Applications and Safety of Methylsulfonylmethane (MSM)

Methylsulfonylmethane: Applications and Safety of a Novel Dietary Supplement –  free full-text PMC5372953

Description and History of MSM

Methylsulfonylmethane (MSM) is a naturally occurring organosulfur compound. 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).

Throughout the mid-1950s to 1970s, DMSO was extensively studied for its unique biological properties including its membrane penetrability with and without the co-transport of other agents,

  • its antioxidant capabilities,
  • its anti-inflammatory effects,
  • its anticholinesterase activity, and
  • its ability to induce histamine release from mast cells 

In the late 1970s, Crown Zellerbach Corporation chemists, Dr. Robert Herschler and Dr. Stanley Jacob of the Oregon Health and Science University, began experimenting with the odorless MSM in search of similar therapeutic uses to DMSO

1.1. MSM Synthesis—The Sulfur Cycle

MSM is a member of the methyl-S-methane compounds within the Earth’s sulfur cycle.

1.2. Absorption and Bioavailability

In rats, between 59% and 79% of MSM is excreted the same day as administration in urine,

MSM is a common metabolite with a steady state concentration dependent upon an assortment of individual-specific factor

In a recent human study involving daily ingestion of MSM at 3 g by 20 healthy men for a period of four weeks, it was noted that serum MSM was elevated in all men following ingestion, with a further increase at week 4 versus week 2 in the majority of men.

These data indicate that oral MSM is absorbed by healthy adults and accumulates over time with chronic intake.

2. 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

2.1. Anti-Inflammation

In vitro 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.

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.

 \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 prostanoids2.2. Antioxidant/Free-Radical Scavenging

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; for that reason, it was proposed that the antioxidant mechanism acts on the mitochondria rather than at the chemical level.

As mentioned previously, MSM can inhibit NF-κB transcriptional activity and thus reduce the expression of enzymes and cytokines involved in ROS production.

2.3. Immune Modulation

Stress 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. 

Through an integrated mechanism including those mentioned above, MSM modulates the immune response through the crosstalk between oxidative stress and inflammation.

2.4. Sulfur Donor/Methylation

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

3. Common Uses

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.

3.1. Arthritis and Inflammation

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.

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

Clinical trials suggest MSM is effective in reducing pain, as indicated by the VAS pain scale

MSM in combination with glucosamine potentiated the improvements in pain, pain intensity, and swelling.

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

Additionally, MSM is also suggested to alleviate the symptoms of seasonal allergic rhinitis

the reduction in systemic exercise-induced inflammation by MSM has been observed

3.2. Cartilage Preservation

Cartilage degradation has long been thought of as the driving force of osteoarthritis

Pro-inflammatory cytokines, particularly IL-1β and TNF-α, are implicated in the destructive process of cartilage ECM.

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 and its possibly normalizing hypoxia-driven alterations to cellular metabolism

MSM supplementation in OA mice significantly decreased cartilage surface degeneration

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

3.3. Improve Range of Motion and Physical Function

With 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.

In studies with osteoarthritic populations given MSM daily, significant improvements in physical function were observed

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

3.4. 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.

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. 

This sounds promising, but with EDS, it’s the manufacturing process of collagen that is defective. No matter what materials we ingest for it, when our collagen is put together wrong, it will be less functional.

Endurance exercise-induced muscle damage was reduced with MSM supplementation, as measured by creatine kinas.

Pre-treatment with MSM reduced muscle soreness following strenuous resistance exercises and endurance exercise.

3.5. Reduce Oxidative Stress

In 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.

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

Combination therapies including MSM have become more popular recently, particularly with ethylenediaminetetraacetic acid (EDTA) due to the permeability enhancement provided by MSM

3.6. Improve Seasonal Allergies

In 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

All these improvements were maintained throughout the 30 days of supplementation.

3.7. Improve Skin Quality and Texture

MSM has been suggested to have therapeutic uses for the improvement of skin quality and texture by acting as a sulfur donor to keratin.

Skin appearance and condition after MSM treatment significantly improved as assessed by expert grading, instrumental analysis, and participant self-assessment

3.8. MSM and Cancer

An 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

MSM independently has been shown to be cytotoxic to cancer cells by inhibiting cell viability through the induction of cell cycle arrest

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.

In vitro studies with cancer cell lines suggest that MSM has the ability to stimulate phenotypic changes more closely resembling non-cancerous cells.

When cancer cells are xenotransplanted into animal models treated with MSM, tumor growth suppression has been observed

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

4. Safety Profile

under the Food and Drug Administration (FDA) GRAS notification, MSM is considered safe at dosages under 4845.6 mg/day

5. Conclusions

MSM 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 or metabolic syndromes


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