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.

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.

These results suggest that the 5-HT(2A)R contributes to the generation of peripheral hyperactivity and rearing and, especially, the hyperthermia evoked by (+)-MDMA and that 5-HT(2A)R antagonists should be further investigated as treatments for the psychological and hyperthermic effects of (+/-)-MDMA.

Objective-This study determined the validity and reliability of a new, abbreviated version of the Spanish Barratt Impulsiveness Scale (BIS-15S) in Colombian subjects. Method-The BIS-15S was tested in non-clinical (n=283) and clinical (n=164) native Spanishspeakers. Intra-scale reliability was calculated using Cronbach's α, and test-retest reliability was measured with Pearson correlations. Psychometric properties were determined using standard statistics. A factor analysis was performed to determine BIS-15S factor structure.Results-447 subjects participated in the study. Clinical subjects were older and more educated compared to non-clinical subjects. Impulsivity scores were normally distributed in each group. BIS-15S total, motor, non-planning and attention scores were significantly lower in non-clinical vs. clinical subjects. Subjects with substance-related disorders had the highest BIS-15S total scores, followed by subjects with bipolar disorders and bulimia nervosa/binge eating. Internal consistency was 0.793 and test-retest reliability was 0.80. Factor analysis confirmed a three-factor structure (attention, motor, non-planning) accounting for 47.87% of the total variance in BIS-15S total scores.Conclusions-The BIS-15S is a valid and reliable self-report measure of impulsivity in this population. Further research is needed to determine additional components of impulsivity not investigated by this measure.

Background/Objectives Marijuana is the most commonly used illicit substance, yet among the least studied in medication development research. Cocaine-dependent individuals frequently also use marijuana; however, little is known about the effect of this combined use on treatment presentation. Methods Marijuana use was assessed in 1183 individuals seeking outpatient treatment for cocaine dependence. Based on past 30 days of use, the sample was divided into three groups: (1) patients reporting no recent marijuana use (n = 634); (2) occasional use (n = 403); (3) and frequent concurrent marijuana use (n = 146). Differences on baseline measures of substance use, addiction severity (ASI), psychopathology, and sociodemographic characteristics were examined as a function of level of marijuana use. Results Frequent marijuana users were more likely to be female, Caucasian, and younger than other groups. Cocaine-dependent patients with frequent marijuana use also used more cocaine and alcohol, and reported more medical, legal, and psychiatric problems, including antisocial personality disorder. Conclusion and Scientific Significance Cocaine-dependent patients with frequent marijuana use present for treatment with more severe impairment. Accounting for this heterogeneity among participants may improve treatment outcome.

Background Amphetamine analogues have been demonstrated to have some efficacy in reducing use in cocaine dependent individuals. However, these agents also have potential for abuse. Lisdexamfetamine (LDX), a lysine+dextroamphetamine formulation, has been approved for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and as a prodrug, has less abuse potential. Objective This pilot study sought to evaluate the safety, tolerability, and efficacy of LDX as a candidate treatment for cocaine dependence. Methods A randomized, double-blind, placebo-controlled parallel group study served to evaluate LDX in 43 cocaine-dependent individuals: (1) Placebo (PBO; 0 mg, n = 21), (2) LDX (70 mg, n = 22). Participants received medication for 14 weeks. Cocaine use was determined based on urine analysis for benzoylecgonine (BE; a cocaine metabolite). Results Retention rates were higher though not significantly different in the PBO (71.4%) than the LDX condition (57.1%). Compared to those in the PBO condition, those receiving LDX were more likely to report experiencing (ps < .05) diarrhea (45.5% vs. 14.3%), headaches (45.5% vs. 9.5%), and anxiety (31.8% vs. 4.8%). No differences in medication conditions were observed for blood pressure, heart rate, or body weight. In the randomized sample, no differences in cocaine use were seen. Those receiving LDX reported significantly less craving for cocaine than participants receiving PBO. Conclusions LDX did not significantly reduce cocaine use compared to PBO in the randomized sample.

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The concept of using stimulants to treat cocaine and methamphetamine dependence is largely based on the "replacement" therapy model that has shown efficacy for treating nicotine and opiate dependence. Although results have been mixed, some evidence supports using stimulant medication to reduce cocaine use. There are not enough data to date to determine the efficacy of stimulants for methamphetamine dependence. Drawbacks of stimulants as treatments include the potential for abuse of the treatment, which necessitates careful screening and monitoring of patients. Possible reasons for efficacy of stimulants include enhancement of monoamine function dysregulated by chronic cocaine or methamphetamine use. Newer medications that enhance dopamine function but lack the abuse potential of older stimulants are being studied. It is hoped that these medications will provide safe, effective treatment for cocaine and methamphetamine dependence, but more research on this topic is needed.