Table 1.

Metabolic treatments tested in ALS

Putative mechanism of action	Metabolic treatment	Effect on ALS models	Effect on ALS patients
Energy buffering and transport	Creatine	Improved lifespan, motor neuron survival, and motor function in mutant SOD1G93A mice [87]	No efficacy in phase II/III clinical trials [55, 139, 151]
Oxidative stress	Coenzyme Q10	Improved survival in mutant SOD1G93A mice—[111]	No efficacy in phase II clinical trial [81]
	MitoQ	Reduced toxicity of mutant SOD1G93A rat astrocytes to healthy motor neurons in co-culture [24] Improved motor function, survival, and histopathology in mutant SOD1G93A mice [114]	To be tested
	Dexpramipexole	Improved survival, and motor function in mutant SOD1G93A mice in one study [36], but not in a second study [177] No effect in patient derived iPSCs [189] No effect in rat cortical neurons transfected with mutant or wild-type TDP-43 [177]	No efficacy in phase III clinical trial [33]
	Edaravone	Delayed motor neuron degeneration and spinal cord SOD1 deposition in mutant SOD1G93A mice [71] Delayed disease progression in wobbler mice [69] Improved motor performance in mutant SOD1H46R rats [5]	Efficacy in a subset of ALS patients [184], FDA-approved
Additional and/or alternative fuel	High caloric diet	Delayed disease onset and extended survival in mutant SOD1G93A, mutant SOD1G86R, and mutant TDP-43A315T mice [30, 46] Delayed motor neuron loss in the spinal cord of mutant SOD1G93A mice [46]	Promising results in a phase II clinical trial [182]
	Ketone bodies	Ketogenic diets delay disease onset, improved motor neuron survival but not lifespan in mutant SOD1G93A mice [195] Ketone esters are to be tested in ALS models	To be tested
	Medium-chain triglycerides	Delayed disease onset, and improved motor neuron survival in mutant SOD1G93A mice [167, 193]	To be tested
	Pyruvate	Improved motor performance, disease progression, and lifespan in mutant SOD1G93A mice [121] but not in a subsequent study [48]	To be tested
Mitochondrial function	Dichloroacetate	Improved survival, delayed disease onset, and improved motor neuron survival in mutant SOD1G93A mice [113, 120]	To be tested
	Acetyl-l-carnitine	Neurotrophic effects in rat embryonic motor neurons [10] Improved survival in mutant SOD1G93A mice [86]	Promising results in a phase II clinical trial [8]