New Tests Revealed THC Withdrawal in Mice Goes Beyond Physical Symptoms
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- THC withdrawal increased stress hormones, suppressed exploratory behavior, and increased despair-like behaviors - symptoms more relevant to human relapse than traditional physical signs.
- Evidence Grade:
- Preliminary - novel animal model development study requiring replication and further validation.
- Study Age:
- Published in 2018.
- Original Title:
- Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.
- Published In:
- Drug and alcohol dependence, 191, 14-24 (2018)
- Authors:
- Trexler, Kristen R(2), Nass, Sara R(3), Crowe, Molly S, Gross, Joshua D, Jones, Margaret S, McKitrick, Austin W, Siderovski, David P, Kinsey, Steven G
- Database ID:
- RTHC-01858
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked 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.
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Cite This Study
https://rethinkthc.com/research/RTHC-01858APA
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
MLA
Trexler, Kristen R, et al. "Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.." Drug and alcohol dependence, 2018. https://doi.org/10.1016/j.drugalcdep.2018.05.029
RethinkTHC
RethinkTHC Research Database. "Novel behavioral assays of spontaneous and precipitated THC ..." RTHC-01858. Retrieved from https://rethinkthc.com/research/trexler-2018-novel-behavioral-assays-of
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.