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

2 | G a r n e r

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

3 | G a r n e r

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

4 | G a r n e r

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

5 | G a r n e r

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:

6 | G a r n e r

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

7 | G a r n e r

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

8 | G a r n e r

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)

9 | G a r n e r

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

10 | G a r n e r

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

11 | G a r n e r

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

12 | G a r n e r

• 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

13 | G a r n e r

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

14 | G a r n e r

• 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

15 | G a r n e r

• 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

16 | G a r n e r

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

17 | G a r n e r

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

18 | G a r n e r

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

19 | G a r n e r

References 1. American Psychiatric Association. DSM-5 Task Force, American Psychiatric Association. Diagnostic and

Statistical Manual of Mental Disorders: DSM-5. 5th ed. Washington, D.C: American Psychiatric Association; 2013.

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, DSM-IV-TR. American Psychiatric Pub; 2000.

3. Center for Behavioral Health Statistics and Quality. (2016). Key substance use and mental health indicators in the United States: Results from the 2015 National Survey on Drug Use and Health (HHS Publication No. SMA 16-4984, NSDUH Series H-51). Retrieved from http://www.samhsa.gov/data/

4. National Vital Statistics System. Provisional counts of drug overdose deaths, as of 8/6/2017. Centers for Disease Control and Prevention Website: https://www.cdc.gov/nchs/data/health_policy/monthly-drug-overdose-death-estimates.pdf. August 6, 2017. Accessed November 1, 2017.

5. Available at: http://cocaine.org/cocaine/what-is-cocaine-made-of/. Accessed December 9, 2017. 6. Volkow ND, Koob GF, Mclellan AT. Neurobiologic Advances from the Brain Disease Model of Addiction. N

Engl J Med. 2016;374(4):363-71. 7. Koob GF, Le moal M. Addiction and the brain antireward system. Annu Rev Psychol. 2008;59:29-53. 8. Mavridis I. The role of the nucleus accumbens in psychiatric disorders. Psychiatriki. 2015;25(4):282-94. 9. Ranaldi R. Dopamine and reward seeking: the role of ventral tegmental area. Rev Neurosci.

2014;25(5):621-30. 10. Lee BR, Ma YY, Huang YH, et al. Maturation of silent synapses in amygdala-accumbens projection

contributes to incubation of cocaine craving. Nat Neurosci. 2013;16(11):1644-51. 11. Hummel M, Unterwald EM. D1 dopamine receptor: a putative neurochemical and behavioral link to

cocaine action. J Cell Physiol. 2002;191(1):17-27. 12. NIDA. Drugs, Brains, and Behavior: The Science of Addiction. National Institute on Drug Abuse website.

https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction. July 1, 2014. Accessed November 28, 2017.

13. Scofield MD, Kalivas PW. Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. Neuroscientist. 2014;20(6):610-22.

14. Siniscalchi A, Bonci A, Biagio mercuri N, et al. The Role of Topiramate in the Management of Cocaine Addiction: a Possible Therapeutic Option. Curr Neuropharmacol. 2015;13(6):815-8.

15. Kampman KM, Pettinati H, Lynch KG, et al. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend. 2004;75(3):233-40.

16. Carroll FI, Blough BE, Mascarella SW, et al. Bupropion and bupropion analogs as treatments for CNS disorders. Adv Pharmacol. 2014;69:177-216.

17. Haney M, Hart CL, Foltin RW. Effects of baclofen on cocaine self-administration: opioid- and nonopioid-dependent volunteers. Neuropsychopharmacology. 2006;31(8):1814-21.

18. Afshar M, Knapp CM, Sarid-segal O, et al. The efficacy of mirtazapine in the treatment of cocaine dependence with comorbid depression. Am J Drug Alcohol Abuse. 2012;38(2):181-6.

19. González G, Desai R, Sofuoglu M, et al. Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients. Drug Alcohol Depend. 2007;87(1):1-9.

20. Winhusen TM, Somoza EC, Harrer JM, et al. A placebo-controlled screening trial of tiagabine, sertraline and donepezil as cocaine dependence treatments. Addiction. 2005;100 Suppl 1:68-77.

21. Kampman KM, Lynch KG, Pettinati HM, et al. A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence. Drug Alcohol Depend. 2015;155:105-10.

22. Gaval-cruz M, Weinshenker D. Mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv. 2009;9(4):175-87.

23. Work Group on Substance Use Disorders; Kleber HD, Weiss RD, Anton RF, et al. Treatment of patients with substance abuse disorders, second edition. American Psychiatric Association. Am J Psychiatry. 2006:163 (8 suppl):5-82.

20 | G a r n e r

24. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed October 16, 2017.

25. Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015;55:294-321.

26. Mcclure EA, Gipson CD, Malcolm RJ, et al. Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs. 2014;28(2):95-106.

27. 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.

28. Bernardo, M., Dodd, S., Gama, C.S., et al. 2009. Effects ofN-acetylcysteine on substance use in bipolar disorder: a randomised placebo-controlled clinical trial. Acta Neuropsychiatr. 21 (6), 285–291.

29. Grant, J.E., Odlaug, B.L., Kim, S.W., 2010. A double-blind, placebo-controlled study of N-acetyl cysteine plus naltrexone for methamphetamine dependence. Eur.Neuropsychopharmacol. 20 (11), 823–828.

30. Gray, K.M., Carpenter, M.J., Baker, N.L., et al. 2012. A double-blind randomized controlled trialof N-acetylcysteine in cannabis-dependent adolescents. Am. J. Psychiatry 169(8), 805–812.

31. Berk, M., Copolov, D., Dean, O., et al. 2008a. N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial. Biol. Psychiatry 64 (5), 361–368.

32. Berk, M., Copolov, D.L., Dean, O., et al. 2008b. N-acetyl cysteine for depressive symptoms in bipolar disorder– a double-blind randomized placebo-controlled trial. Biol. Psychiatry 64 (6),468–475.

33. Adair, J.C., Knoefel, J.E., Morgan, N., 2001. Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease. Neurology 57 (8), 1515–1517.

34. Berk, M., Dean, O., Cotton, S.M., et al. 2014. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J. Clin. Psychiatry 75,628–636.

35. Mardikian PN, Larowe SD, Hedden S, et al. 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.

36. Larowe SD, Kalivas PW, Nicholas JS, et al. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict. 2013;22(5):443-52.

37. 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.