IMPORTANCE Adult attention-deficit/hyperactivity disorder (ADHD) is prevalent but often unrecognized, in part because it tends to co-occur with other disorders such as substance use disorders. Cocaine use disorder is one such disorder with high co-occurrence of ADHD.OBJECTIVE To examine whether treatment of co-occurring ADHD and cocaine use disorder with extended-release mixed amphetamine salts is effective at both improving ADHD symptoms and reducing cocaine use. DESIGN, SETTING, AND PARTICIPANTSThirteen-week, randomized, double-blind, 3-arm, placebo-controlled trial of participants meeting DSM-IV-TR criteria for both ADHD and cocaine use disorder conducted between December 1, 2007, and April 15, 2013, at 2 academic health center substance abuse treatment research sites. One hundred twenty-six adults diagnosed as having comorbid ADHD and cocaine use disorder were randomized to extended-release mixed amphetamine salts or placebo. Analysis was by intent-to-treat population.INTERVENTIONS Participants received extended-release mixed amphetamine salts (60 or 80 mg) or placebo daily for 13 weeks and participated in weekly individual cognitive behavioral therapy. MAIN OUTCOMES AND MEASURESFor ADHD, percentage of participants achieving at least a 30% reduction in ADHD symptom severity, measured by the Adult ADHD Investigator Symptom Rating Scale; for cocaine use, cocaine-negative weeks (by self-report of no cocaine use and weekly benzoylecgonine urine screens) during maintenance medication (weeks 2-13) and percentage of participants achieving abstinence for the last 3 weeks. RESULTSMore patients achieved at least a 30% reduction in ADHD symptom severity in the medication groups (60 mg: 30 of 40 participants [75.0%]; odds ratio [OR] = 5.23; 95% CI, 1.98-13.85; P < .001; and 80 mg: 25 of 43 participants [58.1%]; OR = 2.27; 95% CI, 0.94-5.49; P = .07) compared with placebo (17 of 43 participants [39.5%]). The odds of a cocaine-negative week were higher in the 80-mg group (OR = 5.46; 95% CI, 2.25-13.27; P < .001) and 60-mg group (OR = 2.92; 95% CI, 1.15-7.42; P = .02) compared with placebo. Rates of continuous abstinence in the last 3 weeks were greater for the medication groups than the placebo group: 30.2% for the 80-mg group (OR = 11.87; 95% CI, 2.25-62.62; P = .004) and 17.5% for the 60-mg group (OR = 5.85; 95% CI, 1.04-33.04; P = .04) vs 7.0% for placebo.CONCLUSIONS AND RELEVANCE Extended-release mixed amphetamine salts in robust doses along with cognitive behavioral therapy are effective for treatment of co-occurring ADHD and cocaine use disorder, both improving ADHD symptoms and reducing cocaine use. The data suggest the importance of screening and treatment of ADHD in adults presenting with cocaine use disorder. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00553319

Background No medication is currently approved for the treatment of cocaine dependence, but several preclinical and clinical reports suggest agonist-like medications, e.g. amphetamine analogues, may be a productive strategy for medication development. Objective This current proof-of-concept study sought to evaluate the safety, tolerability, and effectiveness of methamphetamine as a candidate treatment for cocaine dependence. Methods A randomized, double-blind, placebo-controlled study served to evaluate three treatment conditions in 82 cocaine-dependent individuals: (1) placebo (0 mg, 6×/day; n = 27), (2) immediate release (IR) methamphetamine (5 mg, 6×/day; n = 30), (3) sustained release (SR) methamphetamine (30 mg first pill, 1×/day; 0 mg 5×/day; n = 25). The study employed a sequential, two-phase design (i.e., 4 weeks of medication and counseling followed by 4 weeks of medication/counseling plus a contingency management procedure). Results Both preparation forms of methamphetamine were well tolerated, with similar retention to placebo (0 mg, 33%; 30 mg IR, 30%, 30 mg SR, 32%). Methamphetamine SR was associated with decreased sleep and increased weight loss. Medication adherence rates were high for the first dose of the day (95%), while adherence for subsequent capsules was lower. Those in the SR condition exhibited consistently lower rates of cocaine-positive urine samples (0 mg, 60%; 30 mg IR, 66%, 30 mg SR, 29%), p<0.0001, and reported the greatest reduction in craving for cocaine, p<0.05. Conclusions SR methamphetamine significantly reduced cocaine use and craving. Additional research is warranted to develop and evaluate agonist-like medications that may effectively treat cocaine dependence.

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Smokeless tobacco has been proposed as a reduced risk substitute for smoking, but no large studies have investigated exposure to the powerful carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokeless tobacco users versus smokers. The purpose of this study was to carry out such a comparison. Levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of NNK exposure, and cotinine, a biomarker of nicotine exposure, were quantified in the urine of 420 smokers and 182 smokeless tobacco users who were participants in studies designed to reduce their use of these products. The measurements were taken at baseline, before intervention. Levels of total NNAL per milliliter of urine were significantly higher in smokeless tobacco users than in smokers (P < 0.0001). When adjusted for age and gender, levels of total NNAL per milligram of creatinine were also significantly higher in smokeless tobacco users than in smokers (P < 0.001). Levels of cotinine per milliliter of urine and per milligram of creatinine were significantly higher in smokeless tobacco users than in smokers (P < 0.001). These results show similar exposures to the potent tobaccospecific carcinogen NNK in smokeless tobacco users and smokers. These findings do not support the use of smokeless tobacco as a safe substitute for smoking. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1567 -72)

Nicotine replacement therapies (NRTs) represent an effective means of promoting smoking cessation, but they remain underutilized. Negative attitudes and false beliefs about nicotine and nicotine replacement may cause NRT underutilization. In a randomized, controlled, single-blind study of nicotine gum, 97 smokers were assessed on their attitudes and knowledge about nicotine, nicotine replacement, and smoking cessation therapy. Information from these self-report measures was used in an intervention that provided tailored, brief feedback to promote positive attitudes and accurate knowledge about NRT. Considerable variability in pretreatment attitudes and knowledge was observed across individuals. Moreover, attitudes and knowledge showed a consistent pattern of intercorrelation and were systematically related to smoking characteristics (e.g., prior use of NRT, nicotine dependence, treatment completion). The brief feedback intervention led to a significant global elevation in attitudes about nicotine, NRT, and assisted cessation but not knowledge about nicotine. Changes in attitudes and knowledge were not significantly related to gum use or smoking cessation. Recommendations for the appropriate application of brief feedback are offered.

Background: The dopamine precursor levodopa has shown some, albeit relatively weak, promise in treating cocaine dependence. This study sought to identify the most appropriate behavioral therapy platform for levodopa pharmacotherapy by evaluating its effect when administered in combination with behavioral platforms of varying intensities. Method:A total of 161 treatment-seeking cocaine dependent subjects received sustained release levodopa/carbidopa (400/100 mg bid, Sinemet) or placebo delivered in combination with Clinical Management (ClinMan); ClinMan+Cognitive Behavioral Therapy (CBT); or ClinMan+CBT +Voucher-Based Reinforcement Therapy (VBRT) in a 12-week randomized, placebo-controlled, double-blind (for medication condition) trial. Medication compliance was monitored with riboflavin (100 mg/capsule) and the Medication Event Monitoring System. Protocol compliance was addressed in weekly, 10-minute nurse-delivered ClinMan sessions. Weekly, 1-hour CBT sessions focused on coping skills training. VBRT (with escalating reinforcer value) provided cash-valued vouchers contingent on cocaine-negative urine toxicology results. Urine benzoylecgonine assays collected thrice-weekly were analyzed by intention-to-treat criteria using generalized linear mixed models.Results: Levodopa main effects were found on all outcome measures of cocaine use. Contrasts testing the levodopa-placebo difference within each behavioral platform found reliable effects, favoring levodopa, only in the VBRT platform. Levodopa treatment with vouchers produced higher proportions of cocaine-negative urines and longer periods of consecutive abstinence compared to other treatment combinations.Conclusion: This is the first study to find a significant treatment effect for levodopa and, in doing so, to demonstrate that the magnitude of this effect is dependent upon conditions of the behavioral therapy platform. The data support use of levodopa with abstinence-based reinforcement therapy as one efficacious combination in cocaine dependence disorder treatment.

Summary Background Progesterone, a steroid hormone, has been implicated in many CNS functions including reward, cognition, and neuroprotection. The goal of this study was to examine the dose-dependent effects of progesterone on cognitive performance, smoking urges, and smoking behavior in smokers. Methods Thirty female and thirty-four male smokers participated in a double-blind, placebo-controlled study. Female smokers were in the early follicular phase of their menstrual cycle during study participation. Smokers were randomly assigned to either 200 or 400 mg/day of progesterone or placebo, given in two separate doses, during clinic visit. The first 3 days of the treatment period, smokers abstained from smoking, which was verified with breath CO levels. Smokers attended an experimental session on day 4 where the number of cigarettes smoked were recorded starting two hours after the medication treatment. Results Progesterone treatment, 200 mg/day, significantly improved cognitive performance in the Stroop and the Digit Symbol Substitution Test. Progesterone at 400 mg/day was associated with reduced urges for smoking but did not change ad lib smoking behavior. Conclusions These findings suggest a potential therapeutic value of progesterone for smoking cessation.

Objective Previous studies suggest possible modulatory effects of progesterone on nicotine addiction. The goal of this study was to determine the effects of progesterone, on acute physiological and subjective responses to intravenous (IV) nicotine in overnight abstinent male and female smokers. Methods Twelve smokers, 6 males and 6 females, participated in a double-blind, placebo-controlled, crossover study, which consisted of 2 experimental sessions. Before each session, subjects were treated orally with a single dose of either 200 mg progesterone or placebo. Starting 2 hours following the medication treatment, subjects received an IV saline injection, followed by 0.5 and 1.0 mg/70 kg IV nicotine. Results Progesterone treatment, compared to placebo, enhanced the ratings of “bad effects,” from IV nicotine and attenuated the rating of “drug liking.” Progesterone also enhanced suppression of smoking urges by nicotine as assessed by the Brief Questionnaire on Smoking Urges (BQSU). Conclusions These results suggest that progesterone may alter the subjective effects of nicotine as well as urges to smoke cigarettes. Further studies are warranted to examine the modulation of nicotine’s effects by gonadal hormones.