Table 3.

Summary of the current and emerging dietary supplements’ therapeutic landscape

Supplement	Mechanism	Disease(s)/syndrome(s) investigated	Study design/trial phase	N	Most recent update/publication	Results	Trial ID/reference
Monotherapy (74-94)
Alpha-lipoic acid	Antioxidant cofactor for mitochondrial alpha-keto acid dehydrogenases	CPEO	Case report	1	1995	Improved brain and skeletal muscle energy metabolism	[73]
L-arginine	Precursor of nitric oxide that stimulates vasodilation	MELAS	Case series	3	2002	Improved microcirculation and reduced tissue injury from ischemia	[74]
			Open-label clinical trial	24	2005	Reduced frequency and severity of stroke-like symptoms	[75]
			Open-label clinical trial	15	2006	Improved endothelial function	[76]
			Open-label clinical trial	25	2007	Reduced stroke like-symptoms	[77]
Carnitine -	Removal of toxic acetyl coenzyme A metabolites -	PMM CPEO	Crossover	10	2015	Improved aerobic performance	[78]
		CPEO KSS MELAS ME PMM Leigh	Open-label clinical trial	21	1993	Normalization of plasma carnitine levels Improved muscle tone and strength Improved cardiomyopathy	[79]
L-citrulline	Stimulates vasodilation	MELAS	Phase 1	24	2020	Pending	NCT03952234
		MELAS	Small kinetic study	20	2012	Increased NO production	[80]
		MELAS	Small kinetic study	10	2016	Increased NO production	[81]
CoQ10	Antioxidant that transfers electrons from complex I to II and III	Familial cerebellar ataxia with muscle CoQ10 deficiency	Case Series	6	2011	Increased strength Reduced ataxia Reduced seizure frequency	[82]
		MERRF MELAS CPEO	Crossover	8	1997	Increased muscle strength	[83]
		PMDs	Two phase prospective study	44	1990	Increased activity of mitochondrial respiratory chain enzymes Increased muscle strength	[84]
		Ophthalmoplegia plus syndrome CPEO KSS	Open-label	9	1998	Reduced lactate after exercise	[85]
		CPEO ME	Open-label	8	1996	No improvement in exercise performance	[86]
Creatine	Regenerates ATP	MELAS PMM	Crossover	7	1997	Increase in ischemic isometric hand grip strength isometric, dorsiflexion torque	[87]
		KSS MELAS NARP	Open-label	5	2003	Increase in maximal muscle performance	[88]
		CPEO PMM	Phase 2	16	2000	No significant clinical findings	[89]
		CPEO KSS	Phase 2	15	2005	No significant clinical findings	[90]
Folinic acid	Increases brain 5-MTHF levels; believed to reduce white matter demyelination	KSS with cerebral 5-MTHF deficiency	Open-label study	8	2014	Improvements in ataxia and tremor	[91]
		Cerebral folate deficiency and leukoencephalopathy	Case report	1	2006	Improved white matter myelinization	[92]
Niacin	Increased NAD+ and NADH; increase complex I function	MELAS	Case report	1	1996	No significant clinical findings	[93]
		PMM	Phase 2	15	2019	Improves muscle strength	NCT03973203
Mito Q	Mitochondrial targeted antioxidant	Mitochondrial oxidative stress in chronic kidney disease	Phase 3	24	2019	Currently recruiting	NCT02364648
Nicotinamide	NAD+ precursor	PMD	Open-label	15	2019	Currently recruiting	NCT03432871
Riboflavin	Component of electron carriers flavin adenine dinucleotide and flavin mononucleotide.	PMM	Case series	5	1993	Complex I activity appeared normalised but no clinical improvement	[94]
		Myopathic complex I deficiency	Case report	1	1997	Improved muscular metabolic function and strength	[95]
		ME	Case report	1	2013	Improved muscle strength	[96]
Resveratrol	Fatty acid involved in fatty acid oxidation	PMM Fatty acid oxidation defects	Phase 2	20	2019	Completed; awaiting results	NCT03728777
Thiamine	Coenzyme in oxidative decarboxylation	PMD	Case series	2	1981	Reduced perceived fatigue	[97]
Combination therapy
L-arginine and L-citrulline	-	Multi-organ PMD	Crossover	20	2020	Completed; awaiting results	NCT02809170
		MELAS	Phase 1	30	2016	Completed; awaiting results	NCT01339494
ALA, CoQ10, and creatine	-	Multi-organ PMD	Crossover study	18	2007	Improvement in plasma lactate and oxidative stress after exercise	[98]
Carnitine and riboflavin	-	PMM	Case report	1	1991	Increased muscle strength	[99]
Carnitine, CoQ10, vitamin C, vitamin K1 and vitamin B complex	-	LHON CPEO MELAS NARP COXD	Open-label	12	2004	No significant clinical findings	[100]
Carnitine, CoQ10, vitamin C, vitamin E, vitamin K3 and riboflavin	-	CPEO CPEO KSS	Open-label	13	1998	Improvement in mild disease symptoms	[101]
CoQ10, vitamin C, vitamin E and vitamin K3		PMM KSS MELAS MERRF	Open-label	16	1995	No significant clinical findings	[102]
CoQ10, vitamin C, vitamin K3, niacin, riboflavin and thiamin		KSS MERRF PMM PMM with demyelinating neuropathy	Open-label	16	1993	No significant clinical findings	[103]
Folinic acid and riboflavin		ME and cerebral 5-methyltetrahydrofolate deficiency	Case report	1	2007	Reduced white matter demyelination	[104]
Vitamin C and vitamin K3		Complex III deficiency	Case report	1	1986	Improved exercise tolerance	[105]
		Complex III deficiency	Case report	1	1995	No significant clinical findings	[106]

ALA α-Linolenic acid, ATP adenosine triphosphate, COCXD cytochrome C oxidase deficiency, CPEO chronic progressive external ophthalmoplegia, CoQ₁₀ coenzyme Q10, KSS Kearns-Sayre syndrome, LHON Leber's hereditary optic neuropathy, MIDD maternally inherited diabetes-deafness syndrome, MELAS mitochondrial encephalopathy lactic acidosis and stroke-like episodes, MERR myoclonic epilepsy with ragged red fibres, ME mitochondrial encephalopathy, NARP neuropathy ataxia and retinitis pigmentosa, PMD primary mitochondrial disease, PMM primary mitochondrial myopathies