THC Withdrawal Caused Anxiety-Like Behavior in Mice for the First Time | Research

The takeaway

Mice chronically treated with THC showed anxiety-like behavior during precipitated withdrawal on the elevated plus-maze, the first demonstration that cannabinoid withdrawal produces measurable anxiety in an animal model.

Read this if you experience anxiety when you stop using cannabis and want to know the science behind it.

First demonstration of anxiety-like behavior during cannabinoid withdrawal in mice

What the researchers found

Male mice received THC (10 mg/kg) daily for 10 days. Four hours after the last dose, the CB1 antagonist SR141716 was administered to precipitate withdrawal, and mice were tested on the elevated plus-maze 30 minutes later.

In vehicle-treated mice, SR141716 had no significant effect on behavior.

In THC-treated mice, SR141716 produced a significant reduction in open arm exploration, a well-validated measure of anxiety-like behavior. At the highest dose (3.0 mg/kg), SR141716 significantly reduced percentage of open arm entries, percentage of open arm time, and absolute time in open arms.

Closed arm entries and total arm entries were not affected, confirming that the reduced open arm exploration reflected anxiety rather than altered motor activity.

This was the first evidence that cannabinoid withdrawal produces anxiety-like effects in mice.

Why it matters

Anxiety is one of the most commonly reported symptoms of cannabis withdrawal in humans. Having an animal model of withdrawal-induced anxiety allows researchers to investigate the neural mechanisms and test potential treatments.

The numbers in context

THC: 10 mg/kg daily x 10 days. SR141716: 0.3, 1.0, 3.0 mg/kg. At 3.0 mg/kg: significant reduction in % open arm entries, % open arm time, and absolute open arm time. No changes in closed or total arm entries (no motor effect).

How the study worked

Male ICR mice received daily THC (10 mg/kg) or vehicle for 10 days. SR141716 (0.3, 1.0, or 3.0 mg/kg) precipitated withdrawal 4 hours after the last dose. The elevated plus-maze was administered 30 minutes post-SR141716 for 5 minutes.

What this study cannot tell us

Precipitated rather than spontaneous withdrawal. Single mouse strain and sex (male ICR mice). The elevated plus-maze measures a specific aspect of anxiety that may not fully represent the human experience. SR141716 doses may be clinically irrelevant.

How to read the evidence

Preclinical study establishing a novel animal model. Well-controlled but limited to precipitated withdrawal in male mice of one strain.

When this study was published

Published in 2010. Cannabis withdrawal anxiety has since been extensively studied in both animal models and human populations.

The bigger picture

Human cannabis withdrawal commonly includes anxiety, irritability, and sleep disturbance. This mouse model specifically captured the anxiety component, complementing earlier models that measured hyperlocomotion and paw tremors (see RTHC-00359).

Questions still open

Does this anxiety resolve over time without intervention? Would anxiolytic medications reduce cannabinoid withdrawal anxiety? Do female mice show the same or different withdrawal anxiety patterns?

Common questions

Do humans experience anxiety during cannabis withdrawal?

Yes, anxiety is one of the most commonly reported symptoms of human cannabis withdrawal, along with irritability, sleep problems, and decreased appetite. This mouse study provided the first animal model demonstrating this symptom.

What is the elevated plus-maze?

It is a cross-shaped platform with two open (exposed) and two enclosed arms. Anxious animals spend less time in the open arms. It is a standard test for anxiety-like behavior in rodents and is used to evaluate potential anxiety treatments.

Read the original research

Anxiety-like effects of SR141716-precipitated delta9-tetrahydrocannabinol withdrawal in mice in the elevated plus-maze.

Neuroscience letters, 475(3), 165-8

View on PubMed ↗Publisher’s paper ↗

Citation

Huang, Peng; Liu-Chen, Lee-Yuan; Kirby, Lynn G. (2010). Anxiety-like effects of SR141716-precipitated delta9-tetrahydrocannabinol withdrawal in mice in the elevated plus-maze.. Neuroscience letters, 475(3), 165-8. https://doi.org/10.1016/j.neulet.2010.03.071