Posted on

cannabis anti inflammatory effects

Sexton et al. [25] performed a cross-sectional study, evaluating 10 cannabis users. The aim of this study was to evaluate the migratory potential of isolated monocytes from cannabis users. It found that cannabinoids inhibited the migration of monocytes in both groups (naïve and nonnaïve to cannabis), and the monocytes from subjects nonnaïve to cannabis expressed more CB1 messenger ribonucleic acid (mRNA). Although the authors report no limitations, we can infer that unknowing about the acute and long-term effects of phytocannabinoid (pCB) on human circulating monocytes limits the comprehension of the study findings.

Considering the secondary pattern of reviews, the ethical approval was not required because all articles reviewed were approved by their corresponding ethics committees.

Responding to potential aggressions, the immune system activates the innate and adaptive immunities by producing inflammatory cytokines, which mediate and potentiate the inflammatory process [19] that, in turn, signals an alteration of homeostasis. Although the immune system in normal conditions addresses potential aggressions and pathogen antigens, several dysfunctions turn the system to recognize the autoantigens as an aggressor and cause autoimmune diseases. Detailed information about immune cytokines, interleukins, and inflammatory cell function is presented in Table 1.

Cannabis Users

We found 2 studies conducted in healthy volunteers’ samples, conducted by the same research team, Pacifi et al. [23, 24], in 2003 [23] and 2006 [24]. Both were longitudinal observational studies. On the 2003 article [23], 61 volunteers were included and 3 distinct groups were analyzed: polydrug users, cannabis users, and a control group with no drug use. The aim was to compare the cell-mediated immune response and cytokine release in cannabis users in relation to the control group. The major finding was that cannabis users had lower function on immune response, with a considerable decrease in inflammatory cytokine serum levels. The authors state that the small sample size might have been a limitation of that study. On the 2006 article [24], 94 volunteers were included and divided into the same 3 groups of the 2003 article [23]. The article analyzed the cell-mediated immune function and the occurrence of mild infectious diseases. It reported 3 important findings: (i) polydrug users had a big decrease in immune response and a considerable increase in anti-inflammatory transforming growth factor β1; therefore, (ii) polydrug users had an increase in mild common infections; finally, (iii) cannabis users had an intermediate decrease in immune response in relation to the control group. This article also had the small sample size limitation, and it did not consider the possible effect of lifestyle on immune function. Detailed information is presented in Table 2.

Among the cannabis extracts, the THC is the main psychoactive component due to the lipophilic structure that allows the molecule to cross the blood-brain barrier [3]. Once in the central nervous system, the THC acts as a cannabinoid agonist, and its modulation of cannabinoid receptor 1 (CB1) is linked to pleasurable sensations. Such sensations are achieved because the CB1 is heterogeneously distributed around the brain, modulating the dopaminergic transmission in the limbic cortex and the association cortices [4]. The most commonly reported pleasure sensations are feeling of well being, calmness, relaxation, and hilarity [5]. Furthermore, according to Carlini et al. [5], the most common physical symptoms are xerostomia, red eyes, polyphagia, and tachycardia. Medical properties of cannabis extracts, however, are due to the several neurotransmitters involved on CB1 and CB2 (cannabinoid receptor 2) receptors [6].

These findings must be interpreted in light of some limitations. One of them is that we included only publications in English and Portuguese. Although this is a limitation, a previous study has stated that language restriction does not usually alter the main findings of systematic reviews [35]. Moreover, this review focused only on human studies, and the percentage of the CBD/THC relation in each study was not provided. This CBD/THC relation is important because the THC-rich compounds have serious limitations such as unpredictable gastrointestinal absorption and potential intoxication and disorientating central nervous system effects at the higher doses [36]. The addition of CBD to THC should ameliorate the intoxicating effects of THC, paranoia, and euphoria associated with THC, with diminished potential for abuse [37].

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.

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].

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.

Exposure of guinea pigs to LPS induced a 97 ± 7% and 98 ± 3% increase in neutrophils found in bronchoalveolar lavage fluid (BAL) at 4 h and 24 h, respectively. Administration of CBD and CBG formulated with MCT oil did not show any significant effects on the LPS-induced neutrophilia measured in the BAL fluid when compared with the vehicle-treated groups. Conversely, the administration of either cannabinoid formulated with CrEL induced a significant attenuation of the LPS induced recruitment of neutrophils into the lung following both intraperitoneal (IP) and oral (PO) administration routes, with a 55–65% and 50–55% decrease in neutrophil cell recruitment with the highest doses of CBD and CBG respectively. A combination of CBD and CBG (CBD:CBG = 1:1) formulated in CrEL and administered orally was also tested to determine possible interactions between the cannabinoids. However, a mixture of CBD and CBG did not show a significant change in LPS-induced neutrophilia. Surfactants, such as CrEL, improves the dissolution of lipophilic drugs in an aqueous medium by forming micelles and entrapping the drug molecules within them, consequently increasing the drug dissolution rate. Additionally, surfactants increase permeability and absorption by disrupting the structural organisation of the cellular lipid bilayer.

Conclusion

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].

Studies with Cannabis Sativa plant extracts and endogenous agonists of cannabinoid receptors have demonstrated anti-inflammatory, bronchodilator , and antitussive properties in the airways of allergic and non-allergic animals. However, the potential therapeutic use of cannabis and cannabinoids for the treatment of respiratory diseases has not been widely investigated, in part because of local irritation of airways by needing to smoke the cannabis, poor bioavailability when administered orally due to the lipophilic nature of cannabinoids, and the psychoactive effects of Δ9-Tetrahydrocannabinol (Δ9-THC) found in cannabis. The primary purpose of this study was to investigate the anti-inflammatory effects of two of the non-psychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG) alone and in combination, in a model of pulmonary inflammation induced by bacterial lipopolysaccharide (LPS). The second purpose was to explore the effects of two different cannabinoid formulations administered orally (PO) and intraperitoneally (IP). Medium-chain triglyceride (MCT) oil was used as the sole solvent for one formulation, whereas the second formulation consisted of a Cremophor® EL (polyoxyl 35 castor oil, CrEL)-based micellar solution.

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].

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].