Opioid-like effects of the neurokinin 1 antagonist aprepitant in patients maintained on and briefly withdrawn from methadone.

BACKGROUND: Although opioid substitution therapy is an effective clinical tool used to manage opioid abuse and dependence, concerns regarding the current FDA-approved medications have lead to a search for efficacious, non-opioid medications. Preclinical data indicate that neurokinin 1 (NK1) receptor activity may modulate opioid effects and withdrawal. This investigation sought to examine the ability of the NK1 antagonist aprepitant to alter the effects of methadone as well as withdrawal symptoms induced by brief methadone discontinuation. METHODS: This blinded, placebo-controlled, within-subjects study consisted of placebo and aprepitant conditions. Experimental assessments occurred on the first three days (days 1-3: placebo or aprepitant + methadone) and again on days 8-10 (aprepitant or placebo + methadone). Fifteen methadone-maintained patients completed the investigation. Outcome measures were the assessments of opioid withdrawal, as well as subjective measures of opioid-like effects. RESULTS: Statistical trends indicated that aprepitant may reduce opioid withdrawal symptoms. When an active dose of aprepitant was administered an hour before methadone, participants reported less desire to use methadone. However, ratings of methadone "Liking" also appeared to increase. CONCLUSIONS: These data tentatively suggest that aprepitant has some ability to alleviate withdrawal following methadone abstinence, but also appears to increase subjective indicators of methadone's abuse liability. Since few of the differences between aprepitant and placebo reached statistical significance, these data should only be viewed as preliminary. Findings from other studies indicate that higher doses of aprepitant may be more clinically effective. Further clinical investigations are needed in order to determine whether aprepitant is useful for alleviating opioid withdrawal.

Smoking cessation treatment among patients in community-based substance abuse rehabilitation programs: exploring predictors of outcome as clues toward treatment improvement.

BACKGROUND: Predictors of smoking cessation (SC) treatment outcome were explored in a multisite clinical trial of SC treatment at community-based, outpatient, substance abuse rehabilitation programs affiliated with the National Drug Abuse Treatment Clinical Trials Network. OBJECTIVES: To explore baseline demographic and clinical predictors of abstinence during treatment. METHODS: Cigarette smokers from five methadone maintenance programs and two drug and alcohol dependence treatment programs were randomly assigned to SC treatment as an adjunct to substance abuse treatment as usual or to substance abuse treatment as usual. SC treatment consisted of group counseling (weeks 1-8) plus transdermal nicotine patch treatment (21 mg/day, weeks 1-6; 14 mg/day, weeks 7-8). Demographic and clinical predictors of smoking abstinence were evaluated among those patients assigned to the active SC condition (N = 153) using logistic regression. RESULTS: Abstinence during treatment was positively associated with younger age, Hispanic or Caucasian (as opposed to African American) ethnicity/race, employment or student status, fewer cigarettes per day at baseline, lower severity of the primary substance problem at baseline, and higher methadone doses (among the subsample in methadone treatment). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: During future efforts to improve SC treatments among drug- and alcohol-dependent patients, consideration should be given to adequate treatment to reduce the severity of the primary drug or alcohol problem, tailoring treatments for patients with greater severity of smoking and of the primary substance problem, and culturally sensitive interventions. Analysis of predictors of outcome may be a useful tool for treatment development.

Acamprosate determinations in plasma and cerebrospinal fluid after multiple dosing measured by liquid chromatography-mass spectroscopy: a pharmacokinetic study in healthy volunteers.

The central nervous system-active medication acamprosate has been shown to modulate alcohol-related behavior in both preclinical and clinical studies. Although commonly used in the treatment of alcohol dependence, there are still unanswered questions concerning the pharmacokinetic properties of acamprosate. The aims of the present study were to 1) to validate liquid chromatography-mass spectrometry as a method to study the presence of acamprosate in plasma and cerebrospinal fluid (CSF) in humans; and 2) validate previous results on clinically important pharmacokinetic data for acamprosate. In an open label, single-site design, 13 healthy males and females were recruited to 22 days of oral acamprosate treatment (1998 mg/day). Subjects provided in all 256 plasma samples for analysis at regular intervals at Day 1, 7, 14, and 22 of treatment. On Day 22, subjects also left a sample of CSF for measurement of acamprosate. The results showed that steady-state level of acamprosate was accomplished within 5 days after the start of treatment and remained fairly stable for 2 to 3 days after termination of treatment. Variations in plasma concentrations corresponded to earlier studies and did not exceed those for comparable pharmacotherapeutic agents. Acamprosate concentrations in the CSF were below the limit of quantification, ie, estimated concentrations between 9 and 33 ng/mL. Plasma concentrations were more than 25 times higher than in lumbar CSF. The low CSF levels seen after 3 weeks of treatment may provide an explanation to the delay in therapeutic effect noticed in treatment studies on acamprosate. A longer duration of treatment might be necessary to obtain clinically significant brain levels of acamprosate. In summary, the present study validated liquid chromatography-mass spectrometry as a method for assessment of compliance to acamprosate treatment. Furthermore, the results suggest that the mechanism of action of acamprosate needs to be further explored with regard to the peripheral actions of the drug.

The relationship between depression and smoking cessation outcomes in treatment-seeking substance abusers.

The National Drug Abuse Treatment Clinical Trials Network (CTN) recently completed a randomized, open label trial comparing treatment as usual (TAU) combined with nicotine patches plus cognitive behavioral group counseling for smoking cessation (n = 153) to TAU alone (n = 72) for patients enrolled in treatment programs for drug or alcohol dependence, who were interested in quitting smoking. This report is a secondary analysis evaluating the effect of depressive symptomatology (n = 70) or history of depression (n = 110) on smoking cessation outcomes. A significant association was seen between measures of depression and difficulty quitting cigarettes. Specifically, there was a greater probability for smoking abstinence for those with lower baseline Beck Depression Inventory II (BDI-II) scores. These data suggest that evaluation and treatment of depressive symptoms may play an important role in improving smoking cessation outcomes. (Am J Addict 2010;00:1-8).

The effect of acamprosate on alcohol craving and correlation with hypothalamic pituitary adrenal (HPA) axis hormones and beta-endorphin.

Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol dependent patients. The mechanism of acamprosate action is hypothesized to be by modulation of craving responses. Previous research has suggested that acamprosate may affect the hypothalamic pituitary adrenal (HPA) axis as well as beta-endorphin. The aim of the present study was to investigate if acamprosate attenuates alcohol craving following a short-term treatment, and if craving and drinking measures are correlated to changes in HPA-axis hormones and beta-endorphin. In a double-blind design, 56 alcohol dependent treatment seeking patients were randomized to 21 days of either acamprosate (1998 mg/day) or placebo treatment. Subjective, physiological and biological measurements were recorded at inclusion and on day 21. The results showed that acamprosate treated patients showed significantly reduced craving compared to placebo. Further, a significant correlation was shown between craving and alcohol consumption during study. No changes in hormonal levels were found in acamprosate treated patients compared to placebo.

A liquid chromatography-electrospray ionization-tandem mass spectrometry method for quantitation of aripiprazole in human plasma.

A rugged liquid chromatographic-electrospray ionization-tandem mass spectrometric (LC-ESI-MS-MS) method was developed and validated for accurate monitoring of steady-state plasma aripiprazole. Haloperidol-d(4) was chosen as the internal standard. ESI of aripiprazole and haloperidol-d(4) yielded abundant MH(+) ions, m/z 448 and 379, respectively. These ions were collision-dissociated to respective product ions of m/z 285 and 168. Ion-suppression experiments with blank plasma extracts showed substantial depressions of the product ions at retention times between 0.5 to 2 min, prohibiting development of a high-throughput LC-MS-MS method. A steep-gradient elution LC permitted a robust LC-ESI-MS-MS method with a 12-min analysis time. Aripiprazole was quantified from 0.2-mL aliquots of human plasma with acceptable precision and accuracy down to a lower limit of quantitation of 2 ng/mL. Aripiprazole was stable in plasma samples stored at room temperature for 24 h or exposed to three freeze-thaw cycles and in processed extracts stored at -20 degrees C for six days or on the autosampler at 10 degrees C for four days. The method has been successfully used for determinations of steady-state concentrations of aripiprazole in human subjects given daily oral doses of 15 mg. All measured concentrations were well within the quantitative range of 2 to 400 ng/mL.

Modafinil for the treatment of cocaine dependence.

AIM: Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo. METHODS: This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days. RESULTS: The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p>0.79). However, two secondary outcomes showed significant effects by modafinil 200mg: the maximum number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p<0.02). CONCLUSIONS: These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.

Valproate treatment and cocaine cue reactivity in cocaine dependent individuals.

Based on prior clinical trials indicating that gamma-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.

The effects of acamprosate on alcohol-cue reactivity and alcohol priming in dependent patients: a randomized controlled trial.

RATIONALE: Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol-dependent patients; yet, little is known regarding its therapeutic mechanism of action. OBJECTIVES: The aim of the present study was to examine the effect of acamprosate on cue reactivity and alcohol priming in alcohol-dependent patients. METHODS: In a double-blind design, 56 treatment seeking patients were randomized to 21 days of either acamprosate or placebo treatment and then participated in a series of cue- and alcohol-priming sessions. Alcohol cues consisted of a mixture of alcohol related visual, tactile, olfactory, and auditory stimuli. Non-alcohol-related cues were contextually similar but had no connection to alcohol. In the alcohol-priming procedure, patients were provided with an alcohol drink of their own choice at a dose corresponding to 0.20 gr. EtOH/kg bodyweight. Subjective, physiological, and biological measurements were recorded before and after each test session. Following study completion, all patients were referred to formal treatment. RESULTS: The results showed that acamprosate attenuated the subjective craving induced by alcohol priming in comparison to placebo-treated patients. Furthermore, acamprosate reduced alcohol-induced elevation in blood-cortisol levels. Lastly, there was a negative correlation between acamprosate plasma levels and alcohol craving following a priming drink. No effects of acamprosate on cue reactivity, or on the acute rewarding and sedating effects of the priming drink, were observed. CONCLUSION: These results suggest a potential mechanism by which acamprosate mediates its therapeutic effect in the treatment of alcoholism, by attenuating the urge to drink following an alcohol slip.

Predictors of outcome for short-term medically supervised opioid withdrawal during a randomized, multicenter trial of buprenorphine-naloxone and clonidine in the NIDA clinical trials network drug and alcohol dependence.

Few studies in community settings have evaluated predictors, mediators, and moderators of treatment success for medically supervised opioid withdrawal treatment. This report presents new findings about these factors from a study of 344 opioid-dependent men and women prospectively randomized to either buprenorphine-naloxone or clonidine in an open-label 13-day medically supervised withdrawal study. Subjects were either inpatient or outpatient in community treatment settings; however not randomized by treatment setting. Medication type (buprenorphine-naloxone versus clonidine) was the single best predictor of treatment retention and treatment success, regardless of treatment setting. Compared to the outpatient setting, the inpatient setting was associated with higher abstinence rates but similar retention rates when adjusting for medication type. Early opioid withdrawal severity mediated the relationship between medication type and treatment outcome with buprenorphine-naloxone being superior to clonidine at relieving early withdrawal symptoms. Inpatient subjects on clonidine with lower withdrawal scores at baseline did better than those with higher withdrawal scores; inpatient subjects receiving buprenorphine-naloxone did better with higher withdrawal scores at baseline than those with lower withdrawal scores. No relationship was found between treatment outcome and age, gender, race, education, employment, marital status, legal problems, baseline depression, or length/severity of drug use. Tobacco use was associated with worse opioid treatment outcomes. Severe baseline anxiety symptoms doubled treatment success. Medication type (buprenorphine-naloxone) was the most important predictor of positive outcome; however the paper also considers other clinical and policy implications of other results, including that inpatient setting predicted better outcomes and moderated medication outcomes.

Medical and Mental Health Status Among Drug Dependent Patients Participating in a Smoking Cessation Treatment Study.

Substance Abusers have a large number of medical and psychiatric problems, and 70-90% are smokers. The aim of this analysis was to examine the prevalence and correlates of medical and psychiatric problems in this sample of drug dependent patients who were participants in a multi-site study of smoking cessation interventions while engaged in substance abuse treatment. Descriptive analyses showed at baseline, 72.8% of participants had at least one medical problem and 64.1% had at least one psychiatric diagnosis. Medical problems correlated strongly with age, smoking severity, and pack-years; Psychiatric problems correlated with gender and ethnicity. Smoking cessation treatment was associated with a moderate reduction in the ASI Medical composite score. More research is needed on the possible effects of combined treatment of substance abuse and concurrent medical and psychiatric problems. Offering smoking cessation in conjunction with primary care may be a way to address the health needs of this population.

Cocaine cue versus cocaine dosing in humans: evidence for distinct neurophysiological response profiles.

Subjective, physiological and electroencephalographic (EEG) profiles were studied in cocaine dependent study participants in response to cocaine cue exposure or a dose of smoked cocaine. Both stimuli increased subjective ratings of cocaine high and craving, enhanced negative affect, and boosted plasma ACTH and skin conductance levels. However, cocaine dose produced a greater increase in high and a more prolonged increase in plasma ACTH, while cocaine cue produced a decline in skin temperature. Both stimuli produced increases in absolute theta, alpha and beta EEG power over the prefrontal cortex. However, interhemispheric EEG coherence over the prefrontal cortex decreased during cocaine cue exposure but increased following cocaine dose. Moreover, correlation analysis of subjective, physiological and EEG responding to cocaine cue and dose revealed distinct profiles. Delta and theta activity were associated with negative affect during cocaine cue exposure, but were associated with cocaine craving and reward following cocaine dosing. In both conditions, alpha activity was marker for anxiousness but not high. These data demonstrate similar subjective, physiological responding in clinical laboratory states of cocaine craving and reward. However, differences in EEG response profiles, and their relationship to function, indicate distinct neurophysiological mediators of cocaine craving and reward within the prefrontal cortex.

Evaluation of subjective effects of aripiprazole and methamphetamine in methamphetamine-dependent volunteers.

A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for methamphetamine (Meth) addiction. In this study, we investigated the safety and potential efficacy of aripiprazole, an antipsychotic agent acting on both dopamine and serotonin systems. We conducted a double-blind in-patient clinical pharmacology study to assess potential interactions between intravenous (i.v.) Meth (15 mg and 30 mg) and oral aripiprazole (15 mg). In addition, the effects of aripiprazole treatment on abstinence-related craving and cue-induced craving were evaluated. Participants included non-treatment-seeking, Meth-dependent patients (n=16), aged 18-45 yr, currently using Meth. Following baseline Meth dosing (15 mg and 30 mg), participants received 2 wk treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and Meth-related cues. Meth dosing (15 mg and 30 mg) was then repeated. Aripiprazole treatment had no effect on cue-induced Meth craving, or on daily baseline craving assessed over the course of medication treatment, although aripiprazole treatment was associated with increased craving independent of Meth dosing. Aripiprazole treatment was associated with significantly higher ratings on Addiction Research Center Inventory (ARCI) subscales reflecting euphoria and amphetamine-like effects following Meth dosing. Aripiprazole treatment was also associated with significant reductions in ratings of 'bad effects' and reductions on the ARCI subscale for sedation effects following Meth dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following Meth dosing, but had no other effects on cardiovascular responses to Meth. Aripiprazole treatment did not alter the pharmacokinetics of Meth. These findings indicate that aripiprazole treatment appears to be safe in volunteers with Meth dependence, although the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute Meth suggests that 15 mg aripiprazole is unlikely to be efficacious for the treatment of Meth dependence. Further research with lower doses of aripiprazole, possibly using study designs aimed at evaluating efficacy for relapse prevention, are needed before ruling out aripiprazole as a treatment for Meth dependence.

Smoking cessation treatment in community-based substance abuse rehabilitation programs.

Nicotine dependence is highly prevalent among drug- and alcohol-dependent patients. A multisite clinical trial of smoking cessation (SC) treatment was performed at outpatient community-based substance abuse rehabilitation programs affiliated with the National Drug Abuse Treatment, Clinical Trials Network. Cigarette smokers (N=225) from five methadone maintenance programs and two drug and alcohol dependence treatment programs were randomly assigned in a 2:1 ratio to receive either (1) SC treatment as an adjunct to substance abuse treatment-as-usual (TAU) or (2) substance abuse TAU. Smoking cessation treatment consisted of 1 week of group counseling before the target quit date and 8 weeks of group counseling plus transdermal nicotine patch treatment (21 mg/day for Weeks 1-6 and 14 mg/day for Weeks 7 and 8) after the target quit date. Smoking abstinence rates in SC, 10%-11% during treatment and 5%-6% at the 13- and 26-week follow-up visits, were significantly better than those in TAU during treatment (p< .01). In addition, SC was associated with significantly greater reductions as compared with TAU in cigarettes smoked per day (75% reduction, p< .001), exhaled carbon monoxide levels (p< .001), cigarette craving (p< .05), and nicotine withdrawal (p< .05). Smoking cessation did not differ from TAU on rates of retention in substance abuse treatment, abstinence from primary substance of abuse, and craving for primary substance of abuse. Compliance with SC treatment, moderate at best, was positively associated with smoking abstinence rates. Smoking cessation treatment resulted in significant reductions in daily smoking and modest smoking abstinence rates without having an adverse impact on substance abuse rehabilitation when given concurrently with outpatient substance abuse treatment. Substance abuse treatment programs should not hesitate to implement SC for established patients.

Effects of topiramate on cue-induced cigarette craving and the response to a smoked cigarette in briefly abstinent smokers.

RATIONALE: Clinical studies have shown that topiramate, an anticonvulsant medication, may be effective as a treatment for smoking cessation. However, less is known about topiramate effects on nicotine withdrawal and craving and its interactions with a smoked cigarette. OBJECTIVES: The objective of this study was to investigate the effects of topiramate treatment on abstinence-related nicotine withdrawal, cue-induced cigarette craving, and the acute effects of a smoked cigarette. MATERIALS AND METHODS: Fifteen female and 25 male cigarette smokers were randomly assigned to 9-day treatment with topiramate (final titration dose, 75 mg/day) or placebo. On the last day of treatment, after a 3-h smoke-free abstinence period, participants were evaluated for symptoms of nicotine withdrawal and then underwent cigarette and neutral cue reactivity testing. Thirty minutes after completing cue exposure testing, participants were then evaluated for the acute effects of a smoked cigarette. Cue reactivity and acute smoking measures included subjective ratings of cigarette craving and withdrawal and physiological measures of skin conductance and temperature, heart rate, and blood pressure. In addition, smoking topography was measured using a puff volume apparatus. RESULTS: Topiramate treatment enhanced subjective ratings of withdrawal after the 3-h abstinence period and reduced pre-cue skin conductance levels. Cigarette cue exposure resulted in a moderate increase in craving, which was unaffected by treatment. Topiramate treatment enhanced the rewarding effects of a smoked cigarette, even while participants smoked less per puff and achieved lower plasma nicotine levels. CONCLUSION: Results suggest that topiramate enhances both nicotine withdrawal and reward. These findings question the utility of topiramate treatment for smoking cessation.

Attitudes toward the integration of smoking cessation treatment into drug abuse clinics.

This article examines the variables associated with the presence of smoking cessation interventions in drug abuse treatment units, as well as staff attitudes toward the integration of smoking cessation services as a component of care. Surveys were administered to 106 organizations, 348 treatment clinics, and 3,786 employees in agencies that participated in the National Drug Abuse Treatment Clinical Trials Network. Organizational factors, attributes of the treatment setting, and staff attitudes toward smoking cessation treatment were assessed. Use of smoking cessation interventions was associated with the number of additional services offered at clinics, residential detoxification services, and attitudes of the staff toward smoking cessation treatment. Staff attitudes toward integrating smoking cessation services in drug treatment were influenced by the number of pregnant women admitted, the number of ancillary services provided, the attitudes of staff toward evidence-based practices, and whether smoking cessation treatment was offered as a component of care.

Implementation of a Smoking Cessation Treatment Study at Substance Abuse Rehabilitation Programs: Smoking Behavior and Treatment Feasibility Across Varied Community-based Outpatient Programs.

Cigarette smoking is widely prevalent among individuals in treatment for drug or alcohol dependence; however, the treatment of nicotine addiction in this population has numerous obstacles at both programmatic and patient levels. Despite these difficulties, recent studies have demonstrated moderate success in implementing smoking cessation treatment in drug rehabilitation programs. The National Drug Abuse Treatment Clinical Trials Network sponsored a smoking cessation study in 13 community-based outpatient substance abuse rehabilitation programs across the country. The study evaluated the effectiveness of smoking cessation treatment provided as an adjunct to substance abuse treatment-as-usual. This report summarizes the practical and clinical experiences encountered at each of the study sites with regard to implementing the smoking cessation treatment intervention. Smoking behavior of the treatment clientele was assessed by anonymous survey at each site. In addition, sites were systematically characterized by using program review and assessment tools completed by the respective staff and program directors at the site. Survey and recruitment data indicated that cigarette smoking is more prevalent and that smoking cessation treatment is more feasible, in methadone maintenance treatment programs. Other factors associated with smoking behavior and with the recruitment of drug- and alcohol-dependent individuals into the smoking cessation treatment study are described.

Topographic imaging of quantitative EEG in response to smoked cocaine self-administration in humans.

Quantitative electroencephalographic (qEEG) profiles were studied in cocaine-dependent patients in response to an acute, single-blind, self-administered dose of smoked cocaine base (50 mg) vs placebo. qEEG data were averaged using neurometric analytical methods and the spectral power of each primary bandwidth was computed and topographically imaged. Additional measures included cocaine-induced high, craving, and related subjective ratings, heart rate, blood pressure, and plasma cortisol and homovanillic acid levels. In all, 13 crack cocaine-dependent subjects were tested. Cocaine produced a rapid increase in subjective ratings of cocaine high and good drug effect, and a more persistent increase in cocaine craving and nervousness. Cocaine also produced a rapid rise in heart rate and a prolonged increase in plasma cortisol. Placebo, administered in the context of cocaine cues and dosing expectations, had no cocaine-like subjective or physiological effects. Cocaine produced a rapid increase in absolute theta, alpha, and beta power over the prefrontal cortex (FP1, FP2), lasting up to 25 min after dosing. The increase in theta power was correlated with good drug effect, and the increase in alpha power was correlated with nervousness. Cocaine also produced a similar increase in delta coherence over the prefrontal cortex, which was positively correlated with plasma cortisol, and negatively correlated with nervousness. Placebo resulted in an increase in alpha power over the prefrontal cortex. These data demonstrate the involvement of prefrontal cortex in the qEEG response to acute cocaine. Evidence indicates slow wave qEEG, delta and theta activity, involvement in the rewarding properties of cocaine.

A placebo-controlled screening trial of celecoxib for the treatment of cocaine dependence.

AIMS: To conduct a medication screening trial study on the efficacy of celecoxib versus placebo for the treatment of cocaine dependence. DESIGN: A modified blinded, parallel group study in an outpatient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. SETTING: The study was performed at the New York Medications Development Research Unit (MDRU). PARTICIPANTS: All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Twenty-three participants were enrolled in the treatment phase of the study. INTERVENTION: After a 2-week screening period, subjects were assigned randomly to receive either celebrex (200 mg/day) or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. MEASUREMENTS: Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs and extrapyramidal side-effects tests. RESULTS: Study retention was similar across both treatment groups and safety measures indicated that celecoxib was moderately tolerated. Cocaine use, as measured by self-report and urine BE levels at end of treatment, indicated weaker improvement in the celecoxib group. Reductions in the intensity of cocaine craving were also weaker in the celecoxib group. Cocaine abstinence rates, global impression scores and all other related psychometric measures did not differ significantly between treatment groups. CONCLUSION: This study does not support the effectiveness of celecoxib for the treatment of cocaine dependence.

A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/L-carnitine for the treatment of cocaine dependence.

AIMS: To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L-carnitine combination versus placebo for the treatment of cocaine dependence. DESIGN: A four-arm, modified blinded, parallel group study in an out-patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design. SETTING: The study was performed at the New York Medications Development Research Unit (MDRU). PARTICIPANTS: All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Sixty-eight participants were enrolled with 39 completing the study. INTERVENTION: After a 2-week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L-carnitine (500 mg/day) combination or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment. MEASUREMENTS: Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side-effects tests. RESULTS: Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self-report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed. CONCLUSION: This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/L-carnitine combination for the treatment of cocaine dependence.