New Tests Revealed THC Withdrawal in Mice Goes Beyond Physical Symptoms | Research

The takeaway

Novel behavioral tests showed that THC withdrawal in mice includes stress-related and mood-like symptoms beyond the classic physical signs, and boosting endocannabinoid levels partially alleviated withdrawal.

Addiction researchers, pharmacotherapy developers, preclinical scientists.

THC withdrawal increased stress hormones, suppressed exploratory behavior, and increased despair-like behaviors - symptoms more relevant to human relapse than traditional physical signs.

What the researchers found

THC withdrawal (both precipitated and spontaneous) caused increased plasma corticosterone, suppressed marble burying (suggesting anxiety/anhedonia), increased struggling in the tail suspension test (despair-like behavior), and classic somatic withdrawal signs. The MAGL inhibitor JZL184 attenuated somatic withdrawal and spontaneous withdrawal behaviors, and THC itself reduced spontaneous withdrawal.

Why it matters

Human cannabis withdrawal involves mood changes, anxiety, and irritability - symptoms poorly captured by traditional animal models focused on physical signs. These new tests better model the symptoms that drive human relapse, enabling better preclinical testing of treatments.

The numbers in context

THC doses: 1, 10, or 50 mg/kg for 6 days. Spontaneous withdrawal signs appeared at 24-48 hours. JZL184 attenuated somatic but not mood-related withdrawal signs.

How the study worked

Mice received THC (1-50 mg/kg) or JWH-018 for 6 days. Withdrawal was either precipitated with rimonabant or assessed spontaneously after 24-48 hours of abstinence. Novel behavioral assays (marble burying, tail suspension) were used alongside classic somatic sign counts.

What this study cannot tell us

Mouse models may not fully reflect human withdrawal experience. Novel behavioral assays need further validation. Only male C57BL/6J mice were studied. THC doses were relatively high.

How to read the evidence

Preliminary - novel animal model development study requiring replication and further validation.

When this study was published

Published in 2018.

The bigger picture

Understanding the full spectrum of cannabis withdrawal - including emotional and stress-related components - is crucial for developing treatments that address why people relapse. Physical withdrawal management alone may not be sufficient.

Questions still open

Why did JZL184 reduce physical but not mood-related withdrawal signs? Could combining endocannabinoid-boosting drugs with anxiolytics address the full withdrawal spectrum? Do these mood-related withdrawal effects predict relapse?

Common questions

What does THC withdrawal look like?

In mice, this study showed THC withdrawal goes beyond physical symptoms (tremors, head twitches) to include elevated stress hormones, reduced exploratory behavior, and despair-like responses. These more closely resemble the mood changes, anxiety, and irritability reported by humans during cannabis withdrawal.

Can endocannabinoid-boosting drugs help with cannabis withdrawal?

JZL184, which boosts the natural endocannabinoid 2-AG, reduced physical withdrawal signs in this study. However, it did not fully address mood-related symptoms, suggesting withdrawal treatment may need to target multiple systems.

Read the original research

Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.

Drug and alcohol dependence, 191, 14-24

View on PubMed ↗Publisher’s paper ↗

Citation

Trexler, Kristen R; Nass, Sara R; Crowe, Molly S; Gross, Joshua D; Jones, Margaret S; McKitrick, Austin W; Siderovski, David P; Kinsey, Steven G. (2018). Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.. Drug and alcohol dependence, 191, 14-24. https://doi.org/10.1016/j.drugalcdep.2018.05.029