Research Paper: N-Acetylcysteine as a Treatment for Comorbid PTSD and Substance Abuse

Post-traumatic stress disorder (PTSD) is a psychiatric condition that develops in response to chronic and acute stress events that are exceptionally distressing or threatening, such as combat or sexual abuse (1). Individuals who suffer from PTSD tend to experience symptoms such as intrusive memories, emotional blunting, and anhedonia. Among individuals with PTSD, substance use disorder (SUD) commonly occurs as a comorbid condition, evidenced by 38.5% of cannabis users citing PTSD symptoms as their reason for obtaining the drug (2) and by 30 - 50% of veterans diagnosed with PTSD also having a SUD diagnosis (3). SUD is characterized by an inability of an individual to control the use of an addictive substance, such as alcohol, cannabis, or cocaine. Many people who experience SUD have a co-occurring mental illness and seek out these substances as a form of self-medication for their symptoms. Individuals who suffer from comorbid PTSD and SUD have worse outcomes than individuals with just one of the conditions and face higher rates of suicide, increased social problems, and higher rates of violence (5). While comorbid PTSD and SUD has been established as clinically relevant, there is little research and no treatment options have been shown to improve symptoms (4). However, recent studies on N-Acetylcysteine (NAC) treatment suggest NAC may be an effective treatment for both PTSD and SUD as it is hypothesized to treat impaired glutaminergic function.

Acute restraint stress and drug self-administration both produce physiological and morphological changes to the glutamate receptors in the nucleus accumbens and prefrontal cortex, indicating a biological connection between SUD and PTSD (3). In particular, the glial glutamate transporter-1 (GLT-1) shows reduced expression and function after stress-facilitated cocaine administration in rat models (3). Clinical research done on NAC for acetaminophen overdose suggests that the antioxidant may be effective in normalizing extracellular glutamate function through the restoration of glutamate receptors and antiporters in the nucleus accumbens (5). Given that PTSD and SUD share neurobiological impairments within glutamate receptors in the prefrontal cortex and nucleus accumbens, these structures present a promising target for treating the comorbid condition. Clinical research suggests that NAC may be an effective treatment for simultaneous PTSD and SUD as it has been reported to normalize glutamate levels and promote glutathione synthesis (6).

A few researchers have recently investigated this hypothesis to determine if NAC is an effective treatment option for comorbid PTSD and SUD. In a study performed by Garcia-Keller and colleagues, an experimental model was established where the rat subjects sought out cocaine and alcohol self-administration due to conditioned stress through a stress-paired odor (3). The experimental animals were exposed to the stress odor while restrained, then underwent training to self-administer either ethanol or cocaine by activating a lever that triggered the administration of the drugs, followed by an extinction period where levers released no drugs. Upon reinstatement, the animals were exposed to the stress cue and had access to levers that yielded no drugs. The animals who received the stress treatment administered significantly higher amounts of alcohol during the training period and had significantly more lever presses during the extinction period when compared with those who were not exposed to the stress treatment. This pattern remained consistent during the reinstatement period as well, with the stressed rats seeking out significantly more alcohol. This discovery supports the connection between the effects of acute stress and alcohol-seeking behavior, which solidifies previous research on the relationship between PTSD and SUD. However, the animals that self-administered cocaine did not have any significantly different amounts of lever pressing during any stage when compared with the control group. These results may be explained by the additional food training the cocaine self-administration group underwent post-surgical implantation of intravenous catheters.

However, the integration of NAC treatment showed promising results in controlling drug cravings. NAC treatment or vehicle treatment was given to the cocaine and alcohol groups before another period of reinstatement. When the alcohol-seeking group was given NAC treatment prior to reinstatement of the stress odor, the cravings were abolished in the NAC group while they remained in the vehicle group that did not receive the treatment. Similarly, the vehicle group for the cocaine-seeking rats maintained cocaine-seeking behavior when the stress odor was reintroduced while the NAC treated group ceased this behavior. These results support the hypothesis that NAC treatment is effective at preventing drug-seeking behavior for both alcohol and cocaine. The NAC treatment was also provided to a group before, during, and after the stress stimulus was presented. The NAC treatment effectively reduced alcohol-seeking behavior in the self-administration training phase as well as when the stress trigger was reintroduced. Similar results were found when the researchers introduced the NAC treatment during or after the stress stimulus in both the alcohol and cocaine-seeking groups as drug-seeking behavior was reduced. This evidence suggests that NAC can help reduce drug cravings that are triggered by reminders of stress, which is reflective of the human experience of triggers for PTSD.

Another group of researchers used rat models to investigate if NAC could mitigate the effects of THC and alcohol on the developing prelimbic cortex in adolescents when exposed to fear stimuli (2). In this experiment, Smiley and colleagues exposed groups of adolescent rats to different treatments before receiving fear conditioning sessions using tone/shock pairings then subsequently being sacrificed for analysis. The different treatments for the groups included exposure to THC (tetrahydrocannabinol) vapor, exposure to ethanol vapor, exposure to both vapors, and exposure to both vapors as well as a NAC treatment. Animals from each group were implanted with a fiber photometry probe to measure calcium movements through neuronal signaling. The fear reactivity of the animals was measured using their average freezing percent in response to fear stimuli. On the second conditioning day, both the THC + ethanol and the THC groups had significantly higher freezing percentages than the other groups. In addition, the THC + ethanol, THC, and ethanol groups all had significant increases in freezing percentages when compared with the control and NAC treatment groups. Signaling data in the prelimbic cortex prior to the shock and immediately after the shock was recorded on the first and third conditioning days to avoid novelty bias. On the third day, all of the shocks resulted in a significant increase in activity for the THC + ethanol group, while the NAC treatment group combatted this increase. Animals in the THC + ethanol group had significantly higher prelimbic signaling in response to the shock when compared with the other groups.

The rats that received the NAC treatment in addition to alcohol and THC exposure were able to resist the increase in prelimbic activity observed in the alcohol and THC exposed group. This heightened fear response in this group could make the adolescents more susceptible to developing PTSD after trauma. Evidently, NAC treatment is valuable for adolescents exposed to alcohol and cannabis as it can prevent signaling alterations in the prefrontal cortex that occur in response to fear stimuli, which agrees with the previous paper’s findings. NAC can help to regulate the glutamate activity within the prefrontal cortex and work against the dysregulation caused by alcohol and THC.

In addition to reducing drug cravings, it is important to assess how NAC treatment impacts the symptoms of withdrawal. The withdrawal phase is essential to include when discussing SUD as symptoms in this phase can trigger relapse and prevent the individual from escaping the addiction cycle. In a study done by Schneider and colleagues, the researchers investigated how NAC influenced biochemical and behavioral changes that occur as a result of alcohol cessation in rats (6). During withdrawal, the hypothalamic-pituitary-adrenal (HPA) axis is overactivated due to excessive corticotrophin-releasing factor (CRF), causing an increase in anxiety. In order to assess anxiety levels during cessation, rats were placed in two treatments groups and received daily alcohol or glucose injections over a period of 30 days, and then divided again and were given either saline or NAC over four days. Behavioral data was gathered through an open field test and biochemical data was gathered through blood analysis. The group that had daily alcohol administrations and no NAC treatment had significantly fewer peripheral crossings, total crossings, rearing, and total activity than the control group. However, the alcohol-exposed groups treated with NAC were able to resist these decreases and had no significant differences from the control group. These results indicate that NAC is effective in resisting behavioral changes due to increased anxiety during withdrawal. The blood analysis showed similar results as corticosterone and leptin significantly increased in the alcohol withdrawal group treated with saline, whereas rats treated with NAC did not have significant increases in these chemical levels. As increased leptin and corticosterone levels can increase anxiety and lead to increased drug craving, these results highlight that NAC treatment may mitigate the symptoms of withdrawal leading to relapse.

While the results so far suggest that NAC may be a promising treatment option for comorbid SUD and PTSD, they are limited to rat models. It is essential to establish the external validity of these results by replicating this treatment in humans. Back and colleagues conducted a double-blind randomized trial of NAC in veterans with comorbid PTSD and SUD to assess the effectiveness of the antioxidant in human models (5). Veterans with PTSD and SUD were randomly assigned doses of NAC or placebo over an eight-week course as well as cognitive behavioral therapy for SUD. Prior to the treatment, subjects completed a comprehensive assessment to establish baselines, and then a post-treatment assessment 30 days after completing medication. A total of 13 participants received the NAC treatment and 14 received the placebo, and no significant differences were found between group demographics. After eight weeks, the NAC treated group scored significantly lower on the Beck Depressive Inventory, as well as on the PCL-M, a military PTSD diagnostics tool. Participants in this group also reported significantly lower drug craving amounts and frequencies. The clinician-administered PTSD scale (CAPS) score was reduced significantly from the baseline assessment to the assessment in the eighth week when observing the within-group effects of the NAC treatment. These significant changes were not observed in the placebo group, indicating the success of the experimental treatment.

After completing the previous study, Back and colleagues designed another study to investigate human subjects for both short-term and long-term outcomes of NAC treatment on SUD and PTSD (4). In an experiment designed by Back and colleagues, participants are to complete a baseline assessment and fMRI scan, undergo either a placebo or NAC treatment over a period of 12 weeks with simultaneous CBT, and then complete follow-up visits 3, 6, and 12 months after treatment (4). Participants will also complete a second neuroimaging session after 8 weeks of treatment. The results from this study have yet to be released but could provide valuable insight into the long-term effects of NAC treatment on PTSD and SUD symptoms as well as the functional changes that occur as a result of treatment. This neuroimaging information could provide new insights into the changes in biological mechanisms that occur in response to treatment for comorbid SUD and PTSD.

All of these studies support the hypothesis that NAC may be an effective treatment for comorbid PTSD and SUD through glutamatergic modulation. As shown by Garcia-Keller and colleagues, NAC treatment reduced drug craving in rat models when exposed to stress triggers (3). This reduced drug craving was reflected in human subjects in the double-blind randomized trial on veterans with PTSD and SUD, who also reported less PTSD and depression symptoms after an eight-week treatment period (5). NAC was also shown to abolish the negative effects of ethanol and THC on the developing prefrontal cortex (2) and the symptoms of withdrawal from alcohol (6). These studies provide evidence that NAC can effectively stabilize glutamate activity in the prefrontal cortex and nucleus accumbens, improving dysfunction within the reward system and cognitive control center. Further research is needed to determine the functional changes occurring as a result of NAC treatment so that the specific mechanisms can be better understood. It would also be valuable to assess the effects of NAC treatment on individuals suffering from exclusively PTSD or SUD to determine if the results are due to an interaction between the two conditions. However, the current results show promising potential for an accessible over-the-counter drug to provide relief for comorbid PTSD and SUD.

1. National Collaborating Centre for Mental Health (UK). Post-Traumatic Stress Disorder: The Management of PTSD in Adults and Children in Primary and Secondary Care. Gaskell, 2005.

2. Smiley, C. E., Saleh, H. K., Nimchuk, K. E., Garcia-Keller, C., & Gass, J. T. (2021). Adolescent exposure to delta-9-tetrahydrocannabinol and ethanol heightens sensitivity to fear stimuli. Behavioral brain research, 415, 113517. https://doi.org/10.1016/j.bbr.2021.113517

3. Garcia-Keller, C., Smiley, C., Monforton, C., Melton, S., Kalivas, P. W., & Gass, J. (2020). N-Acetylcysteine treatment during acute stress prevents stress-induced augmentation of addictive drug use and relapse. Addiction Biology, 25(5), e12798. https://doi.org/10.1111/adb.12798

4. Back, S. E., Gray, K., Santa Ana, E., Jones, J. L., Jarnecke, A. M., Joseph, J. E., Prisciandaro, J., Killeen, T., Brown, D. G., Taimina, L., Compean, E., Malcolm, R., Flanagan, J. C., & Kalivas, P. W. (2020). N-acetylcysteine for the treatment of comorbid alcohol use disorder and posttraumatic stress disorder: Design and methodology of a randomized clinical trial. Contemporary clinical trials, 91, 105961. https://doi.org/10.1016/j.cct.2020.105961

5. Back, S. E., McCauley, J. L., Korte, K. J., Gros, D. F., Leavitt, V., Gray, K. M., Hamner, M. B., DeSantis, S. M., Malcolm, R., Brady, K. T., & Kalivas, P. W. (2016). A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders. The Journal of clinical psychiatry, 77(11), e1439–e1446. https://doi.org/10.4088/JCP.15m10239

6. Schneider, R., Jr, Santos, C. F., Clarimundo, V., Dalmaz, C., Elisabetsky, E., & Gomez, R. (2015). N-acetylcysteine prevents behavioral and biochemical changes induced by alcohol cessation in rats. Alcohol (Fayetteville, N.Y.), 49(3), 259–263. https://doi.org/10.1016/j.alco...