Based on prior clinical trials indicating that γ-aminobutyric acid (GABA) based anticonvulsant medications reduce drug craving in cocaine dependent study participants, we tested the effects of valproate treatment on cue-induced cocaine craving. Crack cocaine dependent individuals (N=20) were tested in a randomized, placebo-controlled, within-subjects, crossover study design. Valproate treatment was titrated up to 1500 mg/day by Day 6 of treatment, cue testing was completed on Day 8 of treatment, and all study participants underwent a washout period of 5 days between active and placebo medication treatment periods. Testing included both cocaine and neutral cue exposure sessions, presented in a random and counterbalanced order. Main effects of cue exposure were found for subjective ratings of “desire to use cocaine now”, the cocaine craving index, cocaine-like high, and cocaine withdrawal. Treatment interaction effects were found with “desire to use cocaine now”, which underwent a greater increase following cocaine cue exposure in the valproate condition. Main effects of medication treatment were found, in which lower blood pressure and heart rate, and higher plasma cortisol levels, were associated with valproate treatment. Valproate treatment was also associated, at a trend level, with higher pre-test cocaine craving levels. The results demonstrate that cocaine cue reactivity is a robust phenomena across two assessment sessions, but fail to support the use of valproate as a means of reducing spontaneous and cue-induced cocaine craving. The use of valproate as a treatment for cocaine dependence is not supported.
valproate; cocaine; cue exposure; craving; cortisol
Major problems for research on pharmacological treatments for cocaine dependence are lack of comparability of results from different treatment research programs and poor validity and/or reliability of results. Double-blind, placebo-controlled, random assignment, experimental designs, using standard intake and assessment procedures help to reduce these problems. Cessation or reduction of drug use and/or craving, retention in treatment, and medical and psychosocial improvement are some of the outcome variables collected in treatment research programs. A model to be followed across different outpatient clinical trials for pharmacological treatment of cocaine dependence is presented here. This model represents an effort to standardize data collection to make results more valid and comparable.
clinical trials; cocaine; dependence; pharmacotherapy; model
Although improvement in psychosocial functioning is a common goal in substance-abuse treatment, the primary outcome measure in most cocaine trials is urinalysis-verified cocaine use. However, the relationship between cocaine use and psychosocial outcomes is not well documented. To investigate this relationship and identify the optimal urine-screen method, we retrospectively analyzed data from two 25-week randomized controlled trials of abstinence reinforcement (AR) in 368 cocaine/heroin users maintained on methadone. Cocaine use was measured thrice weekly by qualitative urinalysis, benzoylecgonine concentration (BE), and an estimate of New Uses of cocaine by application of an algorithm to BE. Social adjustment (SAS-SR), current diagnosis of cocaine dependence (DSM-IV criteria), and depression symptoms (Beck Depression Inventory) were determined at study exit. Cocaine use was significantly lower in AR groups than in controls. Across groups, in-treatment cocaine use was significantly associated with worse social adjustment, current cocaine dependence, and depression at exit. Significant differences were detected more frequently with New Uses than qualitative urinalysis or BE. Nevertheless, the amount of variance accounted for by the urine screens was typically <15%. Cocaine use during treatment, especially when measured with New Uses criteria, can predict psychosocial functioning, but cannot substitute for direct measures of psychosocial functioning.
urinalysis; substance dependence; treatment; methadone maintenance; abstinence reinforcement; psychosocial function
Crack cocaine use undermines adherence to highly active antiretroviral therapy (HAART). This pilot randomized clinical trial tested the feasibility and efficacy of 2 interventions based on the Information-Motivation-Behavioral Skills model to improve HAART adherence and reduce crack cocaine problems.
Participants were 54 adults with crack cocaine use and HIV with <90% HAART adherence. Most participants were African-American (82%) heterosexual (59%), and crack cocaine dependent (92%). Average adherence was 58% in the past 2 weeks. Average viral loads (VL) were detectable (log VL 2.97). The interventions included 6 sessions of Motivational Interviewing plus feedback and skills building (MI+), or Video information plus debriefing (Video+) over 8 weeks. Primary outcomes were adherence by 14-day timeline follow-back and Addiction Severity Index (ASI) Drug Composite Scores at 3 and 6 months. Repeated measures ANOVA assessed main effects of the interventions and interactions by condition.
Significant increases in adherence and reductions in ASI Drug Composite Scores occurred in both conditions by 3 months and were maintained at 6 months, representing medium effect sizes. No between group differences were observed. No VL changes were observed in either group. Treatment credibility, retention, and satisfaction were high and not different by condition.
A counseling and a video intervention both improved adherence and drug problems durably among people with crack cocaine use and poor adherence in this pilot study. The interventions should be tested further among drug users with poor adherence. Video interventions may be feasible and scalable for people with HIV and drug use.
HIV; Adherence; Crack Cocaine; Motivational Interviewing plus Feedback; Video Intervention
This study examined gender differences among treatment-seeking cocaine dependent outpatients (e.g., on demographics, psychopathology, and substance abuse).
Participants were 2,376 adults with cocaine dependence entering a multisite randomized controlled trial of psychosocial therapies.
Women, compared to men, had less severe lifetime substance use problems but a higher pattern of psychiatric, medical, social/family, and employment problems; they also had more positive expectations and opinions about treatment.
Women may be willing to engage in treatment but may have challenging economic and psychosocial concerns over and above their addiction.
cocaine dependence; psychopathology; gender; treatment
Early environmental events have profound influences on a wide range of adult behavior. In the current study, we assessed the influence of maternal stress during gestation on psychostimulant and neurochemical responsiveness to cocaine, cocaine self-administration, and reinstatement of cocaine-seeking in adult offspring. Pregnant, female Sprague–Dawley rats were subjected to either no treatment or to restraint stress three times per day for the last 7 days of gestation and cocaine-related behavior was assessed in offspring at 10 weeks of age. Relative to controls, a noncontingent cocaine injection elevated locomotor activity as well as nucleus accumbens levels of extracellular dopamine and glutamate to a greater extent in both cocaine-naïve and cocaine-experienced prenatal stress (PNS) rats and elevated prefrontal cortex dopamine in cocaine-experienced PNS rats. To assess the impact of PNS on cocaine addiction-related behavior, rats were trained to lever press for intravenous (i.v.) infusions of cocaine (0.25, 0.5, or 1 mg/kg/infusion), with each infusion paired with a light + tone-conditioned stimulus. Lever-pressing was extinguished and cocaine-seeking reinstated by re-exposure to the conditioned cues or by intraperitoneal cocaine-priming injections (5 or 10 mg/kg). PNS elevated active lever responding both during extinction and cocaine-primed reinstatement, but not during self-administration or conditioned-cued reinstatement. PNS also did not alter intake during self-administration. These findings demonstrate that PNS produces enduring nervous system alterations that increase the psychomotor stimulant, motivational, and neurochemical responsiveness to noncontingent cocaine. Thus, early environmental factors contribute to an individual's initial responsiveness to cocaine and propensity to relapse to cocaine-seeking.
prenatal stress; cocaine; self-administration; reinstatement; dopamine; glutamate
Neuroimaging data suggest that impaired performance on response inhibition and information processing tests in cocaine-dependent subjects is related to prefrontal and frontal cortical dysfunction and that dysfunction in these brain areas may underlie some aspects of cocaine addiction. In subjects with attention-deficit hyperactivity disorder and other psychiatric disorders, the Intra-Individual Reaction Time Variability (IIRTV) has been associated with frontal cortical dysfunction. In the present study, we evaluated IIRTV parameters in cocaine-dependent subjects vs. controls using a cocaine Stroop task. Fifty control and 123 cocaine-dependent subjects compiled from three studies completed a cocaine Stroop task. Standard deviation (SD) and coefficient of variation (CV) for reaction times (RT) were calculated for both trials with neutral and trials with cocaine-related words. The parameters mu, sigma, and tau were calculated using an ex-Gaussian analysis employed to characterize variability in RTs. The ex-Gaussian analysis divides the RTs into normal (mu, sigma) and exponential (tau) components. Using robust regression analysis, cocaine-dependent subjects showed greater SD, CV and Tau on trials with cocaine-related words compared to controls (p < 0.05). However, in trials with neutral words, there was no evidence of group differences in any IIRTV parameters (p > 0.05). The Wilcoxon matched-pairs signed-rank test showed that for cocaine-dependent subjects, both SD and tau were larger in trials with cocaine-related words than in trials with neutral words (p < 0.05). The observation that only cocaine-related words increased IIRTV in cocaine-dependent subjects suggests that cocaine-related stimuli might disrupt information processing subserved by prefrontal and frontal cortical circuits.
Intra-individual reaction time variability; Ex-Gaussian analysis; Cocaine Stroop task; Cocaine dependence
Crack cocaine is a highly addictive drug. To learn more about crack addiction, long-term crack smokers who had never met the DSM-IV criteria for lifetime cocaine dependence were compared with those who had. The study sample consisted of crack users (n=172) from the Dayton, Ohio, area who were interviewed periodically over 8 years. Data were collected on a range of variables including age of crack initiation, frequency of recent use, and lifetime cocaine dependence. Cocaine dependence was common with 62.8% of the sample having experienced it. There were no statistically significant differences between dependent and non-dependent users for age of crack initiation or frequency of crack use. In terms of sociodemographics, only race/ethnicity was significant, with proportionally fewer African-Americans than whites meeting the criteria for cocaine dependence. Controlling for sociodemographics, partial correlation analysis showed positive, statistically significant relationships between lifetime cocaine dependence and anti-social personality disorder, attention deficit/hyperactivity disorder, and lifetime dependence on alcohol, cannabis, amphetamine, sedative-hypnotics, and opioids. These results highlight the importance addressing race/ethnicity and comorbid disorders when developing, implementing, and evaluating interventions targeting people who use crack cocaine. Additional research is needed to better understand the role of race/ethnicity in the development of cocaine dependence resulting from crack use.
Crack cocaine; addiction; dependence; comorbidity; race/ethnicity; substance abuse
Acupuncture is a commonly used treatment option for the treatment of addictions such as alcohol, nicotine and drug dependence. We systematically reviewed and meta-analyzed the randomized controlled trials of acupuncture for the treatment of cocaine addiction.
Two reviewers independently searched 10 databases. Unpublished studies were sought using Clinicaltrials.gov, the UK National Research Register and contacting content experts. Eligible studies enrolled patients with the diagnosis of cocaine dependence of any duration or severity randomly allocated to either acupuncture or sham or other control. We excluded studies of acupuncture methods and trials enrolling patients with polysubstance use or dependence. We abstracted data on study methodology and outcomes. We pooled the studies providing biochemical confirmation of cocaine abstinence.
Nine studies enrolling 1747 participants met inclusion criteria; 7 provided details for biochemical confirmation of cocaine abstinence. On average, trials lost 50% of enrolled participants (range 0–63%). The pooled odds ratio estimating the effect of acupuncture on cocaine abstinence at the last reported time-point was 0.76 (95% CI, 0.45 to 1.27, P = 0.30, I2 = 30%, Heterogeneity P = 0.19).
This systematic review and meta-analysis does not support the use of acupuncture for the treatment of cocaine dependence. However, most trials were hampered by large loss to follow up and the strength of the inference is consequently weakened.
Cocaine-associated biomedical and psychosocial problems are substantial twenty-first century global burdens of disease. This burden is largely driven by a cocaine dependence process that becomes engaged with increasing occasions of cocaine product use. For this reason, the development of a risk-prediction model for cocaine dependence may be of special value. Ultimately, success in building such a risk-prediction model may help promote personalized cocaine dependence prediction, prevention, and treatment approaches not presently available. As an initial step toward this goal, we conducted a genome-environmental risk-prediction study for cocaine dependence, simultaneously considering 948,658 single nucleotide polymorphisms (SNPs), six potentially cocaine-related facets of environment, and three personal characteristics. In this study, a novel statistical approach was applied to 1045 case-control samples from the Family Study of Cocaine Dependence. The results identify 330 low- to medium-effect size SNPs (i.e., those with a single-locus p-value of less than 10−4) that made a substantial contribution to cocaine dependence risk prediction (AUC = 0.718). Inclusion of six facets of environment and three personal characteristics yielded greater accuracy (AUC = 0.809). Of special importance was the joint effect of childhood abuse (CA) among trauma experiences and the GBE1 gene in cocaine dependence risk prediction. Genome-environmental risk-prediction models may become more promising in future risk-prediction research, once a more substantial array of environmental facets are taken into account, sometimes with model improvement when gene-by-environment product terms are included as part of these risk predication models.
cocaine dependence; genome-environmental risk prediction; childhood abuse; GBE1 gene; tree-assembling ROC
Little data exist on the neuropsychological effects of crack–cocaine dependence or crack-cocaine and alcohol dependence. This study examined cognitive function in abstinent crack dependent and crack and alcohol dependent individuals at 6 weeks and 6 months abstinence.
a comprehensive neuropsychological battery, including the MicroCog computerized assessment, was administered to 20 abstinent crack dependent subjects, 37 abstinent crack and alcohol dependent subjects, and 29 normal controls. Depression was examined as a covariate, and the association between substance use variables and neuropsychological performance was examined.
the two substance dependent groups had similar neuropsychological profiles at 6 weeks abstinent, with both groups exhibiting significant cognitive impairment in a wide range of functions compared to controls. The substance dependent groups were still impaired significantly at 6 months of abstinence. Only mild effects of depression on neuropsychological performance were observed.
crack dependence and crack and alcohol dependence may lead to severe and persistent neuropsychological deficits over a wide range of domains. The strongest predictor of brain damage associated with substance dependence in this sample was dose (particularly quantity and duration of peak dose).
Brain damage; Cocaine; Alcoholism; Neuropsychological; Assessment
The mGluR5 antagonist MPEP has effects that suggest potential as a pharmacotherapy for cocaine addiction. MPEP can attenuate self-administration of cocaine in animals; however, studies usually involved only acute treatment with MPEP and a single dose of self-administered cocaine. Cocaine addicts use varied amounts of cocaine over long periods of time, and an effective pharmacotherapy would almost certainly require more chronic treatment.
The present study: 1) compared the effects of repeated treatment with MPEP or the NMDA receptor antagonist dizocilpine on the reinforcing effects of a range of doses of cocaine and 2) determined the pharmacological specificity of the effects of the drugs in attenuating cocaine self-administration compared to food-reinforced behavior. An effective pharmacotherapy should selectively reduce cocaine self-administration.
Groups of monkeys responded under a fixed-ratio schedule of i.v. cocaine self-administration or food-pellet delivery. The effects of daily treatment with MPEP and dizocilpine were determined under both the schedule of i.v. cocaine injection and food delivery.
Treatment with MPEP and dizocilpine significantly reduced cocaine self-administration, producing rightward and downward shifts in the ascending limb of the cocaine dose-response function. MPEP and dizocilpine selectively and significantly attenuated self-administration of a low reinforcing dose of cocaine compared to food without evidence of tolerance.
Both MPEP and dizocilpine functioned as partially surmountable antagonists of the reinforcing effects of cocaine. The similar effects of the two drugs raises the possibility that MPEP attenuated the reinforcing effects of cocaine, at least in part, via mGluR5-mediated inhibition of NMDA receptor activity.
Glutamate; Metabotropic glutamate receptors; Ionotropic glutamate receptors; Cocaine self-administration; Food self-administration; Pharmacotherapy; Squirrel monkey (Saimiri sciureus)
Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.
Substance Abuse; Vaccine; Cocaine; Immunization; Antibody; Conjugate
(−)-Cocaine is a widely abused drug and there is no available anti-cocaine therapeutic. The disastrous medical and social consequences of cocaine addiction have made the development of an effective pharmacological treatment a high priority. An ideal anti-cocaine medication would be to accelerate (−)-cocaine metabolism producing biologically inactive metabolites. The main metabolic pathway of cocaine in body is the hydrolysis at its benzoyl ester group. Reviewed in this article is the state-of-the-art computational design of high-activity mutants of human butyrylcholinesterase (BChE) against (−)-cocaine. The computational design of BChE mutants has been based on not only the structure of the enzyme, but also the detailed catalytic mechanisms for BChE-catalyzed hydrolysis of (−)-cocaine and (+)-cocaine. Computational studies of the detailed catalytic mechanisms and the structure-and-mechanism-based computational design have been carried out through the combined use of a variety of state-of-the-art techniques of molecular modeling. By using the computational insights into the catalytic mechanisms, a recently developed unique computational design strategy based on the simulation of the rate-determining transition state has been employed to design high-activity mutants of human BChE for hydrolysis of (−)-cocaine, leading to the exciting discovery of BChE mutants with a considerably improved catalytic efficiency against (−)-cocaine. One of the discovered BChE mutants (i.e. A199S/S287G/A328W/Y332G) has a ~456-fold improved catalytic efficiency against (−)-cocaine. The encouraging outcome of the computational design and discovery effort demonstrates that the unique computational design approach based on the transition-state simulation is promising for rational enzyme redesign and drug discovery.
Cocaine abuse; anti-cocaine medication; hydrolysis mechanism; transition state; enzymatic reaction; rational enzyme redesign
Contingency management (CM) treatments are efficacious in treating cocaine abuse. Despite high prevalence rates of alcohol dependence (AD) among individuals with cocaine use disorders, relatively little data are available regarding whether cocaine abusing patients with AD have poorer treatment outcomes in general, or in response to CM treatments in particular, than cocaine abusers without AD. Using data from three randomized trials of CM for cocaine abuse, this study compared cocaine abusers (N = 393) with and without AD in terms of 1) abstinence during treatment and at the Month 9 follow-up, and 2) psychosocial adjustment during the 12-week treatment period and through the follow-up period. Compared to non-AD participants, AD participants had more lifetime years of cocaine and alcohol use, and they had greater severity of alcohol and psychiatric problems. CM was positively and significantly associated with longer durations of substance abstinence, regardless of AD status. Although not significantly associated with primary substance use treatment outcomes, the presence of AD was related to improvement in medical and alcohol-related problems during treatment, and these gains were maintained posttreatment. The results suggest that cocaine abusers benefit equally well from CM treatments, regardless of AD status, and that AD participants are able to offset greater baseline severity in some areas of psychosocial functioning during treatment and maintain these improvements posttreatment.
treatment outcome; contingency management; alcohol dependence; cocaine abuse; cocaine dependence
Acamprosate is a medication shown to be effective for the treatment of alcohol dependence. Although the exact mechanism of action of acamprosate is unknown, evidence suggests that it decreases excitatory amino acid activity by postsynaptic inhibition of the NMDA subtype of glutamate receptors. It is possible that the activity of acamprosate via modulating glutamatergic activity could also reduce craving for cocaine and impact abstinence in cocaine dependence. Therefore, we conducted a double-blind placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence.
Sixty male and female cocaine dependent patients were included in a nine-week double-blind, placebo-controlled trial. After a one-week baseline, patients were randomized to receive acamprosate 666 mg three times daily or identical placebo tablets for eight weeks. The primary outcome measure was cocaine use as determined by twice weekly urine drug screens.
Thirty-six patients (60%) completed the trial, with no significant between-group difference in treatment retention. Percent cocaine positive urine drug screens did not differ between the two groups. Acamprosate was no better than placebo in reducing cocaine craving, reducing cocaine withdrawal symptoms, or improving measures of drug use severity from the Addiction Severity Index. Adverse events in this trial were generally mild and were evenly distributed between the two groups.
Acamprosate was well tolerated but was no more efficacious than placebo in promoting abstinence from cocaine in cocaine dependent patients. Acamprosate does not appear to be a promising medication for the treatment of cocaine dependence.
acamprosate; cocaine; clinical trial; placebo
Cocaine dependence is an enduring problem and years of research and drug development has yet to produce an efficacious pharmacotherapy. Recent clinical research suggests that chronic treatment with amphetamine-like medications produces tolerance to cocaine’s reinforcing effects and may offer a viable pharmacotherapy. Three methamphetamine-dependent participants that had been in our clinical laboratory experiments and previously addicted to cocaine are reviewed. Data obtained from initial screen and informal conversation suggested that all participants considered methamphetamine to have helped them stop using cocaine and eliminate cocaine craving. Methamphetamine also significantly decreased their alcohol consumption but did not alter cannabis or nicotine use.
Drug abuse; Stimulants; Tolerance; Pharmacotherapies; Prodrug
Much effort has been devoted to research focused on pharmacotherapies for cocaine dependence yet there are no FDA-approved medications for this brain disease. Preclinical models have been essential to defining the central and peripheral effects produced by cocaine. Recent evidence suggests that cocaine exerts its reinforcing effects by acting on multiple neurotransmitter systems within mesocorticolimibic circuitry. Imaging studies in cocaine-dependent individuals have identified deficiencies in dopaminergic signaling primarily localized to corticolimbic areas. In addition to dysregulated striatal dopamine, norepinephrine and glutamate are also altered in cocaine dependence. In this review, we present these brain abnormalities as therapeutic targets for the treatment of cocaine dependence. We then survey promising medications that exert their therapeutic effects by presumably ameliorating these brain deficiencies. Correcting neurochemical deficits in cocaine-dependent individuals improves memory and impulse control, and reduces drug craving that may decrease cocaine use. We hypothesize that using medications aimed at reversing known neurochemical imbalances is likely to be more productive than current approaches. This view is also consistent with treatment paradigms used in neuropsychiatry and general medicine.
Addiction; Cocaine dependence; Medication development; Dopamine; Glutamate; Norepinephrine; Neurotransmission; Neuroplasticity; Behavioral pharmacology
Cocaine abuse is an ongoing and serious problem which has lead to the growth of a brutal criminal enterprise, particularly in the Americas and Europe. At present, there are no effective pharmacological agents available to treat the addiction by blocking cocaine or reversing its effects. In order to help motivated addicts conquer their addiction, vaccines against cocaine are being developed, and one has progressed to clinical trials. This review will discuss the concept of anti-drug vaccines in general, the successes and limitations of the various anti-cocaine vaccine approaches, the results of the clinical trials with an anti-cocaine vaccine, and some new vaccine-mediated approaches to combat cocaine addiction.
Substance Abuse; Vaccination; Cocaine; Immunotherapy
Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use. We conducted the present study to better understand how disulfiram alters the reinforcing effects of cocaine in cocaine users.
Seventeen non-treatment seeking, cocaine-dependent volunteers participated in this double-blind, placebo-controlled, laboratory-based study. A cross-over design was utilized in which participants received placebo in one phase and disulfiram (250 mg/d) in the other. Following three days of study medication participants completed two choice sessions. In one they made 10 choices between receiving an intravenous infusion of saline or money that increased in value (US$ 0.05–16) and in the other cocaine (20 mg) or money.
Participants chose cocaine more than saline under both disulfiram and placebo conditions (p<0.05). Unexpectedly, disulfiram increased both the number of cocaine and saline infusion choices (p<0.05). We next examined the relationship between disulfiram dose and cocaine choices. Disulfiram dose (mg/kg bodyweight) was negatively correlated with number of choices for cocaine (p<0.05). Disulfiram also enhanced cocaine-induced increases in cardiovascular measures (p's<0.05–0.01).
Disulfiram's impact on the reinforcing effects of cocaine depends on dose relative to body weight. Our results suggest that the use of weight-based medication doses would produce more reliable effects, consistent with weight-based dosing used in pediatrics and in preclinical research.
Crack and cocaine use among adults has been associated with co-occurring psychiatric disorders as well as other drug use and unprotected sex. However, this issue is relatively unstudied in adolescents. This study collected data from 282 adolescents (mean age=14.9 years) treated in intensive psychiatric treatment settings to understand the relationship between crack/cocaine use and HIV risk. Thirteen percent of youth reported ever using crack or cocaine. Use was not associated with age, gender, race/ethnicity or SES. After controlling for known factors that influence unprotected sex, the odds that those with a history of crack/cocaine use engaged in inconsistent condom use was six times greater than that for those youth who did not ever use. Thus, crack/cocaine use is prevalent even among younger adolescents with psychiatric disorders who are not in drug treatment. Its use is associated with high rates of sexual and other risk behaviors. A history of use should alert clinicians to a wide variety of possible behavioral risks. These results can also inform future adolescent HIV prevention intervention development.
adolescent; crack; cocaine; sexual risk behavior; HIV; psychopathology
We examined the ability of several baseline variables to predict treatment outcome in a pharmacotherapy trial that included 164 participants who were both cocaine- and alcohol-dependent and were selected for a randomized, double-blind, placebo-controlled study. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial Urine Drug Screen results, cocaine and alcohol craving and cocaine and alcohol withdrawal symptoms at the start of treatment. Successful treatment was defined as four continuous weeks of self-reported cocaine abstinence verified by urine drug screens. In respect to demographic characteristics, there were no significant differences between patients who achieved four weeks of abstinence from cocaine and those who did not. Baseline variables that most consistently predicted cocaine abstinence included initial urine drug screen (UDS) results, the initial Cocaine Selective Severity Assessment (CSSA) scores, and initial self-reported cocaine use in past 30 days, whereas cocaine craving, cocaine composite scores, alcohol craving, alcohol withdrawal symptoms, and alcohol composite scores did not. The results of this study suggest that cocaine dependence severity in general, and initial UDS results, the CSSA scores and frequency of recent cocaine use in particular, have a significant impact on treatment outcome in the treatment of cocaine-dependent patients with comorbid alcoholism. Initial UDS results and CSSA scores are very useful predictors of treatment outcome and could be used as stratifying variables in outpatient cocaine and alcohol medication trials.
Cocaine addiction continues to be a major health and societal problem in spite of governmental efforts devoted toward educating the public of the dangers of illicit drug use. A variety of pharmacotherapies and psychosocial programs have been proposed in an effort to provide a method for alleviation of the physical and psychological symptoms of cocaine abuse. Unfortunately, these methods have been met with limited success, illustrating a critical need for new effective approaches for the treatment of cocaine addiction. Recently an alternative cocaine abuse treatment strategy was proposed using intranasal administration of an engineered filamentous bacteriophage displaying cocaine-sequestering antibodies on its surface. These phage particles are an effective vector for CNS penetration and are capable of binding cocaine, thereby blocking its behavioral effects in a rodent model. The convergence of phage display and immunopharmacotherapy has allowed for an investigation of the efficacy of protein-based therapeutics acting within the CNS on the effects of cocaine in animal models and has uncovered a new tool in the battle against cocaine addiction.
cocaine; central nervous system; immunopharmacotherapy; virus; phage display
Cocaine dependence, which affects 2.5 million Americans annually, has no FDA approved pharmacotherapy.
To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence.
24 week Phase IIb randomized double-blind placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24.
Cocaine and opioid dependent persons recruited from 2003–2005 from greater New Haven, CT.
115 methadone maintained subjects (67% male, 87% Caucasian, aged 18–46) were randomized to vaccine or placebo and 82% completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and non-prescription opioids (44%).
Over 12 weeks 109/115 subjects received five vaccinations of placebo or succinylnorcocaine linked to cholera B protein.
Main Outcome Measure
Semi-quantitative urinary cocaine metabolite levels measured thrice weekly with positive cutoff of 300 ng/ml.
The 38% of vaccinated subjects who attained serum IgG anti-cocaine levels ≥ 43 µg/mL (high IgG) had significantly more cocaine-free urines than those with < 43 µg/mL (low IgG) and the placebo subjects during weeks 9 to 16 (45% vs 35%). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the high IgG than low IgG subjects (0.53 vs. 0.23) (P<0.04). The most common side effects were injection site induration and tenderness. There were no treatment related serious adverse events, withdrawals, or deaths.
Attaining high (≥ 43 µg/mL) IgG anti-cocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters.
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. (Am J Addict 2006;15:105-110)