The endocannabinoid system as a target for the treatment of cannabis dependence
Jason R. Clapper, Regina A. Mangieri, Daniele Piomelli
Neuropharmacology July 19, 2008 DOI: 10.1016/j.neuropharm.2008.07.018 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Intervention | URB597 |
| Topics | Addiction Cannabis |
| Key findings | The authors argue that frequent cannabis use causes adaptive downregulation of brain endocannabinoid signaling, and that pharmacological agents elevating anandamide and 2-AG, such as the FAAH inhibitor URB597, might alleviate cannabis withdrawal and dependence. They cite preclinical evidence that URB597 produces analgesic, anxiolytic-like, and antidepressant-like effects in rodents without overt signs of abuse liability. |
Abstract
The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive downregulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling; and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.
Comparable studies
Other narrative reviews on cannabis for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The neuropsychopharmacology of cannabis: A review of human imaging studies | 2018 | Review | |
| Substance-Induced Psychoses: An Updated Literature Review General (substance-induced psychosis) | 2021 | Narrative review | |
| New psychoactive substances of natural origin: A brief review | 2017 | Review | |
| New Psychoactive Substances (NPS) – a Challenge for the Addiction Treatment Services | 2017 | Review | |
| Classic Psychedelics in Addiction Treatment: The Case for Psilocybin in Tobacco Smoking Cessation | 2022 | Review |
Citations in the library
Cited by 8
- Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors PLoS Biology July 9, 2015
- Impaired cognitive performance under psycho-social stress in cannabis-dependent males is mediated by attenuated precuneus activity bioRxiv (Cold Spring Harbor Laboratory) September 29, 2018
- PET imaging of FAAH in chronic Cannabis users: longitudinal assessment during short-term abstinence. Neuropsychopharmacology May 9, 2026
- The fatty acid amide hydrolase inhibitor URB 597: interactions with anandamide in rhesus monkeys. British Journal of Pharmacology September 2011
- Abuse potential and psychoactive effects of δ-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opinion on Drug Safety September 2011
and 3 more in the library
Cites 7
- Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis Proceedings of the National Academy of Sciences December 13, 2005
- Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. Schizophrenia Research August 2007
- The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: studies of drug use and dependence in Caucasians. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics July 5, 2007
- Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. Journal of Pharmacology and Experimental Therapeutics July 2006
- The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers. American heart journal March 2006
and 2 more in the library