Herb-Drug Interactions: Glucosamine

2-Amino-2-deoxy-beta-D-glucopyranose

Types, sources and related compounds

Chitosamine, Glucosamine hydrochloride, Glucosamine sulfate potassium chloride, Glucosamine sulfate sodium chloride.

Pharmacopoeias

Glucosamine Hydrochloride (US Ph 32); Glucosamine Sulfate Potassium Chloride (US Ph 32); Glucosamine Sulfate Sodium Chloride (US Ph 32); Glucosamine Tablets (The United States Ph 32).

Use and indications

Glucosamine is a natural substance found in chitin, mucoproteins and mucopolysaccharides. It can be made by the body, and is found in relatively high concentrations in cartilage, tendons and ligaments. The primary use of supplemental glucosamine is for the treatment of osteoarthritis and other joint disorders. It is sometimes given with chondroitin. Glucosamine in supplements may be prepared synthetically, or extracted from chitin.

Pharmacokinetics

The oral bioavailabihty of glucosamine has been estimated to be about 25 to 50%, probably due to first-pass metabolism in the liver. Glucosamine is rapidly absorbed and distributed into numerous tissues, with a particular affinity for articular cartilage.

Interactions overview

Glucosamine supplements have modestly increased the INR in a few patients taking warfarin. Increased blood-glucose has been recorded in patients with diabetes, but no interaction was found in a controlled study. Glucosamine might modestly increase tetracycline or oxytetracycline levels, and very limited evidence suggests that glucosamine may possibly decrease the efficacy of paracetamol and some cytotoxic antineoplastics. Unnamed diuretics may slightly reduce the efficacy of glucosamine.

Glucosamine + Antidiabetics

In a controlled study, glucosamine supplements with chondroitin had no effect on glycaemic control in patients taking oral antidiabetic drugs but one report notes that unexpected increases in blood-glucose levels have occurred.

Evidence, mechanism, importance and management

In 2000, the Canadian Adverse Drug Reaction Monitoring Programme (CADRMP) briefly reported that unexpected increases in blood-glucose levels had occurred in diabetic patients taking glucosamine sulfate, or glucosamine with chondroitin. However, in a well-controlled study, Cosamin DS (glucosamine hydrochloride 1.5 g daily with chondroitin sulfate sodium 1.2 g) daily for 90 days had no effect on the control of diabetes (glycosylated haemoglobin) in 22 patients with type 2 diabetes, 4 who were diet controlled and 18 who were receiving oral antidiabetics (specific drugs not named).

Endogenous glucosamine has a role in glucose metabolism, and may increase insulin resistance. In one case, glucosamine also reduced hypoglycaemic episodes in a patient with metastatic insulinoma.

The interaction is not established, and the results of the controlled study suggest that glucosamine supplements are generally unlikely to affect the control of diabetes. However, it has been suggested that the results of this study may not be applicable to patients in the later stages of diabetes (i.e. those with type 2 diabetes who require, or are expected to require, insulin). Therefore it may be prudent to increase monitoring of blood-glucose in these patients if glucosamine supplements are taken. Also, if glucose control unexpectedly deteriorates, bear the possibility of self-medication with supplements such as glucosamine in mind.

Glucosamine + Antineoplastics

The interaction between glucosamine and antineoplastics is based on experimental evidence only.

Clinical evidence

No interactions found

Experimental evidence

An in vitro study found that colon and ovary cancer cell lines showed resistance to doxorubicin and etoposide after exposure to glucosamine at a concentration of 10 mmol. Only a weak effect of glucosamine was found in the responsiveness of breast cancer cell lines to etoposide.

Mechanism

It is suggested that the expression of topoisomerase II was reduced by the presence of glucosamine. Topoisomerase II is required for doxorubicin and etoposide to exert their antineoplastic effects; therefore decreasing the levels of this enzyme increased the resistance to these antineoplastics.

Importance and management

This possible interaction appears not to have been studied in vivo and, until more data are available, the clinical significance of the findings is unclear. However, the implication is that glucosamine could reduce the efficacy of these antineoplastics. Bear this possibility in mind should an unexpected response to treatment with topoisomerase inhibitors occur.

Glucosamine + Diuretics

Limited evidence from a large open study suggests that unnamed diuretics may slightly reduce the efficacy of glucosamine.

Clinical evidence

In a large open study, 1183 evaluable patients with osteoarthritis were given glucosamine 1.5 g taken daily for an average of 50 days. The overall assessment of efficacy was ‘good’ in about 59% of patients and ‘sufficient’ in 36%. When response was analysed by concurrent treatment, in the 64 patients also taking diuretics (none specifically named), there was a slightly lower incidence of good efficacy (44%) and a slightly higher incidence of sufficient efficacy (52%), which reached statistical significance. However, note that this study was non-randomised, and other patient factors might therefore have accounted for these differences.

Experimental evidence

No relevant data found.

Mechanism

Unknown.

Importance and management

The concurrent use of glucosamine and diuretics is probably quite common, and the fact that this old study appears to be the only report in the literature of a possible interaction, and in itself inconclusive, suggests that any interaction is, in the main, unlikely to be clinically important.

Glucosamine + Food

No interactions found.

Glucosamine + Herbal medicines

No interactions found.

Glucosamine + Paracetamol (Acetaminophen)

Limited evidence suggests that glucosamine may reduce the efficacy of paracetamol (acetaminophen).

Evidence, mechanism, importance and management

In a survey of herbal medicine use in 122 patients from 6 outpatient clinics, 2 patients with osteoarthritis (a 66-year-old man and a 74-year-old woman), had complained of reduced paracetamol (acetaminophen) efficacy when starting glucosamine. The salt of glucosamine used was not mentioned.

It has been suggested that increased serum sulfate levels arising from glucosamine sulfate might lead to increased metabolism of paracetamol by sulfate conjugation. However, there are no studies assessing this. Note that this would only occur with glucosamine sulfate salts and would not occur with glucosamine hydrochloride.

The combined use of glucosamine and paracetamol to alleviate the symptoms of osteoarthritis is common, and the limited evidence here does not provide any reason to suggest any changes to this practice.

Glucosamine + Tetracyclines

Glucosamine modestly increases tetracycline levels.

Clinical evidence

A single-dose study in healthy subjects given tetracycline 250 mg alone or with glucosamine 250 mg found that the serum tetracycline levels were 105%, 50% and 25% higher at 2, 3 and 6 hours after administration, respectively, in those patients who had received the combined treatment. Similar results were found when oxytetracycline was given with glucosamine, with the corresponding increases being 36%, 44% and 30% at 2, 3 and 6 hours after administration, respectively. The AUC of the antibacterials was not reported.

In contrast, in another single-dose study in 12 healthy subjects given tetracycline 250 mg alone, and then with glucosamine 125 mg and 250 mg at 1-week intervals, the addition of glucosamine slightly increased serum tetracycline levels at 2, 3, 6 and 8 hours, but this was not statistically significant.

Experimental evidence

A study in dogs and mice found that giving glucosamine hydrochloride with radioactive oxytetracycline increased the serum radioactivity, suggesting an increase in serum oxytetracycline levels. In the dogs, the increase in radioactivity was over twofold at 30 minutes, 1 hour and 24 hours after drug administration, whereas in the mice the increase was only greater than twofold at 15 minutes after drug administration.

Mechanism

Unknown.

Importance and management

These very early studies from the 1950s suggest that glucosamine might cause a modest increase in tetracycline levels. As a result of these studies, it appears that a preparation of oxytetracycline formulated with glucosamine was tried. A modest increase in tetracycline or oxytetracycline levels is unlikely to have adverse consequences, and, if anything, might be slightly beneficial.

Glucosamine + Warfarin and related drugs

A few reports suggest that glucosamine with or without chondroitin may increase the INR in patients taking warfarin. In contrast, one case of a decreased INR has been reported when glucosamine was given with acenocoumarol.

Clinical evidence

The first indication of a possible interaction was in 2001, when the Canadian Adverse Drag Reaction Monitoring Program briefly reported that an increase in INR had been noted when glucosamine was given to patients taking warfarin, and that INR values decreased when glucosamine was stopped. In 2004, a full case report was published. In this case, a 69-year-old man stabilised on warfarin 47.5 mg weekly had an increase in his INR from 2.58 to 4.52 4 weeks after starting to take 6 capsules of Cosamin DS (glucosamine hydrochloride 500 mg, sodium chondroitin sulfate 400 mg, manganese ascorbate per capsule) daily. His warfarin dose was reduced to 40 mg weekly, and his INR returned to the target range of 2 to 3 (INR 2.15) with continued Cosamin DS therapy. A comment on this report noted that this is twice the usual dose of glucosamine. Since then, one other similar case of a modest rise in INR has been published. A man taking warfarin and glucosamine hydrochloride 500 mg with chondroitin sulfate 400 mg twice daily had a gradual increase in his INR (from 2.3 to 4.7 over 5 weeks) when he trebled the dose of the glucosamine supplement.

Analysis of regulatory authority data has revealed other unpublished reports. In 2006 the CHM in the UK reported that they had received 7 reports of an increase in INR in patients taking warfarin after they started taking glucosamine supplements. In 2007, a search of the FDA database identified 20 possible cases, and a search of the WHO database identified 22 possible case reports of an increase in warfarin effect with glucosamine, which originated from Australia, Canada, Denmark, Sweden, the UK and the USA. In two of the WHO cases, chondroitin was used, but the other cases were with glucosamine alone. Of 15 reports giving details of time to onset, the increased INR was noted within 3 days (in a 99 year old) and up to 6 months; most commonly the interaction took several weeks to manifest.

In contrast, a 71-year-old man stabilised on acenocoumarol 15 mg weekly had a decrease in his INR to 1.6 after taking glucosamine sulfate (Xicil) 1.5 g daily for 10 days. The glucosamine was stopped and the INR reached 2.1. When the glucosamine was restarted, with an increase in acenocoumarol dose to 17 mg weekly, the INR only reached 1.9. The glucosamine was eventually stopped. Similarly, the WHO database contained one report of a decreased effect of warfarin with glucosamine. The Australian Adverse Drag Reactions Advisory Committee have also identidied 12 cases of alterations in INR in patients taking warfarin. Nine of these cases are included in the WHO report.

There do not appear to have been any controlled studies of the effects of glucosamine supplements on the pharmacodynamics or pharmacokinetics of oral anticoagulants.

Experimental evidence

No relevant data found.

Mechanism

Unknown.

Importance and management

Glucosamine is a widely used supplement, particularly in the middle-aged and elderly, who are also the group most likely to be using warfarin or similar anticoagulants. Despite this, there are just three published reports of a possible interaction, two describing moderate rises in INR and one a decrease. Even taking into account the possible cases reported to regulatory authorities, the interaction would seem to be quite rare. Nevertheless, the cases described suggest that it would be prudent to monitor the INR more closely if glucosamine is started or stopped. Also, if a patient shows an unexpected change in INR, bear in mind the possibility of self-medication with supplements such as glucosamine.

Note that in 2006 the CHM in the UK recommend that patients taking warfarin do not take glucosamine, but the subsequent 2007 UK-approved labelling for the prescription-only glucosamine product Alateris recommends close monitoring when a patient taking a coumarin anticoagulant starts or stops glucosamine.