GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia

Joëlle A. Pasman, Karin J. H. Verweij, Jacqueline M. Vink  (August 2018)

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Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health–related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

Cannabidiol administered during peri-adolescence prevents behavioral abnormalities in an animal model of schizophrenia

Fernanda F. Peres, Mariana Diana, Raquel Levin, Mayra Suiama, Valéria Almeida, Ana Vendramini, Antonio W. Zuardi, Jaime Hallak, José Alexandre Crippa and Vanessa C. Abilio  (July 2018)

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Schizophrenia is considered a debilitating neurodevelopmental psychiatric disorder and its pharmacotherapy remains problematic without recent major advances. The development of interventions able to prevent the emergence of schizophrenia would therefore represent an enormous progress. Here, we investigated whether treatment with cannabidiol (CBD – a compound of Cannabis sativa that presents an antipsychotic profile in animals and humans) during peri-adolescence would prevent schizophrenia-like behavioral abnormalities in an animal model of schizophrenia: the Spontaneously Hypertensive Rat (SHR) strain. Wistar rats and SHRs were treated with vehicle or CBD from 30 to 60 post-natal days.

The Metabotropic Glutamate Receptor Subtype 1 Regulates Striatal Dopamine Release via an Endocannabinoid-Dependent Mechanism: Implications for the Treatment of Schizophrenia

Samantha Yohn, Daniel Covey, Daniel Foster, Mark Moehle, Jordan Galbraith, Joseph Cheer, Craig Lindsley and P Jeffrey Conn  (April 2018)  

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Clinical and preclinical studies suggest that selective activators of the muscarinic M4 receptor have exciting potential as a novel approach for treatment of schizophrenia. M4 reduces striatal dopamine (DA) though release of endocannabinoids (eCB), providing a mechanism for local effects on DA signaling in the striatum. M4 signals through Gαi/o and does not couple to Gαq/11 or induce calcium (Ca++) mobilization. This raises the possibility that M4-induced eCB release and inhibition of DA release may require co-activation of another receptor that activates Gαq/11.

Cannabidiol as a Treatment in Different Stages of Psychosis – Efficacy and Mechanisms

Sagnik Bhattacharyya  (April 2018)

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The absence of significant adverse effects associated with CBD, is a critical advantage in relation to the treatment of patients in the various stages of psychosis. Given its tolerability profile, CBD is a treatment of particular interest not just in those with chronic psychosis as in schizophrenia, but also in those in the earlier stages of psychosis.

Possible Mechanisms Involved in the Antipsychotic Effects of Cannabidiol (CBD)

Jose Alexandre Crippa, Antonio Waldo Zuardi and Francisco Silveira Guimaraes  (April 2018)

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Since CBD is also a potent anti-inflammatory, antioxidant and neuroprotective compound, it is possible that these effects are involved in its antipsychotic action. CBD could facilitate endocannabinoids “on demand” synthesis in post-synaptic neurons, acting pre-synaptic terminals and negatively regulating the release of neurotransmitters, particularly GABA and glutamate.

Familial abnormalities of endocannabinoid signaling in schizophrenia

Dagmar Koethe, Franziska Pahlisch, Martin Hellmich, Cathrin Rohleder, Juliane K. Mueller, Andreas Meyer-Lindenberg, E. Fuller Torrey, Daniele Piomelli and F. Markus Leweke  (March 2018)
We suggest that the protective upregulation of endocannabinoid signalling reflects either a hereditary trait or mirrors a modulating response to genetically influenced cerebral function involving, e.g., other neurotransmitters or energy metabolism.

The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia

David W. Volk and David A. Lewis  (April 2016)

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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.

The Endocannabinoid System and Schizophrenia: Links to the Underlying Pathophysiology and to Novel Treatment Approaches

Swapnil Gupta, MBBS, MD; John D. Cahill, MBBS; Mohini Ranganathan, MD; and Christoph U. Correll, MD (January 2014)

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Six decades after the introduction of dopamine D2-receptor–based antipsychotics, schizophrenia remains one of the most severe and difficult-to-treat mental disorders. While a range of alternative therapeutic targets, such as the glutamatergic system, have attracted attention for negative symptoms and cognitive dysfunction, novel treatments for the core symptoms of schizophrenia remain unproven. The endocannabinoid system (ECS) is a largely overlooked brain homeostatic system that is relevant to both the pathophysiology and treatment of schizophrenia.