Category Archives: Uncategorized

State marijuana laws and opioid overdose mortality.

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Image result for Injury Epidemiology “The opioid epidemic in the United States is a national public health crisis.

In recent years, marijuana legalization has been increasingly adopted by state governments as a policy intervention to control the opioid epidemic under the premise that marijuana and opioids are substitutive substances.

The purpose of this systematic review is to synthesize the empirical evidence regarding the impact of state marijuana laws on opioid overdose mortality and other opioid-related health outcomes.

RESULTS:

Of the 16 eligible studies, 4 assessed the association of state marijuana law status with opioid overdose mortality, 7 with prescription opioids dispensed, and the remaining with nonmedical use and opioid-related hospitalizations. Random effects modeling based on pooled data revealed that legalizing marijuana for medical use was associated with a statistically non-significant 8% reduction in opioid overdose mortality (95% confidence interval: - 0.21 to 0.04; p = 0.201) and a 7% reduction in prescription opioids dispensed (95% confidence interval: - 0.13 to - 0.01; p = 0.017). Legalizing marijuana for recreational use was associated with an additional 7% reduction in opioid overdose mortality in Colorado and 6% reduction in opioid prescriptions among fee-for-service Medicaid and managed care enrollees.

CONCLUSIONS:

Legalizing marijuana might contribute to a modest reduction in opioid prescriptions. Evidence about the effect of marijuana legalization on opioid overdose mortality is inconsistent and inconclusive. If any, the effectiveness of state marijuana laws in reducing opioid overdose mortality appears to be rather small and limited to states with operational marijuana dispensaries. It remains unclear whether the presumed benefit of legalizing marijuana in reducing opioid-related harms outweighs the policy’s externalities, such as its impact on mental health and traffic safety.”

https://www.ncbi.nlm.nih.gov/pubmed/31497489

“Legalizing marijuana might contribute to a modest reduction in opioid prescriptions.”

https://injepijournal.biomedcentral.com/articles/10.1186/s40621-019-0213-z

Cannabis use and risk of Clostridioides difficile infection: Analysis of 59,824 hospitalizations.

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Anaerobe“The prevalence of Clostridioides difficile Infection (CDI), the most notorious hospital acquired disease, and of excessive cannabis use (cannabis use disorder (CUD)) have both been steadily rising.

Although cannabidiol, an active ingredient of cannabis, maintains gut integrity and suppresses entero-toxins from Clostridioides difficile, the relationship between CUD and CDI has not been studied.

RESULTS:

Among the matched hospitalizations (n = 59,824), cannabis usage was associated with a reduced prevalence of CDI (prevalence: 455.5 [95% CI: 385.1-538.8] vs. 636.4 [95% CI: 549.9-736.5] per 100,000 hospitalizations), resulting in a 28% reduced risk of CDI (relative risk: 0.72 [95% CI: 0.58-0.88]; p = 0002). Non-dependent and dependent CUD respectively had 23% and 80% reduced likelihood of CDI when compared to non-cannabis users (0.77 [95% CI: 0.60-0.95] and 0.20 [95% CI: 0.06-0.54]; p < 0.05). Furthermore, dependent users had less risk of CDI compared to non-dependent users (0.26 [95% CI: 0.08-0.88]; p = 0.01).

CONCLUSIONS:

CUD was associated with a decreased risk of CDI amongst hospitalized patients. Prospective and molecular mechanistic studies are required to elucidate how cannabis and its contents impacts CDI.”

https://www.ncbi.nlm.nih.gov/pubmed/31493498

“Cannabis use was associated with diminished risk of Clostridioides difficile (CDI) amongst hospitalized individuals. Dependent Cannabis users seemed to be the most protected from CDI.”  https://www.sciencedirect.com/science/article/pii/S1075996419301556?via%3Dihub

Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists.

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Biochemical Pharmacology“Cannabinoid receptors type 1 (CB1) and type 2 (CB2) are promising targets for a number of diseases, including obesity, neuropathic pain, and multiple sclerosis, among others.

Upon ligand-mediated activation of these receptors, multiple receptor conformations could be stabilized, resulting in a complex pattern of possible intracellular effects. Although numerous compounds have been developed and widely used to target cannabinoid receptors, their mode of action and signaling properties are often only poorly characterized.

From a drug development point of view, unraveling the underlying complex signaling mechanism could offer the possibility to generate medicines with the desired therapeutic profile.

Recently, an increased interest has emerged for the development of agonists that are signaling pathway-selective and thereby do not evoke on-target adverse effects. This phenomenon, in which specific pathways are preferred upon receptor activation by certain ligands, is also known as ‘biased signaling’.

For a particular group of cannabinoid receptor ligands (i.e. CB1/CB2 agonists), namely the synthetic cannabinoid receptor agonists (SCRAs), the research on biased signaling is still in its infancy and interesting outcomes are only recently being revealed.

Therefore, this review aims at providing insights into the recent knowledge about biased agonism mediated by SCRAs so far. In addition, as these outcomes are obtained using a distinct panel of functional assays, the accompanying difficulties and challenges when comparing functional outcomes are critically discussed. Finally, some guidance on the conceptualization of ideal in vitro assays for the detection of SCRA-mediated biased agonism, which is also relevant for compounds belonging to other chemical classes, is provided.”

https://www.ncbi.nlm.nih.gov/pubmed/31472128

https://www.sciencedirect.com/science/article/abs/pii/S0006295219303132?via%3Dihub

Activation of Cannabinoid Receptors Promote Periodontal Cell Adhesion and Migration.

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Journal of Clinical Periodontology banner“Medical and recreational cannabis use is increasing significantly, but its impacts on oral health remains unclear.

The aim of this study is to investigate the effects of tetrahydrocannabinol (THC), the major active component in cannabis, on periodontal fibroblast cell adhesion and migration to explore its role in periodontal regeneration and wound healing.

RESULTS:

Both CB1 and CB2 were expressed in periodontal tissues but with different expression patterns. THC promoted periodontal cell wound healing by inducing HPLF cell adhesion and migration. This was mediated by focal adhesion kinase (FAK) activation and its modulation of MAPK activities. The effect of cannabinoids on periodontal fibroblast cell adhesion and migration were mainly dependent on the CB2.

CONCLUSION:

These results suggested that cannabinoids may contribute to developing new therapeutics for periodontal regeneration and wound healing.”

https://www.ncbi.nlm.nih.gov/pubmed/31461164

https://onlinelibrary.wiley.com/doi/abs/10.1111/jcpe.13190

Not in my backyard? Not so fast. The effect of marijuana legalization on neighborhood crime

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Regional Science and Urban Economics“This paper studies the effects of marijuana legalization on neighborhood crime and documents the patterns in retail dispensary locations over time using detailed micro-level data from Denver, Colorado. To account for endogenous retail dispensary locations, we use a novel identification strategy that exploits exogenous changes in demand across different locations arising from the increased importance of external markets after the legalization of recreational marijuana sales.

The results imply that an additional dispensary in a neighborhood leads to a reduction of 17 crimes per month per 10,000 residents, which corresponds to roughly a 19 percent decline relative to the average crime rate over the sample period. Reductions in crime are highly localized, with no evidence of spillover benefits to adjacent neighborhoods. Analysis of detailed crime categories provides insights into the mechanisms underlying the reductions.”

https://www.sciencedirect.com/science/article/pii/S016604621830293X

Myrcene and terpene regulation of TRPV1.

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Publication Cover“Nociceptive Transient Receptor Potential channels such as TRPV1 are targets for treating pain. Both antagonism and agonism of TRP channels can promote analgesia, through inactivation and chronic desensitization.

Since plant-derived mixtures of cannabinoids and the Cannabis component myrcene have been suggested as pain therapeutics, we screened terpenes found in Cannabis for activity at TRPV1.

These data establish TRPV1 as a target of Myrcene and suggest the therapeutic potential of analgesic formulations containing Myrcene.”

https://www.ncbi.nlm.nih.gov/pubmed/31446830

https://www.tandfonline.com/doi/full/10.1080/19336950.2019.1654347

Tetrahydrocannabinol Modulates in Vitro Maturation of Oocytes and Improves the Blastocyst Rates after in Vitro Fertilization.

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Image result for Cellular Physiology & Biochemistry“Among the assisted reproductive techniques, the in vitro maturation of oocytes (IVM) is less developed than other techniques, but its implementation would entail a qualitative advance.

This technique consists in the extraction of immature oocytes from antral ovarian follicles with the patient under low hormone stimulation or without hormone to mature exogenously in culture media supplemented with different molecules to promote maturation.

In this sense, we are interested in the role that cannabinoids could have as IVM promoters because cannabinoid’s molecular pathway is similar to the one by which oocyte’s meiosis resumption is activated.

With the intention of advancing in the possible use of cannabinoids as supplements for the media for in vitro maturation of oocytes, we intend to deepen the study of the function of the phytocannabinoid Δ-9-tetrahydrocannabinol (THC) in the IVM process.

RESULTS:

This study confirms that the incubation of oocytes with THC during IVM accelerated some events of that process like the phosphorylation pattern of ERK and AKT and was able to increase the blastocyst rate in response to IVF. Moreover, it seems that both CB1 and CB2 are necessary to maintain a healthy oocyte maturation.

CONCLUSION:

Our data suggest that THC may be useful IVM supplements in clinic as is more feasible and reliable than any synthetic cannabinoid.”

https://www.ncbi.nlm.nih.gov/pubmed/31436397

https://www.cellphysiolbiochem.com/Articles/000149/

Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts.

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Toxicology and Applied Pharmacology“Cannabidiol (CBD) containing products are available in a plethora of flavors including oral, sublingual, and inhalable forms. Immunotoxicological effects of CBD containing liquids were assessed by hypothesizing that CBD regulates oxidative stress and lipopolysaccharide (LPS) induced inflammatory responses in macrophages, epithelial cells, and fibroblasts.

RESULTS:

CBD showed differential effects on IL-8 and MCP-1, and acellular and cellular ROS levels. CBD significantly attenuated LPS-induced NF-κB activity and IL-8 and MCP-1 release from macrophages. Cytokine array data depicted a differential cytokine response due to CBD. Inflammatory mediators, IL-8, serpin E1, CXCL1, IL-6, MIF, IFN-γ, MCP-1, RANTES, and TNF-α were induced, whereas MCP-1/CCL2, CCL5, eotaxin, IL-1ra, and IL-2 were reduced. CBD and dexamethasone treatments reduced the IL-8 level induced by LPS when the cells were treated individually, but showed antagonistic effects when used in combination via MCPIP (monocytic chemotactic protein-induced protein).

CONCLUSION:

CBD differentially regulated basal pro-inflammatory response and attenuated both LPS-induced cytokine release and NF-κB activity in monocytes, similar to dexamethasone. Thus, CBD has a differential inflammatory response and acts as an anti-inflammatory agent in pro-inflammatory conditions but acts as an antagonist with steroids, overriding the anti-inflammatory potential of steroids when used in combination.”

https://www.ncbi.nlm.nih.gov/pubmed/31437494

https://www.sciencedirect.com/science/article/pii/S0041008X19303217?via%3Dihub

Novel cannabis flavonoid, cannflavin A displays both a hormetic and neuroprotective profile against amyloid β-mediated neurotoxicity in PC12 cells: comparison with geranylated flavonoids, mimulone and diplacone.

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Biochemical Pharmacology

“Flavonoids form a diverse class of naturally occurring polyphenols ascribed various biological activities, including inhibition of amyloid β (Aβ) fibrillisation and neurotoxicity of relevance to Alzheimer’s disease.

Cannabis contains a unique subset of prenylated flavonoids, the cannflavins.

While selected conventional flavonoids have demonstrated anti-amyloid and neuroprotective potential, any neuroprotective bioactivity of prenylated flavonoids has not been determined.

We evaluated the in vitro neuroprotective and anti-aggregative properties of the novel geranylated cannabis-derived flavonoid, cannflavin A against Aβ1-42 and compared it to two similarly geranylated flavonoids, mimulone and diplacone, to compare the bioactive properties of these unique flavonoids more broadly.

RESULTS:

Cannflavin A demonstrated intrinsic hormetic effects on cell viability, increasing viability by 40% from 1-10µM but displaying neurotoxicity at higher (>10-100µM) concentrations. Neither mimulone nor diplacone exhibited such a biphasic effect, instead showing only concentration-dependent neurotoxicity, with diplacone the more potent (from >1 µM). However at the lower concentrations (<10µM), cannflavin A increased cell viability by up to 40%, while 10µM cannflavin A inhibited the neurotoxicity elicited by Aβ1-42 (0-2µM), reducing Aβ aggregate adherence to PC-12 cells and associated neurite loss. The neuroprotective effects of cannflavin A were associated with a direct inhibition of Aβ1-42 fibril and aggregate density, evidenced by attenuated ThT fluorescence kinetics and microscopic evidence of both altered and diminished density of Aβ aggregate and fibril morphology via electron microscopy.

CONCLUSIONS:

These findings highlight a concentration-dependent hormetic and neuroprotective role of cannflavin A against Aβ-mediated neurotoxicity, associated with an inhibition of Aβ fibrillisation. The efficacy of the cannabis flavone may itself direct further lead development targeting neurodegeneration in Alzheimer’s disease. However, the geranylated flavonoids generally displayed a comparatively potent neurotoxicity not observed with many conventional flavonoids in vitro.”

https://www.ncbi.nlm.nih.gov/pubmed/31437460

https://www.sciencedirect.com/science/article/abs/pii/S0006295219302990?via%3Dihub

Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation.

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Image result for frontiers in behavioral neuroscience “Δ9-Tetrahydrocannabinol (THC, a CB1 receptor agonist) and Cannabidiol (CBD, a non-competitive antagonist of endogenous CB1 and CB2 ligands) are two primary components of Cannabis species, and may modulate fear learning in mammals.

The CB1 receptor is widely distributed throughout the cortex and some limbic regions typically associated with fear learning. Humans with posttraumatic disorder (PTSD) have widespread upregulation of CB1 receptor density and reduced availability of endogenous cannabinoid anandamide, suggesting a role for the endocannabinoid system in PTSD.

Pharmacological blockade of memory reconsolidation following recall of a conditioned response modulates the expression of learned fear and may represent a viable target for the development of new treatments for PTSD.

In this study, we focused on assessing the impact of the key compounds of the marijuana plant both singly and, more importantly, in concert on attenuation of learned fear. Specifically, we assessed the impact of THC, CBD, and/or the remaining plant materials (post-extraction; background material), on reconsolidation of learned fear.

Results: CBD alone, but not THC alone, significantly attenuated fear memory reconsolidation when administered immediately after recall. The effect persisted for at least 7 days. A combination of CBD and THC also attenuated the fear response. Plant BM also significantly attenuated reconsolidation of learned fear both on its own and in combination with THC and CBD. Finally, THC attenuated reconsolidation of learned fear only when co-administered with CBD or plant BM.

Conclusion: CBD may provide a novel treatment strategy for targeting fear-memories. Furthermore, plant BM also significantly attenuated the fear response. However, whereas THC alone had no significant effects, its effects were modulated by the addition of other compounds. Future research should investigate some of the other components present in the plant BM (such as terpenes) for their effects alone, or in combination with isolated pure cannabinoids, on fear learning.”

https://www.ncbi.nlm.nih.gov/pubmed/31417379

https://www.frontiersin.org/articles/10.3389/fnbeh.2019.00174/full