The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia.
David W Volk, David A Lewis
Biological Psychiatry April 1, 2016 DOI: 10.1016/j.biopsych.2015.06.015 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Cannabis |
| Keywords | Cb1r Cannabinoid Cognitive Inhibitory Prefrontal cortex |
| Key findings | The authors argue that cannabis increases schizophrenia risk and worsens symptoms by disrupting endocannabinoid regulation of prefrontal inhibitory circuitry. They report that schizophrenia prefrontal cortex shows increased 2-arachidonylglycerol metabolism, greater CB1 receptor binding, and lower CB1 receptor mRNA and protein, and propose these alterations interact with other inhibitory neuron abnormalities to heighten vulnerability to cannabis. |
Abstract
Cannabis use has been reported to increase the risk of developing schizophrenia and to worsen symptoms of the illness. Both of these outcomes might be attributable to the disruption by cannabis of the endogenous cannabinoid system's spatiotemporal regulation of the inhibitory circuitry in the prefrontal cortex that is essential for core cognitive processes, such as working memory, which are impaired in schizophrenia. In the healthy brain, the endocannabinoid 2-arachidonylglycerol 1) is synthesized by diacylglycerol lipase in pyramidal neurons; 2) travels retrogradely to nearby inhibitory axon terminals that express the primary type 1 cannabinoid receptor (CB1R); 3) binds to CB1R, which inhibits gamma-aminobutyric acid release from the cholecystokinin-containing population of interneurons; and 4) is metabolized by either monoglyceride lipase, which is located in the inhibitory axon terminal, or by α-β-hydrolase domain 6, which is co-localized presynaptically with diacylglycerol lipase. Investigations of the endogenous cannabinoid system in the prefrontal cortex of subjects with schizophrenia have found evidence of higher metabolism of 2-arachidonylglycerol, as well as both greater CB1R receptor binding and lower levels of CB1R messenger RNA and protein. Current views on the potential pathogenesis of these alterations, including disturbances in the development of the endogenous cannabinoid system, are discussed. In addition, how interactions between these alterations in the endocannabinoid system and those in other inhibitory neurons in the prefrontal cortex in subjects with schizophrenia might increase the liability to adverse outcomes with cannabis use is considered.
Comparable studies
Other narrative reviews on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Causal association between cannabis and psychosis: examination of the evidence | 2004 | Review | |
| Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. General (historical and pharmacological review) | 2018 | Review | |
| Psychiatric effects of cannabis | 2001 | Review | |
| Beyond THC: The New Generation of Cannabinoid Designer Drugs | 2011 | Review | |
| Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug | 2006 | Review |
Citations in the library
Cited by 8
- Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure Neuropsychopharmacology January 26, 2020
- Unraveling the Intoxicating and Therapeutic Effects of Cannabis Ingredients on Psychosis and Cognition Frontiers in Psychology May 14, 2020
- Role of the Cannabinoid System in the Limbic System The Neuroscience Journal of Shefaye Khatam 2018
- CB1 receptor-enriched functional connectivity analysis revealed target-specific modulation by cannabidiol in early psychosis. Journal of Psychopharmacology August 5, 2026
- The Brain Endocannabinoid System is Differentially Regulated in Male and Female Patients with First-Episode Psychosis Schizophrenia Bulletin April 10, 2026
and 3 more in the library
Cites 9
- Gone to Pot – A Review of the Association between Cannabis and Psychosis Frontiers in Psychiatry May 22, 2014
- The Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia: A Meta-analysis of Existing Findings and New Data in a First-Episode Sample Schizophrenia Bulletin July 25, 2010
- The association between cannabis abuse and subsequent schizophrenia: a Swedish national co-relative control study. Psychological Medicine January 2015
- Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia. Schizophrenia Research October 2014
- Repeated Δ9-tetrahydrocannabinol exposure in adolescent monkeys: persistent effects selective for spatial working memory. American Journal of Psychiatry April 2014
and 4 more in the library