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Key words: red yeast rice, Monascus purpureus, hyper- is monacolin K, which has the same chemical structure as
lipidemia, myopathy, dietary supplement, lovastatin lovastatin. Although levels of lovastatin vary in the product,
2.4 g of red yeast rice daily may contain about 4.8 mg of lov-
ABSTRACT astatin, or 0.2% of the total dose. Red yeast rice supplements
Red yeast rice is a Chinese fermented rice product (Monas- may also contain isoflavonoids, monounsaturated fats, and
cus purpureus) that some have claimed improves blood circu- sterols that help to reduce cholesterol levels even further.3
lation by decreasing cholesterol and triglyceride levels in hu- The natural inclusion of low-dose lovastatin raises concerns
mans. The supplement contains naturally occurring monacolin for patient safety. In 2007, the FDA warned consumers to avoid
K, the active ingredient found in Merck’s prescription agent red yeast rice supplements promoted on the Internet (Red
lovastatin (Mevacor). Lovastatin is associated with various Yeast Rice, Red Yeast Rice/Policosonal Complex, and
adverse effects such as myopathy and abnormal liver function Cholestrix) to lower cholesterol because of the possibility of
test results, which can lead to serious problems if patients are myopathy, leading to kidney impairment.6 The widespread
not monitored and treated. The inclusion of lovastatin in red use of evidence-based medicine has caused health care pro-
yeast rice and the lack of dietary supplement regulation by the fessionals to become skeptical about dietary supplement use.
FDA raise safety concerns for health care professionals as The lack of studies and regulations to ensure the safety of these
well as for patients. Studies have shown that red yeast rice prod- products has the result of steering health care professionals
ucts can be beneficial in lowering serum cholesterol levels, but away from herbal products and toward prescription medica-
they are not without risk. Furthermore, product uniformity, tions that have been demonstrated to be safe and efficacious.
purity, labeling, and safety cannot be guaranteed. Health care practitioners should become aware of herbal prod-
ucts that patients might be using in place of commonly pre-
BACKGROUND scribed medications. This article reviews the safety and
Despite the increase in FDA-approved prescription med- effectiveness of red yeast rice as a “natural” alternative treat-
ications, alternative therapies have become more prevalent in ment to statins for hypercholesterolemia.
the U.S. About 42% of Americans use alternative medicine, and
the demand for these therapies continues to grow.1,2 In 1997, LITERATURE FINDINGS
patients paid approximately 629 million visits to alternative Before performing a MEDLINE search, we identified the most
medicine practitioners, a rate that was 47% higher than in 1990. appropriate search terms using the MeSH (medical subject
At approximately $27 billion, total out-of-pocket expenditures headings) database provided by the National Library of Med-
for alternative therapies exceeded total out-of-pocket expen- icine (www.pubmed.gov). Instead of using this database to
ditures for all hospitalizations in the U.S.1 perform the search, we conducted a “text word” search (from
Red yeast rice, a Chinese dietary supplement, has gained 1966 to November 2008) using PubMed to include articles
popularity because of its properties as a natural statin. This fer- indexed for MEDLINE as well as those not yet indexed (those
mented rice product is used as a medicinal food to improve that do not yet have MeSH terms assigned).
blood circulation by decreasing cholesterol and triglyceride When a relevant article was located, we reviewed the MeSH
levels.3,4 The supplement contains varying amounts of natural terms assigned to that article to identify other relevant search
monacolins as a result of the different strains of Monascus terms. To be as complete as possible, we did not use any lim-
purpureus used in fermentation.5 Monacolins lower choles- itations.
terol by inhibiting HMG–CoA (5-hydroxy-3-methylglutaryl- PubMed includes millions of citations from MEDLINE and
coenzyme A) reductase, the rate-limiting step for cholesterol other life science journals for biomedical articles. We reviewed
synthesis in the liver. The primary monacolin in red yeast rice the bibliographies of all relevant articles to identify any other
pertinent articles that the previous searches might have
missed. Our article includes some of the more provocative data
Matthew Klimek and Adeleye Ogunkanmi are postdoctoral fellows about red yeast rice but might not include all available relevant
at Rutgers University Ernest Mario School of Pharmacy in Piscat- literature.
away, New Jersey. Shan Wang is a clinical pharmacist at Winthrop
University Hospital in Mineola, New York.
Disclosure. The authors have no financial or commercial relation-
Accepted for publication March 9, 2009 ships to report in regard to this article.
entation, he had diffuse body aching, upper-extremity weak- probable drug–herbal interaction between cyclosporine and
ness, and lower-back stiffness along with a CK level of 358 U/L. red yeast rice. Cyclosporine is a commonly prescribed pre-
He had no history of muscle diseases or problems. According scription medication, and taking concomitant red yeast rice can
to the patient, the only new medications in his regimen were result in serious rhabdomyolysis.
ginseng, Chinese red yeast rice, and rofecoxib (Vioxx, Merck).
The patient had started taking ginseng and Chinese red yeast Consistency and Content of Red Yeast Rice
rice four weeks before his symptoms developed and then Besides the adverse effects caused by M. purpureus, the
started to take rofecoxib after the onset of symptoms. He was composition of red yeast rice can cause patient harm if quality
instructed to discontinue both of these products. At the three- control is inadequate. Heber et al. conducted an analysis of nine
week follow-up visit, his muscle weakness and joint pain proprietary Chinese red yeast rice dietary supplements: Cho-
resolved completely and the CK level fell to 179 U/L. Eight lesterex, Cholestene, Cholactive, Cholester-Reg, Beyond Cho-
months later, the patient resumed taking Chinese red yeast lesterol, Hongqu, Cholesterol Power, red yeast rice, and
rice, and his CK level increased again to 212 U/L. Cholestin.13 The authors of this study aimed (1) to determine
whether the cholesterol-lowering effect of red yeast rice was
Mueller11 consistent among all red yeast rice products and (2) to detect
A case of symptomatic myopathy was attributed to red yeast impurities in the product. They measured monacolin concen-
rice in a 61-year-old woman with hyperlipidemia.11 She was trations in each supplement along with citrinin, a nephrotoxic
started on simvastatin 20 mg daily along with estradiol from a by-product of fermentation (Table 1). Citrinin, a dangerous
transdermal patch at a dose of 0.05 mg/week, aspirin 81 mg nephrotoxin, was measured by radioimmunoassay and served
daily, and a multivitamin. The patient was otherwise in good as an indicator of potential danger as a result of its contents
health; vital signs and laboratory parameters were within nor- other than the active ingredients.
mal limits. After four months of therapy, simvastatin was in- Results showed a wide rage of monacolin K (0.15–3.37 mg)
creased to 40 mg daily. At this point, the CK level was 189 U/L. and monacolin L (less than 0.006–0.02 mg) content per capsule.
Within one month, diffuse myalgia and an elevated CK level Only one of the tested products included all 10 monacolin
of 451 U/L were reported. compounds that a quality red yeast rice product should con-
After simvastatin was discontinued, symptoms resolved and tain. Citrinin was found at measurable concentrations in seven
CK levels returned to 170 U/L. Soon afterward, the patient of nine preparations (0.47–64.7 mcg/capsule). The quality and
began using red yeast rice 600 mg twice daily as an alternative contents varied between each product, indicating that not all
treatment. Three months later, diffuse myalgia returned and red yeast rice products are equal. The authors concluded that
CK levels increased to 475 U/L. Red yeast rice was then dis- standardized manufacturing practices and adequate labeling
continued; symptoms resolved, and CK levels decreased to 122 are needed to ensure the equivalence of active ingredients for
U/L. Like simvastatin, red yeast rice caused diffuse myalgia efficacy and a low concentration of unwanted fermentation
and elevated CK levels. After these products were discontin- by-products to ensure safety.13
ued, symptoms resolved soon thereafter.
DISCUSSION
Summar y The efficacy of dietary supplements is usually questionable
Although the effects of red yeast rice are mild, the product because of the lack of controlled clinical trials supporting their
can cause muscle pain and weakness similar to that associated use. Two randomized, double-blind, placebo-controlled trials7,8
with conventional statins. These events can become serious if and an open-label trial9 demonstrated that red yeast rice might
the patient’s intake is not monitored appropriately. Awareness be effective in lowering LDL-C levels.
of the previous two cases can help health care professionals Lu et al. further demonstrated that red yeast rice might be
understand the potential for myopathy when red yeast rice is able to reduce cardiac events and provide positive effects on
used as a natural alternative to statins. cardiovascular outcomes in a fashion similar to that of pre-
scription statin therapy.7 Although larger-scale trials are nec-
Rhabdomyolysis essary to confirm these findings, red yeast rice seems prom-
Prasad et al.12 ising in the treatment of hyperlipidemia. Such efficacy data
Prasad and coworkers reported on a 28-year-old stable renal influence patients to try natural remedies before using more
transplant recipient who developed rhabdomyolysis after ther- common prescription drug therapies. The vast amount of data
apy with red yeast rice.12 The patient experienced an asymp- demonstrating the benefits of statin therapy in cardiovascular
tomatic elevation of CK to 1,050 IU/L; a second assessment disease supports its continued use, but practitioners should be
showed a CK level of 2,600 IU/L. After questioning, the patient aware of alternative therapies being used by their patients.
stated she had taken red yeast rice for the previous two months Unlike prescription drugs, dietary supplements have not
to lower cholesterol naturally. After she stopped taking the sup- traditionally undergone extensive testing by the FDA. Without
plement, her CK levels fell to 600 IU/L within two weeks and adequate testing, dietary supplements are not guaranteed to
she remained clinically asymptomatic. contain the quantity or quality of ingredients stated on the prod-
The patient was also taking cyclosporine to prevent trans- uct label. As shown by Heber et al., red yeast rice is no excep-
plant rejection. Cyclosporine, a known cytochrome P450 3A4 tion.13 Each of the nine products tested had different monacolin
inhibitor, most likely elevated red yeast rice serum concen- levels. Supplements with a lower monacolin content would be
trations by inhibiting its metabolism. It is important to note the less effective in lowering cholesterol.
Table 1 Contents of Monacolin and Citrinin in Chinese Red Yeast Rice Products
Seven of the tested samples contained citrinin, a mycotoxin Lovastatin as a prescription drug is contraindicated in preg-
produced by a variety of fungi in the production of foods in- nancy and is a Category X agent. This labeling is a main rea-
tended for human consumption such as grain, cheese, and red son for the FDA’s rejection of the application submitted by
pigments. Citrinin is a nephrotoxin in all animal species tested, Merck to sell lovastatin over the counter.18 Red yeast rice,
but its acute toxicity varies.14 Citrinin is genotoxic at high con- when used by pregnant women, places the fetus at unneces-
centrations in cultured human lymphocytes; therefore, its con- sary risk of central nervous system defects during the first
centration in supplements should be minimal.15 trimester. Although red yeast rice contains a lower dose of
Inconsistencies such as these led the FDA to require current lovastatin compared with the FDA-approved product, the risk
good manufacturing practices (CGMPs) for dietary supple- posed may be similar.
ments.16 Final CGMPs were expected to become effective in
June 2008 for large companies and are to be implemented in CONCLUSION
June 2009 for companies with fewer than 500 employees and Despite the growing interest in dietary supplements, red
in June 2010 for companies with fewer than 20 employees. yeast rice (M. purpureus) is not recommended for patients with
Under this ruling, all domestic and foreign supplements must hypercholesterolemia. A lack of uniformity among products,
be processed in a consistent manner and to meet quality stan- the possibility of contamination, and the risk of severe ad-
dards. To demonstrate quality and consistency, tests will be verse reactions pose a threat to individuals using this product.
performed on all supplements to ensure their identity, purity, Overall, red yeast rice has not been shown to be a safe alter-
strength, and composition. native to statins for patients with hyperlipidemia despite its
Statin drugs such as Merck’s Mevacor (lovastatin) are demonstrated efficacy in controlled clinical trials. Physicians
associated with various side effects such as headache, dizzi- should be aware of its popularity as a “natural” way to lower
ness, rash, upset stomach, and hepatic dysfunction. The most serum cholesterol, and they should discuss the risks and ben-
common adverse effect is muscle weakness, which can be a efits of this supplement with their patients.
sign of more serious myopathy or, in rare cases, rhabdo-
myolysis.17 Double-blind, controlled clinical trials have dem- REFERENCES
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it to muscular myopathy and rhabdomyolysis. In three cases up national survey. JAMA 1998;280(18):156–175.
described here,4,10,11 red yeast rice caused or exacerbated my- 2. Kessler RC, Davis RB, Foster DF, et al. Long-term trends in the
use of complementary and alternative medical therapies in the
opathy marked by elevated serum CK levels. Rhabdomyolysis, United States. Ann Intern Med 2001;135:262–268.
the most severe adverse ef fect associated with statins, 3. Patrick L, Uzick M. Cardiovascular disease: C-reactive protein and
occurred in a renal transplant patient who used red yeast rice the inflammatory disease paradigm: HMG–CoA reductase inhib-
while concomitantly taking cyclosporine.12 Although the more itors, alpha-tocopherol, red yeast rice, and olive oil polyphenols:
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