A novel technology in ophthalmology, photobiomodulation (PBM) is the medical application of light therapy, which has been investigated for retinal diseases including age-related macular degeneration (AMD) and diabetic retinopathy (DR).¹ Beyond ophthalmology, PBM has also been studied in cardiology and neurology for its tissue-repairing effects.² Photobiomodulation uses wavelengths of near-infrared and visible light to stimulate tissue repair at the cellular level. It targets mitochondrial proteins, specifically activating cytochrome c oxidase, which in turn increases the production of adenosine triphosphate.³ As a result, harmful reactive oxygen species are reduced, and there is increased antioxidant stability. The Valeda Light Delivery System (Alcon) is the first PBM device authorized by the US Food and Drug Administration for early-to-intermediate nonexudative AMD to improve visual acuity.^4-7 The Valeda system uses 3 specific wavelengths of light: yellow (590 nm), red (660 nm), and near-infrared (850 nm).

The LIGHTSITE III clinical trial enrolled 100 patients (148 eyes) with early-to-intermediate dry AMD in a prospective, double-masked, randomized, sham-controlled study. The study met the predetermined primary efficacy endpoint at month 21.^4-7 More than 60% of PBM-treated patients experienced improvement of ≥1 line of vision at about 2 years compared to baseline.^4-7

Candidates for Photobiomodulation

Clinical evidence from LIGHTSITE demonstrated visual acuity benefits from PBM in eyes with intermediate AMD.^4-7 The randomized clinical trials showed statistically significant improvements in best-corrected visual acuity (BCVA) in the PBM-treated eyes compared to active sham-treated eyes. Furthermore, a post-hoc analysis showed a slower rate of progression to geographic atrophy in PBM-treated eyes.^4-7 Based on these findings, eyes with intermediate AMD (presence of medium or large drusen without advanced AMD) may be candidates for PBM. The LIGHTSITE III clinical trial did not evaluate the efficacy of PBM in eyes with advanced AMD (presence of choroidal neovascularization or geographic atrophy involving the foveal center); therefore, it is not known if PBM is beneficial in eyes with advanced AMD.

Pretreatment Evaluation

To evaluate whether a patient is a candidate for PBM, a thorough pretreatment assessment is required to establish the diagnosis of intermediate dry AMD and obtain baseline measurements to monitor treatment response. With the help of a comprehensive ophthalmic exam complemented with multimodal imaging, the underlying retinal pathology should be confirmed to ensure that PBM therapy may be effective in a specific patient.⁶

The pretreatment evaluation should include visual acuity, structural imaging such as optical coherence tomography (OCT), fundus photography, and fundus autofluorescence. If clinically indicated, OCT angiography and fluorescein angiography may also be performed.

Treatment and Delivery Considerations

Multiwavelength PBM is administered in the outpatient clinic setting. Photobiomodulation is noninvasive, takes approximately 4 minutes per eye, and does not require pupillary dilation or topical anesthesia. In the LIGHTSITE III trial for AMD, 1 treatment course consists of 9 applications of PBM over a 3 to 5 week period. Typically, 2 to 3 applications of PBM may be performed per week. This treatment course is repeated 3 times per year, and the LIGHTSITE III trial treated eligible eyes for a 2-year period.^5,6 Because AMD is a chronic condition, it is likely that ongoing PBM treatment may be needed to maintain the benefits. The LIGHTSITE IIIB study was an open-label extension study that enrolled 36 patients (63 eyes).⁸

Monitoring and Follow-Up 

Regular follow-up allows clinicians to evaluate treatment response, monitor disease progression, and identify adverse events. Thorough periodic ophthalmic examinations should be performed with BCVA as well as OCT imaging to assess changes in vision and retinal architecture relative to baseline, specifically after every treatment cycle. Missed treatment sessions should be documented and adherence assessed before proceeding with subsequent treatment cycles. Of note, in AMD, it is critical to monitor conversion to neovascularization, because PBM does not replace established therapies such as antivascular endothelial growth factor (antiVEGF) treatment in such patients. Ongoing discussions with the patient also allow the provider to identify whether there is improvement in quality of life while helping guide expectations and patient satisfaction.

Safety Considerations

Preclinical and clinical ophthalmic studies have indicated that PBM has a satisfactory safety profile. Unlike conventional retinal laser treatments such as photocoagulation, which rely on photothermal tissue destruction, PBM uses low-intensity red-to-near-infrared light and operates via photochemical mechanisms.¹ As a result, PBM does not apply thermal burn to the retina. In the LIGHTSITE III clinical trial, PBM was well tolerated with no reported serious adverse events related to the light therapy and no reported cases of phototoxicity.^5,6 Twelve eyes (12.9%) in the PBM group and 4 eyes (7.3%) in the sham group had a fellow eye that developed neovascular AMD (nAMD). Of these, 5 (41.7%) of the 12 eyes in the PBM-treated group converted to nAMD, and 1 (25.0%) of the 4 eyes in the sham group converted to nAMD.^5,6 Additional real-world data will help retina specialists and ophthalmologists evaluate the safety of PBM with larger sample sizes.

Integrating Photobiomodulation Into Clinical Practice

As a noninvasive therapeutic approach for dry AMD, PBM is increasingly being used in retinal practice. Photobiomodulation may be an appealing treatment approach for patients with intermediate AMD, which has typically been treated with AREDS 2 Preservision vitamins and observation. Photobiomodulation supports the growing therapeutic focus on addressing underlying disease biology rather than just treating disease manifestations by increasing mitochondrial activity and fostering cellular resilience. As a result, PBM is showing promise as an adjunctive treatment for retinal disorders.^9,10

Careful patient selection, adherence to established treatment protocols, and suitable clinician training are necessary for the successful integration of PBM into standard retinal care. According to available data, patients may benefit most from treatment if they have early-to-intermediate stages of retinal disease. ¹¹

A crucial part of implementing PBM is patient counselling. Physicians may emphasize that PBM is a disease-modifying intervention meant to enhance visual function and possibly slow the progression of the disease rather than a curative treatment. Reasonable expectations should be set, as individual responses to treatment vary and long-term efficacy data remain limited. It is anticipated that ongoing research will improve patient selection criteria, enhance treatment protocols, and increase long-term safety and efficacy data.^10,12

Current Challenges and Future Directions

Even though multiwavelength PBM is an FDA-authorized device, several obstacles still prevent it from being widely used in clinical settings. The evaluation of long-term efficacy, durability of response, and safety has been limited by the inclusion of relatively small patient cohorts with 24-month follow-up in the original LIGHTSITE III trial. Although nonexudative AMD currently has the strongest evidence, there are still significant unanswered questions about the long-term clinical impact, generalizability of reported outcomes, and best long-term maintenance treatment schedules.^10,13 Further validation in larger clinical trials would provide additional information on the efficacy and safety of PBM.

Conclusion

Photobiomodulation has emerged as a promising noninvasive therapeutic approach for dry AMD because of its ability to enhance mitochondrial function, improve cellular bioenergetics, reduce oxidative stress, and promote retinal cell survival. A growing body of preclinical evidence has demonstrated neuroprotective and regenerative effects. The LIGHTSITE III randomized clinical trial has provided initial efficacy and safety data for the use of PBM in dry AMD, and these results led to FDA authorization of this device. Retina specialists and ophthalmologists should be knowledgeable about the efficacy and safety of PBM in order to determine if this treatment modality may be appropriate for select patients with dry AMD.

References

1. Geneva II. Photobiomodulation for the treatment of retinal diseases: a review. Int J Ophthalmol. 2016;9(1):145-152. doi:10.18240/ijo.2016.01.24

2. Yoon SR, Hong N, Lee MY, Ahn JC. Photobiomodulation with a 660-nanometer light-emitting diode promotes cell proliferation in astrocyte culture. Cells. 2021;10(7):1664. doi: 10.3390/cells10071664  

3. Gopalakrishnan S, Mehrvar S, Maleki S, et al. Photobiomodulation preserves mitochondrial redox state and is retinoprotective in a rodent model of retinitis pigmentosa. Sci Rep. 2020;10(1):20382. doi:10.1038/s41598-020-77290-w

4. Burton B, Parodi MB, Jürgens I, et al. LIGHTSITE II randomized multicenter trial: evaluation of multiwavelength photobiomodulation in nonexudative age-related macular degeneration. Ophthalmol Ther. 2023;12(2):953-968. doi:10.1007/s40123-022-00640-6

5. Boyer D, Hu A, Warrow D, et al. LIGHTSITE III: 13-month efficacy and safety evaluation of multiwavelength photobiomodulation in nonexudative (dry) age-related macular degeneration using the lumithera valeda light delivery system. Retina. 2024 March 1;44(3):487-497. doi:10.1097/IAE.0000000000003980

6. Munk MR, Gonzalez V, Boyer DS, et al. 24-month analysis: evaluation of multiwavelength photobiomodulation in dry age-related macular degeneration using the Lumithera Valeda light delivery system [abstract]. Invest Ophthalmol Vis Sci. 2023;64(8):5059. https://iovs.arvojournals.org/article.aspx?articleid=2791103

7. Valter K, Tedford SE, Eells JT, Tedford CE. Photobiomodulation use in ophthalmology – an overview of translational research from bench to bedside. Front Ophthalmol. 2024 Aug 15;4:1388602. doi:10.3389/fopht.2024.1388602

8. Koss M, LIGHTSITE III Study Group. LIGHTSITE IIIB: an open-label, prospective, multi-center extension study to assess the long-term safety and efficacy of photobiomodulation in subjects with dry age-related macular degeneration. Paper presented at: Internationaler Kongress der Deutschen Ophthalmochirurgie; May 15-17, 2025; Nürnberg, Germany. doi:10.3205/25doc010

9. Fantaguzzi F, Tombolini B, Servillo A, Zucchiatti I, Sacconi R, Bandello F, Querques G. Shedding light on photobiomodulation therapy for age-related macular degeneration: a narrative review. Ophthalmol Ther. 2023 Dec;12(6):2903-2915. doi:10.1007/s40123-023-00812-y

10. Cannas C, Pintus B, Corgiolu L, et al. Current applications and future perspectives of photobiomodulation in ocular diseases: a narrative review. Appl. Sci. 2024;14,2623. doi:10.3390/app14062623

11. Liu, S., Lv, D., Sun, J., Jia, H., Zheng, F., Pereira, F., Narendran, S., Dong, Z., Liu, H., Gao, S. and Huang, P. (2025), Recent Advancements in the Treatment of Age-Related Macular Degeneration. Med Research, 1: 151-169. https://doi.org/10.1002/mdr2.70009

12. Russell MW, Rachitskaya AV. Photobiomodulation therapy for management of retinal diseases. Curr Ophthalmol Rep. 2025;13,13. doi:10.1007/s40135-025-00340-x

13. Chichan H, Aldujaly IH, Michalakis K, Kanal L. Photobiomodulation in ocular therapy: current status and future perspectives. Int J Ophthalmol. 2025;18(2):351-357. doi:10.18240/ijo.2025.02.20

Mohammad Bagher Rajabi, MD, is a visiting scholar at the Stanford University School of Medicine's Byers Eye Institute in Palo Alto, California. He reports no relevant financial disclosures.

Gunjan Awatramani, MBBS, is a visiting scholar at the Stanford University School of Medicine's Byers Eye Institute in Palo Alto, California. She reports no relevant financial disclosures.

Alan Sherif, MD, is a visiting scholar at the Stanford University School of Medicine's Byers Eye Institute in Palo Alto, California. He reports no relevant financial disclosures.

Gunay Uludag Kirimli, MD, is a clinical instructor at the Stanford University School of Medicine's Byers Eye Institute in Palo Alto, California. She reports no relevant financial disclosures.

Ingrid U. Scott, MD, MPH, is vice chair of public and community health and the Jane Ward Endowed Professor of ophthalmology and professor of public health sciences at the Penn State College of Medicine in Hershey, Pennsylvania. She reports no relevant financial disclosures.

Diana V. Do, MD, is vice chair of clinical affairs and professor of ophthalmology at the Stanford University School of Medicine's Byers Eye Institute in Palo Alto, California. She reports no relevant financial disclosures.