David V. Herin

Effects of oral methamphetamine on cocaine use: A randomized, double-blind, placebo-controlled trial

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 (0mg, 6x/day; n=27), (2) immediate release (IR) methamphetamine (5mg, 6x/day; n=30), (3) sustained release (SR) methamphetamine (30 mg first pill, 1x/day; 0mg 5x/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 (0mg, 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 (0mg, 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.

Agonist-like pharmacotherapy for stimulant dependence: preclinical, human laboratory, and clinical studies

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.

Agonist-like pharmacotherapy for stimulant 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.

Cocaine Dependence and Concurrent Marijuana Use: A Comparison of Clinical Characteristics

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.

Pilot study of the effects of lisdexamfetamine on cocaine use: A randomized, double-blind, placebo-controlled trial

BACKGROUND Amphetamine analogs 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; 0mg, n=21), (2) LDX (70mg, 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<0.05) 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.

Validity and Reliability of the Abbreviated Barratt Impulsiveness Scale in Spanish (BIS-15S)

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 Spanish-speakers. Intra-scale reliability was calculated using Cronbachs 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.

Agonist treatment for stimulant abuse and dependence

Publisher Summary This chapter discusses preclinical and clinical evidence for agonist-like pharmacotherapy for stimulant dependence. Four converging lines of evidence, one preclinical and three clinical, support an agonist approach to pharmacotherapy of stimulant dependence as one component of the armamentarium. Three distinctive lines of clinical activity provide evidence that stimulant dependence can be ameliorated with stimulant administration. A novel pharmacologic strategy being examined for cocaine dependence utilizes disulfiram, an agent long used for alcohol dependence treatment. Disulfiram (DA) decreases alcohol consumption through the inhibition of the enzyme aldehyde dehydrogenase, resulting in accumulation of acetaldehyde and aversive consequences. It is found that data strongly indicate a role for enhanced DA transmission in the appetitive effects of psychostimulants and suggest targeting of the DA system in agonist substitution therapy. It is suggested that the ideal agonist substitution therapy, particularly to attenuate active drug use, should target the DA, 5-HT, and NE systems, as this broad-based strategy has several advantages. It is found that use of an oral cocaine preparation as an agonist substitution therapy is limited by many theoretical and practical difficulties.

Comparison of 3 L-α-acetyl-methadol (LAAM) maintenance strategies for heroin dependence

AimsHeroin dependence continues to be a major public health concern, with high relapse rates. The gold standard treatment for this disorder is long-term opioid maintenance. Dosing strategies for maintenance treatments have evolved over several decades, with lingering questions concerning optimal dosing regimens. Design and SettingThe current study compared the effectiveness of 3 dosing regimens of the opioid agonist L-α-acetyl-methadol (LAAM) in a randomized controlled double-blind trial. InterventionOne hundred and fourteen active heroin-dependent subjects meeting study criteria were randomly assigned to 1 of 3 LAAM dosing strategies (fixed dose, dose on the basis of subject weight, or variable dosing on the basis of efficacy and side effects). Subject selection included a stated goal of subsequent participation in a dose-reduction study. Subjects underwent a 28-day induction period followed by 5 months of LAAM maintenance therapy. FindingsTreatment with LAAM resulted in a significant decrease in non-LAAM opioid-positive urine screens in all dosing groups, with few (∼10%) positive urine screens by the end of the 5-month maintenance period. No differences were detected between the 3 dosing strategies. Rates of attrition during medication induction were 20% and reached 50% by the end of the study period. LAAM was well tolerated, with few side effects. Subjects with methadone treatment experience reported a clear preference for LAAM. ConclusionsThis study demonstrates the efficacy of LAAM, with equivalent results across the 3 dosing conditions. Although no significant difference among the conditions emerged, dosing to weight may be the most useful standardizing strategy for early maintenance beyond research settings.