Steven D. LaRowe

The Role of Cystine-Glutamate Exchange in Nicotine Dependence in Rats and Humans

BACKGROUND The present study determined if, akin to cocaine, nicotine self-administration in rats induces adaptations in the expression of glutamate transporters and cystine-glutamate exchangers in brain nuclei implicated in reinforcement and if treating cigarette smokers with a drug that restores cystine-glutamate exchange affects the number of cigarettes smoked. METHODS Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic minipumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting was performed 12 hours after the last nicotine exposure to determine if the catalytic subunit of the cystine-glutamate exchanger, xCT, or the glial glutamate transporter, GLT-1, were altered in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex, or amygdala. For the smoking reduction study in humans, nicotine-dependent smokers were treated for 4 weeks with N-acetylcysteine (2400 mg daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, and carbon monoxide (CO) measurements and logged daily cigarette and alcohol use. RESULTS Rats receiving nicotine via self-administration or minipumps displayed somatic signs of withdrawal, but only nicotine self-administering rats showed decreased xCT expression in the nucleus accumbens and VTA and decreased GLT-1 expression in the nucleus accumbens. Human smokers treated with N-acetylcysteine reported a reduction in cigarettes smoked, and there was no effect of N-acetylcysteine on estimates of CO levels, craving, or withdrawal. CONCLUSIONS These results indicate that the cystine-glutamate exchanger and the glial glutamate transporter are downregulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.

Safety and Tolerability of N-Acetylcysteine in Cocaine-Dependent Individuals

A double-blind placebo-controlled crossover Phase I trial was conducted to assess the safety and tolerability of N-Acetylcysteine (NAC) in healthy, cocaine-dependent humans. Thirteen participants attended a three-day hospitalization in which they received placebo or NAC. Subjects were crossed over to receive the opposite medication condition during a second three-day hospitalization, which occurred the following week. Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects reporting side effects did not differ. There were trends for a greater reduction in withdrawal symptoms and craving within the NAC condition. These preliminary results suggest that NAC is well tolerated in healthy, cocaine-dependent individuals and may reduce cocaine-related withdrawal symptoms and craving.

Menstrual Cycle Phase Effects on Nicotine Withdrawal and Cigarette Craving: A Review

Evidence suggests that women are less likely to quit smoking than are men. This may reflect differences in nicotine dependence and, more specifically perhaps, nicotine withdrawal and craving. However, there is conflicting research on gender differences on the experience of withdrawal and craving. Menstrual cycle effects may moderate this relationship. Given hormonal changes during the menstrual cycle, abstinence-related symptoms such as withdrawal and craving may vary as a function of menstrual phase as well. This qualitative review summarizes the modest but expanding body of research in this area. One of the challenges inherent in interpreting this literature is the difficulty in distinguishing withdrawal symptomatology from premenstrual symptomatology. Methodological variation, including limited sample size and possible selection bias, in which several studies finding null effects excluded women with severe premenstrual dysphoric disorder, may explain some of the inconsistent findings across studies. Nonetheless, some of the 13 studies included in this review found heightened experiences of withdrawal or craving within the latter days of the menstrual cycle (i.e., the luteal phase). Further research is necessary to replicate these findings, but they may suggest the need for focused cessation treatment during the luteal phase or quit attempts that are well timed relative to specific menstrual phases.

Modafinil: preclinical, clinical, and post-marketing surveillance--a review of abuse liability issues.

Modafinil is an agent that is frequently used in the treatment of narcolepsy. More recently it has been used in the treatment of a variety of psychiatric, neurological, and medical illnesses. Due to its ability to improve wakefulness, modafinil has been viewed as a stimulant. Based on the potential for modafinil to become widely used in a variety of syndromes and settings, evidence from preclinical in vitro and in vivo studies, human laboratory studies, and post-marketing experiences examining the potential abuse liability of modafinil were reviewed. Initial evidence suggests that modafinil has limited potential for large-scale abuse.

Gender Differences in Craving and Cue Reactivity to Smoking and Negative Affect/Stress Cues

There is evidence that women may be less successful when attempting to quit smoking than men. One potential contributory cause of this gender difference is differential craving and stress reactivity to smoking- and negative affect/stress-related cues. The present human laboratory study investigated the effects of gender on reactivity to smoking and negative affect/stress cues by exposing nicotine dependent women (n = 37) and men (n = 53) smokers to two active cue types, each with an associated control cue: (1) in vivo smoking cues and in vivo neutral control cues, and (2) imagery-based negative affect/stress script and a neutral/relaxing control script. Both before and after each cue/script, participants provided subjective reports of smoking-related craving and affective reactions. Heart rate (HR) and skin conductance (SC) responses were also measured. Results indicated that participants reported greater craving and SC in response to smoking versus neutral cues and greater subjective stress in response to the negative affect/stress versus neutral/relaxing script. With respect to gender differences, women evidenced greater craving, stress and arousal ratings and lower valence ratings (greater negative emotion) in response to the negative affect/stressful script. While there were no gender differences in responses to smoking cues, women trended towards higher arousal ratings. Implications of the findings for treatment and tobacco-related morbidity and mortality are discussed.

PTSD and the HPA axis: differences in response to the cold pressor task among individuals with child vs. adult trauma.

Hypothalamic pituitary adrenal (HPA) axis and subjective stress response to a cold-water immersion task, the cold pressor task (CPT), in individuals (N=89) with post-traumatic stress disorder (PTSD) were examined. All tests were conducted at 08:00h after an overnight hospital stay. Plasma adrenocorticotrophin hormone (ACTH), cortisol, and subjective stress were examined at baseline and five post-task time points in controls (n=31), subjects with PTSD as a result of an index trauma during childhood (i.e. before age 18; n=25), and subjects with PTSD as a result of an index trauma as an adult (n=33). Approximately, 50% of individuals in both trauma groups were alcohol dependent, and the impact of this comorbidity was also examined. Subjects with PTSD, regardless of age of index trauma, had a less robust ACTH response as compared to controls. Regardless of the presence or absence of comorbid alcohol dependence, subjects with childhood trauma had lower cortisol at baseline and at all post-task measurement points and did not demonstrate the decrease in cortisol over the course of the 2h monitoring period seen in subjects with adult index trauma and controls. The findings reveal differences in the neuroendocrine response to the CPT in individuals with PTSD compared to control subjects, and differences in PTSD subjects when examined by age of index trauma.

N-Acetylcysteine (NAC) in Young Marijuana Users: An Open-Label Pilot Study

Cannabis use disorders (abuse or dependence) are present in 3.6% of adolescents and 5.9% of young adults, compared with only 0.7% of adults over the age of 25 (1). While a small number of large-scale pharmacotherapy clinical trials targeting cannabis dependence have been undertaken, none have demonstrated significant medication effects on marijuana use and none have focused on young marijuana users (2,3). As such, investigation of novel pharmacotherapeutic agents targeting cannabis dependence in young people is an important focus for research. The neurotransmitter glutamate has emerged as a potential target in the treatment of addictions, including cannabis dependence (4). Within animal studies, the anti-oxidant N-acetylcysteine (NAC) has been shown to reverse drug-induced down-regulation of the cystine-glutamate exchanger (5), which presumably allows for regulation of glutamate release, reducing compulsive drug-seeking behaviors. Consistent with this, preliminary studies have demonstrated significant reductions in cocaine craving (6) and cigarette use (7) during NAC treatment. Taken together, these findings implicate NAC as a potential treatment for addictive disorders, including cannabis dependence. Thus, the purpose of this open-label study was to gather tolerability and preliminary efficacy data for NAC in the treatment of cannabis dependence in young people. Participants were 24 cannabis dependent males (n = 18) and females (n = 6), age range 18–21 (mean age 19 ± SE 0.16) interested in cutting down their marijuana use (i.e., without requirements to quit). Twenty-two were White, one African-American, and one Hispanic. They were required to be medically and psychiatrically stable, have no allergy or intolerance to NAC, have no history of seizures or asthma, and be free of medications known to interact with NAC. Participants were enrolled in a four-week open-label trial of NAC 1200 mg twice daily. A baseline visit was followed by four weekly visits (Weeks 1–4) to assess tolerability and clinical effects. Medication was discontinued at the final (Week 4) visit. Participants were encouraged to gradually reduce marijuana use, but no formal cessation instructions or psychosocial treatments were provided. As assessed by medication adherence logs and weekly pill counts, participants took 82.6% ± SE 2.6% of the scheduled NAC doses during the medication trial. Weekly assessments of adverse events (coded as mild, moderate, or severe) revealed that NAC was generally well tolerated. Fifteen participants (63%) reported at least one adverse event, but all were mild to moderate, and none led to discontinuation of medication. The most common adverse events were abdominal discomfort (5/24), muscle pains/aches (5/24), insomnia (4/24), headache (3/24), nasal congestion/runny nose (3/24), nausea (3/24), weight decrease (3/24), restlessness (3/24), and dizziness (3/24). Marijuana use during the month preceding participation was quantified at the baseline visit using timeline follow-back procedures. From the initial assessment visit forward, daily marijuana use diaries were completed by participants and turned in at weekly visits. During the month preceding the trial, participants reported using marijuana 6.1 ± SE 0.24 days per week. A generalized estimating equation (GEE) analysis revealed a reduction in reported days per week of marijuana use over the course of NAC treatment (overall time effect: p = 0.003). Post-hoc pair-wise comparisons (comparator: baseline visit) revealed significant decrease from baseline in days per week of use during the second (5.2 ± SE 0.33; p = 0.006), third (5.2 ± 0.39 p = 0.001), and fourth (5.3 ± 0.32; p = 0.03) week of NAC treatment. During the month preceding the trial, participants reported using an average of 15.9 ± SE 2.4 potency-adjusted “hits” (8) of marijuana per day, and GEE analysis revealed an overall trend-level reduction in “hits” per day over time (p = 0.07). Average “hits” per day decreased to 14.8 ± SE 1.6 at Week 1, 11.6 ± 1.7 at Week 2, 12.4 ± 2.0 at Week 3, and 11.9 ± 2.1 at Week 4. Pair-wise comparison (comparator: baseline visit) revealed significant reduction at the second week of NAC treatment (p = 0.02). In addition to self-report data, semi-quantitative urine cannabinoid levels (quantitative range 0 to 135 ng/dL) and urine creatinine levels, to determine creatinine-normalized urine cannabinoid levels, were collected at each visit to serve as a biomarker of marijuana use (9). In contrast to self reports, semi-quantitative, creatinine-normalized urine cannabinoid levels did not significantly change over the course of the trial. Of note, though, 13 participants remained above the semi-quantitative urine cannabinoid range (0 – 135 ng/mL) throughout the trial, thus limiting the utility of this measure. Craving for marijuana was measured using the 12-item version of Marijuana Craving Questionnaire (MCQ) (10). The four domains of the MCQ represent four constructs characterizing marijuana craving: Compulsivity (inability to control marijuana use), Emotionality (anticipation of using marijuana to relieve withdrawal or negative mood), Expectancy (anticipation of positive outcomes from smoking marijuana), and Purposefulness (intention and planning to use marijuana for positive outcomes). GEE analyses revealed that participants reported significantly reduced ratings on three of the four MCQ domains over the course of NAC treatment (MCQ Emotionality p < 0.001, Purposefulness p = 0.003, and Compulsivity p = 0.008) (Figure 1). Figure 1 Marijuana Craving Questionnaire (MCQ) domain scores (mean ± SE) over the course of treatment. To our knowledge, this is the first study to date investigating the effects of NAC in young people with cannabis dependence. Results from this preliminary open-label study indicate that treatment with NAC was well tolerated and associated with significant decreases in self-report measures of marijuana use and craving. These reductions parallel those noted in prior NAC treatment studies in cocaine and nicotine dependent individuals (6,7). Although the present findings should be interpreted in light of the limitations of this preliminary study (i.e. open-label study without a control group, limited semi-quantitative urine drug testing), data strongly suggest the need for a more rigorous examination of NAC for treatment of cannabis dependence.

A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence.

BACKGROUND There remains no FDA approved medication for the treatment of cocaine dependence. Preclinical studies and early pilot clinical investigations have suggested that N-acetylcysteine (NAC) may be useful in the treatment of the disorder. OBJECTIVE The present report assessed the efficacy of NAC in the treatment of cocaine dependence. METHODS Cocaine-dependent volunteers (n = 111) were randomized to receive daily doses of 1,200 mg of NAC, 2,400 mg of NAC, or placebo. Participants were followed for 8 weeks (up to three visits weekly). At each of these visits, urine samples were collected, along with self-reports of cocaine use. Urine samples were assessed for quantitative levels of benzoylecognine (ie, cocaine metabolite). RESULTS Overall, the primary results for the clinical trial were negative. However, when considering only subjects who entered the trial having already achieved abstinence, results favored the 2,400 mg NAC group relative to placebo, with the 2,400 mg group having longer times to relapse and lower craving ratings. CONCLUSION While the present trial failed to demonstrate that NAC reduces cocaine use in cocaine-dependent individuals actively using, there was some evidence it prevented return to cocaine use in individuals who had already achieved abstinence from cocaine. SCIENTIFIC SIGNIFICANCE N-acetylcysteine may be useful as a relapse prevention agent in abstinent cocaine-dependent individuals.

Measures of cognitive functioning as predictors of treatment outcome for cocaine dependence

Amlodipine is a calcium-channel antagonist with neuropharmacological properties believed to be protective against cerebral hypoperfusion, microinfarcts, and excitoxic cell death. Based on its pharmacological properties, we hypothesized that amlodipine would be associated with improved attention, processing speed, memory, and executive functioning at treatment follow-up in 84 cocaine-dependent individuals enrolled in a 12-week, placebo-controlled, double-blind clinical trial of amlodipine. We also hypothesized that better cognitive functioning at baseline would be associated with reduced cocaine use (negative urine drug screens) and longer treatment retention (last session attended). Results indicated that amlodipine produced no measurable benefit in cognitive functioning. Percent perseverative errors on Wisconsin Card Sorting Test was negatively correlated with treatment retention (n = 84, r = -.350, p < .01). No other findings were significant. Thus, cocaine-dependent individuals who repeated mistakes and benefited less from corrective feedback on a problem-solving task discontinued treatment earlier. Notably, no other cognitive measures predicted treatment outcome. The observed relationship implicates the relevance of executive functioning to treatment outcome for cocaine dependence.

Menstrual Phase Effects on Smoking Cessation: A Pilot Feasibility Study

BACKGROUND AND OBJECTIVES A growing body of research suggests that nicotine withdrawal and cigarette craving may vary across the menstrual cycle and that the luteal phase of the cycle may be associated with increases in each. This potential relationship suggests that careful timing of quit attempts during the menstrual cycle may improve initial success at abstinence, although there are no direct tests of this approach yet published. Our objectives were to preliminarily test the effect of timing of quit attempts for smoking cessation relative to menstrual cycle and to identify methodological procedures that could guide subsequent, larger clinical trials. METHODS In this pilot study, we randomized female smokers aged 18-40 who were not currently using hormonal contraception to quit smoking during either the follicular (n = 25) or luteal phase (n = 19) of their menstrual cycle. Participants were provided with two sessions of smoking cessation counseling (90 minutes total). All participants were provided with a transdermal nicotine patch contingent on maintenance of abstinence throughout the course of the 6-week study. RESULTS Among participants who initiated treatment, received the patch, and made a quit attempt (n = 35), carbon monoxide-verified repeated point prevalence abstinence 2 weeks after the target quit date was higher in the follicular than the luteal group (32% vs. 19%, respectively; OR = 2.0, 95% CI = 0.4-9.8). Within the overall study population, this difference was slightly lower (24% vs. 16%; OR = 1.7, 95% CI = 0.4-7.8). CONCLUSIONS Timing quit attempts based on menstrual phase is feasible. Insights gained from this study and the recommendations made herein may inform future research on this important clinical question.