A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans with Posttraumatic Stress Disorder and Substance Use Disorders

Warren Han, Mercer University College of Pharmacy

According to the National Institute of Mental Health, posttraumatic stress disorder (PTSD) develops due to a shocking, scary, or dangerous event.  These fearful experiences can trigger the natural “fight or flight” response and other physiological reactions.  When these reactions do not resolve naturally, stress and frightened feelings linger and PTSD may develop. [1]

The antioxidant N-acetylcysteine has been identified as a possible treatment option for a variety of psychiatric disorders, such as addiction, that are caused by impaired executive functioning, impulse control, and top-down regulation. [2]  N-acetylcysteine restores the activity of glutamate transporters and antiporters in the nucleus accumbens.  It is thought that substance used disorders (SUD) down-regulates the glial glutamate transporter (GLT-1, EAAT-2) and treatment with N-acetylcysteine restores this transporter, to normalize synaptic glutamate transmission. [3]

A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans with Posttraumatic Stress Disorder and Substance Use Disorders [4]
Design Double-blind, randomized, controlled; N= 27
Objective To test the efficacy of N-acetylcysteine for veterans suffering from PTSD and SUD
Study Groups N-Acetylcysteine (n= 13); placebo (n= 14)
Methods Veterans with PTSD and SUD were randomly assigned to receive an 8-week course of N-acetylcysteine or placebo, along with group cognitive based therapy (CBT), for SUD.  Upon discontinuation of the medication, a 1-month assessment was conducted.  The following baseline and 1-month assessment measures were used: PTSD checklist-military total score (PCL-M), clinician-administered PTSD scale total score (CAPS), CAPS re-experiencing subscale (CAPS-R), CAPS avoidance subscale (CAPS-A), CAPS hyperarousal subscale (CAPS-H), Beck depression inventory, 2nd edition, amount of craving, frequency of craving, and intensity of craving.
Duration March 2013 – April 2014
Primary Outcome Measure PTSD symptoms, PCL-M, CAPS, and cravings
Baseline Characteristics Placebo,                     n (%) N-Acetylcysteine,  n (%) Total,           n (%)
Gender, male 14 (100.0) 12 (92.3) 26 (96.3)
Race, white 4 (28.6) 4 (30.8) 8 (29.6)
Race, African-American 10 (71.4) 9 (69.2) 19 (70.4)
Relationship, married 3 (21.4) 3 (23.1) 6 (22.2)
Education, at least some college 6 (42.9) 9 (69.2) 15 (55.5)
Unemployed/retired/disabled 9 (64.3) 12 (92.3) 21 (77.7)
Trauma History:
Military, combat 2 (14.3) 3 (23.1) 5 (18.5)
Military, noncombat 4 (28.6) 5 (38.5) 9 (33.3)
Civilian-related event(s) 8 (57.1) 5 (38.5) 13 (48.1)
Substance use disorders:
Alcohol use disorder 12 (85.7) 10 (76.9) 22 (81.5)
Cocaine use disorder 9 (64.3) 11 (84.6) 20 (74.1)
Opioid use disorder 1 (7.1) 0 (0.0) 1 (3.7)
Placebo, mean (SD) N-Acetylcysteine, mean (SD) Total, mean (SD)
Age, years 49.9 (8.1) 48.2 (8.6) 49.0 (8.2)
Substance use severity:
Drinks per day 4.9 (4.5) 3.7 (3.5) 4.3 (3.9)
Drinks per drinking day 12.9 (5.7) 9.77 (6.8) 11.5 (6.2)
Age at onset of alcohol use disorder, years 22.8 (6.7) 26.8 (10.4) 24.9 (8.9)
Dollar amount of cocaine used per day, US dollars 17.3 (10.4) 20.3 (14.6) 18.9 (12.4)
Age at onset of cocaine use disorder, years 29.9 (4.5) 30.4 (9.5) 30.2 (6.9)
PTSD severity:
PCL-M 43.4 (18.6) 45.7 (14.6) 44.5 (16.5)
CAPS 68.6 (23.7) 58.8 (21.2) 63.8 (22.6)
CAPS-R 21.9 (7.3) 18.8 (9.5) 20.4 (8.4)
CAPS-A 25.5 (12.5) 18.3 (8.3) 22.0 (11.1)
CAPS-H 21.2 (6.97) 21.8 (7.5) 21.5 (7.1)
Beck depression inventory, 2nd edition 22.8 (13.1) 19.1 (6.7) 21.0 (10.5)
Results  
Placebo within-group outcomes, weeks N-Acetylcysteine within-group outcomes, weeks Between group differences
Measure 0 4 8 0 4 8 Weeks 0-8
PCL-M 43.4 (18.6) 41.9 (21.7) 41.9 (22.8) 45.7 (14.6) 33.8 (10.6) 31.2 (9.7) -0.355
CAPS total score 68.6 (23.7) 52.8 (36.9) 51.5 (43.1) 58.8 (21.2) 38.7 (20.0) 32.0 (23.5) -0.127
CAPS-R 21.9 (7.3) 15.6 (10.2) 12.4 (13.1) 18.8 (9.5) 12.6 (6.9) 10.1 (8.1) -0.119
CAPS A 25.5 (12.5) 21.6 (16.1) 20.4 (19.6) 18.3 (8.3) 10.5 (9.1) 10.7 (9.2) -0.330
CAPS-H 21.2 (6.9) 15.6 (11.9) 13.6 (13.0) 21.8 (7.5) 15.6 (8.3) 11.8 (9.5) -0.194
Beck depression inventory, 2nd edition 22.8 (13.1) 18.5 (14.8) 19.3 (15.8) 19.1 (6.7) 10.9 (6.4) 9.9 (6.7) -0.325
Amount of craving 4.1 (3.1) 2.8 (2.6) 2.8 (2.8) 3.7 (3.4) 1.8 (1.9) 0.7 (0.7) -0.413
Frequency of craving 4.2 (3.2) 2.4 (2.3) 3.0 (2.9) 3.6 (3.0) 1.8 (2.0) 1.0 (0.9) -0.387
Intensity of craving 3.7 (3.0) 2.9 (2.8) 2.8 (3.1) 3.7 (3.1) 1.8 (2.1) 1.3 (1.9) -0.288
Adverse Events Common Adverse Events: dry mouth, heartburn
Serious Adverse Events: syncopal episode
Percentage that Discontinued due to Adverse Events: 2.9%
Study Author Conclusions The findings provide preliminary support for combining N-acetylcysteine and cognitive-behavioral therapy for SUD among patients with PTSD and SUD. A larger trial and additional research may be needed to fully understand the mechanisms through which N-acetylcysteine promotes symptom reduction among individuals with comorbid PTSD/SUD.

The limitations of this study have to do with the small sample size and the short study duration.  There was also a lack of differences between groups in substance abuse.  This was attributed to the enrollment in an intensive outpatient treatment program for SUD which decreased the overall substance abuse.  More studies are needed to fully assess the benefit of N-acetylcysteine for the treatment of PTSD and SUD.

References

  1. National Institute of Mental Health. https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd/index.shtml. Accessed October 14, 2016.
  2. Kalivas PW, Volkow ND. New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry. 2011;16(10):974-86.
  3. Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci. 2011;36(2):78-86.
  4. Back SE, Mccauley JL, Korte KJ, et al. A Double-Blind, Randomized, Controlled Pilot Trial of N-Acetylcysteine in Veterans With Posttraumatic Stress Disorder and Substance Use Disorders. J Clin Psychiatry. 2016.
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