Nonhallucinogenic Psychedelic Analogs to Mitigate Anxiety, Depression, and Addiction

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and drug abuse in human patients. However, their hallucinogenic side effects often limit their clinical application. The Wetsel lab uses mouse experiments to explore the responses to two different classes of psychedelics—the ergoline hallucinogen lysergic acid diethylamide (LSD) and the phenethylamine hallucinogen 2C-T-7. Both psychedelics produce their hallucinogenic effects through a specific serotonin receptor but through experimentally separable mechanisms based on deleting one member of a pair of specific genes in the mice and observing their reactions to these drugs. These experimental results have led to the development of analog drugs—agonists to the serotonin 2A receptor (5-HT2AR)—that have long-lasting anxiety and depressant reducing activities in mice. Distinct studies explore the reduction in self-administration of the synthetic opioid remifentanil in mice that produces addictive behaviors. Treatment with psilocin, the psychoactive compound in psilocybin mushrooms that acts also on the 5-HT2AR, reduces this drug-abuse behavior. This talk will discuss how, together, these results indicate that compounds that are agonists at the 5-HT2AR can be developed without hallucinogenic effects, while retaining long-lasting beneficial effects at least for anxiety and depression.