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Alternative Medicine Review
®
A Journal of Clinical Therapeutics
December 2011 Volume 16, Number 4
In This Issue: • Complementary and Alternative Medical Therapies for Children with Attention-Deficit/
Hyperactivity Disorder (ADHD) • A Clinical Trial Testing the Safety and Efficacy of a Standardized Eucommia
ulmoides Extract to Treat Hypertension • The Effects of L-Theanine on Objective Sleep Quality in Boys with
Attention Deficit Hyperactivity Disorder (ADHD • A Review of the Use of Mercury in Historic and Current
Ritualistic and Spiritual Practices • The Role of Persistent Organic Pollutants in the Worldwide Epidemic of
Type 2 Diabetes Mellitus and the Possible Connection to Farmed Atlantic Salmon • Astaxanthin, Cell
Membrane Nutrient with Diverse Clinical Benefits and Anti-Aging Potential Monograph • Abstracts
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355 Alternative Medicine Review Volume 16, Number 4
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Monograph
Abstract
Astaxanthin, a xanthophyll carotenoid, is a nutrient with
unique cell membrane actions and diverse clinical benets.
This molecule neutralizes free radicals or other oxidants by
either accepting or donating electrons, and without being
destroyed or becoming a pro-oxidant in the process. Its linear,
polar-nonpolar-polar molecular layout equips it to precisely
insert into the membrane and span its entire width. In this
position, astaxanthin can intercept reactive molecular species
within the membrane’s hydrophobic interior and along its
hydrophilic boundaries. Clinically, astaxanthin has shown
diverse benets, with excellent safety and tolerability. In
double-blind, randomized controlled trials (RCTs), astaxanthin
lowered oxidative stress in overweight and obese subjects and
in smokers. It blocked oxidative DNA damage, lowered
C-reactive protein (CRP) and other inammation biomarkers,
and boosted immunity in the tuberculin skin test. Astaxanthin
lowered triglycerides and raised HDL-cholesterol in another
trial and improved blood ow in an experimental microcircula-
tion model. It improved cognition in a small clinical trial and
boosted proliferation and dierentiation of cultured nerve
stem cells. In several Japanese RCTs, astaxanthin improved
visual acuity and eye accommodation. It improved reproduc-
tive performance in men and reux symptoms in H. pylori
patients. In preliminary trials it showed promise for sports
performance (soccer). In cultured cells, astaxanthin protected
the mitochondria against endogenous oxygen radicals,
conserved their redox (antioxidant) capacity, and enhanced
their energy production eciency. The concentrations used in
these cells would be attainable in humans by modest dietary
intakes. Astaxanthin’s clinical success extends beyond
protection against oxidative stress and inammation, to
demonstrable promise for slowing age-related functional
decline.
(Altern Med Rev 2011;16(4):355-364)
Introduction
Astaxanthin is a carotenoid nutrient with
molecular properties that precisely position it
within cell membranes and circulating lipoproteins,
thereby imbuing them with potent antioxidant and
anti-inflammatory actions.
1,2
Astaxanthin also
effectively protects the double membrane system
of mitochondria, to the point of boosting their
energy production efficiency.
3
As a dietary supple-
ment, astaxanthin demonstrates an exceptional
range of benefits, mostly at very modest dietary
intakes (40 mg/day or less). e molecular struc-
ture of astaxanthin is illustrated in Figure 1.
Humans do not make astaxanthin.
4
Current
human dietary intake is almost exclusively from
seafood. Astaxanthin is produced by algae, bacteria,
and fungi, and concentrates higher up the food
chain as these primary producers are consumed for
food.
5
Its naturally intense red color brightens the
flesh, skin, or exoskeleton of animals, such as crabs,
crayfish, krill, lobsters, salmon, shrimp, and trout.
It is also fed to farmed seafood for this coloring
purpose. Astaxanthin also occurs naturally in
flamingo feathers (where it is responsible for the
characteristic color) and the retinas of quail.
6
Although synthetic astaxanthin is available, it
has a different molecular profile than the natural
material, as do certain manufactured astaxanthin
esters. is review is therefore restricted to natural
astaxanthin, virtually all of which comes from
commercial cultures of the single-celled alga
Haematococcus pluvialis (H. pluvialis).
7
e clinical and basic science research on
astaxanthin is considerable, although a number of
the clinical trials in circulation were not published
Parris M. Kidd, PhD – Cell
biology; University of Califor-
nia, Berkeley; contributing
editor, Alternative Medicine
Review; health educator;
biomedical consultant to the
dietary supplement industry.
Correspondence address:
847 Elm Street, El Cerrito,
CA 94530
Email: dockidd@dockidd.com
Astaxanthin, Cell Membrane Nutrient with
Diverse Clinical Benets and Anti-Aging
Potential
Parris Kidd, PhD
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Volume 16, Number 4 Alternative Medicine Review 356
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Monograph
Key words: astaxanthin,
antioxidant, carotenoid,
cardiovascular, cell mem-
branes, cognition, CRP, DNA
damage, eye accommoda-
tion, free radicals, H. pylori,
inammation, immunity,
male fertility, mitochondria,
oxidative stress, redox, vision,
xanthophyll
in peer-reviewed journals and some were published
only in Japanese. However, the English-language,
peer-reviewed publications sufficiently establish
astaxanthin as a nutrient with broad-ranging
efficacy and safety.
Biochemistry
The Unique Molecular Layout of Astaxanthin
Astaxanthin (3,3’-dihydroxy-beta,beta-carotene-
4,4’-dione) belongs to the xanthophyll subclass of
carotenoids. It has oxygen in its molecular struc-
ture, which sets it apart from beta-carotene and
other molecules of the carotene subclass.
5
e
astaxanthin molecule has an extended shape, with
a polar structure at either end of the molecule and
a nonpolar zone in the middle (Figure 1). e polar
structures are ionone rings that have potent
capacity for quenching free radicals or other
oxidants, primarily in an aqueous environment,
but possibly also in the absence of water.
8,9
e nonpolar middle segment of the astaxanthin
molecule is a series of carbon-carbon double bonds,
which alternate with carbon-carbon single bonds
– termed “conjugated.” is series of conjugated
double bonds gives the molecule a further antioxi-
dant dimension, with a capacity to remove high-
energy electrons from free radicals and “delocalize”
their electronic energy via the carbon-carbon chain
– analogous to a lightning rod on the molecular
level (Figure 2).
10
is polar-nonpolar-polar layout
also allows the astaxanthin molecule to take a
transmembrane orientation, making a precise fit
into the polar-nonpolar-polar span of the cell
membrane.
Complex Three-Dimensional Chemistry
e bonding patterns of natural astaxanthin
generate many different molecular forms (isomers),
each with its unique three-dimensional shape. e
intricacies of astaxanthin’s isomer array are beyond
the scope of this review. Pertaining to its use as a
dietary supplement, virtually all commercially
available natural astaxanthin is predominantly in
the all-trans geometric form 3S,3S’ Astaxanthin, as
occurs in H. pluvialis and as illustrated in Figure 1.
is is the predominant natural astaxanthin used
in all clinical trials to date.
Another complication in the chemistry of natural
astaxanthin is that the molecule in its free form is
relatively uncommon within the various organisms
that produce it. Instead, most of this astaxanthin is
either conjugated with proteins or esterified with
one or two fatty acids (as astaxanthin acyl monoes-
ters or diesters).
11
Acyl esters make up more than
99 percent of the astaxanthin from H. pluvialis and
approximately 80 percent of astaxanthin in
krill.
11,12
us, acyl monoester and diester forms
make up virtually all the astaxanthin currently
available in dietary supplements.
Metabolism: Absorption and Tissue
Distribution
In pharmacokinetic studies, after ingestion of
esterified natural astaxanthin, only unesterified
astaxanthin appears in the blood.
13
is is most
likely due to breaking the ester bonds by digestive
enzymes via their hydrolytic activity. Absorption
into the intestinal lining cells (enterocytes) is
thought to occur by passive diffusion and is
Figure 1. Molecular Layout of All-trans Astaxanthin, the Major Molecular Species in Natural Foods and Dietary
Supplements
HO
OH
O
O
all-trans astaxanthin
Note the polar ionone rings at the ends and the non-polar zone of conjugated carbon-carbon bonds in the middle.
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357 Alternative Medicine Review Volume 16, Number 4
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Monograph
facilitated in the presence of fat or other lipids.
14
e enterocytes then incorporate the unesterified
astaxanthin into chylomicrons, which transport it
to the liver.
13
e liver does not convert this
molecule to vitamin A or otherwise biochemically
transform it.
4
Instead it becomes incorporated into
low-density lipoprotein (LDL) and high-density
lipoprotein (HDL), which then distribute it to the
tissues via the circulation.
13
When astaxanthin is fed to human subjects,
detailed pharmacokinetic data are difficult to
obtain for single doses of less than 10 mg, due to
limitations of assay precision.
13
However, there is
good data to indicate a single 10-mg dose can
persist in the blood for 24 hours and a 100-mg
dose for 76 hours.
13
Doses as low as 1 mg can
significantly increase blood levels when taken once
daily for four weeks.
15
Figure 2. Transverse Cell Membrane Orientation of 3S,3S’ Astaxanthin, the Major Molecular Form from H. pluvialis
10
HO
OH
O
O
HO
OH
O
O
3S, 3S’ Astaxanthin
Extracellular
Space
Vitamin C
Oxidized
phospholipid
3S, 3S’ Astaxanthin
Fatty Acids Tails
(Hydrophobic)
Fatty Acids Tails
(Hydrophobic)
Polar Heads
(Hydrophilic)
Polar Heads
(Hydrophilic)
Cytoplasm
ROS
e-
e-
e-
e-
e-
e-
e-
e-
e-
e-
e-
CholesterolCholesterol
Bi-layer
Membrane
O
O
OH
OH
HO
HO
Polar Heads
(Hydrophilic)
Polar Heads
(Hydrophilic)
The polar end groups overlap the polar boundary zones of the membrane, while the nonpolar middle ts the membrane’s
nonpolar interior. The dashed red line speculatively indicates “lightning-rod” conduction of electrons along the astaxanthin
molecule, possibly to vitamin C or other antoxidants located outside the membrane.
From: Pashkow FJ, Watumull DG, Campbell CL. Astaxanthin: a novel potential treatment for oxidative stress and inammation
in cardiovascular disease. Am J Cardiol 2008;101(suppl):58D-68D. Used with permission.
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Monograph
Astaxanthin’s bioavailability is substantially
affected by meal timing and by smoking. In a 2009
study, a single 48-mg dose was much better
absorbed when taken just after a meal than on an
empty stomach, and was about 40-percent less
bioavailable in subjects who smoked.
14
Mechanisms of Action/Clinical
Indications
A Unique Cell Membrane Antioxidant
Astaxanthin provides cell membranes with
potent protection against free radical or other
oxidative attack. Experimental studies confirm that
this nutrient has a large capacity to neutralize free
radical or other oxidant activity in the nonpolar
(“hydrophobic”) zones of phospholipid aggregates,
as well as along their polar (hydrophilic) boundary
zones.
5
A particularly elegant experimental study
by McNulty et al conclusively established astaxan-
thin’s membrane protection capacity.
1
McNulty’s group assembled model membranes
from phosphatidylcholine and a small amount of
cholesterol, at ratios similar to natural cell mem-
branes.
1
ey then introduced varying amounts of
astaxanthin, zeaxanthin, lutein, beta-carotene, and
lycopene to these model membranes and moni-
tored the packing of the phospholipids by X-ray
diffraction. ey also induced peroxidative pro-
cesses by gently increasing the temperature of the
system. With the exception of astaxanthin, the
carotenoids all disrupted the phospholipid packing
and exacerbated peroxidative breakdown. e
greater the membrane disruption by a carotenoid,
the greater was its peroxidative effect. Only
astaxanthin reduced peroxidation (by 41 percent)
and preserved the membrane structure. e
researchers gave particular credit to astaxanthin’s
unique ionone polar groups.
Astaxanthin’s anti-peroxidative effect was
evident in another study that had considerable
social relevance.
16,17
In 2004, the pharmaceutical
cyclooxygenase-2 (Cox-2) inhibitor rofecoxib was
removed from commercial distribution due to its
increased risk for atherothrombotic events.
16
It was
found to increase the susceptibility of human LDL
and cell membrane lipids to oxidative processes
that contribute to atherosclerosis and thrombus
formation. In a study using model lipid bilayers,
rofecoxib caused peroxidative damage that was
prevented by astaxanthin.
17
As found in the
McNulty experiments,
1
astaxanthin switched the
model membrane-carrying rofecoxib from net
peroxidative balance to healthy anti-peroxidative
balance.
Astaxanthin has also protected human LDL
against oxidative attack. In a Japanese study,
2
astaxanthin purified from krill was provided to
healthy volunteers (average age 28 years; n=24) at
0 mg/day, 1.8 mg/day, 3.6 mg/day, 14.4 mg/day, or
21.6 mg/day, for 14 days. After supplementation,
venous blood was drawn and the LDL analyzed for
susceptibility to oxidation (lag time after a chemi-
cal peroxidative trigger) for each subject compared
to baseline. Astaxanthin significantly increased lag
time, which indicated a protective effect, at the
dose levels of 3.6 mg/day and higher.
Supplementation with astaxanthin may lower
lipid peroxidation in vivo.
18
A double-blind, ran-
domized, controlled trial (RCT) investigated
astaxanthin (8 mg/day) versus a placebo for three
months in Finnish men ages 19-33. Plasma 12- and
15-hydroxy fatty acids, both markers of lipid
peroxidation, were statistically significantly
reduced in the astaxanthin group (both with
p<0.05), but not in the placebo group. e reduc-
tion in 15-hydroxy fatty acid in the astaxanthin
group fell just short of significance when compared
to the placebo group (p=0.056).
e membrane systems of cells are particularly
vulnerable to free radical or other oxidative attack,
owing to their content of polyunsaturated fatty
acids and to their metabolic activities, which
endogenously generate free radicals and other
oxidants.
19
In its position spanning the membrane,
astaxanthin provides versatile antioxidant actions,
including:
1,8,9
➧ donating electrons to unpaired electrons to
neutralize free radicals;
➧ pulling away (“abstracting”) an unpaired electron,
which also can neutralize a radical;
➧ bonding with the radical to form an unreactive
“adduct”;
➧ conducting electrons or electronic energy out of
the membrane (Figure 2);
➧ neutralizing radical species of nitrogen, sulfur, or
carbon, in addition to oxygen; and
➧ carrying very low net molecular energy, there-
fore providing resistance to transformation into
a pro-oxidant molecule.
Evidence of Antioxidant Eects in Clinical Trials
Significant antioxidant powers have been ascribed
to astaxanthin, based primarily on experimental
findings. e real breakthrough with this nutrient,
however, is that it produces clinically significant
antioxidant benefits in human subjects, including
groups especially vulnerable to oxidative stress, such
as smokers, the obese, and the
overweight.
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Monograph
Oxidative stress can be defined as a relative
excess of free radical activity over antioxidant
capacity, which in human subjects can be deter-
mined using blood samples.
20
Alternately, oxidative
breakdown products can be measured in the
blood.
21
People who are overweight or obese tend
to manifest greater “oxidative stress” when
compared to individuals within the normal weight
range.
22
In a Korean double-blind RCT, astaxanthin
“normalized” oxidative stress in individuals with
weight challenges.
21
In this three-week study, overweight and obese
individuals (body mass index [BMI] >25.0 kg/m
2
;
n=23) were randomized to receive astaxanthin at 5
mg/day or 20 mg/day and compared to a control
group (n=10) with normal body weight (BMI <25.0
kg/m
2
) who received no intervention.
21
At baseline,
the plasma levels in overweight and obese individu-
als were significantly higher than normal weight
individuals on two oxidative biomarkers – malondi-
aldehyde (MDA) and isoprostanes (ISP), while
plasma levels in overweight and obese individuals
were significantly lower on two antioxidant
measures – superoxide dismutase (SOD) and total
antioxidant capacity (TAC). At the three-week
mark, when compared against baseline, both
astaxanthin groups showed significant lowering of
oxidative markers MDA (p<0.01 for both groups)
and ISP (p<0.01 for 5 mg/day; p<0.001 for 20 mg/
day). e astaxanthin groups also had significant
increases in SOD and TAC (all p<0.001 versus
baseline). Marked improvements on all four
measures caused the overweight and obese
subjects to become statistically indistinguishable
from the control group, suggesting that supple-
mentation lowered oxidative stress and improved
aspects of the antioxidant defense system. e
improvements were not significantly better for the
20 mg/day group than the 5 mg/day group.
In another RCT conducted by the same group,
and made available as an electronic summary
pending publication (September 2011),
23
heavy
smokers (n=39) were randomly allocated to receive
astaxanthin at 5-, 20-, or 40 mg/day for three
weeks. Compared with baseline, the plasma MDA
and ISP levels decreased, whereas SOD level and
TAC increased in all intervention groups over the
three-week period. In particular, ISP levels showed
a significant dose-dependent decrease after
astaxanthin intake.
Astaxanthin also can protect against oxidative
DNA damage. In a 2010 double-blind RCT con-
ducted by Park et al,
24
healthy women (ages 20-23;
n=42) received either a placebo or astaxanthin at
doses of 2 mg/day or 8 mg/day for eight weeks.
Both astaxanthin dosages significantly lowered
plasma 8-hydroxy-2’-deoxyguanosine (8-OHdG),
an indicator of oxidative DNA breakdown. Plasma
8-isoprostane, a marker of lipid peroxidation, was
not significantly lowered. e authors attributed
this finding to a lack of sensitivity and accuracy in
their assay method.
Anti-inammatory Benets
In the Park double-blind RCT,
24
astaxanthin also
significantly lowered C-reactive protein (CRP), a
biomarker of systemic inflammation.
25
Although
the 2-mg/day dose had a significant CRP-lowering
effect, the 8-mg/day dose fell short of statistical
significance. Compared with the lower dose, the
8-mg/day dose significantly increased the cytokine
interferon-gamma, which may indicate an anti-
inflammatory effect, but also significantly
increased interleukin-6 (IL-6), which can have a
pro-inflammatory effect. e clinical significance of
these findings is unclear, particularly since none of
these, except CRP, is a generally accepted inflamma-
tory marker.
Astaxanthin’s effect on CRP was also investi-
gated in a small double-blind trial that was pub-
lished without peer review.
26
Subjects (ages 40-60
years; n=19), with no diagnosis of cardiovascular
disease, kidney disease, diabetes, or cancer,
received three softgel capsules daily supplying
either astaxanthin at 12 mg/day (with 120 mcg of
lutein, 195 IU of vitamin A activity [in the form of
beta-carotene), and 150 IU of vitamin E) or a
placebo (safflower oil) for eight weeks. e astaxan-
thin combination lowered CRP levels by about 20
percent (from 1.35 mg/dL to 1.07 mg/dL), which
was significantly better than placebo (p<0.05).
An eight-week, double-blind RCT conducted on
rheumatoid arthritis subjects was published in
abstract form.
27
One group (n=14) received the
same combination as in the previously described
study – 12 mg/day astaxanthin plus 120 mcg of
lutein, 195 IU vitamin A activity (from beta-caro-
tene), and 150 IU of vitamin E, while the other
group (n=7) received a placebo. e improvement
in self-reported scores of pain and satisfaction for
the astaxanthin group was significantly better than
for the placebo group, which suggests a possible
anti-inflammatory effect.
Astaxanthin has been reported to benefit other
inflammatory conditions such as canker sores,
carpal tunnel syndrome, and “tennis elbow,” but
the evidence currently available to support these
claims is insufficient.
amr
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Monograph
Promotes Integrated Immune Response
e Park double-blind RCT investigated astaxan-
thin most extensively for its immune system
benefits over the eight-week trial period.
24
At the
2-mg/day dose, total T- and B-cell numbers were
significantly increased over placebo (p<0.05 for
both comparisons). At the 8-mg/day dose, natural
killer cell cytotoxic activity increased, as did
lymphocyte proliferation in response to mitogen
stimulation (p<0.05 for both comparisons). Skin
delayed-type hypersensitivity (DTH), an excellent
measure of integrated cell and humoral mediated
immunity, was significantly improved by the 2-mg/
day dose (p<0.05). e researchers concluded
astaxanthin promotes overall immune competence.
Astaxanthin was also tested for skin immunity
in another double-blind RCT.
7
Patients (ages 19-51
years; n=27) with mild-to-moderate atopic derma-
titis received either 12 mg/day astaxanthin or a
placebo for four weeks. Although astaxanthin did
not significantly improve the dermatitis severity, a
significant shift in T-helper1/T-helper2 (1/2)
balance was observed – with a shift toward 1
dominance. e researchers judged this an impor-
tant finding since atopic dermatitis is considered a
2-dominant disease. ose in the astaxanthin
group also experienced significant improvement in
anxiety and other quality of life symptoms com-
pared to placebo.
Eects on Metabolic Syndrome
Astaxanthin improved certain blood lipids in
subjects with moderately elevated serum triglycer-
ides (TGs). Healthy non-obese subjects (BMI <28
kg/m
2
), ages 20-65 years (n=61) with fasting TGs
in the range 120-200 mg/dL, were recruited into a
double-blind RCT.
28
ey were randomly allocated
to receive astaxanthin at 6 mg/day, 12 mg/day, or
18 mg/day, or a placebo for 12 weeks. Astaxanthin,
as compared to placebo, significantly elevated
HDL-cholesterol at the doses of 6 mg/day (p<0.05)
and 12 mg/day (p<0.01). It also significantly
lowered TGs at doses of 12 mg/day and 18 mg/day
(p<0.05 for both) compared to placebo. ere was
no effect on LDL-cholesterol at any dose.
Astaxanthin also significantly increased blood
adiponectin levels (p<0.01 at 12 mg/day; p<0.05 at
18 mg/day).
Adiponectin is a hormone produced by adipose
tissue, cardiac and skeletal muscle, and vessel
endothelia. Serum levels of adiponectin tend to be
reduced in obese and/or diabetic subjects, smokers,
patients with coronary heart disease, and individu-
als with metabolic syndrome.
29
Although the
results of this study suggest a normalization of
adiponectin levels, 12 weeks of supplementation
had no effect on BMI.
In a small, open-label trial (16 subjects), astaxan-
thin did not produce clinically significant benefits
on any of the criteria for metabolic syndrome.
30
Further investigation is required under better-
controlled conditions in order to clarify astaxan-
thin’s utility for this condition.
Eects on Circulation
As people age, their red blood cells (RBCs) can be
more susceptible to oxidative attack, resulting in
peroxidative damage to the RBC membrane
phospholipids,
31
impairing its oxygen-carrying
capacity. In a 2011 double-blind RCT,
32
healthy
subjects, ages 50-69 years (n=30), were randomly
allocated to receive astaxanthin at 6 mg/day or 12
mg/day or a placebo for 12 weeks. Both astaxan-
thin intakes significantly lowered RBC hydroperox-
ide levels (p<0.05 for both doses versus placebo);
the 12 mg/day dose did not work significantly
better than the 6 mg/day dose.
Astaxanthin also improved an experimental
measure of “rheology” (blood flow capacity) in
healthy men.
33
Venous blood was drawn with
heparin to protect against coagulation, then forced
using mild pressure through tiny “microchannels,”
each just seven millionths of a meter wide, approxi-
mating the diameter of an RBC and the width of a
capillary. e time required to traverse these
capillary-type tubes under a set pressure was
termed the transit time. A total of 20 men were
selected whose blood demonstrated transit times
in the range of 45-70 seconds per 100 microliters.
ey were then randomly allocated to receive either
astaxanthin (6 mg/day) or a placebo for 10 days.
Upon retest, the astaxanthin group had signifi-
cantly faster transit time (p<0.05) compared to
placebo. is finding suggests astaxanthin could
potentially improve microcirculation.
Preliminary Benets for Memory and other Higher
Brain Functions
Astaxanthin might improve cognitive functions.
In a small, open-label trial, 10 healthy men ages
50-69, who had been complaining of forgetfulness,
received astaxanthin (12 mg/day) for 12 weeks.
34
On a computerized test designed to accurately
detect early cognitive deterioration (“CogHealth”
from CogState Ltd, Melbourne, Australia),
35
they
showed improvement on measures of reaction time,
attention, and working memory.
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Monograph
Although this trial clearly was only preliminary,
astaxanthin has shown a variety of brain benefits
under experimental conditions. Unlike much of the
experimental research conducted with this
nutrient, the following studies employed levels
readily achieved by oral intake in humans.
Astaxanthin:
➧ significantly improved the memory performance
of mice in the Morris water maze;
36
➧ effectively protected cultured nerve cells against
hydrogen peroxide toxicity,
37,38
and down-regu-
lated genes linked to cell death and up-regulated
genes linked to cell survival;
38
➧ specifically protected the mitochondria of
cu
ltured nerve cells against toxic attack;
3,37,38
and
➧ stimulated the proliferation of cultured nerve
stem cells.
39
Eect on Vision and Eye Fatigue
Astaxanthin has been extensively researched for
its benefits for vision, especially in Japan. Yuan
11
and Kajita (2009)
40
discussed double-blind and
other controlled trials that were published in
Japanese with English abstracts. ey concluded
that astaxanthin taken at 6 mg/day consistently
improved visual sharpness, even in healthy
subjects.
Astaxanthin also might relieve eye fatigue in
persons using computer monitors. Extended work
at computer monitors is linked to eyes strain and
to blurred vision, often accompanied by tensing of
the muscles of the shoulder and low back.
41
One
double-blind RCT used instrumentation to
measure eye muscle endurance, the usual basis for
eye strain.
42
Japanese visual display terminal (VDT)
workers, ages 38-53 (n=26), received astaxanthin
(5 mg/day) or a placebo for four weeks. A non-VDT
control group received neither astaxanthin nor
placebo. After supplementation, eye strain was
significantly more improved in the astaxanthin
group than in the placebo group (p<0.05).
Many individuals, as they age, suffer decline in
the eye’s ability to focus on near objects (presby-
opia). In an open-label Japanese trial,
40
papillary
constriction capacity was determined using
instrumentation in presbyopic middle-aged and
older subjects (ages 46-65 years; n=22). ey then
received astaxanthin (6 mg/day) for four weeks.
Astaxanthin significantly improved pupillary
constriction, and more than 60 percent of the
subjects indicated on a questionnaire that they also
experienced improvement in the categories of
“difficulty to see near objects,” “eye strain,” “blurred
vision,” and “shoulder and low-back stiffness.”
Muscle Performance and Endurance
In a double-blind RCT,
43
young healthy male
students (ages 17-19 years; n=40) were subjected
to fitness, strength, and endurance testing, then
randomized to receive astaxanthin (4 mg/day) or a
placebo for six months. Astaxanthin significantly
improved performance in the assessment designed
to measure strength/endurance (maximum number
of knee bends [“squats”] performed while carrying
a 42.5 kg barbell) over the placebo group (p<0.05).
e maximum number of knee bends increased by
more than 50 percent in the astaxanthin group
versus 19 percent in the placebo group. No benefit
was detected for the assessments of strength/
explosivity or overall fitness. is finding (and
probably others asserted from unpublished trials)
may have motivated the double-blind trials
currently in progress with astaxanthin for protec-
tion against oxidative stress
44
and for improving
speed and endurance in soccer players.
45
Eect on Helicobacter pylori in Functional Dyspepsia
In a 2008 RCT, astaxanthin was evaluated for
functional dyspepsia (FD).
46
Patients with FD (ages
18-70 years; n=130) were screened by detailed ques-
tionnaires, gastroscopy, and urea breath test for H.
pylori. Of the 130 total patients, 81 (62%) tested
positive for H. pylori. All patients were then ran-
domized to receive, in double-blind fashion, astax-
anthin at 16 mg/day or 40 mg/day or a placebo for
four weeks. Gastrointestinal symptoms were mea-
sured using the Gastrointestinal Symptom Rating
Scale (GSRS) to assess abdominal pain, indigestion,
and reflux; quality of life was assessed using the
SF-36 questionnaire. Treatment lasted four weeks,
with a follow-up after another four weeks.
At the end oftherapy(week 4), a strong placebo
effect was evident, and there was no significant
difference among the threetreatmentgroups for
GSRS scores of abdominal pain, indigestion, and
reflux syndromes; the same results were observed
at the end of follow-up. e researchers concluded
astaxanthin did not have a global curative effect on
FD. However, the higher dose of astaxanthin (40
mg/day) did significantly reduce symptoms
associated with acid reflux, compared to the
16-mg/day dose and the placebo (p<0.05 for both
comparisons).
46
e high-dose astaxanthin also
significantly improved well-being in this group, as
judged from the health transition item on the
SF-36 quality of life questionnaire (p<0.05 for both
comparisons).
amr
Volume 16, Number 4 Alternative Medicine Review 362
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Monograph
Subgroup statistical comparisons of the H.
pylori-positive patients versus the H. pylori-nega-
tive patients revealed that the high-dose astaxan-
thin benefited reflux syndrome significantly better
than placebo (p<0.05) only in the patients positive
for H. pylori. e researchers speculated that
astaxanthin helped suppress the elevation of
oxidative stress associated with H. pylori infection.
Another smaller double-blind RCT, conducted by
this same group, assessed astaxanthin for gastric
inflammation in patients with FD.
47
Patients
(n=44) were randomized to receive either astaxan-
thin (40 mg/day) or a placebo for four weeks, with
a follow-up after another four weeks. Endoscopy
was used to obtain gastric antral biopsies, which
were then histologically scored for gastritis
morphology. Histology was also used to score H.
pylori density and for immunostaining to detect
interleukin cytokines as well as cell surface
immune markers. e researchers found that
patients without H. pylori had no or only mild
chronic inflammation, whereas patients with H.
pylori had mild, moderate, and severe chronic
inflammation in addition to no, mild, or moderate
active gastritis.
e data from this trial for astaxanthin compared
to placebo were inconclusive.
47
No significant
changes were reported for the H. pylori-negative
patients. In those patients with H. pylori, inflamma-
tion was significantly decreased after taking either
astaxanthin or placebo, with no significant superi-
ority of astaxanthin over placebo. e biopsies from
these patients also showed no significant changes
in density of H. pylori or in any of the interleukins.
e researchers reported that in the H. pylori
patients, astaxanthin significantly up-regulated
CD4 lymphocytes (p<0.05) and significantly
down-regulated CD8 lymphocytes (p<0.01), while
the placebo significantly down-regulated CD4 and
significantly up-regulated CD8. However, they did
not provide sufficient statistical data to confirm any
difference between astaxanthin and placebo.
Male Fertility and Reproduction
In a double-blind RCT, astaxanthin was evalu-
ated for protecting sperm function and fertility.
48
irty men were recruited, all from infertile
couples in which the female partner showed no
demonstrable cause of infertility. ey were
randomized to receive either astaxanthin (16 mg/
day) or a placebo for three months. During that
period they were allowed to provide semen for
intrauterine insemination, and pregnancy occur-
rence was recorded.
By the end of three months, sperm linear
velocity was significantly increased in the astaxan-
thin group (p<0.05) but not in the placebo group.
48
Semen oxygen radical generation (upon stimula-
tion by the oxidant phorbol ester) was markedly
decreased in the astaxanthin group (p<0.05).
However, the most telling outcome of this trial was
the pregnancy rate, which was 54.5 percent for the
astaxanthin group compared to 10.5 percent for
the placebo group (p<0.05).
Eect on Mitochondrial Function
e mitochondria have double membranes
crammed with catalytic proteins that utilize
oxygen to generate energy;
16
however, a small
proportion of this oxygen escapes catalytic control
and is transformed into electronically excited
reactive oxygen species (ROS). Some of these are
neutralized by the antioxidant defenses, but others
evade neutralization and pose a threat to the
mitochondrial membranes.
49
Mitochondrial decline
due to cumulative ROS damage has been suggested
as contributing to the aging process.
50
In a series of experiments with various cultured
cell lines,
3
astaxanthin improved cell survival under
oxidative stress (from the addition of antimycin A,
which increases mitochondrial ROS generation). By
adding an oxidant-sensitive molecular probe into
the mitochondria, the researchers found that
astaxanthin reduced the mitochondria’s endog-
enous production of oxygen radicals and protected
the mitochondria against a decline of membrane
function that typically occurs over time in these
cultures. Astaxanthin’s positive activity went even
further; it increased mitochondrial activity in these
cells by increasing oxygen consumption without
increasing generation of ROS.
e researchers then inserted into the mitochon-
dria another molecular probe that measured their
reducing or redox activity, which mirrors their
capacity to conserve glutathione and re-reduce
oxidized biomolecules.
3
e mitochondria were
then challenged with hydrogen peroxide (H
2
O
2
), an
ROS that should normally oxidize and reverse this
redox state. Astaxanthin was found to protect
against the H
2
O
2
oxidant effect. e concentrations
of astaxanthin required for these in vitro effects
(100-800 nM/L) are achievable in humans by
dietary supplementation.
30,51
Its capacities both to
protect mitochondria and to boost their energy
efficiency should stimulate further research into
this nutrient’s potential for possible anti-aging
effects.
amr
363 Alternative Medicine Review Volume 16, Number 4
Copyright © 2011 Alternative Medicine Review, LLC. All Rights Reserved. No Reprint Without Written Permission.
Monograph
Safety/Toxicity
Astaxanthin has demonstrated safety in numer-
ous human clinical trials. In one open-label clinical
study on subjects with metabolic syndrome
(n=17),
30
astaxanthin (16 mg/day, for three
months) significantly raised blood bilirubin
(p≤0.05), potassium (p≤0.05), and creatine kinase
(p≤0.01), although all three values remained within
normal range. Also, astaxanthin significantly
lowered the liver enzyme gamma-glutamyl trans-
peptidase (GGTP; p≤0.05). Since the researchers
noted this enzyme was abnormally elevated in 11
of the 17 subjects at baseline, this astaxanthin
effect may have been beneficial.
Animal experiments have investigated astaxanthin
at levels well over 120 mg/day in human equiva-
lents,
52
without causing apparent harm. Hoffman-La
Roche confirmed its safety with extensive tests,
including acute toxicity, mutagenicity, teratogenicity,
embryotoxicity, and reproductive toxicity.
53
Suggested Dosage
e doses of astaxanthin used in clinical trials
have ranged from 1 mg/day to 40 mg/day (with the
majority in the 6-12 mg range); single-dose
pharmacokinetic studies used up to 100 mg per
dose. As a dietary supplement, astaxanthin should
be taken along with fats, with or immediately prior
to meals, to ensure its optimal absorption.
51
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