Cannabidiol did not induce teratogenicity or neurotoxicity in exposed zebrafish embryos.

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“Cannabidiol (CBD) is a non-psychotomimetic compound of the Cannabis sativa that has been used for the treatment of severe epilepsy as well as other diseases of nervous system. However, toxicity studies of CBD have great relevance to guarantee the patients safety.

In this context, morphological analyses of zebrafish can contribute to evaluate the teratogenic potential, as well as evaluation of acetylcholinesterase activity and motor activity of zebrafish are valuable tools to verify the neurotoxicity potential. In the present work, we use this methodology to test the toxicity of CBD to zebrafish embryos.

No malformation was observed in morphological analysis of embryos exposed to all tested concentrations of CBD.

Embryos exposed to CBD did not show differences in acetylcholinesterase activity, but embryos exposed to CBD 20-300 μg/L were 1.4 up to 1.7-fold more active when compared to the control. Despite that, at 48 hpf, motor activity returned to control values.

Our results suggest that the effects observed after CBD exposure are intimately related to CB1 receptor that is present in zebrafish since early stages of development. The present work showed early light effects induced by CBD exposure in concentrations that did not alter biochemical activity.”

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The impact of Cannabidiol treatment on regulatory T-17 Cells and neutrophil polarization in Acute Kidney Injury.

 American Journal of Physiology-Renal Physiology 0 0 cover image

“Hallmark features of acute kidney injury (AKI) include mobilization of immune and inflammatory mechanisms culminating in tissue injury. Emerging information indicates heterogeneity of neutrophils with pro- and anti-inflammatory functions (N1 and N2, respectively). Also, regulatory T-17 (Treg17) cells curtail Th-17-mediated pro-inflammatory responses. However, the status of Treg17 cells and neutrophil phenotypes in AKI are not established.

Further, cannabidiol exerts immunoregulatory effects but its impact on Treg17 cells and neutrophil subtypes is not established. Thus, we examined the status of Treg17 cells and neutrophil subtypes in AKI and determined whether cannabidiol favors regulatory neutrophils and T cells accompanied with renoprotection.

Importantly, cannabidiol treatment preserved ψm, reduced cell death and KIM-1 accompanied by restoration of N1 and N2 imbalance and preservation of Treg17 cells while decreasing Th-17 cells. The ability of cannabidiol to favor development of Treg17 cells was further established using functional mixed lymphocytic reaction. Subsequent studies showed higher renal blood flow and reduced serum creatinine in cannabidiol-treated IRI animals.

Collectively, our novel observations establish that renal IRI causes neutrophil polarization in favor of N1 and also reduces Treg17 cells in favor of Th-17, effects that are reversed by cannabidiol treatment accompanied with significant renoprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/29897289

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Probing the endocannabinoid system in healthy volunteers: Cannabidiol alters fronto-striatal resting-state connectivity.

European Neuropsychopharmacology Home

“Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are two substances from cannabis sativa that have been implicated in the treatment of mental and neurological disorders.

We concentrated on a previously validated neuroimaging phenotype, fronto-striatal connectivity across different striatal seeds, because of this loop’s relevance to executive functioning, decision making, salience generation and motivation and its link to various neuropsychiatric conditions. Therefore, we studied the effect of THC and CBD on fronto-striatal circuitry by a seed-voxel connectivity approach using seeds from the caudate and the putamen.

We conducted a cross-over pharmaco-fMRI study in 16 healthy male volunteers with placebo, 10 mg oral THC and 600 mg oral CBD. Resting state was measured in a 3 T scanner. CBD lead to an increase of fronto-striatal connectivity in comparison to placebo.

In contrast to our expectation that THC and CBD show opposing effects, THC versus placebo did not show any significant effects, probably due to insufficient concentration of THC during scanning.

The effect of CBD on enhancing fronto-striatal connectivity is of interest because it might be a neural correlate of its anti-psychotic effect in patients.”

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Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels.

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“Cannabidiol (CBD) is a compound of Cannabis sativa with relevant therapeutic potential in several neuropsychiatric disorders including depression. CBD treatment has shown significant antidepressant-like effects in different rodent preclinical models.

However, the mechanisms involved in CBD-induced antidepressant effects are still poorly understood. Therefore, this work aimed at investigating the participation of serotonin (5-HT) and/or noradrenaline (NA) in CBD-induced antidepressant-like effects in the forced swimming test (FST) by: 1) testing if CBD co-administration with serotonergic (fluoxetine, FLX) or noradrenergic (desipramine, DES) antidepressants would have synergistic effects; and 2) investigating if 5-HT or NA depletion would impair CBD-induced behavioral effects.

Results showed that CBD (10 mg/kg), FLX (10 mg/kg) and DES (5 mg/kg) induced antidepressant-like effects in mice submitted to FST. Ineffective doses of CBD (7 mg/kg), when co-administered with ineffective doses of FLX (5 mg/kg) or DES (2.5 mg/kg) resulted in significant antidepressant-like effects, thus implicating synergistic and/or additive mechanisms.

Pretreatment with PCPA (an inhibitor of serotonin synthesis: 150 mg/kg, i.p., once per day for 4 days), but not DSP-4 (a noradrenergic neurotoxin: 1 μg/μl, i.c.v., 24 h before the test), reduced monoamine levels in the brain. However, only PCPA treatment abolished CBD-induced behavioral effects in FST, indicating the participation of serotonergic mechanisms. None of the treatments induced locomotor effects.

Our results suggest that the antidepressant-like effect induced by CBD in the FST is dependent on serotonin levels in the central nervous system (CNS).”

https://www.ncbi.nlm.nih.gov/pubmed/29885468

https://www.sciencedirect.com/science/article/pii/S0278584618301167

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Sub-chronic treatment with cannabidiol but not with URB597 induced a mild antidepressant-like effect in diabetic rats.

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“Depression associated with diabetes has been described as a highly debilitating comorbidity. Due to its complex and multifactorial mechanisms, the treatment of depression associated with diabetes represents a clinical challenge.

Cannabidiol (CBD), the non-psychotomimetic compound derived from Cannabis sativa, has been pointed out as a promising compound for the treatment of several psychiatric disorders.

Here, we evaluated the potential antidepressant-like effect of acute or sub-chronic treatment with CBD in diabetic rats using the modified forced swimming test (mFST).

Also, to better understand the functionality of the endocannabinoid system in diabetic animals we also evaluated the effect of URB597, a fatty acid amide hydrolase inhibitor.

Acute treatment with either CBD or URB induced an antidepressant-like effect in NGL rats, but not in DBT rats. However, sub-chronic treatment with CBD (only at a dose of 30 mg/kg), but not with URB597, induced a mild antidepressant-like effect in DBT animals. Neither body weight nor blood glucose levels were altered by treatments.

Considering the importance of the endocannabinoid system to the mechanism of action of many antidepressant drugs, the mild antidepressant-like effect of the sub-chronic treatment with CBD, but not with URB597 does not invalidate the importance of deepening the studies involving the endocannabinoid system particularly in DBT animals.”

https://www.ncbi.nlm.nih.gov/pubmed/29885450

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The importance of 15-lipoxygenase inhibitors in cancer treatment.

Cancer and Metastasis Reviews

“Cancer-targeted therapy is an expanding and successful approach in treatment of many types of cancers. One of the main categories of targeted therapy is use of small molecule inhibitors. 15-Lipoxygenase (15-LOX) is an enzyme which reacts with polyunsaturated fatty acids and produces metabolites that are implicated in many important human diseases, such as cancer.

Considering the role of 15-LOX (mainly 15-LOX-1) in the progression of some cancers, the discovery of 15-LOX inhibitors could potentially lead to development of novel cancer therapeutics and it can be claimed that 15-LOX inhibitors might be suitable as chemotherapy agents in the near future.

This article reviews relevant publications on 15-LOX inhibitors with focus on their anticancer activities in vitro and in vivo. Many 15-LOX inhibitors have been reported for which separate studies have shown their anticancer activities. This review paves the way to further explore the mechanism of their antiproliferative effects via 15-LOX inhibition.”

“Cannabidiol-2′,6′-Dimethyl Ether, a Cannabidiol Derivative, Is a Highly Potent and Selective 15-Lipoxygenase Inhibitor”  http://dmd.aspetjournals.org/content/37/8/1733.long

“Δ9-tetrahydrocannabinol and its major metabolite Δ9-tetrahydrocannabinol-11-oic acid as 15-lipoxygenase inhibitors.”  https://www.ncbi.nlm.nih.gov/pubmed/20891010

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Systemic Injections of Cannabidiol Enhance Acetylcholine Levels from Basal Forebrain in Rats.

Neurochemical Research

Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion.

Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh).

Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD.

Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.”

https://www.ncbi.nlm.nih.gov/pubmed/29876791

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Medicinal cannabis: presenting possible treatment modalities for the future

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“Cannabis is the most popular recreational drug used in the world. It is estimated that 178 million people aged 15–64 years used cannabis at least once in 2012.

Cannabis or cannabinoids used to manage medical conditions is referred to as medicinal cannabis. There are various formulations of cannabis available on the market.

Cannabis can be administered orally, sublingually, or topically; it can be smoked, inhaled, mixed with food, or made into tea. It can be taken in herbal form, extracted naturally from the plant, gained by isomerization of cannabidiol (CBD), or manufactured synthetically.

The commercially available prescribed cannabinoids include dronabinol capsules, nabilone capsules, and the oromucosal spray nabiximols.

Canada and the Netherlands have government-run programs in which dedicated companies supply quality-controlled herbal cannabis. In the United States, 23 states and Washington, DC (May 2015) have introduced laws permitting the medical use of cannabis; other countries have similar laws.”

https://www.ncbi.nlm.nih.gov/pubmed/29870436

https://insights.ovid.com/crossref?an=01787381-201806000-00001

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Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.

Molecular Neurobiology

“Currently available antidepressants have a substantial time lag to induce therapeutic response and a relatively low efficacy. The development of drugs that addresses these limitations is critical to improving public health.

Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is a promising compound since it shows large-spectrum therapeutic potential in preclinical models and humans.

However, its antidepressant properties have not been completely investigated. Therefore, the aims of this study were to investigate in male rodents (i) whether CBD could induce rapid and sustained antidepressant-like effects after a single administration and (ii) whether such effects could be related to changes in synaptic proteins/function.

These results indicate that CBD induces fast and sustained antidepressant-like effect in distinct animal models relevant for depression. These effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNF-TrkB signaling pathway.

The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug.”

https://www.ncbi.nlm.nih.gov/pubmed/29869197

https://link.springer.com/article/10.1007%2Fs12035-018-1143-4

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Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders?

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“Movement disorders such as Parkinson’s disease and dyskinesia are highly debilitating conditions linked to oxidative stress and neurodegeneration. When available, the pharmacological therapies for these disorders are still mainly symptomatic, do not benefit all patients and induce severe side effects. Cannabidiol is a non-psychotomimetic compound from Cannabis sativa that presents antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. Although the studies that investigate the effects of this compound on movement disorders are surprisingly few, cannabidiol emerges as a promising compound to treat and/or prevent them. Here, we review these clinical and pre-clinical studies and draw attention to the potential of cannabidiol in this field.”

https://www.ncbi.nlm.nih.gov/pubmed/29867488

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