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A properly implemented agonist treatment regimen should improve retention and reduce illicit drug use. Cocaine-dependent subjects (N = 128) were enrolled in a 12-week randomized, double-blind, placebo-controlled trial. In the multistage dosing design, subjects initially received placebo (PBO) or 15 to 30 mg of dextroamphetamine sulfate, sustained-release capsules. At week 5, the dose doubled to 30 mg or 60 mg for active groups. Subjects attended the clinic twice a week, provided urine samples, obtained medication, and had one behavioral therapy session a week. Retention was best for the 15- to 30-mg group, whereas the proportion of benzoylecgonine-positive urine screens was, from lowest to highest, 30 to 60 mg, 15 to 30 mg, and PBO at study end. Dosing must be refined. The results provide support for additional examination of the agonist model in psychostimulant-dependence treatment.

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Concurrent abuse of cocaine and heroin is a common problem. Methadone is effective for opioid dependence. The question arises as to whether combining agonist-like or antagonist-like medication for cocaine with methadone for opioid dependence might be efficacious. Two parallel studies were conducted. One examined sustained release d-amphetamine and the other risperidone for cocaine dependence, each in combination with methadone. In total, 240 subjects (120/study) were recruited, who were both cocaine and heroin dependent and not currently receiving medication. All provided consent. Both studies were carried out for 26 weeks, randomized, double-blind and placebo controlled. Study I compared sustained release d-amphetamine (escalating 15-30 or 30-60 mg) and placebo. Study II examined risperidone (2 or 4 mg) and placebo. All subjects underwent methadone induction and were stabilized at 1.1 mg/kg. Subjects attended clinic twice/week, provided urine samples, obtained medication take-home doses for intervening days, and completed self-report measures. Each had one behavioral therapy session/week. In Study I, reduction in cocaine use was significant for the 30/60 mg dose compared to the 15/30 mg and placebo. Opioid use was reduced in all groups with a trend toward greater reduction in the 30/ 60 mg d-amphetamine group. In Study II, methadone reduced illicit opioid use but cocaine use did not change in the risperidone or placebo groups. There were no adverse medication interactions in either study. The results provide support for the agonist-like (damphetamine) model in cocaine dependence treatment but not for antagonist-like (risperidone) treatment. They coincide with our previous reports of amphetamine or risperidone administered singly in cocaine-dependent individuals.

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

Agonists, or "replacement medications," are useful adjuncts in treatment of opiate and nicotine dependence. They have not been systematically examined in cocaine dependence. Results of early open trials with methylphenidate for treatment of cocaine dependence were equivocal. Twenty-four cocaine-dependent subjects were enrolled in an 11-week double-blind, placebo-controlled study of methylphenidate. Assignment was random. Intake included a 2-day human laboratory procedure in which subjects received initial doses of methylphenidate or placebo. Subjects attended the clinic Monday through Friday and received oral doses of methylphenidate (5 mg plus 20-mg sustained release) or placebo at 8:00 a.m., with afternoon and weekend take-home doses (20 mg sustained-release or placebo) provided in Medication Events Monitoring System bottles to monitor compliance. Clinic visits included therapy sessions, electrocardiograms, self-report measures, and twice-weekly urine screens. The two groups were equivalent in terms of retention (methylphenidate 48% and placebo 42%) and had similar cocaine use outcomes (40% benzoylecgonine-positive urine screens). There were no significant adverse effects. The doses were sufficient to permit detection of psychoactive effects ("stimulant," "more energy") and side effects ("jitteriness," "eating less") without increased "craving." Additional medications with different effects profiles are being studied to further evaluate the replacement model in cocaine dependence.

A variety of natural and synthetic agents have long been used for stimulant properties, with nontherapeutic use producing multiple waves of stimulant abuse and dependence. The multitude of effects of stimulants exist on continua, and accordingly, here we characterize stimulant abuse/dependence and candidate pharmacotherapies in this manner. Behavioral therapy and medications have been investigated for treatment of stimulant abuse/dependence. Effectiveness of some behavioral interventions has been demonstrated. Most medications studied have been found to lack efficacy. However, an expanding literature supports use of agonist-like medications to treat stimulant abuse/dependence, a strategy effective for nicotine and opiate dependence. The agonist-like conceptualization for stimulant dependence posits that medications with properties similar to that of the abused drug, but possessing lesser abuse liability, will normalize neurochemistry and stabilize behavior, thus reducing drug use. Data suggest use of a range of medications, from l-dopa/carbidopa to amphetamine preparations, depending on the severity of use. This report reviews preclinical, human laboratory, and clinical trial data supporting the agonist-like approach, including risks and benefits. Future directions for development of agonist-like medications are also discussed.