Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice.
Kristen R Trexler, Sara R Nass, Molly S Crowe, Joshua D Gross, Margaret S Jones, Austin W McKitrick, David P Siderovski, Steven G Kinsey
Drug and Alcohol Dependence October 1, 2018 DOI: 10.1016/j.drugalcdep.2018.05.029 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | C57BL/6J mice |
| Interventions | JWH-018 rimonabant JZL184 |
| Dose | THC 1, 10 or 50 mg/kg, s.c.; JWH-018 1 mg/kg, s.c.; rimonabant 3 mg/kg, i.p. |
| Duration | 6 days of repeated administration; spontaneous withdrawal assessed after 24-48 h abstinence |
| Measures | plasma corticosterone, marble burying test, tail suspension test, somatic withdrawal signs |
| Topics | Cannabis |
| Keywords | Cannabinoid withdrawal Cannabis use disorder Drug dependence Stress |
| Key points | Precipitated withdrawal from THC or JWH-018 increased plasma corticosterone, suppressed marble burying, increased struggling in the tail suspension test, and elicited somatic withdrawal behaviors. JZL184 attenuated somatic precipitated withdrawal but not marble burying or struggling. Spontaneous withdrawal after 24-48 hours induced paw tremors, head twitches, and increased struggling, which JZL184 or THC attenuated. The authors argue that THC withdrawal is multifaceted, both eliciting and suppressing behaviors in these tests. |
Abstract
A subset of cannabis users develop some degree of Cannabis Use Disorder (CUD). Although behavioral therapy has some success in treating CUD, many users relapse, often citing altered sleep, mood, and irritability. Preclinical animal tests of cannabinoid withdrawal focus primarily on somatic-related behaviors precipitated by a cannabinoid receptor antagonist. The goal of the present study was to develop novel cannabinoid withdrawal assays that are either antagonist-precipitated or spontaneously induced by abstinence. C57BL/6 J mice were repeatedly administered the phytocannabinoid Δ9-tetrahydrocannabinol (THC; 1, 10 or 50 mg/kg, s.c.), the synthetic cannabinoid receptor agonist JWH-018 (1 mg/kg, s.c.), or vehicle (1:1:18 parts ethanol:Kolliphor EL:saline, s.c.) for 6 days. Withdrawal was precipitated with the cannabinoid receptor inverse agonist rimonabant (3 mg/kg, i.p.) or elicited via abstinence (i.e., spontaneous withdrawal), and putative stress-related behavior was scored. Classic somatic signs of cannabinoid withdrawal were also quantified. Precipitated THC withdrawal significantly increased plasma corticosterone. Precipitated withdrawal from either THC or JWH-018 suppressed marble burying, increased struggling in the tail suspension test, and elicited somatic withdrawal behaviors. The monoacylglycerol lipase inhibitor JZL184 attenuated somatic precipitated withdrawal but had no effect on marble burying or struggling. Spontaneous THC or JWH-018 withdrawal-induced paw tremors, head twitches, and struggled in the tail suspension test after 24-48 h abstinence. JZL184 or THC attenuated these spontaneous withdrawal-induced behaviors. Outcomes from tail suspension and marble burying tests reveal that THC withdrawal is multifaceted, eliciting and suppressing behaviors in these tests, in addition to inducing well-documented somatic signs of withdrawal.
Comparable studies
Other preclinical and animal studies on cannabis, most cited first.
Citations in the library
Cited by 7
- Tolerance, physical dependence, and Δ9-THC-like interoceptive effects of cannabinol in mice. Drug and Alcohol Dependence September 1, 2026
- Cannabinoid use generalizes stress responses: involvement of astrocyte plasticity and activation of matrix metalloproteinases in the nucleus accumbens core. Molecular Psychiatry June 11, 2026
- Repeated Tetrahydrocannabinol Injections Induce Tolerance but Do Not Disrupt Ongoing Behaviour Upon Withdrawal in Male and Female Rats With Inflammatory Pain. European Journal of Pain May 1, 2026
- Tolerance but No Spontaneous Withdrawal Following Repeated THC Injections in Male and Female Rats Cannabis and Cannabinoid Research December 1, 2025
- Cannabinoid use generalizes stress responses by altering the astrocyte plasticity through extracellular matrix signaling in the nucleus accumbens core. Research Square August 21, 2025
and 2 more in the library
Cites 8
- Repeated Exposure to the “Spice” Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats Frontiers in Psychiatry February 27, 2018
- Persistent inhibitory circuit defects and disrupted social behaviour following in utero exogenous cannabinoid exposure. Molecular Psychiatry January 2017
- Differential drug-drug interactions of the synthetic Cannabinoids JWH-018 and JWH-073: implications for drug abuse liability and pain therapy. Journal of Pharmacology and Experimental Therapeutics September 2013
- Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay. Pharmacology, Biochemistry, and Behavior March 2011
- JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. British Journal of Pharmacology June 2010
and 3 more in the library