Metylsulfonyl methan - MSM

Snížení NF-kappa B

MSM significantly inhibited the release of nitric oxide and prostaglandin E2 by alleviating the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-stimulated RAW264.7 cells. Furthermore, the levels of interleukin-6 and tumor necrosis factor-? were decreased by MSM treatment in cell culture supernatants. Further study indicated that the translocation of the p65 subunit of nuclear factor (NF)-?B to the nucleus was inhibited by MSM treatment in LPS-stimulated RAW264.7 cells, in which it helped block degradation of inhibitor of NF-?B. In addition, in vivo studies demonstrated that topical administration of MSM at 500—1250 µg/ear resulted in similar inhibitory activities in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema. Collectively, theses results indicate that MSM inhibits LPS-induced release of pro-inflammatory mediators in murine macrophages through downregulation of NF-?B signaling.
www.jstage.jst.go.jp/article/bpb/32/4/32_4_651/_article

Methylsulfonylmethane (MSM) -dimethyl sulfone, methyl sulfone, sulfonylbismethane, organic sulfur, or crystalline dimethyl sulfoxide

Naturally occurring organosulfur compound
Utilized as a complementary and alternative medicine (CAM)

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)

DMSO was extensively studied for membrane penetrability

Antioxidant capabilities
Anti-inflammatory effects
Anticholinesterase activity
Ability to induce histamine release from mast cells

MSM

Smooth and soften skin
Strengthen nails
Blood diluent
Relieve stress, relieve pain,
Treat parasitic infections,
Increase energy,
Boost metabolism,
Enhance circulation,
Improve wound healing

Little supporting scientific evidence

Clinical applications for arthritis
Interstitial cystitis
Allergic rhinitis
Acute exercise-induced inflammation

MSM Synthesis—The Sulfur Cycle

MSM is a member of the methyl-S-methane compounds within the Earth’s sulfur cycle.
Natural synthesis of MSM begins with the uptake of sulfate to produce dimethylsulfoniopropionate (DMSP) by algae, phytoplankton, and other marine microorganisms
DMSP is either cleaved to form dimethyl sulfide (DMS)

Undergoes demethiolation resulting in methanethiol

Can then be converted to DMS

Approximately 1%–2% of the DMS produced in the oceans is aerosolized
Atmospheric DMS is oxidized to form DMSO or sulfur dioxide by:

Ozone,
UV irradiation,
Nitrate (NO3),
Hydroxyl radical (OH)

Atmospheric levels of DMSO and MSM

Appear to be dependent upon the season with a maxima in the spring/summer and minima in the winter

DMS production and volatility being temperature dependent

Oxidized DMS products like sulfur dioxide

Contribute to increased condensation and cloud formation

Providing a vehicle for DMSO to return to Earth dissolved in precipitation

Can undergo disproportionation to either DMS or MSM

Absorbed into the soil

DMSO and MSM will be taken up by plants
Utilized by mutualistic soil bacterium such as Pseudomonas putida

Improve soil conditions

MSM is broadly expressed in a number of fruit, vegetable and grain crops

Dependent upon the plant

MSM and the other sulfur sources are

Consumed as a plant product - hundredths ppm in food sources
Excreted, released as a by-product of plant respiration in the form of sulfide
Eventually decompose as the plant dies

Non-aerosolized sulfur sources

Can then be oxidized to sulfate and incorporated into minerals

Undergo erosion and return to the oceans

Completing this sulfur sub-cycle

Synthetically produced MSM

Oxidation of DMSO with hydrogen peroxide (H2O2)
Purified by either crystallization or distillation
Distillation is more energy intensive

Recognized as the preferred method
Utilized for manufacture of the GRAS OptiMSM® (Bergstrom Nutrition, Vancouver, WA, USA)

Manufactured MSM would have no detectable structural or safety differences from the naturally produced product

Absorption and Bioavailability

Fruits [40,47],
Vegetables [40,47,48],
Grains [47,49],
Beer [47],
Port wine [52],
Coffee [47],
Tea [47,53],
Cow’s milk [47,54]
With MSM, absorbed methionine, methanethiol, DMS, and DMSO

Can be used by the microbiota to contribute to the MSM aggregate within the mammalian host

Diet-induced microbiome changes

Affect serum MSM levels in rats [58] and gestating sows

MSM is rapidly absorbed in rats [63,64] and humans [65], taking 2.1 h and less than 1 h
DMSO in monkeys demonstrate rapid conversion of DMSO to MSM within 1–2 h after delivery via oral gavage
Humans ingesting DMSO oxidized approximately 15% to MSM by hepatic microsomes in the presence of NADPH2 and O2 [56].
Rats, between 59% and 79% of MSM is excreted the same day as administration in urine

Unchanged
Or as another S-containing metabolite

Urine is the most common form of excretion
MSM has been detected in urine of rats [63,67], rabbits [4,5], bobcats [68], cheetahs [69], dogs [70], monkeys [66], and humans [4,62,71,72].
Excretion of MSM can be contained in

Feces [63,64]
Cow’s milk [54,73],
Red deer tail gland secretion [74],
Human saliva [75].

Detected in cerebrospinal fluid

Evenly distributed between the gray and white matter of the brain

Biological half-life within the brain is an estimated 7.5 h
General half-life is suggested to be greater than 12 h
Persisting systemic MSM comprises the bioavailable source

Měření hladin

1987 the first reported baseline MSM levels were 700–1100 ng/mL or 7.44–11.69 mcmol/L [83]

Low micromolar range of 0–25 mcmol/L

Baseline MSM levels ranging from 13.3 to 103 mcM/mL
Human study involving daily ingestion of MSM at 3 g by 20 healthy men for a period of four weeks

Serum MSM was elevated in all men following ingestion
Further increase at week 4 versus week 2 in the majority of men
Oral MSM is absorbed by healthy adults and accumulates over time with chronic intake.

Mechanisms of Actions

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 in vitro and in vivo studies suggest that MSM operates at the crosstalk of inflammation and oxidative stress at the transcriptional and subcellular level. Due to the small size of this organosulfur compound, distinguishing between direct and indirect effects is problematic. In the sections to follow, an attempt will be made to describe each mechanism within a focused scope.2.1. Anti-InflammationIn vitro studies indicate that MSM inhibits transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) [85,86] by impeding the translocation into the nucleus while also preventing the degradation of the NF-?B inhibitor [86]. MSM has been shown to alter post-translational modifications including blocking the phosphorylation of the p65 subunit at Serine-536 [87], 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-?B [88], and thus more details are required to further understand this anti-inflammatory mechanism. Traditionally, the NF-?B pathway is thought of as a pro-inflammatory signaling pathway responsible for the upregulation of genes encoding cytokines, chemokines, and adhesion molecules [89]. The inhibitory effect of MSM on NF-?B results in the downregulation of mRNA for interleukin (IL)-1, IL-6, and tumor necrosis factor-? (TNF-?) in vitro [90,91]. As expected, translational expression of these cytokines is also reduced; furthermore, IL-1 and TNF-? are inhibited in a dose-dependent manner [90].MSM can also diminish the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) through suppression of NF-?B; thus lessening the production of vasodilating agents such as nitric oxide (NO) and prostanoids [86]. NO not only modulates vascular tone [92] but also regulates mast cell activation [93]; 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 [94,95]. MSM negatively affects the expression of the NLRP3 inflammasome by downregulating the NF-?B production of the NLRP3 inflammasome transcript and/or by blocking the activation signal in the form of mitochondrial generated reactive oxygen species (ROS) [90]. The mechanisms by which MSM demonstrates antioxidant properties will be discussed in the following section.2.2. Antioxidant/Free-Radical ScavengingAlthough an excess of ROS can wreak havoc on a number of intracellular components, a threshold amount is required to activate the appropriate pathways in phenotypically normal cells [96]. The antioxidant effect of MSM was first noticed when the neutrophil stimulated production of ROS was suppressed in vitro but unaffected in a cell free system [97]; for that reason, it was proposed that the antioxidant mechanism acts on the mitochondria rather than at the chemical level.MSM influences the activation of at least four types of transcription factors: NF-?B, signal transducers and activators of transcription (STAT), p53, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). By mediating these transcription factors, MSM can regulate the balance of ROS and antioxidant enzymes. It is important to note that each of these is also, in part, activated by ROS.As mentioned previously, MSM can inhibit NF-?B transcriptional activity and thus reduce the expression of enzymes and cytokines involved in ROS production. Downregulation of COX-2 and iNOS reduces the amount of superoxide radical (O2-) and nitric oxide (NO), respectively [86]. Additionally, MSM suppresses the expression of cytokines such as TNF-? [86,90,91], which may reduce any stimulated mitochondrial generated ROS [98]. Decrements in cytokine expression may also be involved in reduced paracrine signaling and activation of other transcription factors and pathways.MSM has been shown to repress the expression or activities of STAT transcription factors in a number of cancer cell lines in vitro [99,100,101]. The janus kinase (Jak)/STAT pathway is involved in regulation of genes related to apoptosis, differentiation, and proliferation, all of which generate ROS as a necessary signaling component [102,103,104]. Signaling through the Jak/STAT pathway may also be stifled by reduced cytokine expression. Downregulation of the Jak/STAT pathway may further reduce ROS generation by decreasing expression of oxidases [105] and B-cell lymphoma-2 (Bcl-2) [106].In macrophage-like cells, pre-treatment with MSM in vitro was found to decrease accumulation of the redox sensitive p53 transcription factor [107]. This p53 exhibits dichotomous oxidative function depending on the intracellular ROS levels, whereby, in a general sense, p53 exerts antioxidative functions at low intracellular ROS levels and prooxidative functions at high ROS levels [108]. The antioxidative function of p53 upregulates scavenging enzymes like Sestrin, glutathione peroxidase (GPx) and aldehyde dehydrogenase (ALDH). The prooxidative function of p53 upregulates oxidases while also suppressing antioxidant genes. For a more in depth summary of p53 and oxidative stress, please see the review by Liu and Xu [108].Murine neuroblastoma cells cultured with human immunodeficiency virus type 1 transactivating regulatory protein (HIV-1 Tat) displayed reduced nuclear translocation of Nrf2; however, co-culturing with MSM returned Nrf2 translocation to the nucleus to control levels [109]. Nrf2 is well documented for its association with antioxidant enzymes including glutamate-cysteine ligase (GCL), superoxide dismutases (SODs), catalase (CAT), peroxiredoxin (Prdx), GPx, glutathione S-transferase (GST), and others [110]. Though it is unclear what direct effect MSM has on Nrf2, it is worth mentioning that Nrf2 can also be regulated by p53 expression of p21 or Jak/STAT expression of B-cell lymphoma-extra large (Bcl-XL) [111].2.3. Immune ModulationStress can trigger an acute response by the innate immune system and an ensuing adaptive immune response if the stressor is pathogenic. Sulfur containing compounds including MSM play a critical role in supporting the immune response [112,113,114]. Through an integrated mechanism including those mentioned above, MSM modulates the immune response through the crosstalk between oxidative stress and inflammation.Chronic exposure to stressors can have detrimental effects to the immune system as it becomes desensitized or over-stressed and unable to elicit a typical immune response. The broad effects of IL-6 have been implicated in the maintenance of chronic inflammation [115]. MSM has been shown to reduce IL-6 in vitro, which may mitigate these chronic deleterious effects [86,87,90]. Pre-treatment with MSM, prior to exhaustive exercise, prevented the over-stress of immune cells as lipopolysaccharide (LPS)-treated blood was still able to mount a response through the secretion of cytokines ex vivo, an effect not observed in the placebo group [24].The adjacent vasculature plays a role in mediating the acute immune response primarily through the activation of mast cells. Histamine release from mast cells is inhibited by DMSO [116]; however, the effects of MSM on histamine release remain unexplored. Previous studies indicate that MSM has an inhibitory role on vascular function [117,118]. Other in vitro studies demonstrate that MSM has the ability to dampen the expression of vasodilating agents such as NO and prostanoids [86]. A reduction in NO protects macrophages against NO stimulated apoptosis [107].Additionally, MSM may serve other immune modulatory effects related to cell cycle and cell death. In vitro studies indicate that MSM can induce apoptosis in gastrointestinal cancer cells [119], hepatic cancer cells [120], and colon cancer cells [121]. Contrary to these findings, MSM did not induce apoptosis in murine breast cancer cells [122]. Rather, MSM was shown to restore normal cellular metabolism to both metastatic murine breast cancer and murine melanoma cells [123]. Cell cycle arrest has also been observed in gastrointestinal cancer cells [119] and myoblasts [124]. These alterations to cell survival may arise from cyclin production modulations to the p53 and Jak/STAT pathways.Though few studies have examined the effectiveness of MSM on wound healing, the innate immune system may also benefit from enhanced wound closure, as assessed by the scratch test in vitro [124,125,126]. Future studies would be needed to confirm these results in vivo.2.4. Sulfur Donor/MethylationMSM has long been thought of as a sulfur donor for sulfur containing compounds such as methionine, cysteine, homocysteine, taurine, and many others. Guinea pigs fed radiolabeled MSM incorporated labeled sulfur into serum proteins containing methionine and cysteine [127]. This study suggested that microbial metabolism may be responsible for the utilization of MSM to form methionine and subsequent synthesis to cysteine. More recent in vivo studies with radiolabeled MSM suggest that this compound is metabolized rapidly in a homogenous distribution of tissues [63,64]. These studies reportedly collected most labeled sulfur as metabolites of MSM in urine but did not determine the metabolites. Further study regarding the activity of MSM as a sulfur donor is ongoing.In humans, no MSM dose-dependent trends are observed between individuals for plasma sulfate and homocysteine changes [65]. With microorganisms largely responsible for sulfur utilization throughout the sulfur cycle, MSM as a sulfur donor may be dependent on the existing microbiome with mammalian hosts.MSM is reportedly a non-alkylating agent and does not methylate DNA [128]. In a letter by Kawai et al., the parent compound of MSM, DMSO, can methylate DNA in the presence of hydroxyl radical (OH) [129], which also has the potential to aid in the oxidation of DMSO to MSM [32,35]. Although it is uncertain whether MSM alkylates DNA, MSM does not appear to cause chromosome aberration in vitro or micronucleation in vivo according to two final study reports. Future studies are needed to determine whether MSM is a methyl donor.3. Common UsesAs 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.3.1. Arthritis and InflammationArthritis is an inflammatory condition of the joints that currently affects approximately 58 million adults, with an estimated increase to 78.4 million by 2040 [130]. This inflammation is characterized by pain, stiffness, and a reduced range of motion with regards to the arthritic joint(s). MSM is currently a CAM 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 [86,87,90,91]. Similar results have been observed with MSM in experimentally induced-arthritic animal models, as evidenced by cytokine reductions in mice [131] and rabbits [86,87,90,91,132]. 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 [133].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 [7]. Clinical trials suggest MSM is effective in reducing pain, as indicated by the VAS pain scale [18,134], WOMAC pain subscale [18,19,135,136], SF36 pain subscale [18,136], and Lequesne Index [134]. Concurrent improvements were also noted in stiffness [18,135,136] and swelling [134]. Furthermore, in the study conducted by Usha and Naidu [134], 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) [137,138]. Only marginal improvements in pain and stiffness were observed when a GCM combination was supplemented on top of modifications to diet and exercise in sedentary obese women diagnosed with osteoarthritis (OA) [139]. MSM was also shown to be effective in reducing arthritis pain when used in combination with boswellic acid [140] and type II collagen [141].In addition to arthritis, MSM improves inflammation in a number of other conditions. For example, MSM attenuated cytokine expression in vivo for induced colitis [142], lung injury [143], and liver injury [143,144]. Hasegawa and colleagues [131] 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 [21]. Additionally, MSM is also suggested to alleviate the symptoms of seasonal allergic rhinitis [22,23]. Though the reduction in systemic exercise-induced inflammation by MSM has been observed [24], 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 [145].3.2. Cartilage PreservationCartilage degradation has long been thought of as the driving force of osteoarthritis [146]. Articular cartilage is characterized by a dense extracellular matrix (ECM) with little to no blood supply driving nutrient extraction from the adjacent synovial fluid [147]. Pro-inflammatory cytokines, particularly IL-1ß and TNF-?, are implicated in the destructive process of cartilage ECM [148]. With minimal blood supply and possible hypoxic microenvironments, in vitro studies suggest that MSM protects cartilage through its suppressive effects on IL-1ß and TNF-? [86,90,91] and its possibly normalizing hypoxia-driven alterations to cellular metabolism [123].Disruption of this destructive autocrine or paracrine signaling by MSM has also been observed in surgically-induced OA rabbits by the reduction in cartilage and synovial tissue [132], TNF-?, 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 [133]. Furthermore, MSM supplementation in OA mice significantly decreased cartilage surface degeneration [149]. 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 [150]. Interestingly, endogenous serum MSM becomes elevated in sheep post-meniscal destabilization caused osteoarthritis [151]; however, the magnitude of this physiological response was not large enough to protect against cartilage erosion.3.3. Improve Range of Motion and Physical FunctionWith the aforementioned improvements in inflammation and cartilage preservation, not surprisingly beneficial changes in overall physical function have also been noted through the use of subjective measurements [18,19,135,136]. In studies with osteoarthritic populations given MSM daily, significant improvements in physical function were observed, as assessed through the WOMAC [18,19,135,136], SF36 [19,135,136], and Aggregated Locomotor Function (ALF) [135]. 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 [152].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 [137]. A GCM supplement was successful in increasing functional ability and joint mobility [138]. MSM in combination with boswellic acid was also shown to improve knee joint function as assessed through the Lequesne Index [140]. MSM with arginine l-?-ketoglutarate, hydrolyzed Type I collagen, and bromelain taken for three months daily post-rotator cuff repair improved repair integrity without affecting objective functional outcomes [153].Other studies exploring the uses of MSM in combination therapies failed to show significant improvements. In one such study in geriatric horses, a GCM combination supplement given orally for three months failed to show significant changes in gait characteristics [154]. 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 [155]. 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 [139].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 [156]. 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 [157].3.4. To Reduce Muscle Soreness Associated with ExerciseProlonged strenuous exercise can result in muscle soreness caused by microtrauma to muscles and surrounding connective tissue leading to a local inflammatory response [158]. 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 [159]. Pre-treatment with MSM reduced muscle soreness following strenuous resistance exercises [152,160,161] and endurance exercise [162].3.5. Reduce Oxidative StressIn vitro studies suggest that MSM does not chemically neutralize ROS in stimulated neutrophils but instead suppresses mitochondrial generation of superoxide, hydrogen peroxide, and hypochlorous acid [97]. Additionally, MSM is able to restore the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio to normal levels, decrease NO production, and reduce neuronal ROS production following HIV-1 Tat exposure [109]. Animal studies using MSM as the primary treatment for experimentally induced injuries show reductions in malondialdehyde (MDA) [142,143,144,163,164,165], GSSG [165], myeloperoxidase (MPO) [142,143,163], NO [164], and carbon monoxide (CO) [164] and/or increases in GSH [142,143,163,164,165,166], CAT [142,143,144,165], SOD [143,144,163,165], and GPx [165]. Treatment modalities for these animal studies were either an acute one time dose or pre-treatment prior to inducing injury [144,163,165].In humans, MSM pre-treatment prior to endurance exercise results in acute attenuation of induced protein oxidation [167,168], bilirubin [159,168], lipid peroxidation [167], creatine kinase [159], oxidized glutathione [167], and uric acid [168] and also an increase in total antioxidant capacity [159,168]. Following endurance exercise, reduced glutathione was elevated with 10 days of pre-treatment [167] but was insignificantly affected by a single oral dose just prior to exercise [168].Pre-treatment with MSM in subjects undergoing resistance exercise exhibits more variability. Supplementation for 28 days with 3.0 g/day prior to exhaustive resistance exercise showed an increase in Trolox equivalent antioxidant capacity (TEAC) and a decrease in homocysteine [161]; whereas, supplementation for 14 days at the same dosage reported no significant changes in TEAC or homocysteine [160]. The longer period of supplementation may have allowed bioavailable MSM stores to reach a level where it could upregulate Nrf2 enough to produce a more significant rise in antioxidant enzymes.Combination therapies including MSM have become more popular recently, particularly with ethylenediaminetetraacetic acid (EDTA) due to the permeability enhancement provided by MSM [169]. For instance, topical EDTA-MSM is effective at reducing oxidative damage in the form of protein-lipid aldehyde adducts [170,171,172]. EDTA-MSM reduced lens opacification in diabetic cataract [172] but was ineffective in reversing experimentally induced intraocular pressure in rats [170]. In humans, EDTA-MSM lotion significantly improved pitting edema symptoms after two weeks of application, with circulating total antioxidant capacity and MDA reductions noted [173].Humans studies show promise for MSM as an antioxidant with similar results noted, including reductions in MDA [19,167,168], protein carbonyls (PC) [167,168], and uric acid [168] and increases in GSH [167] and TEAC [159,161,168]. Contrary to previous literature, Kantor et al. reported that MSM users experienced reduced lymphocyte DNA repair capacity at 60 min. [174]. This conflicting result may be explained by the samples being collected at different points in the day, since the circadian clock can modulate this measure [175].3.6. Improve Seasonal AllergiesIn an evaluation of MSM on seasonal allergies, 2.6 g/day PO MSM for 30 days improved upper and total respiratory symptoms as well as lower respiratory symptoms by week 3 [23]. All these improvements were maintained throughout the 30 days of supplementation. A drawback of this study was the lack of reporting on pollen counts and a symptoms questionnaire [176]. This was later corrected when Barrager and Schauss published the additional requested data [22]. Barrager et al. used a subsection of this sample population to measure histamine release but found no significant changes in plasma IgE or histamine levels [23].3.7. Improve Skin Quality and TextureSince the initial patent awarded to Herschler in 1981, MSM has been suggested to have therapeutic uses for the improvement of skin quality and texture by acting as a sulfur donor to keratin. According to one final study report, MSM is non-irritating to the skin of rabbits via an occlusive patch. Another final study report indicated that MSM may be slightly irritating to skin of guinea pigs. Using a lotion containing EDTA and MSM, mild improvement in burn sites on rats were noticed following three days of topical application every 8 h [171].Skin appearance and condition after MSM treatment significantly improved as assessed by expert grading, instrumental analysis, and participant self-assessment [177]. Human combination studies with four peeling sessions using pyruvic acid and MSM once every two weeks improved the degree of pigmentation of melisma, skin elasticity, and the degree of wrinkling [178]. A combination treatment of silymarin and MSM proved useful in managing rosacea symptoms [179]. A case study of a 44 year old man with severe X-linked type ichthyosis showed improvement of symptoms after four weeks of topical moisturizer containing amino acids, vitamins, antioxidants, and MSM [180].3.8. MSM and CancerAn emerging area of MSM research deals with the anti-cancer effect of the organosulfur compound. In vitro studies using MSM alone or in combination have evaluated the metabolic and phenotypic effects of a number of cancer cell lines including breast [100,101,122,123,126,181], esophagus [119], stomach [119], liver [119,120], colon [121], bladder [99], and skin cancers [123,125] with promising results. MSM independently has been shown to be cytotoxic to cancer cells by inhibiting cell viability through the induction of cell cycle arrest [119,122,123], necrosis [119], or apoptosis [100,101,119,120,121]. The inhibition of cell growth and proliferation may be attributed to the metabolic alterations induced by MSM at the transcriptional and/or post-translational stages. For instance, MSM has been shown to inhibit expression and DNA binding of transcription factors such as STAT3 [100,101] and STAT5b [100,101,181]; meanwhile, the p53 transcription factor is maintained by MSM [100] and does not induce apoptosis [121]. Though MSM inhibition of DNA binding by STAT3 may be an indirect effect of the phosphorylation of Jak2 [99]. Nonetheless, by inhibiting the binding of STAT3 and STAT5b to promoters, the reduced expression of oncogenic proteins such as vascular endothelial growth factor (VEGF) [99,100,101,123], heat shock protein (HSP)90? [100], and insulin-like growth factor-1 receptor (IGF-1R) [99,100,101] has been observed. The reduced expression of IGF-1R and VEGF may help prevent the development of tumors by reducing the insulin-like growth factor-1 (IGF-1)-mediated cell survival and proliferation pathways and preventing tumor-induced angiogenesis [182,183]. These metabolic alterations contribute to profound alterations at the cellular level as well.In vitro studies with cancer cell lines suggest that MSM has the ability to stimulate phenotypic changes more closely resembling non-cancerous cells. Treatment with MSM results in the induction of contact inhibition and cell senescence [122,123,125,126], anchorage-dependent growth [122,125], reduced migration of metastatic lines [101,122,125,126], and normalized wound healing [122,125]. This could in part be attributed to the robust changes to cellular filaments, including the disassembly and indirect reassembly of microtubules [123] and reorganization of actin localization [125]. While preventing angiogenesis may prompt a state of hypoxia, MSM has also been shown to reduce levels of HIF-1? under hypoxic conditions [100,123] and prevent or improve various metastatic biomarkers in response to hypoxia [123]. In vitro MSM studies have also been supported by additional xenograft and in vivo studies confirming the results.When cancer cells are xenotransplanted into animal models treated with MSM, tumor growth suppression has been observed [99,100,101], though two of these studies included a combination treatment of MSM and AG490 [99] or Tamoxifen [101]. Tumor tissue from mice treated exclusively with MSM exhibited reduced expression of IGF-1, STAT3, STAT5b, and VEGF without significant suppression of IGF-1R [100]. Tissues isolated from xenografted mice treated with combination treatments both displayed downregulation of STAT5b and IGF-1R signaling [99,101]. Previous studies also suggest that pre-treatment with MSM for approximately one week prior to inducing cancer in rats results in a significant reduction in the mean time to tumor onset [184,185]. Human trials with MSM as a cancer treatment have not been conducted to date; however, one study suggests that MSM use may be associated with a decreased risk of lung and colorectal cancer [186]. In vitro and in vivo results warrant further investigation of MSM as a treatment for cancer.4. Safety ProfileMSM appears to be well-tolerated and safe. A number of toxicity studies have been conducted in an array of animals including rats [184,185,187,188,189], mice [190], and dogs [191,192]. 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 [25]. A summary of the toxicity studies is listed in Table 1.Table 1. Methylsulfonylmethane (MSM) Toxicity Data.TableMSM and AlcoholMuch 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 [193], 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 [76,77,78,79,80]; 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.5. ConclusionsMSM is a naturally occurring organosulfur compound with broad biological effects. Human absorption and biosynthesis of this compound likely depends heavily on the co-metabolism between microbiota and host. Whether naturally produced or manufactured, MSM exhibits no biochemical differences in its ability to intermediate oxidative stress and inflammation. This micronutrient is well tolerated for arthritis and a number of other conditions related to inflammation, physical function, and performance. Emerging research suggests that MSM may one day aid in the treatment of various types of cancer [49,99,100,101,119,120,121,122,123,125,126,181,184,185,186,194] or metabolic syndromes [195].

www.mdpi.com/2072-6643/9/3/290/htm

Osteoarthritis or rheumatoid arthritis

Bursitis, tendinitis, or tenosynovitis

People also apply MSM to the skin to try to treat problems such as:

Scar tissue or stretch marks

Wrinkles

Wind or sun burn

Wounds, cuts, or abrasions

Rosacea

Or they may take it to try to treat gastrointestinal problems such as:

Chronic constipation

Ulcers

Diverticulosis (a bowel disease)

Hemorrhoids

There is a whole range of other reasons people take MSM. This includes obesity and liver problems, high blood pressure, high cholesterol, gum disease, snoring, infections, lung problems, Alzheimer's, HIV, and cancer.
The evidence to support taking MSM for these is lacking.
However, there is evidence that MSM in combination with other supplements may help a bit with the pain and swelling of knee osteoarthritis. Also, early animal research shows some promise for decreasing joint degeneration.
Limited small studies also show that MSM may help with exercise recovery. But researchers have more work to do to confirm this.
MSM has shown some effectiveness for treating allergies, repetitive stress injuries, certain bladder disorders like interstitial cystitis, and wounds, but more research is needed before it can be recommended for any of these conditions.
People have tried taking from 500 milligrams of MSM twice times daily to 3 grams once daily for osteoarthritis. However, optimal doses of MSM have not been set for any condition. And quality and active ingredients in supplements may vary widely from maker to maker. This makes it hard to set a standard dose.Can you get MSM naturally from foods
Very small amounts of MSM can be found in:

Fruit

Corn

Tomatoes

Tea and coffee

Milk

But the amounts in these foods are a small fraction of the amount in supplements.What are the risks of taking MSM?
Chances are it is safe if you take up to 6 grams of MSM by mouth for six months or fewer.
Side effects. There isn't enough information about MSM's safety when you apply it to the skin.
So far, studies have shown minimal side effects when MSM is taken orally in a dosage of 3 grams daily for six months, but some people may experience mild gastrointestinal side effects such as discomfort or diarrhea.
Risks. Don't take any chances if you are pregnant or breastfeeding. Doctors don't know enough about the safety of MSM in these circumstances. So it's best not to take it. Since MSM is a sulfa drug, do NOT take it if you have allergies to sulfa.
Interactions. There doesn't appear to be an interaction between MSM and medications, herbs, supplements, or foods.
The FDA does not regulate supplements. Be sure to tell your doctor about any supplements you’re taking, even if they’re natural. That way, they can check on any potential side effects or interactions with medications, foods, or other herbs and supplements. Your doctor can let you know if the supplement might raise your risks.

MUDr. Dana Maňasková