Monthly Archives: June 2022

High-CBD Extract (CBD-X) Downregulates Cytokine Storm Systemically and Locally in Inflamed Lungs

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New scientific publication in Frontiers in Immunology - Antineo

“Cytokine storm refers to the dysregulated production of inflammatory mediators leading to hyperinflammation. They are often detrimental, and worsen the severity of COVID-19 and other infectious or inflammatory diseases. Cannabinoids are known to have anti-inflammatory effects but their possible therapeutic value on cytokine storms has not been fully elucidated. In vivo and ex vivo studies were carried out to investigate the effects of high-THC and high-CBD extracts on cytokine production in immune cells. Significant differences between the extracts were observed. Subsequent experiments focusing on a specific high CBD extract (CBD-X) showed significant reductions in pro-inflammatory cytokines in human-derived PBMCs, neutrophils and T cells. In vivo mouse studies, using a systemically inflamed mouse model, showed reductions in pro-inflammatory cytokines TNFα and IL-1β and a concurrent increase in the anti-inflammatory cytokine IL-10 in response to CBD-X extract treatment. Lung inflammation, as in severe COVID-19 disease, is characterized by increased T-cell homing to the lungs. Our investigation revealed that CBD-X extract impaired T-cell migration induced by the chemoattractant SDF1. In addition, the phosphorylation levels of T cell receptor (TCR) signaling proteins Lck and Zap70 were significantly reduced, demonstrating an inhibitory effect on the early events downstream to TCR activation. In a lung inflamed mouse model, we observed a reduction in leukocytes including neutrophil migration to the lungs and decreased levels of IL-1β, MCP-1, IL-6 and TNFα, in response to the administration of the high-CBD extract. The results presented in this work offer that certain high-CBD extract has a high potential in the management of pathological conditions, in which the secretion of cytokines is dysregulated, as it is in severe COVID-19 disease or other infectious or inflammatory diseases.”

https://pubmed.ncbi.nlm.nih.gov/35651623/

https://www.frontiersin.org/articles/10.3389/fimmu.2022.875546/full

Involvement of the cannabinoid system in chronic inflammatory intestinal diseases: opportunities for new therapies

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Intestinal Research

“The components of the endogenous cannabinoid system are widely expressed in the gastrointestinal tract contributing to local homeostasis. In general, cannabinoids exert inhibitory actions in the gastrointestinal tract, inducing anti-inflammatory, antiemetic, antisecretory, and antiproliferative effects. Therefore, cannabinoids are interesting pharmacological compounds for the treatment of several acute intestinal disorders, such as dysmotility, emesis, and abdominal pain. Likewise, the role of cannabinoids in the treatment of chronic intestinal diseases, such as irritable bowel syndrome and inflammatory bowel disease, is also under investigation. Patients with chronic intestinal inflammatory diseases present impaired quality of life, and mental health issues are commonly associated with long-term chronic diseases. The complex pathophysiology of these diseases contributes to difficulties in diagnosis and, therefore, in the choice of a satisfactory treatment. Thus, this article reviews the involvement of the cannabinoid system in chronic inflammatory diseases that affect the gastrointestinal tract and highlights possible therapeutic approaches related to the use of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/35645322/

https://www.irjournal.org/journal/view.php?doi=10.5217/ir.2021.00160

A Randomized Controlled Trial of Topical Cannabidiol for the Treatment of Thumb Basal Joint Arthritis

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The Journal of Hand Surgery

“Purpose: Since the passage of the Agricultural Improvement Act of 2018, hand surgeons have increasingly encountered patients seeking counseling on over-the-counter, topical cannabidiol (CBD) for the treatment of pain. To this end, we designed a human clinical trial to investigate the therapeutic potential of CBD for the treatment of pain associated with thumb basal joint arthritis.

Methods: Following Food and Drug Administration and institutional approval, a phase 1 skin test was completed with 10 healthy participants monitored for 1 week after twice-daily application of 1 mL of topical CBD (6.2 mg/mL) with shea butter. After no adverse events were identified, we proceeded with a phase 2, double-blinded, randomized controlled trial. Eighteen participants with symptomatic thumb basal joint arthritis were randomized to 2 weeks of twice-daily treatment with CBD (6.2 mg/mL CBD with shea butter) or shea butter alone, followed by a 1-week washout period and then crossover for 2 weeks with the other treatment. Safety data and physical examination measurements were obtained at baseline and after completion of each treatment arm.

Results: Cannabidiol treatment resulted in improvements from baseline among patient-reported outcome measures, including Visual Analog Scale pain; Disabilities of the Arm, Shoulder, and Hand; and Single Assessment Numeric Evaluation scores, compared to the control arm during the study period. There were similar physical parameters identified with range of motion, grip, and pinch strength.

Conclusions: In this single-center, randomized controlled trial, topical CBD treatment demonstrated significant improvements in thumb basal joint arthritis-related pain and disability without adverse events.”

https://pubmed.ncbi.nlm.nih.gov/35637038/

https://www.jhandsurg.org/article/S0363-5023(22)00133-2/fulltext

Biological Effects of Cannabidiol on Human Cancer Cells: Systematic Review of the Literature

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Pharmacological Research


“This systematic review examine the biological effects of CBD, a major component of therapeutic Cannabis, on human pathological and cancer cell populations of integumentary, gastro-intestinal, genital and breast, respiratory, nervous, haematopoietic and skeletal districts in terms of cell viability, proliferation, migration, apoptosis, inflammation, metastasis, and CBD receptor expression. The included studies were in English, on human cell lines and primary culture from non-healthy donors with CBD exposure as variable and no CBD exposure as control. Quality assessment was based on ToxRtool with a reliability score ranging from 15 to 18. Following the PRISMA statement 4 independent reviewers performed an electronic search using MEDLINE via PubMed, Scopus and Web of Science. From 3974 articles, 83 studies have been selected. Data showed conflicting results due to different concentration exposure, administrations and time points. CBD inhibited cell viability and proliferation in most cellular districts except the integumentary apparatus. Also a significant inhibition of migration was observed in all cell types, while an increase in apoptosis at both high and low doses (greater and less than 10μM respectively). Considering inflammation, CBD caused an anti-inflammatory effect on nervous cells at low doses and on gastro-intestinal cells at high doses, while metastatic power was reduced even at low doses, but in a skeletal cell line there was an increased angiogenesis. CB1 receptor has been related to viability effects, CB2 to apoptosis and TRPV1 to inflammation and invasiveness. A detailed insight into these aspects would allow therapeutic use of this substance without possible side effects.”

https://pubmed.ncbi.nlm.nih.gov/35643249/

https://www.sciencedirect.com/science/article/abs/pii/S1043661822002122?via%3Dihub


Cannabinoid CB 2 Receptors Modulate Microglia Function and Amyloid Dynamics in a Mouse Model of Alzheimer’s Disease

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Frontiers in Pharmacology welcomes new Field Chief Editor – Science & research news | Frontiers

“The distribution and roles of the cannabinoid CB2 receptor in the CNS are still a matter of debate. Recent data suggest that, in addition to its presence in microglial cells, the CB2 receptor may be also expressed at low levels, yet biologically relevant, in other cell types such as neurons. It is accepted that the expression of CB2 receptors in the CNS is low under physiological conditions and is significantly elevated in chronic neuroinflammatory states associated with neurodegenerative diseases such as Alzheimer’s disease. By using a novel mouse model (CB2 EGFP/f/f), we studied the distribution of cannabinoid CB2 receptors in the 5xFAD mouse model of Alzheimer’s disease (by generating 5xFAD/CB2 EGFP/f/f mice) and explored the roles of CB2 receptors in microglial function. We used a novel selective and brain penetrant CB2 receptor agonist (RO6866945) as well as mice lacking the CB2 receptor (5xFAD/CB2 -/-) for these studies. We found that CB2 receptors are expressed in dystrophic neurite-associated microglia and that their modulation modifies the number and activity of microglial cells as well as the metabolism of the insoluble form of the amyloid peptide. These results support microglial CB2 receptors as potential targets for the development of amyloid-modulating therapies.”

https://pubmed.ncbi.nlm.nih.gov/35645832/

“These data thus suggest a role for microglial cannabinoid CB2 receptors in the initiation, maintenance and removal of plaques and open new venues for the microglia-based therapeutic approaches in AD.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.841766/full

Anti-inflammatory effects of recreational marijuana in virally suppressed youth with HIV-1 are reversed by use of tobacco products in combination with marijuana

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Retrovirology | Home page

“Background: Marijuana’s putative anti-inflammatory properties may benefit HIV-associated comorbidities. How recreational marijuana use affects gene expression in peripheral blood cells (PBC) among youth with HIV-1 (YWH) is unknown.

Approach: YWH with defined substance use (n = 54) receiving similar antiretroviral therapy (ART) were assigned to one of four analysis groups: YWH with detectable plasma HIV-1 (> 50 RNA copies/ml) who did not use substances (H+V+S-), and YWH with undetectable plasma HIV-1 who did not use substances (H+V-S-), or used marijuana alone (H+V-S+[M]), or marijuana in combination with tobacco (H+V-S+[M/T]). Non-substance using youth without HIV infection (H-S-, n = 25) provided a reference group. PBC mRNA was profiled by Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. Differentially expressed genes (DEG) within outcome groups were identified by Significance Analysis of Microarrays and used for Hierarchical Clustering, Principal Component Analysis, and Ingenuity Pathways Analysis.

Results: HIV-1 replication resulted in > 3000 DEG involving 27 perturbed pathways. Viral suppression reduced DEG to 313, normalized all 27 pathways, and down-regulated two additional pathways, while marijuana use among virally suppressed YWH resulted in 434 DEG and no perturbed pathways. Relative to H+V-S-, multiple DEG normalized in H+V-S+[M]. In contrast, H+V-S+[M/T] had 1140 DEG and 10 dysregulated pathways, including multiple proinflammatory genes and six pathways shared by H+V+S-.

Conclusions: YWH receiving ART display unique transcriptome bioprofiles based on viral replication and substance use. In the context of HIV suppression, marijuana use, alone or combined with tobacco, has opposing effects on inflammatory gene expression.”

https://pubmed.ncbi.nlm.nih.gov/35642061/

“Cannabis is effective in the treatment of HIV-associated peripheral neuropathic pain, improves appetite, and enhances overall quality of life in people with HIV. There is emerging evidence that marijuana use attenuates pro-inflammatory pathways in HIV-infected adults, as well as in non-human primates infected with simian immunodeficiency virus.”

https://retrovirology.biomedcentral.com/articles/10.1186/s12977-022-00594-4

Cannabis for the Treatment of Attention Deficit Hyperactivity Disorder: A Report of 3 Cases

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Abstract of Case Report

“Attention deficit hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder that is highly prevalent in children and adults. An increasing number of patients with ADHD are self-medicating with cannabis, despite a lack of evidence on efficacy and safety. This case report describes 3 males (ages 18, 22, and 23) who have integrated cannabis into their treatment regimen with positive results. Semistructured interviews conducted with the patients describe subjective improvements in symptoms and on quality of life. Improvements on validated rating scales conducted post-cannabis initiation, compared to pre-cannabis initiation obtained from the medical chart, corroborated their personal accounts. Scores on the PHQ-9 (measuring depression) improved by 8-22 points (30-81%), and the SCARED (measuring anxiety) ranged from 0 to 27 points (up to 33%). Improvements on the CEER-9 scale (measuring regulation) ranged from 2 to 7 points (22-78%), and the 9-item SNAP scale (measuring inattention) showed improvements of 2-8 points (7-30%). Mild adverse events including short-term memory problems, dry mouth, and sleepiness were reported. Blood samples were also collected from the patients to determine the plasma concentrations of the cannabinoids and relevant metabolites before and after a cannabis administration. After cannabis use, the plasma levels for CBD and THC ranged from 0 to 15.29 ng/mL and 1.32 to 13.76 ng/mL, respectively. Cannabinoids, however, were not detected prior to dosing, suggesting that cannabis played a complimentary role in the therapeutic regimen of these 3 patients. Clinical trials are recommended to confirm the efficacy of cannabis in the treatment of ADHD.”

https://pubmed.ncbi.nlm.nih.gov/35224434/

https://www.karger.com/Article/FullText/521370

The antidepressant and anxiolytic effects of cannabinoids in chronic unpredictable stress: a preclinical systematic review and meta-analysis

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Translational Psychiatry

“Neuroscience research presents contradictory evidence in support of both the protective and destructive effects of cannabinoids in depression. Therefore, this systematic review and meta-analysis summarizes the existing preclinical literature on the effects of cannabinoid administration in the chronic unpredictable stress model of depression in order to evaluate the effects of cannabinoids and identify gaps in the literature. After protocol registration (PROSPERO #CRD42020219986), we systematically searched Scopus, Embase, Psychology & Behavioral Sciences Collection, APA PsychINFO, PubMed, CINAHL Complete, and ProQuest Dissertations & Theses Global from the earliest record of the databases, February 1964, to November 2020 for articles that met inclusion criteria (e.g., rodent subjects and administration of a cannabinoid. A total of 26 articles were included representing a sample size estimate of 1132 rodents with the majority of articles administering daily intraperitoneal injections during chronic unpredictable stress. These articles were evaluated using a modified SYRCLE’s risk-of-bias tool. For each continuous behavioral measure, the standardized mean difference was calculated between cannabinoid and vehicle groups in rodents subjected to chronic unpredictable stress. The effects of cannabinoids on depressive-like behavior was evaluated using a multilevel mixed-effects model with effect size weights nested within control groups. Cannabinoid administration moderately improved the pooled negative effects of chronic unpredictable stress on anhedonia, learned helplessness, novelty suppressed feeding, time in the anxiogenic context, and entries into the anxiogenic context. Although the interpretations are limited, these findings suggest that with further investigation, cannabinoids may be a viable long-term treatment for stress-related psychopathologies such as depression.”

https://pubmed.ncbi.nlm.nih.gov/35641487/

https://www.nature.com/articles/s41398-022-01967-1


Effects of cannabidiol on simulated driving and cognitive performance: A dose-ranging randomised controlled trial

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SAGE Journals

“Background: Cannabidiol (CBD), a major cannabinoid of Cannabis sativa, is widely consumed in prescription and non-prescription products. While CBD is generally considered ‘non-intoxicating’, its effects on safety-sensitive tasks are still under scrutiny.

Aim: We investigated the effects of CBD on driving performance.

Methods: Healthy adults (n = 17) completed four treatment sessions involving the oral administration of a placebo, or 15, 300 or 1500 mg CBD in a randomised, double-blind, crossover design. Simulated driving performance was assessed between ~45-75 and ~210-240 min post-treatment (Drives 1 and 2) using a two-part scenario with ‘standard’ and ‘car following’ (CF) components. The primary outcome was standard deviation of lateral position (SDLP), a well-established measure of vehicular control. Cognitive function, subjective experiences and plasma CBD concentrations were also measured. Non-inferiority analyses tested the hypothesis that CBD would not increase SDLP by more than a margin equivalent to a 0.05% blood alcohol concentration (Cohen’s dz = 0.50).

Results: Non-inferiority was established during the standard component of Drive 1 and CF component of Drive 2 on all CBD treatments and during the standard component of Drive 2 on the 15 and 1500 mg treatments (95% CIs < 0.5). The remaining comparisons to placebo were inconclusive (the 95% CIs included 0 and 0.50). No dose of CBD impaired cognition or induced feelings of intoxication (ps > 0.05). CBD was unexpectedly found to persist in plasma for prolonged periods of time (e.g. >4 weeks at 1500 mg).

Conclusion: Acute, oral CBD treatment does not appear to induce feelings of intoxication and is unlikely to impair cognitive function or driving performance.”

https://pubmed.ncbi.nlm.nih.gov/35637624/

“The results of this study suggest that acute, oral CBD treatment at doses up to 1500 mg does not induce feelings of intoxication and is unlikely to impair cognitive function or driving performance.”

https://journals.sagepub.com/doi/10.1177/02698811221095356

Cannabinoid Receptor-1 suppresses M2 macrophage polarization in colorectal cancer by downregulating EGFR

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Cell Death Discovery

“Cannabinoid receptors, CB1 and CB2, have been implicated as emerging targets for cancer therapy. Herein, we investigated the potential regulation mechanism of CB1 and its implications in colorectal cancer. CB1 and EGFR expression were examined in colorectal cancer cell lines. The effects of CB1 agonist ACEA and its antagonist AM251 on the proliferation, migration and invasion of colorectal cancer cells and the expression of M1 and M2 macrophage markers were examined. EGFR overexpression was performed with plasmids containing EGFR gene. Tumor xenografts were constructed to explore the effects of CB1 activation on tumorigenesis. We showed that CB1 was downregulated while EGFR was upregulated in colorectal cancer cells. The activation of CB1 suppressed the proliferation, migration and invasion of colorectal cancer cells and the differentiation of M2 macrophages, while CB1 inhibition had opposite effects. Moreover, the alterations in tumorigenesis and M2 macrophage activation induced by CB1 activation were counteracted by EGFR overexpression. Besides, CB1 silencing promoted tumor cell proliferation and M2 polarization which was counteracted by EGFR knockdown. In vivo, CB1 activation also repressed tumorigenesis and M2 macrophage activation. The present study demonstrated that CB1 activation suppressed M2 macrophage through EGFR downregulation in colorectal cancers. These findings first unveiled the potential avenue of CB1 as a targeted therapy for colorectal cancer.”

https://pubmed.ncbi.nlm.nih.gov/35641479/

“In conclusion, our study showed that CB1 activation suppressed tumor growth and M2 macrophage activation in colorectal cancer by downregulating EGFR. Our study provided the first evidence that CB1 activation was capable to suppress M2 macrophage activation. Since M2 macrophage are linked with immune evasion in various cancers, CB1 might be a promising target for cancer treatment.”

https://www.nature.com/articles/s41420-022-01064-8

“The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/17583570/