In mice, blocking the enzyme that breaks down 2-AG worsened hypothermia from both cold exposure and bacterial toxin through CB1 receptors, while blocking the enzyme that breaks down anandamide had no effect on temperature.
Read this if you are interested in how the endocannabinoid system regulates body temperature and why cannabis can make you feel cold.
2-AG pathway involved in temperature regulation; anandamide pathway was not
What the researchers found
Researchers tested how two endocannabinoid-degrading enzymes, MAGL (which breaks down 2-AG) and FAAH (which breaks down anandamide), contribute to body temperature regulation under stress.
Inhibiting MAGL with JZL184 made hypothermia worse in mice challenged with either a bacterial endotoxin (LPS) or cold (4 degrees Celsius) environment. These effects were blocked by a CB1 antagonist but not a CB2 antagonist, confirming a CB1-mediated mechanism.
In contrast, inhibiting FAAH with PF-3845, which raises anandamide levels, had no effect on either type of hypothermia. Neither MAGL nor FAAH inhibition affected normal body temperature, showing these enzymes specifically matter during temperature challenges.
Why it matters
This study reveals that the two main endocannabinoid pathways (2-AG and anandamide) play fundamentally different roles in temperature regulation. Since THC activates the same receptors as 2-AG, this helps explain why cannabis use can affect body temperature.
The numbers in context
LPS caused hypothermia lasting 12+ hours; cold (4 degrees Celsius) caused mild hypothermia resolving within 30 minutes; JZL184 worsened both; PF-3845 had no effect on either; effects blocked by rimonabant (CB1) but not SR144528 (CB2)
How the study worked
Mouse study using MAGL inhibitor (JZL184) and FAAH inhibitor (PF-3845) followed by either LPS injection (2 mg/kg) or cold environment (4 degrees Celsius) challenge. Core body temperature measured over 12 hours. CB1 and CB2 antagonists used to identify receptor mechanisms.
What this study cannot tell us
Mouse study with potential species differences. Used pharmacological inhibitors rather than genetic knockouts for the primary experiments. Acute challenges may not reflect chronic conditions.
How to read the evidence
Well-controlled animal study with clear receptor specificity demonstrated, but limited to mouse models.
When this study was published
Published in 2015. Endocannabinoid enzyme pharmacology has continued to develop.
The bigger picture
The differential roles of 2-AG and anandamide in thermoregulation add to growing evidence that these two endocannabinoids are not interchangeable. This has implications for drug development targeting specific endocannabinoid pathways.
Questions still open
- Does chronic cannabis use alter thermoregulatory responses through 2-AG pathway disruption? Could MAGL inhibitors worsen fever or hypothermia in clinical settings? Do these findings explain the hot-bath relief pattern in cannabinoid hyperemesis syndrome?
Common questions
Why does cannabis sometimes make people feel cold?
What is the difference between 2-AG and anandamide?
Read the original research
Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 364-70
Citation
Nass, Sara R; Long, Jonathan Z; Schlosburg, Joel E; Cravatt, Benjamin F; Lichtman, Aron H; Kinsey, Steven G. (2015). Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge.. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 10(2), 364-70. https://doi.org/10.1007/s11481-015-9593-1
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