P atient interest in natural ingredients is on the rise in all medical specialties, particularly dermatology. Natural ingredients are perceived to be safer and, sometimes, more effective — to the point that some patients decline prescription products. You’re probably already attuned to the healing effects of some of the more traditional biologic ingredients, such as colloidal oatmeal, but there are many others that are showing impressive biologic activity, such as soy and green tea to name a few. As dermatologists, we need to familiarize ourselves with the natural ingredients that are being included in skincare formulations as well as those that are being studied. Then we will be able to advise patients about ingredients that are safe and clinically proven to have biologic effects. This article will provide a review of some of the healing effects of natural ingredients that are being used in dermatologic products. Most natural ingredients used in dermatology are botanicals. Botanicals often display a wide array of activities in contrast to pharmaceuticals that are primarily limited to one specific activity. (Table 1: “Benefits of Natural Ingredients” lists some of the skincare benefits of natural ingredients.) Oatmeal: A Traditional Skin Relief Treatment Oatmeal was used for skin health and beauty as early as 2000 B.C. in Arabia and Egypt to soothe and protect dry, or itchy, inflamed skin.1 Colloidal oatmeal is the concentrated starch-protein complex of oatmeal prepared from finely ground de-hulled oats. It is composed of several components, which include polysaccharides, lipids, proteins and saponins. Polysaccharides. Colloidal oatmeal has a high polysaccharide content and forms a gelatinous hydrocolloid in water, which leaves a protective film on the skin that physically retards water loss. Additionally, this film helps to repair and maintain the epidermal barrier.2 Oat lipids. These agents add to oatmeal’s moisturizing, barrier-enhancing properties. Oat proteins. These proteins have the ability to buffer both acids and bases that aid in barrier maintenance and repair.3 Saponins. These ingredients within oatmeal help to solubilize dirt, oil and sebaceous secretions. Colloidal oatmeal is one of few natural ingredients cited to be effective by the FDA in the OTC Skin Protectant Monograph. It is labeled to provide skin relief and protection for insect bites, rashes caused by poison ivy and similar plants, and eczema. A variety of colloidal oatmeal bath products for both the geriatric and pediatric populations have been commercially available for many decades.3,4 These include oatmeal soap and body washes and now oat-containing moisturizers, which are increasingly popular and highly efficacious for dry and inflamed skin. Recent studies have demonstrated the utility of a colloidal oatmeal formulation in treating dry, ashy skin in African-Americans5 and for increasing and maintaining skin moisturization for 24 hours.6 Soy: A “Smart” Moisturizer Soy contains components that are proving useful in several areas of skin care. Most of the known benefits of soy in skin care are based on whole, fresh soy. Whole soy contains not only essential fatty acids and saponins but also a number of small soy proteins including the serine protease inhibitors, soybean trypsin inhibitor (STI) and Bowman-Birk inhibitor (BBI). When soybeans are fermented for consumption, STI and BBI are inactivated by heat. Fermented soy contains isoflavones, genistein, daidzein, and glycitein, which have been shown to have cutaneous photoprotective qualities.7 The two small soymilk-derived proteins STI and BBI, as well as fresh soymilk, inhibit the activation of the protein-activated receptor 2 (PAR-2) pathway. PAR-2 is expressed in keratinocytes and is believed to be responsible for the phagocytosis and transfer of melanosomes from the melanocyte into the keratinocytes. Thus PAR-2 inhibition has been shown to even skin tone related to the appearance of hyperpigmentation. In a clinical trial, Latinas with melasma applied a fresh soy extract to one lesion daily for 12 weeks. There was a mean reduction in hyperpigmentation of the melasma as calculated from investigator assessments using a visual analog scale.8 Additionally, soy has been shown to provide other skincare benefits. Soy has been called a “smart” moisturizer because of its ability to selectively provide moisturization to dry areas while reducing oiliness in other areas in women who have combination skin.9 It has also been shown in laboratory studies to stimulate collagen synthesis in vitro and to initiate elastin repair, resulting in improved facial skin firmness in vivo.10 Lastly, topical soy has been shown to reduce the appearance of unwanted hair.11 A number of facial and body moisturizers presently marketed take advantage of natural soy’s ability to reduce the appearance of unwanted hair. In a randomized, investigator-blinded 8-week study, women shaved their lower legs twice per week and applied a soy-containing moisturizer to one leg. Dermatologist assessments were made at several time points 4 days after shaving. By 4 weeks, dermatologist grading noted improvements in hair softness, fineness and coarseness and improvements in the look and feel of the leg skin when compared to baseline.12 Capturing the skincare benefits of this ingredient, a variety of facial moisturizers currently use whole soy as an ingredient, and soy serves to even skin tone, smoothe and soften the skin, and increase its overall radiance. Whole soy is also incorporated into some facial moisturizers and body lotions to decrease the appearance of unwanted hair as well as for its ability to improve the overall look and feel of skin. Green Tea: An Anti-oxidant Anti-oxidants have gained popularity in the dermatology community as research has demonstrated their beneficial effects on the skin. Green tea contains a variety of polyphenols that have been shown to confer significant photoprotection and to function as anti-oxidants. The most studied of these are (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG). In a study by Elmets et al., the skin of volunteers was treated with green tea polyphenols (GTP) or vehicle and, 30 minutes later, irradiated with two minimal erythema doses (MEDs) of ultraviolet light. Skin treated with GTPs or vehicle and not irradiated served as the controls. On histologic examination, the GTP-treated skin showed a 66% reduction in sunburn cells and a 58% reconstitution of Langerhans cells compared to the two untreated control groups. Objective assessment utilizing a chromameter revealed that the GTP-treated skin also showed a dose-dependent reduction in erythema. In addition, the extent of UV-induced DNA damage, as assessed by a 32p–post-labeling technique revealed significantly less DNA damage following GTP application. Interestingly, GTP conferred protection beginning at 24 hours post-irradiation and continuing for 48 hours to 72 hours. GTP appeared to confer photoprotection by a novel mechanism since it did not absorb wavelengths within the UVB range.13 Green tea extracts are increasingly added to moisturizers designed to help improve the appearance of photodamaged skin and to provide anti-oxidant benefits. An important caveat concerns whether products contain sufficient levels of green tea extracts to deliver these benefits. Feverfew: Anti-Inflammatory Effects Feverfew, a member of the chrysanthemum family, has been used traditionally to treat fever, headaches and arthritis.14,15 Its activity was initially attributed to parthenolide, a sesquiterpene lactone that is a known skin sensitizer. Recently, a parthenolide-free extract (PFE) of feverfew was developed for its anti-inflammatory effects and to remove skin sensitizing potential. In vitro studies have shown the ability of Feverfew PFE to inhibit pro-inflammatory enzyme activity. Feverfew PFE was shown to directly inhibit 5-lipo-oxygenase with an IC50 of 11.8± 4.8 µg/ml when it was incubated with arachidonic acid.14 However, upon incubation of feverfew with cyclo-oxygenase-2 (Cox-2), no Cox-2 activity was demonstrated. Additional studies have demonstrated the anti-inflammatory activity of Feverfew PFE. It reduced the release of nitric oxide, PGE2 and tumor necrosis factor alpha (TNF-a) from lipopolysaccharide- activated murine macrophages.14 In a clinical model, topical extracts of Feverfew PFE at increasing concentration or placebo were applied to human volar forearm skin for 30 minutes. Erythema was induced by the application of methyl nicotinate. A linear dose-response curve with reductions in erythema of more than 66% was noted in the Feverfew PFE-treated skin as assessed by diffuse reflectance spectroscopy. The Feverfew PFE significantly (p<0.05) reduced the intensity-duration of methyl nicotinate-induced erythema.14 In an open-label study, 25 patients with mild inflammatory acne applied Feverfew PFE or placebo twice daily to the facial skin for 45 days. Dermatologist-graded global assessment on days 0 and 45 of the study noted significant (p<=0.05) improvement in global acne assessment with Feverfew PFE treatment vs. baseline and placebo.16 (See the photographs.) Based on these preliminary studies that demonstrate significant anti-inflammatory activity, Feverfew PFE is an excellent candidate to be incorporated into increasing numbers of topical skincare products for sun-exposed, irritated or erythematous skin. Aloe Vera: Wound Healing and Burns Aloe vera, a member of the lily family, has been used for many years as a home remedy. It is now included in many products to treat burns, sunburn and minor wounds. It occludes the skin and helps prevent water loss, thus aiding healing.17 Aloe vera was studied as a vehicle for topical corticosteroids.17 When administered subcutaneously or topically in combination with hydrocortisone acetate, aloe vera appeared to enhance corticosteroid penetration by hydrating the stratum corneum. When tested as a vehicle for hydrocortisone, it was demonstrated to increase the anti-inflammatory effect of the hydrocortisone.17 In a double-blind, placebo-controlled trial of 60 patients with slight-to-moderate chronic plaque psoriasis, subjects applied 0.5% hydrophilic aloe vera cream or placebo three times daily for 5 consecutive days per week for a maximum of 4 weeks. By the end of the 4-week active treatment, 82.8% of the psoriatic plaques were significantly cleared in the aloe group vs. 7.7% in the placebo group. Patients in the aloe group experienced no adverse reactions and no relapses after 8 months of follow-up.18 Chamomile: Topical and Systemic Treatments Chamomile has been used for centuries, both systemically and topically, to treat skin inflammation and relieve gastrointestinal tract symptoms. Its anti-inflammatory effects are partially attributable to inhibition of cyclo-oxygenase and lipo-oxygenase in vitro.19 The flavonoid component of chamomile has been shown to inhibit histamine release from activated human basophilic leukocytes.19 In one study20 chamomile was shown to be 60% as active as 0.25% topical hydrocortisone in the treatment of sodium lauryl sulfate-induced contact dermatitis. Chamomile is included in a variety of skincare products for its emollient, soothing and anti-inflammatory properties. Chamomile oil is also included in products for its aromatherapeutic effects in products designed to promote relaxation and reduce stress levels. Witch Hazel: Reduces Itch Witch hazel extracts, prepared from the flowering shrub, Hamamelis virginiana, have long been used in both folk medicine and allopathic medicine to treat itching and skin inflammation. Witch hazel contains tannins that are believed to be useful in coagulating cell surface proteins, which lead to a reduction in permeability and secretions. Precipitated proteins form a protective layer on skin, which may lead to a reduction in permeability and skin’s secretions. It should be noted that the witch hazel extracts typically sold over-the-counter in the United States are virtually devoid of these tannins; however,19 witch hazel continues to be used topically for its anti-pruritic and anti-inflammatory properties. Lavender: Beyond Soothing and Calming Properties Essential oils from the herb lavendula have been used for centuries for their anti-bacterial, anti-fungal, carminative, sedative and anti-depressant activity as well as for fragrance.21 In vivo and in vitro studies have demonstrated a concentration-dependent inhibition of immediate-type allergic reactions by lavender oil possibly caused by interference with mast cell degranulation. In an in vitro study, topical and intradermal application of lavender oil inhibited anti-dinitrophenyl IgE-induced TNF-a release from mast cells. The same authors found that topical pretreatment with lavender oil for 30 minutes resulted in a concentration-dependent reduction in the ear swelling response to compound 48/80. This inhibition of ear swelling was slightly weaker following intradermal injection of lavender oil.22 In another study, a mixture of thyme, rosemary, lavender and cedarwood oils in a jojoba and grapeseed oil carrier was massaged nightly for 7 months into the scalps of 43 patients with alopecia areata. A significant (p=0.05) degree of improvement was seen on photographic assessment using a 1-4 alopecia scale. Improvement occurred in 44% of the patients vs. 15% of 41 controls (p=0.008).23 Aromatherapy: Stress Reliever Not infrequently, a combination of physiologic and psychologic factors form the basis of skin disorders. Although the understanding of how therapeutic scents can affect the neuro-immuno-cutaneous-endocrine network is in its infancy, treatment with psychotropic scents and scented topical agents have a promise for the future. Currently, some essential oils and plant-derived essences are being incorporated into products that are used as bath additives or for inhalation to produce changes in mood. For example, ylang-ylang, a fragrant tropical flower, has traditionally been used in the tropics to induce feelings of calm. In a recent placebo-controlled trial, 24 healthy volunteers inhaled either ylang-ylang oil or an odorless placebo.24 Ylang-ylang induced significant decreases in blood pressure and pulse rate. Subject self-evaluations noted significant improvements in attentiveness and alertness. The investigators characterized the effect as “harmonizing” rather than sedating because the reduced autonomic nervous system arousal did not lead to feelings of drowsiness or relaxation.24 To further elucidate the effects of aromatherapy, a commercially available foaming bath product containing lavender, chamomile and ylang-ylang oils, as well as colloidal oatmeal, was tested on 24 adult female subjects for its calming and stress-reducing effects. In this study, a significant decrease (p<0.05) in salivary cortisol levels was noted following a warm bath containing this product. In addition to this objective parameter of stress reduction, subject self-assessments noted significant (p<0.05) improvements in relaxation and calmness.25 Seeing the Results Research using modern evaluation techniques is beginning to validate the efficacy of natural botanical agents that have been used empirically in traditional and folk medicine for centuries. While some studies are preliminary, they form an important basis for the continued study of natural ingredients. Studies have already demonstrated that botanical agents, such as Feverfew PFE, colloidal oatmeal, green tea, soy and aloe vera possess biologic activity. While botanical agents cannot replace prescription treatments, many are useful adjuncts in the management of a variety of skin diseases. In addition, patients are enthusiastic about active naturals, such as colloidal oatmeal, soy and lavender, both philosophically and aesthetically, as ingredients in daily skincare formulations. As a greater number of active naturals are formulated in skincare and treatment products, further clinical trials are needed to establish the range of their biologic activities and to evaluate their safety and efficacy as complements to allopathic treatment. We hope this overview of advances in the area of natural ingredients will help you to better guide patients who wish to incorporate these agents into their therapeutic or daily skincare regimens.