Developmental Neurotoxicity Screen of Psychedelics and Other Drugs of Abuse in Larval Zebrafish (Danio rerio).
Robert J Tombari, Paige C Mundy, Kelly M Morales, Lee E Dunlap, David E Olson, Pamela J Lein
ACS chemical neuroscience March 1, 2023 DOI: 10.1021/acschemneuro.2c00642
Summary
Psychedelic compounds like psilocybin and ketamine show promising safety profiles in developing brains compared to LSD and psychostimulants. Using zebrafish larvae as test subjects, researchers compared 13 different psychoactive substances, finding that natural hallucinogens caused fewer behavioral abnormalities and developmental issues than synthetic alternatives. This teratology screening offers valuable insights for therapeutic drug development.
Abstract
In recent years, psychedelics have garnered significant interest as therapeutic agents for treating diverse neuropsychiatric disorders. However, the potential for these compounds to produce developmental neurotoxicity has not been rigorously assessed, and much of the available safety data is based on epidemiological studies with limited experimental testing in laboratory animal models. Moreover, the experimental safety data available thus far have focused on adult organisms, and the few studies conducted using developing organisms have tested a limited number of compounds, precluding direct comparisons between various chemical scaffolds. In the present study, 13 psychoactive compounds of different chemical or pharmacological classes were screened in a larval zebrafish model for teratological and behavioral abnormalities following acute and chronic developmental exposures. We found that the psychedelic tryptamines and ketamine were less neurotoxic to larval zebrafish than LSD and psychostimulants. Our work, which leverages the advantage of using zebrafish for higher throughput toxicity screening, provides a robust reference database for comparing the neurotoxicity profiles of novel psychedelics currently under development for therapeutic applications.