A Retrospective Cohort Study That Examined the Impact of Cannabis Consumption on Long-Term Kidney Outcomes

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“Background: Cannabis consumption for recreational and medical use is increasing worldwide. However, the long-term effects on kidney health and disease are largely unknown. 

Materials and Methods: Post hoc analysis of cannabis use as a risk factor for kidney disease was performed using data from the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study that enrolled hospitalized adults with and without acute kidney injury from four U.S. centers during 2009-2015. Associations between self-reported cannabis consumption and the categorical and continuous outcomes were determined using multivariable Cox regression and linear mixed models, respectively. 

Results: Over a mean follow-up of 4.5±1.8 years, 94 participants without chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2) who consumed cannabis had similar rates of annual eGFR decline versus 889 nonconsumers (mean difference=-0.02 mL/min/1.73 m2/year, p=0.9) and incident CKD (≥25% reduction in eGFR compared with the 3-month post-hospitalization measured eGFR and achieving CKD stage 3 or higher) (adjusted hazard ratio [aHR]=1.2; 95% confidence interval [CI]=0.7-2.0). Nineteen participants with CKD (eGFR <60 mL/min/1.73 m2) who consumed cannabis had more rapid eGFR decline versus 597 nonconsumers (mean difference=-1.3 mL/min/1.73 m2/year; p=0.02) that was not independently associated with an increased risk of CKD progression (≥50% reduction in eGFR compared with the 3-month post-hospitalization eGFR, reaching CKD stage 5, or receiving kidney replacement therapy) (aHR=1.6; 95% CI=0.7-3.5). Cannabis consumption was not associated with the rate of change in urine albumin to creatinine ratio (UACR) over time among those with (p=0.7) or without CKD (p=0.4). 

Conclusions: Cannabis consumption did not adversely affect the kidney function of participants without CKD but was associated with a faster annual eGFR decline among participants with CKD. Cannabis consumption was not associated with changes in UACR over time, incident CKD, or progressive CKD regardless of baseline kidney function. Additional research is needed to investigate the kidney endocannabinoid system and the impact of cannabis use on kidney disease outcomes.”

https://pubmed.ncbi.nlm.nih.gov/36791309/

https://www.liebertpub.com/doi/10.1089/can.2022.0141

Safety Assessment and Redox Status in Rats after Chronic Exposure to Cannabidiol and Cannabigerol

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Toxicology

“Cannabidiol (CBD) and cannabigerol (CBG) are the two main non-psychotropic phytocannabinoids with high application potential in drug development. Both substances are redox-active and are intensively investigated for their cytoprotective and antioxidant action in vitro. In this study, we focused on an in vivo safety evaluation and the effect of CBD and CBG on the redox status in rats in a 90-d experiment. The substances were administered orogastrically in a dose of 0.66mg synthetic CBD or 0.66mg/1.33mg CBG/kg/day. CBD produced no changes in the red or white blood count or biochemical blood parameters in comparison to the control. No deviations in the morphology or histology of the gastrointestinal tract and liver were observed. After 90 d of CBD exposure, a significant improvement in redox status was found in the blood plasma and liver. The concentration of malondialdehyde and carbonylated proteins was reduced compared to the control. In contrast to CBD, total oxidative stress was significantly increased and this was accompanied by an elevated level of malondialdehyde and carbonylated proteins in CBG-treated animals. Hepatotoxic (regressive changes) manifestations, disruption in white cell count, and alterations in the ALT activity, level of creatinine and ionized calcium were also found in CBG-treated animals. Based on liquid chromatography-mass spectrometry analysis, CBD/CBG accumulated in rat tissues (in the liver, brain, muscle, heart, kidney and skin) at a low ng level per gram. Both CBD and CBG molecular structures include a resorcinol moiety. In CBG, there is an extra dimethyloctadienyl structural pattern, which is most likely responsible for the disruption to the redox status and hepatic environment. The results are valuable to further investigation of the effects of CBD on redox status and should contribute towards opening up critical discussion on the applicability of other non-psychotropic cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/36796712/

https://www.sciencedirect.com/science/article/abs/pii/S0300483X2300046X?via%3Dihub

Cannabidiol-loaded poly lactic-co-glycolic acid nanoparticles with improved bioavailability as a potential for osteoarthritis therapeutic

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“Cannabidiol (CBD) is a non-intoxicating cannabinoid from cannabis sativa that has demonstrated efficacious against inflammation, which can be considered as a potential drug for arthritis treatment. However, the poor solubility and low bioavailability limit its clinical application. Here, we report an effective strategy to fabricate CBD-loaded poly lactic-co-glycolic acid nanoparticles (CBD-PLGA-NPs), with a spherical morphology and an average diameter of 238 nm. CBD was sustained release from CBD-PLGA-NPs, which improved the bioavailability of CBD. The CBD-PLGA-NPs effectively protect the damage of LPS to cell viability. We observed that CBD-PLGA-NPs significantly suppressed LPS-induced primary rat chondrocyte expression of inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase 13 (MMP-13). Remarkably, CBD-PLGA-NPs also showed better therapeutic effects of inhibiting the degradation of the extracellular matrix of chondrocytes than equivalent CBD solution. In general, the fabrication CBD-PLGA-NPs showed good protection of primary chondrocytes in vitro and is a promising system for osteoarthritis treatment.”

https://pubmed.ncbi.nlm.nih.gov/36793188/

https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cbic.202200698

CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial

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Biomedicine & Pharmacotherapy

“Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21-4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85-19.05] vs. 9.65 [6.37-12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = -0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.”

https://pubmed.ncbi.nlm.nih.gov/36780785/

“CBD supplementation reduces office blood pressure (BP) and serum catestatin levels.”

“Overall, the results of the present study imply that antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.”

https://www.sciencedirect.com/science/article/pii/S0753332223001750?via%3Dihub

Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity

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“Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAARγ2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI’s pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI’s synaptic effects and dampening hyperexcitability.”

https://pubmed.ncbi.nlm.nih.gov/36787750/

https://www.cell.com/neuron/fulltext/S0896-6273(23)00066-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627323000661%3Fshowall%3Dtrue

Role of Gut Microbiota in Cannabinoid-Mediated Suppression of Inflammation

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“Cannabinoids and the endocannabinoid system have been well established to play a crucial role in the regulation of the immune response. Also, emerging data from numerous investigations unravel the imperative role of gut microbiota and their metabolites in the maintenance of immune homeostasis and gut barrier integrity. In this review, we concisely report the immunosuppressive mechanisms triggered by cannabinoids, and how they are closely associated with the alterations in the gut microbiome and metabolome following exposure to endogenous or exogenous cannabinoids. We discuss how cannabinoid-mediated induction of microbial secondary bile acids, short chain fatty acids, and indole metabolites, produced in the gut, can suppress inflammation even in distal organs. While clearly, more clinical studies are necessary to establish the cross talk between exo- or endocannabinoid system with the gut microbiome and the immune system, the current evidence opens a new avenue of cannabinoid-gut-microbiota-based therapeutics to regulate immunological disorders.”

https://pubmed.ncbi.nlm.nih.gov/36776218/

“The microbiome-eCB signaling modulation exploiting exo- or endogenous cannabinoids opens a new avenue of cannabinoid-gut microbiota-based therapeutics to curb metabolic and immune-oriented conditions.”

https://www.frontierspartnerships.org/articles/10.3389/adar.2022.10550/full

Phytoradiotherapy to enhance cancer treatment outcomes with cannabidiol, bitter melon juice, and plant hemoglobin

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“Despite technological advances in radiation therapy for cancer treatment, many patient populations still experience mediocre survival percentages, local control, and quality of life. Additionally, much of the world lacks access to expensive, modern treatment options. The need for innovative, cost-effective solutions that can improve patient treatment outcomes is essential.

Phytomedicines have been shown to induce apoptotic tumor cell death, diminish tumor progression, reduce cancer incidence, alleviate harmful hypoxic conditions, and more. While an ample amount of research is available that characterizes many phytomedicines as having anti-cancer properties that increase tumor cell killing/control and mitigate the harmful side effects of radiation damage, little work has been done to investigate the synergistic effect of phytoradiotherapy: combining radiation treatment with phytomedicines.

In this study, a protocol for testing the radiosensitizing effects of phytomedicines was validated and used to investigate the well-known plant based medicine cannabidiol (CBD) and the lesser-known medicinal fruit Bitter Melon. Additionally, based on its high concentration of plant hemoglobin which has been shown to abate hypoxia, the African-indigenous Justicia plant was tested in pancreatic adenocarcinoma mouse models.

The studies reveal that these phytomedicines can effectively enhance tumor cell killing, minimize tumor growth, and prolong mice survival. There is certainly the need for additional research in this regard, however, phytoradiotherapy: the use of phytomedicines to enhance radiation therapy treatment outcomes, continues to show potential as a promising, innovative way to improve cancer care.”

https://pubmed.ncbi.nlm.nih.gov/36776362/

“Results showing that both CBD and BMJ are effective radiosensitizing phytomedicines demonstrate promise that the two plant-based medicines have a potential future in radiation therapy as treatment enhancing drugs at a much more affordable rate than their synthetic alternatives.”

https://www.frontiersin.org/articles/10.3389/fonc.2022.1085686/full

The cannabidiol and marijuana research expansion act: Promotion of scientific knowledge to prevent a national health crisis

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The Lancet Regional Health - Americas

“While the use of medical and recreational cannabis is rapidly expanding under state jurisdiction, the convolution of federal regulations is obstructing research progress to the detriment of healthcare equity and the protection of vulnerable populations, such as the underaged. U.S. Senate bill S.253 is designed to accelerate the development of trusted preclinical and clinical principles based on scientific data to guide physicians in their daily practice, inform lawmakers, and thereby protect public health. This goes together with a reinforcement of the legal protection that practitioners have acquired over years of litigation with the federal government when working with their patients. S.253 supports open communication between physicians and their patients when discussing cannabis as a treatment option. The bill passed the U.S. Senate on March 24, 2022.”

https://pubmed.ncbi.nlm.nih.gov/36777382/

https://www.sciencedirect.com/science/article/pii/S2667193X22001429?via%3Dihub

Impact of Cannabis Use on Inpatient Inflammatory Bowel Disease Outcomes in 2 States Legalizing Recreational Cannabis

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“Background: We evaluated the impact of recreational cannabis legalization on use and inpatient outcomes of patients with inflammatory bowel disease (IBD).

Methods: Hospitalized adult patients in Colorado and Washington before (2011) and after (2015) recreational cannabis legalization were compared by chi-square tests for categorical variables and t-tests for continuous variables. Multivariable regression models adjusting for demographic data were fit to assess the association of cannabis use with hospital outcomes.

Results: Reported cannabis use increased after legalization (1.2% vs 4.2%, P < .001). On multivariable analysis, in 2011, cannabis users were less likely to need total parenteral nutrition (odds ratio 0.12, P = .038), and in 2015 had less hospital charges ($-8418, P = .024).

Conclusions: The impact of cannabis legalization and use on IBD is difficult to analyze but may have implications on inpatient IBD outcomes as described in this retrospective analysis. Large, prospective studies are needed to evaluate other IBD outcomes based on cannabis legalization and use.”

https://pubmed.ncbi.nlm.nih.gov/36777043/

“Lay Summary

Colorado and Washington inpatient databases were analyzed before (2011) and after (2015) recreational cannabis legalization assessing use and inflammatory bowel disease outcomes. Cannabis use increased after legalization. In 2011, cannabis users were less likely to need total parenteral nutrition, and in 2015 had less hospital charges.”

https://academic.oup.com/crohnscolitis360/article/4/2/otac015/6576191?login=false


Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway

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“Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated.

In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array.

Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH.

Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.”

https://pubmed.ncbi.nlm.nih.gov/36769042/

“Overall, this proof of concept, which shows that in inflamed human keratinocytes, rare pCBs can indeed interact with specific eCB system elements, opens new perspectives for possible treatments of inflammation-related skin diseases. Incidentally, such interactions between pCBs and eCB system seems to hold therapeutic potential well beyond the skin, such as possible treatments reported for autism spectrum disorders and cancer”

https://www.mdpi.com/1422-0067/24/3/2721

“Effects of Rare Phytocannabinoids on the Endocannabinoid System of Human Keratinocytes”

https://pubmed.ncbi.nlm.nih.gov/35628241/