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A systematic review of randomized controlled trials assessing phytochemicals and natural ingredients for skin and hair care

Cosmetics are marketed and used worldwide for various purposes. Several natural products are used for the development of cosmetic preparations. This paper systematically reviews randomized controlled trials (RCTs) investigating plant extracts, herbal preparations, and isolated plant-derived compounds used particularly for skin and hair care. Two independent electronic searches were conducted through PubMed and EMBASE to identify eligible RCTs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed. Data extraction was performed independently by four authors based on standardized extraction forms. The risk of bias was assessed using the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials. Sixty-three RCTs were identified; 53 were using natural products for skin care and 10 for hair care. The results were summarized in tables including the population, type of intervention, comparisons with placebo or other natural products, outcomes reported, follow-up period (P: Patient, Population; I: Intervention; C: Comparison (or Control); O: Outcome; T: Time), and country in which the study was conducted. Ten plants were identified to be present in different locations in Jordan by referring to the Royal Botanic Gardens’ publication, titled “The Plants of Jordan: An Annotated Checklist.” Some plants were found to have promising findings requiring further investigations in bigger RCTs with robust design and adequate reporting.


INTRODUCTION
In the highly visual consumer culture, the appearance of body shape and beauty is gaining more attention from people as it has become an important factor in the individual's sense of identity. The human body is the most visible expression of a person's self (Domzal and Kernan, 1993;Shilling, 2017), and as a result, people have a high desire to be physically attractive (Kim and Seock, 2009). One way to do that is by using cosmetic products.
Cosmetics are globally used to enhance the appearance or body odor (Ashawat et al., 2009;Shivanand et al., 2010). Cosmetic products are developed in various dosage forms using natural and synthetic ingredients (Ashawat et al., 2009). The use of plants and herbs in cosmetics has gained more popularity in recent years (Ashawat et al., 2009;Gediya et al., 2011;Shivanand et al., 2010). The number of products containing natural ingredients is increasing (Antignac et al., 2011). These products are commonly used with the misconception that they are always more effective and safer than completely synthetic products (Antignac et al., 2011;Ashawat et al., 2009).
Several plants and herbs have the potential for the development of cosmetic preparations due to their chemical composition containing compounds like vitamins, minerals, flavonoids, tannins, and amino acids, which have the potential to influence the human body (Fonseca-Santos et al., 2015;Yoo et al., 2018).
The use of plants and herbs to enhance beauty is well known in the Middle East since around 3000 BC where it was commonly used by ancient Egyptians and Babylonians in Iraq (Sawicka and Noaema, 2015). In the Middle Eastern region, particularly in Jordan, a wide range of plants with medicinal activity are available (Aburjai et al., 2007;Afifi and Abu-Irmaileh, 2000;Alzweiri et al., 2011). The use of natural ingredients in cosmetics is gaining more popularity, not only for their health benefits but also due to the higher demand by consumers for ecologically friendly products (Laroche et al., 2001;Ribeiro et al., 2015).
This study systematically reviewed randomized controlled trials (RCTs) investigating plant extracts, herbal preparations, and isolated plant-derived compounds used for cosmetic purposes focusing on skin and hair care. In addition, it provides a list of the plants/herbs available in Jordan that have been studied in the literature for cosmetic purposes by referring to the Royal Botanic Gardens publication titled "The Plants of Jordan: An Annotated Checklist" (Taifour et al., 2017).

MATERIALS AND METHODS
This systematic review (SR) was based on a registered (PROSPERO CRD42020198926) protocol and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009).

Data sources and searches
RCTs reporting cosmetic clinical outcomes in adults (≥18 years old) in the English language were included. Exclusion criteria included studies involving trials with interventions requiring medical attention and postprocedural treatment, not listing a clear description of botanical/phytochemical intervention.
Eligible trials were identified by electronic searches in PubMed and EMBASE from the beginning of time on the database until 26/7/2020. A combination of the following medical subject heading (MeSH terms) and free-text terms was used: phytotherapy, herbal medicine, plant extract, volatile oil, cosmetics, and skin care.

Study selection
Two authors independently reviewed the trial inclusion and exclusion criteria. Excluded trials were listed with the reason for exclusion (Supplementary Material). Disagreements were resolved by consulting a third researcher and achieving consensus.

Data extraction and quality assessment
Data extraction was performed independently by four authors based on standardized extraction forms. Each article was independently extracted by two authors. Disagreements were resolved through discussions and the corresponding authors were contacted if any of the pieces of required information were not described in the published manuscripts.
The risk of bias was assessed by separate domains: randomization, allocation concealment, selective reporting, blinding of participants and authors, attrition, and other biases using the Cochrane Collaboration's tool for assessing the risk of bias in randomized trials (Higgins et al., 2011). The results of these domains were graded as a "low," "high," or "unclear" risk of bias.

Skin care
The initial search yielded 1,987 abstracts. Removal of duplicates and applying the exclusion criteria identified 63 studies, 53 of which employed natural products for skin care and 10 for hair care. The process of selecting the studies included in this literature review was based on the inclusion and exclusion criteria as illustrated in Figure 1.
The 63 included studies are summarized in Tables 1 and  2 to demonstrate plants, herbs, or isolated compounds tested in the selected RCTs for skin care and hair care, respectively.
The main skin conditions addressed in selected RCTs were acne, hyperpigmentation, wrinkles, hirsutism, inflammation, stretch marks, and scars as well as testing plants and herbs for their moisturizing and skin protection properties. For hair care, the main hair issues addressed in the RCTs were hair thinning and dandruff.
The RCTs investigating natural products for their antiinflammatory properties (n = 3) were published between 2014 and 2019, investigating the constituents Prunus yedoensis (Zhang et al., 2014) and Glycyrrhiza inflata (Boonchai et al., 2018) as a single ingredient preparation within the formulation; one related RCT investigated a combination of extracts of Gentiana lutea, G. glabra, and Salix daphnoides (Seiwerth et al., 2019).
Two studies, published between 2008 and 2016, tested natural products for foot care. In the former, they used a combination of mango butter and olein fraction fortified with vitamin E (Mandawgade and Patravale, 2008), whereas in the latter study, Ziziphus mauritiana (Akhtar et al., 2016) was used.
Rosacea was investigated in one study published in 2015 and used a cream containing medical-grade kanuka honey (Braithwaite et al., 2015). Stretch marks and scars reduction were investigated in two separate studies published in , using O. europaea (Soltanipour et al., 2014 and Allium cepa (Hosnuter et al., 2007), respectively.
Finally, three studies published in 2015, 2018, and 2019 tested plants for multiple effects; the first study investigated Tamarindus indica for its antisebum and antihyperpigmentation properties (Muhammad et al., 2015); the second tested Prunus serrulata for its moisturizing, antihyperpigmentation, antiaging, and overall improvement of skin condition and elasticity  all groups for all months compared to baseline. It is noted that group C (active shampoo + solution) had the best clinical outcomes (p < 0.000001) 2. Phototricogram: compared to baseline, the number of total hairs in groups A, B, and C (active groups) increased significantly in the 4th and 6th months. The decrease in telogen hairs and increase in anagen hairs were also significant in groups A, B, and C (p < 0.001). The (%) changes in telogen and anagen hairs in group D were not significant (p > 0.05) 3. Dermatological evaluation: results not reported 4. Self-assessment score: all questions showed statistically significant results based on the difference from placebo (group D) Group C had the best clinical outcomes (p < 0.000001) The products were well tolerated, and no side effects were recorded   (Matsuyama et al., 2018); and the third study tested Sphaeranthus indicus for its moisturizing, antihyperpigmentation, antisebum, elasticity properties, and overall improvement of the skin condition (Ahmad et al., 2020).

Risk of Bias of the Included Studies
The risk of bias of the included studies in this review was conducted by the researchers, with the bias assessment for all the studies included in detail in Table 3.

Skin care
Eighteen studies were at low risk of randomization bias, as they were randomized using either sequence generation or block randomization. On the other hand, 3 studies were at a high risk due to inadequate randomization. The rest did not provide sufficient information regarding the randomization method; thus, the risk was considered unclear (n = 32). Most studies (n = 42) did not describe the allocation concealment process, so the risk of bias was noted as unclear, whereas 10 studies were considered of low risk as proper concealment techniques were described. Only one study was considered high risk regarding the allocation concealment, as the participants were unblinded. Fifty-two other studies were considered of low-risk selective reporting bias while only one was considered unclear, as the p values were not reported in the results section (Weber et al., 2019). Many studies (n = 39) were double-blinded and therefore at a low risk of performance and detection biases. The participants were not blinded in 9 studies, so these were considered at a high risk of performance bias. Additionally, the assessors were not blinded in 6 studies, so these were at a high risk of detection bias. If it was unclear whether   the participants and/or assessors were blinded, the studies were considered to be at an unclear risk of performance/detection bias. For the attrition bias, attrition rates above 20% were considered of high risk; 2 studies were found to have high dropout rates and were at a high risk of attrition bias, 43 were stated as low risk, and 8 were of unclear risk because it was unclear whether the data of all participants were considered or if any failed to complete the study. Many studies (n = 43) were stated as low risk in the domain of other biases, six were stated as high risk as the researchers were funded from the same companies providing the test products, and eight were considered unclear because the conflict of interest was not declared in these studies.

Hair care
Four studies were at low risk of randomization bias, while six were considered of unclear risk, because the randomization methods were not mentioned. One study was considered at low risk of allocation bias, and nine were considered of unclear risk. In the reporting bias domain, nine were considered low risk and one was of unclear risk. Some studies (n = 7) were double-blinded, so they were at low risk of both performance and detection biases, while the remaining three studies followed an open-label strategy and thus were at a high risk for both performance and detection biases. In the attrition bias domain, seven studies were at low risk, two were at an unclear risk, and one was stated high risk. Regarding other biases, five studies were considered low risk, and the other five were stated as unclear risk.

Skin care
Thirty-six RCTs compared natural product(s) or derived compound(s) with a placebo; 29 preparations were found effective. Nine RCTs compared natural product(s) or derived compound(s) with another treatment; eight preparations were found effective. Eight RCTs compared natural product(s) or derived compound(s) with untreated controls, all of which yielded statistically significant results. One RCT compared silymarin cream with untreated control and placebo was found effective in both cases. The results of the remaining studies were statistically insignificant.

Hair care
Six RCTs compared natural product(s) or derived compound(s) to placebo, and all were found to have statistically significant outcomes. Four RCTs compared natural product(s) or derived compound(s) with active treatments, and the efficacy outcomes were found to be statistically insignificant.
The tested natural product(s) or derived compound(s) showed good tolerability in most studies, but adverse events (AEs) including dryness, scaling, erythema, edema, itching, and pricking were reported with a formulation containing retinol and rose extract (Lee et al., 2011).

Plants present in Jordan
From the above discussed studies, ten plants were identified to be present in different locations in Jordan, as illustrated in Table 4. The plants that are found in Jordan and can be used for skin and hair care were as follows: A. sativa, which was investigated in a study conducted in the United States of America (USA), was found effective in improving skin barrier integrity and increasing its hydration . Portulaca oleracea was reported to be useful in the treatment of melasma in China (Zhang et al., 2019). In addition, it was found to improve skin health and reduce sensitization when used in combination with other plants (Wang et al., 2018). Silybum marianum was also reported to be useful for melasma as was found in an Iraqi study (Altaei, 2012). Foeniculum vulgare and M. sativa were effective in reducing facial hair in two studies, both conducted in Iran (Javidnia et al., 2003;Sargazi et al., 2016). Glycyrrhiza glabra was used in combination with other plants to improve the overall skin condition (Roh et al., 2019;Seiwerth et al., 2019) and in a hair shampoo as an antidandruff agent (Salmanpoor et al., 2012). Myrtus communis was also found useful for the treatment of dandruff when mixed with vinegar in a study conducted in Iran (Chaijan et al., 2018). Ceratonia siliqua and U. urens were used in a combination used to improve hair growth and strength with other plants in a study conducted in Turkey (Pekmezci et al., 2018).

DISCUSSION
The worldwide growth of the cosmetic sector is partially driven by the input of natural products (Cervellon and Carey, 2011). The global market value for natural cosmetics is expecting a positive increase with the upcoming years (Shahbandeh, 2020). This SR is unique as it explored plant extracts, herbal preparations, and isolated plant-derived compounds used for cosmetic purposes, particularly for skin and hair care. Fiftythree RCTs exploring natural products used for skin care were identified. Most of the RCTs were published between the years 2013 and 2019 (n = 34). Thirty-seven RCTs used natural products as a single ingredient (around 70% of the RCTs), while 16 RCTs used them in combinations (around 30% of the RCTs). Creams were the most frequently used dosage form (49% of the topical preparations). Other tested dosage forms were lotions, serums, gels, emulsions, beverages, oils, tablets, and capsules. Ten RCTs were designed to test natural products for hair care, seven of which used natural products as a single ingredient (70% of the RCTs), while the other three used them in combinations (30% of the RCTs). Shampoos were the most common form used (40%); aromatic oils, creams, solutions, capsules, and hair tonics were also used. The population included in this review added up to 3,439 subjects, and about 50% of the studies included females exclusively. The smallest number of participants was 3 and the highest was 203. The most common duration of the RCTs was 12 weeks (around 27% of the RCTs). The shortest duration was 75 minutes (0.0074 weeks), and the longest duration was 7 months (30.42 weeks). Around 87.3% of the reviewed RCTs found the tested natural products to have statistically significant efficacy outcomes. In addition, several treatment preparations were described, highlighting the diverse possibilities for incorporating botanicals into cosmetics. However, these reported outcomes should be interpreted cautiously for several reasons. Firstly, the majority of RCTs did not include power calculations indicating whether the number of participants is representative of the population or not. Secondly, participants were usually from a certain background, and thus the findings might not be applicable to all people of diverse ethnicities, lacking external generalizability.
Thirdly, statistical significance may not necessarily indicate clinical significance, as the outcomes of interest are sometimes surrogate markers. It is important to explore local plants for their cosmetic potential, which may add to the diversity of the local market. In our case, plants that are present in Jordan are of particular interest, as these can be used in developing cosmetics locally and can be marketed internationally to help the country's economy flourish (Workman, 2020). This discussion sheds light on each of these plants to provide needed information for policy makers and investors in the country.

CONCLUSION
Cosmetics are marketed and used worldwide for various purposes, which makes them a subject for academic and market research (Infante et al., 2016). This SR provided a summary of the plants/herbs in the literature which were clinically tested in RCTs from 1997 until 2020 for their cosmetic purposes, particularly skin and hair care. Such information can be helpful for policy makers and investors to make informed decisions regarding the production of cosmetics that can be of benefit locally and internationally. Additionally, this SR provided a list of plants/herbs found in Jordan which evidently showed cosmetic potential. In order to provide clear and comparative results, plants with promising findings are worth further investigations in robust RCTs.

AUTHORS' CONTRIBUTION
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work.

ETHICAL APPROVAL
Not applicable.