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HerbClip™ Laura Bystrom, PhD Amy Keller, PhD
Mariann Garner-Wizard Heather S Oliff, PhD
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File: ■ Turmeric (Curcuma longa) ■ Curcumin ■ Alzheimer's Disease HC 121253-471 Date: April 30, 2013 RE: Study Shows Curcumin Product to Be Safe, but It Has No Beneficial Effects on Symptoms or Biomarkers of Alzheimer's Disease Ringman JM, Frautschy SA, Teng E, et al. Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res Ther. October 29, 2012;4(5):43. doi: 10.1186/alzrt146. Curcumin is a polyphenolic compound from turmeric (Curcuma longa). Curcumin has antioxidant and anti-inflammatory activity, and reduces the pathology in Alzheimer's disease (AD) models in rodents. It is considered a candidate for treating AD in humans. Consumption of turmeric oleoresin (85% curcumin) is classified as Generally Recognized As Safe (GRAS) by the US Food and Drug Administration (FDA). Short-term studies in humans suggest that it may have gastrointestinal (GI) side effects, including diarrhea. While preliminary rat studies of high-dose turmeric oleoresin showed a theoretical concern for hepatotoxicity and thyroid follicular dysplasia, these results have not been borne out in human curcumin studies published since that time. The tolerability and bioavailability of chronic, moderate doses of curcumin in elderly people is not known. The purpose of this randomized, double-blind, placebo-controlled study was to evaluate the safety, tolerability, and efficacy of a curcumin product (Curcumin C3 Complex®; Sabinsa Corporation; East Windsor, New Jersey) in patients with mild-to-moderate AD. Patients (n = 36) with mild-to-moderate AD participated in this study conducted at the Mary S. Easton Center for Alzheimer's Disease Research at the University of California Los Angeles (UCLA); Los Angeles, California. Inclusion criteria were the presence of dementia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV); diagnosis of probable AD by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria; aged > 49 years; a Mini-Mental State Examination (MMSE) score of 17-29; and the availability of a study partner to monitor medication and adverse effects (AEs). Dosages of acetylcholinesterase inhibitors and memantine had to be stable for 1 month. Exclusion criteria included significant systemic illness or recent history of GI bleeding. Exclusionary medications were aspirin at doses > 325 mg/day, nonsteroidal antiinflammatory drugs > 3x/week, coumadin, heparin, ginkgo (Ginkgo biloba), and certain antioxidant supplements; though vitamins C and E were allowed in doses of up to 500 mg and 2000 IU daily, respectively. Patients received either placebo, 2 g/day of Curcumin C3 Complex, or 4 g/day of Curcumin C3 Complex and these were to be taken with fatty meals
for 24 weeks. Curcumin C3 Complex contains 95% curcuminoids (70-80% curcumin), 1525% demethoxycurcumin, and 2.5-6.5% bisdemethoxycurcumin. After the 24-week visit, the placebo group was randomly assigned to receive 2 or 4 g/day of Curcumin C3 Complex and the other patients continued with the same dose for another 24 weeks. Blood and cerebrospinal fluid (CSF) were drawn at baseline and after 24 weeks, and blood count, chemistries, thyroid function, and bleeding times were assessed. Cognition was assessed with the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and the MMSE at baseline, 24 weeks, and 48 weeks; plus using the MMSE also at weeks 4, 12, and 36. Pharmacokinetics of curcumin and its metabolite tetrahydrocurcumin were also assessed. Baseline scores did not differ between groups. Hematocrit was significantly lower (P = 0.014), and glucose levels were significantly higher (P = 0.043), in patients treated with curcumin. However, the changes in hematocrit and blood glucose did not exceed the range of normal. There was no significant difference between treatment groups in any of the efficacy parameters. There were no changes in plasma or CSF markers of AD (e.g., amyloid beta-peptide and tau). Plasma levels or CSF levels of curcumin were not detectable using high-performance liquid chromatography (HPLC) methodology. The more sensitive liquid chromatography/mass spectrometry method detected means of only 7.76 ng/mL of curcumin and 3.73 ng/mL of tetrahydrocurcumin in the plasma 3 hours after dosing, but no CSF levels of curcumin could be detected. Plasma mean levels of glucuronidated curcumin and tetrahydrocurcumin were 96.05 and 298.2 ng/mL, respectively, but these forms cannot cross the blood-brain barrier. Five patients from the curcumin groups withdrew due to AEs; 3 had GI side effects, including black stool and diarrhea, and 2 had difficulty swallowing the pills. There was no significant difference between groups in the overall incidence of AEs. There was no significant difference between groups in the incidence of diarrhea. AEs related to the endocrine system were significantly fewer in the 2 g curcumin group than in the placebo or 4 g curcumin group (P = 0.02). There was a trend for decreased joint pain of 2.5% per gram of curcumin (P = 0.07). Similar to this study, other studies have reported limited bioavailability of curcumin, possibly due to being extensively metabolized in the GI tract. The authors conclude that they were unable to demonstrate clinical or biochemical evidence of efficacy. They state that it is unclear whether the lack of bioavailability, and subsequent lack of effect, can be attributed to the specific formulation or attributed to curcumin itself. They state that they are working on studies with other formulations. It should also be noted that the study size was very small, and more patients may be needed to surpass interpatient variability. Thus for future trials on AD, a longer duration and proper design may provide better insight into the role of curcumin in AD. The authors also think that piperine from Piper spp., with its proven role as a bioavailability-enhancer of curcumin and also in light of its own benefits on cognitive health, could be a potential candidate for improving curcumin's bioavailability in any future trial on AD. —Heather S. Oliff, PhD Referenced article can be found at http://alzres.com/content/pdf/alzrt146.pdf.
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