Steven Dubovsky, MD

Early animal research into an anxiolytic substrate-specific COX-2 inhibitor

Acting through cannabinoid receptors, endogenous endocannabinoids (eCBs), such as anandamide, modulate pain and anxiety, among other things; substances that inhibit enzymes that break down eCBs may have antianxiety properties. Because cyclooxygenase-2 (COX-2), which catalyzes synthesis of prostaglandins from arachidonic acid, also inactivates anandamide, researchers explored the antianxiety qualities of a substrate-selective COX-2 inhibitor that selectively augments eCBs without the other effects of nonselective COX-2 inhibitors, such as nonsteroidal anti-inflammatory drugs (NSAIDs). The researchers hold patent interests in the molecule, LM-4131, a derivative of the COX inhibitor indomethacin.

In mice, LM-4131 increased brain anandamide levels by inhibiting COX-2 without affecting prostaglandins or arachidonic acid or non-eCB lipids. In established animal models, LM-4131 reduced anxiety-like behavior without affecting overall locomotor activity. At the same time, the drug did not produce cannabinoids' bothersome effects, such as hypolocomotion, analgesia, catalepsy, and hypothermia. There was no gastrointestinal toxicity.

Citation(s):

Hermanson DJ et al. Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation. Nat Neurosci 2013 Sep; 16:1291.