Leslie S. Baumann, MD

Stearic acid, a waxlike fatty acid also known as octadecanoic acid, is an important component of stratum corneum lipids. Stearic acid is also found in cocoa butter, shea butter, and other vegetable fats, as well as animal tallow. As an FDA-approved ingredient in several cosmetic products, it is used as a surfactant and emulsifying agent for fragrance and as the base for other fatty acid ingredients that are synthesized into emollients and lubricants. Stearic acid is used most often to thicken and retain the shape of soaps (indirectly, through saponification of triglycerides composed of stearic acid esters), and it is also used in shampoos, shaving creams, and detergents.

There is limited evidence for the potential of exogenously produced stearic acid to play a significant role as a topical dermatologic therapeutic agent. Stearic acid is thought to be associated with behenyltrimethylammonium chloride through salt bridges, and the combination is believed to have the capacity to build bilayer vesicles with the aid of hinokitiol (beta-thujaplicin), a natural monoterpenoid found in the wood of trees in the Cupressaceae family that has been shown to exert topical inhibitory activity against Chlamydia trachomatis (Antimicrob. Agents Chemother. 2005;49:2519-21). These vesicles, used to enhance the skin permeation of hinokitiol, were tested in hairless mice and appear to have the potential to promote hair growth (Drug Dev. Ind. Pharm. 2010;36:556-62).

In 2000, Khalil et al. studied the effects of cream formulations on chemically induced burns in mice based on reports that the ingredients, docosanol or stearic acid, were associated with antiviral and anti-inflammatory activity. Burns were engendered by painting murine abdomens with a chloroform solution of phenol. Investigators then topically applied the test formulations 0.5, 3, and 6 hours after injury. They found that the docosanol- and stearic acid–containing creams significantly mitigated the severity and progression of skin lesions compared with untreated sites, yielding, respectively, 76% and 57% declines in mean lesion scores (Contact Dermatitis 2000;43:79-81).

In 2001, Fluhr et al. studied the effects of the free fatty acid pool on stratum corneum (SC) acidification and function by topically applying two phospholipase inhibitors – bromphenacylbromide and 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol – for 3 days to murine skin. This raised skin pH and yielded permeability barrier abnormality, altered SC integrity, and reduced SC cohesion. All malfunctions were normalized, including SC pH, with the coapplication of either palmitic, stearic, or linoleic acids along with the inhibiting agents (J. Invest. Dermatol. 2001;117:44-51).

In 2010, Mukherjee et al. evaluated a recently marketed mild, moisturizing body wash containing stearic acid and emollient soybean oil to ascertain the location and amount of stearic acid deposited in the SC after in vivo usage of the product. They conducted clinical cleansing studies for 1 and 5 consecutive days using the soybean product or petroleum jelly. The deuterated variant of stearic acid replaced the free stearic acid in the soybean formulation. The researchers detected deuterated stearic acid in all 10 consecutive layers of SC, with a total stearic acid level measured at 0.33 mcg/cm² after five washes with the soybean oil product. They concluded that the estimated total fatty acid delivered to the skin from cleansing, probably incorporated into the SC lipid phase, is comparable to the fatty acid amount in an SC layer (J. Cosmet. Dermatol. 2010;9:202-10).

Stearic acid is incorporated into several over-the-counter products, including formulations by Aveda (Green Science Firming Face Cream), Yves Rocher (Les Plaisirs Nature), Kiss My Face (with alpha hydroxy acid), Valeant Pharmaceuticals’ Kinerase line (including Clear Skin Regulating Mask), Buster’s Skin Care for Men (peptide complex organic face moisturizer), and Dermalogica (Soothing Shaving Cream with Daily Defense Block), among others.

Conclusion

While stearic acid is an important component in stratum corneum lipids and a widely used ingredient in skin care products, there is a dearth of data on its significance, if any, in the topical dermatologic armamentarium beyond its primary activity as a surfactant and emulsifying agent. Specifically, it remains to be seen whether stearic acid can be replenished in the stratum corneum through topical treatment. Much more research is needed in this area to assess the potential of stearic acid as a therapeutic agent.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2009), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. She has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever. E-mail sknews@frontlinemedcom.com to contact Dr. Baumann or to suggest topics for a future column.

Stearic acid, a waxlike fatty acid also known as octadecanoic acid, is an important component of stratum corneum lipids. Stearic acid is also found in cocoa butter, shea butter, and other vegetable fats, as well as animal tallow. As an FDA-approved ingredient in several cosmetic products, it is used as a surfactant and emulsifying agent for fragrance and as the base for other fatty acid ingredients that are synthesized into emollients and lubricants. Stearic acid is used most often to thicken and retain the shape of soaps (indirectly, through saponification of triglycerides composed of stearic acid esters), and it is also used in shampoos, shaving creams, and detergents.

There is limited evidence for the potential of exogenously produced stearic acid to play a significant role as a topical dermatologic therapeutic agent. Stearic acid is thought to be associated with behenyltrimethylammonium chloride through salt bridges, and the combination is believed to have the capacity to build bilayer vesicles with the aid of hinokitiol (beta-thujaplicin), a natural monoterpenoid found in the wood of trees in the Cupressaceae family that has been shown to exert topical inhibitory activity against Chlamydia trachomatis (Antimicrob. Agents Chemother. 2005;49:2519-21). These vesicles, used to enhance the skin permeation of hinokitiol, were tested in hairless mice and appear to have the potential to promote hair growth (Drug Dev. Ind. Pharm. 2010;36:556-62).

In 2000, Khalil et al. studied the effects of cream formulations on chemically induced burns in mice based on reports that the ingredients, docosanol or stearic acid, were associated with antiviral and anti-inflammatory activity. Burns were engendered by painting murine abdomens with a chloroform solution of phenol. Investigators then topically applied the test formulations 0.5, 3, and 6 hours after injury. They found that the docosanol- and stearic acid–containing creams significantly mitigated the severity and progression of skin lesions compared with untreated sites, yielding, respectively, 76% and 57% declines in mean lesion scores (Contact Dermatitis 2000;43:79-81).

In 2001, Fluhr et al. studied the effects of the free fatty acid pool on stratum corneum (SC) acidification and function by topically applying two phospholipase inhibitors – bromphenacylbromide and 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol – for 3 days to murine skin. This raised skin pH and yielded permeability barrier abnormality, altered SC integrity, and reduced SC cohesion. All malfunctions were normalized, including SC pH, with the coapplication of either palmitic, stearic, or linoleic acids along with the inhibiting agents (J. Invest. Dermatol. 2001;117:44-51).

In 2010, Mukherjee et al. evaluated a recently marketed mild, moisturizing body wash containing stearic acid and emollient soybean oil to ascertain the location and amount of stearic acid deposited in the SC after in vivo usage of the product. They conducted clinical cleansing studies for 1 and 5 consecutive days using the soybean product or petroleum jelly. The deuterated variant of stearic acid replaced the free stearic acid in the soybean formulation. The researchers detected deuterated stearic acid in all 10 consecutive layers of SC, with a total stearic acid level measured at 0.33 mcg/cm² after five washes with the soybean oil product. They concluded that the estimated total fatty acid delivered to the skin from cleansing, probably incorporated into the SC lipid phase, is comparable to the fatty acid amount in an SC layer (J. Cosmet. Dermatol. 2010;9:202-10).

Stearic acid is incorporated into several over-the-counter products, including formulations by Aveda (Green Science Firming Face Cream), Yves Rocher (Les Plaisirs Nature), Kiss My Face (with alpha hydroxy acid), Valeant Pharmaceuticals’ Kinerase line (including Clear Skin Regulating Mask), Buster’s Skin Care for Men (peptide complex organic face moisturizer), and Dermalogica (Soothing Shaving Cream with Daily Defense Block), among others.

Conclusion

While stearic acid is an important component in stratum corneum lipids and a widely used ingredient in skin care products, there is a dearth of data on its significance, if any, in the topical dermatologic armamentarium beyond its primary activity as a surfactant and emulsifying agent. Specifically, it remains to be seen whether stearic acid can be replenished in the stratum corneum through topical treatment. Much more research is needed in this area to assess the potential of stearic acid as a therapeutic agent.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2009), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. She has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever. E-mail sknews@frontlinemedcom.com to contact Dr. Baumann or to suggest topics for a future column.

Stearic acid, a waxlike fatty acid also known as octadecanoic acid, is an important component of stratum corneum lipids. Stearic acid is also found in cocoa butter, shea butter, and other vegetable fats, as well as animal tallow. As an FDA-approved ingredient in several cosmetic products, it is used as a surfactant and emulsifying agent for fragrance and as the base for other fatty acid ingredients that are synthesized into emollients and lubricants. Stearic acid is used most often to thicken and retain the shape of soaps (indirectly, through saponification of triglycerides composed of stearic acid esters), and it is also used in shampoos, shaving creams, and detergents.

There is limited evidence for the potential of exogenously produced stearic acid to play a significant role as a topical dermatologic therapeutic agent. Stearic acid is thought to be associated with behenyltrimethylammonium chloride through salt bridges, and the combination is believed to have the capacity to build bilayer vesicles with the aid of hinokitiol (beta-thujaplicin), a natural monoterpenoid found in the wood of trees in the Cupressaceae family that has been shown to exert topical inhibitory activity against Chlamydia trachomatis (Antimicrob. Agents Chemother. 2005;49:2519-21). These vesicles, used to enhance the skin permeation of hinokitiol, were tested in hairless mice and appear to have the potential to promote hair growth (Drug Dev. Ind. Pharm. 2010;36:556-62).

In 2000, Khalil et al. studied the effects of cream formulations on chemically induced burns in mice based on reports that the ingredients, docosanol or stearic acid, were associated with antiviral and anti-inflammatory activity. Burns were engendered by painting murine abdomens with a chloroform solution of phenol. Investigators then topically applied the test formulations 0.5, 3, and 6 hours after injury. They found that the docosanol- and stearic acid–containing creams significantly mitigated the severity and progression of skin lesions compared with untreated sites, yielding, respectively, 76% and 57% declines in mean lesion scores (Contact Dermatitis 2000;43:79-81).

In 2001, Fluhr et al. studied the effects of the free fatty acid pool on stratum corneum (SC) acidification and function by topically applying two phospholipase inhibitors – bromphenacylbromide and 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol – for 3 days to murine skin. This raised skin pH and yielded permeability barrier abnormality, altered SC integrity, and reduced SC cohesion. All malfunctions were normalized, including SC pH, with the coapplication of either palmitic, stearic, or linoleic acids along with the inhibiting agents (J. Invest. Dermatol. 2001;117:44-51).

In 2010, Mukherjee et al. evaluated a recently marketed mild, moisturizing body wash containing stearic acid and emollient soybean oil to ascertain the location and amount of stearic acid deposited in the SC after in vivo usage of the product. They conducted clinical cleansing studies for 1 and 5 consecutive days using the soybean product or petroleum jelly. The deuterated variant of stearic acid replaced the free stearic acid in the soybean formulation. The researchers detected deuterated stearic acid in all 10 consecutive layers of SC, with a total stearic acid level measured at 0.33 mcg/cm² after five washes with the soybean oil product. They concluded that the estimated total fatty acid delivered to the skin from cleansing, probably incorporated into the SC lipid phase, is comparable to the fatty acid amount in an SC layer (J. Cosmet. Dermatol. 2010;9:202-10).

Stearic acid is incorporated into several over-the-counter products, including formulations by Aveda (Green Science Firming Face Cream), Yves Rocher (Les Plaisirs Nature), Kiss My Face (with alpha hydroxy acid), Valeant Pharmaceuticals’ Kinerase line (including Clear Skin Regulating Mask), Buster’s Skin Care for Men (peptide complex organic face moisturizer), and Dermalogica (Soothing Shaving Cream with Daily Defense Block), among others.

Conclusion

While stearic acid is an important component in stratum corneum lipids and a widely used ingredient in skin care products, there is a dearth of data on its significance, if any, in the topical dermatologic armamentarium beyond its primary activity as a surfactant and emulsifying agent. Specifically, it remains to be seen whether stearic acid can be replenished in the stratum corneum through topical treatment. Much more research is needed in this area to assess the potential of stearic acid as a therapeutic agent.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2009), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. She has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever. E-mail sknews@frontlinemedcom.com to contact Dr. Baumann or to suggest topics for a future column.

Often in this column, several species within a family might be discussed in relation to a broad range of health benefits. Licorice and mushrooms are good examples. In this case, and in this column, the focus will be on several species within a family that are thought to confer the same type of dermatologic benefit. The Morus genus within the Moraceae family appears to include several species that display skin-lightening properties.

Tyrosinase is the enzyme that controls the production of melanin. Suppressing tyrosinase activity to achieve skin lightening is a well-established method in dermatologic practice. The desire for products with fewer side effects than the mainstay, hydroquinone, or natural products such as kojic acid or arbutin, has led to investigations of several species in the Moraceae family. Notably, several Moraceae trees have been found to exhibit antioxidant activity (Int. J. Mol. Sci. 2012;13:2472-80; Biol. Pharm. Bull. 2002;25:1045-8; Biosci. Biotechnol. Biochem. 2010;74:2385-95; J. Pharm. Pharmacol. 2004;56:1291-8). The focus here, though, will be on the skin-lightening activity of various parts of Morus (commonly known as mulberry) trees.

In 2013, Singh et al. assessed the effects of mulberry, kiwi, and Sophora extracts on melanogenesis and melanin transfer in human melanocytes and in cocultures with phototype-matched normal adult epidermal keratinocytes. The extracts were evaluated against isobutylmethylxanthine, hydroquinone, vitamin C, and niacinamide. The investigators found that compared with unstimulated control, mulberry, kiwi, and Sophora extracts significantly reduced melanogenesis in normal adult epidermal melanocytes and human melanoma cells. Melanin transfer also was lowered, as was filopodia expression on melanocytes. The authors concluded that the test compounds compared well with standard-bearing depigmenting agents and warrant consideration as topical agents for diminishing hyperpigmentation (Exp. Dermatol. 2013;22:67-9).

Encouraging results in melasma treatment

A randomized, single-blind, placebo-controlled trial of 50 Filipino patients (49 women, 1 man) to examine the safety and efficacy of 75% Morus alba (white mulberry) extract oil was conducted by Alvin et al. in 2011. Patients were evaluated at weeks 4 and 8. The Melasma Area and Severity Index (MASI) score, Mexameter score, and Melasma Quality of Life (MelasQOL) score were measured, with the mulberry extract group performing significantly better than the placebo group according to all metrics.

The 25 patients treated with mulberry extract showed improvement in the MASI score, from 4.076 at baseline to 2.884 at week 8 (mean difference, 1.19); the mean difference for the placebo group was 0.06. The mean Mexameter reading revealed a significant difference, with a slight increase for the mulberry group (indicating lighter pigmentation), and the placebo group scored a slightly higher value. In addition, the MelasQOL score for the mulberry group improved markedly from baseline to week 8 (58.84 to 44.16), whereas the placebo group score improved only slightly, from 57.44 at baseline to 54.28 at week 8.

Adverse events were rare, with mild itching in 4 patients reported from the mulberry group, and 12 cases of either itching or erythema reported by the placebo group.

The investigators concluded that 75% mulberry extract oil objectively diminishes the hyperpigmentation of melasma in skin types III-V, although they recommend additional research with a larger sample size and longer treatment duration and follow-up (J. Drugs Dermatol. 2011;10:1025-31).

Paper mulberry

The bark of paper mulberry (Broussonetia papyrifera, also known as Morus papyrifera) is composed of extremely strong fibers used to produce high-quality paper and cloth. In China, the leaves, stem, leaf juice, roots, fruits, and bark have all been found to impart various health benefits, with the stem and leaf juice used to treat skin disorders and insect bites (Phytother. Res. 2012;26:1-10).

In one study, a 0.4% concentration of paper mulberry extract was demonstrated to suppress tyrosinase activity by 50% compared with 5.5% hydroquinone and 10% kojic acid. Notably, paper mulberry is not considered a significant irritant even at 1% concentration (J. Drugs Dermatol. 2009;8:s5-9).

White mulberry

In 2002, Lee et al. investigated the in vitro effects of an 85% methanol extract of dried white mulberry leaves on melanin biosynthesis. They found that one of the primary bioactive constituents, mulberroside F (moracin M-6, 3’-di-O-beta-D-glucopyranoside), inhibited the tyrosinase activity that converts dopa to dopachrome in the melanin synthesis process and also suppressed the melanin formation of melan-a cells. In addition, the mulberry extract inhibited tyrosinase activity more potently than did kojic acid (Biol. Pharm. Bull. 2002;25:1045-8).

The following year, a different team found that the young twigs of white mulberry also suppressed tyrosinase activity as well as melanin production in B-16 melanoma cells. In vivo, the extracts decreased melanin synthesis in a guinea pig model without displaying toxicity (J. Cosmet. Sci. 2003;54:133-42).

In 2006, Wang et al. investigated 25 traditional Chinese herbal medicines potentially useful in dermatology, particularly for skin whitening, and found that white mulberry was one of four species to potently inhibit tyrosinase activity, and more strongly than arbutin did (J. Ethnopharmacol. 2006;106:353-9).

Chinese mulberry/shimaguwa

In 2012, Zheng et al. isolated constituents from the roots of Chinese mulberry and found that several ingredients, including oxyresveratrol, moracenin D, sanggenon T, and kuwanon O, displayed more potent tyrosinase inhibition than kojic acid did. They concluded that Chinese mulberry is a good natural source of tyrosinase inhibitors and is potentially useful in cosmetic skin-lightening products as well as in foods as antibrowning agents (Fitoterapia 2012;83:1008-13).

Conclusion

Mulberry is actively used within the dermatologic armamentarium as one of the many options for skin lightening. A significant body of evidence has emerged over the past 15 years to establish the antityrosinase activity of various mulberry species, particularly white mulberry and paper mulberry.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, 2009), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Often in this column, several species within a family might be discussed in relation to a broad range of health benefits. Licorice and mushrooms are good examples. In this case, and in this column, the focus will be on several species within a family that are thought to confer the same type of dermatologic benefit. The Morus genus within the Moraceae family appears to include several species that display skin-lightening properties.

Tyrosinase is the enzyme that controls the production of melanin. Suppressing tyrosinase activity to achieve skin lightening is a well-established method in dermatologic practice. The desire for products with fewer side effects than the mainstay, hydroquinone, or natural products such as kojic acid or arbutin, has led to investigations of several species in the Moraceae family. Notably, several Moraceae trees have been found to exhibit antioxidant activity (Int. J. Mol. Sci. 2012;13:2472-80; Biol. Pharm. Bull. 2002;25:1045-8; Biosci. Biotechnol. Biochem. 2010;74:2385-95; J. Pharm. Pharmacol. 2004;56:1291-8). The focus here, though, will be on the skin-lightening activity of various parts of Morus (commonly known as mulberry) trees.

In 2013, Singh et al. assessed the effects of mulberry, kiwi, and Sophora extracts on melanogenesis and melanin transfer in human melanocytes and in cocultures with phototype-matched normal adult epidermal keratinocytes. The extracts were evaluated against isobutylmethylxanthine, hydroquinone, vitamin C, and niacinamide. The investigators found that compared with unstimulated control, mulberry, kiwi, and Sophora extracts significantly reduced melanogenesis in normal adult epidermal melanocytes and human melanoma cells. Melanin transfer also was lowered, as was filopodia expression on melanocytes. The authors concluded that the test compounds compared well with standard-bearing depigmenting agents and warrant consideration as topical agents for diminishing hyperpigmentation (Exp. Dermatol. 2013;22:67-9).

Encouraging results in melasma treatment

A randomized, single-blind, placebo-controlled trial of 50 Filipino patients (49 women, 1 man) to examine the safety and efficacy of 75% Morus alba (white mulberry) extract oil was conducted by Alvin et al. in 2011. Patients were evaluated at weeks 4 and 8. The Melasma Area and Severity Index (MASI) score, Mexameter score, and Melasma Quality of Life (MelasQOL) score were measured, with the mulberry extract group performing significantly better than the placebo group according to all metrics.

The 25 patients treated with mulberry extract showed improvement in the MASI score, from 4.076 at baseline to 2.884 at week 8 (mean difference, 1.19); the mean difference for the placebo group was 0.06. The mean Mexameter reading revealed a significant difference, with a slight increase for the mulberry group (indicating lighter pigmentation), and the placebo group scored a slightly higher value. In addition, the MelasQOL score for the mulberry group improved markedly from baseline to week 8 (58.84 to 44.16), whereas the placebo group score improved only slightly, from 57.44 at baseline to 54.28 at week 8.

Adverse events were rare, with mild itching in 4 patients reported from the mulberry group, and 12 cases of either itching or erythema reported by the placebo group.

The investigators concluded that 75% mulberry extract oil objectively diminishes the hyperpigmentation of melasma in skin types III-V, although they recommend additional research with a larger sample size and longer treatment duration and follow-up (J. Drugs Dermatol. 2011;10:1025-31).

Paper mulberry

The bark of paper mulberry (Broussonetia papyrifera, also known as Morus papyrifera) is composed of extremely strong fibers used to produce high-quality paper and cloth. In China, the leaves, stem, leaf juice, roots, fruits, and bark have all been found to impart various health benefits, with the stem and leaf juice used to treat skin disorders and insect bites (Phytother. Res. 2012;26:1-10).

In one study, a 0.4% concentration of paper mulberry extract was demonstrated to suppress tyrosinase activity by 50% compared with 5.5% hydroquinone and 10% kojic acid. Notably, paper mulberry is not considered a significant irritant even at 1% concentration (J. Drugs Dermatol. 2009;8:s5-9).

White mulberry

In 2002, Lee et al. investigated the in vitro effects of an 85% methanol extract of dried white mulberry leaves on melanin biosynthesis. They found that one of the primary bioactive constituents, mulberroside F (moracin M-6, 3’-di-O-beta-D-glucopyranoside), inhibited the tyrosinase activity that converts dopa to dopachrome in the melanin synthesis process and also suppressed the melanin formation of melan-a cells. In addition, the mulberry extract inhibited tyrosinase activity more potently than did kojic acid (Biol. Pharm. Bull. 2002;25:1045-8).

The following year, a different team found that the young twigs of white mulberry also suppressed tyrosinase activity as well as melanin production in B-16 melanoma cells. In vivo, the extracts decreased melanin synthesis in a guinea pig model without displaying toxicity (J. Cosmet. Sci. 2003;54:133-42).

In 2006, Wang et al. investigated 25 traditional Chinese herbal medicines potentially useful in dermatology, particularly for skin whitening, and found that white mulberry was one of four species to potently inhibit tyrosinase activity, and more strongly than arbutin did (J. Ethnopharmacol. 2006;106:353-9).

Chinese mulberry/shimaguwa

In 2012, Zheng et al. isolated constituents from the roots of Chinese mulberry and found that several ingredients, including oxyresveratrol, moracenin D, sanggenon T, and kuwanon O, displayed more potent tyrosinase inhibition than kojic acid did. They concluded that Chinese mulberry is a good natural source of tyrosinase inhibitors and is potentially useful in cosmetic skin-lightening products as well as in foods as antibrowning agents (Fitoterapia 2012;83:1008-13).

Conclusion

Mulberry is actively used within the dermatologic armamentarium as one of the many options for skin lightening. A significant body of evidence has emerged over the past 15 years to establish the antityrosinase activity of various mulberry species, particularly white mulberry and paper mulberry.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, 2009), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Often in this column, several species within a family might be discussed in relation to a broad range of health benefits. Licorice and mushrooms are good examples. In this case, and in this column, the focus will be on several species within a family that are thought to confer the same type of dermatologic benefit. The Morus genus within the Moraceae family appears to include several species that display skin-lightening properties.

Tyrosinase is the enzyme that controls the production of melanin. Suppressing tyrosinase activity to achieve skin lightening is a well-established method in dermatologic practice. The desire for products with fewer side effects than the mainstay, hydroquinone, or natural products such as kojic acid or arbutin, has led to investigations of several species in the Moraceae family. Notably, several Moraceae trees have been found to exhibit antioxidant activity (Int. J. Mol. Sci. 2012;13:2472-80; Biol. Pharm. Bull. 2002;25:1045-8; Biosci. Biotechnol. Biochem. 2010;74:2385-95; J. Pharm. Pharmacol. 2004;56:1291-8). The focus here, though, will be on the skin-lightening activity of various parts of Morus (commonly known as mulberry) trees.

In 2013, Singh et al. assessed the effects of mulberry, kiwi, and Sophora extracts on melanogenesis and melanin transfer in human melanocytes and in cocultures with phototype-matched normal adult epidermal keratinocytes. The extracts were evaluated against isobutylmethylxanthine, hydroquinone, vitamin C, and niacinamide. The investigators found that compared with unstimulated control, mulberry, kiwi, and Sophora extracts significantly reduced melanogenesis in normal adult epidermal melanocytes and human melanoma cells. Melanin transfer also was lowered, as was filopodia expression on melanocytes. The authors concluded that the test compounds compared well with standard-bearing depigmenting agents and warrant consideration as topical agents for diminishing hyperpigmentation (Exp. Dermatol. 2013;22:67-9).

Encouraging results in melasma treatment

A randomized, single-blind, placebo-controlled trial of 50 Filipino patients (49 women, 1 man) to examine the safety and efficacy of 75% Morus alba (white mulberry) extract oil was conducted by Alvin et al. in 2011. Patients were evaluated at weeks 4 and 8. The Melasma Area and Severity Index (MASI) score, Mexameter score, and Melasma Quality of Life (MelasQOL) score were measured, with the mulberry extract group performing significantly better than the placebo group according to all metrics.

The 25 patients treated with mulberry extract showed improvement in the MASI score, from 4.076 at baseline to 2.884 at week 8 (mean difference, 1.19); the mean difference for the placebo group was 0.06. The mean Mexameter reading revealed a significant difference, with a slight increase for the mulberry group (indicating lighter pigmentation), and the placebo group scored a slightly higher value. In addition, the MelasQOL score for the mulberry group improved markedly from baseline to week 8 (58.84 to 44.16), whereas the placebo group score improved only slightly, from 57.44 at baseline to 54.28 at week 8.

Adverse events were rare, with mild itching in 4 patients reported from the mulberry group, and 12 cases of either itching or erythema reported by the placebo group.

The investigators concluded that 75% mulberry extract oil objectively diminishes the hyperpigmentation of melasma in skin types III-V, although they recommend additional research with a larger sample size and longer treatment duration and follow-up (J. Drugs Dermatol. 2011;10:1025-31).

Paper mulberry

The bark of paper mulberry (Broussonetia papyrifera, also known as Morus papyrifera) is composed of extremely strong fibers used to produce high-quality paper and cloth. In China, the leaves, stem, leaf juice, roots, fruits, and bark have all been found to impart various health benefits, with the stem and leaf juice used to treat skin disorders and insect bites (Phytother. Res. 2012;26:1-10).

In one study, a 0.4% concentration of paper mulberry extract was demonstrated to suppress tyrosinase activity by 50% compared with 5.5% hydroquinone and 10% kojic acid. Notably, paper mulberry is not considered a significant irritant even at 1% concentration (J. Drugs Dermatol. 2009;8:s5-9).

White mulberry

In 2002, Lee et al. investigated the in vitro effects of an 85% methanol extract of dried white mulberry leaves on melanin biosynthesis. They found that one of the primary bioactive constituents, mulberroside F (moracin M-6, 3’-di-O-beta-D-glucopyranoside), inhibited the tyrosinase activity that converts dopa to dopachrome in the melanin synthesis process and also suppressed the melanin formation of melan-a cells. In addition, the mulberry extract inhibited tyrosinase activity more potently than did kojic acid (Biol. Pharm. Bull. 2002;25:1045-8).

The following year, a different team found that the young twigs of white mulberry also suppressed tyrosinase activity as well as melanin production in B-16 melanoma cells. In vivo, the extracts decreased melanin synthesis in a guinea pig model without displaying toxicity (J. Cosmet. Sci. 2003;54:133-42).

In 2006, Wang et al. investigated 25 traditional Chinese herbal medicines potentially useful in dermatology, particularly for skin whitening, and found that white mulberry was one of four species to potently inhibit tyrosinase activity, and more strongly than arbutin did (J. Ethnopharmacol. 2006;106:353-9).

Chinese mulberry/shimaguwa

In 2012, Zheng et al. isolated constituents from the roots of Chinese mulberry and found that several ingredients, including oxyresveratrol, moracenin D, sanggenon T, and kuwanon O, displayed more potent tyrosinase inhibition than kojic acid did. They concluded that Chinese mulberry is a good natural source of tyrosinase inhibitors and is potentially useful in cosmetic skin-lightening products as well as in foods as antibrowning agents (Fitoterapia 2012;83:1008-13).

Conclusion

Mulberry is actively used within the dermatologic armamentarium as one of the many options for skin lightening. A significant body of evidence has emerged over the past 15 years to establish the antityrosinase activity of various mulberry species, particularly white mulberry and paper mulberry.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, 2009), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Calophyllum inophyllum is a large, nondeciduous tree native to a wide swath of regions including Central and East Africa; a north-to-south swath of India; Southeast Asia; Polynesia; the Philippines; and Australia. A member of the mangosteen family (Clusiaceae, also known as Guttiferae), C. inophyllum is now cultivated in much of the tropical world.

The oil derived from this abundant plant is known by a wide variety of names, including Alexandrian laurel, beach mahogany, beauty leaf, beach calophyllum, dilo, and kamani. But perhaps it is best known by the French Polynesian name: tamanu. Tamanu oil has been used for hundreds of years in cuisine and to treat various medical conditions. Ocular burn and cutaneous wound healing are some distinct conditions for which the oil of C. inophyllum has a long history of use in traditional folk medicine (Oncol. Rep. 2012;28:1096-102; Int. J. Cosmet. Sci. 2002;24:341-8).

Wound healing and eye protection

The C. inophyllum components to which wound-healing activity have been attributed include calophyllolide and inophyllum, as well as various polyphenols, many of which exert antioxidant effects (Int. J. Cosmet. Sci. 2002;24:341-8).

Courtesy Wikimedia Commons/B.navez/Creative Commons License

Modern research buttresses the use of tamanu oil for corneal protection from burns. In 2007, Said et al. explored the anti-UV activity of tamanu oil for eye protection. They found that the botanical oil displayed a significant capacity to absorb UV radiation, even at low concentrations (1/10,000, v/v), with a sun protection factor ranging from 18 to 22. Concentrations of C. inophyllum oil of up to 1% were not cytotoxic to human conjunctival epithelial cells, with the agent acting against oxidative stress and DNA damage. In light of the apparent antioxidant and cytoprotective effects of C. inophyllum oil in the study, the researchers concluded that the oil has potential as a natural UV filter in ophthalmic formulations (Eur. J. Pharm. Sci. 2007;30:203-10).

In 2009, Said et al. performed in vitro, in vivo, and ex vivo studies to assess the effects of different rinsing and healing protocols for alkali-induced ocular burn and inflammation in rabbits. The researchers used NaOH to induce corneal reactions in the rabbits, followed by rinses with NaCl 0.9% or controlled-ionization marine formula combined with N-acetylcysteine or vegetable oils (from C. inophyllum and Aleurites moluccana). The investigators assessed corneal epithelium regeneration and inflammatory cell infiltration using in vivo confocal microscopy and ex vivo histological cuts. They found that the combination of controlled-ionization marine solution with 10% C. inophyllum oil and 90% A. moluccana oil promoted corneal epithelium regeneration while reducing inflammatory cells, suggesting its viability as ocular burn therapy (Ophthalmologica 2009;223:52-9).

Other medical benefits

A wide range of health benefits have been ascribed to tamanu oil, and the ingredient has been found in an increasing number of topical products. It is thought to impart anti-inflammatory, antioxidant, antibacterial, antiviral, and photoprotective activity.

In 2011, Ayyanar et al. concluded a 4-year study intended to ascertain the herbs used in traditional medicine practiced by the Kani tribes in the Tirunelveli hills of Western Ghats, India. The researchers identified 90 species of plants used traditionally as ethnomedicinal treatments, with 65 different indications reported, particularly dermatologic conditions and gastrointestinal illnesses. Based on their study, they identified 16 species, including C. inophyllum, for additional ethnopharmacological investigation as potential sources of new drug agents (J. Ethnopharmacol. 2011;134:851-64).

In 2004, Yimdjo et al. investigated the chemical constituents of the root bark and nut of C. inophyllum, resulting in the isolation of several compounds and the discovery of antibacterial activity against several microbes (Phytochemistry 2004;65:2789-95).

C. inophyllum leaf extracts from the islands of French Polynesia have also been touted for several constituents that hold promise as anti-HIV-1 agents, including inophyllum B and P (Anal. Chim. Acta 2008;624:147-53). In addition, quantitative high-performance liquid chromatography (HPLC) analysis of callus cultures of C. inophyllum has revealed the anti-HIV activity of the dipyranocoumarins inophyllum B and P (J. Biotechnol. 2007;130:346-53).

Tamanu oil also has demonstrated potential use for humans and domestic animals as an insect repellent, specifically against the stable fly, Stomoxys calcitrans (J. Med. Entomol. 2010;47:575-80; Pest Manag. Sci. 2010;66:1191-8).

In 2012, Tsai et al. investigated the anti-inflammatory properties of an acetone extract of C. inophyllum leaves using lipopolysaccharide (LPS)-induced RAW 264.7 cells to assess the impact of the extract on nitric oxide (NO) expression and inducible nitric oxide synthase (iNOS). They found that C. inophyllum significantly inhibited, in dose-dependent fashion, the LPS-induced synthesis of NO, in addition to the expression of iNOS, cyclooxygenase (COX)-2, and nuclear factor–kappa B (NF-kappaB). The researchers concluded that the C. inophyllum extract exhibits anti-inflammatory activity and has potential application to inflammatory conditions in human beings (Oncol. Rep. 2012;28:1096-102).

Cancer

Recent work suggests the anti-cancer potential of C. inophyllum. In a study just over a decade ago, Itogawa et al. examined the potential inhibitory effects of C. inophyllum 4-phenylcoumarin isolates on Epstein-Barr virus early antigen (EBV-EA) activation caused by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All 10 of the isolates displayed inhibitory activity against EBV and no cytotoxicity. The strongest compound tested was calocoumarin-A (5), which also demonstrated a significant capacity to suppress murine skin tumor promotion in a two-stage cancer model. The investigators concluded that some 4-phenylcoumarin constituents of C. inophyllum warrant further study as possible antitumor agents (Cancer Lett. 2001;169:15-19).

C. inophyllum was one of 155 extracts from 93 plant species found on peninsular Malaysia during a screening by Ong et al. in 2009 for in vitro photocytotoxic activity using human leukemia cells (cell line HL60). Further, C. inophyllum was among the 29 plants to lower the in vitro cell viability by more than 50% after exposure to 9.6 J/cm² of a broad-spectrum light when tested at a concentration of 20 mcg/mL (J. Photochem. Photobiol. B 2009;96:216-22). In addition, Li et al. isolated one new friedelane-type triterpene and seven previously discovered triterpenoids from the stems and leaves of C. inophyllum, and ascertained that they exhibited growth inhibitory activity against human leukemia HL-60 cells (Fitoterapia 2010;81:586-9).

In 2008, Xiao et al. isolated a new prenylated xanthone (caloxanthone) as well as two previously known xanthones from the ethanolic extract of C. inophyllum twigs and reported that two of the constituents (including the new xanthone) demonstrated cytotoxicity against myelogenous leukemia (cell line K562) (J. Asian Nat. Prod. Res. 2008;10:993-7).

C. inophyllum is known to contain an abundance of phytosterols – primarily stigmasterol and beta-sitosterol, which are steroids associated with several healthy benefits (stigmasterol is a potent antioxidant) – as well as delta-tocotrienol, a form of vitamin E that acts as an antioxidant and is associated with anticancer activity, particularly against murine melanoma (Phytochemistry 2005;66:1825-31; J. Nutr. 1997;127:668-74).

Conclusion

Tamanu oil certainly isn’t a passing fad for the numerous traditional societies in the mainly eastern and southern hemispheres who have used the botanical for medicinal and culinary purposes for centuries. As an ingredient in skin care products, though, more research is needed. While modern studies are promising, randomized, placebo-controlled clinical trials are necessary to establish a potential role of C. inophyllum in the large array of topical dermatologic formulations.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever. To respond to this column, or to suggest topics for future columns, write to her at sknews@frontlinemedcom.com.

Calophyllum inophyllum is a large, nondeciduous tree native to a wide swath of regions including Central and East Africa; a north-to-south swath of India; Southeast Asia; Polynesia; the Philippines; and Australia. A member of the mangosteen family (Clusiaceae, also known as Guttiferae), C. inophyllum is now cultivated in much of the tropical world.

The oil derived from this abundant plant is known by a wide variety of names, including Alexandrian laurel, beach mahogany, beauty leaf, beach calophyllum, dilo, and kamani. But perhaps it is best known by the French Polynesian name: tamanu. Tamanu oil has been used for hundreds of years in cuisine and to treat various medical conditions. Ocular burn and cutaneous wound healing are some distinct conditions for which the oil of C. inophyllum has a long history of use in traditional folk medicine (Oncol. Rep. 2012;28:1096-102; Int. J. Cosmet. Sci. 2002;24:341-8).

Wound healing and eye protection

The C. inophyllum components to which wound-healing activity have been attributed include calophyllolide and inophyllum, as well as various polyphenols, many of which exert antioxidant effects (Int. J. Cosmet. Sci. 2002;24:341-8).

Courtesy Wikimedia Commons/B.navez/Creative Commons License

Modern research buttresses the use of tamanu oil for corneal protection from burns. In 2007, Said et al. explored the anti-UV activity of tamanu oil for eye protection. They found that the botanical oil displayed a significant capacity to absorb UV radiation, even at low concentrations (1/10,000, v/v), with a sun protection factor ranging from 18 to 22. Concentrations of C. inophyllum oil of up to 1% were not cytotoxic to human conjunctival epithelial cells, with the agent acting against oxidative stress and DNA damage. In light of the apparent antioxidant and cytoprotective effects of C. inophyllum oil in the study, the researchers concluded that the oil has potential as a natural UV filter in ophthalmic formulations (Eur. J. Pharm. Sci. 2007;30:203-10).

In 2009, Said et al. performed in vitro, in vivo, and ex vivo studies to assess the effects of different rinsing and healing protocols for alkali-induced ocular burn and inflammation in rabbits. The researchers used NaOH to induce corneal reactions in the rabbits, followed by rinses with NaCl 0.9% or controlled-ionization marine formula combined with N-acetylcysteine or vegetable oils (from C. inophyllum and Aleurites moluccana). The investigators assessed corneal epithelium regeneration and inflammatory cell infiltration using in vivo confocal microscopy and ex vivo histological cuts. They found that the combination of controlled-ionization marine solution with 10% C. inophyllum oil and 90% A. moluccana oil promoted corneal epithelium regeneration while reducing inflammatory cells, suggesting its viability as ocular burn therapy (Ophthalmologica 2009;223:52-9).

Other medical benefits

A wide range of health benefits have been ascribed to tamanu oil, and the ingredient has been found in an increasing number of topical products. It is thought to impart anti-inflammatory, antioxidant, antibacterial, antiviral, and photoprotective activity.

In 2011, Ayyanar et al. concluded a 4-year study intended to ascertain the herbs used in traditional medicine practiced by the Kani tribes in the Tirunelveli hills of Western Ghats, India. The researchers identified 90 species of plants used traditionally as ethnomedicinal treatments, with 65 different indications reported, particularly dermatologic conditions and gastrointestinal illnesses. Based on their study, they identified 16 species, including C. inophyllum, for additional ethnopharmacological investigation as potential sources of new drug agents (J. Ethnopharmacol. 2011;134:851-64).

In 2004, Yimdjo et al. investigated the chemical constituents of the root bark and nut of C. inophyllum, resulting in the isolation of several compounds and the discovery of antibacterial activity against several microbes (Phytochemistry 2004;65:2789-95).

C. inophyllum leaf extracts from the islands of French Polynesia have also been touted for several constituents that hold promise as anti-HIV-1 agents, including inophyllum B and P (Anal. Chim. Acta 2008;624:147-53). In addition, quantitative high-performance liquid chromatography (HPLC) analysis of callus cultures of C. inophyllum has revealed the anti-HIV activity of the dipyranocoumarins inophyllum B and P (J. Biotechnol. 2007;130:346-53).

Tamanu oil also has demonstrated potential use for humans and domestic animals as an insect repellent, specifically against the stable fly, Stomoxys calcitrans (J. Med. Entomol. 2010;47:575-80; Pest Manag. Sci. 2010;66:1191-8).

In 2012, Tsai et al. investigated the anti-inflammatory properties of an acetone extract of C. inophyllum leaves using lipopolysaccharide (LPS)-induced RAW 264.7 cells to assess the impact of the extract on nitric oxide (NO) expression and inducible nitric oxide synthase (iNOS). They found that C. inophyllum significantly inhibited, in dose-dependent fashion, the LPS-induced synthesis of NO, in addition to the expression of iNOS, cyclooxygenase (COX)-2, and nuclear factor–kappa B (NF-kappaB). The researchers concluded that the C. inophyllum extract exhibits anti-inflammatory activity and has potential application to inflammatory conditions in human beings (Oncol. Rep. 2012;28:1096-102).

Cancer

Recent work suggests the anti-cancer potential of C. inophyllum. In a study just over a decade ago, Itogawa et al. examined the potential inhibitory effects of C. inophyllum 4-phenylcoumarin isolates on Epstein-Barr virus early antigen (EBV-EA) activation caused by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All 10 of the isolates displayed inhibitory activity against EBV and no cytotoxicity. The strongest compound tested was calocoumarin-A (5), which also demonstrated a significant capacity to suppress murine skin tumor promotion in a two-stage cancer model. The investigators concluded that some 4-phenylcoumarin constituents of C. inophyllum warrant further study as possible antitumor agents (Cancer Lett. 2001;169:15-19).

C. inophyllum was one of 155 extracts from 93 plant species found on peninsular Malaysia during a screening by Ong et al. in 2009 for in vitro photocytotoxic activity using human leukemia cells (cell line HL60). Further, C. inophyllum was among the 29 plants to lower the in vitro cell viability by more than 50% after exposure to 9.6 J/cm² of a broad-spectrum light when tested at a concentration of 20 mcg/mL (J. Photochem. Photobiol. B 2009;96:216-22). In addition, Li et al. isolated one new friedelane-type triterpene and seven previously discovered triterpenoids from the stems and leaves of C. inophyllum, and ascertained that they exhibited growth inhibitory activity against human leukemia HL-60 cells (Fitoterapia 2010;81:586-9).

In 2008, Xiao et al. isolated a new prenylated xanthone (caloxanthone) as well as two previously known xanthones from the ethanolic extract of C. inophyllum twigs and reported that two of the constituents (including the new xanthone) demonstrated cytotoxicity against myelogenous leukemia (cell line K562) (J. Asian Nat. Prod. Res. 2008;10:993-7).

C. inophyllum is known to contain an abundance of phytosterols – primarily stigmasterol and beta-sitosterol, which are steroids associated with several healthy benefits (stigmasterol is a potent antioxidant) – as well as delta-tocotrienol, a form of vitamin E that acts as an antioxidant and is associated with anticancer activity, particularly against murine melanoma (Phytochemistry 2005;66:1825-31; J. Nutr. 1997;127:668-74).

Conclusion

Tamanu oil certainly isn’t a passing fad for the numerous traditional societies in the mainly eastern and southern hemispheres who have used the botanical for medicinal and culinary purposes for centuries. As an ingredient in skin care products, though, more research is needed. While modern studies are promising, randomized, placebo-controlled clinical trials are necessary to establish a potential role of C. inophyllum in the large array of topical dermatologic formulations.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever. To respond to this column, or to suggest topics for future columns, write to her at sknews@frontlinemedcom.com.

Calophyllum inophyllum is a large, nondeciduous tree native to a wide swath of regions including Central and East Africa; a north-to-south swath of India; Southeast Asia; Polynesia; the Philippines; and Australia. A member of the mangosteen family (Clusiaceae, also known as Guttiferae), C. inophyllum is now cultivated in much of the tropical world.

The oil derived from this abundant plant is known by a wide variety of names, including Alexandrian laurel, beach mahogany, beauty leaf, beach calophyllum, dilo, and kamani. But perhaps it is best known by the French Polynesian name: tamanu. Tamanu oil has been used for hundreds of years in cuisine and to treat various medical conditions. Ocular burn and cutaneous wound healing are some distinct conditions for which the oil of C. inophyllum has a long history of use in traditional folk medicine (Oncol. Rep. 2012;28:1096-102; Int. J. Cosmet. Sci. 2002;24:341-8).

Wound healing and eye protection

The C. inophyllum components to which wound-healing activity have been attributed include calophyllolide and inophyllum, as well as various polyphenols, many of which exert antioxidant effects (Int. J. Cosmet. Sci. 2002;24:341-8).

Courtesy Wikimedia Commons/B.navez/Creative Commons License

Modern research buttresses the use of tamanu oil for corneal protection from burns. In 2007, Said et al. explored the anti-UV activity of tamanu oil for eye protection. They found that the botanical oil displayed a significant capacity to absorb UV radiation, even at low concentrations (1/10,000, v/v), with a sun protection factor ranging from 18 to 22. Concentrations of C. inophyllum oil of up to 1% were not cytotoxic to human conjunctival epithelial cells, with the agent acting against oxidative stress and DNA damage. In light of the apparent antioxidant and cytoprotective effects of C. inophyllum oil in the study, the researchers concluded that the oil has potential as a natural UV filter in ophthalmic formulations (Eur. J. Pharm. Sci. 2007;30:203-10).

In 2009, Said et al. performed in vitro, in vivo, and ex vivo studies to assess the effects of different rinsing and healing protocols for alkali-induced ocular burn and inflammation in rabbits. The researchers used NaOH to induce corneal reactions in the rabbits, followed by rinses with NaCl 0.9% or controlled-ionization marine formula combined with N-acetylcysteine or vegetable oils (from C. inophyllum and Aleurites moluccana). The investigators assessed corneal epithelium regeneration and inflammatory cell infiltration using in vivo confocal microscopy and ex vivo histological cuts. They found that the combination of controlled-ionization marine solution with 10% C. inophyllum oil and 90% A. moluccana oil promoted corneal epithelium regeneration while reducing inflammatory cells, suggesting its viability as ocular burn therapy (Ophthalmologica 2009;223:52-9).

Other medical benefits

A wide range of health benefits have been ascribed to tamanu oil, and the ingredient has been found in an increasing number of topical products. It is thought to impart anti-inflammatory, antioxidant, antibacterial, antiviral, and photoprotective activity.

In 2011, Ayyanar et al. concluded a 4-year study intended to ascertain the herbs used in traditional medicine practiced by the Kani tribes in the Tirunelveli hills of Western Ghats, India. The researchers identified 90 species of plants used traditionally as ethnomedicinal treatments, with 65 different indications reported, particularly dermatologic conditions and gastrointestinal illnesses. Based on their study, they identified 16 species, including C. inophyllum, for additional ethnopharmacological investigation as potential sources of new drug agents (J. Ethnopharmacol. 2011;134:851-64).

In 2004, Yimdjo et al. investigated the chemical constituents of the root bark and nut of C. inophyllum, resulting in the isolation of several compounds and the discovery of antibacterial activity against several microbes (Phytochemistry 2004;65:2789-95).

C. inophyllum leaf extracts from the islands of French Polynesia have also been touted for several constituents that hold promise as anti-HIV-1 agents, including inophyllum B and P (Anal. Chim. Acta 2008;624:147-53). In addition, quantitative high-performance liquid chromatography (HPLC) analysis of callus cultures of C. inophyllum has revealed the anti-HIV activity of the dipyranocoumarins inophyllum B and P (J. Biotechnol. 2007;130:346-53).

Tamanu oil also has demonstrated potential use for humans and domestic animals as an insect repellent, specifically against the stable fly, Stomoxys calcitrans (J. Med. Entomol. 2010;47:575-80; Pest Manag. Sci. 2010;66:1191-8).

In 2012, Tsai et al. investigated the anti-inflammatory properties of an acetone extract of C. inophyllum leaves using lipopolysaccharide (LPS)-induced RAW 264.7 cells to assess the impact of the extract on nitric oxide (NO) expression and inducible nitric oxide synthase (iNOS). They found that C. inophyllum significantly inhibited, in dose-dependent fashion, the LPS-induced synthesis of NO, in addition to the expression of iNOS, cyclooxygenase (COX)-2, and nuclear factor–kappa B (NF-kappaB). The researchers concluded that the C. inophyllum extract exhibits anti-inflammatory activity and has potential application to inflammatory conditions in human beings (Oncol. Rep. 2012;28:1096-102).

Cancer

Recent work suggests the anti-cancer potential of C. inophyllum. In a study just over a decade ago, Itogawa et al. examined the potential inhibitory effects of C. inophyllum 4-phenylcoumarin isolates on Epstein-Barr virus early antigen (EBV-EA) activation caused by 12-O-tetradecanoylphorbol-13-acetate in Raji cells. All 10 of the isolates displayed inhibitory activity against EBV and no cytotoxicity. The strongest compound tested was calocoumarin-A (5), which also demonstrated a significant capacity to suppress murine skin tumor promotion in a two-stage cancer model. The investigators concluded that some 4-phenylcoumarin constituents of C. inophyllum warrant further study as possible antitumor agents (Cancer Lett. 2001;169:15-19).

C. inophyllum was one of 155 extracts from 93 plant species found on peninsular Malaysia during a screening by Ong et al. in 2009 for in vitro photocytotoxic activity using human leukemia cells (cell line HL60). Further, C. inophyllum was among the 29 plants to lower the in vitro cell viability by more than 50% after exposure to 9.6 J/cm² of a broad-spectrum light when tested at a concentration of 20 mcg/mL (J. Photochem. Photobiol. B 2009;96:216-22). In addition, Li et al. isolated one new friedelane-type triterpene and seven previously discovered triterpenoids from the stems and leaves of C. inophyllum, and ascertained that they exhibited growth inhibitory activity against human leukemia HL-60 cells (Fitoterapia 2010;81:586-9).

In 2008, Xiao et al. isolated a new prenylated xanthone (caloxanthone) as well as two previously known xanthones from the ethanolic extract of C. inophyllum twigs and reported that two of the constituents (including the new xanthone) demonstrated cytotoxicity against myelogenous leukemia (cell line K562) (J. Asian Nat. Prod. Res. 2008;10:993-7).

C. inophyllum is known to contain an abundance of phytosterols – primarily stigmasterol and beta-sitosterol, which are steroids associated with several healthy benefits (stigmasterol is a potent antioxidant) – as well as delta-tocotrienol, a form of vitamin E that acts as an antioxidant and is associated with anticancer activity, particularly against murine melanoma (Phytochemistry 2005;66:1825-31; J. Nutr. 1997;127:668-74).

Conclusion

Tamanu oil certainly isn’t a passing fad for the numerous traditional societies in the mainly eastern and southern hemispheres who have used the botanical for medicinal and culinary purposes for centuries. As an ingredient in skin care products, though, more research is needed. While modern studies are promising, randomized, placebo-controlled clinical trials are necessary to establish a potential role of C. inophyllum in the large array of topical dermatologic formulations.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever. To respond to this column, or to suggest topics for future columns, write to her at sknews@frontlinemedcom.com.

Structured in lamellar sheets, the primary lipids of the epidermis – ceramides, cholesterol, and free fatty acids – play a crucial role in the barrier function of the skin. Ceramides have come to be known as a complex family of lipids (sphingolipids – a sphingoid base and a fatty acid) involved in cell signaling in addition to their role in barrier homeostasis and water retention. In fact, ceramides are known to play a critical role in cell proliferation, differentiation, and apoptosis (Food Chem. Toxicol. 2009;47:681-6). Significantly, they cannot be replenished or obtained through natural sources, but synthetic ceramides, studied since the 1950s, are increasingly sophisticated and useful.

This column will review some key aspects of natural human ceramides as well as topically applied synthetic versions (also known as pseudoceramides), which are thought to ameliorate the structure and function of ceramide-depleted skin.

Ceramide structure and function

Lipids in the stratum corneum (SC) play an important role in the barrier function of the skin. The intercellular lipids of the SC are thought to be composed of approximately equal proportions of ceramides (J. Invest. Dermatol. 1987;88:2s-6s), cholesterol, and fatty acids (Am. J. Clin. Dermatol. 2003;4:107-29). Ceramides are not found in significant supply in lower levels of the epidermis, such as the stratum granulosum or basal layer. This implies that terminal differentiation is an important component of the natural production of ceramides, of which there are at least nine classes in the SC. Ceramide 1 was first identified in 1982. In addition to ceramides 1 to 9, there are two protein-bound ceramides classified as ceramides A and B, which are covalently bound to cornified envelope proteins, such as involucrin (Bouwstra JA, Pilgrim K, Ponec M. Structure of the skin barrier, in "Skin Barrier," Elias PM, Feingold KR, Eds. New York: Taylor & Francis, 2006, p. 65) .

Ceramides are named based on the polarity and composition of the molecule. As suggested above, the foundational ceramide structure is a fatty acid covalently bound to a sphingoid base. The various classes of ceramides are grouped according to the arrangements of sphingosine (S), phytosphingosine (P), or 6-hydroxysphingosine (H) bases, to which an alpha-hydroxy (A) or nonhydroxy (N) fatty acid is attached, in addition to the presence or absence of a discrete omega-esterified linoleic acid residue (J. Lipid. Res. 2004;45:923-32).

Courtesy Wikimedia Commons/Karol Langner/Public Domain

Ceramide 1 is unique in that it is nonpolar, and it contains linoleic acid. The special function of ceramide 1 in the SC is typically ascribed to its unique structure, which is thought to allow it to act as a molecular rivet, binding the multiple bilayers of the SC (J. Invest. Dermatol. 1987;88:2s-6s). This would explain the stacking of lipid bilayers in lamellar sheets observed in the barrier. Ceramides 1, 4, and 7 exhibit critical functions in terms of epidermal integrity by serving as the primary storage areas for linoleic acid, an essential fatty acid with significant roles in the epidermal lipid barrier (J. Invest. Dermatol. 1980;74:230-3). Although all epidermal ceramides are produced from a lamellar body–derived glucosylceramide precursor, sphingomyelin-derived ceramides (ceramides 2 and 5) are essential for maintaining the integrity of the SC (J. Lipid. Res. 2000;41:2071-82). It is worth noting that because an alkaline pH suppresses beta-glucocerebrosidase and acid sphingomyelinase activity (J. Invest. Dermatol. 2005;125:510-20), alkaline soaps can exacerbate poor barrier formation.

Exposure to UVB radiation and cytokines has been associated with an increase in the regulatory enzyme for ceramide synthesis, serine palmitoyltransferase, and it has been determined that in response to UVB exposure, the epidermis upregulates sphingolipid synthesis at the mRNA and protein levels (J. Lipid. Res. 1998;39:2031-8).

Synthetic ceramides

Skin conditions such as atopic dermatitis (AD), psoriasis, contact dermatitis, and some genetic disorders have been associated with depleted ceramide levels (Am. J. Clin. Dermatol. 2005;6:215-23), but these diseases can be ameliorated through the use of exogenous ceramides or their analogues (topical ceramide replacement therapy) (Curr. Med. Chem. 2010;17:2301-24; J. Dermatol. Sci. 2008;51:37-43; Am. J. Clin. Dermatol. 2005;6:215-23). Notably, the activities of enzymes in the SC, particularly ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase, have been shown to be elevated in epidermal AD (Am. J. Clin. Dermatol. 2005;6:215-23).

Synthetic ceramides, or pseudoceramides, contain hydroxyl groups, two alkyl groups, and an amide bond – the same key structural components as natural ceramides. Consequently, various synthetic ceramides have been reported to form the multilamellar structure observed in the intercellular spaces of the SC (J. Lipid. Res. 1996;37:361-7).

Coderch et al., in a review of ceramides and skin function, endorsed the potential of topical therapy for several skin conditions using complete lipid mixtures and some ceramide supplementation, as well as the topical delivery of lipid precursors (Am. J. Clin. Dermatol. 2003;4:107-29). And, in fact, the topical application of synthetic ceramides has been shown to speed up the repair of impaired SC (J. Clin. Invest. 1994;94:89-96; Dermatology 2005;211:128-34). Recent reports by Tokudome et al. also indicate that the application of sphingomyelin-based liposomes effectively augments the levels of various ceramides in cultured human skin models (Skin Pharmacol. Physiol. 2011;24:218-23; J. Liposome Res. 2010;20:49-54).

In 2005, de Jager et al. used small-angle and wide-angle x-ray diffraction to show that lipid mixtures prepared with well-defined synthetic ceramides exhibit organization and lipid-phase behavior that are very similar to those of lamellar and lateral SC lipids, and can be used to further elucidate the molecular structure and roles of individual ceramides (J. Lipid. Res. 2005;46:2649-56).

In light of the uncertainty regarding the metabolic impact of pseudoceramides, in 2008, Uchida et al. compared the effects of two chemically unrelated, commercially available products to exogenous cell-permeant or natural ceramide on cell growth and apoptosis thresholds. Using cultured human keratinocytes, the investigators found that the commercial ceramides did not suppress keratinocyte growth or increase cell toxicity, as did the cell-permeant. The investigators suggested that these findings buttress the preclinical studies indicating that these pseudoceramides are safe for topical application (J. Dermatol. Sci. 2008;51:37-43).

Kang et al. recently conducted studies of synthetic ceramide derivatives of PC-9S (N-ethanol-2-mirystyl-3-oxostearamide), which, itself, has been shown to be effective in atopic and psoriatic patients. Both studies, conducted in NC/Nga mice, demonstrated that the topical application of the derivative K6PC-9 or the derivative K6PC-9p reduced skin inflammation and AD symptoms. According to the authors, K6PC-9 warrants consideration as a topical agent for AD, and K6PC-9p warrants consideration as a treatment for inflammatory skin diseases in general (Int. Immunopharmacol. 2007;7:1589-97; Exp. Dermatol. 2008;17:958-64).

Subsequently, Kang et al. studied the effects of another ceramide derivative of PC-9S, K112PC-5 (2-acetyl-N-(1,3-dihydroxyisopropyl)tetradecanamide), on macrophage and T-lymphocyte function in primary macrophages and splenocytes, respectively. The researchers also studied the impact of topically applied K112PC-5 on skin inflammation and AD in NC/Nga mice. Among several findings, the investigators noted that K112PC-5 suppressed AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, with the pseudoceramide exhibiting in vitro and in vivo anti-inflammatory activity. They concluded that K112PC-5 is another synthetic ceramide derivative with potential as a topical agent for the treatment of AD (Arch. Pharm. Res. 2008;31:1004-9).

In 2009, Morita et al. studied the potential adverse effects of the synthetic pseudoceramide SLE66, which has demonstrated the capacity to improve xerosis, pruritus, and scaling of human skin. They found that the tested product failed to provoke cutaneous irritation or sensitization in animal and human studies. In addition, they did not observe any phototoxicity or photosensitization, and they established 1,000 mg/kg/day (the highest level tested) as the no-observed-adverse-effect (NOAEL) for systemic toxicity after oral administration or topical application (Food Chem. Toxicol. 2009;47:669-73).

Conclusion

Ceramides are among the primary lipid constituents, along with cholesterol and fatty acids, of the lamellar sheets found in the intercellular spaces of the SC. Together, these lipids maintain the water permeability barrier role of the skin. Ceramides also play an important role in cell signaling. Research over the last several decades, particularly the last 20 years, indicates that topically applied synthetic ceramide agents can effectively compensate for diminished ceramide levels associated with various skin conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at sknews@elsevier.com. 

Structured in lamellar sheets, the primary lipids of the epidermis – ceramides, cholesterol, and free fatty acids – play a crucial role in the barrier function of the skin. Ceramides have come to be known as a complex family of lipids (sphingolipids – a sphingoid base and a fatty acid) involved in cell signaling in addition to their role in barrier homeostasis and water retention. In fact, ceramides are known to play a critical role in cell proliferation, differentiation, and apoptosis (Food Chem. Toxicol. 2009;47:681-6). Significantly, they cannot be replenished or obtained through natural sources, but synthetic ceramides, studied since the 1950s, are increasingly sophisticated and useful.

This column will review some key aspects of natural human ceramides as well as topically applied synthetic versions (also known as pseudoceramides), which are thought to ameliorate the structure and function of ceramide-depleted skin.

Ceramide structure and function

Lipids in the stratum corneum (SC) play an important role in the barrier function of the skin. The intercellular lipids of the SC are thought to be composed of approximately equal proportions of ceramides (J. Invest. Dermatol. 1987;88:2s-6s), cholesterol, and fatty acids (Am. J. Clin. Dermatol. 2003;4:107-29). Ceramides are not found in significant supply in lower levels of the epidermis, such as the stratum granulosum or basal layer. This implies that terminal differentiation is an important component of the natural production of ceramides, of which there are at least nine classes in the SC. Ceramide 1 was first identified in 1982. In addition to ceramides 1 to 9, there are two protein-bound ceramides classified as ceramides A and B, which are covalently bound to cornified envelope proteins, such as involucrin (Bouwstra JA, Pilgrim K, Ponec M. Structure of the skin barrier, in "Skin Barrier," Elias PM, Feingold KR, Eds. New York: Taylor & Francis, 2006, p. 65) .

Ceramides are named based on the polarity and composition of the molecule. As suggested above, the foundational ceramide structure is a fatty acid covalently bound to a sphingoid base. The various classes of ceramides are grouped according to the arrangements of sphingosine (S), phytosphingosine (P), or 6-hydroxysphingosine (H) bases, to which an alpha-hydroxy (A) or nonhydroxy (N) fatty acid is attached, in addition to the presence or absence of a discrete omega-esterified linoleic acid residue (J. Lipid. Res. 2004;45:923-32).

Courtesy Wikimedia Commons/Karol Langner/Public Domain

Ceramide 1 is unique in that it is nonpolar, and it contains linoleic acid. The special function of ceramide 1 in the SC is typically ascribed to its unique structure, which is thought to allow it to act as a molecular rivet, binding the multiple bilayers of the SC (J. Invest. Dermatol. 1987;88:2s-6s). This would explain the stacking of lipid bilayers in lamellar sheets observed in the barrier. Ceramides 1, 4, and 7 exhibit critical functions in terms of epidermal integrity by serving as the primary storage areas for linoleic acid, an essential fatty acid with significant roles in the epidermal lipid barrier (J. Invest. Dermatol. 1980;74:230-3). Although all epidermal ceramides are produced from a lamellar body–derived glucosylceramide precursor, sphingomyelin-derived ceramides (ceramides 2 and 5) are essential for maintaining the integrity of the SC (J. Lipid. Res. 2000;41:2071-82). It is worth noting that because an alkaline pH suppresses beta-glucocerebrosidase and acid sphingomyelinase activity (J. Invest. Dermatol. 2005;125:510-20), alkaline soaps can exacerbate poor barrier formation.

Exposure to UVB radiation and cytokines has been associated with an increase in the regulatory enzyme for ceramide synthesis, serine palmitoyltransferase, and it has been determined that in response to UVB exposure, the epidermis upregulates sphingolipid synthesis at the mRNA and protein levels (J. Lipid. Res. 1998;39:2031-8).

Synthetic ceramides

Skin conditions such as atopic dermatitis (AD), psoriasis, contact dermatitis, and some genetic disorders have been associated with depleted ceramide levels (Am. J. Clin. Dermatol. 2005;6:215-23), but these diseases can be ameliorated through the use of exogenous ceramides or their analogues (topical ceramide replacement therapy) (Curr. Med. Chem. 2010;17:2301-24; J. Dermatol. Sci. 2008;51:37-43; Am. J. Clin. Dermatol. 2005;6:215-23). Notably, the activities of enzymes in the SC, particularly ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase, have been shown to be elevated in epidermal AD (Am. J. Clin. Dermatol. 2005;6:215-23).

Synthetic ceramides, or pseudoceramides, contain hydroxyl groups, two alkyl groups, and an amide bond – the same key structural components as natural ceramides. Consequently, various synthetic ceramides have been reported to form the multilamellar structure observed in the intercellular spaces of the SC (J. Lipid. Res. 1996;37:361-7).

Coderch et al., in a review of ceramides and skin function, endorsed the potential of topical therapy for several skin conditions using complete lipid mixtures and some ceramide supplementation, as well as the topical delivery of lipid precursors (Am. J. Clin. Dermatol. 2003;4:107-29). And, in fact, the topical application of synthetic ceramides has been shown to speed up the repair of impaired SC (J. Clin. Invest. 1994;94:89-96; Dermatology 2005;211:128-34). Recent reports by Tokudome et al. also indicate that the application of sphingomyelin-based liposomes effectively augments the levels of various ceramides in cultured human skin models (Skin Pharmacol. Physiol. 2011;24:218-23; J. Liposome Res. 2010;20:49-54).

In 2005, de Jager et al. used small-angle and wide-angle x-ray diffraction to show that lipid mixtures prepared with well-defined synthetic ceramides exhibit organization and lipid-phase behavior that are very similar to those of lamellar and lateral SC lipids, and can be used to further elucidate the molecular structure and roles of individual ceramides (J. Lipid. Res. 2005;46:2649-56).

In light of the uncertainty regarding the metabolic impact of pseudoceramides, in 2008, Uchida et al. compared the effects of two chemically unrelated, commercially available products to exogenous cell-permeant or natural ceramide on cell growth and apoptosis thresholds. Using cultured human keratinocytes, the investigators found that the commercial ceramides did not suppress keratinocyte growth or increase cell toxicity, as did the cell-permeant. The investigators suggested that these findings buttress the preclinical studies indicating that these pseudoceramides are safe for topical application (J. Dermatol. Sci. 2008;51:37-43).

Kang et al. recently conducted studies of synthetic ceramide derivatives of PC-9S (N-ethanol-2-mirystyl-3-oxostearamide), which, itself, has been shown to be effective in atopic and psoriatic patients. Both studies, conducted in NC/Nga mice, demonstrated that the topical application of the derivative K6PC-9 or the derivative K6PC-9p reduced skin inflammation and AD symptoms. According to the authors, K6PC-9 warrants consideration as a topical agent for AD, and K6PC-9p warrants consideration as a treatment for inflammatory skin diseases in general (Int. Immunopharmacol. 2007;7:1589-97; Exp. Dermatol. 2008;17:958-64).

Subsequently, Kang et al. studied the effects of another ceramide derivative of PC-9S, K112PC-5 (2-acetyl-N-(1,3-dihydroxyisopropyl)tetradecanamide), on macrophage and T-lymphocyte function in primary macrophages and splenocytes, respectively. The researchers also studied the impact of topically applied K112PC-5 on skin inflammation and AD in NC/Nga mice. Among several findings, the investigators noted that K112PC-5 suppressed AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, with the pseudoceramide exhibiting in vitro and in vivo anti-inflammatory activity. They concluded that K112PC-5 is another synthetic ceramide derivative with potential as a topical agent for the treatment of AD (Arch. Pharm. Res. 2008;31:1004-9).

In 2009, Morita et al. studied the potential adverse effects of the synthetic pseudoceramide SLE66, which has demonstrated the capacity to improve xerosis, pruritus, and scaling of human skin. They found that the tested product failed to provoke cutaneous irritation or sensitization in animal and human studies. In addition, they did not observe any phototoxicity or photosensitization, and they established 1,000 mg/kg/day (the highest level tested) as the no-observed-adverse-effect (NOAEL) for systemic toxicity after oral administration or topical application (Food Chem. Toxicol. 2009;47:669-73).

Conclusion

Ceramides are among the primary lipid constituents, along with cholesterol and fatty acids, of the lamellar sheets found in the intercellular spaces of the SC. Together, these lipids maintain the water permeability barrier role of the skin. Ceramides also play an important role in cell signaling. Research over the last several decades, particularly the last 20 years, indicates that topically applied synthetic ceramide agents can effectively compensate for diminished ceramide levels associated with various skin conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at sknews@elsevier.com. 

Structured in lamellar sheets, the primary lipids of the epidermis – ceramides, cholesterol, and free fatty acids – play a crucial role in the barrier function of the skin. Ceramides have come to be known as a complex family of lipids (sphingolipids – a sphingoid base and a fatty acid) involved in cell signaling in addition to their role in barrier homeostasis and water retention. In fact, ceramides are known to play a critical role in cell proliferation, differentiation, and apoptosis (Food Chem. Toxicol. 2009;47:681-6). Significantly, they cannot be replenished or obtained through natural sources, but synthetic ceramides, studied since the 1950s, are increasingly sophisticated and useful.

This column will review some key aspects of natural human ceramides as well as topically applied synthetic versions (also known as pseudoceramides), which are thought to ameliorate the structure and function of ceramide-depleted skin.

Ceramide structure and function

Lipids in the stratum corneum (SC) play an important role in the barrier function of the skin. The intercellular lipids of the SC are thought to be composed of approximately equal proportions of ceramides (J. Invest. Dermatol. 1987;88:2s-6s), cholesterol, and fatty acids (Am. J. Clin. Dermatol. 2003;4:107-29). Ceramides are not found in significant supply in lower levels of the epidermis, such as the stratum granulosum or basal layer. This implies that terminal differentiation is an important component of the natural production of ceramides, of which there are at least nine classes in the SC. Ceramide 1 was first identified in 1982. In addition to ceramides 1 to 9, there are two protein-bound ceramides classified as ceramides A and B, which are covalently bound to cornified envelope proteins, such as involucrin (Bouwstra JA, Pilgrim K, Ponec M. Structure of the skin barrier, in "Skin Barrier," Elias PM, Feingold KR, Eds. New York: Taylor & Francis, 2006, p. 65) .

Ceramides are named based on the polarity and composition of the molecule. As suggested above, the foundational ceramide structure is a fatty acid covalently bound to a sphingoid base. The various classes of ceramides are grouped according to the arrangements of sphingosine (S), phytosphingosine (P), or 6-hydroxysphingosine (H) bases, to which an alpha-hydroxy (A) or nonhydroxy (N) fatty acid is attached, in addition to the presence or absence of a discrete omega-esterified linoleic acid residue (J. Lipid. Res. 2004;45:923-32).

Courtesy Wikimedia Commons/Karol Langner/Public Domain

Ceramide 1 is unique in that it is nonpolar, and it contains linoleic acid. The special function of ceramide 1 in the SC is typically ascribed to its unique structure, which is thought to allow it to act as a molecular rivet, binding the multiple bilayers of the SC (J. Invest. Dermatol. 1987;88:2s-6s). This would explain the stacking of lipid bilayers in lamellar sheets observed in the barrier. Ceramides 1, 4, and 7 exhibit critical functions in terms of epidermal integrity by serving as the primary storage areas for linoleic acid, an essential fatty acid with significant roles in the epidermal lipid barrier (J. Invest. Dermatol. 1980;74:230-3). Although all epidermal ceramides are produced from a lamellar body–derived glucosylceramide precursor, sphingomyelin-derived ceramides (ceramides 2 and 5) are essential for maintaining the integrity of the SC (J. Lipid. Res. 2000;41:2071-82). It is worth noting that because an alkaline pH suppresses beta-glucocerebrosidase and acid sphingomyelinase activity (J. Invest. Dermatol. 2005;125:510-20), alkaline soaps can exacerbate poor barrier formation.

Exposure to UVB radiation and cytokines has been associated with an increase in the regulatory enzyme for ceramide synthesis, serine palmitoyltransferase, and it has been determined that in response to UVB exposure, the epidermis upregulates sphingolipid synthesis at the mRNA and protein levels (J. Lipid. Res. 1998;39:2031-8).

Synthetic ceramides

Skin conditions such as atopic dermatitis (AD), psoriasis, contact dermatitis, and some genetic disorders have been associated with depleted ceramide levels (Am. J. Clin. Dermatol. 2005;6:215-23), but these diseases can be ameliorated through the use of exogenous ceramides or their analogues (topical ceramide replacement therapy) (Curr. Med. Chem. 2010;17:2301-24; J. Dermatol. Sci. 2008;51:37-43; Am. J. Clin. Dermatol. 2005;6:215-23). Notably, the activities of enzymes in the SC, particularly ceramidase, sphingomyelin deacylase, and glucosylceramide deacylase, have been shown to be elevated in epidermal AD (Am. J. Clin. Dermatol. 2005;6:215-23).

Synthetic ceramides, or pseudoceramides, contain hydroxyl groups, two alkyl groups, and an amide bond – the same key structural components as natural ceramides. Consequently, various synthetic ceramides have been reported to form the multilamellar structure observed in the intercellular spaces of the SC (J. Lipid. Res. 1996;37:361-7).

Coderch et al., in a review of ceramides and skin function, endorsed the potential of topical therapy for several skin conditions using complete lipid mixtures and some ceramide supplementation, as well as the topical delivery of lipid precursors (Am. J. Clin. Dermatol. 2003;4:107-29). And, in fact, the topical application of synthetic ceramides has been shown to speed up the repair of impaired SC (J. Clin. Invest. 1994;94:89-96; Dermatology 2005;211:128-34). Recent reports by Tokudome et al. also indicate that the application of sphingomyelin-based liposomes effectively augments the levels of various ceramides in cultured human skin models (Skin Pharmacol. Physiol. 2011;24:218-23; J. Liposome Res. 2010;20:49-54).

In 2005, de Jager et al. used small-angle and wide-angle x-ray diffraction to show that lipid mixtures prepared with well-defined synthetic ceramides exhibit organization and lipid-phase behavior that are very similar to those of lamellar and lateral SC lipids, and can be used to further elucidate the molecular structure and roles of individual ceramides (J. Lipid. Res. 2005;46:2649-56).

In light of the uncertainty regarding the metabolic impact of pseudoceramides, in 2008, Uchida et al. compared the effects of two chemically unrelated, commercially available products to exogenous cell-permeant or natural ceramide on cell growth and apoptosis thresholds. Using cultured human keratinocytes, the investigators found that the commercial ceramides did not suppress keratinocyte growth or increase cell toxicity, as did the cell-permeant. The investigators suggested that these findings buttress the preclinical studies indicating that these pseudoceramides are safe for topical application (J. Dermatol. Sci. 2008;51:37-43).

Kang et al. recently conducted studies of synthetic ceramide derivatives of PC-9S (N-ethanol-2-mirystyl-3-oxostearamide), which, itself, has been shown to be effective in atopic and psoriatic patients. Both studies, conducted in NC/Nga mice, demonstrated that the topical application of the derivative K6PC-9 or the derivative K6PC-9p reduced skin inflammation and AD symptoms. According to the authors, K6PC-9 warrants consideration as a topical agent for AD, and K6PC-9p warrants consideration as a treatment for inflammatory skin diseases in general (Int. Immunopharmacol. 2007;7:1589-97; Exp. Dermatol. 2008;17:958-64).

Subsequently, Kang et al. studied the effects of another ceramide derivative of PC-9S, K112PC-5 (2-acetyl-N-(1,3-dihydroxyisopropyl)tetradecanamide), on macrophage and T-lymphocyte function in primary macrophages and splenocytes, respectively. The researchers also studied the impact of topically applied K112PC-5 on skin inflammation and AD in NC/Nga mice. Among several findings, the investigators noted that K112PC-5 suppressed AD induced by extracts of dust mites, Dermatophagoides pteronyssinus and Dermatophagoides farinae, with the pseudoceramide exhibiting in vitro and in vivo anti-inflammatory activity. They concluded that K112PC-5 is another synthetic ceramide derivative with potential as a topical agent for the treatment of AD (Arch. Pharm. Res. 2008;31:1004-9).

In 2009, Morita et al. studied the potential adverse effects of the synthetic pseudoceramide SLE66, which has demonstrated the capacity to improve xerosis, pruritus, and scaling of human skin. They found that the tested product failed to provoke cutaneous irritation or sensitization in animal and human studies. In addition, they did not observe any phototoxicity or photosensitization, and they established 1,000 mg/kg/day (the highest level tested) as the no-observed-adverse-effect (NOAEL) for systemic toxicity after oral administration or topical application (Food Chem. Toxicol. 2009;47:669-73).

Conclusion

Ceramides are among the primary lipid constituents, along with cholesterol and fatty acids, of the lamellar sheets found in the intercellular spaces of the SC. Together, these lipids maintain the water permeability barrier role of the skin. Ceramides also play an important role in cell signaling. Research over the last several decades, particularly the last 20 years, indicates that topically applied synthetic ceramide agents can effectively compensate for diminished ceramide levels associated with various skin conditions.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at sknews@elsevier.com. 

Retinyl palmitate, a storage and ester form of retinol (vitamin A) and the prevailing type of vitamin A found naturally in the skin (Toxicol. Ind. Health 2005;21:167-75), has become increasingly popular during the past 2 decades. It is widely used in more than 600 skin care products, including cosmetics and sunscreens, and, with FDA approval, over-the-counter and prescription drugs (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67). It was also the subject of a controversial summer 2010 report by the Environmental Working Group (EWG) in which the organization warned of possible photocarcinogenicity associated with retinyl palmitate (RP)-containing sunscreens.

Although vitamin A storage in the epidermis takes the form of retinyl esters and retinols, they act differently when exposed to UV light. The retinols display UVB-resistant and UVB-sensitive characteristics not exhibited by retinyl esters such as RP (Dermatology 1999;199:302-7). The EWG used "vitamin A" and "retinyl palmitate" interchangeably in their criticisms and follow-ups, which is misleading. The vitamin A family of drugs includes retinyl esters, retinol, tretinoin, adapalene, tazarotene, and oral isotretinoin (Accutane), in addition to four carotenoids, including beta-carotene, many of which have been shown to prevent or protect against cancer (Br. J. Cancer 1988;57:428-33; Cancer Epidemiol. Biomarkers Prev. 1997;6:949-56; J. Invest. Dermatol. 1981;76:178-80; Arch. Dermatol. Res. 1981;270:453-62). That does not mean that RP prevents cancer just because oral retinol, beta-carotene, or tretinoin have been shown to do so, for example. In fact, the study that the EWG refers to shows evidence that RP may lead to skin tumors in mice.

In response to the EWG report, Wang et al. acknowledged that of the eight in vitro studies published by the Food and Drug Administration from 2002 to 2009, four revealed that reactive oxygen species were produced by RP after UVA exposure (J. Am. Acad. Dermatol. 2010;63:903-6; Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Toxicol. Ind. Health 2007;23:625-31; Toxicol. Lett. 2006;163:30-43; Int. J. Environ. Res. Public Health 2006;3:185-90; Chem. Res. Toxicol. 2005;18:129-38). However, they questioned the relevance of these results in the context of the convoluted mechanisms of the antioxidant setting in human skin. They also contended that the National Toxicology Program (NTP) study on which the EWG based its report failed to prove that the combination of RP and UV results in photocarcinogenesis and, in fact, was rife with reasons for skepticism (J. Am. Acad. Dermatol. 2010;63:903-6; Photodermatol. Photoimmunol. Photomed. 2011;27:58-67). The EWG offered its own counterarguments and stood by its report. Rather than wade further into the debate that occurred in 2010 and found its way into the pages of the Journal of the American Academy of Dermatology (2010;63:903-6), let’s review what is known about RP.

What else do we know about RP?

In 1997, Duell et al. showed that unoccluded retinol is more effective at penetrating human skin in vivo than RP or retinoic acid (J. Invest. Dermatol. 1997;109:301-5).

In 2003, Antille et al. used an in vitro model to evaluate the photoprotective activity of RP, and then applied topical RP on the back of hairless mice before exposing them to UVB. They also applied topical RP or a sunscreen on the buttocks of human volunteers before exposing them to four minimal erythema doses of UVB. The investigators found that RP was as efficient in vitro as the commercial filter octylmethoxycinnamate in preventing UVB-induced fluorescence or photobleaching of fluorescent markers. Topical RP also significantly suppressed the formation of thymine dimers in mouse epidermis and human skin. In the volunteers, topical RP was as efficient as an SPF (sun protection factor) 20 sunscreen in preventing sunburn erythema (J. Invest. Dermatol. 2003;121:1163-7).

In 2005, Yan et al. studied the phototoxicity of RP, anhydroretinol (AR), and 5,6-epoxyretinyl palmitate (5,6-epoxy-RP) in human skin Jurkat T cells with and without light irradiation. Irradiation of cells in the absence of a retinoid rendered little damage, but the presence of RP, 5,6-epoxy-RP, or AR (50, 100, 150, and 200 micromol/L) yielded DNA fragmentation, with cell death occurring at retinoid concentrations of 100 micromol/L or greater. The investigators concluded that DNA damage and cytotoxicity are engendered by RP and its photodecomposition products in association with UVA and visible light exposure. They also determined that UVA irradiation of these retinoids produces free radicals that spur DNA strand cleavage (Toxicol. Ind. Health 2005;21:167-75).

RP accounts for most of the retinyl esters endogenously formed in skin. In 2006, Yan et al., noting that exogenous RP accumulates via topically applied cosmetic and skin care formulations, investigated the time course for buildup and disappearance of RP and retinol in the stratified layers of skin from female SKH-1 mice singly or repeatedly dosed with topical creams containing 0.5% or 2% RP. The researchers observed that within 24 hours of application, RP quickly diffused into the stratum corneum and epidermal skin layers. RP and retinol levels were lowest in the dermis, intermediate in the stratum corneum, and highest in the epidermis. In separated skin layers and intact skin, RP and retinol levels declined over time, but for 18 days, RP levels remained higher than control values. The investigators concluded that topically applied RP changed the normal physiological levels of RP and retinol in the skin of mice (Toxicol. Ind. Health 2006;22:181-91).

Having previously shown that irradiation of RP with UVA leads to the formation of photodecomposition products, synthesis of reactive oxygen species, and lipid peroxidation induction, Xia et al. demonstrated comparable results, identifying RP as a photosensitizer following irradiation with UVB light (Int. J. Environ. Res. Public Health 2006;3:185-90).

Recommendations

In light of the controversy swirling around RP and the appropriate concern it has engendered, in addition to the weight of evidence as well as experience from personal observation, I advise patients to avoid daytime use of products with RP high on the ingredient list. I add that it poses real risks while offering minimal benefits. Such patients should be using retinol or tretinoin. I recommend the use of retinoids at night, to avoid the photosensitizing action induced by UVA or UVB on retinoids left on the skin.

Conclusion

Retinyl palmitate does not penetrate very well into the skin. Consequently, for over-the-counter topical formulations, I recommend retinol instead. Because of the slow penetration of RP into the skin, the RP that remains on the skin will undergo photoreaction more than a substance that is rapidly absorbed. When exposed to light, RP on the skin may undergo metabolism and/or photoreaction to generate reactive oxygen species. These reactive oxygen species or free radicals can theoretically lead to increased skin cancer. That said, sufficient evidence to establish a causal link between RP and skin cancer has not been produced. Nor, I’m afraid, are there any good reasons to recommend the use of RP. More research on this subject is needed and will likely emerge in a timely fashion.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at dermnews@frontlinemedcom.com. This column, "Cosmeceutical Critique," appears regularly in Skin & Allergy News.

Retinyl palmitate, a storage and ester form of retinol (vitamin A) and the prevailing type of vitamin A found naturally in the skin (Toxicol. Ind. Health 2005;21:167-75), has become increasingly popular during the past 2 decades. It is widely used in more than 600 skin care products, including cosmetics and sunscreens, and, with FDA approval, over-the-counter and prescription drugs (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67). It was also the subject of a controversial summer 2010 report by the Environmental Working Group (EWG) in which the organization warned of possible photocarcinogenicity associated with retinyl palmitate (RP)-containing sunscreens.

Although vitamin A storage in the epidermis takes the form of retinyl esters and retinols, they act differently when exposed to UV light. The retinols display UVB-resistant and UVB-sensitive characteristics not exhibited by retinyl esters such as RP (Dermatology 1999;199:302-7). The EWG used "vitamin A" and "retinyl palmitate" interchangeably in their criticisms and follow-ups, which is misleading. The vitamin A family of drugs includes retinyl esters, retinol, tretinoin, adapalene, tazarotene, and oral isotretinoin (Accutane), in addition to four carotenoids, including beta-carotene, many of which have been shown to prevent or protect against cancer (Br. J. Cancer 1988;57:428-33; Cancer Epidemiol. Biomarkers Prev. 1997;6:949-56; J. Invest. Dermatol. 1981;76:178-80; Arch. Dermatol. Res. 1981;270:453-62). That does not mean that RP prevents cancer just because oral retinol, beta-carotene, or tretinoin have been shown to do so, for example. In fact, the study that the EWG refers to shows evidence that RP may lead to skin tumors in mice.

In response to the EWG report, Wang et al. acknowledged that of the eight in vitro studies published by the Food and Drug Administration from 2002 to 2009, four revealed that reactive oxygen species were produced by RP after UVA exposure (J. Am. Acad. Dermatol. 2010;63:903-6; Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Toxicol. Ind. Health 2007;23:625-31; Toxicol. Lett. 2006;163:30-43; Int. J. Environ. Res. Public Health 2006;3:185-90; Chem. Res. Toxicol. 2005;18:129-38). However, they questioned the relevance of these results in the context of the convoluted mechanisms of the antioxidant setting in human skin. They also contended that the National Toxicology Program (NTP) study on which the EWG based its report failed to prove that the combination of RP and UV results in photocarcinogenesis and, in fact, was rife with reasons for skepticism (J. Am. Acad. Dermatol. 2010;63:903-6; Photodermatol. Photoimmunol. Photomed. 2011;27:58-67). The EWG offered its own counterarguments and stood by its report. Rather than wade further into the debate that occurred in 2010 and found its way into the pages of the Journal of the American Academy of Dermatology (2010;63:903-6), let’s review what is known about RP.

What else do we know about RP?

In 1997, Duell et al. showed that unoccluded retinol is more effective at penetrating human skin in vivo than RP or retinoic acid (J. Invest. Dermatol. 1997;109:301-5).

In 2003, Antille et al. used an in vitro model to evaluate the photoprotective activity of RP, and then applied topical RP on the back of hairless mice before exposing them to UVB. They also applied topical RP or a sunscreen on the buttocks of human volunteers before exposing them to four minimal erythema doses of UVB. The investigators found that RP was as efficient in vitro as the commercial filter octylmethoxycinnamate in preventing UVB-induced fluorescence or photobleaching of fluorescent markers. Topical RP also significantly suppressed the formation of thymine dimers in mouse epidermis and human skin. In the volunteers, topical RP was as efficient as an SPF (sun protection factor) 20 sunscreen in preventing sunburn erythema (J. Invest. Dermatol. 2003;121:1163-7).

In 2005, Yan et al. studied the phototoxicity of RP, anhydroretinol (AR), and 5,6-epoxyretinyl palmitate (5,6-epoxy-RP) in human skin Jurkat T cells with and without light irradiation. Irradiation of cells in the absence of a retinoid rendered little damage, but the presence of RP, 5,6-epoxy-RP, or AR (50, 100, 150, and 200 micromol/L) yielded DNA fragmentation, with cell death occurring at retinoid concentrations of 100 micromol/L or greater. The investigators concluded that DNA damage and cytotoxicity are engendered by RP and its photodecomposition products in association with UVA and visible light exposure. They also determined that UVA irradiation of these retinoids produces free radicals that spur DNA strand cleavage (Toxicol. Ind. Health 2005;21:167-75).

RP accounts for most of the retinyl esters endogenously formed in skin. In 2006, Yan et al., noting that exogenous RP accumulates via topically applied cosmetic and skin care formulations, investigated the time course for buildup and disappearance of RP and retinol in the stratified layers of skin from female SKH-1 mice singly or repeatedly dosed with topical creams containing 0.5% or 2% RP. The researchers observed that within 24 hours of application, RP quickly diffused into the stratum corneum and epidermal skin layers. RP and retinol levels were lowest in the dermis, intermediate in the stratum corneum, and highest in the epidermis. In separated skin layers and intact skin, RP and retinol levels declined over time, but for 18 days, RP levels remained higher than control values. The investigators concluded that topically applied RP changed the normal physiological levels of RP and retinol in the skin of mice (Toxicol. Ind. Health 2006;22:181-91).

Having previously shown that irradiation of RP with UVA leads to the formation of photodecomposition products, synthesis of reactive oxygen species, and lipid peroxidation induction, Xia et al. demonstrated comparable results, identifying RP as a photosensitizer following irradiation with UVB light (Int. J. Environ. Res. Public Health 2006;3:185-90).

Recommendations

In light of the controversy swirling around RP and the appropriate concern it has engendered, in addition to the weight of evidence as well as experience from personal observation, I advise patients to avoid daytime use of products with RP high on the ingredient list. I add that it poses real risks while offering minimal benefits. Such patients should be using retinol or tretinoin. I recommend the use of retinoids at night, to avoid the photosensitizing action induced by UVA or UVB on retinoids left on the skin.

Conclusion

Retinyl palmitate does not penetrate very well into the skin. Consequently, for over-the-counter topical formulations, I recommend retinol instead. Because of the slow penetration of RP into the skin, the RP that remains on the skin will undergo photoreaction more than a substance that is rapidly absorbed. When exposed to light, RP on the skin may undergo metabolism and/or photoreaction to generate reactive oxygen species. These reactive oxygen species or free radicals can theoretically lead to increased skin cancer. That said, sufficient evidence to establish a causal link between RP and skin cancer has not been produced. Nor, I’m afraid, are there any good reasons to recommend the use of RP. More research on this subject is needed and will likely emerge in a timely fashion.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at dermnews@frontlinemedcom.com. This column, "Cosmeceutical Critique," appears regularly in Skin & Allergy News.

Retinyl palmitate, a storage and ester form of retinol (vitamin A) and the prevailing type of vitamin A found naturally in the skin (Toxicol. Ind. Health 2005;21:167-75), has become increasingly popular during the past 2 decades. It is widely used in more than 600 skin care products, including cosmetics and sunscreens, and, with FDA approval, over-the-counter and prescription drugs (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67). It was also the subject of a controversial summer 2010 report by the Environmental Working Group (EWG) in which the organization warned of possible photocarcinogenicity associated with retinyl palmitate (RP)-containing sunscreens.

Although vitamin A storage in the epidermis takes the form of retinyl esters and retinols, they act differently when exposed to UV light. The retinols display UVB-resistant and UVB-sensitive characteristics not exhibited by retinyl esters such as RP (Dermatology 1999;199:302-7). The EWG used "vitamin A" and "retinyl palmitate" interchangeably in their criticisms and follow-ups, which is misleading. The vitamin A family of drugs includes retinyl esters, retinol, tretinoin, adapalene, tazarotene, and oral isotretinoin (Accutane), in addition to four carotenoids, including beta-carotene, many of which have been shown to prevent or protect against cancer (Br. J. Cancer 1988;57:428-33; Cancer Epidemiol. Biomarkers Prev. 1997;6:949-56; J. Invest. Dermatol. 1981;76:178-80; Arch. Dermatol. Res. 1981;270:453-62). That does not mean that RP prevents cancer just because oral retinol, beta-carotene, or tretinoin have been shown to do so, for example. In fact, the study that the EWG refers to shows evidence that RP may lead to skin tumors in mice.

In response to the EWG report, Wang et al. acknowledged that of the eight in vitro studies published by the Food and Drug Administration from 2002 to 2009, four revealed that reactive oxygen species were produced by RP after UVA exposure (J. Am. Acad. Dermatol. 2010;63:903-6; Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Toxicol. Ind. Health 2007;23:625-31; Toxicol. Lett. 2006;163:30-43; Int. J. Environ. Res. Public Health 2006;3:185-90; Chem. Res. Toxicol. 2005;18:129-38). However, they questioned the relevance of these results in the context of the convoluted mechanisms of the antioxidant setting in human skin. They also contended that the National Toxicology Program (NTP) study on which the EWG based its report failed to prove that the combination of RP and UV results in photocarcinogenesis and, in fact, was rife with reasons for skepticism (J. Am. Acad. Dermatol. 2010;63:903-6; Photodermatol. Photoimmunol. Photomed. 2011;27:58-67). The EWG offered its own counterarguments and stood by its report. Rather than wade further into the debate that occurred in 2010 and found its way into the pages of the Journal of the American Academy of Dermatology (2010;63:903-6), let’s review what is known about RP.

What else do we know about RP?

In 1997, Duell et al. showed that unoccluded retinol is more effective at penetrating human skin in vivo than RP or retinoic acid (J. Invest. Dermatol. 1997;109:301-5).

In 2003, Antille et al. used an in vitro model to evaluate the photoprotective activity of RP, and then applied topical RP on the back of hairless mice before exposing them to UVB. They also applied topical RP or a sunscreen on the buttocks of human volunteers before exposing them to four minimal erythema doses of UVB. The investigators found that RP was as efficient in vitro as the commercial filter octylmethoxycinnamate in preventing UVB-induced fluorescence or photobleaching of fluorescent markers. Topical RP also significantly suppressed the formation of thymine dimers in mouse epidermis and human skin. In the volunteers, topical RP was as efficient as an SPF (sun protection factor) 20 sunscreen in preventing sunburn erythema (J. Invest. Dermatol. 2003;121:1163-7).

In 2005, Yan et al. studied the phototoxicity of RP, anhydroretinol (AR), and 5,6-epoxyretinyl palmitate (5,6-epoxy-RP) in human skin Jurkat T cells with and without light irradiation. Irradiation of cells in the absence of a retinoid rendered little damage, but the presence of RP, 5,6-epoxy-RP, or AR (50, 100, 150, and 200 micromol/L) yielded DNA fragmentation, with cell death occurring at retinoid concentrations of 100 micromol/L or greater. The investigators concluded that DNA damage and cytotoxicity are engendered by RP and its photodecomposition products in association with UVA and visible light exposure. They also determined that UVA irradiation of these retinoids produces free radicals that spur DNA strand cleavage (Toxicol. Ind. Health 2005;21:167-75).

RP accounts for most of the retinyl esters endogenously formed in skin. In 2006, Yan et al., noting that exogenous RP accumulates via topically applied cosmetic and skin care formulations, investigated the time course for buildup and disappearance of RP and retinol in the stratified layers of skin from female SKH-1 mice singly or repeatedly dosed with topical creams containing 0.5% or 2% RP. The researchers observed that within 24 hours of application, RP quickly diffused into the stratum corneum and epidermal skin layers. RP and retinol levels were lowest in the dermis, intermediate in the stratum corneum, and highest in the epidermis. In separated skin layers and intact skin, RP and retinol levels declined over time, but for 18 days, RP levels remained higher than control values. The investigators concluded that topically applied RP changed the normal physiological levels of RP and retinol in the skin of mice (Toxicol. Ind. Health 2006;22:181-91).

Having previously shown that irradiation of RP with UVA leads to the formation of photodecomposition products, synthesis of reactive oxygen species, and lipid peroxidation induction, Xia et al. demonstrated comparable results, identifying RP as a photosensitizer following irradiation with UVB light (Int. J. Environ. Res. Public Health 2006;3:185-90).

Recommendations

In light of the controversy swirling around RP and the appropriate concern it has engendered, in addition to the weight of evidence as well as experience from personal observation, I advise patients to avoid daytime use of products with RP high on the ingredient list. I add that it poses real risks while offering minimal benefits. Such patients should be using retinol or tretinoin. I recommend the use of retinoids at night, to avoid the photosensitizing action induced by UVA or UVB on retinoids left on the skin.

Conclusion

Retinyl palmitate does not penetrate very well into the skin. Consequently, for over-the-counter topical formulations, I recommend retinol instead. Because of the slow penetration of RP into the skin, the RP that remains on the skin will undergo photoreaction more than a substance that is rapidly absorbed. When exposed to light, RP on the skin may undergo metabolism and/or photoreaction to generate reactive oxygen species. These reactive oxygen species or free radicals can theoretically lead to increased skin cancer. That said, sufficient evidence to establish a causal link between RP and skin cancer has not been produced. Nor, I’m afraid, are there any good reasons to recommend the use of RP. More research on this subject is needed and will likely emerge in a timely fashion.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to her at dermnews@frontlinemedcom.com. This column, "Cosmeceutical Critique," appears regularly in Skin & Allergy News.

Used in foods, some traditional medicines, herbal tea, herbal toothpastes, and aromatherapy, Melissa officinalis (lemon balm) is a perennial herb in the Lamiaceae (mint) family found in southern Europe and the Mediterranean area. The medicinal use of lemon balm dates back at least 2,000 years (Ann. N. Y. Acad. Sci. 1965;130:474-82). Lower abdominal distress and nervous conditions are some of the ailments treated with lemon balm in folk medicine; herpes lesions are a modern indication (Nat. Prod. Res. 2008;22:1433-40). The essential oil and phenylpropanoid derivatives are thought to be the two primary groups of active constituents in lemon balm (Phytochemistry. 2011;72:572-8).

©Design Pics

The main individual components of M. officinalis essential oil have been identified as the monoterpenaldehydes citral a, citral b, and citronellal (Phytomedicine. 2008;15:734-40). The chief phenolic compounds are rosmarinic acid, which is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid, as well as caffeic acid, which is isolated from the fresh leaves and stems (J. Nat. Prod. 2009;72:1512-5Phytochemistry. 2011;72:572-8). Six flavonoids, including luteolin and apigenin, have also been isolated from the leaves of lemon balm (Acta. Pol. Pharm. 2002;59:139-43; J. Nat. Prod. 2007;70:1889-94). Given the presence of such ingredients known to exhibit antioxidant properties, it is not surprising that such a capacity is considered one of the main medicinal benefits of M. officinalis. Indeed, lemon balm is reputed to display significant antioxidant, anxiolytic (Med. J. Nutrition. Metab. 2011;4:211-8; Phytomedicine. 2010;17:397-403; Psychosom. Med. 2004;66:607-13), and antiviral (particularly antiherpetic) activity (Proc. Soc. Exp. Biol. Med. 1964;117:431-4; Virol. J. 2011;8:188). M. officinalis is also a component, with two other herbs, in a mixture (Ob-X) recently shown to lower body weight gain and adipose tissue mass in genetically obese mice (Pharm. Biol. 2011;49:614-9).

Antioxidant Activity

In a 2009 study, investigators examined the antioxidant potential of three plants (M. officinalis, Matricaria recutita (German chamomile), and Cymbopogon citrus [lemon grass]) used in Brazil to treat neurologic conditions. M. officinalis was found to deliver the greatest reduction in thiobarbituric acid reactive species (TBARS) and the most salient antioxidant effect as evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The investigators concluded that M. officinalis warrants consideration as a treatment for oxidative stress–associated neurologic diseases (Neurochem. Res. 2009;34:973-83).

Additional evidence of its antioxidant activity is emerging. In early 2012, Martins et al. reported on their study in which an aqueous extract of M. officinalis significantly mitigated manganese-induced brain oxidative stress in mice. They found that the extract attenuated oxidative damage (TBARS) and reduced total thiol levels, and concluded that their findings show the potent antioxidant activity of M. officinalis (Brain. Res. Bull. 2012;87;74-9). In addition, a recent study found that lemon balm infusion in a tea, after 30 days of daily consumption, significantly lowered oxidative stress and DNA damage in radiology staff exposed to low doses of radiation at work (Toxicol. Ind. Health. 2011;27:205-12).

Antiviral Activity

In 2006, Gaby reported on various natural substances, used in the diet or topically, that exert activity against herpes simplex lesions and prevent recurrences, serving as effective alternatives to acyclovir and its attendant side effects. He cited lemon balm as having exhibited antiviral properties in two studies in the 1990s (Altern. Med. Rev. 2006;11:93-101).

In 1994, 116 patients with acute herpes simplex applied a standardized lemon balm cream (containing 1% Lo-701) or a placebo cream two to four times daily in a randomized, double-blind trial over a 5- to 10-day period within 72 hours of symptom onset. While only 19% of the placebo group reported satisfactory healing, 41% of the active treatment group was satisfied (Phytomedicine. 1994;1:25-31). In 1999, a double-blind, placebo-controlled trial randomized 66 patients with a minimum of four herpes simplex episodes per year to treatment (four times daily for 5 days) with the same standardized lemon balm cream or placebo. Symptom scores were significantly lower in the treatment group than the control group by the second day of the protocol, though the trend supporting active treatment over 5 days was not significant (Phytomedicine 1999;6:225-30).

In 2008, Mazzanti et al. evaluated the antiviral activity against herpes simplex virus type 2 (HSV-2) of a hydroalcoholic extract of lemon balm leaves using a cytopathic effect inhibition assay on Vero cells. They found that lemon balm diminished the cytopathic effect of HSV-2 on Vero cells, with a maximum suppression effect with 0.5 mg/mL. The extract, shown through NMR (nuclear magnetic resonance) and HPLC (high-performance liquid chromatography) analysis to contain rosmarinic acid (4.1% w/w), did not prevent the entry of HSV-2 into cells, indicating postpenetration activity by the botanical agent. The investigators concluded that their work supports the use of lemon balm for treating herpes lesions, and justifies its further study in clinical trials (Nat. Prod. Res. 2008;22:1433-40).

Also that year, Schnitzler et al. evaluated the antiviral effect of lemon balm oil on HSV-1 and HSV-2 in vitro on monkey kidney cells. They found that plaque formation was significantly lowered (by 98.8% for HSV-1 and 97.2% for HSV-2) by noncytotoxic lemon balm oil concentrations, with higher concentrations nearly eradicating infections. Using time-on-addition assays, the investigators determined that pretreatment with lemon balm oil significantly suppressed both viruses before infection of cells, suggesting that the oil impacted the virus prior to adsorption, but not after reaching the host cell. They concluded that this implies the capacity for direct antiviral activity. The authors added that the lipophilic nature of lemon balm oil allows for its penetration into the skin, further supporting its suitability as a topical treatment of herpes (Phytomedicine. 2008;15:734-40).

In a more recent in vitro experiment evaluating antiviral activity against HSV-1, Astani et al. compared an aqueous extract of M. officinalis and phenolic extract compounds (caffeic acid, p-coumaric acid, and rosmarinic acid). The lemon balm extract exhibited high virucidal activity against HSV-1, even at concentrations of 1.5 mcg/mL; phenolic compounds showed similar results only at concentrations 100 times greater. Further, lemon balm extract and rosmarinic acid dose-dependently suppressed HSV-1 attachment to host cells. The researchers concluded that rosmarinic acid was the primary constituent responsible for the antiviral activity displayed by lemon balm, but noted that M. officinalis extract, which imparted virucidal activity against HSV-1 in vitro with low toxicity, has a greater selectivity index against HSV than that of its constituents alone (Chemotherapy. 2012;58:70-7).

In 2008, Geuenich et al. investigated several species of the Lamiaceae family (including lemon balm) for their potency in suppressing HIV-1 infection. The aqueous extracts from the leaves of lemon balm (as well as peppermint and sage) dose-dependently displayed substantial activity against HIV-1 infection in T-cell lines, primary macrophages, and in ex vivo tonsil histocultures. The investigators also found that exposure of extracts to free virions strongly and quickly suppressed infections, though no antiviral effect was seen in exposure to surface-bound virions or target cells alone. Noting the antiherpetic activity of these Lamiaceae family extracts, the investigators suggested that the development of virucidal topical microbicides using such ingredients is warranted (Retrovirology. 2008;5:27).

Hypopigmentary Potential

A potential hypopigmentary application of lemon balm also may be emerging. In 2011, Fujita et al. isolated 16-hydroxy-9-oxo-10E,12E,14E-octadecatrienoic acid (also called Corchorifatty acid B [CFAB]) from the ethanol extracts of the aerial parts of M. officinalis, and found that it suppresses pigmentation in human melanocytes and murine melanoma B16 cells, probably by promoting accelerated degradation of tyrosinase in B16 cells. Further, they noted that the mechanism of action of CFAB is markedly different from those of many other hypopigmentary agents, which facilitate tyrosinase degradation in proteasomes or lysosomes. That is, the reductions in tyrosinase caused by CFAB are thought to take place in post–Golgi complex areas, not in proteasomal or lysosomal ones (Exp. Dermatol. 2011;20(5):420-4).

Conclusions

Like many botanical ingredients studied and harnessed in our modern pharmacopeia, lemon balm has a history of use in traditional medicine. Recent studies suggest antioxidant, anxiolytic, and, especially, antiviral properties, notably in the treatment of herpes viruses. More research is necessary, however, to establish a broader role for M. officinalis in the dermatologic armamentarium.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to Dr. Baumann at sknews@elsevier.com.

Used in foods, some traditional medicines, herbal tea, herbal toothpastes, and aromatherapy, Melissa officinalis (lemon balm) is a perennial herb in the Lamiaceae (mint) family found in southern Europe and the Mediterranean area. The medicinal use of lemon balm dates back at least 2,000 years (Ann. N. Y. Acad. Sci. 1965;130:474-82). Lower abdominal distress and nervous conditions are some of the ailments treated with lemon balm in folk medicine; herpes lesions are a modern indication (Nat. Prod. Res. 2008;22:1433-40). The essential oil and phenylpropanoid derivatives are thought to be the two primary groups of active constituents in lemon balm (Phytochemistry. 2011;72:572-8).

©Design Pics

The main individual components of M. officinalis essential oil have been identified as the monoterpenaldehydes citral a, citral b, and citronellal (Phytomedicine. 2008;15:734-40). The chief phenolic compounds are rosmarinic acid, which is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid, as well as caffeic acid, which is isolated from the fresh leaves and stems (J. Nat. Prod. 2009;72:1512-5Phytochemistry. 2011;72:572-8). Six flavonoids, including luteolin and apigenin, have also been isolated from the leaves of lemon balm (Acta. Pol. Pharm. 2002;59:139-43; J. Nat. Prod. 2007;70:1889-94). Given the presence of such ingredients known to exhibit antioxidant properties, it is not surprising that such a capacity is considered one of the main medicinal benefits of M. officinalis. Indeed, lemon balm is reputed to display significant antioxidant, anxiolytic (Med. J. Nutrition. Metab. 2011;4:211-8; Phytomedicine. 2010;17:397-403; Psychosom. Med. 2004;66:607-13), and antiviral (particularly antiherpetic) activity (Proc. Soc. Exp. Biol. Med. 1964;117:431-4; Virol. J. 2011;8:188). M. officinalis is also a component, with two other herbs, in a mixture (Ob-X) recently shown to lower body weight gain and adipose tissue mass in genetically obese mice (Pharm. Biol. 2011;49:614-9).

Antioxidant Activity

In a 2009 study, investigators examined the antioxidant potential of three plants (M. officinalis, Matricaria recutita (German chamomile), and Cymbopogon citrus [lemon grass]) used in Brazil to treat neurologic conditions. M. officinalis was found to deliver the greatest reduction in thiobarbituric acid reactive species (TBARS) and the most salient antioxidant effect as evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The investigators concluded that M. officinalis warrants consideration as a treatment for oxidative stress–associated neurologic diseases (Neurochem. Res. 2009;34:973-83).

Additional evidence of its antioxidant activity is emerging. In early 2012, Martins et al. reported on their study in which an aqueous extract of M. officinalis significantly mitigated manganese-induced brain oxidative stress in mice. They found that the extract attenuated oxidative damage (TBARS) and reduced total thiol levels, and concluded that their findings show the potent antioxidant activity of M. officinalis (Brain. Res. Bull. 2012;87;74-9). In addition, a recent study found that lemon balm infusion in a tea, after 30 days of daily consumption, significantly lowered oxidative stress and DNA damage in radiology staff exposed to low doses of radiation at work (Toxicol. Ind. Health. 2011;27:205-12).

Antiviral Activity

In 2006, Gaby reported on various natural substances, used in the diet or topically, that exert activity against herpes simplex lesions and prevent recurrences, serving as effective alternatives to acyclovir and its attendant side effects. He cited lemon balm as having exhibited antiviral properties in two studies in the 1990s (Altern. Med. Rev. 2006;11:93-101).

In 1994, 116 patients with acute herpes simplex applied a standardized lemon balm cream (containing 1% Lo-701) or a placebo cream two to four times daily in a randomized, double-blind trial over a 5- to 10-day period within 72 hours of symptom onset. While only 19% of the placebo group reported satisfactory healing, 41% of the active treatment group was satisfied (Phytomedicine. 1994;1:25-31). In 1999, a double-blind, placebo-controlled trial randomized 66 patients with a minimum of four herpes simplex episodes per year to treatment (four times daily for 5 days) with the same standardized lemon balm cream or placebo. Symptom scores were significantly lower in the treatment group than the control group by the second day of the protocol, though the trend supporting active treatment over 5 days was not significant (Phytomedicine 1999;6:225-30).

In 2008, Mazzanti et al. evaluated the antiviral activity against herpes simplex virus type 2 (HSV-2) of a hydroalcoholic extract of lemon balm leaves using a cytopathic effect inhibition assay on Vero cells. They found that lemon balm diminished the cytopathic effect of HSV-2 on Vero cells, with a maximum suppression effect with 0.5 mg/mL. The extract, shown through NMR (nuclear magnetic resonance) and HPLC (high-performance liquid chromatography) analysis to contain rosmarinic acid (4.1% w/w), did not prevent the entry of HSV-2 into cells, indicating postpenetration activity by the botanical agent. The investigators concluded that their work supports the use of lemon balm for treating herpes lesions, and justifies its further study in clinical trials (Nat. Prod. Res. 2008;22:1433-40).

Also that year, Schnitzler et al. evaluated the antiviral effect of lemon balm oil on HSV-1 and HSV-2 in vitro on monkey kidney cells. They found that plaque formation was significantly lowered (by 98.8% for HSV-1 and 97.2% for HSV-2) by noncytotoxic lemon balm oil concentrations, with higher concentrations nearly eradicating infections. Using time-on-addition assays, the investigators determined that pretreatment with lemon balm oil significantly suppressed both viruses before infection of cells, suggesting that the oil impacted the virus prior to adsorption, but not after reaching the host cell. They concluded that this implies the capacity for direct antiviral activity. The authors added that the lipophilic nature of lemon balm oil allows for its penetration into the skin, further supporting its suitability as a topical treatment of herpes (Phytomedicine. 2008;15:734-40).

In a more recent in vitro experiment evaluating antiviral activity against HSV-1, Astani et al. compared an aqueous extract of M. officinalis and phenolic extract compounds (caffeic acid, p-coumaric acid, and rosmarinic acid). The lemon balm extract exhibited high virucidal activity against HSV-1, even at concentrations of 1.5 mcg/mL; phenolic compounds showed similar results only at concentrations 100 times greater. Further, lemon balm extract and rosmarinic acid dose-dependently suppressed HSV-1 attachment to host cells. The researchers concluded that rosmarinic acid was the primary constituent responsible for the antiviral activity displayed by lemon balm, but noted that M. officinalis extract, which imparted virucidal activity against HSV-1 in vitro with low toxicity, has a greater selectivity index against HSV than that of its constituents alone (Chemotherapy. 2012;58:70-7).

In 2008, Geuenich et al. investigated several species of the Lamiaceae family (including lemon balm) for their potency in suppressing HIV-1 infection. The aqueous extracts from the leaves of lemon balm (as well as peppermint and sage) dose-dependently displayed substantial activity against HIV-1 infection in T-cell lines, primary macrophages, and in ex vivo tonsil histocultures. The investigators also found that exposure of extracts to free virions strongly and quickly suppressed infections, though no antiviral effect was seen in exposure to surface-bound virions or target cells alone. Noting the antiherpetic activity of these Lamiaceae family extracts, the investigators suggested that the development of virucidal topical microbicides using such ingredients is warranted (Retrovirology. 2008;5:27).

Hypopigmentary Potential

A potential hypopigmentary application of lemon balm also may be emerging. In 2011, Fujita et al. isolated 16-hydroxy-9-oxo-10E,12E,14E-octadecatrienoic acid (also called Corchorifatty acid B [CFAB]) from the ethanol extracts of the aerial parts of M. officinalis, and found that it suppresses pigmentation in human melanocytes and murine melanoma B16 cells, probably by promoting accelerated degradation of tyrosinase in B16 cells. Further, they noted that the mechanism of action of CFAB is markedly different from those of many other hypopigmentary agents, which facilitate tyrosinase degradation in proteasomes or lysosomes. That is, the reductions in tyrosinase caused by CFAB are thought to take place in post–Golgi complex areas, not in proteasomal or lysosomal ones (Exp. Dermatol. 2011;20(5):420-4).

Conclusions

Like many botanical ingredients studied and harnessed in our modern pharmacopeia, lemon balm has a history of use in traditional medicine. Recent studies suggest antioxidant, anxiolytic, and, especially, antiviral properties, notably in the treatment of herpes viruses. More research is necessary, however, to establish a broader role for M. officinalis in the dermatologic armamentarium.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to Dr. Baumann at sknews@elsevier.com.

Used in foods, some traditional medicines, herbal tea, herbal toothpastes, and aromatherapy, Melissa officinalis (lemon balm) is a perennial herb in the Lamiaceae (mint) family found in southern Europe and the Mediterranean area. The medicinal use of lemon balm dates back at least 2,000 years (Ann. N. Y. Acad. Sci. 1965;130:474-82). Lower abdominal distress and nervous conditions are some of the ailments treated with lemon balm in folk medicine; herpes lesions are a modern indication (Nat. Prod. Res. 2008;22:1433-40). The essential oil and phenylpropanoid derivatives are thought to be the two primary groups of active constituents in lemon balm (Phytochemistry. 2011;72:572-8).

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The main individual components of M. officinalis essential oil have been identified as the monoterpenaldehydes citral a, citral b, and citronellal (Phytomedicine. 2008;15:734-40). The chief phenolic compounds are rosmarinic acid, which is an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid, as well as caffeic acid, which is isolated from the fresh leaves and stems (J. Nat. Prod. 2009;72:1512-5Phytochemistry. 2011;72:572-8). Six flavonoids, including luteolin and apigenin, have also been isolated from the leaves of lemon balm (Acta. Pol. Pharm. 2002;59:139-43; J. Nat. Prod. 2007;70:1889-94). Given the presence of such ingredients known to exhibit antioxidant properties, it is not surprising that such a capacity is considered one of the main medicinal benefits of M. officinalis. Indeed, lemon balm is reputed to display significant antioxidant, anxiolytic (Med. J. Nutrition. Metab. 2011;4:211-8; Phytomedicine. 2010;17:397-403; Psychosom. Med. 2004;66:607-13), and antiviral (particularly antiherpetic) activity (Proc. Soc. Exp. Biol. Med. 1964;117:431-4; Virol. J. 2011;8:188). M. officinalis is also a component, with two other herbs, in a mixture (Ob-X) recently shown to lower body weight gain and adipose tissue mass in genetically obese mice (Pharm. Biol. 2011;49:614-9).

Antioxidant Activity

In a 2009 study, investigators examined the antioxidant potential of three plants (M. officinalis, Matricaria recutita (German chamomile), and Cymbopogon citrus [lemon grass]) used in Brazil to treat neurologic conditions. M. officinalis was found to deliver the greatest reduction in thiobarbituric acid reactive species (TBARS) and the most salient antioxidant effect as evaluated by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The investigators concluded that M. officinalis warrants consideration as a treatment for oxidative stress–associated neurologic diseases (Neurochem. Res. 2009;34:973-83).

Additional evidence of its antioxidant activity is emerging. In early 2012, Martins et al. reported on their study in which an aqueous extract of M. officinalis significantly mitigated manganese-induced brain oxidative stress in mice. They found that the extract attenuated oxidative damage (TBARS) and reduced total thiol levels, and concluded that their findings show the potent antioxidant activity of M. officinalis (Brain. Res. Bull. 2012;87;74-9). In addition, a recent study found that lemon balm infusion in a tea, after 30 days of daily consumption, significantly lowered oxidative stress and DNA damage in radiology staff exposed to low doses of radiation at work (Toxicol. Ind. Health. 2011;27:205-12).

Antiviral Activity

In 2006, Gaby reported on various natural substances, used in the diet or topically, that exert activity against herpes simplex lesions and prevent recurrences, serving as effective alternatives to acyclovir and its attendant side effects. He cited lemon balm as having exhibited antiviral properties in two studies in the 1990s (Altern. Med. Rev. 2006;11:93-101).

In 1994, 116 patients with acute herpes simplex applied a standardized lemon balm cream (containing 1% Lo-701) or a placebo cream two to four times daily in a randomized, double-blind trial over a 5- to 10-day period within 72 hours of symptom onset. While only 19% of the placebo group reported satisfactory healing, 41% of the active treatment group was satisfied (Phytomedicine. 1994;1:25-31). In 1999, a double-blind, placebo-controlled trial randomized 66 patients with a minimum of four herpes simplex episodes per year to treatment (four times daily for 5 days) with the same standardized lemon balm cream or placebo. Symptom scores were significantly lower in the treatment group than the control group by the second day of the protocol, though the trend supporting active treatment over 5 days was not significant (Phytomedicine 1999;6:225-30).

In 2008, Mazzanti et al. evaluated the antiviral activity against herpes simplex virus type 2 (HSV-2) of a hydroalcoholic extract of lemon balm leaves using a cytopathic effect inhibition assay on Vero cells. They found that lemon balm diminished the cytopathic effect of HSV-2 on Vero cells, with a maximum suppression effect with 0.5 mg/mL. The extract, shown through NMR (nuclear magnetic resonance) and HPLC (high-performance liquid chromatography) analysis to contain rosmarinic acid (4.1% w/w), did not prevent the entry of HSV-2 into cells, indicating postpenetration activity by the botanical agent. The investigators concluded that their work supports the use of lemon balm for treating herpes lesions, and justifies its further study in clinical trials (Nat. Prod. Res. 2008;22:1433-40).

Also that year, Schnitzler et al. evaluated the antiviral effect of lemon balm oil on HSV-1 and HSV-2 in vitro on monkey kidney cells. They found that plaque formation was significantly lowered (by 98.8% for HSV-1 and 97.2% for HSV-2) by noncytotoxic lemon balm oil concentrations, with higher concentrations nearly eradicating infections. Using time-on-addition assays, the investigators determined that pretreatment with lemon balm oil significantly suppressed both viruses before infection of cells, suggesting that the oil impacted the virus prior to adsorption, but not after reaching the host cell. They concluded that this implies the capacity for direct antiviral activity. The authors added that the lipophilic nature of lemon balm oil allows for its penetration into the skin, further supporting its suitability as a topical treatment of herpes (Phytomedicine. 2008;15:734-40).

In a more recent in vitro experiment evaluating antiviral activity against HSV-1, Astani et al. compared an aqueous extract of M. officinalis and phenolic extract compounds (caffeic acid, p-coumaric acid, and rosmarinic acid). The lemon balm extract exhibited high virucidal activity against HSV-1, even at concentrations of 1.5 mcg/mL; phenolic compounds showed similar results only at concentrations 100 times greater. Further, lemon balm extract and rosmarinic acid dose-dependently suppressed HSV-1 attachment to host cells. The researchers concluded that rosmarinic acid was the primary constituent responsible for the antiviral activity displayed by lemon balm, but noted that M. officinalis extract, which imparted virucidal activity against HSV-1 in vitro with low toxicity, has a greater selectivity index against HSV than that of its constituents alone (Chemotherapy. 2012;58:70-7).

In 2008, Geuenich et al. investigated several species of the Lamiaceae family (including lemon balm) for their potency in suppressing HIV-1 infection. The aqueous extracts from the leaves of lemon balm (as well as peppermint and sage) dose-dependently displayed substantial activity against HIV-1 infection in T-cell lines, primary macrophages, and in ex vivo tonsil histocultures. The investigators also found that exposure of extracts to free virions strongly and quickly suppressed infections, though no antiviral effect was seen in exposure to surface-bound virions or target cells alone. Noting the antiherpetic activity of these Lamiaceae family extracts, the investigators suggested that the development of virucidal topical microbicides using such ingredients is warranted (Retrovirology. 2008;5:27).

Hypopigmentary Potential

A potential hypopigmentary application of lemon balm also may be emerging. In 2011, Fujita et al. isolated 16-hydroxy-9-oxo-10E,12E,14E-octadecatrienoic acid (also called Corchorifatty acid B [CFAB]) from the ethanol extracts of the aerial parts of M. officinalis, and found that it suppresses pigmentation in human melanocytes and murine melanoma B16 cells, probably by promoting accelerated degradation of tyrosinase in B16 cells. Further, they noted that the mechanism of action of CFAB is markedly different from those of many other hypopigmentary agents, which facilitate tyrosinase degradation in proteasomes or lysosomes. That is, the reductions in tyrosinase caused by CFAB are thought to take place in post–Golgi complex areas, not in proteasomal or lysosomal ones (Exp. Dermatol. 2011;20(5):420-4).

Conclusions

Like many botanical ingredients studied and harnessed in our modern pharmacopeia, lemon balm has a history of use in traditional medicine. Recent studies suggest antioxidant, anxiolytic, and, especially, antiviral properties, notably in the treatment of herpes viruses. More research is necessary, however, to establish a broader role for M. officinalis in the dermatologic armamentarium.

Dr. Baumann is in private practice in Miami Beach. She did not disclose any conflicts of interest. To respond to this column, or to suggest topics for future columns, write to Dr. Baumann at sknews@elsevier.com.