Light therapy in medicine: where do we stand?

Introduction

Light therapy has rapidly gained prominence as a non-invasive treatment modality across diverse medical disciplines, offering potential benefits for conditions ranging from seasonal affective disorder (SAD) and dermatological diseases to sleep disturbances (1,2) and cardiovascular disorders (3). However, it is critical to distinguish between the various interventions grouped under the term ‘light therapy’, as these comprise biologically and clinically distinct modalities. Bright light therapy, peripheral photobiomodulation (PBM), photoneuromodulation, ultraviolet (UV) phototherapy, and laser ablation each have unique mechanisms, routes of delivery (ocular vs. cutaneous), dosimetry parameters, and clinical targets. The review will clarify these conceptual differences and avoid conflating their effects or evidence base. Defined as the use of specific wavelengths of light to treat medical conditions, light therapy encompasses modalities such as blue or red light for skin conditions and intense bright full-spectrum light (10,000 lux) for mood and circadian rhythm regulation (4). The underlying mechanisms modulating circadian rhythms, melatonin secretion, and mitochondrial function differ fundamentally depending on whether light is delivered through the visual system (retinal pathways) or directly to peripheral tissues. For example, bright light therapy addresses challenges such as delirium in critically ill patients via visual/circadian pathways, while PBM and UV phototherapy achieve effects through direct tissue irradiation. Some studies suggest a potential reduction in delirium incidence with high-intensity light therapy in intensive care settings, though evidence remains limited to small trials (5). Beyond mental health, recent research has explored possible cardioprotective effects of intense light exposure in patients after spine surgery (6), broadening light therapy’s relevance to organ protection and recovery from ischemic events; however, most findings in this domain are based on preclinical or mechanistic studies rather than established clinical data. These multifaceted applications position light therapy as a promising tool in modern medicine, but its transformative potential should be interpreted with caution, given the varying levels of evidence and the distinct nature of its modalities.

Scope and purpose

This review synthesizes current research on light therapy’s mechanisms, efficacy, and safety across key clinical domains, including its impact on mood and skin disorders, sleep disturbances, and organ diseases such as heart ischemia. The growing body of evidence supporting light therapy’s diverse benefits underscores the importance of ongoing research to optimize treatment protocols and expand its clinical applications, with a particular emphasis on conditions such as delirium in intensive care unit (ICU) patients or cardioprotection in surgical patients.

Definition of light therapy

Light therapy broadly refers to the medical use of specific wavelengths of light, but this umbrella term encompasses multiple biological and clinically distinct interventions. For conceptual and mechanistic clarity, light therapy can be divided into two major modalities.

Visual/photoneuromodulatory light therapy

Involves ocular (retinal) exposure to intense, broad-spectrum or blue-enriched intense light (e.g., 10,000 lux) to target the circadian system and central neural circuits. This approach underlies the treatment of SAD, circadian rhythm sleep disorders, and certain neuropsychiatric symptoms by leveraging effects on circadian rhythms and melatonin secretion. For the sake of consistency, we will not use the term “bright light”, as it is less technical and likely inaccurate. Bright light is a perceptual quality that refers to how the human eye perceives a light source or a lit area. It depends on the amount of light and how our eyes interpret color and brightness. Intense Light is the physics definition. It is a technical measurement of power. In physics, light intensity is the amount of energy or power per unit area [e.g., (Watts/m²) or lumens per square meter] hitting a surface, independent of human perception. This accurately describes the light intensities used in research.

Peripheral PBM and UV phototherapy

Involves direct application of red, near infrared, UV light to peripheral tissues (skin, mucosa, or brain), mediating effects via mitochondrial, anti-inflammatory, regenerative, or immunomodulatory pathways. This includes treatment for dermatological conditions, wound healing, musculoskeletal pain, and selected neurological indications (e.g., transcranial PBM).

Each modality uses distinct dosimetry, delivery routes, and biological targets. Mechanisms and clinical applications should not be conflated. For clarity, Table 1 contrasts visual/retinal and peripheral/tissue-directed light therapies by route, units, mechanisms, and indications. Throughout this review, we will explicitly distinguish these categories when discussing light-based interventions and their evidence base.

SAD therapy uses intense, bright, full-spectrum light (10,000 lux) and is rooted in its ability to influence circadian rhythms and modulate melatonin secretion. Similar mechanisms are involved when using intense light to improve sleep quality and reduce delirium in critically ill patients (5,7). In contrast, PBM and UV phototherapy act locally to promote tissue healing, modulate immunity, or provide analgesia via direct tissue irradiation. Recent studies have also highlighted the cardioprotective effects of intense light exposure on myocardial ischemia, revealing its potential for broader therapeutic applications (6,8,9). As we delve into the implications and efficacy of light therapy, its relevance in modern medicine becomes increasingly apparent, provided that mechanistic distinctions and evidence hierarchies are maintained.

Historical background of light therapy in medicine

The historical background of light therapy in medicine highlights a profound evolution in understanding its therapeutic benefits. Emerging from ancient practices in which sunlight was used to treat various ailments, light therapy has seen significant advancements over the centuries. In the 19th century, the advent of heliotherapy (10) marked a pivotal shift, with clinicians such as Dr. Niels Finsen advocating controlled light exposure to treat tuberculosis and skin conditions, culminating in his Nobel Prize in 1903 (11). The integration of artificial light sources, notably fluorescent and light emitting diode (LED) technologies, has broadened therapeutic applications. A study by Taguchi et al. found that intense light therapy may reduce the incidence of postoperative delirium and enable early ambulation (12). More studies underscore the physiological mechanisms at play, as light exposure influences circadian rhythms and metabolic processes, emphasizing its role in contemporary health strategies (13,14). Consequently, light therapy is increasingly recognized as a viable option in integrative medicine, bridging traditional practices with modern scientific understanding (see overview of light applications in Figure 1).

Figure 1 Biomedical applications, mechanisms, and benefits of light therapy. Multiple wavelengths are relevant in light therapy, including blue light (415–450 nm), red light (630–700 nm), NIR, green, and UV light. Full-spectrum and intense light therapy are described by their intensity (e.g., 10,000 or 5,000 lux), which refers to illuminance rather than wavelength. Lux should not be presented as an equivalent category to wavelength, since it measures light intensity rather than spectral composition. Clinical applications should reflect this diversity: blue, red, NIR, green, and UV wavelengths are used for skin conditions, while full-spectrum and intense light are applied in mood and circadian disorders. The mechanisms presented should be interpreted with caution; while some disorders may involve mitochondrial or hormonal modulation, this is not established for all indications. The systemic effects of intense light exposure, including potential cardioprotective effects, remain under investigation and require further confirmation. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; NIR, near-infrared; UV, ultraviolet.

Mechanisms of light therapy

Light therapy has emerged as a promising intervention across various medical fields, operating through mechanisms that modulate biological rhythms and enhance cellular function. While interaction with mitochondrial proteins, particularly activation of cytochrome c oxidase by red or near-infrared (NIR) light in PBM, has been proposed as one mechanism, it should not be overstated as the primary or universal pathway. Other mechanisms underlying central-based light therapy are well described and often better supported by experimental evidence, including modulation of circadian rhythms, regulation of melatonin secretion, and activation of diverse cellular chromophores and photoreceptors. As such, central or peripheral light-based therapies involve a variety of proteins, such as opsins, and macrocyclic organic compounds, or flavins and porphyrins, each relying on distinct photoactivation mechanisms to initiate downstream signaling cascades. Regarding peripheral light-based therapy, specific wavelengths of light can activate important pathways, such as the Wnt/β-catenin and ERK pathways, which influence cell proliferation and growth (15). These signaling mechanisms translate light energy into biological responses that promote healing and tissue regeneration. This increased energy availability supports cellular repair and regeneration processes. Similarly, PBM promotes oxidative phosphorylation while simultaneously inhibiting glycolysis in microglia, suggesting a metabolic reorientation from glucose-dependent to mitochondrial-dependent energy production (16).

In contrast, central-based light therapy acts through non-image-forming visual pathways that influence circadian rhythms. Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express melanopsin, send light information to the suprachiasmatic nucleus (SCN), the brain’s master clock, thereby synchronizing the body’s internal biological rhythms (17). Although ipRGCs are part of the visual system, they do not contribute to image formation but are instead specialized for circadian photoentrainment and other non-image-forming visual functions.

The melanopsin/ipRGC pathway in circadian phototransduction

The entrainment of the central circadian clock to environmental light is primarily mediated by a specialized subset of retinal ganglion cells known as ipRGCs. These cells express the photopigment melanopsin, which is maximally sensitive to blue light at approximately 480 nm (18,19). Unlike rods and cones, ipRGCs are uniquely suited for non-image-forming visual functions such as circadian photoentrainment, pupillary light reflex, and regulation of sleep and alertness.

Upon exposure to light, ipRGCs depolarize and send direct projections to the SCN of the hypothalamus, the master circadian pacemaker. This ipRGC-to-SCN pathway is the principal route by which environmental light resets and entrains the circadian clock (20). The SCN, in turn, orchestrates daily rhythms in physiology and behavior throughout the body by regulating downstream neuroendocrine and autonomic pathways.

The significance of the melanopsin/ipRGC pathway has been demonstrated in both animal and human studies. Action spectrum experiments show that circadian phase shifting, melatonin suppression, and alertness modulation are most efficiently driven by wavelengths near 480 nm, corresponding to melanopsin’s peak sensitivity (21). Disruption or genetic ablation of ipRGCs impairs circadian photoentrainment and related physiological functions. Importantly, understanding this pathway underscores why blue light is particularly potent in circadian regulation and why the spectral composition of light therapy devices is critical for optimizing therapeutic outcomes (4). However, blue light can cause discomfort and damage retinal cells under certain circumstances, and as such, it is no longer used by most lighting companies (22).

This circadian regulation affects sleep-wake patterns, hormone production, and various other physiological processes. Central to its efficacy is the influence of specific wavelengths of light on circadian biology, which regulates multiple physiological processes. Research further indicates that exposure to intense light can stabilize the circadian protein PER2, which is crucial for cardiac adaptation during ischemic events, thereby reducing myocardial injury (8). Additionally, light therapy improves metabolic responses through pathways involving adenosine signaling, which is crucial for cardioprotection (23). Furthermore, its application in critical care settings has demonstrated potential to reduce the incidence of delirium among patients, particularly when administered at adequate intensity and duration (7). Moreover, research shows that intense light therapy affects myocardial ischemia, acute lung injury (ALI), cognitive dysfunction, hemorrhagic shock, and platelet aggregation in both animal and human studies (6,8,14,23-41). Collectively, these studies underline the therapeutic potential of light therapy. While these findings are promising, further research is required to determine the precise clinical applications and to distinguish where current data support translation versus where additional investigation is needed (Figure 2).

Figure 2 Mechanisms of light therapy. The current illustration focuses primarily on mitochondrial and circadian pathways, which represent only a subset of the mechanisms by which light therapy exerts its effects. Light therapy is known to modulate a broad range of biological pathways, including but not limited to mitochondrial activation, circadian regulation, melatonin synthesis, immune modulation, anti-inflammatory signaling, nitric oxide production, and opioid system activation (particularly with green light in pain management). Other pathways, such as modulation of cytokine networks, collagen synthesis, and neuroprotective signaling, are well described and have substantial supporting evidence. A more comprehensive depiction of the mechanisms is needed to avoid bias and better represent the field. Future revisions of the figure should incorporate these diverse, well-established mechanistic pathways and clarify that the selected mechanisms are not exhaustive or universally dominant across all forms of light therapy. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; ATP, adenosine triphosphate; ICU, intensive care unit; IR, ischemia-reperfusion; PER2, Period 2; SCN, suprachiasmatic nucleus.

Biological effects of light on human physiology

Light has profound biological effects on human physiology, particularly through its regulation of circadian rhythms, hormone secretion, and overall health (17). Building on the mechanistic overview, this section connects those cellular and molecular insights to the broader physiological and clinical context. The circadian pathway enables the body to synchronize its internal biological clock with the external solar cycle. The key role of light exposure in synchronizing biological clocks underscores its importance for mental and physical health; disruptions can lead to significant disorders, including sleep disturbances and metabolic issues. Indeed, exposure to light at night has been shown to cause circadian disruption and metabolic disorders. Several studies have established a connection between artificial light at night and obesity (42). Circadian misalignment, wherein eating and sleeping patterns oppose their natural inclination from the light-dark cycle, disrupts internal homeostasis and has been linked to metabolic syndrome and cancer (43). Chronic circadian disruption from shift work, irregular sleep-wake cycles, or misaligned lifestyle habits is strongly associated with increased cardiovascular risk (44). Research indicates that disrupted circadian rhythms increase susceptibility to metabolic syndrome, cardiovascular diseases, and other chronic conditions (45). Recent evidence reveals large individual variations in circadian photosensitivity, including differences in melatonin suppression in response to artificial light exposure (46). Factors such as age, sex, chronotype, and genetic variation influence how different individuals respond to light exposure (46). These individual differences target biological mechanisms within the retina and downstream in the central circadian clock, emphasizing the need for personalized lighting recommendations. The emerging field of circadian medicine recognizes that optimizing light exposure represents a key intervention for maintaining health. Light therapy, along with melatonin supplementation and time-restricted eating, can help resynchronize disrupted circadian rhythms (47). By understanding how light regulates circadian physiology, healthcare providers can develop strategies to prevent disease and improve patient outcomes through better alignment of daily behaviors with internal biological timing. Indeed, light exposure has been shown to stabilize crucial proteins like PER2, promoting better cardiac function during ischemic conditions, thus highlighting the intricate connections between light therapy and various physiological processes. In fact, recent studies in patients undergoing spine surgery have found reduced myocardial injury (6). Figure 3 illustrates the interplay between circadian rhythms and metabolic health, reinforcing the argument for integrating light therapy into clinical practices.

Figure 3 Light, circadian rhythms, and metabolic health: pathways and clinical implications. Light signals detected by ipRGCs are transmitted to the SCN, synchronizing internal rhythms with the external light-dark cycle. Individual differences in light sensitivity, shaped by age, sex, chronotype, and genetics, modulate circadian responses. Proper daytime light exposure supports aligned sleep-wake patterns, hormonal rhythms (e.g., melatonin and cortisol), and metabolic homeostasis. In contrast, nighttime artificial light and circadian misalignment (e.g., shift work, irregular eating and sleeping) reduce melatonin, disrupt clock synchronization, and increase risk of obesity, metabolic syndrome, cardiovascular disease, and cancer. Clinical interventions such as structured light therapy, melatonin supplementation, and time-restricted eating aim to restore circadian alignment and improve cardiometabolic health. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; ipRGCs, intrinsically photosensitive retinal ganglion cells; PER2, Period 2; SCN, suprachiasmatic nucleus.

Types of light used in therapy

Light therapy encompasses a variety of modalities, notably including LED and laser treatments, each demonstrating unique therapeutic applications (48,49). LED therapy employs low-level light to promote healing and reduce inflammation and is effectively utilized for conditions such as acne and psoriasis (50,51). LEDs emit monochromatic or narrowband light at specific wavelengths, with red and blue light demonstrating particularly promising therapeutic effects (48). Red light therapy, operating at wavelengths around 650 nm, has been shown to improve mitochondrial function, enhance collagen production, and optimize vascular dynamics. Blue light, with wavelengths of 400–500 nm, offers distinct therapeutic properties, including notable antimicrobial and immunomodulatory effects (52). The antimicrobial properties of blue light function through the generation of reactive oxygen species (ROS) that target and destroy pathogenic microorganisms such as Cutibacterium acnes, making it valuable for acne treatment (52). Red LED therapy has demonstrated significant benefits in cellular metabolism and vascular health. Research examining low-power red LED light at 655 nm shows effective promotion of metabolic activation and induces morphological changes in vascular endothelial cells, suggesting considerable potential in angiogenesis and wound healing applications (53). These findings highlight the safety and accessibility of LED-based PBM for soft tissue regeneration in both clinical and home-care settings.

Alternatively, laser therapy, which utilizes concentrated light to target specific tissues, is instrumental in various medical fields, including oncology and surgery, particularly for its precision in ablation and tissue regeneration. Research shows that low-level laser therapy (wavelength around 650 nm) significantly reduces oral mucositis in cancer patients undergoing chemotherapy, yielding promising results (54,55). The mechanisms of action of laser therapy include mitochondrial stimulation, enhanced adenosine triphosphate (ATP) production, and modulation of cell membrane transporters (56). NIR laser wavelengths, typically ranging from 800–1,100 nm, exhibit superior tissue penetration compared to visible light, enabling non-invasive application to various tissues at deeper anatomical levels (57). This extended penetration depth makes lasers particularly suitable for treating injuries in deeper tissue and chronic conditions.

Additionally, light exposure has been shown to stabilize circadian rhythms, enhancing metabolic responses during ischemia, highlighting the intricate relationship between light and health outcomes (58). Light profoundly influences the body’s metabolic processes. When exposed to intense light, especially in the morning, it enhances metabolic responsiveness and energy regulation (59). Conversely, acute intense light exposure prior to bedtime can significantly decrease fat oxidation and increase reliance on carbohydrate metabolism, suggesting that chronic exposure to artificial light at night may increase obesity risk through changes in metabolic fuel utilization (60).

The effects extend beyond simple energy metabolism. Blue-enriched light at night, particularly wavelengths around 460–480 nm, suppresses melatonin production and desynchronizes both the central clock and hepatic clocks, disrupting glucose and lipid metabolism and leading to insulin resistance and oxidative stress (61). Regular exposure to artificial light at night also alters gut microbiota composition, suggesting a “light-gut-liver axis” that contributes to metabolic dysfunction in humans (61,62). The consequences of poor light hygiene extend far beyond metabolism. Chronic artificial light at night exposure is linked to increased risk of metabolic syndrome, obesity, type 2 diabetes, hypertension, cardiovascular disease, and possibly certain cancers, such as breast and prostate cancer, although evidence for cancer risk remains limited and under investigation (58). Shift workers, who experience forced circadian misalignment due to nighttime light exposure, show significantly elevated metabolic and cardiometabolic disease risk.

Understanding the intricate relationship between light and biological rhythms is essential for maintaining health. Both excessive nighttime light exposure and insufficient daytime light can disrupt the circadian system and metabolic function, highlighting the importance of consciously managing the light environment throughout the day (63).

For illustration, Figure 4 captures light therapy devices in clinical use, underscoring their role in modern therapeutic practices.

Figure 4 Therapeutic light modalities: LED, laser, and biological pathways. (A) LED therapy uses low-level red (≈650 nm) and blue (400–500 nm) light to enhance mitochondrial function, collagen synthesis, vascular dynamics, and antimicrobial responses, supporting wound healing and dermatological applications. (B) Laser therapy delivers coherent light (650 nm; near-infrared 800–1,100 nm) to stimulate ATP production and cellular signaling, enabling precise treatment of superficial and deep tissues, including oral mucositis and chronic injuries. (C) Light exposure regulates circadian rhythms and metabolism: daytime light stabilizes central and peripheral clocks, whereas nighttime artificial light suppresses melatonin, disrupts metabolic homeostasis, and increases cardiometabolic risk. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; ATP, adenosine triphosphate; CVD, cardiovascular disease; LED, light emitting diode; ROS, reactive oxygen species; SCN, suprachiasmatic nucleus; T2D, type 2 diabetes.

Having established the types and modalities of light used in therapy, the discussion now turns to the importance of wavelength selection and its direct impact on therapeutic outcomes. Overall, the diverse applications of different light types continue to evolve, presenting new avenues for therapeutic exploration.

Role of wavelengths in therapeutic outcomes

The clinical effectiveness of light therapy depends on selecting appropriate wavelengths, as different wavelengths target tissues at varying depths and have distinct biological effects. Blue light (400–500 nm) is primarily used for dermatological conditions due to its superficial penetration and antimicrobial properties, making it effective for acne and some inflammatory skin diseases (52). Red light (around 660 nm) penetrates deeper into the skin, promoting tissue repair, wound healing, and pain management by enhancing mitochondrial function and microcirculation. NIR wavelengths (700–1,100 nm) reach the deepest tissues, supporting regeneration and recovery in musculoskeletal and neurological applications (64,65). The combination of wavelengths, such as red and NIR, can produce synergistic effects, further optimizing clinical outcomes in certain contexts (66,67).

Importantly, recent research emphasizes that both the energy dose and the wavelength distribution, not just intensity, are critical for optimal results. However, clinical translation remains challenging due to heterogeneity in treatment parameters and an incomplete understanding of precise molecular mechanisms. As the field advances, greater standardization of protocols and continued investigation into wavelength-specific effects and combinations will help improve evidence-based application in clinical settings (Figure 5).

Figure 5 Role of wavelengths in therapeutic outcomes. (A) Spectrum and tissue penetration: Blue light (400–500 nm) primarily acts at superficial skin layers with antimicrobial effects. Red light (~660 nm) penetrates into dermal and subcutaneous tissues, promoting cellular repair and ATP production. NIR (NIR-I: 700–900 nm; NIR-II: 900–1,100 nm) achieves the deepest tissue penetration, enabling effects in deep tissues and the central nervous system. The use of the term NIR-II (900–1,100 nm) here follows a convention adopted in some PBM and biomedical optics literature, though definitions vary, and other sources may define NIR-II as extending up to 1,700 nm. However, there is no universally accepted standard for NIR-II in the context of PBM. (B) Mechanisms of action by wavelength: blue light reduces microbial load and inflammation. Red light enhances mitochondrial activity, collagen synthesis, and microcirculation. NIR modulates cytochrome c oxidase activity and mitochondrial respiration, contributing to tissue repair and neuroprotection. (C) Synergy and wavelength combinations: dual- or multi-wavelength approaches (e.g., 660 nm + 810/850 nm) amplify ATP production and anti-inflammatory responses, often producing superior clinical outcomes compared to single wavelengths. (D) Immunomodulation and mechanistic precision: specific wavelengths influence macrophage polarization (M1 to M2), cytokine profiles, and brain network activity, highlighting wavelength-dependent biological targeting. (E) Key determinants of efficacy: therapeutic success depends on wavelength selection, photon fluence (the total number of photons delivered per unit area, typically measured in J/cm2), power density, and temporal distribution rather than intensity alone. (F) Future directions: standardization of protocols, investigation of wavelength combinations, personalized dosimetry, and deeper mechanistic understanding are essential for precision light therapy. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; ATP, adenosine triphosphate; LED, light emitting diode; NIR, near-infrared; PBM, photobiomodulation; ROS, reactive oxygen species.

Safety and side effects of light exposure

Light therapy has emerged as a promising therapeutic intervention for various medical conditions, yet careful attention to safety remains essential. While considered safe, light therapy can produce both acute and chronic side effects depending on intensity, wavelength, duration, and individual factors. The most frequently reported side effects of intense light therapy include headache, eye strain, irritability, and nausea. Research examining acute side effects found that among patients with SAD exposed to 10,000-lux light therapy, 45.7% experienced some side effects, with headaches and vision problems being most common. However, these effects are typically mild and transient. In clinical studies of intense light therapy for mood disorders, reported side effects such as nausea, diarrhea, headache, and eye irritation are generally rare and mild (68). Red-light therapy for myopia management demonstrates a favorable safety profile, with minimal adverse effects reported in short-term studies (69). A systematic review found that repeated low-level red-light therapy resulted in temporary afterimages as the most common ocular symptom, resolving within minutes of treatment cessation, with no cases of permanent vision loss (70-72). However, more comprehensive long-term data are still needed to fully confirm safety (69,73-77). In contrast, UV-C light exposure, commonly used in germicidal lamps, poses significant health risks even with brief exposure. Research demonstrates that UV-C radiation can trigger irreversible cellular damage in skin cells and retinal cells, with epithelial retinal cells showing heightened sensitivity and substantial apoptosis. Proper implementation of light therapy protocols can minimize adverse effects. Standard guidelines recommend 10,000 lux exposure for 30–60 min early in the morning as optimal for SAD. Additionally, ophthalmologic assessment every 2–3 years may be helpful, particularly for individuals at greater risk for ocular disease. Consultation with ophthalmologists is recommended for patients with significant retinal pathology or those taking photosensitizing medications. Blue light therapy for dermatological conditions shows promise with relatively good safety profiles, though standardized treatment protocols and long-term safety studies remain needed to fully integrate this modality into clinical practice (52). Transcranial PBM using NIR wavelengths demonstrates minimal adverse effects in preliminary clinical studies, though larger, rigorously designed randomized controlled trials are essential to establish efficacy and optimize parameters. Light therapy in non-clinical populations undergoing brief treatment demonstrates fewer adverse effects than previously reported in psychiatric populations, suggesting that treatment duration and individual characteristics significantly influence safety outcomes. While light therapy presents a safe and effective therapeutic option with minimal adverse effects when properly administered, careful attention to wavelength selection, intensity, duration, and individual patient factors remains essential. Standardized protocols, proper device selection, and ongoing ophthalmologic monitoring in appropriate cases help optimize patient outcomes while minimizing risks. Future research should continue to establish evidence-based guidelines for long-term safety, particularly for novel applications and vulnerable populations (Figure 6).

Figure 6 Safety and side effects of therapeutic light exposure. (A) Types of light therapy and main uses: common modalities include bright white light (e.g., for seasonal affective disorder), red and blue light devices for dermatological and ophthalmic applications, near-infrared devices for transcranial photobiomodulation, and UV-C lamps for germicidal use (hazardous to humans). (B) Side effects by wavelength: bright, red, blue, and near-infrared light therapies are generally associated with mild and transient side effects (e.g., headache, eye strain, skin irritation, temporary afterimages). In contrast, UV-C exposure may cause severe and irreversible cellular damage to skin and retinal tissue. (C) Mechanism and Risk modifiers: safety depends on wavelength, intensity, exposure duration, and individual patient factors (e.g., age, ocular disease, medications). Appropriate parameter selection optimizes benefit-risk balance. (D) Safety optimization and recommendations: standardized protocols (e.g., 10,000 lux for 30–60 min in the morning), ophthalmologic screening in at-risk individuals, avoidance of UV-C exposure, personalization of therapy, and monitoring during long-term use improve safety. (E) Gaps and future directions: further research is needed to establish long-term safety and standardized guidelines, particularly for emerging applications and vulnerable populations. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; UV, ultraviolet.

Populations at risk with light therapy

While light therapy is generally safe and well-tolerated, certain populations are at increased risk of adverse effects or have specific contraindications. Clinical guidelines recommend careful screening and monitoring for the following groups:

• Bipolar disorder and mania: light therapy, particularly intense light or early morning exposure, can precipitate manic or hypomanic episodes in individuals with bipolar disorder. Use should be closely monitored by a mental health professional, and lower-intensity or midday protocols may be considered (78).
• Photosensitive conditions (e.g., lupus erythematosus): patients with systemic lupus erythematosus or other photodermatoses may experience disease flares or skin reactions with light exposure, particularly UV-based therapies (79).
• Use of photosensitizing medications: drugs such as certain antibiotics (e.g., tetracyclines), antipsychotics, and diuretics can increase the risk of phototoxic or photoallergic reactions. A comprehensive medication review is essential before initiating therapy (80).
• Ocular disorders: individuals with macular degeneration, retinal dystrophies, or other light-sensitive eye conditions should avoid direct intense light exposure to the eyes; alternative protocols or ophthalmology consultation may be appropriate (81).
• Epilepsy: although rare, intense light exposure can theoretically lower the seizure threshold in photosensitive epilepsy. Caution and individualized assessment are warranted (82).
• Active skin cancer or pre-cancerous lesions: light therapy, especially UV-based, may be contraindicated in those with a history of melanoma or other skin malignancies unless under specialist supervision.

Neonatal phototherapy for hyperbilirubinemia

Phototherapy is the first-line treatment for neonatal hyperbilirubinemia (83), a common and potentially serious condition in newborns caused by elevated levels of unconjugated bilirubin. Left untreated, severe hyperbilirubinemia can result in acute bilirubin encephalopathy and kernicterus, leading to permanent neurological damage. Phototherapy utilizes blue light in the 460–490 nm range to convert unconjugated bilirubin into more water-soluble, excretable isomers through a process called photoisomerization. Multiple large randomized controlled trials and meta-analyses have confirmed the efficacy and safety of phototherapy in lowering serum bilirubin and preventing serious complications (84). Advancements in technology have led to the development of fiber-optic phototherapy blankets and LED-based phototherapy units, which offer improved energy efficiency, less heat production, and greater comfort for neonates compared to traditional fluorescent lamps.

Jet lag and shift work

Disruption of circadian rhythms due to transmeridian travel (jet lag) or shift work can result in sleep disturbances, reduced cognitive performance, and adverse health outcomes. Light therapy, specifically, timed exposure to intense light (2,500–10,000 lux), is an established intervention for circadian rhythm alignment in both jet lag and shift work disorder. Clinical studies and meta-analyses demonstrate that morning light exposure can advance and evening light exposure can delay the circadian phase, enabling more rapid adaptation to new time zones or irregular work schedules (85). The effectiveness of light therapy depends on careful timing, intensity, and duration, and individualized protocols are recommended for optimal results. Light therapy combined with behavioral interventions, such as sleep hygiene and strategic napping, further enhances adaptation and performance.

Premenstrual dysphoric disorder (PMDD)

PMDD is a severe mood disorder associated with the luteal phase of the menstrual cycle, affecting up to 5–8% of reproductive-aged women (86). Intense light therapy has been investigated as a non-pharmacological treatment option. Randomized controlled trials indicate that morning or evening intense light (2,500–10,000 lux) for 30–60 min daily during the luteal phase can significantly reduce depressive symptoms and improve mood in women with PMDD. The proposed mechanisms include modulation of circadian rhythms, melatonin secretion, and serotonergic neurotransmission. While results are promising, larger and more definitive trials are needed to establish standardized protocols and assess long-term efficacy.

Light therapy for sleep in traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD)

Sleep disturbances, including insomnia and fragmented sleep, are common after TBI and in PTSD, often exacerbating cognitive and emotional symptoms. Pilot studies and small randomized trials have shown that daytime intense light therapy (5,000–10,000 lux for 30–45 min) can improve sleep onset latency, sleep continuity, and daytime alertness in patients with TBI. Similar benefits have been observed in PTSD populations, where morning intense light exposure has led to improvements in sleep quality, mood, and PTSD symptom severity (87). The hypothesized mechanisms include stabilization of circadian rhythm, reduction in hyperarousal, and normalization of melatonin secretion. While these findings are encouraging, larger, multi-center trials are necessary to confirm efficacy and refine treatment recommendations.

Applications in mental health

Light therapy has become an established treatment for SAD and other mental health conditions. By exposing individuals to intense light, typically at 10,000 lux, this non-pharmacological intervention effectively modifies circadian rhythms and enhances mood regulation (88). Research demonstrates that light therapy improves both mood and sleep quality among people with depression (89) and anxiety, making it an accessible and well-tolerated option that can be used alone or combined with other treatments. Beyond SAD, light therapy shows promise in clinical settings for reducing postoperative delirium in critically ill patients by promoting daytime alertness and stabilizing circadian patterns. The therapeutic mechanisms appear to involve regulation of serotonin production, melatonin levels, and circadian rhythm normalization (5,38,88). Evidence indicates that the appropriate light intensity and exposure duration are crucial for treatment effectiveness. As more research continues to clarify these mechanisms, light therapy is increasingly recognized as a valuable, evidence-based intervention for mental health treatment. In fact, there is now emerging research exploring modern homogeneous light ceilings for mental health outcomes, emphasizing that the old light systems or current ICU bed designs either caused glare or were beyond efficient light intensities (<1,000 lux) (5,88). See also Figure 7 for current and general limitations of light exposure in hospitals. In 1980, a landmark study convincingly demonstrated that higher intensities such as 2,500 lux are necessary to reliably suppress melatonin levels in humans. Indeed, studies in humans using higher intensities (>2,500 lux) have consistently shown positive and significant effects on metabolism or on protection against inflammation, thrombosis, delirium, cardiac injury, or diabetes (6,8,90-92).

Figure 7 Impact of indoor light attenuation on patient circadian health. The schematic illustrates the drastic reduction in natural light intensity (lux) from the outside environment to a hospital patient bed, highlighting how factors like window glass, room depth, and shading limit biological light exposure. The inset graph contrasts actual light levels at the bed (500 lux) against the minimum requirement for circadian regulation (1,200 lux) and therapeutic boost phases (2,000 lux). Prolonged light deficiency is linked to fatigue, poor concentration, and sleep disorders, underscoring the clinical need for coordinated artificial lighting systems. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence.

Use of light therapy for SAD

SAD is a recurrent pattern of major depression that occurs during autumn and winter months, typically remitting in spring and summer. SAD is characterized by persistent low mood, loss of interest in activities, lethargy, excessive sleep, carbohydrate cravings, and weight gain (30). Light therapy has emerged as a highly effective, non-pharmacological treatment for this condition, involving daily exposure to intense light through specialized light boxes or other delivery devices. The therapeutic mechanism of light therapy operates primarily through the visual system’s influence on circadian rhythms and neurotransmitter regulation (88). Exposure to intense light regulates the circadian rhythm, influences the production of serotonin and melatonin, and restores proper biological clock function (88). The standard treatment protocol involves sitting in front of a light box emitting 10,000 lux at 20 cm from the eyes for approximately 30 min/day, preferably in the morning (93). Research has demonstrated that morning light exposure yields faster improvement than evening treatment (94). Light therapy has proven remarkably effective, with most patients experiencing symptom improvement within the first week (30). Meta-analysis of randomized controlled trials confirms that intense light therapy is significantly superior to placebo (95), with response rates of around 70–80% in well-selected patient populations. Beyond alleviating depressive symptoms, light therapy also reduces excessive sleepiness, improves fatigue, and enhances health-related quality of life (96). The treatment is particularly effective for patients with atypical depressive features such as hypersomnia and increased appetite (97). Light therapy has a favorable safety profile compared to antidepressant medications (98), making it an attractive option, particularly for vulnerable populations. Mild side effects such as eye irritation, headache, or nausea can occur but are generally temporary and rare (68). The non-pharmacological nature of light therapy also makes it compatible with other treatments, including antidepressant medications, which can result in accelerated improvement (98).

Impact on sleep disorders and circadian rhythms

Transitioning from mental health, the next focus is on the role of light therapy in sleep disorders and circadian rhythm regulation. Light therapy has emerged as a powerful non-pharmacological intervention for addressing both sleep disorders and circadian rhythm disruptions. The circadian system, which is regulated by the SCN in the brain, controls sleep-wake cycles and is fundamentally influenced by light exposure. Intense light acts as the body’s strongest time cue (zeitgeber), helping to synchronize internal biological rhythms with the external environment. Research demonstrates significant efficacy across multiple applications. In adults with insomnia, pre-sleep dim light therapy has shown improvements in sleep quality and efficiency, with notable advances in melatonin timing, the hormone that regulates sleep (99). The treatment works by directly influencing circadian clock genes, which provide the molecular foundation for proper sleep regulation. For individuals with circadian rhythm sleep disorders characterized by misalignment between their internal clock and desired sleep schedules, appropriately timed intense light exposure can shift the sleep-wake cycle earlier or later as needed. Beyond general insomnia, light therapy has proven beneficial for specialized populations. In older adults experiencing sleep disturbances, both frequent sunlight exposure and artificial lighting aligned with circadian rhythms demonstrate positive effects on sleep outcomes (100). Additionally, intense light therapy has shown promise as an effective treatment for sleep problems in patients with Parkinson’s disease, with improvements appearing to result from restoration of proper circadian function (101). The mechanism is elegant: light therapy works by regulating melatonin secretion, enhancing alertness, and influencing neurotransmitter pathways that control mood and sleep (68). With a strong safety profile and rapid effects often observed within 1-week, light therapy offers a valuable alternative to pharmacological interventions, particularly for vulnerable populations like pregnant women and older adults.

Efficacy in treating depression and anxiety

Light therapy has emerged as a promising non-pharmacological intervention for treating mood and anxiety disorders. This treatment involves exposure to intense light, typically using specialized light therapy devices, and works through mechanisms involving circadian rhythm regulation and neurobiological pathways. As mental health conditions continue to affect millions worldwide, understanding light therapy’s role in treatment is increasingly important. The evidence for light therapy in treating depression is substantial across multiple populations. A comprehensive meta-analysis of non-seasonal depression found that light therapy demonstrated a beneficial effect, with results showing significant improvements in depressive symptom severity (102). This finding is particularly noteworthy because it challenges the historical view that light therapy only benefits SAD. For older adults specifically, light therapy has proven significantly more effective than comparative treatments such as placebo or dim light, with both bright white light and pale blue light showing clinically meaningful reductions in geriatric depression (103). Recent research has also examined light therapy as part of combination treatments. When combined with other therapeutic approaches, intense light therapy shows promise in treating various mood disorders. The effectiveness of intense light therapy appears to depend on an individual’s baseline inflammatory state, suggesting a personalized approach may optimize outcomes (69). Additionally, portable light therapy devices have been developed to improve treatment accessibility and compliance, allowing patients to integrate therapy into their daily routines (104). While light therapy’s evidence base is strongest for depression, research demonstrates positive effects on anxiety symptoms as well. In one pilot study, color therapy interventions delivered through specialized light devices resulted in a 60% reduction in anxiety and depression symptoms (105). When combined with cognitive-behavioral therapy, morning light therapy in adolescents showed modest reductions in anxiety alongside improvements in sleep and other outcomes (106). Light therapy has also been evaluated across different anxiety-related sleep disorders. Blue light therapy improved subjective sleep quality, reduced nighttime awakenings, and improved daytime functioning in patients with delayed sleep-wake phase disorder (107). These improvements in sleep disturbance often accompany reductions in anxiety and mood symptoms, as sleep quality is intricately linked to emotional regulation. One of light therapy’s major advantages lies in its safety profile. Research indicates that light therapy is a safe intervention with minimal or mild side effects (108). This makes it particularly valuable as an augmentative or alternative treatment option for patients who cannot tolerate or do not respond adequately to pharmaceutical interventions. The evidence supports light therapy as an effective, well-tolerated intervention for treating depression across various populations and presentations. While the research base for anxiety treatment is somewhat more limited, emerging evidence suggests meaningful benefits. Light therapy’s safety profile, accessibility through portable devices, and potential for combination with other treatments position it as an important tool in comprehensive mental health care. However, treatment should be personalized based on individual characteristics and baseline inflammatory and immunological status to optimize outcomes. As research continues to evolve, light therapy will likely play an increasingly significant role in multimodal treatment approaches for mood and anxiety disorders.

Light approaches to treating substance disorders

Building on the discussion of sleep and circadian regulation, the review next examines the intersection of circadian biology and substance use disorders (SUDs). The relationship between circadian rhythm disruption and SUDs has emerged as an important area of research (109). There is a bidirectional relationship between circadian rhythm dysfunction and addiction behavior, with circadian rhythm dysfunction, neuroadaptation in reward circuits, and alterations in clock gene expression influencing SUDs. Importantly, chronotherapy has shown potential benefits as a treatment strategy for addiction (108). Environmental factors like artificial light exposure at night and chronic jet lag can influence circadian rhythm dysfunction, impair neurotransmitter release, disrupt neural circuits, and lead to endocrine and metabolic disorders, all of which may contribute to the development or persistence of SUDs (110). This suggests that light exposure management and circadian rhythm regulation could be therapeutic targets.

Recent preclinical studies have shown that circadian misalignment can increase vulnerability to substance use and relapses, likely through alterations in dopaminergic reward pathways. For example, animal studies demonstrate that chronic disruption of light-dark cycles can enhance drug-seeking behavior and reduce the effectiveness of extinction training in models of addiction. Some human research has linked disrupted sleep-wake cycles and evening chronotypes with increased risk for substance use and poor recovery outcomes (110). However, direct clinical trials investigating the effects of light therapy in SUDs are limited, and the current evidence base is primarily extrapolated from work in other neuropsychiatric disorders and preclinical models.

A few pilot studies suggest that intense light therapy may help reduce craving and improve sleep quality in patients with alcohol or stimulant use disorders, but findings are preliminary and require replication in larger, controlled trials (111). Mechanistically, it is hypothesized that stabilizing circadian rhythms through appropriately timed light exposure could modulate reward system neurobiology, reduce craving, and support recovery. Nevertheless, it remains unclear whether light therapy alone is sufficient or best used as an adjunct to established treatments.

Current evidence-based treatments for SUDs include neuromodulation (111) approaches such as transcranial magnetic stimulation, cognitive-behavioral therapy, and pharmacological interventions, which have stronger empirical support. Additional research is needed to determine optimal light therapy protocols (timing, intensity, duration) and to clarify which subpopulations of SUD patients may benefit most. In summary, while the intersection of light, circadian regulation, and addiction neurobiology is an important and promising area, further development and rigorous testing are necessary before light therapy can be recommended as a standard intervention for SUDs (Figure 8).

Figure 8 Light therapy applications in mental health and substance use disorders. Environmental factors such as artificial light at night and chronic jet lag disrupt circadian rhythms and clock gene expression, contributing to neurotransmitter imbalance, impaired neural circuitry, and metabolic dysfunction. Circadian rhythm dysfunction is bidirectionally linked to SUDs, influencing reward circuitry and addiction behaviors. Light-based interventions, including chronotherapy and structured light exposure management, aim to restore circadian alignment and potentially normalize reward-related pathways. While light therapy shows promise as an adjunctive strategy in SUDs, current evidence remains limited. Established treatments with stronger empirical support include transcranial magnetic stimulation, cognitive behavioral therapy, and pharmacological approaches. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; SUDs, substance use disorders.

Light therapy applications in dermatology

Transitioning from neuropsychiatric and behavioral applications, this section explores the expanding role of light therapy in dermatology. Light therapy has become an increasingly vital treatment modality in dermatology, encompassing various technologies including lasers, LEDs, and photodynamic therapy (PDT). These therapies operate on the principle of PBM, where light energy activates cellular photoacceptors to induce therapeutic effects (112). The fundamental mechanism involves the interaction of specific light wavelengths with cellular chromophores, leading to modulation of immune responses, cellular proliferation inhibition, and enhanced tissue regeneration (113). Skin cancer and precancerous lesions: PDT is particularly established for treating non-melanoma skin cancers. It demonstrates high efficacy for actinic keratosis, Bowen’s disease, and superficial basal cell carcinoma, with cosmetic outcomes superior to destructive modalities. The mechanism involves topical application of photosensitizers like 5-aminolevulinic acid (ALA), which accumulates in affected tissues and generates reactive oxygen species (ROS) upon light exposure (114). Chronic inflammatory conditions: phototherapy effectively addresses chronic conditions such as psoriasis, vitiligo, and atopic dermatitis (112). For vitiligo specifically, red light therapy (HeNe laser at 632.8 nm) stimulates melanocyte stem cell differentiation and migration through mitochondrial signaling pathways, promoting perifollicular repigmentation (115). Acne and Acne-Related Conditions: Both conventional PDT and LED-based therapies have shown promising results in treating acne vulgaris through antimicrobial effects and immune modulation (116). Blue light demonstrates notable antimicrobial and immunomodulatory effects, making it particularly suitable for acne treatment (48). Recent advancements have significantly expanded therapeutic options. LED therapy offers advantages of safety, non-invasiveness, and ease of use compared to traditional laser systems (117). Red light therapy improves mitochondrial function, collagen production, and vascular dynamics, while wearable organic LED devices have demonstrated up to 23% increases in fibroblast proliferation, enhancing wound healing (75). Innovations such as daylight PDT and fractional laser-assisted PDT have improved tolerability and broadened clinical applicability. While phototherapy demonstrates considerable therapeutic potential, standardization remains a significant challenge. The efficacy of light therapy depends critically on precise wavelength, energy dose, and exposure parameters, necessitating personalized treatment protocols (48). Future research should focus on developing standardized dosimetry protocols, integrating biomarker-guided treatment monitoring, and optimizing device engineering to achieve more consistent clinical outcomes (118). Light therapy continues to evolve as a cornerstone of modern dermatologic practice, offering non-invasive, effective solutions for diverse skin conditions while opening new therapeutic horizons in cosmetic and regenerative medicine.

Treatment of acne and skin conditions

Light therapy has emerged as a promising non-invasive treatment option for acne and various skin conditions. Among the most studied approaches are blue light therapy, red light therapy, and intense pulsed light (IPL) therapy, each offering distinct mechanisms of action and clinical benefits. Blue light therapy operates through multiple therapeutic pathways. The specific wavelength of blue light (400–500 nm) generates ROS that target and destroy Cutibacterium acnes (formerly Propionibacterium acnes), the primary bacterium responsible for acne vulgaris (52). Beyond its antimicrobial effects, blue light demonstrates anti-inflammatory properties by modulating cytokine production and reducing inflammatory cell infiltration (52). Additionally, blue light reduces sebaceous gland activity, thereby decreasing sebum production, which is a key factor in acne development (119). Research has shown that blue light exposure causes significant decreases in sebum content and can be lethal to acne-causing bacteria at submilliwatt levels (120). Red light therapy operates through different mechanisms, primarily through PBM effects that influence cellular proliferation and differentiation, supporting skin healing and rejuvenation (52). Importantly, studies confirm that red light therapy does not induce DNA damage in human dermal fibroblasts, supporting its safety profile (121). The clinical evidence supporting light-based therapies is robust. A meta-analysis examining LED treatments found both red and blue LED lights play important roles in treating acne vulgaris with statistically significant results (122). In a prospective clinical study of a hand-held low-level light therapy device combining red laser (680 nm) and blue light (450 nm), treatment resulted in statistically significant decreases in inflammatory acne lesions at weeks 4 and 8 (P<0.001), with no severe adverse reactions reported (123). IPL therapy has also demonstrated effectiveness, with excellent results achieved in 22% of patients and good results in 49% when treating inflammatory facial acne (124). Furthermore, IPL therapy proves effective for treating post-inflammatory sequelae, with 81.7% of patients showing complete or partial clearance of erythema and hyperpigmentation following treatment (125). A significant advantage of light therapy is its non-invasive nature and minimal side effects compared to conventional treatments. Unlike chemical peels and dermabrasion, which carry risks of redness, scabbing, and irritation, light-based treatments offer a pain-free alternative (119). Studies have consistently reported minimal reversible side effects, making these therapies suitable for various patient populations. PDT, which combines light activation with photosensitizers, has shown high efficacy with advantages over systemic drug therapy, including fast results, high selectivity, absence of systemic adverse reactions, and low recurrence rates (126). Light therapy represents a valuable therapeutic option in the modern dermatological toolkit, particularly for patients seeking alternatives to antibiotic-based treatments or those experiencing adverse effects from conventional medications. As technology advances and LED devices become increasingly accessible, light therapy will likely play an expanding role in acne management and broader skin condition treatment (119).

Phototherapy is generally well tolerated with low rates of adverse effects (72). Short- and long-term effects are limited, though long-term safety monitoring remains important (127). Blue light has shown no major adverse effects to date, though long-term studies are needed (128). This favorable safety profile makes phototherapy suitable for extended treatment periods when effectively managed.

Role in wound healing and tissue repair

PBM has emerged as a promising non-invasive therapeutic approach for accelerating wound healing and tissue repair. As the review turns from dermatological indications to tissue repair, this section details how PBM and related modalities facilitate healing at the molecular and clinical levels. This therapy employs light at specific wavelengths in the visible to NIR spectrum to stimulate cellular function and promote the body’s natural healing processes. PBM works through several key biological pathways. At the cellular level, light energy interacts with mitochondrial chromophores, particularly cytochrome c oxidase, leading to increased ATP production (118). This enhanced cellular energy metabolism triggers a cascade of beneficial effects. The therapy modulates ROS and nitric oxide (NO) signaling, which regulate inflammatory responses and support tissue regeneration (129). Additionally, light therapy activates fibroblasts, which are the primary cells responsible for collagen synthesis, thereby enhancing their proliferation, migration, and extracellular matrix remodeling (129). Through these molecular mechanisms, PBM reduces inflammation and accelerates cell migration and proliferation, essential processes for wound recovery (130). Research demonstrates that various light wavelengths show therapeutic potential. Red light and NIR light have proven particularly effective, with specific wavelengths showing superior outcomes (66). A comprehensive meta-analysis revealed significant positive effects across multiple wound healing parameters, with collagen formation showing the most dramatic improvement (effect size of +2.78), followed by increased healing rate and enhanced tensile strength (131). Studies using 808 and 904 nm wavelengths have shown enhanced DNA and protein synthesis, decreased inflammatory markers, and improved wound contraction in burn wounds (132). Additionally, both LED and laser PBM devices demonstrate similar preclinical effects on tissue repair, promoting relevant cellular mechanisms essential for wound healing (67). The therapeutic benefits extend across multiple healing phases. During the inflammatory phase, light therapy dampens excessive inflammation while promoting fibroblast proliferation and extracellular matrix deposition (66). In diabetic wounds, PBM accelerates cell migration and proliferation while reducing oxidative stress (133). The therapy also enhances angiogenesis and lymphatic drainage, addressing common postoperative complications such as edema and tissue swelling (134). Furthermore, optimal treatment parameters reveal that effectiveness follows an inversely proportional relationship between wavelength and intensity, with lower intensities combined with shorter wavelengths producing superior biomodulatory effects (135). While PBM shows considerable promise, clinical translation requires standardized treatment protocols and dosimetry guidelines (118). Future research should focus on biomarker-guided treatment monitoring and personalized therapeutic modeling to optimize outcomes across diverse medical conditions. Despite ongoing development, PBM represents an innovative and accessible approach to enhancing wound healing, offering patients non-pharmacological options with minimal side effects.

Applications in pain management and rehabilitation

PBM therapy offers a non-invasive, safe, drug-free alternative to conventional pain management methods (136). Light therapy works through specific biological mechanisms and has demonstrated effectiveness across multiple musculoskeletal conditions (136). The therapy has shown efficacy in reducing pain intensity associated with diverse conditions, including non-specific knee pain, osteoarthritis, post-surgical pain from total hip arthroplasty, fibromyalgia, temporomandibular disorders, neck pain, and low back pain (136). Low back pain: when combined with exercise therapy, high-intensity laser therapy (HILT) provides superior pain relief and may improve exercise compliance by reducing pain-related limitations, allowing patients to engage more thoroughly in rehabilitation (137). Tendinopathy: low-level laser therapy demonstrates utility as both a standalone and adjunctive treatment for tendinopathy disorders, with greater effectiveness when combined with exercise compared to exercise alone (138). Temporomandibular disorders: both red LED light and low-level laser therapies effectively relieve pain associated with myogenic temporomandibular disorders, with similar efficacy levels (139). Post-fracture recovery: light therapy combined with conventional treatment accelerates pain reduction and prevents complex regional pain syndrome, with treated patients achieving better functional outcomes (140). Beyond musculoskeletal conditions, light therapy has broader applications in brain function modulation and rehabilitation, showing positive regulatory effects on various diseases including mood disorders, cognitive dysfunction, sleep disorders, and pain (141). Light therapy is particularly valuable in rehabilitation settings because it provides a multimodal approach to pain management when combined with other therapeutic interventions (136). Its safety profile and lack of adverse effects make it suitable for diverse patient populations, contributing to high treatment compliance.

Mechanisms of pain modulation through light

The primary molecular mechanism underlying peripheral PBM therapy centers on the interaction between light and cellular mitochondria, specifically targeting cytochrome c oxidase, a key enzyme in the electron transport chain. When red and NIR light (typically 600–1,100 nm) is absorbed by this mitochondrial chromophore, it stimulates oxidative phosphorylation and increases ATP production (141). This enhanced cellular bioenergetic foundation supports a cascade of secondary effects that contribute to pain modulation. Beyond mitochondrial activation, PBM exerts multifaceted effects on cellular metabolism and immune homeostasis, including modulation of ROS production, NO signaling, and cytokine regulation (118). The efficacy of peripherally applied PBM should not be conflated with effects mediated by visual (retinal) exposure. In contrast, recent discoveries in pain research highlight that visual (ocular) exposure to certain wavelengths, such as green light, modulates central pain-processing circuits via the visual system, notably the ventral lateral geniculate nucleus (vLGN). For example, green light exposure (500–565 nm) through the eyes preferentially activates glutamatergic neurons in the vLGN, resulting in antinociceptive (pain-reducing) effects, while red light may activate GABAergic neurons and promote nociceptive responses (142). These visual effects are distinct from and should not be conflated with the direct tissue effects of peripheral PBM.

A particularly important mechanism for green light-based analgesia via visual pathways involves stimulation of the endogenous opioid system. Research has demonstrated that green light-emitting diode exposure stimulates the release of β-endorphin and proenkephalin in the central nervous system, specifically within the spinal cord (143). Both µ- and δ-opioid receptors are required for the antinociceptive effect of green light in both naive animals and those experiencing neuropathic pain. This mechanism provides a biological basis for green light’s effectiveness in managing chronic pain conditions while avoiding the adverse effects associated with exogenous opioid administration (143). In contrast, peripherally applied PBM operates partly through anti-inflammatory mechanisms that reduce neuroinflammatory responses underlying chronic pain states, suppressing mediators such as cyclooxygenase-2 (COX-2) and proinflammatory cytokines in local tissues. The anti-inflammatory and bioenergetic effects of PBM are thus distinct from the central opioid-mediated effects of visually mediated light therapies (Figure 9).

Figure 9 Wavelength-specific mechanisms of light-mediated pain modulation. 1: red and near-infrared light enhance mitochondrial ATP production and activate anti-inflammatory signaling pathways. 2: green and red light differentially modulate neuronal subpopulations within pain-processing circuits such as the vLGN. Green light preferentially activates glutamatergic neurons and induces antinociception, whereas red light can enhance nociceptive signaling via GABAergic pathways. Although green light has demonstrated analgesic effects, its direct impact on mitochondrial function remains unclear and not well established in the literature; most current evidence suggests that green light primarily acts through central nervous system pathways, such as opioid system activation, rather than through mitochondrial modulation. 3: opioid system activation: green light stimulates endogenous opioid release (β-endorphin, proenkephalin) and engages μ- and δ-opioid receptors, contributing to analgesic effects without exogenous opioid administration. 4: PBM also reduces inflammatory mediators (e.g., COX-2, IL-6) and modulates peripheral and central nociceptive pathways. 5-7: therapeutic efficacy depends on wavelength, irradiance, fluence, and exposure route (cutaneous vs. visual). Applications include dental pain, temporomandibular disorders, neuropathic pain, migraine, fibromyalgia, and multimodal analgesia. Emerging approaches integrate personalized dosimetry and photopharmacology to enhance precision in pain management. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; ATP, adenosine triphosphate; IL-6, interleukin 6; LED, light emitting diode; PBM, photobiomodulation; PER2, Period 2; vLGN, ventral lateral geniculate nucleus;

It is critical for both the literature and clinical application to specify the route of light delivery (ocular vs. cutaneous/tissue), the biological target, and the underlying mechanism, as these details determine therapeutic outcomes and interpretation of the evidence base.

Applications for organ protection

Intense light therapy represents an emerging paradigm in organ protection medicine, harnessing the fundamental biological principle that circadian rhythm integrity is essential to physiological homeostasis. Over the past decade, preclinical studies have demonstrated that exposure to intense light can enhance the expression and functionality of key circadian proteins, particularly the Period 2 (PER2) gene product, which orchestrates protective mechanisms across multiple organ systems. This therapeutic approach moves beyond traditional pharmaceutical intervention to leverage the endogenous circadian machinery. However, while animal studies show promise, suggesting that circadian amplitude enhancement through intense light exposure can protect organs from acute injury, including bacterial infection, ischemic injury, and hemorrhagic shock, human clinical evidence remains sparse and largely preliminary at this time. The circadian clock is far more than a timekeeping mechanism; it represents a fundamental regulatory system that coordinates multiple physiological processes essential for survival. At the molecular level, clock genes including PER1/PER2, cryptochrome (CRY), Clock, and Bmal1 function together to generate a self-sustaining oscillatory network. This molecular circadian circuit drives rhythmic gene expression patterns that optimize cellular metabolism, immune function, DNA repair, and stress responses (34). When circadian rhythms are intact and properly entrained to environmental light-dark cycles, organisms display enhanced resilience to injury and disease. Conversely, circadian disruption, whether from irregular light exposure, shift work, or other chronodisruptive factors, is associated with increased susceptibility to infections, metabolic dysfunction, cardiovascular disease, and cancer (144). Among the circadian clock proteins, PER2 has emerged as a particularly critical regulator of organ protection. PER2 functions as a transcriptional regulator that couples circadian timekeeping with multiple protective pathways. The amplitude of circadian rhythms, the magnitude of oscillation between peak and trough expression levels of circadian genes, is a key determinant of physiological robustness. Greater circadian amplitude is associated with more dramatic daily fluctuations in gene expression, which optimizes cellular preparedness for predictable daily challenges and stresses (144). Recent studies have demonstrated that housing animals under intense light conditions rather than ambient light significantly enhances circadian amplitude, particularly in PER2 expression levels. When mice are exposed to intense light using light-dark cycles with extended light periods (such as 14 hours light:10 hours dark, representing approximately 10,000 lux), pulmonary PER2 trough and peak levels increase robustly, resulting in a markedly increased circadian amplitude (34). The enhancement of circadian amplitude through intense light exposure has profound implications for immune function and inflammatory control. Circadian rhythms regulate virtually all aspects of immune cell biology, including migration, differentiation, homing, and effector functions (71). Key immune mediators including cytokines, chemokines, and adhesion molecules display strong circadian oscillations, with peak expression at times optimized for pathogen defense. PER2 specifically regulates multiple components of innate immunity, including the inflammasome, toll-like receptor signaling, and neutrophil recruitment (144). The maintenance and enhancement of robust circadian amplitude is therefore critical for preserving efficient immune surveillance and enabling rapid, proportionate responses to pathogenic threats. Furthermore, circadian disruption has been shown to impair immune tolerance and increase susceptibility to autoimmune disease (145). The reciprocal relationship between circadian amplitude and immune homeostasis suggests that therapeutic approaches aimed at enhancing circadian amplitude through intense light may confer broad benefits beyond protection against acute infection, potentially improving outcomes in chronic inflammatory conditions and autoimmunity as well (146) (Figure 10).

Figure 10 Intense light therapy enhances circadian amplitude for multisystem organ protection. Intense light exposure (e.g., 10,000 lux, extended light-dark cycles) increases circadian amplitude, particularly through upregulation of PER2 within the molecular clock network (PER/CRY/CLOCK/BMAL1). Enhanced circadian oscillations optimize gene expression programs involved in metabolism, innate immunity, and stress resilience. This amplification of circadian signaling improves organ protection against infection, ischemia, and hemorrhagic shock in lung, heart, and kidney. In contrast, circadian disruption (e.g., shift work, irregular light exposure) reduces resilience and increases susceptibility to inflammatory, metabolic, and cardiovascular disease. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; PER2, Period 2.

Light therapy in lung injury

One of the most striking discoveries in intense light therapy research concerns the cell-type-specific protective roles of PER2 in the lung. Using a series of elegant experiments employing genetic deletion of Per2 in specific lung cell populations, researchers compared mice with Per2 deletion in alveolar type II (ATII) cells, endothelial cells, or myeloid cells. This head-to-head comparison revealed a dramatic and unexpected phenotype: only the mice with Per2 deletion specifically in ATII cells showed catastrophic susceptibility to bacterial pneumonia (34). The experimental results were striking in their clarity and magnitude. When challenged with Pseudomonas aeruginosa-induced ALI, mice lacking functional PER2 specifically in ATII cells demonstrated 0% survival, while 85% of control mice with intact PER2 in ATII cells survived the same bacterial challenge (34). This represents a complete failure of the alveolar epithelial barrier and immune response in the absence of ATII-specific PER2, demonstrating that this single genetic modification and eliminating one circadian protein in a single cell type is sufficient to render animals completely susceptible to a serious bacterial infection. Subsequent mechanistic studies demonstrated that intense light therapy exerted protective effects during Pseudomonas aeruginosa-induced ALI through multiple coordinated mechanisms. First, intense light dampens excessive pulmonary inflammation, preventing the tissue-damaging inflammatory response that can occur during bacterial infection. Second, intense light improved alveolar barrier function, maintaining the critical epithelial tight junctions that prevent bacterial translocation and fluid accumulation in the alveolar space (34). Both of these protective effects were completely abolished in mice lacking functional ATII-specific PER2, definitively establishing that the protective effects of intense light in bacterial pneumonia are entirely dependent on PER2 function in these specialized lung epithelial cells. To understand the molecular mechanisms by which ATII-specific PER2 protects against bacterial lung injury, researchers performed genome-wide mRNA microarray analysis. These unbiased screening experiments identified bactericidal/permeability-increasing fold-containing family B member 1 (BPIFB1) as a critical downstream target of intense light-elicited ATII-PER2 mediated lung protection (34). BPIFB1 is a member of the lipopolysaccharide-binding protein family and plays direct antibacterial roles as well as roles in immune regulation. The identification of BPIFB1 represents an important step toward understanding the complete molecular cascade through which light-enhanced PER2 protects the lung. The practical implications of this work became more apparent with the discovery that the pharmacological enhancement of PER2 using small-molecule activators can recapitulate the protective effects of intense light. Nobiletin, a polymethoxylated flavonoid derived from citrus peel, functions as a PER2 amplitude enhancer (34). When mice were treated with nobiletin, researchers observed that both the lung-protective and anti-inflammatory effects previously achieved with intense light were reproduced, and this protection was mediated through the same BPIFB1 pathway. This cross-validation using both environmental (intense light) and pharmacological (nobiletin) approaches to enhance PER2 provides strong evidence that the protective mechanisms are specific to PER2 activation and circadian amplitude enhancement rather than off-target or non-specific effects of light exposure (37). The findings in bacterial pneumonia establish a new paradigm for understanding the relationship between circadian homeostasis and infectious disease. Prior to these studies, while circadian regulation of immune function was well-established, the magnitude of protection conferred by intact circadian signaling in a specific cell type had not been quantified. The complete failure of immune defense in mice lacking ATII-specific PER2 suggests that circadian disruption in critical cell types may be a significant but underappreciated contributor to susceptibility to respiratory infections in humans. This is particularly relevant in clinical populations prone to circadian disruption, including intensive care unit patients, shift workers, and individuals with sleep disorders (Figure 11).

Figure 11 Cell-type-specific roles of PER2 in lung protection: using a conditional knockout approach employing genetic deletion of Per2 in specific lung cell populations, researchers compared mice with Per2 deletion in ATII cells, endothelial cells, or myeloid cells. These experiments demonstrated that PER2 in ATII cells is essential for survival in Pseudomonas aeruginosa-induced ALI, whereas deletion in endothelial or myeloid cells does not abolish protection. Intense light exposure or pharmacologic PER2 enhancement (nobiletin) increases circadian amplitude and upregulates BPIFB1 in ATII cells, promoting antibacterial defense, reducing inflammation, and preserving alveolar barrier integrity. Loss of ATII-specific PER2 eliminates these protective effects, highlighting a cell-type-specific circadian mechanism of lung resilience with potential clinical relevance in populations with circadian disruption. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; ALI, acute lung injury; ATII, alveolar type II; BPIFB1, bactericidal/permeability-increasing fold-containing family B member 1; ICU, intensive care unit; KO, knockdown; LPS, lipopolysaccharide; PER2, Period 2; WT, wild-type.

Light therapy in ischemia reperfusion injury

Myocardial ischemia-reperfusion (IR) injury remains one of the most significant clinical challenges in cardiovascular medicine. While timely restoration of coronary blood flow through percutaneous coronary intervention or thrombolytic therapy is essential for salvaging ischemic myocardium, the reperfusion process itself paradoxically causes additional injury. During the initial minutes of reperfusion, a sudden burst of ROS production, calcium overload, and inflammatory activation can damage myocardial tissue, sometimes accounting for up to 50% of the final infarct size (9). This harsh reality has motivated decades of research aimed at developing cardioprotective therapies to limit reperfusion injury, yet clinical translation of most promising preclinical approaches has proven frustratingly difficult. Building on earlier work establishing PER2 as a cardioprotective protein, researchers identified a specific molecular pathway through which light-enhanced PER2 confers protection during myocardial IR injury. This pathway centers on the interaction between PER2 and the hypoxia-inducible transcription factor hypoxia-inducible factor 1 alpha (HIF1A). During ischemia, HIF1A is stabilized in response to low oxygen, triggering a transcriptional program that includes the expression of angiopoietin-like 4 (ANGPTL4) (6). ANGPTL4 is an endothelial-specific factor with critical roles in maintaining the integrity of the endothelial barrier, the cellular lining of blood vessels that is particularly vulnerable to reperfusion-induced injury. During reperfusion, excessive vascular permeability can develop due to calcium overload and oxidative stress in endothelial cells, leading to microvascular edema, myocardial hemorrhage, and inflammatory cell infiltration. The endothelial protective factor ANGPTL4 helps maintain tight junctions between endothelial cells, preserving barrier function and preventing these reperfusion-mediated complications (6). Critically, studies using endothelial-specific Per2-deficient mice demonstrated that the HIF1A activator dimethyloxalylglycine (DMOG) and the PER2 enhancer nobiletin could protect from myocardial IR injury in control mice, but these protections were abolished in mice lacking endothelial PER2. However, when recombinant ANGPTL4 was administered directly, it was able to overcome the endothelial PER2 deficiency and provide protection during myocardial IR injury (6). This elegant series of experiments established that ANGPTL4 functions as the critical downstream effector through which PER2 and HIF1A coordinate cardioprotection, and that activation of this pathway is both necessary and sufficient for limiting IR injury. Moving beyond animal models, researchers conducted a groundbreaking preliminary human study examining whether intense light therapy could activate the PER2/HIF1A/ANGPTL4 pathway and reduce cardiac injury in patients. The study enrolled patients undergoing elective spine surgery, a procedure known to carry risk of perioperative myocardial injury [myocardial injury in non-cardiac surgery (MINS)]. Postoperatively, patients were exposed for 5 days to intense light for 30 min at sunrise. Plasma samples were collected and analyzed for melatonin, ANGPTL4, and cardiac troponin levels (6). The results provided the first clinical evidence that intense light therapy can activate the protective pathway identified in animal models. Patients receiving intense light therapy demonstrated significantly increased plasma levels of ANGPTL4, consistent with activation of the PER2/HIF1A/ANGPTL4 pathway. More importantly, these patients also showed decreased troponin plasma levels, an indicator of reduced myocardial injury, when compared to historical controls and baseline measurements (6). While these preliminary results require validation in larger, more rigorous trials, they provide the first clinical evidence supporting the translational potential of intense light therapy for cardiac protection in surgical patients. The identification of the PER2/HIF1A/ANGPTL4 pathway and its modulation by intense light has significant implications for perioperative medicine. Perioperative myocardial injury is a common and serious complication affecting approximately 8% of patients undergoing noncardiac surgery, with profound impacts on morbidity and mortality. Current preventive strategies, including beta-blockers, statins, and antiplatelet agents, have provided only modest improvements in outcomes. The identification of a novel, circadian-based protective pathway offers a fundamentally different therapeutic target and suggests that timing of surgical procedures or perioperative light exposure may represent overlooked variables in optimizing cardiac outcomes (9). Hemorrhagic shock represents a critical condition characterized by insufficient tissue perfusion due to severe blood loss, leading to widespread organ dysfunction, irreversible shock, and death if not rapidly corrected. The pathophysiology of hemorrhagic shock involves not only the direct effects of decreased oxygen delivery but also a complex cascade of inflammatory responses triggered by tissue hypoxia and reperfusion injury during resuscitation. In military medicine, hemorrhagic shock is the leading cause of preventable death in combat casualties, making the development of novel protective strategies a high priority (91). In a murine model of hemorrhagic shock, researchers investigated whether pretreatment with intense light could improve outcomes during the shock and resuscitation period. Mice were housed under either standard room light or intense light (10,000 lux) prior to being subjected to 90 min of hemorrhagic shock with maintenance of mean arterial pressure (MAP) at 30–35 mmHg. Following this hemorrhagic episode, mice were resuscitated with their own shed blood and saline infusion over a 3-hour period (91). The results demonstrated significant protective effects of intense light pretreatment. Mice that had been pretreated with intense light exhibited improved hemodynamics during the resuscitation phase, recovering to higher blood pressures and more stable cardiovascular parameters compared to controls. More importantly, at the end of resuscitation, bronchoalveolar lavage fluid analysis revealed significantly lower markers of alveolar epithelial injury and inflammation in the intense light-pretreated animals. Specifically, albumin, interleukin-6 (IL-6), and interleukin-8 (IL-8) levels in the bronchoalveolar lavage were substantially reduced compared to controls, indicating that intense light pretreatment had suppressed the excessive inflammatory response that characterizes hemorrhagic shock and IR injury (91).

To explore the relevance of these findings to human pathophysiology, researchers performed a proteomics screen examining the effects of intense light therapy on lung injury biomarkers in plasma from healthy volunteers. Following intense light therapy administered to healthy subjects, plasma proteins known to promote ALI and inflammation were significantly downregulated. This finding suggests that the anti-inflammatory effects of intense light observed in the hemorrhagic shock model are not confined to mice but represent a genuine biological phenomenon relevant to human physiology (91). The protection against hemorrhagic shock-induced organ injury provided by intense light pretreatment has direct implications for trauma and critical care medicine. In the acute care setting, opportunities for pretreatment are limited; however, the mechanisms by which light pretreatment enhances resilience to shock may inform the development of pharmacological approaches that could be rapidly administered to trauma patients. Furthermore, for patients undergoing elective high-risk surgery with anticipated blood loss, perioperative light exposure optimization might represent a simple, low-cost intervention to enhance physiological reserve and reduce complications (Figure 12).

Figure 12 Mechanism and clinical potential of intense light therapy in ischemia-reperfusion and hemorrhagic shock injury. Coronary artery occlusion induces myocardial ischemia. Upon reperfusion, a burst of ROS, calcium overload, and inflammatory cell activation leads to endothelial and myocardial injury, contributing substantially to infarct size. Intense light exposure enhances PER2 expression and activates the PER2/HIF1A/ANGPTL4 pathway, promoting endothelial barrier integrity and limiting oxidative stress, inflammation, and calcium overload during myocardial ischemia-reperfusion injury. ANGPTL4 preserves tight junctions, reduces vascular leakage, and attenuates myocardial damage. In surgical patients, perioperative intense light increased plasma ANGPTL4 and reduced troponin levels, suggesting decreased myocardial injury (MINS). In murine hemorrhagic shock models, light pretreatment improved hemodynamic stability and reduced inflammatory markers with translational anti-inflammatory effects observed in human plasma proteomics. Collectively, these findings support intense light therapy as a potential circadian-based adjunct for organ protection in perioperative and critical care settings. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. AI, artificial intelligence; ANGPTL4, angiopoietin-like 4; HIF1A, hypoxia-inducible factor 1 alpha; IL-6, interleukin 6; IL-8, interleukin 8; IR, ischemia-reperfusion; MAP, mean arterial pressure; MINS, myocardial injury in non-cardiac surgery; PER2, Period 2; ROS, reactive oxygen species.

Light in clotting disorders

Platelet function exhibits pronounced circadian variation under the control of endogenous and exogenous circadian cues, with platelet reactivity demonstrating peak values in the early morning (147). PER2 directly regulates multiple aspects of platelet physiology, including aggregation responses to various agonists, secretory granule release, and integrin-mediated adhesion (92). Studies utilizing tissue-specific knockout approaches have demonstrated that ablation of Per2 in the megakaryocyte lineage results in significantly accelerated platelet aggregation and shortened clotting times, phenocopying a prothrombotic state (92). Notably, these Per2-deficient platelets display enhanced responsiveness to both thrombin and adenosine diphosphate (ADP), suggesting that PER2 functions as a negative regulator of platelet activation (92). Beyond direct effects on platelet function, PER2 regulates the expression and activity of key coagulation factors, tissue factors (TFs), von Willebrand factor (vWF), and fibrinolytic enzymes. The circadian regulation of TF, the primary initiator of the extrinsic coagulation cascade, demonstrates highest expression during early morning hours, coinciding with peak myocardial infarction incidence (148). PER2 expression inversely correlates with TF activity, suggesting that enhanced PER2 levels suppress TF-mediated coagulation initiation (148). Additionally, the fibrinolytic system exhibits circadian variation in plasminogen activator inhibitor (PAI-1) expression, with elevated PAI-1 levels in the early morning reducing fibrinolytic capacity and promoting thrombotic potential (148). These coordinate temporal changes in procoagulant and anticoagulant factors underscore the sophisticated circadian control of hemostatic balance. Recent studies demonstrating that intense light therapy directly inhibits blood coagulation in both preclinical models and human subjects represent a paradigm shift in understanding light’s biological effects (92). Intense light exposure administered for 30 min daily at approximately 1,300 lux (comparable to bright sunlight) increases PER2 protein levels in multiple tissue compartments including the heart, endothelium, and megakaryocytes within hours of light administration (6). Remarkably, this light-elicited PER2 enhancement produces a pronounced anticoagulant effect, with whole blood from light-exposed subjects demonstrating significantly prolonged clotting times and reduced prothrombin complex activation (92). These anticoagulant effects occur without affecting bleeding times, indicating that light therapy suppresses secondary hemostasis (coagulation cascade) while preserving primary hemostasis (platelet plug formation), thereby reducing thrombotic risk without increasing hemorrhagic risk. The mechanisms by which light-enhanced PER2 inhibits coagulation involve multiple coordinated effects on both cellular and acellular coagulation pathways. In platelets, elevated PER2 expression directly reduces aggregation responses to agonists by altering calcium mobilization, integrin signaling, and cytoskeletal dynamics (92). At the endothelial level, PER2 enhancement increases the expression of anticoagulant molecules including thrombomodulin, endothelial protein C receptor (EPCR), and tissue factor pathway inhibitor (TFPI), while simultaneously reducing TF expression (44). These coordinated changes at the endothelial surface shift the balance from procoagulant to anticoagulant, thereby reducing thrombus initiation and propagation. Furthermore, light-enhanced PER2 increases the expression and activity of natural anticoagulants (protein C, protein S, antithrombin) and fibrinolytic enzymes (tissue plasminogen activator, urokinase plasminogen activator), creating a holistic antithrombotic environment. Beyond direct effects on coagulation cascade components, light therapy enhances endothelial barrier function through multiple PER2-dependent mechanisms, which indirectly reduces thrombotic risk by limiting cellular adhesion molecule expression and leukocyte-endothelial interactions (92). Endothelial dysfunction characterized by increased permeability, adhesion molecule expression (ICAM-1, VCAM-1, selectins), and reduced NO bioavailability represents a critical early step in both atherothrombotic disease initiation and acute thrombotic events (149). PER2-mediated enhancement of endothelial barrier function through ANGPTL4 signaling reduces the exposure of subendothelial TF to circulating platelets, thereby reducing thrombus initiation on the vessel wall (8). Additionally, PER2 regulates endothelial-derived nitric oxide (NO) production through multiple pathways, including direct transcriptional control of endothelial nitric oxide synthase (eNOS) and indirect effects through enhanced vascular endothelial growth factor (VEGF) signaling (148). NO functions as a potent platelet inhibitor and vasodilator, with reduced NO bioavailability contributing significantly to thrombotic diseases including atherosclerosis and acute coronary syndromes (150). Light-enhanced PER2 increases eNOS expression and activity, thereby elevating endothelial NO production and providing sustained platelet inhibition and improved vascular tone regulation (8). These endothelial protective mechanisms represent an important distinction between light therapy and conventional anticoagulation, as anticoagulant drugs typically provide no direct vascular protection and may in some cases increase vascular permeability.

The circadian timing of light therapy administration proves critical for maximizing therapeutic benefit, with recent evidence demonstrating that light therapy administered during the early dark phase (simulating pre-dawn/early morning light) produces superior anticoagulant and cardioprotective effects compared to light therapy administered during the light phase (151). This finding aligns with the endogenous circadian rhythm of PER2 expression and other hemostatic factors. When light therapy is administered at zeitgeber times consistent with early morning (ZT12-ZT14 in nocturnal rodents), the light-elicited enhancement of PER2 occurs precisely when endogenous PER2 levels are beginning to increase naturally, thereby amplifying the physiological rhythm and producing maximal effects (151). Conversely, light therapy administered during peak circadian PER2 expression (late dark phase, ZT18-ZT22) produces smaller incremental increases in PER2 and corresponding smaller therapeutic benefits (151).

These timing-dependent effects have important clinical implications, suggesting that light therapy protocols should be standardized to early morning administration to align with endogenous circadian biology. A typical effective protocol involves 30 min of intense light exposure administered between 30 min before and 1 hour after habitual wake time (6,8,23,92). This timing optimizes the circadian phase-advancing effects of light and maximizes PER2 enhancement during the critical morning hours when endogenous hemostatic prothrombotic factors peak naturally. Importantly, adherence to consistent daily light exposure timing proves essential for maintaining the cardioprotective and anticoagulant effects, as inconsistent light exposure patterns disrupt the entrained circadian rhythm and reduce therapeutic benefit (77).

Light therapy appears to partially normalize the circadian variation in thrombotic risk through sustained enhancement of PER2 expression and consequent suppression of prothrombotic factors across all circadian phases (151). Studies examining circadian variation in coagulation parameters in light therapy-treated subjects demonstrate flattened circadian rhythms with reduced amplitude of diurnal coagulation oscillations, resulting in lower peak prothrombotic factor levels in early morning and reduced circadian variation in thrombotic risk (151). This “circadian normalization” effect may explain why light therapy produces consistent anticoagulant effects throughout the day despite being administered only once daily in early morning (151).

As with many chronobiological interventions, response to light therapy exhibits substantial interindividual variability based on factors including circadian phase preference (chronotype), baseline Per2 expression levels, genetic variations in circadian clock genes, age, and comorbid conditions (77). Recent research has identified genetic polymorphisms in Per2 (rs35333999), Clock, and Cry2 genes that associate with altered cardiovascular risk and potentially predict responsiveness to light therapy (152). Patients carrying protective alleles in circadian clock genes demonstrate baseline resistance to myocardial infarction and potentially greater benefit from light therapy, whereas those with pro-thrombotic genotypes may require higher intensity or more frequent light therapy. Additionally, chronotype (inherent preference for early or late sleep timing) significantly modulates light therapy responsiveness, with morning-type individuals showing greater baseline PER2 expression and potentially less additional benefit from light therapy, whereas evening-type individuals with phase-delayed circadian rhythms demonstrate maximal PER2 enhancement and cardioprotection following light therapy (153). Future clinical application of light therapy should incorporate circadian phenotyping through questionnaires (Morningness-Eveningness Questionnaire) or objective measures (actigraphy, dim-light melatonin onset) to identify patients likely to benefit most from light therapy and to personalize the timing and intensity of light exposure. In conclusion, intense light therapy represents a paradigm shift in organ protection, moving from acute pharmacological intervention to physiological system optimization. As understanding of circadian biology deepens and clinical evidence accumulates, circadian medicine will likely become standard care in perioperative and critical care settings, representing a new frontier in precision medicine and personalized health optimization. The translation of intense light therapy from bench to bedside has the potential to substantially improve outcomes in patients facing life-threatening organ injury, while simultaneously advancing our fundamental understanding of how biological timing systems regulate health, disease, and survival (Figure 13).

Figure 13 Intense light therapy in circadian regulation of blood coagulation. Platelet reactivity and coagulation factors exhibit pronounced early-morning peaks, coinciding with increased thrombotic risk. PER2 acts as a negative regulator of platelet activation and TF-mediated coagulation. Genetic deletion of Per2 in megakaryocytes accelerates aggregation and shortens clotting time, supporting its antithrombotic role. Intense light exposure enhances PER2 expression in platelets and endothelium, reduces platelet aggregation, suppresses TF activity, and increases anticoagulant pathways (thrombomodulin, EPCR, TFPI, protein C/S) while preserving primary hemostasis. Light-enhanced PER2 also improves endothelial barrier integrity and nitric oxide signaling. Morning-timed light therapy flattens circadian variation in prothrombotic factors, reducing peak thrombotic risk. Clinical translation supports early-morning light exposure as a potential non-pharmacological strategy to lower thrombosis risk without increasing bleeding complications. This illustration was generated via the FigureLabs AI-assisted scientific illustration platform and subsequently edited in Inkscape. EPCR, endothelial protein C receptor; NO, nitric oxide; PER2, Period 2; SCN, suprachiasmatic nucleus; TF, tissue factor; TFPI, tissue factor pathway inhibitor.

Conclusions

Light therapy operates through several key biological pathways. One mechanism centers on PBM, where red and NIR light (600–1,100 nm) interacts with mitochondrial cytochrome c oxidase, stimulating oxidative phosphorylation and increasing ATP production. Beyond mitochondrial activation, light therapy modulates cellular metabolism through effects on ROS, NO signaling, and cytokine regulation. Notably, different wavelengths produce distinct effects: green light (500–565 nm) and red light activate different neuronal populations within pain-processing circuits, resulting in opposite pain modulation effects. Green light specifically stimulates endogenous opioid release, providing a biological mechanism for managing chronic pain without exogenous opioid administration. In pain management, PBM provides relief for musculoskeletal disorders, temporomandibular disorders, post-fracture recovery, and neuropathic pain conditions, though the strength of evidence varies and is often limited to moderate clinical studies or preliminary data. For instance, studies of neuropathic pain demonstrate rapid reduction from baseline pain scores of 7.6 to 3.9 within one month, outperforming standard pharmacological therapies in small trials, but broad clinical adoption requires further validation. Light therapy also shows promise for multimodal analgesia when combined with conventional pain management strategies, reducing reliance on pharmaceuticals while maintaining pain control, though these findings should be interpreted as exploratory.

A particularly significant area of ongoing research involves intense light therapy’s potential role in organ protection through circadian rhythm enhancement. Preclinical studies show that intense light exposure increases PER2 protein expression, which orchestrates protective mechanisms across multiple organ systems. For example, in bacterial pneumonia models, animals with intact PER2 in alveolar epithelial cells had an 85% survival rate, compared with 0% in PER2-deficient mice. Similar protective pathways have been reported in animal models of myocardial IR injury and hemorrhagic shock. While these results are compelling, clinical evidence in humans remains preliminary, and further studies are needed to determine translational relevance. Table 2 summarizes current light therapy applications and their evidence levels.

Light therapy demonstrates excellent safety profiles with minimal adverse effects, making it suitable for diverse patient populations. The review emphasizes that while clinical translation is advancing, continued research is necessary to standardize dosimetry and optimize therapeutic protocols for consistent clinical outcomes. While light therapy may represent a paradigm shift in clinical medicine, moving from acute pharmaceutical intervention toward physiological system optimization and precision medicine approaches, this perspective requires further validation as evidence accumulates. It is essential that future research clearly distinguishes among established clinical applications, exploratory findings, and preclinical mechanisms to avoid overstating the field’s maturity.

Acknowledgments

We would like to acknowledge Uwe Mueller and Frans van Beers from 24LUMO for their scientific input on light therapy as a circadian regulator. We further acknowledge the support of the FigureLabs AI-assisted scientific illustration platform. Illustrations were generated via this platform and subsequently edited in Inkscape.

Footnote

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0041/prf

Funding: This work was supported by National Heart, Lung, and Blood Institute (NIH-NHLBI) (No. R56HL156955, to T.d.l.G.E.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0041/coif). T.d.l.G.E. serves as an unpaid editorial board member of Annals of Translational Medicine from November 2025 to December 2027. T.d.l.G.E. also reports support from the National Heart, Lung, and Blood Institute. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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