Valproate‐associated hair abnormalities: Pathophysiology
and management strategies
Samir Kumar Praharaj | Ravindra N. Munoli | Suma T. Udupa |
Sivapriya Vaidyanathan
Department of Psychiatry, Kasturba Medical
College Manipal, Manipal Academy of Higher
Education, Manipal, Karnataka, India
Correspondence
Samir Kumar Praharaj, Department of
Psychiatry, Kasturba Medical College Manipal,
Manipal Academy of Higher Education,
Manipal, Udupi, Karnataka‐576104, India.
Email: [email protected];
[email protected]
Abstract
Objective: To review the literature on valproate‐associated hair abnormalities and
the available treatment options.
Methods: We searched PubMed and Google Scholar with keywords including
“valproate”, “valproic acid”, “hair”, “alopecia”, and “effluvium,” supplemented with
hand search from cross‐references. We included all types of studies including case
reports in this review.
Results: The pathophysiology of hair loss includes telogen effluvium, biotin, mineral
deficiency, and possibly hyperandrogenism. Diagnosis is based on history of
hair loss or abnormalities following valproate treatment, and is confirmed by use of
simple clinical tests such as pull test and modified wash test. Treatment
involves reassurance and advice on hair care, and if possible drug discontinua￾tion or dose reduction. Medications such as biotin and other vitamins with
minerals supplementation is effective for most individuals with hair loss. Other
treatment options are agomelatine, topical valproate or minoxidil, though these
lack evidence.
Conclusion: Hair abnormalities with valproate are common, benign adverse
effects, and management includes general measures and specific treatment
options.
KEYWORDS
alopecia, hair loss, telogen effluvium, valproate, valproic acid
1 | INTRODUCTION
Valproate is a widely used antiepileptic and mood stabilizer with a
broad spectrum of effects. Long‐term use of valproate is associated
with increased risk for major adverse effects such as hepatotoxicity,
hyperammonemia, pancreatitis, and thrombocytopenia. Among the
less severe adverse effects, hair loss and other hair abnormalities are
commonly reported with valproate (Covanis et al., 1982; Ebrahimi
et al., 2005; Kakunje et al., 2018). Although these adverse effects are
considered minor, they can cause concern among patients and could
potentially lead to the discontinuation of medication because of
cosmetic effects.
Several reviews have summarized the effects of valproate on
hair (Bublin & Thompson, 1992; Kakunje et al., 2018; McKinney
et al., 1996; Mercke et al., 2000; Tosti et al., 1994; Wang
et al., 2019); however, management strategies are not clearly
mentioned. This narrative review summarizes our current under￾standing of valproate‐associated hair abnormalities and the available
treatment options. We searched PubMed and Google Scholar with
keywords including “valproate”, “valproic acid”, “hair”, “alopecia”, and
Hum Psychopharmacol Clin Exp. 2021;e2814. wileyonlinelibrary.com/journal/hup © 2021 John Wiley & Sons Ltd.- 1 of 7

https://doi.org/10.1002/hup.2814

“effluvium.” This was supplemented with hand search from cross‐
references. We included all types of studies including case reports
in this review.
2 | PATHOPHYSIOLOGY
The normal hair cycle includes three phases: the anagen or growth
phase (2–6 years), the catagen or transition phase (2 weeks), and the
telogen or resting phase (2–4 months). Normally, most of the hair
(80%–85%) are in the anagen phase, and only 5%–10% are in the
telogen phase, and account for the shedding of hair. Diffuse hair loss
mostly occurs with early entry into the resting phase (i.e. telogen
effluvium), and rarely due to damage to hair follicles (i.e. anagen ef￾fluvium). Hair lost during the telogen phase grows back in about
three months.
2.1 | Telogen effluvium
Valproate can cause telogen effluvium, a diffuse, non‐scarring (non‐
cicatricial) form of hair loss that occurs by precipitating the follicles
into a premature rest phase. It is seen after 2–4 months of starting
the drug, and the number of hairs lost is usually less than 300 per day
(Rebora, 1993). The proportion of telogen hairs on the scalp rises to
25%–50% and lasts for more than the usual 3–6 months if the cause
is not alleviated.
2.2 | Biotin deficiency
Biotin deficiency (<100 ng/L) and suboptimal biotin levels (100–
400 ng/L) have been reported in 38% and 49% of healthy women
complaining of hair loss, respectively (Trüeb, 2016). Valproate
treatment is associated with biotin deficiency, possibly by altering the
biotin‐producing gut microflora. Patients taking valproate have
decreased biotinidase levels, the enzyme responsible for releasing
biotin from food. Low biotinidase activity has been reported in
humans (Schulpis et al., 2001; Yilmaz et al., 2009) and in rats (Arslan
et al., 2009; Korkmazer et al., 2006) with valproate therapy. How￾ever, at lower valproate doses, biotinidase enzyme activity can be
normal (Castro‐Gago et al., 2010). The possible mechanisms include
disruption of the carboxylase functions in the biotin cycle and
impairment in liver mitochondrial function by valproate (Luís
et al., 2012; Mock & Dyken, 1997).
2.3 | Trace elements
Deficiencies of trace elements such as zinc and selenium has been
associated with valproate therapy (Hurd et al., 1984). In addition,
deficiencies of iron, copper and magnesium could be contributory
(Cheung et al., 2016). Valproate has chelating effect on metals
(zinc and selenium) thus impairing their absorption. These trace
elements are required for keratinization and hair growth. Several
assays performed in valproate‐treated patients demonstrated
controversial results, including decreased or unchanged serum zinc
and/or copper concentrations (Hurd et al., 1984; Kaji et al., 1992;
Kuzuya et al., 1993; Sözüer et al., 1995; Suzuki et al., 1992). A lon￾gitudinal study found persistent lower zinc levels at 3 and 6 months
of valproate therapy (Yilmaz et al., 2009).
2.4 | Hyperandrogenism
Valproate is a potent aromatase inhibitor. Aromatase is essential for
conversion of androgens to estrogens in hair follicles (Schweikert
et al., 1975). Aromatase inhibitors lead to male pattern of hair loss in
women (Rossi et al., 2013). Valproate increases androgen in women
(Uchida et al., 2005), and 4‐androstenedione levels (Isojärvi
et al., 2005), a precursor of testosterone and estrone, in men. This
hyperandrogenism leads to androgenic alopecia in men and male
pattern of alopecia and hirsutism in women. Polycystic ovary syn￾drome (PCOS), a syndrome of dysfunction of the ovaries associated
with hyperandrogenism and insulin resistance, has been associated
with valproate therapy in women of reproductive age group (Hu
et al., 2011; Isojärvi et al., 1993). It is suggested that women with hair
loss on valproate could have an underlying PCOS (Bilo & Meo, 2008).
2.5 | Vitamin D deficiency
Integrity of dermis, epidermis and hair cycles is essential for main￾tenance of normal hair. Vitamin D plays a pivotal role in preserving
integrity of hair follicle and in epidermal differentiation (Amor
et al., 2010; Damiani et al., 2020). Lower vitamin D levels, along with
other deficiencies have been associated with valproate therapy
(Cheung et al., 2016). The role of valproate in Vitamin D deficiency
has been documented (Menon & Harinarayan, 2010; Nicolaidou
et al., 2006; Qiu et al., 2020), possibly contributing to hair
abnormalities.
3 | CLINICAL PRESENTATION
The incidence of hair loss with valproate is estimated to be 3.5%–
12% (Calabrese et al., 1992; Covanis et al., 1982; Ebrahimi
et al., 2005; McKinney et al., 1996). A meta‐analysis of 25 studies
estimated the overall incidence of alopecia associated with valproate
to be 11% (95% confidence interval 0.08–0.13) (Wang et al., 2019).
The incidence is possibly dose‐related, as it was observed in those
with plasma valproate levels more than 100 μg/ml (Mercke
et al., 2000; Ramakrishnappa & Belhekar, 2013; Tomita et al., 2015).
A lower incidence of alopecia (4%) was reported in patients with
lower plasma valproate levels (25–50 μg/ml), compared to 28% of
those with higher levels (85–150 μg/ml) (Beydoun et al., 1997).
2 of 7 - PRAHARAJ ET AL.
However, Wang et al. (2019) meta‐analysis did not find any associ￾ation with dose or duration of valproate therapy. Hair changes are
usually evident after 3 to 6 months of starting valproate (Wilting
et al., 2007). When given during pregnancy, the newborn may have
aplasia cutis congenita of the scalp and may present with a sharply
circumscribed patch of alopecia (Govindan & Mandadi, 2021; Hubert
et al., 1994).
Hair loss is diffuse and non‐scarring (Mercke et al., 2000; Tosti
et al., 1994). There is no history of febrile illnesses, chronic systemic
illnesses, childbirth, major surgery, stress, or exposure to other drugs
which explains hair loss. The hair loss is noticed by the patients
usually after 3 months of starting valproate. Typically, they report
excess shedding with brushing, combing or shampooing. Sometimes,
patients report of excess hair fall even while running the hand
through the hair (Rebora, 2019). However, there are no clumps of
hair loss. It may be more common in women. Usually patients will
report gradual but steady hair loss, commonly beginning 2 to
6 months after initiating treatment. Complete hair loss is not re￾ported. Thinning usually becomes clinically noticeable when 25%–
50% of the hair is lost (Tosti et al., 1994).
The hair loss with valproate (and other drugs) is usually
reversible, after the discontinuation of medication (Tosti
et al., 1994). Hair grows typically 2 to 3 months after alopecia onset
following dose reduction or discontinuation (Mercke et al., 2000).
Alopecia may or may not be evident, depending on hair growth prior
to starting treatment. The presence of erythema, scaling, or inflam￾mation; altered or uneven hair distribution; or changes in shaft
caliber, length, shape, or fragility may suggest other diagnoses
(Rebora, 2019).
There are also reports of changes in hair color with valproate
treatment (Bublin & Thompson, 1992; Gerstner et al., 2008; Herranz
et al., 1981). Also, changes in texture such as thinning of hair, wavi￾ness, and curling of hair akin to ‘perming’ can occur (Covanis
et al., 1982; Gupta, 1988; Jeavons et al., 1977; Uygur & Uygur, 2019;
Yasemin, 2016). Hair structure changes were reported in 9% of pa￾tients on valproate therapy (Bittencourt, 1986). Although usually
reversible, curly hair could occasionally persist after discontinuation
of valproate (Mercke et al., 2000). Hair loss may be a cause for
noncompliance with valproate therapy.
For clinical diagnosis, a pull test may be used; 40 to 60 hairs at
their base using the thumb, index, and middle fingers, and gentle
traction is applied away from the scalp (Guarrera & Rebora, 2017). A
modified wash test may be used to confirm the diagnosis of telogen
effluvium, which is defined as hair loss of more than 100, every
5 days (Guarrera & Rebora, 2017).
4 | MANAGEMENT
Screening for predisposing factors such as hypothyroidism, heredity,
lichen planus, menstrual abnormalities, scalp infections, history of
cosmetic side effects (such as weight gain, acne) and other
dermatological risk factors before initiating the drug is recommended
(Chen et al., 2015; Rebora, 2019; Thomson et al., 2017).
Laboratory investigations may be required to identify other causes
of hair loss including complete blood count, liver functions, endocrine
functions (thyroid, androgens, prolactin), and nutritional status (zinc,
iron, proteins, folate and vitamin B12) (Cheung et al., 2016). Serum
valproate levels can be measured, as levels more than 100 μg/ml
though considered within therapeutic range, can be potentially toxic
(Fleming & Chetty, 2006; Tomita et al., 2015).
Treatment will include general measures (reassurance, hair care
techniques) and specific treatment options.
4.1 | Reassurance
Hair fall is a benign adverse effect, and usually reversible after
discontinuation of medication. Educating patients and simple reas￾surance to allay anxiety may be helpful.
4.2 | Hair care techniques
Practical suggestions to reduce hair fall include using soft brushes
and mild shampoos, and avoiding use of the dyes, heated curlers, and
hair dryers (Draelos, 2015). Occasionally, patients may benefit from
camouflaging techniques (Draelos, 2015).
4.3 | Drug discontinuation
Discontinuation of valproate reverses the hair loss and may be
considered if feasible clinically. If clinically indicated, substituting
with another medication can be tried. It may take 3‐6 months for hair
regrowth after discontinuation.
4.4 | Dose reduction
If it is not possible to discontinue, a dose reduction may be tried as
hair loss is more common with higher valproate levels (Desp￾land, 1994). Wherever possible, the serum levels can be maintained
below 100 μg/ml (Ramakrishnappa & Belhekar, 2013; Tomita
et al., 2015). Usually dose reduction leads to regrowth of hair in in￾dividuals with valproate‐associated alopecia (Henriksen & Johan￾nessen, 1982). If clinically feasible, initiating valproate at a lower
dose and increasing it gradually to reach the target dose may help.
4.5 | Dietary advice
Advise not to take valproate during meals to reduce its chelating
effect on metals (zinc and selenium) required for hair growth.
PRAHARAJ ET AL. - 3 of 7
4.6 | Mineral supplements
Zinc, iron, magnesium, and selenium may be useful in the treatment
of alopecia (Almohanna et al., 2019; Kanekura et al., 2005; Park
et al., 2009; Slonim et al., 1992; Trost et al., 2006), and can be added
along with valproate therapy. In a single case study, valproate‐related
alopecia responded to therapy with zinc 15 mg and selenium 150 mcg
for 5 weeks (Fatemi & Calabrese, 1995).
4.7 | Biotin
Alopecia associated with valproate improves with the oral adminis￾tration of biotin (10 mg/day) in 3 months in patients with epilepsy
(Castro‐Gago et al., 2010; Grootens & Hartong, 2017; Schulpis
et al., 2001; Yilmaz et al., 2009).
4.8 | Other vitamins
In addition to biotin, possibly vitamins A, D, C, E, B6, and B12 could
be prescribed (Almohanna et al., 2019; Beoy et al., 2010; Guo &
Katta, 2017), however, evidence for their efficacy is lacking.
4.9 | Agomelatine
The newer antidepressant, agomelatine, a serotonin and melatonin
agonist, at 25 mg/day has been found to reduce hair loss associated
with valproate (Sahin et al., 2017). Possibly, melatonin has a cyto￾protective role in hair growth cycle by downregulating apoptosis and
activating DNA repair system (Fischer et al., 2008), and has been
found to reduce hair loss (Fischer et al., 2004, 2012). Agomelatine
may alleviate hair loss by stimulating melatonin receptors (Sahin
et al., 2017).
4.10 | Minoxidil
When the drug responsible for telogen effluvium cannot be dis￾continued, chronic telogen loss may precipitate or aggravate andro￾genic alopecia in genetically predisposed patients. In such cases,
treatment with topical minoxidil may be useful. However, this is an
expensive option, and there is only a case report documenting its use
(in combination with Zinc supplementation and topical azelaic acid
and tretinoin) for alopecia caused by valproate (Thomson
et al., 2017).
4.11 | Topical valproate therapy
Although systemic treatment with valproate causes hair loss, topical
application of valproate is found to promote hair growth (Agrawal &
Das, 2017; Jo et al., 2014; Kakunje et al., 2018). Valproate promotes
transition of hair follicles from telogen to anagen; this transition is by
upregulation of β‐catenin expression by inhibition of glycogen syn￾thase kinase 3β (Lee et al., 2015). Furthermore, topical application
has shown increase in β‐catenin in mice skin (Lee et al., 2012).
Paradoxically, oral valproic acid treatment in a 60‐year‐old with
androgenic alopecia showed reduction in hair loss in 3 months, and
improvement in hair density and thickness after 2 years of treatment
with significant hair growth on the frontal area (Choi et al., 2014). It is
possible that the effect of valproate therapy could be related to in￾dividual predisposition, hence, it is considered as a double‐edged
sword (Agrawal & Das, 2017).
5 | CONCLUSIONS
Hair loss and other abnormalities are commonly reported with val￾proate. The pathophysiology includes telogen effluvium, biotin defi￾ciency, deficiency of trace elements, and possibly hyperandrogenism.
Treatment includes reassurance, advice on hair care, and if possible
drug discontinuation or dose reduction. Medications such as biotin
and other vitamins with mineral supplementation is effective in most
individuals. Sometimes other options such as agomelatine, topical
valproate or minoxidil may be considered. Early identification and
discussion with the patient may allay anxiety and possibly reduce
noncompliance related to this benign adverse effect.
ACKNOWLEDGMENTS
None.
CONFLICTS OF INTEREST
All authors declare that they have no conflict of interest.
AUTHORS’ CONTRIBUTIONS
Samir Kumar Praharaj wrote the first draft. All the authors have
contributed and approved the final manuscript.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were
generated or analysed during the current study.
ORCID
Samir Kumar Praharaj https://orcid.org/0000-0001-8530-1432
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How to cite this article: Praharaj, S. K., Munoli, R. N., Udupa,
S. T., & Vaidyanathan, S. (2021). Valproate‐associated hair
abnormalities: Pathophysiology and management strategies.
Human Psychopharmacology: Clinical and Experimental, e2814.

https://doi.org/10.1002/hup.2814

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