Some of the most established data on the endocannabinoid system’s immune related roles and the effects of phyto- and synthetic- cannabinoids on immunity, come from pre-clinical studies of autoimmune diseases [20,89]. Several groups have shown that cannabinoids can influence the balance between inflammatory Th17 and regulatory T-cells [33,90,91], inducing a regulatory phenotype. The clinical effects of cannabinoid-based treatments were studied in several inflammatory, autoimmune related diseases. Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases, statistics show it is among the main causes of disability worldwide, causing unbalanced pain and joint malformation and destruction. Malfait et al. showed that the CBD treatment effectively blocks the progression of arthritis in a murine collagen-induced arthritis model [92]. Similarly, Gui et al. demonstrated that the activation of cannabinoid receptor 2 attenuates synovitis and joint destruction in collagen-induced arthritis in mice [93]. Another interesting approach is elevating endocannabinoid levels by inhibition of their degrading enzymes. Lowin et al. and McDougll et al. demonstrated beneficial effects for treatments that include FAAH inhibitors in murine models for osteoarthritis (OA) and RA [94,95]. In patients with OA and RA increased FAAH activity was detected in the synovia and the endocannabinoids AEA and 2-AG were identified in the synovial fluid [96]. However, although several FAAH inhibitors were entered into clinical trials for different applications, none of them have reached approval for clinical use thus far, [97] and one of the phase I studies was terminated due to neurologic adverse effects in some of the participants [98]. The efficacy, tolerability, and safety of a Cannabis-based medicine (Sativex) to relieve pain caused by RA was assessed in one clinical trial [99]. In this randomized, double-blind, parallel group study with 58 patients over five weeks of treatment, a significant analgesic effect was observed and disease activity was significantly suppressed. A study that will test the efficacy and safety of using CBD and THC for the treatment of pain in patients with inflammatory arthritis is planned (Table 1).

Multiple sclerosis (MS) is a progressive, long-term autoimmune demyelinating disease of the central nervous system. Neuroprotection in experimental autoimmune encephalomyelitis by Cannabis-based cannabinoids was demonstrated in animal models [51,100,101,102]. Cannabinoid-based treatments were also examined clinically in MS patients. Sexton et al. detected a significant increase in the endocannabinoid AEA, in serum from individuals with MS compared to control subjects. The effect of Cannabis use on the tested immunological properties was similar in patients and in control subjects. For example, serum levels of IL-17 were significantly reduced in non-naive subjects, whether cases or controls [103]. Several randomized clinical trials examined the efficacy of cannabinoid treatment in MS. In a meta-analysis of clinical trials on the use of cannabinoids for spasticity due to MS, da Rovare et al. found an insignificant difference related to spasticity between cannabinoids and placebo (p = 0.18) [104]. Recently, Akgün et al. systematically reviewed publications on the THC:CBD spray use for refractory MS spasticity and found that the proportion of patients reaching the threshold of minimal clinical important (CI) difference, with at least a 20% reduction of the spasticity Numeric Rating Scale score after four weeks ranged from 41.9% to 82.9% [105]. A current study examines the efficacy of Cannabis in spasticity due to MS (Table 1).

Inflammatory bowel disease (IBD) is a general classification based on symptomology. It is comprised of well-known gastrointestinal inflammatory disorders such as Ulcerative colitis (UC), Crohn’s (CD), etc. Cannabinoid receptors as well as endocannabinoids are upregulated in inflammation, and their presence and stimulation attenuates murine colitis, while cannabinoid receptor antagonism and cannabinoid receptor deficient models reverse these anti-inflammatory effects [8,106]. Both FAAH and MAGL inhibitors reduce disease scores in colitis mouse models [107,108]. In patients, some endocannabinoid molecules were differentially expressed in various bowel diseases. For example, AEA and oleoylethanolamide (OEA) were increased in the plasma of UC and CD patients while 2-AG was elevated in patients with CD, but not UC [109].

Several questionnaire-based studies have validated Cannabis use in 6.8–15.9% of adult patients with IBD. The most common reasons given were to alleviate abdominal pain, diarrhea, or anorexia [110]. In a small prospective placebo-controlled study, Naftali et al. demonstrated significant clinical, steroid-free benefits for 10 out of 11 patients with an active CD treated with THC rich Cannabis; although induction of remission was not achieved within the eight-week study [111]. Irving et al. performed a randomized, double-blind, placebo-controlled, parallel-group, study of cannabidiol-rich botanical extract in the symptomatic treatment of UC. In this study, the physician’s global assessment of illness severity, subject global impression of change, and patient-reported quality-of-life were improved for patients taking a CBD-rich botanical extract (p = 0.069, p = 0.003, and p = 0.065, respectively). However, patients were less tolerant of the CBD-rich botanical extract compared with the placebo [112]. Recently, Mbachi et al. evaluated several UC-related complications and clinical endpoints in a total of 298 Cannabis users with UC as compared to a propensity score matched group of nonusers with UC. Their results show that the prevalence of partial or total colectomy was lower in Cannabis users compared to nonusers (p = 0.01) and there was a trend toward a lower prevalence of bowel obstruction (p = 0.057). Cannabis users had a shorter duration of hospitalization (p < 0.007) compared to their nonuser counterparts [113]. Current studies examine combined THC and CBD drops for the treatment of Crohn’s disease and the use of a synthetic cannabinoid, Nabilone, in IBD patients (Table 1). In addition to their anti-inflammatory effects, the beneficial consequences of the cannabinoids’ treatment in IBD may be attributed by their influence on the permeability of the gastrointestinal tract. Couch et al. recently demonstrated that aspirin causes an increase in the absorption of lactulose and mannitol, which could be reversed by palmitoylethanolamide (PEA) or CBD treatment (p < 0.001) in a human, randomized, double-blind, controlled trial [114].

There is also evidence that suggests the involvement of cannabinoids in other autoimmune diseases. For example, Hegde et al. demonstrated attenuation of experimental autoimmune hepatitis by cannabinoids [115]. In a mouse model of myasthenia gravis, a cannabinoid receptor agonist reversed fatiguing failure of neuromuscular transmission [116]. Anti-inflammatory effects were also evident in a rodent model of autoimmune uveoretinitis treated with a CB2-selective agonist [117]. In a murine model for systemic lupus erythematosus (SLE), the CBD treatment was found to accelerate disease progression [118] and in patients, an involvement of the endocannabinoid system in the pathogenesis of this disease was described [119,120]. An ongoing study will examine the efficacy of JBT-101, a CB2 agonist, in SLE patients (Table 1). A decreased likelihood of diabetes for Cannabis users versus non-users was also suggested [121,122] and currently the anti-inflammatory properties of Cannabis and their relevance to insulin sensitivity in Type 2 diabetes is being examined (Table 1).