Author Archives: David Worrell

PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment.

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pharmaceutics-logo“The intraperitoneal administration of chemotherapeutics has emerged as a potential route in ovarian cancer treatment. Nanoparticles as carriers for these agents could be interesting by increasing the retention of chemotherapeutics within the peritoneal cavity. Moreover, nanoparticles could be internalised by cancer cells and let the drug release near the biological target, which could increase the anticancer efficacy.

Cannabidiol (CBD), the main nonpsychotropic cannabinoid, appears as a potential anticancer drug. The aim of this work was to develop polymer nanoparticles as CBD carriers capable of being internalised by ovarian cancer cells.

The drug-loaded nanoparticles (CBD-NPs) exhibited a spherical shape, a particle size around 240 nm and a negative zeta potential (-16.6 ± 1.2 mV). The encapsulation efficiency was high, with values above 95%. A controlled CBD release for 96 h was achieved. Nanoparticle internalisation in SKOV-3 epithelial ovarian cancer cells mainly occurred between 2 and 4 h of incubation. CBD antiproliferative activity in ovarian cancer cells was preserved after encapsulation. In fact, CBD-NPs showed a lower IC50 values than CBD in solution. Both CBD in solution and CBD-NPs induced the expression of PARP, indicating the onset of apoptosis. In SKOV-3-derived tumours formed in the chick embryo model, a slightly higher-although not statistically significant-tumour growth inhibition was observed with CBD-NPs compared to CBD in solution.

To sum up, poly-lactic-co-glycolic acid (PLGA) nanoparticles could be a good strategy to deliver CBD intraperitoneally for ovarian cancer treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/32397428

https://www.mdpi.com/1999-4923/12/5/439

Totality of the Evidence Suggests Prenatal Cannabis Exposure Does Not Lead to Cognitive Impairments: A Systematic and Critical Review

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Special issue Frontiers in Psychology“Despite limited data demonstrating pronounced negative effects of prenatal cannabis exposure, popular opinion and public policies still reflect the belief that cannabis is fetotoxic.

This article provides a critical review of results from longitudinal studies examining the impact of prenatal cannabis exposure on multiple domains of cognitive functioning in individuals aged 0 to 22 years.

The current evidence does not suggest that prenatal cannabis exposure alone is associated with clinically significant cognitive functioning impairments.

The current review of the literature found that there are relatively few cognitive alterations noted in offspring exposed to cannabis prenatally.

In general, prenatal cannabis exposure was associated with few effects, negative or positive.”

https://www.frontiersin.org/articles/10.3389/fpsyg.2020.00816/full

Beneficial effects of the phytocannabinoid Δ9-THCV in L-DOPA-induced dyskinesia in Parkinson’s disease.

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Neurobiology of Disease“The antioxidant and CB2 receptor agonist properties of Δ9-tetrahydrocannabivarin (Δ9-THCV) afforded neuroprotection in experimental Parkinson’s disease (PD), whereas its CB1 receptor antagonist profile at doses lower than 5 mg/kg caused anti-hypokinetic effects.

In the present study, we investigated the anti-dyskinetic potential of Δ9-THCV (administered i.p. at 2 mg/kg for two weeks), which had not been investigated before.

In summary, our data support the anti-dyskinetic potential of Δ9-THCV, both to delay the occurrence and to attenuate the magnitude of dyskinetic signs. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for patients with PD.”

https://www.ncbi.nlm.nih.gov/pubmed/32387338

“Δ9-THCV exhibited anti-dyskinetic properties in L-DOPA-treated Pitx3ak mutant mice. It delayed the onset of dyskinetic signs and reduced their neurochemical changes. It also reduced their intensity when given once dyskinesia was already present. This potential adds to other properties of Δ9-THCV as antiparkinsonian therapy.

In summary, our data support the anti-dyskinetic potential of Δ9-THCV to ameliorate adverse effects caused by L-DOPA, in particular delaying the occurrence and attenuating the magnitude of dyskinetic signs. This adds to its promising symptom-alleviating and neuroprotective properties described previously. Although further studies are clearly required to determine the clinical significance of these data in humans, the results nevertheless situate Δ9-THCV in a promising position for developing a cannabinoid-based therapy for PD patients.”

https://www.sciencedirect.com/science/article/pii/S0969996120301674?via%3Dihub

Anti-inflammatory effects of lenabasum, a cannabinoid receptor type 2 agonist, on macrophages from cystic fibrosis.

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Home Page: Journal of Cystic Fibrosis“Lenabasum is an oral synthetic cannabinoid receptor type 2 agonist previously shown to reduce the production of key airway pro-inflammatory cytokines known to play a role in cystic fibrosis (CF). In a double-blinded, randomized, placebo-control phase 2 study, lenabasum lowered the rate of pulmonary exacerbation among patients with CF. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum exhibits in CF macrophages.

RESULTS:

Lenabasum had no effect on differentiation, polarization and function of macrophages from healthy individuals. However, in CF macrophages lenabasum downregulated macrophage polarization into the pro-inflammatory M1 phenotype and secretion of the pro-inflammatory cytokines IL-8 and TNF-α in a dose-dependent manner. An improvement in phagocytic activity was also observed following lenabasum treatment. Although lenabasum did not restore the impaired polarization of anti-inflammatory M2 macrophage, it reduced the levels of IL-13 and enhanced the endocytic function of CF MDMs. The effects of lenabasum on MDMs with CFTR inhibited by C-172 were not as obvious.

CONCLUSION:

In CF macrophages lenabasum modulates macrophage polarization and function in vitro in a way that would reduce inflammation in vivo. Further studies are warranted to determine the link between activating the CBR2 receptor and CFTR.”

https://www.ncbi.nlm.nih.gov/pubmed/32387042

https://www.cysticfibrosisjournal.com/article/S1569-1993(20)30094-1/pdf

Cross-Generational THC Exposure Alters Heroin Reinforcement in Adult Male Offspring.

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Drug and Alcohol Dependence“An emerging area of preclinical research has investigated whether drug use in parents prior to conception influences drug responsivity in their offspring.

The present work sought to further characterize such effects with cannabis by examining whether a parental THC history modified locomotor sensitization to morphine and self-administration of heroin in adult progeny.

RESULTS:

Germline THC exposure had no effect on morphine locomotor sensitization. However, F1-THC males displayed a reduced motivation to self-administer heroin relative to F1-Veh males.

CONCLUSIONS:

The present data indicate that parental THC exposure alters the reinforcing properties of heroin in a sex-specific manner. As such, mild to moderate cannabis use during adolescence may alter heroin abuse liability for males in the subsequent generation, but have limited effects on females.”

https://www.ncbi.nlm.nih.gov/pubmed/32386920

https://www.sciencedirect.com/science/article/abs/pii/S0376871620301502?via%3Dihub

Activation of CB1R Promotes Lipopolysaccharide-Induced IL-10 Secretion by Monocytic Myeloid-Derived Suppressive Cells and Reduces Acute Inflammation and Organ Injury.

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The Journal of Immunology: 204 (10)“Cannabis sativa and its principal components, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, are increasingly being used to treat a variety of medical problems, including inflammatory conditions.

Although studies suggest that the endocannabinoid system has immunomodulatory properties, there remains a paucity of information on the effects of cannabinoids on immunity and on outcomes of infection and injury.

We investigated the effects and mechanism(s) of action of cannabinoid receptor agonists, including Δ9-THC, on inflammation and organ injury in endotoxemic mice.

Administration of Δ9-THC caused a dramatic early upregulation of plasma IL-10 levels, reduced plasma IL-6 and CCL-2 levels, led to better clinical status, and attenuated organ injury in endotoxemic mice. The anti-inflammatory effects of Δ9-THC in endotoxemic mice were reversed by a cannabinoid receptor type 1 (CB1R) inverse agonist (SR141716), and by clodronate-induced myeloid-cell depletion, but not by genetic invalidation or blockade of other putative Δ9-THC receptors, including cannabinoid receptor type 2, TRPV1, GPR18, GPR55, and GPR119. Although Δ9-THC administration reduced the activation of several spleen immune cell subsets, the anti-inflammatory effects of Δ9-THC were preserved in splenectomized endotoxemic mice. Finally, using IL-10-GFP reporter mice, we showed that blood monocytic myeloid-derived suppressive cells mediate the Δ9-THC-induced early rise in circulating IL-10.

These results indicate that Δ9-THC potently induces IL-10, while reducing proinflammatory cytokines, chemokines, and related organ injury in endotoxemic mice via the activation of CB1R. These data have implications for acute and chronic conditions that are driven by dysregulated inflammation, such as sepsis, and raise the possibility that CB1R-signaling may constitute a novel target for inflammatory disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32385136

https://www.jimmunol.org/content/early/2020/05/07/jimmunol.2000213

Full-Spectrum Cannabis Extract Microdepots Support Controlled Release of Multiple Phytocannabinoids for Extended Therapeutic Effect.

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 Go to Volume 0, Issue ja“The therapeutic effect of the Cannabis plant largely depends on the presence and specific ratio of a spectrum of phytocannabinoids. While prescription of medicinal Cannabis for various conditions constantly grows, its consumption is mostly limited to oral or respiratory pathways, impeding its duration of action, bioavailability and efficacy. Herein, a long-acting formulation in the form of melt-printed polymeric microdepots for full-spectrum cannabidiol(CBD)-rich extract administration is described. When injected subcutaneously in mice, the microdepots facilitate sustained release of the encapsulated extract over a two-week period. The prolonged delivery results in elevated serum levels of multiple, major and minor, phytocannabinoids for over 14 days, compared to Cannabis extract injection. A direct analysis of the microdepots retrieved from the injection site gives rise to an empirical model for the release kinetics of the phytocannabinoids as a function of their physical traits. As a proof of concept, we compare the long-term efficacy of a single administration of the microdepots to a single administration of Cannabis extract in pentylenetetrazol-induced convulsions model. One week following administration, the microdepots reduce the incidence of tonic-clonic seizures by 40%, increase the survival rate by 50%, and the latency to first tonic-clonic seizures by 170%. These results suggest that a long-term full-spectrum Cannabis delivery system may provide new form of Cannabis administration and treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/32369348

https://pubs.acs.org/doi/10.1021/acsami.0c04435

Inhibitory Effect of Cannabidiol on the Activation of NLRP3 Inflammasome Is Associated with Its Modulation of the P2X7 Receptor in Human Monocytes.

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 Go to Volume 0, Issue 0“Cannabidiol (CBD), a phytocannabinoid, has been reported to have anti-inflammatory effects associated with NLRP3 inflammasome activation, but its mechanism of anti-inflammasome action remains unclear.

Herein, we report CBD’s effect on NLRP3 inflammasome activation and its modulation of P2X7, an inflammasome activation-related receptor, in human THP-1 monocytes.

Overall, the observed CBD suppressive effect on NLRP3 inflammasome activation in THP-1 monocytes was associated with decreased potassium efflux, as well as in silico prediction of P2X7 receptor binding.

CBD inhibitory effects on the NLRP3 inflammasome may contribute to the overall anti-inflammatory effects reported for this phytocannabinoid.”

https://www.ncbi.nlm.nih.gov/pubmed/32374168

https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00138

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Acute and residual mood and cognitive performance of young adults following smoked cannabis.

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Pharmacology Biochemistry and Behavior“To examine acute and residual mood and cognitive performance in young adult regular cannabis users following smoked cannabis.

METHODS:

Ninety-one healthy young adults completed this double-blind, placebo-controlled, parallel-groups study. Participants were randomized to receive active (12.5% THC) or placebo cannabis with a 2:1 allocation ratio, and mood [Profile of Mood States (POMS)] and cognitive performance [Hopkins Verbal Learning Test – Revised (HVLT-R), Digit Symbol Substitution Test (DSST), Continuous Performance Test (CPT), grooved pegboard (GPB)] were assessed before and 1, 24, and 48 h after smoking cannabis ad libitum. High and Low THC groups were based on blood THC concentrations.

RESULTS:

One hour after smoking cannabis, compared to Placebo, in both the High and Low THC groups, there were increases in POMS Arousal and Positive Mood, and in the High THC group only, increases in Confusion, Friendliness, and Elation, and a decrease in Fatigue. Increases in Friendliness and Elation in the High THC group remained significant for 24 h. The only significant acute effect of cannabis on cognition was a decrease in the percent of words retained in the HVLT-R in the High THC group compared to Placebo (mean difference = 15.8%, 95% CI = 3.6-28.0%, p = 0.006). Unexpectedly, compared to Placebo, both the High and Low THC groups improved in DSST performance at 48 h (p ≤ 0.016).

CONCLUSIONS:

Under the present experimental conditions, in young regular cannabis users, smoking cannabis ad libitum had significant effects on mood, some of which persisted 24 h later, yet minimal effects on cognition, and no evidence of residual cognitive impairment.”

https://www.ncbi.nlm.nih.gov/pubmed/32360692

“There were few acute effects of cannabis on cognitive performance.”

https://www.sciencedirect.com/science/article/pii/S0091305719306276?via%3Dihub

Two-weeks treatment with cannabidiol improves biophysical and behavioral deficits associated with experimental type-1 diabetes.

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Neuroscience Letters“The prevalence rates of depression and anxiety are at least two times higher in diabetic patients, increasing morbidity and mortality.

Cannabidiol (CBD) has been identified as a therapeutic agent viable to treat diverse psychiatric disorders. Thus, this study aimed to investigate the effect of CBD treatment (once a day for 14 days starting two weeks after diabetes induction; at doses of 0, 3, 10 or 30 mg/kg, i.p.) on depression- and anxiety-like behaviors associated with experimental diabetes induced by streptozotocin (60 mg/kg; i.p.) in rats.

Levels of plasma insulin, blood glucose, and weight gain were evaluated in all experimental groups, including a positive control group treated with imipramine. The rats were tested in the modified forced swimming test (mFST) and elevated plus maze (EPM) test. Besides, the levels of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in two emotion-related brain regions, the prefrontal cortex (PFC) and hippocampus (HIP) were evaluated using high-pressure liquid chromatography.

Our results showed that CBD treatment (only at the higher dose of 30 mg/kg) reduced the exaggerated depressive- and anxiogenic-like behaviors of diabetic (DBT) rats, which may be associated with altered 5-HT, NA and/or DA levels observed in the PFC and HIP. Treatment with CBD (higher dose) also induced a significant increase in weight gain and the insulin levels (and consequently reduced glycemia) in DBT rats. The long-term CBD effects gave rise to novel therapeutic strategies to limit the physiological and neurobehavioral deficits in DBT rats.

This approach provided evidence that CBD can be useful for treating psychiatry comorbidities in diabetic patients.”

https://www.ncbi.nlm.nih.gov/pubmed/32360935

“Treatment of diabetic rats with cannabidiol induced antidepressant- and anxiolytic-like behaviors.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394020302901?via%3Dihub