Author Archives: David Worrell

Cannabichromene is a cannabinoid CB2 receptor agonist.

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British Journal of Pharmacology banner“Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest anti-nociceptive and anti-inflammatory effects and potentiates some effects of Δ9 – tetrahydrocannabinol (THC) in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at CB1 and CB2 receptors.

KEY RESULTS:

CBC activated CB2 but not CB1 receptors to produce a hyperpolarization of AtT20 cells. This activation was inhibited by a CB2 antagonist AM630, and sensitive to pertussis toxin. Application of CBC reduced activation of CB2 receptors (but not CB1 receptors) by subsequent co-application of CP55,940, an efficacious CB1 and CB2 agonist. Continuous CBC application induced loss of cell surface CB2 receptors and desensitisation of the CB2-induced hyperpolarization.

CONCLUSIONS AND IMPLICATIONS:

CBC is a selective CB2 receptor agonist displaying higher efficacy than THC in hyperpolarising AtT20 cells. CBC can also recruit CB2 receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB2-mediated modulation of inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31368508

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14815

The Endocannabinoid System May Modulate Sleep Disorders In Aging.

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“Aging is an inevitable process that involves changes along life in multiple neurochemical, neuroanatomical, hormonal systems, and many others. In addition, these biological modifications lead to an increase in age-related sickness such as cardiovascular diseases, osteoporosis, neurodegenerative disorders, and sleep disturbances, among others that affect activities of daily life. Demographic projections have demonstrated that aging will increase its worldwide rate in the coming years. The research on chronic diseases of the elderly is important to gain insights into this growing global burden.

Novel therapeutic approaches aimed for treatment of age-related pathologies have included the endocannabinoid system as an effective tools since this biological system shows beneficial effects in preclinical models. However, and despite these advances, little has been addressed in the arena of the endocannabinoid system as option for treating sleep disorders in aging since experimental evidence suggests that some elements of the endocannabinoid system modulate the sleep-wake cycle.

This article addresses this less-studied field, focusing on the likely perspective of the implication of the endocannabinoid system in the regulation of sleep problems reported in aged. We conclude that beneficial effects regarding the putative efficacy of the endocannabinoid system as therapeutic tools in aging is either inconclusive or still missing.”

https://www.ncbi.nlm.nih.gov/pubmed/31368874

http://www.eurekaselect.com/174043/article

Cannabidiol (CBD) Consumption and Perceived Impact on Extrahepatic Symptoms in Patients with Autoimmune Hepatitis.

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 “Utilization and safety of cannabidiol (CBD) in patients with autoimmune hepatitis (AIH) are currently unknown.

We aimed to identify the frequency of CBD use, impact on symptoms, and safety profile.

The most common reason cited for CBD use was pain (68%), poor sleep (62%), and fatigue (38%). Most respondents using CBD for these symptoms reported a significant improvement in pain (82%), sleep (87%), and fatigue (61%).

In ever CBD users, 17.3% were able to stop a prescription medication because of CBD use: pain medication (47%), immunosuppression (24%), and sleep aids (12%).

Side effects attributed to CBD use were reported in 3% of CBD users, yet there were no reported emergency department visits or hospitalizations.

CBD use was not uncommon in patients with AIH, and its use was associated with reports of improvement in extrahepatic symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/31363952

https://link.springer.com/article/10.1007%2Fs10620-019-05756-7

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

In-hospital outcomes of inflammatory bowel disease in cannabis users: a nationwide propensity-matched analysis in the United States.

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“Literature suggests the role of cannabis (marijuana) as an anti-inflammatory agent. However, the impact of recreational marijuana usage on in-hospital outcomes of inflammatory bowel disease (IBD) remains indistinct.

We assessed the outcomes of Crohn’s disease (CD) as well as ulcerative colitis (UC) with vs. without recreational marijuana usage using a nationally illustrative propensity-matched sample.

RESULTS:

Propensity-matched cohorts included 6,002 CD (2,999 cannabis users & 3,003 non-users) and 1,481 UC (742 cannabisusers & 739 non-users) hospitalizations. In CD patients, prevalence of colorectal cancer (0.3% vs. 1.2%, P<0.001), need for parenteral nutrition (3.0% vs. 4.7%, P=0.001) and anemia (25.6% vs. 30.1%, P<0.001) were lower in cannabis users. However, active fistulizing disease or intraabdominal abscess formation (8.6% vs. 5.9%, P<0.001), unspecific lower gastrointestinal (GI) hemorrhage (4.0% vs. 2.7%, P=0.004) and hypovolemia (1.2% vs. 0.5%, P=0.004) were higher with recreational cannabis use. The mean hospital stay was shorter (4.2 vs. 5.0 days) with less hospital charges ($28,956 vs. $35,180, P<0.001) in cannabis users. In patients with UC, cannabis users faced the higher frequency of fluid and electrolyte disorders (45.1% vs. 29.6%, P<0.001), and hypovolemia (2.7% vs.<11) with relatively lower frequency of postoperative infections (<11 vs. 3.4%, P=0.010). No other complications were significant enough for comparison between the cannabis users and non-users in this group. Like CD, UC-cannabis patients had shorter mean hospital stay (LOS) (4.3 vs. 5.7 days, P<0.001) and faced less financial burden ($30,393 vs. $41,308, P<0.001).

CONCLUSIONS:

We found a lower frequency of colorectal cancer, parenteral nutrition, anemia but a higher occurrences of active fistulizing disease or intraabdominal abscess formation, lower GI hemorrhage and hypovolemia in the CD cohort with cannabis usage. In patients with UC, frequency of complications could not be compared between the two cohorts, except a higher frequency of fluid and electrolyte disorders and hypovolemia, and a lower frequency of postoperative infections with cannabis use. A shorter length of stay (LOS)  and lesser hospital charges were observed in both groups with recreational marijuana usage.”

https://www.ncbi.nlm.nih.gov/pubmed/31355219

http://atm.amegroups.com/article/view/25637/24217

Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells.

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 biomolecules-logo“The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties.

The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells.

We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells.

These results indicated that CBD could induce G0-G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/31349651

“These findings may be utilized in the development of CBD as a potential drug for the treatment of gastric cancer.”

https://www.mdpi.com/2218-273X/9/8/302

Therapeutic potential of cannabinoids as neuroprotective agents for damaged cells conducing to movement disorders.

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International Review of Neurobiology“The basal ganglia (BG), an organized network of nuclei that integrates cortical information, play a crucial role in controlling motor function. In fact, movement disorders such as Parkinson’s disease (PD) and Huntington’s disease (HD) are caused by the degeneration of specific structures within the BG.

There is substantial evidence supporting the idea that cannabinoids may constitute novel promising compounds for the treatment of movement disorders as neuroprotective and anti-inflammatory agents.

This potential therapeutic role of cannabinoids is based, among other qualities, on their capacity to reduce oxidative injury and excitotoxicity, control calcium influx and limit the toxicity of reactive microglia.

The mechanisms involved in these effects are related to CB1 and CB2 receptor activation, although some of the effects are CB receptor independent.

Thus, taking into account the aforementioned properties, compounds that act on the endocannabinoid system could be useful as a basis for developing disease-modifying therapies for PD and HD.”

https://www.ncbi.nlm.nih.gov/pubmed/31349929

https://www.sciencedirect.com/science/article/pii/S0074774219300327?via%3Dihub

Modulators of the endocannabinoid system influence skin barrier repair, epidermal proliferation, differentiation and inflammation in a mouse model.

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Experimental Dermatology banner“Endocannabinoids (ECs) are important regulators of cell signaling.

Cannabinoid receptors are involved in keratinocyte proliferation/differentiation.

Elevation of the endogenous cannabinoid tone leads to strong anti-inflammatory effects.

Here, we explored the influence of endocannabinoid system (ECS) modulators on skin permeability barrier repair, epidermal proliferation, differentiation and inflammation in hairless mice.

We used WOBE440, a selective fatty acid amide hydrolase (FAAH) inhibitor, WOL067-531, an inhibitor of endocannabinoid reuptake with no relevant FAAH activity, which both signal via cannabinoid receptor-1and 2 (CB-1R and CB-2R) and compared them to WOBE15 which signals via CB-2R.

We found that barrier repair was significantly delayed by WOL067-531.

In summary, we showed that WOL067-531 exhibits a significant effect on skin barrier repair, epidermal proliferation/differentiation and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31350927

https://onlinelibrary.wiley.com/doi/abs/10.1111/exd.14012

Development of An Oral Treatment with the PPAR-γ-Acting Cannabinoid VCE-003.2 Against the Inflammation-Driven Neuronal Deterioration in Experimental Parkinson’s Disease.

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molecules-logo “In a recent study, we described the neuroprotective properties of VCE-003.2-an aminoquinone derivative of the non-psychotropic phytocannabinoid cannabigerol (CBG)-administered intraperitoneally (i.p.) in an inflammatory model of Parkinson’s disease (PD). We also demonstrated that these properties derive from its activity on the peroxisome proliferator-activated receptor-γ, in particular at a regulatory site within this receptor type.

In the present study, we wanted to further confirm this neuroprotective potential using an oral lipid formulation of VCE-003.2, developed to facilitate the clinical development of this phytocannabinoid derivative.

To this end, we evaluated VCE-003.2, administered orally at two doses (10 and 20 mg/kg), to mice subjected to unilateral intrastriatal injections of lipopolysaccharide (LPS), a classic model of inflammation-driven neuronal deterioration that recapitulates characteristics of PD.

In summary, our data confirm the neuroprotective potential of an oral formulation of VCE-003.2 against neuronal injury in an in vivo model of PD based on neuroinflammation, and this study opens the possibility to further the development of oral VCE-003.2 in the clinic.”

https://www.ncbi.nlm.nih.gov/pubmed/31349553

https://www.mdpi.com/1420-3049/24/15/2702