FAAH variant Pro129Thr modulates subjective effects produced by cocaine administration.

BACKGROUND AND OBJECTIVES: The endogenous cannabinoid anandamide (AEA), an agonist at type-1 cannabinoid (CB1) receptors, is metabolized by fatty acid amide hydrolase (FAAH). The common variant rs324420 C->A within the FAAH gene on chromosome 1 codes for a missense substitution (Pro129Thr), resulting in decreased FAAH activity and increased endocannabinoid potentiation. This FAAH variant has been linked to alterations in mood and stress reactivity, as well as being independently linked to increased risk for addiction. We hypothesized that cocaine use disordered (CUD) participants with the FAAH Pro129 Thr variant would exhibit a distinct profile of cocaine-induced subjective effects in the laboratory. METHODS: A total of 70 CUD participants received intravenous doses of saline (placebo, 0 mg) and cocaine (20, 40 mg) in a lab-controlled setting and rated 10 subjective effect measures prior to and following saline and cocaine administration, using a Visual Analog Scale (VAS). RESULTS: The variant allele was associated with increased cocaine-induced subjective ratings for "Drug Effect," "High," and "Depressed." The prevalence of the variant allele A and the AA genotypes were greater in our CUD group than in the general population (A allele: 47% vs. 34%; AA genotype: 30% vs. 13%; p < .05). Finally, the reported amount and frequency of tobacco and cocaine use was higher in subjects with the AC/AA allele. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: These results add to existing evidence that this variant of the FAAH genotype may be over-represented among those who have CUD, and this over-representation may result from greater subjective responses to cocaine administration. (Am J Addict 2018;27:567-573).

Comparison of three measurement models of discounting among individuals with methamphetamine use disorder.

BACKGROUND AND OBJECTIVES: Delay discounting is associated with numerous clinically significant aspects of substance use disorders (SUDs). Recent studies have demonstrated that different models for assessing discounting may result in disparate conclusions. The current study compared two discounting tasks: money now versus money later (M-M) and methamphetamine now versus money later (MA-M) among non-treatment seeking individuals (N = 59) with methamphetamine use disorder (MAUD). Results from each task were assessed using three different models for assessing delay discounting. METHODS: Discounting data were fit to three models of discounting, log k using Mazur's hyperbolic formula, area under the curve (AUC), and an alternative AUC model in which the delay values have been log transformed (AUClog). RESULTS: For both discounting tasks, the distribution of model-related outcomes were normally distributed when using log k and AUClog, but skewed for AUC. Discounting in the MA-M task was significantly greater compared to the M-M task when using log k and AUClog but not AUC. CONCLUSION: To our knowledge, the current study is the first to report significantly greater discounting in a MA-M relative to M-M discounting task among individuals with MAUD, an outcome consistent with other psychomotor stimulants and drugs of abuse. SCIENTIFIC SIGNIFICANCE: The differential results observed across the three discounting models reaffirm potential issues with AUC noted in recent studies and highlight that researchers must be cautious when deciding on their final model of discounting. (Am J Addict 2018;XX:1-8).

Exenatide once weekly for smoking cessation: study protocol for a randomized clinical trial.

BACKGROUND: Cigarette smoking is the greatest preventable cause of morbidity and premature mortality in the United States. Approved pharmacological treatments for smoking cessation are marginally effective, underscoring the need for improved pharmacotherapies. A novel approach might use glucagon-like peptide-1 (GLP-1) agonists, which reduce alcohol and drug use in preclinical studies. GLP-1 is produced in the intestinal L-cells and in the hindbrain. The peptide maintains glucose homeostasis and reduces food intake. Several GLP-1 agonists are used clinically to treat type 2 diabetes and obesity, but none have been tested in humans to reduce smoking. AIMS: We will examine whether extended-release exenatide reduces smoking, craving, and withdrawal symptoms, as well as cue-induced craving for cigarettes. METHODS: We will enroll prediabetic and/or overweight treatment seeking smokers (n = 90) into a double-blind, placebo-controlled, randomized clinical trial. Participants will be randomized in a 1:1 ratio to receive exenatide or placebo. All participants will receive transdermal nicotine replacement therapy (NRT) and behavioral counseling. Abstinence from smoking (verified via expired CO level of ≤5 ppm), craving (Questionnaire of Smoking Urges score), and withdrawal symptoms (Wisconsin Scale of Withdrawal Symptoms score) will be assessed weekly during 6 weeks of treatment and at 1 and 4 weeks posttreatment. Cue-induced craving for cigarettes will be assessed at baseline and at 3 weeks of treatment following virtual reality exposure. EXPECTED OUTCOMES: We hypothesize that exenatide will increase the number of participants able to achieve complete smoking abstinence above that achieved via standard NRT and that exenatide will reduce craving and withdrawal symptoms, as well as cue-induced craving for cigarettes.

Guanfacine Attenuates Adverse Effects of Dronabinol (THC) on Working Memory in Adolescent-Onset Heavy Cannabis Users: A Pilot Study.

The cannabinoid-1 receptor (CB1R) agonist Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, adversely effects working memory performance in humans. The α2A-adrenoceptor (AR) agonist guanfacine improves working memory performance in humans. The authors aimed to determine the effects of short-term (6 days) treatment with guanfacine on adverse cognitive effects produced by THC. Employing a double-blind, placebo-controlled crossover design, the cognitive, subjective, and cardiovascular effects produced by oral THC (20 mg) administration were determined twice in the same cannabis users: once after treatment with placebo and once after treatment with guanfacine (3 mg/day). Compared with performance at baseline, THC negatively affected accuracy on spatial working memory trials while participants were maintained on placebo (p=0.012) but not guanfacine (p=0.497); compared with placebo, accuracy was significantly (p=0.003, Cohen's d=-0.640) improved while individuals were treated with guanfacine. Similarly, compared with baseline, THC increased omission errors on an attentional task while participants were maintained on placebo (p=0.017) but not on guanfacine (p=0.709); compared with placebo, there were significantly (p=0.034, Cohen's d=0.838) fewer omissions while individuals were maintained on guanfacine. Although THC increased visual analog scores of subjective effects and heart rate, these increases were similar during treatment with placebo and guanfacine. THC did not significantly affect performance of a recognition memory task or blood pressure while individuals were maintained on either treatment. Although preliminary, these results suggest that guanfacine warrants further testing as a potential treatment for cannabis-induced cognitive deficits.

A COMPARISON OF MAZUR'S k AND AREA UNDER THE CURVE FOR DESCRIBING STEEP DISCOUNTERS.

Delay discounting describes how a reward loses value as a function of increasing delay to its receipt and has been reliably associated with a variety of vulnerable populations including those with substance use disorders (SUDs). Two commonly used models to assess delay discounting in the field of SUDs include log k derived from Mazur's hyperbolic equation and area under the curve (AUC). In the current study, we compared log k with AUC on delay discounting data obtained from non-treatment seeking, cocaine- and methamphetamine-dependent volunteers. We specifically chose this population in order to obtain a distribution of relatively steep discounters. The results show that the relationship between AUC and log k is better described by a quadratic rather than a linear function. In other words, changes in discounting, as measured by AUC and log k, are reflected differently across a range of obtained responses. Additionally, the distribution of AUC values was skewed, which appears to be more likely among populations exhibiting greater discounting. Finally, closer examination of indifference points revealed that AUC was almost perfectly predicted by the area from the two longest delays, with relatively less input from shorter delays. Given these results, researchers should exercise additional caution when deciding which method to assess discounting data and how final results are to be interpreted, particularly when dealing with relatively high rates of discounting. High rates of discounting are likely in populations with impulsive disorders such as those with SUDs.

The limited impact that cocaine use patterns have on neurocognitive functioning in individuals with cocaine use disorder.

It is well-documented in the literature that cocaine use is associated with neurocognitive impairment. The manner in which patterns of cocaine use, such as years of use, recent use over the past month, and daily amount of cocaine use, moderate neurocognition has been studied in a relatively piecemeal manner. Hence, the purpose of the study was to evaluate whether cocaine use patterns modulate neurocognition in individuals with cocaine use disorder. Cocaine users who were cocaine-negative ( n=125) were divided into tertiles based on cocaine use patterns and the performances of the highest and lowest groups were compared on the following cognitive measures: Continuous Performance Task-II, n-back, and Hopkins Verbal Learning Task-Revised. Participants with cocaine use disorder who used for more years (25.2±0.6 versus 10.1±0.6 years; mean±standard error of the mean) and who had more recent cocaine use over the past month (26.3±0.5 versus 6.0±0.6 days) did not differ significantly on any of the neurocognitive variables when compared to those with use patterns of shorter duration and less frequency (all p's >0.05). Lastly, participants reporting the greatest amount daily cocaine use (1.8±0.0 g) demonstrated better performance on an auditory working memory task when compared to those with the lowest daily use (0.7±0.0 g; p=0.04). While one might expect that individuals who used greater amounts of cocaine over longer periods of time would demonstrate relatively poorer performance on measures of neurocognition, particularly in the initial phase of abstinence, our findings did not confirm this. While speculative, a potential explanation for these findings is that after an individual uses cocaine for a certain number of years, or uses a specific amount over time, then the deleterious effects of cocaine on neurocognition stabilizes, and increased duration of cocaine use does not further exacerbate those impairments.

Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes.

OBJECTIVE: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. METHODS: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self-reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. RESULTS: Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carrying the TPH2 rs4290270 A allele reported higher 'good effect' and lower 'depressed' effect relative to the TT genotype group. Those carrying the SLC6A4 5-HTTLPR S' allele reported greater 'desire' and 'access' compared with the L'L' genotype group. CONCLUSION: These findings indicate that TPH1, TPH2, and SLC6A4 variants moderate the subjective effects of cocaine in non-treatment-seeking cocaine-dependent participants.

Electrocardiographic characteristics in individuals with cocaine use disorder.

BACKGROUND AND OBJECTIVES: Chronic cocaine use has been linked to several abnormalities in cardiac functioning. The objective of this study was to further characterize baseline heart rate and electrocardiograph (ECG) profiles of individuals with cocaine use disorder (CUD) by evaluating demographic and drug use variables that may impact cardiovascular profiles. METHODS: Participants with CUD (n = 335, primarily African-American males) provided demographic and drug use data and ECG profiles (eg, heart rate, PR Interval, QRS, and QTc) were obtained via 12-lead ECG. RESULTS: Forty-eight percent and ten percent of cocaine users met criteria for sinus bradycardia (heart rate ≤60) and severe bradycardia (heart rate ≤50), respectively. Females had significantly higher heart rate (p = .020, d = .30) and QTc (p < .001, d = .75) and significantly lower QRS (p = .002, d = .42) in comparison to males. Those who were cocaine positive had higher QTc (p = .025, d = .26) with a higher prevalence of bradycardia (chi-square = 3.91, p = .048) than those who were negative. Cocaine users who also used alcohol had significantly lower PR Interval (p = .003, d = .36), QRS (p = .014, d = .29), and QTc (p = .037, d = .25) than those who denied alcohol use. CONCLUSIONS: These findings characterize the baseline heart rate and ECG profiles of individuals with CUD, confirm previous reports of cocaine-induced alterations in cardiovascular function, and demonstrate factors impacting cardiovascular profiles. SCIENTIFIC SIGNIFICANCE: While exploratory, these results suggest the presence of bradycardia may serve as a useful biomarker for initiating therapy for individuals with CUD and averting potential adverse cardiovascular events. Future prospective studies are needed to assess this possibility. (Am J Addict 2017;26:221-227).

The relationship between premorbid IQ and neurocognitive functioning in individuals with cocaine use disorders.

OBJECTIVE: To determine whether premorbid IQ mediates performance on neurocognitive tests in individuals diagnosed with cocaine use disorder (CUD). METHOD: Recently abstinent cocaine users (N = 113) completed measures sensitive to the effects of cocaine on cognition: Conners' Continuous Performance Task-II (CPT-II), n-back working memory test, and Hopkins Verbal Learning Task-Revised (HVLT-R). Premorbid IQ was calculated using the Oklahoma Premorbid Intelligence Estimate, which integrates scores from the Wechsler Adult Intelligence Scale-III and demographic variables. Participants were grouped according to their premorbid IQ using commonly accepted classifications of ability level (above average [>110], average [90-109], and below average [<90]) and comparisons in neurocognitive performance were performed using one-way analysis of variance. RESULTS: Significant differences were detected between groups on the HVLT-R including Trial 1 (p = .002), total word recall across the 3 list-learning trials (p < .001), and recall following a delay (p < .001). Significant differences were also detected on the N-back, including auditory and visual accuracy (p = .022 and p < .001, respectively) and mean and maximum block length (p < .001). Although significant differences were observed between the above average and average groups (mean effect size = .418 [Cohen's d]), the magnitude of group differences was greatest between the average and below average groups (mean effect size = .716). CONCLUSIONS: These results raise questions as to whether the neurocognitive impairment observed in individuals diagnosed with CUD predated the onset of cocaine use or whether the impairments were caused by cocaine use. Because these impairments are potential risk factors for poor treatment outcomes, it is important to consider the need to modify treatment programs to account for lower premorbid IQ. (PsycINFO Database Record

Treadmill exercise improves fitness and reduces craving and use of cocaine in individuals with concurrent cocaine and tobacco-use disorder.

Exercise may be a useful treatment for substance use disorders. Participants (N=24) included treatment-seeking individuals with concurrent cocaine and tobacco-use disorder (cigarette smokers). Participants were randomized to either running or walking (30min per session, 3 times per week) or sitting (control condition) for 4 consecutive weeks. Several metrics indicated significant differences among runners, walkers, and sitters during sessions, including mean distance covered and calories burned. In addition, remote physiological monitoring showed that the groups differed significantly according to mean maximum heart rate (HR), respiration, and locomotor activity. Across the 4-week study, exercise improved fitness measures including significantly decreasing resting HR. Though not statistically significant, exercise improved abstinence from cocaine and increased self-reports of no cocaine use in last 24h. In general, reductions in tobacco use and craving were not as robust. To our knowledge, this is the first study to evaluate the effects of a multi-week exercise program in individuals with concurrent cocaine and tobacco-use disorder. The data clearly show significant improvements in basic fitness measures and several indices reveal that exercise improved both self-report and biochemically verified reports of cocaine abstinence. Taken together, the data from this study provide preliminary evidence for the efficacy of exercise for improving fitness and reducing cocaine use.

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

OBJECTIVES: We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals. METHODS: This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40 mg, IV), and subjective responses were assessed 15 min before receiving an infusion and at 5 min intervals for the subsequent 20 min. The rs1048101 variant of the α1A-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine. RESULTS: Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype showed greater responses for 'desire' (P<0.0001), 'high' (P<0.0001), 'any drug effect' (P<0.0001), 'like cocaine' (P<0.0001), and 'likely to use cocaine if given access' (P<0.05) with experiment-wise significance. CONCLUSION: This study indicates that the ADRA1A genotype could be used to identify individuals for whom acute cocaine exposure may be more rewarding and by inference may result in greater difficulty in establishing and/or maintaining abstinence from cocaine.

Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.

BACKGROUND: In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. METHODS: Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at .0, .18, and .36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. RESULTS: Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo-treated participants. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil. (Am J Addict 2016;25:392-399).

Doxazosin XL reduces symptoms of posttraumatic stress disorder in veterans with PTSD: a pilot clinical trial.

BACKGROUND: Serotonin and norepinephrine reuptake inhibitors are effective first-line agents for the treatment of posttraumatic stress disorder (PTSD), but treatment is associated with a range of side effects that limit treatment adherence. Prazosin, an α1-noradrenergic antagonist with a half-life of roughly 2-3 hours, has shown promise in the treatment of sleep disturbance and nightmares. Doxazosin extended release (XL) is also an α1-noradrenergic antagonist but with a half-life of approximately 15-19 hours. METHODS: We conducted a double-blind, placebo-controlled, within-subjects trial to characterize the impact of doxazosin XL on PTSD symptoms. Participants (N = 8) were diagnosed using DSM-IV criteria. They completed the study twice, once during treatment with doxazosin XL and once during treatment with matched placebo, with a 2-week washout separating the 2 episodes. Doxazosin XL was titrated from 4 mg/d to 16 mg/d over 12 days. After 4 days of treatment at 16 mg/d or the equivalent number of placebo capsules, PTSD symptoms were assessed using the Clinician-Administered PTSD Scale (CAPS17) and the PTSD Checklist-Military version (PCL-M). Repeated measures analysis of variance were used to evaluate effects of treatment, time, and treatment × time. This study was run from November 20, 2013, to June 31, 2014. RESULTS: Doxazosin XL treatment was associated with a nonsignificant treatment × time reduction in ratings on the CAPS hyperarousal subscale (P < .10) (but not on the CAPS Total score) and with significant treatment × time reductions in PCL-M ratings (P = .002). CONCLUSIONS: Doxazosin XL may be an effective alternative to prazosin for the treatment of some PTSD symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:NCT02308202.

Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study.

BACKGROUND: Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine. We characterized the impact of a wider range of perindopril doses on methamphetamine-induced effects in a larger group of non-treatment-seeking, methamphetamine-using volunteers. METHODS: Before treatment, participants received 30mg methamphetamine. After 5 to 7 days of perindopril treatment (0, 4, 8, or 16mg/d), participants received 15 and 30mg of methamphetamine on alternate days. Before and after treatment, participants rated subjective effects and cardiovascular measures were collected. RESULTS: Prior to treatment with perindopril, there were no significant differences between treatment groups on maximum or peak subjective ratings or on peak cardiovascular effects. Following perindopril treatment, there were significant main effects of treatment on peak subjective ratings of "anxious" and "stimulated"; compared to placebo treatment, treatment with 8mg perindopril significantly reduced peak ratings of both anxious (P=.0009) and stimulated (P=.0070). There were no significant posttreatment differences between groups on peak cardiovascular effects. CONCLUSIONS: Moderate doses of perindopril (8mg) significantly reduced peak subjective ratings of anxious and stimulated as well as attenuated many other subjective effects produced by methamphetamine, likely by inhibiting angiotensin II synthesis. Angiotensin II is known to facilitate the effects of norepinephrine, which contributes to methamphetamine's subjective effects. The lack of a classic dose-response function likely results from either nonspecific effects of perindopril or from between-group differences that were not accounted for in the current study (i.e., genetic variations and/or caffeine use). The current findings suggest that while angiotensin-converting enzyme inhibitors can reduce some effects produced by methamphetamine, more consistent treatment effects might be achieved by targeting components of the renin-angiotensin system that are downstream of angiotensin-converting enzyme.

Safety and Preliminary Efficacy of the Acetylcholinesterase Inhibitor Huperzine A as a Treatment for Cocaine Use Disorder.

BACKGROUND: Cholinergic transmission is altered by drugs of abuse and contributes to psychostimulant reinforcement. In particular, acetylcholinesterase inhibitors, like huperzine A, may be effective as treatments for cocaine use disorder. METHODS: The current report describes results from a double-blind, placebo-controlled study in which participants (n=14-17/group) were randomized to huperzine A (0.4 or 0.8 mg) or placebo. Participants received randomized infusions of cocaine (0 and 40 mg, IV) on days 1 and 9. On day 10, participants received noncontingent, randomized infusions of cocaine (0 and 20mg, IV) before making 5 choices to receive additional infusions. RESULTS: Huperzine A was safe and well-tolerated and compared with placebo, treatment with huperzine A did not cause significant changes in any cocaine pharmacokinetic parameters (all P>.05). Time-course and peak effects analyses show that treatment with 0.4 mg of huperzine A significantly attenuated cocaine-induced increases of "Any Drug Effect," "High," "Stimulated," "Willing to Pay," and "Bad Effects" (all P>.05). CONCLUSIONS: The current study represents a significant contribution to the addiction field since it serves as the first published report on the safety and potential efficacy of huperzine A as a treatment for cocaine use disorder.

Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans.

Pramipexole is a D3 dopamine receptor-preferring agonist indicated for the treatment of Parkinson disease. Studies associate pramipexole with pathological gambling and impulse control disorders suggesting a role for D3 receptors in reinforcement processes. Clinical studies showed pramipexole decreased cocaine craving and reversed central deficits in individuals with cocaine use disorder. Preclinical studies have shown acute administration of pramipexole increases cocaine's reinforcing effects whereas other reports suggest chronic pramipexole produces tolerance to cocaine. In a randomized, double-blind, placebo-controlled study we examined the impact of pramipexole treatment on the subjective effects produced by cocaine in volunteers with cocaine use disorder. Volunteers received pramipexole titrated up to 3.0mg/d or placebo over 15 days. Participants then received intravenous cocaine (0, 20 and 40mg) on day 15. Cardiovascular and subjective effects were obtained with visual analog scales at time points across the session. Pramipexole alone increased peak heart rate following saline and diastolic blood pressure following cocaine. Pramipexole produced upwards of two-fold increases in positive subjective effects ratings following cocaine. These results indicate that chronic D3 receptor activation increases the subjective effects of cocaine in humans. Caution should be used when prescribing pramipexole to patients that may also use cocaine.

Application of programmable bio-nano-chip system for the quantitative detection of drugs of abuse in oral fluids.

OBJECTIVE: There is currently a gap in on-site drug of abuse monitoring. Current detection methods involve invasive sampling of blood and urine specimens, or collection of oral fluid, followed by qualitative screening tests using immunochromatographic cartridges. While remote laboratories then may provide confirmation and quantitative assessment of a presumptive positive, this instrumentation is expensive and decoupled from the initial sampling making the current drug-screening program inefficient and costly. The authors applied a noninvasive oral fluid sampling approach integrated with the in-development chip-based Programmable bio-nano-chip (p-BNC) platform for the detection of drugs of abuse. METHOD: The p-BNC assay methodology was applied for the detection of tetrahydrocannabinol, morphine, amphetamine, methamphetamine, cocaine, methadone and benzodiazepines, initially using spiked buffered samples and, ultimately, using oral fluid specimen collected from consented volunteers. RESULTS: Rapid (∼10min), sensitive detection (∼ng/mL) and quantitation of 12 drugs of abuse was demonstrated on the p-BNC platform. Furthermore, the system provided visibility to time-course of select drug and metabolite profiles in oral fluids; for the drug cocaine, three regions of slope were observed that, when combined with concentration measurements from this and prior impairment studies, information about cocaine-induced impairment may be revealed. CONCLUSIONS: This chip-based p-BNC detection modality has significant potential to be used in the future by law enforcement officers for roadside drug testing and to serve a variety of other settings, including outpatient and inpatient drug rehabilitation centers, emergency rooms, prisons, schools, and in the workplace.

Genetic variation of the dopamine transporter (DAT1) influences the acute subjective responses to cocaine in volunteers with cocaine use disorders.

OBJECTIVE: The aim of this study was to identify gene variants of DAT1 (SLC6A3) that modulate subjective responses to acute cocaine exposure. METHODS: Non-treatment-seeking volunteers (n=66) with cocaine use disorders received a single bolus infusion of saline and cocaine (40 mg, intravenous) in a randomized order. Subjective effects were assessed with visual analog scales administered before (-15 min) and up to 20 min after infusion. Ratings of subjective effects were normalized to baseline, and saline infusion values were subtracted. Data were analyzed using repeated measures analysis of variance. DNA from the participants was genotyped for the DAT1 intron 8 (rs3836790) and 3'-untranslated region (rs28363170) variable number of tandem repeats. RESULTS: Participants were mostly male (∼80%) and African American (∼70%). No differences were found among drug use variables between groups for either polymorphism. Carriers of the 9-allele of the DAT1 3'-untranslated region (9,9 and 9,10) exhibited greater responses to cocaine for 'high', 'any drug effect', 'anxious', and 'stimulated' (all P-values<0.001) compared with individuals homozygous for the 10-allele. For the intron 8 polymorphism, individuals homozygous for the 6-allele exhibited greater responses for 'anxious' compared with carriers of the 5-allele (P<0.001). Individuals possessing the genotype pattern of 10,10 and at least one 5-allele reported lower responses to 'good effects', 'bad effects', 'depressed', and 'anxious' (all P-values<0.01). CONCLUSION: The data presented here show for the first time support for the hypothesis that genetic differences in DAT1 contribute to the variation in subjective responses to cocaine among participants with cocaine use disorders.

Evaluation of the dopamine ß-hydroxylase (DßH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

In the present study, we tested the hypothesis that the potent and selective dopamine-ß-hydroxylase (DßH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.

Next Generation Programmable Bio-Nano-Chip System for On-Site Detection in Oral Fluids.

Current on-site drug of abuse detection methods involve invasive sampling of blood and urine specimens, or collection of oral fluid, followed by qualitative screening tests using immunochromatographic cartridges. Test confirmation and quantitative assessment of a presumptive positive are then provided by remote laboratories, an inefficient and costly process decoupled from the initial sampling. Recently, a new noninvasive oral fluid sampling approach that is integrated with the chip-based Programmable Bio-Nano-Chip (p-BNC) platform has been developed for the rapid (~ 10 minutes), sensitive detection (~ ng/ml) and quantitation of 12 drugs of abuse. Furthermore, the system can provide the time-course of select drug and metabolite profiles in oral fluids. For cocaine, we observed three slope components were correlated with cocaine-induced impairment using this chip-based p-BNC detection modality. Thus, this p-BNC has significant potential for roadside drug testing by law enforcement officers. Initial work reported on chip-based drug detection was completed using 'macro' or "chip in the lab" prototypes, that included metal encased "flow cells", external peristaltic pumps and a bench-top analyzer system instrumentation. We now describe the next generation miniaturized analyzer instrumentation along with customized disposables and sampling devices. These tools will offer real-time oral fluid drug monitoring capabilities, to be used for roadside drug testing as well as testing in clinical settings as a non-invasive, quantitative, accurate and sensitive tool to verify patient adherence to treatment.