Prevention of Cannabinoid Withdrawal Syndrome by Lithium: Involvement of Oxytocinergic Neuronal Activation
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Cannabis (i.e., marijuana and cannabinoids) is the most commonly used illicit drug in developed countries, and the lifetime prevalence of marijuana dependence is the highest of all illicit drugs in the United States. To provide clues for finding effective pharmacological treatment for cannabis-dependent patients, we examined the effects and possible mechanism of lithium administration on the cannabinoid withdrawal syndrome in rats. A systemic injection of the mood stabilizer lithium, at serum levels that were clinically relevant, prevented the cannabinoid withdrawal syndrome. The effects of lithium were accompanied by expression of the cellular activation marker Fos proteins within most oxytocin-immunoreactive neurons and a significant increase in oxytocin mRNA expression in the hypothalamic paraventricular and supraoptic nuclei. Lithium also produced a significant elevation of oxytocin levels in the peripheral blood. We suggest that the effects of lithium against the cannabinoid withdrawal syndrome are mediated by oxytocinergic neuronal activation and subsequent release and action of oxytocin within the CNS. In support of our hypothesis, we found that the effects of lithium against the cannabinoid withdrawal syndrome were antagonized by systemic preapplication of an oxytocin antagonist and mimicked by systemic or intracerebroventricular injection of oxytocin. These results demonstrate that oxytocinergic neuronal activation plays a critical role in the action of lithium against the cannabinoid withdrawal syndrome in rats, thus providing a potentially novel strategy for the treatment of cannabis dependence in humans.
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Preclinical studies in rats found that systemic injection of lithium leads to a significant elevation of peripheral oxytocin levels.
“As regard OT, preclinical studies in rats found that a systemic injection of lithium leads to a significant elevation of peripheral OT levels (Cui et al., 2001;You et al., 2001).”
From Peripheral oxytocin and vasopressin: Biomarkers of psychiatric disorders? A comprehensive systematic review and preliminary meta-analysis (2016) · cites this paper as Cui et al., 2001
In Cui's study, oxytocin was shown to block anxiety-associated withdrawal symptoms.
“in Cui’s study oxytocin was shown to block anxiety-associated withdrawal symptoms (Cui et al, 2001).”
From Effect of oxytocin on craving and stress response in marijuana-dependent individuals: A pilot study (2013) · cites this paper as Cui et al, 2001
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- Authors
- Cui, S.-S., Bowen, R. C., Gu, G.-B., Hannesson, D. K., Yu, P. H., & Zhang, X.
- Affiliations
- University of Saskatchewan (CA)
- ORCID
- Zhang, Xia
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-12-15
- Volume
- 21
- Issue
- 24
- Pages
- 9867-9876
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6763020
- OpenAlex
- W2147042597
- Cited by
- 84
- References
- 57
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 4 · 2016: 5 · 2015: 7 · 2014: 3 · 2013: 4 · 2012: 7
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- lithium, oxytocin, cannabis use disorder, oxytocinergic neurons, Fos expression, hypothalamic paraventricular nucleus, supraoptic nucleus, oxytocin antagonist, pharmacological treatment of addiction
- MeSH terms
- Animals, Behavior, Animal, Camphanes, Brain, Cannabinoids, Densitometry, Dose-Response Relationship, Drug, Immunohistochemistry, Lithium, Male, Morpholines, Neurons, Oxytocin, Piperazines, Pyrazoles, Radioimmunoassay, Receptors, Drug, Substance Withdrawal Syndrome, Dronabinol, Proto-Oncogene Proteins c-fos, In Situ Hybridization, Receptors, Oxytocin, Rats, Long-Evans, Receptors, Cannabinoid, Rats
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