Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

Leweke, F. Markus; Piomelli, Daniele; Pahlisch, Franziska; Muhl, Daniela; Gerth, Christoph W.; Hoyer, Carolin; Klosterkötter, Joachim; Hellmich, Martin; Koethe, Dagmar

doi:10.1038/tp.2012.15

Cited by 898 publications

(891 citation statements)

References 34 publications

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“…The opposite effects of delta-9-THC and CBD on functional connectivity provide further complementary evidence for the potential role of CBD as an antipsychotic Leweke et al, 2012;Morgan and Curran, 2008;Morgan et al, 2010b;Zuardi et al, 2012) and suggest that the antipsychotic effects of CBD might be related to its effects on brain activation in regions, which have been consistently found to be associated with psychosis, such as the striatum and the temporal cortex.…”

Section: Discussionmentioning

confidence: 90%

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Bhattacharyya

Falkenberg

Martín‐Santos

et al. 2014

Neuropsychopharmacol

105

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There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli.

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Section: Discussionmentioning

confidence: 90%

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Bhattacharyya

Falkenberg

Martín‐Santos

et al. 2014

Neuropsychopharmacol

105

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“…FAAH inhibition also alleviates psychotic symptoms in patients with schizophrenia [281]. CBD is a potent inhibitor of FAAH; therefore, it is worth investigating if this will provide a therapeutic effect.…”

Section: Cbd Enzyme Targets In Psychosismentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…Most nonacid plant cannabinoids inhibit, albeit not very potently, the cellular reuptake of anandamide, and CBD is also a moderate inhibitor of anandamide hydrolysis by FAAH [13,26], an effect that has been recently reported to also occur in vivo in mice and humans [27,28]. If one remembers that several endocannabinoid-like mediators are also inactivated by FAAH (Fig.…”

Section: Other Ways Through Which Non-thc Plant Cannabinoids Influencmentioning

confidence: 99%

The Endocannabinoid System and its Modulation by Phytocannabinoids

2015

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The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ 9 -tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)-cannabinoid receptor type-1 (CB 1 R) and cannabinoid receptor type-2 (CB 2 R); their two most studied endogenous ligands, the "endocannabinoids" N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism. However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB 1 R and CB 2 R. Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with "endocannabinoid-like" mediators that may or may not interact with the same proteins as Δ 9 -tetrahydrocannabinol and other phytocannabinoids. In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors. Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets. Here, we review the whole world of ligands, receptors, and enzymes, a true "endocannabinoidome", discovered after the cloning of CB 1 R and CB 2 R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.

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Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

Cited by 898 publications

References 34 publications

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Molecular Targets of Cannabidiol in Neurological Disorders

The Endocannabinoid System and its Modulation by Phytocannabinoids

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