Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer

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“Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.

Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities.

This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies.

Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME).

Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.

We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice.

Taken together, we provide new insights into the anti-tumor effects of CBD.”

https://pubmed.ncbi.nlm.nih.gov/37577382/

“CBD shapes the TME to prevent tumor progression.”

https://www.sciencedirect.com/science/article/pii/S2095177923000746?via%3Dihub

Medical cannabis laws lower individual market health insurance premiums

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“Background: To evaluate the impact of medical cannabis laws (MCLs) on health insurance premiums. We study whether cannabis legalization significantly impacts aggregate health insurer premiums in the individual market. Increases in utilization could have spillover effects to patients in the form of higher health insurance premiums.

Methods: We use 2010-2021 state-level U.S. private health insurer financial data from the National Association of Insurance Commissioners. We examined changes to individual market health insurance premiums after the implementation of medical cannabis laws. We employed a robust difference-in-differences estimator that accounted for variation in policy timing to exploit temporal and geographic variation in state-level medical cannabis legalization.

Results: Seven years after the implementation of Medical Cannabis laws, we observe lower health insurer premiums in the individual market. Starting seven years post-MCL implementation, we find a reduction of $-1662.7 (95% confidence interval [CI -2650.1, -605.7]) for states which implemented MCLs compared to the control group, a reduction of -$1541.8 (95% confidence interval [CI 2602.1, -481.4]) in year 8, and a reduction of $-1625.8, (95% confidence interval [CI -2694.2, -557.5]) in year 9. Due to the nature of insurance pooling and community rating, these savings are appreciated by cannabis users and non-users alike in states that have implemented MCLs.

Conclusions: The implementation of MCLs lowers individual-market health insurance premiums. Health insurance spending, including premiums, comprises between 16% and 34% of household budgets in the United States. As healthcare costs continue to rise, our findings suggest that households that obtain their health insurance on the individual (i.e., not employer sponsored) market in states with MCLs appreciate significantly lower premiums.”

https://pubmed.ncbi.nlm.nih.gov/37572391/

https://www.sciencedirect.com/science/article/abs/pii/S0955395923001901?via%3Dihub

Cannabis reduces anxiety in dementia

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MMW - Advances in Medicine 14/2023

“Neuropsychiatric symptoms occur in almost 90% of people with dementia. Agitated and aggressive behavior significantly reduces the quality of life of those affected and those around them, but it is difficult to access therapy. One option could be medicinal cannabis. The results of a double-blind, placebo-controlled study indicate that a full-spectrum cannabis extract with a high content of cannabidiol (CBD) can reduce dementia-related agitation [1]. In the study, 60 patients with severe neurocognitive disorder and associated behavioral disorders received a full-spectrum cannabis extract with 1% tetrahydrocannabinol (THC) and 30% CBD (Re:cannis) or a placebo oil. After 16 weeks, sleep disturbances, Agitation and aggression significantly improved compared to the placebo group. Since the effects only became apparent in the 14th week, patience is required.”

https://www.springermedizin.de/agitiertheit/demenz/cannabis-daempft-die-unruhe-bei-demenz/25883850?fulltextView=true&doi=10.1007%2Fs15006-023-2867-2

Cannabidiol Enhances Cabozantinib-Induced Apoptotic Cell Death via Phosphorylation of p53 Regulated by ER Stress in Hepatocellular Carcinoma

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“Cannabidiol (CBD), a primary constituent in hemp and cannabis, exerts broad pharmacological effects against various diseases, including cancer. Additionally, cabozantinib, a potent multi-kinase inhibitor, has been approved for treating patients with advanced hepatocellular carcinoma (HCC). Recently, there has been an increase in research on combination therapy using cabozantinib to improve efficacy and safety when treating patients. Here, we investigated the effect of a combination treatment of cabozantinib and CBD on HCC cells. CBD treatment enhanced the sensitivity of HCC cells to cabozantinib-mediated anti-cancer activity by increasing cytotoxicity and apoptosis. Phospho-kinase array analysis demonstrated that the apoptotic effect of the combination treatment was mainly related to p53 phosphorylation regulated by endoplasmic reticulum (ER) stress when compared to other kinases. The inhibition of p53 expression and ER stress suppressed the apoptotic effect of the combination treatment, revealing no changes in the expression of Bax, Bcl-2, cleaved caspase-3, cleaved caspase-8, or cleaved caspase-9. Notably, the effect of the combination treatment was not associated with cannabinoid receptor 1 (CNR1) and the CNR2 signaling pathways. Our findings suggest that the combination therapy of cabozantinib and CBD provides therapeutic efficacy against HCC.”

https://pubmed.ncbi.nlm.nih.gov/37568803/

https://www.mdpi.com/2072-6694/15/15/3987

Cannabidiol and Cannabigerol Modify the Composition and Physicochemical Properties of Keratinocyte Membranes Exposed to UVA

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“The action of UVA radiation (both that derived from solar radiation and that used in the treatment of skin diseases) modifies the function and composition of keratinocyte membranes. Therefore, this study aimed to assess the effects of phytocannabinoids (CBD and CBG), used singly and in combination, on the contents of phospholipids, ceramides, lipid rafts and sialic acid in keratinocyte membranes exposed to UVA radiation, together with their structure and functionality. The phytocannabinoids, especially in combination (CBD+CBG), partially prevented increased levels of phosphatidylinositols and sialic acid from occurring and sphingomyelinase activity after the UVA exposure of keratinocytes. This was accompanied by a reduction in the formation of lipid rafts and malondialdehyde, which correlated with the parameters responsible for the integrity and functionality of the keratinocyte membrane (membrane fluidity and permeability and the activity of transmembrane transporters), compared to UVA-irradiated cells. This suggests that the simultaneous use of two phytocannabinoids may have a protective effect on healthy cells, without significantly reducing the therapeutic effect of UV radiation used to treat skin diseases such as psoriasis.”

https://pubmed.ncbi.nlm.nih.gov/37569799/

“Since UVA radiation modifies the composition, structure and functionality of the lipid bilayer of keratinocyte membranes, the use of natural compounds, especially lipophilic compounds such as phytocannabinoids, is important for maintaining the proper condition of the skin and, consequently, for the proper functioning of the skin over the entire human body. “

https://www.mdpi.com/1422-0067/24/15/12424

Early Administration of the Phytocannabinoid Cannabidivarin Prevents the Neurobehavioral Abnormalities Associated with the Fmr1-KO Mouse Model of Fragile X Syndrome

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“Phytocannabinoids, including the non-addictive cannabis component cannabidivarin (CBDV), have been reported to hold therapeutic potential in several neurodevelopmental disorders (NDDs). Nonetheless, the therapeutic value of phytocannabinoids for treating Fragile X syndrome (FXS), a major NDD, remains unexplored. Here, we characterized the neurobehavioral effects of CBDV at doses of 20 or 100 mg/kg in the Fmr1-knockout (Fmr1-KO) mouse model of FXS using two temporally different intraperitoneal regimens: subchronic 10-day delivery during adulthood (Study 1: rescue treatment) or chronic 5-week delivery at adolescence (Study 2: preventive treatment). Behavioral tests assessing FXS-like abnormalities included anxiety, locomotor, cognitive, social and sensory alterations. Expression of inflammatory and plasticity markers was investigated in the hippocampus and prefrontal cortex. When administered during adulthood (Study 1), the effects of CBDV were marginal, rescuing at the lower dose only the acoustic hyper-responsiveness of Fmr1-KO mice and at both doses their altered hippocampal expression of neurotrophins. When administered during adolescence (Study 2), CBDV at both doses prevented the cognitive, social and acoustic alterations of adult Fmr1-KO mice and modified the expression of several inflammatory brain markers in both wild-type littermates and mutants. These findings warrant the therapeutic potential of CBDV for preventing neurobehavioral alterations associated with FXS, highlighting the relevance of its early administration.”

https://pubmed.ncbi.nlm.nih.gov/37566006/

“Overall, these data demonstrate that CBDV, when administered chronically and starting at juvenile age, holds a solid therapeutic potential for FXS as it prevented the most relevant behavioral alterations shown by Fmr1-KO mice.”

https://www.mdpi.com/2073-4409/12/15/1927

Cannabis use may attenuate neurocognitive performance deficits resulting from methamphetamine use disorder

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“Objective: Methamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.

Method: 423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.

Results: Globally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory.

Conclusions: Our findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.”

https://pubmed.ncbi.nlm.nih.gov/37553288/

https://www.cambridge.org/core/journals/journal-of-the-international-neuropsychological-society/article/abs/cannabis-use-may-attenuate-neurocognitive-performance-deficits-resulting-from-methamphetamine-use-disorder/8AC3E796BDBD8E387D685EB892C63244

Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70

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“Although it has been established that cannabidiol (CBD), the major non-psychoactive constituent of cannabis, exerts antitumoral activities, the exact mechanism(s) via which tumor cells are killed by CBD are not well understood.

This study provides new insights into the potential mechanisms of CBD-induced mutual antagonism of apoptosis and macroautophagy using wild type (HCT116 p53wt, LS174T p53wt), knockout (HCT116 p53-/-) and mutant (SW480 p53mut) human colorectal cancer cells (CRC).

CBD causes a more pronounced loss in the viability of p53wt cells than p53-/- and p53mut cells, and a 5-week treatment with CBD reduced the volume of HCT116 p53wt xenografts in mice, but had no effect on the volume of HCT116 p53-/- tumors.

Mechanistically, we demonstrate that CBD only significantly elevates ROS production in cells harboring wild-type p53 (HCT116, LS174T) and that this is associated with an accumulation of PARP1. CBD-induced elevated ROS levels trigger G0/G1 cell cycle arrest, a reduction in CDK2, a p53-dependent caspase-8/9/3 activation and macroautophagy in p53wt cells. The ROS-induced macroautophagy which promotes the activation of keap1/Nrf2 pathway might be positively regulated by p53wt, since inhibition of p53 by pifithrin-α further attenuates autophagy after CBD treatment.

Interestingly, an inhibition of heat shock protein 70 (Hsp70) expression significantly enhances caspase-3 mediated programmed cell death in p53wt cells, whereas autophagy-which is associated with a nuclear translocation of Nrf2-was blocked.

Taken together, our results demonstrate an intricate interplay between apoptosis and macroautophagy in CBD-treated colorectal cancer cells, which is regulated by the complex interactions of p53wt and Hsp70.”

https://pubmed.ncbi.nlm.nih.gov/37542074/

https://www.nature.com/articles/s41420-023-01578-9

CBD-oil as a potential solution in case of severe tamoxifen-related side effects

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“Tamoxifen may lead to bothersome side effects contributing to non-compliance and decreased quality of life.

Patients searching for relief are increasingly turning to cannabinoids such as CBD-oil. However, CBD-oil might affect tamoxifen pharmacokinetics (PK) through CYP2D6 inhibition. The aims of this open-label, single-arm study were (1) to determine the PK profile of tamoxifen when using CBD-oil, and (2) to subsequently investigate whether CBD-oil has a beneficial influence on side effects.

Study patients had to have steady-state endoxifen concentrations ≥16 nM (conservative threshold). PK sampling and side effect assessment was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen AUC fell within the [-20%; +25%] interval. The effect of CBD-oil on side effects was evaluated using the FACT-ES questionnaire.

Endoxifen AUC decreased after CBD-oil by 12.6% (n = 15, 90% CI -18.7%, -6.1%) but remained within bio-equivalence boundaries. The endocrine sub-scale of the FACT-ES improved clinically relevant with 6.7 points (n = 26, p < 0.001) and health-related quality of life improved with 4.7 points after using CBD (95% CI + 1.8, +7.6).

We conclude that CBD-oil, if of good quality and with a dosage below 50 mg, does not have to be discouraged in patients using it for tamoxifen-related side effects.”

https://pubmed.ncbi.nlm.nih.gov/37543688/

“In conclusion, endoxifen levels remained within bio-equivalence boundaries when CBD-oil was used in combination with tamoxifen. Therefore, sublingual CBD-oil, if of good quality and not higher than the highest over-the-counter dose (<50 mg per day), does not have to be discouraged in patients using it as complementary medication. In addition, the use of CBD-oil in this single arm study resulted in a promising improvement in endocrine symptoms and quality of life, but the real effect of CBD-oil has yet to be proven in a placebo-controlled study that is currently being set up.”

https://www.nature.com/articles/s41523-023-00570-x

Dramatic efficacy of cannabidiol on refractory chronic pain in an adolescent with sickle cell disease

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“Here, we report a dramatic efficacy of cannabidiol in an adolescent with SCD suffering from chronic pain refractory to other analgesics, with complete regression of chronic pain and rapid plasma histamine level normalization after treatment.”

https://pubmed.ncbi.nlm.nih.gov/37540761/

“In conclusion, we report here for the first time a case of refractory chronic pain with dramatic improvement after CBD treatment in an adolescent with SCD. The CBD oral solution Epidiolex has been approved by the US Food and Drug Administration since June 2018 and by the European Medicine Agency since January 2023 for management of refractory epilepsy. As it seems to be a well-tolerated drug, CBD could represent a promising therapeutic perspective for patients with SCD suffering from chronic pain.”

https://onlinelibrary.wiley.com/doi/10.1002/ajh.27049