Efficacy and safety of silymarin containing antioxidant serum as an adjuvant treatment of mild‐to‐moderate acne vulgaris: A prospective, open‐label pilot study

Abstract

Background

Silymarin is the active component of milk thistle, which has antioxidant properties by scavenging free radicals and potential comedolytic properties.

Aims

This study aimed to assess the efficacy and safety of 0.5% silymarin‐loaded antioxidant serum (SAS) used to treat mild‐to‐moderate acne.

Patients and Methods

A prospective, open‐label pilot study was conducted. We enrolled 22 Korean acne patients who applied the 0.5% SAS on the whole face twice daily while continuing the current anti‐acne medications. Grade of acne severity, individual lesion counts, sebum output levels, skin erythema, and melanin pigmentation were assessed.

Results

After a 4‐week application, the modified Global Acne Grading Score (mGAGS), Global Evaluation Acne (GEA) scale, and the acne lesion counts were significantly decreased. Sebum secretion, skin pigmentation, and erythema were also reduced during the study period, yet only the melanin pigmentation index reached statistical significance. Subgroup analysis revealed that the patients who took the low‐dose oral isotretinoin during the study period showed more noticeable improvements in skin sebum output and melanin pigmentation. Additionally, no adverse event was associated with using the 0.5% SAS.

Conclusion

The 0.5% silymarin‐containing antioxidant formulation improved acne's clinical severity and related skin biophysical parameters.

INTRODUCTION

Acne is a prevalent inflammatory skin condition mainly affecting adolescents and young adults. Although the treatment parameters based on acne severity are well established, acne is still regarded as a chronic and relapsing inflammatory illness with different degrees of severity. Furthermore, due to the complex nature of acne vulgaris, most treatments have only modest efficacy.

Current research indicates that its pathogenesis is well defined by the following four pathognomic factors: follicular hyperkeratinization, sebaceous hyperplasia, and cutibacterium acnes colonization are the primary causes underlying the onset of acne, as well as inflammation. Anti-androgens (e.g., spironolactone), retinoids (isotretinoin), and oral contraceptives are all systemic medications that alter sebum production yet are only applicable in certain patients. Numerous cosmetic formulations have been proposed based on prior research, and specific components are known to inhibit sebum production during acne development. Several active compounds in dermo-cosmetics have been demonstrated to decrease sebum production. Topical antioxidants such as fullerene and epigallocatechin-3-gallate (EGCG) have been playing an increasing role, demonstrated by in vitro and controlled trials.

Silymarin is an extract from the dried seeds and fruits of the milk thistle plant (Silybum marianum). Silymarin is composed of flavonolignan isomers, which act as a free radical scavenger and modulate enzymes associated with the development of cellular damage. Apart from its well-established hepatoprotective properties, oral supplementation of silymarin is a promising anti-diabetic and lipid-lowering effect. A topical application has been examined with the positive effects of silymarin as a dietary supplement.

Here, we analyzed the efficacy and tolerability of adjuvant treatment with 0.5% silymarin-loaded antioxidant serum along with conventional medical treatment with acne.

MATERIAL AND METHODS

Study design and participant selection

We conducted a prospective, open-label pilot study to evaluate the efficacy and safety of 0.5% silymarin-loaded antioxidant serum (SAS) in acne patients. Twenty-two adults exhibiting mild-to-moderate acne for more than 6 months were eligible for this study. The exclusion criteria were a history of active facial dermatosis, pregnancy, uncontrolled medical illness, and the history of chemical peeling, plastic surgery, or laser treatment within the prior 1 month. The Institutional Review Board of our institution approved this study (IRB No. 9-2021-0039), and informed consent was obtained from each subject. The study was conducted according to the principles of Good Clinical Practices and the declaration of Helsinki.

Test product and treatment regimen

The subjects were instructed to apply 3–5 drops of the 0.5% SAS on the whole face twice a day. The test product Silymarin CF® (Skinceuticals, Loreal) is classified as cosmeceutical, which contains 0.5% silymarin, 15% L-ascorbic acid, 0.5% ferulic acid, and 0.5% salicylic acid. SAS is designed to be used as an adjuvant in acne patients while concurrently using oral medications or topical pharmaceutical products. Therefore, subjects were advised to keep anti-acne medications during the study period, if they were taking them for more than 3 months before the study. However, they were advised not to change the dosage or type of the medication and not to use any other cosmeceutical products or emollients other than the test products during the study. The study duration was 4 weeks and included two assessment visits: inclusion visits in Week 0 (baseline) and a follow-up visit at 4 weeks.

Assessment of treatment efficacy

The study's primary endpoint was the assessment of the grade of acne severity. A blinded board-certified dermatologist independently evaluated the acne severity using the modified Global Acne Grading Score (mGAGS) and Global Evaluation Acne (GEA) scale by comparing digital photographs in a non-chronological order. Also, the artificial intelligence-assisted labeling program automatically counted individual acne lesions (papules, pustules, nodules, open and closed comedones) (lululab Inc).

Along with physician assessment, we have utilized non-invasive measurement modalities to assess the skin's sebum levels and biophysical parameters. Sebum output levels from the seborrheic area (nose, forehead) and non-seborrheic area (both cheeks) were measured by Sebumeter® SM 8155 (Courage Khazaka Electronic). In addition, skin erythema and pigmentation were measured using the Mexameter® MX18 (Courage Khazaka Electronics), presented as erythema and melanin indexes. All measurements were conducted both at Week 0 and 4-week follow-up visits.

Safety and tolerability assessment

At every visit, subjects underwent a physical examination to assess unwanted adverse events by test product. Participants also were asked to report side effects during the study period. Also, the participants were questioned to score their satisfaction rates using the following scale: 1 = unsatisfied, 2 = no change, 3 = slightly satisfied, 4 = satisfied, and 5 = very satisfied.

Statistical analysis

Data were presented as mean ± standard deviation or number (percentage) according to the data type. Wilcoxon signed-rank test was used to compare two matched pairs, and the Mann–Whitney U test was used to compare two non-paired groups. Also, the linear-by-linear association test was used when variables were in categorical 2 × 4 tables. All statistical analyses were performed using SPSS version 25.0 (SPSS Inc). p < 0.05 was considered statistically significant in all cases.

RESULTS

Patient characteristics

In this prospective pilot trial, we enrolled twenty-two Korean patients with mild to moderate acne (corresponds to GEA scale 1–3) were enrolled, and no subject dropped out from the clinical trial. Fourteen patients (63.6%) were females, and the average age was 29.2 ± 6.67 years (range, 20–47 years). Fifteen patients (68.2%) developed acne from adolescence, and the remaining seven (31.8%) developed in adulthood (after 20 years of age). Among the patients in this trial, 10 (45.5%) were treated with oral isotretinoin, and 7 (31.8%) were treated with oral antibiotics (doxycycline or minocycline). Patients who received isotretinoin maintained low-dose therapy at 10–20 mg daily, corresponding to 0.13–0.38 mg/kg/day. Also, all patients (5 patients) who were not prescribed oral medications were using topical treatment, and among patients taking oral medications, many (13 patients) concurrently applied local medications.

Acne grading scales

Compared with baseline pre-treatment grade (grade 1, 8 patients; grade 2, 9 patients; and grade 3, 3 patients), the GEA scale improved significantly after 4-weeks of treatment, with 13 (59.1%) achieving at least 1 grade of improvement on the GEA scale (Table ). Figure  represents clinical digital photographs illustrating improvements after a 4-week test product application. The mGAGS of the subjects significantly decreased from 9.95 ± 5.87 (initial) to 6.91 ± 4.39 (4 weeks, p < 0.001), and the acne lesion counts also significantly reduced from 14.0 ± 8.27 (initial) to 10.5 ± 6.52 (4 weeks, p = 0.001). Based on mGAGS, six patients (7 patients based on lesion count) did not appear to achieve an improvement during the study period (Figure ).

TABLE 1 Evaluation of clinical acne severity and skin biophysical parameters

Feature	Baseline	Post-treatment	Improvement rate	p value
Mean ± SD or N (%)	Percentage (%)
Acne severity
GEA scale
Clear/no lesion	0 (0.0)	2 (9.1)	59.1	<0.001
Almost clear	8 (36.4)	13 (59.1)
Mild	9 (40.9)	6 (27.3)
Moderate	5 (22.7)	1 (4.5)
mGAG score	9.95 ± 5.87	6.91 ± 4.39	30.6	<0.001
Lesion count	14.0 ± 8.27	10.5 ± 6.52	25.0	0.001
Mexameter
Melanin index	160.8 ± 41.1	153.2 ± 34.8	4.7	0.046
Erythema index	302.9 ± 84.7	285.6 ± 83.5	5.7	0.22
Sebumeter (μg/cm2)
Seborrheic area	141.4 ± 61.9	137.2 ± 70.8	3.0	0.52
Non-seborrheic area	45.9 ± 39.3	39.1 ± 30.3	14.8	0.074

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Objective skin parameters

We measured and compared sebum secretion in seborrheic and non-seborrheic areas with Sebumeter® (Table ; Figure ). In the seborrheic area, the average sebum secretion at baseline was 141.4 ± 61.9 μg/cm² and reduced to 137.2 ± 70.8 μg/cm² after 4 weeks, but statistically insignificant (p = 0.52). In non-seborrheic area, mean sebum output was decreased 14.8% (from 45.9 ± 39.3 μg/cm² to 39.1 ± 30.3 μg/cm²) yet failed to reach statistical significance (p = 0.07).

We evaluated the skin pigmentation and erythema via Mexameter® (Table ; Figure ). 4-week application of the test product induced a significant decrease in the melanin index (from 160.8 ± 41.1 to 153.2 ± 34.8, p = 0.046). Erythema index also reduced from 302.9 ± 84.7 to 285.6 ± 83.5 after 4 weeks, but statistically insignificant (p = 0.22).

Subgroup analysis

We performed a subgroup analysis to compare the differences in efficacy outcomes according to the clinical characteristics of the patients presented in Table . Patients were classified as isotretinoin group (n = 10) if they took the low-dose oral isotretinoin during the study period; if not, they were classified as a non-isotretinoin group (n = 12). Both mGAGS and lesion counts showed a significant decrease in each subgroup compared with baseline, yet no statistical significance was noticed in the inter-group comparison (Figure ). During the study period, skin sebum output in the seborrheic and non-seborrheic areas was significantly decreased only in the isotretinoin group. Sebum secretion at 4-week was substantially lower in the study period in the isotretinoin group than in the non-isotretinoin group (Figure ). In addition, both melanin and erythema index were significantly decreased only in the isotretinoin group after 4 weeks; the erythema index of the isotretinoin group at the baseline was significantly higher than non-isotretinoin group (Figure ). Subgroup analysis classified by other patient characteristics except taking oral isotretinoin (e.g., gender, disease onset, BMI, oral antibiotics, and local treatment) does not show any meaningful differences (data not shown).

TABLE 2 Patient demographics and clinical findings

Feature	Mean ± SD or N (%)
Gender
Male	8 (36.4)
Female	14 (63.6)
Age, years	29.2 ± 6.67
The onset of the disease
Childhood/adolescence	15 (68.2)
Adult	7 (31.8)
Body mass index (BMI)	21.9 ± 2.78
Severity of acne
Almost clear (1)	8 (36.4)
Mild (2)	9 (40.9)
Moderate (3)	5 (22.7)
Current treatment regimens
Systemic treatment
Oral isotretinoin (10–20 mg/day)	10 (45.5)
Oral antibiotics	7 (31.8)
None	5 (22.7)
Local treatment
Topical retinoid ± BPO	2 (9.1)
Topical antimicrobial ± BPO	16 (72.7)
None	4 (18.2)

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Adverse events and patient satisfaction

The 0.5% SAS was well-tolerated by subjects without significant skin irritation. Furthermore, no participant reported any serious adverse event during the study period. No side effects were denoted, such as permanent erythema, itching, pain, hyperpigmentation, or hypopigmentation. Several patients reported side effects such as transient erythema, edema, and stinging sensation, which resolved within minutes after application.

After a 4-week study period, 68.2% of the participants reported being “very satisfied” and “satisfied” with the treatment. Furthermore, 77.2% of the subjects responded that their skin sebum secretion was reduced after applying the test product.

DISCUSSION

Inflammatory acne and acne scars have substantial social implications, especially in young adults. Current systemic or topical options are ineffective treatments for post-acne erythema or post-inflammatory hyperpigmentation. Our study established the efficacy and tolerability of the 0.5% silymarin antioxidant formulation when used in conjunction with conventional acne treatment. Our findings indicate that SAS significantly improved the investigator-assessed acne severity scale and lesion counts. During the study period, no patient experienced adverse skin reactions. Additionally, a decrease in sebum production and melanin pigmentation index was noted with the SAS application. These improvements in the sebum output and melanin pigmentation were more prominent in the patients taking oral isotretinoin during the study period.

In our study, all patients were on medical treatment for acne, either systemic, topical, or both. We expected that topical application of SAS could reduce sebum production. Systemic isotretinoin is the only therapeutic option that acts on all stages of acne pathogenesis, yet its application can be limited to moderate to severe patients. Retinoids and benzoyl peroxide are commonly used topical medication, yet it is frequently associated with skin irritation, which may result in decreased patient compliance with treatment. Considering its chronic and relapsing nature, patient adherence to medical treatment can lead to more favorable clinical results. A recent study of a worldwide cohort showed that regular use of active ingredients could increase patients' adherence to the treatment.

Topical application of 0.7% silymarin showed significant improvement in melasma area and severity index score (MASI Score) to a degree similar to hydroquinone when applied for up to 3 months. Treatment with Silybum marianum fruit extract (SMFE) shows in vitro and in vivo efficacy in comedolytic properties by reducing the infundibular keratin expression. Test product SAS contained other active ingredients targeting acne pathogenesis, such as 15% l-ascorbic acid, 0.5% ferulic acid, and 0.5% salicylic acid. Especially salicylic acid is a β-hydroxy acid with comedolytic properties when used in higher concentrations (10 ~ 30%) for chemical peeling agents.

There are a few limitations to this study. First, a 4-week study duration may not be sufficient to assess the sustained effect of SAS. As a result, long-term studies are necessary to shed light on the potential effects of SAS. In addition, since the test product was applied concurrently without interruption of the conventional anti-acne treatment during the study period, there was a limitation in proving the individual effect of the test product. Additionally, this research lacks a controlled assessment of each component of its formulation. On the contrary, combination formulations have demonstrated efficacy in improving sebum production in acne patients, according to previously published reports. Thus, a prospective, split-face study accompanied by histological examination is required to assess acne patients' molecular changes.

However, to the best of our knowledge, this is the first prospective trial to date to examine the use of topical silymarin in acne patients. Moreover, this is the first study to objectively evaluate the efficacy of silymarin-containing antioxidant formulation along with concomitant isotretinoin intake.

AUTHOR CONTRIBUTIONS

Jemin Kim, Yun Na Lee, and Jihee Kim contributed to the study concept and design. Hyun Kim and Ye Seul Choi did the subject enrollment, measurement, and data collection. Sang Gyu Lee, Yun Na Lee, and Joohee Lee did the data validation and statistical analysis. Writing of the original draft was conducted by Jemin Kim and Yun Na Lee. Jihee Kim and Zoe Diana Draelos contributed to data interpretation and provided expert insight into the report's writing. All the authors approved the final version of the manuscript.

ACKNOWLEDGMENTS

The study product (Silymarin CF® Skinceuticals Co.) was provided by Skinceuticals Co. However, Skinceuticals had no role in the study implementation, data collection, data analysis, data interpretation, manuscript preparation, manuscript review, or manuscript approval.

FUNDING INFORMATION

This work was supported by the Yonsei University Faculty Research Grant (6-2020-0081 and 6-2021-0223).

CONFLICT OF INTEREST

None.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

ETHICAL APPROVAL

The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to, and the appropriate ethical review committee approval has been received. In addition, informed consent was obtained from the subjects included in the figure image in this study. IRB approval status: This study was reviewed and approved by the Institutional review board of Yongin Severance Hospital (approval no.: 9–2021-0039).

References

Thiboutot DM, Dreno B, Abanmi A, et al. Practical management of acne for clinicians: an international consensus from the global Alliance to improve outcomes in acne. J Am Acad Dermatol. 2018;78(2):S1‐S23.e1.

Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet. 2012;379(9813):361‐372.

Dreno B, Araviiskaia E, Berardesca E, et al. The science of dermocosmetics and its role in dermatology. J Eur Acad Dermatol Venereol. 2014;28(11):1409‐1417.

Araviiskaia E, Dreno B. The role of topical dermocosmetics in acne vulgaris. J Eur Acad Dermatol Venereol. 2016;30(6):926‐935.

Yoon JY, Kwon HH, Min SU, Thiboutot DM, Suh DH. Epigallocatechin‐3‐gallate improves acne in humans by modulating intracellular molecular targets and inhibiting P. acnes. J Invest Dermatol. 2013;133(2):429‐440.

Inui S, Aoshima H, Nishiyama A, Itami S. Improvement of acne vulgaris by topical fullerene application: unique impact on skin care. Nanomedicine. 2011;7(2):238‐241.

Saller R, Brignoli R, Melzer J, Meier R. An updated systematic review with meta‐analysis for the clinical evidence of silymarin. Forsch Komplementmed. 2008;15(1):9‐20.

de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: systematic review with meta‐analysis. World J Gastroenterol. 2017;23(27):5004‐5017.

Shie Morteza M, Hayati Z, Namazi N, Abdollahimajd F. Efficacy and safety of oral silymarin in comparison with oral doxycycline and their combination therapy in the treatment of acne vulgaris. Dermatol Ther. 2019;32(6): [eLocator: e13095].

Juranova J, Aury‐Landas J, Boumediene K, et al. Modulation of skin inflammatory response by active components of silymarin. Molecules. 2018;24(1):123.

Nofal A, Ibrahim AM, Nofal E, Gamal N, Osman S. Topical silymarin versus hydroquinone in the treatment of melasma: a comparative study. J Cosmet Dermatol. 2019;18(1):263‐270.

Thuangtong R, Tangjaturonrusamee C, Rattanaumpawan P, Ditre CM. Comparison of salicylic acid 30% peel and pneumatic broadband light in the treatment of mild to moderately severe facial acne vulgaris. Cutis. 2017;100(1):43‐48.

Dréno B, Poli F, Pawin H, et al. Development and evaluation of a global acne severity scale (GEA scale) suitable for France and Europe. J Eur Acad Dermatol Venereol. 2011;25(1):43‐48.

Dreno B, Tan J, Kang S, et al. How people with facial acne scars are perceived in society: an online survey. Dermatology Ther. 2016;6(2):207‐218.

Layton AM, Dreno B, Gollnick H, Mobaken H, Shear N. Isotretinoin therapy and the incidence of acne relapse: a nested case‐control study. Br J Dermatol. 2009;160(1):217‐218. author reply 218‐219.

Boyraz N, Mustak PK. Comparison of the efficacies of intermittent and continuous low‐dose isotretinoin regimens in the treatment of moderate acne vulgaris. Int J Dermatol. 2013;52(10):1265‐1267.

Rao PK, Bhat RM, Nandakishore B, Dandakeri S, Martis J, Kamath GH. Safety and efficacy of low‐dose isotretinoin in the treatment of moderate to severe acne vulgaris. Indian J Dermatol. 2014;59(3):316.

de Lucas R, Moreno‐Arias G, Perez‐Lopez M, et al. Adherence to drug treatments and adjuvant barrier repair therapies are key factors for clinical improvement in mild to moderate acne: the ACTUO observational prospective multicenter cohort trial in 643 patients. BMC Dermatol. 2015;15:17.

Dreno B, Thiboutot D, Gollnick H, et al. Large‐scale worldwide observational study of adherence with acne therapy. Int J Dermatol. 2010;49(4):448‐456.

Fontao F, von Engelbrechten M, Seilaz C, Sorg O, Saurat JH. Microcomedones in non‐lesional acne prone skin new orientations on comedogenesis and its prevention. J Eur Acad Dermatol Venereol. 2020;34(2):357‐364.

Baumann LS, Oresajo C, Yatskayer M, Dahl A, Figueras K. Comparison of clindamycin 1% and benzoyl peroxide 5% gel to a novel composition containing salicylic acid, capryloyl salicylic acid, HEPES, glycolic acid, citric acid, and dioic acid in the treatment of acne vulgaris. J Drugs Dermatol. 2013;12(3):266‐269.

Sarkar R, Ghunawat S, Garg VK. Comparative study of 35% glycolic acid, 20% salicylic‐10% Mandelic acid, and phytic acid combination peels in the treatment of active acne and Postacne pigmentation. J Cutan Aesthet Surg. 2019;12(3):158‐163.

Campos V, Pitassi L, Kalil C, Goncalves Junior JE, Sant'Anna B, Correia P. Clinical evaluation of the efficacy of a facial serum containing dioic acid, glycolic acid, salicylic acid, LHA, citric acid, and HEPES in treating post‐inflammatory hyperchromia and controlling oily skin in patients with acne vulgaris. J Cosmet Dermatol. 2021;20(6):1766‐1773.