Medication-Induced Repigmentation of Gray Hair: A Systematic Review

Abstract

Hair graying is a common sign of aging resulting from complex regulation of melanogenesis. Currently, there is no medical treatment available for hair repigmentation. In this article we review the literature on medication-induced hair repigmentation, discuss the potential mechanisms of action, and review the quality of the literary data. To date, there have been 27 studies discussing medication-induced gray hair repigmentation, including 6 articles on gray hair repigmentation as a primary objective, notably with psoralen treatment or vitamin supplementation, and 21 reports on medication-induced gray hair repigmentation as an incidental finding. Medications noted in the literature include anti-inflammatory medications (thalidomide, lenalidomide, adalimumab, acitretin, etretinate, prednisone, cyclosporin, cisplatinum, interferon-α, and psoralen), stimulators of melanogenesis (latanoprost, erlotinib, imatinib, tamoxifen, and levodopa), vitamins (calcium pantothenate and para-amino benzoic acid), a medication that accumulates in tissues (clofazimine), and a medication with an undetermined mechanism (captopril). Diffuse repigmentation of gray hair can be induced by certain medications that inhibit inflammation or stimulate melanogenesis. There is also low-quality evidence that some vitamin B complex supplementation can promote gray hair darkening. While these compounds are not currently indicated for the treatment of gray hair, their mechanisms shed light on targets for future medications for hair repigmentation.

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Review Article
Skin Appendage Disord 2020;6:1–10
Medication-Induced Repigmentation of
Gray Hair: A Systematic Review
Katerina Yale Margit Juhasz Natasha Atanaskova Mesinkovska
Department of Dermatology, University of California, Irvine, Irvine, CA, USA
Received: July 18, 2019
Accepted: October 28, 2019
Published online: December 17, 2019
Katerina Yale, MD
Department of Dermatology, University of California, Irvine
843 Health Sciences Road
Irvine, CA 92617 (USA)
E-Mail yalekl @ uci.edu
© 2019 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/sad
DOI: 10.1159/000504414
Keywords
Gray hair · Treatment · Repigmentation · Medication
Abstract
Hair graying is a common sign of aging resulting from com-
plex regulation of melanogenesis. Currently, there is no
medical treatment available for hair repigmentation. In this
article we review the literature on medication-induced hair
repigmentation, discuss the potential mechanisms of action,
and review the quality of the literary data. To date, there
have been 27 studies discussing medication-induced gray
hair repigmentation, including 6 articles on gray hair repig-
mentation as a primary objective, notably with psoralen
treatment or vitamin supplementation, and 21 reports on
medication-induced gray hair repigmentation as an inciden-
tal finding. Medications noted in the literature include anti-
inflammatory medications (thalidomide, lenalidomide,
adalimumab, acitretin, etretinate, prednisone, cyclosporin,
cisplatinum, interferon-α, and psoralen), stimulators of me-
lanogenesis (latanoprost, erlotinib, imatinib, tamoxifen, and
levodopa), vitamins (calcium pantothenate and para-amino
benzoic acid), a medication that accumulates in tissues (clo-
fazimine), and a medication with an undetermined mecha-
nism (captopril). Diffuse repigmentation of gray hair can be
induced by certain medications that inhibit inflammation or
stimulate melanogenesis. There is also low-quality evidence
that some vitamin B complex supplementation can promote
gray hair darkening. While these compounds are not cur-
rently indicated for the treatment of gray hair, their mecha-
nisms shed light on targets for future medications for hair
repigmentation. © 2019 S. Karger AG, Basel
Introduction
Hair color has long been a symbol of youth and health,
with graying signifying advanced age. Topical means of
hair coloring such as permanent hair dyes are affordable
and easy to use; however, they can cause irritation of the
scalp, allergic reactions, and damage to the hair shaft [1].
Semipermanent and temporary hair dyes are gentler, but
since they do not penetrate the hair cortex, they do not
camouflage gray hair as well [1].
An optimal therapy would permanently reverse the
gray back to its original hair color, without causing dam-
age to the hair shaft or scalp irritation. In a quest for de-

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velopment of this type of therapy, anecdotal reports of
medications associated with hair repigmentation have
been described. Unfortunately, many cases are not de-
finitively reproducible, and little is understood about the
pathophysiology behind hair repigmentation.
Clinical Presentation
Graying of hair, also called canities or achromotrichia,
is part of the natural aging process. It has been reported
that worldwide 6–23% of people have 50% gray hair by 50
years of age [2]. Graying typically begins in the mid-30s
for Caucasians, the late-30s for Asians, and the mid-40s
for Africans [3–5]. Premature hair graying is considered
when the onset of gray hair begins before the age of 20
years in Caucasians, before the age of 25 years in Asians,
and before the age of 30 years in Africans [5, 6].
In men, gray hair typically begins at the temples and
sideburns, then spreads to the vertex and lastly the oc-
ciput. In women, graying develops at the boundaries of
the scalp and moves towards the vertex. Progression of
hair graying depends on genetic factors; however, early
onset of gray hair does not necessarily correlate with rap-
id progression [7].
Some causes of premature hair graying are reversible,
such as nutritional deficiencies. Vitamin B12, iron, and
copper deficiency, as well as severe protein malnutrition,
have been linked to hair hypopigmentation [4, 8, 9]. Oth-
er risk factors significantly associated with premature
gray hair include a vegetarian diet and atopy [10].
Pathophysiology
The human hair shaft is composed of two main con-
centric regions: an inner cortex surrounded by an outer
cuticle. In a small proportion of hairs, another innermost
layer, the medulla, may be present [3]. Within the unit,
there are 5–6 different subpopulations of melanocytes
[11]. Melanogenically-active melanocytes are located at
the infundibulum, sebaceous gland, and hair bulb around
the dermal follicular papilla. Additionally, undifferenti-
ated inactive melanocytes are located in the upper hair
follicle reservoir near the arrector pili muscle insertion
site, within the outer root sheath of the hair follicle, and
in the hair bulb matrix [11]. Active melanocytes produce
and transfer melanin to the keratinocytes of the hair shaft
cortex, with a small amount also transferred to the me-
dulla, and rarely to the cuticle [5]. The role of the inactive
melanocytes is poorly understood, but they are thought
to act as a stem cell reserve which can be induced to
become melanin-producing cells if the skin is wound-
ed [3, 5].
Hair melanogenesis is tightly linked to the stages of the
hair cycle and is actively pigmented during anagen
(growth) but not in catagen (involution) or telogen (qui-
escence) [4, 5]. Anagen for human scalp hair on average
lasts 3.5 years, which requires the small population of fol-
licular melanocytes to produce large amounts of melanin
[12]. Follicle-based melanocytes are larger than epider-
mis-based melanocytes, with a more extensive Golgi ap-
paratus and rough endoplasmic reticulum, thus produc-
ing larger melanosomes [13]. Follicular melanin also de-
grades more slowly than melanin in the epidermis.
Because of this, the pigmentation at the distal and proxi-
mal ends of the hair shaft is similar [11]. The specific hair
color is controlled by the type of melanin pigment pro-
duced by follicular melanocytes, including black-brown
eumelanin and reddish-brown pheomelanin [4].
Numerous factors control stimulation of melanogen-
esis at the level of the hair follicle, including melanin-stim-
ulating hormone, ACTH, endothelin-1, prostaglandins,
leukotrienes, neutrophils, fibroblast growth factor, nitric
oxide, and catecholamines [6]. In contrast, inhibitors of
melanogenesis include sphingolipids, bone morphoge-
netic protein 4, and autoimmune processes (such as vit-
iligo and alopecia areata) [3, 4, 11, 14]. Certain compounds
or diseases can affect the production of these factors and
alter hair pigmentation. Conditions occasionally associ-
ated with darkening of hair color include Addison’s dis-
ease, neurodermatitis, porphyria cutanea tarda, and in-
flammatory scalp conditions [3, 15–17]. Conversely, con-
ditions linked to hair lightening or graying include cystic
fibrosis, celiac disease, hyperthyroidism/hypothyroidism,
vitiligo, alopecia areata, and genetic diseases such as Wer-
ner syndrome, Louis-Bar syndrome, Waardenburg syn-
drome, or Griscelli syndrome [3, 14, 18, 19].
The development of gray hair is ultimately due to a
decrease in the number of melanocytes. This can be either
due to a defect in the melanocytic stem cells or destruc-
tion of the follicular stem cell population [3–5, 20]. A
common issue leading to follicular melanocyte death is
oxidative stress due to the development of reactive oxy-
gen species (ROS) from hydrogen peroxide build-up (a
natural product of the hair growth process) or ultraviolet
(UV) light [3, 4, 20, 21]. Antioxidants such as Bcl-2, cata-
lase, and methionine sulfoxide reductase are naturally
produced by melanocytes to protect against ROS damage.
These protective molecules are notably absent in gray hair
follicles [20, 21]. For example, studies on BCL-2-deficient
mice have noted the development of gray hair by the sec-
ond hair cycle [20, 21]. Interestingly, melanocytes in the
outer root sheath appear to be less affected by ROS dam-

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age, and they may be a pigment source for reversal of hair
color [20]. Other causes of oxidative stress, including pol-
lution, emotional stress, alcohol consumption, and ciga-
rette smoking, have been linked to the premature devel-
opment of gray hair [22, 23].
Hair graying is a complex process regulated by multi-
ple intrinsic and extrinsic factors, with treatment options
for hair repigmentation currently being investigated. In
this systematic review, we identify medications linked to
gray hair repigmentation to further delineate potential
targets of hair repigmentation therapy.
Methods
A systematic literature search was performed using PubMed
and CINAHL ending in May 2019. The search terms were: (((grey
OR gray) AND hair) OR canities OR achromotrichia) AND (treat-
ment OR repigmentation OR reversal OR darkening OR therapy).
All clinical trials, retrospective studies, case series, and case reports
on gray hair and medication-induced color change in humans
were included. Excluded were articles written in a language other
than English; articles not about hair; review articles; and reports
on patients starting with a hair color other than gray or white, or
grey hair related to chronic nutritional deficiencies or diseases
such as vitiligo or Griscelli syndrome. The quality of the evidence
for each article was determined using the Oxford Centre for Evi-
dence-Based Medicine criteria [24].
Results
Two hundred and forty-one articles were evaluated
and 27 were included in this systematic review. These
consist of 4 prospective cohort studies, 3 retrospective co-
hort studies, 1 case series, and 19 case reports. This in-
cludes an aggregate of 133 patients with medication-in-
duced gray hair repigmentation. Of these studies, 3 pro-
spective studies and 1 case series focused specifically on
premature hair graying, while the remaining articles in-
vestigated patients with age-related canities. Overall, the
quality of the evidence is low, given that most cases were
documented as solitary case reports, or in studies which
were not reproducible. A summary of the articles and
their level of evidence quality is found in Table 1.
The medications reported in the literature can be di-
vided into five categories: anti-inflammatory medications
(thalidomide, lenalidomide, adalimumab, acitretin, etret-
inate, prednisone, cyclosporin, cisplatinum, interferon-α,
and psoralen), stimulators of melanogenesis (erlotinib,
imatinib, latanoprost, tamoxifen, and levodopa), vita-
mins (calcium pantothenate and para-amino benzoic
acid [PABA]), medications that accumulate in tissues
(clofazimine), and those with a mechanism yet to be de-
termined (captopril).
Anti-Inflammatory Medications
While a majority of the anti-inflammatory medica-
tions were documented in case reports, 1 prospective co-
hort study and 1 retrospective study were noted in the
literature, totaling 39 patients.
Psoralen plus UVA light (PUVA) was reported by
Pavithran [25] to induce gray hair repigmentation direct-
ly in patients with premature gray hair. The author states
that the idea stemmed from clinical experience while
treating patients with PUVA for psoriasis. Because of this,
a prospective study was performed specifically on healthy
patients, aged 10–20 years, with premature gray hair (n =
37). After 13 months of treatment, 46% of these patients
noted complete scalp hair repigmentation, with no re-
lapse at the 8-month follow-up [25]. Seven additional pa-
tients showed partial repigmentation, with pigmented
proximal ends of the gray hair shafts or repigmentation
with a diffuse or patchy light-brown color [25].
In a retrospective study on men receiving cisplatinum-
based chemotherapy for germ cell neoplasms, patients
aged 15–54 years were observed at the time of hair re-
growth for changes in hair color. Of the 69 patients, 16%
noted darkening of the hair color [26]. Two patients not-
ed reversion of the hair color within 2 years after having
stopped chemotherapy.
The remaining cases of anti-inflammatory medica-
tions inducing gray hair repigmentation were noted in
sporadic case reports. The retinoic acid receptor-activat-
ing medications acitretin and etretinate were associated
with gray hair repigmentation in 2 patients with pityriasis
rubra pilaris and 1 patient with psoriasis after 6–12
months of treatment [27–29]. A patient receiving
interferon-α for the treatment of chronic hepatitis C de-
scribed scalp hair repigmentation beginning 2 months af-
ter treatment, and persistent pigmentation after having
discontinued the therapy [30]. Single case reports on a
variety of other anti-inflammatory medications known to
inhibit proinflammatory cytokine activity (including tha-
lidomide, lenalidomide, adalimumab, cyclosporin, and
prednisone) have also been linked to hair repigmentation
after 2–24 months of treatment [31–37].
Stimulators of Melanogenesis
Five medications thought to stimulate melanogene-
sis were documented in 1 retrospective study and 6 case
reports of hair repigmentation. In a retrospective study

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Table 1. Summary of the articles describing medications associated with gray hair repigmentation
Study [Ref.], year Study type
(quality)
Patients,
n
Patient characteristics Medication
Anti-inflammatory medications
Lovering et al. [32],
2016
Case report (5) 1 75-yo F with gray hair and
multiple myeloma
Thalidomide 200 mg daily for 2 yrs, then
100 mg every other day for maintenance
Tintle et al. [33],
2015
Case report (5) 1 75-yo F with gray hair and
rheumatoid arthritis
Adalimumab 40 mg subcutaneously
q2wks for 4 mo, switched to golimumab
50mg subcutaneously q4wks for 1 yr
Ward et al. [27],
2014
Case report (5) 1 61-yo M with white hair and
pityriasis rubra pilaris
Acitretin 25 mg daily
Dasanu et al. [34],
2013
Case report (5) 1 81-yo M with gray hair and
multiple myeloma
Lenalidomide 10 mg daily 21 of 28 days
and dexamethasone 40 mg weekly
Seckin and Yildiz
[28], 2009
Case report (5) 1 70-yo F with white hair and
psoriasis (not involving scalp)
Acitretin 0.3 mg/kg/day (25 mg/day)
Khaled et al. [35],
2008
Case report (5) 1 81-yo M with white hair
and bullous pemphigoid
(not involving scalp)
Prednisone 0.5 mg/kg/day for 2 mo,
then 10 mg/day as maintenance for 20 mo
Sadighha and Zahed
[36], 2008
Case report (5) 1 59-yo M with white hair
and psoriasis
Cyclosporin 5 mg/kg/day for 4 mo,
then reduced to 2.5 mg/kg/day
Kavak et al. [30],
2005
Case report (5) 1 59-yo M with white hair
and chronic hepatitis C
Interferon (IFN)-α2 6 mIU 3×/wk and
ribavirin 1,000 mg/day for 1 yr,
pegylated-IFN 100 μg/week
subcutaneously and ribavirin 1,000 mg/day
for 1 yr
Rebora et al. [37],
1999
Case report (5) 1 73-yo M with white hair and
severe eczematous dermatitis
Cyclosporin A 5 mg/kg/day
for a few days, then lowered to 150 mg/day
for maintenance
Vesper and Fenske
[29], 1996
Case report (5) 1 73-yo M with grey hair and
pityriasis rubra pilaris
Etretinate 0.5 mg/kg/day PO
Babu et al. [31],
1995
Case report (5) 1 65-yo M with grey hair and
colorectal carcinoma
5-Flurouracil (5-FU) 1,000 mg plus
leucovorin 30 mg every 4 wks with
levamisole 50 mg TID every 2 wks for
3 mo; switched to cisplatinum
100 mg plus 5-FU 100 mg every 4 wks
Robinson and Jones
[26], 1989
Retrospective
cohort study (3)
11 Men with metastatic germ cell
neoplasms, all with alopecia
from chemotherapy, median age
30 yrs (15–54), 69 pts total
Cisplatinum-based chemotherapy
(unknown dose or duration of therapy)
Pavithran [25],
1986
Prospective
cohort study (2)
17 37 patients with premature
graying, aged 10–20 yrs, 1 pt
with Werner syndrome, 1 pt
with hyperthyroidism, 1 pt with
diabetes mellitus, 2 pts with
psoriasis, and 4 pts with vitiligo
8-Methoxy psoralen 0.6 mg/kg PO every
other day, followed 2 h later with
10–15min of sun exposure, 19-mo
treatment period
Stimulation of melanogenesis
Cheng et al. [39],
2014
Case report (5) 1 68-yo F with gray hair and
metastatic adenocarcinoma of
the lung
Erlotinib 150 mg daily

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Study [Ref.], year Study type
(quality)
Patients,
n
Patient characteristics Medication
Bellandi et al. [41],
2011
Case report (5) 1 65-yo F with white hair and
open-angle glaucoma
Latanoprost 0.0005% eye drop per eye
daily
Alexandrescu et al.
[40], 2009
Case report (5) 1 76-yo F with white hair and
metastatic adenocarcinoma of
the lung
Erlotinib 150 mg daily
Etienne et al. [38],
2002
Retrospective
cohort study (3)
9 5 men and 4 women, median
age 63.4 yrs, all with grey hair
and chronic myeloid leukemia,
133 pts total in study
Imatinib mesylate (dose unknown)
Hampson et al. [42],
1995
Case report (5) 1 68-yo F with white hair and
breast cancer
Tamoxifen 20 mg daily
Reynolds et al. [43],
1989
Case report (5) 1 61-yo M with white hair and
Parkinson’s disease
Levodopa 250 mg BID for 16 yrs, then
transitioned to levodopa 100 mg daily
with carbidopa 25 mg daily, bromocriptine
2.5 mg daily added 5 mo later
Grainger [44], 1973 Case report (5) 1 51-yo M with white hair and
Parkinson’s disease
Levodopa 1.5 g daily
Vitamin supplementation
Pasricha [46], 1986 Prospective
cohort study (2)
4 7 women, aged 12–31 yrs,
with premature gray hair
followed for 3 yrs
Patients received calcium pantothenate
200 mg PO daily, with some patients also
taking Basiton Forte (thiamine 10 mg,
riboflavin 10 mg, calcium pantothenate
50 mg, cyanocobalamin 15 μg, sodium
ascorbate 50 mg, folic acid 1.5 mg) daily
and/or vitamin E 200 mg daily, gray hair
was evulsed prior to starting the
supplement, follow-up every 3 mo for
gray hair counting and evulsion
Pasricha [45], 1981 Case series (4) 2 Pt 1: 13-yo F with diffuse
graying of hair over 1.5 yrs of
unknown etiology, no family Hx
Pt 2: 15-yo F with progressive
hair graying over 2 yrs of
unknown etiology, no family Hx
Pt 1: calcium pantothenate 200 mg daily
Pt 2: calcium pantothenate 100 mg daily,
increased to 200 mg after 1 mo
Zarafonetis [48],
1950
Retrospective
cohort study (3)
5 20 pts total (7 men and 13
women), aged 43–86 yrs, with
gray hair
Pt 1: 63-yo M with gray hair and
lymphoblastoma cutis
Pt 2: 50-yo F with gray hair and
dermatomyositis
Pt 3: 68-yo M with gray hair and
dermatitis herpetiformis
Pt 4: 57-yo F with gray hair and
lymphoblastoma cutis
Pt 5: 42-yo F with gray hair and
scleroderma
Pt 1: Potassium p-amino benzoate
(K PABA) 18 g daily initially, then 12–15 g
for maintenance
Pt 2: K PABA 24 g daily for 2 wks, then
12–14 g daily for 6 mo, then 6–8 g daily
for 20 mo
Pt 3: K PABA 18–21 g daily
Pt 4: K PABA 14 g daily
Pt 5: K PABA 12 g daily
Table 1 (continued)

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on patients receiving imatinib for chronic myeloid leu-
kemia, 7% of 133 patients were reported to experience
repigmentation of gray hair 2–14 months into treat-
ment [38]. Another tyrosine kinase inhibitor, erlotinib,
was also reported to induce progressive hair repigmen-
tation 3 months and 2 years after treatment in 2 separate
cases of patients with metastatic lung adenocarcinoma
[39, 40]. One case of erlotinib-associated hair repig-
mentation began after an episode of folliculitis on the
scalp [39].
A case of latanoprost eye drop use was connected
with diffuse scalp hair repigmentation 3 years after hav-
ing started a therapy for open-angle glaucoma [41]. An-
other patient reported scalp hair repigmentation 2.5
years after having started tamoxifen therapy for breast
cancer [42]. Lastly, 2 patients receiving levodopa for
Parkinson’s disease reported diffuse hair repigmenta-
tion within 8–9 months after having begun treatment
[43, 44].
Vitamin Supplementation
Studies of vitamin B supplementation with calcium
pantothenate or potassium PABA are some of the earliest
ones directed specifically at gray hair repigmentation.
Successful repigmentation of premature gray hair in 2
healthy patients with high-dose calcium pantothenate
(200 mg daily) was noted to begin as soon as 1 month af-
ter treatment [45]. A follow-up 3-year prospective cohort
study of 7 women with premature gray hair, aged 12–31
years, reported that 28% of the patients noted repigmen-
tation with 200 mg daily, while 28% noted repigmenta-
tion with 100 mg within 3 months [46]. One prospective
cohort study and 1 retrospective study investigated the
use of PABA for gray hair [47, 48]. In 1941, Sieve [47]
performed the first documented study on repigmentation
of gray hair on 50 patients with premature or age-related
hair graying using PABA at 200 mg daily. He reported
subjective marked hair darkening in all patients after 2
months of treatment. Another study investigated the ef-
Study [Ref.], year Study type
(quality)
Patients,
n
Patient characteristics Medication
Brandaleone et al.
[49], 1943
Prospective
cohort study (2)
16 Group 1: 19 elderly (>55-yo) men
and women with white/gray hair
and chronic diseases (RA,
parkinsonism, arteriosclerosis
with hemiplegia)
Group 2: 8 young pts (29–38 yo)
Group 3: 6 women with
premature grey hair
Group 1: 7 pts received 100 mg calcium
pantothenate plus 50 g brewer’s yeast for
8 mo; 5 pts received 200 mg PABA + 50g
brewer’s yeast daily for 6 mo; 7 pts received
100 mg calcium pantothenate, 200mg
PABA, and 50 g brewer’s yeast daily for
6 mo
Group 2: 6 pts received 100 mg calcium
pantothenate, 200 mg PABA, and 50 g
yeast daily; 2 pts received 100 mg Ca P
and 200 mg PABA
Group 3: received 20 mg calcium
pantothenate and 3.5 g brewer’s yeast
for 6–10mo
Sieve [47], 1941 Prospective
cohort study (2)
50 50 pts with gray or white hair,
ages 21–55 yrs
30 pts given PABA 100 mg BID; 20 pts
given PABA plus “endocrine products”
Accumulates in tissues
Philip et al. [50],
2012
Case report (5) 1 45-yo M with grey hair and
borderline lepromatous leprosy
Clofazimine 300 mg daily for 2 mo,
then 50 mg daily for 12 mo
Unknown etiology
Read [51], 1991 Case report (5) 1 65-yo F with grey hair and
hypertension
Captopril 25 mg BID and slow-release
verapamil 240 mg daily, added to
bendrofluazide 2.5 mg daily
yo, years old; yrs, years; pt, patient; pts, patients; wks, weeks; mo, months; Hx, history; RA, rheumatoid arthritis; PO, per os; BID, bis
in die; TID, ter in die.
Table 1 (continued)

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fect of PABA at high doses (12–24 g/day) on age-related
gray hair when used for the treatment of systemic dis-
eases such as lymphoblastoma cutis, dermatomyositis,
dermatitis herpetiformis, and scleroderma (n = 20) [48].
Thirty-five percent of the patients noted hair darkening
after 2–10 months of treatment. Conversely, a prospec-
tive study on the use of 100 mg calcium pantothenate with
200 mg PABA daily for gray hair (27 subjects with age-
related canities and 6 with premature graying) found 6%
of the patients (all age-related graying) with a definite hair
color change and 21% with a slight color change on clin-
ical evaluation after 8 months of supplementation [49].
This study also noted that the repigmented hair returned
to gray after supplement discontinuation.
Accumulation in Tissues
Hair repigmentation with high-dose clofazimine dur-
ing treatment of borderline lepromatous leprosy was not-
ed as increased pigmentation of the skin initially, fol-
lowed by hair repigmentation at 6 months of treatment.
Increased skin pigmentation is a common side effect of
clofazimine due to drug crystal accumulation in body tis-
sues and fluids; however, it is not commonly reported to
induce hair color darkening [50]. The hair repigmenta-
tion persisted for 8 months after having completed treat-
ment.
Unknown Etiology
A case of frontal scalp hair repigmentation was de-
scribed 1 year after adding captopril and slow-release
verapamil to a patient’s hypertension regimen. The con-
nection between these medications and hair repigmenta-
tion is yet to be determined [51].
Discussion
As evidenced by the many cases of gray hair repigmen-
tation in the literature, the development of gray hair may
not be an irreversible process. The implication of hair pig-
mentation reversibility could have a noteworthy impact
on the quality of life of a significant number of patients,
and clinicians should be made aware of this. Most medi-
cations linked to repigmentation play an anti-inflamma-
tory role, while fewer compounds affect melanogenesis,
provide vitamin supplementation, or act on an unidenti-
fied target in the hair pigmentation process. While there
are over 130 cases of medication-induced gray hair repig-
mentation reported in the literature, it is noteworthy that
many of the medications mentioned have been used by
millions of patients and only a small minority of patients
have experienced hair repigmentation. This may be par-
tially due to a lack of patients reporting hair color chang-
es, but might more likely be due to the complex nature of
hair follicle pigmentation regulation, which highlights
that targeting one mechanism may not be enough to ma-
nipulate it.
Given that the data on gray hair repigmentation main-
ly stems from case reports, the overall quality of evidence
is low. Because of this, the strongest data derive from pro-
spective and retrospective cohort studies on PUVA, ima-
tinib, and cisplatinum-based chemotherapy, as well as on
the supplemental vitamins calcium pantothenate and
PABA. Given the nature of these medications, their indi-
cation, and associated side effects, conducting trials with
these toxic medications solely for the purpose of reversing
hair color is prohibitive. Nonetheless, the information
analyzed provides possible mechanisms of hair repig-
mentation that can be applied to new medications in the
future, hopefully without similar adverse systemic effects.
The anti-inflammatory medications listed in this re-
view inhibit proinflammatory cytokines. Adalimumab,
thalidomide, and lenalidomide block tumor necrosis
factor-α [52]. Similarly, cyclosporin inhibits the produc-
tion and activity of IL-2. Acitretin and etretinate bind the
retinoic acid receptor and inhibit expression of IL-6.
Prednisone, psoralen, cisplatinum, and interferon-α have
more generalized anti-inflammatory activities by de-
creasing immune cell activation and cytokine expression
[52]. Proinflammatory cytokines such as tumor necrosis
factor-α, IL-6, and IL-1 are known inhibitors of melano-
genesis [6]. These cytokines are produced by many cells,
including macrophages, which are located around the
hair follicle in the perifollicular connective tissue sheath
[53]. While the hair follicle is thought to be an area of im-
mune privilege, aging melanocytes may play a role in in-
creasing inflammation around the hair follicle bulb. Re-
sidual melanocytes in age-related graying hair bulbs are
found to have blunted dendrites, defective melanosome
transfer, and failure of precortical keratinocytes to receive
melanin granules [5]. Defective compartmentalization of
melanogenesis leads to accumulation of ROS and attracts
inflammatory cells to the hair follicle [5]. The broken-
down immune barrier of the hair follicle allows proin-
flammatory cytokines to access and further inhibit mela-
nogenesis. It is possible that inhibition of these cytokines
may break the feedback inhibition on hair pigmentation,
allowing melanogenesis to resume.
While suppression of inflammation within the hair
follicle appears to play a role in promoting repigmenta-

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8
DOI: 10.1159/000504414
tion, the fact that hair repigmentation does not occur in
100% of patients treated with these medications signifies
that repigmentation is a multifactorial process controlled
by both inhibition of inflammatory cytokines and mela-
nogenesis simulation. Medications such as psoralen, ima-
tinib, erlotinib, latanoprost, tamoxifen, and levodopa are
associated with stimulation of pigmentation. Prostaglan-
dins such as latanoprost have previously been shown to
cause periocular and iris hyperpigmentation when used
for glaucoma [54]. In vivo studies have shown that PGF2α
analogs promote melanocyte dendricity and melanogen-
esis [55]. Similarly, estrogens increase skin and hair pig-
mentation by stimulating melanin release by melanocytes
[56]. Tamoxifen, a selective estrogen receptor modulator,
may act as an agonist in this process leading to increased
pigmentation in rare cases. Furthermore, levodopa, a me-
tabolite of melanin production, may also lead to hair pig-
mentation when circulating blood levels reach a certain
threshold [52]. While we can hypothesize mechanisms
for these medications to promote hair follicle repigmen-
tation, the fact that there are only sporadic cases with the
use of these commonly prescribed medications points to
the fact that the process of hair repigmentation is not a
simple one. Many of the solitary case reports could actu-
ally be coincidental timing of medication initiation and
sporadic hair repigmentation instead of true causation. In
the literature, there are reports of a 21-year-old male and
a 67-year-old male with sporadic hair repigmentation
without changes in medication or health status [57, 58].
Intermittent melanogenesis dysfunction may be related
to a problem in the hair growth cycle, such as incomplete
catagen signaling [57].
The cohort study on PUVA in patients with premature
gray hair showed promising results. However, these find-
ings may be due to the fact that patients with premature
gray hair typically have a smaller percentage of gray hairs.
Furthermore, the process of premature hair graying may
be more amenable to reversal than age-related hair gray-
ing. As noted above, age-related gray hairs have defective
melanocytes, which may not be as abundant in premature
gray hair [5]. Nonetheless, psoralen may influence hair fol-
licle pigmentation through multiple pathways. Its anti-
inflammatory properties include alteration in cytokine and
cytokine receptor expression, which may reduce inflam-
mation and melanocyte destruction within the hair follicle.
Furthermore, psoralen stimulates melanocyte prolifera-
tion and transfer of melanosomes to keratinocytes, which
could lead to increased hair pigmentation [52].
Tyrosine kinase inhibitors such as imatinib and erlo-
tinib also showed promise for repigmentation in the lit-
erature. A known side effect of these medications is fol-
liculitis. Postinflammatory hyperpigmentation of the
area may incite hair repigmentation in some cases. How-
ever, imatinib is also reported in the literature to cause
hyperpigmentation of the oral mucosa, skin, and nails
[59]. Imatinib inhibits c-Kit, which plays a key role in me-
lanocyte homeostasis [59]. In vivo studies have shown
that inhibition of c-Kit influences the number, size, and
dendricity of melanocytes, which may influence hair pig-
mentation in rare cases [60].
Calcium pantothenate and PABA supplementation ini-
tially were studied to repigment hair having grayed due to
specific vitamin deficiencies. Pantothenic acid (vitamin
B5) deficiency is rare in the developed world and is un-
likely to be the cause of gray hair in the USA [61]. While it
is considered safe to take doses of up to 5 g/day, larger
doses can cause diarrhea and abdominal pain. PABA, an-
other member of the vitamin B complex family, has been
reported to be useful in sclerotic skin disorders such as
scleroderma, morphea, and Peyronie’s disease at doses up
to 12 g/day without adverse effects [52]. Larger doses lead
to an upset stomach, nausea, and hypoglycemia, which can
be serious. While studies such as the cohort study by Sieve
in 1941 noted impressive hair repigmentation, these trials
have not been replicated or verified. With the validity of
these studies in question, it is unlikely that vitamin supple-
mentation truly impacts hair repigmentation in the ab-
sence of severe vitamin deficiencies. Due to the absence of
more recent and repeatable data on vitamin supplementa-
tion for gray hair treatment, the use of these vitamins is not
strongly supported solely for use for gray hair reversal.
Medications currently in development for gray hair re-
pigmentation target both inhibition of inflammation and
stimulation of melanogenesis. Harris [62] reports on a
new combination compound, RT1640 (cyclosporin A, mi-
noxidil, and a pigment-promoting drug), which induces
gray hair repigmentation in a mouse model. An increase
in pigmentation of gray mouse hairs was associated with
increased melanocyte progenitor cell counts in up to 80%
of hair bulbs. Furthermore, hair was shaved after treat-
ment discontinuation and noted to regrow with contin-
ued repigmentation. Similarly, an α-melanin-stimulating
hormone agonist, palmitoyl tetrapeptide-20, was found to
preserve follicular melanocyte function and increase pig-
mentation during melanogenesis in a mouse model [63].
Saha et al. [64] describe the use of C18: 0 sphingolipid-rich
placental extract to induce microphthalmia-associated
transcription factor (Mitf) and activate quiescent melano-
cyte stem cells in gray-haired mice. There was significant
growth of dense black hair on mice treated with this ex-

Repigmentation of Gray Hair
9
Skin Appendage Disord 2020;6:1–10
DOI: 10.1159/000504414
tract, suggesting reactivation of melanocyte stem cells.
Lastly, in a mouse model, flavonoids such as sterubin, lu-
teolin, and hydroxygenkwanin have recently been shown
to regenerate pigmented hair when applied during wound
healing [65]. Flavonoids are antioxidants and anti-inflam-
matory compounds which scavenge free radicals and pro-
mote melanogenesis through the Wnt signaling pathway.
As evident by many of these investigational treatments,
inhibiting inflammation as well as promoting melanogen-
esis may be the key to hair repigmentation.
Conclusions
Gray hair is a natural course of aging; however, it may
not be an inevitable or permanent process. Medications
which target inflammatory cytokines, such as psoralen
and cyclosporin, or stimulate melanogenesis, such as
imatinib or latanoprost, have been reported to induce
gray hair repigmentation in rare cases. While the evi-
dence for these medications is of low quality, and the abil-
ity to effectively study them for gray hair treatment is dif-
ficult, their limited success sheds light on possible mech-
anisms to target for future development of hair re-
pigmentation medications.
Disclosure Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors did not receive any funding to complete this re-
search.
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