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Inhibiting Re-Uptake To Enable Treatment: The Endocannabinoid System and New Medicines

In popular culture, we like to think of an inventor as someone who notices a problem, thinks really hard about a solution, and solves that problem with a novel device or approach. Oftentimes however, discovery proceeds in reverse: first a solution is found and then a clever inventor looks for a problem that the solution might apply to. For instance, the invention of the Post-it Note® occurred when a scientist attempting to develop a better superglue accidentally developed a glue with low adhesion but high re-usability. Although that scientist attempted to promote the glue, the company that had financed the research tossed it to the side, chalking it up as a failure. After all it was not the superglue they wanted. Six years later a colleague managed to develop a use outside of the company; he noticed he could apply it to the back of a bookmark to keep it from falling out without developing a permanent bond that would tear the page. Thus the Post-it Note® was born and subsequently became one of 3M’s most successful products.

Drug development, as Christopher Fowler argues, might also proceed more effectively this way. Fowler, a clinical neuroscience researcher at Umea Unversity of Sweden, recently reviewed studies involving inhibitors of cannabinoid metabolism. Metabolism, whether specific to nutrients or in this case chemicals in general, simply means how something is broken back down to be disposed of or recycled by the body. The idea is that rather than supplying the brain with more cannabinoids, as happens when we consume cannabis, the body could be enabled to retain more of its own production.

Why would this be better? Natural cannabinoids (called “endocannabinoids”), unlike many other neurologically-active signaling molecules, are produced only at the spot where needed. This is important because not all areas of the brain naturally produce cannabinoids. Imagine, for instance, that your car has run low on oil; few would recommend opening the hood and pouring oil over the entire engine! In the case of cannabinoids, this is especially relevant, because cannabinoids have a multi-phasic response. In treating anxiety for instance, a small dose of THC may be helpful, while a lot of THC may increase anxiety. Keeping cannabinoids where the body intends them would make it easier to find the correct dosage window. Furthermore, researchers speculate that some of the unwanted side effects of cannabis (such as paranoia) can come from cannabinoids being in places they are not intended. However, the issue is not just about where the cannabinoids end up, but also about the patterns of their levels in those places. When cannabinoid metabolism inhibitors are used, the natural pattern of the body is amplified, whereas when external cannabinoids are applied, the natural pattern is entirely erased, and the levels are simply dependent on the dose and time passed since the dose was given. Allowing endocannabinoids to stay active for longer would therefore be a great approach to medicating through the cannabinoid system.

For this reason, Fowler has reviewed recent evidence of studies involving cannabinoid metabolism inhibitors. Readers should note that this is how many modern anti-depressant drugs were created. Scientists faced frustration with substances that worked with rodents but not in human populations. Serotonin re-uptake inhibitors were developed after researchers noticed beneficial side effects in human studies that were meant to test other medical effects of those drugs. So far, the two most common cannabinoid uptake inhibitors tested have been URB597 (an FAAH inhibitor) and JZL184 (an MGL inhibitor). Since readers are probably not very familiar with these molecules, FAAH and MGL are two of the most common cannabinoid metabolic enzymes, breaking down 2-AG and anandamide (natural endocannabinoids) respectively.

Reviewing the list Fowler accumulated, URB597 shows an impact ranging from no-effect to decreasing anxiety significantly. Most tests seem to use the time rodents hold open-arm positions as an indication of comfort vs. anxiety, so likewise, application of URB597 generally corresponded to an increase in open-arm time. However, this impact is blocked in mice without cannabinoid receptors and sometimes blocked by cannabinoid antagonists as well. JZL184 could be characterized similarly. Some studies separated the most anxious group of rodents from the least anxious and noticed a difference in response to inhibitors. If the same were to hold with human trials, we could expect a decrease in anxiety in some individuals and no effect in others.

Although this is not particularly promising, these results do not exclude the possibility of future treatment models based on inhibitors, and more remain to be tested. The good news is that inhibitors do not mimic external cannabinoid application in terms of psychoactivity. In other words, patients would not receive a “high” from the medicine and would therefore be able to take these at work or in situations where psychoactivity is undesired. Finally, these medicines can play a role when used in conjunction with other substances that alter the pharmacological landscape of the brain. For those looking to see cannabinoid metabolism inhibitors on the market soon, expect to be disappointed. However, for those looking to the future of cannabinoid-based medicine and anxiety medication, these inhibitors represent a very likely possibility.


Works Cited

Christopher Fowler. (2014) “The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs – A practical view.” European Neuropsychopharmacology (2015) 25: 749-762.