Myopathies associated with red yeast rice and liquorice: spontaneous reports from the Italian Surveillance System of Natural Health Products

Many drugs can be responsible for muscle injuries. Besides statins, recognised as the drugs most commonly associated with severe myopathies, other medications such as neuroleptics, proton pump inhibitors and recently gabapentin [1] have been associated with this type of adverse drug reaction (ADR).

Recent case reports have highlighted that active compounds from medicinal plants can also be responsible for myopathies [2, 3], including rhabdomyolysis but a systematic evaluation of reporting databases is still lacking.

In the present study, the Italian ADR database [4, 5] of natural health products was analyzed with the aim of evaluating the possible ‘signal alarms’ due to herbal medicines and muscle injuries. A panel of experts, including a medical toxicologist, a pharmacist and a physician expert in herbal medicine reviewed all reports of myopathy to define the causality assessment using the Naranjo probability scale [6].

From April 2002 to December 2007, nine reports of muscle disorders were identified, of which seven were reported by phytotherapy specialists, one by a hospital physician, and one by a general practitioner. As shown in Table 1 most disorders (7/9) were due to red yeast rice (Monascus purpureus) (n = 4) and liquorice (n = 3) (Glycyrrhiza glabra). In all reports Monascus purpureus was used to treat hypercholesterolaemia, and all events were assessed as ‘probable’, according to the Naranjo probability scale; all cases showed increased concentrations of serum creatinine phosphokinase (CPK) and their onset varied from 2 to 6 months. One of the patients reported previous statin intolerance, while the one who showed the highest increase in CPK (401 IU l⁻¹; normal range 24–195 IU l⁻¹) reported concurrent muscle pain. In the latter case the ADR did not resolve after discontinuation of red yeast rice.

Table 1.

Reports of myopathies associated with use of herbal drugs

Sex, age (years)	Product; dosage; indication	Concomitant medications and notes	Reported ADRs; time to onset	Action taken; outcome
F, 53	Colestat®, contains red yeast rice (Monascus purpureus); 1 tablet a day; hypercholesterolaemia	None	Increase of CPK§ (288 IU l−1), ALT and AST and GGT 2 months	Drug withdrawn; complete recovery
M, 49	Statinat crinos®, contains red yeast rice (Monascus purpureus); 5 mg, 1 tablet a day; hypercholesterolaemia	None	Increase of CPK§ (386 IU l−1), total cholesterol, ALT and AST; 2 months	Drug withdrawn; complete recovery
F, 43	Red yeast rice (Monascus purpureus) 400 mg, 1 tablet/3 times a day; hypercholesterolaemia	None	Increase of CPK§ (401 IU l−1), muscle pain; 6 months	Drug withdrawn; complete recovery
F, 60	Armolipid plus®, contains red yeast rice (Monascus purpureus 200 mg + berberine extract Berberis aristata 500 mg); 1 tablet a day; hypercholesterolaemia	None; statin-intolerant	Increase of CPK§ (356 IU l−1), AST# 37 IU l−1, ALT# 28 IU l−1; 6 months	Drug withdrawn; reaction unresolved
M, 30*	Liquorice, (Glycyrrhiza glabra); 30g day−1 orally; nutrient	None	Increase of CPK, rhabdomyolysis; 1 month	Drug withdrawn; complete recovery
M, 73*	Herbadulx regola®, contains liquorice (Glycyrrhiza glabra); 2 tablets a day; laxative	Simvastatin, atenolol, cardioaspirin, lansoprazole, ursodesossicolic acid, lisinopril, nitrodur (from 8 years)	Rhabdomyolysis, increase of CPK§ (8000 IU l−1), blood nitrogen† 6.0 mg dl−1; 20 days	Drug withdrawn; reaction unresolved
M, 81*	Liquorice (Glycyrrhiza glabra) concentrate juice; 2–3 g day−1, chronic hypotension	β-blockers, anxiolytics	Hypertension, hypokalaemia, hypernatraemia, increase of CPK, 3 months	Drug withdrawn, anthialdosterone therapy, supplementation; complete recovery

^#normal range: 10–35 IU l⁻¹;

^§normal range: 24–195 IU l⁻¹;

^†normal range: 0.2–6.0 mg dl⁻¹;

^*Hospitalization due to ADR. ADR, adverse drug reaction; ALT, alanine aminotrasferase; AST, glutaryl aminotransferase; CPK, creatinine phosphokinase; GGT, gamma glutaril transpeptidase; LDH, lactate dehydrogenase.

A case of rhabdomyolysis was diagnosed after 3 months of liquorice consumption (30–40 g day⁻¹) but signs and symptoms disappeared after dechallenge. Laboratory data were unavailable. Another patient presented with a remarkable increase in CPK (8000 IU l⁻¹) and blood nitrogen (6.0 mg dl⁻¹, normal range: 0.2–6.0 mg l⁻¹) after 20 days of self-administration of a laxative product containing liquorice. At a 6-month follow up, CPK concentrations were still elevated. Causality was assessed as ‘possible’ since the patient had undergone a previous 8-year consumption of simvastatin and lansoprazole, two drugs possibly associated with muscle injury. Although both drugs were stopped several weeks before the onset of rhabdomyolysis, their previous consumption was taken into account when assessing the causality relationship.

A case of hypertension, hypokalaemia, hypernatraemia and increased CPK was also reported after 3 months of liquorice juice consumption as self-medication for chronic hypotension. After dechallenge and anti-aldosterone treatment, the patient completely recovered. According to a WHO critical term list, all reports referring to liquorice consumption were classified as ‘serious’ due to hospital admission and two out of three reactions were assessed as ‘probable’. In two cases, symptoms completely resolved after product discontinuation.

Major alternative causes of muscle disorders, including alcohol abuse, illicit drug use, infections, metabolic, endocrine or inflammatory diseases were excluded in all seven patients.

We can confirm the recent ‘signal’ seen in the medical literature of case reports of muscle disorders associated with red yeast rice and liquorice through our analysis of the Italian national database of adverse reactions to natural health products. All reported cases of ADRs are biologically plausible and supported by preclinical and physiopathological rationale. For instance, chronic or acute liquorice use, through glycyrrhizic acid, is able to inhibit 11β-hydroxysteroid deydrogenase-2 impairing lipid metabolism in muscle cells [3], while Monascus purpureus contains mevalonic acid and Monacolin K, an agent that has the same structure and activity as lovastatin [2, 7].

Although some case reports [4, 8, 9] have already raised this concern, favourable attitudes towards herbal preparations are still strong in industrialized countries [10]. In the majority of the cases reported here, red yeast rice was used to treat dyslipidaemia, often as a self-medication, without a physician's and/or pharmacist's supervision. Many patients could therefore be exposing themselves dangerously to the additive effect of herbal and synthetic drugs, such as statins, whose potential adverse effect on muscle is well documented. Moreover, a previous statin intolerance constitutes a critical point for red yeast rice use; this should be taken into account by physicians when suggesting this kind of natural remedy to their patients, as well as by statin-intolerant patients seeking natural alternatives to synthetic drugs, who might be unaware of the real benefit–harm profile of these products.