Glucosamine or MSM: what's the difference

Glucosamine and MSM are the two most popular ingredients in “joint” supplements, and they are often sold in the same jar. But in chemical nature, presumed mechanism and volume of research these are very different substances. Our editorial team examined what distinguishes glucosamine from methylsulfonylmethane and how well-founded the expectations of each are.

What glucosamine and MSM are

Glucosamine is an amino sugar — that is, a glucose molecule in which one hydroxyl group is replaced by an amino group. In the body it is formed from glucose and glutamine and is the starting material for the synthesis of glycosaminoglycans — long polysaccharides that are part of cartilage, tendons and synovial fluid.

For supplements, glucosamine is obtained mainly from the shells of crustaceans (shrimp, crabs) or by fermentation of corn raw material. There are two main salts on the market: glucosamine sulphate (usually stabilised with sodium or potassium chloride) and glucosamine hydrochloride. This difference turned out to be important for interpreting studies.

MSM, or methylsulfonylmethane (dimethyl sulfone), is a simple organic sulphur compound: a sulphur atom to which two methyl groups and two oxygen atoms are attached. In small amounts MSM occurs in plants, milk and coffee, and in the human body it is also formed as a metabolite of dimethyl sulfoxide (DMSO).

So glucosamine is a “building” precursor of the cartilage matrix, whereas MSM is a sulphur donor and a low-molecular-weight compound with a presumed anti-inflammatory action. The former has a long history of clinical study; the latter has been studied much less.

Presumed mechanisms of action

The logic behind using glucosamine is simple: if cartilage is made of glycosaminoglycans, and glucosamine is their precursor, then additional intake may support matrix synthesis. Laboratory studies also describe glucosamine's ability to inhibit some pro-inflammatory signalling pathways (in particular NF-κB) and enzymes that destroy cartilage.

However, the concentrations used in cell cultures often greatly exceed those achieved in plasma after ordinary doses. So a mechanism that is convincing “in the test tube” is not necessarily reproduced in humans.

Several mechanisms have been proposed for MSM: supplying sulphur for the synthesis of sulphur-containing amino acids and compounds (in particular glutathione), inhibiting the activation of NF-κB and the production of pro-inflammatory cytokines, and antioxidant effects. The review by Butawan and colleagues (2017) describes these hypotheses in detail, but most of the data were obtained in cells and animals.

Importantly, sulphur in the human diet comes mainly from proteins (methionine, cysteine), so the “sulphur deficiency” sometimes mentioned in MSM advertising is not confirmed in people with adequate protein intake.

The evidence base: from large trials to pilots

Glucosamine has been studied in dozens of randomised trials, and the results turned out to be contradictory. In the two-year study by Reginster and colleagues (2001), published in the Lancet, crystalline glucosamine sulphate (1500 mg per day) slowed the narrowing of the joint space in the knee compared with placebo.

By contrast, the large American GAIT trial (Clegg et al., 2006) with glucosamine hydrochloride showed no significant advantage over placebo for pain in the overall group of patients with knee osteoarthritis. The network meta-analysis by Wandel and colleagues (2010) in the BMJ also concluded that there is no clinically significant difference from placebo.

Part of the discrepancy is explained by the different glucosamine salts, study designs and sources of funding: more positive results were more often obtained in studies of prescription crystalline sulphate.

The evidence base for MSM is much more modest. The pilot randomised study by Kim and colleagues (2006) with 6 g of MSM per day for 12 weeks in patients with knee osteoarthritis showed a reduction in pain and an improvement in function compared with placebo, but there were few participants. Usha and Naidu (2004) compared glucosamine, MSM and their combination and reported an effect of each of them and a somewhat greater one for the combination.

So for glucosamine we have a large but contradictory body of data; for MSM there are encouraging but small studies that require confirmation.

Safety, tolerability and interactions

Glucosamine is generally well tolerated. The most common adverse effects are digestive upsets: nausea, heartburn, diarrhoea or constipation. People allergic to seafood should choose glucosamine of non-crustacean origin or consult a doctor.

A possible enhancement of warfarin's effect while taking glucosamine has been described, so patients on anticoagulants need caution and INR monitoring. Earlier there were concerns about an effect on blood glucose, but in studies at ordinary doses no clinically significant effect was found in most cases; people with diabetes should nonetheless monitor their glycaemia.

MSM turned out to be of low toxicity in studies. In people the most common reports are of mild stomach discomfort, bloating, headache or sleep disturbance. Butawan and colleagues note that in studies of MSM at doses up to several grams per day no serious adverse events were described.

There are insufficient data on the safety of both substances during pregnancy and breastfeeding, so during this period it is better to refrain from taking them unless a doctor advises otherwise.

A comparison table and the position of guidelines

Clinical guidelines assess these supplements cautiously. The American College of Rheumatology, in its 2019 guidelines, strongly recommends against glucosamine in osteoarthritis of the knee, hip and hand joints. OARSI (2019) also does not recommend glucosamine for the treatment of knee osteoarthritis.

The European society ESCEO takes a different position: in its 2019 algorithm it considers prescription crystalline glucosamine sulphate as a possible agent for the baseline therapy of knee osteoarthritis, emphasising that the data cannot be transferred to other forms of glucosamine.

MSM is not separately recommended in major osteoarthritis clinical guidelines: there is insufficient evidence for that.

Editorial conclusions

Glucosamine and MSM differ in chemical nature and presumed mechanism: the first is a precursor of the cartilage matrix, the second a sulphur donor with a hypothetical anti-inflammatory action.

For glucosamine a large but contradictory body of research has accumulated, and the form (sulphate or hydrochloride) matters. For MSM the data are encouraging but limited by small studies.

Neither substance is a “medicine for cartilage”, and the effects, if any, are moderate.

To make a practical choice, read our article “Glucosamine vs MSM: what to choose and for whom”, as well as pieces on chondroitin and on exercises for knee osteoarthritis.

References

1. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet. 2001;357(9252):251–256.
2. Clegg DO, Reda DJ, Harris CL, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med. 2006;354(8):795–808.
3. Wandel S, Jüni P, Tendal B, et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. BMJ. 2010;341:c4675.
4. Kim LS, Axelrod LJ, Howard P, et al. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis Cartilage. 2006;14(3):286–294.
5. Usha PR, Naidu MUR. Randomised, double-blind, parallel, placebo-controlled study of oral glucosamine, methylsulfonylmethane and their combination in osteoarthritis. Clin Drug Investig. 2004;24(6):353–363.
6. Butawan M, Benjamin RL, Bloomer RJ. Methylsulfonylmethane: applications and safety of a novel dietary supplement. Nutrients. 2017;9(3):290.
7. Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the management of osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2020;72(2):149–162.
8. Bruyère O, Honvo G, Veronese N, et al. An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). Semin Arthritis Rheum. 2019;49(3):337–350.