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On a mellow spring night, I gazed at the setting desert sun in Joshua Tree National Park in California. The sun glowed a warm blood-orange and the sky shimmered pink and purple.
I had just defended my Ph.D. in neuroscience, and my partner and I had flown west to celebrate and exhale. It was early March 2020, and we were hoping to quiet our minds in the desert. I was also hoping to change mine.
I had been curious about psychedelics for years, but it wasn’t until I read How to Change Your Mind by Michael Pollan about the new science of psychedelics, that I felt ready. The book made a compelling case that psychedelics provided a fascinating introspective experience. Still, I was nervous. I’d heard stories about bad trips and flashbacks. I knew enough neuroscience to know these were serious drugs—compounds that could temporarily dismantle how the brain makes sense of reality and potentially change it irreversibly.
I also knew I was burned out. My Ph.D. had been hard in the way Ph.D.s often are: thrilling, lonely, disorienting. My advisor had left academia halfway through, and I’d spent years without much supervision, never quite sure whether I was on the right track and if I had a future in academia. But I didn’t take LSD seeking healing or clarity. I just wanted to see what the fuss was about. After years of hunkering down, I was craving a freeing experience.
The air shimmered. The little bird dolls hanging in the cabin started telling me their secrets.
We put on Bach’s Partitas for keyboard, wrapped ourselves in Navajo blankets, and waited.
What followed was strange, intense, and beautiful. The wooden floorboards of our cabin turned into a bustling cityscape. The mirror in the bathroom showed my face aged beyond recognition: The natural lines in my skin became deep wrinkles, my eyes sunken, as if time had decided to give me a sneak peak of what would come. Later, absorbed with coloring pencils, I watched the marks I was making dissolve in real time, as if the paper were being erased by invisible rain.
The air shimmered. The plants breathed. The little bird dolls hanging in a corner of the cabin started telling me their secrets. My body felt porous, as if boundaries had loosened. I didn’t fully lose my sense of self, but I did feel a kind of communion—with the rocks, the scrub, the sky. It was deeply, inexplicably moving. Everything was love.
As a neuroscientist, I can’t help but wonder what was happening in my brain on acid. Was my default mode network—a network of brain regions most active when our minds are at rest, drifting through memories, daydreams, and self-reflection—collapsing, as Pollan had described? I wasn’t sure. What I did know was that my perception had changed, not just in content, but in form. My brain was generating coherent sights, emotions, meanings, all from its own imagination, based on my prior experiences. It all seemed both impossibly real and completely made up.
Neuroscientists have tried to explain experiences like mine by turning to physics. Robin Carhart-Harris, a professor of neurology, psychiatry, and behavioral sciences at the University of California, San Francisco, and one of the most influential figures in the psychedelic renaissance, believes that psychedelics increase the brain’s entropy—a term borrowed from thermodynamics that, loosely speaking, refers to disorder or unpredictability.
According to Carhart-Harris, normal waking consciousness is governed by structured patterns of brain activity: Certain regions talk mostly to each other, networks like the default mode network enforce order, and the brain efficiently predicts the world around it based on experience.
Psychedelics, he argues, disrupt this order. The brain becomes more chaotic, more fluid. Rigid beliefs loosen. Novel connections emerge. Freud’s ideas on the id and the ego—particularly the ego’s role in imposing order on unruly unconscious drives—inspired in Carhart-Harris a language to frame the psychedelic state as a temporary loosening of the ego’s grip, reflected in fMRI data as a breakdown of brain organization.
A different kind of conversation about psychedelics has begun taking shape.
The therapeutic effect of psychedelics stems from this breakdown. “The principal component of mental illness is ‘stuckness,’ this rootedness of thoughts, feelings, behaviors that characterizes so much of psychopathology or mental illness,” Carhart-Harris told me. To cure afflictions ranging from depression to PTSD, eating disorders to OCD, the mind and brain must get un-stuck. And this is where psychedelics shine: “Psychedelics promote plasticity,” Carhart-Harris said. “Formally, a definition of plasticity is changeability, the ability to change.”
And that presents an exciting question, Carhart-Harris said. “How does the entropic brain phenomenon relate to plasticity? I see the entropy of spontaneous brain activity as the thing that we can modulate acutely. It’s like an entropy dial: Dial it down and consciousness drops; dial it up, consciousness enriches.”
His model has appeal. It offers a story that links molecular action to neuronal networks to psychology. And it matches up beautifully with the kinds of testimonies that began to surface in clinical trials and across media accounts of the psychedelic renaissance: the feeling of becoming unstuck, the flood of insights, the sense of seeing clearly for the first time. Rachel Drayer, a physician assistant in emergency medicine, told me how her psilocybin experience in a clinical trial helped her shed the anger and depression that had burdened her since working on the frontlines of the COVID-19 pandemic. (You can read Drayer’s story here.)
But what if Carhart-Harris’ model is not what’s happening in the brain?
As the psychedelic renaissance has matured, a different kind of conversation has begun taking shape. Some neuroscientists have started raising uncomfortable questions: Were these theories supported by the data? What, exactly, was being measured when researchers claimed an increase in entropy? And how solid was the foundation beneath this shimmering structure of metaphor and model?
The critiques didn’t question whether psychedelics had real, even life-changing effects. They questioned whether we understood why. And whether the neuroscience story the researchers had been telling—to patients, clinicians, funders, and the public—was grounded in a robust interpretation of the observed changes in the brain.
Entropy, when applied to the brain, is a slippery concept. In physics and information theory, entropy is a measure of uncertainty or complexity—like the difference between a clear radio signal and one filled with static. A pure tone has very low entropy; a song clearly transmitted has medium entropy; pure static, with no pattern at all, has high entropy. In neuroscience, it often depends on what exactly is being measured—fMRI signals? EEG rhythms? Is it the uncertainty of coordination among brain regions? Or perhaps the randomness of a neuron’s firing over time?
To understand how fuzzy this is, picture a jazz band. A highly ordered brain might resemble a tight ensemble playing a familiar tune, with each musician sticking to their role. A more entropic brain might sound like free jazz, with unexpected riffs, shifting rhythms, new combinations emerging on the fly.
That captures the vibe. But what exactly are we measuring? Is it the unpredictability of a single player? Or the variability in how two players coordinate? Or the diversity of patterns across the whole band? In the brain, depending on what signals you record—fMRI, EEG, spikes, synchrony—and what questions you ask of them, you’ll get different measures, and possibly different answers.
“Entropy means how predictable is my next state from my previous ones?” said Amy Kuceyeski, a professor at Weill Cornell Medicine. The challenge is determining what aspect of brain signaling is being measured by entropy.
Kuceyeski used Carhart-Harris’s LSD and psilocybin fMRI data to craft an analysis that treats brain states as a dynamical system. The brain is never static. It constantly shifts between different states, such as those relevant to reasoning or solving problems, or ones that guide muscle control and movement. Scientists can map the shift between states by quantifying the energy used for the transition. They refer to this as “control” or “transition” energy.
As a neuroscientist, I can’t help but wonder what was happening in my brain on acid.
Kuceyeski and her team found that brain activity generally clustered into two large-scale networks—one focused on planning and the other on attention. They discovered that relative to placebo, LSD and psilocybin lowered control energy and shifted brain activity from planning to attention, a dynamic that normally quiets our inner executive. Kuceyeski told me the flattening of the brain’s control energy correlates with an increase in entropy.
“I think it’s measuring the same thing, to be honest,” she said. “People who have bigger decreases in transition energy also have larger increases in entropy.”
Yet Kuceyeski did not find a correlation between the lessening of transition energy and the subjective experience. While a rise in entropy and drop in transition energy seem to overlap, they don’t seem to have the same relationship to the strength of the psychedelic experience.
The overlap has another problem: If two supposedly distinct metrics—entropy and control energy—are capturing the same underlying signal, it’s unclear which one, if either, reflects a meaningful mechanism. Without conceptual clarity or empirical separation between metrics such as these, it’s hard to know what exactly we’re measuring when we look at a tripping brain.
The entropy story has other troubles. In some datasets it appears that entropy is increased during a trip, and that it scales with the intensity of the subjective experience. But the proper way to demonstrate that dialing entropy up leads to enriched consciousness would be to increase entropy directly, perhaps through some electrical or other stimulation of neurons, and observe the resulting changes to conscious experience. Such an experiment is nightmarishly difficult to design and implement and hasn’t been performed. Without it, we haven’t ruled out that a third factor mediates both entropy and the subjective experience, and that entropy of brain activity doesn’t affect conscious experience.
A recent study from a group in Copenhagen evaluated 13 different ways to measure entropy from fMRI data collected from patients under the influence of psilocybin. Only 3 of the 13 showed reliable increases of entropy during the trip. Others, including many of the static or region-specific metrics, didn’t change at all. Rather than supporting a brain-wide shift into chaos, the results suggest that any increase in complexity depends entirely on how—and where—you look.
Last year, Joshua Siegel and colleagues at Washington University collected fMRI scans before, during, and after psilocybin or an active control (methylphenidate, aka Ritalin). During the trip itself, brain-wide entropy rose in lockstep with self-reported mystical experience scores. But after the trip, entropy returned to baseline. “Preliminary efforts to identify network changes in the weeks after psilocybin have yielded mixed results,” the authors wrote in Nature.
Manoj Doss, an assistant professor in the Department of Psychiatry and Behavioral Sciences at the University of Texas, Austin, explained to me that the apparent increase in brain complexity, or entropy, during a psychedelic trip could be misinterpreted by researchers. Doss has studied the effects of various psychoactive drugs—including psychedelics—on learning and memory, having subjects perform various cognitive tasks while he scans their brains. When Doss had people under LSD perform real tasks—like watching a movie—their brain complexity went up, but so did the complexity of sober and alert brains also watching a movie. “If you match the mental activity,” Doss said, “the complexity looks the same.”
If entropy doesn’t reliably increase under psychedelics—or our tools aren’t even measuring it accurately—then the explanatory edifice for the therapeutic efficacy of psychedelics begins to wobble. We’re left without a full understanding of the network-wide effect that psychedelics have on the brain. Studies of “bad trips” during the psychedelic renaissance underscore the unpredictability of the drugs’ effect and aftermath.
The inconclusive research into psychedelics also raises the provocative possibility that the brain might not be reorganizing itself in the way Carhart-Harris and others have suggested. Psychedelics may not be lifting us from ruts by dialing up neural chaos. The powerful experience may not be driven by entropy but by something far harder to pin down: the placebo effect.
Placebo is typically understood as the mind’s expectation nudging the body toward healing. Simply believing that a treatment will work can activate real physiological responses, even when the treatment itself is inert. But drugs that affect consciousness, and psychedelics in particular, complicate this picture. What happens when the thing you’re trying to heal is the mind? If someone expects relief and is then given a powerful hallucinogen that radically alters their consciousness, that expectation isn’t just a subliminal hope—it becomes an overwhelming sensory and emotional reality. In that state, could the mind’s belief in healing become even more powerful?
Boris Heifets, a Stanford anesthesiologist, has been on a quest to break down the elements of psychedelic experience. Determining the cause of an intense experience, he’s reported, is not clear cut. “It is quite difficult to say whether a lasting change in mood or outlook was a result of the drug—a biochemical effect—or of the trip itself, the experiential effect,” he told Scientific American in 2024.
The powerful experience may be driven by something far harder to pin down: the placebo effect.
Placebo is difficult to introduce in psychedelic experiments. If patients have, say, read Pollan’s book or heard stories about the transformational effects of a psychoactive drug substance, they will have expectations of a similar experience, even if they know they may receive a placebo in their session.
Heifets got around that problem by conducting a clinical trial in which he gave ketamine (which has psychoactive effects) or a placebo to patients with clinical depression undergoing surgery for other issues. Their expectant minds would be silent while they were under anesthesia and unconscious. Heifets’s team found that changes in depression scores were statistically similar for the ketamine and placebo groups: The scores decreased for the placebo and ketamine group alike after surgical anesthesia. And these were large changes, cutting the depression scores by nearly 50 percent in both cases, and persisting after the operations, patients reported.
Heifets has also shown that patients experience a relief from depression and post-traumatic stress disorder from intense dream states induced by anesthesia. “Patients are having a very powerful experience,” he’s said, similar to ones reported by those who’ve taken psychedelics; again, without the drug.
Could it be that some kind of integration effort is the vessel where raw experience is distilled into lasting change? That after the profound experience, the real improvements to mental health happen not because of the drug, but because of the mind’s own work on itself? That psychedelics have clear and strong molecular effects is unquestionable; but to me, it’s more likely the experience than changes in entropy that make this possible.
For months after that night in Joshua Tree, quarantined in the early days of the pandemic, I would notice strange new things. Shifting shadows, dancing dust motes, ghosts taunting my peripheral vision. They weren’t distressing or startling; just little blips that tugged at my attention, as if my brain was still tuned to a different sensitivity, a heightened edge-detection filter no one had reminded it to turn off.
It didn’t feel like some grand unlocking of consciousness, or a permanent new mode of being. It felt small, subcortical almost: a tweak to a circuit, not a transformation of the self. And that, I think, is what science is telling us now, too.
Something is happening in the brain when psychedelics do therapeutic wonders. But it may not be what the theories have claimed. It may not be neural entropy, or predictive processing, or ego disintegration via control energy gradients. And yet when setting out with the intention to get better, people do, and often in profound ways. Maybe, for now, it’s enough to say: Science doesn’t quite know why. But for some, the experience is still worth the trip. 
Read more on Nautilus about the psychedelic renaissance:
Out of Your Head: Exploring psychedelic experiences that seem wider than the brain.
Cary Grant Made LSD Therapy Fashionable: Benjamin Breen on his 3 greatest revelations while writing Tripping on Utopia, about the birth of psychedelic science.
Can Ecstasy Save a Marriage? A new wave of experimental therapy is enlisting MDMA in relationship counseling.
The Bad Trip Detective: The researcher delving into the downsides of psychedelic drugs.
Will Psychedelics Replace Antidepressants? Psychedelic treatment is helping patients make difficult emotional breakthroughs.
Lead image by Tasnuva Elahi; with image by Jorm Sangsorn / Shutterstock
