Boosting Both Endocannabinoids Together Was Needed to Mimic THC's Subjective Effects in Rats | Research

The takeaway

Neither anandamide nor 2-AG alone could fully replicate THC's discriminative stimulus effects in rats, but simultaneously elevating both endocannabinoids approached full substitution.

Read this if you want to understand which natural brain chemicals produce the cannabis-like experience.

Both endocannabinoids (anandamide + 2-AG) needed together to replicate THC's effects

What the researchers found

Mice and rats trained to discriminate THC from vehicle were tested with various endocannabinoid-enhancing strategies. Directly administering anandamide or 2-AG did not substitute for THC, even when combined with enzyme inhibitors. However, the FAAH inhibitor PF3845 enhanced anandamide's ability to produce THC-like effects in mice, and the MAGL inhibitor JZL184 increased THC-like responding on its own.

In rats, neither FAAH inhibition (URB597) nor MAGL inhibition (JZL184) alone produced significant THC-like effects. But combining both inhibitors approached full substitution for THC, suggesting that simultaneous elevation of both anandamide and 2-AG is necessary to replicate THC's subjective effects.

Species differences were notable: what worked in mice did not always work in rats, highlighting the importance of species selection in preclinical cannabinoid research.

Why it matters

Understanding which endocannabinoids contribute to THC's subjective effects helps explain why cannabis produces the specific psychoactive experience it does. The finding that both endocannabinoids are needed to replicate THC's effects reveals the complexity of the endocannabinoid system.

The numbers in context

THC discrimination doses: 5.6 mg/kg (mice), 3 mg/kg (rats). FAAH inhibitor PF3845 enhanced anandamide substitution. MAGL inhibitor JZL184 increased THC-like responding. Combined FAAH+MAGL inhibition approached full substitution in rats.

How the study worked

Mice and rats were trained in a drug discrimination paradigm to distinguish THC from vehicle. Various combinations of exogenous endocannabinoids and enzyme inhibitors (FAAH and MAGL) were tested for their ability to substitute for THC. Brain endocannabinoid levels were measured after some treatments.

What this study cannot tell us

Drug discrimination studies measure whether animals perceive a drug as "THC-like" but cannot directly measure subjective experience. Species differences between mice and rats complicate interpretation. The doses and routes of administration may not translate to human use.

How to read the evidence

This is a preclinical pharmacology study providing mechanistic insight into endocannabinoid contributions to THC's effects.

When this study was published

Published in 2014. Drug discrimination remains an important tool for studying cannabinoid pharmacology.

The bigger picture

THC activates CB1 receptors directly, but the subjective experience it produces depends on how it mimics or differs from natural endocannabinoid signaling. This study shows that replicating THC's full subjective profile requires elevating both major endocannabinoids simultaneously.

Questions still open

Would dual enzyme inhibition produce cannabis-like subjective effects in humans? Are there other endocannabinoid system components needed beyond anandamide and 2-AG? Could this information help develop non-psychoactive therapeutic cannabinoids?

Common questions

What is drug discrimination?

Animals are trained to press one lever when they receive a drug (THC) and a different lever when they receive a placebo. Then researchers test whether other drugs produce the same internal sensation as THC, measured by which lever the animal chooses.

Why does this require both endocannabinoids?

Anandamide and 2-AG act through overlapping but distinct mechanisms. THC broadly activates CB1 receptors in a way that apparently mimics the combined effect of both endocannabinoids acting together, rather than either one alone.

Read the original research

Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.

European journal of pharmacology, 737, 97-105

View on PubMed ↗Publisher’s paper ↗

Citation

Wiley, Jenny L; Walentiny, D Matthew; Wright, M Jerry; Beardsley, Patrick M; Burston, James J; Poklis, Justin L; Lichtman, Aron H; Vann, Robert E. (2014). Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents.. European journal of pharmacology, 737, 97-105. https://doi.org/10.1016/j.ejphar.2014.05.013