What makes LSD different?

Scientists are examining the responses of mice to learn more about how psychedelic drugs such as LSD, mescaline and "magic mushrooms" work on the brain.

Besides providing new insights into hallucinogens, the study opens a door to understanding how drugs used to treat psychiatric disorders may work, too. It may even point the way to new and better medications for mental illness, the team said.

"We were trying to find out why hallucinogens have their unique effects when very closely related drugs don't have similar effects on behaviour and perception," explained co-researcher Dr Stuart C. Sealfon, a professor of neurology, neuroscience, pharmacology and biological chemistry at Mount Sinai School of Medicine, in New York City.

The findings are published in the February 1 issue of Neuron.

Acts on specific receptors
The researchers found that hallucinogens act on specific serotonin receptors in the brain called 5-HT2A receptors (2ARs). Hallucinogens act somewhat differently from other drugs that also target that receptor, Sealfon said.

"It's as if the receptor was a switch that can get turned on in one position for drugs that are not hallucinogens, and it turns on in another position for drugs that are hallucinogens," he explained.

In the study, the researchers closely observed mice to compare differences between the effects of LSD and lisuride, a non-hallucinogenic chemical that also activates 2AR receptors on brain cells.

"Of course, we don't know what the mice experience when they are treated with these drugs," Sealfon said. "But we do know that there is a head twitch response in the mice that provides a good correlation with drugs that are known to be hallucinogenic in humans."

Receptors tied to hallucinogenic effect
Sealfon's group looked at whether 2AR receptors were essential to the hallucinogenic effect of LSD. In mice genetically engineered to lack the receptors, the researchers observed no hallucinogenic response to LSD. However, restoring the receptors did produce indications of LSD hallucinations in the animals.

This finding has implications for drugs that are used to treat psychiatric and neurological diseases, Sealfon said.

"It suggests the differential reacting of receptors is likely to be important in understanding why different drugs, used for treating brain diseases, have different effects even if they are directed at the same target. We can use that information to develop new drugs that are more specific and have reduced chances of causing undesirable side effects," he said.

One expert believes the findings may not cover all hallucinogens, however.

"It would be nice to see these findings replicated in a different mammal," said Dr John Halpern, associate director for substance abuse research at McLean Hospital, Harvard Medical School, Boston. "It would also be interesting to expand this to drugs that are not considered part of the classic hallucinogens, such as PCP, which target other receptors," said Halpern, who's done his own research in this area.

Far reaching implications
Halpern agreed that the findings "will have far-reaching implications in understanding underlying mechanisms" that underlie the effects of certain drugs. "It will also help tease out why these substances claim to have religious effects, positive effects and their negative effects," he said.

In addition, the findings could lead to new and better drugs to treat mental illness.

"There are many medications that we have in psychopharmacology that we don't quite understand how they work," Halpern said. "We can say what they do in the brain, but this may bring us one step closer to peeling away the veil of why drugs that alter our perceptions of reality can have therapeutic or harmful effects," he said. – (HealthDayNews)

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Substance abuse Centre

February 2007