N-Acetyl Cysteine Plus Behavioral Therapy for Nicotine Dependent Pathological Gamblers

The objective of this application is to examine whether, given its mechanism of action, the dietary supplement, N-acetyl cysteine (NAC) will reduce both tobacco use and pathological gamblers (PG) symptoms in nicotine dependent pathological gamblers.

Among US adults, 12.8% report nicotine dependence, and nicotine dependence is highly associated with a variety of DSM-IV Axis I and II disorders (Grant BF et al., 2004). Pathological gambling (PG), a serious public health problem with detrimental effects on individuals and families, and with an estimated yearly cost to society of 5 billion dollars due to lost jobs, debt, bankruptcy, and incarcerations, is associated with elevated proportions of nicotine dependence (41% - 55%), and tobacco smoking in clinical samples of pathological gamblers has been associated with increased gambling severity and more frequent psychiatric problems (Smart \& Ferris, 1996; Crockfod \& El-Guebaly, 1998; Shaffer et al., 1999; Petry \& Oncken, 2002; Potenza et al., 2004; Grant et al., 2005; Falk et al., 2006; Fagan et al., 2007). In addition, research suggests that continued nicotine use is associated with greater rates of relapse among pathological gamblers who received behavioral therapy. Despite increased awareness of the relationship between nicotine dependence and PG, and the possible effects of nicotine dependence on gambling severity, no previous research has focused on how assessment and treatment of nicotine dependence may aid in the successful treatment of PG or smoking cessation. Preliminary research suggests that behavioral therapy using imaginal desensitization and motivational interviewing (IDMI) has shown promise in reducing the symptoms of PG (Grant et al., in press). Despite the efficacy of treatments for PG and nicotine dependence, relapse is common among individuals with nicotine dependence and PG. Preclinical studies have suggested that levels of glutamate within the nucleus accumbens mediate reward-seeking behavior and may underlie relapse seen in addictions. N-acetyl cysteine, a dietary supplement, amino acid and cysteine pro-drug, appears to modulate glutamate within the nucleus accumbens and has shown benefit in reducing the reward-seeking behavior in individuals with cocaine dependence and in pathological gamblers (Baker et al., 2003; LaRowe et al., 2006; Grant et al., 2006). If successful in treating nicotine dependent pathological gamblers, N-acetyl cysteine may serve as a viable, low-cost, and easily available treatment option for nicotine dependent pathological gamblers who receive behavioral therapy.

We therefore propose to examine how a dietary supplement, N-acetyl cysteine, used in combination with behavioral therapy, will affect both the urge to smoke and gamble in nicotine dependent pathological gamblers and smoking and gambling behaviors. We therefore propose a randomized placebo-controlled trial of N-acetyl cysteine or placebo with 80 nicotine dependent pathological gamblers who will all receive brief standardized smoking cessation treatment (Ask, Advise, and Refer model) for nicotine cessation and 6 sessions of IDMI for PG. We hypothesize that N-acetyl cysteine plus behavioral therapy will result in greater reduction in both nicotine dependence and PG symptoms during the acute treatment phase and will enhance greater long-term abstinence. Our research will contribute to an improved understanding of the treatment of nicotine-dependent pathological gamblers as well as a greater understanding of the treatment of co-occurring addictions. If our intervention is successful, it will have the potential to set a new standard of care for a range of psychiatric disorders that co-occur with nicotine dependence.

Eligibility Criteria:
Inclusion Criteria:

1. Male and female outpatients, age 18-75 years;
2. Presence of current DSM-IV nicotine dependence and PG for at least 6 months duration;
3. Stable psychotropic drug dose for a period of at least 3 months prior to study entry;
4. Completion of complete blood count, urinalysis, liver function tests, thyroid function tests, and pregnancy test with no evidence of significant lab abnormalities;
5. Signed informed consent

Exclusion Criteria:

1. Subjects who are currently receiving individual or group therapy specifically for nicotine dependence or PG symptoms;
2. Currently receiving pharmacotherapies for either nicotine dependence or pathological gambling;
3. Subjects who have started attending Gamblers Anonymous within the 3 months prior to study initiation;
4. Subjects who have an unstable and significant medical illness;
5. Current clinically significant suicidality (score or 3 or 4 on item 3 of the Hamilton Depression Rating Scale) or any other disorder requiring immediate intervention;
6. Lifetime history of bipolar disorder type I or II, dementia, or psychotic disorder;
7. Current (past 12 months) DSM-IV substance abuse or dependence (except nicotine dependence);
8. Borderline or antisocial personality disorder based on the SCID-II;
9. Positive urine drug screen at screening;
10. Asthma (given possible worsening of asthma due to NAC);
11. Cognitive impairment that interferes with the capacity to understand and self-administer medication or provide written informed consent;
12. Current pregnancy or lactation, or inadequate contraception in women of childbearing potential; and
13. Previous treatment with NAC