Support compounds

Adapalene (Differin)

Updated · 30 sources · Editorial policy

Adapalene is a topical retinoid, a vitamin A–related drug applied to the skin to treat acne. Galderma sells it as Differin. The FDA first approved Differin Gel 0.1% as a prescription drug in 1996, and on July 8, 2016 approved the same 0.1% gel for over-the-counter (OTC) sale. A stronger 0.3% gel remains prescription-only.

It appears in an anabolic steroid library because acne is one of the most common visible side effects of anabolic-androgenic steroids (AAS). The single most important fact is that adapalene has been tested in large trials of ordinary acne, not in people using steroids. We found no published trial of adapalene in steroid-related acne, so its use there rests on general acne evidence.

This page summarizes what the FDA labels, clinical trials and published reviews report. It is for education only and is not medical advice.

Property Detail
Drug class Topical retinoid (naphthoic acid derivative)
Single-ingredient products Differin Gel 0.1%: approved 1996, OTC since 2016. Differin Gel 0.3%: approved 2007, prescription only
Combination products With benzoyl peroxide (Epiduo, Epiduo Forte, Differin Epiduo Acne Gel) and with clindamycin plus benzoyl peroxide (Cabtreo)
Route and labeled use Thin layer on affected skin once daily, ages 12 and older
Half-life (0.3% gel label) Mean 17.2 h (range 7–51 h) after 2 g/day on face, chest and back; usually undetectable in blood at normal use
Mechanism Binds retinoic acid receptors (RAR-β and RAR-γ) in the cell nucleus; does not bind the cytosolic retinoic acid binding protein
Main side effect Local irritation: redness, scaling, dryness, stinging, mostly in the first 4 weeks
US status 0.1% gel OTC; 0.3% gel prescription; not a controlled substance
WADA status Not named on the 2026 Prohibited List

What it is

Adapalene’s chemical name is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid: formula C₂₈H₂₈O₃, molecular weight 412.53 (Differin Gel 0.3% label). Unlike tretinoin (all-trans retinoic acid), it is not built on the flexible vitamin A chain. It has rigid aromatic rings instead, which is why it is grouped with tazarotene and bexarotene as a “third-generation” retinoid (Williams et al., Birth Defects Res 2020).

Galderma’s researchers designed it for chemical stability and better skin tolerance than tretinoin. In laboratory binding and transactivation assays, its retinoid activity ran through two nuclear receptors, RAR-β and RAR-γ, and it also showed anti-inflammatory activity (Shroot and Michel, JAAD 1997).

The FDA label describes the mechanism more cautiously. Adapalene binds specific retinoic acid nuclear receptors and modulates how skin cells differentiate and form keratin (the process that can plug pores), and it modulates inflammation. The label adds that how these effects translate into acne improvement is unknown (Differin Gel 0.3% label).

How it compares with the other acne drugs on this site

Drug Route How it works US access
Adapalene Topical Retinoid: modulates skin-cell differentiation and keratinization; anti-inflammatory 0.1% OTC; 0.3% Rx
Isotretinoin (Accutane) Oral Retinoid: shrinks the oil glands Rx only, through the iPLEDGE program
Clascoterone (Winlevi) Topical Blocks androgen receptors in the skin Rx only

How it works in the body

Very little topically applied adapalene reaches the blood. The Differin Gel 0.3% label reports two studies (label):

Study Exposure Blood levels
16 acne patients, 2 g/day of 0.3% gel on face, chest and back for 10 days High-exposure test (≈2 mg/cm²) 15 of 16 had measurable levels; mean peak 0.553 ng/mL; mean AUC 8.37 ng·h/mL; half-life 7–51 h (mean 17.2 h); not detectable 72 h after the last dose in all but one person
78 patients on 0.3% or 0.1% gel for 12 weeks (average 1 g/day) Ordinary use, face with or without trunk 206 of 209 samples below detection (0.15 ng/mL); 3 samples showed only traces

Excretion appears to be mainly through the bile. With the 0.3%/2.5% benzoyl peroxide combination at ≈2.3 g/day for 4 weeks in severe acne, 62% of patients had measurable adapalene, with a mean peak of 0.16 ng/mL (Epiduo Forte label).

Approved medical use

US products and approval history

All adapalene products are approved for acne vulgaris in people 12 years and older.

Product Strength Approved Status
Differin Gel (NDA 020380) Adapalene 0.1% May 31, 1996 Switched from Rx to OTC on July 8, 2016
Differin Gel 0.3% (NDA 021753) Adapalene 0.3% June 19, 2007 Prescription
Epiduo (NDA 022320) Adapalene 0.1% + benzoyl peroxide 2.5% December 8, 2008 Prescription product now listed as discontinued
Epiduo Forte (NDA 207917) Adapalene 0.3% + benzoyl peroxide 2.5% July 15, 2015 Prescription
Cabtreo (NDA 216632) Clindamycin 1.2% + adapalene 0.15% + benzoyl peroxide 3.1% October 20, 2023 Prescription
Differin Epiduo Acne Gel (NDA 220736) Adapalene 0.1% + benzoyl peroxide 2.5% May 22, 2026 OTC (partial Rx-to-OTC switch)

Until 2016, all topical retinoids in the US were prescription-only (Weiss et al., J Drugs Dermatol 2021). The 2026 OTC carton for Differin Epiduo Acne Gel describes it as the first FDA-approved OTC acne treatment with two active ingredients (Differin Epiduo Acne Gel label).

Labeled directions

  • OTC 0.1% gel (Drug Facts): once daily, a thin layer over the entire affected area (for example the whole face), not as a spot treatment. Applying more often “will not provide faster or better results” but may worsen irritation. Results may take up to 3 months; the label says to stop and ask a doctor if there is no improvement by then (Differin Gel 0.1% Drug Facts).
  • Rx 0.3% gel: a thin film once daily in the evening after gentle washing, avoiding the eyes, lips and mucous membranes; re-evaluate if there is no result after 12 weeks (label).
  • Combinations with benzoyl peroxide: applied once daily; benzoyl peroxide can bleach hair and colored fabrics (Epiduo Forte label).

The American Academy of Dermatology’s 2024 guideline gives topical retinoids, along with benzoyl peroxide, a strong recommendation for acne, and recommends combining topical treatments with different mechanisms as good practice (Reynolds et al., JAAD 2024).

What the research shows

Adapalene vs tretinoin

The comparisons below were mostly in mild-to-moderate acne; one was an irritation study in healthy volunteers.

Comparison Design and size Main finding
Adapalene 0.1% gel vs tretinoin 0.025% gel (Cunliffe et al., Br J Dermatol 1998) Meta-analysis of 5 multicenter, randomized, investigator-blinded trials; 900 patients (450 per arm) Equivalent reduction in total lesion count; faster response at week 1; better local tolerability at every visit
Adapalene 0.1% gel vs tretinoin 0.025% gel in China (Tu et al., JEADV 2001) Randomized, 150 patients, 8 weeks Both reduced lesion counts by ≈69–74%; over 70% in each arm cleared or markedly improved; irritation more common and more severe with tretinoin
Adapalene 0.1% gel vs tretinoin microsphere 0.1% gel (Thiboutot et al., Cutis 2001) Randomized, investigator-masked, 168 patients, 12 weeks Comparable efficacy and onset; significantly better tolerability and fewer treatment-related adverse events with adapalene
Adapalene 0.1% gel vs tretinoin 0.025% gel (Goh et al., J Dermatolog Treat 2009) Healthy volunteers, split-application irritation test, 21 days on the face Adapalene significantly less irritating in all ethnic groups tested

A 2025 network meta-analysis of 35 randomized trials (33,472 participants) of topical treatments for mild-to-moderate acne found no significant difference between most single agents in lesion-count reduction. The adapalene–benzoyl peroxide combination was among the most effective options compared with placebo, for example a ratio of means of 1.67 (95% CI 1.47–1.90) for total lesion reduction (Kakpovbia et al., JEADV 2025).

0.3% vs 0.1%

The 0.3% gel was approved on one 12-week, double-blind trial of 653 people aged 12–52 with mild-to-moderate acne, randomized 2:2:1 (Thiboutot et al., JAAD 2006; label):

Week 12 outcome Adapalene 0.3% (n = 258) Adapalene 0.1% (n = 261) Vehicle (n = 134)
“Clear” or “almost clear” 21% 16% 9%
Inflammatory lesions −51.6% −49.7% −40.7%
Non-inflammatory lesions −39.7% −35.2% −27.2%
Total lesions −45.3% −41.8% −33.7%

The trial authors reported a consistent dose-dependent effect, with 0.3% significantly better than 0.1% and vehicle. In absolute terms the gain over 0.1% was modest: 5 percentage points more patients reached clear or almost clear.

Combinations with benzoyl peroxide

Benzoyl peroxide is an oxidizing agent with bactericidal (bacteria-killing) and keratolytic (peeling) effects (Epiduo Forte label). In a 12-week trial, 517 people were randomized to adapalene 0.1%–benzoyl peroxide 2.5%, either drug alone, or vehicle. The combination was significantly more effective than either drug alone, with differences in total lesion counts from week 1, and its tolerability was similar to adapalene alone (Thiboutot et al., JAAD 2007).

The higher-strength combination was tested in 503 people with moderate or severe acne (Epiduo Forte label):

Week 12 outcome Adapalene 0.3%/BPO 2.5% (n = 217) Adapalene 0.1%/BPO 2.5% (n = 217) Vehicle (n = 69)
Two-grade improvement and clear or almost clear 33.7% 27.3% 11.0%
Inflammatory lesions −68.7% −69.3% −39.2%
Non-inflammatory lesions −68.3% −68.0% −37.4%

The label notes this trial was not designed to compare the two strengths with each other.

Acne associated with anabolic steroid use

Androgens enlarge the oil glands and increase oil output, and acne is a well-documented effect of steroid use:

  • Skin changes: skin biopsies from AAS users show marked enlargement of the sebaceous (oil) glands. High androgen doses raise skin surface lipids and the skin population of acne bacteria (Scott and Scott, Cutis 1992).
  • How common: a German dermatology review estimated that acne occurs in about 50% of AAS users and called it an important clinical sign of use in men aged 18–26. AAS can trigger severe forms such as acne conglobata and acne fulminans (Melnik et al., JDDG 2007).
  • Prospective data: in the Dutch HAARLEM study, which followed 100 men through a self-chosen steroid cycle, clinicians observed acne in 28%. One year after the cycle started, the prevalence of observed effects had returned to baseline (Smit et al., Scand J Med Sci Sports 2021).
  • Prescribed testosterone: a 2026 scoping review of 38 studies in transmasculine patients on testosterone found acne rates of 29.6–61.9%, depending on how acne was measured. Testosterone dose and route were not associated with acne, but younger age was (Seibert et al., JAMA Dermatol 2026).

No trial has tested adapalene in steroid-related acne. We searched PubMed for adapalene combined with anabolic steroids, testosterone, bodybuilding and transgender patients and found no clinical trial. Adapalene is not an androgen blocker: its labeled mechanism involves skin-cell differentiation, keratinization and inflammation, not the hormonal driver itself. Severe, scarring or nodular forms linked to steroids, such as acne fulminans, also fall outside the mild-to-moderate acne in which adapalene was mostly studied. For acne that is severe, scarring or not responding to standard therapy, the AAD guideline strongly recommends oral isotretinoin (Reynolds et al., JAAD 2024). Clascoterone, a topical androgen receptor blocker, has also not been tested in steroid users (clascoterone page).

Side effects and risks

Skin irritation

Irritation is the main side effect. In the 0.3% gel trial, physicians recorded these reactions as worse than at baseline in 253 patients (Differin Gel 0.3% label):

Reaction Mild Moderate Severe
Erythema (redness) 26.1% 13.0% 0.4%
Scaling 43.5% 18.6% 1.2%
Dryness 44.7% 17.0% 0.8%
Burning or stinging 28.5% 14.2% 3.6%

These reactions were most likely in the first 4 weeks, were mostly mild to moderate, and usually lessened with continued use. A one-year open-label study of 551 people showed the same pattern. The OTC Drug Facts add that acne may appear to worsen in the early weeks before it improves.

The labels list ways to reduce irritation and situations to avoid:

  • use a moisturizer, and avoid moisturizers with alpha hydroxy or glycolic acids;
  • apply less often or stop if irritation becomes severe;
  • do not apply to cuts, abrasions, eczema or sunburned skin;
  • do not wax treated skin, because of the risk of skin erosions;
  • use caution with other drying or irritating products, such as medicated or abrasive cleansers and high-alcohol astringents.

Sun sensitivity

The labels advise limiting sun and tanning-bed exposure and using sunscreen and protective clothing. Wind and cold may also irritate treated skin.

Allergic reactions

Post-marketing reports include anaphylaxis, angioedema (deep swelling), facial and eyelid swelling and lip swelling, sometimes needing medical treatment. Known allergy to adapalene or any ingredient is the only contraindication on the 0.3% gel label (label). Cabtreo, because it contains clindamycin, is also contraindicated with a history of regional enteritis, ulcerative colitis or antibiotic-associated colitis (Cabtreo label).

Pregnancy and breastfeeding

Oral retinoids such as isotretinoin cause severe birth defects. The evidence for topical adapalene is much more limited:

  • Label: human data are insufficient to establish a drug-associated risk. Given by mouth to pregnant rats and rabbits at ≥25 mg/kg/day (40 and 81 times the maximum human dose), adapalene caused malformations including cleft palate and skeletal and kidney abnormalities. Applied to the skin of rats and rabbits at up to 6.0 mg/kg/day, it caused no fetal toxicity and only minor skeletal variations (Differin Gel 0.3% label).
  • OTC Drug Facts: ask a doctor before use if pregnant or breastfeeding, and stop and ask a doctor if you become pregnant or plan to while using it (Drug Facts).
  • Case report: a 1997 letter described anophthalmia (absent eye) and agenesis of the optic chiasm in a baby exposed to adapalene gel in early pregnancy (Autret et al., Lancet 1997). A single case cannot show causation.
  • Pooled data: a 2015 meta-analysis of topical retinoids as a class (654 exposed and 1,375 unexposed pregnancies) found no significant rise in major malformations (OR 1.22, 95% CI 0.65–2.29) or miscarriage (OR 1.02, 95% CI 0.64–1.63). The authors said it was too small to justify use in pregnancy (Kaplan et al., Br J Dermatol 2015).
  • OTC switch review: a safety review prepared for the OTC switch calculated a margin of safety of 70 for teratogenicity and found no malformations attributable to topical adapalene in safety databases. It noted that animal studies do not always predict human effects and that voluntary reports are incomplete (Weiss et al., J Drugs Dermatol 2021).

A 2020 teratology review concluded that the data offer some reassurance after accidental exposure, but recommended avoiding topical retinoids in pregnancy because epidemiologic data are scarce (Williams et al., Birth Defects Res 2020).

For breastfeeding, there are no human milk data. The label advises using the smallest area for the shortest time and avoiding areas where the infant could ingest it or get it in the eyes.

Overdose and systemic effects

Systemic effects are not expected at labeled topical use, given the very low blood levels above. The label states that chronic ingestion could cause the same effects as excess vitamin A.

  • United States: the 0.1% gel and the 0.1%/2.5% benzoyl peroxide gel are sold OTC; the 0.3% gel, Epiduo Forte and Cabtreo require a prescription. Adapalene is not an anabolic steroid and is not listed in Schedule III (21 CFR 1308.13).
  • Sport: adapalene and other retinoids are not named on the WADA 2026 Prohibited List.

Key takeaways

  • A topical retinoid, OTC since 2016. Differin Gel 0.1% was approved by prescription in 1996 and switched to OTC in 2016; the 0.3% gel remains prescription-only, and a 0.1% adapalene–benzoyl peroxide gel was approved for OTC sale in May 2026.
  • As effective as tretinoin, and gentler. A meta-analysis of 5 trials in 900 patients found equal efficacy to tretinoin 0.025% gel with better tolerability; trials against other tretinoin forms agreed.
  • Combinations work better. Adding benzoyl peroxide improved results over either drug alone, and adapalene–benzoyl peroxide ranked among the most effective topical options in a 2025 network meta-analysis.
  • Irritation is expected early. Redness, scaling, dryness and stinging are common in the first 4 weeks and usually fade; sun sensitivity and waxing injuries are labeled risks.
  • Pregnancy data are limited. Oral doses caused malformations in animals; human data on topical use are reassuring but too small to rule out risk, and reviews advise avoiding it in pregnancy.
  • Not tested in steroid acne. Acne affects roughly a quarter to a half of AAS users in published studies, but no trial has tested adapalene in this group, and it is not an androgen blocker.

Sources

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