect drug might be hiding in the near-limitless parameter space of synthetic chemistry. Who wouldn’t want to take a little pill that could help you slough off your old self and see the world anew, a half-day therapy that would leave you with a feeling of enlightenment, if not in the exalted state itself?
“Nature’s compounds aren’t always optimal,” Manoj Doss, a professor of psychiatry at the University of Texas at Austin, told me. Take ibogaine, a naturally occurring psychedelic derived from an African shrub. A single dose of it seems to help people liberate themselves from opioids, quelling their cravings and mellowing their withdrawal symptoms. But ibogaine is a dirty drug, a blunt biochemical instrument that travels all across the body and puts particular stress on the heart. “If we could remove ibogaine’s cardio risks and preserve its therapeutic benefit, that’s something we should do,” Doss said. And indeed, a gentler analog has already been developed in the lab, although it hasn’t yet reached clinical trials.
Doss has noticed a proliferation of lab-modified psychedelics. He recently heard that researchers had synthesized a promising new compound in the same class that includes MDMA. This one is supposed to be “the best ever,” he said. “It’s said to be less intense than MDMA, and socially lubricating, but not the full out ‘I love you!’—and it’s followed by way less of a crash. It just kind of cruises to the end.”
Psilocybin, the “magic mushroom” compound, could also be improved. It’s hardly toxic—no one dies from overdosing on psilocybin—but its effects are at times unpleasant or even tragic. People who use psilocybin recreationally may become confused and jump off a building, David Yaden, a researcher at the Center for Psychedelic and Consciousness Research at Johns Hopkins University, told me. Even in the lab at Hopkins, where the drug is carefully tested as a treatment for a number of mental-health disorders, patients can have adverse reactions. In that setting, every user will be screened for cardiac issues and a family history of psychosis, and guided through their trip by two professional facilitators who have a doctor on call—and even then, some users experience a psychotic break or profound dissociative episodes. It’s an intense experience, Yaden said, “like running a marathon or climbing a mental mountain. Some people don’t do well with it.”
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One way to make psilocybin trips less intense is to shorten them. A standard trip on the drug tends to last six to eight hours, and like other powerful psychedelics, it can leave a residue on the windowpanes of your consciousness that may not rinse clean until you’ve slept. Several companies are now working on milder versions of psilocybin that can be delivered via nasal sprays, injectables, and Listerine-style strips. They activate similar receptors across the nervous system but metabolize more rapidly, shortening the trip. A psilocybin analog developed by Reunion Neuroscience appears to produce a high that lasts just three or four hours, according to findings from a Phase 2 trial of 84 women with postpartum depression. The drug showed signs of being clinically effective too, though Yaden is not yet fully sold on the idea that shorter-acting psychedelics can have the same therapeutic pop as a daylong trip on psilocybin. He’d like to see more evidence.
In San Francisco, a start-up called Mindstate Design Labs is trying to extend this work on engineering psychedelics beyond the modest goal of inducing shorter and more easygoing trips. “We don’t want to just develop a more convenient psilocybin,” its CEO, Dillan DiNardo, told me on a recent call. “We want to provide mental states that aren’t yet reliably accessible.” The company is starting with a compound that aims to enhance aesthetic perception, for example. “It makes the world around them into a sort of sensory feast,” DiNardo said. In theory, it could be used to treat a person suffering from anhedonia, and it would have obvious recreational appeal.
Mindstate started by compiling a large database of more than 70,000 trip reports. Some of the reports were pulled from Erowid, an online library of information about psychoactive substances. Others are from books that contain first-person psychedelic accounts, which DiNardo said the company transcribed. And still more were taken from clinical materials. The reports contain descriptions of the subjective effects of hundreds of psychoactive drugs, including many that were first synthesized by Alexander “Sasha” Shulgin, the underground researcher who almost single-handedly drove the field of psychedelic chemistry forward from the 1960s to the 1990s. (Ann Shulgin, his widow, was a co-owner of Mindstate until her death, in 2022.) Then the company used an AI model to turn that database into a drug-discovery engine. By linking the subjective reports from each psychoactive compound to its receptor-binding profiles, it tries to predict the underlying neurobiology of specific emotional states.
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DiNardo claimed that Mindstate’s AI works like AlphaFold, the model from Google DeepMind that has wowed structural biologists—and the Nobel Committee for Chemistry—by predicting the three-dimensional structures of proteins. We won’t know whether this is true for a long while. Only one of the company’s compounds has reached the testing phase in humans, and it wasn’t discovered by the model; Shulgin synthesized a version of it in the 1980s. Human trials for the other drugs that Mindstate has in development could be years away. Doss, the UT Austin psychiatrist, told me that he is skeptical of Mindstate’s approach to automated drug discovery. The trip reports may constitute the richest database of recreational pharmacology that we have, but they’re still “crap,” he said. They’re colored by all kinds of biases and limited by people’s inability to cram psychedelic states into words.
Boris Heifets, an anesthesiologist and a neuroscientist at Stanford University, also has doubts about Mindstate. “I am cheering them on and I would love to be wrong, but my deep suspicion is that they’re barking up the wrong tree,” he told me. He thinks that simply adjusting the intensity of a trip will have the most important effects on the psychedelic experience. He also said that in his lab, he’s seen evidence that altering a person’s pre- and post-trip experiences can have more transformative clinical effects than tweaks to the drugs. “That context of care is an enormous determinant of a patient’s outcome,” he said. If this context didn’t matter, he continued, then anyone who took these drugs on their own might end up cured of mental illness or otherwise enlightened. The average rave attendee would be a guru.
Recreational users of psychedelics do tinker with the experience on their own terms, by choosing to trip with different kinds of people or in different kinds of places—in cities, or on mountaintops, or while camping at the beach. On the one hand, “you could imagine that being in the natural world and feeling awe would be beneficial,” Yaden said. “On the other hand, if people are more engaged with their perceptual environment and the novelty that’s around them, they might lose the benefit of being left with the workings of their own mind, which might be part of what produces insight during these experiences.” Testing this in any formal way would be dangerous, however. A clinical trial of psilocybin in the wilderness could easily result in a participant running away, or worse.
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But even indoors, in labs, scientists could try to engineer a particular psychedelic high just by varying the conditions. They might provide patients with preparatory materials that go beyond the typical one-page handout. They could encourage patients to engage in certain kinds of introspection, invite them to bring in a photo to focus on during their session, or ask them to look into a mirror for a sustained period while they’re tripping. They could pipe in a greater variety of music. (Doss said that he hates “the Hopkins playlist,” which consists primarily of Western classical music.) Yaden said that not nearly enough of this kind of work has been done.
But even if researchers did perform all of these experiments, and many more, there’s no guarantee that they’d be able to observe and analyze any shifts in experience that were triggered. The “perfect trip” may always be beyond the reach of engineering, biochemical or otherwise. Psychedelic journeys might be too ineffable and too particular to a person’s individual consciousness for the methods of science. We may instead be stuck with storytelling, folk knowledge, and the nuggets of wisdom that have come down to us in ancient texts. For 17 centuries, Chinese Taoists have been preserving one such text called Baopuzi. It was written by the scholar Ge Hong, and it tells of a “flesh spirit mushroom” that could, when eaten raw, allow one to “see a little person” and experience transcendence.
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