Blocking Endocannabinoid Breakdown Could Treat Anxiety, Cancer, and Neurodegenerative Diseases | Research

The takeaway

Research identified the enzymes FAAH and MAGL as critical regulators of endocannabinoid levels, suggesting that drugs blocking these enzymes could boost the body's own cannabinoid system to treat anxiety, cancer, and neurodegenerative disorders.

Read this if you are interested in how the body's natural cannabinoid system works and how it could be targeted for new medicines.

FAAH and MAGL inhibitors could boost natural cannabinoid signaling without introducing external cannabinoids

What the researchers found

This review focused on the enzymes responsible for endocannabinoid synthesis and degradation. Two endocannabinoids, anandamide (AEA) and 2-AG, are produced on demand and their activity is terminated by specific enzymes: fatty acid amide hydrolase (FAAH) for anandamide and monoacylglycerol lipase (MAGL) for 2-AG.

These enzymes are pivotal regulators of endocannabinoid levels in the body. Specific inhibitors of FAAH, MAGL, or the anandamide membrane transporter (AMT) could serve as therapeutic targets by boosting the body's own cannabinoid signaling rather than introducing external cannabinoids.

The review also described the biosynthetic enzymes NAPE-PLD and DAGL that produce endocannabinoids. Animal studies of endocannabinoid degradation inhibitors showed promise for treating anxiety, cancer, and neurodegenerative disorders.

Why it matters

Inhibiting endocannabinoid breakdown is a fundamentally different approach from administering THC or other cannabinoids. By boosting the body's own cannabinoid signaling at specific sites, this approach could provide therapeutic benefits with fewer psychoactive side effects, since endocannabinoid levels would only increase where they are naturally being produced.

The numbers in context

Key enzymes: FAAH (degrades anandamide), MAGL (degrades 2-AG), AMT (transports anandamide), NAPE-PLD (synthesizes anandamide), DAGL (synthesizes 2-AG). Therapeutic targets tested in animal models: anxiety, cancer, neurodegenerative disorders.

How the study worked

Review of molecular biology research on endocannabinoid synthesis and degradation pathways. Covered enzyme characterization, inhibitor development, and animal model studies of therapeutic applications.

What this study cannot tell us

All therapeutic evidence was from animal models. The complexity of endocannabinoid signaling means inhibiting degradation enzymes affects multiple biological systems. The review was published before significant human clinical data was available.

How to read the evidence

Molecular biology review with animal model therapeutic evidence. Provides strong mechanistic understanding but lacks human clinical data.

When this study was published

Published in 2006. FAAH inhibitor research has continued, though a clinical trial incident in 2016 highlighted the challenges of this approach.

The bigger picture

The FAAH inhibitor approach eventually led to clinical trials, though a tragic incident in France (2016) involving a FAAH inhibitor (BIA 10-2474) caused one death and injured five volunteers. Despite this setback, FAAH inhibition remains an active area of pharmaceutical research with other compounds in development.

Questions still open

Can FAAH or MAGL inhibitors provide therapeutic benefits without the psychoactive effects of THC? Which conditions are most amenable to this indirect approach to boosting endocannabinoid signaling?

Common questions

Can the body's own cannabinoid system be boosted for treatment?

Yes. This review describes how blocking the enzymes that break down endocannabinoids (FAAH and MAGL) can increase the body's natural cannabinoid signaling. This approach has shown promise in animal models for anxiety, cancer, and neurodegenerative conditions.

How is this different from using cannabis?

Instead of introducing external cannabinoids (like THC), this approach amplifies the body's own cannabinoid molecules at the sites where they are naturally produced. This could potentially provide more targeted effects with fewer psychoactive side effects.

Read the original research

New insights into endocannabinoid degradation and its therapeutic potential.

Mini reviews in medicinal chemistry, 6(3), 257-68

View on PubMed ↗

Citation

Bari, M; Battista, N; Fezza, F; Gasperi, V; Maccarrone, M. (2006). New insights into endocannabinoid degradation and its therapeutic potential.. Mini reviews in medicinal chemistry, 6(3), 257-68.