Cannabidiol attenuates insular dysfunction during motivational salience processing in subjects at clinical high risk for psychosis.

Image result for translational psychiatry “Accumulating evidence points towards the antipsychotic potential of cannabidiol. However, the neurocognitive mechanisms underlying the antipsychotic effect of cannabidiol remain unclear.

We investigated this in a double-blind, placebo-controlled, parallel-arm study. We investigated 33 antipsychotic-naïve subjects at clinical high risk for psychosis (CHR) randomised to 600 mg oral cannabidiol or placebo and compared them with 19 healthy controls.

We used the monetary incentive delay task while participants underwent fMRI to study reward processing, known to be abnormal in psychosis. Reward and loss anticipation phases were combined to examine a motivational salience condition and compared with neutral condition.

We observed abnormal activation in the left insula/parietal operculum in CHR participants given placebo compared to healthy controls associated with premature action initiation. Insular activation correlated with both positive psychotic symptoms and salience perception, as indexed by difference in reaction time between salient and neutral stimuli conditions.

CBD attenuated the increased activation in the left insula/parietal operculum and was associated with overall slowing of reaction time, suggesting a possible mechanism for its putative antipsychotic effect by normalising motivational salience and moderating motor response.”

https://www.ncbi.nlm.nih.gov/pubmed/31439831

https://www.nature.com/articles/s41398-019-0534-2

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The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review.

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“The endogenous cannabinoid (eCB) system plays an important role in the pathophysiology of both psychotic disorders and substance use disorders (SUDs). The non-psychoactive cannabinoid compound, cannabidiol (CBD) is a highly promising tool in the treatment of both disorders. Here we review human clinical studies that investigated the efficacy of CBD treatment for schizophrenia, substance use disorders, and their comorbidity. In particular, we examined possible profiles of patients who may benefit the most from CBD treatment. CBD, either as monotherapy or added to regular antipsychotic medication, improved symptoms in patients with schizophrenia, with particularly promising effects in the early stages of illness. A potential biomarker is the level of anandamide in blood. CBD and THC mixtures showed positive effects in reducing short-term withdrawal and craving in cannabis use disorders. Studies on schizophrenia and comorbid substance use are lacking. Future studies should focus on the effects of CBD on psychotic disorders in different stages of illness, together with the effects on comorbid substance use. These studies should use standardized measures to assess cannabis use. In addition, future efforts should be taken to study the relationship between the eCB system, GABA/glutamate, and the immune system to reveal the underlying neurobiology of the effects of CBD.”

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Cannabidiol improves behavioural and neurochemical deficits in adult female offspring of the maternal immune activation (poly I:C) model of neurodevelopmental disorders.

Brain, Behavior, and Immunity“Cognitive impairment is a major source of disability in schizophrenia and current antipsychotic drugs (APDs) have minimal efficacy for this symptom domain.

Cannabidiol (CBD), the major non-intoxicating component of Cannabis sativa L., exhibits antipsychotic and neuroprotective properties.

We recently reported the effects of CBD on cognition in male offspring of a maternal immune activation (polyinosinic-polycytidilic acid (poly I:C)) model relevant to the aetiology of schizophrenia; however, the effects of CBD treatment in females are unknown. Sex differences are observed in the onset of schizophrenia symptoms and response to APD treatment.

Furthermore, the endogenous cannabinoid system, a direct target of CBD, is sexually dimorphic in humans and rodents. Therefore, the present work aimed to assess the therapeutic impact of CBD treatment on behaviour and neurochemical signalling markers in female poly I:C offspring.

Overall, the findings of this study support the therapeutic benefits of CBD on recognition memory and sociability in female poly I:C offspring, and provide insight into the neurochemical changes that may underlie the therapeutic benefits of CBD in the poly I:C model.”

https://www.ncbi.nlm.nih.gov/pubmed/31326506

“These findings suggest that CBD is an efficacious treatment for behavioural and neurochemical changes in a female rodent model relevant to schizophrenia.”

https://www.sciencedirect.com/science/article/pii/S0889159119302806?via%3Dihub

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Endocannabinoid system imbalance in the postmortem prefrontal cortex of subjects with schizophrenia.

Image result for Journal of Psychopharmacology“The present findings reveal an imbalance in the expression and function of different elements of the endocannabinoid system in schizophrenia.

This outcome highlights the relevance of the endocannabinoid system in the pathophysiology of schizophrenia and emphasises its elements as potential targets in the search for new therapeutic strategies.”

https://www.ncbi.nlm.nih.gov/pubmed/31237179

https://journals.sagepub.com/doi/abs/10.1177/0269881119857205?journalCode=jopa

“Therapeutic potential of cannabinoids in schizophrenia.”   https://www.ncbi.nlm.nih.gov/pubmed/24605939

Cannabinoids for the Treatment of Schizophrenia: An Overview. Cannabinoids are found to be very useful in psychiatry because of their antipsychotic properties suggesting a therapeutic use. Cannabinoids treatments are both able to reduce the typical symptoms of schizophrenia and to slow down the disease aggravation.”   https://www.ncbi.nlm.nih.gov/pubmed/26845552

http://www.thctotalhealthcare.com/category/schizophrenia/

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Quetiapine induces myocardial necroptotic cell death through bidirectional regulation of cannabinoid receptors.

Toxicology Letters

“Quetiapine is a common atypical antipsychotic used to treat mental disorders such as schizophrenia, bipolar disorder, and major depressive disorder. There has been increasing number of reports describing its cardiotoxicity. However, the molecular mechanisms underlying quetiapine-induced myocardial injury remain largely unknown.

Herein, we reported a novel cell death type, quetiapine-induced necroptosis, which accounted for quetiapine cardiotoxicity in mice and proposed novel therapeutic strategies.

Quetiapine-treated hearts showed inflammatory infiltration and evident fibrosis after 21-day continuous injection. The specific increases of protein levels of RIP3, MLKL and the phosphorylation of MLKL showed that quetiapine-induced necroptotic cell death both in vivo and in vitro. Pharmacologic blockade of necroptosis using its specific inhibitor Necrostatin-1 attenuated quetiapine-induced myocardial injury in mice.

In addition, quetiapine imbalanced the endocannabinoid system and caused opposing effects on two cannabinoid receptors (CB1R and CB2R).

Specific antagonists of CB1R (AM 281, Rimonabant), but not its agonist ACEA significantly ameliorated the heart histopathology induced by chronic quetiapine exposure. By contrast, specific agonists of CB2R (JWH-133, AM 1241), but not its antagonist AM 630 exerted beneficial roles against quetiapine cardiotoxicity.

The protective agents (AM 281, Rimonabant, AM 1241, and JWH-133) consistently inactivated the quetiapine-induced necroptosis signaling. Quetiapine bidirectionally regulates cannabinoid receptors and induces myocardial necroptosis, leading to cardiac toxic effects.

Therefore, pharmacologic inhibition of CB1R or activation of CB2R represents promising therapeutic strategies against quetiapine-induced cardiotoxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/31220554

https://www.sciencedirect.com/science/article/pii/S0378427419301766?via%3Dihub

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Effect of cannabidiol on endocannabinoid, glutamatergic and GABAergic signalling markers in male offspring of a maternal immune activation (poly I:C) model relevant to schizophrenia.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

“The mainstay treatment for schizophrenia is antipsychotic drugs (APDs), which are mostly effective against the positive symptoms (e.g. hallucinations), but provide minimal benefits for the negative symptoms (e.g. social withdrawal) and cognitive deficits.

We have recently shown that treatment with the non-intoxicating phytocannabinoid, cannabidiol (CBD), can improve cognition and social interaction deficits in a maternal immune activation (MIA) model relevant to the aetiology of schizophrenia, however, the mechanisms underlying this effect are unknown.

An imbalance in the main excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems in the brain plays a role in the pathophysiology of schizophrenia. Therefore, the endocannabinoid system could represent a therapeutic target for schizophrenia as a regulator of glutamate and GABA release via the CB1 receptor (CB1R).

Overall, these findings show that CBD can restore cannabinoid/GABAergic signalling deficits in regions of the brain implicated in schizophrenia pathophysiology following maternal poly I:C exposure. These findings provide novel evidence for the potential mechanisms underlying the therapeutic effects of CBD treatment in the poly I:C model.”

https://www.ncbi.nlm.nih.gov/pubmed/31202911

https://www.sciencedirect.com/science/article/pii/S027858461930106X?via%3Dihub

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Effect of cannabidiol on muscarinic neurotransmission in the pre-frontal cortex and hippocampus of the poly I:C rat model of schizophrenia.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Cognitive impairment is a core symptom of schizophrenia; however, current antipsychotic drugs have limited efficacy to treat these symptoms and can cause serious side-effects, highlighting a need for novel therapeutics.

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid that has demonstrated pro-cognitive effects in multiple disease states, including a maternal immune activation (poly I:C) model of schizophrenia, but the mechanisms underlying the efficacy of CBD require investigation.

We examined alterations in markers of muscarinic neurotransmission in the pre-frontal cortex (PFC) and hippocampus (HPC) following CBD treatment.

These findings demonstrate that CBD can normalise muscarinic neurotransmission imbalances in male poly I:C offspring in regions of the brain implicated in cognition.”

https://www.ncbi.nlm.nih.gov/pubmed/31108177

https://www.sciencedirect.com/science/article/pii/S0278584618308121?via%3Dihub

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Role of the endocannabinoid and endovanilloid systems in an animal model of schizophrenia-related emotional processing/cognitive deficit.

Neuropharmacology

“Studies suggest that the endocannabinoid and endovanilloid systems are implicated in the pathophysiology of schizophrenia.

The Spontaneously Hypertensive Rats (SHR) strain displays impaired contextual fear conditioning (CFC) attenuated by antipsychotic drugs and worsened by pro-psychotic manipulations. Therefore, SHR strain is used to study emotional processing/associative learning impairments associated with schizophrenia and effects of potential antipsychotic drugs.

Here, we evaluated the expression of CB1 and TRPV1 receptors in some brain regions related to the pathophysiology of schizophrenia. We also assessed the effects of drugs that act on the endocannabinoid/endovanilloid systems on the CFC task in SHRs and control animals (Wistar rats – WRs).

These results reinforce the involvement of the endocannabinoid/endovanilloid systems in the SHRs CFC deficit and point to these systems as targets to treat the emotional processing/cognitive symptoms of schizophrenia.”

https://www.ncbi.nlm.nih.gov/pubmed/31103618

https://www.sciencedirect.com/science/article/pii/S0028390819301649?via%3Dihub

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Cannabidiol attenuates aggressive behavior induced by social isolation in mice: Involvement of 5-HT1A and CB1 receptors.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Long-term single housing increases aggressive behavior in mice, a condition named isolation-induced aggression or territorial aggression, which can be attenuated by anxiolytic, antidepressant, and antipsychotic drugs.

Preclinical and clinical findings indicate that cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, has anxiolytic, antidepressant, and antipsychotic properties. Few studies, however, have investigated the effects of CBD on aggressive behaviors.

Here, we investigated whether CBD (5, 15, 30, and 60 mg/kg; i.p.) could attenuate social isolation-induced aggressive behavior in the resident-intruder test.

Taken together, our findings suggest that CBD may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31054943

https://www.sciencedirect.com/science/article/pii/S0278584618308340?via%3Dihub

cannabidiol reduces aggressiveness, study concludes”  https://globalhealthnewswire.com/2019/07/31/cannabidiol-reduces-aggressiveness-study-concludes/

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Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity.

Image result for journal of psychopharmacology

“Two major constituents of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main psychoactive component; CBD may buffer the user against the harmful effects of THC.

AIMS:

We examined the effects of two strains of cannabis and placebo on the human brain’s resting-state networks using fMRI.

CONCLUSIONS:

THC disrupts the DMN, and the PCC is a key brain region involved in the subjective experience of THC intoxication. CBD restores disruption of the salience network by THC, which may explain its potential to treat disorders of salience such as psychosis and addiction.”

https://www.ncbi.nlm.nih.gov/pubmed/31013455

https://journals.sagepub.com/doi/abs/10.1177/0269881119841568?journalCode=jopa

“CBD in cannabis could reduce psychosis risk from high strength skunk, study shows. Buffer effect could point to a protective mechanism that may help ‘treat disorders like psychosis and addiction’. Cannabidiol (CBD), a chemical derived from the cannabis plant, can counteract the effects of high strength “skunk” strains and may help to reduce the risk of serious mental health conditions like psychosis, according to a new study.” https://www.independent.co.uk/news/health/cannabis-skunk-cbd-thc-psychosis-addiction-ucl-a8882991.html

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