Mice genetically lacking the enzyme FAAH, which breaks down the endocannabinoid anandamide, showed enhanced sensitivity to the subjective-like effects of anandamide and a MAGL inhibitor in a THC discrimination task.
Readers interested in the neuroscience of how natural cannabinoids and THC produce their effects.
Anandamide fully mimicked THC only when its breakdown enzyme was absent
What the researchers found
Researchers compared mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for breaking down anandamide, with normal mice in a drug discrimination test using THC.
Both groups learned to discriminate THC at similar rates and showed similar THC dose-response curves. However, anandamide fully substituted for THC only in FAAH knockout mice, not in normal mice. A metabolically stable anandamide analog worked in both groups but was more potent in knockouts.
The MAGL inhibitor JZL184, which boosts 2-AG levels, produced near-full THC-like effects in normal mice and full substitution in FAAH knockouts. Combined FAAH and MAGL inhibition produced similar effects in both groups.
Why it matters
Understanding how the endocannabinoid system's own signaling molecules produce THC-like effects informs research on both cannabis pharmacology and potential therapeutic approaches that target endocannabinoid metabolism rather than directly activating cannabinoid receptors.
The numbers in context
THC training dose: 5.6 mg/kg. Anandamide fully substituted for THC in FAAH knockouts but not wildtypes. JZL184 produced near-full substitution in wildtypes and full substitution in knockouts. Brain anandamide was elevated in FAAH knockouts. JZL184 increased 2-AG levels equally in both genotypes.
How the study worked
FAAH knockout and wildtype mice were trained to discriminate THC (5.6 mg/kg) from vehicle in a two-lever operant task. Various cannabinoid compounds were tested for substitution. Brain endocannabinoid levels were quantified. The CB1 antagonist rimonabant was used to confirm receptor involvement.
What this study cannot tell us
Drug discrimination in mice does not directly translate to human subjective experiences. Genetically engineered mice may have developmental compensations that differ from pharmacological enzyme inhibition. The study examined acute effects and may not reflect chronic exposure patterns.
How to read the evidence
This is an animal study using genetically modified mice. It provides mechanistic insights about endocannabinoid pharmacology that require validation in other contexts.
When this study was published
Published in 2015. Research on FAAH inhibitors as potential therapeutics has continued with some clinical trials in humans.
The bigger picture
This study illustrates that THC's subjective effects can be mimicked by boosting the brain's own cannabinoids. The finding that FAAH knockout mice respond normally to THC despite having chronically elevated anandamide suggests that baseline endocannabinoid tone does not alter THC sensitivity, a nuance relevant to developing FAAH inhibitor therapeutics.
Questions still open
- Would FAAH inhibitors produce THC-like subjective effects in humans? How does chronic elevation of one endocannabinoid affect sensitivity to changes in the other?
Common questions
Does this mean anandamide normally produces a high like THC?
Why would researchers want to boost endocannabinoids instead of just using THC?
Read the original research
Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.
Neuropharmacology, 93, 237-42
Citation
Walentiny, D Matthew; Vann, Robert E; Wiley, Jenny L. (2015). Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice.. Neuropharmacology, 93, 237-42. https://doi.org/10.1016/j.neuropharm.2015.02.004
Explore the wider topic
- How THC Affects Your Amygdala: The Brain's Threat Detector and Cannabis
- The Anandamide Connection: Your Body's Natural Bliss Molecule
- How Long for Cannabinoid Receptors to Return to Normal
- Physical vs Psychological Cannabis Dependence: What Science Actually Shows
- Cannabis and the Developing Brain: What Every Teenager (and Parent) Should Know
- The Gap Between Cannabis Perception and Science: Why What We Believe Outpaces What We Know
- Cannabis Use Disorder: Am I Addicted? Self-Assessment Guide
- Why Can't I Enjoy Anything Without Weed? The Science Behind It
- Cross-Addiction After Quitting Weed: When One Habit Replaces Another
- Dopamine Recovery After Quitting Weed: What the Science Says
- The Endocannabinoid System Explained Simply: What It Does and Why It Matters
- Your Endocannabinoid System Explained: Why Withdrawal Happens
- Is Weed Addictive? What the Research Actually Shows
- Is Cannabis Addictive? What the DSM-5 and Brain Science Say
- Your Nervous System After Quitting Weed: Fight or Flight
- Quitting Weed and Alcohol Together: What to Know About Dual Cessation
- Is Rehab Necessary for Weed? An Honest Assessment
- Signs You May Have Cannabis Use Disorder: An Honest Self-Assessment
- Using Weed Under 18: What It Does to Your Developing Brain
- What THC Does to Your Brain: Why Withdrawal Happens
- THC and Your Prefrontal Cortex: What Cannabis Does to Your Decision-Making Brain
- Weed, Cortisol, and Stress: What Cannabis Does to Your Stress Hormones
- Weed and Memory: What the Science Says About THC and Your Hippocampus
- Weed and Motivation: Is Amotivational Syndrome Real?
- Weed and Your Nervous System: What THC Actually Does to Your Brain and Body
- How Weed Rewires Your Reward System (And How to Reset It)
- Weed Vape Pen Addiction: Why Vaping Makes It Harder to Quit