9- cis –Rich β-Carotene Powder of the Alga Dunaliella Reduces the Severity of Chronic Plaque Psoriasis: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract

Synthetic retinoids are one of the mainstay treatments of psoriasis. However, their use is occasionally limited by adverse effects, especially mucocutaneous, hepatic, and lipid profile toxicity. Thus, a search for retinoid metabolites that are both safe and active is essential. The alga Dunaliella bardawil is a natural source of the retinoid precursor 9-cis β-carotene that has a good adverse effect profile.
To test the effect of the alga Dunaliella bardawil on psoriasis.
Thirty-four adult patients with mild, chronic, plaque-type psoriasis were included in this monocentric, prospective, randomized, double-blinded pilot study. Patients received either capsules of the alga D. bardawil or starch powder capsules, as the placebo, for 12 weeks. The response to treatment was evaluated by changes in Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores. Safety of the treatment was evaluated.
At the end of 6 weeks, the reduction in the mean PASI score was significantly higher in the Dunaliella group than in the placebo group (61.3% vs 34%, respectively, p = 0.002). The DLQI change did not reach significance (8.5% and 5.9% in the Dunaliella and in the control group, respectively, p = 0.9). We observed no significant change in the liver function tests or in the lipid profile.
9-cis β-carotene, in the form of D. bardawil, is an effective and safe treatment for patients with mild, chronic, plaque-type psoriasis. A larger study is warranted.

Full text

Original Research
9-cis–Rich b-Carotene Powder of the Alga Dunaliella
Reduces the Severity of Chronic Plaque Psoriasis:
A Randomized, Double-Blind, Placebo-Controlled
Clinical Trial
Shoshana Greenberger, MD, PhD, Dror Harats, MD, Fares Salameh, MD, Tamar Lubish, RN, Ayelet Harari, PhD,
Henri Trau, MD, Aviv Shaish, PhD
Department of Dermatology (S.G., F.S., H.T.) and The Bert W. Strassburger Lipid Center (S.G., D.H., T.L., A.H., A.S.), Chaim Sheba
Medical Center, Tel Hashomer, ISRAEL
Key words: psoriasis, 9-cis b-carotene, Dunaliella, double-blind, placebo-controlled clinical trial
Background: Synthetic retinoids are one of the mainstay treatments of psoriasis. However, their use is
occasionally limited by adverse effects, especially mucocutaneous, hepatic, and lipid profile toxicity. Thus, a
search for retinoid metabolites that are both safe and active is essential. The alga Dunaliella bardawil is a natural
source of the retinoid precursor 9-cis b-carotene that has a good adverse effect profile.
Objective: To test the effect of the alga Dunaliella bardawil on psoriasis.
Methods: Thirty-four adult patients with mild, chronic, plaque-type psoriasis were included in this
monocentric, prospective, randomized, double-blinded pilot study. Patients received either capsules of the alga D.
bardawil or starch powder capsules, as the placebo, for 12 weeks. The response to treatment was evaluated by
changes in Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores. Safety
of the treatment was evaluated.
Results: At the end of 6 weeks, the reduction in the mean PASI score was significantly higher in the
Dunaliella group than in the placebo group (61.3%vs 34%, respectively, p¼0.002). The DLQI change did not
reach significance (8.5%and 5.9%in the Dunaliella and in the control group, respectively, p¼0.9). We observed
no significant change in the liver function tests or in the lipid profile.
Conclusions: 9-cis b-carotene, in the form of D. bardawil, is an effective and safe treatment for patients with
mild, chronic, plaque-type psoriasis. A larger study is warranted.
INTRODUCTION
Psoriasis is a chronic skin disease affecting approximately
2%to 3%of the world population [1,2], which could have a
devastating influence on the affected individual’s life quality
[3–5]. Presently, psoriasis is without a permanent cure, and
treatment is aimed mainly at reducing the clinical symptoms.
Although new biological-immunological therapies are being
developed, oral retinoids remain one of the mainstay treatments
[6].
Since the 1930s, vitamin A deficiency has been known to
cause hyperkeratosis of the skin (phrynoderma), and as early as
the 1960s, synthetic vitamin A (composed mainly of all-trans-
retinol) has been used for the treatment of psoriasis [7–9],
although with low efficacy over the toxicity ratio. Further
research resulted in the development of the second generation
of retinoids, etretinate and its pharmacologically active
metabolite acitretin [10]; both represent highly effective
systemic treatments for psoriasis [11]. However, despite the
demonstrated clinical success of retinoid therapy, this treatment
has a significant potential for toxicity, especially elevated liver
functions, elevated plasma triglycerides, and low-density
lipoprotein (LDL) cholesterol; therefore, it requires close
Address correspondence to Shoshana Greenberger, The Bert W. Strassburge r Lipid Center and the Department of Dermatology, Sheba Medical Ce nter, Tel Hashomer,
52621 ISRAEL. E-mail: shoshana.greenberger@sheba.health.gov.il
Conflict of interest declaration: This work was supported by Nikken Sohonsha Corpora tion, Japan.
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Journal of the American College of Nutrition, Vol. 31, No. 5, 000 –000 (2012)
Published by the American College of Nutrition
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laboratory supervision [11]. Thus, a search for a retinoid
metabolite that is both safe and active is essential.
In the current study, we sought to investigate the effect of
the natural 9-cis retinoic acid precursor, 9-cis b-carotene, on
psoriasis. In contrast to synthetic metabolites, the therapeutic
effect of 9-cis b-carotene on psoriasis has not been explored. 9-
cis b-carotene is present in many fruits and vegetables.
However, its highest levels are found in the micro-alga
Dunaliella bardawil [12]. The b-carotene of the alga is
composed of approximately 50%all-trans b-carotene and
50%9-cis b-carotene [13,14]. The 9-cis b-carotene has been
shown to be a precursor of 9-cis retinoic acid and of all-trans-
retinoic acids [15]. In contrast to eterinate and acitretin, which
are selective agonists of retinoic acid receptors (RARs), 9-cis
retinoic acid is a ligand of 2 retinoid receptor subgroups: RARs
and retinoid X receptors (RXRs; Table 1) [16]. Several studies
have demonstrated the effectiveness of 9-cis retinoic acid in the
treatment of chronic hand eczema [17–19]. Furthermore,
bexarotene, a novel synthetic RXR-selective retinoid, has
shown efficacy in the systemic treatment of psoriasis [20,21].
We previously showed that treatment with the alga D.
bardawil can elevate plasma high-density lipoprotein (HDL)
cholesterol levels and reduce triglyceride levels in patients
treated with fibrates [22]. In this pilot clinical trial, we
examined the effects of oral treatment with capsules containing
9-cis b-carotene–rich D. bardawil powder on patients with
chronic, plaque-type psoriasis.
MATERIALS AND METHODS
Patients and Methods
The study was a monocentric, prospective, parallel,
randomized, double-blind, and placebo-controlled study. Eli-
gible patients were 18 years of age or older with stable, active
plaque psoriasis. As this was a pilot study, with no previous
demonstration of Dunaliella’s effect on psoriasis, we included
only patients with mild psoriasis, involving 10%body surface
area or less. Exclusion criteria were serious or unstable medical
or psychological conditions, active liver or renal disease,
smoking or history of alcohol or drug abuse within the past 1
year, pregnancy, or planning to become pregnant. No
concomitant antipsoriatic therapy was allowed throughout the
study as well as 2 weeks prior to the beginning of the study,
except for emollients and antihistamines. Patients, investiga-
tors, and all study staff were blinded to treatment assignments.
Participants were enrolled and assigned to interventions by the
study coordinator (T.L.). A dermatologist (S.G.) assessed the
eligibility to the study. Patients were randomly assigned at a
2:1 ratio into 2 groups: 22 subjects were treated with
Dunaliella capsules, and 12 subjects were treated with capsules
containing starch powder, as the placebo. Treatment dosage
was 4 capsules of the alga D. bardawil (Nikken Sohonsha
Corporation, Gifu, Japan), 2 capsules after breakfast and 2 after
dinner. Each capsule contained 15–20 mg of b-carotene, with a
ratio of all-trans b-carotene to 9-cis b-carotene of about 1:1.
The total amount of b-carotene was 60–80 mg/d, of which 30–
40 mg was 9-cis b-carotene. This dosage was set given our
previous experience, which showed good tolerability as well as
beneficial effect on the lipid profile.
An institutional review board or ethics committee approved
the study protocol. Written informed consent was obtained
from patients before the start of any study-related procedure.
Clinical Efficacy Evaluation
As a measure of the clinical response, Psoriasis Area and
Severity Index (PASI) scores were given by an investigator
blinded to the treatment assignment (S.G. or F.S.) at baseline,
after the first 6-week period, and at completion of the study (12
weeks). The primary efficacy parameter was a change in PASI
score between baseline and 6 weeks of treatment. Change in
PASI scores between the 2 groups, from baseline to 12 weeks,
served as a secondary efficacy parameter. The Dermatology
Life Quality Index (DLQI) questionnaire was used to evaluate
the quality of life of patients at 0, 6, and 12 weeks. As a marker
of inflammation, the acute phase protein C-reactive protein
(CRP) was measured using a commercial kit by auto analyzer.
Safety and Tolerability Evaluation
At the prestudy visit, the patient’s medical history was
recorded and a physical examination, including vital parame-
ters (e.g., blood pressure, pulse, weight, and temperature), was
completed. Blood samples were taken for analysis of complete
blood cell counts, liver and renal functions, and fasting lipid
profiles.
Carotenoid Plasma Concentrations
All-trans b-carotene isomer levels were determined at week
0 and at week 12 by high-performance liquid chromatography,
according to the method described by Shaish et al [19].
Nutritional Evaluation
Patients’ dietary intakes were assessed by the 24-hour recall
method, delivered by an experienced nurse and directed by a
Table 1. Main Retinoid Receptors and Ligands
Nuclear Receptor Proposed Natural Ligand
RARa,b,cAll-trans retinoic acid
9-cis retinoic acid
RXRa,b,c9-cis retinoic acid
Phytol
Docosahexaenoic acid (DHA)
IQR ¼interquartile range.
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clinical dietitian (A.H.) on 3 days during the 12-week period: 2
days in the middle of the week and 1 day on the weekend. The
data were analyzed for nutrient content by the nutrition data
system Zameret of the Israely Health Ministry.
Statistical Analysis
The paired ttest was used to compare the results of the
baseline to posttreatment. The Mann-Whitney test was used to
compare the results of the 2 groups; a per-protocol analysis was
used. Parametric and nonparametric correlations (Pearson and
Spearman rho) between b-carotene consumption, PASI, and
DLQI were performed using SPSS software (SPSS Inc for
nutritional analysis). Statistical tests were all 2 sided. p,0.05
was accepted as statistically significant.
RESULTS
Efficacy
Thirty-seven patients were screened, and 34 were recruited.
Twenty-two subjects were treated with Dunaliella capsules,
and 12 subjects were treated with placebo. Twenty-eight
patients completed the study; of these, 17 had received
treatment with Dunaliella and 11 with the control, placebo
capsules (Fig. 1). The characteristics of the 2 patient cohorts are
given in Table 2. The treatment groups were similar in
demographic and disease characteristics at baseline. All
participants who completed the trial were at least 85%
compliant with the treatment regimen, as determined by patient
interviews and capsule counts.
To verify the bioavailability of carotenoid from Dunaliella,
we measured plasma b-carotene at baseline and at week 12
(Fig. 2). Following Dunaliella consumption, the plasma mean
for b-carotene increased ;3 times, from 13 to 32 ng/ml ( p¼
0.027). No change in the carotenoid plasma level was detected
in the control group.
The average PASI at baseline was 5.8 63.9 and 4.2 62.0
in the Dunaliella and the control groups, respectively ( p¼
0.22). At the end of 6 weeks, PASI scores were significantly
reduced from baseline in patients treated with Dunaliella,
whereas the control group scores did not reach significance
(paired ttest, p¼0.001 vs p¼0.074, respectively). The
reduction in the mean PASI score was significantly higher in
the Dunaliella group than in the placebo group (61.3%vs 34%,
p¼0.002; Fig. 3A). Similarly, at the end of 12 weeks, a
significant PASI score reduction from baseline was obtained in
patients treated with Dunaliella but not in the control group
(paired ttest, p¼0.01 vs p¼0.06, respectively). However, the
reduction in the mean PASI score was not statistically
significant between the groups: 50.7%vs 36.4%for Dunaliella
and control, respectively (p¼0.28). At week 12, PASI75 was
achieved in 40.0%of the patients receiving Dunaliella and in
27.3%of the control patients. To evaluate the effect of
Dunaliella on the patients’ quality of life, DLQI assays were
performed. The mean change from baseline to week 6 was
8.5%and 5.9%in the Dunaliella and in the control group,
respectively. This change was not statistically significant ( p¼
0.09 and p¼0.27, respectively). At the end of 12 weeks, the
DLQI improved significantly in the Dunaliella group but not in
the control group (26.5%,p¼0.019 and 21.9%,p¼0.9,
respectively; Fig. 3B). As a surrogate marker for inflammation,
we analyzed CRP levels at baseline and in weeks 6 and 12 (Fig.
4). Blood CRP levels decreased in the Dunaliella group from
baseline to 6 weeks and from baseline to 12 weeks, without
Fig. 1. Flow diagram of the randomized clinical trial.
Table 2. Baseline Demographics and Baseline Blood Test
Results
Control
(Median, IQR)
Dunaliella
(Median, IQR)
Age 52 (39–65) 52 (39–56)
Males (n) 8 11
Females (n) 3 6
Weight (kg) 83 (81–87) 79 (72–84)
Body mass index (kg/m
2
) 27 (26–30) 27 (26–29)
Systolic blood pressure
(mm Hg)
130 (128–133) 120 (110–130)
Diastolic blood pressure
(mm Hg)
85 (80–90) 80 (73–90)
Pulse (beats per minute) 71 (68–75) 76 (70–80)
Fasting glucose (mg%) 90 (86–96) 91 (88–105)
Blood creatinine (mg%) 1 (0.97–1.14) 1 (0.91–1.06)
Total cholesterol (mg%) 204 (182–219) 200 (174–214)
Triglycerides (mg%) 128 (108–149) 108 (80–162)
High-density lipoprotein
(mg%)
43 (39–48) 49 (43–60)
IQR ¼interquartile range.
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Fig. 2. All-trans b-carotene plasma levels (ng/ml) at baseline and at week 12 in patients receiving Dunaliella or placebo (control). Asterisks denote
statistically significance (p,0.05 ) compared with baseline. Bars represent mean of the group. The T bars indicate standard error of means (SEM).
Fig. 3. (A) Mean Psoriasis Area and Severity Index changes from baseline (in percentages) at 6 and 12 weeks in patients receiving Dunaliella or
placebo (control). Asterisks denote statistical significance (p,0.05 ) compared with the control, placebo group. Bars represent the mean of the group.
The T bars indicate standard errors (SEM). (B) Mean Dermatology Life Quality Index from baseline (in percentages) at 6 and 12 weeks in patients
receiving Dunaliella or placebo (control). Asterisks denote statistical significance (p,0.05) compared with the control, placebo group. Bars represent
the mean of the group. The T bars indicate standard errors (SEM).
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reaching statistical significance (p¼0.26 and p¼0.09 at 6 and
12 weeks, respectively).
Nutritional Analysis
No difference in consumption of total calories, fat, protein,
or carbohydrates was found between groups (Table 3). We
found no correlation between baseline PASI and b-carotene or
retinol equivalent consumption. No association was found
between the daily consumption of vitamin A and b-carotene
and any of the analyzed parameters (PASI and DLQI change in
6 or 12 weeks).
Safety
There were no treatment-related adverse events in the
overall study. In the Dunaliella group, 1 patient had a
myocardial infarction during percutaneous transluminal coro-
nary angioplasty, leading to an emergency coronary artery
bypass. In the control group, 1 patient had syncope, without a
known cause. We observed no increase in liver function in the
Dunaliella-treated group. In addition, we found no significant
change in the lipid profile (total cholesterol, triglycerides, HDL,
LDL, lipoprotein[a], apo A1, apo B, apo C2, or apo C3) in the
Dunaliella or in the control group (see Supplementary Fig. 1).
DISCUSSION
In the present pilot study, we studied the safety and the
clinical efficacy of Dunaliella, a natural source of 9-cis b-
carotene, in the treatment of psoriasis. We found mild
improvement in PASI (at weeks 6 and 12) and DLQI scores
(at week 12) in patients receiving D. bardawil powder
compared with control patients.
Carotenoid levels have not been clearly linked to psoriasis.
Although it has been shown that levels were mildly lower than
normal in psoriatic patients, no significant differences have
been shown between the patients’ lesional and nonlesional skin
[23]. Also, previous works, beginning as early as the 1960s,
have shown only minimal effects from synthetic vitamin A on
plaque-type psoriasis. The difference between the past findings
and our observed efficacy may result from the different retinoid
precursor used. Synthetic vitamin A is composed solely of all-
trans-retinol as opposed to the natural precursors, 9-cis b-
carotene that is converted both to 9-cis retinoic acid and all-
trans-retinoic acid. Whereas the all-trans metabolites can
activate only RAR, the combination of 9-cis retinoic acid and
all-trans retinoic acid can bind and activate both RAR and
RXR [16]. Accordingly, it is assumed that D. bardawil
consumption leads to the formation of activated retinoid
nuclear receptors heterodimers (RAR/RXR) and homodimers
(RAR/RAR or RXR-RXR). Importantly, retinoid-sensitive
target genes in the human skin have been shown to be
responsive predominantly to RXR/RAR heterodimers [24,25].
Also, epidermal keratinocytes are a plausible target of
carotenoids, as human melanocytes and keratinocytes were
shown to be able to accumulate b-carotene and convert it to
retinol [26].
We observed none of the common adverse effects of
acitretin. Dunaliella consumption did not lead to mucocutane-
ous side effects (brittle nails, hair loss, cheilitis, etc.). In
addition, liver function tests or triglycerides and LDL, very
commonly increased by acitretin [27–29], did not change.
These findings are in accordance with our previous studies,
showing no adverse effects of Dunaliella capsules consump-
tion [22,30]. The dissimilarity in the adverse effects profile may
be related to the retinoid dose. The binding of acitretin and 9-
cis retinoic acid to different receptor subtypes may provide an
alternative explanation.
Several limitations apply to our study. First, as the crude
Dunaliella powder is used, the exact carotenoid composition
and the effect of the different isomers on chronic plaque
psoriasis cannot be established. Second, the study was
conducted on a small group, and last, patients withdrawn from
Fig. 4. Mean C-reactive protein (mg/ml) at baseline and at weeks 6 and
12 in patients receiving Dunaliella or placebo (control). Bars represent
the mean of the group. The T bars indicate standard errors (SEM).
Supplementary Fig. 1. Mean change of glucose (mg%), liver
functions (aminotransferase and alanine aminotransferase, in units),
and lipid profiles (mg%) from baseline to week 12 in patients receiving
Dunaliella or placebo (control). Bars represent the mean of the group.
The T bars indicate standard errors (SEM).
Table 3. Baseline Nutritional Consumption
Control Dunaliella
Energy (kcal) 2017 6523 1764 6463
Carbohydrates (g) 203 692 176 665
Protein (g) 89 622 80 624
Fat (g) 88 626 79 624
Fiber (g) 19 652167.6
b-carotene (lg) 1307 61971 734 6524
Retinol equivalent (lg) 2855 62106 3175 62889
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the study could not be examined, and thus, an intention-to-treat
analysis could not be performed.
CONCLUSIONS
In sum, in this pilot study, we demonstrate the effect of
Dunaliella alga, a natural source of 9-cis b-carotene, on mild,
chronic plaque psoriasis. Our preliminary results exemplify the
diversity of the retinoid compounds, both in terms of efficacy
and safety. We believe that our encouraging findings merit a
more extensive study on the antipsoriatic effect of the D.
bardawil alga. As psoriasis is a chronic, lifelong disease, there
is a crucial need for the development of inexpensive and
effective therapies.
ACKNOWLEDGEMENT
Shoshana Greenberger is supported by the Talpiot Medical
Leadership Program, Sheba Medical Center, Israel. This work
was supported by Nikken Sohonsha Corporation, Japan.
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