A dual FAAH/MAGL inhibitor produced a broader range of cannabinoid effects than inhibiting either enzyme alone, revealing that anandamide and 2-AG pathways interact to regulate specific behaviors including drug-related responses.
Read this if you want to understand why the body has two main endocannabinoid pathways and how they work together.
Only dual enzyme blockade, not FAAH or MAGL alone, produced THC-like drug discrimination
What the researchers found
Researchers developed JZL195, a drug that simultaneously blocks both FAAH and MAGL, the enzymes that break down the endocannabinoids anandamide and 2-AG.
JZL195 produced analgesia, reduced movement, and catalepsy, covering a broader range of cannabinoid-like effects than blocking either enzyme alone.
Critically, in drug discrimination tests (where animals indicate whether a drug feels like THC), dual FAAH/MAGL blockade produced THC-like responses, but inhibiting either enzyme alone did not.
This revealed that anandamide and 2-AG pathways have both unique and overlapping functions. Some behaviors (like reduced movement) are regulated mainly by the 2-AG/MAGL pathway, while others (like drug-related responses) require both pathways working together.
Why it matters
This study explained why individual FAAH or MAGL inhibitors produce only a subset of THC-like effects. The finding that both pathways must be disrupted to fully mimic THC has important implications for understanding cannabis pharmacology and developing endocannabinoid-based therapies.
The numbers in context
JZL195 produced analgesia, hypomotility, and catalepsy. Only dual blockade (not FAAH or MAGL inhibition alone) substituted for THC in drug discrimination. All effects were reversed by a CB1 antagonist.
How the study worked
Preclinical study using the novel dual FAAH/MAGL inhibitor JZL195 in mice. Behavioral effects were measured using the tetrad test (analgesia, hypothermia, catalepsy, hypomotility) and drug discrimination. Results were compared to selective FAAH and MAGL inhibitors. CB1 antagonist reversal confirmed cannabinoid receptor involvement.
What this study cannot tell us
Animal study results may not directly translate to humans. The dual inhibitor was novel and its specificity and safety profile were not fully characterized. Long-term effects were not examined.
How to read the evidence
Well-controlled preclinical study with novel pharmacological tools, published in a top-tier journal (PNAS). Mechanistic findings are robust but limited to animal models.
When this study was published
Published in 2009. This was a landmark study in endocannabinoid pharmacology that shaped subsequent research on selective versus dual enzyme inhibition strategies.
The bigger picture
This study helped resolve a puzzle in endocannabinoid pharmacology: why boosting a single endocannabinoid does not reproduce all the effects of THC. The answer is that the two main endocannabinoid pathways have both distinct and cooperative roles.
Questions still open
- Could dual FAAH/MAGL inhibitors produce dependence similar to THC? Does the cooperative effect mean single-enzyme inhibitors are safer because they do not produce the full cannabinoid spectrum? How do these pathways interact at the synaptic level?
Common questions
What are FAAH and MAGL?
Does this mean single-enzyme inhibitors are safer than THC?
Read the original research
Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.
Proceedings of the National Academy of Sciences of the United States of America, 106(48), 20270-5
Citation
Long, Jonathan Z; Nomura, Daniel K; Vann, Robert E; Walentiny, D Matthew; Booker, Lamont; Jin, Xin; Burston, James J; Sim-Selley, Laura J; Lichtman, Aron H; Wiley, Jenny L; Cravatt, Benjamin F. (2009). Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo.. Proceedings of the National Academy of Sciences of the United States of America, 106(48), 20270-5. https://doi.org/10.1073/pnas.0909411106
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