THCV Increased Brain Responses to Both Rewarding and Unpleasant Food Stimuli | Research

The takeaway

A single 10mg dose of tetrahydrocannabivarin (THCV), a neutral CB1 antagonist from cannabis, increased brain reward and aversion responses to food stimuli without altering subjective ratings.

Read this if you want to understand how different cannabis compounds affect appetite and food reward in the brain.

First human study: THCV enhanced both reward and aversion brain responses to food

What the researchers found

Twenty healthy volunteers received either 10mg THCV or placebo in a double-blind crossover design. While subjective ratings of pleasantness, intensity, and wanting for food stimuli did not differ between conditions, brain imaging revealed significant differences.

THCV increased neural responses to chocolate-related stimuli (rewarding) in the midbrain, anterior cingulate cortex, caudate, and putamen. It also increased responses to aversive food stimuli (moldy strawberries/unpleasant taste) in the amygdala, insula, mid-orbitofrontal cortex, caudate, and putamen.

This pattern differs from rimonabant (a CB1 inverse agonist withdrawn for causing depression), which diminished reward responses and increased aversion. THCV's profile of enhancing both reward and aversion responses suggests it could reduce overeating without the depressive side effects that plagued rimonabant.

Why it matters

Rimonabant, the first CB1 antagonist for obesity, was withdrawn due to psychiatric side effects including depression and suicidality. THCV is a neutral CB1 antagonist (not an inverse agonist like rimonabant) and shows a different neural profile that might reduce appetite without causing depression, offering a potentially safer approach to cannabinoid-based obesity treatment.

The numbers in context

20 volunteers, single 10mg dose, double-blind crossover. THCV increased reward responses in midbrain, ACC, caudate, putamen. Increased aversion responses in amygdala, insula, OFC, caudate, putamen. No subjective rating differences.

How the study worked

Within-subject, double-blind, placebo-controlled design with 20 healthy volunteers. Each participant received 10mg THCV and placebo on separate occasions in randomized order. fMRI measured neural responses to rewarding stimuli (sight/flavor of chocolate) and aversive stimuli (picture of moldy strawberries/unpleasant strawberry taste).

What this study cannot tell us

Only a single dose was tested in 20 healthy volunteers. The study measured neural responses, not actual eating behavior or weight loss. Long-term effects are unknown. The lack of subjective rating differences, despite brain activation changes, raises questions about the functional significance of the findings.

How to read the evidence

This is a well-designed double-blind crossover RCT, but with only 20 participants and a single dose, providing moderate preliminary evidence.

When this study was published

Published in 2014. THCV research has continued but clinical development for obesity remains early-stage.

The bigger picture

The distinction between neutral antagonists and inverse agonists at CB1 receptors has important clinical implications. This is the first human study demonstrating that THCV, a natural cannabis compound, modulates food reward and aversion neurocircuitry differently from rimonabant, supporting its potential as a safer anti-obesity agent.

Questions still open

Would chronic THCV administration reduce food intake and body weight? Does the increased reward response to food contradict an anti-obesity effect? How does THCV affect actual eating behavior over time?

Common questions

What is THCV?

Tetrahydrocannabivarin is a naturally occurring cannabinoid found in cannabis that acts as a neutral CB1 receptor antagonist. Unlike THC, it does not produce intoxication. Unlike rimonabant (which blocks and suppresses CB1 activity), THCV blocks without suppressing, a distinction that may reduce psychiatric side effects.

Why was rimonabant withdrawn?

Rimonabant (Acomplia) was a CB1 inverse agonist approved in Europe for obesity. It was withdrawn in 2008 after causing serious psychiatric side effects including depression, anxiety, and suicidal ideation. The inverse agonist mechanism appears to have suppressed reward processing too broadly.

Read the original research

Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers.

The international journal of neuropsychopharmacology, 18(6)

View on PubMed ↗Publisher’s paper ↗

Citation

Tudge, Luke; Williams, Clare; Cowen, Philip J; McCabe, Ciara. (2014). Neural effects of cannabinoid CB1 neutral antagonist tetrahydrocannabivarin on food reward and aversion in healthy volunteers.. The international journal of neuropsychopharmacology, 18(6). https://doi.org/10.1093/ijnp/pyu094