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Official websites use. Share sensitive information only on official, secure websites. To whom correspondence should be addressed. This is an open-access article. Rheumatoid diseases, including rheumatoid arthritis, osteoarthritis, and fibromyalgia, are characterized by progressive inflammation in the musculoskeletal system, predominantly affecting the joints and leading to cartilage and bone damage. The resulting pain and ongoing degradation of the musculoskeletal system contribute to reduced physical activity, ultimately impacting quality of life and imposing a substantial socioeconomic burden. Unfortunately, current therapeutics have limited efficacy in slowing disease progression and managing pain. Thus, the development of novel and alternative therapies is imperative. Cannabinoids possess beneficial properties as potential treatments for rheumatoid diseases due to their anti-inflammatory and analgesic properties. Preclinical studies have demonstrated promising results in halting disease progression and relieving pain. However, there is a scarcity of patient clinical studies, and the available data show mixed results. Consequently, there are currently no established clinical recommendations regarding the utilization of cannabis for treating rheumatoid diseases. In this review, we aim to explore the concept of cannabis use for rheumatoid diseases, including potential adverse effects. We will provide an overview of the data obtained from preclinical and clinical trials and from retrospective studies on the efficacy and safety of cannabis in the treatment of rheumatoid diseases. Rheumatoid diseases are characterized by progressive chronic inflammation of the musculoskeletal system, afflicting primarily the joints but can lead to systemic comorbidities, such as pulmonary diseases or vasculitis. Chronic inflammation results in cartilage and bone damage, whose deterioration can lead to the disability of the affected patient. Rheumatoid diseases inflict a significant individual and societal burden. Pain and musculoskeletal deficits lead to a progressive decline in physical activity and quality of life and carry the risk of cumulative comorbidities. Treating rheumatoid disease is challenging not only because of its progressive nature but also because of the side effects of available therapies. Thus, therapy efforts are divided into preventive medicine starting treatment before clinical manifestation and developing new drugs. One approach is medicinal cannabis use, which takes advantage of its pain-reducing and immune-modulating features. Cannabis is the most widely used illicit drug in the world. Cannabis is not a single substance but consists of more than different chemical constituents accumulated in the cannabis plant, among them approximately psychoactive and non-psychoactive cannabinoids and over non-cannabinoids. The cannabis plant Cannabis sativa belongs to the Cannabaceae family. There are two major forms of Cannabis sativa : marijuana, which has high levels of the psychoactive tetrahydrocannabinol THC ; and hemp, which has high levels of non-psychoactive cannabinoids and low THC levels. The main non-psychoactive pharmacologically active cannabinoids include cannabinol, cannabidiol CBD , and cannabigerol Figure 1 , as well as non-cannabinoids like flavonoids, terpenes, and fatty acids. Cannabinoids mediate their biological and therapeutic effects through the G-protein coupled receptors cannabinoid receptor 1 CB1R and 2 CB2R. Additionally, CB2R is also located in the brain, 20 where it is primarily localized to microglia, the central nervous system resident macrophages. The fact that both CB1 and CB2 receptors are expressed by immune cells suggests that cannabinoids play an important role in immune system regulation. For example, cannabinoids have been shown to exert anti-inflammatory effects in various in vivo and in vitro experimental models. In addition, several studies have shown that cannabinoids downregulate cytokine and chemokine production and upregulate T-regulatory cells to suppress inflammatory responses. Several studies have reported that CBD reduces the formation of reactive oxygen species and nitric oxide in various cell lines and animal models of inflammation. Additionally, a specific strain with high CBD content CBD-X demonstrates a potent capacity to effectively suppress cytokine storm in a mouse model. Additionally, CBD upregulated miR34a in BV-2 microglia cells, which has several roles in cell survival, such as cell cycle, apoptosis, and differentiation. Several murine rheumatoid disease animal models have been used to investigate the possible anti-rheumatic efficacy of cannabinoids. For example, Zurier et al. In this model, oral administration of DMHC reduced the number of polymorphonuclear leukocytes in the pouches 6 hours after inducing inflammation. This adjuvant-induced chronic polyarthritis was prevented by DMHC. Similarly, tetrahydrocannabinolic acid and THC alleviate collagen-induced arthritis in mice via CB1 by preventing the infiltration of inflamed cells into the synovium, which reduces hyperplasia and cartilage damage. The CB1 receptor antagonist SRA blocks anti-nociception developed after administering THC but not anandamide, suggesting that anandamide signaling is not limited to the CB1 receptor pathway. However, the effects of THC and anandamide can be inhibited by naloxone, indicating that they induce the release of endogenous opioids that mediate the anti-nociceptive effect. Oral or intraperitoneal administration of CBD has an anti-arthritic effect in acute and chronic relapsing collagen-induced arthritis CIA. The synthetic non-psychoactive cannabinoid HU has potent anti-inflammatory and immunosuppressive properties. These anti-arthritic effects were observed in a murine collagen-induced arthritis model. Transdermal CBD administration also reduces inflammation and pain-related behaviors in an adjuvant-induced arthritis model in Sprague-Dawley rats. Cannabidiol CBD gel, applied for four consecutive days on the afflicted joint, significantly reduced joint swelling and pro-inflammatory markers. The paw withdrawal latency to noxious heat stimulation recovered to near baseline, but exploratory behavior was not altered, suggesting that CBD had a limited impact on brain function. These results indicate that transdermal administration of CBD can exert long-lasting anti-arthritic effects achieved without neuronal side effects summarized in Table 1. In , Richardson et al. The authors examined the synovial fluid of 32 patients with osteoarthritis OA and 13 with RA after total knee arthroplasty. These results suggest the involvement of the endocannabinoid system in the development of rheumatoid diseases. In RA, pro-inflammatory cytokines and matrix metalloproteinases MMPs are released into the synovial tissue, where they promote cartilage degradation and bone erosion, leading to bone deformities. This study showed that this effect was not mediated by CB1 and CB2, 43 suggesting the involvement of other cannabis-related receptors. Moreover, blocking the mitochondrial permeability transition pore by cyclosporine A prevented the CBD effects on cell viability and IL-8 production. Alongside, the pain was significantly decreased, which led to a dose-dependent increase in mobility. These results point to the safe therapeutic potential of cannabinoids for alleviating pain. In accordance with these studies, we published similar results using high-THC or high-CBD extracts in mouse models of systemic or local lung inflammation. However, of the three tested high-CBD extracts, only one showed these inhibitory effects, explaining why studies on the influence of cannabinoids show ambiguous results. More research is needed into this phenomenon, including clinical studies on humans with extracts that showed therapeutic effects in previous animal studies. In contrast to the anti-arthritic properties observed in animal and ex vivo studies, Kotschenreuther et al. The authors argue that the variability of CBD receptors between animal models and humans could contribute to the discrepancies. Moreover, many animal studies use CB1 or CB2 inhibitors to investigate the function of cannabinoids. Therefore, the authors suggest using cannabinoids in RA patients with caution summarized in Table 2. Rheumatoid disease is characterized by chronic pain, which significantly decreases the quality of life of those afflicted. Currently, efficacious treatment and adequate pain management are unavailable for rheumatoid diseases. Thus, alternative therapies for pain management are needed. The impact of medicinal cannabis extracts on chronic pain has been evaluated in several randomized, double-blind, placebo-controlled clinical trials. For example, Notcutt et al. The THC-based extracts were most effective in pain control when used as a sublingual spray, with only mild side effects. Patients were evaluated for movement and resting pain, morning stiffness, and sleep quality using the Short Form McGill Pain Questionnaire and the DAS28 measure of disease activity. In addition, no signs of withdrawal and severe side effects were observed. Other studies tested the analgesic effects of cannabis in patients with neuropathic pain when administered via a vaporizer. In one double-blind, placebo-controlled crossover study, 35 patients with central and peripheral neuropathic pain received THC-based cannabis medium-dose 3. As measured by the pain intensity score of a visual analogue scale, the analgesic response showed an effect similar to efficacies obtained by conventional pain relievers. Only mild reversible psychoactive effects of limited time duration were measured. Four different cannabis variants with known THC and CBD content were tested on a small group of 20 fibromyalgia patients. Varieties with high THC content significantly reduced the pressure pain threshold relative to placebo after a single inhalation. A recent review of clinical trials of pain reduction by cannabis showed that cannabis-based medicines were most effective as adjuvant therapeutics in refractory multiple sclerosis and in managing chronic rheumatoid pain. Therefore, they concluded that due to a lack of clear evidence, doctors should not be advised to prescribe cannabis-based medicines for arthritis. Retrospective studies in the form of exploratory cross-sectional surveys about recreational cannabis use among diagnosed rheumatology patients before and after cannabis legalization in Canada revealed that, after legalization, the percentage of cannabis users tripled from 4. Half of the users had OA and used it for pain relief. Usually, the medicinal cannabis users were previous or current recreational users or with a history of drug abuse, younger than non-users, male, and of a low socioeconomic background. Different routes of application were used, ranging from smoking, vaporizing, and oral administration, and users lacked knowledge about product content. Similar results were obtained in a retrospective nationwide survey from the United Kingdom, carried out from to Medicinal cannabis use was associated with younger age, male gender, and previous recreational use. The authors concluded that this survey gave a broad picture of medicinal cannabis use and supported further development of safe and effective cannabis-based medicines. A recent meta-analysis came to a similar conclusion. Of 29, patients, 10, were cannabis users A higher percentage of patients with fibromyalgia Cannabis users were younger of age Cannabis consumption helped reduce the pain intensity on a VAS scale from 8. Although adverse effects of cannabis-based medicinal extracts have been mainly described as mild and reversible, some studies have shown that patients consuming natural cannabis discontinued use due to side effects. These adverse effects mainly concern psychomotor and cognitive skills and the cardiovascular system. Moreover, driving ability and alertness are seriously impaired for up to 24 hours after herbal cannabis consumption, 63 so it is not surprising that 0. Severe cardiovascular events in connection with acute herbal cannabis use include tachycardia, hypotension, 65 and an increased risk of myocardial infarction for people with angina pectoris. Regular cannabis use, especially in adolescents, might lead to a dose-dependent decline in cognitive performance and short-term memory, as well as mood disorders and even psychosis. The prevalence of medical cannabis use is steadily rising in the medical histories of individuals suffering from chronic pain. With respect to cancer development, cannabis is often perceived as relatively benign, particularly in comparison to tobacco. However, recent research has revealed that smoking cannabis can lead to the production of carcinogens, such as nitrosamines and polycyclic aromatic hydrocarbons, which are akin to those found in cigarette smoke. Nonetheless, basic laboratory studies have demonstrated the mutagenic potential of cannabis in vitro. This double-blind, placebo-controlled, crossover study is currently recruiting 76 patients with psoriatic and rheumatoid arthritis to investigate the impact of cannabis on inflammation and pain. Cannabis with medium THC or medium CBD content will be administered via vaporization in two experimental sessions, and pain will be evaluated via self-reports. This phase 2 clinical trial will be the first study worldwide to examine the impact of two different cannabinoids in a clinical trial among patients with psoriatic arthritis or RA and may help develop a standard of care for the use of cannabinoids for arthritic treatment. Additionally, an observational study with participants diagnosed with RA, spondyloarthritis, or psoriatic arthritis is examining the prevalence of cannabis use and aims to refine the characteristics of consumption and risk factors. This study hopes to further improve the overall management of patients with inflammatory rheumatic diseases. Preclinical in vitro and in vivo studies show promising results regarding the anti-arthritic properties of cannabinoids, psychoactive and non-psychoactive cannabinoids alike. These anti-arthritic properties are mediated by anti-inflammatory effects of cannabinoids, including inhibiting the production of pro-inflammatory cytokines and nitric oxide, as well as the proliferation of synovial fibroblasts Figure 2. Scheme depicts the most important immune cells in the synovial fluid that contribute to the development of rheumatoid diseases and where cannabis has an anti-arthritic impact. Cannabis inhibits the proliferation of synovial fibroblasts, secretion of pro-inflammatory cytokines from immune cells, and the secretion of nitric oxide synthases, such as inducible NO synthase iNOS , from chondrocytes, which prevents cartilage damage. These effects were primarily observed in preclinical in vitro and ex vivo studies as well as in animal models since clinical studies are scarce. One clinical study observed an increase in pro-inflammatory Th17 helper cells after the consumption of CBD oil in patients with RA. It was suggested that cannabinoid receptor variability might contribute to this discrepancy between preclinical animal and human results. Future research should focus on determining the exact anti-inflammatory properties of cannabis components for specific strains to more accurately provide targeted therapy to appropriate patients. This is one aspect of cannabis research that our research center is pursuing. Conflict of interest: No potential conflict of interest relevant to this article was reported. Cannabinoids and Inflammation Research Grant. As a library, NLM provides access to scientific literature. Rambam Maimonides Med J. Find articles by Nicole Paland. Haya Hamza , B. Find articles by Haya Hamza. Antonina Pechkovsky , Ph. Find articles by Antonina Pechkovsky. Miran Aswad , Ph. Find articles by Miran Aswad. Dayana Shagidov , M. Find articles by Dayana Shagidov. Igal Louria-Hayon , Ph. Find articles by Igal Louria-Hayon. Collection date Oct. Open in a new tab. Lewis rats assigned to groups and treated 3 days after adjuvant Tx: untreated treated with safflower oil treated with 0. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Zurier et al. Oral administration of DMHC: Acute inflammation: reduced accumulation of pouch-filled polymorphonuclear leukocytes Chronic polyarthritis: - diminished arthritis severity - prevented severe joint tissue injury - chronic polyarthritis rats remained active with no weight loss compared to arthritic control rats - developed only mild joint synovitis. Smith et al. Malfait et al. Anti-arthritic properties of non-psychoactive CBD. Sumariwalla et al. Anti-inflammatory and immunosuppressive effects of synthetic cannabinoid HU HU or vehicle control mixture of cremophor-EL, absolute ethanol, and PBS administered peritoneally for 10 days to arthritic mice at different doses from day 1 of clinical signs appearance at 0. Cox et al. Male Sprague-Dawley rats injected intradermally at the tail base with 0. Hammell et al. Anti-inflammatory and anti-nociceptive effects of CBD gels. Transdermal administering of CBD gels: - significantly reduced joint swelling - reduced immune cell infiltration and thickening of the synovial membrane - paw withdrawal latency recovered to near baseline - dose-dependent reduction of pro-inflammatory biomarkers - did not alter exploratory behavior. Palomares et al. Johnson et al. Synovial fluid extracted from joints of RA, OA, or psoriatic arthritis pts. Richardson et al. Determine if cannabinoid signaling elements are present in synovia of RA or OA pts. Endocannabinoid levels were quantified in synovial biopsies. Selvi et al. Synovial fluid from 5 pts with RA and knee joint involvement OA knee joint replacement surgery. Lowin et al. Anti-arthritic properties of synthetic cannabinoid WIN. Evaluation of anti-arthritic properties of CBD. Kotschenreuther et al. Analysis of cannabinoid impact on Th17 differentiation in RA pts. Investigation of T helper cells differentiation ex vivo in peripheral blood cells of RA pts. Notcutt et al. Randomized, double-blind, placebo-controlled crossover trial. Highest efficacy of THC-based cannabis shown in pain regulation with only very mild side effects. Blake et al. Randomized, double-blind, parallel-group trial. Wilsey et al. Short-term effects of CBME for neuropathic pain. Randomized, double-blind, placebo-controlled, crossover study. THC-based Medium dose 3. Randomized, placebo-controlled 4-way crossover study. Haleem and Wright Ware et al. Prevalence of medicinal cannabis users in the UK. Ste-Marie et al. Prevalence of marijuana users among rheumatology patients with confirmed diagnosis in Canada. Exploratory study and cross-sectional survey with coded questionnaires: 1 diagnosis entered by physician; 2 marijuana use entered by patient. Jennings et al. Change in self-reported marijuana use in patients after the legalization of cannabis. Fitzcharles et al. Prevalence of marijuana users among rheumatology patients with confirmed diagnosis in Canada after marijuana legalization. Observational study, two questionnaires: 1 filled by the physician concerning diagnosis, 2 filled by patient concerning marijuana use. Guillouard et al.

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