Study Finds Key to Hallucinogenic Response

People have been taking hallucinogenic drugs for thousands of years. Now scientists think they've figured out a key mechanism that allows tiny amounts of substances like LSD to have a powerful effect on the brain.

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A tiny amount of LSD can produce mind-bending results. It can also induce a psychotic episode. But no one has been able to figure out exactly what LSD and other hallucinogenic drugs do in the brain. Well, now some researchers think that they have at least part of the answer, and it may lead to a better understanding of psychiatric disorders like schizophrenia.

NPR's Jon Hamilton reports.

JON HAMILTON: The LSD mystery began in 1943 with a bicycle ride. A Swiss scientist named Albert Hoffman had been experimenting in his laboratory with a compound he discovered. What happens next has become a part of science history. Jay Gingrich is a psychiatrist at Columbia University.

JAY GINGRICH: He was working with a compound when all of a sudden he felt very, very strange and was actually a bit frightened by what was happening. And he asked his assistant to escort him home. And since it was during wartime, the only thing they had available was a bicycle.

HAMILTON: And it was quite a trip. The compound was something called LSD-25. Ever since then, scientists have been fascinated by LSD's ability to produce psychedelic experiences in the human brain. But for 60 years, they knew very little about how it worked. Researchers recently discovered that LSD and other hallucinogens flipped molecular switches in the brain. These switches are called serotonin 2A receptors. And LSD turns them on.

But that didn't solve the mystery. Lots of other compounds also flip these switches and they didn't cause any hallucinations. So what was LSD doing differently? Okay, fast forward to a few months ago. Jay Gingrich was part of a team giving hallucinogenic drugs to mice. Gingrich says a typical mouse responds to the drugs in a distinctive way.

GINGRICH: That's called a head twitch, which is just a brief, rapid side-to-side motion of the head.

HAMILTON: Lots of twitches mean a mouse is tripping, more or less. Gingrich and his colleagues used the mice in an elegant experiment. They showed that at least in one part of the brain, the 2A receptor is more than a simple on-off switch. Stuart Sealfon is a neurologist at Mount Sinai School of Medicine and a member of the team.

STUART SEALFON: In this case, it's as if it's a switch that instead of just going up or down, it could be turned on to the right by hallucinogens, and it will have one effect on the cell, and it'd be turned on the left, to the left by non-hallucinogens, and it will have a different effect on the cell.

HAMILTON: Flip the switch right and you're experiencing the God within. Flip left and you're just staring at the walls of your cubicle. Researchers say the finding may do much more than solve a medical mystery. Mark Geyer is a neuroscientist at the University of California, San Diego. He says the new study shows why researchers working on mental illness should take another look at studies of hallucinogenic drugs.

MARK GEYER: There's a real message that these compounds can teach us about what happens in patients that have some of those, similar kinds of experiences but they can't attribute it to a drug.

HAMILTON: People with schizophrenia, for example. Geyer says there's a huge need for better drugs to treat this disorder.

GEYER: We still have patients who may be less danger to themselves and less danger to society, but they still can't think straight. They still can't have jobs. They can't hold jobs. Some 80 percent of those discharged from the VA psychiatric wards are homeless in Los Angeles.

HAMILTON: Geyer says one answer may be drugs that manipulate the serotonin 2A receptors that were the focus of the new LSD study. Actually, it turns out the newest schizophrenia drugs already affect these switches. And now that this study has shown that they have more than one on position, it may be possible to develop better drugs to manipulate them. The new research appears in the current issue of the journal Neuron.

Jon Hamilton, NPR News.

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