Original Paper
Skin Pharmacol Physiol 2017;30:139–145
DOI: 10.1159/000464335
Topical Histamine Stimulates Repigmentation of
Nonsegmental Vitiligo by a Receptor-Dependent
Mechanism
Jun Liu a Yan Xu a Tzu-Kai Lin b Chengzhi Lv a Peter M. Elias c
Mao-Qiang Man c  
a
Dalian Skin Disease Hospital, Dalian, People’s Republic of China; b Institute of Clinical Medicine and Department
of Dermatology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China;
c
  Department of Dermatology, University of California San Francisco, and Veterans Affairs Medical Center,
San Francisco, CA, USA
Keywords
Vitiligo · Histamine · Pigmentation · Epidermal permeability
barrier · Transepidermal water loss
Abstract
Background: Though vitiligo is a common depigmentary
disorder, it still represents a substantial therapeutic chal-
lenge. Therapeutic options are limited in part due to its un-
certain etiology. Objective: Because recent studies suggest
that histamine stimulates melanogenesis in vitro, we deter-
mined here whether topical histamine stimulates repigmen-
tation in patients with stable, nonsegmental vitiligo. Meth-
ods: A total of 23 otherwise normal volunteers with vitiligo,
including 14 males and 9 females aged 6–59 years (mean age
29.2 ± 2.8), were enrolled in this study. 1% histamine in dis-
tilled water was applied to the lesions twice daily for 5 weeks,
while comparable lesions, treated with distilled water alone,
served as the controls. The melanin index was measured on
the uninvolved and lesional skin sites before and after 5
weeks of treatments using the melanin/erythema probe
connected to a Courage-Khazaka MPA5 (Cologne, Germa-
ny). Changes in epidermal permeability barrier were also as-
sessed at the same time point. To determine whether hista-
mine-induced repigmentation is receptor-dependent, both
© 2017 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/spp
Received: July 15, 2016
Accepted after revision: February 17, 2017
Published online: April 19, 2017
ears of C57BL/6J mice were treated topically with 5% cimeti-
dine, a histamine type 2 receptor (H2r) antagonist, twice dai-
ly for 10 days. One hour after each cimetidine application,
the right ear was treated topically with 10% histamine, while
vehicle alone was applied to the left ear. Changes in melanin
index were measured 24 h after the last application of hista-
mine and vehicle as described in the human study. Results:
In patients with vitiligo treated with vehicle alone for 5
weeks, the melanin index remained unchanged, while topi-
cal histamine treatment increased the melanin index by 38%
(p < 0.001 vs. both vehicle and pretreatment), which was par-
alleled by a >60% reduction in lesion surface area. Moreover,
topical histamine accelerated permeability barrier recovery.
No adverse events were observed following histamine ap-
plications. In mice, topical histamine significantly increased
the melanin index, while topical co-applications of the H2r
antagonist (cimetidine) prevented the expected histamine-
induced increase in melanin index. Conclusions: These stud-
ies indicate that topical histamine or an H2r agonist could be
useful for treating nonsegmental vitiligo, but further clinical
studies in large populations will be required to validate the
efficacy and safety of this approach. © 2017 S. Karger AG, Basel
Jun Liu and Yan Xu contributed equally to this work.
Mao-Qiang Man, MD
Dermatology Service (190), University of California San Francisco
Veterans Affairs Medical Center
4150 Clement Street, San Francisco, CA 94121 (USA)
E-Mail mqman @ hotmail.com or liujun15309801118 @ 163.com
 Introduction
The prevalence of vitiligo exceeds 8% in certain re-
gions of the world [reviewed in 1]. Although the lesions
are asymptomatic, vitiligo negatively impacts the quality
of patients’ lives [2, 3]. With regard to the etiology of vit-
iligo, there are several competing hypotheses, including
autoimmune, gene mutations, oxidative stress, trauma,
psychological stress, and/or combinations of these factors
[4–12]. In part due to uncertainty about its etiology, op-
timal treatments are not yet available, although many
approaches, including laser, high-potency topical ste-
roids, topical immunomodulators, herbal medicines, as
well as melanocyte/epidermal transplantation have yield-
ed mixed results [13–20]. Notably, the efficacy of most of
these regimens is not only moderate, but also costly [21,
22], and can provoke substantial side effects such as skin
infections [23–26], skin atrophy, and/or disturbed epi-
dermal permeability barrier homeostasis [27, 28], which
is already compromised in vitiligo [29].
The pathological changes in the involved skin of vit-
iligo include loss of melanocytes, and reduced expression
of histamine receptor 2 (H2r), but neither H1r nor H3r
[30–32]. Because histamine stimulates melanogenesis
and melanocyte proliferation in vitro [32–34], we hy-
pothesized that topical histamine could be efficacious in
vitiligo. In the present study, we assessed the efficacy of
topical histamine on skin pigmentation in normal pig-
mented mice and in patients with stable, nonsegmental
vitiligo.
Materials and Methods
Human Study
Patients
A total of 23 Chinese volunteers with stable, nonsegmental vit-
iligo vulgaris, including 14 males and 9 females aged 6–59 years,
were enrolled in this study (Table  1). The duration of vitiligo
ranged from 0.2 to 6 years (2.39 ± 0.35). All subjects displayed at
least 2 lesions, and all were of skin types III or IV (Fitzpatrick clas-
sification). None had been treated with topical or systemic medica-
tions for at least 2 weeks prior to enrollment and throughout the
study period. The clinical diagnosis of vitiligo was verified by a
dermatologist who is a vitiligo specialist, working in the Vitiligo
Clinic of Dalian Skin Disease Hospital, PR China. Clinical exami-
nation showed no signs of inflammation in lesions. The study was
approved by the Human Research Committee of Dalian Skin Dis-
ease Hospital, and it adhered to the ethical guidelines of the Dec-
laration of Helsinki. All procedures performed in these studies in-
volving human participants were performed in Dalian Skin Dis-
ease Hospital and were in accordance with the ethical standards of
the institutional research committee, and with the 1964 Helsinki
140 Skin Pharmacol Physiol 2017;30:139–145
DOI: 10.1159/000464335
Table 1. Characteristics of subjects
Gender Number Age, years Involved sites
face trunk others
Female 9 32.89 ± 5.55 6 3 0
Male 14 26.79 ± 2.84 5 2 7
Total 23 29.17 ± 2.77 11 5 7
declaration and its later amendments or comparable ethical stan-
dards. Informed consent was obtained from all individual subjects
prior to inclusion in this study.
Reagents and Treatment
Pure histamine was purchased from Macro-Union Pharma-
ceutical (Beijing, China). Because some patients have preference
for the treated side, this study was not randomized. Six subjects
wanted the lesion on the right side to serve as treated lesion while
17 patients had no preferences and a lesion on the left side served
as treated site. One lesion on one side of each patient was covered
with cotton gauze presoaked in 1% histamine in distilled water for
30 min twice daily for 5–11 weeks, while the adjacent or contralat-
eral involved sites were covered with cotton gauze presoaked in
distilled water alone, serving as control sites. All studies were car-
ried out between the months of June and March.
Assessment of Efficacy
Melanin indices of histamine- and vehicle-treated sites, as well
as contralateral, uninvolved normal skin sites were measured at
baseline using a Mexameter® MX 18 probe connected to a Multi-
probe Adapter System (Courage-Khazaka, Cologne, Germany),
and again after 5 weeks of treatments [29]. Melanin indices were
expressed as percentage of normal skin, calculated according to the
equation: (lesion melanin index/contralateral normal skin) × 100.
For quantitative analysis of efficacy, lesions were also photo-
graphed before and after 5 weeks of treatments. Pictures of hista-
mine-treated lesions were printed at the same magnification on
glossy photo paper. Thirteen lesions, in which development of re-
pigmentation began only on the edge, were cut out of the photos
and weighed in a Mettler Toledo AG285 balance. Reduction in
lesion size was calculated using the equation: (pretreatment
weight – posttreatment weight)/pretreatment × 100. Transepider-
mal water loss rates, an indicator of epidermal permeability bar-
rier function in lesions, were measured with a TM300 probe, con-
nected to a Courage-Khazaka MPA5 prior to and after 5 weeks of
treatments, as described previously [29]. After 5 weeks of treat-
ments, the barrier recovery rate was assessed 3 h after acute bar-
rier perturbation by sequential D-squame applications [29].
Animal Study
Eight- to 10-week-old C57BL/6J mice were purchased from the
Animal Center of National Cheng Kung University (Tainan, Tai-
wan). Both pure histamine and pure cimetidine were purchased
from Sigma (St. Louis, MO, USA). Due to the movement of mice
and skin surface tension, it is difficult to keep water solution on a
mouse ear for long enough following topical application. There-
Liu/Xu/Lin/Lv/Elias/Man
fore, ethanol was used as vehicle in the animal study. In one group
of mice, both ears were treated topically with vehicle (30 μL of 90%
ethanol) twice daily for 2 weeks. One hour after each vehicle ap-
plication, 30 μL of 10% histamine in 90% ethanol was applied to
one ear, while vehicle was applied to the contralateral ear. In an-
other group of mice, both ears were treated with 30 μL of 5% ci-
metidine twice daily for 2 weeks. One hour after each cimetidine
application, 30 μL of vehicle and 10% histamine, respectively, were
applied to the opposite ears. Before these experiments and 24 h
after the last topical histamine applications, melanin indices were
measured, as described above.
This study was approved by the animal research committee of
National Cheng Kung University. All applicable international, na-
tional, and/or institutional guidelines for the care and use of ani-
mals were followed. All procedures involving animals were in ac-
cordance with the ethical standards of the institution or practice at
National Cheng Kung University.
Statistics
Data are expressed as means ± SEM. GraphPad Prism 4 soft-
ware was used for all statistical analyses. A paired 2-tailed Student
t test was used to determine the significance of reductions in lesion
size before and after treatment. A 1-way ANOVA test was used to
determine the significances in melanin indices and barrier recov-
ery rates among treatment groups.
Results
Topical Histamine Induces Repigmentation in Stable,
Nonsegmental Vitiligo
Since previous studies showed that histamine stimu-
lates melanogenesis in vitro, we first assessed whether
topical histamine induces repigmentation in stable, non-
segmental vitiligo. Our results showed that topical hista-
mine began to induce repigmentation in most subjects
after 2 weeks of treatment, becoming increasingly evident
in most treated lesions by 3 weeks (red arrows in Fig. 1a
vs. b). Still more dramatic reductions in lesion size were
seen after 11 weeks of treatments (red arrows in Fig. 1c
vs. d). In contrast, vehicle treatments did not induce re-
pigmentation (data not shown). Notably, repigmentation
appeared to begin both from hair follicles (red arrows in
Fig.  1b) and from the edge of lesions (red arrows in
Fig. 1d).
Because the melanin index can objectively assess the
response of vitiligo to treatments [35], we next the mea-
sured melanin index before and after 5 weeks of treat-
ments. The melanin index of vitiligo-involved sites de-
clined by 71% in comparison to the uninvolved sites
(Fig. 1e; 29.14 ± 4.41% of normal skin; p < 0.001). After 5
weeks of histamine treatment, the melanin index in-
creased by over 130% from the pretreatment (188.91 ±
12.99 vs. 56.22 ± 8.62, p < 0.001). In contrast, the melanin
Topical Histamine Benefits Vitiligo
index on vehicle-treated sites remained unchanged (60.83
± 11.13). The improvement of melanin index did not cor-
relate with disease duration (r2 = 0.007063).
We next quantified the extent of changes in lesion size
by comparing the weights of cut-out lesions, printed on
paper, before and after 5 weeks of treatments. Histamine
significantly reduced lesion size as demonstrated by 64.6
± 8.9% reductions in paper weight in comparison to pre-
treatment (posttreatment vs. pretreatment, p = 0.0395).
Because there were no visible signs of improvement in
pigmentation after vehicle treatment, we did not assess
the changes in lesion size in vehicle-treated sites. Togeth-
er, these results demonstrate that topical histamine in-
creases the melanin index and reduces lesion size in non-
segmental vitiligo.
While mild erythema and pruritus occurred in 6 pa-
tients after initial twice daily applications of histamine,
these patients considered this adverse event to be tolera-
ble. After given histamine once – rather than twice – dai-
ly, their symptoms disappeared after 3 days. Fifteen pa-
tients were followed up for 8 months, with lesion recur-
rence in 1 patient.
Topical Histamine Accelerates Permeability Barrier
Recovery in Stable, Nonsegmental Vitiligo
Our previous studies demonstrated that epidermal
pigmentation benefits the epidermal permeability barrier
[36, 37]. To determine whether the topical histamine-in-
duced improvement in pigmentation is paralleled by an
enhancement of permeability barrier homeostasis, both
basal transepidermal water loss and barrier recovery ki-
netics were assessed following 5 weeks of treatment of
vitiligo lesions with topical histamine. Although basal
transepidermal water loss rates of histamine-treated and
vehicle-treated sites were comparable (12.4 ± 1.0 vs. 12.1
± 1.0), permeability barrier recovery significantly acceler-
ated in histamine-treated lesions in parallel with repig-
mentation in comparison with either untreated or vehi-
cle-treated lesional sites (Fig. 2). In contrast, barrier re-
covery was delayed in involved vitiligo sites (p < 0.05,
histamine-treated vs. vehicle-treated and untreated le-
sional sites), as we demonstrated previously [29]. These
results indicate that topical histamine-induced repig-
mentation is paralleled by enhanced epidermal permea-
bility barrier homeostasis.
Taken together, these results demonstrate that topical
histamine induces epidermal repigmentation and reduc-
es lesion size in nonsegmental vitiligo, while enhancing
rather than disrupting epidermal permeability barrier
function.
Skin Pharmacol Physiol 2017;30:139–145 141
DOI: 10.1159/000464335
 After 3 weeks

a b

After 11 weeks

Fig. 1. Topical histamine induces repig-

mentation. In each patient, 1 lesion was
covered with cotton gauze presoaked in 1%
histamine in distilled water for 30 min
twice daily for 5–11 weeks. A contralateral
lesion covered with cotton gauze presoaked
in distilled water alone served as control.
Clinical photos were taken before and after
treatment: a 12-year-old boy before (a) and
after 3 weeks of treatment with histamine
(b); a 25-year-old male before (c) and after
11 weeks of treatment with histamine (d).
e The melanin index on treated and un-
treated lesions, as well as contralateral nor- c d
mal skin, was measured at baseline using Before After
the Mexameter® MX 18 probe connected
100 Normal
to an MPA5 (Courage-Khazaka, Cologne,
Germany) and repeated after 5 weeks of
treatments. Melanin indices were ex-
75
pressed as percent of normal skin (shown
% of normal skin
Melanin index,

as 100% at the dashed line), calculated us-

ing the equation: (lesion melanin index/
50
contralateral normal skin) × 100. The
GraphPad Prism 4 software was used for all *
*
statistical analyses. One-way ANOVA was
25
used to determine the significance in mela-
nin indices among pretreatment, vehicle
and histamine treatment. Changes in mela-
nin index after 5 weeks of histamine treat- 0
ments are shown (n = 23). * p < 0.0001 vs. e Before Vehicle Histamine
histamine treatment.

Topical Histamine Increases Skin Melanin Index
via H2r
Because prior studies have shown that histamine stim-
ulated melanogenesis via H2r in vitro [30–32], we next
determined whether topical histamine increases the mel-
anin index via H2r in vivo. We measured the melanin
index in mouse ears cotreated with histamine and an H2r
antagonist, cimetidine. As shown in Figure 3, 2 weeks of
treatment of ears with topical histamine caused a modest,
but significant increase in the skin melanin index (5.1%
over the vehicle treatment, p = 0.0086). In contrast, pre-
treatment of ears with cimetidine, an H2r antagonist,
completely prevented the changes in melanin index in-
duced by histamine, while cimetidine alone did not affect
melanin indices. These results are consistent with previ-
ous in vitro findings that histamine stimulates melano-
genesis via H2r [32].

142 Skin Pharmacol Physiol 2017;30:139–145 Liu/Xu/Lin/Lv/Elias/Man

DOI: 10.1159/000464335
 100
0 13
Barrier recovery, %
–100
–200
–300
–400
–500
Untreated Vehicle 1% histamine
Fig. 2. Topical histamine improves epidermal permeability barrier
homeostasis. Barrier perturbation was achieved by repeated D-
squame applications. Transepidermal water loss rates were mea-
sured on untreated, vehicle-treated and histamine-treated sites
immediately and 3 h after barrier disruption with a Tewameter
TM300 probe connected to an MPA5 unit. Data were normalized
to normal skin, setting the recovery rate on normal skin as 100%.
One-way ANOVA with Tukey’s multiple comparison test was
used to determine significances (p < 0.05 treated sites vs. both un-
treated and vehicle-treated lesional sites).
Discussion
Previous studies have shown that histamine stimulates
melanocyte proliferation and melanogenesis in vitro [24–
32]. We now show here that topical histamine consistent-
ly induces repigmentation in stable, nonsegmental vitili-
go in humans, in parallel with increased melanin indices
in histamine-treated normal mouse skin. The improve-
ment of pigmentation likely does not result from residual
benefits of prior treatments because vehicle-treated sites
showed no improvement. The underlying mechanisms
by which histamine benefits vitiligo likely reflect stimula-
tion of melanocyte proliferation and melanogenesis, be-
cause addition of histamine to melanocyte cultures also
stimulates melanocyte proliferation and melanogenesis
[32–34]. However, histamine can also stimulate keratino-
cytes to secrete granulocyte-macrophage colony-stimu-
lating factor [38], which has been shown to stimulate me-
lanocyte proliferation and differentiation [39]. Thus, his-
tamine appears to increase melanin production by both
direct and indirect mechanisms.
Although ethanol can affect the skin such as causing
irritation, leading to skin pigmentation, the fact that co-
applications of the H2r antagonist (cimetidine) prevent-
ed the histamine-induced hyperpigmentation in mice
Topical Histamine Benefits Vitiligo
% changes over vehicle-treated ears
p = 0.0021
8
Melanin index,
3
–2
–7
Vehicle + histamine Cimetidine + histamine
Fig. 3. Topical histamine increases melanin content in mice. Ears
of 8-to 10-week-old C57BL/6J mice were treated topically with ei-
ther histamine + vehicle or histamine in combination with cimeti-
dine twice daily for 2 weeks. Ears treated with vehicle alone served
as controls. The skin melanin index was measured with a Mexa-
meter® MX 18 probe connected to an MPA5. The significances
between histamine + vehicle and cimetidine + histamine were de-
termined using GraphPad Prism 4 software with Mann-Whitney
test: p = 0.0021 between these 2 groups. The number for each group
is indicated by the dots in the figure.
strongly suggests that (a) topical histamine solution-in-
duced pigmentation is unlikely due to an ethanol-in-
duced nonspecific effect and (b) the induction of melanin
production by histamine occurs via the H2r, consistent
with prior in vitro studies [32]. These results suggest that
H2r agonists and likely antagonists could be used to ma-
nipulate skin pigmentation in clinical settings.
Although prior studies showed that histamine impairs
the epidermal permeability barrier in vitro [40] and the
antihistamines improve permeability barrier homeostasis
[41], we did not find any differences in basal transepider-
mal water loss rates between histamine- and vehicle-
treated vitiligo sites. In contrast, topical histamine-in-
duced pigmentation is accompanied by an acceleration of
permeability barrier recovery, consistent with our prior
findings that pigmentation benefits permeability barrier
homeostasis [36, 37]. While the mechanisms by which
topical histamine improves the permeability barrier in
vitiligo are unknown, Gutowska-Owsiak et al. [42] re-
ported that histamine upregulates the expression of cor-
nified envelope proteins, such as small proline-rich pro-
teins and protease inhibitors. Pertinently, inhibition of
proteases accelerates permeability barrier recovery in
vivo [43]. Moreover, histamine-induced pigmentation
could also attenuate the negative impact of histamine on
Skin Pharmacol Physiol 2017;30:139–145 143
DOI: 10.1159/000464335
permeability barrier homeostasis. Accordingly, the pres-
ent study clearly shows that topical histamine improves
pigmentation and permeability barrier homeostasis in
stable, nonsegmental vitiligo.
It is worth noting that only 1 out of 15 patients in the
present study relapsed during an 8-month follow-up pe-
riod, while the 1-year relapse rate after treatment is over
30% in other studies [44], mandating that maintenance
therapy may be required to sustain the improvements of
repigmentation [45]. Moreover, no serious adverse reac-
tions were observed in the present study. Finally, while
the efficacy of laser treatment correlates negatively with
disease duration [46], the efficacy of histamine in the im-
provement of skin pigmentation is not affected by disease
duration, suggesting that topical histamine could be an
alternative approach for those with longer-term vitiligo.
Acknowledgements
The authors are grateful to George Man for his assistance with
data analysis. This work was supported in part by Merit Review,
and the resources and facilities of the Veterans Affairs Medical
Center, San Francisco, CA, USA.
Statement of Ethics
The study was approved by the Human Research Committee
of Dalian Skin Disease Hospital, and it adhered to the ethical
guidelines of the Declaration of Helsinki. All procedures per-
formed in these studies involving human participants were in ac-
cordance with the ethical standards of the institutional research
committee, and with the 1964 Helsinki Declaration and its later
amendments or comparable ethical standards. Informed consent
was obtained from all individual subjects prior to inclusion in this
study.

Conclusion Disclosure Statement

This study demonstrates that topical histamine bene- An invention disclosure entitled “Using Histamine Receptors
fits nonsegmental vitiligo with minimal side effects, pos- 1 and 2 Antagonists and Agonists to Modulate Skin Pigmentation”
sibly providing a new therapeutic regimen for nonseg- has been filed with the UCSF Office of Innovation, Technology,
and Alliances by M.Q. Man and P.M. Elias.
mental vitiligo. However, a double-blind, randomized
study in a large population is required before histamine
is widely employed in such clinical settings.

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