NAC has been an established drug since the 1960s; it is on the World Health Organization’s List of 40 Essential Medicines [33] and is available as an inexpensive generic drug. It has been classically used in paracetamol overdose [34] and as a mucolytic [35], as well as to combat the toxicity of various substances that can cause generation of free radicals, such as carbon monoxide and x-ray contrasts [36]. The NAC products currently approved by Food and Drug Administration (FDA) are listed in Table 1. NAC is also used in the complementary treatment of neurological and neuropsychiatric disorders [5,35]. One death due to an anaphylactic reaction was described following an intravenous (IV) injection of 150 mg/kg of NAC in a 40 year old asthmatic woman in 2002. At comparable IV doses, vomiting was also reported in 11% of patients [37]. However, oral NAC seems to be associated with very few side effects and is considered to have an excellent safety profile [35]. One case of angioedema after oral NAC administration was described in 1997 [38]. Clinical studies have revealed benefits of NAC also in non-alcoholic steatohepatitis [39], arterial hypertension of diabetic etiology [40], chronic obstructive pulmonary disease (COPD) [41,42] and chronic bronchitis [43], substance abuse disorders [44], recurrent unexplained pregnancy loss [45], male infertility [46], polycystic ovary syndrome [47], diabetic retinopathy, age-related macular degeneration, and cataract and dry eye syndrome [4]. In total, 300 clinical studies (291 clinical trials) of NAC are listed in ClinicalTrials.gov [48] in April 2019 (Table 2). The most common disorders that were investigated by listed interventional trials with NAC (without the currently active studies) included renal disorders (48 trials) with an emphasis on radiocontrast nephropathy prevention, chronic kidney disease, and renoprotection during surgery; and neurological and psychiatric disorders (36 trials), leading with Parkinson’s disease, schizophrenia, bipolar, autistic, and behavioral disorders. Schizophrenia, for instance, has been linked to mitochondrial abnormalities, glutathione deficiency, and increased oxidative stress in the brain. Negative and general symptoms in schizophrenia may be reduced after 8–24 weeks of adjunctive treatment with NAC [49] in neuropsychiatric disorders and are discussed in greater detail in a recent review [50]. Addictive disorders (23 trials) are also a common target, with alcohol, tobacco, cocaine, cannabis, and other types of dependence. The NMDA receptors that NAC modulates may be involved in addiction [51], and at least three reviews discuss the use of NAC in addictive disorders [44,52,53] and emphasize the reduction of cravings for the substance in question. Among other commonly investigated uses of NAC were applications in gastrointestinal and pulmonary diseases. The majority of the 54 currently active interventional studies are investigating the role of NAC in addictive disorders, mental health, and neurodegenerative diseases, followed by cancer/cancer treatment side-effects, cardiovascular diseases, and surgery complications/trauma.

The suspended, terminated, or withdrawn studies listed in ClinicalTrals.gov are in Table 3. Termination reasons, such as no improvement and opposite results, are recorded in only 3 out of the 23 trials. Insufficient funds and insufficient recruitment are the major termination/ suspension/ withdrawal reason [48]. There are a few reports of the NAC study premature termination in the literature. High doses of NAC did not improve respiratory health in patients with COPD and chronic bronchitis; the study was prematurely terminated [54]. The decision was based on a potential safety issue, as it was reported that NAC and vitamin E, given orally, induced lung cancer in mice. This finding was reproduced in cell lines from human and mice lung tumors [55]. Additionally, there was no indication of improvement of COPD/chronic bronchitis in the 23 patients that received 1800 mg NAC twice daily for 8 weeks compared to the equal number of subjects receiving placebo [54]. Results of a 24-week oral NAC supplementation of cystic fibrosis patients revealed that NAC recipients maintained their lung function without a significant effect on the biomarkers of neutrophilic inflammation [56]. Another trial was prematurely terminated in 2018 due to the absence of between-group differences in the rates of contrast-associated acute kidney injury; there was no noticeable benefit of the oral NAC on the contrast-associated acute kidney injury prevention, no noticeable improvement on the need for dialysis, persistent kidney injury or death in subjects at high risk of renal complications because of angiography [57]. Similar conclusions were reached from the “Acetylcysteine for contrast-induced neuropathy” trial [58].

Pre-clinical studies imply that NAC could have more uses in supportive care and preventing human disease. Examples include Alzheimer’s disease [59,60], asthma [61], inflammatory bowel disease [62], influenza [63], intrauterine growth retardation [64], obesity and insulin resistance [65,66,67,68], ischemic cardiovascular disease [69,70], heavy metal toxicity [71,72], diabetic neuropathy [73], and age-related memory impairment [74]. Due to its capacity to break down biofilms and improve antibiotic permeability, it is promising as an adjuvant antimicrobial drug [75]. Several pre-clinical studies have also demonstrated that NAC supplementation leads to life extension and diminished effects of aging, in invertebrates [76,77,78,79] as well as mammals [80] and in human breast epithelial stem cells [81]. Such findings have yet to be replicated in humans. This is likely not solely due to NAC’s radical scavenging activity but also at least in part to telomerase activation and apoptosis inhibition [82], as is evidenced also by its capacity to delay oocyte aging [83]. However, antioxidants have the potential to either lengthen or shorten lifespan, depending on the dose and redox balance [84].

The role of NAC in the prevention and treatment of cancer is controversial, and it is discussed in more detail in the original manuscript. NAC has also attracted considerable attention as a sports supplement that can reduce muscle fatigue, improve athletic performance, and aid muscle recovery [85]. Although NAC is a well-known antioxidant and an old generic drug with several established clinical applications, more potential uses are still inadequately investigated. One of the main challenges of NAC as a medicine and a supplement is its broad range of effects and applications, far too few of which are well studied, in spite of a large effort in conducting preclinical and clinical trials.