PHYTOTHERAPY RESEARCH

Phytother. Res. 29: 1439–1451 (2015)

Published online 14 August 2015 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.5432

REVIEW
Phytochemical and Botanical Therapies for
Rosacea: A Systematic Review

Whitney A. Fisk,1† Hadar A. Lev-Tov,2† Ashley K. Clark3 and Raja K. Sivamani1*

1
Department of Dermatology, University of California—Davis, Sacramento, CA, USA
2
Department of Dermatology, Albert Einstein College of Medicine, Bronx, NY, USA
3
School of Medicine, University of California—Davis, Sacramento, CA, USA

Botanical and cosmeceutical therapies are commonly used to treat symptoms of rosacea such as facial erythema,
papules/pustule counts, and telangiectasia. These products may contain plant extracts, phytochemicals, and
herbal formulations. The objective of this study was to review clinical studies evaluating the use of botanical
agents for the treatment of rosacea. MEDLINE and Embase databases were searched for clinical studies
evaluating botanical therapies for rosacea. Major results were summarized, and study methodology was analyzed.
Several botanical therapies may be promising for rosacea symptoms, but few studies are methodologically
rigorous. Several plant extract and phytochemicals effectively improved facial erythema and papule/pustule
counts caused by rosacea. Many studies are not methodologically rigorous. Further research is critical, as many
botanicals have been evaluated in only one study. Botanical agents may reduce facial erythema and effectively
improve papule/pustule counts associated with rosacea. Although promising, further research in the area is imperative.
Copyright © 2015 John Wiley & Sons, Ltd.
Keywords: ROSACEA; plants; herbs; botanical; alternative; phytochemical.

External factors that can precipitate symptoms of

INTRODUCTION
Rosacea is a disorder characterized by facial erythema,
flushing, and telangiectasias. Some subtypes present
with inflamed papules, pustules, and fibrosis (Wilkin
et al., 2004). People with lighter skin pigmentation are
more commonly affected and prevalence increases with
age (Tan and Berg, 2013). The symptoms can be
distressing, uncomfortable, and frequently resistant to
treatment (Bohm et al., 2014). The National Rosacea
Society has defined four subtypes of rosacea:
erythematotelangiectatic (ET), papulopustular (PP),
ocular and phymatous subtypes (Wilkin et al., 2004).
The pathogenesis of rosacea is complex and
incompletely understood. Several key contributing
factors include immune dysregulation, compromised
epidermal barrier function, and vascular hyper-reactivity.
Documented vascular abnormalities include increased
expression of angiogenic mediators (Gomaa et al.,
2007) and compromised vascular integrity (Neumann
and Frithz, 1998; Aroni et al., 2008; Steinhoff et al.,
2013). Hyperactive inflammatory responses may
precipitate these abnormalities (Jones, 2004; Bakar
et al., 2007). In particular, the increased expression of
antimicrobial peptides and protease-activity may be
important in pathogenesis (Reinholz et al., 2012).
Demodex folliculorum, a facial mite that inhabits hair
follicles, may contribute to rosacea’s pathogenesis
(Georgala et al., 2001).
* Correspondence to: Raja Sivamani, MD MS CAT, Department of
Dermatology, University of California—Davis, 3301 C Street, Suite 1400,
Sacramento, CA, USA.
E-mail: rksivamani@ucdavis.edu
†
These authors contributed equally in this manuscript.
Copyright © 2015 John Wiley & Sons, Ltd.
rosacea (mainly flushing) include sun exposure, emo-
tional stress, and ingestion of alcohol, spicy foods, and
caffeine. These likely trigger symptoms by stimulating
inflammatory cascades and production of reactive
oxygen species (ROS) (Del Rosso, 2012). Ultraviolet
(UV) radiation exposure, for example, leads to in-
creased ROS in the skin, which elicits an immune
response and increases expression of angiogenic factors
(Murphy, 2004). Other known extrinsic triggers of
rosacea, including emotional stress and alcohol intake,
also are associated with increased production of ROS
and proinflammatory mediators (Del Rosso, 2012).
Rosacea is commonly treated with topical therapies
including metronidazole, azelaic acid, erythromycin,
and sodium sulfacetamide 10%/sulfur 5% (Fallen and
Gooderham, 2012). Patients with severe PP rosacea or
ocular rosacea may require systemic therapies such as
tetracycline or macrolide antibiotics, metronidazole, or
isotretinoin (Erdogan et al., 1998; Pelle et al., 2004).
These systemic medications carry a risk of significant
side effects when used for extended periods of time
and chronic antibiotic use may encourage the growth
of resistant organisms (Chon et al., 2012). Newer anti-
biotic dosing regimens do not appear to have as many
side effects and do not promote the development of
resistant bacteria (Berman et al., 2007; Del Rosso,
2009) but can still be expensive. These treatments are
generally most effective for patients with the PP sub-
type and may not significantly improve facial erythema
or telangiectasia (Korting and Schollmann, 2009). In
ET rosacea, the recently approved topical brimonidine
tartrate is an effective therapy (Fowler et al., 2013) but
may be expensive. Laser and light-based therapies may
improve erythema and telangiectasia, but their use is
Received 30 April 2015
Revised 12 July 2015
Accepted 22 July 2015
1440 W. A. FISK ET AL.
limited by high cost, which is often not covered by in-
surance (Pelle et al., 2004).
Botanical therapies are increasingly popular for skin
conditions, including rosacea. These include products
made with plant extracts, herbal formulations, and
phytochemicals. Phytochemicals are plant-derived com-
pounds that are thought to be responsible for the health-
promoting effects of the plant (Arts and Hollman,
2005). These chemicals include flavonoids, lignans, and
catechins. One study found that 22% of patients with
rosacea utilized alternative medicine, such as botanical
therapies (McAleer and Powell, 2008). Interestingly,
none of the surveyed subjects were aware of any poten-
tial adverse effects associated with these therapies and
over half stated that they would not spontaneously
discuss their use of complementary therapies with their
dermatologist. Given the increasing popularity of these
therapies, physicians should be aware of their benefits,
risks, and clinical utility. This review describes the
available clinical research regarding botanical therapies
for rosacea. The effects on the primary symptoms
of rosacea are discussed, with special emphasis on
improvement in facial erythema, as current treatments
for erythema are limited to one FDA approved
therapy (Fowler et al., 2013). Study methodology of
each reviewed article is evaluated, and strategies
for incorporating botanical therapies into treatment
regimens are discussed.
METHODS
Search strategy. Pubmed and Embase databases were
searched for clinical trials evaluating botanical therapies
in subjects with rosacea between. Pubmed was searched
using the following MeSH terms: rosacea, erythema,
phytotherapy, plants-medicinal, plant extracts, flavo-
noids, and drugs-Chinese herbal. The terms flavonoid
and herbaceous agent were included in these searches
under the umbrella term ‘plant medicinal product’.
Embase was searched using Emtree terms: rosacea, face
erythema, plant medicinal product, phytotherapy, flavo-
noids, herbal medication, and Chinese drug. Searches
were filtered to return only clinical studies published in
English. The references of included studies were
searched for additional applicable articles that were
not discovered in our database search.
Study selection. Abstracts were reviewed based on
predefined inclusion and exclusion criteria. When
necessary, full texts were retrieved to assess study eli-
gibility. Studies meeting the following inclusion and
exclusion criteria were included:
Inclusion criteria:
(1) published in English;
(2) randomized clinical trial, clinical study, or cohort
study;
(3) subjects diagnosed with rosacea;
(4) intervention included a botanical agent (plant extract,
herbal formulation, phytochemical, and vitamin
derivatives); and
(5) outcome measures included evaluation of change in
severity of rosacea symptoms.
Copyright © 2015 John Wiley & Sons, Ltd.
Exclusion criteria
(1) in vitro and non-human trials and
(2) studies evaluating prescription medication commonly
used in clinical practice for rosacea (for example
azelaic acid) alone, without botanical agents.
Data extraction. Data were extracted from chosen
studies. From each study, the following information
was extracted and documented in a table:
(1) Study design
(2) Description of participants (number and type of
rosacea)
(3) Method of assessing rosacea severity
(4) Botanical agent including vehicle formulation
(5) Extraction method of botanical agent, when applicable
(6) Major results and conclusions
(7) Adverse events
(8) Potential sources of bias including appropriate-
ness of randomization, blinding, subject selection
and thoroughness of reporting data.
RESULTS AND DISCUSSION
Eleven published manuscripts and two poster abstracts
met inclusion criteria (Fig. 1, Table 1). Botanical inter-
ventions included phytochemicals (n = 8), plant extracts
(n = 2), and herbal formulations (n = 1). Three plant
extracts were studied, Quasia amara extract (n = 1)
(Ferrari and Diehl, 2012), Chrysanthellum indicum
extract (n = 1) (Rigopoulos et al., 2005), and silymarin
(n = 2) (Nield and Ippersiel, 2002; Berardesca et al.,
2008). Phytochemicals studied were licochalcone
(n = 2) (Weber et al., 2006; Broniarczyk-Dyla et al.,
2011), epigallocatechin gallate (EGCG) (n = 1)
(Domingo et al., 2010), niacinamide (n = 1) (Draelos
et al., 2005), ‘Nicomide’ nicotinamide/zinc/copper/folate
oral tablet (n = 1) (Niren and Torok, 2006), and Kinetin
N6-furfuryladenine (n = 1) (Wu et al., 2007). The phyto-
chemical structures are shown in Fig. 2. One manuscript
evaluated an herbal formulation from traditional
Chinese medicine, Chibixiao Recipe (n = 1) (Yu et al.,
2006). Two studies were only found in abstract form;
one evaluated a flavonoid cream (Grazyna et al., 2012)
and the other a combination cream containing palmitoyl
tripeptide-8 epurea extract, caffeine, zinc gluconate, and
bisabolol (Raab et al., 2012). Five papers identified the
botanical intervention as a commercially produced
product (Table 2). Meta-analysis was not performed be-
cause each botanical was studied in only one or two
studies, and outcome measures were heterogeneous.
Instead, we focus on a systematic review of the literature
and discuss botanicals individually.
Botanicals were most effective for improving facial
erythema and papule/pustule counts. Only one botani-
cal, Quassia amara extract, improved the appearance
of telangiectasias. One study of EGCG did not report
clinical improvements in telangiectasia but noted that
the overexpression of pro-angiogenic mediators char-
acteristic of rosacea skin was suppressed with therapy.
Reviewed studies are limited by multiple methodologi-
cal flaws including lack of appropriate blinding and
Phytother. Res. 29: 1439–1451 (2015)
 PHYTOCHEMICAL AND BOTANICAL THERAPIES FOR ROSACEA
Figure 1. Flow chart of systematic search selection process. EGCG, epigallocatechin gallate.
control groups. Study findings and assessment of meth-
odology are discussed in more detail below.
Treatment strategies utilizing botanicals
Botanical agents may be used as topical therapy, oral
therapy, adjuvant therapy with conventional treatments,
or as preventative therapy in patients with mild/early
symptoms. Each of these strategies has been studied.
Two clinical trials evaluated treatment regimens com-
bining botanical therapies with conventional treatment.
The addition of Chibixiao recipe (herbal formulation) to
treatment with minocycline and spironolactone sig-
nificantly improved the overall appearance of ET and
PP rosacea and decreased recurrence rates at 4-month
follow-up (Yu et al., 2006). A treatment regimen con-
sisting of topical metronidazole and licochalcone contain-
ing creams significantly improved facial erythema and
pustule counts in patients with ET and PP rosacea (Weber
et al., 2006). This study shows that the botanical agent and
metronidazole were compatible therapies. However, the
study was not designed to compare the efficacy of metro-
nidazole with and without licochalcone cream.
Rosacea patients who do not tolerate conventional
therapies may benefit from botanical interventions,
and some studies suggest that botanical therapies may
be used as alternatives to conventional treatments.
Patients taking an oral supplement containing a mixture
of nicotinamide, zinc, copper, and folate responded
equally well to a single topical therapy as they did to
multiple topical therapies (Niren and Torok, 2006).
Copyright © 2015 John Wiley & Sons, Ltd.
1441
Also, adding an oral antibiotic to the nicotinamide
supplement did not significantly improve treatment
outcomes. Given this, the authors suggest that oral
nicotinamide/zinc/copper/folate might be an alternative
to oral antibiotic therapies. Furthermore, they report
that 82% of participants who had previously received
antibiotic therapy considered nicotinamide/zinc/copper/
folate tablets to be as effective or superior to previously
trialed antibiotics. Trials directly comparing nicotin-
amide and antibiotics are lacking but needed. Similarly,
the authors of a randomized clinical trial of C. indicum
extract suggest that its efficacy may be similar to the
reported efficacies of metronidazole, based on a 41.2%
reduction in erythema in study subjects (Rigopoulos
et al., 2005). However, this study used vehicle cream as
a control, and a head to head study of C. indicum to
metronidazole is needed to assess this suggestion.
Several studies suggest that botanical therapies may
be useful as preventative agents. Domingo et al. show
that EGCG cream suppresses vascular endothelial
growth factor (VEGF) and hypoxia inducible factor-1α
(HIF-1 α), two compounds that stimulate angiogenesis
(Domingo et al., 2010). They suggest that the cream
may prevent or slow development of telangiectasias
and erythema and thus may be useful as a preventative
therapy. However, chromameter measurements did not
show a significant difference in the clinically observable
erythema between split face assessment of topical
EGCG and placebo. Of note this split-face study
included only four participants. Broniarczyk-Dyla et al.
(2011) investigated the efficacy of a licochalcone cream
regimen and recommended its use in patients with
Phytother. Res. 29: 1439–1451 (2015)
 Table 1. Summary of clinical studies evaluating botanical therapies for rosacea
1442

Outcome Limitations Previous medication Diagnosing Jadad

Intervention Study design Comparison Subjects measure Major results and notes course practitioner Author scale

Chibixiao Recipe RCT 8 weeks Control group N = 68 ET and 1) Clinically evaluated 1) Treatment 1) Also used Patients had Dermatologist (Yu et al., 1
combined with received only PP subtypes erythema, capillary combination cryotherapy for received no 2006)
minocycline and minocycline dilatation papule significantly more capillary dilation systemic drug
spironolactone and spirono- and pustule count effective than in both groups therapy in the
lactone after 8-week study control (for past half-month.
and 4-month follow-up both ET and
papular subtypes)
2) Serum testosterone 2) Serum 2) Criteria for

Copyright © 2015 John Wiley & Sons, Ltd.

levels testosterone assessing
levels significantly clinical signs
less after therapy not described
in treatment group
(same at baseline)
3) Significantly 3) Outcomes
less recurrence presented
at 4 months in categorically
treatment group
Chrysanthellum RCT 12 weeks Vehicle cream N = 246, 1) Severity of erythema 1) Significant Authors suggest Topical medication, Clinical (Rigopoulos 5
indicum 1% moderate referenced against improvement in similar treatment oral therapy, diagnosis et al., 2005)
extract (cream) 2rosacea six photographs erythema and efficacy as CNS, vasoactive
overall rosacea topical nor cosmetics
severity compared metronidazole could be used within
to placebo and in discussion 6 weeks of the
W. A. FISK ET AL.

baseline study.
2) Surface area 2) No significant
of erythema difference in area
and rosacea involved between
3) Overall severity groups
scores by physician
and subject
EGCG 2.5% Split face Vehicle cream N = 4 (split 1) Biopsies for 1) Significant Subjects included N/A N/A (Domingo 3
(cream) RCT 6 weeks face trial), immunohistochemistry decrease in those with ET et al., 2010)
ET subtype (VEGF and HIF-1a – VEGF and rosacea and
hypoxia inducible HIF-1a those with facial
factor-1-alpha) expression in erythema not
treated skin because of
2) Colorimetry 2) No significant rosacea
3) Skin exam difference in
vascularity in
biopsy samples
or colorimetric
assessment
of erythema

Phytother. Res. 29: 1439–1451 (2015)

(Continues)
 Table 1. (Continued)
Outcome Limitations Previous medication Diagnosing Jadad
Intervention Study design Comparison Subjects measure Major results and notes course practitioner Author scale

Kinetin lotion Single group None N = 18, mild 1) Inflammatory 1) No significant Subjects also N/A N/A (Wu et al., 1
(Kinerase®) efficacy trial to moderate papule count change in used SPF 30 2007)
12 weeks rosacea (<10 papule count and no control
papules, or telangiectasia group to isolate
persistent score this effect
erythema, 2) Erythema and 2) Significant
telangiectasia) telangiectasia decrease in
scored on a erythema score
four-point scale

Copyright © 2015 John Wiley & Sons, Ltd.

3) Overall severity 3) Product well
on a seven-point scale tolerated
4) Overall
improvement on a
six-point scale
compared with
baseline
Licochalcone-A Single group None N = 32 mild 1) Scale of 1–3 1) Significant Overall Patients did not N/A (Weber et al., 0
(cleanser, SPF15 efficacy trial to moderate for erythema, improvements in improvement use topical or 2006) Study I
day and night 8 weeks ET rosacea burning, itching, erythema scores rated as 2.56 oral medication,
creams, concealer) stinging, tingling in both rosacea (between no including OTC
and tightness and non-rosacea and mild antiinflammatory
group improvement) agents, nor
N = 30 non- 2) Digital 2) More recently used
rosacea with photography with significant results retinols or
red facial skin and without cross in non-rosacea hydroxyl-acid
polarizing filter group preparations prior
3) QOL 3) Significant to the study.
questionnaire improvement in
converted to QOL index
QOL index
Licochalcone-A Single group None N = 32, ET 1) Scale of 1–3 for 1) Significant 1) Lic-A used Patients did not N/A (Weber et al., 0
combined with efficacy trial (n = 25) and erythema, burning, improvement in for only second use topical or 2006) Study 2
metronidazole 4 weeks PP (n = 8) itching, stinging, erythema, burning, half of 4-week oral medication,
PHYTOCHEMICAL AND BOTANICAL THERAPIES FOR ROSACEA

subtypes tingling and tightness stinging, itching, study including OTC

tightness and antiinflammatory
tingling compared agents, nor
to baseline after recently used
2 and 4 weeks retinols or
2) Papule and 2) Significant 2) Authors note hydroxyl-acid
pustule counts decreases in that this study preparations prior
(n = 8) lesion counts at proves that to the study.
2 and 4 weeks two products
for papules and are compatible.
at 4 weeks for LicA not studied

Phytother. Res. 29: 1439–1451 (2015)

1443

pustules independently.

(Continues)
 Table 1. (Continued)
1444

Outcome Limitations Previous medication Diagnosing Jadad

Intervention Study design Comparison Subjects measure Major results and notes course practitioner Author scale

Licochalcone Single group None N = 35, pre- 1) Four point Significant Patients also All patients Clinical (Broniarczyk- 0
(cream efficacy trial rosacea, ET NRS (national decrease in used moisturizer completed assessment Dyla et al.,
moisturizer) 8 weeks and PP rosacea society) erythema severity, with SPF during treatment based on 2011)
subtypes scale increase in morning and with other four-step
2) Severity of skin moisture night cream with agents that NRS scale
erythema and decrease panthenol which could affect
(mexameter) in TEWL values may have the results at
3) Skin hydration compared with contributed least 2 weeks
(corneometer) baseline to efficacy before the

Copyright © 2015 John Wiley & Sons, Ltd.

4) TEWL (tewameter) (Note: Unclear study.
whether change
in NRS score
was significant)
Niacinamide- RCT 4 weeks Untreated N = 50, 1) Instrumental 1) Significant 1) Single blind Subjects using Dermatologist (Draelos et al., 2
containing forearm (forearms advanced assessment improvement in 2) Barrier oral corticosteroids, 2005)
moisturizer used to test rosacea, ET of barrier skin barrier function tested topical antiaging
(Olay Total barrier functions, and PP function of function on forearm products, antiacne
Effects 7 Visible not rosacea subtypes forearm (DMSO parameters (randomization products, or topical
Anti-Aging symptoms) probe) refers to which corticosteroids
Vitamin Complex) forearm was within 2 weeks prior
treated) to study enrollment.
2) Instrumental 2) Erythema 3) Did not Other prescribed
assessment improved ‘markedly’ evaluate vehicle medications for
W. A. FISK ET AL.

of stratum over 4 weeks independently rosacea were

corneum and papule/pustule for effect allowed during
counts decreased on TEWL the study, but
(no statistics) no change in
3) Dermatologist 3) No change in therapy was
evaluation of rosacea telangiectasias permitted.
severity (4-point scale)
4) Subject self-
assessment
Oral Nicotinamide Multi-center N/A N = 198, 1) Self-reported patient 1) 75% (of rosacea 1) Self-reported N/A (Niren and 0
and Zinc prospective subjects with global evaluation subgroup) reported outcomes by Torok, 2006)
(‘Nicomide’ 750-mg cohort trial acne vulgaris (scale 1–5) appearance was questionnaire
nicotinamide, 24-mg 8 weeks andor rosacea moderately or (no objective
zinc, 1.5-mg copper, (rosacea n = 49) much better evaluation by
500-μg folic acid) after 8 weeks independent
observer)*
2) Self-reported 2) Significant 2) Did not control
reduction in reduction in IL (in for other
inflammatory rosacea subgroup) treatments but
lesions (IL) after 8 weeks of did ask
treatment (slower

Phytother. Res. 29: 1439–1451 (2015)

(Continues)
 Table 1. (Continued)
Outcome Limitations Previous medication Diagnosing Jadad
Intervention Study design Comparison Subjects measure Major results and notes course practitioner Author scale

onset of action participants to

compared with report these
acne patients)
3) Patient satisfaction 3) Participants
taking an oral
antibiotic and
Nicomide did not
improve
significantly more

Copyright © 2015 John Wiley & Sons, Ltd.

than those taking
Nicomide as their
only oral medication
Quassia amara, Single group None N = 30, grade 1) Papule and 1) Significant Authors note: A washout period N/A (Ferrari
4% extract (gel) efficacy trial I–IV rosacea pustule count decrease in patients with of 4 weeks after and
6 weeks (Wilkin et al., 1 flushing score, severe rosacea topical and/or Diehl,
2002) papule and were most systemic 2012)
pustule score, improved treatment of
erythema score rosacea was
and conducted.
telangiectasia Patients treated
score with any
2) Severity of systemic, topical
flushing (0–3) or cosmetic
3) Severity of 2) Complete treatment that
tenlangiectasia resolution of could influence
(0–3) pustules the parameters of
evaluation of the
study were
rejected.
Approximately
33% of patients
had received
previous
PHYTOCHEMICAL AND BOTANICAL THERAPIES FOR ROSACEA

treatment for
rosacea
4) Overall improvement
Silymarin and RCT 1 mo Placebo (vehicle N = 46, stage 1) Clinical evaluation 1) Significant Improvement in N/A N/A (Berardesca 3
methylsulfon- cream) I–III rosacea, ET for erythema, itch, reductions in papule corneometry may et al., 2008)
lmethane (cream) and PP subtypes stinging, burning count, erythema, be because of
and papules on a stinging and itch moisturizing
five-point scale scores compared effects and is
to placebo present in both
2) Corneometer for 2) Significant groups
skin hydration decrease in

Phytother. Res. 29: 1439–1451 (2015)

1445

(Continues)
 Table 1. (Continued)
1446

Outcome Limitations Previous medication Diagnosing Jadad

Intervention Study design Comparison Subjects measure Major results and notes course practitioner Author scale

erythema index
compared to
placebo and baseline
3) Erythema index 3) Significant
with mexameter improvement in
corenometry in both
groups
Silymarin cream Single group None N = 32, mild to Clinical evaluation of Statistically 1) Participants N/A N/A (Nield and 0
(‘Rosacure®’: efficacy trial moderate erythema on each facial significant also given Ippersiel,

Copyright © 2015 John Wiley & Sons, Ltd.

Synchrose 12 weeks rosacea, ET area (nose, cheek, improvement in sunscreen which 2002)
Intensive®) subtype forehead and chin) on a erythema may have
six-point scale and compared to contributed to
telangiectasia on a five- baseline but not efficacy
point scale in telangiectasia 2) Cream also
contains
tocopheryl
acetate,
hyaluronic acid
and acetyl
glucosamine
Abstracts

Flavanoid creams Single group None N = 33 with 1) four-point NRS scale 1) Reduction in Incomplete N/A N/A (Grazyna N/A
W. A. FISK ET AL.

(contents not efficacy trial rosacea severity of information in et al., 2012)

specified in erythema oral presentation
abstract) 2) Tewameter 2) Reduction in
measurement average TEWL
3) Mexameter values after
measurement treatment
Palmitoyl tripeptide-8, Single group None N = 50 mild to 1) Clinical evaluation 1) Significant Sponsored by N/A N/A (Raab et al., N/A
epurea extract, efficacy trial moderate of redness, flushing, improvements in L’Oreal Research 2012)
bisabolol, caffeine rosacea with at overall appearance and redness, flushing, and Innovation.
and zinc gluconate least three rosacea severity overall appearance,
(lotion) inflammatory using a five-point scale rosacea severity
papules and lesion count
compared to
baseline.
2) Instrumental 2) TEWL Incomplete
assessment of TEWL, measurements information in
hydration and steady throughout oral presentation
skin redness the study

Phytother. Res. 29: 1439–1451 (2015)

 PHYTOCHEMICAL AND BOTANICAL THERAPIES FOR ROSACEA 1447

rosacea as well as ‘pre-rosacea’, which they define as

Figure 2. Phytochemical structures. This figure is available in colour
online at wileyonlinelibrary.com/journal/ptr.
sensitive skin with increased vascular reactivity. Theo-
retically, controlling these early symptoms could help
prevent progression to more advanced stages of rosacea
for some patients (Lowe, 2003). This suggestion
requires more clinical investigation but is supported by
evidence that extended remission of rosacea symptoms
decreases baseline erythema (Dahl et al., 1998).
Overall, the clinical data suggest that botanicals may
have a role in rosacea therapy and may serve as adjuvants
with conventional therapies. However, more high quality
studies are needed to assess their role in therapy. Preven-
tative treatment strategies may be appropriate for pa-
tients with early symptoms or a strong likelihood of
developing symptoms. Using botanical and conventional
therapies simultaneously may be beneficial, as long as
their pharmacological effects do not interfere with the ef-
fects of conventional therapies. However, as discussed in
more detail in the succeeding text, studies are limited by
multiple methodological limitations, and only five of the
studies included appropriate placebo or control groups.
Efficacy of botanicals for specific rosacea symptoms

Rosacea is a heterogeneous disease characterized by four

primary symptoms: flushing, erythema, telangiectasias,

Table 2. Reproducibility of active agents in studies evaluated

Method of obtaining Reproducibility of

Botanical agent Formulation active agent active ingredient

Chibixiao recipe Herbal formulation Not described 2

(Yu et al., 2006)
Chrysanthellum Plant extract Product supplied. Referred to 3
indicum extract as manufactured
(Rigopoulos et al., 2005) product in acknowledgements
but more details not provided
EGCG cream (Domingo Phytochemical Not described 2
et al., 2010)
Kinetin 0.1% Phytochemical Product supplied (Kinerase, Valeant 1
moisturizing lotion Pharmaceuticals International, CA)
(Wu et al., 2007)
Licochalcone Phytochemical Not described 2
(Broniarczyk-Dyla
et al., 2011)
Licochalcone Phytochemical Not described 2
(Weber et al., 2006)
Niacinamide-containing facial Commercial formulation Product supplied (Olay Total 1
moisturizer Effects 7 Visible
(Draelos et al., 2005) Anti-Aging Vitamin
Complex Fragrance Free)
Oral nicotinamide Commercial formulation Product supplied (‘Nicomide’ 1
and zinc 750 mg nicotinamide,
(Niren and Torok, 2006) 24 mg zinc, 1.5 mg copper,
500 μg folic acid)
Quassia amara (Ferrari Plant extract Hydroglycolic extraction 2
and Diehl, 2012) (more details not provided)
Silymarin (Berardesca et al., 2008) Plant extract Not described 2
Silymarin (Nield and Ippersiel, 2002) Commercial formulation Product supplied (Rosacure®: Synchrose) 1
containing phytochemical Intensive®, Canderm Pharma Inc.,
agent Ville St-Laurent, Canada)

1—Reasonably reproducible.
2—Some information missing to be reasonably reproducible.
3—No information is provided in order to be reasonably reproducible.

Copyright © 2015 John Wiley & Sons, Ltd. Phytother. Res. 29: 1439–1451 (2015)
1448 W. A. FISK ET AL.

Table 3. Mechanisms of action of plant extracts

Plant extracts

Scientific name Common name Mechanisms of action Active constituents

Chrysanthellum indicum N/A 1) Antiinflammatory Flavonoids, saponosids, and

2) Anti-oxidant phenylpropenoic acids
3) Stabilizes vasculature
Quassia amara Amargo, Bitter wood 1) Antiinflammatory Triterpenoids
2) Anti-oxidant
3) Anti-parasitic
Silybum marianum Silymarin (standardized extract) 1) Antiinflammatory Flavonoids
2) Anti-oxidant
3) Stabilizes vasculature
5) Inhibits angiogenesis

papules and pustules (Wilkin et al., 2004). The reviewed
studies include subjects with the ET and PP subtypes,
and many evaluated improvement in each of the
primary rosacea symptoms separately. Botanicals were
most effective for improving facial erythema and
papule/pustule counts.
Q. amara (Ferrari and Diehl, 2012) extract, lichochalcone
moisturizer (Weber et al., 2006; Broniarczyk-Dyla
et al., 2011), silymarin extract (Berardesca et al., 2008),
C. indicum extract, kinetin cream, nicotinamide/zinc/
copper/folate oral tablet, and Chibixiao recipe im-
proved facial erythema. Q. amara extract (Ferrari and
Diehl, 2012), niacinamide (Draelos et al., 2005), silymarin
(Berardesca et al., 2008), and oral nicotinamide/zinc/
copper/folate supplementation (Niren and Torok,
2006) improved papule and pustule counts. Q. amara
extract reportedly led to the complete resolution of
pustules in participants; although, of note, this study
did not utilize a control group (Ferrari and Diehl,
2012). This study had a greater proportion of darker
skin types (Fitzpatrick skin type 3 and type 4) and not
as much of the lighter skin types (type 1 or type 2) that
are typical of most rosacea studies.
Only Q. amara extract improved the appearance of
telangiectasias (Ferrari and Diehl, 2012); several other
botanicals were ineffective including silymarin (Nield
and Ippersiel, 2002) and niacinamide cream (Nield and
Ippersiel, 2002). Topical EGCG cream did not clinically
improve the appearance of telangiectasias; however,
based on histochemical analysis of treated skin,
Domingo et al. (2010) suggest that the cream may be
effective in slowing telangiectasia formation. Conceiv-
ably, measurable clinical improvement may not have
been evident in this trial after only 6 weeks of topical
therapy (Domingo et al., 2010).
Botanical mechanism of action
Rosacea pathophysiology involves dysregulated im-
mune and vascular systems and an impaired epidermal
barrier function (Steinhoff et al., 2013). Endogenous
and exogenous triggers illicit hyperactive immune and
vascular responses, resulting in excessively dilated blood
vessels, inappropriate angiogenesis, and exaggerated in-
flammatory responses. This manifests clinically as facial
erythema, flushing and the formation of telangiectasias,
papules and pustules. Botanical products may improve
these symptoms through antiinflammatory, anti-
angiogenic, photoprotective, and anti-oxidant effects
(Tables 3 and 4.). Previous work has shown that patients
with rosacea have an altered skin surface lipid profile
(Ni Raghallaigh et al., 2012). Accordingly, product vehi-
cles may stabilize skin barrier function and improve
symptoms. Vehicle-controlled trials are thus imperative
to determine the efficacy of the active ingredient and
that of the vehicle.

Table 4. Mechanisms of action of phytochemicals

Phytochemicals/isolated compounds

Phytochemical Origin Mechanisms of action

EGCG Compound found in green tea (Camilla sinensis) 1) Antiinflammatory

2) Anti-oxidant
3) Inhibits angiogenesis
Kinetin(N6-furfuryladenine) A plant cytokinin/ growth factor 1) Enhances antioxidant enzyme
activity (catalase)
2) Anti-oxidant
Licochalcone Compound found in licorice 1) Antiinflammatory
(extract of Glycyrrhiza inflata) 2) Anti-oxidant
3) Anti-microbial/anti-parasitic
Niacinamide Derivative of vitamin B3 (niacin) 1) Antiinflammatory
2) Anti-oxidant
Nicotinamide Derivative of vitamin B3 (niacin) 1) Antiinflammatory
2) Anti-oxidant

Copyright © 2015 John Wiley & Sons, Ltd. Phytother. Res. 29: 1439–1451 (2015)
 PHYTOCHEMICAL AND BOTANICAL THERAPIES FOR ROSACEA
Botanicals that normalize vascular abnormalities are
studied for their ability to improve facial erythema, flush-
ing and reduce telangiectasia formation. EGCG and
Silymarin both suppress the release of pro-angiogenic
mediators and theoretically are useful for preventing
telangiectasia formation; however, topical application of
EGCG and silymarin did not improve telangiectasia
scores in 6-week and 12-week clinical trials, respectively
(Nield and Ippersiel, 2002; Domingo et al., 2010). C.
indicum, a plant extract that contains many phyto-
chemicals including flavonoids and phenylpropenoic acids
decreases vascular permeability and is shown to signifi-
cantly improve facial erythema (Rigopoulos et al., 2005).
Sun exposure is a common trigger for erythemo-
telangiectatic rosacea flares, likely because of increased
production of reactive oxygen species in the skin
(Murphy, 2004). Cumulative actinic damage is also im-
plicated in erythemotelangiectatic rosacea pathogenesis
(Bae et al., 2009). Thus, botanicals with photoprotective
effects may slow disease progression and suppress
acute flares. Botanical products may protect skin from
UV-damage through several mechanisms including (i)
scavenging free radicals, (ii) replenishing endogenous
antioxidant systems, (iii) suppressing inflammatory re-
sponses or (iv) directly absorbing UV-radiation (Stahl
and Sies, 2007). As is evident from Tables 3 and 4, each
of the reviewed botanicals has free radical scavenging or
antiinflammatory activities. EGCG and silymarin in par-
ticular are known to inhibit UV damage (Katiyar et al.,
1997; Elmets et al., 2001; Katiyar and Elmets, 2001;
Katiyar, 2003). Both oral and topical niacin derivatives
prevent UV-induced depletion of DNA repair proteins
involved in repairing free radical damage (Surjana and
Damian, 2011). Kinetin, a plant growth factor, enhances
the activity of antioxidant enzymes (Hsiao et al., 2003)
and improves signs of photodamage (Chiu et al., 2007).
The sensitive skin characteristic of rosacea may be
related to a damaged epidermal barrier function (Farage
et al., 2006). Several studies state that botanicals improve
rosacea by strengthening epidermal barrier function;
these include lichochalcone (Broniarczyk-Dyla et al.,
2011), niacinamide cream (Draelos et al., 2005), and
flavanoid creams (Raab et al., 2012). Although products
containing each of these agents effectively decreased
transepidermal water loss (TEWL), the effect of the prod-
uct vehicles on TEWL was inadequately evaluated in
each study. Because moisturizing creams may improve
barrier function in the absence of botanical ingredients,
future studies need to evaluate the effect of product
vehicles on such measurements.
Antibiotic resistance
Antibiotics are commonly used to treat rosacea, often for
extended periods of time. However, their benefit may be
because of antiinflammatory properties, rather than
anti-microbial activity (Akamatsu et al., 1992; Del Rosso
et al., 2007; Layton and Thiboutot, 2013). In fact, sub-
antimicrobial dose antibiotics are shown to improve rosa-
cea symptoms. Given this, alternative antiinflammatory
therapies may be preferable to reduce the risk of antibi-
otic side effects and the development of resistant organ-
isms (Berman and Zell, 2005). As is evident from
Tables 3 and 4, many botanicals have antiinflammatory
properties. Although research comparing botanicals with
Copyright © 2015 John Wiley & Sons, Ltd.
1449
antibiotic therapy is limited, Niren et al. suggest that oral
nicotinimide/zinc/copper/folate tablets may be as effective
as oral antibiotic use (based on participant questionnaire)
(Niren and Torok, 2006). This study needs to be viewed
with caution as the outcome measure was based on a sub-
jective patient questionnaire instead of objective mea-
sures. Clinical studies of patients with acne vulgaris have
demonstrated that botanical products can be as effective
as topical antibiotic therapy for reducing lesion counts
(Shalita et al., 1995). Similar studies of patients with PP
rosacea are lacking but warranted.
Adverse reactions
Mild adverse reactions, such as transient burning or pruri-
tus, were noted in the reviewed studies. However, patients
and physicians should be aware of the potential for hyper-
sensitivity reactions and adverse effects from botanical
products. Of note, several botanicals commonly used for
rosacea have not yet been studied clinically and these
may have more significant side effect profiles than those
described in this review (Emer et al., 2011). Feverfew ex-
tract, for example, can elicit a hypersensitivity reaction,
despite its antioxidant and antiinflammatory properties
(Sharma and Sethuraman, 2007).
Limitations
The results of this review offer optimism about botanical
agents but identify areas for improving future studies.
Many of the reviewed studies were single group efficacy
trials that lacked placebo or control groups. Also,
several protocols recommended participants simulta-
neously use multiple therapies, such as sunscreens and
moisturizing products, without controlling for these
potentially confounding effects. Most studies did not
control for common triggers of rosacea, including caf-
feine, sunlight exposure and emotional stress. Outcome
measures were most commonly subjective scales, and
none of the studies provided inter-rater reliability
analysis. Many of the described results have yet to be
duplicated. Given that all studies reported positive
results, there is a high likelihood of publication bias.
A major challenge of studying rosacea therapies is a
lack of standardization in the methods used to evaluate
rosacea severity and treatment efficacy. Both objective
measures (such as colorimetry) and subjective measures
(such as global assessment, erythema, and telangiectasia
scales) are used in studies, and because of heterogeneity
of outcome measures, comparing results among studies
is difficult. Many studies reported only changes in
point-based global assessment scales, rather than
describing improvement in each rosacea symptoms.
Global assessments are shown to correlate well only
with facial erythema and correlate poorly with pustules
and telangiectasia (Bamford et al., 2004). Also, inter-
rater reliability of point-based scales in rosacea is weak
(Bamford et al., 2004). The National Rosacea Society
Expert Committee developed a standard grading system
for rosacea symptoms, which is utilized by some of the
studies (Wilkin et al., 2004). This involves grading the
primary symptoms as absent, mild, moderate, or severe
(flushing, erythema, papules/pustules, and telangiecta-
sia) and secondary features (including burning, dryness,
Phytother. Res. 29: 1439–1451 (2015)
1450 W. A. FISK ET AL.
and edema) as present or absent. Researchers are en-
couraged to supplement this basic grading system with
technology, such as colorimetry or immunohistochemis-
try. Such objective measurement techniques are
underutilized in the reviewed studies.
CONCLUSIONS
Botanical therapies are increasingly popular for derma-
tologic conditions including rosacea. Based on the lim-
ited available clinical data, several botanicals and
phytochemicals are promising therapies for rosacea.
Overall, botanicals seem to be most effective for reduc-
ing facial erythema and reducing papule/pustule counts.
There is some evidence from preclinical and clinical
studies that botanical agents, including those used for
the treatment of rosacea, are photoprotective and thus
may reduce flares triggered by UV exposure (Katiyar
et al., 1997; Katiyar et al., 2000; Elmets et al., 2001;
Katiyar and Elmets, 2001; Katiyar, 2003; Chiu et al.,
2007; Katiyar et al., 2007; Stahl and Sies, 2007; Surjana
and Damian, 2011). Several botanicals interfere with an-
giogenesis at a molecular level, although only one has
been shown to clinically improve telangiectasias and this
finding has yet to be duplicated.
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Conflict of Interest
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