Hurdles in Melasma Management: An AI-Assisted Review of Placebo- and Hydroquinone-Controlled Clinical Studies (2014–2024)

Melasma is a chronic hyperpigmentation disorder that significantly impacts quality of life. Given the persistent challenges in melasma management, there is a need to evaluate therapies that may offer long-term treatment. This review analyzes placebo- and hydroquinone (HQ)-controlled interventional studies of melasma published between January 1, 2014, and December 31, 2024. Screening, data extraction, and discussion synthesis were performed with artificial intelligence assistance under human oversight. Treatments were grouped into five categories: HQ-based Standard Treatments, Isolated Molecules as Depigmenting Therapies, Botanical and Antioxidant-Based Therapies, Regenerative and Microenvironment-Modulating Therapies, and Procedure-Assisted and Combination Treatments. HQ remained a key benchmark, although recurrence and tolerability limitations were frequently observed. Several non-HQ or adjunctive approaches demonstrated benefit when administered orally, topically, intradermally, or via iontophoresis. Botanical antioxidants, synbiotics, epidermal growth factor, and platelet-rich plasma also showed promising efficacy. Nevertheless, the evidence base was constrained by small sample sizes, heterogeneous comparators, inconsistent endpoints, mixed objective and subjective assessments, and variable follow-up durations, which prevented meta-analysis. Research on melasma treatment is growing worldwide, with several promising non-HQ and adjunctive strategies emerging. However, standardization of outcomes, comparator selection, and longer follow-up periods is needed to clarify efficacy, tolerability, and relapse prevention throughout diverse skin tones.