LSD, mescaline and brain receptors

That the brain has specific receptors for various drugs is now an established fact, but it took a long, strange trip by George K. Aghajanian, M.D. ’58, HS ’61, FW ’63, a pioneer in neuropharmacology, to turn that theory into a certainty.

In 1958, for his thesis research, Aghajanian said at a Leadership in Biomedicine lecture in January, he compared the effects of mescaline and LSD in animals and speculated that the receptors mediating their effects were closely linked. But he faced a largely dubious senior faculty in psychiatry. “There was the belief at the time that the brain was not relevant to psychiatry,” he said.

In the ensuing decades, Aghajanian, the Foundations Fund Professor of Psychiatry and Pharmacology at Yale, showed that LSD and related hallucinogens promote “spillover” of the excitatory transmitter glutamate from synapses in the prefrontal cortex, causing miscommunication between adjacent groups of neurons. His research helped pave the way for a new generation of antipsychotic drugs, which target brain receptors that modify the release of glutamate. “It just took 50 years,” he said. “I hope that the students who go on to become physician-scientists have better luck than I did—or better timing.”