A Drug That Blocks 2-AG Breakdown Revealed Hidden Cannabinoid Effects in Mice
Blocking the enzyme that degrades 2-AG (using NAM) unmasked cannabinoid-like effects in mice and provided evidence for cannabinoid receptors beyond CB1 and CB2.
Quick Facts
What This Study Found
Researchers tested N-arachidonyl maleimide (NAM), a potential MAGL inhibitor, for its ability to enhance the effects of the endocannabinoid 2-AG in mice.
NAM unmasked 2-AG activity across a standard battery of cannabinoid tests: reduced locomotion, catalepsy, hypothermia, and pain insensitivity. Without NAM, 2-AG was rapidly degraded before it could produce these effects.
NAM increased 2-AG's potency in biochemical assays but did not affect anandamide (the other major endocannabinoid), confirming selectivity for the MAGL pathway.
A surprise finding emerged: the effects of 2-AG enhanced by NAM were only partially blocked by the CB1 antagonist SR141716A and were only partially reduced in CB1 knockout mice. This provided evidence for the existence of non-CB1, non-CB2 cannabinoid receptors that respond to 2-AG.
Key Numbers
NAM unmasked 2-AG effects across all four tetrad measures. Effects were partially (not fully) blocked by SR141716A and partially reduced in CB1-knockout mice. NAM increased brain 2-AG levels in vitro. NAM enhanced 2-AG potency but not anandamide potency.
How They Did This
Mice received NAM followed by 2-AG or anandamide, and were assessed using the standard cannabinoid tetrad (locomotion, catalepsy, body temperature, pain sensitivity). CB1-knockout mice and the CB1 antagonist SR141716A were used to determine receptor involvement. In vitro assays measured brain 2-AG levels and receptor activation.
Why This Research Matters
This study demonstrated that MAGL inhibition could be a viable therapeutic strategy for enhancing endocannabinoid signaling. The finding of non-CB1/non-CB2 cannabinoid activity also suggested the cannabinoid receptor system is more complex than previously thought.
The Bigger Picture
This study contributed to two important developments: the validation of MAGL inhibition as a therapeutic approach (now in clinical trials) and the growing recognition that the cannabinoid receptor system extends beyond CB1 and CB2 (GPR55 and other receptors have since been identified).
What This Study Doesn't Tell Us
NAM may have off-target effects beyond MAGL inhibition. The partial CB1-dependence of effects complicates interpretation. Mouse endocannabinoid pharmacology may differ from human. Only acute effects were examined.
Questions This Raises
- ?Which non-CB1, non-CB2 receptors mediate the residual 2-AG effects?
- ?Could selective MAGL inhibitors be developed into medications with fewer side effects than direct cannabinoid agonists?
Trust & Context
- Key Stat:
- 2-AG effects only partially blocked by CB1 antagonists, suggesting unknown cannabinoid receptors
- Evidence Grade:
- This is an animal pharmacology study providing mechanistic insights. The findings are preliminary but have been supported by subsequent research identifying additional cannabinoid-responsive receptors.
- Study Age:
- Published in 2008. MAGL inhibitors have since advanced into clinical trials, and several novel cannabinoid-responsive receptors (GPR55, GPR18, GPR119) have been identified.
- Original Title:
- N-arachidonyl maleimide potentiates the pharmacological and biochemical effects of the endocannabinoid 2-arachidonylglycerol through inhibition of monoacylglycerol lipase.
- Published In:
- The Journal of pharmacology and experimental therapeutics, 327(2), 546-53 (2008)
- Authors:
- Burston, James J(4), Sim-Selley, Laura J(6), Harloe, John P, Mahadevan, Anu, Razdan, Raj K, Selley, Dana E, Wiley, Jenny L
- Database ID:
- RTHC-00303
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
What is MAGL?
Monoacylglycerol lipase (MAGL) is the enzyme primarily responsible for breaking down 2-AG, one of the brain's main endocannabinoids. Blocking MAGL allows 2-AG to accumulate and produce stronger effects.
Why does it matter that effects weren't fully blocked by CB1 antagonists?
If 2-AG's effects were entirely through CB1 receptors, blocking CB1 would eliminate them completely. The partial effect suggests 2-AG also acts through other receptors, meaning the cannabinoid system is more complex than the two known receptors.
Read More on RethinkTHC
- THC-amygdala-anxiety-brain
- anandamide-weed-withdrawal
- cannabinoid-receptors-recovery-time
- cannabis-developing-brain-teenagers
- cant-enjoy-anything-without-weed
- dopamine-recovery-after-quitting-weed
- endocannabinoid-system-explained-simply
- endocannabinoid-system-withdrawal
- nervous-system-weed-withdrawal-fight-flight
- teen-weed-use-under-18-effects-brain
- thc-brain-withdrawal
- thc-prefrontal-cortex-brain-effects
- weed-cortisol-stress-hormones
- weed-memory-loss-recovery
- weed-motivation-amotivational-syndrome
- weed-nervous-system-effects
- weed-reward-system-brain
Cite This Study
https://rethinkthc.com/research/RTHC-00303APA
Burston, James J; Sim-Selley, Laura J; Harloe, John P; Mahadevan, Anu; Razdan, Raj K; Selley, Dana E; Wiley, Jenny L. (2008). N-arachidonyl maleimide potentiates the pharmacological and biochemical effects of the endocannabinoid 2-arachidonylglycerol through inhibition of monoacylglycerol lipase.. The Journal of pharmacology and experimental therapeutics, 327(2), 546-53. https://doi.org/10.1124/jpet.108.141382
MLA
Burston, James J, et al. "N-arachidonyl maleimide potentiates the pharmacological and biochemical effects of the endocannabinoid 2-arachidonylglycerol through inhibition of monoacylglycerol lipase.." The Journal of pharmacology and experimental therapeutics, 2008. https://doi.org/10.1124/jpet.108.141382
RethinkTHC
RethinkTHC Research Database. "N-arachidonyl maleimide potentiates the pharmacological and ..." RTHC-00303. Retrieved from https://rethinkthc.com/research/burston-2008-narachidonyl-maleimide-potentiates-the
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.