MSM

Methylsulfonylmethane (MSM; also known as dimethyl sulfone or DMSO₂^[5]) is the oxidized form of dimethyl sulfoxide (DMSO), an organic sulfur compound from lignan^[6] and naturally occurs in some green vegetables and other food products.^[7] MSM is one of the more popular joint health supplements in the western world, behind both glucosamine and chondroitin^[8][9] and similar to DMSO it is a potent solvent^[10] and percutaneous absorption enhancer.

Sources of MSM include (when available, quantity of the oxidized form of DMSO also included):

• Bovine dairy at 6.1−8.2ppm (0.0006-0.0008%)^[11] with lower estimates at 3.3ppm^[12]
• Chicken (liver and contractile tissue)^[13]
• Alfalfa (0.07ppm of MSM; 0.10ppm of DMSO)^[12]
• Beets (0.12ppm DMSO)^[12]
• Cabbage (0.10-0.40ppm DMSO)^[12]
• Corn (0.12-0.36ppm DMSO; up to 0.11ppm MSM)^[12]
• Swiss chard (0.05-0.18ppm MSM; 0.12-0.15ppm DMSO)^[12]
• Tomatoes; both the fruits (0.2-0.32ppm MSM; 0.16-0.69ppm DMSO) and tomato paste (0.64-0.86ppm MSM; 2.9-3.7ppm DMSO)^[12]
• Tea from Camellia sinensis (0.3ppm MSM, 16ppm DMSO)^[12]
• Beer (0.14ppm MSM; 1.4ppm DMSO)^[12]
• Coffee (1.6ppm MSM; 2.6ppm DMSO)^[12]

Methylsulfonylmethane (MSM) appears to be a naturally occurring small sulfur containing molecule in a variety of food products, although the quantity in these food products is much less than that in supplementation and MSM from the diet is not likely to be a significant contributor

MSM is water soluble, the powder form is white and odorless, and the molecule is 34% sulfur by weight.^[5]

MSM is the oxidized byproduct of dimethylsulfoxide (DMSO), which is a process that occurs naturally in plants^[14] as the roots and foliage can absorbed DMSO;^[12] MSM may be degraded into the metabolite dimethylsulfide (DMS) but this is an instable and gaseous metabolite.^[14] DMS is actually the origin of MSM in plants as well, as microscopic plankton create dimethyl sulfonium salts that convert to DMS which is then delivered to plants via the air; photosynthesis and radiation converts DMS into DMSO.^[5]

In otherwise healthy individuals, the plasma range of MSM tends to range between undetectable to 25μmol/L^[15][16]

Approximately 5-10mg of MSM is excreted via the urine daily in humans regardless of supplementation,^[11] and may be relevant to more species than humans as it has been detected in the urine of felines (cheetah),^[17] wild dogs,^[18] and rabbits.^[19]

Following a single oral dose of 500mg/kg MSM to rats, serum MSM peaked at a C_max of 622+/-37μg/mL recorded at a T_max of 2.1+/-1.2 hours with a prolonged half-life of 12.2+/-1.4 hours; the overall AUC was 15,124+/-1082μg/h/mL.^[7] When measured 48 hours after ingestion, MSM was still detectable in serum at 63.7+/-12.3μg/mL but was not detectable at 120 hours after ingestion (limit of quantification of 0.816μg/mL ).^[7]

Is detectable in serum following oral ingestion and appears to have a very long half life, can be detected in serum for up to two days following an acute dosage

MSM has been noted to be incorporated into serum proteins^[20] which may explain distribution throughout the body (as the high water solubility of MSM suggests a carrier is needed).

MSM has been detected in the tissue of rats following oral ingestion of 500mg/kg MSM and when measured at 48 hours after the dose, with concentrations recorded in the liver (54.7+/-11.4), heart (59.4+/-11.7μg/mL), kidney (71.1+/-15.7μg/mL), spleen (58.2+/-14.4μg/mL), testes (69.4+/-16.2μg/mL), brain (58.7+/-11.8μg/mL), eyes (66.7+/-12.9μg/mL), skin (51.8+/-13.7μg/mL), and bone (35.2+/-0.9μg/mL); no detectable MSM was present 120 hours after oral ingestion, and the ratios of tissue:blood MSM was recorded at 0.856 (liver), 0.932 (heart), 1.11 (kidney), 0.909 (spleen), 1.08 (testes), 0.921 (brain), 1.05 (eyes), 0.807 (skin), and 0.563 (bone).^[7]

Can bioaccumulate in all measured tissues following oral intake

A single oral dose of MSM (500mg/kg) has been noted to have a clearance rate of 38.7+/- 2.2mL/h/kg.^[7]

A week of supplementation of MSM at 470mg/kg daily to rats noted that 70% of radiolabelled MSM was excreted in the urine and 10% excreted in the feces.^[21] Elsewhere, the urinary excretion rate has been determined at 85.8% with a lower fecal excretion rate (3.08%).^[7] 58.7% of this oral dose appears to be excreted within one day of ingestion, and 79.0% of the ingested dose is eliminated by the second day with no significant differences between 96 and 120 hours after ingestion (suggesting full excretion).^[7]

MSM has been detected in neural tissue of persons consuming MSM supplements^[22][23][24] with no detectable levels in persons who do not consume MSM supplements^[23] and has also been confirmed to increase cerebrospinal fluid levels of MSM (where it screwed with proton magnetic resonance testing).^[25] One case study suggested that there was a 7.5 day washout half-life period with MSM supplementation.^[24]

For rat studies, MSM following an acute oral intake of 500mg/kg bodyweight (estimated human dose of 80mg/kg) resulted in a brain concentration of 58.7+/-11.8μg/mL wet weight with a 0.921 tissue:serum ratio; this suggests MSM easily passes the blood brain barrier.^[7] The human case study with an unspecified oral intake of MSM initially reported a concentration of 2.36mM with lower levels on day 2 (1.95mM), day 5 (1.11mM), and day 10 (0.75mM) following supplement cessation,^[24] and a subsequent small trial of seven persons ingesting 1-3g MSM noted a variable concentration range of 0.42-3.40mM and appeared to evenly accumulate in grey and white brain matter^[23] (the response to this article^[26] is a clarification on the supplement brand used).

MSM appears to be able to bioaccumulate in the brain according to a variety of case studies and small trials, a full pharmacokinetic study on brain accumulation of MSM does not appear to have been conducted yet

When looking at other brain metabolites via MRI (creatine, choline, myo-inositol, NAA, and Glx), ingestion of 1-3g MSM does not appear to alter their quantity or function according to a small preliminary test.^[23]

The reduced form of MSM (DMSO) has been demonstrated to block peripheral nerve conductance,^[27] which is thought to be a mechanism of analgesia.

In rats given pulmonary hypertension (monocrotaline induced^[28][29]), preloading of MSM at 100-400mg/kg for 10 days was able to dose-dependently suppress the increase in heart and lung relative weight^[30] (increased by the toxin) and this was thought to be related to the direct antioxidative effects of MSM^[31] due to reductions in MDA and improvements in the glutathione REDOX couplet (GSSG:GSH)^[30] and dose-dependent increases in the main antioxidant enzymes (Catalase, SOD, and glutathione peroxidase) have been noted to correlate with the antihypertensive effect.^[30] These protective effects have been linked to sulfur dioxide,^[32] and may be secondary to increasing sulfur status of the body.

A study investigating correlations between levels of C-Reactive protein and dietary supplements has failed to find a link between MSM supplementation and any influence on C-RP.^[33]

In vitro, DSMO shows general antiinflammatory properties by inhibiting the secretion of cytokines (IL-6 and TNF-α) and COX-2 induction in response to lipopolysaccharide^[36] and in chondrocytes.^[37] This has been noted with MSM as well in isolated macrophages stimulated with LPS.^[38]

MSM has been noted in rats fed 0.06 or 0.6g/kg MSM daily for 13 weeks to dose-dependent reduce total arthritic symptoms and markers of damage without altering osteophytes (and synovial hypertrophy decreased equally in both groups).^[39]

Appears to have general anti-inflammatory properties in standard macrophage testing

Sulfur is a component of cartilage^[40] and its provision to persons with poor dietary sulfur intake is thought to exert a protective effect on cartilage as an independent predictor of joint health.^[31] This is a possible explanation for why glucosamine appears to be more effective as sulfate relative to its other form (hydrochloride), as although sulfur (as sulfate) is used for providing a negative ion for proteoglycans to trap water in a cartilage matrix^[41] this may only be relevant when a sulfur deficiency is corrected.^[42]

Additionally, if sulfur is the main bioactive of concern then the benefits observed with MSM supplementation can be mimicked with other sulfur containing compounds such as the sulfur containing amino acids Cysteine and Methionine (in high levels in whey protein) or supplemental N-Acetylcysteine.

A possible theory for the joint health effects of MSM is through provision of dietary sulfur, as a deficiency of sulfur has been linked to joint complications and attenuating a deficiency can explain the wide range of variability seen with sulfur containing joint supplements (as well as explain how glucosamine sulfate works, but hydrochloride does not)

In 55 persons with allergic rhinitus (stuffed nose from allergies) given 2600mg MSM supplementation in an open-label trial for one month, allergic symptoms and respiratory complications were reduced by day 7 with symptoms reduction increasing at day 14 (not much more benefit between day 14 and 30) with no alterations in plasma IgE and histamine when subgroups were sampled; the potency was approximately 20-40% symptoms reduction (SASQ) but was not quantified.^[43] This study was initially criticized for not providing enough information (pollen related counts)^[44] which was later provided.^[45]

Potential usage as an anti-allergic compound, but this currently does not have blinded tested (lone trial was open-label without control group) and is not compared to a reference drug; it is currently impossible to assess the potency of MSM supplementation in allergy symptom reduction against other compounds

3,000mg of MSM daily for 30 days in moderately active men is able to reduce muscle soreness (DOMS) by 1.5 points on a 5-point Likert scale when measured 48 hours after exercise, with 1,500mg being less effective (0.5 points) and not statistically significant; this study failed to note any changes in work volume or fatigue^[46] and may be related to the demonstrated antioxidant capacity of MSM supplementation (50mg/kg in this study) which reduces markers of muscle damage^[47] as well as both lipid peroxidation and protein carbonylation.^[48]

May be able to attenuate delayed onset muscle soreness (DOMS) slightly

One trial has been conducted pairing hydrolyzed collagen, Arginine (as L-alpha-ketoglutarate), bromelain, and MSM in a model of rotator cuff injury for daily supplementation over 6 months; combination therapy was more effective than control in improving repair integrity and pain after the trial ended, although did not assess healing rates.^[49]

Insufficient evidence to suggest the role MSM may play in joint recovery

4-6g of MSM have been used in studies^[50][51] with some reports noting that up to 20g have been used (not in clinical trials).^[6] On a body weight basis, the recommendation (non-legitimate, but recommended by supplement manufacturers) tends to be around 0.06g/kg and appears to be safe at even 10-fold this dose (although 100-fold, or a 6g/kg human equivalent, was toxic).^[39]

One systemic review^[6] was able to find two trials assessing the interactions of MSM and osteoarthritis, with one study using 1500mg MSM (either in isolation or with 1500mg glucosamine) daily for 12 weeks; although the primary outcome measure (3 point reduction on the Lequesne Index) was not reported, there appeared to be more pain reduction with all treatment groups relative to placebo with no significant differences between glucosamine and MSM.^[51] Another trial using a higher dose of MSM (2g daily for 2 weeks followed by 6g for 10 weeks) confirmed pain reducing effects associated with MSM^[50] and a trial using 3.375g MSM for 12 weeks in persons with knee osteoarthritis noted 20% symptoms reduction with MSM (placebo down 14%) and 21% less pain while placebo increased 9%.^[52]

The review^[6] noted that the magnitude of benefit seen with high dose MSM (VAS rating scale reduction of 13.6mm^[50]) is less than the pharmaceutical Celecoxib (28.6mm^[53]) and also notes that this pilot study was underpowered. The trial not covered in the review^[52] had a similar magnitude of pain reduction (15mm total symptoms), and all studies with MSM note high variability and confidence intervals.

Other trials using MSM for arthritis-related pathology noted that 5g MSM paired with 7.2mg boswellic acids (bioactives of boswellia serrata) failed to outperform placebo for symptoms reduction yet reduced the need for pain killer usage (suggestive of limited efficacy)^[54]

Currently, although there is promise associated with MSM treatment in osteoarthritis there does not appear to be any indication that it is better than other options (Celecoxib, glucosamine, acetominophen). MSM supplementation shows the same variability and effect size as glucosamine sulfate, but with less overall evidence

In osteoblasts, provision of MSM to the cell culture increased the protein content of the IGF-1 and growth hormone receptors (inhibited by AG490 (Tyrphostin B42) and thus thought to be via the Jak2/STAT5b pathway) which subsequently increased genomic activity of these receptors in a concentration dependent manner up to 20mM.^[55] MSM was then confirmed to promote osteoclastic differentiation of mesenchymal cells, with the biomarker of ALP increasing to around 220% of control levels.^[55]

When rats are fed 0.06-0.6g/kg MSM daily for 13 weeks, there is no significant effect on bone mineral density; 6g/kg reduced bone growth secondary to toxicity.^[39]

MSM, in vitro, shows general cytotoxic effects on cancer cells including gastrointestinal cells (IC₅₀ between 21.07-28.04mg/mL^[56]), breast (MDA-MB 231; IC₅₀ 300mM^[57]), and melanoma (Cloudman S-91).^[58]

MSM has been shown to have anti-cancer effects in breast cancer cells in a concentration dependent manner (IC₅₀ of 300mM in MDA-MB 231 cells in regards to inducing apoptosis) by downregulating STAT3 (and reducing subsequent binding to the angiogenic VEGF promoter sites) and both downregulating and inhibiting phosphorylation of STAT5b (and subsequent binding to the IGF-1R receptor) with other downregulations including Brk/PTK6 and HIF1-α.^[57] Inhibition of IGF-1 signalling, due to IGF-1 being a potent mitogen in breast cancer cells,^[59][60] is thought to underlie reductions in tumor size and proliferation.^[57]

It was later noted in animals implanted with tumors (MDA-MB 231 cells) that MSM (given 2 weeks after tumor inoculation for 30 days) at 3-5% of a 100μL drink experienced slightly dose-dependent reductions in tumor size with the diameter of the tumor being reduced to 43% of baseline and overall growth reduced 70%;^[57] inhibition of IGF-1 signalling in these cancer cells was confirmed in vivo,^[57] and this mechanism is the direct opposite of that observed in healthy bone cells where STAT5 signalling downstream of GH is enhanced.^[55]

In breast cancer cells, appears to downregulate IGF-1 signalling via STAT proteins which confers anti-tumor effects; these have been confirmed in mice following oral ingestion of MSM

A study conducted in Cloudman S-91 (M3) murine melanoma cells with 200-400mM MSM incubation over 96 hours noted that exerted general anti-cancer effects (potent inhibition of DNA synthesis and reduction of cell contact, migration, and proliferation) and appeared to fully reverse the anchorage-independence of melanoma cells.^[58] These effects were transient rather than curative (normalizing upon removal of MSM, reoccurring with reintroduction) and after two weeks of incubation induced senesence in all melanoma cells (senesence is normally reduced in cancer cells^[61] and is sometimes a chemotherapeutic target goal^[62][63]) which then took on a melanocyte phenotype.^[58]

Limited evidence with MSM in Melanoma, but the lone in vitro study is actually remarkable in its effect size (200mM fully inducing sensence in cancer cells in 2 weeks) and very novel among supplements. This topic requires further research to see if the promise holds in vivo

Oral intake of MSM in rats with colitis (400mg/kg) for four days was able to increase antioxidative parameters (enzymes and lipid peroxidation biomarker of MDA) and benefit histological examination (about halfway to control) of the tissue, and was noted to reduce levels of both TNF-α and IL-1β (inflammatory cytokines) relative to disease control with the former being fully normalized and the latter trending to such.^[64]

Possible protective effects on acetic-acid induced ulcerative colitis in the rat, but although a high oral dose was used the protective effects were rather impressive. Requires replication in humans, and MSM may have a role in treating inflammatory bowel diseases

MSM is commonly used alongside other compounds in topical creams or gels^{[65][66][67][68]} due to structural similarity to DMSO, which is a potent absorption enhancer.^[69][70] DMSO tends to enhance absorption in a concentration dependent manner with 60% of a solution containing DMSO allowing most compounds to reach the stratum corneum within a few minutes to hours,^[71][72] although this concentration dependent relationship seems to be associated with skin irritability and possible toxicity issues/structural changes at higher concentrations^[73][74] which led to disuse of DSMO.^[75]

MSM is thought to be a better alternative due to it being more polar and less reactive,^[76] and MSM itself has shown this permeability enhancement (5.6% of solution) when in combination with the mineral chelator EDTA (2.6% of solution);^[76] this combination has been confirmed in at least one human study to be more effective than either EDTA or MSM alone^[65] which is notable as previous studies were in retinal tissue^[76][77] and this absorption enhancement does not appear to discriminate.

When measuring EDTA in plasma, the serum concentration reached with EDTA in isolation (19.9nM) was noted to be enhanced to 60μM; a 3000-fold enhancement with only 5-fold more EDTA concentration.^[76] In vitro testing suggests that MSM shows similar concentration-dependent absorption enhancement as DSMO (in the range of 27-54mg/mL with 2.7mg/mL not being highly effective^[76]). Currently, no comparative studies between DSMO and MSM can be located to assess potency.

MSM may have a role in protecting the skin (currently unexplored, but theoretical due to the antioxidant properties and bioaccumulation) but currently preliminary evidence suggests that it may play a role in enhancing absorption of other topically applied agents.

90 days of 1500mg/kg of MSM has failed to exert any toxic clinical or biochemical signs in rats^[78] and 1000mg/kg bodyweight MSM to pregnant rats has failed to exert teratogenic effects to pups.^[79] It has been noted that these doses correlate to 30-42g in humans^[6] which suggest a safety buffer associated with MSM supplementation. Side effects noted in human trials are limited to gastrointestinal upset, allergy, and skin rashes which do not appear to be to a clinically relevant degree.^[6]