White Paper by Khadiga Fouad

Peer Reviewed by Emily Morgan, Shikha Jha

NAC: Addiction Treatment

N-Acetylcysteine (NAC) is a precursor of cysteine, an amino acid. NAC is a known antioxidant and anti-inflammatory drug that is used to treat various diseases, such as acetaminophen toxicity, chronic bronchitis, asthma, Alzheimer’s, and Parkinson’s disease. (Mokhtari et al., 2016). 

Several studies have focused on NAC as a potential treatment for cocaine, heroin, nicotine, and alcohol use disorders. The studies have focused on understanding the neurological mechanism of NAC and its effects on reducing drug seeking behaviors, cravings, and withdrawal symptoms (Mcclure et al., 2014). NAC would be most beneficial if used by treatment-seeking adults as an anti-relapse medication (Brown et al., 2013) and “in preventing relapse after an individual has achieved abstinence” (Tomko et al., 2018). 

FDA Approval

The Food and Drug Administration (FDA) approved NAC to be used in liquid form to treat cystic fibrosis and in oral and intravenous form to treat acetaminophen overdose. (LaRowe et al., 2006). Since 1963, NAC has long been established, by the FDA, as safe to administer to both adults and children (Mcclure et al., 2014).

There are currently no FDA approved treatments for stimulant use disorders such as, cocaine  or amphetamine use,  or cannabis use disorder (LaRowe et al., 2006; Mcclure et al., 2014; Tomko et al., 2018). In terms of tobacco use disorder, the approved therapies include  nicotine replacement products, varenicline, and bupropion. However, these treatments do not grant cessation of tobacco use (Tomko et al., 2018). The treatments for alcohol use disorder consist of naltrexone, acamprosate, and disulfiram (Tomko et al., 2018). Treatments that have been approved for substance use disorders (SUDs) are classified as replacement or agonist therapies. Reduction therapies work to cease drug use by replacing the effects of the desired substance (Tomko et al., 2018). There are also therapies that aim to treat the associated withdrawal and craving symptoms (Tomko et al., 2018). 

Mechanism of Action

Research has shown that drug seeking behavior is linked with increased glutamate release, leading to the activation of extra-synaptic glutamate receptors, which are found at non-synaptic sites on neurons (Brown et al., 2013). High levels of glutamate are concentrated in the brain, in the nucleus accumbens (NAc) (LaRowe et al., 2006; Tomko et al., 2018), which plays an important part in motivation and learning (Tomko et al., 2018). 

Continuous exposure to drugs downregulates the glutamate reuptake by glial glutamate transporter-1 (GLT-1) in the NAc (Brown et al., 2013).  GLT-1 works by removing excess glutamate from the NAc (Tomko et al., 2018). As a result, glutamate remains in the synapse longer and contributes to the overflow of glutamate that is released when individuals resort to drug seeking behaviors once again (Brown et al., 2013; Mcclure et al., 2014). This process is illustrated in Figure 1a. Additionally, animal studies have shown that a decrease in the amount of glutamate in the NAc is linked to drug-seeking behavior and relapse (Asevedo et al., 2014). 

(Mcclure et al., 2014)

Figure 1.

a. glutamatergic activity found between synapses in the NAc and prefrontal cortex during withdrawal from drugs such as cocaine, nicotine, and heroin. b. glutamate restoration after administration of NAC.

NAC is the acetylated version of cysteine, therefore, once it is digested, the acetyl functional group is removed, and NAC is broken down into cysteine. This amino acid is then stored in the liver and released in the form of glutathione (GSH). GSH removes toxic substances from the bloodstream, acts as a coenzyme, and is an essential part of the electron transport chain (History of N-acetylcysteine). 

Once NAC is deacetylated and oxidized into cystine, it enters the cell via cysteine transporters (Mcclure et al., 2014). In the cell, it is then reduced to GHS (Mcclure et al., 2014). High concentrations of NAC in tissue leads to glutamate release from cystine-glutamate exchange that increases the power or effect of excitatory postsynaptic currents (EPSCs) in NAc medium spiny cells (Mcclure et al., 2014). The cysteine that is produced from deacetylated and oxidized NAC enters the cell, while intracellular glutamate is transported out of the cell through the cysteine-glutamate transporter (Asevedo et al., 2014). 

NAC works by raising the amount of non-synaptic glutamate and restoring levels of cysteine/glutamate exchange (Mcclure et al., 2014) and GLT1 (Brown et al., 2013; Mcclure et al., 2014). This leads to the reinstatement of normal glutamate levels, thus activating presynaptic inhibitory metabotropic glutamate 2/3 (mGluR2/3) receptors (Brown et al., 2013; Mcclure et al., 2014), leading to reduction of synaptic glutamate release (Murray et al., 2012) and, thus, a reduction in drug seeking behavior.  This process is illustrated in Fig. 1b.

Administration, Dosages, Contraindications, and Adverse Effects

NAC can be administered orally or intravenously. The recommended dosages for treatment vary based on the type of substance use disorder. It is suggested for treatment of cocaine and tobacco use disorder that 1,200 to 3,600 mg/d be administered to patients. It is given as 600 to 1,800 mg twice a day. The potential effective dosage to treat cannabis use disorder is 2,400 mg/d, administered as 1,200 mg twice a day. The suggested amount for treatment of alcohol use disorder is 1,000 to 2,400 mg/d, taken as 500 to 1,200 mg twice a day. (Tomko et al., 2018).

The contraindications of NAC include patients who have or at risk of “cardiomyopathy or congestive heart failure” (Ershad et al., 2020), hepatic encephalopathy, asthma, and gastric hemorrhage (NAC drug interactions). One source claimed that not enough studies have been conducted monitoring pregnant women being treated with NAC, to deem it safe. (Acetylcysteine (acetylcysteine) dose, indications, adverse effects, interactions... from PDR.net. n.d.). While another source asserted that there are “no maternal or fetal harmful effects of NAC treatment.” (Mokhtari et al., 2016).

The adverse effects of NAC treatment range from mild to severe reactions. Reactions include, fever, nausea, edema, hypotension, anaphylactoid reactions, or bronchospasm (Acetylcysteine (acetylcysteine) dose, indications, adverse effects, interactions. n.d.). The side effects of NAC administered intravenously include vomiting and diarrhea  (LaRowe et al., 2006). Additionally, a double-blind placebo study, found that participants receiving NAC over a course of three days, found that patients receiving NAC reported side effects such as: pruritus, headache, flatulence/diarrhea, abdominal cramps, local rash, fatigue, increased blood pressure, sweat, ears “popping,” increased appetite, canker sores, chest pain, and crying (LaRowe et al., 2006).

Safety and Tolerability of NAC

A double-blind placebo-controlled study (LaRowe et al., 2006) was conducted to evaluate the safety and tolerability of NAC in the treatment of individuals with cocaine use dependence. 13 participants, six males and seven females, between the ages 23 and 45, took part in this clinical trial. Participants must meet certain requirements, such as meeting the DSM-IV criteria for cocaine-dependence, should not be seeking treatment, should provide a positive urine drug screen (UDS), fixed housing, and an emergency contact. (LaRowe et al., 2006).

This study was divided into three phases; screening, hospitalization, and follow-up. During the hospitalization phase, participants were admitted into the hospital and evaluated using the Cocaine Selective Severity Assessment (CSSA). Two hours after admission, participants received either 600 mg of NAC or a placebo. Then, two hours following administration of the medication, participants were assessed again, taking into account vital signs, cravings, and any adverse reactions. This process was repeated every 12 hours (4 times) for a total administration of 2400 mg of NAC. Cravings and adverse reactions were monitored 14 and 26 hours after the last dose of NAC was administered (LaRowe et al., 2006).

Results looked at side effects and laboratory tests. There were twenty side effects reported by the NAC group and thirteen reported by the placebo group. There was no significant difference between the two groups in terms of severity of the side effects reported. The laboratory tests looked for changes in creatinine, bilirubin, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and white blood cell count (WBC), and hemoglobin levels. It was found that there was no significant change in any of the categories mentioned above. Based on the results, this study determined that NAC is safe and tolerable in the thirteen participants (LaRowe et al., 2006).

Current Studies and Results

According to the U.S National Library of Medicine, there are currently eight clinical trials that focus on NAC as a treatment of some form of addiction. Three of the eight studies have been completed, one of which has results, two are of unknown status, two are currently recruiting participants, and one is active but not recruiting anyone at this time. 

“N-acetylcysteine in the Treatment of PTSD and Addiction” is the only completed study with results, regarding NAC treatments, found on the NIH website. The study was conducted by the Medical University of South Carolina in 2015 and the results were posted in 2018. This was an interventional study, with the primary purpose of treating Post-Traumatic Stress Disorder (PTSD) and addiction. Participants were randomized into either the NAC or the placebo group. Individuals received NAC (2400 mg/day) or the placebo for 8 weeks. NAC was administered at 1200 mg twice a day. Both NAC and the placebo contained 25 mg of riboflavin, to act as an indicator for medication compliance. A total of 35 participants began the clinical trial. 27 of those participants completed the treatment and their results were analyzed for the study. 13 participants received NAC and 14 received the placebo. All individuals were between the ages of 18 and 65. 26 of the participants were male and one was female. In the NAC group, 10 individuals were struggling with alcohol and 11 with cocaine. In the placebo group, 12 were struggling with alcohol, 9 with cocaine, and one with opioid use. (N-acetylcysteine in the treatment of PTSD and addiction).

 “A Double-Blind Randomized Controlled Pilot Trial of N-Acetylcysteine in Veterans with PTSD and Substance Use Disorders” highlights the objectives, method, results, and conclusion of the 2015 study. The methods used in this study to monitor the effects of the treatment on the participants substance use disorder included assessing subjective cravings (Visual Analogue Scale) and substance use (Timeline Follow Back, urine drug screens). Figure 2 demonstrates that the amount of subjective craving was 81% less during week 8 of treatment, compared to cravings at baseline. Additionally, the frequency of cravings in the NAC group was 72% less during week 8, in contrast to 29% less in the placebo group. (Back et al., 2016). 

The Alcohol Timeline Follow-back (TLFB) Method revealed that the difference in drug and alcohol use between the NAC and placebo groups was not significant. Moreover, UDS tests were also used to compare substance use between groups. It was found that the NAC group had a slightly smaller number of positive UDS tests than the placebo group. (Back et al., 2016).

The adverse events (AEs) were recorded in each group. In the NAC group, 66.7% of participants experienced AEs. While in the placebo group, 47.1% of participants experienced AEs. Of the 31 reported AEs, the most commonly were dry mouth and heartburn. Three serious adverse events (SAE) were reported by three participants. The SAEs included cardiac arrhythmia, hospitalization due to pancreatitis, syncopal episode, and hospitalization for suicidality. The syncopal episode was the only SAE considered to be related to the trial. (Back et al., 2016).

The limitations of this study include a small sample size and self-reporting biases. It is important to note that this study combined NAC with cognitive-behavioral therapy (CBT) to reduce the symptoms of PTSD and depression, as well as, decrease drug use cravings. (Back et al., 2016).

(Back et al., 2016)

Figure 2.

Using VAS, participants' weekly subjective cravings were measured every week during the duration of the trial. B=Baseline, F=Follow-Up

References

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