Beyond THC: New Drug Strategies That Boost the Brain's Own Cannabinoids | Research

The takeaway

A comprehensive review examined alternative approaches to modulating the endocannabinoid system, including FAAH, MAGL, and COX-2 inhibitors, as well as endocannabinoid transport blockers, offering therapeutic potential with fewer side effects than directly activating cannabinoid receptors.

Readers interested in the future of cannabinoid-based medicine beyond THC and CBD.

Multiple drug targets beyond CB1/CB2 receptors offer new therapeutic opportunities

What the researchers found

This review examined strategies for modulating the endocannabinoid system that go beyond directly activating CB1 and CB2 receptors, which has produced limited therapeutic success due to CB1-mediated side effects.

Alternative approaches include inhibitors of the enzymes that break down endocannabinoids (FAAH for anandamide, MAGL for 2-AG, ABHD6, and ABHD12), as well as COX-2 inhibitors, diacylglycerol lipase inhibitors, and blockers of the endocannabinoid membrane transporter.

The review also discussed polypharmacological approaches that combine mild inhibition of multiple targets simultaneously. These indirect strategies aim to boost endocannabinoid levels at sites where they are naturally produced, providing more targeted effects than flooding all receptors with a direct agonist like THC.

Why it matters

Direct cannabinoid receptor activation (as THC does) produces significant side effects. These alternative approaches could potentially deliver therapeutic benefits for conditions like pain, anxiety, and neurological diseases with improved safety profiles.

The numbers in context

Multiple enzyme targets reviewed: FAAH, MAGL, ABHD6, ABHD12, COX-2, diacylglycerol lipases, endocannabinoid transporter. Approaches span 10-15 years of development.

How the study worked

Comprehensive review of patent literature, clinical trial registries, and published scientific literature on compounds targeting various elements of the endocannabinoid system beyond direct receptor activation.

What this study cannot tell us

Many of the compounds reviewed were in early development stages. A FAAH inhibitor clinical trial by Bial resulted in serious adverse events in 2016 (though this was not discussed in this review). Translation from promising preclinical compounds to safe, effective drugs has proven challenging.

How to read the evidence

This is a comprehensive review of drug development literature spanning patents, clinical trials, and basic science, providing moderate evidence on the therapeutic landscape.

When this study was published

Published in 2016. Several of the approaches discussed have progressed in clinical development, though safety concerns have also emerged.

The bigger picture

This review captures an important shift in cannabinoid drug development: from trying to mimic THC to trying to enhance the body's own cannabinoid signaling. This approach could lead to more targeted therapeutics with fewer psychoactive side effects.

Questions still open

Can polypharmacological approaches targeting multiple endocannabinoid system components offer better therapeutic ratios? Which CNS conditions are most amenable to endocannabinoid modulation?

Common questions

Why not just use THC or CBD as medicine?

THC directly activates CB1 receptors throughout the brain, causing psychoactive effects and other side effects. CBD works differently but has its own limitations. The approaches reviewed here aim to boost the body's own cannabinoids only where and when they are naturally needed, potentially reducing side effects.

What is the endocannabinoid membrane transporter?

It is a proposed mechanism by which endocannabinoids are taken up from the extracellular space back into cells. Blocking this transporter would increase endocannabinoid levels in the synapse, similar to how SSRI antidepressants increase serotonin by blocking its reuptake.

Read the original research

Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases.

Recent patents on CNS drug discovery, 10(2), 122-141

View on PubMed ↗

Citation

Chicca, Andrea; Arena, Chiara; Manera, Clementina. (2016). Beyond the Direct Activation of Cannabinoid Receptors: New Strategies to Modulate the Endocannabinoid System in CNS-Related Diseases.. Recent patents on CNS drug discovery, 10(2), 122-141.