“Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids, N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception, but with minimal cannabimimetic side effects.

Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to CB1 receptor functional tolerance, which represents another challenge in this potential therapeutic strategy.

Therefore, the present study tested whether full FAAH inhibition, combined with partial MAGL inhibition, would produce sustained antinociceptive effects with minimal cannabimimetic side effects…

Thus, full FAAH inhibition combined with partial MAGL inhibition reduces neuropathic and inflammatory pain states, with minimal cannabimimetic effects.”