Clinical Use and Safety of Self-Tanner (Topical Dihydroxyacetone) in Dermatology: A Systematic Review

Abstract

Background:

Dihydroxyacetone (DHA) is the key ingredient in commercially available self-tanners, which are a popular alternative to sun-tanning.

Objectives:

This systematic review (PROSPERO: CRD42024558929) presents safety and clinical data about topical DHA in human and animal models since its discovery, to guide dermatologists in counseling their patients about DHA, its possible use in cutaneous diseases, and sun protection.

Methods:

This systematic review includes 16 studies retrieved in July 2023 from Embase, Medline, Cochrane, and Web of Science, following the preferred reporting items for systematic reviews and meta-analyses guidelines, and from searches of retrieved articles’ bibliographies. All studies were critically appraised using Cochrane’s Risk of Bias in Non-Randomized Studies of Interventions and the Risk of Bias Tool for Randomized Trials (second version) tools.

Results:

Murine model data suggest DHA may provide minimal photoprotection, insufficient to replace sunscreen, and may delay ultraviolet radiation-linked tumor development. Patients with erythropoietic protoporphyria (EPP) and vitiligo may benefit from DHA. No link has been established between DHA and clinically relevant vitamin deficiency and contact dermatitis. Concerns remain about cutaneous free-radical formation and product absorption. DHA’s use in psoralen-UVA therapy does not warrant further development. DHA’s role in altering the evaluation of melanocytic lesions with dermoscopy is minor.

Conclusions:

DHA may have some use in patients with vitiligo and EPP. No studies demonstrated harm related to DHA use, though most studies were low-quality, conducted on a few humans or animals, occasionally with product concentrations over the threshold permitted by the European Commission. Unresolved safety concerns about free-radical formation require high-quality research to clarify DHA’s long-term health impacts.

Introduction

The growing cognizance of ultraviolet radiation’s (UVR) hazards catalyzed a shift toward sunless tanning products containing dihydroxyacetone (DHA), whose skin-darkening properties were discovered during the 1950s. ¹ In 2023, the worldwide self-tanner market was valued at USD 1.09 billion. ²

DHA, a simple saccharide, interacts with skin through the Maillard reaction, which also imparts color to cooked foods.^3,4 When applied topically, DHA irreversibly reacts with amino acids in the stratum corneum to form melanoidins, pigmented compounds that mimic the appearance of a UV-induced tan, which are distinct from melanin produced by melanocytes.^3,4 The result is a tanned appearance within hours, which deepens over 24 to 72 hours, then fades as the skin naturally exfoliates. ⁵

In 2020, the European Commission’s Scientific Committee on Consumer Safety (SCCS) recommended limiting DHA to 10% in lotion/cream and 6.25% in hair products. ⁶ No limit has been set by the US Food and Drug Administration (FDA), but it has not approved DHA use in spray tan booths due to concerns about inhalation and mucous membrane exposure.^5,7

DHA has been explored as a treatment in erythropoietic protoporphyria (EPP), vitiligo, and in psoralen plus UVA (PUVA) for psoriasis.^1,8-13 Concerns regarding DHA’s potential carcinogenicity, free-radical generation, allergenicity, systemic absorption and lack of photoprotection require scrutiny.

We present the first systematic review that thoroughly examines studies conducted with topical DHA to evaluate its properties and safety profile.

Methods

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. ¹⁴

Literature Search

The literature search was performed on Embase, MEDLINE, Cochrane/Evidence-Based Medicine Reviews, and Web of Science from inception to July 19, 2023 (see Supplemental File 6 for complete research strategy). To ensure comprehensive data retrieval, the bibliographies of retrieved articles were manually screened for additional relevant studies.

Inclusion and Exclusion

All peer-reviewed controlled trials, cohort studies, case control studies, and case series pertaining to the cutaneous health effects and safety of topical DHA application in mammalian models, including human models, were included.

Excluded studies:

• Studies that focused exclusively on colorimetry, aesthetics, body image, or demographics were excluded as they do not provide clinically relevant safety, efficacy or clinical data. These studies typically assessed consumer preferences, tanning persistence, or cosmetic acceptance.

• In vitro studies were excluded because they represent isolated simple models without direct translational relevance to in vivo human exposure, especially regarding cutaneous penetration, systemic absorption, and both short-term and long-term clinical outcomes. Their physiologic complexity is limited, especially as it pertains to inflammatory, immunological, and metabolic responses to topical product absorption.

• Studies that were not in English or French were excluded due to feasibility constraints in translation and interpretation.

• Studies using DHA in non-dermatologic applications (e.g., biochemical or food industry uses) were excluded as they were not relevant to clinical dermatology.

After removing duplicate articles, 2 authors (C.L. and S.O.) independently screened articles for inclusion and assessed for eligibility as detailed in the PRISMA diagram (Supplemental File 3). Persistent disagreements (eg, classification of a study design) were referred to the senior author (K.P.) for arbitration. Data was extracted independently by 2 authors (C.L. and S.O.).

Quality Assessment

The Cochrane Risk Of Bias In Non-Randomized Studies of Interventions (ROBINS-I) and the second version of the Risk of Bias Tool for Randomized Trials (RoB2) were used independently (by C.L. and S.O.) for quality assessment (Supplemental File 4, 5). ¹⁵ Disagreements were resolved by consensus, with conflicts settled by the senior author (K.P.).

Level of Evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used independently (by S.O. and C.L.) to evaluate the quality of evidence (Supplemental File 2). ¹⁶ All disagreements were resolved by consensus, with disagreements decided by the senior author (K.P.).

Results

Ultimately, 16 studies were included (Supplemental Files 1, 3).

ROBINS-I, RoB-2, and GRADE Assessment

Of the 18 included experiments, 4 were judged as moderate risk of bias, 12 serious risk, and 2 critical risk (Supplemental Files 4, 5). One study was critical due to poor methodology and poor correlation between intervention measurement (edema) and outcome (photoprotection). ¹⁷ The second was due to uncontrolled exposures to natural UVR, diet, and vitamin intake, which could affect outcome (change in 25-hydroxyvitamin D [25(OH)D] levels) and likely unreported difference in baseline skin pigmentation between experimental and control groups. ¹⁸

All studies were rated very low or low in certainty using the GRADE criteria, primarily due to their small sample sizes, short duration, lack of methodology transparency, and/or use of animal models (Supplemental File 2).

Evidence Synthesis

Photoprotection

A 2004 study in humans (n = 10) with Fitzpatrick skin type (FST) II/III exposed to UVB demonstrated that DHA lotion (20%) offered a sun protection factor (SPF) of 3.0 at day 1 (range 2.1 and 4.9), decreasing to 1.7 by day 7 (P = .001). ¹⁹ Starting SPF varied slightly among individuals, but DHA declined at a consistent rate, with an SPF reduction of 0.17 per day. ¹⁹ An SPF of 3.0 is considered inadequate for sun protection by modern North American regulatory standards, which require a minimum SPF of 15, while dermatology associations recommend a minimum SPF of 30.^{20 -23} The concentration used was over the 10% limit currently recommended by the European Commission’s SCCS. ⁶

In a 1961 experiment, 2% DHA lotion, 10% para-aminobenzoic acid (PABA) ointment, and no treatment were tested on “white” men (n = 10). ²⁴ After exposure to UVR (unknown dose), all control sites developed 4+ erythema; PABA-treated sites no erythema; whereas 6 DHA sites developed 4+ erythema, two 3+, and two 2+. ²⁴ In a second experiment, “white” men (n = 2) applied 2% DHA lotion daily for 1 week before exposure to unspecified UVR. ²⁴ All treatment and control sites developed 4+ erythema, with no histological differences observed. ²⁴

A 1987 study conducted in rats (n = unknown) measured paw edema 48 hours after exposure to UVA, in paws with pre-applied DHA (3%), different DHA analogs, or no pre-treatment. ¹⁷ After 15 minutes, rats in the no treatment group developed the same level of edema as the rats with DHA solution on their paws developed after 30 to 60 minutes. ¹⁷

In 2003, a study reported that twice-weekly application of DHA lotion (20%) to mice (n = 143) exposed to 4 standard erythema (SED) doses of UVR significantly delayed the time to the first and third cutaneous tumors when compared to the untreated control group (P = .0012, .000002 respectively), but did not prevent their appearance. ³ Results for the second tumor were not reported. ³ Results at 8 SED were unreliable since this dose resulted in skin peeling and interruption of UVR. ³ 5% DHA was nonprotective. ³

Erythropoietic Protoporphyria

In a 2023 study, FST I patients (n = 19) applied different DHA products (dose and vehicle varied) weekly during spring/summer from 2018 to 2019. ¹¹ After 1 season, 68.4% reported reduced photosensitivity and adhered to the treatment, 16% reported no effect, and 16% were unable to assess the effect. ¹¹ After 4 cycles, 11 patients (57.9%) were still adherent to the treatment and self-reported positive outcomes. ¹¹

In a 1992 experiment severely lacking in methodology transparency, EPP patients (n = 3) with initial sunlight exposure limits of 15, 20, and 200 minutes increased their tolerance to 150, 270, and 480 minutes respectively post-DHA (concentration unknown) application. ⁸

Psoriasis (PUVA)

A 1999 randomized control trial (RCT) with 24 patients with plaque psoriasis (FST II-VI, body surface area (BSA) of 20%-40%) was divided into 6 PUVA groups: American PUVA ± lactic acid, European PUVA ± DHA twice weekly (15% lotion), and turbo-PUVA (an original regimen with increments based on phototoxic protection factors) with DHA twice weekly ± lactic acid. ¹⁰ Turbo-PUVA groups experienced a statistically significant faster lesion clearance compared to American-style groups, required fewer treatments to achieve 90% resolution (P = .001) and allowed greater increases in doses, but delivered a higher mean cumulative UVA dose than American-style groups and lower or equivalent in the European-style groups (Supplemental File 1). ¹⁰

Another 2010 RCT compared American PUVA to turbo-PUVA (triple starting doses, 25% dose increases) with DHA (15% lotion) in 30 patients with plaque psoriasis (FST II-IV, ≥20% BSA). ⁹ Turbo-PUVA achieved a higher average reduction in the psoriasis area and severity index (92.16% vs 74.73%, P < .0001), required fewer mean treatments for >90% reduction (11.2 vs 30, no P calculated), delivered a lower cumulative UVA dose (188.44 J/cm² vs 255.13 J/cm², P = .0235), but had a shorter mean time to relapse (1.4 months vs 3.75 months, no p calculated). ⁹ Both studies used concentrations surpassing the 10% safety threshold recommended by the European Commission’s SCCS. ⁶

Vitiligo

In a 2021 study, a 4.2% DHA-containing cosmetic camouflage was used alongside topical corticosteroids and narrowband UVB in vitiligo patients (n = 28) with lesions in all body areas, excluding genitals and scalp. ¹³ At 12 weeks, no significant difference in repigmentation patterns, repigmentation rates or transepidermal water loss was found. ¹³ No serious adverse events were reported. ¹³

A 2008 study of unknown duration in patients (n = 20) who applied 6% DHA at non-standardized frequencies to vitiliginous areas reported a mean satisfaction score of 6.5 out of 10 (±1.97) with no adverse events. ¹² 15% of patients were unable to darken vitiliginous patches. ¹² 15% discontinued treatment due to dissatisfaction. ¹²

In a third study on patients (n = 10) with lesions on their face and/or hands, 5% DHA cream was applied “in a thin layer” overnight post-scale-removal every 2 days for 2 weeks. ¹ DHA was applied onto healthy skin borders to “blend” the browning effect. ¹ At week two, cosmetic results were satisfactory in 80% of patients, though it is unclear if this was self-reported. ¹

Carcinogenicity and Free-Radical Production

One study involved application of 0.1 mL of aqueous solution (40% DHA vs 5% DHA vs control) to mice (n = 300) once a week for 80 weeks. ²⁵ There was no significant difference in the incidence of hematological or solid malignancies. ²⁵ Furthermore, there were no observed differences in survival rates, behavior, excretion, vital signs, and dermatopathology findings. ²⁵

In 2001, mice (n = unknown) treated with a 18.2% DHA solution at inconsistent intervals for approximately 2 days exhibited a strong single line in electron spin resonance (ESR) signals, suggesting increased stable free-radical formation. ²⁶ Untreated areas and areas treated with 500mM phosphate-buffer showed no increase. ²⁶ Other DHA concentrations (0.9%-9.1%) resulted in a proportional ESR signal intensity, as did glyceraldehyde, a DHA isomer, indicating that carbohydrates in general may induce free radicals. ²⁶

Other Safety Concerns

A 2009 histopathological analysis performed on dogs (n = 3) showed that twice weekly application of 5% DHA solution led to mild to moderate irritant dermatitis by day 21 and exfoliation with necrosis and blistering by day 42. ²⁷ At 21 days browning and naturally occurring melanin granules were present in the epidermis, however they were absent at day 42. ²⁷ On both day 21 and 42, control sites showed no changes. ²⁷

In 2009, female participants (n = 3) applied DHA (9%) spray approximately weekly and received UVB (40 mJ/cm²) 3 times per week. ¹⁸ Serum 25(OH)D levels increased by 22.6 nmol/L with DHA, compared to a previous 29.9 nmol/L without DHA. ¹⁸

A 2013 study involved dermoscopic images taken before and 1 week after DHA (unknown %) application. ²⁸ After application, the number of facial solar lentigo/initial seborrhoeic keratosis (n = 15) deemed equivocal by 2 independent evaluators increased significantly (from 12% to 42%, P = .021; from 19% to 69%, P = .001). ²⁸ Follicular pigmentation, mimicking lentigo maligna, also increased significantly post-DHA (12%-81%, P < .001; 15%-69%, P < .001), leading to increased biopsy recommendations. ²⁸ Most changes disappeared 1 to 2 months post-DHA. ²⁸ There was no statistically significant difference in the evaluation of naevi on the body (n = 10). ²⁸

Discussion

This systematic review is the first to comprehensively evaluate the impact of DHA application.

Photoprotective Potential

Studies suggest that 20% DHA may provide an SPF of around 3.0 for UVB and minimal protection against UVA as a physical sunscreen.^17,19,24 However, these findings are inconsistent and limited by a lack of detailed reporting, small sample sizes (22 humans total), exclusion of FST IV to VI, and use of murine models.^17,19,24 Concentration may impact photoprotection since only studies using 20% DHA demonstrated photoprotection.^17,19,24 Other influencing factors include the UVR source (its type, distance from the skin, and exposure time), DHA formulation (ingredients, stability, vehicle composition), and application technique (applied quantity). ²⁹ Notably, 1 study used paw edema as a surrogate outcome for photoprotection instead of erythema, which does not translate into a reliable assessment of photoprotection. ¹⁷ In addition, an in vitro study indicated that DHA (3%, 5%), when combined with specific amino acids, provides minimal UV protection (SPF 2.25 ± 0.12, UVA protection 2.18 ± 0.13) and reaches 90% cumulative UVR absorbance (critical wavelength) at 384 nm. ³⁰ The controlled nature of the experiment and its narrow focus limit its relevance. ³⁰

Whereas an SPF of 3.0 theoretically blocks 67% of sun rays, to decrease the risk of developing skin cancer, Health Canada and the FDA require a minimum SPF of 15, which blocks 93% of UV rays.^20-22 A broad-spectrum water-resistant sunscreen with a minimum SPF of 30 is recommended to the Canadian public, in part due to under-application in real-life conditions compared to study conditions. ³¹ DHA’s SPF of 3.0 may explain its ability to extend EPP patients’ sun tolerance over a single exposure, while failing to provide long-term cutaneous tumor prevention.^3,8 DHA’s theoretical potential as a photoprotective product lies in its semi-permanence. DHA’s SPF decreased by 56.67% over 7 days (3.0-1.7), whereas 8 SPF UVA/UVB sunscreen decreased by 55-58% in 8 hours with physical activity and bathing, and by a factor of 55% per day without them.^19,32,33 DHA’s physical photoprotective properties, possibly similar to those offered by melanin, warrant further exploration.^{17,19,23,24,34,35} However, given its insufficient SPF, DHA should not be considered a substitute for sunscreen.^{17,19-21,24,31}

Risk Factor for Skin Cancer?

The relationship between DHA and skin cancer is complex.^3,25,26 One well-designed murine study found no evidence of DHA-induced tumorigenicity in the absence of UVR, and another suggested that 20% DHA may delay tumor development post-UVR-exposure via photoprotection.^3,25 However, a third manuscript in an unspecified sample size of mice introduced cause for caution by highlighting DHA’s role in generating stable free radicals. ²⁶ These may have been melanoidin radicals, formed through the Maillard reaction, which are unusually stable, as opposed to most highly reactive, short-lived free radicals.^{26,36 -38} Existing in vitro studies posit that, when exposed to UVR, DHA (10%, 20%, unknown%) generates increased reactive oxygen species (ROS).^39,40 DHA-induced free-radical production warrants investigation, as does mutagenicity in the presence of UVR.^3,25,26 ROS’s association with increased skin aging and cancer rates requires further investigation to ensure that industry interests do not compromise patient safety.^26,29,39-41 As of this writing, there is insufficient published evidence for dermatologists to recommend against DHA use in any patient population. Some literature suggests concerns may be addressed by adding antioxidants to DHA formulations and regulating the maximum DHA concentration permitted.^29,40,42 Notably, multiple ROS-active ingredients in topical products such as benzoyl peroxide, retinoids, and sunscreens with titanium dioxide and zinc oxide are considered safe by Health Canada.^20,43-48 Another unresolved concern is DHA’s potential to form advanced glycation products in skin, which are linked to aging and chronic diseases.^40,49,50

Systemic Absorption

While DHA’s low absorption may explain the lack of induced tumorigenicity, the extent of its absorption remains ambiguous. ²⁵ In an unpublished SCCS study, 6.25% DHA was applied to human tissue samples in a diffusion cell. ⁶ After 24 hours, 1.67% penetrated through to the receptor fluid to total a bioavailable dose of 7.22%. ⁶ In contrast, an in vitro study reported that only 0.4-0.5% of the applied DHA (in concentrations of 2.5% and 5%) was found in the receptor fluid after 24 hours. ⁵¹ The FDA’s safety threshold for systemic bioavailability in sunscreens is 0.5 ng/mL. ⁵² Based on SCCS data (1.67% penetration from 6.25% DHA), applying 25 to 30 mL of self-tanner on a 70 kg adult would potentially exceed FDA safety limits. ⁶

However, these estimates vary with usage patterns, BSA, definition of bioavailability, and DHA concentration, which can reach up to 15% in some products. ²⁹ Further studies are needed to fully assess DHA’s bioavailability and systemic effects.

Clinical Potential

Erythropoietic Protoporphyria

EPP is a rare genetic photosensitivity disorder for which traditional UV protection is insufficient. ⁵³ DHA has shown potential as a photoprotective agent, with 2 studies suggesting it may reduce photosensitivity and enhance quality of life without adverse effects.^8,11 However, evidence is limited by small sample sizes, self-reported outcomes, and methodological shortcomings, including attrition bias.^8,11

Current EPP management includes afamelanotide, a synthetic α-melanocyte-stimulating hormone (αMSH) analog that increases melanin production. ⁵⁴ Although effective, its accessibility is restricted, unlike DHA, which is widely sold and comparatively affordable.^8,11,55

Psoriasis (PUVA)

PUVA is associated with significant adverse effects, including an increased risk of nonmelanoma skin cancer. ⁵³ Both included studies showed faster lesion clearance with DHA-enhanced PUVA; however, they are limited by significant methodological biases, including lack of blinding and performance bias, and long-term follow-up.^9,10 In addition, lack of long-term safety data precludes the recommendation of DHA-modified PUVA protocols.

Vitiligo

The 3 studies reviewed indicate that DHA effectively darkens skin in vitiligo patients, achieving patient satisfaction with no reported serious adverse effects, offering a viable alternative to traditional cosmetic masking.^1,12,13 Unlike traditional products, which have to be reapplied daily, DHA-based cosmetic pigmentation is durable and was found not interfere with UVB therapy. ¹³ All studies were conducted with small sample sizes, without long-term follow-up, which limited the assessment of the treatment’s durability and sustainability.^1,12,13 Two of the 3 studies were uncontrolled.^1,12,13 No standardized outcome measures were used; 1 study relied on self-reported results, whereas another was unclear as to whether self-reporting was used, which limited interpretability.^1,12,13

Other Safety Concerns

While the well-designed study in a small sample of dogs reported contact dermatitis, in humans, only a few cases of potential allergic contact dermatitis from DHA have been documented.^27,56-60 Patch testing confirmed reactions in 4 patients, particularly with higher concentrations of DHA.^56,57 In another 4 potential cases, only 1 was positive during patch testing. ⁵⁹ One vitiligo patient who applied DHA on the arms and neck experienced irritation confined to the neck, which was not replicated in patch testing. ⁶⁰ The existing body of evidence is insufficient for dermatologists to recommend limiting the use of DHA in patients with reactive skin.

A poorly designed study with a low sample size, inadequate control of sunlight exposure, and descriptive statistical analysis suggests that DHA may partially and weakly inhibit serum 25(OH)D synthesis. ¹⁸

DHA can temporarily alter the dermatoscopy of pigmented lesions, potentially leading to misdiagnosis and unnecessary biopsies. ²⁸ Due to this study’s small sample size and exclusion of malignant lesions, its generalizability may be limited despite its robust methodology and routine questioning of patients is not yet recommended. ²⁸

Spray Tan Booths

No in vivo studies have examined DHA inhalation in spray tanning booths; however, an in vitro experiment used an airway epithelial tissue model to simulate exposure conditions. ⁶¹ DHA at concentrations encountered in spray tanning booths caused transient toxic effects such as decreased cilia function (0.4 M, 1.0 M concentrations), which normalized after 3 days, and reduced mucin component MUC5AC secretion (0.2 M, 0.4 M, 1.0 M), which normalized before 7 days. ⁶¹ Repeated exposures of DHA (1.0 M, 0.4 M) reduced matrix metalloproteinase release (MMP10, MMP13); however, levels approached baseline by the fifth weekly exposure. ⁶¹ No differences in cell morphology, apoptotic rate, or adenylate kinase production between DHA (0.2 M, 0.4 M, 1.0 M) and control groups were observed. ⁶¹

These results suggest potential respiratory risks from DHA inhalation, highlighting the need for caution and the pertinence of government regulation of spray tanning booths. ⁶¹

Future Studies

To strengthen the credibility of findings, maximize generalizability, and reduce publication bias, future studies should prioritize publicly registered multicenter RCTs with standardized intervention protocols and long-term follow-up periods. Given DHA’s widespread availability and its minimal proven health risks, large-scale human studies in controlled conditions are feasible and ethical. Though previous research conducted with high concentrations of DHA presents valuable information, new research should focus on concentrations currently available on the market, with the goal of proposing standardized concentration limits to be adopted worldwide. Future areas of interest include unresolved concerns about free radicals, ROS, and potential respiratory toxicity in spray tanning, which is unregulated in North America.

Strengths and Limitations

Strengths

This is the first systematic review on DHA’s efficacy and safety in dermatology. These findings are clinically relevant and applicable to practice, with comprehensive analysis using GRADE criteria and bias evaluation through ROBINS-I and ROB-2 tools (Supplemental Files 2, 4, 5).

Limitations

This systematic review is limited by the high risk of bias and low quality of evidence in included studies, primarily due to small sample sizes, short durations, and methodological flaws such as lack of blinding and unclear randomization, which limit generalizability. Of the human studies, 4 of 12 focused exclusively on FST I-III, and 2 of 12 included a minority of FST IV-VI patients (16.7% and 20.0% of total patients), limiting the applicability of the findings to FSTs IV-VI.^{9 -11,19,24} All other human studies did not specify included FSTs.^{1,8,12,13,18,28} Findings on photoprotection and tumorigenicity were inconsistent, likely due to differences in DHA concentration and formulation, UVR sources, application methods, and study designs. Animal models, though informative, may not fully translate to human skin responses. For comparison, human skin has a stratum corneum thickness of 10 to 20 µm, in contrast to murine skin, which is only 2 to 5 µm thick, whereas rats’ is 9 to 24 µm thick.^3,62,63 In vitro studies were excluded due to their limited clinical relevance, but their insights on oxidative stress and DNA damage remain important. DHA concentrations in reviewed studies often exceeded regulatory limits, highlighting gaps in safety assessments.

Conclusion

DHA, a widely used skin-darkening agent since the 1950s, may provide a minimal SPF of approximately 3 and slight protection to the visible and UVA light; however, it is insufficient to comply with regulatory standards required for adequate photoprotection, including Health Canada and the FDA.^{9,10,17,19-22,24,31} DHA may hold promise for patients with EPP and vitiligo due to its prolonged pigmentation effects; however, its use in PUVA is not recommended over safer psoriasis treatments due to a lack of data on long-term safety.^{1,8 -13} For clinicians, DHA may complicate the dermoscopy of pigmented lesions, which is a minor concern. ²⁸ No in vivo studies have established a link between topical DHA and severe adverse events, tumorigenicity, clinically relevant 25(OH)D insufficiency, and considerable contact dermatitis; however, its potential for increased stable free-radical production and concerns surrounding systemic absorption highlight the need for further research.^{6,18,25 -27,56 -60} The above conclusions are based on low-quality studies with many biases; to address this issue, future research should prioritize commercially available concentrations of DHA (<10%), standardized methodologies, larger RCTs, and long-term safety data to improve clinical applicability and regulatory guidance. Establishing uniform concentration limits across international markets may serve as the first step toward standardizing research to inform evidence-based clinical recommendations.

Data Availability Statement

This systematic review is registered in the PROSPERO international prospective register of systematic reviews.