Higher cannabidiol plasma levels are associated with better seizure response following treatment with a pharmaceutical grade cannabidiol.

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“The objective of this study was to determine the relationship between cannabidiol (CBD) dose, CBD plasma level, and seizure control in a large open-label single-center study.

METHODS:

All participants with treatment-refractory epilepsy participating in our expanded access program (EAP) were approached for participation. Highly purified grade CBD (Epidiolex®) dosing was weight-based and could be increased every 2 weeks by 5 mg/kg/day up to a maximum dosage of 50 mg/kg/day depending on tolerance and seizure control. Seizure counts were obtained at each visit with frequency calculated per 2-week periods. Cross-sectional plasma peak levels of CBD were obtained ~4 h after dosing in consecutively presenting patients.

RESULTS:

We evaluated 56 adults and 44 children (100 total; 54 female) at two time points – one before initiating CBD and one at the time of CBD plasma level testing. There was a positive linear correlation between CBD dosage (range from 5 to 50 mg/kg/day) and level (range from 7.1-1200 ng/mL) in all participants (r = 0.640; p < 0.001). The quantile regression model supported the notion of increased CBD levels being associated with improvement in seizure frequency after adjusting for age – specifically, a 100 ng/mL increase in CBD level was associated with approximately two counts reduction in seizure frequency per time period (1.87 96% confidence interval [CI] 0.34-3.39; p = 0.018). In participants with the same CBD level, differences in seizure improvement did not depend on age (p = 0.318).

CONCLUSIONS:

In this open-label study, we found evidence of a linear correlation between CBD dosage and plasma levels, and that higher dose/levels are associated with a higher response rate for seizure improvement. Children and adults responded to CBD similarly. However, seizure control response rates suggest children may respond to lower dosages/plasma levels than adults. Findings reported in this study are specific to Epidiolex® and should not be extrapolated to other CBD products.”

https://www.ncbi.nlm.nih.gov/pubmed/31048098

https://www.epilepsybehavior.com/article/S1525-5050(19)30051-4/fulltext

Oral Cannabidiol Prevents Allodynia and Neurological Dysfunctions in a Mouse Model of Mild Traumatic Brain Injury.

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 Image result for frontiers in pharmacology“Neurological dysfunctions are the most impactful and persistent consequences of traumatic brain injury (TBI). Indeed, previous reports suggest that an association between TBI and chronic pain syndromes, as well anxio-depressive behaviors, tends to be more common in patients with mild forms of TBI. At present, no effective treatment options are available for these symptoms.

In the present study, we used a weight drop mild TBI mouse model to investigate the effect of a commercially available 10% Cannabidiol (CBD) oil on both the sensorial and neuropsychiatric dysfunctions associated with mild TBI through behavioral and biomolecular approaches.

TBI mice developed chronic pain associated with anxious and aggressive behavior, followed by a late depressive-like behavior and impaired social interaction. Such behaviors were related with specific changes in neurotransmitters release at cortical levels.

CBD oral treatment restored the behavioral alterations and partially normalized the cortical biochemical changes.

In conclusion, our data show some of the brain modifications probably responsible for the behavioral phenotype associated with TBI and suggest the CBD as a pharmacological tool to improve neurological dysfunctions caused by the trauma.”

https://www.ncbi.nlm.nih.gov/pubmed/31040777

https://www.frontiersin.org/articles/10.3389/fphar.2019.00352/full

Marijuana for Parkinson’s Disease?

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“Marijuana is popular in the United States and is being widely legalized for recreational and medicinal purposes. It remains a Schedule 1 substance without fully proven risks and benefits; yet, it is increasingly available in many US states and territories.

Cannabis might have medicinal efficacy in Parkinson’s disease as a form of medical marijuana. Endocannabinoid receptors exist throughout the nervous system and are documented to influence receptors affecting a wide variety of areas. Neuroprotective aspects might be induced by cannabis exposure that might yield benefit against the nigrostriatal degeneration of patients with Parkinson’s disease.

Animal investigations support suggestions of improvement in bradykinesia and/or tremors, but this is unsubstantiated in human studies. However, some patient surveys and anecdotal or case reports indicate that marijuana attenuates some motor manifestations of parkinsonism and also of non-motor, mood and/or cognitive symptoms. Medical marijuana might benefit motor and nonmotor aspects of Parkinson’s disease patients. Currently, these assertions are not substantiated in human investigations and cannabis can also induce side effects. Until studies clarify the safety and efficacy of pharmacotherapy with cannabis products, medical marijuana remains largely without scientific endorsement. Research has yet to document the full benefits, risks, and clinical applications of marijuana as a treatment for patients with Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31037227

Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms.

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Journal of Chemical Neuroanatomy

“Significant limitations with the currently available antidepressant treatment strategies have inspired research on finding new and more efficient drugs to treat depression. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa, and emerges in this regard as a promising compound. In 2010, we were the first laboratory to demonstrate that CBD is effective in animal models of predictive of antidepressant effect, a finding now confirmed by several other groups. Recent evidence suggests that CBD promotes both a rapid and a sustained antidepressant effect in animal models. CBD has a complex pharmacology, with the ability to interact with multiple neurotransmitter systems involved in depression, including the serotonergic, glutamatergic, and endocannabinoid systems. Moreover, CBD induces cellular and molecular changes in brain regions related to depression neurobiology, such as increased Brain Derived Neurotrophic Factor (BDNF) levels and synaptogenesis in the medial prefrontal cortex, as well as it increases neurogenesis in the hippocampus. This review presents a comprehensive critical overview of the current literature related to the antidepressant effects of CBD, with focus at the possible mechanisms. Finally, challenges and perspectives for future research are discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/31039391

https://www.sciencedirect.com/science/article/pii/S0891061818302114?via%3Dihub

Comparison of different methods for the extraction of cannabinoids from cannabis.

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“Cannabis oils, namely concentrated cannabis extracts, are getting plenty of attention because of their therapeutic potential for treatment of patients with cancer, HIV, multiple sclerosis and several other pathologies. Here we propose the use of ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) as alternative methods to the current protocols followed by pharmacists, the only authorized to manipulate standardized Cannabis. A third method, consisting of the use of Tween 20 as surfactant, was considered. Our best extraction methodology for commercial hemp extraction was applied to medicinal cannabis. Here we report the results obtained for ‘Eletta campana’, ‘Carmagnola selezionata’, Bediol®, FM2® and Bedrocan®.”

https://www.ncbi.nlm.nih.gov/pubmed/31035854

https://www.tandfonline.com/doi/abs/10.1080/14786419.2019.1601194?journalCode=gnpl20

Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands.

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“In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c–j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB1 receptor ligands (KiCB1 = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB1antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB1 partial agonist behaviour. CB1 antagonist activity of 1b was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB1antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.”

https://www.ncbi.nlm.nih.gov/pubmed/31035548

https://www.mdpi.com/1420-3049/24/9/1656

Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications.

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ijms-logo “Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.”

https://www.ncbi.nlm.nih.gov/pubmed/31035653

https://www.mdpi.com/1422-0067/20/9/2109

Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol.

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“Muscle wasting, anorexia, and metabolic dysregulation are common side-effects of cytotoxic chemotherapy, having a dose-limiting effect on treatment efficacy, and compromising quality of life and mortality.

Extracts of Cannabis sativa, and analogues of the major phytocannabinoid Δ9-tetrahydrocannabinol, have been used to ameliorate chemotherapy-induced appetite loss and nausea for decades. However, psychoactive side-effects limit their clinical utility, and they have little efficacy against weight loss.

We recently established that the non-psychoactive phytocannabinoid (CBG) stimulates appetite in healthy rats, without neuromotor side-effects. The present study assessed whether CBG attenuates anorexia and/or other cachectic effects induced by the broad-spectrum chemotherapy agent cisplatin.

RESULTS:

CBG (120 mg/kg) modestly increased food intake, predominantly at 36-60hrs (p<0.05), and robustly attenuated cisplatin-induced weight loss from 6.3% to 2.6% at 72hrs (p<0.01). Cisplatin-induced skeletal muscle atrophy was associated with elevated plasma corticosterone (3.7 vs 13.1ng/ml, p<0.01), observed selectively in MHC type IIx (p<0.05) and IIb (p<0.0005) fibres, and was reversed by pharmacological rescue of dysregulated Akt/S6-mediated protein synthesis and autophagy processes. Plasma metabonomic analysis revealed cisplatin administration produced a wide-ranging aberrant metabolic phenotype (Q2Ŷ=0.5380, p=0.001), involving alterations to glucose, amino acid, choline and lipid metabolism, citrate cycle, gut microbiome function, and nephrotoxicity, which were partially normalized by CBG treatment (Q2Ŷ=0.2345, p=0.01). Lipidomic analysis of hypothalami and plasma revealed extensive cisplatin-induced dysregulation of central and peripheral lipoamines (29/79 and 11/26 screened, respectively), including reversible elevations in systemic N-acyl glycine concentrations which were negatively associated with the anti-cachectic effects of CBG treatment.

CONCLUSIONS:

Endocannabinoid-like lipoamines may have hitherto unrecognized roles in the metabolic side-effects associated with chemotherapy, with the N-acyl glycine subfamily in particular identified as a potential therapeutic target and/or biomarker of anabolic interventions. CBG-based treatments may represent a novel therapeutic option for chemotherapy-induced cachexia, warranting investigation in tumour-bearing cachexia models.”

https://www.ncbi.nlm.nih.gov/pubmed/31035309

“Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non-psychotropic and is abundant in some industrial hemp varieties. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling.”
“Cannabigerol displayed significant antitumor activity.” https://link.springer.com/article/10.1007/BF02976895
“Antitumor activity of cannabigerol against human oral epitheloid carcinoma cells. Cannabigerol exhibited the highest growth-inhibitory activity against the cancer cell lines.” https://www.ncbi.nlm.nih.gov/pubmed/9875457

Aging circadian rhythms and cannabinoids.

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Neurobiology of Aging

“Numerous aspects of mammalian physiology exhibit cyclic daily patterns known as circadian rhythms. However, studies in aged humans and animals indicate that these physiological rhythms are not consistent throughout the life span. The simultaneous development of disrupted circadian rhythms and age-related impairments suggests a shared mechanism, which may be amenable to therapeutic intervention.

Recently, the endocannabinoid system has emerged as a complex signaling network, which regulates numerous aspects of circadian physiology relevant to the neurobiology of aging.

Agonists of cannabinoid receptor-1 (CB1) have consistently been shown to decrease neuronal activity, core body temperature, locomotion, and cognitive function. Paradoxically, several lines of evidence now suggest that very low doses of cannabinoids are beneficial in advanced age.

One potential explanation for this phenomenon is that these drugs exhibit hormesis-a biphasic dose-response wherein low doses produce the opposite effects of higher doses. Therefore, it is important to determine the dose-, age-, and time-dependent effects of these substances on the regulation of circadian rhythms and other processes dysregulated in aging.

This review highlights 3 fields-biological aging, circadian rhythms, and endocannabinoid signaling-to critically assess the therapeutic potential of endocannabinoid modulation in aged individuals. If the hormetic properties of exogenous cannabinoids are confirmed, we conclude that precise administration of these compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.”

https://www.ncbi.nlm.nih.gov/pubmed/31035036

https://www.sciencedirect.com/science/article/pii/S0197458019300867?via%3Dihub

Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway.

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“Cannabidiol (CBD), an abundant nonpsychoactive constituent of marijuana, has been reported previously to protect against hepatic steatosis.

In this study, we studied further the functions and mechanisms of CBD on liver inflammation induced by HFC diet.

Mice feeding an HFC diet for 8 weeks were applied to test the protective effect of CBD on livers. RAW264.7 cells were incubated with LPS + ATP ± CBD to study the mechanisms of the effect of CBD against inflammasome activation.

We found that CBD alleviated liver inflammation induced by HFC diet.

CBD significantly inhibited the nuclear factor-κappa B (NF-κB) p65 nuclear translocation and the activation of nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome both in vivo and in vitro studies, which lead to the reduction of the expression of inflammation-related factors in our studies.

In addition, Inhibitor of activation of NF-κB partly suppressed the NLRP3 inflammasome activation, while adding CBD further inhibited NF-κB activation and correspondingly suppressed the NLRP3 inflammasome activation in macrophages.

In conclusion, the suppression of the activation of NLRP3 inflammasome through deactivation of NF-κB in macrophages by CBD might be one mechanism of its anti-inflammatory function in the liver.”

https://www.ncbi.nlm.nih.gov/pubmed/31032942

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.28728