Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig's Disease)

Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig's Disease)

1 Overview

Summary and Quick Facts

  • Amyotrophic lateral sclerosis (ALS) is a degenerative neuromuscular disease, also called Lou Gehrig’s disease after the famous baseball player who died from this condition. The average survival time after being diagnosed with ALS is three to five years.
  • This protocol describes possible causes of ALS, diagnosis and conventional treatment, emerging medical therapies and nutritional interventions.
  • Conventional medicine, which has fared poorly in the treatment of ALS, attempts to lessen symptoms by slowing disease progression. By adding scientifically studied natural interventions to conventional therapies, one may be able to target pathogenic mechanisms of ALS from multiple angles in hopes of slowing disease progression and improving quality of life.

What is Amyotrophic Lateral Sclerosis?

Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) is a degenerative neuromuscular disease. ALS destroys motor neurons, the nerves that control movement, resulting in loss of motor function and eventual paralysis. Respiratory failure due to nerve damage that affects the muscles that control breathing is the most common cause of death in ALS patients.

There are two main forms of ALS: sporadic and familial. While familial ALS is typically caused by hereditary genetic mutations, the cause of sporadic ALS (comprising 90% of all cases) is not completely understood. It is generally believed that sporadic ALS is caused by multiple factors that converge to damage motor neurons, including oxidative stress and glutamate toxicity, among others.

Natural interventions such as vitamin B12 and ginseng, in addition to conventional therapies, may help slow disease progression and improve quality of life by targeting multiple pathogenic mechanisms of ALS.

What are the Causes and Risk Factors for Amyotrophic Lateral Sclerosis?

  • Genetic mutations
  • Oxidative stress
  • Glutamate (an important neurotransmitter) accumulation and toxicity
  • While causal relationships have not been established, exposure to heavy metals, pesticides, and other environmental toxins has been linked with ALS development.

What are the Signs and Symptoms of Amyotrophic Lateral Sclerosis?

Note: Early symptoms vary depending on which muscles are affected first. Common symptoms can include:

  • Tingling in fingers or toes
  • Cramping in arms or legs
  • Difficulty with tongue and facial movements, including chewing and swallowing

What are the Conventional Medical Treatments for Amyotrophic Lateral Sclerosis?

  • Riluzole—blunts the effects of glutamate accumulation and can extend survival by a few months
  • Edaravone—a free radical scavenger that can reduce oxidative stress
  • Other treatments may help relieve symptoms and improve quality of life:
    • Non-invasive positive pressure ventilation
    • Medications to relieve painful muscle cramps
    • Medications to reduce excessive salivation
    • Physical, occupational, and speech therapy
    • Mobility aids

What are Emerging Therapies for Amyotrophic Lateral Sclerosis?

  • Stem cell therapy
  • Multiple proteins and mutations have been linked to ALS pathogenesis. Gene replacement therapy and pharmaceutical interventions are being explored as potential treatments.
  • Insulin-like growth factor-1 (IGF-1) modulates neuronal growth and function, and injections may help slow disease progression, but results have been mixed.
  • Many other treatments are being explored. More updated information can be found online at the ALS Association website.

What Nutritional Interventions May Be Beneficial for Amyotrophic Lateral Sclerosis?

  • Vitamin B12. Vitamin B12 deficiency has been associated with nerve damage in animal models. High intramuscular doses in ALS patients have been shown to slow muscle wasting.
  • Zinc. Mutations in the superoxide dismutase enzyme (which stabilizes superoxide radicals and is implicated in the pathology of certain kinds of ALS) can decrease its affinity for zinc and cause it to become toxic to motor neurons. Altering brain zinc levels is being explored in many nervous system diseases.
  • Ginseng. Ginseng significantly delayed the onset of symptoms in an animal model of ALS. Ginseng may also protect motor neurons from apoptosis and membrane damage.
  • Ginkgo biloba. Ginkgo biloba has antioxidant properties that have shown in experimental models to protect against glutamate-induced excitotoxicity and neuronal death due to oxidative stress.
  • Coenzyme Q10 (CoQ10). Patients with ALS have a higher percentage of oxidized CoQ10. Administering CoQ10 in an animal model of ALS extended lifespan.
  • Acetyl-L-carnitine. Acetyl-L-carnitine has been found to reduce neuromuscular degeneration and increase lifespan in animal models of ALS. Acetyl-L-carnitine also appears to enhance the growth and repair of neurons.
  • Lipoic acid. Lipoic acid is an antioxidant shown to protect cells against glutamate-induced excitotoxicity. In one study, administering lipoic acid improved survival in a mouse model of ALS.
  • Whey protein. Protein supplementation may help improve the nutritional and functional status of ALS patients. Preliminary data suggest whey protein may protect motor neurons from oxidative damage.
  • Creatine. In several animal studies, creatine has been shown to provide protection against neurodegenerative diseases. Additionally, a small study found that creatine supplementation improved muscle strength in ALS patients.
  • Other natural interventions that may be helpful for ALS patients are glutathione and N-acetyl-cysteine (NAC), green tea, pycnogenol, and resveratrol.

2 Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease)

Amyotrophic lateral sclerosis (ALS) is a degenerative neuromuscular disease, also called Lou Gehrig’s disease after the famous baseball player who died from this condition. ALS affects the nervous system and destroys motor neurons (nerve cells that help control movement) while sparing the abilities to see, hear, feel, touch and taste. ALS is characterized by progressive dysfunction resulting in symptoms such as tripping, clumsiness, difficulty talking, slurred speech, muscle cramps, twitching and ultimately, paralysis. The most common cause of death among ALS patients is respiratory failure, which occurs when nerve damage eventually affects the muscles that control breathing. The average survival time after being diagnosed with ALS is three to five years (ALSA 2012).

There are two main forms of ALS: sporadic and familial. The sporadic form comprises 90 percent of all ALS cases. However, many scientists study the familial forms in order to try to understand the mechanisms of the disease. While familial ALS is typically caused by mutations in different genes (including a gene known as SOD1), researchers still do not completely understand the pathogenesis of sporadic ALS. Scientists are pursuing a number of theories including oxidative stress, glutamate toxicity, and mitochondrial dysfunction (Rowland 1994; Cleveland 1999; Rothstein 2009). Other possible risk factors include viral infections (Woodall 2004) and environmental toxins (Mitchell 2000). The current consensus is that many factors may converge to cause the motor neuron damage typified by ALS (Rothstein 2009).

Conventional medicine, which has fared poorly in the treatment of ALS, attempts to lessen symptoms by slowing disease progression. There are only two disease-modifying drugs currently approved in the United States for ALS patients: riluzole and edaravone (Miller 2007; FDA 2017). By adding scientifically studied natural interventions to conventional therapies, one may be able to target pathogenic mechanisms of ALS from multiple angles in hopes of slowing disease progression and improving quality of life.

3 Possible Causes of ALS

Superoxide Dismutase

Because SOD1 gene mutations can cause familial ALS, many researchers have studied this protein to determine how it plays a role in the death of motor neurons. SOD1 is a gene that codes for superoxide dismutase (SOD), an enzyme which helps convert superoxide radicals into less harmful molecules. Superoxide molecules are a form of free radical or reactive oxygen species, a class of molecules that can damage the DNA, proteins, and membranes of cells causing them to die (Rothstein 2009). If SOD is either functioning poorly or is present in inadequate quantities, rampant oxidative stress driven by unabated superoxide molecules can damage tissue and contribute to disease.

Approximately 20% of familial cases and 2% of all ALS cases are linked to SOD1 gene mutations (Sung 2002; Andersen 2006; Chiò 2008). This suggests that the accumulation of superoxide molecules and other free radicals could contribute to ALS. In addition to increasing superoxide levels, SOD1 mutations can damage neurons in other ways. For example, mutant SOD1 produces abnormal SOD molecules which are theorized to serve as the seed for large clusters of misfolded proteins that are toxic to neurons (Karch 2009; Lindberg 2002).

Oxidative stress

Studies have found elevated levels of oxidative stress within the central nervous system as well as peripherally in ALS (Miana-Mena 2011; Hensley 2006; Ilieva 2007; Kanekura 2009). This suggests that motor neuron death in ALS is related to increased levels of reactive oxygen species. These conditions contribute to the neuronal death and muscle wasting common in ALS. Oxidative stress can be relieved by increasing the concentration of antioxidants such as beta-carotene (Dawson 2000), vitamins C (Mandl 2009) and E (Colombo 2010), as well as the mineral selenium (Sanmartin 2011). Many other supplements, such as coenzyme Q10, also have antioxidant properties.

Glutamate Toxicity

Glutamate is an important neurotransmitter. Under normal conditions, its concentrations are tightly regulated. However, it appears the system regulating glutamate concentration in patients with ALS may be disturbed (Rothstein 1995b), resulting in an accumulation of glutamate in the space (synapse) between cells (Cameron 2002). This excess glutamate may excite nerve cells beyond their capacity resulting in nerve cell death. Patients with ALS have elevated levels of glutamate in their cerebrospinal fluid, support this hypothesis (Rothstein 1990, Shaw 1995). Mutant glutamate transport proteins are also associated with sporadic forms of ALS, further supporting the idea that elevated levels of glutamate-mediated excitation can kill motor neurons in ALS patients (Lin 1998; Rothstein 1995; Dunlop 2003). Some of the most powerful evidence supporting the critical role that glutamate plays in the pathology of ALS is the effectiveness of the medication riluzole, which inhibits glutamate’s effects on the nervous system. It modulates the release of glutamate, thereby improving survival for ALS patients. Its effect however is modest, suggesting that excess glutamate is not the sole cause of the disease.

Mitochondrial Dysfunction

The mitochondria provide energy for all cells, including neurons. Unfortunately, mitochondria also produce reactive oxygen species as a byproduct of energy generation. Mitochondrial dysfunction can result in the production of excessive amounts of superoxide, causing extensive cell damage and death. Accumulation of superoxide is prevented by SOD and other enzymes (Brand 2011).

There are a number of ways in which the mitochondria in motor neurons may become impaired in ALS (Shi 2010). In animal models of ALS, dysfunction of mitochondria in motor neurons occurs before any other observable pathologic changes, suggesting this is an early event in the progression of the disease (Kong 1998). Mutant forms of SOD appear to lead to mitochondrial dysfunction (Liu 2004). Studies of both human and animal neurons have found extensive mitochondrial dysfunction associated with ALS (Cassarino 1999; Beal 2005; Martin 2011; Cozzolino 2011; Kawamata 2011; Faes 2011). In addition, some patients with ALS appear to have impaired mitochondrial function in their muscle fibers (Crugnola 2010).

Animal models of ALS show abnormal transport of mitochondria in their motor neurons which could further contribute to the progression of the disease (De Vos 2007). Additionally, because proper mitochondrial function is so essential, other yet unidentified processes could be altered when mitochondrial health is impaired (Fosslien 2001). Along these lines, an emerging theory linking excitotoxicity and mitochondrial dysfunction suggests that an accumulation of lactate, a metabolic byproduct which is toxic (especially to nerve cells) at high concentrations may play a role in ALS progression (Vadakkadath Meethal 2012). This theory (a.k.a. the lactate dyscrasia theory) proposes that mitochondrial dysfunction partly contributes to an accumulation of lactate in the junction of motor neurons and muscle cells (the neuromuscular junction (NMJ)) leading to death of both the nerve and muscle cells, thereby requiring the remaining muscle cells to work harder-than-normal to generate the force necessary for motor control. However, since lactate is a metabolic byproduct and greater metabolic demand increases lactate production, the remaining muscle cells produce even more lactate than usual due to their increased workload, hastening the accumulation of lactate and exacerbating neuronal destruction and muscular atrophy. This theory also proposes that malfunction of an as yet undiscovered lactate shuttle within the NMJ may be a pathological feature of ALS, suggesting that supporting mitochondrial function may optimize lactate metabolism and combat the toxicity caused by accumulation of excess lactate. If this theory is correct, then combining drugs that inhibit lactate accumulation such as nizofenone (Matsumoto 1994) with nutrients that support mitochondrial function (like coenzyme Q10 and pyrroloquinoline quinone (PQQ) might be an effective therapy for ALS.

Heavy metals and environmental agents. The role of heavy metals in ALS is highly controversial. Since clusters of ALS patients have been found in certain geographical areas, researchers have searched for an underlying environmental theme such as heavy metal poisoning. For example, researchers have found that elevated levels of lead are associated with a higher risk of ALS (Fang 2010). Another toxin which has been identified as a potential mediator for ALS is mercury, though the link between mercury and ALS risk is not as clear (Callaghan 2011, Mano 1990). These toxins can lead to subtle cellular changes such as interfering with the methylation of DNA (Rooney 2011). Other studies however have failed to show a link between ALS and any of the common heavy metals (Gresham 1986).

Beta-N-methylamino-L-alanine (BMAA), a neurotoxin made by certain bacteria may play an important role in the development of ALS. BMAA may be implicated in the high incidence of ALS in Guam, where these bacteria are commonly found in the seeds of the Cycas circinalis plant (Banack 2010).

Exposure to pesticides may also increase the risk of developing ALS (Johnson 2009). Exposure to pesticides in the grass on the playing field is one theory put forth to explain the unusually high incidence of ALS in Italian soccer players (Chio 2009).

While there is good reason to think that neurotoxic agents like these may be somehow linked to degenerative brain and nerve conditions like ALS, researchers have been unable to meet the demanding scientific standard needed to establish a causal relationship (Caban-Holt 2005, Johnson 2009).

4 Diagnosis and Conventional Treatment of ALS

Like many neuromuscular diseases, it can be difficult to make an early diagnosis of ALS. Depending on which muscle group is affected first, its symptoms vary from person to person and can include:

  • tingling in the fingers or toes
  • cramping in the arms or legs
  • trouble with tongue and facial movements, including chewing and swallowing.

As the disease progresses, it spreads through the affected limb until eventually all muscle groups become involved. This spread into all muscle groups is the defining characteristic of ALS. In fact, the term amyotrophy refers to the atrophy (wasting) of muscle tissue, while lateral sclerosis refers to the hardening of the spinal column from the buildup of scar tissue (Rowland 2001). The diagnosis of ALS is primarily a clinical one and requires the appearance of both upper (increased tone and reflexes) and lower (fasciculations and muscle atrophy) motor neuron involvement in many segments of the body. Electromyography, nerve conduction studies, and transcranial magnetic stimulation can all be used to support the diagnosis of amyotrophic lateral sclerosis.

Riluzole, an FDA approved drug for the treatment of ALS, blunts the effects of glutamate by decreasing its release and blocking the ability of glutamate to bind to its receptors, thereby decreasing the excitotoxicity that leads to cell death. Albeit small, its two to three month increase in survival time (Miller 2007) indicates that controlling glutamate levels in the brain could be an essential component in fighting ALS and provides valuable information toward ultimately finding a more effective treatment for the disease (Carlesi 2011).

Edaravone (Radicava) was approved by the FDA in 2017 to treat ALS patients (FDA 2017). Edaravone has free radical-scavenging abilities and may reduce oxidative stress, an important aspect of ALS pathogenesis. Edaravone was shown in two controlled clinical trials to slow functional deterioration in a certain subset of ALS patients. The first was a randomized trial of 206 subjects treated with intravenous infusions of either edaravone or placebo for 24 weeks (Abe 2014). While there was no significant difference in overall ALS functional rating scores (ALSFRS-R) between the groups after treatment, post-hoc analysis revealed that subjects in earlier stages of the disease showed a greater treatment effect (Edaravone [MCI-186] ALS 16 Study Group 2017). In order to demonstrate the efficacy in this subgroup, a second trial including 137 subjects in early stages of ALS was conducted. The edaravone group experienced a 33% slower decline in function than the placebo group (Writing Group 2017). Edaravone is generally recommended in addition to riluzole as an adjuvant therapy.

Concerns have been raised regarding the safety and efficacy of edaravone treatment (Turnbull 2018). The majority of patients in the second study experienced treatment-related adverse events, likely due to the nature of drug delivery (ie, intravenous infusion). Edaravone has also only been shown to be effective in a small subset of patients with ALS.

The remainder of conventional medical treatment for ALS patients focuses on relieving symptoms and improving quality of life. For example, non-invasive positive pressure ventilation is often used to help patients with ALS breathe, especially at night (Mustfa 2006; Lo Coco 2006). Physicians frequently recommend prescription medications to relieve painful muscle cramps (e.g. carbamazepine and phenytoin) (Andersen 2005), excessive salivation (e.g. atropine, amitriptyline, hyoscamine, and injections of botulinum toxin into the salivary glands) (Giess 2000; Lipp 2003; Stone 2009), and other symptoms. ALS patients are often advised to engage in moderate exercise and seek physical therapy to maintain muscle strength and function. As the disease progresses, splints, braces, and wheelchairs are used to help with mobility. Also, higher toilet seats, headrests and specialized utensils may help improve the quality of life for ALS patients (Borasio 2001). Occupational and speech therapy help patients as their motor control gradually deteriorates.

5 Emerging Medical Therapies

Stem Cells

Stem cells, immature cells that can differentiate into specialized adult cells, may represent the next generation of ALS therapy.

However, due to federal restrictions on stem cell therapy as well as the difficulty of designing studies, very few trials have been conducted to date on the treatment of ALS with stem cells. Those that have been conducted, however, are encouraging and early trials show great promise. Researchers have found the following:

  • Bone marrow derived “stem-cell transplantation in the motor cortex delays ALS progression and improves quality of life” (Martinez 2009).
  • Direct injection of bone marrow derived stem cells into the frontal motor cortex (a brain region) of human ALS patients is generally safe and well tolerated (Martinez 2012).

Researchers have also experimented with the use of stem cells that express beneficial growth factors as a way of comprehensively treating ALS (Suzuki 2008; Lunn 2009). This therapy offers the potential to alter the course of ALS in afflicted patients.

TAR DNA-binding protein 43 (TDP-43) and FUS (fused in sarcoma)

Research has identified the cellular protein TDP-43 as an important factor in the cause of ALS, especially the sporadic forms (Mackenzie 2007). TDP-43 binds DNA and RNA in cells, including motor neurons. Aggregates of TDP-43 are found in the motor neurons of patients with ALS, suggesting that they may contribute to ALS pathogenesis. Identification of TDP-43’s involvement in ALS rapidly fueled a breakthrough discovery of an additional causative mutation in the gene encoding another RNA/DNA binding protein called FUS (fused in sarcoma) (Kwiatkowski 2009; Vance 2009). Because both of these proteins have been implicated in ALS, they may represent a novel pathway by which the motor neurons are damaged. This has also opened up the potential for gene therapy, allowing researchers to try to replace defective genes with functional ones, thus slowing or reversing the loss of motor neurons associated with ALS (Lagier-Tourenne 2009; Hester 2009). Researchers are also searching for ways to inhibit TDP-43 aggregation using chemicals such as methylene blue and latrepirdine (Yamashita 2009).

IGF-1 and Growth Hormone

Insulin-like Growth Factor-1 (IGF-1) is a potent modulator of neuronal growth and function. This neurotrophic factor has the ability to protect neurons both in the central and peripheral nervous system. Researchers have examined the possibility in cell and animal models that IGF-1 could be an effective therapeutic treatment for ALS (Sakowski 2009). Human studies, however, have produced mixed results. Whereas one study found some slowing of the progression of ALS in patients treated with IGF-1 injections (Nagano 2005), others found that subcutaneous (under the skin) injections are not effective in ALS patients (Sorenson 2008). However, the lack of effect with subcutaneous injections could be due to an inability to access the central nervous system. Intraspinal cord delivery has shown promise in animal models (Franz 2009). The use of retroviruses as a potential delivery method for administering IGF-1 to ALS patients has also shown promise (Lepore 2007).

Similarly, growth hormone (GH) may be related to ALS as one trial found that ALS patients had impaired GH secretion compared to healthy controls (Morselli 2006). However, the potential therapeutic value of GH replacement therapy needs further investigation as a recent clinical trial found no improvement in ALS patients receiving GH compared to placebo (Sacca 2012).

Other Treatments

  • Arimoclomol is an investigational drug that improves the expression of “heat shock proteins”, thereby helping prevent the accumulation of misfolded proteins. Comprehensive in vivo and in vitro studies demonstrated its effect in the prevention of neuronal loss and promotion of motor neuron survival, even after the onset of symptoms. Clinical trials have reported good safety and tolerability (Phukan 2010).
  • Ceftriaxone, a commonly used antibiotic, may also be able to treat ALS by improving reuptake of glutamate. When used in an animal model of ALS, ceftriaxone delayed loss of neurons and muscle strength, thus increasing survival (Rothstein 2005).
  • Dexpramipexole is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for ALS (Cheah 2010). While it has been shown to be safe and well tolerated (Bozik 2011), more research needs to be done to determine its efficacy.
  • Another new medication which is currently being studied in clinical trials is TRO19622 ( 2010). TRO19622 is a cholesterol-like molecule and displays remarkable neuroprotective properties both in vitro and in vivo. TRO19622 is expected to preserve existing neuronal function by delaying or even stopping further progression of the disease. TRO19622 has been granted orphan drug designation status for the treatment of ALS in the USA. This status allows the opportunity to seek ‘fast track’ review by the FDA ( 2012).

6 Nutritional Interventions

Adequate nutrition is crucial for ALS patients. As the disease progresses, patients gradually lose the ability to chew or swallow with ease. At the same time, the abdominal and pelvic muscles weaken, oftentimes resulting in depression. Patients often lose the ability and desire to eat, making malnutrition a common problem. The recognition that aggressive nutritional intervention is paramount among ALS patients has spurred ardent research efforts aimed at elucidating the potential therapeutic value of dietary supplementation (Cameron 2002).

Vitamins and Minerals

Vitamin B12 (methylcobalamin). Whereas ultra-high (25mg daily for 4 weeks) intramuscular doses of methylcobalamin (a form of vitamin B12) have been shown to slow muscle wasting (Izumi 2007), low levels of vitamin B12 have been associated with nerve damage in many different animal models. One of the main problems associated with low levels of vitamin B12 is elevated levels of methylmalonic acid (MMA) which is toxic to neurons (Ganji 2012). Low levels of vitamin B12 are also associated with poorly functioning peripheral nerves which can be exacerbated by ALS (Leishear 2011). Vitamin B12 can also prevent damage to the opthalmic nerves by reducing MMA and homocysteine levels, both being associated with oxidative damage (Pott 2012). Low levels of vitamin B12 have also been associated with neuronal degeneration in other models (Moore 2012).

Zinc. Mutations to the copper/zinc superoxide dismutase gene are responsible for 2-3% of ALS cases. These mutations result in the SOD enzyme having a reduced affinity for zinc (Ermilova 2005). In fact, the loss of zinc from SOD1 results in the remaining copper in SOD1 becoming extremely toxic to motor neurons (Trumbull 2009). Altering zinc levels within the brain is being studied as a method for treating many different nervous system diseases, including ALS (Grabrucker 2011). However, a study conducted at the Linus Pauling Institute found that large doses of zinc inhibit copper absorption, which can lead to anemia. In the study, researchers added a small dose of copper to animal ALS models receiving zinc and found that the copper prevented early death associated with high doses of zinc (Ermilova 2005). In summary, adding a small amount of copper to the subject’s diets prevented this lethal anemia, suggesting that moderate amounts of zinc supplementation combined with small amounts of copper might help prevent neuron death in ALS.

Herbal Supplements

Ginseng. In an animal model of ALS, ginseng was shown to significantly delay the onset of ALS symptoms (Jiang 2000). An extract from the ginseng plant called ginsenoside has also been found to increase the expression of SOD1 (Kim 1996). Ginseng and its extracts may also be able to protect motor neurons from apoptosis and membrane damage, further helping to slow the progression of ALS (Radad 2011).

Ginkgo biloba. Ginkgo biloba has antioxidant properties (Ernst 2002). Additionally, it has been shown to promote healthy mitochondrial function (Fosslien 2001). During an in vitro study, it was found to protect against glutamate-induced excitotoxicity (Kobayashi 2000). Ginkgo biloba also reduced weight loss in a mouse model of ALS (Ferrante 2001). Ginkgo biloba extract has been shown to protect neurons from death due to oxidative stress (Shi 2009).

Additional Support

Coenzyme Q10 (CoQ10) acts as an antioxidant and is essential for proper mitochondrial function (Mancuso 2010). Human studies have found that ALS patients have a higher percentage of oxidized CoQ10 (ubiquinone), a condition the researchers blamed on oxidative stress caused by the disease (Sohmiya 2005). Supplementation with ubiquinol, the reduced (non-oxidized) form of CoQ10 may ameliorate this problem, though no studies have tested this hypothesis. Several animal studies, including the following have supported the benefit of CoQ10 treatment in ALS:

  • In an animal model of familial ALS, administration of coenzyme Q10 significantly extended life span and oral administration significantly increased CoQ10 concentrations in the brains and mitochondria of the test animals (Matthews 1998).

As a result of these promising studies in mice, researchers have been testing the benefits of CoQ10 on humans with ALS. One phase II study did not find any substantial benefit of CoQ10 supplementation in patients with ALS (Kauffman 2009). However, more research still needs to be done as CoQ10 plays an important role in mitochondrial function and controlling oxidative stress - two key components of ALS. In addition, it has been noted that high doses of CoQ10 are generally safe (Ferrante 2005).

Acetyl-L-carnitine has been shown to improve mitochondrial function (Carta 1993; Virmani 2002; Jin 2008). Acetyl-L-carnitine appears to increase the growth and repair of neurons (Wilson 2010; Kokkalis 2009) while protecting neurons from high levels of glutamate when combined with lipoic acid (Babu 2009). Acetyl-L-carnitine also protects neuron cell cultures from excitotoxicity, one of the putative mechanisms of disease in ALS (Bigini 2002). Acetyl-L-carnitine has also been found to reduce neuromuscular degeneration and increase life span in animal models of ALS (Kira 2006). In one animal study, the effects of acetyl-L-carnitine were increased when administered in conjunction with lipoic acid (Hagen 2002).

Lipoic acid. Lipoic acid has been shown to have antioxidant properties as well as increase intracellular levels of glutathione (Suh 2004a; Yamada 2011). It also chelates metals both in the test tube and in animal models (Suh 2004b and 2005). As a result, lipoic acid supplementation might protect neurons from some of the changes that lead to ALS (Liu 2008). Furthermore, lipoic acid has been shown to protect cells against glutamate-induced excitotoxicity (Muller 1995). In one study, administration of lipoic acid improved survival in a mouse model of ALS (Andreassen 2001b).

Protein and Amino acids. Adequate protein intake is essential for patients with amyotrophic lateral sclerosis. Protein supplementation may help improve the nutritional status of ALS patients, thereby slowing the progression of the disease. A 2010 study found that patients with ALS taking whey protein supplements had improved nutritional and functional parameters as compared to the control group (Carvalho-Silva 2010). Some preliminary data suggests that whey protein may also directly protect motor neurons from oxidative stress, thus delaying the progression of ALS (Ross 2011). A Portuguese study suggested that dietary supplementation with amino acids may have some beneficial effects on the course of the disease (Palma 2005).

Creatine. In cells, creatine aids in the formation of adenosine triphosphate (ATP), the primary source of cellular energy. In multiple animal studies, creatine has been shown to provide protection against neurodegenerative diseases. For example, it has been suggested that creatine helps to stabilize cellular membranes (Persky 2001). Creatine may also lessen the burden of the excitotoxin glutamate in the brain, thus improving survival time in animals with ALS (Andreassen 2001a). In human ALS patients, there is evidence to suggest that creatine may improve mitochondrial function (Vielhaber 2001). In addition, a small preliminary study found that creatine supplementation improves muscle strength in ALS patients (Mazzini 2001). More recent research has confirmed that creatine can protect neurons from toxic processes such as those that drive the progression of ALS. Creatine, due to its antioxidant and anti-excitotoxic properties, has been found to have a significant therapeutic effect in mouse models of ALS (Klopstock 2011; Beal 2011). However, human studies have yielded mixed results (Pastula 2010) which may be due to insufficient sample size (Klopstock 2011). Creatine can cross the blood-brain barrier and gain access to the brain, a treatment which lowered levels of glutamate in the cerebrospinal fluid which may help to protect the brain (Atassi 2010).

Glutathione and N-acetyl-cysteine (NAC). Glutathione is an antioxidant which is naturally synthesized by the body. Increasing glutathione levels could help prevent free radical damage to cells (Exner 2000). The glutathione precursor N-acetyl-cysteine (NAC) boosts blood levels of glutathione (Carmeli 2012). Patients with ALS tend to have higher levels of oxidized glutathione (glutathione that has already been used to protect the body from free radicals) (Baillet 2010). Increased levels of glutathione can also protect neurons from degeneration in models of ALS (Vargas 2008). Interestingly, cell culture models have shown that ALS is associated with reduced glutathione levels due to mitochondrial dysfunction, and that reduced glutathione levels can result in elevated levels of glutamate (D’Alessandro 2011). Along with being a glutathione precursor, NAC has antioxidant activity of its own. In animal models of ALS, NAC administration has been shown to decrease motor neuron loss, improve muscle mass, and increase survival time and motor performance (Andreassen 2000; Henderson 1996). In addition, NAC supplementation can help thin mucous secretions in the oral cavity which may make swallowing easier (Kuhnlein 2008).

Green tea. Green tea contains high concentrations of catechins, flavonoids with strong antioxidant properties (Hu 2002). Green tea extract has been demonstrated to have anti-inflammatory properties as well (Hong 2000). One of these catechins known as epigallocatechin-3-gallate (EGCG) is of particular interest in the context of ALS. EGCG and other catechins may be able to protect neurons from a variety of diseases (Mandel 2008). EGCG has been found to protect cultures of motor neurons from death due to excessive levels of glutamate (Yu 2010). Motor neurons can also be protected from mitochondrial dysfunction with the addition of EGCG in culture (Schroeder 2009). EGCG can also bind to and inactivate iron, which may help protect motor neurons from the effects of ALS (Benkler 2010). Epidemiological data further supports the following role of tea in its potential protection of neurons: green tea consumption reduces the risk of neurodegenerative diseases (Mandel 2011) and people who drink tea may have a lower risk of developing ALS (Morozova 2008).

Pycnogenol® is an extract of marine pine bark that includes procyanidins and phenolic acids (Packer 1999). It has been shown to have antioxidant properties (Packer 1999) as well as protective effects against glutamate excitotoxicity (Kobayashi 2000). Pycnogenol® is a common complementary therapy option among ALS patients (Cameron 2002). In addition, pycnogenol® increased the levels of SOD produced in an animal study (Kolacek 2010).

Resveratrol is a powerful antioxidant found in red grape skins and Japanese knotweed (Polygonum cuspidatum). Resveratrol has been found to suppress the influx of excitatory ions into some cell types which is associated with reduced glutamate-induced cell toxicity (Wu 2003). Another way resveratrol may target neurodegenerative diseases is by reducing oxidative stress, both on its own and by increasing the expression of SIRT1 (Sun 2010), a stress-response gene associated with longevity and protection against a number of cellular assaults. Although it is not known what role this gene plays in ALS, increasing SIRT1 expression via resveratrol administration helps protect motor neurons from ALS in cell culture (Kim 2007; Wang 2011). In addition, resveratrol can increase the activity of SOD in cells and protect them from apoptosis and oxidative stress (Yoon 2011). Adding the cerebrospinal fluid from ALS patients to rat motor neuron cell cultures causes the cultured cells to die. One of the intriguing aspects of resveratrol is that it can protect the motor neuron cell cultures from death which is something that riluzole, the only FDA approved drug for ALS, cannot do (Yanez 2011).

Abe K, Itoyama Y, Sobue G, et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15(7-8):610-7.

ALS Association (ALSA). Available at: Accessed 3/14/2012

Andersen PM, Borasio GD, Dengler R, et al. EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives. Eur J Neurol 2005; 12:921.

Andersen PM. Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene. CurrNeurolNeurosci Rep 2006; 6:37.

Andreassen OA, Dedeoglu A, et al. Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice. Exp Neurol. 2001b;168(2):419–424.

Andreassen OA, Dedeoglu A, et al. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Neuroreport. 2000;11(11):2491–2493.

Andreassen OA, Jenkins BG, et al. Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation. J Neurochem. 2001a; 77(2):383–390.

Atassi N, Ratai EM, et al. A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010 December;11(6): 508–513.

Babu GN, Kumar A, et al. Chronic Pretreatment with Acetyl-l-Carnitine and ±DL-α-Lipoic Acid Protects Against Acute Glutamate-Induced Neurotoxicity in Rat Brain by Altering Mitochondrial Function. Neurotoxicity Research, 2009;19(2).

Baillet A, Chantepedrix V, et al. The Role of Oxidative Stress in Amyotrophic Lateral Sclerosis and Parkinson’s Disease. Neurochem Res (2010) 35:1530–1537.

Banack SA, Caller TA, et al. The Cyanobacteria Derived Toxin Beta-N-Methylamino-L-Alanine and Amyotrophic Lateral Sclerosis. Toxins (Basel), 2010;2(12).

Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol. 2005;58:495.

Beal MF. Neuroprotective Effects of Creatine. Amino Acids (2011) 40:1305–1313.

Benkler C, Offen D, et al. Recent advances in amyotrophic lateral sclerosis research: perspectives for personalized clinical application. EPMA Journal (2010) 1:343–361.

Bigini P, Larini S, et al. Acetyl-l-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motoneurons. Neuroscience Letters 329 (2002) 334–338.

Borasio GD, Voltz R, Miller RG. Palliative care in amyotrophic lateral sclerosis. NeurolClin 2001;19:829.

Bozik ME, Mather JL, Kramer WG, et al. Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J ClinPharmacol 2011;51:1177.

Brand MD and Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011 Apr 15;435(2):297-312.

Caban-Holt A, Mattingly M, et al. Neurodegenerative memory disorders: a potential role of environmental toxins. NeurolClin. 2005;23(2):485–521.

Callaghan B, Feldman D, et al. The Association of Exposure to Lead, Mercury, and Selenium and the Development of Amyotrophic Lateral Sclerosis and the Epigenetic Implications. Neurodegenerative Dis 2011;8:1–8.

Cameron A, Rosenfeld J. Nutritional issues and supplements in amyotrophic lateral sclerosis and other neurodegenerative disorders. CurrOpinClinNutrMetab Care. 2002;5(6):631–643.

Carlesi C, et al. Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis. Arch Ital Biol. 2011 Mar;149(1):151-67.

Carmeli C, Knyazeva MG, et al. Glutathione Precursor N-Acetyl-Cysteine Modulates EEG Synchronization in Schizophrenia Patients: A Double-Blind, Randomized, Placebo-Controlled Trial. PLos One, 2012;7(2).

Carta A, Calvani M, et al. Acetyl-L-carnitine and Alzheimer's disease: pharmacological considerations beyond the cholinergic sphere. Ann N Y Acad Sci. 1993;695:324–326.

Carvalho-Silva LB, Mourao LF, et al. Effect of nutritional supplementation with milk whey proteins in amyotrophic lateral sclerosis patients. Arquivos de Neuro-Psiquiatria, 2010; 68(2).

Cassarino DS, Bennett JP Jr. An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev 1999;29:1.

Cheah BC and Kiernan MC. Dexpramipexole, the R(+) enantiomer of pramipexole, for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010 Dec;13(12):911-20.

Chio A, Calva A, et al. ALS in Italian professional soccer players: The risk is still present and could be soccer-specific. Amyotrophic Lateral Sclerosis, 2009.

Chiò  A, Traynor BJ, Lombardo F, et al. Prevalence of SOD1 mutations in the Italian ALS population. Neurology 2008; 70:533.

Cleveland DW. From Charcot to SOD1: mechanisms of selective motor neuron death in ALS. Neuron. 1999;24(3):515–520. Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From Amyotrophic Lateral Sclerosis (ALS) (MITOTARGET). Updated 05/2010: Accessed 03/06/2012.

Colombo ML. An update on vitamin E, tocopherol and tocotrienol-perspectives. Molecules. 2010 Mar 24;15(4):2103-13.

Cozzolino M and Carri MT. Mitochondrial Dysfunction in ALS. Progress in Neurobiology, 2011.

Crugnola V, Lamperti C, et al. Mitochondrial Respiratory Chain Dysfunction in Muscle From Patients With Amyotrophic Lateral Sclerosis. Arch Neurol. 2010;67(7):849-854.

D’Alessandro G, Calcagno E, et al. Glutamate and glutathione interplay in a motor neuronal model of amyotrophic lateral sclerosis reveals altered energy metabolism. Neurobiology of Disease 2011; 43.

Dawson MI. The importance of vitamin A in nutrition. Curr Pharm Des. 2000 Feb;6(3):311-25.

De Vos KJ, Chapman AL, et al. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Human Molecular Genetics, 2007; 16(22).

Dunlop J, Beal McIlvain H, She Y, Howland DS. Impaired spinal cord glutamate transport capacity and reduced sensitivity to riluzole in a transgenic superoxide dismutase mutant rat model of amyotrophic lateral sclerosis. J Neurosci 2003; 23:1688.

Edaravone (MCI-186) ALS 16 Study Group. A post-hoc subgroup analysis of outcomes in the first phase III clinical study of edaravone (MCI-186) in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017; 18(sup1):11-19.

Ermilova IP, Ermilov VB, et al. Protection by dietary zinc in ALS mutant G93A SOD transgenic mice. NeurosciLett. 2005;379(1):42–46.

Ernst E. The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John's Wort, Ginseng, Echinacea, Saw Palmetto, and Kava. Ann Intern Med. 2002;136(1):42–53.

Exner R, Wessner B, et al. Therapeutic potential of glutathione. Wien KlinWochenschr. 2000;112(14):610–616.

Faes L and Callewaert G. Mitochondrial Dysfunction in Familial Amyotrophic Lateral Sclerosis. Journal of Bioenergetics and Biomembranes, 2011; 43(6).

Fang F, Kwee LC, et al. Association Between Blood Lead and the Risk of Amyotrophic Lateral Sclerosis. American Journal of Epidemiology, 2010; 171(10).

FDA. Food and Drug Administration. News & Events page. FDA approves drug to treat ALS. 5/5/2017. Accessed 5/2017.

Ferrante KL, Shefner J, et al. Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS. Neurology December 13, 2005 vol. 65 no. 11: 1834-1836.

Ferrante RJ, Klein AM, et al. Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. J MolNeurosci. 2001;17(1):89–96.

Fosslien E. Mitochondrial medicine—molecular pathology of defective oxidative phosphorylation. Ann Clin Lab Sci. 2001;31(1):25–67.

Franz CK, Federici T, Yang J, et al. Intraspinal cord delivery of IGF-1 mediated by adeno-associated virus 2 is neuroprotective in a rat model of familial ALS. Neurobiol Dis. 2009 ;33(3):473-81.

Ganji V and Kafal MR. Population prevalence, attributable risk, and attributable risk percentage for high methylmalonic acid concentrations in the post-folic acid fortification period in the US. Nutrition & Metabolism 2012, 9:2.

Giess  R, Naumann M, Werner E, et al. Injections of botulinum toxin A into the salivary glands improve sialorrhoea in amyotrophic lateral sclerosis. J NeurolNeurosurg Psychiatry 2000; 69:121.

Grabrucker AM, Rowan M, et al. Brain-Delivery of Zinc-Ions as Potential Treatment for Neurological Diseases: Mini Review. Drug DelivLett. 2011 September;1(1): 13–23.

Gresham LS, Molgaard CA , et al. Amyotrophic lateral sclerosis and occupational heavy metal exposure: a case-control study. Neuroepidemiology. 1986;5(1):29–38.

Hagen TM, Liu J, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. ProcNatlAcadSci USA. 2002;99(4):1870–1875.

Henderson JT, Javaheri M, et al. Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-L-cysteine. J Neurosci. 1996;16(23):7574–7582.

Hensley K, Mhatre M, et al. On the Relation of Oxidative Stress to Neuroinflammation: Lessons Learned from the G93A-SOD1 Mouse Model of Amyotrophic Lateral Sclerosis. Antioxidants & Redox Signaling, 2006; 8(11-12).

Hester ME, FouseKD, et al. AAV as a Gene Transfer Vector for the Treatment of Neurological Disorders: Novel Treatment Thoughts for ALS. Current Gene Therapy, Volume 9, Number 5, October 2009, pp. 428-433(6).

Hong JT, Ryu SR, et al. Neuroprotective effect of green tea extract in experimental ischemia-reperfusion brain injury. Brain Res Bull. 2000;53(6):743–749.

Hu M, SkibstedLH. Kinetics of reduction of ferrylmyoglobin by (-)-epigallocatechingallate and green tea extract. J Agric Food Chem. 2002;50(10):2998–3003.

Ilieva EV, Ayala V, et al. Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis Brain (2007), 130.

Izumi Y and Kaji R. [Clinical trials of ultra-high-dose methylcobalamin in ALS]. Brain Nerve. 2007 Oct;59(10):1141-7.

Jiang F, DeSilva S, et al. Beneficial effect of ginseng root in SOD-1 (G93A) transgenic mice. J NeurolSci, 2000;180(1–2):52–54.

Jin HW, Flatters SJ, et al. Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-L-carnitine: Effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells. Experimental Neurology 210 (2008) 229–237.

Johnson FO and Atchison WD. The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis. NeuroToxicology 30 (2009) 761–765.

Kanekura K, Suzuki H, et al. ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis. MolNeurobiol (2009) 39:81–89.

Karch CM, Prudencio M, Winkler DD, et al. Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS. ProcNatlAcadSci USA 2009; 106:7774.

Kauffman P, Thompson JL, et al. Phase II Trial of CoQ10 for ALS Finds Insufficient Evidence to Justify Phase III. Ann Neurol. 2009;66:235–244.

Kawamata K and Manfredi G. Mitochondrial Dysfunction and Intracellular Calcium Dysregulation in ALS. Mechanisms of Ageing and Development, 2011; 131(7-8).

Kim D, Nguyen MD, et al. SIRT1deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. The EMBO Journal (2007) 26, 3169–3179.

Kim YH, Park KH, et al. Transcriptional Activation of the Cu,Zn-Superoxide Dismutase gene through the AP2 site by ginsenosideRb2 extracted from a medicinal plant, Panax ginseng. J Biol Chem. 1996 Oct 4;271(40):24539-43.

Kira Y, Nishikawa M, et al. L-Carnitine suppresses the onset of neuromuscular degeneration and increases the life span of mice with familial amyotrophic lateral sclerosis. Brain Research, 2006; 1070.

Klopstock T, Elstner M, et al. Creatine in mouse models of neurodegeneration and aging. Amino Acids (2011) 40:1297–1303.

Kobayashi MS, Han D, Packer L. Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity. Free Radic Res. 2000;32(2):115–124.

Kokkalis ZT, SoucacosPN, et al. Effect of Acetyl-L-Carnitine on Axonal Sprouting Following Donor Nerve Injury Distal to an End-to-Side Neurorrhaphy Model. Journal of reconstructive Microsurgery, 2009; 25(8).

Kolacek M, Muchova J, et al. Effect of Natural Polyphenols, Pycnogenol® on Superoxide Dismutase and Nitric Oxide Synthase in Diabetic Rats. Prague Medical Report, 2010; 111 (4).

Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci 1998; 18:3241.

Kuhnlein P, Gdynia HJ, et al. Diagnosis and treatment of bulbar symptoms in amyotrophic lateral sclerosis. Nature Clinical Practice, 2008; 4(7).

Kwiatkowski TJ, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27;323(5918):1205-8.

Lagier-Tourenne C and Cleveland DW. Rethinking ALS: The FUS about TDP-43. Cell 136, March 20, 2009.

Leishear K, Lucci F, et al. Vitamin B12 and Homocysteine Levels and 6-Year Change in Peripheral Nerve Function and Neurological Signs. Journal of Gerentology, 2011.

Lepore AC, Haenggeli C, et al. Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS. Brain Research, 2007; 1185.

Lin CL, Bristol LA, Jin L, et al. Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 1998; 20:589.

Lindberg MJ, Tibell L, Oliveberg M. Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: decreased stability of the apo state. ProcNatlAcadSci USA 2002; 99:16607.

Lipp A, Trottenberg T, Schink T, et al. A randomized trial of botulinum toxin A for treatment of drooling. Neurology 2003; 61:1279.

Liu J, Lillo C, Jonsson PA, et al. Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron 2004; 43:5.

Liu J. The Effects and Mechanisms of Mitochondrial Nutrient α-Lipoic Acid on Improving Age-Associated Mitochondrial and Cognitive Dysfunction: An Overview. Biomedical and Life Sciences, 2008; 33(1).

Lo Coco D, Marchese S, Pesco MC, et al. Noninvasive positive-pressure ventilation in ALS: predictors of tolerance and survival. Neurology 2006; 67:761.

Lunn JS, Hefferan MP, et al. Stem cells: comprehensive treatments for amyotrophic lateral sclerosis in conjunction with growth factor delivery. Growth Factors, June 2009; 27(3): 133–140.

Mackenzie IR, Bigio EH, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Annals of Neurology, 2007; 61(5).

Mancuso M, Orsucci D, et al. Coenzyme Q10 in Neuromuscular and Neurodegenerative Disorders. Current Drug Targets, 2010 , 11, 111-121.

Mandel SA, Amit T, et al. Targeting Multiple Neurodegenerative Diseases Etiologies with Multimodal-Acting Green Tea Catechins. The Journal of Nutrition, 2008.

Mandel SA, Amit T, et al. Understanding the Broad-Spectrum Neuroprotective Action Profile of Green Tea Polyphenols in Aging and Neurodegenerative Diseases. Journal of Alzheimer’s Disease, 2011; 25(2).

Mandl J, et al.Vitamin C: update on physiology and pharmacology. Br J Pharmacol. 2009 Aug;157(7):1097-110. Epub 2009 Jun 5.

Mano Y, Takayanagi T, et al. [Amyotrophic lateral sclerosis and mercury—preliminary report]. RinshoShinkeigaku. 1990;30(11):1275–1277.

Martin LJ. Mitochondrial pathobiology in ALS. J Bioenerg Biomembr. 2011;43(6):569-79.

Martinez HR, et al. Stem cell transplantation in amyotrophic lateral sclerosis patients. Methodological approach, safety, and feasibility. Cell Transplant. 2012 Feb 13. [Epub ahead of print]

Martinez HR, et al. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Cytotherapy. 2009;11(1):26-34.

Matsumoto Y, et al. Nizofenone, a neuroprotective drug, suppresses glutamate release and lactate accumulation. Eur J Pharmacol. 1994 Sep 1;262(1-2):157-61.

Matthews RT, Yang L, et al. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. ProcNatlAcadSci USA. 1998;95(15):8892–8897.

Mazzini L, Balzarini C, et al. Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci. 2001;191(1–2):139–144.

Miana-Mena FJ, Gonzalez-Mingot C, et al. Monitoring systemic oxidative stress in an animal model of amyotrophic lateral sclerosis J Neurol (2011) 258:762–769.

Miller RG, et al. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001447.

Mitchell J. Amyotrophic lateral sclerosis: toxins and environment. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(4):235–250.

Moore E, Mander A, et al. Cognitive impairment and vitamin B12: a review. International Psycogeriatrics, 2012.

Morozova N, Weisskopf MG, et al. Diet and Amytorophic Lateral Sclerosis. Epidemiology, 2008; 19(2).

Morselli LL, et al. Growth hormone secretion is impaired in amyotrophic lateral sclerosis. ClinEndocrinol (Oxf). 2006 Sep;65(3):385-8.

Muller U, Krieglstein J. Prolonged pretreatment with alpha-lipoic acid protects cultured neurons against hypoxic, glutamate-, or iron-induced injury. J Cereb Blood Flow Metab. 1995;15(4):624–630.

Mustfa N, Walsh E, Bryant V, et al. The effect of noninvasive ventilation on ALS patients and their caregivers. Neurology 2006; 66:1211.

Nagano I, Shiote M, et al. Beneficial effects of intrathecalIGF-1 administration in patients with amyotrophic lateral sclerosis. Neurological Research, 2005; 27(7).

Packer L, Rimbach G, et al. Antioxidant activity and biologic properties of a procyanidin-rich extract from pine (Pinusmaritima) bark, pycnogenol. Free RadicBiol Med. 1999;27(5–6):704–724.

Palma A, de Carvalho M, et al. Biochemical characterization of plasma in amyotrophic lateral sclerosis: amino acid and protein composition. Amyotoph Lateral Scler Other Motor Neuron Disord. 2005;6(2):104–110.

PastulaDM, Moore DH, et al. Creatine for amyotrophic lateral sclerosis/motor neuron disease. The Cochrane Collaboration, 2010.

Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. 2001;53(2):161–176.

Phukan J. Arimoclomol, a coinducer of heat shock proteins for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010;13(7):482-96.

Pott JW, Wassink-Ruiter JS, et al. Methylmalonic acid and homocysteine assessment in the detection of vitamin B12 deficiency in patients with bilateral visual loss. Acta Opthamologica, 2012.

Radad K, Moldzio R, et al. Ginsenosides and their CNS Targets. CNS Neuroscience and Therapeutics, 2011; 17.

Rooney J. Further Thoughts on Mercury, Epigenetics, Genetics and Amyotrophic Lateral Sclerosis. Neurodegenerative Dis 2011;8:523–524.

Ross E, Wilkins H, et al. A non-denatured whey protein supplement (Immunocal®) protects neurons from mitochondrial oxidative stress and delays disease onset in the mutant SOD1 mouse model of ALS. 2011.

Rothstein JD, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005 Jan 6;433(7021):73-7.

Rothstein JD, Kuncl RW. Neuroprotective strategies in the model of chronic glutamate-mediated motor neuron toxicity. J Neurochem. 1995b;65(2):643-51.

Rothstein JD, Tsai G, Kuncl RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 1990; 28:18.

Rothstein JD, Van Kammen M, Levey AI, et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995; 38:73.

Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009 Jan;65Suppl1:S3-9.

Rowland L. Amyotrophic lateral sclerosis: theories and therapies. J Neorol Sci. 1994;31(169):126–127.

Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001;344(22):1688–1700.

Sacca F, et al. A randomized controlled clinical trial of growth hormone in amyotrophic lateral sclerosis: clinical, neuroimaging, and hormonal results. J Neurol. 2012 Jan;259(1):132-8. Epub 2011 Jun 25.

Sakowski SA, Schuyler AD, et al. Insulin-like growth factor-I for the treatment of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 2009; 10(2).

Sanmartin C, et al. Selenium and clinical trials: new therapeutic evidence for multiple diseases. Curr Med Chem. 2011;18(30):4635-50.

Schroeder EK, Keley NA, et al. Green Tea Epigallocatechin 3-Gallate Accumulates in Mitochondria and Displays a Selective Antiapoptotic Effect Against Inducers of Mitochondrial Oxidative Stress in Neurons. Antioxidants & Redox Signaling. March 2009, 11(3): 469-480.

Shaw PJ, Forrest V, Ince PG, et al. CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration 1995; 4:209.

Shi C, Zhao L, et al. Dosage Effects of EGb761 on Hydrogen Peroxide-Induced Cell Death in SH-SY5Y Cells. ChemBiol Interact, 2009; 180(3):389-97.

Shi P, Gal J, et al. Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis. Biochimica et BiophysicaActa 1802 (2010) 45–51.

Sohmiya M, Tanaka M, et al. An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients. J Neurol Sci. 2005;228(1):49–53.

Sorenson EJ, WindbankAJ, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology, 2008; 71(22).

Stone CA, O'Leary N. Systematic review of the effectiveness of botulinum toxin or radiotherapy for sialorrhea in patients with amyotrophic lateral sclerosis. J Pain Symptom Manage 2009; 37:246.

Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep.2005;10:52–60.

Suh JH, Shenvi SV, et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. PNAS, 2004a; 101(10).

Suh JH, Zhu BZ, DeSzoeke E, et al. Dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. Redox Rep.2004b;9:57–61.

Sun AY, Wang Q, et al. Resveratrol as a Therapeutic Agent for Neurodegenerative Diseases. MolNeurobiol (2010) 41:375–383.

Sung JJ, Kim HJ, et al. Homocysteine induces oxidative cytotoxicity in Cu, Zn-superoxide dismutase mutant motor neuronal cell. Neuroreport. 2002;13(4):377–381.

Suzuki M and SvendsenCN. Combining growth factor and stem cell therapy for amyotrophic lateral sclerosis. Trends in Neurosciences, 2008; 31(4). Therapeutic Pipeline Accessed 3/16/2012

Trumbull KA and Beckman JS. A Role for Copper in the Toxicity of Zinc-Deficient Superoxide Dismutase to Motor Neurons in Amyotrophic Lateral Sclerosis. Antioxid Redox Signal. 2009 Jul;11(7):1627-39.

Turnbull J. Is edaravone harmful? (A placebo is not a control). Amyotroph Lateral Scler Frontotemporal Degener. 2018;19(7-8): 477-482

VadakkadathMeethal S and Atwood CS. e dyscrasia: a novel explanation for amyotrophic lateral sclerosis. Neurobiol Aging. 2012 Mar;33(3):569-81.

Vance C, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27;323(5918):1208-11.

Vargas MR, Johnson DA, et al. Nrf2 Activation in Astrocytes Protects against Neurodegeneration in Mouse Models of Familial Amyotrophic Lateral Sclerosis. The Journal of Neuroscience, December 10, 2008; 28(50):13574 –13581.

Vielhaber S, Kaufmann J, et al. Effect of creatine supplementation on metabolite levels in ALS motor cortices. Exp Neurol. 2001;172(2):377–382.

Virmani A, Gaetani F, et al. The Protective Role of L-Carnitine against Neurotoxicity Evoked by Drug of Abuse, Methamphetamine, Could Be Related to Mitochondrial Dysfunction. Ann. N.Y. Acad. Sci. 965: 225–232 (2002).

Wang J, Zhang Y, et al. Protective effects of resveratrol through the up-regulation of SIRT1 expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of amyotrophic lateral sclerosis. Neuroscience Letters 503 (2011) 250– 255.

Wilson AD, Hart A, et al. Acetyl-l-carnitine increases nerve regeneration and target organ reinnervation – a morphological study. The Journal of Plastic, Reconstructive and Aesthetic Surgery, 2010; 63(7).

Woodall CJ and Graham DI. Evidence for neuronal localisation of enteroviral sequences in motor neurone disease/amyotrophic lateral sclerosis by in situ hybridization. The European Journal of Histochemistry, 2004; 48(2).

Writing Group. Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017; 16(7):505.

Wu SN. Large-conductance Ca2+- activated K+ channels: physiological role and pharmacology. Curr Med Chem. 2003;10(8):649–661.

Yamada T, Hashida K, et al. α-Lipoic acid (LA) enantiomers protect SH-SY5Y cells against glutathione depletion. Neurochemistry International, 2011; 59(7).

Yamashita M, Nonaka T, et al. Methylene blue and dimebon inhibit aggregation of TDP-43 in cellular models FEBS Letters, 2009; 583(14).

Yanez M, Galan L, et al. CSF from amyotrophic lateral sclerosis patients produces glutamate independent death of rat motor brain cortical neurons: Protection by resveratrol but not riluzole. Brain Research, 2011; 1423.

Yoon DH, Kwon OY, et al. Protective potential of resveratrol against oxidative stress and apoptosis in Batten disease lymphoblast cells. Biochemical and Biophysical Research Communications 414 (2011) 49–52.

Yu J, Jia Y, et al. Epigallocatechin-3-gallate Protects Motor Neurons and Regulates Glutamate Levels. FEBS Letters 584 (2010) 2921–2925.