Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Cannabinoids as Key Regulators of Inflammasome Signaling: A Current Perspective

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Segura Lab - New publication in Frontiers in Immunology“Inflammasomes are cytoplasmic inflammatory signaling protein complexes that detect microbial materials, sterile inflammatory insults, and certain host-derived elements. Inflammasomes, once activated, promote caspase-1-mediated maturation and secretion of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18, leading to pyroptosis. Current advances in inflammasome research support their involvement in the development of chronic inflammatory disorders in contrast to their role in regulating innate immunity.

Cannabis (marijuana) is a natural product obtained from the Cannabis sativa plant, and pharmacologically active ingredients of the plant are referred to as cannabinoids. Cannabinoids and cannabis extracts have recently emerged as promising novel drugs for chronic medical conditions. Growing evidence indicates the potent anti-inflammatory potential of cannabinoids, especially Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and synthetic cannabinoids; however, the mechanisms remain unclear. Several attempts have been made to decipher the role of cannabinoids in modulating inflammasome signaling in the etiology of chronic inflammatory diseases.

In this review, we discuss recently published evidence on the effect of cannabinoids on inflammasome signaling. We also discuss the contribution of various cannabinoids in human diseases concerning inflammasome regulation. Lastly, in the milieu of coronavirus disease-2019 (COVID-19) pandemic, we confer available evidence linking inflammasome activation to the pathophysiology of COVID-19 suggesting overall, the importance of cannabinoids as possible drugs to target inflammasome activation in or to support the treatment of a variety of human disorders including COVID-19.”

https://pubmed.ncbi.nlm.nih.gov/33584697/

“Cannabis has been shown to possess anti-inflammatory effects owing to its constituents, cannabinoids and terpenoids. Overall, cannabinoids hold a great promise as additional therapeutics to support the current treatment of chronic inflammatory diseases, along with COVID-19”

https://www.frontiersin.org/articles/10.3389/fimmu.2020.613613/full

A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma

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British Journal of Cancer“Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM.

Results: The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK.

Conclusions: With personalised dosing, nabiximols had acceptable safety and tolerability with no drug-drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial.”

https://pubmed.ncbi.nlm.nih.gov/33623076/

https://www.nature.com/articles/s41416-021-01259-3

Cannabis-Derived Compounds Cannabichromene and Δ9-Tetrahydrocannabinol Interact and Exhibit Cytotoxic Activity against Urothelial Cell Carcinoma Correlated with Inhibition of Cell Migration and Cytoskeleton Organization

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molecules-logo“Cannabis sativa contains more than 500 constituents, yet the anticancer properties of the vast majority of cannabis compounds remains unknown. We aimed to identify cannabis compounds and their combinations presenting cytotoxicity against bladder urothelial carcinoma (UC), the most common urinary system cancer.

An XTT assay was used to determine cytotoxic activity of C. sativa extracts on T24 and HBT-9 cell lines. Extract chemical content was identified by high-performance liquid chromatography (HPLC). Fluorescence-activated cell sorting (FACS) was used to determine apoptosis and cell cycle, using stained F-actin and nuclei. Scratch and transwell assays were used to determine cell migration and invasion, respectively. Gene expression was determined by quantitative Polymerase chain reaction (PCR).

The most active decarboxylated extract fraction (F7) of high-cannabidiol (CBD) C. sativa was found to contain cannabichromene (CBC) and Δ9-tetrahydrocannabinol (THC). Synergistic interaction was demonstrated between CBC + THC whereas cannabinoid receptor (CB) type 1 and type 2 inverse agonists reduced cytotoxic activity.

Treatments with CBC + THC or CBD led to cell cycle arrest and cell apoptosis. CBC + THC or CBD treatments inhibited cell migration and affected F-actin integrity. Identification of active plant ingredients (API) from cannabis that induce apoptosis and affect cell migration in UC cell lines forms a basis for pre-clinical trials for UC treatment.”

https://pubmed.ncbi.nlm.nih.gov/33477303/

https://www.mdpi.com/1420-3049/26/2/465

The effectiveness of inhaled Cannabis flower for the treatment of agitation/irritability, anxiety, and common stress

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Cognetivity publishes MS paper in BMC Neurology Journal - Cognetivity Neurosciences

“Background: An observational research design was used to evaluate which types of commonly labeled Cannabis flower product characteristics are associated with changes in momentary feelings of distress-related symptoms.

Results: In total, a decrease in symptom intensity levels was reported in 95.51% of Cannabis usage sessions, an increase in 2.32% of sessions, and no change in 2.16% of sessions. Fixed effects models showed, on average, respondents recorded a maximum symptom intensity reduction of 4.33 points for agitation/irritability (SE = 0.20, p < 0.01), 3.47 points for anxiety (SE = 0.13, p < 0.01), and 3.98 for stress (SE = 0.12, p < 0.01) on an 11-point visual analog scale. Fixed effects regressions showed that, controlling for time-invariant user characteristics, mid and high tetrahydrocannabinol (THC) levels were the primary independent predictor of increased symptom relief, and that when broken out by symptom type, this effect was only statistically significant for our largest sample of users, those reporting anxiety rather than agitation/irritability or stress. Cannabidiol (CBD) levels were generally not associated with changes in symptom intensity levels. In a minority of cannabis use sessions (< 13%), cannabis users reported anxiogenic-related negative side effects (e.g., feeling anxious, irritable, paranoid, rapid pulse, or restless), whereas in a majority of sessions (about 66%), users reported positive anxiolytic side effects (e.g., feeling chill, comfy, happy, optimistic, peaceful, or relaxed).

Conclusions: The findings suggest the majority of patients in our sample experienced relief from distress-related symptoms following consumption of Cannabis flower, and that among product characteristics, higher THC levels were the strongest predictors of relief.”

https://pubmed.ncbi.nlm.nih.gov/33526145/

“Our findings suggest that self-directed use of Cannabis flower, especially that with higher THC levels, is associated with significant improvements in at least short-term feelings of distress in many users, likely a contributing factor to its widespread popularity and consumption in the U.S.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-00051-z

Cannabinoids in Dermatologic Surgery

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JAAD Journals on Twitter: "Have questions for JAAD authors? Join the new JAAD Virtual Journal Club and start engaging with authors today: https://t.co/KWSzvAEPd5… https://t.co/ip6aG4d2fm"“Though known as a medicinal herb for centuries, the recent legalization of cannabinoids across many states has ushered in a new era where cannabinoids have become a popular treatment option amongst clinicians and patients alike. Cannabinoids have demonstrated efficacy in wound healing, reducing inflammation, ameliorating pain, and have shown potential as an anti-tumor agent. As a result, cannabinoids have been rapidly woven into the fabric of modern medicine. However, the utility of cannabinoids in dermatologic surgery has not been explored to date. In this paper, we review the current literature to discuss the potential impact of cannabinoid use in dermatologic surgery.”

https://pubmed.ncbi.nlm.nih.gov/33422628/

https://www.jaad.org/article/S0190-9622(21)00104-3/pdf

Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the “Big Two”

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 Go to Volume 0, Issue 0“Plant-based therapies date back centuries. Cannabis sativa is one such plant that was used medicinally up until the early part of the 20th century.

Although rich in diverse and interesting phytochemicals, cannabis was largely ignored by the modern scientific community due to its designation as a schedule 1 narcotic and restrictions on access for research purposes. There was renewed interest in the early 1990s when the endocannabinoid system (ECS) was discovered, a complex network of signaling pathways responsible for physiological homeostasis. Two key components of the ECS, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), were identified as the molecular targets of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC).

Restrictions on access to cannabis have eased worldwide, leading to a resurgence in interest in the therapeutic potential of cannabis. Much of the focus has been on the two major constituents, Δ9-THC and cannabidiol (CBD). Cannabis contains over 140 phytocannabinoids, although only a handful have been tested for pharmacological activity. Many of these minor cannabinoids potently modulate receptors, ionotropic channels, and enzymes associated with the ECS and show therapeutic potential individually or synergistically with other phytocannabinoids.

The following review will focus on the pharmacological developments of the next generation of phytocannabinoid therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/33356248/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.0c00965

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Cannabinoid receptor activation on hematopoietic cells and enterocytes protects against colitis

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Oxford University Press“Cannabinoid receptor (CB) activation can attenuate inflammatory bowel disease (IBD) in experimental models and human cohorts. However, the role of the microbiome, metabolome, or the respective contributions of hematopoietic and non-hematopoietic cells in the anti-colitic effects of cannabinoids has yet to be determined.

Methods: Female C57BL/6 mice were treated with either cannabidiol (CBD), Δ 9-tetrahydrocannabinol (THC), a combination of CBD and THC or vehicle, in several models of chemically induced colitis. Clinical parameters of colitis were assessed by colonoscopy, histology, flow cytometry and detection of serum biomarkers; single-cell RNA sequencing and qRT-PCR were used to evaluate the effects of cannabinoids on enterocytes. Immune cell transfer from CB2 knockout mice was used to evaluate the contribution of hematopoietic and non-hematopoietic cells to colitis protection.

Results: We found that THC prevented colitis, and that CBD, at the dose tested, provided little benefit to the amelioration of colitis, or when added synergistically with THC. THC increased colonic barrier integrity by stimulating mucus, tight junction and antimicrobial peptide production, and these effects were specific to the large intestine. THC increased colonic gram-negative bacteria, but the anti-colitic effects of THC were independent of the microbiome. THC acted on both immune cells via CB2 and on enterocytes to attenuate colitis.

Conclusions: Our findings demonstrate how cannabinoid receptor activation on both immune cells and colonocytes is critical to prevent colonic inflammation. These studies also suggest how cannabinoid receptor activation can be used as a preventive and therapeutic modality against colitis.”

https://pubmed.ncbi.nlm.nih.gov/33331878/

https://academic.oup.com/ecco-jcc/advance-article-abstract/doi/10.1093/ecco-jcc/jjaa253/6040793?redirectedFrom=fulltext

Role of marijuana components on the regenerative ability of stem cells

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“Stem cell therapy promotes tissue regeneration and wound healing. Efforts have been made to prime stem cells to enhance their regenerative abilities.

Certain marijuana components, namely the non-psychoactive cannabidiol (CBD) and psychoactive tetrahydrocannabinol (THC), are defined as immunomodulators.9 We test whether two sources of stem cells, primed with CBD or THC, would demonstrate improved regenerative abilities.

Human adipose-derived stem cells (ASCs) and bone marrow-derived stem cells (BMDSCs), not obtained from the same individual, were treated with low (300 nM) or high (3 μM) concentration CBD. Porcine ASCs and BMDSCs were isolated from a single pig, and treated with either low or high concentrations of CBD or THC. Transwell migration and MTT proliferation assays were performed on the human ASCs and BMDSCs. Also, transwell migration assay was performed on the porcine ASCs and BMDSCs. Finally, a wound healing scratch assay in porcine primary fibroblasts (PFs) was performed, co-cultured with the cannabinoid-treated ASCs.

CBD priming at low concentration induces migration by 180% (P < .01) in porcine ASCs, and by only 93% (P < .02) in porcine BMDSCs. In porcine stem cells, THC priming at low concentration induces migration by 91.6% (P < .01) in ASCs but by only 44.3% (P < .03) in BMDSCs. Compared to PFs co-cultured with untreated ASCs, PFs co-cultured with low CBD-primed ASCs had 75% faster wound closure at 18 hours (P < .01).

CBD and THC priming of ASCs and BMDSCs, particularly at lower doses, enhances a number of regenerative parameters, suggesting that these major marijuana components may improve stem cell-based therapies.

SIGNIFICANCE OF THE STUDY: Our study demonstrates that cannabinoids can enhance the regenerative capacity of two major sources of stem cells, adipose- and bone marrow-derived, from human and porcine donors. Stem cell isolation and expansion is invasive, costly and time consuming. Stem cells with improved regenerative properties may be effective in the treatment of acute or chronic wounds. This is the first study to compare the priming potential of two sources of stem cells from the same animal, with the same genetic and epigenetic profile, as well as the first to prime with THC.”

https://pubmed.ncbi.nlm.nih.gov/33349985/

https://onlinelibrary.wiley.com/doi/10.1002/cbf.3609

Cannabinoid control of neurogenic inflammation

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 British Journal of Pharmacology“A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation. Neurogenic inflammation occurs when a noxious signal is detected in the periphery initiating an antidromic axon reflex in the same sensory neurone leading to depolarization of the afferent terminal. Neuropeptides are subsequently released and contribute to vasodilation, plasma extravasation and modulation of immune cells. Endocannabinoids, synthetic cannabinoids and phytocannabinoids can reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release. Thus, in addition to a direct effect on vascular smooth muscle and inflammatory cells, cannabinoids can reduce inflammation by silencing small diameter neurones. This review examines the neuropharmacological processes involved in regulating antidromic depolarization of afferent nerve terminals by cannabinoids and the control of neurogenic inflammation in different diseases.”

https://pubmed.ncbi.nlm.nih.gov/33289534/

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15208

Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches

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International Journal of Biological Macromolecules“Effective treatment choices to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are limited because of the absence of effective target-based therapeutics. The main object of the current research was to estimate the antiviral activity of cannabinoids (CBDs) against the human coronavirus SARS-CoV-2.

In the presented research work, we performed in silico and in vitro experiments to aid the sighting of lead CBDs for treating the viral infections of SARS-CoV-2. Virtual screening was carried out for interactions between 32 CBDs and the SARS-CoV-2 Mpro enzyme. Afterward, in vitro antiviral activity was carried out of five CBDs molecules against SARS-CoV-2.

Interestingly, among them, two CBDs molecules namely Δ (Yu et al., 2020 [9])-tetrahydrocannabinol (IC50 = 10.25 μM) and cannabidiol (IC50 = 7.91 μM) were observed to be more potent antiviral molecules against SARS-CoV-2 compared to the reference drugs lopinavir, chloroquine, and remdesivir (IC50 ranges of 8.16-13.15 μM). These molecules were found to have stable conformations with the active binding pocket of the SARS-CoV-2 Mpro by molecular dynamic simulation and density functional theory.

Our findings suggest cannabidiol and Δ (Yu et al., 2020 [9])-tetrahydrocannabinol are possible drugs against human coronavirus that might be used in combination or with other drug molecules to treat COVID-19 patients.”

https://pubmed.ncbi.nlm.nih.gov/33290767/

“In summary, this report demonstrates the antiviral potencies of CBD and Δ9-THC against SARS-CoV-2. Based on privileged safety index CBD and Δ9-THC in human and their current in vitro potencies against SARS-CoV-2, it can be concluded that these compounds are potential antiviral molecules towards SARS-CoV-2 and may have worked as dual-acting against SARS-CoV-2, not only block the viral translation procedure by inhibiting SARS-CoV-2 Mpro but also reduce pro-inflammatory cytokines levels in lung cells by acting as agonists of CB-2 receptor. The successful in vitro work here of CBD and Δ9-THC lays the framework for their application in human clinical trials for the treatment of human coronavirus infections. Thus, CBD and Δ9-THC may be used in combination or with other drugs to treat COVID-19 patients.”

https://www.sciencedirect.com/science/article/pii/S0141813020351783?via%3Dihub

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