Dimethylsulfoxide (DMSO) and Methylsulfonylmethane (MSM) and for the Treatment of Arthritis
October 2000; Volume 3; 115-119
By Sharon L. Kolasinski, MD, FACP, FACR
Methylsulfonylmethane (msm) has enjoyed a recent surge in interest as an arthritis remedy. This follows the 1999 publication of The Miracle of MSM1 as well as recent media attention to actor James Coburn, who publicly offered his personal testimonial as to MSM’s efficacy for his rheumatoid arthritis (RA). Similar anecdotes can be found on some of the more than 800 Web sites devoted to MSM, but most of these sites simply offer home delivery of MSM tablets or lotions. Vendors market MSM for a variety of conditions, including RA, osteoarthritis (OA), fibromyalgia, gout, constipation, allergies, dyspepsia, parasitic infections, cancer prevention, and snoring. However, clinical data of any sort regarding its appropriate indications or use are distinctly lacking.
Historical Perspective
MSM is an odorless, white, crystalline, water-soluble powder that is the irreversible oxidation product of dimethylsulfoxide (DMSO). MSM is also known as crystalline DMSO and dimethyl sulfone.
DMSO has had its own checkered history as an arthritis treatment. First synthesized in the mid-1800s, it became widely available by 1940 as an industrial solvent. Used as a veterinary liniment into the 1960s, DMSO was adopted by up to 100,000 humans for various arthritides. After being linked to ocular toxicity in experimental animals, the FDA halted human use, and only permitted gradual resumption of clinical trials after the ocular complaints were not found in humans. The FDA also attempted to restrict the use of DMSO to less than two weeks when used for acute musculoskeletal conditions.
A leading figure in the use and promotion of DMSO and MSM is Stanley Jacob, MD, of the Oregon Health Sciences University in Portland, OR.2 Jacob was involved in early research efforts concerning the use of DMSO as a preservative in transplantation. Subsequently, he found that DMSO was metabolized to MSM, and he contends that it shares some of the same properties as DMSO. However, there are no peer-reviewed articles to substantiate this claim. A search of MEDLINE and PubMed failed to disclose any peer-reviewed publications by Jacob on these substances. Jacob serves as medical director for a company that produces and sells MSM.3
DMSO is now found in paint thinners and antifreeze. It is available in health food stores and other retail outlets as a topical preparation for arthritis. However, these commercial products may contain impurities since they are industrial grade, rather than formulated for human use. DMSO’s only FDA-approved medical use is for intravesicular instillation for interstitial cystitis. A pharmaceutical-grade liquid is available by prescription. A topical preparation combining DMSO and the non-steroidal anti-inflammatory drug, diclofenac, currently is under consideration by the FDA. However, anecdotal reports of adverse reactions by arthritis patients using industrial-grade DMSO have contributed to a decline in its use. It remains popular in Russia and some European countries for the treatment of pain caused by OA and RA. Most use remains topical, but it has been given orally and intravenously as well. While DMSO remains in use, MSM has been marketed as an oral alternative, despite the lack of laboratory or clinical trials comparing the two.
Mechanism of Action
The biochemical relationship of MSM to DMSO has led to the suggestion that the two might work in a similar manner. Laboratory studies in the 1960s showed that DMSO was detectable in the blood within five minutes of topical application and persisted at a plateau level for 36-72 hours.4 Reported in vitro effects include free radical scavenging and reductions in prostaglandin production. Results in adjuvant arthritis models have been contradictory, but where they have been positive, topical use was more effective than oral administration for treating inflammation. More recent reports suggest, however, that a clinically meaningful anti-inflammatory effect is unlikely.5,6 In animal models, topical DMSO has been shown to reduce C fiber nerve conduction, consistent with its purported analgesic effect.4 An interesting recent report of the effects of topical application of DMSO to equine cartilage explants showed that prostaglandin synthesis and release were inhibited in a dose- and time-dependent fashion. Chondrocyte viability was not affected. The authors cautioned that cartilage matrix metabolism may be affected adversely by direct exposure to DMSO when DMSO is added to intraarticular lavage solutions.7
According to Jacob, about 15% of DMSO is metabolized to MSM (August 2000); it is unclear how many of the properties of DMSO can be attributed to MSM. According to Jacob, MSM does not share the potent free-radical scavenger properties of DMSO. MSM may act as a sulfur donor in amino acid metabolism, based on a study demonstrating incorporation of radiolabeled sulfur into methionine and cysteine in guinea pigs after oral administration of 35S-MSM (radiolabeled sulfur MSM).8 However, the role of dietary sulfur supplementation in the treatment of arthritis or other diseases is unclear.
One abstract has reported on a reduction in synovial proliferation in DMSO- and MSM-treated MLR-lpr mice that are prone to develop a lupus-like autoimmune disease.9 Fewer mice treated with solutions of either DMSO or MSM showed the severe histological changes associated with inflammatory arthritis than those receiving plain water, but no statistical analysis of these results was performed.
No peer-reviewed data exist to support claims that MSM protects or repairs cartilage or alters the progression of cartilage damage related to arthritis. Little laboratory evidence supports claims of anti-inflammatory or immunological mechanisms of action.
Clinical Studies
Numerous clinical trials in the 1960s examined DMSO for the treatment of musculoskeletal conditions. A synthesis of reports from 76 clinical trials involving approximately 1,900 patients was published in the Annals of the New York Academy of Sciences.10 Each trial used a 90% DMSO/10% water solution for topical use and concentrated on one of several categories of clinical presentations (sprain, bursitis, strain, trauma, myositis, tenosynovitis, neuritis, muscle spasm, arthritis) for treatment. The length of treatment was generally days to weeks. These results were reported for "acute" and "chronic" patients as a group.
About 80-85% of acute patients responded in pain, swelling, range of motion, stiffness, and tenderness; 65% responded in grip strength. About 65-70% of chronic patients responded in all categories except grip strength, where 51% responded. Response was excellent in 46% of acute patients and in 24% of chronic patients.
Of the 1,900 patients evaluated, 530 experienced side effects. All but 74 of these patients reported cutaneous complaints—burning, erythema, "roughness," pruritis, blistering, "dermatitis," desquamation, and edema. However, only 69 of the 530 affected patients discontinued therapy because of these side effects. Additional reported side effects included shooting pain at the application site, localized urticaria, dizziness, trembling, headache, increased urinary frequency, and acne.
The difficulties with interpreting these data are substantial. The clinical categories are vague (e.g., "sprain" and "strain") and do not conform to current standards of case definition. Patients within diagnostic categories are surely heterogeneous as a result. Furthermore, data are presented primarily for "acute" and "chronic" patients without any definition as to what that might mean. No entry criteria were specified. The outcome measures are completely subjective and not standardized, nor are they reproducible since they are undefined. There was no active or placebo control. Adverse reactions may have been underreported since "reports of side effects were not ordinarily elicited."
A second report in the Annals of the New York Academy of Sciences also reported on a large population of patients treated with topical DMSO.11 In this study of 4,180 orthopedic patients, diagnoses included trauma, soft tissue problems, OA, gout, and RA, as well as pain related to neuralgia, peripheral vascular disease, and metastases.
About 86% of patients with traumatic injuries responded to DMSO in a 90% solution applied for an unspecified amount of time. About half of patients with rheumatic diseases and 37% of patients with other conditions responded if "long-term" use was undertaken. Immediate results were reported to be "amazing" in bursitis. In this study, only 6.3% of patients experienced no cutaneous side effects, while about 7% had "severe" skin reactions. Interpretation of these data is constrained by the same considerations as noted above.
Subsequent double-blind, placebo-controlled trials of topical DMSO failed to show a difference between DMSO and a placebo ointment when used for RA12 or OA.13
Early anecdotes suggested that DMSO might be helpful for the treatment of scleroderma. However, a subsequent double-blind, prospective, controlled study by the Cooperating Clinics of the Cooperative Systematic Studies of Rheumatic Diseases Program of the American Rheumatism Association could not demonstrate efficacy.14
A single placebo-controlled trial of the use of MSM in OA has been published. In this report, MSM was given at a dose of 2,250 mg in divided doses vs. placebo. Pain reduction was reported in 80% of patients who received MSM for six weeks, compared to 18% of the placebo group.15 Although these data are positive, this was a single trial; randomized, double-blind, controlled trials of MSM are needed.
Adverse Effects
The expected results of topical application of DMSO include a skin reaction of erythema and warmth. This reaction may be severe. One of the most notable side effects of DMSO is the fact that even topical use can cause a foul taste in the mouth and a body odor reminiscent of garlic or oysters. This undoubtedly contributed to waning in its popularity, though it remains available in retail outlets and continues to be used. Because it has the ability to transport other substances transdermally, caution should be exercised with the use of DMSO and concomitant topical preparations. One case report documents the development of peripheral neuropathy in a patient who used DMSO in combination with sulindac.16
MSM occasionally has been associated with gastrointestinal upset, including diarrhea and abdominal cramping, which may be dose-related, but within the usual dose recommendations for treatment of arthritis (2-8 g/d). It does not, however, share the disagreeable skin irritant or odor-causing properties of DMSO.
Drug Interactions
No data exist on the potential interaction of sulfur-containing compounds like MSM or DMSO with other medications. Given that sulfur moieties may be highly reactive, appropriate caution is advised.
Formulation
DMSO is available in pharmaceutical grade by prescription. Sold under the brand name Rimso-50® from Research Medical, it comes in as a 50% aqueous solution in a 50 ml vial ready for use. For interstitial cystitis, it is instilled in the bladder for 15 minutes and treatment may be repeated in two weeks. Prescription DMSO is modified for use by practitioners for mostly topical but occasionally oral or intravenous administration depending on the condition to be treated. DMSO is sold in industrial grade in retail stores and on the Internet as a liquid or gel. All use of this grade is topical.
Although MSM does occur naturally in fresh fruits and vegetables, milk, fish, and grains, commercially available preparations are synthesized from DMSO.
MSM is available in retail outlets and on the Internet as powder, tablets, or in topical preparations, including eyedrops. Powder delivers 4 g/teaspoon MSM. Tablets are generally 500-1,000 mg each. MSM also is found in a variety of oral preparations that may contain other ingredients aimed at treating arthritis and musculoskeletal complaints, such as glucosamine sulfate and chondroitin sulfate. Dose recommendations range from 500 mg/d for migraine to 6,000 mg/d for more severe problems. (See Table 1.)
| Table 1-Dimethylsulfoxide (DMSO) and methylsulfonylmethane (MSM) price and formulation comparison | |||
| Manufacturer/Product | Formulation per Serving | Manufacturer's Recommended Dose | Price/Quantity |
| GNC MSM 1000 | 1,000 mg MSM, potency verified by GNP procedure #5405, meets USP weight and disintegration requirements |
1-3 capsules/d | $31.99/180 capsules |
| Trimedica Prodaptive MSM | 1,000 mg MSM | 1-3 capsules/d | $23.99/120 capsules |
| DMSO Gel | 70% DMSO, 30% distilled water | not sold for medicinal purposes | $21.65/16 oz |
| Natrol MSM | 500 mg MSM | 1 capsule tid with meals | $17.99/200 capsules |
| GNC MSM Plus | 1,500 mg MSM, 500 mg D-Glucosamine sulfate |
2 tablets/d | $14.99/60 tablets |
| PharmAssure MSM Plex | 500 mg MSM, 500 mg D-Glucosamine | 1-3 capsules/d | $14.99/60 capsules |
| Balanced Joint Support | sulfate, potency verified by GNP procedure | ||
| Formula | #5405, meets USP weight and disintegration requirements |
||
| Nourish MSM Creme | Liposome contains 4% MSM | apply to affected areas 3-4 times/d |
$12.99/2 oz |
| Source: online mail-order companies | |||
Conclusion
DMSO remains available worldwide and is approved for use in arthritis in a number of countries. However, over-the-counter preparations in the United States are graded for industrial use and may contain impurities. A pharmacological grade solution is available by prescription and approved for intravesicular use for interstitial cystitis. Decades-old, uncontrolled clinical observations suggest that topical application can be associated with analgesia for a number of musculoskeletal indications, but associated cutaneous side effects may be frequent.
MSM is a popular substance for the treatment of numerous conditions, but recent interest has been for the treatment of musculoskeletal conditions. It is chemically related to DMSO, which enjoyed its own popularity as a cure-all in the 1960s, but has fallen into disuse. It is unclear how many chemical and biological properties MSM shares with DMSO. Scientifically acceptable data about the use of these substances in the treatment of human disease are lacking. Virtually no information is available regarding in vitro or clinical effects of MSM.
Recommendation
Since all non-prescription DMSO is specifically graded for other than human use, it should be avoided. Prescription DMSO should be used under medical supervision and patients should be aware that side effects are frequent. Patients should be made aware that transdermal transport of other topical agents can occur in the presence of DMSO. Since it is not known what effects MSM has in the body, whether it has efficacy in the treatment of human disease, or what its short- or long-term side effects are, MSM cannot be recommended for use at this time.
Dr. Kolasinski is Assistant Professor of Medicine; Director, Rheumatology Fellowship Program; and Chief of Clinical Service, Division of Rheumatology at the University of Pennsylvania School of Medicine in Philadelphia.
References
1. Jacob SW, et al. The Miracle of MSM. New York: Putnam; 1999.
2. Jacob SW, Herschler R. Dimethyl sulfoxide after twenty years. Ann N Y Acad Sci 1983;411:xiii-xvii.
3. Horstman J. MSM and DMSO. Arthritis Today 1999;52-54.
4. Jimenez RA, Willkens RF. Dimethyl sulfoxide: A perspective of its use in rheumatic diseases. J Lab Clin Med 1982;100:489-500.
5. Bennett RM, et al. Dimethyl sulfoxide does not suppress an experimental model of arthritis in rabbits. J Rheumatol 1983;10:533-538.
6. Trentham DE, Rowland D. Dimethyl sulfoxide does not suppress the clinical manifestations of collagen arthritis. J Rheumatol 1983;10:114-116.
7. Smith CL, et al. In vitro evaluation of the effect of dimethyl sulfoxide on equine articular cartilage matrix metabolism. Vet Surg 2000;29:347-357.
8. Richmond VL. Incorporation of methylsulfonylmethane sulfur into guinea pig serum proteins. Life Sciences 1986;39:263-268.
9. Moore RD, Moore JI. Diminished inflammatory joint disease in MRL-lpr mice ingesting dimethyl sulfoxide (DMSO) or dimethylsulfone (MSM). Federation of American Societies for Experimental Biology Annual Meeting; April 1985:692.
10. Demos CH, et al. DMSO in musculoskeletal disorders. Annals N Y Acad Sci 1967;141:517-522.
11. John H, Laudahn G. Clinical experiences with the topical application of DMSO in orthopedic diseases: Evaluation of 4180 cases. Annals N Y Acad Sci 1967;141:506-516.
12. Vuopala U, et al. Dimethyl sulfoxide (DMSO) ointment in the treatment of rheumatoid arthritis. Acta Rheumatol Scand 1969;15:139-144.
13. Vuopala U, et al. The analgesic action of dimethyl sulfoxide (DMSO) ointment in arthrosis. Acta Rheumatol Scand 1971;17:57-60.
14. Williams HJ, et al. Double-blind, multicenter controlled trial comparing topical dimethyl sulfoxide and normal saline for treatment of hand ulcers in patients with systemic sclerosis. Arthritis Rheum 1985;28:308-314.
15. Lawrence RM. Methylsulfonylmethane: A double blind study of its use in degenerative arthritis. Int J Anti-Aging Med 1998;1:50.
16. Reinstein L, et al. Peripheral neuropathy after concomitant dimethyl sulfoxide use and sulindac therapy. Arch Phys Med Rehabil 1982;63:581-584.
October 2000; Volume 3; 115-119
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