Red Light Therapy for Leishmaniasis: A Professional Analysis of Photodynamic and Photobiomodulation Approaches

Cutaneous leishmaniasis (CL) remains a neglected parasitic disease with significant global morbidity, particularly in endemic regions across South America, Asia, and Africa. Conventional treatments, including pentavalent antimonials and miltefosine, present challenges ranging from parenteral administration and toxicity to emerging drug resistance. Red light therapy—encompassing both photodynamic therapy (PDT) and low-level laser therapy (LLLT)—has emerged as a non-invasive investigational approach for CL management. This article provides a professional, evidence-based review of red light therapy’s mechanisms, clinical evidence, and comparative efficacy against standard treatments, drawing from peer-reviewed literature including systematic reviews, in vitro studies, and clinical trials.

Introduction

Cutaneous leishmaniasis, caused by protozoan parasites of the genus Leishmania, manifests as chronic ulcerative skin lesions that can lead to permanent disfiguring scars. With over 90 countries reporting endemic transmission, the disease burden is substantial, yet treatment options remain limited . Conventional therapies, while effective in many cases, are complicated by painful injections, systemic toxicity, and the increasing emergence of drug-resistant strains .

Red light therapy has garnered attention in recent years as a potential alternative, operating through two distinct mechanisms: photodynamic therapy (PDT), which uses a photosensitizing agent activated by red light to generate reactive oxygen species (ROS), and photobiomodulation (PBM) , which uses red or near-infrared light to stimulate cellular repair processes. Understanding the distinction between these modalities is essential for clinicians evaluating therapeutic options.

Mechanistic Foundations

Photodynamic Therapy: Targeted Parasite Destruction

PDT relies on three components: a photosensitizer (PS), a light source of appropriate wavelength, and molecular oxygen. Upon activation by red light (typically 630–660 nm), the PS transfers energy to oxygen molecules, generating ROS—particularly singlet oxygen and superoxide anions—that oxidize cellular biomolecules including lipids, proteins, and DNA .

Leishmania parasites are uniquely susceptible to this oxidative assault. Unlike mammalian cells, they lack glutathione/glutathione reductase and catalase systems, relying instead on the trypanothione/trypanothione reductase system for antioxidant defense. This metabolic vulnerability makes them particularly sensitive to ROS-mediated damage . Furthermore, PDT generates oxidative stress through multiple pathways, theoretically preventing the selection of resistant strains—a significant advantage over conventional monotherapies .

Photobiomodulation: Immunomodulatory Effects

Low-level laser therapy (LLLT), in contrast, does not use photosensitizers. Instead, red or near-infrared light is absorbed by cytochrome c oxidase in mitochondria, increasing ATP production and modulating inflammatory pathways. Studies have demonstrated reduced pro-inflammatory cytokine expression and enhanced regulation of immune responses, creating a more favorable environment for wound healing .

However, the evidence for LLLT’s direct antiparasitic effect is less robust. One quasi-experimental study found that LLLT did not significantly alter parasite viability in vitro, suggesting its primary benefit may be in wound healing rather than parasite clearance .

Key Research Findings

Systematic Review Evidence

A systematic review published in Lasers in Medical Science (2024) evaluated 21 studies involving 304 patients with CL treated with PDT. The review, which included two randomized controlled trials, four open-label single-center studies, one case series, and 14 case reports, concluded that PDT is both effective and safe for CL treatment, with mild and transient side effects including pain, burning, erythema, and pigmentary changes .

In Vitro Efficacy Against Drug-Resistant Strains

Cabral et al. (2023) investigated red LED-mediated PDT with methylene blue against wild-type and miltefosine-resistant Leishmania amazonensis. Both strains demonstrated susceptibility to PDT, supporting its potential as a strategy to overcome drug resistance .

Novel Photosensitizers

Recent research has expanded the photosensitizer repertoire:

Temoporfin-mediated PDT: Çalışkan et al. (2025) demonstrated that temoporfin combined with red light (1.71 J/cm²) significantly reduced L. tropica promastigote viability, with an IC50 of 1.924 μM. Neither component alone had significant effect at this concentration. Molecular docking analysis revealed binding affinities comparable to amphotericin B .

Ruthenium-based derivatives: Studies by the NIH (2025) showed that novel ruthenium-complexed photosensitizers (NMB-B and NMB-P) produced significant ROS increases (up to 4.67-fold higher than controls) with IC50 values 4- to 9-fold lower than miltefosine, demonstrating enhanced potency .

Indocyanine green nanomicelles: Jalili et al. (2025) demonstrated synergistic PDT/PTT effects against L. major using ICG-loaded nanomicelles and 808 nm laser irradiation, significantly reducing lesion size in mouse models .

Clinical Outcomes

The systematic review reported complete resolution of lesions across diverse patient populations (ages 1–82 years), with 3–28 PDT sessions administered and follow-up periods ranging from 4 weeks to 24 months. Lesions were predominantly located on exposed areas including face, limbs, neck, ears, and nose, characterized by plaques, papules, erythema, and ulcerations .

Comparative Analysis: PDT vs. Conventional Treatments

Parameter	Red Light PDT	Conventional Antimonials	Miltefosine
Administration	Topical PS + non-invasive light	Intralesional or IV injections	Oral
Treatment Duration	3–28 sessions typically	Prolonged courses	Weeks to months
Key Side Effects	Pain, erythema, pigmentary changes (mild, transient)	Cardiotoxicity, hepatotoxicity, pancreatitis	GI disturbances, teratogenicity
Resistance Profile	Multi-target ROS mechanism (resistance less likely)	Increasing reports of resistance	Emerging resistance documented
Cosmetic Outcome	Favorable (minimal scarring)	Variable, often significant scarring	Variable
Accessibility	Requires specialized equipment	Widely available in endemic areas	Variable

Important Distinction: PDT vs. Low-Level Laser Therapy (LLLT)

A critical nuance in interpreting the literature is the distinction between PDT and LLLT. Studies using PDT (photosensitizer + light) consistently demonstrate antileishmanial activity . However, LLLT alone (without photosensitizer) has shown mixed or negative results.

A double-blind, quasi-experimental study by Scarcella et al. (2023) involving 7 patients with CL found no statistically significant difference in lesion healing between the LLLT group and standard care group . The authors concluded that low-level laser therapy does not appear to improve cutaneous leishmaniasis lesion healing. Similarly, in vitro testing showed LLLT alone had no significant effect on promoting programmed cell death of parasites .

This distinction is clinically significant: PDT is the photodynamic modality with demonstrated antiparasitic efficacy, while LLLT appears to have limited direct effect on Leishmania and should not be equated with PDT in clinical decision-making.

Clinical Considerations

Advantages of Red Light PDT

Non-invasive: Topical application of photosensitizer followed by light exposure
Outpatient procedure: Can be performed in clinical settings
Favorable safety profile: Mild, transient side effects
Potential for resistant infections: Multi-target mechanism
Cosmetic outcomes: Superior scar appearance

Limitations

Equipment requirements: Specialized light sources and photosensitizers
Cost: Photosensitizer availability in endemic regions
Light penetration: Limited depth, may be less effective for deep lesions
Pain: Some patients experience discomfort during irradiation
Standardization: Protocols vary across studies

Future Directions

The literature remains in early stages, with limited high-quality human trials. Ongoing needs include:

Larger randomized controlled trials: Comparing PDT to standard care
Protocol standardization: Photosensitizer choice, light dose, and treatment frequency
Amastigote studies: Most research focuses on promastigotes; clinical efficacy depends on amastigote inactivation
Combination therapy: Potential synergy with conventional drugs
Cost-effectiveness analysis: Particularly relevant for endemic regions

Conclusion

Red light photodynamic therapy represents a promising, non-invasive alternative for cutaneous leishmaniasis, particularly in the context of emerging drug resistance. The systematic review evidence supports its efficacy and safety, with mild and transient side effects. However, clinicians must recognize that PDT (with photosensitizer) and LLLT (without photosensitizer) are distinct modalities, and the evidence for LLLT alone in treating CL is insufficient.

As research continues, PDT may become an increasingly valuable tool in the dermatologist’s armamentarium for this neglected tropical disease, though further high-quality studies are required to establish standardized protocols and compare long-term outcomes with conventional therapy.

References

Ullah N, Sagar M, Abidin ZU, et al. Photodynamic therapy in management of cutaneous leishmaniasis: A systematic review. Lasers Med Sci. 2024;39(1):226.
Cabral FV, Yoshimura TM, da Silva DF, et al. Photodynamic therapy mediated by a red LED and methylene blue inactivates resistant Leishmania amazonensis. J Opt Soc Am A. 2023;40(5):996-1005.
Çalışkan M, et al. The Effects of Temoporfin-Mediated Photodynamic Inactivation on Leishmania tropica Promastigotes and Molecular Docking Analysis. Mikrobiyol Bul. 2025;59(1):57-70.
Scarcella MFS, Silva CSO, Barbosa AX, et al. The use of low-level laser therapy in the treatment of cutaneous leishmaniasis: a quasi-experimental study. Online Braz J Nurs. 2023;22(suppl 2).
Light, Dyes, and Action: Photodynamic Inactivation of Leishmania amazonensis Using Methylene Blue, New Methylene Blue, and Novel Ruthenium-Based Derivatives. Biology. 2025;14(12):1710.
Jalili S, et al. In vitro and in vivo evaluation of photo-induced antileishmanial activity of indocyanine green-loaded nanomicelles. Iran J Basic Med Sci. 2025.