N-acetylcysteine, Acetyl-L-carnitine, and Citicoline: A Potential Synergism in Neurological and Psychiatric Disorders

The cellular oxidative balance is finely regulated by glutathione (GSH) levels and its reduced form. N-acetylcysteine (NAC) is an antioxidant agent that reduces disulphide bonds, scavenges reactive oxygen species (ROS), and serves as a precursor for GSH biosynthesis. Moreover, NAC can modulate glutamatergic transmission in the central nervous system (CNS), stimulating the system xc- activity and thus enhancing the endogenous activation of metabotropic glutamate receptors type 2 and 3 presinaptically, which restrains the excessive release of glutamate. Acetyl-Lcarnitine (ALC) is an acetylated form of L-carnitine and plays a key role in cellular energy metabolism. NAC and ALC show great neuroprotective potential, owing to their ability to counteract oxidative stress, modulate the glutamatergic system and neurotransmission, and maintain mitochondrial bioenergy and membrane integrity, acting synergistically. Several preclinical and clinical studies suggest that NAC and ALC may have effects in different psychiatric and neurological disorders, including mood disorders, schizophrenia, substance use disorder, chronic pain, and neurodegenerative diseases. The combination of the two products together with citicoline could also be beneficial when cognitive fatigue or cognitive impairment are clinical manifestations. These agents act on complementary pathways-redox regulation, mitochondrial support, and membrane integrity-potentially enhancing each other's neuroprotective effects. The purpose of this review is to explore the fields (psychiatric, neurological, and also rheumatological), in which the combination of these compounds may benefit patient management, starting with preclinical evidence and focusing on clinical trials conducted over the years.