Combinatorial use of cannabidiol and the serine hydrolase inhibitor AKU-005 to enhance endocannabinoids for treatment of migraine

Migraine is a common multifaceted neurovascular disease.

Traditional medications have limitations and even newer CGRP monoclonal antibodies only effectively treat 50% of patients.

Instead of using highly addictive painkillers, such as opioids, there is a great need for alternative, effective and safe medications.

Despite psychoactive side-effects of cannabis, its derivative compounds (cannabinoids) have emerged as a new class of analgesic and anti-migraine agents. Indeed, the frequency of migraine headaches decreases with medical marijuana.

To avoid cannabis psychotropic effects, an alternative is to recruit the anti-nociceptive actions of endogenous cannabinoids (endocannabinoids). The two main endocannabinoids are 2-arachidonoylglycerol (2-AG) and anandamide (AEA).

The anti-nociceptive efficiency of 2-AG and AEA is determined by their enzymatic synthesis, activity on receptors CB1 and CB2, and degradation by monoacylglycerol lipase (MAGL) and fatty acid hydrolase (FAAH), respectively.

There is recent progress in the development of selective and potent MAGL and FAAH inhibitors, providing excellent starting points for enhancing endocannabinoid activity. A key point is that the enzymes are distinctly active in different migraine pain signaling areas. Therefore, we propose that at least a dual FAAH and MAGL inhibition would be ideal.

We have shown that the serine hydrolases inhibitor AKU-005 potently reduces migraine-related nociceptive activation.

Of further relevance, the combination of CB1/2 orthosteric delta-9-tetrahydrocannabinol (THC) and allosteric cannabidiol (CBD) agonists can reduce central and peripheral-induced light aversion in CGRP migraine models.

Our hypothesis is that enhancement of endocannabinoids by the inhibitor AKU-005 in combination with CBD treatment could safely inhibit migraine-related pain pathways, representing an alternative, non-addictive therapeutic target to help bridge the therapeutic gap and reduce the significant burden in migraine.