Nerve Agents Accidentally Revealed What Happens When Both Endocannabinoid Enzymes Are Blocked at Once | Research

The takeaway

Organophosphorus nerve agents simultaneously blocked both endocannabinoid-degrading enzymes, causing massive brain cannabinoid increases and full cannabinoid-like behavioral effects, unlike blocking either enzyme alone.

Read this if you're interested in the complex regulation of the endocannabinoid system and what happens when its safety controls are removed.

10-fold brain endocannabinoid increase from dual enzyme blockade produced THC-like effects

What the researchers found

Researchers discovered that certain organophosphorus compounds (normally studied as nerve agents) simultaneously inhibit both MAGL and FAAH, the two main enzymes that break down endocannabinoids in the brain.

This dual blockade produced greater than 10-fold increases in brain levels of both 2-AG and anandamide and caused robust CB1-dependent behavioral effects (reduced movement, catalepsy, hypothermia, pain insensitivity) that mirrored those of directly administering THC.

This was strikingly different from blocking FAAH alone, which produces only analgesic and anxiolytic effects without cognitive impairment or cannabinoid-like intoxication.

An unexpected finding: brain arachidonic acid levels decreased by amounts equivalent to the 2-AG increases, revealing that endocannabinoid and eicosanoid (inflammatory lipid) signaling pathways are coordinately regulated in the brain.

Why it matters

This study made two important contributions: it showed that blocking both endocannabinoid enzymes simultaneously produces very different effects than blocking either alone, and it revealed an unexpected connection between the endocannabinoid and inflammatory lipid systems.

The numbers in context

Greater than 10-fold increases in both brain 2-AG and anandamide. CB1-dependent behavioral effects matching THC. Arachidonic acid decreased by amounts equivalent to 2-AG increases. FAAH inhibition alone: analgesia/anxiolysis without CB1-like behavioral effects.

How the study worked

Selected organophosphorus agents were administered to mice. Brain endocannabinoid levels (anandamide and 2-AG) and arachidonic acid levels were measured. Behavioral effects were assessed using the cannabinoid tetrad. CB1 receptor involvement was confirmed using antagonists.

What this study cannot tell us

Organophosphorus agents have multiple mechanisms of action beyond endocannabinoid enzyme inhibition (notably acetylcholinesterase inhibition), complicating interpretation. The doses used may not reflect typical environmental or occupational exposures.

How to read the evidence

This is a well-designed animal study published in a high-impact journal (Nature Chemical Biology), providing moderate to strong mechanistic evidence.

When this study was published

Published in 2008. This study was influential in shaping the strategy of developing selective (not dual) endocannabinoid enzyme inhibitors as therapeutics.

The bigger picture

This study had implications for both drug development (selective vs. dual enzyme inhibition produces very different outcomes) and toxicology (organophosphorus poisoning may partly involve the endocannabinoid system). The connection between endocannabinoid and eicosanoid pathways remains an active research area.

Questions still open

Does the endocannabinoid system contribute to organophosphorus poisoning symptoms? Could the endocannabinoid-eicosanoid connection be therapeutically exploited for inflammatory conditions?

Common questions

Does this mean nerve agents get you high?

Not in a recreational sense. The organophosphorus compounds used have devastating toxic effects (they're nerve agents). This study revealed that part of their mechanism happens to involve the endocannabinoid system, producing some cannabinoid-like effects alongside their primary toxic actions.

Why is it important that blocking one enzyme is different from blocking both?

Blocking FAAH alone produces therapeutic effects (pain relief, reduced anxiety) without intoxication. Blocking both FAAH and MAGL together produces THC-like intoxication. This tells drug developers to focus on selective enzyme inhibitors to get therapeutic benefits without unwanted effects.

Read the original research

Activation of the endocannabinoid system by organophosphorus nerve agents.

Nature chemical biology, 4(6), 373-8

View on PubMed ↗Publisher’s paper ↗

Citation

Nomura, Daniel K; Blankman, Jacqueline L; Simon, Gabriel M; Fujioka, Kazutoshi; Issa, Roger S; Ward, Anna M; Cravatt, Benjamin F; Casida, John E. (2008). Activation of the endocannabinoid system by organophosphorus nerve agents.. Nature chemical biology, 4(6), 373-8. https://doi.org/10.1038/nchembio.86