Numerous studies support the use of N-acetylcysteine (NAC) for mood disorders and substance use cessation
N-acetylcysteine (NAC), well-known for its function as an antioxidant and anti-inflammatory,[1],[2] is commonly used in the clinic as a mucolytic,[3],[4] the treatment of choice for acetaminophen overdose,[5] and to help prevent liver damage resulting from acetaminophen and other toxic substances.[6],[7] NAC provides cysteine, the rate-limiting amino acid for the synthesis of glutathione,[8] the body’s main antioxidant and master detoxifier.[9] As a precursor to glutathione, NAC also supports the normal immune response to viruses (much like selenium does), and has been studied as an adjunctive agent in conditions such as human immunodeficiency virus (HIV), where the glutathione levels are diminished in addition to the low levels of the protective immune cells which typifies the disease.[10]
Studies have shown that NAC is neuroprotective, crossing the blood-brain barrier and accumulating in the central nervous system (CNS).
Studies have shown that NAC is neuroprotective, crossing the blood-brain barrier and accumulating in the central nervous system (CNS).[11] NAC has been shown to improve mitochondrial function in the brain and reduce neuroinflammation in various animal models.[12],[13] This gives it great potential for use in diseases associated with CNS dysfunction and oxidative stress, including mental health conditions, neurodegenerative disease, and traumatic brain injury.[14]
Although B vitamins are a primary therapy for hyperhomocysteinemia, NAC also has been shown to reduce homocysteine (HCY) levels,[15] which are often high in individuals with depression and those who abuse substances, particularly alcohol.[16],[17] In the CNS, high HCY levels are also related to the development of dementia and Alzheimer’s disease, and it is a well-established cardiovascular disease risk factor.[18],[19],[20] Levels of HCY in individuals with psychiatric disease may be high due to reduced clearance of this molecule by the kidneys[21] – which is the very aspect of elimination that NAC helps improve. NAC also helps reduce the oxidative damage caused by HCY in the brain.[22] Administration of NAC (or glutathione) to animals has been shown to reduce HCY levels by more than 50%.[23] In humans, at a dosage of 1,800 mg daily for four weeks, NAC significantly reduced HCY levels, decreasing systolic and diastolic blood pressure as well.[24]
Administration of NAC (or glutathione) to animals has been shown to reduce homocysteine levels by more than 50%.
In an animal model of obsessive-compulsive disorder (OCD), NAC was shown to reduce marble-burying behavior (a mouse “obsessive-compulsive” symptom), while another antioxidant, vitamin E, had no effect on this behavior, suggesting the mechanism was different than simply reducing oxidative stress or improving mitochondrial function, both of which vitamin E is also known to do.[25] Indeed, NAC has been shown to reduce compulsive behavior via modulation of glutamate, a primary excitatory neurotransmitter that has been demonstrated to be dysregulated in mood disorders and addiction.[26],[27],[28],[29] NAC appears to activate a cellular transporter that moves glutamate into the extracellular space, which inhibits further glutamate release, thereby improving compulsive behaviors.[30] These and the other aforementioned findings have spurred many clinical studies investigating NAC as a treatment for a variety of neuropsychiatric conditions and to support cessation of addictive behaviors and substance use.[31],[32],[33]
The use of NAC in psychiatry
Numerous animal and human studies suggest NAC may be a useful tool in mood disorders including depression, bipolar disorder, and OCD. The dose of NAC in these studies generally varies from 1,200 to 3,000 mg per day in divided doses, with some increasing from the initial dose after a month or so if improvements were not seen.
A 2016 systemic review and meta-analysis of the use of NAC for the treatment of depressive symptoms found that NAC ameliorated depressive symptoms, improved functionality, and was well tolerated.[34] Since this review, another study found that NAC significantly improved anxiety and depression symptoms, but only in those with a high level of inflammation, as assessed by a parameter known as high-sensitivity C-reactive protein (hs-CRP).[35] Individuals receiving NAC also had a significantly greater reduction in hs-CRP levels than those receiving placebo. Another study found that treatment with NAC significantly improved post-traumatic stress disorder symptoms and depression in veterans compared to placebo.[36] A further study investigating NAC as an add-on agent for major depressive disorder refractory to treatment is ongoing.[37]
In individuals with bipolar disorder, NAC, as an add-on therapy, has been shown to improve depressive symptoms in multiple studies, with two studies showing it improved manic symptoms as well.
In individuals with depression associated with bipolar disorder, a condition that often is difficult to treat due to the cycling between manic and depressive states, NAC, as an add-on therapy, has been shown to improve depressive symptoms in multiple studies,[38],[39] with two studies showing it improved manic symptoms as well.[40],[41] Similar to the interaction effects shown with depressed patients having a higher level of inflammation, one study found that treatment with NAC was more advantageous in individuals who had other systemic cardiovascular or endocrine illness, pathologies that also often involve inflammation.[42] Unfortunately, not all studies have duplicated these findings, however, a worsening of symptoms has not been reported.[43],[44]
NAC has also been shown to reduce the severity of obsessive-compulsive symptoms in individuals with OCD.
Multiple clinical trials and case reports of the treatment of OCD using NAC have been reported, with doses ranging from 2,000 to 3,000 mg per day (in divided doses), usually for a period of about 12 weeks.[45],[46],[47] Overall, NAC has been shown to reduce the severity of obsessive-compulsive symptoms and be well tolerated. Significant improvements have also been seen in adults with compulsive hair-pulling symptoms (a condition known as trichotillomania with many similarities to OCD),[48] however in children with this same condition, improvements were not seen with NAC.[49]
NAC, addiction, and substance use
Given the benefits seen with obsessive-compulsive behaviors and depression, it should not be surprising that numerous studies exist evaluating the potential use of NAC for the reduction of addictive behaviors and substance use. In an open-label outpatient study of cocaine-dependent patients, NAC at dosages of 2,400 or 3,600 mg/day was found to support the termination or reduced use of cocaine.[50] In an additional small, double-blind study in cocaine-dependent patients, 2,400 mg/day of NAC significantly attenuated the reinforcing effects of cocaine use.[51] In a systemic review of the research related to cocaine addiction, NAC was found in four of the six clinical trials to reduce craving, desire to use cocaine, cocaine-cue viewing time, and cocaine-related spending, with animal models showing a reversal of cocaine use-related disruption of glutamate homeostasis.[52]
NAC was found in multiple clinical trials to reduce craving, desire to use cocaine, cocaine-cue viewing time, and cocaine-related spending.
In addition to cocaine-use disorder, NAC has also been investigated as a tool to support smoking cessation, and reduce pathological gambling, cannabis dependency, and alternate substance use during cannabis cessation. In a short-term pilot study of smoking cessation, compared to placebo, 3,600 mg/day of NAC significantly reduced the reward that smokers experienced with the first cigarette after a 3.5-day abstinence period.[53] In an open-label study of 27 subjects being treated for gambling addiction, NAC was found to significantly reduce scores related to pathological gambling, with the mean effective dose being roughly 1,500 mg/day.[54] The 16 responders to NAC then entered a double-blind placebo-controlled phase, and of those receiving NAC, 83.3% had improvement of behaviors, compared to 28.6% of those receiving placebo.
In the setting of cannabis cessation, treatment with 2,400 mg/day of NAC increased the odds of simultaneous alcohol abstinence, reduced weekly alcohol use, and decreased drinking days.
In treatment-seeking cannabis-dependent adolescents, 2,400 mg/day of NAC more than doubled the likelihood that participants would have a negative urine cannabis test result compared to placebo.[55] A subsequent study found that adolescents with lower levels of pretreatment impulsivity and higher rate of adherence to NAC treatment increased the odds that participants would refrain from cannabis use.[56] Notably, treatment adherence only was a factor that influenced abstinence in those taking NAC, and did not affect the amount of individuals taking placebo who were abstinent. Finally, in the setting of cannabis cessation in individuals not having an alcohol use disorder, treatment with 2,400 mg/day of NAC increased the odds of simultaneous alcohol abstinence, reduced weekly alcohol use, and decreased drinking days.[57] Unfortunately, similar results were not seen with regards to the amount of cigarette smoking during cannabis cessation.[58]
Given the low rate of adverse effects and promising results from many of these studies, NAC is worthy of consideration as an adjunctive therapy for those who experience mood disorders and for support in the cessation of addictive substances and patterns. Despite the safety seen with the use of NAC in these clinical studies, given the nature of each of these conditions, the use of this as a therapy should be under the care of a physician or psychotherapist, ideally one who also is aware of the research backing NAC.
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