Nausea selectively increased the endocannabinoid 2-AG (not anandamide) in the brain's visceral insular cortex, and boosting 2-AG in this region reduced nausea by dampening neural activity.
Read this if you want to understand exactly how the endocannabinoid system suppresses nausea at the brain level.
2-AG, not anandamide, was the specific endocannabinoid elevated during nausea in the brain's nausea-processing center.
What the researchers found
Researchers identified the precise brain mechanism by which the endocannabinoid system suppresses nausea. During episodes of nausea, the brain region called the visceral insular cortex (VIC) showed selective increases in 2-AG, one of the two main endocannabinoids. Anandamide, the other main endocannabinoid, was not affected.
Blocking the enzyme that breaks down 2-AG (MAGL) in the VIC reduced nausea-related behavior through CB1 receptors. Blocking the enzyme that breaks down anandamide (FAAH) had no effect on nausea.
The mechanism of action was revealed by measuring neural activation: MAGL inhibition reduced the number of activated neurons (Fos-positive cells) in the VIC during nausea, showing that 2-AG suppresses nausea by reducing neural activity in this brain region.
Why it matters
This study precisely identifies where and how the brain's natural anti-nausea system works. Understanding that 2-AG (not anandamide) in the visceral insular cortex is the key molecule could enable development of nausea treatments that are more targeted than whole-plant cannabis, potentially with fewer side effects.
The numbers in context
2-AG was selectively elevated in the VIC during nausea episodes. MAGL inhibition increased 2-AG and reduced nausea via CB1 receptors. FAAH inhibition did not affect anandamide or nausea. MAGL inhibition reduced Fos immunoreactivity in the VIC.
How the study worked
Rat study using conditioned gaping (a validated model of nausea behavior) induced by lithium chloride. Researchers performed local infusions of enzyme inhibitors into the visceral insular cortex, measured endocannabinoid levels during nausea using mass spectrometry, and quantified neural activation using c-Fos immunoreactivity. CB1 receptor involvement was confirmed with the antagonist AM251.
What this study cannot tell us
Rat nausea models may not fully capture human nausea experience. Local brain infusions are precise but do not replicate how cannabis reaches the brain in real use. The study focused on one brain region, but nausea involves a network of brain areas. The results apply to acute, toxin-induced nausea and may not extend to all causes of nausea.
How to read the evidence
Moderate evidence from a thorough animal study combining pharmacological, biochemical, and neuroanatomical approaches to build a consistent mechanistic picture.
When this study was published
Published in 2016. MAGL inhibitors for nausea continue to be explored as potential therapeutics.
The bigger picture
Cannabis has been used for nausea for centuries, but this study pinpoints the exact molecular and anatomical basis: 2-AG in the visceral insular cortex. This level of precision opens the door to targeted therapeutics that could help chemotherapy patients and others with severe nausea without the full spectrum of cannabis effects.
Questions still open
- Would systemic MAGL inhibitors reduce nausea in humans? Does chronic cannabis use desensitize this 2-AG-based anti-nausea system, potentially explaining cannabinoid hyperemesis syndrome? Could 2-AG-targeted therapies work for chemotherapy-induced nausea?
Common questions
How does the brain fight nausea naturally?
Why does cannabis help with nausea?
Read the original research
Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.
Neuropharmacology, 102, 92-102
Citation
Sticht, Martin A; Limebeer, Cheryl L; Rafla, Benjamin R; Abdullah, Rehab A; Poklis, Justin L; Ho, Winnie; Niphakis, Micah J; Cravatt, Benjamin F; Sharkey, Keith A; Lichtman, Aron H; Parker, Linda A. (2016). Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex.. Neuropharmacology, 102, 92-102. https://doi.org/10.1016/j.neuropharm.2015.10.039
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