Addiction, PTSD
Conditions
Brief summary
Examine the effects of N-acetylcysteine on PTSD symptoms, craving and substance use in veterans with PTSD and comorbid substance use disorders.
Detailed description
With the increased number of military veterans returning from conflicts in Afghanistan and Iraq diagnosed with posttraumatic stress disorder (PTSD), there is a high vulnerability of these individuals to develop a substance use disorder (SUD). While there have been a host of studies focused largely on dopaminergic mechanisms of drug reward, they have not led to the development of adequate treatments for either preventing people diagnosed with PTSD from developing SUD or for treating comorbid PTSD/SUD. Based on extensive work with addictive drugs and preliminary data from our group, the investigators propose that stress impairs prefrontal cortex regulation of the basal ganglia habit circuitry and this pathology renders PTSD patients susceptible to developing SUD. Moreover, the known effects of addictive drugs to further impair prefrontal regulation are synergistic with this pathology, thereby making treatment of comorbid PTSD/SUD particularly difficult. Preclinical studies have revealed that glutamate levels within the nucleus accumbens have been implicated in drug seeking behavior in the animal model of relapse. The amino acid precursor N-acetylcysteine (NAC) appears to restore glutamate to normal levels and may also prevent glutamate levels from spiking following subsequent stimulant use. The primary goal of the proposed study is to evaluate the efficacy and safety of N-acetylcysteine in preventing relapse in drug dependent individuals with PTSD or subthreshold PTSD. Veterans with substance use disorders who have achieved at lease one week of abstinence will be randomized to either placebo or NAC (2400-3600mg/day) for 8 weeks.
Interventions
DRUGN-acetylcysteine
NAC pills were administered each week. NAC is a N acetyl pro-drug of the naturally-occurring amino acid cystine. NAC is a white, crystalline powder with the molecular formula C5H9NO3S and with a molecular weight of 163.2.
DRUGPlacebo
Identical looking placebo pills were administered each week.
Sponsors
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 18-65 year old * U.S. military Veteran, Reservist, or National Guard member * DSM-IV diagnostic criteria for current (past 6 months) SUD and PTSD or subthreshold PTSD (i.e., met criteria for cluster B (re-experiencing) and either cluster C (avoidance) or D (hyperarousal), as well as duration of one month and clinically significant impairment) * Score of \> 21 on the Mini-Mental State Exam (MMSE).
Exclusion criteria
* Unstable medical conditions * Bipolar or psychotic disorders * Seizures or asthma * Prior treatment with NAC * Suicidality * Enrolled in ongoing PTSD treatment (pharmacotherapy or psychosocial) * Females: could not be pregnant or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PTSD Symptoms | 8 weeks | Clinician Administered PTSD Scale IV (CAPS) The CAPS IV measures seventeen symptoms based on intensity and frequency. Intensity and frequency scores are summed to create a severity score for each question. Severity scores are summed to get a total score. A higher total score indicates a higher severity of PTSD symptoms.The full range for CAPS IV is 0-136. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depression | 8 weeks | Beck Depression Inventory (BDI) The BDI measures presence and severity of depression. It has 21 questions that are rated from 0-3 with a highest possible score of 63. A higher score indicates a higher severity of depression. |
| Craving | 8 weeks | Visual Analogue Scale (VAS) The VAS measures alcohol craving on a scale from 0 to 10. A higher score indicates a higher level of craving. |
| PTSD Symptoms | 8 weeks | PTSD Checklist - Military (PCL-M) The PCL-M is a seventeen question self-report, scored on a scale from 1 to 5, with possible scores ranging from 17 to 85. The scores from each question are summed to get a total score (17-85). A higher total indicates a higher severity of PTSD symptoms. |
Participant flow
Recruitment details
Participants were recruited from the VA medical center between March 2013 and April 2014.
Participants by arm
| Arm | Count |
|---|---|
| N-Acetylcysteine Eligible participants were randomized to either NAC (2400 mg/day) or placebo for 8 weeks. The starting dose of NAC was 1200 mg twice daily (2400 mg/day). All NAC and placebo capsules contained riboflavin 25 mg, which was used as a biomarker for medication compliance.
N-acetylcysteine: NAC pills were administered each week. NAC is a N acetyl pro-drug of the naturally-occurring amino acid cystine. NAC is a white, crystalline powder with the molecular formula C5H9NO3S and with a molecular weight of 163.2. | 13 |
| Placebo Identical appearing placebo capsules were dispensed. All NAC and placebo capsules contained riboflavin 25 mg, which was used as a biomarker for medication compliance. Study medications (USP-grade NAC and matched placebo capsules) dispensed to participants by the medical clinician or study staff. Treatment assignment followed a pre-arranged randomization scheme and was carried out by study personnel at the pharmacy (i.e., personnel not involved in clinical management of participants to preserve the double-blind design).
Placebo: Identical looking placebo pills were administered each week. | 14 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Physician Decision | 2 | 1 |
Baseline characteristics
| Characteristic | N-Acetylcysteine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 14 Participants | 27 Participants |
| Age, Continuous | 48.2 years STANDARD_DEVIATION 8.6 | 49.9 years STANDARD_DEVIATION 8.1 | 49.0 years STANDARD_DEVIATION 8.2 |
| Post Traumatic Stress Disorder (PTSD) CAPS IV | 58.8 units on a scale STANDARD_DEVIATION 21.2 | 68.6 units on a scale STANDARD_DEVIATION 23.7 | 63.8 units on a scale STANDARD_DEVIATION 22.6 |
| Post Traumatic Stress Disorder (PTSD) PCL-M | 45.7 units on a scale STANDARD_DEVIATION 14.6 | 43.4 units on a scale STANDARD_DEVIATION 18.6 | 44.5 units on a scale STANDARD_DEVIATION 16.5 |
| Region of Enrollment United States | 13 Participants | 14 Participants | 27 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 12 Participants | 14 Participants | 26 Participants |
| Substance Use Disorder (SUD) Alcohol | 10 Participants | 12 Participants | 22 Participants |
| Substance Use Disorder (SUD) Cocaine | 11 Participants | 9 Participants | 20 Participants |
| Substance Use Disorder (SUD) Opioid | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 18 | 7 / 17 |
| serious Total, serious adverse events | 2 / 18 | 2 / 17 |
Outcome results
Primary
PTSD Symptoms
Clinician Administered PTSD Scale IV (CAPS) The CAPS IV measures seventeen symptoms based on intensity and frequency. Intensity and frequency scores are summed to create a severity score for each question. Severity scores are summed to get a total score. A higher total score indicates a higher severity of PTSD symptoms.The full range for CAPS IV is 0-136.
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | PTSD Symptoms | 4 Weeks | 38.7 units on a scale | Standard Deviation 20 |
| N-Acetylcysteine | PTSD Symptoms | 8 Weeks | 32.0 units on a scale | Standard Deviation 23.5 |
| Placebo | PTSD Symptoms | 4 Weeks | 52.8 units on a scale | Standard Deviation 36.9 |
| Placebo | PTSD Symptoms | 8 Weeks | 51.5 units on a scale | Standard Deviation 43.1 |
Secondary
Craving
Visual Analogue Scale (VAS) The VAS measures alcohol craving on a scale from 0 to 10. A higher score indicates a higher level of craving.
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Craving | Amount of Craving Week 4 | 1.8 units on a scale | Standard Deviation 1.9 |
| N-Acetylcysteine | Craving | Amount of Craving Week 8 | .7 units on a scale | Standard Deviation 0.7 |
| N-Acetylcysteine | Craving | Frequency of Craving Week 4 | 1.8 units on a scale | Standard Deviation 2 |
| N-Acetylcysteine | Craving | Frequency of Craving Week 8 | 1.0 units on a scale | Standard Deviation 0.9 |
| N-Acetylcysteine | Craving | Intensity of Craving Week 4 | 1.8 units on a scale | Standard Deviation 2.1 |
| N-Acetylcysteine | Craving | Intensity of Craving Week 8 | 1.3 units on a scale | Standard Deviation 1.9 |
| Placebo | Craving | Intensity of Craving Week 4 | 2.9 units on a scale | Standard Deviation 2.8 |
| Placebo | Craving | Amount of Craving Week 4 | 2.8 units on a scale | Standard Deviation 2.6 |
| Placebo | Craving | Frequency of Craving Week 8 | 3.0 units on a scale | Standard Deviation 2.9 |
| Placebo | Craving | Amount of Craving Week 8 | 2.8 units on a scale | Standard Deviation 2.8 |
| Placebo | Craving | Intensity of Craving Week 8 | 2.8 units on a scale | Standard Deviation 3.1 |
| Placebo | Craving | Frequency of Craving Week 4 | 2.4 units on a scale | Standard Deviation 2.3 |
Secondary
Depression
Beck Depression Inventory (BDI) The BDI measures presence and severity of depression. It has 21 questions that are rated from 0-3 with a highest possible score of 63. A higher score indicates a higher severity of depression.
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | Depression | Week 4 | 10.9 units on a scale | Standard Deviation 6.4 |
| N-Acetylcysteine | Depression | Week 8 | 9.9 units on a scale | Standard Deviation 6.7 |
| Placebo | Depression | Week 4 | 18.5 units on a scale | Standard Deviation 14.8 |
| Placebo | Depression | Week 8 | 19.3 units on a scale | Standard Deviation 15.8 |
Secondary
PTSD Symptoms
PTSD Checklist - Military (PCL-M) The PCL-M is a seventeen question self-report, scored on a scale from 1 to 5, with possible scores ranging from 17 to 85. The scores from each question are summed to get a total score (17-85). A higher total indicates a higher severity of PTSD symptoms.
Time frame: 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| N-Acetylcysteine | PTSD Symptoms | Week 4 | 33.8 units on a scale | Standard Deviation 10.6 |
| N-Acetylcysteine | PTSD Symptoms | Week 8 | 31.2 units on a scale | Standard Deviation 9.7 |
| Placebo | PTSD Symptoms | Week 4 | 41.9 units on a scale | Standard Deviation 21.7 |
| Placebo | PTSD Symptoms | Week 8 | 41.9 units on a scale | Standard Deviation 22.8 |
Comparison: A series of hierarchical linear regression analyses were conducted to examine the effects of treatment group (NAC or placebo) on PTSD symptomatology, craving, substance use, and depression. Baseline levels of the respective outcome measures were entered in Step 1 of the model to adjust for any baseline differences. Treatment group was entered as the predictor in Step 2. The significance threshold was set at a p-value of .05 (two-sided) for all statistical tests.p-value: 0.05Regression, Linear