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The synthetic cannabinoid dehydroxylcannabidiol restores the function of a major GABAA receptor isoform in a cell model of hyperekplexia.

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Image result for journal of biological chemistry“The functions of the glycine receptor (GlyR) and γ-aminobutyric acid type A receptor (GABAAR) are both impaired in hyperekplexia, a neurological disorder that is usually caused by GlyR mutations.

Although emerging evidence indicates that cannabinoids can directly restore normal GlyR function, whether they affect the GABAAR in hyperekplexia remains unknown.

Here, we show that dehydroxylcannabidiol (DH-CBD), a synthetic nonpsychoactive cannabinoid, restores both the GABA- and glycine-activated currents (IGABA and IGly ) in HEK-293 cells co-expressing a major GABAAR isoform (α1β2γ2) and GlyRα1 carrying a human hyperekplexia-associated mutation (GlyRα1 R271Q). Using co-immunoprecipitation and FRET assays, we found that DH-CBD disrupts the protein interaction between GABAAR and GlyRα1 R271Q

Furthermore, a point mutation of GlyRα1, changing Ser-296 to Ala-296, which is critical for cannabinoid binding on GlyR, significantly blocked the DH-CBD-induced restoration of IGABA and IGly currents. This S296A substitution also considerably attenuated the DH-CBD-induced disruption of the interaction between GlyRα1 R271Q and GABAAR.

These findings suggest that because it restores the functions of both GlyRα1 and GABAAR, DH-CBD may represent a potentially valuable candidate drug to manage hyperekplexia.”

https://www.ncbi.nlm.nih.gov/pubmed/31757808

http://www.jbc.org/content/early/2019/11/22/jbc.RA119.011221

Investigating the causal effect of cannabis use on cognitive function with a quasi-experimental co-twin design.

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Drug and Alcohol Dependence“It is unclear whether cannabis use causes cognitive decline; several studies show an association between cannabis use and cognitive decline, but quasi-experimental twin studies have found little support for a causal effect.

Here, we evaluate the association of cannabis use with general cognitive ability and executive functions (EFs) while controlling for genetic and shared environmental confounds in a longitudinal twin study.

CONCLUSIONS:

We found little support for a potential causal effect of cannabis use on cognition, consistent with previous twin studies. Results suggest that cannabis use may not cause decline in cognitive ability among a normative sample of cannabis users.”

https://www.ncbi.nlm.nih.gov/pubmed/31753729

“Overall, there was little evidence for causal effect of cannabis on cognition.”

https://www.sciencedirect.com/science/article/abs/pii/S0376871619304892?via%3Dihub

Cannabinoid receptor 2 activation decreases severity of cyclophosphamide-induced cystitis via regulating autophagy.

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Publication cover image“Cannabinoids have been shown to exert analgesic and anti-inflammatory effects, and the effects of cannabinoids are mediated primarily by cannabinoid receptors 1 and 2 (CB1 and CB2).

The objective of this study was to determine efficacy and mechanism of CB2 activation on cyclophosphamide (CYP)-induced cystitis in vivo.

CONCLUSIONS:

Activation of CB2 decreased severity of CYP-induced cystitis and ameliorated bladder inflammation. CB2 activation is protective in cystitis through the activation of autophagy and AMPK-mTOR pathway may be involved in the initiation of autophagy.”

https://www.ncbi.nlm.nih.gov/pubmed/31729056

https://onlinelibrary.wiley.com/doi/abs/10.1002/nau.24205

The Cannabinoid WIN 55,212-2 Reduces Delayed Neurologic Sequelae After Carbon Monoxide Poisoning by Promoting Microglial M2 Polarization Through ST2 Signaling.

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 “Delayed neurologic sequelae (DNS) are among the most serious complications of carbon monoxide (CO) poisoning caused partly by elevated neuroinflammation.

WIN 55,212-2, a non-selective agonist of cannabinoid receptors, has been demonstrated to have anti-inflammatory properties in various brain disorders.

The anti-inflammatory action of WIN 55,212-2 is potentially associated with driving microglial M2 polarization. ST2 signaling is important in regulating inflammatory responses and microglial polarization. Therefore, we aimed to investigate the neuroprotective effect of WIN 55,212-2 on DNS after CO poisoning and elucidate its relationship with ST2-mediated microglial M2 polarization.

The behavioral tests showed that treatment with WIN 55,212-2 significantly ameliorates the cognitive impairment induced by CO poisoning.

This behavioral improvement was accompanied by reduced neuron loss, decreased production of pro-inflammatory cytokines, and a limited number of microglia in the hippocampus. Moreover, WIN 55,212-2 elevated the protein expression of IL-33 (the ligand of ST2) and ST2, increased the ratio of CD206-positive (M2 phenotype) and ST2-positive microglia, and augmented production of M2 microglia-associated cytokines in the hippocampus of CO-exposed rats.

Furthermore, we observed that the WIN 55,212-2-mediated increases in ST2 protein expression, CD206-positive and ST2-positive microglia, and microglia-associated cytokines were blocked by the cannabinoid receptor 2 (CB2R) antagonist AM630 but not by the cannabinoid receptor 1 (CB1R) antagonist AM251. In contrast, the WIN 55,212-2-induced upregulation of the IL-33 protein expression was inhibited by AM251 but not by AM630.

Altogether, these findings reveal cannabinoid receptors as promising therapeutic agents for CO poisoning and identify ST2 signaling-related microglial M2 polarization as a new mechanism of cannabinoid-induced neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31732924

https://link.springer.com/article/10.1007%2Fs12031-019-01429-2

Cannabidiol Protects Dopaminergic Neuronal Cells from Cadmium.

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ijerph-logo“The protective effect of cannabidiol (CBD), the non-psychoactive component of Cannabis sativa, against neuronal toxicity induced by cadmium chloride (CdCl2 10 μM) was investigated in a retinoic acid (RA)-differentiated SH-SY5Y neuroblastoma cell line.

CBD (1 μM) was applied 24 h before and removed during cadmium (Cd) treatment. In differentiated neuronal cells, CBD significantly reduced the Cd-dependent decrease of cell viability, and the rapid reactive oxygen species (ROS) increase.

CBD significantly prevented the endoplasmic reticulum (ER) stress (GRP78 increase) and the subcellular distribution of the cytochrome C, as well as the overexpression of the pro-apoptotic protein BAX. Immunocytochemical analysis as well as quantitative protein evaluation by western blotting revealed that CBD partially counteracted the depletion of the growth associated protein 43 (GAP43) and of the neuronal specific class III β-tubulin (β3 tubulin) induced by Cd treatment.

These data showed that Cd-induced neuronal injury was ameliorated by CBD treatment and it was concluded that CBD may represent a potential option to protect neuronal cells from the detrimental effects of Cd toxicity.”

https://www.ncbi.nlm.nih.gov/pubmed/31718076

https://www.mdpi.com/1660-4601/16/22/4420

Cell Suspensions of Cannabis sativa (var. Futura): Effect of Elicitation on Metabolite Content and Antioxidant Activity.

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molecules-logo“Cannabis sativa L. is one of the most-studied species for its phytochemistry due to the abundance of secondary metabolites, including cannabinoids, terpenes and phenolic compounds. In the last decade, fiber-type hemp varieties have received interest for the production of many specialized secondary metabolites derived from the phenylpropanoid pathway. The interest in these molecules is due to their antioxidant activity.

Since secondary metabolite synthesis occurs at a very low level in plants, the aim of this study was to develop a strategy to increase the production of such compounds and to elucidate the biochemical pathways involved. Therefore, cell suspensions of industrial hemp (C. sativa L. var. Futura) were produced, and an advantageous elicitation strategy (methyl jasmonate, MeJA) in combination with precursor feeding (tyrosine, Tyr) was developed.

The activity and expression of phenylalanine ammonia-lyase (PAL) and tyrosine aminotransferase (TAT) increased upon treatment. Through 1H-NMR analyses, some aromatic compounds were identified, including, for the first time, 4-hydroxyphenylpyruvate (4-HPP) in addition to tyrosol. The 4-day MeJA+Tyr elicited samples showed a 51% increase in the in vitro assay (2,2-diphenyl-1-picrylhydrazyl, DPPH) radical scavenging activity relative to the control and a 80% increase in the cellular antioxidant activity estimated on an ex vivo model of human erythrocytes.

Our results outline the active metabolic pathways and the antioxidant properties of hemp cell extracts under the effect of specific elicitors.”

https://www.ncbi.nlm.nih.gov/pubmed/31717508

https://www.mdpi.com/1420-3049/24/22/4056

Whole blood transcriptome analysis in ewes fed with hemp seed supplemented diet.

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Image result for scientific reports “The hemp plant (Cannabis sativa L.) has a long tradition of being used for many different purposes such as industry, medicine and nutrition. In particular, because hemp seed (HS) is rich in oil protein and considerable amounts of dietary fiber, vitamins and minerals that are particularly suitable also for animal nutrition.

Different studies have evaluated HS on qualitative and quantitative properties of livestock products but as of today, nobody has investigated the molecular pathway behind HS supplementation in farm animals. Thus, in this study, we will report the first RNA sequencing of the whole-blood transcriptome of ewes fed either with a controlled diet (CTR, n = 5) or with a diet supplemented with 5% of hemp seed (HSG, n = 5).

These results indicate that HS supplementation positively affects the energy production pathway in lactating ewes conferring them also more resistance to adverse climatic conditions such as low temperature. Finally, the higher milk lactose content makes the derived dairy products more profitable.”

https://www.ncbi.nlm.nih.gov/pubmed/31700124

“In conclusion, in this study, we have assessed the transcriptome signature induced by 5% hemp seed supplemented diet in ewes. The findings suggest that pathways related to energy production were the most affected. In addition, we found that this condition could also be potentially beneficial for adaptation to low temperatures. Moreover, we found a higher content of lactose, which makes the derived dairy products more profitable.”

https://www.nature.com/articles/s41598-019-52712-6

Relieving tension: effects of cannabinoids on vagal afferent sensitivity.

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Publication cover image“Endocannabinoids are produced within the gastrointestinal (GI) tract and modulate energy homeostasis and food intake, at least in part, via vagally-dependent actions. The recent paper by Christie et al., [Christie, et al. J Physiol, 2019] demonstrate, for the first time, that cannabinoids exert biphasic effects on the mechanosensitivity of tension-sensitive gastric vagal afferents. At higher concentrations, anandamide increased vagal afferent sensitivity in a CB1 and TRPV1 receptor dependent manner. At lower concentrations, however, anandamide decreased afferent mechanosensitivity; while this was also dependent upon CB1 and TRPV1 receptors, it also appeared dependent upon signaling via the potent orexigenic neurohormone, ghrelin. These results provide further evidence to support the remarkable degree of neuroplasticity within vagal afferent signaling, and suggest that untangling the complex interactions of cannabinoid effects on food intake and energy homeostasis will require careful physiological and pharmacological investigations.”

https://www.ncbi.nlm.nih.gov/pubmed/31707736

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP279173

“A clear understanding of the mechanisms which mediate these events may provide novel therapeutic targets for the treatment of gastrointestinal disorders due to vago-vagal pathway malfunctions.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318799/

Cannabis use disorder among people using cannabis daily/almost daily in the United States, 2002–2016

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Drug and Alcohol Dependence“Cannabis use disorder (CUD) prevalence among people reporting past-year cannabis use declined from 2002–2016.

We examined whether similar reductions in CUD were observed among people reporting daily/almost daily cannabis use.

We expected that CUD prevalence among people reporting daily/almost daily use would not decrease.

Results

From 2002–2016, the prevalence of CUD among people reporting daily/almost daily cannabis use decreased by 26.8% in adolescents, by 29.7% in ages 18–25, and by 37.5% in ages 26 + . Prevalence of DSM-IV cannabis dependence decreased significantly among adolescents (-43.9%) and young adults (-26.8%) but remained stable in adults 26 + . Reductions in most dependence items were observed in young adults, with less consistent patterns in adolescents and adults 26 + . Prevalence of DSM-IV cannabis abuse decreased overall and for each abuse item across all age groups.

Conclusions

Contrary to expectations, CUD prevalence decreased significantly across all ages reporting daily/almost daily cannabis use between 2002–2016. Cannabis dependence prevalence decreased for adolescents and young adults and was stable only among adults ages 26+ reporting daily/almost daily cannabis use. Potential drivers of this decrease should be further explored.

The prevalence of cannabis use disorder decreased in frequent cannabis users. Endorsement of cannabis abuse items decreased in adolescents and young adults. Endorsement of cannabis dependence items decreased mainly in young adults. Changes in social attitudes and frequent users’ features may explain findings.”

https://www.sciencedirect.com/science/article/abs/pii/S0376871619303989

“Cannabis use disorder is declining among young adolescents and young adults. The prevalence of cannabis use disorder decreased in 2002 to 2016 among frequent users. Changes in social attitudes and the traits of frequent users may explain the decline, according to researchers. This is one of the first studies to examine the general health profile of people using cannabis daily or almost daily and the trends in the prevalence of cannabis use disorder in this population.”

https://www.sciencedaily.com/releases/2019/10/191031100512.htm

The Impact of Medical Marijuana Laws and Dispensaries on Self-Reported Health

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 “Growing evidence suggests that medical marijuana laws have harm reduction effects across a variety of outcomes related to risky health behaviors. This study investigates the impact of medical marijuana laws on self-reported health using data from the Behavioral Risk Factor Surveillance System from 1993 to 2013. In our analyses we separately identify the effect of a medical marijuana law and the impact of subsequent active and legally protected dispensaries. Our main results show surprisingly limited improvements in self-reported health after the legalization of medical marijuana and legally protected dispensaries. Subsample analyses reveal strong improvements in health among non-white individuals, those reporting chronic pain, and those with a high school degree, driven predominately by whether or not the state had active and legally protected dispensaries. We also complement the analysis by evaluating the impact on risky health behaviors and find that the aforementioned demographic groups experience large reductions in alcohol consumption after the implementation of a medical marijuana law.”

https://www.degruyter.com/view/j/fhep.ahead-of-print/fhep-2019-0002/fhep-2019-0002.xml

“Study Links Medical Marijuana Access To Better Health. Access to medical marijuana appears to improve the health of some patients, even reducing their alcohol intake, according to new research.” https://thefreshtoast.com/cannabis/study-links-legal-marijuana-access-to-better-health/