Black Pepper Compound Boosted Endocannabinoid Levels and Produced Cannabis-Like Effects in Mice

High-content screening identified guineensine from black pepper. Its effects on endocannabinoid uptake were tested in cell lines. Activity-based protein profiling confirmed it did not inhibit serine hydrolases. In vivo effects were assessed in BALB/c mice using the cannabinoid tetrad (catalepsy, body temperature, locomotion, tail-flick analgesia). The CB1 antagonist rimonabant was used to confirm endocannabinoid system involvement.

Guineensine represents a new class of endocannabinoid modulator with a mechanism distinct from FAAH or MAGL inhibition. Its identification in black pepper adds to the list of dietary compounds that interact with the endocannabinoid system and could serve as a scaffold for developing new drugs that enhance endocannabinoid tone without directly activating cannabinoid receptors.

The discovery of dietary compounds that modulate the endocannabinoid system opens new avenues for both drug development and understanding how food compounds affect neurochemistry. Guineensine's unique mechanism of action (blocking cellular uptake without affecting degradation enzymes) may help identify previously unknown proteins involved in endocannabinoid transport.

This was a preclinical study using cell lines and mice. The concentrations of guineensine achievable through dietary black pepper consumption are likely far below those needed for pharmacological effects. The molecular target through which guineensine blocks endocannabinoid uptake was not identified.