Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high

Phytochemical studies on the liverwort Radula genus have previously identified the bibenzyl (−)-cis-perrottetinene (cis-PET), which structurally resembles (−)-Δ(9)-trans-tetrahydrocannabinol (Δ(9)-trans-THC) from Cannabis sativa L. Radula preparations are sold as cannabinoid-like legal high on the internet, even though pharmacological data are lacking. Herein, we describe a versatile total synthesis of (−)-cis-PET and its (−)-trans diastereoisomer and demonstrate that both molecules readily penetrate the brain and induce hypothermia, catalepsy, hypolocomotion, and analgesia in a CB1 receptor–dependent manner in mice. The natural product (−)-cis-PET was profiled on major brain receptors, showing a selective cannabinoid pharmacology. This study also uncovers pharmacological differences between Δ(9)-THC and PET diastereoisomers. Most notably, (−)-cis-PET and (−)-trans-PET significantly reduced basal brain prostaglandin levels associated with Δ(9)-trans-THC side effects in a CB1 receptor–dependent manner, thus mimicking the action of the endocannabinoid 2-arachidonoyl glycerol. Therefore, the natural product (−)-cis-PET is a psychoactive cannabinoid from bryophytes, illustrating the existence of convergent evolution of bioactive cannabinoids in the plant kingdom. Our findings may have implications for bioprospecting and drug discovery and provide a molecular rationale for the reported effects upon consumption of certain Radula preparations as moderately active legal highs.