NAC of all trades, master of none: N-Acetylcysteine for stimulant use disorder (cocaine)
Lindsey M. Garner, Pharm.D, MBA, BCPS PGY-2 Psychiatric Pharmacy Resident
South Texas Veterans Health Care System, San Antonio, TX The University of Texas at Austin College of Pharmacy
Pharmacotherapy Grand Rounds December 15, 2017
Objectives 1. Identify Diagnostic and Statistical Manual (5th ed) criteria for diagnosing stimulant use disorder2. Describe the mechanism of cocaine and its effect on neurotransmitters in the brain3. Evaluate available literature on N-acetylcysteine use in stimulant use disorder (cocaine)4. Defend or refute a recommendation for N-acetylcysteine use in a specific patient
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Introduction to Stimulant Use Disorder I. Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-5)1
a. Stimulant use disorder is specified by the type of stimulant used (i.e. amphetamine and amphetamine-type stimulants, cocaine, or other unspecified stimulants)
b. Diagnostic criteria are as follows: A pattern of amphetamine-type substance, cocaine, or other stimulant use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:
i. The stimulant is often taken in larger amounts or over a longer period than was intended
ii. There is a persistent desire or unsuccessful efforts to cut down or control stimulant use
iii. A great deal of time is spent in activities necessary to obtain the stimulant, use the stimulant, or recover from its effects
iv. Craving, or a strong desire or urge to use the stimulant v. Recurrent stimulant use resulting in a failure to fulfill major role obligations at work,
school, or home vi. Continued stimulant use despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of the stimulant vii. Important social, occupational, or recreational activities are given up or reduced
because of stimulant use viii. Recurrent stimulant use in situations in which it is physically hazardous
ix. Stimulant use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the stimulant
x. Tolerance, as defined by either of the following: 1. A need for markedly increased amounts of the stimulant to achieve
intoxication or desired effect 2. A markedly diminished effect with continued use of the same amount of the
stimulant xi. Withdrawal, as manifested by either of the following:
1. The characteristic withdrawal syndrome for the stimulant (refer to Table 1) 2. The stimulant (or a closely related substance) is taken to relieve or avoid
withdrawal symptoms c. Stimulant use can be classified as episodic, daily, or binge
i. Episodic use tends to be separated by two or more days of non-use ii. Daily use can involve high or low doses, but typically it increases over time
iii. Binges involve continuous high-dose use over hours or days, and are often limited only when stimulant supply runs out or exhaustion sets in
d. Severity of use i. Mild: 2-3 criteria met
ii. Moderate: 4-5 criteria met iii. Severe: 6 or more symptoms
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e. Stimulant intoxication and withdrawal
Table 1. Stimulant intoxication and withdrawal symptoms Intoxication Withdrawal Definition Clinically significant problematic behavioral or
psychological changes that developed during, or shortly after, use of a stimulant
Cessation of (or reduction in) prolonged amphetamine-type substance, cocaine, or other stimulant use
Symptoms Two or more symptoms are required during or shortly after stimulant use: 1. Tachycardia or bradycardia 2. Pupillary dilation 3. Elevated or lowered blood pressure 4. Perspiration or chills 5. Nausea or vomiting 6. Evidence of weight loss 7. Psychomotor agitation or retardation 8. Muscular weakness, respiratory depression,
chest pain, or cardiac arrhythmias 9. Confusion, seizures, dyskinesias, dystonias, or
comas
Dysphoric mood with two or more of the following symptoms: 1. Fatigue 2. Vivid, unpleasant dreams 3. Insomnia or hypersomnia 4. Increased appetite 5. Psychomotor retardation or
agitation
Specifiers With perceptual disturbances (noted when hallucinations with intact reality testing or auditory, visual, or tactile illusions occur in the absence of a delirium)
Not applicable
Cocaine II. Prevalence and impact3-4
a. In a 2015 survey, 896,000 people aged 12 or older reported a cocaine use disorder within the past 12 months1
b. Drug overdose deaths associated with cocaine in the United States in a one year period: i. 2015-2016: 6,986
ii. 2016-2017: 10,619 c. No current FDA approved medications for the treatment of stimulant use disorder (cocaine)
III. Cocaine3, 5, 8-10 a. Stimulant made from leaves of the Coca plant
i. Paste is extracted from the dried Coca leaf using a solvent, such as kerosene ii. The extracted paste is then reconstituted with potassium permanganate, and
diluted with ammonia iii. The precipitated base is then dissolved again, filtered, and mixed with hydrochloric
acid to produce a more pure form of cocaine
NOTE: The studies discussed in this handout use the DSM-IV criteria for Substance Dependence, which is not significantly different from the DSM-V criteria for Substance Use Disorder.1-2
• Main difference is the addition of “craving” to the diagnostic criteria in DSM-V • Terminology changed to Stimulant Use Disorder (cocaine), but this and Substance
Dependence, Cocaine Dependence, and Cocaine use Disorder can be used interchangeably
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iv. Typically used recreationally, but can be used to constrict blood vessels during surgery
b. Alternative names i. Blow
ii. Coke iii. Crack iv. Rock
c. Dosage forms i. Powder
ii. Crystals (“Crack cocaine”) d. How used
i. Insufflation (“snorting”) ii. Injection
iii. Smoking e. Health Effects
Table 2. Health effects of cocaine use Acute Narrowed blood vessels, enlarged pupils, increased blood pressure and
heart rate, headache, nausea and abdominal pain, insomnia, anxiety Chronic Loss of sense of smell, nosebleeds, nasal damage and trouble swallowing
from snorting, infection and/or death of bowel tissue due to decreased blood flow, poor nutrition and weight loss from decreased appetite
Other related issues Risk of HIV, hepatitis, and other communicable diseases from shared needles; Use during pregnancy can result in low birth weight, premature delivery, neonatal abstinence syndrome
f. Mechanism i. Binds to dopamine, serotonin, and norepinephrine transporters
ii. ↑ dopamine, serotonin, and norepinephrine in the presynaptic synapse iii. ↑ dopamine in the mesocorticolimbic pathway, which originates from the ventral
tegmental area (VTA) and projects to the frontal cortex, nucleus accumbens, caudate putamen, olfactory tubercle, hippocampus, and amygdala
iv. Chronic use ↑ extracellular glutamate levels in the nucleus accumbens
Figure 1. Illustration of mechanism of cocaine
Dopamine Dopamine transporter Dopamine receptor Vesicle Cocaine
Presynaptic neuron
Postsynaptic neuron
Presynaptic neuron
Postsynaptic neuron
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g. Benzoylecgonine i. Diagnostic marker of cocaine use
ii. Metabolite of cocaine iii. Typically remains in urine 1-3 days after single use iv. May be present up to 7-12 days after repeated high doses v. Low likelihood of false positives
IV. Brain anatomy of addiction4-10 a. Brain structures9-10
i. Nucleus accumbens 1. Core structure between the amygdala, basal ganglia, mesolimbic
dopaminergic regions, and prefrontal cortex 2. Dopamine is the main neurotransmitter within the nucleus accumbens 3. Plays a key role in food intake, sexual behavior, reward-motivated behavior,
stress-related behavior, and substance-dependence ii. Ventral tegmental area
1. Plays a role in reward pathway 2. Unclear how conditioned stimuli, such as cocaine use, acquires the capacity
to activate the VTA dopamine neurons iii. Amygdala
1. Signals to the nucleus accumbens when the cocaine has run out 2. Results in a persistent cocaine craving, and leads to relapse after withdrawal
iv. Prefrontal cortex 1. Allows for ability to initiate and carry out new and goal-directed behaviors 2. Plays a key role in sustained attention, motor attention, short term
memory, information processing, planning, emotional regulation b. Neurotransmitters8-10
i. Dopamine 1. Plays a role in reward, motivation, pleasure, euphoria, and motor function 2. Enhancing dopamine exposure in the midbrain is responsible for the
euphoria associated with cocaine ii. Glutamate
1. Primary excitatory neurotransmitter 2. Signals from prefrontal cortex to the ventral tegmental area and increases
dopamine release iii. Gamma-aminobutyric acid (GABA)
1. Primary inhibitory neurotransmitter 2. Signals from the nucleus accumbens to the ventral pallidum and ventral
tegmental area which inhibits dopamine release V. American Psychiatric Association Guideline recommended treatment22
a. Psychosocial approaches should be first-line i. Cognitive behavioral therapy
1. Helps patients anticipate problems and enhance self-control 2. Teaches to identify and correct problematic behaviors
ii. Behavioral therapies iii. Psychodynamic and interpersonal therapies iv. Self-help groups and 12-step oriented treatments
b. Pharmacologic treatment options (when combined with psychosocial therapy) that show promise:
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i. Topiramate ii. Disulfiram
iii. Modafinil c. Address co-existing psychiatric disorders (e.g. depressive symptoms)
VI. Table 3. Selected studied therapies for cocaine use disorder
Drug Mechanism Proposed Benefit
Topiramate13-14 ↑ GABA transmission Inhibits glutamatergic transmission ↓ Dopamine release
↓ cocaine use ↓ craving
Bupropion15 Inhibits DA and NE reuptake ↑DA in synapse ↑NE in synapse
↓ cocaine use ↓ craving
Baclofen16 Activates GABAB ↓ Dopamine in nucleus accumbens ↓ cocaine use
Mirtazapine17 ↓ cocaine use by ↓ depressive symptoms ↓ cocaine use Tiagabine18-19 ↑ GABA presynaptically ↓ cocaine use Gabapentin18 ↑ GABA ↓ cocaine use
Modafinil20 ↑ Glutamate (blunts cocaine euphoria) ↓ cocaine use ↓ craving
Disulfiram21 Inhibits dopamine β-hydroxylase ↓ conversion of DA to NE ↓ cocaine use
Introduction to N-Acetyl Cysteine (NAC) VII. Introduction
a. N-Acetyl prodrug of the naturally occurring amino acid cysteine, that acts on the glutamatergic system
b. FDA approved indications23 Brand names: Acetadote, Cetylev, Mucomyst
i. Acetaminophen overdose ii. Mucolytic therapy
c. How supplied: i. Sterile solution for inhalation
ii. Powder for injection iii. Effervescent tablets iv. Capsules
d. Cost (per capsule) i. 600mg capsule: $0.056
ii. 1000mg capsule: $0.26 VIII. Pharmacokinetic and pharmacodynamics of NAC
a. Bioavailability: 4-10% b. Bioavailability: 4-10% c. Time to max effect: ~2 hours d. Protein binding: 66-87% e. Metabolism:
i. Hepatic
Oral forms are associated with a sulfur-like smell
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ii. Deacetylation to cysteine or oxidation to diacetylcysteine f. Excretion
i. Renal: 13-38% ii. Dialyzable by hemodialysis: 51%
g. Half-life: ~18.1 hours IX. Adverse effects
a. Nausea b. Vomiting c. Rash
X. Toxicities a. Insufficient evidence for use in pregnancy b. Not expected to be toxic in pediatric or geriatric populations
XI. Drug interactions a. Nitroglycerin: NAC may increase vasodilatory effects of nitroglycerin b. Others: not well documented
*Note, several medications were used as exclusion criteria in the trials reviewed, but there are no specific indications as to why these medications were chosen, and interactions between these and NAC are not readily available in literature
XII. Monitoring a. Hepatic function (alanine aminotransferase, aspartate aminotransferase, bilirubin, INR) b. Renal function (Creatinine, blood urea nitrogen) c. Blood glucose d. Electrolytes
XIII. Review of studied indications24 (See Appendix A) a. Substance use disorders (nicotine, methamphetamine, cocaine, alcohol) b. Bipolar c. Schizophrenia d. Others
XIV. Theorized mechanisms25-26 a. Oxidative homeostasis:
i. NAC has been used to restore levels of γ-glutamylcysteinylglycine (GSH), as it is the antioxidant precursor to GSH
ii. GSH is released into extracellular space and is broken down into a cysteine-glyceine dipeptide and glutamate
iii. A deficiency in GSH has been associated with increased oxidative stress, and patients with schizophrenia have lower GSH levels in their cerebrospinal fluid
b. Glutamate: i. Cysteine assists in the regulation of neuronal intracellular and extracellular
exchange of glutamate through the cysteine-glutamate antiporter ii. Chronic exposure to addictive drugs is known to decrease the elimination of
glutamate from the extracellular space, and contributes to synaptically released glutamate during reinstated drug seeking
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Clinical question: Is NAC a safe and effective treatment option for patients with cocaine use disorder? XV. Studies
Table 4. An open-label trial of NAC for treatment of cocaine dependence34
Mardikian PN, Larowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(2):389-94.
Objectives To assess the safety and tolerability of three doses of NAC for treatment of cocaine dependence Design & Methods
• Four-week, open-label pilot study • Eligible patients entered a four week medication phase with two visits per week.
Patient Population
Inclusion Exclusion • Treatment-seeking
males and females (18-60 years) who met DSM-IV criteria for cocaine dependence
• Met dependence criteria for any substance other than cocaine, alcohol, nicotine, or marijuana
• Alcohol-=dependent subjects requiring medical detoxification were excluded as well
• Serious medical conditions • Major Axis I psychiatric disorders that would impair ability to
participate safely in the study • Past medical history of asthma or seizures • Subjects who had recently used medications (<14 days) felt to be
hazardous if taken with NAC (e.g. carbamazepine) • Pregnant or nursing females
Study Groups • The first 8 subjects were given 600mg NAC BID (1200mg/day) • After these patients demonstrated sufficient tolerance, the next 9 subjects were given
1200mg NAC BID (2400mg/day) • After these patients demonstrated tolerance at this dose, the final 6 patients were given
1200mg NAC TID (3600mg/day) • Of these 23 patients who took at least one dose of medication, 7 failed to complete the trial.
Outcomes • Primary: overall tolerability and safety of medication, retention and compliance • Secondary: self-reported cocaine use (as verified by urine drug screens), and self-reported
cocaine abstinence symptoms Statistical Analysis
• Safety data were examined qualitatively for all subjects using counts of adverse effects • Proportion of subjects reporting at least one adverse event as well as retention rates were
compared between groups using Chi Square • Cocaine use and measure of abstinence symptoms were evaluated using only the subjects
completing the entire 4-week trial Baseline
Characteristics Table 4a. Baseline characteristics
Demographic Variables Completers (n=16)
Non-completers (n=7)
% Male 100 85.7 Mean age in years (SE) 39.2 (1.7) 41.3 (2.6) % African American 50 42.9 % Alcohol dependence 25 28.6 % Marijuana users 43.8 57.1 % Nicotine users 68.5 85.7 # of days of cocaine use (SE) 8.3 (1.4) 9 (1.3)
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Dollars spent on cocaine during 28 d prior to treatment (SE)
1292.8 (768.9) 847.7 (182.8)
Years of cocaine use (lifetime) (SE) 12.6 (1.6) 14.9 (3.3)
Results • Of the 44 subjects who consented to participate, eight were excluded for the following reasons: one was court ordered to receive drug treatment, three subjects presented with unstable medical conditions, three subjects were experiencing suicidal thoughts, and one subject had a history of asthma
• No serious adverse effects occurred and no patients were discontinued due to medication intolerance
Table 4b. Side effects reported in each NAC dosage group Side effect 1200 mg/d (n=8) 2400 mg/d (n=9) 3600 mg/d (n=6) Pruritus 4* 2** 0 Headache 1 2** 3*** High BP 0 0 5* Stomachache 1 1 2** Fatigue 0 2** 2** Insomnia 1 0 0 Dry Mouth 0 2** 0 Lightheaded 0 1 0 Sinus congestion 0 1 0 Palpitation 0 1 0 Diminution sexual arousal 0 0 1 Total 7 12 13
*All instances reported by one subject. **One instance reported by two separate subjects ***One subject reported symptom twice, one additional subject reported once.
• The baseline mean total days of use (totaled regardless of NAC group), was clinically and statistically different compared to during treatment (8.1 days vs. 1.1; p=0.001)
Table 4c. Results NAC 1200mg/d
(n=3) NAC 2400mg/d
(n=8) NAC 3600 mg/d
(n=5) # days of cocaine use at baseline; mean (SE)
11.3 (1.5) 4.3 (0.8) 12.2 (5.9)
# days of cocaine use during treatment; mean (SE)
0.7 (0.7) 0.9 (0.4) 1.6 (1.2)
% Positive UDS during treatment (SE) 0 (0) 22.5 (11.5) 25.7 (19.4)
Conclusions This open-label study suggests that all three doses of NAC were safe and well tolerated by treatment-seeking cocaine-dependent subjects. Although no there were no statistically different side effects between groups, a qualitative review suggests that the higher doses of NAC may have a higher frequency of side effects.
Presenter Critique
Strengths Weaknesses • Established tolerability at multiple doses • Broke down side effect reporting by #
patients
• Not blinded • No adherence measures such as riboflavin • Population was primarily male
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Table 5. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence34
Larowe SD, Kalivas PW, Nicholas JS, Randall PK, Mardikian PN, Malcolm RJ. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict. 2013;22(5):443-52.
Objectives To assess the efficacy of NAC in the treatment of cocaine dependence Design & Methods
• Randomized, double blind, placebo controlled study • Treatment-seeking adult males and females who met DSM-IV criteria for cocaine dependence
Patient Population
Inclusion Exclusion • Help-seeking males and
females meeting DSM-IV criteria for cocaine dependence
• Willing to attend research visits three times weekly
• Participate in weekly counseling for cocaine dependence
• Required medical detoxification from alcohol • Met dependence criteria for any substance other than
alcohol, nicotine, or marijuana • Females who were pregnant or nursing • Serious medical conditions • Psychiatric disorders that would impair ability to
participate safely in the study • Past medical history of asthma or seizures • Recent use (<14 days) of medications felt to be hazardous
if taken with NAC Study Groups • Daily dose of 1200mg NAC (600mg BID) (n = 43)
• Daily dose of 2400mg NAC (1200mg BID) (n = 41) • Identically appearing and smelling placebo (n = 42)
Outcomes • Timeline follow back (TLFB) – assessed self-reported cocaine use (in number of days) occurring in the 30 days prior to engaging in the treatment study
• Riboflavin levels – used to assess compliance as each capsule (both medication and placebo) contained 50mg riboflavin
• Evaluation of side effects and adverse events – participants reported at each visit any and all physical symptoms, side effects, and adverse events experienced
• Urine screens for quantitative benzoylecognine (BE) levels – urine samples were analyzed for quantitative levels of BE at each research visit
• Days of confirmed abstinence – participant reported days of use and non-use of cocaine, and reports were verified using urine drug screens
• Brief substance craving scale (BSCS) – includes three items on a 5-point Likert scale that assesses intensity, length, and frequency of cocaine craving
• Cocaine selective severity assessment (CSSA) – an 18 item clinician-administered instrument that assesses severity of early cocaine abstinence symptoms
Statistical Analysis
• Baseline characteristics were evaluated using one-way ANOVAs for continuous variables, χ2 and Fisher Exact tests for categorical data, and Cox regression for time to drop out
• Group differences in frequencies of participants reporting side effect were analyzed using χ2 and Fisher exact tests
• Generalized Estimating Equations (GEE) method was used to determine whether NAC reduced overall weekly cocaine use. Independent variables included treatment group (between-subjects variable) and treatment week (repeated-measure, within-subject variable)
• Mean weekly log transformed benzoylecognine (BE) levels, craving, and measures of cocaine withdrawal were analyzed using a 2-way GEE model
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Baseline Characteristics
Table 5a. Baseline characteristics Placebo 1200mg 2400mg P value Group Total (n) 38 40 33 ---- Male (n) 28 30 25 0.98 # Positive for cocaine at 1st visit (n) 27 30 24 0.93 More than 10 days use at Baseline (n) 22 26 24 0.43 Non-white (n) 23 21 19 0.77 Mood DO (n) 11 10 7 0.76 Anxiety DO (n) 5 3 0 0.10 ETOH Abuse/dependence (n) 14 15 11 0.95 Smoked cocaine (n) 25 29 26 0.64 High baseline use (n) 18 22 18 0.76 Mean (SD) Age (years) 42.8 (8.7) 43.5 (10.1) 43.3 (8.9) 0.93 Years education 13.0 (1.9) 12.6 (2.6) 13.5 (2.1) 0.25 Years cocaine use 12.5 (7.8) 15.9 (8.0) 14.2 (8.3) 0.18 Years ETOH use 20.3 (11.6) 20.0 (13.3) 19.8 (11.5) 0.99
Results • Number of 8 week completers was 25, 25, and 21 in the placebo, 1200mg NAC, and 2400mg NAC groups respectively. Mean number of weeks completed was 6.9 (SD=1.8), 6.6 (SD=2.0), and 6.7 (SD=1.9) for each group respectively
• Based on riboflavin monitoring, groups did not differ with respect to percent compliance. The overall mean compliance was 70.8% (SD=31.0)
• Reported adverse effects were not statistically different between groups • Most commonly reported were gastrointestinal symptoms (including heartburn, flatus, and
cramps), headache, and dermatological • There was no difference in the number of participants reporting any side effects between
groups • There were no between-group differences in BE levels, but BE levels changed over time and
were significant at particular treatment weeks
Figure 5a. Benzyolecognine levels in low vs. high baseline cocaine users across 8 treatment weeks
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• Relapse prevention exploratory analysis found 2400mg to give the highest chance of maintaining sobriety
Figure 5b. Exploratory analysis of time to relapse for patients who were abstinent for at least one week prior to treatment
Conclusions This study failed to demonstrate that NAC reduces cocaine use among cocaine dependent individuals who are actively using cocaine.
Presenter Critique
Strengths Weaknesses • Larger number of participants included • Well matched groups with more
females than other trials • Appropriate blinding
• No subgroup analysis on alcohol use • May have been stronger if only two randomized
groups instead of three • Outcomes were not well defined
Table 6. A randomized controlled trial of NAC for PTSD and Substance use disorders36
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;77(11):e1439-e1446.
Objectives To assess the efficacy of NAC in the treatment of posttraumatic stress disorder (PTSD), which frequently co-occurs with substance use disorder and shares impaired prefrontal cortex regulation of the basal ganglia circuitry, in particular at glutamate synapses in the nucleus accumbens
Design & Methods
• Randomized, double blind, placebo controlled • Veterans with PTSD and substance use disorder per DSM-IV criteria were randomly assigned
to receive an 8 week course of NAC (2400mg/d) or placebo plus cognitive-behavioral therapy for SUD
Patient Population
Inclusion Exclusion • Enrolled in the Substance Abuse
Treatment Clinic at the study VA • Unstable medical conditions • Significant cognitive impairment • Bipolar or psychotic disorders
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between March 2014 and April 2014
• Aged 18-65 years • US military veterans • Met DSM-IV criteria for the past
six months for SUD and PTSD • Scored >21 on MMSE
• Seizures or asthma • Prior treatment with NAC • Ongoing PTSD treatment • Or use of carbamazepine, phenytoin, nitrous oxide,
methotrexate, or nitroglycerin within the past 14 days • Female participants could not be pregnant or lactating
Study Groups • NAC 2400mg/d (n=18) • Placebo (n=17) • Both groups used capsules containing riboflavin 25mg to track adherence • All groups went through cognitive-behavioral therapy
Outcomes • Primary outcome measures included PTSD symptoms (Clinician-administered PTSD Scale, PTSD Checklist-Military) and craving (visual analog scale)
• Substance use (cocaine, alcohol, and marijuana) and depression were also assessed Statistical Analysis
• Demographic characteristics were compared using χ2 tests for categorical variables and t tests for continuous variables
• Secondary analyses examined the effect of NAC on substance use and depression • A series of linear regression analyses were conducted to examine the effects on PTSD
symptomatology, craving, substance use, and depression • Paired t tests were used to examine within group changes in PTSD symptoms, depressive
symptoms, craving, and substance use Baseline
Characteristics Table 6a. Baseline characteristics
Placebo (n=14), n (%)
NAC (n=13), n (%)
Total (N=27), n (%)
Gender, male 14 (100) 12 (92.3) 26 (96.3) Race, white 4 (28.6) 4 (30.8) 8 (29.6) Race, African-American 10 (71.40 9 (69.2) 19 (70.4) Education, at least some college 6 (42.9) 9 (69.2) 15 (55.5) Military, combat trauma 2 (14.3_ 3 (23.1) 5 (18.5) Military, non-combat trauma 4 (28.6) 5 (38.5) 9 (33.3) Civilian-related trauma 8 (57.1) 5 (38.5) 13 (48.1) Alcohol Use Disorder 12 (85.7) 10 (76.9) 22 (21.5) Cocaine Use Disorder 9 (64.3) 11 (84.6) 20 (74.1) Opioid Use Disorder 1 (7.1) 0 (0) 1 (3.7) Mean (SD) Age, years 49.9 (8.1) 48.2 (8.6) 49 (8.2) PCL-M Total Score 43.4 (18.6) 45.7 (14.6) 44.5 (16.5) CAPS Total Score 68.6 (23.7) 58.8 (21.2) 63.8 (22.6) BDI-II Total Score 22.8 (13.1) 19.1 (6.7) 21.0 (10.5)
Results • The majority of randomized patients (77%) completed the 8-week treatment phase, and there were no group differences in retention
• Medication compliance, as measured by ≥1000ng/mL of riboflavin, was 82.9% and did not differ by groups
• The PCL-M (self-reported PTSD symptoms) was reduced by 32% in the NAC group verses 3% in the placebo group from baseline to week 8
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• The CAPS was reduced by 46% in the NAC group verses 25% in the placebo group from baseline to week 8
• Amount of craving was reduced by 81% in the NAC group as compared to 32% in the placebo group from baseline to week 8. Subjective craving reports over 8 weeks are illustrated in the figure 6a below
Figure 6a. Patient reported cocaine craving in placebo and NAC groups *indicates p<0.05 (statistically significant) • At week 12 follow up, the NAC group reported significantly lower frequency of craving than
the placebo group (p<0.05) • Substance use was low in both groups, and there were no significant between-group
differences • The BDI-II was reduced by 48% in the NAC group verses 15% in the placebo group from
baseline to week 8 Table 6b. Results of measured symptom scales
Placebo (n=14) within-group outcomes
NAC (n=13) within-group outcomes
Between Groups
Measure Mean (SD) Week 0 Week 4 Week 8 Week 0 Week 4 Week 8 Weeks 0-8
PCL-M 43.4 (18.6) 41.9 (21.7) 41.9 (22.9) 45.7 (14.6) 33.8 (10.6) 31.2 (9.7) -0.355 CAPS 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 BDI-II 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 Craving-A 4.1 (3.1) 2.8 (2.6) 2.38 (2.8) 3.7 (3.4) 1.8 (1.9) 0.7 (0.7) -0.413 Craving-F 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 Craving-I 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
Conclusions NAC combined with CBT significantly reduced PTSD symptoms and craving. NAC produced reductions in craving that were more than 2.5 times the magnitude of placebo.
Presenter Critique
Strengths Weaknesses • Placebo controlled • Measured adherence
• Small trial • Primarily men • Primary outcomes related to PTSD rather than SUD • SUD inclusion criteria were both for alcohol and cocaine
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• Side effects not reported • Results were difficult to interpret (presented in paragraph form)
Summary and Conclusions34-36 • NAC is overall safe and well tolerated • When considering for patients with cocaine use disorder, it may be a reasonable option if the
patient is also engaged in psychosocial interventions • Oral doses of 1200-2400mg per day are typically well tolerated with minimal side effects
Trial Safe? Effective? ↓ Cravings ↓ Cocaine use Relapse prevention
Mardikian 2007 Yes --- Yes --- Larowe 2013 Yes Yes Yes* Yes (for 2400mg)
Back 2016 Yes Yes No --- *Only for patients with low baseline use receiving 1200mg NAC daily
• Head to head trials of NAC with other medications being studied for cocaine use disorder would be helpful for decision making purposes
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Appendix A. Controlled trials of NAC for miscellaneous disease states27-33
Key available in Appendices B and C.
Authors Disease State # participants per group
Study Design Treatment Intervention
Outcome measure Effect of NAC Adverse effects
Bernardo et al. 2009
Nicotine NAC: 38 PB: 37
DBPC parallel 1-2g NAC or PB for 24 weeks
CGI-SU (alcohol, tobacco, caffeine)
No change in alcohol and tobacco use; significant decrease in caffeine use in NAC group at week 2
Not reported
Grant et al. 2010 Methamphetamine NAC: 14 PB: 17
DBPC parallel Up to 2.4g/d NAC + 200mg naltrexone or PB for 8 weeks
Penn Craving Scale, CGI, UDS, frequency of use
No significant differences
None
Gray et al. 2012 Cannabis NAC: 58 PB: 58
DBPC parallel 2.4g/d NAC or PB for 8 weeks
Urine cannabinoid testing
OR in favor of NAC Vivid dreams, irritability, severe heartburn
Berk et al. 2008a Schizophrenia NAC: 69 PB: 71
DBPC parallel 2g/day NAC or PB for 4 months
PANSS, CGI, GAF, SOFAS, BAS, SAS, AIMS
Improvement on CGI, PANSS, but no other outcome measures
Not significant
Berk et al. 2008b Bipolar Disorder NAC: 38 PB: 37
DBPC parallel 1g NAC BID for 24 weeks or PB
MADRS, BDRS, YMRS, CGI, GAF, SOFAS, SLICE-LIFE, LIFE-RIFT, Q-LES-Q
Moderate-to-large effect on MADRS and BDRS
Changed energy, headaches, increased joint pain, heartburn, 3 serious AEs
Adair et al. 2001 Alzheimer’s Disease NAC: 23 PB: 20
DBPC parallel 50mg/kg/day NAC in 3 divided doses for 24 weeks or PB
MMSE, ADL, cognitive battery
Improvement in some cognitive tests
Transient headaches
Berk et al. 2014 Depressive Disorder NAC: 127 PB: 125
DBPC parallel 1g BID NAC for 12 weeks or PB add on to usual treatment
MADRS, CGI-I, CGI-S, HARS, GAF, SOFAS, SLICE/LIFE, LIFERIFT, Q-LES-Q at 12 weeks and 4 week post discontinuation
No significant effect on MADRS, response rate, remission rate at 12 week, but significant effect at 16 weeks
Gastrointestinal and musculoskeletal AE
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Appendix B. Commonly used rating scales for substance use Name Description Results / Interpretation
Abnormal Involuntary Movement Scale (AIMS)
• Clinician-administered; 12 item • Qualifies involuntary movements • Measurements include facial/oral
movements, global judgement and dental status
Scoring: 0 (none) 4 (severe) Items 11/12 are yes/no • Score range: 0-40 • Higher scores = more involuntary movement
Barnes Akathisia Scale (BAS)
• Clinician-administered; 4 item • Determines akathisia presence
• Objective akathisia: score 0-3 • Subjective awareness: score 0-3 • Distress of patient: score 0-3 • Global: score 0-5 • ≥2 indicates akathisia
Brief Substance Craving Scale (BSCS)
• Clinician-administered; 4 item • Assesses intensity, frequency, length,
and number of cravings in a 24 hour period
Score: 0 (none) 4 (extreme)
Clinical Global Impressions Scale (CGI)
• Clinician or patient administered • Rated relative to the past week • CGI-Severity: how mentally ill is the
patient at this time? • CGI-Improvement: measures response
after medication initiated
• CGI-S: 1 (normal) 7 (amongst the most extremely ill)
• CGI-I (very much improved since initiation of medication) 7 (very much worse since initiation of medication)
Cocaine Selective Severity Assessment (CSSA)
• Clinician administered; 18 item • Assesses symptoms associated with
early cocaine abstinence • Depression, fatigue, anhedonia,
anxiety, irritability, sleep disturbance, concentration
Scoring: 0 (none) 7 (significant sx)
Hamilton Depression Scale (HAM-D)
• Clinician-administered; 17 item • Used to assess response to treatment • Reviews patient-reported symptoms
over the past week
Scoring: 0 (absent) 4 (very severe) • 0-7: Normal • 8-13: Mild depression • 14-18: Moderate depression • 19-22: Severe depression • ≥23: Very severe depression
Montgomery-Asberg Depression Rating Scale (MADRS)
• Clinician-administered; 10 item • Assesses response to depression
treatment • Also used for measuring severity of
bipolar depression
Scoring: 0 (absent) 6 (severe) • 0-6: No symptoms • 7-19: Mild depression • 20-34: Moderate depression • 35-60: Severe depression
Positive and Negative Syndrome Scale (PANSS)
• Clinician-administered; 30 item • Assesses psychosis symptoms and
response • Subscale: positive, negative, general
psychopathology
Scoring: 1 (not present) (extremely severe) Score range: 30-210 (usual scores 60-150) Response: 20-30% ↓ in symptoms Remission: Score ≤3 for ≥6 months on each selected item
Simpson Angus Scale (SAS)
• Clinician-administered; 10 item • Used to screen Parkinson’s disease and
other EPS • Assess gait, arm dropping, shoulder
shaking, elbow rigidity, wrist rigidity or fixation of position, leg pendulousness, head dropping, glabella tap, tremor
Scoring: 0 (absent) 4 (most extreme form) Global score: sum of score/total items • <0.3: normal range
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Appendix C. Abbreviations used
Abbreviation Full Name ADL Activities of daily living AE Adverse effects AIMS Abnormal Involuntary Movement Scale BAS Barnes Akathisia Scale BDRS Bipolar Depression Rating Scale BE Benzoylecognine BSCS Brief Substance Craving Scale CGI Clinical Global Impression Severity Scale CGI-I Clinical Global Impression - Improvement CGI-S Clinical Global Impression Severity CGI-SU Clinical Global Impression - Substance Use CSSA Cocaine Selective Severity Assessment DA Dopamine DBPC Double Blind Placebo Controlled DSM Diagnostic and Statistical Manual of Mental Disorders GAF Global Assessment of Functioning GEE Generalized Estimating Equations HARS Hamilton Anxiety Rating Scale LIFE-RIFT Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool MADRS Montgomery-Asberg Depression Scale MMSE Mini-Mental Status Examination NAC N-Acetyl Cysteine OR Odds Ratio PANSS Positive and Negative Syndrome Scale PB Placebo PTSD Posttraumatic Stress Disorder Q-LES-Q Quality of Life Engoyment and Satisfaction Questionairre SAS Simpson-Angus Scale SLICE-LIFE Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation SOFAS Social and Occupational Functioning Assessment Scale SUD Substance Use Disorder UDS Urine Drug Screen VTA Ventral Tegmental Area YMRS Young Mania Rating Scale
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