The Acid Test

At an Indiana lab, better thinking through chemistry

Objects appeared to gain in relief; they assumed unusual dimensions; and colors became more glowing. Even self-perception and the sense of time were changed. When the eyes were closed, colored pictures flashed past in a quickly changing kaleidoscope. After a few hours, the not unpleasant inebriation, which had been experienced whilst I was fully conscious, disappeared. What had caused this condition?Albert Hofmann, the discoverer of LSD, writing in his laboratory notebook in 1943


A carefully trained rat crawls inside of a Skinner box. If it pushes the metal lever on the right, it means it's on LSD. Bingo! A little white sugar pellet—the rat's reward for pushing the correct lever—pops out and falls on the floor of the box. The rat scrambles to eat it.

Albert Hofmann (left), discoverer of LSD, and Purdue's David Nichols at the 2004 ASC conference in Zurich
photo: David Nichols
Albert Hofmann (left), discoverer of LSD, and Purdue's David Nichols at the 2004 ASC conference in Zurich

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    I can't tell by looking at the rat that it's on LSD. The rat doesn't seem too fazed. It looks kind of placid, unlike the fanged beasts that haunt Manhattan apartments. I start to wonder what a rat version of Dark Side of the Moon would sound like.

    A scientist whisks me to the next room, which houses a maze. It looks like a giant plastic octopus lined with red lights, and it's for rats on various substances to wander through for more tests. The greenish glow of computer screens fills the next room, where a team of researchers is inputting data they hope will support new theories on how LSD, the common name for d-lysergic acid diethylamide, produces its profound effects on the human brain.

    I'm out in bucolic West Lafayette, Indiana, about an hour's drive from Indianapolis. Cornfields are everywhere. The vast spaces not taken up by Purdue University or the highway are dotted with sports bars and houses. I've traveled all the way out here because this is one of the only labs in America doing pioneering LSD research. I'm searching for clues to a mystery: How, in terms of brain chemistry, does the fabled "acid trip" initially produce an overpowering swirl of visual effects, only to "come down" into something that's nonvisual, heavily introspective, and—in some cases—downright creepy?

    The rats don't know it, but they're helping to find the answer.


    I'm in the office of 60-year-old David Nichols, a medicinal chemistry and pharmacology professor at Purdue and a leading expert in the field of hallucinogenic substances. He's also one of the founders of the private Heffter Research Institute in New Mexico, which provides support for scientific research on hallucinogens. His office is stacked with teetering piles of technical-journal articles, science books, and ball-and-stick molecular models in cheerful primary colors. A sign on the door reads, "The Doctor Is In."

    Grandfatherly, loquacious, and amiable, he discusses complicated neurotransmitter theories, cheesecake recipes, and childhood memories of smoke bomb experiments with equal fondness. He's been working to understand the LSD molecule since 1969, and its bizarre qualities still fascinate him.

    "Tell me how, under what kind of philosophical basis, a hundred micrograms going into someone's brain could permanently change the way they are," he asks. "Now it's not true with everyone, obviously. But some people might have a religious revelation. It may change their life in some fundamental way. Maybe in a few people it precipitates a psychosis. But how could taking this thing make somebody think they had talked to God, or seen the Big Bang and watched the evolution of the cosmos? How can a chemical molecule do that?"

    No one really knows. Scientists try to quantify abstract, subjective reaches of the LSD experience in several different ways. Last year, top professors, psychiatrists, and even Zen meditation experts gathered for the Altered States of Consciousness conference to swap findings and theories. In 1975, Swiss researcher Adolf Dittrich devised a meticulous questionnaire to measure various drug-induced states using existential-sounding metrics like "oceanic boundlessness," "dread of ego dissolution," and "visionary restructuralization." At the University of Zurich, Franz Vollenweider and his research team routinely conduct trailblazing research, often through clinical studies, on how hallucinogens affect people; a recent study by his lab examined the physiological effects of psilocybin—the active ingredient in psychedelic mushrooms—on human volunteers.

    The brain chemistry aspect of the LSD—the language of serotonin, dopamine, and other neurotransmitters—is one of the most heavily investigated, but it's also endlessly confounding. On the level of chemical structure, LSD looks quite a bit like the serotonin molecule, and the LSD-serotonin connection has been explored since the 1950s. The debate over whether LSD is a good model for how schizophrenia works has been raging for nearly half a century. Recently, dopamine, the "feel-good" chemical also implicated in disorders like schizophrenia, is finding a larger role in the LSD story. And as scientists learn more about serotonin receptors, they've localized specific aspects of the LSD experience to different receptors. The flood of kaleidoscopic visual effects that happens upon taking LSD and substances like it seems to be tied to the activation of a particular serotonin receptor called 5-HT2A.

    In a study that will soon be published, Nichols and his group trained 25 rats to push levers to distinguish between having received an injection of LSD and an injection of regular old saline solution. Rats don't trip exactly like people do; for one, they don't have the massively overdeveloped frontal lobes of humans that allow for higher cognitive functions and dorm room philosophizing. But they do show some measurable behavioral changes that can be related to the human trip; at first, the rats don't seem to move around too much, and then there's increased locomotor activity.

    The first phase of the rats' LSD experience, Nichols found, was indeed mediated by the 5-HT2A receptor, the one responsible for the visuals. But the second phase of the rats' trip was a full-on dopamine response. The "coming down" phase—where bad trips are more likely to form—is where the dopamine D2 receptor kicks in, a receptor that's implicated, among other things, in schizophrenia. It seems that an LSD trip is a two-phase experience—a story that begins with serotonin and ends with dopamine.

    Nichols hopes that this study and several others that his lab is on the brink of finishing will finally reveal answers to some of the basic questions about how LSD works, answers he's been chasing down for over half his lifetime.

    "When I was a little kid I used to play with pyrotechnics," he says with a smile. "This is the closest I could get to a pyrotechnic molecule in the brain."

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