To revist this article, visit My Profile, then View saved stories.To revist this article, visit My Profile, then View saved stories.Rachel NuwerAbout a month into the 2020 pandemic lockdown, Gül Dölen, a neuroscientist, noticed that she had come untethered from reality. “Everything felt sort of swooshy,” she says, as if she was in an “altered, mystical state.” She wasn’t constantly obsessing over her lab at Johns Hopkins University. She chilled out. And for the first time in her life, she found she could meditate for a good 45 minutes at a time. Her senses were unusually sharp too. On long walks under the monochrome slab of Baltimore’s April sky, she felt hyper-attuned to the natural world. She smiled at the turtles poking their heads out of the inky water of Fell’s Point. She reveled in the crickets’ evening chorus on eerily empty streets. When she happened across a fallen bird’s nest with a broken egg inside, she came close to tears as she imagined the “deep, deep pain of the mother bird.” She felt like she was on drugs. Or on a spiritual excursion, experiencing what an enlightenment-seeking Zen monk might find sitting alone in a cave. One day, she grabbed a pen and started to crank out haikus. One of her favorites nods to the writer Aldous Huxley’s mescaline-induced notion, immortalized in The Doors of Perception, of being one with a chair: By asymptoticsThe distance between us isinfinite and noneThe poem gets at a simple, profound notion in physics—that the particles making up Huxley and those of a chair always mingle, whether the two are rooms apart or butt-smashed-to-seat. That’s how she felt, too, as if the rules that had always governed her perceivable reality were blurring with those of a different plane of being. In the midst of this creative explosion, she had an epiphany. The extreme isolation of lockdown might have tipped her into an exceptional brain state. Absurd coincidence, if true. Dölen has spent much of her career studying this exact state: a time of heightened receptiveness, usually in childhood, called a Critical Period. Critical periods are well known to neuroscientists and ethologists, because they lay the groundwork for a creature’s behavior. They are finite windows of time, ranging from days to years, when the brain is especially impressionable and open to learning. It’s during a critical period that songbirds learn to sing and humans learn to speak. There are critical periods for walking, seeing, and hearing as well as bonding with parents, developing absolute pitch, and assimilating into a culture. Some neuroscientists suspect there are as many critical periods as there are brain functions. Eventually, all critical periods close, and for good reason. After a while, extreme openness becomes inefficient, or downright dysfunctional. Floating through downtown Baltimore like a disembodied spirit, or sitting alone at her kitchen table eating rolls of nori filled with peanut butter and jelly, Dölen realized she’d been spending too much time worrying about her career, and not enough time on her simple love of science, and her sometimes outlandish-seeming questions. Like the one she was contemplating now: If she could reopen critical periods, what mind- and life-altering changes might come about? She believed that if she could crack the code of critical periods—how to trigger them, how to do so safely, what to do once they’re open—vast possibilities awaited. People who lost their vision or hearing might regain those senses. Stroke patients might recover movement or relearn to speak. Might an adult learn a new language or musical instrument with the ease of a child? Scientists have spent decades trying to safely and easily nudge the brain into these states, with little to show for it. They’d managed to reopen a vision-related critical period in mice—but only by first suturing shut the animals’ eyelids. Their methods were not exactly human-compatible. Just before lockdown, Dölen had begun to think she was on the cusp of an answer—something she describes as the “master key” for reopening critical periods. It was something Indigenous cultures had recognized for millennia as able to provide healing and growth. The key, she suspected, was psychedelic drugs. Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodThe West was only starting to tap into their therapeutic power, and now, Dölen might have a scientific, brain-based explanation for how they help people heal. Finding that answer, Dölen realized in her “very, very altered state” of pandemic consciousness, was “the thing I had to come back down to Earth to finish.” With that realization, something in her seemed to shift. She returned to her default state of consciousness, but with a renewed commitment to boldly follow her curiosity, wherever it might lead. Dölen traces her obsession with science to when she was 8 years old and first encountered a sea urchin while on vacation in Turkey. It was freshly plucked from the Mediterranean Sea and cradled in her grandmother’s hands. The otherworldly creature was jet black and covered in aggressive spikes that reminded Dölen of the cactuses back home in San Antonio, Texas. Her grandmother pointed out the urchin’s remarkably humanoid teeth, and vibrant orange innards. Dölen felt as though she’d been transported to another planet. That day on the beach in Antalya, her grandmother introduced her to the strangeness of the natural world. “That’s how I’ve been lured into science,” Dölen says, “through that childlike wonder and amazement.” In college, she was drawn to “the big questions,” as she puts it, about the nature of consciousness and humans’ place in the cosmos. She designed her own major, “comparative perspectives on the mind”—a grab-bag of philosophy, neuroscience, Eastern religion, linguistics, and art. She was most attracted to neuroscience. Exciting new methods were becoming available. Genome editing, neuron culturing, genetic engineering: Neuroscientists suddenly found themselves able to explore the brain in previously unimaginable detail. “Everyone could feel it,” she says. “There was about to be a big, molecular revolution in neuroscience.” In one of Dölen’s favorite classes, Drugs, Brain and Behavior, she learned that psychedelics hijack the machinery used by molecules that occur naturally in the brain. When her professor projected side-by-side images of the strikingly similar molecular structures of the neurotransmitter serotonin and of LSD, she immediately saw how the drug might be a staggeringly powerful tool for getting at the nature of subjective reality. Everything you think and feel, everything you think makes you uniquely alive and aware of the world, boils down to molecules, Dölen realized with awe. Change the molecules with psychedelics and you change everything. Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodYet while mind-altering drugs struck Dölen as the perfect tools for exploring the unseen underpinnings of consciousness, this was the late 1990s. “We were still very much in the middle of the War on Drugs,” she points out. So Dölen shelved her interest in psychedelics and enrolled in a dual MD/PhD program at Brown University and MIT. She joined a lab that studied learning and memory, including critical periods. Dölen’s research focused on fragile X syndrome, a neurodevelopmental disorder that is the leading identified cause of autism. She studied a specific brain receptor and found that when she tinkered with it in a certain way—in mouse models of fragile X and autism—the animals functioned much better. People in the field thought the finding would be life-altering. But clinical trials with human volunteers failed. “I was gutted, because I was so hopeful that it would work,” Dolen says, “but also confused because I couldn’t understand why it hadn’t.” Dölen and some of her colleagues began to suspect that it wasn’t a difference in species that thwarted the clinical trial but a difference in ages. The mice had been juveniles. The human participants had been adults. Perhaps the treatment had worked on the young mice because a relevant critical period was still open. But the scientists left their hypothesis at that.The trial’s failure meant Dölen needed a new project. So she joined a lab at Stanford focused on studying the brain’s reward system, especially how drugs like cocaine hijack it to produce intense pleasure. She immediately noticed, however, that no one in the lab was looking at “the other most obvious natural reward,” she says, “which was social reward”—the joy that gregarious animals such as mice and humans get from being around others. At the time, not many neuroscientists were taking this subject seriously.Her adviser was incredulous, but he agreed to let her pursue social reward. After years of painstaking work—including engineering her own specialized mice—she had her first results. Oxytocin and serotonin, she found, work together in a brain region called the nucleus accumbens to produce the good feelings that come from social interaction. Or, as Dölen summarizes, “oxytocin plus serotonin equals love.” A fine result. But Dölen was still ascending her mountain.By the time she started her own lab at Johns Hopkins, in 2014, the field at large had caught on to the idea that social behavior was worth studying. Seeking to differentiate herself, Dölen acquired an impressive suite of fancy neuroscience tools and started looking for the next “weird, unexplored rabbit hole.” She had no idea that search would lead her to arguably the weirdest neuroscience phenomena in existence—psychedelic drugs and their effects on the brain. In her office, Dölen keeps a collection of fossils, shells, succulents, and vintage science posters. She converted the entire wall behind her stand-up desk into a black erase board, which on a chilly December afternoon was covered in neon-marker sketches of molecular structures, brain diagrams, phylogenetic trees, and Einstein quotes. A visitor cannot help notice, though, that the real owner of this space is the genus Octopus. Wherever the eyes land are octopus mugs and octopus artworks, octopus figurines and octopus toys. They’re all gifts she received after she published a stunner of a paper in 2018.Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodIf you’ve heard of Dölen before, it’s probably because of that study. In it, she dosed a handful of octopuses—notoriously antisocial by nature—with MDMA, and she found that they reacted to the drug in much the same way humans do: by loosening up, dancing around their tank, and even, improbably, taking an interest in fellow octopuses. Rather than avoiding their own kind, the rolling octopuses sought out their tank mates and tried to wrap them in eight-armed hugs. An octopus brain is more like the brain of a snail than that of a human. The octopuses' humanlike behavior in the study indicated that serotonin, the primary brain chemical that MDMA mimics, plays an ancient and fundamental role in sociality. Countless media outlets covered her paper, and Dölen became something of a folk hero in the psychedelics community. But to Dölen, the research that really matters is her work on critical periods. Dölen probably wouldn’t have found her way to it were it not for one of her postdocs, a nerdy French neuroscientist named Romain Nardou. He joined Dölen’s lab after latching on to a footnote-like observation in Dölen’s own postdoctoral research: The buzz that mice get from socializing seemed to diminish as the animals got older, a strong hint that a critical period might be involved. But when Nardou told Dölen he wanted to explore that observation—and look into how oxytocin signaling changes as mice mature—Dölen’s initial response was “meh.” For starters, she told him, the study he was proposing seemed too technically basic to be of much interest. “I want you to do something that’s going to take advantage of all the technical whizzbangery we have,” she said.  Nardou was stubborn. “I’m sure it’s gonna be cool,” he insisted. Eventually, Dölen agreed to give it a try.   In 2015, Nardou began meticulously gathering data. His experiment was based on a simple, well-established protocol: Mice are put in an enclosure with one type of bedding and given access to cocaine (or some other desirable drug). Then they’re moved elsewhere, with different bedding and no cocaine. Later, the mice show a clear preference for hanging out on the bedding they associate with getting high. Young mice, old mice—they all behave the same way. As Dölen puts it, “There’s not a critical period for cocaine reward learning. Adults love cocaine as much as kids.” In Nardou’s version of this experiment, he replaced the cocaine with other mice. After the rodents either hung out with their friends in one comfy spot or sat alone in another, he’d offer the two beddings to see if they had developed a preference. Over and over, he ran the experiment, amassing data from 900 animals across 15 ages. What emerged, Dölen says, was a “beautiful curve.” Nardou had found clear evidence of a critical period for social reward learning. Young mice—especially adolescent ones—strongly preferred hanging out on the bedding they associated with their friends. The adult mice didn’t seem to give a damn about the composition of their bed. They weren’t connecting it to the pleasures of company. The younger mice, in their highly impressionable state, were. “The social world is something that you learn, just like the visual or olfactory world,” Dölen explains. It’s not that the older mice were antisocial, just that they were no longer the equivalent of insecure, angsty teens who form preferences based on what their friends say is cool. Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodShe and Nardou confirmed his observations using one of Dölen’s favorite tools—whole cell patch-clamp electrophysiology. You take a slice of a mouse’s brain, place an electrode on the surface of a single neuron, and measure the electrical activity of that cell. When they hooked up neurons from the nucleus accumbens of a juvenile mouse’s brain and exposed them to oxytocin—the hormone that Dölen, as a postdoc, had found to be involved in social reward learning—the cells responded with a jolt. The neurons of adult mice remained unperturbed. Discovering a critical period was publication-worthy on its own, but Dölen wanted to go bigger. She wanted to reopen the critical period. She knew from the scientific literature that the most reliable way to do so is with sensory deprivation, something that “no one in their right mind” would voluntarily submit to, she remembers thinking.As she pondered their options, she remembered the pictures she'd seen of the dozens-strong cuddle puddles at Burning Man, where attendees were likely to be blissed out on MDMA. She was also familiar with the results emerging from clinical trials using MDMA to treat PTSD, and with other scientific evidence that the drug causes a massive release of oxytocin in the brain. Could MDMA perhaps be useful for reopening critical periods too? When she ran her thoughts by Nardou—a straight-edger who is “not part of the counterculture in any way,” Dölen says—he was skeptical, but he ultimately agreed to try his adviser’s idea. Again they ran the bedding experiments—to see if mice preferred the beds where they’d hung out with friends—and this time gave the rodents MDMA. Sure enough, in the two weeks following their drug session, the adult mice behaved like youngsters, preferring the cozy paper pulp or wood shavings they associated with other animals. When, as before, the researchers checked the neurons of the adult mice, they saw they responded to oxytocin as though the cells came from youngsters. In 2019, Dölen published these results in Nature and assumed that would be the end of this particular line of investigation. But for due diligence, she decided to perform the same experiment using LSD, a psychedelic that is not usually associated with hugs or cuddle puddles. That’s when things got really weird. Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodIn the corner of an equipment-crammed lab—and beneath the benevolent gazes of drug pioneers Alexander and Ann Shulgin on a poster pinned to the wall—postdoctoral researcher Ted Sawyer hunches over a set of knobs and dials that could be mistaken for a 1950s sci-fi flick control panel. A screen in front of him displays the magnified contents of a petri dish held by a nearby microscope. To an outsider, it might look like a satellite image of Antarctica after a snowstorm. To Sawyer, who’s done this hundreds of times, it’s clearly a 250-micrometer-thin slice of mouse brain. Within seconds, Sawyer spots his target: the ever-so-faint outline of a neuron suspended in a sea of artificial cerebrospinal fluid. Gingerly fingering one of the panel’s black circular dials, he remotely maneuvers the fine tip of a glass pipette so it’s just touching the cell’s body in the petri dish. He leans over to the microscope, lowers his mask, and sucks on a plastic tube connected to the pipette to form a vacuum seal, which will let him measure current across the cell’s membrane. A sudden jump in resistance readings on Sawyer’s computer screen indicates that he’s made contact. Cells are finicky, delicate things, though, and after an initial success, the readings begin to fall. He’s lost it. “You just have to sit and screw up a lot,” Sawyer tells me. A good day will get him maybe 12 successful measurements, each a burst of insight into whether the rodent brain that produced the cell was primed to form new social attachments or was hardened in its adult ways. When Dölen decided to look into LSD, she knew that people under its influence often want alone time. But the data that Nardou, Sawyer, and others collected was revealing something else: LSD worked just as well as MDMA for reopening critical periods and restoring social reward learning in mice. Well, you fucked up, do it again, she thought, chiding herself. But it just kept happening. And then, it happened again with tests of ketamine (a dissociative), psilocybin (aka magic mushrooms) and ibogaine (a psychedelic derived from an African plant)—all drugs that don’t make people feel terribly social. The critical periods of mice given cocaine, meanwhile, remained solidly shut, suggesting that there’s something unique about how psychedelic drugs target the brain. Dölen had been thinking about MDMA as “a sort of super oxytocin,” she says. Now she thinks the drug’s prosocial effect was a red herring. MDMA may be associated in popular culture with hugs and love, but if Dölen had, say, put the mice through an auditory exercise rather than a social one, she suspects that their auditory critical period would have reopened instead. In the vernacular, that’s “set and setting”—the mental state a person is in when they trip, and their physical environment. Those contextual details explain why most people with PTSD are not miraculously cured after partying all night at an MDMA-fueled rave, but why, in the supportive environment of a therapist’s office, the same drug permits them to undertake the cognitive reappraisal needed to heal. It also tantalizingly suggests that different critical periods could be opened—not just for PTSD, but for stroke, vision or hearing correction, or acquiring a new language or skill, or any number of other things—simply by changing what a person is doing while on the drug. Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodSome outside evidence backs up this hunch. In 2021, for example, researchers in Austria inadvertently found that ketamine reopens a vision-related critical period in mice—but only when the K-holed rodents also engage in a visual exercise. Seeing the Austria finding, Dölen became all the more convinced that psychedelics might be the master key for reopening virtually any critical period. The drug neurologically primes a mouse (or, presumably, a person) for learning; whatever that animal ends up doing while on the drug determines which critical period reopens. That an array of drugs have this potential also means that something deeper must unite these psychedelics in their ability to transfigure the mind. That deeper thing, Dölen’s findings indicate so far, happens not at the level of brain regions or neurons’ receptors, as scientists have previously thought, but at the level of gene expression. So far, her lab has pinpointed 65 genes that seem to be involved in this process, and their involvement suggests that psychedelics' effects last well beyond an acute “high.” Piecing together the details of this mechanistic puzzle, Dölen suspects, will keep her occupied for the next decade. Meanwhile, she’s got other big questions to chase. For one, each psychedelic activates a mouse’s critical period for a different length of time. The longer the drug trip, the longer the openness lasts—and, perhaps, the more durable the therapeutic response. A ketamine trip for a human lasts 30 minutes to an hour, and in mice, the drug opens a critical period for two days. The four- to five-hour trips of psilocybin and MDMA keep the critical period open for two weeks. LSD’s eight- to ten-hour human trips translate to three weeks of openness for a mouse. And ibogaine’s trips (36 hours in people) put mice in the open state for at least four weeks, after which Dölen stopped taking measurements. Assuming the drugs can in fact reopen critical periods in humans, Dölen’s work, which she and her colleagues published in June, suggests that the brains of people who undergo psychedelic therapy are likely in a state conducive to learning for days, weeks, or even months after the drug has technically cleared their system. This leaves room for further gains long after they’ve come down, Dölen says, and suggests that people would benefit from continued therapeutic support well after their trip. Outside experts are generally effusive in their appraisals of Dölen’s findings. People often talk about psychedelic therapy functioning like a “reset button” for the mind, but until Dölen’s work came out, no one could provide a scientifically plausible explanation for “how something that is so short in duration can have lasting and transformative effects that go well beyond the time period that the drug is in there,” says Rachel Yehuda, a psychiatrist and neuroscientist at the Icahn School of Medicine at Mount Sinai in New York City. Dölen’s findings, she adds, are “what our field needs—we need some new ideas.”There is, of course, a catch. For mice, having a critical period open for too long causes neural disruptions. Some experts fear that, for people, carelessly flinging wide the doors of personal development could put the very core of their identity in jeopardy by erasing the habits and memories that make them them. A critical period is also a time of vulnerability. While childhood can be filled with wonder and magic, children are also more impressionable. “We can really screw kids up much more than we can adults,” she says. This is why responsible adults intuitively know to protect children from exposure to potentially scary or disturbing material. Or, as Dölen puts it, “You want to teach children new things, but you don’t want them to learn Japanese from Japanese porn.”  Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodAn adult who undergoes this kind of treatment to heal PTSD could, in the wrong hands, end up traumatized further. In the worst scenarios, patients could be vulnerable to abuse. Unscrupulous therapists or other predators could try to use psychedelics to manipulate others, Dölen says. This is more than paranoid speculation. Quite a few experts, Dölen included, think that Charles Manson’s ability to completely brainwash his followers relied on the high doses of LSD he regularly gave them prior to bombarding their minds with hate-filled lectures and murderous orders. Given all this, Dölen sees hacking critical periods with psychedelics as not inherently good or bad. She calls it a “wildly agnostic” tool.On the wall-sized screen in front of me, a bubble or two drifts upward through the blue, and light filters in from above. Out of the murk, a swimming form emerges and comes into focus: a smiling dolphin. “Hello, my name is Bandit,” a subtitle reads. “We’re going on a very special journey today. My creators built me to heal you. Connect to me, embody me, eat the fish and sharks that nourish me.” The dolphin lets out a high-pitched squeal—a real recording, it turns out, made at Baltimore’s National Aquarium. The surreal underwater scene is interrupted by a small square that appears in the upper left-hand corner. In it, I see myself, standing on the opposite side of the room. Red dots overlay the image of my body, indicating that a 3D-tracking camera has locked onto me. The dolphin and I are one. Moving my right hand, I cause Bandit to awkwardly veer right. Fish dart across the screen, and they’re impossibly fast for my clumsy avatar to catch. But as I sweep my hand to and fro, I begin to get the hang of it. I realize the watery realm I’m operating in is 3D, and I start to incorporate back-and-forth motions. Finally, I ram into my first fish, and Bandit happily scarfs it down. A few fish later, I’ve completed the first level. A fireworks show explodes onto the screen in celebration. The game is surprisingly addictive, and I’m disappointed that I won’t have time to see what else is in store for Bandit. Bandit, who I became acquainted with in the Brain Rescue Unit of Johns Hopkins Hospital, is the culmination of more than a decade of effort by a multidisciplinary team of Johns Hopkins doctors, scientists, and engineers called Kata Design Studio. He was designed to help stroke patients regain movement. The 3D-tracking camera allows the dolphin to exactly mirror a patient’s movements. “We call it being jacked into the animal,” explains Promit Roy, the software lead for Kata. The game encourages patients to practice complex movements, and keep at it, simply because it’s fun.Stroke patients have only a short window of time in which they can regain even some of what they’ve lost. Immediately after a stroke, a critical period naturally opens—and then closes some months later. No one knows why this is, but Dölen has a hunch: Just as pandemic-era isolation caused a “radical destabilization” of the social world, a stroke causes a radical destabilization of a sufferer’s motor world. That person’s motor cortex is no longer receiving information from their muscles. So a sudden change in the motor world—a stroke—could fling open a critical period for motor skills. Dölen thinks that these naturally occurring critical periods are the brain’s way of trying to adapt to profound, existential change. Dhruv MehrotraMatt LasloDell CameronJennifer M. WoodEven in the best circumstances for stroke patients, though, therapy usually only helps them compensate for lost dexterity. They don’t recover full movement. The Kata team and Dölen are now planning a study to see if adding psychedelics could help stroke patients truly recover—“an unbelievably powerful idea,” says Kata member Steven Zeiler, a stroke physician and associate professor of neurology. If Dölen is right about psychedelics, then Bandit, when paired with those drugs, would be the environmental prompt that guides the brain to reopen its critical period for motor learning—regardless of when someone had their stroke. If this turns out to be true, then banishing addiction, treating social anxiety, restoring a damaged sense—all might be possible with psychedelics if researchers can identify the right context to open the appropriate critical period. Over a plate of mussels and onion rings at Bertha’s, a classic Baltimore dive, Dölen half-joked to me that she even daydreams about using psychedelic-assisted therapy to cure her severe allergies to dogs, cats, and horses. “Cure stroke? Naw,” she laughed. “I just want to go horseback riding again!” For now, this is all the stuff of theory—but it’s a theory Dölen is betting on in a big way. She’s launched a new scientific group to investigate psychedelics as potential keys for reopening all kinds of critical periods. The group’s name, PHATHOM, stands for Psychedelic Healing: Adjunct Therapy Harnessing Opened Malleability—a mouthful that came to her in a dream. “I woke up at 2 am and I had it, the whole acronym,” she says. She latched on to the homophone for “fathom” because of the vast sense of “oceanic boundlessness” that some people experience while on psychedelics, and because she liked the connotation of “taking something unfathomable and making it fathomable, which is what reopening critical periods is all about for me.” She imagines a future in which psychedelics are given with any number of treatments to increase the odds of success, similar to how anesthetics are always given before surgeries, or how physical therapy accompanies a knee replacement. But, for a moment, let’s set aside the practical applications. If psychedelics really are this master key, then scientists suddenly have at their disposal an instrument for deducing the rules and boundaries that define who we are. Critical periods, after all, lay the foundations for our habits, culture, memories and mannerisms, our likes and dislikes—and everything in between that ultimately distinguishes us as individuals and, collectively, as a species. Critical periods also play a heavy hand in determining our experience of consciousness, including whether we view the world through a rose-tinted framing inherited from a childhood full of support, or through the cloudy lens of a life shaped by trauma. And given that being in an altered state of mind might just be what the reopening of a critical period feels like, then investigating how, exactly, psychedelics produce these effects could even help researchers home in on the nature of consciousness itself. This goes straight back to the realization Dölen had all those years ago as she gazed up at the serotonin molecule projected side by side with LSD: that psychedelics were the tool that would finally provide us answers to “the hard problems of neuroscience.” “What is consciousness? How is it that we know what exists in the world?” Dölen says. “These are the metaphysical problems that most neuroscientists start out with but eventually give up on.” If Dölen’s undergraduate self was right, then sure, the internal landscape of our minds really does boil down to molecules. But those neurologic formulations contain it all—what distinguishes adult from child, wellness from trauma, memory from forgetfulness, you from me.Let us know what you think about this article. 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