What is MSM supplement
MSM is the acronym for Methylsulfonylmethane. Methylsulfonylmethane (MSM) is the oxidised form of dimethyl sulfoxide. It is found in very low amounts in fruits, corn, tomatoes, tea, coffee, and milk 1). Methylsulfonylmethane and dimethyl sulphoxide are two related nutritional supplements used for symptomatic relief of osteoarthritis 2). Prior to being used as a clinical application, MSM primarily served as a high-temperature, polar, aprotic, commercial solvent, as did its parent compound, dimethyl sulfoxide (DMSO) 3).
MSM is broadly expressed in a number of fruit, vegetable and grain crops, though the extent of MSM bioaccumulation is dependent upon the plant. Alternatively, synthetically produced MSM is manufactured through the oxidation of DMSO with hydrogen peroxide (H2O2) and purified by either crystallization or distillation. While distillation is more energy intensive, it is recognized as the preferred method 4). Biochemically, this manufactured MSM would have no detectable structural or safety differences from the naturally produced product 5). Since the concentration of MSM is in the hundredths ppm in food sources, synthetically produced MSM makes it possible to ingest bioactive quantities without having to consume unrealistic amounts of food.
Exogenous sources of MSM are introduced into the body through supplementation or consumption of foods like fruits, vegetables, grains, beer, port wine, coffee, tea, and cow’s milk. Along with MSM, absorbed methionine, methanethiol, DMS, and DMSO can be used by the microbiota to contribute to the MSM aggregate within the mammalian host 6). Diet-induced microbiome changes have been shown to affect serum MSM levels in rats 7) and gestating sows 8). That said, the gut flora is readily manipulated by diet, exercise or other factors and likely affects bioavailable MSM sources, as suggested in pregnancy 9).
Osteoarthritis is the most common of all joint disorders and affects over 30 million people in the US and 1 in 10 people aged 35–75 in the UK 10) and is associated with pain and functional disability, which in turn leads to reduced quality of life and increased risk of further morbidity and mortality 11). The treatment of osteoarthritis is largely symptomatic and includes analgesics, NSAIDs as well as exercise and surgical intervention 12).
Two nutritional supplements, dimethyl sulfoxide (DMSO, an organic form of sulfur commercially prepared from lignin) and its oxidized form, methylsulfonylmethane (MSM, occurring in green plants fruits and vegetables) have been used to treat arthritic conditions 13). DMSO (dimethyl sulfoxide) is converted in the body to MSM (methylsulfonylmethane) and as MSM remains in the body for longer than DMSO 14), it is suggested that many of the beneficial effects of DMSO are due to the long lasting fraction of DMSO which is converted to MSM 15). Both have similar pharmacological properties and their putative effects and mechanisms have been reviewed previously [MSM 16); DMSO 17)]. In a 12-week double-blind placebo-controlled randomized clinical trial on knee osteoarthritis, 500 mg of MSM three times a day, used alone or in combination with 500 mg of glucosamine three times a day, significantly improved a Likert scale of pain and Lequesne functional index 18). The combination of both ingredients was not more efficacious than each ingredient used alone. In a second 12-week double-blind placebo-controlled randomized clinical trial on knee osteoarthritis, 3 g of MSM given twice daily was more efficient than placebo in decreasing Western Ontario and McMaster universities (WOMAC) pain index and functional scores 19).
MSM and DMSO have been reported to reduce peripheral pain 20), inflammation 21) and arthritis 22), and might inhibit the degenerative changes occurring in osteoarthritis 23). These compounds may act through their ability to stabilize cell membranes, slow or stop leakage from injured cells and scavenge hydroxyl free radicals which trigger inflammation 24). Their sulfur content may also rectify dietary deficiencies of sulfur improving cartilage formation 25).
MSM is used orally and topically. Like DMSO, the treatment duration for osteoarthritis is at least three months. The optimum dosage has not been clearly defined as no dose ranging studies have been carried out 26). As a Generally Recognized As Safe (GRAS) status by the Food and Drug Administration in 2007 27), MSM is well-tolerated by most individuals at dosages of up to four grams daily, with few known and mild side effects 28). The suggested oral therapeutic doses is 4–6 g per day 29), although doses of up to 20 g/day have also been used 30); over the counter preparations are typically 1–5 g daily. There is limited formal safety data and no long term assessment. However, MSM is rapidly excreted from the body and animal toxicity studies of MSM showed only minor adverse events using doses of 1.5 g/kg and 2.0 g/kg of MSM for 90 days. This dose represents a human dose of 105–140 g/day, which is equivalent to 17–23 times the proposed maximum recommended human dose of 6 g/day 31). A further study confirmed MSM had no toxic effects on either pregnant rats or their foetus 32). Only minor adverse effects are associated with MSM administration in humans and include allergy, gastrointestinal upsets and skin rashes 33).
MSM supplement benefits
Due to its enhanced ability to penetrate membranes and permeate throughout the body, the full mechanistic function of MSM may involve a collection of cell types and is therefore difficult to elucidate. Results from laboratory test tube and animal studies suggest that MSM operates at the crosstalk of inflammation and oxidative stress at the transcriptional and subcellular level 34). Due to the small size of this organosulfur compound, distinguishing between direct and indirect effects is problematic.
In laboratory test tube studies indicate that MSM inhibits transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) by impeding the translocation into the nucleus while also preventing the degradation of the NF-κB inhibitor 35). MSM has been shown to alter post-translational modifications including blocking the phosphorylation of the p65 subunit at Serine-536, though it is unclear whether this is a direct or indirect effect. Modifications to subunits such as these contribute heavily to the regulation of the transcriptional activity of NF-κB 36), and thus more details are required to further understand this anti-inflammatory mechanism. Traditionally, the NF-κB pathway is thought of as a pro-inflammatory signaling pathway responsible for the upregulation of genes encoding cytokines, chemokines, and adhesion molecules . The inhibitory effect of MSM on NF-κB results in the downregulation of mRNA for interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α) in vitro 37). As expected, translational expression of these cytokines is also reduced; furthermore, IL-1 and TNF-α are inhibited in a dose-dependent manner 38).
MSM can also diminish the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) through suppression of NF-κB; thus lessening the production of vasodilating agents such as nitric oxide (NO) and prostanoids 39). NO not only modulates vascular tone 40) but also regulates mast cell activation ; therefore, MSM may indirectly have an inhibitory role on mast cell mediation of inflammation. With the reduction in cytokines and vasodilating agents, flux and recruitment of immune cells to sites of local inflammation are inhibited.
At the subcellular level, the nucleotide-binding domain, leucine-rich repeat family pyrin domain containing 3 (NLRP3) inflammasome senses cellular stress signals and responds by aiding in the maturation of inflammatory markers. MSM negatively affects the expression of the NLRP3 inflammasome by downregulating the NF-κB production of the NLRP3 inflammasome transcript and/or by blocking the activation signal in the form of mitochondrial generated reactive oxygen species (ROS) 41).
MSM dietary supplement
As a therapeutic agent, MSM utilizes its unique penetrability properties to alter physiological effects at the cellular and tissue levels. Furthermore, MSM has the ability to act as a carrier or co-transporter for other therapeutic agents, even furthering its potential applications.
In addition to arthritis, MSM improves inflammation in a number of other conditions. For example, MSM attenuated cytokine expression in animal study for induced colitis 42), lung injury 43) and liver injury 44). Hasegawa and colleagues 45) reported that MSM was useful in protecting against UV-induced inflammation when applied topically and acute allergic inflammation after pre-treatment with a 2.5% aqueous drinking solution.
MSM is effective at reducing other inflammatory pathologies in humans as well. In a physician’s review of clinical case studies, MSM was an effective treatment for four out of six patients suffering from interstitial cystitis 46). Additionally, MSM is also suggested to alleviate the symptoms of seasonal allergic rhinitis 47). Though the reduction in systemic exercise-induced inflammation by MSM has been observed 48), human studies have not explored the inflammatory effects directly at the cartilage or synovium, as seen in the reduced synovitis inflammation in mice given MSM 49).
MSM joint supplement
Arthritis and Inflammation
Arthritis is an inflammatory condition of the joints that currently affects approximately 58 million adults, with an estimated increase to 78.4 million by 2040 50). This inflammation is characterized by pain, stiffness, and a reduced range of motion with regards to the arthritic joint(s). MSM is currently a alternative medicine treatment alone and in combination for arthritis and other inflammatory conditions. MSM, as a micronutrient with enhanced penetrability properties, is commonly integrated with other anti-arthritic agents including glucosamine, chondroitin sulfate, and boswellic acid.
As mentioned previously, a number of in vitro studies suggest that MSM exerts an anti-inflammatory effect through the reduction in cytokine expression. Similar results have been observed with MSM in experimentally induced-arthritic animal models, as evidenced by cytokine reductions in mice 51) and rabbits 52). Additionally, MSM in a combinatorial supplement with glucosamine and chondroitin sulfate effectively reduced C-reactive protein (CRP) in rats with experimentally-induced acute and chronic rheumatoid arthritis 53).
To date, most arthritic human studies have been non-invasive and assess joint condition through the use of subject questionnaires such as the Western Ontario and McMaster Universities Arthritis Index (WOMAC), 36-Item Short Form Survey (SF36), Visual Analogue Scale (VAS) pain, and the Lequesne Index. In his overview of MSM, Dr. Stanley Jacob references eleven case studies of patients suffering from osteoarthritis who experienced improved symptoms following supplementation with MSM 54). Clinical trials suggest MSM is effective in reducing pain, as indicated by the VAS pain scale, WOMAC pain subscale, SF36 pain subscale and Lequesne Index. Concurrent improvements were also noted in stiffness and swelling. Furthermore, in the study conducted by Usha and Naidu 55), MSM in combination with glucosamine potentiated the improvements in pain, pain intensity, and swelling.
Other human studies utilizing combination therapies report similar results. For instance, arthritis associated pain and stiffness was significantly improved through the use of Glucosamine, Chondroitin sulfate, and MSM (GCM) 56). Only marginal improvements in pain and stiffness were observed when a Glucosamine, Chondroitin sulfate, and MSM (GCM) combination was supplemented on top of modifications to diet and exercise in sedentary obese women diagnosed with osteoarthritis 57). MSM was also shown to be effective in reducing arthritis pain when used in combination with boswellic acid 58) and type II collagen 59).
Cartilage degradation has long been thought of as the driving force of osteoarthritis 60). Articular cartilage is characterized by a dense extracellular matrix with little to no blood supply driving nutrient extraction from the adjacent synovial fluid 61). Pro-inflammatory cytokines, particularly IL-1β and TNF-α, are implicated in the destructive process of cartilage extracellular matrix 62). With minimal blood supply and possible hypoxic microenvironments, in vitro studies suggest that MSM protects cartilage through its suppressive effects on IL-1β and TNF-α 63) and its possibly normalizing hypoxia-driven alterations to cellular metabolism 64).
Disruption of this destructive autocrine or paracrine signaling by MSM has also been observed in surgically-induced osteoarthritis rabbits by the reduction in cartilage and synovial tissue 65), TNF-α, and the protected articular cartilage surface during OA progression. Histopathology of a rheumatoid arthritis (RA) rat model supplemented with a GCM combination demonstrated decreased synovium proliferation and the development of an irregular edge at the articular joint 66). Furthermore, MSM supplementation in osteoarthritis mice significantly decreased cartilage surface degeneration 67). In fact the protective effects of MSM can be seen as far back as 1991, when Murav’ev and colleagues described the decreased knee joint degeneration of arthritic mice 68). Interestingly, endogenous serum MSM becomes elevated in sheep post-meniscal destabilization caused osteoarthritis 69); however, the magnitude of this physiological response was not large enough to protect against cartilage erosion.
Improve Range of Motion and Physical Function
In studies with osteoarthritic populations given MSM daily, significant improvements in physical function were observed, as assessed through the WOMAC, SF36 and Aggregated Locomotor Function 70). Objective kinetic knee measurements following eccentric exercise-induced muscle damage were not conclusive but suggest that MSM may aid in maximal isometric knee extensor recovery 71).
MSM has been used in a number of combination therapies with positive results. Supplementation with glucosamine, chondroitin sulfate, MSM, guava leaf extract, and Vitamin D improved physical function in patients with knee osteoarthritis based on the Japanese Knee OA Measure 72). A GCM supplement was successful in increasing functional ability and joint mobility 73). MSM in combination with boswellic acid was also shown to improve knee joint function as assessed through the Lequesne Index 74). MSM with arginine l-α-ketoglutarate, hydrolyzed Type I collagen, and bromelain taken for three months daily post-rotator cuff repair improved repair integrity without affecting objective functional outcomes 75).
Other studies exploring the uses of MSM in combination therapies failed to show significant improvements. In humans, MSM and boswellic acid reduced the need for anti-inflammatory drugs but was not more effective than the placebo as a treatment for gonarthrosis 76). However, when a GCM combination supplement was administered in addition to dietary and exercise interventions, no significant improvements were noted when compared to the non-supplemented group 77).
Subjects with lower back pain undergoing conventional physical therapy with supplementation of a glucosamine complex containing MSM reported an improvement in their quality of life 78). A 2011 systematic review of GCM supplements as a treatment for spinal degenerative joint disease and degenerative disc disease failed to come to a conclusion on efficacy due to the scarcity of quality literature 79).
To Reduce Muscle Soreness Associated with Exercise
Prolonged strenuous exercise can result in muscle soreness caused by microtrauma to muscles and surrounding connective tissue leading to a local inflammatory response 80). MSM is alluded to be an effective agent against muscle soreness because of its anti-inflammatory effects as well as its possible sulfur contribution to connective tissue. Endurance exercise-induced muscle damage was reduced with MSM supplementation, as measured by creatine kinase 81). Pre-treatment with MSM reduced muscle soreness following strenuous resistance exercises 82) and endurance exercise 83).
MSM supplement side effects
MSM appears to be well-tolerated and safe. Only minor side effects are associated with MSM in humans including allergy, upset stomach, and skin rashes 84).
A number of toxicity studies have been conducted in an array of animals including rats 85), mice 86) and dogs 87). In a preliminary toxicity study report, a single mortality was reported in a female rat given an oral aqueous dose of 15.4 g/kg after two days; however, a post-mortem necropsy examination showed no gross pathological alterations. Other technical reports indicate that mild skin and eye irritation have been observed when MSM is applied topically. Nonetheless, under the Food and Drug Administration (FDA) GRAS notification, MSM is considered safe at dosages under 4845.6 mg/day 88).
MSM and Alcohol
Much anecdotal evidence from web forums and videos exists regarding chronic MSM use and increased sensitivity to alcohol. Since other sulfur containing molecules, such as disulfiram, are used to combat alcoholism by causing adverse reactions when consuming alcohol 89), it is worth mentioning there have been no studies to date examining the effects of MSM usage on alcohol metabolism or addiction pathways. As mentioned previously, MSM readily crosses the blood brain barrier and becomes evenly distributed throughout the brain 90); however, studies have not focused on the metabolic effects on the different neural pathways. Further studies are needed to assess the safety of MSM use with recreational alcohol use.
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