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- Turmeric (Curcuma longa)
- Curcumin
- Alzheimer's Disease
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Date:
04-30-2013 | HC# 121253-471
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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 (DSM-IV); 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 anti-inflammatory 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), 15-25% 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
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