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Abstract
Caffeine is ubiquitous in our society—not only in the drinks consumed but also increasingly in dermatologic topicals. Given that coffee and caffeine are increasingly used for the production of many dermatologic anti-cancer topicals, sunscreens, and cosmetics, it is of imperative importance to review the basic science and clinical evidence for such claims. In this concise review, we outline the current evidence.
Keywords: Anti-ageing, alopecia, caffeine, coffee, cosmetic, cosmetics, cosmeceuticals, cellulite, melanoma, non-melanoma skin cancer, sunscreen, skin cancer, wound healing
Introduction 
Caffeine is ubiquitous in our society—not only in the drinks consumed but also increasingly in dermatologic topicals. In the liver, caffeine is metabolised by the cytochrome P450 oxidase system into three derivative dimethylxanthines: Theobromine expands blood vessels, paraxanthine stimulates lipolysis, and theophylline relaxes bronchial smooth muscles.[1] These metabolites eventually convert into xanthine and uric acid. The kidneys only excrete 10% of the caffeine in unchanged form.[2] Given that coffee and caffeine are increasingly used for the production of many dermatologic anti-cancer topicals, sunscreens, and cosmetics, it is imperative to review the basic science and clinical evidence for such claims.
Skin cancer
Both topical and ingested forms of caffeine hold associations with skin cancer. The incidence of non-melanoma skin cancer (NMSC) and melanoma have shown an inverse relationship with increasing caffeine consumption.[3],[4],[5] Recently, a 2019 article called for an investigation into the non-caffeine components of coffee that reduce skin cancer rates—specifically NMSC.[6] The piece argues that the limited randomised control trials for caffeine have not adequately upheld caffeine ingestion over other components of coffee in decreasing the rates of cutaneous malignancies. The authors state that a variety of non-caffeine metabolites, including anti-inflammatory phytochemicals, maybe the key mediators in decreasing NMSC risk. However, a reply to the article held that, to the best of our knowledge, none of these metabolites except caffeine has demonstrated protective effects against UV(ultra-violet)-induced carcinogenesis.[7]
Indeed, numerous studies have supported caffeine as the pro-apoptotic agent in opposition to UV-induced carcinogenesis.[8],[9],[10] Topical applications of 0.4 mg/ml caffeine (1.2 mg or 6.2 μmol of caffeine in 100 μl of acetone) to the dorsal skin of mice pretreated with UVB resulted in enhanced apoptosis of focal basal cell hyperplasia.[11] A 2007 study also supported the concept that topical application of caffeine (dissolved in acetone at 1%–2% weight by volume) after UV irradiation promotes the deletion of DNA-damaged keratinocytes and may partially diminish photodamage or photocarcinogenesis.[12] Another 2016 study found that topical caffeine in solution prevented UVB-induced photoaging by down-regulating matrix metalloproteinases; therefore, upholding caffeine's potential as an anti-photoaging agent.[13]
Sun protection
Caffeine is associated with UV-protective properties—holding implications for both cancer and age-related UV damage. In one study, topical application of caffeine in solution significantly reduced the UVB-induced wrinkle formation in mice's dorsal skin. The application led to a decrease in the wrinkle area by over 35% when compared with the UVB-treated control.[13],[14] Caffeine has been shown to inhibit UVB-induced formation of thymine dimers and enhances UVB-induced apoptosis in both neoplasms and UV-damaged keratinocytes—earning a unique status as both a sunscreen and pro-apoptotic agent.[11],[12],[15] Caffeine administration enhances UVB-induced apoptosis by both p53-dependent and p53-independent mechanisms.[6],[7],[8] Basic science research has supported caffeine's inhibition of UVB-induced carcinogenesis through obstruction of the “ataxia telangiectasia and rad3-related” (ATR) kinase—a DNA damage response kinase.[8],[9],[10],[16] Applying these basic science findings to a more clinical setting, a 2019 study demonstrated caffeine as an effective sunscreen adjuvant. Caffeine supplementation to sunscreen increased the sun protection factor (SPF) value both in vitro and in vivo, without causing erythema or impairing the skin barrier. Caffeine supplementation increased anti-UVB protection by 25%.[17] No studies to date have looked specifically at caffeine's protection against UV-A.
Cosmetics and cosmeceuticals
A large interest in caffeine in dermatology comes from the cosmetics industry. Frequently available as caffeine topicals, these products target issues from cellulite to alopecia.[1] Caffeine's antioxidant properties bolster its stance in cosmetics as a protective and preventative agent for UV damage or photoaging.
Caffeine has shown efficacy in recent studies for male androgenic alopecia. Androgenic alopecia currently only has two (food and drug administration) FDA-approved treatment options: Finasteride and minoxidil. In vitro, studies have shown that caffeine solution increases the dermal microcirculation flow and inhibits 5-α-reductase activity for increased terminal hair growth.[18] The 5-α-reductase converts testosterone into dihydrotestosterone, a steroid that contributes to androgenic alopecia by shortening the anagen phase. An ancillary mechanism for caffeine's effect on hair growth is its inhibition of phosphodiesterase enzymes. This inhibition indirectly increases the cyclic adenosine monophosphate (cAMP) and, subsequently, increases metabolic cellular activity.1 Concerning the application and the penetrance of topical caffeine, two in vivo studies demonstrated that a contact time of two minutes between a shampoo caffeine topical and the skin surface was sufficient for the formulation to penetrate deeply into the hair follicles and to remain there for up to 48 hours, even after washing.[19] After 24 hours, the caffeine was still detectable in the hair follicles—thereby demonstrating a long-term reservoir function.[20]
There has been increasing clinical evidence of caffeine's benefits in alopecia. A recent study analysed hair follicles from balding vertex area scalp biopsies of men affected by androgenetic alopecia. The study was split into biopsies incubated with corticotropin-releasing hormone with or without caffeine solution medium (0.001% or 0.005%). They concluded that stress, similar to telogen effluvium unmasking androgenic hair loss, can impair human hair physiology and induce hair loss; caffeine may effectively counteract stress-induced hair damage.[21] A different randomised, open-label, multicentre trial with over 200 male patients treated either with 5% minoxidil solution or 0.2% caffeine solution demonstrated statistically equivalent increases in the percentage change of anagen hairs from baseline to six months using a frontal and occipital trichogram.[22] More studies are needed for caffeine's role in females or other forms of non-scarring hair loss. Nevertheless, caffeine topicals show promise in treating androgenic alopecia through multiple mechanisms.
Caffeine has shown promise as a cellulite (gynoid lipodystrophy) treatment. The treatment of cellulite is complex because it requires extensive fat, collagen, and connective tissue remodelling. Commonly affecting the thighs and buttocks of women, cellulite results from the presence of excess subcutaneous fat that bulges superiorly into the dermis, causing a dimpling “orange-peel” effect.[1] Enhancing lipolysis locally would combat this process. Lipases located on adipocyte membranes may be activated or inhibited by catecholamines or hormones. Caffeine has been shown not only to increase catecholamine levels—indirectly increasing lipolysis—but also activate lipases directly and block adipocyte alpha-adrenergic receptors.[23] This alpha blockade prevents fat accumulation and hastens lipolysis.[1] In addition, caffeine stimulates lipolysis via the inhibition of phosphodiesterase, thereby increasing the cAMP levels in adipocytes.[24] Caffeine also enhances microcirculation as well as lymphatic drainage by removing accumulated fats arising during lipolysis, which may better foster the clearance of cellulite.[1] Small clinical studies support topical caffeine for cellulite treatment. A recent study trialling 3.5% water-soluble caffeine on the upper arms and thighs of 15 participants showed significantly decreased circumferences just below 1 cm after six weeks of treatment—without any major adverse effects.[25] Another double-blind, randomised, placebo-controlled study involving 44 healthy women, showed that after 2.5 months, skin tonicity, orange-peel appearance, circumference, and general qualitative appearance were significantly improved over placebo.[26] Larger studies with long-term follow-up are needed before caffeine is upheld as a standard cellulite treatment option.
Caffeine has demonstrated other miscellaneous cosmetic benefits. In males, the higher proportions of androgens contribute to reduced viability of hair and reduced epidermal barrier repair capacity—presumably from lower cAMP levels due to androgenic effects. Caffeine can combat this effect by inhibiting phosphodiesterase. A double-blind placebo-controlled study with healthy volunteers showed that topical 0.5% caffeine in a hydroxyethyl cellulose gel preparation protected against transepidermal water loss in males, but not females, and therefore could function to increase barrier protection in men.[27] In addition, small clinical trials with caffeine swabs and gel application to dark puffy eyes have also shown promise in lightening the dark complexion as well as decreasing this soft tissue oedema—believed to be due to caffeine's vasoconstrictive effects on this thin skin tissue.[28],[29] Caffeine also reduces phototoxicity related to other topical ingredients. For example, popular skin whitening products such as 5-methoxypsoralen are commonly used in China, though the phototoxicity of these products can limit application. A recent publication showed that combining caffeine with such products reduces phototoxic reactions with UVC exposure—allowing such products to be used more safely.[30]
Adverse effects
Caffeine in skin products is not without risk. Basic science studies have found that topical caffeine restricts in vitro proliferation of keratinocytes and cell migration in a dose-dependent manner.[31] The same study found that caffeine also impedes human ex vivo epithelialization. These findings are in line with previous studies showing adenosine as a promoter of wound healing and angiogenesis.[32] Thus, caffeine, an adenosine antagonist, would be expected to have opposing effects—suggesting that topical caffeine may have a hindering effect on wound healing. Topical caffeine has also been evaluated based on collagen—the loss of which causes skin atrophy, loss of elasticity, fine lines, and wrinkles. Basic science research has demonstrated that caffeine inhibits collagen biosynthesis in a dose-dependent manner—possibly through the blockage of β1-integrin and insulin-like growth factor receptors in fibroblasts.[33] These preliminary basic science results still necessitate clinical studies but suggest that caffeine-containing products may partially promote wrinkle formation and skin atrophy. A 2016 trial on mice's skin supports possible atrophy, as treated mice experienced an epidermal thickness reduction of 40%.[13]
Conclusion Caffeine has shown promise in numerous areas of dermatology involving cancer prevention, sun protection, and cosmetics [Table 1]. However, many of these studies either involve basic science results that have yet demonstrated translational efficacy or are small clinical trials that lack the robust statistical power of large sample sizes. The compound's safety profile and wide array of potential benefits make caffeine a reasonable adjuvant therapy for dermatologists. In all respects, larger high-quality clinical studies are necessary before caffeine's role is established.
Key points
Caffeine is a common product in skin products, which used as anti-cancer topicals, sunscreens, and cosmeticsThis piece reviews the current evidence for caffeine's role in dermatology'.Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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