Intravenous glutathione for skin lightening: Inadequate safety data

Abstract

Background:
Glutathione (GSH) is the most abundant naturally occurring non-protein thiol that protects mammalian cells from oxidative stress. Intravenous (IV) GSH for skin lightening is advertised by clinics in South Africa and internationally online, yet to date no published review on the subject exists. Methods. We conducted a MEDLINE search (to 30 September 2015) of GSH use for skin lightening and of all indications in medicine, to evaluate its safety. Results. Two controlled clinical trials (GSH capsules: 60 patients; 2% glutathione disulphide lotion: 30 patients) and a case series (GSH lozenges: 30 patients) reported a significantly decreased melanin index. A case series (GSH soap: 15 patients) reported skin lightening based on photography. Two systematic reviews of IV GSH for preventing chemo-induced toxicity and a third review of adjuvant therapy for Parkinson's disease altogether included 10 trials. Most trials reported either no or minimal GSH adverse effects, but all had treatment durations of a few doses (IV) or 4 -12 weeks. No study reported long-term IV GSH use. Conclusion. In spite of widespread reported use, there are no studies of IV GSH use for skin lightening or of its safety for chronic use (for any indication). The switch from brown to red melanin production may increase the risk of sun-induced skin cancers in previously protected individuals. Regulatory assessment of systemic GSH administration for cosmetic use by the Medicines Control Council seems urgently warranted to protect consumers from potential side-effects and from complications of IV infusions. This is especially concerning because of reports of GSH bought online. Effective topical GSH may be useful for hyperpigmented skin disorders, but this requires scientific scrutiny. The debate on the merits of cosmetic skin lightening is best handled by multidisciplinary teams.

Full text

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782 August 2016, Vol. 106, No. 8
Dermatologists use depigmenting creams with various active ingre-
dients in the treatment of melasma and post-inflammatory hyper-
pigmentation.[1] Skin lightening or bleaching refers to the cosmetic
practice of applying depigmenting agents not as treatment for
hyperpigmentation but with the deliberate aim of achieving a lighter
skin colour. It is a practice that is common in many places (e.g. India,
Africa and America) with pigmented populations and a history of
improved social status with lighter complexion. Adverse effects are
associated with active ingredients (mercury, hydroquinone and potent
steroids) in depigmenting creams and are illegal in cosmetics in many
countries. Further illegal ingredients in Africa have been shown to be
imported from Europe (in spite of a European Union ban).[2]
Glutathione (GSH) was first discovered by Hopkins[3[ in 1921 in
yeasts, and subsequently in other tissues.[4] It is a tripeptide com-
posed of L-cysteine, glycine and glutamate that is synthesised
intra cellularly.[5,6] It is considered the main redox buffer in human
cells owing to its large amount of reducing equivalents,[7] and is an
impor tant enzyme cofactor that serves as a neuromodulator in the
central nervous system. The tripeptide exists intracellularly either in
an oxidised glutathione disulphide (GSSG) or reduced state (GSH),
and maintaining an optimal GSH:GSSG ratio in the cell is critical
for prevention of oxidative damage and for cell survival (Fig. 1).[8]
An imbalance in GSH and its use as a marker of oxidative stress
is reported in many diseases including cancer, neurodegenerative
disorders, cystic fibrosis, HIV,[9] diabetes mellitus,[10] anorexia
nervosa[11] and autism[12,13] and in low-birth-weight neonates.[14]
Reports of systemic skin lightening with GSH have appeared with
increasing frequency on social media, and clinics advertise it online
in many countries (Africa, the USA, Canada, Mexico, etc.). Our
objective was to conduct a literature search to identify all academic
reports of GSH use for skin lightening and all clinical trials of GSH
use for all indications in medicine.
Methods
Two MEDLINE searches for studies published up to September 2015
were conducted. The search terms for the first were ‘glutathione AND
skin lightening’, and for the second ‘glutathione AND randomised
controlled trial’. Inclusion criteria were any treatment report of
GSH for skin lightening (or hyperpigmentation) and GSH for any
randomised control trial (RCT) for the first and second searches,
respectively. Abstracts were read independently by two authors to
identify relevant articles.
Results
Nine articles were identified from the first MEDLINE search. Six
publications mentioned GSH as part of reviews related to melanin
(kojic acid in rats,[15] piceatannol inhibition of mushroom tyrosin-
ase,[16] oral zinc sulphate murine hair hypopigmentation,[17] hydro-
quin one occupational exposure[18] (and toxicity for skin lightening)
[19]
and natural ingredient-containing treatments for hyperpigmen-
tation.[20] A seventh article was an extensive review of biochemical
mechanisms of how GSH causes depigmentation in cell cultures and
laboratory animals.[21] Five clinical reports (4 published since 2012)
of the use of GSH for skin lightening were identified (2 from the
MEDLINE search and 3 from references). The first, a pharmacokinetic
study of GSH in seven participants, did not measure skin lightening
CLINICAL UPDATE
Intravenous glutathione for skin lightening:
Inadequate safety data
L M Davids, 1 PhD; J C van Wyk, 2 PhD; N P Khumalo,2 MB ChB, FCDerm, PhD
1 Department of Human Biology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
2 Division of Dermatology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Corresponding author: N P Khumalo (n.khumalo@ uct.ac.za)
Background. Glutathione (GSH) is the most abundant naturally occurring non-protein thiol that protects mammalian cells from oxidative
stress. Intravenous (IV) GSH for skin lightening is advertised by clinics in South Africa and internationally online, yet to date no published
review on the subject exists.
Methods. We conducted a MEDLINE search (to 30 September 2015) of GSH use for skin lightening and of all indications in medicine, to
evaluate its safety.
Results. Two controlled clinical trials (GSH capsules: 60 patients; 2% glutathione disulphide lotion: 30 patients) and a case series (GSH
lozenges: 30 patients) reported a significantly decreased melanin index. A case series (GSH soap: 15 patients) reported skin lightening
based on photography. Two systematic reviews of IV GSH for preventing chemo-induced toxicity and a third review of adjuvant therapy
for Parkinson’s disease altogether included 10 trials. Most trials reported either no or minimal GSH adverse effects, but all had treatment
durations of a few doses (IV) or 4 - 12 weeks. No study reported long-term IV GSH use.
Conclusion. In spite of widespread reported use, there are no studies of IV GSH use for skin lightening or of its safety for chronic use
(for any indication). The switch from brown to red melanin production may increase the risk of sun-induced skin cancers in previously
protected individuals. Regulatory assessment of systemic GSH administration for cosmetic use by the Medicines Control Council seems
urgently warranted to protect consumers from potential side-effects and from complications of IV infusions. This is especially concerning
because of reports of GSH bought online. Effective topical GSH may be useful for hyperpigmented skin disorders, but this requires scientific
scrutiny. The debate on the merits of cosmetic skin lightening is best handled by multidisciplinary teams.
S Afr Med J 2016;106(8):782-786. DOI:10.7196/SAMJ.2016.v106i8.10878

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783 August 2016, Vol. 106, No. 8
or report side-effects.[22] A case series of
15 patients from India treated with a GSH-
containing soap for melanosis of the face
reported lightening (in 11/15 after 3 months)
based on clinical photographs. However, no
mention was made of how the conditions for
photography were standardised or of follow-
up on stopping treatment.[23] A controlled
trial from Thailand tested 250 mg GSH
capsules twice daily in two groups each of 30
medical students over 4 weeks. They repor-
ted a decreased melanin index measured at
six body sites (but statistically significant
only at two sites, namely the right side of
the face (p=0.021) and the sun-exposed left
forearm (p=0.036)).[24] Wata na be et al.[25]
from Japan reported a significant reduction
in the melanin index (mean (standard
deviation), week0: 272.77 (26.17); week 10:
243.47 (26.31)) in subjects treated with a
GSSG-containing lotion measured with a
Mexameter MX18 (Courage + Khazaka Elec-
tronic GmbH, Germany). Investigators and
participants also subjectively scored GSSG-
treated skin as lighter. The most recent
study is an uncontrolled trial of 30Filipino
women. The authors reported a significant
reduc tion in melanin index (measured with
a portable mexameter) (p<0.0001) after
500 mg GSH lozenges were administered
daily for 8 weeks.
[26] None of the studies
repor ted significant adverse effects or follow-
up beyond the study period (Table 1).
Of the plethora of articles retrieved from
the second MEDLINE search, we identi-
fied 28 systematic reviews of animal stud-
ies,[39-41] GSH-related genetic polymorphisms
linked to various cancers (colo rectal can-
cer,[42] leukaemia,[43,44] lung cancer,[45,46] blad-
der can cer,[47] gastric cancer,[48,49] prostate
cancer,[50-53] adult brain tumours,[54] basal cell
carcinoma[55]) and linked to other disorders
(autism,[12,13] hyper tension,[56,57] respiratory
diseases,[58,59] cataract,[60] myelo dysplastic
syndrome,[61,62] glioma[63] and male idio-
pathic infertility.
[64]) There were 9 RCTs
identified from two systematic reviews of
the use of GSH to reduce chemotherapy-
induced toxicity (6 cisplatin, 2 axaliplatin,
1platinum); most suggested less toxicity in
GSH groups. A systematic review of GSH as
an adjuvant therapy in Parkinson’s disease
identified one controlled trial[65] showing
doubtful benefit. It was noteworthy that
most studies did not report adverse events of
GSH, and any reported were mild (Table 1).
Discussion
The idea of GSH-induced hypopigmenta-
tion may stem from early studies linking
sulfhydral-containing compounds to the
inhi bition of melanogenesis or from early
anecdotal observations in Parkin son’s dis-
ease. Proposed mechanisms of its action
include inactivation of the melano genic
enzyme, tyrosinase, influen cing the switch
from eumelanin to phaeo melanin.
[66,67]
During melano genesis, tyrosinase is res-
ponsible for the con version of L-tyro sine
to L-DOPA and subse quently to dopa-
quinone, then the path way bifurcates to
produce eumela nin or phaeomelanin. At
a critical point in the melanogenic path-
way (asterisk, Fig. 1), thiols (cysteine and
GSH) can react with L-dopaquinone to
produce gluta thionyldopa, or act as a reser-
voir of L-cysteine by conjugating with L-dopa-
quinone to produce cysteinyl dopa.These two
thioldopa substrates serve as a precursor to
enhance the switch from eumelano genesis to
phaeomelano genesis, resulting in lighter skin
pigmentation.[68,69] This effect of GSH on skin
pigmentation was reported half a century ago,
with black human skin shown to exhibit lower
levels of GSH than white skin.[70] In addition,
GSH can act to lighten the skin directly
through the quenching of free radicals and
peroxides that have been shown to induce
tyrosinase activity.[71] However, more evi-
dence is needed to prove this unequivocally.
GSH therefore has the potential to light-
en human skin. However, the only relia ble
safety data on GSH are of sporadic use dur-
ing chemo therapy cycles, for a few weeks at
most. There are no data on adverse effects
of chronic high-dose GSH as used for skin
lightening.
All chemotoxicity studies used injectable
GSH. Reactive oxygen species are easily
de com posed in aqueous solution; this may
explain the novelty of drug delivery as
lozenges, which may be more stable
(although two participants complained about
the taste). The oral route reduces potential
adverse events associated with intravenous
(IV) administration but is associated with
low bioavailability. Effective topical GSH[25]
may be useful for dermatologists treating
hyperpigmentation, but it is worth noting
that GSH as a thiol interacts with metalloid
complexes that render it ineffective. Patients
should be advised to avoid using GSH with
over-the-counter skin lightening creams that
may contain mercury.[1]
All identified published trials report mild
or no side-effects of GSH use. However,
study duration was a maximum of 12weeks.
We identified one case series that reported
intolerable adverse effects leading to discon-
tinuation of 5 mg oral GSH daily as adjuvant
treatment for hepatocellular carcinoma
(HCC). Seven of 8 patients died within
Dopachrome
Tyrosine
DOPA
L-dopaquinone
Tyrosinase
Tyrosinase ROS
ROS
GSH
GSSG
GST
GSH or cysteine
DHICA
melanins
(brown)
DHICA
Indole-5,6-quinone
carboxylic acid
DHI melanins
(black)
DHI
Indole-5,6-
quinone
Dopachrome
tautomerase
(TRP2)
DHICA oxidase
(TRP1)
MELANOGENESIS
EUMELANINS PHAEOMELANIN
(yellow/red)
Glutathionyldopas
Cysteinyldopas
Benzodiazepine metabolites
Fig. 1. GSH and its eect on skin lightening. Reactive oxygen species (ROS) have a direct activation eect
on tyrosinase. Reduced GSH neutralises ROS formation and thus indirectly inhibits tyrosinase. At the
dopachrome step* of the melanogenic pathway, interaction of thiols such as reduced GSH and cysteine
bind with dopaquinone to produce thioldopas and favour phaeomelanogenesis. GST catalyses binding
of GSH and dopaquinone. (DOPA = dihydroxyphenylalanine; DHI = dihydroxyindole; DHICA=
dihydroxyindole carboxylic acid.)

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784 August 2016, Vol. 106, No. 8
1year. However, the very severe prognosis associated with HCC was
a likely confounder.
[72] The effect of long-term administration of high
doses of GSH on cells or organ systems remains unclear. Further-
more, since GSH causes a switch from eumelanin to phaeomelanin,
it may increase UV photosensitivity, DNA damage and skin cancers
in previously protected populations.[73] Of major concern are
Table 1. Current list of human clinical trials associated with GSH
Reference
Country of origin
Study type
Indication
Subjects, n (sex), age
GSH dose and duration
Study duration Outcomes Adverse events
Skin whitening
Hong et al.,[22]
2005
Korea
Cases (uncontrolled)
Pharmacokinetic study
7 (male), 22 - 23 yr
65.5 (SD 4.5) kg, 50 mg
GSH/kg body weight IV
over 10 min, 10 d
IV GSH oxidised to GSSG (half-life =
10 min)
Loading dose = 1.69 g/kg
Maintenance dose = 5.70 g/h/kg to
reach extracellular concentration
required to suppress intracellular ROS
None reported
Arjinpathana and
Asawonda,[24] 2012
Bangkok, Thailand
RCT (double-blind,
placebo)
Skin whitening
60 (18 male, 42 female),
19 - 22 yr
250 mg capsules GSH twice
daily, 4 wk
Significant reduction in melanin indices
(UV spots) as measured by VISIA
(Canfield Scientific Inc., USA) at all six sites
in subjects who received GSH v. controls
Flatulence
Sriharsha et al.,[23]
2015
India
Pilot study
GSH soap: melanosis of
the face
15, 15 - 70 yr
3 mo
Decreased hyperpigmentation in 11/15
patients after 3 mo
None reported
Wat an ab e et al.,[25]
2014
Ibaraki, Japan
RCT (double-blind, placebo)
Skin whitening
30 (female), 30 - 50 yr
2% GSSG lotion twice daily,
10 wk
Weeks 6 and 10:
Melanin index sign lower GSSG v. placebo
Keratin index sign lower GSSG v. placebo
Mild erythema of
the face (n=1)
Handog et al.,[26]
2015
Manilla, Phillipines
Single-arm trial (not
blinded)
GSH-containing lozenges
Skin whitening
30 (female), 22 - 42 yr
500 mg daily, 8 wk
Decreased melanin index after 2 wk
All subjects showed a significant
decrease in melanin index from baseline
(p<0.0001)
Sore gums (n=1)
Undesirable
flavour/texture of
lozenge (n=1)
Chemotherapy drugs neuroprotection
Cascinu et al.,[27]
1995
Italy
RCT (double-blind, placebo)
Prevent cisplatin toxicity
in gastric cancer
50
GSH 1.5 g/m2 in 100 mL
saline IV over 15 min
600 mg GSH IM, days 2 - 5
15 wk
Neuropathy
Week 9: 0 GSH v. 16 placebo
Week 15: 4/24 GSH v. 16/18 placebo
None reported
Colombo et al.,[28]
1995
Italy
Random, phase II
Prevent cisplatin toxicity
in relapsed ovarian cancer
33
50 mg/m2 weekly ± 2.5 g/m2
GSH, 9 wk
Higher (100% dose) cisplatin intensity
was received by 56% GSH v. 27%
control
None reported
Parnis et al.,[29]
1995
Australia
RCT (double-blind,
placebo)
Prevent cisplatin toxicity
in ovarian cancer
12
GSH 1.5 g/m2 over 15 min
CDDP 40 mg/m2 over 2 h for
2, 3 or 4 consecutive days
NR
No significant protection None reported
Bogliun et al.,[30]
1992
Italy
Placebo controlled
Prevent cisplatin toxicity
in ovarian cancer
33
CDDP total dose 500 - 675
mg/m2 ± GSH 2.5 g/m2 IV
over 15 min, 1 wk
Less severe neurotoxicity after
co-treatment with all methods
Similar in both
groups except
oliguria greater in
placebo group
Smyth et al.,[31]
1997
United Kingdom
RCT (double-blind,
placebo)
Prevent cisplatin toxicity
in ovarian cancer
151 (female), 21 - 76 yr
6 cycles of 100 mg/m2 ± 3 g/
m2 + GSH IV over 15 min,
3 wk
6 courses of cisplatin, 58% GSH v. 39%
control
Improved creatinine, GSH 74% v. 62%
(p=0.006)
GSH improved depression, emesis,
neurotoxicity, hair loss, shortness of breath
None reported
Continued ...

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785 August 2016, Vol. 106, No. 8
potentially severe complications (septicaemia, infective endocarditis
and transmission of blood-borne infections) of IV administration of
GSH by people with no health qualifications. Recent Food and Drug
Administration warnings also point to a need for increased public
awareness of potential harm.[74]
Conclusion
This brief review evaluates recent clinical studies on the use of GSH.
Despite widespread use of IV GSH, no clinical report was identified.
Large RCTs of long-enough duration and follow-up are warranted
for the safe treatment of pigmentary disorders. The psychosocial
impact of systemic skin lightening is a Pandora’s box best addressed
by multidisciplinary teams including social scientists, psychologists
and psychiatrists.
Source of funding. Funded by the South African Medical Research
Council.
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Table 1. (continued) Current list of human clinical trials associated with GSH
Reference
Country of origin
Study type
Indication
Subjects, n (sex), age
GSH dose and duration
Study duration Outcomes Adverse events
Schmidinger et
al.,[32] 2000
Austria
RCT (blinding, pilot)
GSH v. intensive
hydration in cisplatin
chemo regimen for solid
tumours
20
80 mg/m2, 4 wk
GSH 5 gIV + 2 000 mL
saline control + 4 000 mL
saline + forced diuresis
NR
Haemoglobin: GSH 10.7 mg v. placebo
9.5 mg (p=0.039)
White cells: GSH 3.3 × 103/mL v.
placebo 2.2 × 103/mL (p=0.004)
Platelets: GSH 167 × 103/mL v. placebo
95 × 103/mL (p=0.02)
None reported
Cascinu et al.,[33]
2002
Italy
RCT (double-blind,
placebo)
Prevent oxaliplatin
toxicity in advanced
colorectal cancer
52
GSH 1 500 mg/m2 IV over
15 min prior to oxaliplatin
12 treatment cycles
Neuropathy
Cycle 4: 7 GSH v. 11 placebo
Cycle 8: 9/21 GSH v. 15/19 placebo
Cycle 12: 3 GSH arm v. 8 placebo
None reported
Milla et al.,[34]
2009
Italy
Oxaliplatin neurotoxicity
in colorectal cancer
treated with FOLFOX4
adjuvant regimen
27
GSH 1 500 mg/m2 IV or
saline solution before
oxaliplatin infusion
12 treatment cycles
Reduced neurotoxicity GSH v. placebo
(p=0.0037)
None reported
Leal et al.,[35] 2014 USA
RCT (double-blind, placebo)
Prevent platinum
peripheral neuropathy
185
1.5 g/m2 GSH IV or placebo
over 15 min
18 wk
No statistically significant differences
in peripheral neurotoxicity, degree of
paclitaxel acute pain syndrome, time to
disease progression or apparent toxicities
None reported
Neurodegenerative disorders
Sechi et al.,[36]
1996
Italy
Cases (uncontrolled)
Parkinson’s disease
9
600 mg GSH IV twice daily,
30 d, 4 mo
42% decline in disability, therapeutic
effect lasted 2 - 4 mo
None reported
Hauser et al.,[37]
2009
USA
RCT, pilot trial (placebo)
Safety and preliminary
efficacy in Parkinson’s
disease
21
1 400 mg GSH IV or
placebo 3 times a wk, 4 wk
3 mo
Unified Parkinson’s Disease Rating Scale
(UPDRS) motor scores higher in GSH
group v. placebo
No adverse events
due to GSH
Mischley et al.,[38]
2015
USA
Safety and tolerability
of intranasal GSH in
Parkinson’s disease
30
600 mg/d of intranasal
GSH v. placebo (saline) in
3divided daily doses
3 mo
All groups met tolerability criteria No adverse events
due to GSH
NR = not reported; IM = intramuscular.

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786 August 2016, Vol. 106, No. 8
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Accepted 11 April 2016.