THC withdrawal in mice disrupts dopamine, sleep, and behavior, especially in males | Research

The takeaway

Mice undergoing spontaneous THC withdrawal showed altered striatal dopamine release, sleep disturbances matching human withdrawal patterns, and behavioral changes, with effects more consistently observed in males.

Addiction researchers, sleep scientists, and clinicians treating cannabis withdrawal.

Withdrawal effects more consistent in males than females

What the researchers found

THC withdrawal produced altered striatal dopamine release, sleep disturbances that mimic clinical observations (disrupted sleep architecture), and affect-related behavioral changes. These effects were more consistently observed in male mice than in females, suggesting sex-specific vulnerability to withdrawal.

Why it matters

Sleep disturbances are a primary driver of cannabis relapse in humans. This mouse model replicates key features of human THC withdrawal and provides a platform for studying the neural mechanisms involved.

The numbers in context

Dopamine release measured in multiple striatal subregions during early and late abstinence. Sleep architecture assessed before, during, and after THC treatment. Behavioral measures modeled human withdrawal symptoms.

How the study worked

Mice received a THC treatment regimen known to produce tolerance. During early and late abstinence, researchers measured electrically evoked dopamine release in brain slices, long-term polysomnographic sleep recordings, and withdrawal-related behaviors.

What this study cannot tell us

Mouse model may not fully replicate human withdrawal. Spontaneous withdrawal paradigm better mimics human cessation but produces subtler effects than precipitated withdrawal. Sex differences in mice may not translate directly to humans.

How to read the evidence

Well-designed animal study with multiple objective measures (dopamine, sleep, behavior), but mouse model has inherent limitations.

When this study was published

Published in 2022.

The bigger picture

The sex differences in withdrawal severity align with emerging human data suggesting men and women experience cannabis withdrawal differently, which has implications for personalized treatment approaches.

Questions still open

What drives the sex difference in withdrawal severity? Could targeting striatal dopamine specifically help manage withdrawal-related sleep disturbances?

Common questions

Does THC withdrawal affect sleep?

Yes. In this mouse study, THC withdrawal disrupted sleep architecture in patterns that mirror clinical observations in humans, where sleep disturbance is one of the most common withdrawal symptoms.

Do males and females experience THC withdrawal differently?

In mice, withdrawal-related changes in dopamine, sleep, and behavior were more consistently observed in males, suggesting sex-specific differences in withdrawal vulnerability.

Read the original research

Changes in striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence in male and female mice.

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(8), 1537-1549

View on PubMed ↗Publisher’s paper ↗

Citation

Kesner, Andrew J; Mateo, Yolanda; Abrahao, Karina P; Ramos-Maciel, Stephanie; Pava, Matthew J; Gracias, Alexa L; Paulsen, Riley T; Carlson, Hartley B; Lovinger, David M. (2022). Changes in striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence in male and female mice.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 47(8), 1537-1549. https://doi.org/10.1038/s41386-022-01326-0