Exploring targets and therapies for amyotrophic lateral sclerosis: current insights into dietary interventions

Figures & data

Figure 1 Mechanisms of impaired appetite control in amyotrophic lateral sclerosis (ALS).

Notes: Appetite control in ALS may be compromised by progressive worsening of disability or dysfunction of mechanisms that control hunger and satiety. Disability may result in dysphagia, upper extremity weakness resulting in a reduced capacity to access food or self-feed, social isolation during mealtimes, and/or fatigue and prolonged mealtimes resulting in reduced calorie or liquid consumption. Evidence suggests dysfunction of endogenous processes that control appetite regulation in ALS, including gastric discomfort and delayed gastric emptying, reduced release of gastric hormones that control appetite, or dysfunction of neuronal processes that control appetite.

Table 1 Dietary interventions proposed to improve capacity to meet energy needs or treat complications associated with ALS

Symptom/intervention	Approach/rationale	Outcomes
Dysphagia
Customized dietary strategies	Progressive adjustment to diet to degree of physical impairment; nutritional education	Improved weight management extends survival^Citation8
Enteral nutrition	PEG, RIG, and PIG to supplement or provide nutrition	Hypercaloric feeding improved survival;^Citation43,Citation46 Early introduction, use to prevent weight loss extended survival^Citation34,Citation35
Weight loss
High-calorie diets	Calorie-rich diet to prevent or reverse weight loss	Slowed functional decline,^Citation43 extended survival;^Citation46 clinical trials in progress (NCT02306590)
Reduced appetite
Cannabis	Activation of CB1 to stimulate appetite	Patients report improved appetite and sialorrhoea;^Citation51 adverse health effect concerns;^Citation59 no clinical trials specific to appetite regulation
Dietary fiber	Aid laxation^Citation67 to reduce gut discomfort and promote appetite	No change in ALS risk relative to fiber intake;^Citation68 diet rich in fiber associated with improved function in ALS^Citation69
Cramps and fasciculations
Quinine	Reduce nocturnal leg cramps,^Citation78 life-threatening complications,^Citation79 prohibition of use for cramps	Patient reports of reduced muscle cramps following consumption as tonic water; no validated clinical trials in ALS
Vitamin E	Plant-based antioxidants;^Citation80 suggested improvements in leg cramps with vitamin E deficiency^Citation81	Reduction in the risk for ALS with higher vitamin E levels^Citation82 and with supplementation when vitamin E levels are low;^Citation85^–^Citation87 no impact on survival and quality of life;^Citation88^–^Citation91 clinical trial completed, data not available
Magnesium	Deficiency may lead to neuronal excitability, enhancing neuromuscular transmission^Citation92 to cause cramps	No protective effects, no association between magnesium intake and ALS risk;^Citation94 no validated studies assessing the use of magnesium to treat cramps in ALS
Spasticity and stiffness
L-Threonine	Essential α-amino acid, acting as precursor to increase glycine to treat spasticity^Citation100	Modest antispasmodic effect in spinal spasticity;^Citation101 no effect in ALS;^Citation102 evidence for the use in the treatment of ALS of low quality;^Citation103 use for spasticity not supported
Cannabis	THC transiently improved spasticity in MS;^Citation104 use of cannabinoid agonists to ameliorate spasticity in MS is established^Citation106,Citation107	Benefits for spasticity limited to patient self-reports;^Citation51 did not improve cramp intensity;^Citation111 use to treat spasticity in ALS is not clinically supported and studies are needed to explore other treatment effects^Citation112
Low energy, fatigue, and weakness
Caffeine	Stimulant, promotes alertness, memory, performance, and coordination^Citation113	Reduced ALS risk with increased coffee intake^Citation115
Ketogenic diet	High fat, restricted protein, and carbohydrate intake^Citation121 to promote ketone use as alternative fuel;^Citation125 proposed to aid mitochondrial function^Citation126^–^Citation130 and glucose metabolism in muscle^Citation131,Citation132	No human data to support the use of ketogenic diet in ALS; clinical trial (NCT01016522) initiated in 2009, study terminated, data not available; promotes weight loss by reducing appetite and increasing breakdown of fat stores^Citation134 and thus could exacerbate malnutrition
Deanna protocol	Treat disease processes including glutamate excitotoxicity/oxidative stress,^Citation135 and increase protein^Citation136 and alpha-ketoglutarate synthesis^Citation135,Citation137	Benefits limited to anecdotal patient reports;^Citation135 further research in ALS is needed
Creatine	Proposed to increase phosphocreatine availability,^Citation139 stimulating mitochondrial respiration,^Citation140 antioxidant^Citation141	Patient reports suggest improved muscle function,^Citation145 no improvement in strength,^Citation146,Citation147 function or survival^Citation148
Protein	Thought to aid muscle recovery and slow muscle loss	Supplementation prevented weight loss in ALS, stabilizing functional decline over 4 months;^Citation45 may improve nutritional status
Vitamin D	Improves musculoskeletal function in elderly^Citation149 suggesting possible benefits for treatment in ALS	Low vitamin D status correlates with a faster functional decline, reduced life expectancy in vitamin D-deficient patients;^Citation152 modest slowing of functional decline with supplementation may have some benefits^Citation153
Pathological mechanisms of ALS
Vitamin B12	Supports health of the nervous system^Citation158	Phase III clinical trial (NCT00444613) found lesser decline in ALSFRS-R and prolonged survival if active vitamin B12 was administered within 12 months of symptom onset;^Citation161 replication of findings and further validation of use needed^Citation162
Carnitine	Proposed to protect against oxidative stress and damage^Citation163	Slower functional decline and increased median survival when used in combination with riluzole^Citation164
Coenzyme Q10 (CoQ10)	Proposed to boost mitochondrial function and act as free radical scavenger	Doses of up to 3000 mg/day were found safe and tolerable in ALS;^Citation166 no significant treatment benefit in ALS was observed^Citation167
Mitoquinone (MitoQ)	A synthetic derivative of CoQ10, strong antioxidant^Citation168	Trial in Parkinson’s Disease demonstrated no positive effects;^Citation170 no clinical trials in ALS
Edaravone	Potent antioxidant and ROS scavenger^Citation171	Clinical trial (NCT01492686) showed lesser decline in ALSFRS-R and less deterioration in quality of life at 6 months;^Citation175 oral formulation returned positive results in a Phase I trial, and Phase II/III trial in progress

Abbreviations: PEG, endoscopic gastrostomy; RIG, radiologically inserted gastrostomy; PIG, per-oral image-guided gastrostomy; CBI, cannabinoid receptors; MS, multiple sclerosis; ROS, reactive oxygen species; ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS Functional Rating Scale-Revised.

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