Cannabidiol exerts teratogenic effects on developing zebrafish through the sonic hedgehog signaling pathway

The increasing legalization and decriminalization of cannabis for therapeutic and recreational purposes in various regions have influenced public perceptions and attitudes toward cannabidiol (CBD)-containing products, including their use during pregnancy. However, there is a knowledge gap regarding the effect of CBD on fetal development, and the mechanisms by which CBD induces developmental deficits have not been well studied. In this study, we investigated whether the teratogenic effects of CBD on developing zebrafish are mediated through Sonic hedgehog signaling (Shh), a critical pathway in development. Embryonic exposure to CBD reduced hatching and survival rates and suppressed Shh pathway activity, leading to decreased ptch2 expression-a regulatory receptor expressed in response to Shh signaling. Larval swimming activity was impaired by CBD exposure. However, coexposure to CBD and a synthetic Shh pathway activator significantly improved developmental outcomes, including decreased mortality, increased hatching rates, elevated ptch2 expression, and increased locomotor activity. These findings underscore the developmental risks associated with CBD use during pregnancy and highlight the involvement of the Shh signaling pathway in driving these effects. The results of this study can inform regulations for cannabis use during pregnancy and emphasize the need to develop therapeutic guidelines for the safe use of CBD-based treatments.