March 14, 2023

To: Angela Clauson, PharmD

From: Morgan Tucker, 2023 PharmD Candidate
CC: Samantha Triplett, PharmD
Genevieve Engle, PharmD, BCMAS
Re: Nutrafol and post-menopausal hair loss
__________________________________________________________________________

In response to your request regarding the benefits of natural products to hair thinning, the
following information is provided.

Response and Recommendation:

In response to the first question about the data supporting the use of the ingredients contained
in Nutrafol® for postmenopausal hair thinning, there are three trials comparing this product to
placebo in which there are slight benefits to overall hair growth. The trials found a statistically
significant increase in total hair count as well as a statistically significant decrease in total shed
hair count at the end of 360 days. At baseline, there was an average of 78.4 total hairs. This
increased to 87.6 by the end of 360 days. This was a total 11.7% improvement compared to the
baseline total hair count, p-value<0.0001. Similarly, there was a shed hair count of 38.2 at
baseline and a count of 22.3 at day 360, a decrease of 43.2% at day 360, p-value<0.001.

Products similar to Nutrafol® currently available in the market are hypothesized to aid in the
prevention of hair thinning. The majority of ingredients contained in Nutrafol® can be taken
individually for the treatment of hair thinning. The vitamin ingredients found in Nutrafol® will only
produce results in patients deficient in that vitamin. In general, there is a lack of evidence
indicating the overall benefit of these ingredients in the treatment of hair thinning, but they are
considered safe when taken in recommended daily amounts.

Additionally, there is an overall lack of literature in regards to the use of topical biotin and any
potential benefit in the treatment of hair thinning.

Analysis and Synthesis:

Of the inactive ingredients contained in Nutrafol®, vitamins A, C, D, E, as well as zinc, iodine,
selenium, capsaicin, curcumin and japanese knotweed may be beneficial in the treatment of hair
thinning.

Vitamin A works to produce sebum, an oil necessary to keep the scalp moisturized to provide a
healthy environment for hair to grow.1 Vitamin A has been found to be important to the
maintenance of follicle growth and health, but taken in larger quantities can actually increase
hair loss.2 Therefore, a patient that is deficient in vitamin A, may benefit from the
supplementation of vitamin A, but a patient without a vitamin deficiency may experience hair
loss.

Vitamin C, otherwise known as ascorbic acid, is necessary for the production of collagen
precursors, known as hydroxyproline.1 Collagen production decreases due to aging, leading to
brittle hair and hair loss. Vitamin C has the potential to increase the amount of collagen and
therefore hair growth. Vitamin C is also a potent antioxidant, and is involved in the intestinal
absorption of iron.3 Hair loss associated with iron deficiency may be treated with vitamin C,
however there is a lack of data of its use for this indication.

Vitamin D maintains serum calcium levels in the body and is involved in the activity of
parathyroid hormone, phosphate, and calcitonin.1 Additionally, vitamin D helps maintain calcium
levels in the body. Low levels of calcium and vitamin D can lead to hyperparathyroidism, which
causes hair thinning or loss. Vitamin D deficiency has been associated with androgenic
alopecia. Therefore, supplementation of vitamin D when an individual is deficient may be
beneficial in the prevention of hair thinning or loss.

Vitamin E is an antioxidant with the potential to reduce the number of free radicals that
ultimately lead to the breakdown of hair follicle cells.1 Therefore, the supplementation of vitamin
E when a patient is known to be deficient may prevent hair shedding, leading to an increase of
hairs maintained in the scalp.

Iodine is essential in the production of T4 and T3 from the thyroid.1 Without iodine,
hypothyroidism eventually develops leading to hair loss. Thus, if an individual is deficient in
iodine, supplementation may help in the prevention of hair loss.

Zinc functions as a cofactor involved in the synthesis of DNA and RNA, and works to mobilize
vitamin A from the liver.1 When mobilized, vitamin A is then capable of moving from the liver to
tissues where it is needed. A zinc deficiency may lead to hair thinning.4 Therefore,
supplementation of zinc in a deficient patient may aid in the treatment of hair thinning. However,
when studied in patients with normal baseline zinc levels, some studies have shown no benefit
in hair regrowth while others have shown benefit. These studies were conducted over periods of
3 months, therefore longer studies and studies in zinc deficient patients would be useful to
determine the true impact of zinc on hair growth.

Zinc Clinical Trial

In Sharquei KE, et al., a crossover study conducted in 67 participants, zinc supplementation
was compared to placebo for a period of 3 months to determine effectiveness of zinc
supplementation to the treatment of alopecia areata.5 Forty-one of these participants were men
and twenty-six were women. Effectiveness of zinc supplementation was measured by grade I
and II regrowth with grade I regrowth defined as partial hair regrowth with villous (fine, thin,
short) hair, and grade II regrowth defined as complete hair regrowth with terminal (coarse,
pigmented, and long) hair. Participants in the zinc-to-placebo group (n=37) were to receive zinc
supplementation at 5 mg/kg/day in three divided doses for a period of 3 months and then were
switched to placebo for the remaining 3 months for the completion of the crossover. In the zinc-
to-placebo group, a total of 5 participants achieved grade I regrowth and 22 participants
experience grade II regrowth. After the zinc-to-placebo group switched to placebo, 6 participants
achieved grade I regrowth, and 23 participants achieved grade II regrowth. Participants in the
placebo-to-zinc supplementation group (n=30) were to receive placebo for a period of 3 months
and then were switched to zinc supplementation for the remaining 3 months to complete the
crossover period. During the initial 3 months with placebo, 3 participants achieved grade I
regrowth and 3 participants achieved grade II regrowth. When switched to zinc
supplementation, 6 participants achieved grade I regrowth and 20 participants experienced
grade II regrowth after 3 months. For Grade I regrowth, statistical significance between
treatment and placebo groups was not discussed. Grade II regrowth in the zinc
supplementation period was statistically significantly increased compared to the placebo period,
p-value<0.0001. Across both patient groups, the only side effect listed was mild gastric upset,
which was seen in 8 (11.9%) of patients. Gastric upset occurrence in each group was not
reported.

Antioxidants and Hair Loss

Selenium is classified as an antioxidant similar to vitamins A, C, and E.1 Oxidative stress may
play a role in the multifactorial process, contributing to androgenic alopecia. Therefore, selenium
along with vitamins A, C, and E are commonly used together in supplementation for the
prevention of hair loss. Several studies combining these antioxidants have found to increase
hair density, thickness, and prevent hair loss. These studies were conducted in relatively small
patient populations with the baseline cause of hair loss unknown. It is also notable that excess
supplementation of these antioxidants has also led to hair loss.

Vitamins C and E Clinical Trial

In Le Floc’h C, et al., a 6 month randomized trial conducted in Italy, 120 healthy females
between the ages of 18 and 65 with stage I hair loss on the Ludwig scale were recruited to
determine the efficacy of a nutritional supplement containing 460 mg fish oil, 460 mg
blackcurrant seed oil, 5 mg vitamin E, 30 mg vitamin C, and 1 mg lycopene when compared to
placebo.6 Stage I hair loss, according to the Lugwig scale, is defined as mild hair loss occurring
at the part line. Of note, 60 participants were premenopausal and the remaining 60 participants
were postmenopausal. A total of 118 participants were included in the intention-to-treat
population. After 6 months, 62% of supplemented participants experienced an increase in hair
density compared to 28.2% of participants in the placebo group, p-value<0.001. The
supplement was well tolerated, with no serious adverse events reported. If mild adverse events
were experienced, they were not listed.

Capsaicin (Capsicum) Clinical Trial

Capsaicin, typically used as a topic analgesic, has been studied for hair loss due to topical
capsaicin and isoflavones potential to increase dermal IGF-1 production.1 IGF-1 has been found
to be helpful in hair follicle development. In Harada, et al., a five-month randomized clinical trial,
researchers sought to determine the effect of 6 mg oral capsaicin and 75 mg isoflavone on
blood levels of IGF-1 as well as hair growth in participants with various types of alopecia.7 Both
IGF-1 levels and promotion of hair growth were statistically significantly increased in the
capsaicin group (n=31) compared to the placebo group (n=17). IGF-1 levels saw a statistically
significant increase from 60 ng/mL to 70 ng/mL in all 31 participants in the treatment group, p-
value <0.01. Participants in the placebo group experienced a non-statistically significant
increase in IGF-1 levels from 68 ng/mL to 73 ng/mL. This data was presented in a figure, so
levels listed are approximate. A total of 20 participants in the treatment group experienced an
increase in hair growth, while only 2 participants in the placebo group had an increase in hair
growth, p-value<0.01. Adverse events were not reported.

Saw Palmetto Clinical Trial

Saw palmetto has been studied for the treatment of androgenic alopecia in men. In a systematic
review, trials were summarized regarding saw palmetto being researched in men with
androgenic alopecia (AGA).4 In Prager N, et al., a randomized, double-blind, placebo-controlled
trial, 200 mg saw palmetto was compared to placebo to determine the impact on mild to
moderate AGA in men aged 23 to 64.8 A total of 26 men were enrolled in this study, and 19
completed the trial in its entirety. Of the patients in the treatment group, 60% showed improved
scalp hair growth compared to 11% in the placebo group. P-values were not addressed in this
study due to the small sample size, therefore, statistical significance cannot be determined.
Adverse events reported included nausea, constipation, and diarrhea. Frequency of these
adverse events was not reported. In Rossi A, et al., a two-year, open-label trial, a sample of 100
male participants between the ages of 20 and 40 years with mild to moderate AGA were
selected to receive either 320 mg saw palmetto or 1 mg finasteride.9 Photos were taken of
various areas of the scalp, and a scale was used to determine improvements at the end of the
trial, rated on a scale from 0 to 3. A score of 0 was no change, 1 was slightly increased, 2 was
moderately increased, and 3 was greatly increased. In the finasteride group, 34/50 (68%) of
participants had a score greater than 0 at the end of the trial and 19/50 (38%) in the saw
palmetto group had a score greater than 0. A total of 3/50 (6%) of participants in the finasteride
group achieved a score of 2, and 1/50 (2%) achieved a score of 3 at the end of treatment. Of
note, all 19 participants in the saw palmetto group achieved a score of 1 at the end of the trial,
and no participants received scores of 2 or 3. P-values were not provided in this study,
therefore, statistical significance cannot be determined. No adverse events were observed in
this study. Additionally, since saw palmetto is hypothesized to inhibit 5-alpha reductase, it may
have an impact in female postmenopausal hair loss as well.

Curcumin Clinical Trial

Curcumin, an antioxidant, is thought to increase the level of vitamin E, another antioxidant
capable of decreasing oxidative damage to the hair follicle.10 However, in Mohammadi A, et al.,
1 g/day curcumin failed to increase vitamin E levels when compared to placebo.11 After six
weeks of supplementation with curcumin, vitamin E levels changes by an average of 0.00
μmol/L in the treatment group, while the placebo group had a change of vitamin E levels of
approximately 0.29 μmol/L, p-value=0.005.

Japanese knotweed has been shown to have some antioxidant effects in animal data, however,
there is a lack of information linking its use and benefit to human hair loss.12

Nutrafol Clinical Trials

In Ablon G, et al., 2018, a six-month, randomized, double-blind, placebo controlled study,
researchers aimed to evaluate the safety and efficacy of Nutrafol® in promoting hair growth in
women with thinning hair.13 This study was relatively small, with 26 participants in the treatment

group and 14 participants in the placebo group. Of note, the mean age was 48.3 土 10.5 years
in the treatment group and 53.14 土 5.7 years in the placebo group. Women with Fitzpatrick skin
types I to IV were included, limiting the results to lighter skin types. Additionally, both the
inclusion and exclusion criteria were subjected to procedure selection bias due to investigator
involvement in the confirmation of self-perceived thinning hair, skin type, as well as any health
conditions that may have been a safety concern for the patient to be enrolled in the study. A
statistically significant difference in the levels of stress was increased in participants that
received placebo compared to the treatment group, respectively (78.6% vs 42.3%), p-
value=0.028. Though stated as significant, the method by which stress was measured and
determined was not provided. In regard to the results from this study, the mean number of
terminal (coarse, pigmented, and long) and vellus (fine, thin, short) hairs as well as total hair
count were calculated as the primary endpoint. Participants randomized to the Nutrafol® group
had a total hair count of 155 at baseline, 166 at day 90, and 171.8 at day 180. Participants
randomized to the placebo group had a total hair count of 150 at baseline, 150.6 at day 90, and
154.5 at day 180. At day 90, there was a statistically significant difference in total hair count of
Nutrafol® compared to placebo, p-value=0.003 and at day 180, p-value=0.002. No treatment-
related adverse events were reported.

In Ablon G, et al., 2021, a six-month, randomized, double-blind, placebo-controlled study,

researchers sought to determine the safety and efficacy of Nutrafol® in perimenopausal,
menopausal, and postmenopausal women.14 Women aged 40-65 years who were either
perimenopausal, menopausal, or postmenopausal were included in this study. Patients that
were taking medications that could impact hair loss and/or growth, recent life stressors, and
uncontrolled diseases that could impact hair loss and/or growth were excluded from this study.
A total of 54 participants were enrolled in the study with 27 randomized to receive Nutrafol® and
27 to receive placebo for a period of 180 days. The primary endpoint, mean target area hair
count, indicated a statistically significant increase in the treatment group compared to the
placebo group. The total hair count in the Nutrafol® group was an average of 78.4 at day 0, 81.3
at day 90, and 86.3 at day 180. While the placebo group had a total hair count of 78.4 at day 0,
78.2 at day 90, and 78.1 at day 180, p-value<0.01 at days 90 and 180 in the treatment group
compared to placebo. A total of 3 participants experienced adverse events. In the treatment
group, 2 participants experienced nausea, bloating and diarrhea. In the placebo group, one
participant experienced nausea and a headache.

In Ablon G, et al., 2022, an open-label, six month extension study of Ablon G, et al., 2021,
researchers aimed to determine the continued safety and efficacy of Nutrafol® in promoting hair
growth.15 After continuing Nutrafol® for twelve months, the total hair count increased from a
baseline of 78.4 from day 0 to 87.6 at day 360, p-value<0.0001. In addition, at one year there
was improvement in the amount of hair shed from day 0, 38.2 hairs shed to one year, 22.3 hairs
shed, p-value<0.001. No adverse events were reported in Phase II of this study.

Medline was searched for literature using the following search terms:
● (MH “alopecia”) AND (MH “dietary supplements”) AND woman OR female - 46 results
● (MH “administration, topical”) AND biotin - 21 results

Thank you for contacting the Christy Houston Foundation Drug Information Center at the
Belmont University College of Pharmacy. Please do not hesitate to contact the Drug Information
Center at 615-460-8382 or druginfo@belmont.edu with any additional questions.

References:
1. Bridgeman MM, Rollins CJ. Essential and Conditionally Essential Nutrients. In: Krinsky
DL, Ferreri SP, Hemstreet BA, Hume AL, Rollins CJ, Tietze KJ, eds. Handbook of
Nonprescription Drugs: An Interactive Approach to Self-Care. 20th ed. American
Pharmacists Association; 2021:chap 23. Accessed March 7, 2023.
https://pharmacylibrary.com/doi/full/10.21019/9781582123172.ch23
2. Everts HB. Endogenous retinoids in the hair follicle and sebaceous gland. Biochim
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(double blind; cross-over study). J Clin Exp Dermatol Res. 2012;3(150).
doi:10.4172/2155-9554.1000150
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doi:10.1111/jocd.12127
7. Harada N, Okajima K, Arai M, Kurihara H, Nakagata N. Administration of capsaicin and
isoflavone promotes hair growth by increasing insulin-like growth factor-I production in
mice and in humans with alopecia. Growth Horm IGF Res. 2007;17(5):408-415.
doi:10.1016/j.ghir.2007.04.009
8. Prager N, Bickett K, French N, Marcovici G. A randomized, double-blind, placebo-
controlled trial to determine the effectiveness of botanically derived inhibitors of 5-α-
reductase in the treatment of androgenetic alopecia. J Altern Complement Med.
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repens in male androgenetic alopecia: a two-year study. Int J Immunopathol Pharmacol.
2012;25(4):1167-1173. doi:10.1177/039463201202500435
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November 21, 2022. Accessed March 8, 2023. https://online.lexi.com
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vitamin E concentrations in individuals with metabolic syndrome. Phytother Res.
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Updated August 5, 2022. Accessed March 8, 2023. https://online.lexi.com
13. Ablon G, Kogan S. A six-month, randomized, double-blind, placebo-controlled study
evaluating the safety and efficacy of a nutraceutical supplement for promoting hair
growth in women with self-perceived thinning hair. J Drugs Dermatol. 2018;17(5):558-
565.
14. Ablon G, Kogan S. A randomized, double-blind, placebo-controlled study of a
nutraceutical supplement for promoting hair growth in perimenopausal, menopausal, and
postmenopausal women with thinning hair. J Drugs Dermatol. 2021;20(1):55-61.
doi:10.36849/JDD.2021.5701
15. Ablon G, Kogan S, Raymond I. A long-term study of the safety and efficacy of a
nutraceutical supplement for promoting hair growth in perimenopausal, menopausal, and
postmenopausal women. J Drugs Dermatol. 2022;21(7):776-783.
doi:10.36849/JDD.6912