Self-Reported Cannabis Use Is Associated With a Lower Rate of Persistent Opioid Use After Total Joint Arthroplasty

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Arthroplasty Today (@ArthroToday) / Twitter

“Background: Legalization of cannabis, along with concern over prescription opiate use, has garnered interest in cannabis for adjuvant pain control. This study examines the relationship between cannabis and opioid consumption after total hip (THA) or knee (TKA) arthroplasty.

Methods: Patients undergoing primary THA or TKA with minimum 6-month follow-up who self-reported cannabis use were retrospectively reviewed. A total of 210 patients (128 TKAs and 82 THAs) were matched by age; gender; type of arthroplasty; Charlson Comorbidity Index; and use of nicotine, antidepressants, or benzodiazepines to patients who did not self-report cannabis use. Patients receiving an opioid prescription after 90 days postoperatively were classified as persistent opioid users (POUs). Duration of opioid use (DOU) was calculated for non-POU patients as the time between surgery and their last opioid prescription. Differences in inpatient morphine milligram equivalents (MMEs), outpatient MMEs, POU, and DOU were analyzed.

Results: Cannabis users required equivalent inpatient and outpatient MMEs. There was no difference in DOU. There was a significant difference in POU between cannabis users and matched controls (1.4% [n = 3] vs 9.5% [n = 20], P < .001, respectively). Grouping patients by TKA or THA, there remained a difference in POU for TKA (1.5% [n = 2] vs 10.9% [n = 14], P = .002) and THA (1.2% [n = 1] vs 7.3% [n = 6], P = .04). There was no difference in inpatient or outpatient MMEs or DOU for THA and TKA patients.

Conclusions: There is a reduced rate of POU in patients who self-report perioperative cannabis use. Prospective studies are needed to clarify the role of cannabis as an adjunct to perioperative pain control.”

https://pubmed.ncbi.nlm.nih.gov/36158462/

“This study helps to shed light on what role if any cannabis should play as a part of an opioid-sparing multimodal pain protocol after TJA. Self-reported perioperative cannabis use appeared to significantly reduce the number of patients that persistently used opioids greater than 90 days after TJA from 9.5% to 1.4%.”

https://www.arthroplastytoday.org/article/S2352-3441(22)00164-9/fulltext

Oral inhalation of cannabidiol delivered from a metered dose inhaler to alleviate cytokine production induced by SARS-CoV-2 and pollutants

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Journal of Drug Delivery Science and Technology

“Cannabidiol (CBD) was formulated as a metered dose inhaler (CBD-MDI) and evaluated in vitro for its efficacy as an inhaled dosage form against inflammation caused by the SARS-CoV-2 virus, lipopolysaccharide (LPS) from Escherichia coli, silica particles, nicotine, and coal tar.

A CBD-MDI formulation was prepared with 50 mg of CBD in 10 mL for a CBD dose of 250 μg/puff. The formulation ingredients included CBD, absolute ethanol as a cosolvent, and HFA-134a as the propellant. High aerosol performance of CBD-MDI was obtained with mass median aerodynamic diameter of 1.25 ± 0.01 μm, geometric standard deviation of 1.75 ± 0.00, emitted dose of 244.7 ± 2.1 μg, and fine particle dose of 122.0 ± 1.6 μg. The cytotoxicity and anti-inflammatory effectiveness of CBD-MDI were performed in alveolar macrophage (NR8383) and co-culture of alveolar macrophage (NR8383) and human lung adenocarcinoma (A549) cell line.

CBD delivered from an MDI was safe on respiratory cells and did not trigger an immune response in alveolar macrophages. CBD-MDI effectively reduced the generation of cytokines in immune cells treated with viral antigen S-RBD, bacterial antigen LPS, silica particles, and coal tar. The efficacy of CBD-MDI was comparable to budesonide. Furthermore, the findings demonstrated that the use of CBD-MDI was more effective in treatment rather than prevention when inflammation was induced by either a viral or bacterial stimulant.”

https://pubmed.ncbi.nlm.nih.gov/36159727/

https://www.sciencedirect.com/science/article/pii/S177322472200716X?via%3Dihub

Comparison of the in vitro Anti-Inflammatory Effect of Cannabidiol to Dexamethasone

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“Background: Cannabidiol (CBD) is a non-psychoactive phytocannabinoid constituent of Cannabis sativa with pain-relieving and anti-inflammatory properties. With the emphasis on natural ingredients in cosmetics, CBD has become a new cosmetic ingredient due to its ability to alleviate inflammation. However, in-depth studies that directly compare the effective mechanism and the therapeutic potential of CBD are still needed.

Purpose: The aim of the present study was to investigate the anti-inflammatory effect of CBD in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and compare it to dexamethasone (DEX).

Methods: RAW264.7 macrophages in the logarithmic growth phase were incubated in the presence or absence of LPS. After that, the production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. A luciferase reporter assay for nuclear factor kappa B (NF-κB) was performed, and the phosphorylation levels of the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways were measured.

Results: The present study indicated that CBD had a similar anti-inflammatory effect to DEX by attenuating the LPS-induced production of NO, IL-6, and TNF-α. However, only CBD attenuated JNK phosphorylation levels, and only DEX attenuated IKK phosphorylation levels.

Conclusion: These results suggested that CBD and DEX exhibit similar anti-inflammatory effects on LPS-induced RAW264.7 macrophages mainly through suppressing the MAPK and NF-κB signaling pathways, but with different intracellular mechanisms. These findings suggested that CBD may be considered a natural anti-inflammatory agent for protecting skin from immune disorders.”

https://pubmed.ncbi.nlm.nih.gov/36159203/

“As alternative and complementary therapies grow in dermatology, plant extracts such as CBD have garnered significant attention in dermatology. The present study provided new insight of CBD against LPS-induced inflammation. Our results suggested that CBD and DEX suppress the LPS-induced activation of the MAPK and NF-κB signaling pathways in RAW264.7 cells through different intracellular components, indicating that the anti-inflammatory biological mechanism of CBD is different from other immuno-suppressants. Because macrophages exert various pro-inflammatory functions through multiple intracellular pathways, further in vivo and in vitro studies are necessary to enrich the theoretical knowledge of CBD and promote its future clinical application.”

https://www.dovepress.com/comparison-of-the-in-vitro-anti-inflammatory-effect-of-cannabidiol-to–peer-reviewed-fulltext-article-CCID

Dynamic Changes in the Endocannabinoid System during the Aging Process: Focus on the Middle-Age Crisis

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“Endocannabinoid (eCB) signaling is markedly decreased in the hippocampus (Hip) of aged mice, and the genetic deletion of the cannabinoid receptor type 1 (CB1) leads to an early onset of cognitive decline and age-related histological changes in the brain. Thus, it is hypothesized that cognitive aging is modulated by eCB signaling through CB1.

In the present study, we detailed the changes in the eCB system during the aging process using different complementary techniques in mouse brains of five different age groups, ranging from adolescence to old age.

Our findings indicate that the eCB system is most strongly affected in middle-aged mice (between 9 and 12 months of age) in a brain region-specific manner. We show that 2-arachidonoylglycerol (2-AG) was prominently decreased in the Hip and moderately in caudate putamen (CPu), whereas anandamide (AEA) was decreased in both CPu and medial prefrontal cortex along with cingulate cortex (mPFC+Cg), starting from 6 months until 12 months. Consistent with the changes in 2-AG, the 2-AG synthesizing enzyme diacylglycerol lipase α (DAGLα) was also prominently decreased across the sub-regions of the Hip.

Interestingly, we found a transient increase in CB1 immunoreactivity across the sub-regions of the Hip at 9 months, a plausible compensation for reduced 2-AG, which ultimately decreased strongly at 12 months. Furthermore, quantitative autoradiography of CB1 revealed that [3H]CP55940 binding markedly increased in the Hip at 9 months. However, unlike the protein levels, CB1 binding density did not drop strongly at 12 months and at old age. Furthermore, [3H]CP55940 binding was significantly increased in the lateral entorhinal cortex (LEnt), starting from the middle age until the old age.

Altogether, our findings clearly indicate a middle-age crisis in the eCB system, which could be a potential time window for therapeutic interventions to abrogate the course of cognitive aging.”

https://pubmed.ncbi.nlm.nih.gov/36142165/

“In conclusion, our observations indicate that the eCB system is most affected during the middle age in a brain region-specific manner. Taken together, the middle-age crisis in the eCB signaling corresponds well with the onset of neuroinflammatory glial activity and cognitive deficits in mice. We now hypothesize that late middle-age is the time period when a therapy based on the activation of the cannabinoid system has the highest efficacy to prevent cognitive aging and pathologies related to brain aging.”

https://www.mdpi.com/1422-0067/23/18/10254/htm

Antibacterial Effects of Phytocannabinoids

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“Antibiotics are used as the first line of treatment for bacterial infections. However, antibiotic resistance poses a significant threat to the future of antibiotics, resulting in increased medical costs, hospital stays, and mortality. New resistance mechanisms are emerging and spreading globally, impeding the success of antibiotics in treating common infectious diseases.

Recently, phytocannabinoids have been shown to possess antimicrobial activity on both Gram-negative and Gram-positive bacteria. The therapeutic use of phytocannabinoids presents a unique mechanism of action to overcome existing antibiotic resistance.

Future research must be carried out on phytocannabinoids as potential therapeutic agents used as novel treatments against resistant strains of microbes.”

https://pubmed.ncbi.nlm.nih.gov/36143430/

“Current antibiotic treatments have limited efficacy against multidrug-resistant bacteria, causing a significant challenge for prescribing physicians. A lack of effective therapies or new antibiotics requires the development of alternative antimicrobial therapies. Research has shown phytocannabinoids and CB2 agonists to exhibit antibiotic activity against a variety of Gram-positive and Gram-negative bacteria. Although their antimicrobial activity is limited in terms of Gram-negative bacteria, they offer therapeutic potential when administered as an adjunct treatment with an outer membrane perturbing molecule to facilitate the permeation of compounds that are effective on Gram-positive bacteria. Research has also shown synergy supporting the potential for combination therapy both in vivo and in vitro. Furthermore, CB2 agonists, such as β-caryophyllene, are widely used in industry as food additives and traditional medicine, and many are FDA approved and generally recognised as safe (GRAS), making them a good option for a novel therapeutic. The studies presented in this review suggest an attractive potential for cannabinoid-based antibacterial treatments.”

https://www.mdpi.com/2075-1729/12/9/1394/htm

Identification of SARS-CoV-2 Main Protease Inhibitors from a Library of Minor Cannabinoids by Biochemical Inhibition Assay and Surface Plasmon Resonance Characterized Binding Affinity

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“The replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its main protease (Mpro), which is a plausible therapeutic target for coronavirus disease 2019 (COVID-19). Although numerous in silico studies reported the potential inhibitory effects of natural products including cannabis and cannabinoids on SARS-CoV-2 Mpro, their anti-Mpro activities are not well validated by biological experimental data. Herein, a library of minor cannabinoids belonging to several chemotypes including tetrahydrocannabinols, cannabidiols, cannabigerols, cannabichromenes, cannabinodiols, cannabicyclols, cannabinols, and cannabitriols was evaluated for their anti-Mpro activity using a biochemical assay. Additionally, the binding affinities and molecular interactions between the active cannabinoids and the Mpro protein were studied by a biophysical technique (surface plasmon resonance; SPR) and molecular docking, respectively. Cannabinoids tetrahydrocannabutol and cannabigerolic acid were the most active Mpro inhibitors (IC50 = 3.62 and 14.40 μM, respectively) and cannabigerolic acid had a binding affinity KD=2.16×10-4 M). A preliminary structure and activity relationship study revealed that the anti-Mpro effects of cannabinoids were influenced by the decarboxylation of cannabinoids and the length of cannabinoids’ alkyl side chain. Findings from the biochemical, biophysical, and computational assays support the growing evidence of cannabinoids’ inhibitory effects on SARS-CoV-2 Mpro.”

https://pubmed.ncbi.nlm.nih.gov/36144858/

“In summary, the inhibitory effects of a collection of cannabinoids on SARS-CoV-2 3CL Mpro were screened by a biochemical assay. Several minor cannabinoids (e.g., THCB and CBGA) showed promising anti-Mpro activity. In addition, we observed that decarboxylated cannabinoids, such as CBG and CBD, showed undermined inhibition capacity, as compared to the precursing cannabinoid acids (i.e., CBGA and CBDA, respectively). This SAR was supported by the binding affinities between these cannabinoids and the Mpro protein obtained from the SPR assays. Furthermore, the impact of the length of the alkyl side chain of cannabinoids on their anti-Mpro activity was explored. Our study is the first to evaluate the anti-Mpro activity of minor cannabinoids and their mechanisms of action, which contribute to a better understanding of cannabinoids’ potential roles in the management of COVID-19.”

https://www.mdpi.com/1420-3049/27/18/6127

Analysis of Anti-Cancer and Anti-Inflammatory Properties of 25 High-THC Cannabis Extracts

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“Cannabis sativa is one of the oldest cultivated plants. Many of the medicinal properties of cannabis are known, although very few cannabis-based formulations became prescribed drugs. Previous research demonstrated that cannabis varieties are very different in their medicinal properties, likely due to the entourage effect-the synergistic or antagonistic effect of various cannabinoids and terpenes.

In this work, we analyzed 25 cannabis extracts containing high levels of delta-9-tetrahydrocannabinol (THC). We used HCC1806 squamous cell carcinoma and demonstrated various degrees of efficiency of the tested extracts, from 66% to 92% of growth inhibition of cancer cells.

Inflammation was tested by induction of inflammation with TNF-α/IFN-γ in WI38 human lung fibroblasts. The efficiency of the extracts was tested by analyzing the expression of COX2 and IL6; while some extracts aggravated inflammation by increasing the expression of COX2/IL6 by 2-fold, other extracts decreased inflammation, reducing expression of cytokines by over 5-fold.

We next analyzed the level of THC, CBD, CBG and CBN and twenty major terpenes and performed clustering and association analysis between the chemical composition of the extracts and their efficiency in inhibiting cancer growth and curbing inflammation.

A positive correlation was found between the presence of terpinene (pval = 0.002) and anti-cancer property; eucalyptol came second, with pval of 0.094. p-cymene and β-myrcene positively correlated with the inhibition of IL6 expression, while camphor correlated negatively. No significant correlation was found for COX2. We then performed a correlation analysis between cannabinoids and terpenes and found a positive correlation for the following pairs: α-pinene vs. CBD, p-cymene vs. CBGA, terpenolene vs. CBGA and isopulegol vs. CBGA.

Our work, thus, showed that most of high-THC extracts demonstrate anti-cancer activity, while only certain selected extracts showed anti-inflammatory activity. Presence of certain terpenes, such as terpinene, eucalyptol, cymene, myrcene and camphor, appear to have modulating effects on the activity of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/36144796/

“Cannabis sativa is a plant with a long history of consumption as food and medicine. Delta-9-tetrahydrocannabinol (THC) is one of the main cannabinoids in cannabis; it has many properties, including anti-cancer, anti-inflammatory, analgetic and others.”

https://www.mdpi.com/1420-3049/27/18/6057/htm

Extraction, Physicochemical Properties, Anti-Aging, and Antioxidant Activities of Polysaccharides from Industrial Hemp Residues

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“A large amount of hemp polysaccharides remain in industrial hemp residues (IHR) after cannabidiol extraction, resulting in the waste of resources. Therefore, the systematic study of hemp polysaccharides is beneficial to the development of IHR in the future. In this study, the extraction of industrial hemp residues polysaccharide (IHRPs) was optimized by single-factor experiment and orthogonal experimental design. The optimum heating extraction conditions were extraction temperature 98 °C, solid-liquid ratio 1:10, extraction time 1 h, number of successive extractions 2, and pH at 4. The extraction ratio and the polysaccharide content were 20.12 ± 0.55% and 12.35 ± 0.26% at the conditions, respectively. Besides, the best alcohol precipitation conditions were pumping with 2 L/h, stirring continuously, and ice-water bath for 4 h. The crude IHRPs was further purified by column chromatography and the polysaccharide/protein contents of purified IHRPs were 34.44% and 1.61%. IHRPs was mainly made up of ten monosaccharides and some non-sugar components including organic acids, flavonoids, steroids, and glycoside. The FT-IR demonstrated the polysaccharide skeleton of IHRPs. Moreover, the DPPH and ABTS scavenging rate of IHRPs were 76.00% and 99.05% at the concentrations of 1 mg/mL. IHRPs could promote the epidermal cells proliferation and healing of cell scratches. Meanwhile, IHRPs could promoted the expression of anti-aging-related genes. Overall, IHRPs could be a desirable natural source of antioxidants and anti-aging products in many aspects.”

https://pubmed.ncbi.nlm.nih.gov/36144481/

https://www.mdpi.com/1420-3049/27/18/5746

Terpenes and Cannabinoids in Supercritical CO 2 Extracts of Industrial Hemp Inflorescences: Optimization of Extraction, Antiradical and Antibacterial Activity

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“Natural products are increasingly in demand in dermatology and cosmetology. In the present study, highly valuable supercritical CO2 (sCO2) extracts rich in bioactive compounds with antiradical and antibacterial activity were obtained from the inflorescences of industrial hemp. Volatile compounds were analyzed by gas chromatography in tandem with mass spectrometry (GC-MS), while cannabinoids were determined by high performance liquid chromatography (HPLC-DAD). Extraction yields varied from 0.75 to 8.83%, depending on the pressure and temperature applied. The extract obtained at 320 bar and 40 °C with the highest content (305.8 µg mg-1) of cannabidiolic acid (CBDA) showed the best antiradical properties. All tested extract concentrations from 10.42 µg mL-1 to 66.03 µg mL-1 possessed inhibitory activities against E. coli, P. aeruginosa, B. subtilis, and S. aureus. The sCO2 extract with the highest content of cannabidiol (CBD) and rich in α-pinene, β-pinene, β-myrcene, and limonene was the most effective. The optimal conditions for sCO2 extraction of cannabinoids and volatile terpenes from industrial hemp were determined. The temperature of 60 °C proved to be optimal for all responses studied, while the pressure showed a different effect depending on the compounds targeted. A low pressure of 131.2 bar was optimal for the extraction of monoterpenes, while extracts rich in sesquiterpenes were obtained at 319.7 bar. A high pressure of 284.78 bar was optimal for the extraction of CBD.”

https://pubmed.ncbi.nlm.nih.gov/36145338/

https://www.mdpi.com/1424-8247/15/9/1117

Promising Nanocarriers to Enhance Solubility and Bioavailability of Cannabidiol for a Plethora of Therapeutic Opportunities

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“In recent years, the interest in cannabidiol (CBD) has increased because of the lack of psychoactive properties. However, CBD has low solubility and bioavailability, variable pharmacokinetics profiles, poor stability, and a pronounced presystemic metabolism. CBD nanoformulations include nanosuspensions, polymeric micelles and nanoparticles, hybrid nanoparticles jelled in cross-linked chitosan, and numerous nanosized lipid formulations, including nanostructured lipid carriers, vesicles, SNEEDS, nanoemulsions, and microemulsions. Nanoformulations have resulted in high CBD solubility, encapsulation efficiency, and stability, and sustained CBD release. Some studies assessed the increased Cmax and AUC and decreased Tmax. A rational evaluation of the studies reported in this review evidences how some of them are very preliminary and should be completed before performing clinical trials. Almost all the developed nanoparticles have simple architectures, are well-known and safe nanocarriers, or are even simple nanosuspensions. In addition, the conventional routes of administration are generally investigated. As a consequence, many of these studies are almost ready for forthcoming clinical translations. Some of the developed nanosystems are very promising for a plethora of therapeutic opportunities because of the versatility in terms of the release, the crossing of physiological barriers, and the number of possible routes of administration.”

https://pubmed.ncbi.nlm.nih.gov/36144803/

https://www.mdpi.com/1420-3049/27/18/6070