Low Level Laser Therapy (LLLT)

Five studies on the efficacy of photobiomodulation as of Feb 2018

Here are my annotations of five studies showing the efficacy of photobiomodulation (as of Feb 2018), also called LLLT, for pain and depression (and muscle function).

The Nuts and Bolts of Low-level Laser (Light) Therapy – Ann Biomed Eng. 2012 Feb;  /PMC3288797/

This full-text article explains how LLLT works.

Soon after the discovery of lasers in the 1960s it was realized that laser therapy had the potential to improve wound healing and reduce pain, inflammation and swelling.

In recent years the field sometimes known as photobiomodulation has broadened to include light-emitting diodes and other light sources, and the range of wavelengths used now includes many in the red and near infrared  

The term “low level laser therapy” or LLLT has become widely recognized and implies the existence of the biphasic dose response or the Arndt-Schulz curve

This review will cover the mechanisms of action of LLLT at a cellular and at a tissular level and will summarize the various light sources and principles of dosimetry that are employed in clinical practice.

The range of diseases, injuries, and conditions that can be benefited by LLLT will be summarized with an emphasis on those that have reported randomized controlled clinical trials. Serious life-threatening diseases such as stroke, heart attack, spinal cord injury, and traumatic brain injury may soon be amenable to LLLT therapy.


Low level laser therapy (LLLT), also known as photobiomodulation, came into being in its modern form soon after the invention of the ruby laser in 1960, and the helium–neon (HeNe) laser in 1961. In 1967, Endre Mester, working at Semmelweis University in Budapest, Hungary, noticed that applying laser light to the backs of shaven mice could induce the shaved hair to grow back more quickly than in unshaved mice

LLLT has now developed into a therapeutic procedure that is used in three main ways:

  1. to reduce inflammation, edema, and chronic joint disorders;
  2. to promote healing of wounds, deeper tissues, and nerves; and
  3. to treat neurological disorders and pain.

LLLT involves exposing cells or tissue to low levels of red and near infrared (NIR) light, and is referred to as “low level” because of its use of light at energy densities that are low compared to other forms of laser therapy that are used for ablation, cutting, and thermally coagulating tissue.

LLLT is also known as “cold laser” therapy as the power densities used are lower than those needed to produce heating of tissue

It was originally believed that LLLT or photobiomodulation required the use of coherent laser light, but more recently, light emitting diodes (LEDs) have been proposed as a cheaper alternative. A great deal of debate remains over whether the two light sources differ in their clinical effects.

Although LLLT is now used to treat a wide variety of ailments, it remains controversial as a therapy for two principle reasons: first, its underlying biochemical mechanisms remain poorly understood, so its use is largely empirical.

Second, a large number of parameters such as the wavelength, fluence, power density, pulse structure, and timing of the applied light must be chosen for each treatment.

A less than optimal choice of parameters can result in reduced effectiveness of the treatment, or even a negative therapeutic outcome. As a result, many of the published results on LLLT include negative results simply because of an inappropriate choice of light source and dosage.

This choice is particularly important as there is an optimal dose of light for any particular application, and doses higher or lower than this optimal value may have no therapeutic effect. In fact, LLLT is characterized by a biphasic dose response: lower doses of light are often more beneficial than high doses


Light and Laser

Light is part of the spectrum of electromagnetic radiation (ER), which ranges from radio waves to gamma rays. ER has a dual nature as both particles and waves.

As a wave which is crystallized in Maxwell’s Equations, light has amplitude, which is the brightness of the light, wavelength, which determines the color of the light, and an angle at which it is vibrating, called polarization. The wavelength (λ) of light is defined as the length of a full oscillation of the wave, such as shown in Fig. 1a.

In terms of the modern quantum theory, ER consists of particles called photons, which are packets (“quanta”) of energy which move at the speed of light. In this particle view of light, the brightness of the light is the number of photons, the color of the light is the energy contained in each photon, and four numbers (X, Y, Z and T) are the polarization, where X, Y, Z are the directions and T is the time.

A laser is a device that emits light through a process of optical amplification based on the stimulated emission of photons. The term “laser” originated as an acronym for light amplification by stimulated emission of radiation. The emitted laser light is notable for its high degree of spatial and temporal coherence

Spatial coherence typically is expressed through the output being a narrow beam which is diffraction-limited, often a so-called “pencil beam.” Laser can be launched into a beam of very low divergence to concentrate their power at a large distance.

Light Emitting Diodes (LED)

A light-emitting diode (LED) is a semiconductor light source. Introduced as a practical electronic component in 1962 early LEDs emitted low-intensity red light, but modern versions are available across the visible, ultraviolet and infrared wavelengths, with very high brightness.

When a light-emitting diode is forward biased (switched on), electrons are able to recombine with electron holes within the device, releasing energy in the form of photons.

This effect is called electroluminescence and the color of the light (corresponding to the energy of the photon) is determined by the energy gap of the semiconductor. An LED is often small in area (less than 1 mm2), and integrated optical components may be used to shape its radiation pattern

Optical Properties of Tissue

When the light strikes the biological tissue, part of it is absorbed, part is reflected or scattered, and part is further transmitted.

Most of the light is absorbed by the tissue. The energy states of molecules are quantized; therefore, absorption of a photon takes place only when its energy corresponds to the energy difference between such quantized states.

The phenomenon of absorption is responsible for the desired effects on the tissue. The coefficient μa (cm−1) characterizes the absorption. The inverse, la, defines the penetration depth (mean free path) into the absorbing medium.

The scattering behavior of biological tissue is also important because it determines the volume distribution of light intensity in the tissue. This is the primary step for tissue interaction, which is followed by absorption.

Scattering of a photon is accompanied by a change in the propagation direction without loss of energy.

Scattering is not isotropic. Forward scattering is predominant in biological tissue.

Light Distribution in Laser-irradiated Tissue

Most of the recent advances in describing the transfer of light energy in tissue are based upon transport theory

The approximate solutions of light distribution in tissue are dependent upon the type of light irradiation (diffuse or collimated) and the optical boundary conditions (matched or unmatched indexes of refraction).


The precise biochemical mechanism underlying the therapeutic effects of LLLT are not yet well-established.

From observation, it appears that LLLT has a wide range of effects at the molecular, cellular, and tissular levels. In addition, its specific modes of action may vary among different applications

Within the cell, there is strong evidence to suggest that

  1. LLLT acts on the mitochondria to increase adenosine triphosphate (ATP) production,
  2. modulation of reactive oxygen species (ROS), and
  3. the induction of transcription factors.

transcription factors then cause protein synthesis that triggers further effects down-stream, such as increased cell proliferation and migration, modulation in the levels of cytokines, growth factors and inflammatory mediators, and increased tissue oxygenation.Figure 2 shows the proposed cellular and molecular mechanisms of LLLT.

Mast cells, which play a crucial role in the movement of leukocytes, are of considerable importance in inflammation. Specific wavelengths of light are able to trigger mast cell degranulation, which results in the release of the pro-inflammatory cytokine TNF-a from the cells

Immune cells, in particular, appear to be strongly affected by LLLT

Lymphocytes become activated and proliferate more rapidly, and epithelial cells become more motile, allowing wound sites to close more quickly. The ability of macrophages to act as phagocytes is also enhanced under the application of LLLT.

At the most basic level, LLLT acts by inducing a photochemical reaction in the cell, a process referred to as biostimulation or photobiomodulation.

When a photon of light is absorbed by a chromophore in the treated cells, an electron in the chromophore can become excited and jump from a low-energy orbit to a higher-energy orbit. This stored energy can then be used by the system to perform various cellular tasks

There are several pieces of evidence that point to a chromophore within mitochondria being the initial target of LLLT.

Radiation of tissue with light causes an increase in mitochondrial products such as ATP, NADH, protein, and RNA, as well as a reciprocal augmentation in oxygen consumption, and various in vitro experiments have confirmed that cellular respiration is upregulated when mitochondria are exposed to an HeNe laser or other forms of illumination.

The relevant chromophore can be identified by matching the action spectra for the biological response to light in the NIR range to the absorption spectra of the four membrane-bound complexes identified in mitochondria

This procedure indicates that complex IV, also known as cytochrome c oxidase (CCO), is the crucial chromophore in the cellular response to LLLT.

CCO is a large transmembrane protein complex, consisting of two copper centers and two heme–iron centers, which is a component of the respiratory electron transport chain.

The electron transport chain passes high-energy electrons from electron carriers through a series of transmembrane complexes (including CCO) to the final electron acceptor, generating a proton gradient that is used to produce ATP.

the application of light directly influences ATP production by affecting one of the transmembrane complexes in the chain: in particular, LLLT results in increased ATP production and electron transport.

The precise manner in which light affects CCO is not yet known. The observation that NO is released from cells during LLLT has led to speculation that CCO and NO release are linked by two possible pathways

The influence of LLLT on the electron transport chain extends far beyond simply increasing the levels of ATP produced by a cell

Oxygen acts as the final electron acceptor in the electron transport chain and is, in the process, converted to water

Among its many effects, LLLT has been shown to cause vasodilation by triggering the relaxation of smooth muscle associated with endothelium, which is highly relevant to the treatment of joint inflammation

This vasodilation increases the availability of oxygen to treated cells, and also allows for greater traffic of immune cells into tissue. These two effects contribute to accelerated healing.

NO is a potent vasodilator via its effect on cyclic guanine monophosphate production, and it has been hypothesized that LLLT may cause photodissociation of NO, not only from CCO, but from intracellular stores such as nitrosylated forms of both hemoglobin and myoglobin, leading to vasodilation


Currently, one of the biggest sources of debate in the choice of light sources for LLLT is the choice between lasers and LEDs.

LEDs have become wide-spread in LLLT devices.

It was originally believed that the coherence of laser light was crucial to achieve the therapeutic effects of LLLT, but recently this notion has been challenged by the use of LEDs, which emit non-coherent light over a wider range of wavelengths than lasers

It has yet to be determined whether there is a real difference between laser and LED, and if it indeed exists, whether the difference results from the coherence or the monochromaticity of laser light, as opposed to the non-coherence and wider bandwidth of LED light.

A future development in LLLT devices will be the use of organic light emitting diodes (OLEDs). These are LEDs in which the emissive electroluminescent layer is a film of organic compounds which emit light in response to an electric current.

The wavelengths of light used for LLLT fall into an “optical window” at red and NIR wavelengths (600–1070 nm)

Effective tissue penetration is maximized in this range, as the principal tissue chromophores (hemoglobin and melanin) have high absorption bands at wavelengths shorter than 600 nm. Wavelengths in the range 600–700 nm are used to treat superficial tissue, and longer wavelengths in the range 780–950 nm, which penetrate further, are used to treat deeper-seated tissues

Wavelengths in the range 700–770 nm have been found to have limited biochemical activity and are therefore not used


The power of light used typically lies in the range 1–1000 mW, and varies widely depending on the particular application.

There is evidence to suggest that the effectiveness of the treatment varies greatly on both the energy and power density used: there appears to be upper and lower thresholds for both parameters between which LLLT is effective.

Outside these thresholds, the light is either too weak to have any effect, or so strong that its harmful effects outweigh its benefits.

Response to LLLT changes with wavelength, irradiance, time, pulses and maybe even coherence and polarization, the treatment should cover an adequate area of the pathology, and then there is a matter of how long to irradiate for.

Biphasic Dose Response

It is well established that if the light applied is not of sufficient irradiance or the irradiation time is too short then there is no response. If the irradiance is too high or irradiation time is too long then the response may be inhibited.

Somewhere in between is the optimal combination of irradiance and time for stimulation. This dose response often likened to the biphasic response known as “Arndt-Schulz Law” which dates back to 1887 when Hugo Schulz published a paper showing that various poisons at low doses have a stimulatory effect on yeast metabolism when given in low doses

This idea of low doses of poisons being beneficial is also applicable to radiation: Beneficial Effects of Low-Dose Radiation


LLLT is used for three main purposes:

  1. to promote wound healing, tissue repair, and the prevention of tissue death;
  2. to relieve inflammation and edema because of injuries or chronic diseases; and
  3. as an analgesic and a treatment for other neurological problems.

TABLE 3: Pre-clinical studies on animals with low level light therapy for different conditions:

TABLE 4: Clinical studies on patients with low level light therapy for different conditions

There appears to be more firm evidence to support the success of LLLT in alleviating pain and treating chronic joint disorders, than in healing wounds

A review of 16 randomized clinical trials including a total of 820 patients found that LLLT reduces acute neck pain immediately after treatment, and up to 22 weeks after completion of treatment in patients with chronic neck pain

LLLT has also been shown to relieve pain because of cervical dentinal hypersensitivity,

A study of 88 randomized controlled trials indicated that LLLT can significantly reduce pain and mprove health in chronic joint disorders such as osteoarthritis, patellofemoral pain syndrome, and mechanical spine disorders.

LLLT for Serious Diseases

LLLT is also being considered as a viable treatment for serious neurological conditions such as traumatic brain injury (TBI), stroke, spinal cord injury, and degenerative central nervous system disease.

Intravascular Laser Therapy

Intravenous or intravascular blood irradiation involves the in vivo illumination of the blood by feeding low level laser light generated by a 1–3 mW low power laser at a variety of wavelengths through a fiber optic inserted in a vascular channel, usually a vein in the forearm, under the assumption that any therapeutic effect will be circulated through the circulatory system

The technique was developed primarily in Asia (including Russia) and is not extensively used in other parts of the world. It is claimed to improve blood flow and its transport activities, but has not been subject to randomized controlled trials and is subject to skepticism

Laser Acupuncture and Trigger Points

Low power lasers with small focused spots can be used to stimulate acupuncture points using the same rules of point selection as in traditional Chinese needle acupuncture

Laser acupuncture may be used solely or in combination with needles for any given condition over a course of treatment.

Trigger points are defined as hyperirritable spots in skeletal muscle that are associated with palpable nodules in taut bands of muscle fibers. They may also be found in ligaments, tendons, and periosteum. Higher doses of LLLT may be used for the deactivation of trigger points. Direct irradiation over tendons, joint margins, bursae etc. may be effective in the

LLLT for Hair Regrowth

One of the most commercially successful applications of LLLT is the stimulation of hair regrowth in balding individuals. The photobiomodulation activity of LLLT can cause more hair follicles to move from telogen phase into anagen phase. The newly formed hair is thicker and also more pigmented


While the body of evidence for LLLT and its mechanisms is still weighted in favor of lasers and directly comparative studies are scarce, ongoing work using non-laser irradiation sources is encouraging and provides support for growth in the manufacture and marketing of affordable home-use LED devices.

The almost complete lack of reports of side effects or adverse events associated with LLLT gives security for issues of safety that will be required.

The day may not be far off when most homes will have a light source (most likely a LED device) to be used for aches, pains, cuts, bruises, joints, and which can also be applied to the hair and even transcranially to the brain.

Proposed Mechanisms of Photobiomodulation or Low-Level Light Therapy IEEE J Sel Top Quantum Electron. 2016 May – /PMC5215870/

Good summary of biological actions resulting from LLLT

Photobiomodulation (PBM) also known as low-level laser (or light) therapy (LLLT), has been known for almost 50 years but still has not gained widespread acceptance, largely due to uncertainty about the molecular, cellular, and tissular mechanisms of action.

However, in recent years, much knowledge has been gained in this area, which will be summarized in this review.

One of the most important chromophores is cytochrome c oxidase (unit IV in the mitochondrial respiratory chain), which contains both heme and copper centers and absorbs light into the near-infra-red region.

  • The leading hypothesis is that the photons dissociate inhibitory nitric oxide from the enzyme, leading to an increase in electron transport, mitochondrial membrane potential and ATP production
  • Another hypothesis concerns light-sensitive ion channels that can be activated allowing calcium to enter the cell

After the initial photon absorption events, numerous signaling pathways are activated via reactive oxygen species, cyclic AMP, NO and Ca2+, leading to activation of transcription factors

These transcription factors can lead to increased expression of genes related to protein synthesis, cell migration and proliferation, anti-inflammatory signaling, anti-apoptotic proteins, antioxidant enzymes.

Stem cells and progenitor cells appear to be particularly susceptible to LLLT.

Review of transcranial photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative stress, and neurogenesis Neurophotonics 2016 Jul; –  /PMC4777909/


We examined the use of near-infrared and red radiation (photobiomodulation, PBM) for treating major depressive disorder (MDD).

Based on the data collected to date, PBM appears to be a promising treatment for depression that is safe and well-tolerated. However, large randomized controlled trials are still needed to establish the safety and effectiveness of this new treatment for MDD.

1. Introduction

Infrared (IR) light is ubiquitously present to most life on the earth. Of the total amount of solar energy reaching the human skin, 54% is IR and 30% is IR type A—near-infrared—(NIR; with a wavelength range of 760 to 1440 nm), which penetrates through the human skin and reaches deeply into tissue, depending on wavelength and energy.

The use of transcranial phototherapy for treating brain disorders started with its application to acute stroke.

Numerous preclinical animal studies suggested that the application of NIR laser (810 nm) to the head at various times (hours) after induction of an acute stroke had beneficial effects on subsequent neurological performance and reduced lesion size.

Evidence was obtained for the anti-inflammatory, anti-apoptotic, and proneurogenesis effects in the brain stimulated by this approach

For the transcranial treatment of major depressive disorder (MDD), both PBM LEDs and lasers have been experimentally tested, although PBM is not FDA-approved for the treatment of MDD.

Certain forms of PBM treatment are also referred to as low-level light therapy (LLLT), since it utilizes light at a low power (0.1 to 0.5 W output at the source) to avoid any heating of tissue.

The irradiance of the PBM medical devices (or power density) typically ranges from 1 to 10 times the NIR irradiance from sunlight on the skin (33.6 mW/cm2 at the zenith). However, most PBM medical devices only deliver light energy at one or two selected wavelengths, as opposed to the whole spectrum of IR that is contained in sunlight.

In this review, we will first discuss the mechanisms of action by which NIR and red light (PBM) might improve symptoms of depression, and then present the clinical evidence for their use as a treatment for MDD and other comorbid psychiatric syndromes.

2. Methods

We found clinical and preclinical studies via PubMed search (December 15, 2015), using the following keywords: “near-infrared radiation,” “NIR,” “low-level light therapy,” “low-level laser therapy,” or “LLLT” plus “depression.” We chose studies that had a clinical focus, and we excluded studies involving NIR spectroscopy.

In addition, we used PubMed to find articles that examined the link between PBM and each of the various biological processes including metabolism, inflammation, oxidative stress, and neurogenesis.

3. Targeting Brain Metabolism

Multiple studies have reported regional and global hypometabolism in MDD, which could be related (either causally or consequentially) to the neurobiology of mood disorders

Positron emission tomography studies have shown abnormalities in glucose consumption rates and in blood flow in several brain regions of subjects with major depression.

Moreover, metabolic abnormalities in the anterior cingulate, the amygdala-hippocampus complex, the dorsolateral prefrontal cortex (DLPFC), and inferior parietal cortex seem to improve after antidepressant treatment or after recovery.

In experimental and animal models, PBM (NIR and red light) noninvasively delivers energy to the cytochrome c oxidase and by stimulating the mitochondrial respiratory chain leads to increased ATP production.

A study of the effects of NIR on patients with MDD found that a single session of NIR led to a marginally significant increase in regional cerebral blood flow

Given the correlation of both hypometabolism and abnormal cerebral blood flow with MDD, the beneficial effect of NIR on brain metabolism is one potential mechanism for its antidepressant effect.

4. Targeting Inflammation

Animal and clinical research suggests that the inflammatory arm of the immune system contributes to MDD. Post-mortem gene expression profiling on tissue samples from Brodmann area 10 (BA10—prefrontal cortex) have shown that MDD is characterized by increased inflammation and apoptosis.

In a case-control study, Simon et al. found that antidepressant-naive MDD subjects had significant elevations in the following cytokines and chemokines when compared to healthy controls:

  • MIP-1α,
  • IL-1α,
  • IL-1β,
  • IL-6,
  • IL-8,
  • IL-10,
  • Eotaxin,
  • GM-CSF, and
  • IFNγ.

Although IL-10 is an anti-inflammatory cytokine, the results suggested that the elevated levels of this IL-10 were likely induced in response to the overall elevation of proinflammatory cytokine levels.

In a review of the research on inflammation in MDD, Raison et al. proposed that proinflammatory cytokines might cause brain abnormalities that are characteristic of MDD. Indeed, animal research has shown that IL-1 mediates chronic depression in mice by suppressing hippocampal neurogenesis

One proinflammatory cytokine that may be of particular relevance to depression is CSF IL-6 (IL6 measured in cerebrospinal fluid). In a recent report, patients with MDD had significantly higher CSF IL-6 levels compared to healthy controls; CSF IL-6 levels were significantly higher than in the serum, and there was no significant correlation between CSF and serum IL-6 levels.

NIR light and red light (600 to 1600 nm) decreased synovial IL-6 gene expression (decreased mRNA levels) in a rat model of rheumatoid arthritis

In another study, NIR (810 nm) used as a treatment for pain in patients with rheumatoid arthritis decreased production of the following proinflammatory cytokines: TNF-α, IL-1β, and IL-8.

In summary, it is reasonable to predict that transcranial NIR treatment would likewise have an anti-inflammatory effect in patients suffering from MDD.

6. Targeting Neurogenesis

A large body of research has demonstrated a link between stress-induced suppression of neurogenesis in the dentate gyrus (DG) and episodes of major depression.

Additionally, MDD patients tend to exhibit significant hippocampal atrophy

Although there is a general consensus among reviewers that stress-induced suppression of hippocampal neurogenesis is not by itself a causal factor in the development of depression, studies demonstrate that many of the therapeutic effects of antidepressant treatments might be dependent on increasing DG neurogenesis

Animal research has shown that PBM stimulates neurogenesis and protects against cell death. Data suggest that red light, close to the NIR spectrum (670 nm), protects the viability of cell culture after oxidative stress, as indicated by mitochondria membrane potentials

NIR also stimulates neurite outgrowth mediated by nerve growth factor, and this effect could also have positive implications for axonal protection.

Red light close to NIR spectrum (670 nm) has also been shown to protect neuronal cells against cyanide

In addition, NIR improves memory performance in middle-aged mic

In summary, PBM increases neurotrophins, neurogenesis, synaptogenesis, and ATP, while it reduces inflammation, apoptosis, and oxidative stress. Through these mechanisms, PBM has the potential to be an effective treatment for MDD and comorbid disorders.

7. Treatment Parameters and Penetration of Transcranial Photobiomodulation

Prior to examining the effects of transcranial PBM on depressive symptoms, it is necessary to clarify that in our review the reported dosimetry refers to the properties of the light at the skin surface.

It is critical to distinguish between the light energy delivered to the skin surface and that delivered to the target tissue. In the mouse brain, the distance from skin surface to the depth of the brain is about 2 mm. In contrast, in humans, up to 2 to 3 cm of intervening skin, skull, cerebrospinal fluid, and brain needs to be penetrated to adequately irradiate a target site, such as the prefrontal cortex.

Different groups have found quite different levels of penetration for LED devices.

depending on parameters used, the expected brain depth of irradiation might vary from only the most superficial cortex to its whole width (including sulci), always in proximity of the light source.

8. Transcranial Photobiomodulation in Healthy Volunteers

In a study from the University of Texas (Austin), Barrett and Gonzalez-Lima tested the effect of transcranial PBM on memory and attention in undergraduates enrolled in an introductory psychology class

They delivered one session of NIR light to the right forehead, targeting the right frontal pole of the cerebral cortex, which is the most anterior portion of the right prefrontal cortex (Brodmann’s area 9 and 10). They used the EEG sites (FP2) to center their light source toward the right frontal eminence

The instrument used was a class-IV laser CG-5000 (Cell Gen Therapeutics) and the parameters were the following: wavelength: 1064 nm (NIR light), irradiance: 250 mW/cm2, fluence: 60 J/cm2, time: 4 min per site (two sites).

Similar parameters have been used clinically with comparable instruments (by Cell Gen Therapeutics) for the treatment of lower back pain, sciatica, and migraine headaches. It was estimated that 2% of the NIR light passed the cranial bone and reached the brain

The authors observed that the undergraduates who received the NIR light

  • had faster reaction times after 2 weeks, measured by the psychomotor vigilance test.
  • They were more attentive to the light signals on the test screen and responded more promptly.
  • The undergraduates who underwent PBM (NIR) also performed better in terms of memory.

Barrett and Gonzalez-Lima also observed a lasting benefit in the overall affect of the undergraduates exposed to NIR light after 2 weeks, including in several dimensions possibly related to anxiety, such as being “afraid, scared, nervous, jittery, irritable, ashamed, upset, and distressed.” This was assessed by the PANAS rating scale, which explores both positive and negative affect.

9. Preliminary Clinical Evidence for the Treatment of Depression with Transcranial Photobiomodulation

To this date, there are only two preliminary open studies of transcranial PBM for the treatment of MDD that have been published

Schiffer et al. (McLean Hospital, Belmont, Massachusetts) studied 10 depressed subjects

The study showed good tolerability of PBM, and a single exposure of the forehead to 810 nm LED gave a significant reduction in depression (HAM-D scale) in just 2 weeks, despite the fact that the PBM treatment was tested on a sample of patients suffering from treatment-resistant depression.

The treatment consisted of a single session of PBM at two sites on the forehead, aiming at the DLPFC (on EEG sites F3 and F4 bilaterally).

The LED instrument used was produced by the Marubeni America Corp. and the following parameters were applied: wavelength: 810 nm, irradiance: 250 mW/cm2, fluence: 60 J/cm2, and time: 4 min per site (two sites).

  • Depressive symptoms were significantly decreased at weeks 2 and 4
  • The authors reported a 60% remission rate of MDD at week 2

Noticeably, depressive symptoms tended to creep back up at week 4 from the NIR treatment, suggesting that one single treatment, while sufficient in this population to produce remission, might have been inadequate to maintain it

Given the open and uncontrolled design, a placebo effect could not be assessed and ruled out; however, placebo effect tends to be marginal in patients with resistant depression.

Our group (Massachusetts General Hospital, Boston, Massachusetts) obtained preliminary data on the safety and efficacy of multiple sessions of transcranial PBM in MDD patients.

We conducted a 7-week double-blind sham-controlled treatment, involving 3 weeks of NIR or sham twice a week followed by cross-over to 3 more weeks of NIR or sham, after a washout week. We reported data on the only four completers, who all received 3 weeks of active NIR followed by 3 weeks of sham

  • The baseline HAM-D-17 total scores averaged 19.8 ± 4.35 (SD).
  • At endpoint, the mean HAM-D-17 total scores was 13 ± 5.35 (SD

While our findings were limited by our small sample size, they support the hypotheses that transcranial PBM could be an effective treatment for MDD.

While most transcranial PBM treatments have been conducted with sources of continuous light, at least one group (Neuro-Laser Foundation in Denver, Colorado) has experimented with pulsed light in TBI.

This contribution is potentially relevant to the field, as in animal models of TBI it appears that pulsed NIR light might be more effective than continuous wave light

While all 10 TBI subjects experienced symptoms of depression [Quick Inventory of Depressive Symptomatology (QIDS) mean total score 12.9 ± 4.6 SD], six from this case series were also diagnosed with MDD.

Morries et al. used class-IV lasers for transcranial PBM (LiteCure and Diowave), delivering a dual wavelength of 980 and 808 nm with 9 to 13 W average power.

Morries et al. were able to irradiate such a wide area using a paced scanning technique, with the light source in continuous motion over the skin surface,

All six subjects with MDD responded to the treatment (decrease of QIDS total score  ≥ 50% from baseline) and five remitted from depression (QIDS total score  ≤ 5).

Similar benefits were observed in a separate cohort of TBI patients with comorbid depression.


Transcranial PBM is safe and well-tolerated.

The preliminary data reviewed in this paper suggest the efficacy of transcranial PBM for the treatment of depression, anxiety, and cognitive impairment

This review paper is intended to draw more attention from the scientific community toward a promising field in need of further research. Given the low cost of LED devices and the FDA approval for their over-the-counter use, there is potential for wide dissemination of transcranial PBM, if proven to be safe and effective in psychiatric patients

Does Phototherapy Enhance Skeletal Muscle Contractile Function and Postexercise Recovery? A Systematic Review J Athl Train. 2013 Jan-Feb; /PMC3554033/

Again, nature follows the maxim of moderation.



Recently, researchers have shown that phototherapy administered to skeletal muscle immediately before resistance exercise can enhance contractile function, prevent exercise-induced cell damage, and improve postexercise recovery of strength and function.


To critically evaluate original research addressing the ability of phototherapeutic devices, such as lasers and light-emitting diodes (LEDs), to enhance skeletal muscle contractile function, reduce exercise-induced muscle fatigue, and facilitate postexercise recovery.

Data Extraction

Data of interest included elapsed time to fatigue, total number of repetitions to fatigue, total work performed, maximal voluntary isometric contraction (strength), electromyographic activity, and postexercise biomarker levels. We recorded the PEDro scores, beam characteristics, and treatment variables and calculated the therapeutic outcomes and effect sizes for the data sets.

Data Synthesis

Exposing skeletal muscle to single-diode and multidiode laser or multidiode LED therapy was shown to positively affect physical performance by delaying the onset of fatigue, reducing the fatigue response, improving postexercise recovery, and protecting cells from exercise-induced damage.


Phototherapy administered before resistance exercise consistently has been found to provide ergogenic and prophylactic benefits to skeletal muscle.

Key Points

  • Phototherapy administered before resistance exercise may enhance contractile function, reduce exercise-induced muscle damage, and facilitate postexercise recovery.
  • The effectiveness of phototherapy is dose dependent, so selecting appropriate treatment variables, such as wavelength and output power, is important.
  • In attempting to reproduce clinical outcomes, clinicians and researchers should use evidence-based decision making when selecting treatment variables in phototherapy.
  • Given the increased beam reflection and attenuation at the skin interface, a larger treatment dose may be necessary when using light-emitting diodes (LEDs) instead of a semiconductor las


The use of light as a clinical modality has increased greatly over the past decade. The beneficial outcomes of phototherapy for the treatment of acute and chronic musculoskeletal disorders include pain control,2,3 enhanced blood circulation,4 and improved tissue repair

The biological effects of phototherapy are mediated by the absorption of photons (light particles) by endogenous chromophores and the subsequent transduction of light energy into chemical energy inside the plasma membrane or cytosolic organelle

Membrane-bound chromophores act as photosensitizers that induce changes in membrane permeability and transport mechanisms that give rise to intracellular changes in pH, ion concentrations, and membrane excitability.

Photons that penetrate the cell membrane often will enter mitochondria, where they readily are absorbed by cytochrome enzymes (eg, cytochrome c oxidase), generating physiologic responses conducive to the production of reactive oxygen species and increased rates of adenosine 5′-triphosphate (ATP) and protein synthesis.

The reactive oxygen species concentrations below cytotoxic levels have been shown to create biostimulatory effects for the cell.

The decrease in muscle function associated with fatigue is believed to be a result of metabolic alterations, such as substrate depletion (lack of ATP and glycogen), oxidative stress, tissue hypoxia, and blood acidification

Researchers also have indicated that specific doses of phototherapy reduce blood lactate and inflammatory biomarker levels after strenuous upper and lower extremity exercise.

Based on these findings, one may infer that phototherapy also provides a prophylactic effect to tissue by limiting exercise-induced cellular damage. Limiting inflammation and cell damage during exercise also can improve recovery of muscle strength and function postexercise

Therefore, the purpose of our systematic review was to determine the ability of phototherapeutic devices, such as lasers and light-emitting diodes (LEDs), to enhance muscle contractile function, reduce exercise-induced muscle fatigue, and facilitate postexercise recovery.

Dose Dependency

Therapeutic dose is reported to have the greatest influence on tissue healing and clinical outcome.

Achieving a therapeutic dose without understimulating or overstimulating the target tissues is often the most difficult component of clinical phototherapy practice.

Optimal doses have been established experimentally in cell and tissue cultures. This therapeutic laser dose or level of photostimulation must be attained; if the amount of energy absorbed is insufficient to stimulate the absorbing tissues, no reactions or changes can occur in body tissues.

Weak stimuli (underdosing) produce no effect or only a minimal effect on cellular function, moderate to strong stimuli positively enhance cellular function, and very strong stimuli (overdosing) suppress or inhibit cellular function.

problems exist when attempting to translate light therapy studies from animal models to human participants. No known or universally accepted method is available to calculate a comparable treatment dose in humans from those doses used in cell and animal models

In our review, light treatment doses and the type of light source varied among studies, with the trend favoring a higher dose when using an LED device than when using a laser diode. This finding makes sense because the light emanating from LEDs has a wider bandwidth, is not coherent, and is more divergent than the light emanating from laser diodes, resulting in more reflection and less transmission of LED-generated light through the skin. Therefore, a higher dose whe


Phototherapy administered immediately before a bout of resistance exercise consistently was shown to provide an ergogenic effect to skeletal muscle by improving physical performance (extending the elapsed time and total number of repetitions to fatigue, reducing the deficit in maximal voluntary isometric contraction pre-exercise to postexercise) and improving the clearance of blood lactate immediately after exercise.

It also consistently was shown to provide a protective effect for skeletal muscle by reducing postexercise plasma levels of CK and CRP.

The information gained from this novel use of laser therapy can open a therapeutic window into the treatment of musculoskeletal conditions in which muscle fatigue and fatigue-related impairment are barriers to treating musculoskeletal injuries.

Red (660 nm) and infrared (830 nm) low-level laser therapy in skeletal muscle fatigue in humans: what is better? – Lasers Med Sci. 2012 Mar – /PMC3282894/

Red (660 nm) and infrared (830 nm) low-level laser therapy in skeletal muscle fatigue in humans: what is better?


Some of the main physiological effects attributed to LLLT are related to soft tissue metabolism

Across different pathologies, increased microcirculation, enhanced ATP synthesis and stimulation of the mitochondrial respiratory chain and mitochondrial function have been observed after LLLT

Reductions in the release of reactive oxygen species (ROS) and in creatine phosphokinase activity, and increased production of antioxidants and heat shock proteins have also been found after LLLT

Several animal and human trials have shown that LLLT with red and infrared wavelengths has modulatory effects on inflammatory markers (PGE2, TNF-α, IL-1β, plasminogen activator), reduces the inflammatory process itself (edema, hemorrhage, necrosis, neutrophil cell influx) and modulates leukocyte activity (macrophages, lymphocytes, neutrophils)

In animal experiments, phototherapy with 655 nm red and 904 nm infrared wavelengths, and clinical trials employing red, infrared, and mixed wavelengths has been shown to delay the development of skeletal muscle fatigue.

Skeletal muscle fatigue is a novel area of research in phototherapy

However, the parameters of application (such as power output, time of irradiation, doses, etc.) employed in these studies do not allow a conclusion as to whether red or infrared wavelengths produce better results in delaying the development of skeletal muscle fatigue.

With this perspective in mind, we decided to compare the effects of red and infrared LLLT (with the same parameters of application for both wavelengths) on skeletal muscle fatigue.


We conclude that both red and infrared LLLT are effective in delaying the development of skeletal muscle fatigue and in enhancing skeletal muscle performance.

The optimal parameters of application, as well as dose–response patterns for several wavelengths still need to be identified in further studies. Further studies are also needed to identify the specific mechanisms by which each wavelength acts.

Collection of PubMed articles as of July 2014:

Here are ten articles from a PubMed search for “chronic pain” and either “photobiostimulation” or the more commonly used term “low level laser treatment” (LLLT).  I found 2 articles from 2004 using the term “photobiostimulation”, and 8 articles from the last 5 years on LLLT that seem to indicate this treatment has a potential for pain management.

An evaluation of laser photobiostimulation as a factor supporting rehabilitation in spinal pain syndromes... [Ortop Traumatol Rehabil. 2000] – PubMed – NCBI

Biostimulating lasers have analgesic, anti-inflammatory, and antiallergenic effects, and relieve muscle cramps; they also improve metabolism and regenerate cells and tissue. Laser photobiostimulation is an effective, quick, aseptic therapy, with no age limitations or side effects.

Free full text http://protein.bio.msu.ru/biokhimiya/contents/v69/full/69010103.html

Photobiological Principles of Therapeutic Applications of Laser Radiation… [Biochemistry (Mosc). 2004] – PubMed – NCBI

Laser therapy based on the stimulating and healing action of light of low-intensity lasers (LIL), along with laser surgery and photodynamic therapy, has been lately widely applied in the irradiation of human tissues in the absence of exogenous photosensitizers. Besides LIL, light-emitting diodes are used in phototherapy (photobiostimulation) whose action, like that of LIL, depends on the radiation wavelength, dose, and distribution of light intensity in time but, according to all available data, does not depend on the coherence of radiation.

Exposure to lasers as well as LED light is currently applied in therapy. The most effective irradiation is that in the red and near infrared range of the spectrum

The main reason for using the sources radiating in the red and near infrared spectral region is the fact that hemoglobin does not absorb in this region and light can penetrate deep into living tissue.

The effect of 300 mW, 830 nm laser on chronic neck pain: a double-blind, randomized, placebo-controlled study… [Pain. 2006] – PubMed – NCBI

A randomized, double-blind, placebo-controlled study of low-level laser therapy (LLLT) in 90 subjects with chronic neck pain was conducted with the aim of determining the efficacy of 300 mW, 830 nm laser in the management of chronic neck pain.

Subjects were randomized to receive a course of 14 treatments over 7 weeks with either active or sham laser to tender areas in the neck. The primary outcome measure was change in a 10 cm Visual Analogue Scale (VAS) for pain.

Secondary outcome measures included Short-Form 36 Quality-of-Life questionnaire (SF-36), Northwick Park Neck Pain Questionnaire (NPNQ), Neck Pain and Disability Scale (NPAD), the McGill Pain Questionnaire (MPQ) and Self-Assessed Improvement (SAI) in pain measured by VAS.

Measurements were taken at baseline, at the end of 7 weeks’ treatment and 12 weeks from baseline.

The mean VAS pain scores improved by 2.7 in the treated group and worsened by 0.3 in the control group (difference 3.0, 95% CI 3.8-2.1).

Significant improvements were seen in the active group compared to placebo for SF-36-Physical Score (SF36 PCS), NPNQ, NPAD, MPQVAS and SAI. The results of the SF-36 – Mental Score (SF36 MCS) and other MPQ component scores (afferent and sensory) did not differ significantly between the two groups.

Low-level laser therapy (LLLT), at the parameters used in this study, was efficacious in providing pain relief for patients with chronic neck pain over a period of 3 months.

Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials… [Lancet. 2009] – PubMed – NCBI


Neck pain is a common and costly condition for which pharmacological management has limited evidence of efficacy and side-effects. Low-level laser therapy (LLLT) is a relatively uncommon, non-invasive treatment for neck pain, in which non-thermal laser irradiation is applied to sites of pain. We did a systematic review and meta-analysis of randomised controlled trials to assess the efficacy of LLLT in neck pain.


We searched computerised databases comparing efficacy of LLLT using any wavelength with placebo or with active control in acute or chronic neck pain. Effect size for the primary outcome, pain intensity, was defined as a pooled estimate of mean difference in change in mm on 100 mm visual analogue scale.


We identified 16 randomised controlled trials including a total of 820 patients. In acute neck pain, results of two trials showed a relative risk (RR) of 1.69 (95% CI 1.22-2.33) for pain improvement of LLLT versus placebo. Five trials of chronic neck pain reporting categorical data showed an RR for pain improvement of 4.05 (2.74-5.98) of LLLT. Patients in 11 trials reporting changes in visual analogue scale had pain intensity reduced by 19.86 mm (10.04-29.68). Seven trials provided follow-up data for 1-22 weeks after completion of treatment, with short-term pain relief persisting in the medium term with a reduction of 22.07 mm (17.42-26.72). Side-effects from LLLT were mild and not different from those of placebo.


We show that LLLT reduces pain immediately after treatment in acute neck pain and up to 22 weeks after completion of treatment in patients with chronic neck pain.

[Phototherapy for chronic pain treatment]. [Masui. 2009] – PubMed – NCBI – (“Phototherapy”, not “Prolotherapy”)

Three types of machines are used in the field of phototherapy for chronic pain. One type is an instrument for low reactive level laser therapy (LLLT), one is an instrument for linear polarized infrared light irradiation (SUPER LIZER), and the last one is an instrument for Xenon light irradiation (beta EXCEL Xe10).

The available machines for LLLT all project laser by semiconductor. The newest machine (MEDILASER SOFT PULSE10) has peak power of 10 W and mean power of 1 W. This machine is as safe as 1 W machine and is effective twice as deep as the 1 W machine.

The irradiation by low reactive level laser induces hyperpolarization, decreased resistance of neuronal membrane, and increased intra-cellular ATP concentrations. The effects of low reactive level laser might be induced by the activation of ATP-dependent K channel. The significant analgesic effects of 1 W and 10 W LLLT were reported with double blind test. The significant analgesic effects of linear polarized near infrared light irradiation with double blind test were also reported. The effects of low reactive level laser upon the sympathetic nerve system were thought to result from its normalization of the overloaded sympathetic nerve system.

Inhibitory effects of laser irradiation on peripheral mammalian nerves and relevance to analgesic effects: a systematic review … [Photomed Laser Surg. 2011] – PubMed – NCBI


The objective of this review was to systematically identify experimental studies of non-ablative laser irradiation (LI) on peripheral nerve morphology, physiology, and function. The findings were then evaluated with special reference to the neurophysiology of pain and implications for the analgesic effects of low-level laser therapy (LLLT).


We searched computerized databases and reference lists for studies of LI effects on animal and human nerves using a priori inclusion and exclusion criteria.

We identified 44 studies suitable for inclusion. In 13 of 18 human studies, pulsed or continuous wave visible and continuous wave infrared (IR) LI slowed conduction velocity (CV) and/or reduced the amplitude of compound action potentials (CAPs). In 26 animal experiments, IR LI suppressed electrically and noxiously evoked action potentials including pro-inflammatory mediators. Disruption of microtubule arrays and fast axonal flow may underpin neural inhibition.


This review has identified a range of laser-induced inhibitory effects in diverse peripheral nerve models, which may reduce acute pain by direct inhibition of peripheral nociceptors. In chronic pain, spinal cord changes induced by LI may result in long-term depression of pain. Incomplete reporting of parameters limited aggregation of data.

Inhibitory effects of visible 650-nm and infrared 808-nm laser irradiation on somatosensory and compound muscle action potentials in rat sciatic nerve: implications for laser-induced analgesia… [J Peripher Nerv Syst. 2011] – PubMed – NCBI

Low-level laser therapy (LLLT) has been shown in clinical trials to relieve chronic pain and the World Health Organization has added LLLT to their guidelines for treatment of chronic neck pain. The mechanisms for the pain-relieving effects of LLLT are however poorly understood.

We therefore assessed the effects of laser irradiation (LI) on somatosensory-evoked potentials (SSEPs) and compound muscle action potentials (CMAPs) in a series of experiments using visible (λ = 650 nm) or infrared (λ = 808 nm) LI applied transcutaneously to points on the hind limbs of rats overlying the course of the sciatic nerve. This approximates the clinical application of LLLT.

The 650-nm LI decreased SSEP amplitudes and increased latency after 20 min. CMAP proximal amplitudes and hip/ankle (H/A) ratios decreased at 10 and 20 min with increases in proximal latencies approaching significance. The 808-nm LI decreased SSEP amplitudes and increased latencies at 10 and 20 min. CMAP proximal amplitudes and H/A ratios decreased at 10 and 20 min. Latencies were not significantly increased. All LI changes for both wavelengths returned to baseline by 48 h.

These results strengthen the hypothesis that a neural mechanism underlies the clinical effectiveness of LLLT for painful conditions.

Low level laser therapy (LLLT) for patients with sacroiliac joint pain … [Laser Ther. 2011] – PubMed – NCBI

Background and Aims:

Sacroiliac joint pain not associated with a major etiological factor is a common problem seen in the orthopedic clinical setting, but diagnosis is difficult because of the anatomical area and thus it is sometimes difficult to effect a complete cure. Low level laser therapy (LLLT) has been well-reported as having efficacy in difficult pain types, so the following preliminary study was designed to assess the efficacy of LLLT for sacroiliac pain.

Materials and Methods:

Nine patients participated, 4 males and 5 females, average age of 50.4 yrs, who attended the outpatient department with sacroiliac pain. The usual major disorders were ruled out. Pain was assessed subjectively pre-and post-LLLT on a visual analog scale, and trunk range of motion was examined with the flexion test to obtain the pre- and post-treatment finger to floor distance (FFD). The LLLT system used was an 830 nm CW diode laser, 1000 mW, 30 sec/point (20 J/cm(2)) applied on the bilateral tender points twice/week for 5 weeks. Baseline and final assessment values (after the final treatment session) were compared with the Wilcoxon signed rank test (nonparametric score).


All patients completed the study. Eight of the 9 patients showed significant pain improvement and 6 demonstrated significantly increased trunk mobility (P pain, and this may be due to improvement of the blood circulation of the strong ligaments which support the sacroiliac joint, activation of the descending inhibitory pathway, and the additional removal of irregularities of the sacroiliac joint articular surfaces. Further larger-scale studies are warranted.

Free PMC Article  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799023/

The Effect of Low-level Laser Therapy on Trigeminal Neuralgia: A Review of Literature. … [J Dent Res Dent Clin Dent Prospects. 2014] – PubMed – NCBI

The effect of low intensity laser radiation in the treatment of acute and chronic pain is now established in many studies.

Tri-geminal neuralgia is a pain passes through nerve’s branches and its trigger is located in skin or mucosa that could lead to pain with a trigger stimulus. The pain involved branches of trigeminal nerve that sometimes has patients to seek the treatment for several years.

Nowadays different treatments are used for relief of pain that most of them cause tolerance and various side effects. This paper reviews and summarizes scientific papers available in English literature publishedin PubMed, Scopus, Science Direct, Inter science, and Iran Medex from 1986 until July 2011 about the effect of these types of lasers on trigeminal neuralgia which is one of the most painful afflictions known. In different studies, the effect of laser therapy has been compared with placebo irradiation or medicinal and surgical treatment modalities.

Low-level laser therapy (LLLT) is a treatment strategy which uses a single wavelength light source. Laser radiation and monochromatic light may alter cell and tissue function. However, in most studies laser therapy was associated with significant reduction in the intensity and frequency of pain compared with other treatment strategies, a few studies revealed that between laser and placebo group there was not any significant difference according to the analgesic effect. Low-level laser therapy could be considered in treatment of trigeminal neuralgia without any side effects.

Free PMC Article

4 thoughts on “Low Level Laser Therapy (LLLT)

  1. Pingback: Unique Use of Near-Infrared Light Source to Treat Pain | EDS Info (Ehlers-Danlos Syndrome)

  2. Pingback: The Practice of Low-Level Laser Therapy | EDS Info (Ehlers-Danlos Syndrome)

  3. Pingback: High-Intensity Laser Therapy Improves Chronic Pain | EDS and Chronic Pain News & Info

  4. Pingback: The Nuts and Bolts of Low-level Laser (Light) Therapy | EDS and Chronic Pain News & Info

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