Supplements and Topicals that Enhance Red Light Therapy: Combination Therapy

What supplements can you take to make red light therapy more effective? Are there topicals to apply to the skin that enhance red light therapy benefits? Can taking antioxidants improve the effects of red light therapy by mitigating the ROS production? Or do they have negative effects by increasing photosensitivity and reducing the beneficial ROS?

Red Light Therapy is a great way to support a wide variety of health and wellness goals.

However, Light only provides cellular energy and signalling, but our cells still need the basic building blocks from proper diet and hydration to function optimally.

Like most holistic alternative treatments, red light therapy is optimized by combining it with proper macro-nutrients, micro-nutrients, vitamins, minerals, antioxidants, and healthy lifestyle choices like sleep and exercise.

In this blog we seek to identify some synergistic supplements and topicals that have been used in the Red Light Therapy clinical literature. In this way it helps us learn about the mechanisms and methods of these interactions to help improve red light therapy.

Summary:

We categorized several types of supplements and topicals that have been used in red light therapy studies.

Complimentary/Holistic Combinations:

• Simply combine PBM with exercise, physical therapy, and nutrition that helps support your wellness goals in complimentary ways - even if they are not directly synergistic.

Mitochondria Support - Electron Donors:

• Methylene Blue
• Coenzyme Q₁₀ (CoQ10) / Ubiquinol
• Quercetin
• Curcurmin

Nitric Oxide Donors:

• Arginine
• Citrulline

Antioxidants:

• N-acetyl cysteine (NAC)
• Molecular Hydrogen
• Vitamin C
• Resveratrol
• Chia Seeds

Metals:

• Iron and Copper play an important role in mitochondrial function and should be checked if they are in the normal range.

Blue Light and UV Photoprotection:

• Niacinamide (aka Nicatiomide, a form of Vitamin B3)
• Cartenoids (beta-carotene, lutine, astaxanthin)
• Vitamin E

Herbal Extracts:

• Green Tea?
• Goji Berry Extract
• Other Herbal Extracts

Practical Recommendations:

• Always start with Red Light Therapy alone and minimize other dietary or supplement changes so you can monitor your body's response to red light therapy on it's own.
• Most of these are small studies, often on small animals or isolated tissues, which would only lead to speculation that these supplements may enhance red light therapy benefits. So it may be a good idea to abstain from any of these supplements or topicals until more comprehensive data arrives. Especially since some of the data shows downsides to these combinations as well as benefits.
• Most red light therapy studies do not involve additional interventions, showing that most benefits of red light therapy can be gotten entirely on it's own without extra interventions other than common-sense diet and lifestyle improvements.
• Work with a practitioner to evaluate additional supplements, dietary changes, or topicals are appropriate for your condition. As always start low and slow even with supplements to see how your body responds.
• The preliminary data shows that topicals should be applied after red light therapy treatment has ended. There is a high risk of a photosensitization effect if applying topicals before red light therapy. So we still recommend the optimal use of red light therapy is on clean dry bare skin whenever possible.

Precautions: More Effective or Photosensitive?

We should be mindful of precautions when combining Red Light Therapy and other interventions. Always consult a doctor when considering adding red light therapy or supplements for your particular condition.

There are two major potential drawbacks to "enhancing" red light therapy effects with additional supplements or topicals.

1. Hindering ROS

Chugging antioxidants and slathering them on the skin can inhibit the benefits of red light therapy when used recklessly. A major benefit of Red Light Therapy has been the production of signalling ROS. Taking away that mechanism must be carefully considered depending on the context.

Bodybuilders have already learned a long time ago that even though taking antioxidants seems to reduce muscle soreness, it actually hinders the the gains by blunting the ROS and RNS produced by exercise that would promote growth. [1]

Another study mentions the usage of antioxidants on healthy individuals have no apparent benefit, but only speculative benefits on reducing excess ROS that could lead to age-related illness. [2]

"chronic supplementation with mitochondrial-targeted antioxidants may not be immediately beneficial to healthy individuals but may offer some protection against future development of mitochondrial-ROS related pathologies, particularly in those individuals with antioxidant deficiencies (Margaritelis et al.2 018; Paschalis et al. 2018)." [2]

2. Photosensitization

Anything that claims to "increase absorption" or "increase effectiveness" can act as a photosenitizer too. Essentially, we still need to consider biphasic dose response and possibly reduce the therapeutic dose required.

In that way these supplements don't inherently "enhance" red light therapy at all, but now you need to titrate the dose of red light therapy and juggle titrating the dose of additional supplements to see how they interact. Adding more variables like supplementation doesn't automatically improve red light therapy, it just makes it more complicated.

In most sections as we review different supplements and topicals, we will also note where the same exact combination can decrease the effectiveness of photobiomodulation.

A different form of light therapy is called Photodynamic Therapy (PDT). PDT is intentionally meant to damage or inhibit unwanted cells like bacteria or cancer cells. They use a photosensitizer chemical that enhances light absorption, then the appropriate wavelength to cause damage. Examples of photosensitizers are Methylene Blue, Curcurmin, Arginine, and Ascorbic Acid - which are the exact same we will also note can be synergistically beneficial to red light therapy in lower doses. [3][4][5][6]

So we should take pause when supplements or topicals claim to enhance light absorption, since that would imply it could have a PDT effect and not a PBM effect.

Holistic Combinations

The examples in this section illustrate the need to combine red light therapy with other holistic interventions to maximize results. In other words, these examples are not specifically synergistic to red light therapy, but simply help fulfill the goals and benefits by using multiple modalities.

Kitchen Sink Approach

The best clinical example of a holistic approach was a case study recently published in September 2023 in the Journal of Avian Medicine and Surgery.

In it, a parrot had suffered a spinal cord injury and was struggling with it's health. The treatment was to administer fluids, Vitamin A, D, E, anti-inflammatory drugs and painkillers. It also underwent Photobiomodulation, acupuncture, Tui-na massage, and rehabilitation exercises. After 20 days it was released with significant improvement. [7]

So it is valuable to consider a near-future that photobiomodulation is not only a standard of care, but will be used as a combination therapy with other modalities that help achieve the health goals of the patient.

Hair Growth Combination:

One article combined Red Light Therapy and several topical treatments including arginine (Arg), arterial extract (AE) or biotin tripeptide-1 (BT-1) enhanced the effectiveness of the treatment. [93]

Hashimotos Thyroid Combination:

One article combined Vitamin D and Selenium supplementation with PBM for treating the thyroid. They also advised all participants to avoid gluten and sugar.

They found that the PBM+Supplements group performed significantly better than the Supplements-Only group. [94]

Weight and Health Markers:

One study combined Low Level Laser Therapy (LLLT) with the Mediterranean Diet to help manage fatty liver disease and help weight loss. [8]

Another study combined LLLT with exercise and found an improvement over exercise alone to improve lipid markers and manage weight. This study was performed on rats being fed a high-fat diet, and interestingly they tended to gain more weight with LLLT alone without exercise. [9]

Exercise and PBM for Pain Management:

One study treated osteoarthritis by combining LLLT and exercise - and found the combination worked best. [10]

Another study on chronic low back pain combined LLLT, spinal manipulations (chiropractic adjustments), and exercise. They found the combination of all 3 treatments performed best. [11]

This is essentially what I did to solve my own personal chronic low back pain several years ago. It likely would not have been resolved with light therapy alone, it was in combination with working with a chiropractor and exercises.

B Vitamins and PBM

One study combined B Vitamins and PBM to manage neuropathic pain in rats. They found the combination worked faster than the individual interventions.[12]

For reference, here are the B Vitamins used for this trial on combination with PBM:

"vitamins B complex, thiamine, pyridoxine and cyanocobalamin (B1, B6 and B12, respectively)". [12]

Another study also used B Vitamins and PBM to treat pain in rats. While all groups showed an improvement, the combination did not show a significant advantage over the individual interventions. [13]

Weight Loss and Body Circumference:

A review of LLLT on fat reduction makes this statement about the recommended supplements to combine with the LLLT treatments.

"In addition, manufacturers encourage consumers to use some supplements such as vitamin B5 and L-carnitine, Ginkgo biloba or green tea to reinforce circulatory and lymphatic systems (56)." [14]

Another study made this comment that the results were confounded by the combination of supplements and LLLT. Even though the patients lost significant inches during the trial, they can't say for sure if it was from the LLLT, the supplements, or the combination.[15]

"However, the study had several limitations such as lack of control group as well as administration of dietary supplements (niacin, niacinamide, l-carnitine, omega-3 fish oil, ginko biloba, and decaffeinated green tea) in the study subjects [68]." [15]

So despite confounding the variables, it may be complimentary to take some of these supplements if the goal is weight loss or reduced body circumference.

Mitochondrial Support: Electron Donor Supplements 

Now lets look at some supplements that offer synergistic mechanisms to red light therapy.

The following supplements not only have obvious antioxidant and anti-inflammatory actions, but specifically support mitochondrial function that have been studied to be synergistic with Red Light therapy.

• Methylene Blue
• Ubiquinol / CoQ10
• Quercetin
• Curcumin

On the mitochondrial membrane is the Electron Transport Chain, which we know Photobiomodulation up-regulates primarily through Complex IV called Cytochrome C Oxidase (CCO). CCO is the "rate limiting" step on the chain to produce ATP, which is why Photobiomodulation is extremely effective entirely on it's own.

Other studies confirm PBM up-regulates Complex III also.[16] And we know that from the EZ Water mechanism that PBM improves Complex V aka ATP Synthase.

As the name implies, the Electron Transport Chain facilitates the transfer of electrons through various exchanges that we know as Oxidation and Reduction. These chemical reactions are two sides of the same coin, often shortened to Redox Reactions.

Thus, while red light therapy will mostly upregulate CCO and ATP Synthase (Complex IV and V), it is often helpful to the mitochondria to have supplements that support Redox and the other steps of the Electron Transport Chain.

Methylene Blue, Ubiquinol (CoQ10), Quercetin, and Curcumin are all related to each other via the Quinone family of chemicals. Either in their original state like MB and CoQ10, or in their oxidized states like Quercetin and Curcumin. [17]

Essentially these supplements can cycle between their Oxidized and Reduced forms while exchanging electrons at various points in the Electron Transport Chain.

The three supplements (CoQ10, Quercetin, and Curcumin) have been shown to boost NAD+ levels or at least play a role in supporting NAD+/NADH exchange through the Redox Reactions. Which plays another important role in supporting mitochondrial function. [18]

Unsurprisingly, all four of these supplements have been studied in combination with red light therapy.

Methylene Blue (MB):

Methylene Blue is a synthetic blue dye that has been used as a medication in malaria treatment, methemoglobinemia, and cyanide poisoning. Methylene Blue has been shown to seek out high-metabolic cells and cross the blood-brain-barrier and act as an electron donor to the mitochondrial respriation process. [19]

A review article covers the mechanisms and synergies with combining methylene blue and photobiomodulation for neuroprotection like in Alzheimer's, Stroke, and Parkinson's disease. [19]

Another review article also describes the methods of neuroprotection with MB and PBM. [20]

One study combined oral MB with PBM to manage COVID-19 symptoms on 8 human case studies. 6 of them reported no long-covid symptoms after follow-up, and they all showed to hold lasting immunity. [21]

A study found the combination of MB and PBM improved brain metabolism in rats suffering from cognitive decline. [22]

Note that Methylene Blue has high absorption in the Red wavelengths, which as we mentioned earlier can be used as a destructive therapy called Photodynamic Therapy (PDT). There are many studies using MB and Red light for PDT, but that is outside the scope of this blog other than mentioning it as a precaution.

CoQ10 / Ubiquinone

If taking an artificial dye is too daunting, then the dietary supplement CoQ10 may be a preferred alternative for supporting the mitochondria.

One review article notes that while CoQ10 is found in all cells, it is concentrated in the cells that have the highest metabolic activity like the heart - which confirms it's role it is playing in supporting the mitochondria. The human body synthesizes and recycles most of it's CoQ10 levels naturally, but there have been studies where theraputic supplementation has been effective. It notes the average daily intake from the diet is about 5mg/day, but clinical trials with CoQ10 supplementaiton is about 300mg/day for 2-4 weeks to reach theraputic levels.[88]

In the diet, CoQ10 is predictably found in mitochondria-rich organ meats like liver and heart. It is also found in fatty fish and whole grains. One article dubbed CoQ10 as an essential nutrient. [74]

One PBM article describes CoQ10 as:

 "Coenzyme Q10 (CoQ10) also known as ubiquinone, is an essential cofactor for the activity of complexes I-III of the mitochondrial electron transfer chain acting either as a donor or acceptor of electrons(Dallner and Sindelar, 2000)." [23]

So we can see it's synergistic value that CoQ10 supports Complex 1-3, while we know PBM upregulates Complex 4 and 5.

1. One study combined Near Infrared light and CoQ10 on mice suffering from depression. They found the combination performed slightly better than the separate treatments. [23]
2. Another study used PBM and CoQ10 on mice suffering from cognitive decline and showed improvements in brainpower and ATP production. [24]
3. One study combined PBM and CoQ10 to enhance wound healing in diabetic mice. [25]
4. One study combined PBM and topical CoQ10 to enhance burn healing in rats. [26]

So there could be merits to supplementing CoQ10 entirely on its own for heart health and brain health to support the mitochondria, and here we find some preliminary studies on rats that show the potential to combine CoQ10 supplementation with red light therapy for additional synergy.

Quercetin:

Quercetin is a flavanoid that also holds similar mitochondrial mechanisms as CoQ10.[27] Its action is often on the Complex 1 of the electron transport chain. [27]

1. One study showed improved wound healing when combining Quercetin and PBM in rats. [28]
2. Another study showed improved wound healing with combined Quercetin and PBM in diabetic rats. They found the combination to be superior. [29]
3. One study used Quercetin and LLLT on a peripheral neuropathy model in vitro (isolated tissue, not a whole human or animal). [30]
4. One human study conducted on type 2 diabetes mellitus showed improvements in oxidative markers when Quercetin and 532nm green laser LLLT were used. [31]

So again we have some preliminary data and one small human study showing the potential to combine Quercetin with light therapy for additional effectiveness.

Curcumin:

Curcumin is the active compound found in Tumeric root, giving the distinctive yellow color to many curry dishes. Curcumin alone has been studied for a wide range of health benefits particularly as a powerful antioxidant. [32]

Three studies have found positive results when combining Curcumin and PBM for wound healing in rats. [33][34][35]

Nitric Oxide Donor Supplements 

Nitric Oxide is an important metabolite in the body that is often correlated with blood flow, heart health, and vasodilation.

Red Light Therapy famously increases Nitric Oxide levels as one of it's primary mechanisms.

Interestingly, PBM does not directly affect the usual Nitric Oxide (NO) production cycle. In fact one study excluded participants taking any drugs or supplements that would affect Nitric Oxide synthesis so they could monitor the NO pathways. [36]

Instead, PBM releases intracellular stores of Nitric Oxide often assumed to be in the blood or bound to CCO.

"Nitric oxide (NO) may be photo-released from extra intracellular storage, such as nitrosylated hemoglobin and nitrosylated myoglobin, in addition to being photo-dissociated from Cox [11]. Furchgott first identified light-mediated vasodilation in 1968 while working on the nitric oxide project that would earn him the 1998 Nobel Prize [12, 13]." [37]

However, there could be cases where NO stores are depleted, or additional NO could be beneficial.

One study combined LLLT and a Nitric Oxide producing drug and found improved wound healing. [38]

Arginine is an amino acid that is a precurser to Nitric Oxide. Topical Arginine has been used in 3 studies in conjunction with PBM to enhance wound healing in rats. [39][40][41]

Arginine and its relative Citrulline are both popular Nitric Oxide booster supplements on their own. Although it hasn't been studied in conjunction with PBM, L-Citrulline and Citrulline Malate seem to be preferred for their better oral absorption and they metabolize into Arginine in the body to act as a NO donor. [89]

As a precaution - one study combined LLLT with NO donor drugs and found the LLLT effectiveness reduced. [42] Likely because excess NO is a primary reason for the biphasic dose response (overdose of red light therapy). Which is also why Arginine has been used in Photodynamic Therapy as well.

Antioxidant Supplements 

Antioxidants famously counteract inflammation and Reactive Oxygen Species (ROS).

The speculation is that antioxidants can mitigate the excess ROS produced by Red Light Therapy. While this may be true, we cannot be sure if this is always a good thing, as the signalling aspects of ROS also provide many benefits.

Paradoxically, Red Light Therapy often acts as an antioxidant itself, and the net effect of red light therapy is that it promotes better antioxidant balance with less oxidative stress. [43][44]

So, potentially intervening with the Red Light Therapy by applying exogenous antioxidants could produce different or unexpected results until these combinations are fully studied.

N-Acetyl-Cysteine (NAC):

NAC is sulfur-containing compound that is a precursor to glutathione (a master antioxidant) and a powerful antioxidant/anti-inflammatory even on its own.

NAC has a wide range of applications including heart health, lung health, neurological health, liver health, and much more. [45]

Low Level Laser Therapy and NAC have been confirmed to have synergistic benefits in a study on inflammation markers. [46]

Another study combined LLLT and NAC to reduce hearing loss in rats. [47]

One study notes the mechanism that NAC protected against inhibitory ROS from Blue and Green light, but it did not affect the activity of Red light. Again potentially confirming a synergistic action with Red light while offering protection from Blue light damage. [48]

Another article found that Photobiomodulation combined with NAC or Vitamin C were able to reduce the ROS-induced inflammatory marker NF-kB, but the cells still showed increased ATP production. [49] So that is overall a good thing if we want to increase ATP production but use the antioxidants to mitigate the ROS.

"The fact that antioxidants do not abrogate the ATP increase suggests that the action of light increases electron transport, which in the absence of antioxidants can cause increased electron leakage producing superoxide." [49]

However, one study showed that NAC hindered the benefits of laser therapy, and directly mentioning that ROS plays an important role in the benefits of red light therapy. So blunting the ROS is not always a good thing for red light therapy.

"On the contrary, in the presence of NAC, laser irradiation was not able to induce any cell proliferation, suggesting a crucial role of ROS in this laser-induced cell effect." [50]

An another study showed that using NAC hindered the beneficial Nitric Oxide typically generated from laser therapy.

"Interestingly, upon treating cells with NAC, NO generation with 1064 nm laser exposure was significantly inhibited" [51]

However, most of these studies used NAC directly on isolated tissues. We assume that oral ingestion by a human would help disperse the antioxidant and reduce the risk of hindering too much of the ROS capacity of red light therapy.

Molecular Hydrogen:

Molecular Hydrogen is the therapeutic usage of H2 (hydrogen gas). It can be ingested when dissolved in water or inhaled as hydrogen gas. Molecular Hydrogen has been shown to be a powerful selective antioxidant.

One pilot study recruted 18 individuals with Parkinson's disease for a trial with a 940nm LED panel emitting 6 mW/cm^2, combined with oral ingestion of 2.5ppm hydrogen water. [52]

The pilot study concluded that this combination of Molecular Hydrogen and Red Light Therapy was safe and offered relief from the severity and symptoms of the disease.

Vitamin C:

Vitamin C (ascorbic acid) is a famous antioxidant found in citrus fruits and many other fruits and vegetables.

Vitamin C has long been known to play a role in dermatology and photoprotection of the skin from sunlight. And may even play an important role in regulating pigmentation and melasma. [53]

One study on isolated tissue showed a synergistic benefit of Vitamin C and PBM on cell proliferation. [54]

A human study with 20 people in the active group used Vitamin C and glycolic peels combined with non-thermal Blue and Near-Infrared light therapy for an improved result over the topicals alone. The 5% Vitamin C cream called Active C by La Roche was applied after the irradiation at night. [55]

However, one study did note that ascorbic acid prevented the effects of Photobiomodulation.

"Additionally, the effect of ascorbic acid on preventing PBM effects in PDT shows that ROS play an important role in the early mechanisms of PBM-PDT." [57]

Another recent article found that Vitamin E attenuated (reduced) the effects of red light therapy. [92] https://pubmed.ncbi.nlm.nih.gov/38929107/

So again confirming the importance of ROS from Red Light Therapy, that it is not something that we need to inhibit since it could reduce the overall effectiveness of red light therapy itself.

Resveratrol and Vitamin C Protects from High Dose Red Light Therapy:

One application of red light therapy is to purposefully do high doses that specifically causes high ROS and cell death. Which is why we always promote low doses for true Photobiomodulation therapy. For example one study used 120 J/cm^2 from 633nm laser to induce apoptosis (cell death). [57]

"High fluence low-power laser irradiation (HF-LPLI) is a newly discovered stimulus through generating reactive oxygen species (ROS) to trigger cell apoptosis." [57]

These studies will often use antioxidants to see if it can inhibit the ROS mechanism of cell death. Indeed, one study used Vitamin C and others have used Resveratrol to reduce the ROS from high dose red light therapy. [58][59][57]

It seems to be an excellent business model to sell overpowered devices that generate high ROS and then sell a recurring cost of a supplement or topical that protects you from the excess ROS. When a more effective and cost-saving solution would be to just sell appropriate low-intensity devices and promote low doses that are proven clinically effective on their own without supplementation.

Chia Seeds

Chia Seeds are the seeds of the Salvia hispanica L. plant. Chia Seeds are a popular dietary supplement for for it's nutritional profile. [60]

Two separate articles investigate the combination of chia seeds and 670nm photobiomodulation on rats with diabetic retinopathy with positive results for the combination. [61][62] So this combination could play in important role in supporting eye health.

Herbal Extracts and PBM

Many herbal extracts have been used in combination with red light therapy.

Famously, an article with a single patient claims a vast improvement by using a Green Tea preparation on the skin before red light therapy treatment. [78] However, we have not seen any follow-up studies from that 2009 article to confirm the results in a larger population.

One 2011 article on 60 females does confirm the use of Green Tea and other polyphenols as photoprotective from UV light. This study had the participants consume a green tea as a beverage, not as a topical.[79]

Indeed, one excellent review article covers a wide range of plant extracts and their ability to offer photoprotection. They included Green Tea, Rooibos Tea (Aspalathus linearis), Coffee, Bergamot Tea, Orange, Grapefruit, Fennel, Ginsing, and more. [80] Most of these have been tested topically or orally to protect from UV-B light, but we do not see any direct studies on Red/NIR light therapy. But they do note the potential to incorporate these compounds in cosmetics to mitigate photoaging.[80]

One study by Silva et al. investigated various herbal extracts and it's combination with PBM on isolated cells.[81] They make a valuable observation that even herbal extracts have a dose-response curve, so more is not better even for herbals and antioxidants.

"However, the administration of polyphenols should respect the dose-response concept, since adverse effects may be observed when larger amounts of polyphenols are used. The literature reports that excessive doses of polyphenols may promote adverse effects, such as toxicity [34]."[81]

They found their preparations of green tea, rosemary, and pomegranite all presented toxicity so they chose not to combine with PBM. The combination of PBM and Fig extract yielded no significant improvement. The combination of PBM and Nutwood extract resulted in a negative response of cell death, the authors note it is from the photosensitization of the cells to red light caused by the nutwood.[81]

Another study combined a 5% Lycium barbarum fruit (goji berry) extract combined with 660nm PBM to test its effects on photoprotection from UV.[82]

They found that applying the Goji Berry extract before PBM had worse results than using PBM first then applying the Goji Berry extract second.[82]

"However, in our study, the application of LBPF followed by PBM promoted a decrease in birefringent collagen fibers. Therefore, an inhibitory effect may have occurred due to PBM-associated fraction composition (LBPF) in this order of application." [82]

 This study even references the previous study in saying:

"Silva et al. [17] have shown that combining PBM with natural extracts may be a useful strategy, but choosing a natural extract is very challenging due to work concentration and other properties, such as photosensitivity, which may bring
unwanted results." [82]

Another study used Porophyllum ruderale leaf extract combined with 670nm PBM for wound healing.[83] Once again, they found that the extract applied before PBM led to worse results than either component separately:

"A probable explanation for this fact may be related to the permanence of the green pigment of leaves in P. ruderale extract"[83]

Essentially, various plant pigments and phytochemicals from plants can act as photosensitizers, light absorbing/blocking mediums, or add to their own oxidation or toxicity especially under direct light exposure.[84] So even if the "active ingredient" is shown to be safe, the extraction process may include other unwanted phytochemicals.

One study combined Calendula officinalis (marigold) oil and 658nm LLLT to heal diabetic ulcers in humans.[85] They applied the LLLT first, then the oil which was successful in reducing pain and wound size. The order is particularly important as many essential oils have been shown to be photosensitizers (to UV, not tested with Red/NIR). [86]

Another study made this comment about how antioxidants can have a pro-oxidant effect when light is applied to them.

"Other extracts with antioxidants properties have also showed to be oxidative when exposed to light in a specific wavelength [19]." [87]

Interestingly that study was using a plant extract and blue light as a Photodynamic Therapy for it's antimicrobial action on halitosis. [87]

So there is a vague line between using topicals for destructive Photodynamic Therapy (PDT) versus stimulatory Photobiomodulation (PBM) Therapy. We cannot assume benefits until these have been tested, since we could falsely assume that something is an antioxidant but it could have pro-oxidant effects when it is irradiated with light.

Bottom Line: Topical Extracts and Antioxidants should be applied after red light therapy, not before. They have a higher probability of causing a detrimental response according to the current research. In our previous blogs, we know the peak of metabolic activity occurs 3-6 hours after the red light therapy session has ended. This gives a huge window to apply the topicals shortly after red light therapy to still mitigate the ROS and give supportive cosmetic phytochemicals, while avoiding directly irradiating the topicals which would cause unwanted effects. 

Conclusions:

Photobiomodulation is extremely effective entirely on its own. It upregulates the electron transport chain on the mitochondria, promotes NO liberation, and improves antioxidant balance on its own accord. In that way, photobiomodulation is the most effective "supplement" you can use.

In that way, many of these supplements and topicals may be redundant to PBM effects in the same ways they are potentially synergistic. Using combination therapy should be considered only after individual therapies are attempted.

The challenge with red light therapy is threading the needle of balancing stimulatory and inhibitory mechanisms - and additional supplements don't universally enhance red light therapy but need to be considered as part of the overall dosing protocol.

Based on the current research, is it likely safer (and more effective) to use topicals after red light therapy. Red light therapy should be applied to bare, clean, dry skin. In some cases with dry skin - exfoliating the skin, applying a no-active-ingredient moisturiser, and then cleaning it off before red light therapy treatment can be helpful.[90]

Unless the doctor or formulator of the topical has clear data showing safety of their specific formula with the specific wavelengths, intensity, and dosage of light that you will be using - you don't want to become a guinea pig based on speculative benefits.

Oral ingestion of mitochondrial supplements and antioxidants is likely fine, as there will be limited absorption and the supplement being metabolized and dispersed around the body - to the point that the amount actually reaching the cells being irradiated with PBM will only have minimal amounts of the supplement. This is a good thing as the body will be limiting the potential downsides of the supplements interfering directly with PBM effects.

In most cases, this blog is not meant to "sell" you on supplements or topicals. Red Light Therapy works best with adequate diet, exercise, sleep, and lifestyle habits that support good health. Addressing basic nutrient and mineral deficiencies may play an important role in overall health and red light therapy responsiveness. We speculate that Red Light Therapy will be synergistic with a wide variety of supplements, and only a limited number have been clinically tested so far.

The risk is that brands are selling overpowered devices and encouraging overdosing where the benefits will be limited by the biphasic dose response - then they sell you a supplement and topical that counteracts the inhibitory ROS. When the real solution is to just use lower intensity and doses, such that way you don't need supplements to protect you from the low levels of beneficial ROS.

This preliminary research only gives some small guidance about how to use combination therapies properly. And more interestingly it highlights the importance of the ROS mechanisms and that we cannot make assumptions about whether a supplement will act as an "enhancer" or "photosensitizer" until there are clear studies for each interaction.

References:

[1]

Merry, Troy L, and Michael Ristow. “Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training?.” The Journal of physiology vol. 594,18 (2016): 5135-47. doi:10.1113/JP270654

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023714/

[2]

Pham T, MacRae CL, Broome SC, D'souza RF, Narang R, Wang HW, Mori TA, Hickey AJR, Mitchell CJ, Merry TL. MitoQ and CoQ10 supplementation mildly suppresses skeletal muscle mitochondrial hydrogen peroxide levels without impacting mitochondrial function in middle-aged men. Eur J Appl Physiol. 2020 Jul;120(7):1657-1669. doi: 10.1007/s00421-020-04396-4. Epub 2020 May 26. PMID: 32458156.

https://pubmed.ncbi.nlm.nih.gov/32458156/

[3]

Zhang A, Wu H, Chen X, Chen Z, Pan Y, Qu W, Hao H, Chen D, Xie S. Targeting and arginine-driven synergizing photodynamic therapy with nutritional immunotherapy nanosystems for combating MRSA biofilms. Sci Adv. 2023 Jul 14;9(28):eadg9116. doi: 10.1126/sciadv.adg9116. Epub 2023 Jul 14. PMID: 37450586; PMCID: PMC10348676.

https://pubmed.ncbi.nlm.nih.gov/37450586/

[4]

Kramarenko, Galina G et al. “Ascorbate enhances the toxicity of the photodynamic action of Verteporfin in HL-60 cells.” Free radical biology & medicine vol. 40,9 (2006): 1615-27. doi:10.1016/j.freeradbiomed.2005.12.027

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626188/

[5]

Tardivo JP, Del Giglio A, de Oliveira CS, Gabrielli DS, Junqueira HC, Tada DB, Severino D, de Fátima Turchiello R, Baptista MS. Methylene blue in photodynamic therapy: From basic mechanisms to clinical applications. Photodiagnosis Photodyn Ther. 2005 Sep;2(3):175-91. doi: 10.1016/S1572-1000(05)00097-9. Epub 2005 Nov 21. PMID: 25048768.

https://pubmed.ncbi.nlm.nih.gov/25048768/

[6]

Liguo Xie, Xiuling Ji, Qi Zhang, Yunlin Wei,

Curcumin combined with photodynamic therapy, promising therapies for the treatment of cancer,

Biomedicine & Pharmacotherapy,

Volume 146,

2022,

112567,

ISSN 0753-3322,

https://doi.org/10.1016/j.biopha.2021.112567.

(https://www.sciencedirect.com/science/article/pii/S0753332221013548)

[7]

Hale Mitchell LK, Koh RB, Nevarez JG. Successful Treatment of a Cervical Injury and Myopathy Using Integrative Medicine Techniques in an Eclectus Parrot (Eclectus roratus) Following Cervical Entrapment. J Avian Med Surg. 2023 Sep;37(2):175-179. doi: 10.1647/22-00013. PMID: 37733456.

https://pubmed.ncbi.nlm.nih.gov/37733456/

[8]

Nagy EN, Ibrahim FM, Jouda AA, Elsayed MM. The Effect of Laser Therapy Along With Mediterranean Diet Versus Mediterranean Diet Only on Older Adults With Non-alcoholic Fatty Liver Disease: A Randomized Clinical Trial. J Lasers Med Sci. 2021 Jul 24;12:e39. doi: 10.34172/jlms.2021.39. PMID: 34733762; PMCID: PMC8558722.

https://pubmed.ncbi.nlm.nih.gov/34733762/

[9]

Aquino, Antonio E Jr et al. “Low-level laser therapy (LLLT) combined with swimming training improved the lipid profile in rats fed with high-fat diet.” Lasers in medical science vol. 28,5 (2013): 1271-80. doi:10.1007/s10103-012-1223-z

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594357/

[10]

Kholvadia A, Constantinou D, Gradidge PJ. Exploring the efficacy of low-level laser therapy and exercise for knee osteoarthritis. S Afr J Sports Med. 2019 Jan 1;31(1):v31i1a6058. doi: 10.17159/2078-516X/2019/v31i1a6058. PMID: 36817986; PMCID: PMC9924591.

https://pubmed.ncbi.nlm.nih.gov/36817986/

[11]

Nambi G, Kamal W, Es S, Joshi S, Trivedi P. Spinal manipulation plus laser therapy versus laser therapy alone in the treatment of chronic non-specific low back pain: a randomized controlled study. Eur J Phys Rehabil Med. 2018 Dec;54(6):880-889. doi: 10.23736/S1973-9087.18.05005-0. Epub 2018 Apr 24. PMID: 29687966.

https://pubmed.ncbi.nlm.nih.gov/29687966/

[12]

Martins, D O et al. “Photobiomodulation and B vitamins administration produces antinociception in an orofacial pain model through the modulation of glial cells and cytokines expression.” Brain, behavior, & immunity - health vol. 2 100040. 26 Jan. 2020, doi:10.1016/j.bbih.2020.100040

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474295/

[13]

Marques DP, Chacur M, Martins DO. Photobiomodulation and vitamin B treatment alleviate both thermal and mechanical orofacial pain in rats. Photochem Photobiol Sci. 2023 Oct;22(10):2315-2327. doi: 10.1007/s43630-023-00452-y. Epub 2023 Jun 20. PMID: 37340216.

https://pubmed.ncbi.nlm.nih.gov/37340216/

[14]

Alizadeh, Zahra et al. “Review of the Mechanisms and Effects of Noninvasive Body Contouring Devices on Cellulite and Subcutaneous Fat.” International journal of endocrinology and metabolism vol. 14,4 e36727. 3 Jul. 2016, doi:10.5812/ijem.36727

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5236497/

[15]

Avci, Pinar et al. “Low-level laser therapy for fat layer reduction: a comprehensive review.” Lasers in surgery and medicine vol. 45,6 (2013): 349-57. doi:10.1002/lsm.22153

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769994/

[16]

Amaroli A, Pasquale C, Zekiy A, Utyuzh A, Benedicenti S, Signore A, Ravera S. Photobiomodulation and Oxidative Stress: 980 nm Diode Laser Light Regulates Mitochondrial Activity and Reactive Oxygen Species Production. Oxid Med Cell Longev. 2021 Mar 3;2021:6626286. doi: 10.1155/2021/6626286. PMID: 33763170; PMCID: PMC7952159.

https://pubmed.ncbi.nlm.nih.gov/33763170/

[17]

Chem. Res. Toxicol. 2017, 30, 1, 13–37

Publication Date:September 12, 2016

https://doi.org/10.1021/acs.chemrestox.6b00256

Copyright © 2022 American Chemical Society. This publication is licensed under these Terms of Use.

https://pubs.acs.org/doi/10.1021/acs.chemrestox.6b00256

[18]

Sharma, Arastu et al. “Potential Synergistic Supplementation of NAD+ Promoting Compounds as a Strategy for Increasing Healthspan.” Nutrients vol. 15,2 445. 14 Jan. 2023, doi:10.3390/nu15020445

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9861325/

[19]

Yang, L., Youngblood, H., Wu, C. et al. Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener 9, 19 (2020). https://doi.org/10.1186/s40035-020-00197-z

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-020-00197-z#citeas

[20]

Gonzalez-Lima F and Auchter A (2015) Protection against neurodegeneration with low-dose methylene blue and near-infrared light. Front. Cell. Neurosci. 9:179. doi: 10.3389/fncel.2015.00179

https://www.frontiersin.org/articles/10.3389/fncel.2015.00179/full

[21]

Hepburn, Juliette et al. “A Novel Approach of Combining Methylene Blue Photodynamic Inactivation, Photobiomodulation and Oral Ingested Methylene Blue in COVID-19 Management: A Pilot Clinical Study with 12-Month Follow-Up.” Antioxidants (Basel, Switzerland) vol. 11,11 2211. 8 Nov. 2022, doi:10.3390/antiox11112211

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9686966/

[22]

Méndez M, Fidalgo C, Arias JL, Arias N. Methylene blue and photobiomodulation recover cognitive impairment in hepatic encephalopathy through different effects on cytochrome c-oxidase. Behav Brain Res. 2021 Apr 9;403:113164. doi: 10.1016/j.bbr.2021.113164. Epub 2021 Feb 4. PMID: 33549685.

https://pubmed.ncbi.nlm.nih.gov/33549685/

[23]

Salehpour, Farzad et al. “Near-infrared photobiomodulation combined with coenzyme Q₁₀ for depression in a mouse model of restraint stress: reduction in oxidative stress, neuroinflammation, and apoptosis.” Brain research bulletin vol. 144 (2019): 213-222. doi:10.1016/j.brainresbull.2018.10.010

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309497/

[24]

Salehpour, Farzad et al. “Photobiomodulation and Coenzyme Q₁₀ Treatments Attenuate Cognitive Impairment Associated With Model of Transient Global Brain Ischemia in Artificially Aged Mice.” Frontiers in cellular neuroscience vol. 13 74. 19 Mar. 2019, doi:10.3389/fncel.2019.00074

[25]

Mao, Z., Wu, J., Dong, T. et al. Additive enhancement of wound healing in diabetic mice by low level light and topical CoQ10. Sci Rep 6, 20084 (2016). https://doi.org/10.1038/srep20084

[26]

Anju Yadav, Ashok Priyadarshi, Gaurav K. Keshri, Saurabh Verma, Asheesh Gupta,

Superpulsed 904 nm laser photobiomodulation combined with coenzyme Q10 synergistically augment burn wound healing,

Journal of Photochemistry and Photobiology,

Volume 7,

2021,

100053,

ISSN 2666-4690,

https://doi.org/10.1016/j.jpap.2021.100053.

(https://www.sciencedirect.com/science/article/pii/S2666469021000385)

[27]

de Oliveira MR, Nabavi SM, Braidy N, Setzer WN, Ahmed T, Nabavi SF. Quercetin and the mitochondria: A mechanistic view. Biotechnol Adv. 2016 Sep-Oct;34(5):532-549. doi: 10.1016/j.biotechadv.2015.12.014. Epub 2015 Dec 29. PMID: 26740171.

[28]

Ahmed OM, Mohamed T, Moustafa H, Hamdy H, Ahmed RR, Aboud E. Quercetin and low level laser therapy promote wound healing process in diabetic rats via structural reorganization and modulatory effects on inflammation and oxidative stress. Biomed Pharmacother. 2018 May;101:58-73. doi: 10.1016/j.biopha.2018.02.040. Epub 2018 Feb 22. PMID: 29477473.

[29]

Ahmed, Osama & Aboud, Ebtesam & Mohamed, Tarek & Hamdy, Hany & Moustafa, Hala. (2016). Efficacy of Quercetin Treatment and Low Level Laser Therapy on Wound Healing in Normal and Diabetic Rats. International Journal of Science and Research (IJSR). 5. 45. 10.21275/ART20162545.

[30]

Unay S, Bilgin MD. Investigation of effects of quercetin and low-level laser therapy in cisplatin-induced in vitro peripheral neuropathy model. Lasers Med Sci. 2023 Jan 23;38(1):49. doi: 10.1007/s10103-023-03718-0. PMID: 36689023.

[31]

Danik M. Martirosyan, Mohammad Reza Ashoori, Alireza Rezaeinezhad, Fahimeh Jahanbakhshi, Shaghayegh Pezeshki, Afsaneh Seyed Mikaeili, Saham Alkhamis, Hossein Mirmiranpour

Effects of quercetin and low-level laser on oxidative and inflammatory factors among patients with type 2 diabetes mellitus and mild cognitive impairment

BCHD: Online ISSN: 2574-0334, Print ISSN: 2769-2426
Bioactive Compounds in Health and Disease

[32]

Liu, Siyu et al. “A Comprehensive Review on the Benefits and Problems of Curcumin with Respect to Human Health.” Molecules (Basel, Switzerland) vol. 27,14 4400. 8 Jul. 2022, doi:10.3390/molecules27144400

[33]

Amini A, Soleimani H, Abdollhifar MA, Moradi A, Ghoreishi SK, Chien S, Bayat M. Stereological and gene expression examinations on the combined effects of photobiomodulation and curcumin on wound healing in type one diabetic rats. J Cell Biochem. 2019 Oct;120(10):17994-18004. doi: 10.1002/jcb.29102. Epub 2019 May 30. PMID: 31148250.

[34]

Amini A, Soleimani H, Rezaei F, Ghoreishi SK, Chien S, Bayat M. The Combined Effect of Photobiomodulation and Curcumin on Acute Skin Wound Healing in Rats. J Lasers Med Sci. 2021 Feb 23;12:e9. doi: 10.34172/jlms.2021.09. PMID: 34084735; PMCID: PMC8164908.

[35]

Soleimani H, Amini A, Taheri S, Sajadi E, Shafikhani S, Schuger LA, Reddy VB, Ghoreishi SK, Pouriran R, Chien S, Bayat M. The effect of combined photobiomodulation and curcumin on skin wound healing in type I diabetes in rats. J Photochem Photobiol B. 2018 Apr;181:23-30. doi: 10.1016/j.jphotobiol.2018.02.023. Epub 2018 Feb 21. PMID: 29486459.

[36]

Rola, Piotr et al. “Low-Level Laser Irradiation Exerts Antiaggregative Effect on Human Platelets Independently on the Nitric Oxide Metabolism and Release of Platelet Activation Markers.” Oxidative medicine and cellular longevity vol. 2017 (2017): 6201797. doi:10.1155/2017/6201797

[37]

Sayed, Mahmoud Abdulbasser et al. “Effect of low-level laser physiotherapy on left ventricular function among patients with chronic systolic heart failure.” The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology vol. 75,1 12. 13 Feb. 2023, doi:10.1186/s43044-023-00337-6

[38]

Spitler, Ryan et al. “Combination of low level light therapy and nitrosyl-cobinamide accelerates wound healing.” Journal of biomedical optics vol. 20,5 (2015): 051022. doi:10.1117/1.JBO.20.5.051022

[39]

Mostafavinia, Atarodsadat et al. “Combined Treatment of Photobiomodulation and Arginine on Chronic Wound Healing in an Animal Model.” Journal of lasers in medical sciences vol. 12 e40. 24 Jul. 2021, doi:10.34172/jlms.2021.40

[40]

Mostafavinia A, Amini A, Sajadi E, Ahmadi H, Rezaei F, Ghoreishi SK, Chien S, Bayat M. Photobiomodulation therapy was more effective than photobiomodulation plus arginine on accelerating wound healing in an animal model of delayed healing wound. Lasers Med Sci. 2022 Feb;37(1):403-415. doi: 10.1007/s10103-021-03271-8. Epub 2021 Mar 18. PMID: 33738614.

[41]

Mostafavinia, Atarodsadat et al. “An improvement in acute wound healing in rats by the synergistic effect of photobiomodulation and arginine.” Laboratory animal research vol. 35 28. 11 Dec. 2019, doi:10.1186/s42826-019-0025-x

[42]

Karu TI, Pyatibrat LV, Afanasyeva NI. Cellular effects of low power laser therapy can be mediated by nitric oxide. Lasers Surg Med. 2005 Apr;36(4):307-14. doi: 10.1002/lsm.20148. PMID: 15739174.

[43]

Mostafavinia A, Ahmadi H, Amini A, Roudafshani Z, Hamblin MR, Chien S, Bayat M. The effect of photobiomodulation therapy on antioxidants and oxidative stress profiles of adipose derived mesenchymal stem cells in diabetic rats. Spectrochim Acta A Mol Biomol Spectrosc. 2021 Dec 5;262:120157. doi: 10.1016/j.saa.2021.120157. Epub 2021 Jul 6. PMID: 34271236.

[44]

Silva Macedo R, Peres Leal M, Braga TT, Barioni ÉD, de Oliveira Duro S, Ratto Tempestini Horliana AC, Câmara NO, Marcourakis T, Farsky SH, Lino-Dos-Santos-Franco A. Photobiomodulation Therapy Decreases Oxidative Stress in the Lung Tissue after Formaldehyde Exposure: Role of Oxidant/Antioxidant Enzymes. Mediators Inflamm. 2016;2016:9303126. doi: 10.1155/2016/9303126. Epub 2016 May 17. PMID: 27293324; PMCID: PMC4886066.

[45]

Tenório, Micaely Cristina Dos Santos et al. “N-Acetylcysteine (NAC): Impacts on Human Health.” Antioxidants (Basel, Switzerland) vol. 10,6 967. 16 Jun. 2021, doi:10.3390/antiox10060967

[46]

de Lima FM, Villaverde AB, Albertini R, de Oliveira AP, Faria Neto HC, Aimbire F. Low-level laser therapy associated to N-acetylcysteine lowers macrophage inflammatory protein-2 (MIP-2) mRNA expression and generation of intracellular reactive oxygen species in alveolar macrophages. Photomed Laser Surg. 2010 Dec;28(6):763-71. doi: 10.1089/pho.2009.2638. PMID: 21142721.

[47]

Rhee CK, Chang SY. Combination photobiomodulation/N-acetyl-L-cysteine treatment appears to mitigate hair cell loss associated with noise-induced hearing loss in rats. Lasers Med Sci. 2021 Dec;36(9):1941-1947. doi: 10.1007/s10103-021-03304-2. Epub 2021 Apr 6. PMID: 33822307.

[48]

Wang, Y., Huang, YY., Wang, Y. et al. Red (660 nm) or near-infrared (810 nm) photobiomodulation stimulates, while blue (415 nm), green (540 nm) light inhibits proliferation in human adipose-derived stem cells. Sci Rep 7, 7781 (2017). https://doi.org/10.1038/s41598-017-07525-w

[49]

Chen, Aaron C-H et al. “Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts.” PloS one vol. 6,7 (2011): e22453. doi:10.1371/journal.pone.0022453

[50]

Migliario M, Pittarella P, Fanuli M, Rizzi M, Renò F. Laser-induced osteoblast proliferation is mediated by ROS production. Lasers Med Sci. 2014 Jul;29(4):1463-7. doi: 10.1007/s10103-014-1556-x. Epub 2014 Mar 5. PMID: 24595962.

[51]

Yokomizo, Shinya et al. “Near-infrared II photobiomodulation augments nitric oxide bioavailability via phosphorylation of endothelial nitric oxide synthase.” FASEB journal : official publication of the Federation of American Societies for Experimental Biology vol. 36,9 (2022): e22490. doi:10.1096/fj.202101890R

[52]

Hong CT, Hu CJ, Lin HY, Wu D. Effects of concomitant use of hydrogen water and photobiomodulation on Parkinson disease: A pilot study. Medicine (Baltimore). 2021 Jan 29;100(4):e24191. doi: 10.1097/MD.0000000000024191. PMID: 33530211; PMCID: PMC7850666.

[53]

Correia G, Magina S. Efficacy of topical vitamin C in melasma and photoaging: A systematic review. J Cosmet Dermatol. 2023 Jul;22(7):1938-1945. doi: 10.1111/jocd.15748. Epub 2023 May 2. PMID: 37128827.

[54]

Pedroni ACF, Diniz IMA, Abe GL, Moreira MS, Sipert CR, Marques MM. Photobiomodulation therapy and vitamin C on longevity of cell sheets of human dental pulp stem cells. J Cell Physiol. 2018 Oct;233(10):7026-7035. doi: 10.1002/jcp.26626. Epub 2018 May 10. PMID: 29744863.

[55]

Fournier N, Fritz K, Mordon S. Use of nonthermal blue (405- to 420-nm) and near-infrared light (850- to 900-nm) dual-wavelength system in combination with glycolic acid peels and topical vitamin C for skin photorejuvenation. Dermatol Surg. 2006 Sep;32(9):1140-6. doi: 10.1111/j.1524-4725.2006.32251.x. PMID: 16970694.

[56]

de Faria CMG, Costa CS, Bagnato VS. Photobiomodulation effects on photodynamic therapy in HNSCC cell lines. J Photochem Photobiol B. 2021 Apr;217:112170. doi: 10.1016/j.jphotobiol.2021.112170. Epub 2021 Feb 27. PMID: 33676286.

[57]

Huang L, Wu S, Xing D. High fluence low-power laser irradiation induces apoptosis via inactivation of Akt/GSK3β signaling pathway. J Cell Physiol. 2011 Mar;226(3):588-601. doi: 10.1002/jcp.22367. PMID: 20683916.

[58]

Mamalis A, Jagdeo J. The Combination of Resveratrol and High-Fluence Light Emitting Diode-Red Light Produces Synergistic Photobotanical Inhibition of Fibroblast Proliferation and Collagen Synthesis: A Novel Treatment for Skin Fibrosis. Dermatol Surg. 2017 Jan;43(1):81-86. doi: 10.1097/DSS.0000000000000921. PMID: 28027199.

[59]

Mamalis A, Koo E, Isseroff RR, Murphy W, Jagdeo J. Resveratrol Prevents High Fluence Red Light-Emitting Diode Reactive Oxygen Species-Mediated Photoinhibition of Human Skin Fibroblast Migration. PLoS One. 2015 Oct 21;10(10):e0140628. doi: 10.1371/journal.pone.0140628. PMID: 26488596; PMCID: PMC4619307.

[60]

Teoh SL, Lai NM, Vanichkulpitak P, Vuksan V, Ho H, Chaiyakunapruk N. Clinical evidence on dietary supplementation with chia seed (Salvia hispanica L.): a systematic review and meta-analysis. Nutr Rev. 2018 Apr 1;76(4):219-242. doi: 10.1093/nutrit/nux071. PMID: 29452425.

[61]

Abdelkawi, Salwaa; Ibrahim, Amal E.a; Ghoneim, Dina F.b; Hassan, Aziza A.b; Eldaiem, Maha S.A.c. The combined effect of photobiomodulation therapy and chia seeds supplementation for the treatment of diabetic retinopathy in experimental rats. Journal of The Arab Society for Medical Research 14(2):p 130-139, July-December 2019. | DOI: 10.4103/jasmr.jasmr_16_19

[62]

Mahmoud, Abdel Rahman Hassan et al. “Mitigation of photoreceptors abnormalities after low-level laser therapy and chia seeds supplementation in experimental diabetic retinopathy.” Oman journal of ophthalmology vol. 15,3 347-352. 2 Nov. 2022, doi:10.4103/ojo.ojo_251_21

[63]

Wright, Josephine A et al. “The role of iron in the skin and cutaneous wound healing.” Frontiers in pharmacology vol. 5 156. 10 Jul. 2014, doi:10.3389/fphar.2014.00156

[64]

Oliveira Sampaio SC, de C Monteiro JS, Cangussú MC, Pires Santos GM, dos Santos MA, dos Santos JN, Pinheiro AL. Effect of laser and LED phototherapies on the healing of cutaneous wound on healthy and iron-deficient Wistar rats and their impact on fibroblastic activity during wound healing. Lasers Med Sci. 2013 May;28(3):799-806. doi: 10.1007/s10103-012-1161-9. Epub 2012 Jul 20. PMID: 22814898.

[65]

Berman, Marvin H et al. “Photobiomodulation with Near Infrared Light Helmet in a Pilot, Placebo Controlled Clinical Trial in Dementia Patients Testing Memory and Cognition.” Journal of neurology and neuroscience vol. 8,1 (2017): 176. doi:10.21767/2171-6625.1000176

[66]

Zeng H, Saari JT, Johnson WT. Copper deficiency decreases complex IV but not complex I, II, III, or V in the mitochondrial respiratory chain in rat heart. J Nutr. 2007 Jan;137(1):14-8. doi: 10.1093/jn/137.1.14. PMID: 17182794.

[67]

Sanderson, T.H., Wider, J.M., Lee, I. et al. Inhibitory modulation of cytochrome c oxidase activity with specific near-infrared light wavelengths attenuates brain ischemia/reperfusion injury. Sci Rep 8, 3481 (2018). https://doi.org/10.1038/s41598-018-21869-x

[68]

King A, Gottlieb E, Brooks DG, Murphy MP, Dunaief JL. Mitochondria-derived reactive oxygen species mediate blue light-induced death of retinal pigment epithelial cells. Photochem Photobiol. 2004 May;79(5):470-5. doi: 10.1562/le-03-17.1. PMID: 15191057.

[69]

Xinli Ouyang, Jing Yang, Zexin Hong, Yide Wu, Yongfang Xie, Guohui Wang,

Mechanisms of blue light-induced eye hazard and protective measures: a review,

Biomedicine & Pharmacotherapy,

Volume 130,

2020,

110577,

ISSN 0753-3322,

https://doi.org/10.1016/j.biopha.2020.110577.

(https://www.sciencedirect.com/science/article/pii/S0753332220307708)

[70]

Lin CW, Yang CM, Yang CH. Protective Effect of Astaxanthin on Blue Light Light-Emitting Diode-Induced Retinal Cell Damage via Free Radical Scavenging and Activation of PI3K/Akt/Nrf2 Pathway in 661W Cell Model. Mar Drugs. 2020 Jul 25;18(8):387. doi: 10.3390/md18080387. PMID: 32722441; PMCID: PMC7459684.

[71]

Kim, Tae Gi et al. “Photochemical Retinopathy induced by blue light emitted from a light-emitting diode Face Mask: A case report and literature review.” Medicine vol. 99,24 (2020): e20568. doi:10.1097/MD.0000000000020568

[72]

Mann, Tobias et al. “High-energy visible light at ambient doses and intensities induces oxidative stress of skin-Protective effects of the antioxidant and Nrf2 inducer Licochalcone A in vitro and in vivo.” Photodermatology, photoimmunology & photomedicine vol. 36,2 (2020): 135-144. doi:10.1111/phpp.12523

[73]

Campiche, R et al. “Pigmentation effects of blue light irradiation on skin and how to protect against them.” International journal of cosmetic science vol. 42,4 (2020): 399-406. doi:10.1111/ics.12637

[74]

Saini, Rajiv. “Coenzyme Q10: The essential nutrient.” Journal of pharmacy & bioallied sciences vol. 3,3 (2011): 466-7. doi:10.4103/0975-7406.84471

[75]

Boo, Yong Chool. “Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide (Niacinamide) to Control Skin Aging and Pigmentation.” Antioxidants (Basel, Switzerland) vol. 10,8 1315. 21 Aug. 2021, doi:10.3390/antiox10081315

[76]

Damian DL. Photoprotective effects of nicotinamide. Photochem Photobiol Sci. 2010 Apr;9(4):578-85. doi: 10.1039/b9pp00146h. PMID: 20354654.

[77]

Trigo, Diogo et al. “Novel therapeutic strategies targeting mitochondria as a gateway in neurodegeneration.” Neural regeneration research vol. 18,5 (2023): 991-995. doi:10.4103/1673-5374.355750

[78]

Sommer AP, Zhu D. Green tea and red light--a powerful duo in skin rejuvenation. Photomed Laser Surg. 2009 Dec;27(6):969-71. doi: 10.1089/pho.2009.2547. PMID: 19817517.

[79]

Heinrich U, Moore CE, De Spirt S, Tronnier H, Stahl W. Green tea polyphenols provide photoprotection, increase microcirculation, and modulate skin properties of women. J Nutr. 2011 Jun;141(6):1202-8. doi: 10.3945/jn.110.136465. Epub 2011 Apr 27. PMID: 21525260.

[80]

Cavinato, Maria et al. “Plant extracts and natural compounds used against UVB-induced photoaging.” Biogerontology vol. 18,4 (2017): 499-516. doi:10.1007/s10522-017-9715-7

[81]

Silva ES, Machado GB, Lino-Dos-Santos-Franco A, Pavani C. Combination of Natural Extracts and Photobiomodulation in Keratinocytes Subjected to UVA Radiation. Photochem Photobiol. 2019 Mar;95(2):644-649. doi: 10.1111/php.13026. Epub 2018 Oct 29. PMID: 30267581.

[82]

Neves, L.M.G., Tim, C.R., Floriano, E.M. et al. Lycium barbarum polysaccharide fraction associated with photobiomodulation protects from epithelium thickness and collagen fragmentation in a model of cutaneous photodamage. Lasers Med Sci 36, 863–870 (2021). https://doi.org/10.1007/s10103-020-03132-w

[83]

Catarino HR, de Godoy NP, Scharlack NK, Neves LM, de Gaspi FO, Esquisatto MA, do Amaral ME, Mendonça FA, dos Santos GM. InGaP 670-nm laser therapy combined with a hydroalcoholic extract of Solidago chilensis Meyen in burn injuries. Lasers Med Sci. 2015 Apr;30(3):1069-79. doi: 10.1007/s10103-014-1707-0. Epub 2015 Jan 20. PMID: 25600614.

[84]

Muniyandi, Kasipandi et al. “Role of Photoactive Phytocompounds in Photodynamic Therapy of Cancer.” Molecules (Basel, Switzerland) vol. 25,18 4102. 8 Sep. 2020, doi:10.3390/molecules25184102

[85]

Carvalho AF, Feitosa MC, Coelho NP, Rebêlo VC, Castro JG, Sousa PR, Feitosa VC, Arisawa EA. Low-level laser therapy and Calendula officinalis in repairing diabetic foot ulcers. Rev Esc Enferm USP. 2016 Jul-Aug;50(4):628-634. English, Portuguese. doi: 10.1590/S0080-623420160000500013. PMID: 27680049.

[86]

Sharmeen, Jugreet B et al. “Essential Oils as Natural Sources of Fragrance Compounds for Cosmetics and Cosmeceuticals.” Molecules (Basel, Switzerland) vol. 26,3 666. 27 Jan. 2021, doi:10.3390/molecules26030666

[87]

Gonçalves, Marcela & Mota, Ana & Deana, A.M. & Cavalcante, Lisyanne & Horliana, Anna & Pavani, Christiane & Motta, Lara & Fernandes, Kristianne & Mesquita-Ferrari, Raquel & Silva, Daniela & Motta, Pamella & Prates, Renato & Bussadori, Sandra. (2020). Antimicrobial photodynamic therapy with Bixa orellana extract and blue LED in the reduction of halitosis—A randomized, controlled clinical trial. Photodiagnosis and Photodynamic Therapy. 30. 101751. 10.1016/j.pdpdt.2020.101751.

[88]

Mantle, David, and Alex Dybring. “Bioavailability of Coenzyme Q₁₀: An Overview of the Absorption Process and Subsequent Metabolism.” Antioxidants (Basel, Switzerland) vol. 9,5 386. 5 May. 2020, doi:10.3390/antiox9050386

[89]

Agarwal U, Didelija IC, Yuan Y, Wang X, Marini JC. Supplemental Citrulline Is More Efficient Than Arginine in Increasing Systemic Arginine Availability in Mice. J Nutr. 2017 Apr;147(4):596-602. doi: 10.3945/jn.116.240382. Epub 2017 Feb 8. PMID: 28179487; PMCID: PMC5368575.

[90]

Barolet D, Roberge CJ, Auger FA, Boucher A, Germain L. Regulation of skin collagen metabolism in vitro using a pulsed 660 nm LED light source: clinical correlation with a single-blinded study. J Invest Dermatol. 2009 Dec;129(12):2751-9. doi: 10.1038/jid.2009.186. Epub 2009 Jul 9. PMID: 19587693.

https://pubmed.ncbi.nlm.nih.gov/19587693/

[91]

Xu, Wenjing et al. “Iron and copper in mitochondrial diseases.” Cell metabolism vol. 17,3 (2013): 319-28. doi:10.1016/j.cmet.2013.02.004

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594794/

[92]

Keszler A, Weihrauch D, Lindemer B, Broeckel G, Lohr NL. Vitamin E Attenuates Red-Light-Mediated Vasodilation: The Benefits of a Mild Oxidative Stress. Antioxidants (Basel). 2024 May 29;13(6):668. doi: 10.3390/antiox13060668. PMID: 38929107; PMCID: PMC11200653.

[93]

Qiu S, Pan Z, Jiang X, Lv G, Feng A, Chen H. The synergistic effect of phototherapy and active substances on hair growth. J Photochem Photobiol B. 2024 Oct;259:113008. doi: 10.1016/j.jphotobiol.2024.113008. Epub 2024 Aug 10. PMID: 39146875.

[94]

Berisha-Muharremi V, Tahirbegolli B, Phypers R, Hanna R. Efficacy of Combined Photobiomodulation Therapy with Supplements versus Supplements alone in Restoring Thyroid Gland Homeostasis in Hashimoto Thyroiditis: A Clinical Feasibility Parallel Trial with 6-Months Follow-Up. J Pers Med. 2023 Aug 19;13(8):1274. doi: 10.3390/jpm13081274. PMID: 37623524; PMCID: PMC10455109.