Synthetic Cannabinoids Influence the Invasion of Glioblastoma Cell Lines in a Cell- and Receptor-Dependent Manner.

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“The current treatment of glioblastoma is not sufficient, since they are heterogeneous and often resistant to chemotherapy.

Earlier studies demonstrated effects of specific cannabinoid receptor (CB) agonists on the invasiveness of glioblastoma cell lines, but the exact mechanism remained unclear.

Three human glioblastoma cell lines were treated with synthetic CB ligands. The effect of cannabinoids on microRNAs (miRs), Akt, and on the expression of proliferation and apoptosis markers were analyzed.

Furthermore, in a model of organotypic hippocampal slice cultures cannabinoid mediated changes in the invasiveness were assessed. MicroRNAs and the activation of Akt which are related to cell migration, apoptosis, and proliferation were evaluated and found not to be associated with changes in the invasiveness after treatment with CB ligands.

Also proliferation and/or apoptosis were not altered after treatment. The effects of cannabinoids on invasiveness could be blocked by the application of receptor antagonists and are likely mediated via CB₁/CB₂.

In conclusion, our results suggest that cannabinoids can influence glioblastoma cell invasion in a receptor and cell type specific manner that is independent of proliferation and apoptosis. Thus, cannabinoids can potentially be used in the future as an addition to current therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/30709059
https://www.mdpi.com/2072-6694/11/2/161

Opposite effects of cannabinoid CB1 and CB2 receptors on antipsychotic clozapine-induced cardiotoxicity.

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“Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis but the risk of severe cardiotoxicity limits its clinical use.

The present study investigated the myocardial injury effects of clozapine and assessed the involvement of cannabinoid receptors in clozapine cardiotoxicity.

Our data provided evidence that cannabinoid CB1 and CB2 receptors had opposite effects and selective antagonists of CB1R or agonists of CB2R might confer protective effects against clozapine.”

https://www.ncbi.nlm.nih.gov/pubmed/30707759

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14591

Activation of the cannabinoid CB2 receptor increases renal perfusion.

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“Acute kidney injury (AKI) is an increasing problem clinically and is associated with chronic kidney disease progression.

Cannabinoid type 2 receptor activation has been shown to mitigate some of the deleterious tubular effects due to AKI, but its role on the renal vasculature has not been fully described.

In this study, we investigated the effects of our novel cannabinoid CB2 receptor agonist, SMM-295, on renal vasculature by assessing cortical perfusion using laser Doppler flowmetry and changes in luminal diameter using isolated afferent arterioles.

These data provide new insight into the potential benefit of SMM-295 by activating vascular and non-vascular CB2 receptors to promote renal vasodilation, and provide a new therapeutic target to treat renal injuries that impact renal blood flow dynamics.”

 https://www.ncbi.nlm.nih.gov/pubmed/30707046
https://www.physiology.org/doi/abs/10.1152/physiolgenomics.00001.2019

Is cannabidiol the ideal drug to treat non-motor Parkinson’s disease symptoms?

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 “Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rest tremor, postural disturbances, and rigidity. PD is also characterized by non-motor symptoms such as sleep disturbances, cognitive deficits, and psychiatric disorders such as psychosis, depression, and anxiety. The pharmacological treatment for these symptoms is limited in efficacy and induce significant adverse reactions, highlighting the need for better treatment options.

Cannabidiol (CBD) is a phytocannabinoid devoid of the euphoriant and cognitive effects of tetrahydrocannabinol, and preclinical and preliminary clinical studies suggest that this compound has therapeutic effect in non-motor symptoms of PD.

In the present text, we review the clinical studies of cannabinoids in PD and the preclinical and clinical studies specifically on CBD.

We found four randomized controlled trials (RCTs) involving the administration of agonists/antagonists of the cannabinoid 1 receptor, showing that these compounds were well tolerated, but only one study found positive results (reductions on levodopa-induced dyskinesia).

We found seven preclinical models of PD using CBD, with six studies showing a neuroprotective effect of CBD.

We found three trials involving CBD and PD: an open-label study, a case series, and an RCT. CBD was well tolerated, and all three studies reported significant therapeutic effects in non-motor symptoms (psychosis, rapid eye movement sleep behaviour disorder, daily activities, and stigma). However, sample sizes were small and CBD treatment was short (up to 6 weeks). Large-scale RCTs are needed to try to replicate these results and to assess the long-term safety of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/30706171

https://link.springer.com/article/10.1007%2Fs00406-019-00982-6

How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

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“We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders.

Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a  meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists.

THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.”

https://www.ncbi.nlm.nih.gov/pubmed/30706168

https://link.springer.com/article/10.1007%2Fs00406-019-00984-4

Potential Use of Cannabinoids for the Treatment of Pancreatic Cancer.

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“Cannabinoid extracts may have anticancer properties, which can improve cancer treatment outcomes.

The aim of this review is to determine the potentially utility of cannabinoids in the treatment of pancreatic cancer.

Results: Cannabinol receptors have been identified in pancreatic cancer with several studies showing in vitroantiproliferative and proapoptotic effects. The main active substances found in cannabis plants are cannabidiol (CBD) and tetrahydrocannabinol (THC). There effects are predominately mediated through, but not limited to cannabinoid receptor-1, cannabinoid receptor-2, and G-protein-coupled receptor 55 pathways. In vitro studies consistently demonstrated tumor growth-inhibiting effects with CBD, THC, and synthetic derivatives. Synergistic treatment effects have been shown in two studies with the combination of CBD/synthetic cannabinoid receptor ligands and chemotherapy in xenograft and genetically modified spontaneous pancreatic cancer models. There are, however, no clinical studies to date showing treatment benefits in patients with pancreatic cancer.

Conclusions: Cannabinoids may be an effective adjunct for the treatment of pancreatic cancer. Data on the anticancer effectiveness of various cannabinoid formulations, treatment dosing, precise mode of action, and clinical studies are lacking.”

 https://www.ncbi.nlm.nih.gov/pubmed/30706048
“Endogenous cannabinoids, synthetic or cannabis extracted from plants, can reduce tumor invasion and growth, induce tumor cell death, and inhibit tumor angiogenesis via cannabinoid receptor or receptor-independent pathways. Cannabinoid receptors appear to be highly expressed in pancreatic cancer compared with normal pancreatic tissue. CBD and THC appear to have antiproliferative and proapoptotic effects.”
https://www.liebertpub.com/doi/10.1089/pancan.2018.0019

Cannabinoids and Bone Regeneration.

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 Publication Cover“Bone is a complex tissue of the with unique properties such as high strength and regeneration capabilities while carrying out multiple functions. Bone regeneration occurs both in physiological situations (bone turnover) and pathological situations (e.g. fractures), being performed by osteoblasts and osteoclasts. If this process is inadequate, fracture nonunion or aseptic loosening of implants occurs and requires a complex treatment.

Exogenous factors are currently used to increase bone regeneration process when needed, such as bisphosphonates and vitamin D, but limitations do exist. Cannabinoid system has been shown to have positive effects on bone metabolism. Cannabinoids at bone level mainly act on two receptors called CB-1 and CB-2, but GPR55, GPR119, TPRV1, TPRV4 receptors may also be involved. The CB-2 receptors are found in bone cells at higher levels compared to other receptors.

Endocannabinods represented by anandamide and 2-arachidonoylglycerol, can stimulate osteoblast formation, bone formation and osteoclast activity. CB-2 agonists including HU-308, HU-433, JWH133 and JWH015 can stimulate osteoblast proliferation and activity, while CB-2 antagonists such as AM630 and SR144528 can inhibit osteoclast differentiation and function. CB-1 antagonist AM251 has been shown to inhibit osteoclast differentiation and activity, while GPR55 antagonist cannabidiol increases osteoblast activity and decreases osteoclast function.

An optimal correlation of dose, duration, moment of action and affinity can lead to an increased bone regeneration capacity, with important benefits in many pathological situations which involve bone tissue. As adverse reactions of cannabinoids haven’t been described in patients under controlled medication, cannabinoids can represent future treatment for bone regeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30702341

https://www.tandfonline.com/doi/abs/10.1080/03602532.2019.1574303?journalCode=idmr20

Recreational marijuana legalization and prescription opioids received by Medicaid enrollees.

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“Medical marijuana use may substitute prescription opioid use, whereas nonmedical marijuana use may be a risk factor of prescription opioid misuse. This study examined the associations between recreational marijuana legalization and prescription opioids received by Medicaid enrollees. In models comparing eight states and DC, legalization was not associated with Schedule II opioid outcomes; having recreational marijuana legalization effective in 2015 was associated with reductions in number of prescriptions, total doses, and spending of Schedule III opioids by 32%, and 31%, respectively. In models comparing eight states and DC to six states with medical marijuana legalization, recreational marijuana legalization was not associated with any opioid outcome. No evidence suggested that recreational marijuana legalization increased prescription opioids received by Medicaid enrollees. There was some evidence in some states for reduced Schedule III opioids following the legalization.” https://www.ncbi.nlm.nih.gov/pubmed/30390550

https://www.sciencedirect.com/science/article/pii/S0376871618307567?via%3Dihub

Impact of Medical Marijuana Legalization on Opioid Use, Chronic Opioid Use, and High-risk Opioid Use.

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“Medical marijuana legalization was found to be associated with a lower odds of any opioid use. In states where marijuana is available through medical channels, a modestly lower rate of opioid and high-risk opioid prescribing was observed. Policy makers could consider medical marijuana legalization as a tool that may modestly reduce chronic and high-risk opioid use.” https://www.ncbi.nlm.nih.gov/pubmed/30684198

https://link.springer.com/article/10.1007%2Fs11606-018-4782-2

Marijuana Consumption in Liver Transplant Recipients.

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“Marijuana is legalized for either medical or recreational use in over half of the United States and in Canada, but many transplant centers will not list patients who are using marijuana. However, the effect of marijuana on transplant outcomes remains unclear. Thus, we performed a retrospective analysis of all adult (≥18 years old) liver transplant patients treated at our center between 2007 and 2017. After adjustment, current tobacco users were over three times as likely to die within 5 years, compared to never users, but no difference was seen between current/former and never marijuana users. No significant differences in inpatient respiratory complications, reintubation, or >24 hours intubation was seen. Overall, pre-transplant marijuana use, past or current, does not appear to impact liver transplant outcomes; however, tobacco smoking remains detrimental.”

https://www.ncbi.nlm.nih.gov/pubmed/30693668

https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/lt.25417