Tag Archives: cannabinoid

Cannabinoid signalling in the immature brain: encephalopathies and neurodevelopmental disorders.

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Biochemical Pharmacology

“The endocannabinoid system exerts a crucial neuromodulatory role in many brain areas that is essential for proper regulation of neuronal activity. The role of cannabinoid signalling controlling neuronal activity in the adult brain is also evident when considering its contribution to adult brain insults or neurodegenerative diseases.

In the context of brain genetic or acquired encephalopathies administration of cannabinoid-based molecules has demonstrated to exert symptomatic relief and hence, they are proposed as new potential therapeutic compounds.

This review article summarizes the main evidences indicating the beneficial action of cannabinoid-derived molecules in preclinical models of neonatal hypoxia/ischemic damage. In a second part, we discuss the available evidences of therapeutic actions of cannabidiol in children with refractory epilepsy syndromes. Finally, we discuss the current view of cannabinoid signalling mechanisms active in the immature brain that affect in neural cell fate and can contribute to long-term neural cell plasticity.”

https://www.ncbi.nlm.nih.gov/pubmed/30118663

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303344

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

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“The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30100226

https://www.epilepsybehavior.com/article/S1525-5050(18)30473-6/fulltext

Treatment of Periodontal Ligament Stem Cells with MOR and CBD Promotes Cell Survival and Neuronal Differentiation via the PI3K/Akt/mTOR Pathway.

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“Periodontal ligament mesenchymal stem cells (hPDLSCs), as well as all mesenchymal stem cells, show self-renewal, clonogenicity, and multi-tissue differentiation proprieties and can represent a valid support for regenerative medicine. We treated hPDLSCs with a combination of Moringin (MOR) and Cannabidiol (CBD), in order to understand if treatment could improve their survival and their in vitro differentiation capacity. Stem cells survival is fundamental to achieve a successful therapy outcome in the re-implanted tissue of patients. Through NGS transcriptome analysis, we found that combined treatment increased hPDLSCs survival, by inhibition of apoptosis as demonstrated by enhanced expression of anti-apoptotic genes and reduction of pro-apoptotic ones. Moreover, we investigated the possible involvement of PI3K/Akt/mTOR pathway, emphasizing a differential gene expression between treated and untreated cells. Furthermore, hPDLSCs were cultured for 48 h in the presence or absence of CBD and MOR and, after confirming the cellular viability through MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide) assay, we examined the presence of neuronal markers, through immunofluorescence analysis. We found an increased expression of Nestin and GAP43 (growth associated protein 43) in treated cells. In conclusion, hPDLSCs treated with Moringin and Cannabidiol showed an improved survival capacity and neuronal differentiation potential.”

https://www.ncbi.nlm.nih.gov/pubmed/30096889

http://www.mdpi.com/1422-0067/19/8/2341

Medical marijuana laws and workplace fatalities in the United States

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International Journal of Drug Policy

“The aim of this research was to determine the association between legalizing medical marijuana and workplace fatalities.

To date, 29 states and the District of Columbia have legalized the use of marijuana for medicinal purposes. Although there is increasing concern that legalizing medical marijuana will make workplaces more dangerous, little is known about the relationship between medical marijuana laws (MMLs) and workplace fatalities.

 

Findings

Legalizing medical marijuana was associated with a 19.5% reduction in the expected number of workplace fatalities among workers aged 25–44 (incident rate ratio [IRR], 0.805; 95% CI, .662–.979). The association between legalizing medical marijuana and workplace fatalities among workers aged 16–24, although negative, was not statistically significant at conventional levels. The association between legalizing medical marijuana and workplace fatalities among workers aged 25–44 grew stronger over time. Five years after coming into effect, MMLs were associated with a 33.7% reduction in the expected number of workplace fatalities (IRR, 0.663; 95% CI, .482–.912). MMLs that listed pain as a qualifying condition or allowed collective cultivation were associated with larger reductions in fatalities among workers aged 25–44 than those that did not.

Conclusions

The results provide evidence that legalizing medical marijuana improved workplace safety for workers aged 25–44. Further investigation is required to determine whether this result is attributable to reductions in the consumption of alcohol and other substances that impair cognitive function, memory, and motor skills.”

https://www.sciencedirect.com/science/article/pii/S0955395918301968

“Workplace Deaths Drop After States Legalize Medical Marijuana”  https://www.marijuanamoment.net/workplace-deaths-drop-after-states-legalize-medical-marijuana/

“Medical Marijuana States Have Lower Rates Of Workplace Death, According To New Study” https://www.civilized.life/articles/medical-marijuana-states-have-lower-rates-of-workplace-death-according-to-new-study/

“States with legal medical marijuana have seen a drop in workplace deaths” https://www.businessinsider.com/fatal-work-injuries-decline-in-states-with-medical-marijuana-laws-2019-4

“Legalizing Medical Marijuana Could Make Workplaces Safer.”  https://thefreshtoast.com/cannabis/legalizing-medical-marijuana-could-make-workplaces-safer/

Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

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“To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment.

The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved.

Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile.”

https://www.ncbi.nlm.nih.gov/pubmed/30092753

Glial Endocannabinoid System in Pain Modulation.

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“Pain is affecting the human for centuries and there still is no satisfactory strategy for patients suffering pain particularly chronic pain although intensive studies about its mechanism have been performed in order to improve the treatment of pain.

Cannabinoid is a group of chemicals extracted from plants and has a long history in treating pain through the endogenous cannabinoid receptor in the body, however, its application in pain treatment is limited due to its inverse effects.

Recent studies have indicated that glial cells play critical role in mediating pain processing through multiple pathway, including excitatory and inhibitory neurotransmission in different levels of the nervous system.

Furthermore, the glial cells are found to express cannabinoid receptors.

This review summarized the recent studies about the cannabinoid system in glial cells, which may provide some insight for the studying of pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30084280

https://www.tandfonline.com/doi/abs/10.1080/00207454.2018.1503178

Neuronal preservation and reactive gliosis attenuation following neonatal sciatic nerve axotomy by a fluorinated cannabidiol derivative.

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Neuropharmacology

“Immature peripheral nervous system damage, such as the transection of a peripheral nerve, results in the extensive degeneration of motoneurons and dorsal root ganglia (DRG) sensory neurons, mostly due to apoptotic events.

We have previously shown that cannabidiol (CBD), the most abundant non-psychotropic molecule present in the Cannabis sativa plant, exhibits neuroprotective action when administered daily at a dose of 15 mg/kg.

This study shows that use of the fluorinated synthetic version of CBD (4′-fluoro-cannabidiol, HUF-101) significantly improves neuronal survival by 2-fold compared to that achieved with traditional CBD at one-third the dose. Furthermore, we show that HUF-101 administration significantly upregulates anti-apoptotic genes and blocks the expression of pro-apoptotic nuclear factors.

Two-day-old Wistar rats were subjected to unilateral sectioning of the sciatic nerve and treated daily with HUF-101 (1, 2.5, 5 mg/kg/day, i.p.) or a vehicle solution for five days.

The results were evaluated by Nissl staining, immunohistochemistry, and qRT-PCR. Neuronal counting revealed a 47% rescue of spinal motoneurons and a 79% rescue of DRG neurons (HUF-101, 5 mg/kg). Survival was associated with complete depletion of p53 and a 60-fold elevation in BCL2-like 1 gene expression.

Additionally, peroxisome proliferator-activated receptor gamma (PPAR-gamma) gene expression was downregulated by 80%. Neuronal preservation was coupled with a high preservation of synaptic coverage and a reduction in astroglial and microglial reactions that were evaluated in nearby spinal motoneurons present in the ventral horn of the lumbar intumescence.

Overall, these data strongly indicate that HUF-101 exerts potent neuroprotective effects that are related to anti-apoptotic protection and the reduction of glial reactivity.”

 https://www.ncbi.nlm.nih.gov/pubmed/30096328
https://www.sciencedirect.com/science/article/pii/S0028390818304830?via%3Dihub

Targeted inhibition of the type 2 cannabinoid receptor is a novel approach to reduce renal fibrosis.

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Kidney International Home

“The cannabinoid receptor type 2 (CB2) is a G protein-coupled seven transmembrane receptor that transmits endogenous cannabinoid signaling. The role of CB2 in the pathogenesis of kidney injury and fibrosis remains poorly understood.

Here we demonstrate that CB2 was induced, predominantly in kidney tubular epithelium, in various models of kidney disease induced by unilateral ureteral obstruction, adriamycin or ischemia/reperfusion injury.

By using in silico screening and medicinal chemistry modifications, we discovered a novel compound, XL-001, that bound to CB2 with high affinity and selectivity and acted as an inverse agonist. Delayed administration of XL-001 was also effective in ameliorating kidney fibrosis and inflammation.

Thus, CB2 is a pathogenic mediator in kidney fibrosis and targeted inhibition with the novel inverse agonist XL-001 may provide a strategy in the fight against fibrotic kidney diseases.”

 https://www.ncbi.nlm.nih.gov/pubmed/30093080
https://www.kidney-international.org/article/S0085-2538(18)30397-1/fulltext

Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials.

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“Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects.

Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD.

Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system.

These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well.

Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD.

The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.”

https://www.ncbi.nlm.nih.gov/pubmed/30087591

https://www.frontiersin.org/articles/10.3389/fnins.2018.00502/full

Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs.

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“The objectives of this study were to determine basic oral pharmacokinetics, and assess safety and analgesic efficacy of a cannabidiol (CBD) based oil in dogs with osteoarthritis (OA).

Results: Pharmacokinetics revealed an elimination half-life of 4.2 h at both doses and no observable side effects. Clinically, canine brief pain inventory and Hudson activity scores showed a significant decrease in pain and increase in activity (p < 0.01) with CBD oil. Veterinary assessment showed decreased pain during CBD treatment (p < 0.02). No side effects were reported by owners, however, serum chemistry showed an increase in alkaline phosphatase during CBD treatment (p < 0.01).

Clinical significance: This pharmacokinetic and clinical study suggests that 2 mg/kg of CBD twice daily can help increase comfort and activity in dogs with OA.”

https://www.ncbi.nlm.nih.gov/pubmed/30083539

https://www.frontiersin.org/articles/10.3389/fvets.2018.00165/full