Too Much Red Light Therapy? Optimal Dosing Models

What is the optimal dose for red light therapy? Can you have too much red light therapy? Are bigger doses always more effective? What happens when you overdose red light therapy?

This blog reviews some of the basics for why red light therapy dosing is confined to certain ranges of J/cm^2 (Joules Per Centimeter Squared) for optimal benefits.

Like most drugs or therapy: too little has no effect, but too much will have negative effects. We are always seeking an optimal "Goldilocks dose" for red light therapy. This is well summarized by the following quote from a PBM review article by Dr. Hamblin et al. 

"Dosages that are either substantially less or substantially more than those “sweet spot” values, can have either less benefit or no benefit at all. In some cases very high dosages can even have a negative effect, which is sometimes said to be on the inhibitory side of the Arndt-Schulz curve for the biphasic dose response [20]." [1]

Like learning any science, we start with the most basic concepts - which is the biphasic dosing model. Then we realize that human biology is much more complicated than a simple 2D model and a linear dosing calculation.

"It is suggested that the PBM dose response as a simple binary model of PBM effects as represented by the Arndt-Schulz law is clinically less useful than a multiphasic biological response." [2]

Studies find complex and paradoxical dosing models like:

1. Biphasic Dosing
2. 3-D Dosing model based on time and intensity
3. Triphasic Dosing [6]
4. Multi-Phasic Dosing [2]
5. Cumulative Dosing
6. Deep Tissue Dosing
7. Mitochondrial Density Dosing
8. Titrating Dosing

In this blog we review several human studies that exhibit biphasic dose response (where lower doses perform better than higher doses). There have been myths that humans don't have a biphasic response due to the lack of studies confirming it. However, we find studies that indeed show that lower doses perform equally or better in humans.

We find an excellent new dosing model that promotes biostimulation at 2-10 J/cm^2. At higher doses 10-30 J/cm^2 will have an inhibitory response. At >30J/cm^2 the risk of damage occurs. However, the inhibitory dose can be properly used for analgesia (pain) at the detriment of slower healing. [2] [3]

Basic Biphasic Dose Model

Red Light Therapy follows the same dosing concept for medicine and pharmacology called the Arndt-Schultz Law, where it is stated:

"For every substance, small doses stimulate, moderate doses inhibit, large doses kill." [4]

In Red Light Therapy and other modalities, this theory is often simply called the Biphasic Dose response. It is often represented as this simple chart.

• Extremely low doses have no cellular response.
• Moderate doses of Red/NIR will have a stimulation response leading to the beneficial healing that red light therapy has become famous for.
• High doses of Red/NIR have an inhibitory response, where the cellular up-regulation for healing is forsaken - however it can be utilized to inhibit nerve cells for temporary analgesia. Note that there is no damage at this point, however it would lead to a lack of benefits.
• Extremely high intensities and/or doses will cause tissue damage.

Most clinical researchers are aware of this theory, and are careful to design the studies with intensity and dosages that are safe and effective. It is only the clever salespeople whom encourage excessively high intensity panels and doses.

Rodent Biphasic Dose Response

Assuming you are using reasonable non-thermal intensity and doses - the line between "stimulatory dose" and "inhibitory dose" is extremely vague. In some cases, we don't know if healing from red light therapy is slow due to non-optimal doses, or due to the persons bio-individual response.

There are many studies documenting the Biphasic Dose response in isolated cells, tissues, and small animals. This is rather easy and predictable. Laboratory rodents can be nearly genetically identical and raised in the exact same environments, diets, and conditions. So they exhibit the biphasic dose response in a predictable manner. Humans, not so much.

This is well documented in these two entire review articles about biphasic dose response. Both are free to read and very informative with co-authors YY Huang, SK Sharma, James Carroll, and Michael R Hamblin.

• 2009 - Biphasic Dose Response in Low Level Light Therapy
• 2011 - Biphasic Dose Response in Low Level Light Therapy: An Update

Biphasic dose response has been confirmed in many more recent studies.

For example a 2023 study on healing diabetic ulcers in rats used 4, 6, 8, 10, 12 and 15 J/cm^2. They found the 4, 6, and 8 had the best wound healing response, and the higher doses were not as effective. [5]

Another 2023 study on treating Erectile Dysfunction in rats inflicted with diabetes used 0 J/cm^2, 4 J/cm^2, 8 J/cm^2, or 16 J/cm^2 with 808 nm Near-Infrared light therapy. They found the optimal dose was at 4 J/cm^2. [17]

So we can find many studies on isolated cells and small animals confirming the biphasic dose response, however it has been challenging to find similar studies on humans.

This lack of data has allowed many salespeople to promote "the highest intensity" and high doses as an easy marketing gimmick. Even though they don't have evidence behind their claims, they also know there hasn't been any direct evidence refuting their claims either. Until now.

Human Biphasic Dose Response

Recently we have found several human studies confirming a biphasic dose response. Meaning the higher doses were less effective than the lower doses.

1. Dose Response for Blood Sugar control in human diabetics.

A recent study using an LED flexible pad with 830nm LEDs on 10 patients with type 2 diabetes. [6]

They used a dose of either 5.71 J/cm^2 or 13.72 J/cm^2 and found that the lower dose promoted better response in blood sugar control. The higher dose was not at effective. [6]

They also note a possible Triphasic dose response and that exposure time is important. 

2. Human Biphasic Dose for brain treatments.

A study that was reviewed on the excellent brain-PBM YouTube channel covers a clinical trials for blood flow and depression with transcranial light therapy treatments.

https://youtu.be/jO8Yta1jZp4

It seems to report on the results for this study:

https://www.mdpi.com/2304-6732/10/1/90

They used 3 different sets of dosing with an 808nm wavelength.

A high dose of 166.7 J/cm^2, a medium dose of 97 J/cm^2, and low dose of 50 J/cm^2. 

The medium and low doses had the most positive response, and the high dose was not as effective.

Interestingly, the high dose was delivered with 40Hz pulse to reduce the potential heat damage, and the other two doses were delivered as continuous wave.

In addition to being a biphasic dose response where blasting the brain with high doses isn't superior, this is also an example of a brain treatment where continuous modes performed better than the pulse mode. As we have noted in previous blogs; pulsing doesn't magically improve results - having proper dosing is more important.

3. Osteoarthritis 

A systematic review article of LLLT for Osteoarthritis made this statement.

"Lower dosage of LLLT was found as effective than higher dosage for reducing pain and improving knee range of motion." [7]

Where typically in medicine if a lower dose can deliver the same result as a higher dose, it is prudent to choose the lower dose.

4. Eye Health

You may recall some papers on supporting eye health with 670nm flashlights became viral on many mainstream news outlets.

The first wave of hype was based on this 2020 article using 40 mW/cm^2 for 3 minutes in the mornings. [8]

However, the same group did a follow-up study in 2021 with only 8 mW/cm^2 for 3 minutes in the mornings.[9]

In the second article the researchers specifically comment that they used drastically lower intensities and thus lower doses for this study, and still found good results. For example the first study would be 7.2 J/cm^2 and the second study was only 1.44 J/cm^2.

However, note that since the intensity was dropped and the exposure time stayed the same, this is another point that the exposure time may be more important than either intensity or dose alone.

So particularly for eye health where the eye is most sentitive to light and there are concerns of cataracts from heating effects of high intensity red light therapy - if we can get equal benefits from a high dose or low dose - it is prudent to choose the lower intensity and dose.

5. Musculoskeletal Pain

A review article of high-intensity laser therapy for Musculoskeletal therapy categorized 3 groups of dosing for analysis. They consistently found a trend where the lower doses and medium doses were better than high doses in the various categories. Even for pain.

"No differences were observed in terms of dosage when 10–50 J/cm², 50–100 J/cm², 100–300 J/cm²) but the effect tended to decrease with higher dosages" [10]

6. LLLT for Neck Pain

A review article that analyzed the doses used for neck pain found this range of effective treatment.

"Investigators who used doses outside the minimum (0·075 J and 0·06 J)40,49 and maximum (54 J)44 limits of these ranges did not show any effect of LLLT, lending further support to a dose-dependent response for LLLT in neck pain." [18]

Again showing a clear limitation that exceeding 54 J did not show any effect, which is just as bad as being too low.

The authors make this important comment in the discussion.

"Additionally, a very high dose (54 J) of 830 nm LLLT used in one trial did not cause beneficial nor harmful effects.44 This finding suggests not only that doses of this magnitude are higher than the therapeutic window, but also that LLLT is safe even if such an overdose is delivered." [18]

Similar to what we stated earlier, we may not be able to detect if an "overdose" was delivered since there are practically no side effects to red light therapy. There is only a lack of benefits or slowed benefits when you overdose. They are clearly mentioning a "therapeutic window" of proper dosing that refers to the biphasic dose response in humans. 

7. Biphasic Dose in Athletic Performance

Many studies have been conducted on using Photobiomodulation/LLLT for improving athletic performance and recovery.

Some recent review articles discuss the biphasic dose response in human athlete studies.

One study with 40 male volunteers used 10 J, 30 J, 50 J, or placebo in 6 points on the thighs. They found better performance and less DOMS with the optimal dose at 30 J.

"They administered 10, 30, and 50 J, or placebo, in six points on the front of the thighs ... concluding that the 30 J dose was the best." [11]

Another review article summarized several articles and noticed that studies using doses higher than 80 J led to a negative response.

"We could identify a therapeutic window, or PBM window, suggesting a biphasic dose-response [73,74] for total energy applied on the biceps brachii (20–80 J), regardless whether PBM was applied as a muscular pre-conditioning protocol or after exercise." [12]

This quote is clearly attributing the effect to the biphasic dose response in these human studies.

8.  Human Biphasic Dose for Oral Mucositus

For treatment of oral mucositis there are also clear examples and recommendations to use proper low doses for healing.

Where one group proposes a range of 2 - 10 J/cm^2 for healing and biostimulation, and higher doses of 10-30 J/cm^2 will have an inhibitory response.

Here is their commentary about one human trial with too high of a dose.

"This was clearly appreciated by Simoes et al. who applied 10 J/cm2 at a delivery power of 1.0 W as a pain relief PBM dose, which was recorded as beneficial, although the healing associated with the OM was subsequently found to be slower than that found at a lower applied dose [67]." [3]

So the higher dose still delivered some healing benefits, it is just slower and less optimal. However, this "overdosing" leads to enhanced temporary pain relief, which obviously can be advantageous in many contexts.

New Dosing Model

The research group led by Dr. Mark Cronshaw introduces their dosing model we stated in the introduction. That 2 to 10 J/cm^2 is the optimal red light therapy dose range for a stimulatory response, and 10 to 30 J/cm^2 is the inhibitory range.[2][3]

This is their new multiphasic dose model, which has some subtle but important differences than the original one we presented.

Dosing Model Reminiscent to those seen in the following studies. [2][3]

https://www.mdpi.com/2304-6767/8/3/87

https://pubmed.ncbi.nlm.nih.gov/31329512/

Doses for Deeper Tissues

This dosing model is for direct treatment on the tissues. For example for deeper penetration you may use higher dose at the skin surface because you want to have a sufficient dose reach the deeper tissues like the brain.

So lets take the example of the brain treatments that used 166.7 J/cm^2, a medium dose of 97 J/cm^2, and low dose of 50 J/cm^2.

Even though we are clearly overdosing at the skin level on the medium and high doses, lets look at the estimated dose that would reach the brain.

Since we know only 1-3% of the light will reach the brain, then that brings the actual dose that reaches the brain down to:

• High 1.6 to 5 J/cm^2
• Medium 1 to 3 J/cm^2
• Low 0.5 to 1.5 J/cm^2

So the 0.5 to 3 J/cm^2 could be an adequate dose for the brain, since we certainly don't want to overdose the brain to an inibitory response as it is highly sensitive to light.

The typical dosing range for deep tissue treatments ranges up to 10 to 60 J/cm in red light therapy.

According to the following quote, superficial targets follow the range we established above, however deeper tissues need higher doses at the skin surface:

 "Another respected source suggests that doses used for superficial targets tend to be in the region of 4J/cm2 with a range of 1 to 10J/cm2.16–18 Doses for deeper-seated targets should be in the 10 to 50/cm2 range.19–21^" [4]

A clear limitation would be to not damage the skin with excessively high doses because you are targeting deeper tissue.

"It is noteworthy that LLLT irradiation can induce both proliferation (low energy density—0.8 J/cm²) and apoptosis (higher energy density—60 J/cm2)" [13]

Since naturally damaging the skin would be counterproductive to induce ROS and inflammation, and would likely be overdosing the more sensitive deeper tissues anyway.

So that is why we still see an upper limit to deeper tissue treatments at up to 50-60 J/cm^2 as skin level maximum per session. 

Doses Based on Mitochondrial Density

Then we can appreciate that the brain cells have the highest mitochondria compared to normal cells, so it will be more responsive to lower doses.

Further, the brain will be more sensitive to biphasic dose response at relatively lower doses than what the model established.

This theory of adjusting the dose based on the mitochondrial density of the cells is reviewed in an excellent article titled "Review of light parameters and photobiomodulation efficacy: dive into complexity" [4]

For example, a conclusion they draw is:

"Ineffective studies on cells with higher numbers of mitochondria are as likely to be due to over-dosing as they are to under-dosing." [4]

Essentially they summarize that it is much easier to overdose high-mitochondria density cells like the eyes and brain. It is less likely to overdose cells that have less mitochondria like skin cells.

Highest Intensity Panel Business Model

People using high intensity and doses are likely still enjoying some benefits like temporary pain relief. However, long term cellular healing will be slowed and less optimal than lower doses as demonstrated by these human studies confirming the biphasic dose response.

Brands have an incentive to make ineffective panels by making them as powerful as possible. The slow healing will encourage consumers to purchase more "modular" units, which may even make the healing even slower. Thus making repeat customers where a properly designed low intensity unit could have sufficed.

Our sentiment is confirmed in the following quote written in a paper by Dr. Hamblin et al.

High Intensity Class IV (4) lasers are using irrelevant Class 3B studies to justify their devices - then falsely imply having more power would be superior. When the studies show the opposite is true and over-dosing is more likely to cause poor results.

"There are manufacturers of class IV laser devices that refer to clinical trials performed with a class 3B laser. These same class IV device manufacturers then claim that because 3B laser results are sometimes negative, the extra power of a class IV laser will be more effective (systematic reviews show that the opposite is true, that over-treatment is more often the problem)." [1]

The same way the "highest intensity" LED panels are basing their claims on much lower power and lower doses studies, but then falsely imply their devices will be superior than the studies. When in reality high intensity LED panels will suffer the same problem and could produce worse results.

Another quote states the following:

"A common misconception is that energy (in J) or energy density (J/cm²) is all that is necessary to replicate a successful treatment, irrespective of the original power, power density, and duration parameters (14, 15)." [14]

As this quote implies, the intensity and exposure time are often more important than just the "dose" in J/cm^2. So even though this blog focuses on reviewing the Energy Density (J/cm^2), the true "dose" is considering all of the parameters together.

Brands that use very high intensity that market as a time-savings could be encouraging the users to get less results by getting inadequate exposure time or causing less effects due to the biphasic dose response.

Real Medical Dosing Logic

Like most medicine, the goal is to obtain consistent results with the Minimum Effective Dose (MED).

A so-called "Maximum Effective Dose" is not really a thing in medicine, except perhaps now as a sales fallacy for selling red light devices.

The Maximum Tolerated Dose (MTD) is the highest dose with toxicity below a certain level. Naturally as you increase the intensity and dose, you are increasing the potential for risks and side effects, without much promise of actually getting better benefits. [15]

This article titled "Why maximum tolerated dose?" by Dr. Stampfer et al. is an excellent free review of the basic principals of pharmacology dosing. [15]

The ED50 (Effective Dose 50) is the center of the dose response curve which achieves half of the maximum drug effect in the average population.

The article recommends starting at an ED50 for most drugs, then titrating up as needed and monitoring for progress or possible adverse effects.

Dr. Stampfer recommends an old maxim of "start low and go slow" when implementing medicine and incrementing the dose.

Starting at the Maximum Tolerated Dose is unwise with little promise of performing better and can only result in higher risks of adverse events.

"In most illness, there is merit in maintaining patients on the lowest effective dose, with close clinical monitoring for efficacy, tolerability and adverse events." [15]

The goal is to maintain a minimum effective dose. However, notice there is no "one-size-fits-all" for drugs or red light therapy. Monitoring your results and adjusting the dose will be the only way to optimize.

Conclusion - Titrate the Dose

If Red Light Therapy wants to be taken seriously as a "clinical grade" therapy, then the influencers and brands should understand basic pharmacology principals.

It is prudent to understand the Arnlt-Shulz Law for biphasic dose response, follow the Minimum Effective Dose, avoid the Maximum Tolerated Dose, learn to titrate the dose, and not fall prey to fallacies that "more is better".

These examples helped prove the old adage that "less is more" is literally true for red light therapy even in humans.

In addition to the extremely large body of research confirming biphasic dose response in tissues and small animals, which informs the rationale that nearly all clinical researchers design their dose around.

Put another way, Dr. Hamblin states it as follows in one article:

"It is often said in this context that “more does not mean more”."[16]

This blog explored the complexities of dose in red light therapy, where the optimal dose range for normal tissues is between 2-10 J/cm^2. Higher doses from 10-30 J/cm^2 will have a slower response but may be advantageous in certain contexts like analgesia.

When targeting deeper tissues we may need higher doses at the skin surface to get a sufficient dose to the deeper tissues. However, even that seems to be limited at a maximum of 60 J/cm^2 at the skin surface for deep tissue targets.

Dosing red light therapy becomes increasingly complex when we adjust for large complex mammals (humans), different skin thicknesses, skin phototype, mitochondrial density of the target cells, genders, age, medical conditions, and long term cumulative dosing.

Starting with reasonable doses and low intensities at a routine interval is always the best way to get started with Red Light Therapy.

Being informed of these dosing models, you can titrate your dose up or down to find what works best for your bioindividuality and lifestyle and specific conditions.

"Titrating adequate doses and defining the essential PBM parameters as per evidence gathered in a systematic way for each indication is a prerequisite for the successful use of this treatment modality." [14]

However, the challenge is the consumer needs to be educated and empowered to control their own dosing - and not rely on false medical authorities to tell them backdoor generic prescriptions with red light therapy devices.

Applying some mindfullness, being aware of reasonable doses, and adjusting your personal dose is always going to be the best way to optimize your red light therapy.

References:

[1]

Michael R. Hamblin, Marcelo Victor Pires de Sousa, Praveen R. Arany, James D. Carroll, Donald Patthoff D.D.S., "Low level laser (light) therapy and photobiomodulation: the path forward," Proc. SPIE 9309, Mechanisms for Low-Light Therapy X, 930902 (5 March 2015); https://doi.org/10.1117/12.2084049

https://www.spiedigitallibrary.org/conference-proceedings-of-spie/9309/930902/Low-level-laser-light-therapy-and-photobiomodulation--the-path/10.1117/12.2084049.short?SSO=1

[2]

Cronshaw M, Parker S, Arany P. Feeling the Heat: Evolutionary and Microbial Basis for the Analgesic Mechanisms of Photobiomodulation Therapy. Photobiomodul Photomed Laser Surg. 2019 Sep;37(9):517-526. doi: 10.1089/photob.2019.4684. Epub 2019 Jul 19. PMID: 31329512.

https://pubmed.ncbi.nlm.nih.gov/31329512/

[3]

Cronshaw M, Parker S, Anagnostaki E, Mylona V, Lynch E, Grootveld M. Photobiomodulation and Oral Mucositis: A Systematic Review. Dentistry Journal. 2020; 8(3):87. https://doi.org/10.3390/dj8030087

 https://www.mdpi.com/2304-6767/8/3/87

[4]

Randa Zein, Wayne Selting, Michael R. Hamblin, "Review of light parameters and photobiomodulation efficacy: dive into complexity," J. Biomed. Opt. 23(12) 120901 (11 December 2018) https://doi.org/10.1117/1.JBO.23.12.120901

https://www.spiedigitallibrary.org/journals/journal-of-biomedical-optics/volume-23/issue-12/120901/Review-of-light-parameters-and-photobiomodulation-efficacy--dive-into/10.1117/1.JBO.23.12.120901.full?SSO=1&tab=ArticleLink

[5]

Karkada G, Maiya GA, Arany P, Rao Kg M, Adiga S, Kamath SU. Dose-Response Relationship of Photobiomodulation Therapy on Matrix Metalloproteinase in Healing Dynamics of Diabetic Neuropathic Ulcers-An in vivo Study. Photochem Photobiol. 2023 Jul-Aug;99(4):1172-1180. doi: 10.1111/php.13754. Epub 2023 Jan 15. PMID: 36477863.

https://pubmed.ncbi.nlm.nih.gov/36477863/

[6]

Clara Maria Cobra Branco Scontri, Flávio de Castro Magalhães, Ana Paula Moraes Damiani, Michael R. Hamblin, Antonio Roberto Zamunér, Cleber Ferraresi Dose and time–response effect of photobiomodulation therapy on glycemic control in type 2 diabetic patients combined or not with hypoglycemic medicine: A randomized, crossover, double-blind, sham-controlled trial

First published: 12 May 2023

https://doi.org/10.1002/jbio.202300083

https://onlinelibrary.wiley.com/doi/10.1002/jbio.202300083#pane-pcw-references

[7]

Brosseau L, Welch V, Wells G, DeBie R, Gam A, Harman K, Morin M, Shea B, Tugwell P. Low level laser therapy (Classes I, II and III) for treating osteoarthritis. Cochrane Database Syst Rev. 2004;(3):CD002046. doi: 10.1002/14651858.CD002046.pub2. Update in: Cochrane Database Syst Rev. 2007;(1):CD002046. PMID: 15266461.

https://pubmed.ncbi.nlm.nih.gov/15266461/

[8]

Harpreet Shinhmar, MSc and others, Optically Improved Mitochondrial Function Redeems Aged Human Visual Decline, The Journals of Gerontology: Series A, Volume 75, Issue 9, September 2020, Pages e49–e52, https://doi.org/10.1093/gerona/glaa155

https://academic.oup.com/biomedgerontology/article/75/9/e49/5863431

[9]

Shinhmar, Harpreet et al. “Weeklong improved colour contrasts sensitivity after single 670 nm exposures associated with enhanced mitochondrial function.” Scientific reports vol. 11,1 22872. 24 Nov. 2021, doi:10.1038/s41598-021-02311-1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613193/

[10]

Arroyo-Fernández R, Aceituno-Gómez J, Serrano-Muñoz D, Avendaño-Coy J. High-Intensity Laser Therapy for Musculoskeletal Disorders: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Journal of Clinical Medicine. 2023; 12(4):1479. https://doi.org/10.3390/jcm12041479

https://www.mdpi.com/2077-0383/12/4/1479

[11]

Ailioaie LM, Litscher G. Photobiomodulation and Sports: Results of a Narrative Review. Life. 2021; 11(12):1339. https://doi.org/10.3390/life11121339

https://www.mdpi.com/2075-1729/11/12/1339#:~:text=Photobiomodulation%20from%20red%20to%20near,resistance%2C%20and%20speed%20of%20recovery.

[12]

Ferraresi, Cleber et al. “Photobiomodulation in human muscle tissue: an advantage in sports performance?.” Journal of biophotonics vol. 9,11-12 (2016): 1273-1299. doi:10.1002/jbio.201600176

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167494/

[13]

Rola P, Włodarczak S, Lesiak M, Doroszko A, Włodarczak A. Changes in Cell Biology under the Influence of Low-Level Laser Therapy. Photonics. 2022; 9(7):502. https://doi.org/10.3390/photonics9070502

https://www.mdpi.com/2304-6732/9/7/502

[14]

Robijns, Jolien et al. “Photobiomodulation therapy in management of cancer therapy-induced side effects: WALT position paper 2022.” Frontiers in oncology vol. 12 927685. 30 Aug. 2022, doi:10.3389/fonc.2022.927685

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9468822/

[15]

Stampfer, Hans G et al. “Why maximum tolerated dose?.” British journal of clinical pharmacology vol. 85,10 (2019): 2213-2217. doi:10.1111/bcp.14032

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783596/

[16]

Hamblin MR. Shining light on the head: Photobiomodulation for brain disorders. BBA Clin. 2016 Oct 1;6:113-124. doi: 10.1016/j.bbacli.2016.09.002. PMID: 27752476; PMCID: PMC5066074.

[17]