Mechanisms Involved in the Therapeutic Effect of Cannabinoid Compounds on Gliomas: A Review with Experimental Approach

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“Introduction: Brain tumors have high morbidity and mortality rates, accounting for 1.4% of all cancers. Gliomas are the most common primary brain tumors in adults. Currently, several thera-peutic approaches are used; however, they are associated with side effects that affect pa-tients’quality of life. Therefore, further studies are needed to develop novel therapeutic protocols with a more favorable side effect profile. In this context, cannabinoid compounds may serve as potential alternatives.

Objective: This study aimed to review the key enzymatic targets involved in glioma pathophysi-ology and evaluate the potential interaction of these targets with four cannabinoid derivatives through molecular docking simulations.

Methods: Molecular docking simulations were performed using four cannabinoid compounds and six molecular targets associated with glioma pathophysiology.

Results: Encouraging interactions between the selected enzymes and glioma-related targets were observed, suggesting their potential activity through these pathways. In particular, cannabigerol showed promising interactions with epidermal growth factor receptors and phosphatidylinositol 3-kinase, while Δ-9-tetrahydrocannabinol showed remarkable interactions with telomerase reverse transcriptase.

Conclusion: The evaluated compounds exhibited favorable interactions with the analyzed enzy-matic targets, thus representing potential candidates for further in vitro and in vivo studies.”

Cannabidiol acts as molecular switch in innate immune cells to promote the biosynthesis of inflammation-resolving lipid mediators

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“Cannabinoids are phytochemicals from cannabis with anti-inflammatory actions in immune cells. Lipid mediators (LM), produced from polyunsaturated fatty acids (PUFA), are potent regulators of the immune response and impact all stages of inflammation. How cannabinoids influence LM biosynthetic networks is unknown. Here, we reveal cannabidiol (CBD) as a potent LM class-switching agent that stimulates the production of specialized pro-resolving mediators (SPMs) but suppresses pro-inflammatory eicosanoid biosynthesis. Detailed metabololipidomics analysis in human monocyte-derived macrophages showed that CBD (i) upregulates exotoxin-stimulated generation of SPMs, (ii) suppresses 5-lipoxygenase (LOX)-mediated leukotriene production, and (iii) strongly induces SPM and 12/15-LOX product formation in resting cells by stimulation of phospholipase A2-dependent PUFA release and through Ca2+-independent, allosteric 15-LOX-1 activation. Finally, in zymosan-induced murine peritonitis, CBD increased SPM and 12/15-LOX products and suppressed pro-inflammatory eicosanoid levels in vivo. Switching eicosanoid to SPM production is a plausible mode of action of CBD and a promising inflammation-resolving strategy.”

Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study

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“The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.”

Therapeutic Potential of Minor Cannabinoids in Dermatological Diseases-A Synthetic Review

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“Dermatological diseases pose a significant burden on the quality of life of individuals and can be challenging to treat effectively. In this aspect, cannabinoids are gaining increasing importance due to their therapeutic potential in various disease entities including skin diseases. In this synthetic review, we comprehensively analyzed the existing literature in the field of potential dermatological applications of a lesser-known subgroup of cannabinoids, the so-called minor cannabinoids, such as cannabidivarin (CBDV), cannabidiforol (CBDP), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabielsoin (CBE), cannabimovone (CBM) or cannabinol (CBN), while drawing attention to their unique pharmacological properties. We systematically searched the available databases for relevant studies and analyzed the data to provide an overview of current thematic knowledge. We looked through the full-text, bibliographic and factographic databases, especially Scopus, Web of Science, PubMed, Polish Scientific Journals Database, and selected the most relevant papers. Our review highlights that minor cannabinoids exhibit diverse pharmacological activities, including anti-inflammatory, analgesic, antimicrobial, and anti-itch properties. Several studies have reported their efficacy in mitigating symptoms associated with dermatological diseases such as psoriasis, eczema, acne, and pruritus. Furthermore, minor cannabinoids have shown potential in regulating sebum production, a crucial factor in acne pathogenesis. The findings of this review suggest that minor cannabinoids hold therapeutic promise in the management of dermatological diseases. Further preclinical and clinical investigations are warranted to elucidate their mechanisms of action, determine optimal dosage regimens, and assess long-term safety profiles. Incorporating minor cannabinoids into dermatological therapies could potentially offer novel treatment options of patients and improve their overall well-being.”

Therapeutic Potential of Cannabinoids in Glaucoma

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“Glaucoma is a leading cause of irreversible blindness worldwide. To date, intraocular pressure (IOP) is the only modifiable risk factor in glaucoma treatment, but even in treated patients, the disease can progress. Cannabinoids, which have been known to lower IOP since the 1970s, have been shown to have beneficial effects in glaucoma patients beyond their IOP-lowering properties. In addition to the classical cannabinoid receptors CB1 and CB2, knowledge of non-classical cannabinoid receptors and the endocannabinoid system has increased in recent years. In particular, the CB2 receptor has been shown to mediate anti-inflammatory, anti-apoptotic, and neuroprotective properties, which may represent a promising therapeutic target for neuroprotection in glaucoma patients. Due to their vasodilatory effects, cannabinoids improve blood flow to the optic nerve head, which may suggest a vasoprotective potential and counteract the altered blood flow observed in glaucoma patients. The aim of this review was to assess the available evidence on the effects and therapeutic potential of cannabinoids in glaucoma patients. The pharmacological mechanisms underlying the effects of cannabinoids on IOP, neuroprotection, and ocular hemodynamics have been discussed.”

The Use of CBD and Its Synthetic Analog HU308 in HIV-1-Infected Myeloid Cells

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“Currently, there is no cure for human immunodeficiency virus type 1 (HIV-1) infection. However, combined antiretroviral therapy (cART) aids in viral latency and prevents the progression of HIV-1 infection into acquired immunodeficiency syndrome (AIDS). cART has extended many lives, but people living with HIV-1 (PLWH) face lifelong ailments such as HIV-associated neurocognitive disorders (HAND) that range from asymptomatic HAND to HIV-1-associated dementia. HAND has been attributed to chronic inflammation and low-level infection within the central nervous system (CNS) caused by proinflammatory cytokines and viral products. These molecules are shuttled into the CNS within extracellular vesicles (EVs), lipid bound nanoparticles, and are released from cells as a form of intercellular communication. This study investigates the impact of cannabidiol (CBD), as a promising and potential therapeutic for HAND patients, and a similar synthetic molecule, HU308, on the EVs released from HIV-1-infected myeloid cells as well as HIV-1-infected 3D neurospheres. The data shows that both CBD and HU308 decrease non-coding and coding viral RNA (TAR and env) as well as proinflammatory cytokines as IL-1β and TNF-α mRNA. This decrease in viral RNA occurs in in vitro differentiated primary macrophages, in EVs released from HIV-1-infected cells monocytes, and infected neurospheres. Furthermore, a 3D neurosphere model shows an overall decrease in proinflammatory mRNA with HU308. Finally, using a humanized mouse model of HIV-1 infection, plasma viral RNA was shown to significantly decrease with HU308 alone and was most effective in combination with cART, even when compared to the typical cART treatment. Overall, CBD or HU308 may be a viable option to decrease EV release and associated cytokines which would dampen the virus spread and may be used in effective treatment of HAND in combination with cART.”

“Taken together, these data indicate that HU308 or CBD decrease viral RNA, and that HU308 and, to some extent, CBD decrease proinflammatory cytokine mRNA released in EVs. Therefore, either CBD or HU308 could potentially be used in combination with cART to target both pro-inflammatory and viral gene expression for the prevention of HAND.”

Cannabinoids for symptom management in children with cancer: A systematic review and meta-analysis

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“Background: Despite the widespread use of medical cannabis, little is known regarding the safety, efficacy, and dosing of cannabis products in children with cancer. The objective of this study was to systematically appraise the existing published literature for the use of cannabis products in children with cancer.

Methods: This systematic review, registered with the International Prospective Register of Systematic Reviews (CRD42020187433), searched four databases: MEDLINE, Embase, PsycINFO, and the Cochrane Library. Abstracts and full texts were screened in duplicate. Data on types of cannabis products, doses, formulations, frequencies, routes of administration, indications, and clinical and demographic details as well as reported efficacy outcomes were extracted. Data on cannabinoid-related adverse events were also summarized.

Results: Out of 34,611 identified citations, 19 unique studies with a total of 1927 participants with cancer were included: eight retrospective chart reviews, seven randomized controlled trials, two open-label studies, and two case reports. The included studies reported the use of various cannabis products for the management of symptoms. Cannabinoids were commonly used for the management of chemotherapy-induced nausea and vomiting (11 of 19 [58%]). In controlled studies, somnolence, dizziness, dry mouth, and withdrawal due to adverse events were more commonly associated with the use of cannabinoids. Across all included studies, no serious cannabis-related adverse events were reported.

Conclusions: Although there is evidence to support the use of cannabis for symptom management, in children with cancer, there is a lack of rigorous evidence to inform the dosing, safety, and efficacy of cannabinoids. Because of the increasing interest in using cannabis, there is an urgent need for more research on medical cannabis in children with cancer.”

“In conclusion, cannabinoids have been used for the management of multiple symptoms in children with cancer, including CINV, anorexia, tumor-related epilepsy, and cancer-related pain. Cannabis products may have therapeutic applications for symptom management in children with cancer. “

Etoricoxib-Cannabidiol Combo: Potential Role in Glioblastoma Treatment and Development of PLGA-Based Nanoparticles

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“Background: Glioblastoma (GBM) is the most frequently occurring primary malignant central nervous system tumor, with a poor prognosis and median survival below two years. Administration of a combination of non-steroidal anti-inflammatory drugs and natural compounds that exhibit a curative or prophylactic effect in cancer is a new approach to GBM treatment. This study aimed to investigate the synergistic antitumor activity of etoricoxib (ETO) and cannabidiol (CBD) in a GBM cell line model, and to develop poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) for these two substances.

Methods: The activity of ETO+CBD was determined using the MTT test, cell-cycle distribution assay, and apoptosis analysis using two GBM cell lines, namely, T98G and U-138 MG. The PLGA-based NPs were developed using the emulsification and solvent evaporation method. Their physicochemical properties, such as shape, size, entrapment efficiency (EE%), in vitro drug release, and quality attributes, were determined using scanning electron microscopy, diffraction light scattering, high-performance liquid chromatography, infrared spectroscopy, and differential scanning calorimetry.

Results: The combination of ETO and CBD reduced the viability of cells in a dose-dependent manner and induced apoptosis in both tested GBM cell lines. The developed method allowed for the preparation of ETO+CBD-NPs with a spherical shape, mean particle size (MPS) below 400 nm, zeta potential (ZP) values from -11 to -17.4 mV, polydispersity index (PDI) values in the range from 0.029 to 0.256, and sufficient EE% of both drugs (78.43% for CBD, 10.94% for ETO).

Conclusions: The combination of ETO and CBD is a promising adjuvant therapeutic in the treatment of GBM, and the prepared ETO+CBD-NPs exhibit a high potential for further pharmaceutical formulation development.”

Cannabinoids and standardized cannabis extracts inhibit migration, invasion, and induce apoptosis in MCF-7 cells through FAK/MAPK/Akt/NF-κB signaling

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“Background: Breast cancer is the highest incidence of all types of cancer in women, and the cancer metastasis process accounts for a majority of cancer deaths. Two major cannabinoids, Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), from Cannabis sativa are expected to have anti-cancer activity. This study aimed to investigate the effects of THC, CBD, and standardized cannabis extracts (F1, F2, and F3) on migration, invasion, and apoptosis of human breast cancer (MCF-7) cells.

Methods: Cell viability, survival, and apoptosis were determined using the MTT, clonogenic, and nuclear staining assays, respectively, while cancer cell migration and invasion were evaluated by the wound healing, trans-well, and filopodia assays. Western blot analysis was used to find out the mechanisms of the cannabinoids against MCF-7 cells.

Results: CBD, THC, and F1 inhibited filopodia formation, migration, and invasion of MCF-7 cells through suppressing the expression of the FAK, Akt, ERK1/2, p38MAPKs, and NF-κB upstream pathways, as well as inhibiting the Rac1/Cdc42 downstream pathways. In addition, CBD significantly inhibited the mTOR pathway. Furthermore, CBD and F1 induced apoptosis in MCF-7 cells via the Bcl-2/caspase-3 pathways.

Conclusion: These results indicate that THC, CBD, and F1 have great abilities for preventing breast cancer cell metastasis in in vitro experiments.”

Cannabidiol and Tetrahydrocannabinol Use in Parkinson’s Disease: An Observational Pilot Study

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“Background: There is a need for more research examining the use of cannabis, tetrahydrocannabinol (THC), and cannabidiol (CBD) products in people with Parkinson’s disease (PD), especially given the recent increase in the use of these products.

Objectives: Given the recent increase in over-the-counter CBD use as well as the prescription of medical cannabis by treating physicians, the utilization method, effects on motor and non-motor symptoms, side effects, and attitude toward cannabis use were examined in a naturalistic sample of patients with PD.

Methods: A total of 15 individuals with PD, eight of whom were prescribed CBD/THC treatment and seven who were not taking any CBD/THC product, were assessed cross-sectionally. Participants completed structured neuropsychological testing, motor assessment, and questionnaires regarding mood, subjective cognition, and symptom levels. T-tests were completed for quantitative measures and descriptive data were examined and described. Due to the small sample size, Shapiro-Wilk tests for normality were utilized and Mann-Whitney U analyses were completed when appropriate.

Results: We found a wide range of prescribed products and methods as well as variability in perceived benefits and untoward effects, even in our small sample. Individuals with PD who were taking a CBD/THC product had lower global cognition scores on the Montreal Cognitive Assessment (MoCA) but no detectable differences among more specific neuropsychological measures. They also had more non-motor symptoms of PD but no differences in motor symptom levels. Qualitatively, some participants with PD who were taking CBD/THC reported improved pain levels, sleep, and reductions in anxiety. A few negative effects were endorsed, including sleepiness, concentration difficulties, and forgetfulness.

Conclusion: CBD/THC utilization in PD is varied. In our small sample, individuals who utilized the treatment had lower MoCA scores, more non-motor symptoms, and descriptively reported improvements in sleep, anxiety, and pain, and had side effects of sleepiness and cognitive difficulty. Future studies should focus on clinical trials with standardized CBD/THC methods of use.”!/