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Review
. 2021 Jun;157(5):1674-1696.
doi: 10.1111/jnc.15369. Epub 2021 May 16.

Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings

Andrew J Kesner  1 , David M Lovinger  1
Affiliations
Review

Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings

Andrew J Kesner et al. J Neurochem. 2021 Jun.

Abstract

Cannabis sativa is the most widely used illicit drug in the world. Its main psychoactive component is delta-9-tetrahydrocannabinol (THC), one of over 100 phytocannabinoid compounds produced by the cannabis plant. THC is the primary compound that drives cannabis abuse potential and is also used and prescribed medically for therapeutic qualities. Despite its therapeutic potential, a significant subpopulation of frequent cannabis or THC users will develop a drug use syndrome termed cannabis use disorder. Individuals suffering from cannabis use disorder exhibit many of the hallmarks of classical addictions including cravings, tolerance, and withdrawal symptoms. Currently, there are no efficacious treatments for cannabis use disorder or withdrawal symptoms. This makes both clinical and preclinical research on the neurobiological mechanisms of these syndromes ever more pertinent. Indeed, basic research using animal models has provided valuable evidence of the neural molecular and cellular actions of cannabis that mediate its behavioral effects. One of the main components being central action on the cannabinoid type-one receptor and downstream intracellular signaling related to the endogenous cannabinoid system. Back-translational studies have provided insight linking preclinical basic and behavioral biology research to better understand symptoms observed at the clinical level. This narrative review aims to summarize major research elucidating the molecular, cellular, and behavioral manifestations of cannabis/THC use that play a role in cannabis use disorder and withdrawal.

Keywords: CB1; CUD; THC; cannabinoids; endocannabinoids; marijuana; tolerance.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Effects of acute cannabis/THC exposure, chronic use, and withdrawal on behavior and synaptic eCB signaling. The stage of cannabis/THC use is listed inside arrows across the top of the figure, with the relevant synaptic cellular/molecular components and behavioral elements beneath. In the synapse cartoons, the left (acute use) includes many of the well‐established components, while middle (chronic use) and right (withdrawal) cartoons have bolded the critical changes associated with that stage, while the other components are dimmed. For behavioral elements, the subtitles indicate whether the behavior(s) occur in clinical (human) or preclinical (animal model) settings
See this image and copyright information in PMC

References

    1. Abood, M. E. , Sauss, C. , Fan, F. , Tilton, C. L. , & Martin, B. R. (1993). Development of behavioral tolerance to Δ9‐THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain. Pharmacology Biochemistry and Behavior, 46, 575–579. 10.1016/0091-3057(93)90546-6 - DOI - PubMed
    1. Aceto, M. D. , Scates, S. M. , Lowe, J. A. , & Martin, B. R. (1995). Cannabinoid precipitated withdrawal by the selective cannabinoid receptor antagonist, SR 141716A. European Journal of Pharmacology, 282, R1–2. 10.1016/0014-2999(95)00447-S - DOI - PubMed
    1. Ade, K. K. , & Lovinger, D. M. (2007). Anandamide regulates postnatal development of long‐term synaptic plasticity in the rat dorsolateral striatum. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 27, 2403–2409. 10.1523/JNEUROSCI.2916-06.2007 - DOI - PMC - PubMed
    1. Agrawal, A. , & Lynskey, M. T. (2006). The genetic epidemiology of cannabis use, abuse and dependence. Addiction, 101, 801–812. 10.1111/j.1360-0443.2006.01399.x - DOI - PubMed
    1. Ahmed, S. A. , Ross, S. A. , Slade, D. , Radwan, M. M. , Khan, I. A. , & ElSohly, M. A. (2015). Minor oxygenated cannabinoids from high potency Cannabis sativa L. Phytochemistry, 117, 194–199. 10.1016/j.phytochem.2015.04.007 - DOI - PMC - PubMed

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