A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia.

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“Cognitive impairment is a core symptom domain of schizophrenia, neurological disorders and substance abuse. It is characterised by deficits in learning, memory, attention and executive functioning and can severely impact daily living.

Antipsychotic drugs prescribed to treat schizophrenia provide limited cognitive benefits and novel therapeutic targets are required. Cannabidiol (CBD), a component of the cannabis plant, has anti-inflammatory and antipsychotic-like properties; however, its ability to improve cognitive impairment has not been thoroughly explored. The aim of this systematic review was to evaluate preclinical and clinical literature on the effects of CBD in cognitive domains relevant to schizophrenia.

CBD improves cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric (schizophrenia), neurodegenerative (Alzheimer’s disease), neuro-inflammatory (meningitis, sepsis and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia). To-date, there is one clinical investigation into the effects of CBD on cognition in schizophrenia patients, with negative results for the stroop test. CBD attenuates Δ9-THC-induced cognitive deficits.

 

The efficacy of CBD to improve cognition in schizophrenia cannot be elucidated due to lack of clinical evidence; however, given the ability of CBD to restore cognition in multiple studies of impairment, further investigation into its efficacy in schizophrenia is warranted. Potential mechanisms underlying the efficacy of CBD to improve cognition are discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/27884751

Endocannabinoid system in sexual motivational processes: is it a novel therapeutic horizon?

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“The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana’s psychoactive ingredient Δ9-tetrahydrocannabinol (Δ9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors.

For centuries, in addition to its recreational actions, several contradictory claims regarding the effects of Cannabis use in sexual functioning and behavior (e.g. aphrodisiac vs anti-aphrodisiac) of both sexes have been accumulated. The identification of Δ9-THC and later on, the discovery of the ECS have opened a potential therapeutic target for sexual dysfunctions, given the partial efficacy of current pharmacological treatment.

In agreement with the bidirectional modulation induced by cannabinoids on several behavioral responses, the endogenous cannabinoid AEA elicited biphasic effects on sexual behavior as well. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of several aspects of sexuality in preclinical and human studies, highlighting their therapeutic potential.”

https://www.ncbi.nlm.nih.gov/pubmed/27884725

“Cannabis As An Aphrodisiac? The Evidence Is Mounting”  https://www.civilized.life/articles/aphrodisiac-evidence-is-mounting/

Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor.

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“The cannabinoid CB1 receptor is a G protein coupled receptor and plays an important role in many biological processes and physiological functions.

A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids, and synthetic cannabinoids, have been discovered or developed over the past 20 years.

In 2005, it was discovered that the CB1 receptor contains allosteric site(s) that can be recognized by small molecules or allosteric modulators.

A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists.

Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands.

This review details the complex pharmacological profiles of these allosteric modulators, their structure-activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators.

The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/27879006

Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence

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“There is urgent need for the development of mechanistically different and less side-effect prone antipsychotic compounds.

The endocannabinoid system has been suggested to represent a potential new target in this indication.

Although, results from animal studies are inconsistent to a certain extent and seem to depend on behavioral paradigms, treatment duration and experimental conditions applied, cannabidiol has shown antipsychotic properties in both rodents and rhesus monkeys.

After some individual treatment attempts, the first randomized, double-blind controlled clinical trial demonstrated that in acute schizophrenia cannabidiol exerts antipsychotic properties comparable to the antipsychotic drug amisulpride while being accompanied by a superior, placebo-like side effect profile.

As the clinical improvement by cannabidiol was significantly associated with elevated anandamide levels, it appears likely that its antipsychotic action is based on mechanisms associated with increased anandamide concentrations.

The antipsychotic potential of cannabidiol has been investigated in various behavioral paradigms and different animal models of aspects of schizophrenia.

Although the results were partially inconsistent, they indicate that cannabidiol treatment ameliorates impairments of PPI, social interaction behavior and cognition in rodents and rhesus monkeys.

In addition, individual treatment attempts as well as one randomized, double-blind clinical study, demonstrated the antipsychotic potential of cannabidiol and its superior side effect profile compared to conventional antipsychotics. In addition, a recently conducted clinical trial investigating cannabidiol as an add-on medication showed promising results, although these have not yet been published in a peer reviewed process.

Obviously more clinical trials are needed to substantiate the current findings, and in particular to investigate long-term efficacy and safety in larger cohorts.

However, cannabidiol seems to represent a mechanistically different and less side-effect prone antipsychotic compound for the treatment of schizophrenia, even though the underlying pharmacological mechanisms are still under debate.

Nevertheless, the association between increased anandamide levels and reduced psychotic symptoms in schizophrenic patients treated with cannabidiol, points to a potentially new antipsychotic mechanism of action involving anandamide.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099166/

Cannabidiol Mellows Out Resurgent Sodium Current

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“Cannabidiol has received abundant media attention as a potential therapy for intractable epilepsy, based mainly on anecdotal evidence.

These findings suggest that cannabidiol could be exerting its anticonvulsant effects, at least in part, through its actions on voltage-gated sodium channels, and resurgent current may be a promising therapeutic target for the treatment of epilepsy syndromes.”

http://www.epilepsycurrents.org/doi/full/10.5698/1535-7511-16.6.399

Anti-excitotoxic effects of cannabidiol are partly mediated by enhancement of NCX2 and NCX3 expression in animal model of cerebral ischemia.

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“Excitotoxicity and imbalance of sodium and calcium homeostasis trigger pathophysiologic processes in cerebral ischemia which can accelerate neuronal death.

Neuroprotective role of cannabidiol (CBD), one of the main non-psychoactive phytocannabinoids of the cannabis plant, has attracted attention of many researchers in the neurodegenerative diseases studies.

The present investigation was designed to determine whether cannabidiol can alleviate the severity of ischemic damages and if it is able to exert its anti-excitotoxic effects through sodium and calcium regulation.

The present results indicate that administration of cannabidiol (100 and 200 ng/rat) in the MCAO-induced cerebral ischemia caused a remarkable reduction in neurological deficit, infarction, brain edema, and BBB permeability in comparison with the vehicle group. Up-regulation of NCX2 and NCX3 in cannabidiol-received groups was also observed.

These findings support the view that the reduction of ischemic injuries elicited by cannabidiol can be at least partly due to the enhancement of NCX protein expression and its cerebro-protective role in those cerebral territories supplied by MCA.”

https://www.ncbi.nlm.nih.gov/pubmed/27856160

State of the evidence: Cannabinoids and cancer pain-A systematic review.

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“Cannabinoids are widely used to alleviate intractable symptoms such as pain, nausea, and muscle spasticity. The purpose of this review was to ascertain the current state of the science regarding use of cannabinoids for cancer pain.

CONCLUSIONS:

Eight randomized control trials met the inclusion criteria for review. Most trials found analgesic effects from cannabinoids when compared to placebo, although not all associations reached statistical significance. The analgesic effects of cannabinoids were also limited by dose-dependent side effects. Side effects most commonly reported were changes in cognition, sedation, and dizziness.

IMPLICATIONS FOR PRACTICE:

There is evidence that cannabinoids are effective adjuvants for cancer pain not completely relieved by opioid therapy, but there is a dearth of high-quality studies to support a stronger conclusion. Cannabinoids appear to be safe in low and medium doses. Methodological limitations of the trials limited the ability to make sound conclusions. Further research is warranted before efficacy, safety, and utility of cannabinoids for cancer pain can be determined.”

https://www.ncbi.nlm.nih.gov/pubmed/27863159

Modulation of Type-1 and Type-2 Cannabinoid Receptors by Saffron in a Rat Model of Retinal Neurodegeneration.

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“Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death.

The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS).

These data suggest that BCL modulates only distinct ECS elements like CB1 and CB2, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.”

 https://www.ncbi.nlm.nih.gov/pubmed/27861558

Overactivation of cannabinoid receptor type 1 in rostral ventrolateral medulla promotes cardiovascular responses in spontaneously hypertensive rats.

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“Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic nerve activity (RSNA) and blood pressure (BP) in rats.

Thus, we hypothesized that abnormal expression of CB1 receptor in the RVLM may play a critical role in the pathogenesis of essential hypertension.

Taken together, our results suggested that alterations of CB1 receptor desensitization in the RVLM may play a role in the pathogenesis of essential hypertension.”

https://www.ncbi.nlm.nih.gov/pubmed/27861247

Medical Cannabis – another piece in the mosaic of autoimmunity?

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“Legalization of cannabis’ medicinal use is rapidly increasing worldwide, raising the need to evaluate medical implications of cannabis. Currently evidence supports cannabis and its active ingredients as an immune-modulating agents, affecting T-cells, B-cells, Monocytes and Microglia-cells, causing an overall reduction in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokines. Due to the supporting evidence of cannabinoids as an immune-modulating agent, research focusing on cannabinoids and autoimmunity has emerged. Several clinical trials in multiple sclerosis, inflammatory bowel disease and fibromyalgia suggest cannabis’ effectiveness as an immune-modulator. However, contradicting results and lack of large scale clinical trials obscure these results. Though lacking clinical research, in-vitro and in-vivo experiments in rheumatoid arthritis, diabetes type 1 and systemic sclerosis, demonstrate a correlation between disease activity and cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/27859024