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cannabis anti inflammatory effects

Our results have extended the observations that CBD and CBG can demonstrate a clear anti-inflammatory effect in the lung by reducing the ability of LPS to induce neutrophil infiltration. However, more importantly, we have shown the relevance of determining the most appropriate formulation for any drug, as notwithstanding how effective an agent is in vitro, ultimately there is a need to deliver a sufficient amount of drug safely in an in vivo setting, and many factors other than the drug itself

COPD is a chronic respiratory disease with considerable unmet medical needs [18]. In 2017, 3.91 million people died from COPD worldwide, and because of its growing prevalence and mortality rate, COPD is expected to become the world's third most common cause of death by 2030 [19]. COPD includes a group of chronic lung conditions characterised by poorly reversible airflow obstruction, abnormal and chronic non-allergic inflammation of the airway, mucous plugging and airway remodelling [20]. This chronic and pathological airway response can result in excessive cough and mucus production (chronic bronchitis), alveolar destruction (emphysema) and/or lesions in the smaller conducting airways (bronchiolitis) [21]. The aberrant inflammatory response in the lungs, particularly in the small airways, is the outcome of the innate and adaptive immune responses to long-term exposure to toxic particles and gases, especially cigarette smoke and other oxidant pollution [20]. Other sources may trigger the development of the disease, such as alpha1-antitrypsin deficiency and telomerase polymorphisms [22]. This response is associated with an increased number of activated macrophages, neutrophils (both part of the innate immune response), T lymphocytes (Tc1, Th1 and ILC3 cells; adaptative immunity) [18] and in some cases, eosinophils [23]. These activated inflammatory cells release inflammatory mediators such as interleukin 8 (IL-8), leukotriene B4 (LTB4), and tumour necrosis factor α (TNF-α), which orchestrate the pathological structural and airway changes in COPD. These changes include tissue remodelling, chronic airways inflammation, oxidative stress, proteinase imbalances and accelerated ageing [24]. As the disease progresses, the degree of inflammation driven primarily by neutrophils also evolves [18].

Various studies have suggested the use of cannabinoids as possible treatments for inflammatory diseases in the airways, such as chronic obstructive pulmonary disease (COPD) [7,8]. The phytocannabinoids Δ 9 -THC [9], cannabidiol (CBD) [10] and cannabigerol (CBG) [11] are of particular interest due to their important effects on inflammation and the immune system, including inhibiting the activation of pro-inflammatory cells and the synthesis of pro-inflammatory mediators or reducing intracellular and mitochondrial oxidative stress [12]. Additionally, it has been reported that CBD exhibits apoptotic properties in immune cell populations, leading to cannabinoid-induced immunosuppression [13]. CBD and CBG alone, and in combination, have demonstrated apoptotic effects in tumour cells, in addition to their off-target effects essential for effective palliative care such as increased appetite, analgesic and anxiolytic properties [14]. On the other hand, CBD [15] and CBG [16] have been demonstrated to exhibit anti-apoptotic properties in healthy cells under oxidative and inflammatory conditions. The anti-apoptotic effects of cannabinoids are mainly associated with cytokine modulation and antioxidant activity via downregulation of nitric oxide production [17].

Conclusions

The discovery of the endocannabinoid system (ECS) has enabled the growth of scientific evidence supporting the use of cannabis and cannabinoids as therapeutic agents for various diseases. The ECS is a complex lipid cell-signalling system comprised of: the cannabinoid receptors (CBRs; CB1 and CB2); the endogenous cannabinoids (endocannabinoids, ECs), anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG); the AEA transporter protein (TP) and the enzymes responsible for the synthesis and degradation of endocannabinoids (fatty acid amide hydrolase, FAAH, or monoacylglycerol lipase, MGL) [6].

The second purpose of this study was to investigate the anti-inflammatory effects of cannabinoids formulated in two different formulations. The lipophilic nature of cannabinoids is a significant challenge for developing an effective formulation and bioavailability for optimal therapeutic effect [25]. Due to their lipophilicity, cannabinoids present negligible aqueous solubility. Additionally, they are vulnerable to degradation by auto-oxidation, light and temperature [26]. The first formulation tested in this study was composed of medium-chain triglycerides (MCT). They are lipids with a carbon chain length of 6–12 carbon atoms, making MCTs easier to absorb and metabolise than long-chain fatty acids (LCTs). Due to these characteristics, MCTs have been suggested as a drug vehicle for lipophilic drugs [27]. Our second formulation was a micellar solution composed of ethanol (EtOH), Cremophor® EL (polyoxyl 35 castor oil, CrEL) and sodium chloride 0.9% in purified water (saline). EtOH, a short-chain alcohol, is widely used as a solvent and co-surfactant for lipophilic drugs. CrEL is a non-ionic hydrophilic surfactant used to emulsify and solubilise lipophilic molecules by forming micelles and entrapping the lipophilic molecules within them in aqueous solutions. CrEL can also increase drug absorption by enhancing the dissolution rate of the drug by disrupting the lipid bilayer of cells [28]. Lastly, saline is a water-based solvent included in the formulation to obtain a final isotonic mixture.

Cannabis, often referred to as marijuana, is a botanical product derived from the Cannabis Sativa L. plant, a dioicous species of the Cannabaceae and broadly distributed all over the world [1]. The use of the cannabis plant for its medicinal properties, source of textile fibre (hemp), and psychoactive/medical effects, stretches back approximately 5000 years. The term ‘cannabinoid’ or ‘phytocannabinoid’ (plant-based cannabinoids) refers to a group of lipophilic and pharmacologically active, oxygenated C21-22 aromatic hydrocarbon compounds found in the leaves and flowering plants of the Cannabis Sativa plant [2]. Since the isolation of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) [3], more than 144 unique cannabinoid compounds, 100 terpenes, and 20 phenolic compounds synthesised by the cannabis plant have been identified [4]. In addition to the plant-derived cannabinoids, many structurally and biologically associated compounds have been created, which are known as synthetic cannabinoids [5].

Challenge of animals [29] and people [30] with bacterial lipopolysaccharide (LPS) has been extensively used as a model to mimic the neutrophilia characterising COPD and to investigate the actions of novel anti-inflammatory drugs in development for the treatment of this disease [31]. Therefore, we have investigated the effects of highly purified CBD and CBG administered alone or in combination for their impact on LPS-induced neutrophilia.

Killestein et al. [27] performed a randomized controlled trial (RCT) in Germany with 16 volunteers: 10 had secondary progressive MS and 6, primary progressive MS. The aim of this paper was to evaluate immune function in MS patients treated with orally administered cannabinoids. This 2-fold study treated their volunteers with identical-appearing capsules containing dronabinol, Cannabis sativa plant extract or placebo. Volunteers were treated with 84 capsules for 4 weeks each. The study found modest increase in TNF-α and no significant changes in T-cell proliferation, leukocyte subsets, or cytokines. The small sample size is also a limitation to this study.

Data were independently extracted by the first author (M.G.L.) using a structured form and reviewed by the senior author (T.M.F.). The following variables were extracted: (1) author’s name, (2) year of publication, (3) country where the study was conducted, (4) sample size, (5) sample characteristics, (6) study design, (7) age range of the sample, (8) statistical analysis performed, (9) instrument(s) utilized, (10) exposure covariates, (11) outcome measures, (12) major findings, and (13) study limitations. Discrepancies were resolved by consensus, and a third author (E.B.) was consulted when needed. Data concerning cannabis use and its relationship with inflammatory markers were described, when available. It was not possible to describe or standardize cannabinoid consumption for all papers reviewed because many of them did not mention smoke patterns and also because articles applied very heterogeneous measurement methods. Publication including only cannabidiol or synthetic cannabinoids was not included.

MS is an autoimmune inflammatory disease with several physical and mental symptoms, which affects deeply the patient’s quality of life [30-33]. These MS-associated symptoms can be treated by current drug therapies that cause considerable side effects, including hallucinations, hypotension, seizures, anxiety, weakness, and nausea [34]. According to Goodin et al. [34], the effectiveness of the disease-modifying therapeutics agents in reducing disability progression in relapsing-remitting MS patients is unclear. The articles analyzed in this study, on the contrary, reveal that cannabis extracts and cannabinoids promote improvement in MS symptoms and seemed to have little impact on the serum inflammatory markers’ levels [26, 27], which suggests that improvements may occur through different mechanisms involving the cannabinoids. Considering that immune diseases, such as MS, systemic lupus erythematosus, and rheumatoid arthritis are considerably disabling both physically and mentally, the potential of decrease in the immune function caused by cannabis extracts and cannabinoids could provide a pathway through which inflammatory diseases could be addressed by reducing disease immune activity.

Highest Evidence

The aim of this study was to review the literature about the effect of cannabis use on inflammatory markers. The main findings were as follows: (i) among healthy volunteers and among cannabis users, cannabinoids seemed to decrease the inflammatory response, thus decreasing the immune response leading in turn to a higher risk of infections; (ii) among patients with MS, cannabinoids seemed to have little impact on the inflammatory markers’ levels.

The results will be thoroughly presented in 3 subcategories: studies conducted among (i) healthy volunteers; (ii) cannabis users; and (iii) medical cannabis use in volunteers with general medical conditions. We considered that these categories should be analyzed separately as the clinical and medical profiles of participants should vary across them.

The cannabis extracts are capable of modulating immune function [20]. This modulation occurs because these extracts serve as secondary modulators. When mobilized coincidently with or shortly after first-line immune modulators such as lymphokines, they increase or decrease immune activity [18]. Furthermore, the CB2 is present in the immune system cells, thereby regulating cell migration and cytokine release [21]. These are the underlying mechanisms of the immunomodulatory effect of cannabinoids.

Five out of the 6 papers in our review were longitudinal studies. In 4 of the papers, cannabis or its extracts were found to be negatively associated with immunity status, indicating that the higher the cannabis consumption, the lower the immunity cytokine levels went. The remaining 2 articles showed no association between cannabis use and serum immunity cytokine levels. The most commonly reported exposure covariates were age, sex, cannabis use, alcohol use, and tobacco use.

The discovery of the endocannabinoid system (ECS) has enabled the growth of scientific evidence supporting the use of cannabis and cannabinoids as therapeutic agents for various diseases. The ECS is a complex lipid cell-signalling system comprised of: the cannabinoid receptors (CBRs; CB1 and CB2); the endogenous cannabinoids (endocannabinoids, ECs), anandamide (N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol (2-AG); the AEA transporter protein (TP) and the enzymes responsible for the synthesis and degradation of endocannabinoids (fatty acid amide hydrolase, FAAH, or monoacylglycerol lipase, MGL) [6].

Male adult Dunkin-Hartley guinea pigs were obtained from Marshalls Laboratories (Hull, UK). All guinea pigs weighed 250–350 g at the time of experimentation. All experiments were performed at King's College London according to the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines, the UK Animals (Scientific Procedures) Act 1986, and the 2012 amendments, and were approved by the King's College London ethics committee. The animals were housed in rooms under controlled

Introduction

Challenge of animals [29] and people [30] with bacterial lipopolysaccharide (LPS) has been extensively used as a model to mimic the neutrophilia characterising COPD and to investigate the actions of novel anti-inflammatory drugs in development for the treatment of this disease [31]. Therefore, we have investigated the effects of highly purified CBD and CBG administered alone or in combination for their impact on LPS-induced neutrophilia.

Various studies have suggested the use of cannabinoids as possible treatments for inflammatory diseases in the airways, such as chronic obstructive pulmonary disease (COPD) [7,8]. The phytocannabinoids Δ 9 -THC [9], cannabidiol (CBD) [10] and cannabigerol (CBG) [11] are of particular interest due to their important effects on inflammation and the immune system, including inhibiting the activation of pro-inflammatory cells and the synthesis of pro-inflammatory mediators or reducing intracellular and mitochondrial oxidative stress [12]. Additionally, it has been reported that CBD exhibits apoptotic properties in immune cell populations, leading to cannabinoid-induced immunosuppression [13]. CBD and CBG alone, and in combination, have demonstrated apoptotic effects in tumour cells, in addition to their off-target effects essential for effective palliative care such as increased appetite, analgesic and anxiolytic properties [14]. On the other hand, CBD [15] and CBG [16] have been demonstrated to exhibit anti-apoptotic properties in healthy cells under oxidative and inflammatory conditions. The anti-apoptotic effects of cannabinoids are mainly associated with cytokine modulation and antioxidant activity via downregulation of nitric oxide production [17].

In conclusion, this study has provided evidence that CBD and CBG formulated appropriately exhibit anti-inflammatory activity. Our observations suggest that these non-psychoactive cannabinoids may have beneficial effects in treating diseases characterised by airway inflammation.