Multiple lines of evidence support the hypothesis that the cannabinoids, THC and CBD, do more than act on specific GPCRs. Recent evidence in my laboratory points to how cannabinoids drive broad changes in the lipidome with data suggesting that many of the changes are dependent on the enzyme NAPE-PLD. We have also shown that cannabinoid effects on the lipidome are sex and age dependent. Taken together, these data provide a novel framework for how cannabinoids change multiple signaling pathways by fundamentally changing lipid signaling throughout the CNS.