Category Archives: THC (Delta-9-Tetrahydrocannabinol)

The Acute Activation of the CB1 Receptor in the Hippocampus Decreases Neurotoxicity and Prevents Spatial Memory Impairment in Rats Lesioned with β-Amyloid 25-35.

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Neuroscience“Given their anti-inflammatory properties, cannabinoids have been shown to be neuroprotective agents and to reduce excitotoxicity, through the activation of the Cannabinoid receptor type 1 (CB1r).

These properties have led to CB1r being proposed as pharmacological targets for the treatment of various neurodegenerative diseases.

This study aimed to evaluate the neuroprotective effect of an acute activation of CB1r on spatial memory and its impact on iNOS protein expression, NO● levels, gliosis and the neurodegenerative process induced by the injection of Aβ(25-35) into the CA1 subfield of the hippocampus.

The data obtained in the present research suggest that the acute early activation of CB1r is crucial for neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31400487

https://www.sciencedirect.com/science/article/abs/pii/S0306452219305433?via%3Dihub

Application device for THC:CBD oromucosal spray in the management of resistant spasticity: pre-production testing.

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 Publication Cover“Patients with multiple sclerosis spasticity (MSS) and upper limb/hand impairment who are taking 9-delta-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) may have difficulty self-administering their medication, possibly limiting adherence and treatment effectiveness.

A Class I EU device is available to support administration of THC:CBD spray. Pre-production testing was undertaken in a patient sample.

Results: Fifteen patients participated. Mean treatment time with THC:CBD spray was 4 (range: 0.1-6.1) years. 87% of participants ‘always’, ‘often’ or ‘sometimes’ had hand impairment, and 53% reported difficulty administering THC:CBD spray. Participants reported better application using the device (73%), with less strength required (54%). Most participants (93%) considered the instruction leaflet to be clear and many (66%) expressed interest in using the device. Most HCPs (93%) did not foresee any difficulties in use of the device.

Conclusion: The proposed adherence device was useful to address self-application difficulties with THC:CBD spray in our sample. Providing the device to MSS patients with upper limb/hand spasticity impairment may restore autonomy and support adherence to THC:CBD spray.”

https://www.ncbi.nlm.nih.gov/pubmed/31393179

https://www.tandfonline.com/doi/abs/10.1080/17434440.2019.1653182?journalCode=ierd20

Cannabinoid CB2 Receptor Modulation by the Transcription Factor NRF2 is Specific in Microglial Cells.

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 “Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor that has neuroprotective and anti-inflammatory effects, regulating more than 250 genes. As NRF2, cannabinoid receptor type 2 (CB2) is also implicated in the preservation of neurons against glia-driven inflammation. To this concern, little is known about the regulation pathways implicated in CB2 receptor expression. In this study, we analyze whether NRF2 could modulate the transcription of CB2 in neuronal and microglial cells. Bioinformatics analysis revealed an antioxidant response element in the promoter sequence of the CB2 receptor gene. Further analysis by chemical and genetic manipulations of this transcription factor demonstrated that NRF2 is not able to modulate the expression of CB2 in neurons. On the other hand, at the level of microglia, the expression of CB2 is NRF2-dependent. These results are related to the differential levels of expression of both genes regarding the brain cell type. Since modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neurodegeneration, our findings will contribute to disclose the potential of CB2 as a novel target for treating different pathologies.”

https://www.ncbi.nlm.nih.gov/pubmed/31385133

https://link.springer.com/article/10.1007%2Fs10571-019-00719-y

Δ9-Tetrahydrocannabinol suppresses monocyte-mediated astrocyte production of MCP-1 and IL-6 in a TLR7-stimulated human co-culture.

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Journal of Pharmacology and Experimental Therapeutics“Cannabis is widely used in the United States with an estimated prevalence of 9.5%. Certain cannabinoids in Cannabis sativa, in particular, Δ9-tetrahydrocannabinol (THC), possess immune modulating and anti-inflammatory activity. Depending on the context, the anti-inflammatory activity of cannabinoids may be beneficial, such as in treating inflammatory diseases, or detrimental to normal immune defense against pathogens. The potential beneficial impact of cannabinoids on chronic neuroinflammation has gained recent attention. Monocyte migration to the brain has been implicated as a key event in chronic neuroinflammation and in the etiology of central nervous system diseases including viral infection (e.g., HIV-associated neurocognitive disorder). In the brain, monocytes can contribute to neuroinflammation through interactions with astrocytes, including inducing astrocyte secretion of cytokines and chemokines. In a human co-culture system, monocyte-derived IL-1β due to toll-like receptor 7 (TLR7)-activation, has been identified to promote astrocyte production of MCP-1 and IL-6. THC treatment of TLR7-stimulated co-culture suppressed monocyte secretion of IL-1β resulting in decreased astrocyte production of MCP-1 and IL-6. Furthermore, THC displayed direct inhibition of monocytes, as TLR7-stimulated monocyte monocultures treated with THC also showed suppressed IL-1β production. The cannabinoid receptor 2 (CB2) agonist, JWH-015, impaired monocyte IL-1β production similar to that of THC, suggesting THC is, in part, acting through CB2. THC also suppressed key elements of the IL-1β production pathway, including IL1B mRNA levels and caspase-1 activity. Collectively, this study demonstrates that the anti-inflammatory properties of THC suppress TLR7-induced monocyte secretion of IL-1β, through CB2, which results in decreased astrocyte secretion of MCP-1 and IL-6.

SIGNIFICANCE STATEMENT: As cannabis use is highly prevalent in the United States and has putative anti-inflammatory properties, it is important to investigate the effect of cannabinoids on immune cell function. Furthermore, cannabinoids have garnered particular interest due to their potential beneficial effects on attenuating viral-induced chronic neuroinflammation. This study utilized a primary human co-culture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC) and a cannabinoid receptor-2 (CB2) selective agonist, suppress specific monocyte-mediated astrocyte inflammatory responses. In the context of viral-induced chronic neuroinflammation, the findings presented here suggest that cannabinoids via CB2 ligation may have beneficial anti-inflammatory effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31383729

http://jpet.aspetjournals.org/content/early/2019/08/05/jpet.119.260661

THE EFFECTS OF MEDICAL MARIJUANA DISPENSARIES ON ADVERSE OPIOID OUTCOMES

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 Publication cover image“As more states enact laws liberalizing marijuana use and the U.S. opioid epidemic surges to unprecedented levels, understanding the relationship between marijuana and opioids is growing increasingly important.

Using a unique self‐constructed marijuana dispensary dataset, I estimate the impact of increased marijuana access on opioid‐related harms.

I exploit within‐ and across‐state variation in dispensary openings and find county‐level prescription opioid‐related fatalities decline by 11% following the opening a dispensary.

The estimated dispensary effects are qualitatively similar for opioid‐related admissions to treatment facilities. These results are strongest for males and suggest a substitutability between marijuana and opioids.”

https://onlinelibrary.wiley.com/doi/full/10.1111/ecin.12825

“I find that core-based statistical areas (CBSAs) with dispensary openings experience a 20 percentage point relative decrease in painkiller treatment admissions over the first two years of dispensary operations.”

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3012381

“Access to medical marijuana reduces opioid prescriptions”  https://www.health.harvard.edu/blog/access-to-medical-marijuana-reduces-opioid-prescriptions-2018050914509

THE EFFECTS OF RECREATIONAL MARIJUANA LEGALIZATION AND DISPENSING ON OPIOID MORTALITY

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Publication cover image“This study documents how the changing legal status of marijuana has impacted mortality in the United States over the past two decades.

We use a difference‐in‐difference approach to estimate the effect of medical marijuana laws (MML) and recreational marijuana laws (RML) on fatalities from opioid overdoses, and we find that marijuana access induces sharp reductions in opioid mortality rates.

Our research corroborates prior findings on MMLs and offers the first causal estimates of RML impacts on opioid mortality to date, the latter of which is particularly important given that RMLs are far more expansive in scope and reach than MMLs.

In our preferred econometric specification, we estimate that RMLs reduce annual opioid mortality in the range of 20%–35%, with particularly pronounced effects for synthetic opioids. In further analysis, we demonstrate how RML impacts vary among demographic groups, shedding light on the distributional consequences of these laws.

Our findings are especially important and timely given the scale of the opioid crisis in the United States and simultaneously evolving attitudes and regulations on marijuana use.”

https://onlinelibrary.wiley.com/doi/full/10.1111/ecin.12819

“Marijuana legalization reduces opioid deaths. A new Economic Inquiry study finds that marijuana access leads to reductions in opioid-related deaths.” https://medicalxpress.com/news/2019-08-marijuana-legalization-opioid-deaths.html

Endocannabinoid System and Alcohol Abuse Disorders.

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“Δ9-tetrahydrocannabinol (Δ9-THC), the primary active component in Cannabis sativa preparations such as hashish and marijuana, signals by binding to cell surface receptors. Two types of receptors have been cloned and characterized as cannabinoid (CB) receptors. CB1 receptors (CB1R) are ubiquitously present in the central nervous system (CNS) and are present in both inhibitory interneurons and excitatory neurons at the presynaptic terminal. CB2 receptors (CB2R) are demonstrated in microglial cells, astrocytes, and several neuron subpopulations and are present in both pre- and postsynaptic terminals.

The majority of studies on these receptors have been conducted in the past two and half decades after the identification of the molecular constituents of the endocannabinoid (eCB) system that started with the characterization of CB1R. Subsequently, the seminal discovery was made, which suggested that alcohol (ethanol) alters the eCB system, thus establishing the contribution of the eCB system in the motivation to consume ethanol. Several preclinical studies have provided evidence that CB1R significantly contributes to the motivational and reinforcing properties of ethanol and that the chronic consumption of ethanol alters eCB transmitters and CB1R expression in the brain nuclei associated with addiction pathways.

Additionally, recent seminal studies have further established the role of the eCB system in the development of ethanol-induced developmental disorders, such as fetal alcohol spectrum disorders (FASD). These results are augmented by in vitro and ex vivo studies, showing that acute and chronic treatment with ethanol produces physiologically relevant alterations in the function of the eCB system during development and in the adult stage. This chapter provides a current and comprehensive review of the literature concerning the role of the eCB system in alcohol abuse disorders (AUD).”

https://www.ncbi.nlm.nih.gov/pubmed/31332736

https://link.springer.com/chapter/10.1007%2F978-3-030-21737-2_6

“Binge Alcohol Exposure Transiently Changes the Endocannabinoid System: A Potential Target to Prevent Alcohol-Induced Neurodegeneration.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742761/

The curative effect of cannabinoid 2 receptor agonist on functional failure and disruptive inflammation caused by intestinal ischemia and reperfusion.

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Fundamental & Clinical Pharmacology banner“Ischemia and reperfusion of intestinal tissue (intestinal I/R) induces disruption of ileal contractility and chain responses of inflammatory.

The aim of this study was to reveal whether therapeutic value of cannabinoid 2 (CB2) receptor activity in the intestinal I/R, via to the exogenous administration of CB2 agonist (AM-1241).

Intestinal I/R injury were performed through 30 min ischemia and 150 min reperfusion of mesenteric artery in Wistar rats. The pre-administered doses of 0.1, 1, and 5 mg/kg of CB2 agonist were studied to inhibit inflammation of intestinal I/R injury including ileum smooth muscle contractility, polymorphonuclear cell migration, oxidant/antioxidant defence system, and provocative cytokines.

Pre-administration with CB2 receptor agonist ensured to considerable improving the disrupted contractile responses in ileum smooth muscle along with decreased the formation of MDA that production of lipid peroxidation, reversed the depleted glutathione, inhibited the expression of TNF-α and of IL-1β in the intestinal I/R of rats.

Taken together results of this research, the agonistic activity of CB2 receptor for healing of intestinal I/R injury is ensuring associated with anti-inflammatory mechanisms such as the inhibiting of migration of inflammatory polymorphonuclear cells that origin of acute and initial responses of inflammation, the inhibiting of production of provocative and pro-inflammatory cytokines like TNF-α and IL-1β, the rebalancing of oxidant/antioxidant redox system disrupted in injury of reperfusion period, and the supporting of physiologic defensive systems in endothelial and inducible inflammatory cells.”

https://www.ncbi.nlm.nih.gov/pubmed/31373049

https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12502

Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome.

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Brain, Behavior, and Immunity“Currently, a combination of marijuana cannabinoids including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is used as a drug to treat muscle spasticity in patients with Multiple Sclerosis (MS).

Because these cannabinoids can also suppress inflammation, it is unclear whether such patients benefit from suppression of neuroinflammation and if so, what is the mechanism through which cannabinoids act.

In the currently study, we used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to study the role of gut microbiota in the attenuation of clinical signs of paralysis and inflammation caused by cannabinoids.

THC+CBD treatment attenuated EAE and caused significant decrease in inflammatory cytokines such as IL-17 and IFN-γ while promoting the induction of anti-inflammatory cytokines such as IL-10 and TGF-β. Use of 16S rRNA sequencing on bacterial DNA extracted from the gut revealed that EAE mice showed high abundance of mucin degrading bacterial species, such as Akkermansia muciniphila (A.muc), which was significantly reduced after THC+CBD treatment.

Fecal Material Transfer (FMT) experiments confirmed that THC+CBD-mediated changes in the microbiome play a critical role in attenuating EAE. In silico computational metabolomics revealed that LPS biosynthesis, a key component in gram-negative bacteria such as A.muc, was found to be elevated in EAE mice which was confirmed by demonstrating higher levels of LPS in the brain, while treatment with THC+CBD reversed this trend. EAE mice treated with THC+CBD also had significantly higher levels of short chain fatty acids such as butyric, isovaleric, and valeric acids compared to naïve or disease controls.

Collectively, our data suggest that cannabinoids may attenuate EAE and suppress neuroinflammation by preventing microbial dysbiosis seen during EAE and promoting healthy gut microbiota.”

https://www.ncbi.nlm.nih.gov/pubmed/31356922

https://www.sciencedirect.com/science/article/pii/S0889159119306476?via%3Dihub

Associations between adolescent cannabis use frequency and adult brain structure: A prospective study of boys followed to adulthood.

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Drug and Alcohol Dependence“Few studies have tested the hypothesis that adolescent cannabis users show structural brain alterations in adulthood.

The present study tested associations between prospectively-assessed trajectories of adolescent cannabis use and adult brain structure in a sample of boys followed to adulthood.

Boys in different trajectory subgroups did not differ on adult brain structure in any subcortical or cortical region of interest. Adolescent cannabis use is not associated with structural brain differences in adulthood.”

https://www.ncbi.nlm.nih.gov/pubmed/31357120

 

“Adolescent cannabis users did not differ in adult brain structure. Adolescent cannabis use is not associated with lasting structural brain differences.”

 

https://www.sciencedirect.com/science/article/abs/pii/S0376871619302352?via%3Dihub