Boosting the Body's Own Cannabinoids Reduced Anticipatory Nausea in Rats | Research

The takeaway

A drug that blocks the breakdown of natural endocannabinoids suppressed anticipatory nausea in rats through CB1 receptor activation.

Read this if you want to understand how the body's own cannabinoid system regulates nausea.

CB1-mediated: blocking CB1 receptors completely reversed the anti-nausea effect

What the researchers found

Rats that received JZL195, a dual inhibitor of the enzymes FAAH and MAGL, showed significantly less anticipatory nausea behavior (contextually elicited gaping) compared to untreated animals. The effect was mediated through CB1 receptors, as blocking CB1 with an antagonist reversed the anti-nausea effect.

When JZL195 was combined with anandamide or 2-AG (the body's own cannabinoid molecules), the suppression of nausea was amplified beyond what JZL195 achieved alone. Anandamide on its own also reduced nausea behavior, but 2-AG alone did not.

Brain analysis showed that JZL195 elevated levels of anandamide and related fatty acid molecules. The primary mechanism appeared to be FAAH inhibition, though MAGL inhibition also contributed.

Why it matters

Anticipatory nausea is a significant problem for chemotherapy patients and others who develop conditioned nausea responses. Current anti-nausea medications are largely ineffective against anticipatory nausea. This research suggests that enhancing the body's existing endocannabinoid system, rather than directly activating cannabinoid receptors with external compounds, could offer a targeted approach to this specific type of nausea.

The numbers in context

JZL195 was administered at 10 mg/kg. AEA was given at 5.0 mg/kg and 2-AG at 1.25 mg/kg. The anti-nausea effect was CB1-mediated (reversed by SR141716) but not CB2-mediated (not reversed by AM630).

How the study worked

Researchers used a rat model of anticipatory nausea in which animals were conditioned to associate a specific context with lithium chloride-induced illness. After four conditioning sessions, rats received various drug combinations before being placed back in the illness-paired context. Gaping behavior (an established measure of nausea in rats) was recorded. CB1 and CB2 receptor antagonists were used to determine which receptor pathway mediated the effects. Brain tissue was analyzed for endocannabinoid levels.

What this study cannot tell us

This was an animal study using rats, and gaping behavior is a proxy measure for nausea that may not fully translate to the human experience. The drug doses and combinations used may not be directly applicable to human pharmacology. JZL195 is a research compound not available for clinical use.

How to read the evidence

This is a preclinical animal study using a rat model. While well-controlled, findings in rats require human trials to confirm relevance.

When this study was published

Published in 2014. FAAH inhibitor research has continued, though clinical translation has been challenging.

The bigger picture

This study adds to a growing body of research exploring whether boosting the body's own cannabinoid system could treat nausea more effectively than traditional approaches. The endocannabinoid system plays a role in regulating nausea and vomiting circuits, and FAAH inhibitors represent a class of drugs that enhance these natural pathways without the psychoactive effects associated with THC.

Questions still open

Would FAAH inhibitors reduce anticipatory nausea in chemotherapy patients? Could endocannabinoid-enhancing drugs work alongside existing anti-nausea medications? What is the optimal balance between FAAH and MAGL inhibition for nausea control?

Common questions

What is anticipatory nausea?

It is nausea triggered by environmental cues associated with previous episodes of illness, such as the sights and smells of a chemotherapy clinic. It develops through classical conditioning and is resistant to standard anti-nausea drugs.

How does this differ from using cannabis for nausea?

Instead of adding external cannabinoids like THC, this approach boosts the body's own endocannabinoids by preventing their breakdown. This may produce more targeted anti-nausea effects with fewer psychoactive side effects.

Read the original research

Attenuation of anticipatory nausea in a rat model of contextually elicited conditioned gaping by enhancement of the endocannabinoid system.

Psychopharmacology, 231(3), 603-12

View on PubMed ↗Publisher’s paper ↗

Citation

Limebeer, Cheryl L; Abdullah, Rehab A; Rock, Erin M; Imhof, Elizabeth; Wang, Kai; Lichtman, Aron H; Parker, Linda A. (2014). Attenuation of anticipatory nausea in a rat model of contextually elicited conditioned gaping by enhancement of the endocannabinoid system.. Psychopharmacology, 231(3), 603-12. https://doi.org/10.1007/s00213-013-3282-7