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.

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).

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).

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 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.

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.

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).

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.

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.

Safety and efficacy of varenicline to reduce positive subjective effects produced by methamphetamine in methamphetamine-dependent volunteers.

Methamphetamine use is increasing in the US. Although there are no Food and Drug Administration (FDA)-approved medications for methamphetamine dependence, preclinical and clinical studies suggest that methamphetamine users may benefit from treatments that enhance cholinergic neurotransmission. Consequently, we determined the safety and the efficacy of varenicline treatment, a partial agonist at α4ß2 and a full agonist at α7 nicotinic acetylcholine receptors, to reduce positive subjective effects produced by smoked methamphetamine. Additionally, the effects of treatment with varenicline on the cardiovascular and reinforcing effects of methamphetamine were determined. We conducted a double-blind, placebo-controlled, within-subjects trial of varenicline vs. placebo in methamphetamine-dependent volunteers who were not seeking treatment. Participants were randomly assigned to receive one dose of varenicline (0, 1, or 2 mg) po BID, titrated up to the target dose over days 1-7, during each of three separate inpatient phases. Safety measures included the frequency, duration, severity, and relatedness of adverse events reported. Positive subjective effects included 'Any drug effect', 'High', 'Good effects', 'Stimulated', and 'Drug liking', which were rated by participants before and for 1 h after smoking methamphetamine (0, 10, and 30 mg). There were no serious adverse events and no differences in adverse events reported during the three phases. Varenicline (2 mg) significantly reduced ratings of 'Any drug effect' and 'Stimulated', as well as attenuated ratings of 'High', 'Drug liking', and 'Good effects', produced by methamphetamine (30 mg). The ability of varenicline to attenuate the positive subjective effects of methamphetamine in the laboratory suggests that varenicline should continue to be explored as a treatment for methamphetamine dependence.

Acute modafinil exposure reduces daytime sleepiness in abstinent methamphetamine-dependent volunteers.

The purpose of this study was to evaluate the effects of acute, oral modafinil (200 mg) exposure on daytime sleepiness in methamphetamine (Meth)-dependent individuals. Eighteen Meth-dependent subjects were enrolled in a 7-d inpatient study and were administered placebo or modafinil on day 6 and the counter-condition on day 7 (randomized) of the protocol. Subjects completed several subjective daily assessments (such as the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Beck Depression Inventory and visual analogue scale) throughout the protocol as well as objective assessments on days 5-7, when the Multiple Sleep Latency Test was performed. The results of the current study suggest that short-term abstinence from Meth is associated with increased daytime sleepiness and that a single dose of 200 mg modafinil reduces daytime somnolence in this population. In addition, a positive correlation was found between subjective reporting of the likelihood of taking a nap and craving and desire for Meth, as well as the likelihood of using Meth and whether Meth would make the participant feel better. The results of this study should be considered when investigating candidate medications for Meth-dependence, especially in those individuals who attribute their Meth use to overcoming deficits resulting from sleep abnormalities.

The angiotensin-converting enzyme inhibitor perindopril treatment alters cardiovascular and subjective effects of methamphetamine in humans.

A variety of medications have been assessed for their potential efficacy for the treatment of methamphetamine dependence. We conducted this study in an attempt to evaluate the potential of a novel class of medications, angiotensin-converting enzyme inhibitors, as treatments for methamphetamine dependence. All participants met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, third revision (DSM-IV-TR) criteria for methamphetamine abuse or dependence and were not seeking treatment at the time of study entry. The study was conducted using a double-blind design. Subjects received a baseline series of intravenous (IV) doses of methamphetamine (15 mg and 30 mg) and placebo. Subjects received a second identical series of methamphetamine doses 3 and 5 days after initiation of once-daily oral placebo or perindopril treatment. The dose of perindopril was 2 mg, 4mg, or 8 mg administered in the morning. Perindopril treatment was tolerated well. There were no main effects of perindopril on methamphetamine-induced changes in cardiovascular or subjective effects. There were significant perindoprilmethamphetamine interactions for diastolic blood pressure and for ratings of "Any Drug Effect", indicating inverted U dose-effect functions for these indices.

Modafinil administration improves working memory in methamphetamine-dependent individuals who demonstrate baseline impairment.

Modafinil improves working memory in healthy subjects and individuals diagnosed with schizophrenia and Attention Deficit/Hyperactivity Disorder, though the effects of modafinil have not been evaluated on working memory in methamphetamine-dependent subjects. This double-blind, placebo-controlled study evaluated whether a daily dose of 400 mg of modafinil, administered over three consecutive days, would enhance performance on a measure of working memory relative to test performance at baseline and following 3 days of placebo administration in 11 methamphetamine addicted, nontreatment-seeking volunteers. The results revealed that participants demonstrating relatively poor performance on the third day of a 3-day washout period (ie, at baseline), showed significant improvement on measures of working memory, but not on measures of episodic memory or information processing speed. In contrast, for participants demonstrating relatively high performance at baseline, modafinil administration did not affect test scores. The findings provide an initial indication that modafinil can reverse methamphetamine-associated impairments in working memory.

Quantitative EEG abnormalities are associated with memory impairment in recently abstinent methamphetamine-dependent individuals.

This study examined the association between brain electrical activity, measured using quantitative electroencephalography (QEEG), and performance on measures of episodic memory in a sample of nine methamphetamine-dependent individuals who were evaluated after 4 days of monitored abstinence and 10 non-drug-using comparison subjects. In methamphetamine users, but not in comparison subjects, increased theta power was correlated with poorer performance on the delayed recall subtests of the Rey Auditory Verbal Learning Test and the Rey-Osterrieth Complex Figure Test (p<0.05). There was no association between alpha, beta, and delta power and performance on the memory tests. These results complement previous findings by demonstrating that the electrophysiological abnormalities associated with methamphetamine dependence are likely to affect behavior in an observable and important manner (i.e., memory deficits) when users are not intoxicated.

Influence of verbal recall of a recent stress experience on anxiety and desire for cocaine in non-treatment seeking, cocaine-addicted volunteers.

It has long been postulated that stress increases the risk of drug abuse and relapse. The principal goal of this project was to evaluate the effects of verbal recall of a recent stress experience (specifically meaningful to each individual) on physiological and subjective measures in cocaine-addicted participants. Subjects described a recent stressful non-drug-related experience and a neutral non-stressful experience, and then completed mood and drug effect questionnaires, while heart rate and blood pressure were recorded. Participants (N = 25) were predominantly African American and male. As a group, participants used cocaine for more than 15 years and approximately 18 of the last 30 days, and a majority reported use of nicotine and/or alcohol. All participants were evaluated during a time in which they tested positive for cocaine metabolite. On a scale of 1-10, participants reported their verbal recall of a recent stress event as highly stressful and their verbal recall of a recent neutral event as non-stressful (p < 0.0001). The self-reported vividness of this recall was high (>8 out of 10) for both the stress and neutral events. Heart rate and systolic and diastolic blood pressure did not differ after verbal recall of either stress or neutral events. Similarly, self-reported subjective effects (including ratings of anxiety and craving for cocaine) did not differ after verbal recall of either stress or neutral events. In summary, despite the fact that participants recounted highly stressful and vivid memories, this experience did not elicit significant changes in cardiovascular or subjective effects. These data suggest that simply recalling a stressful event may not be a sufficient enough stimulus to contribute to craving or relapse in cocaine-addicted individuals.

Theories of addiction: methamphetamine users' explanations for continuing drug use and relapse.

A variety of preclinical models have been constructed to emphasize unique aspects of addiction-like behavior. These include Negative Reinforcement ("Pain Avoidance"), Positive Reinforcement ("Pleasure Seeking"), Incentive Salience ("Craving"), Stimulus Response Learning ("Habits"), and Inhibitory Control Dysfunction ("Impulsivity"). We used a survey to better understand why methamphetamine-dependent research volunteers (N = 73) continue to use methamphetamine, or relapse to methamphetamine use after a period of cessation of use. All participants met DSM-IV criteria for methamphetamine abuse or dependence, and did not meet criteria for other current Axis I psychiatric disorders or dependence on other drugs of abuse, other than nicotine. The questionnaire consisted of a series of face-valid questions regarding drug use, which in this case referred to methamphetamine use. Examples of questions include: "Do you use drugs mostly to make bad feelings like boredom, loneliness, or apathy go away?", "Do you use drugs mostly because you want to get high?", "Do you use drugs mostly because of cravings?", "Do you find yourself getting ready to take drugs without thinking about it?", and "Do you impulsively take drugs?". The scale was anchored at 1 (not at all) and 7 (very much). For each question, the numbers of participants rating each question negatively (1 or 2), neither negatively or affirmatively (3-5), and affirmatively (6 or 7) were tabulated. The greatest number of respondents (56%) affirmed that they used drugs due to "pleasure seeking." The next highest categories selected were "impulsivity" (27%) and "habits"(25%). Surprisingly, many participants reported that "pain avoidance" (30%) and "craving" (30%) were not important for their drug use. Results from this study support the contention that methamphetamine users (and probably other drug users as well) are more heterogeneous than is often appreciated, and imply that treatment development might be more successful if treatments targeted subtypes of patients, though a range of limitations to the approach used are acknowledged.

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.

Presence and persistence of psychotic symptoms in cocaine- versus methamphetamine-dependent participants.

The primary objective of this study was to compare and contrast psychotic symptoms reported by cocaine- and methamphetamine-dependent individuals. Participants included 27 cocaine-dependent and 25 methamphetamine-dependent males, as well as 15 cocaine-dependent and 18 methamphetamine-dependent females. After screening, participants were excluded if they met criteria for any Axis I diagnosis other than nicotine dependence, or methamphetamine or cocaine dependence (ie, participants had to use either methamphetamine or cocaine but were excluded if they met dependence criteria for both). The participants were administered the newly developed Psychotic Symptom Assessment Scale (PSAS), which assesses psychotic symptoms. A high proportion of both cocaine- and methamphetamine-dependent men and women reported delusions of paranoia and auditory hallucinations. However, during the abstinent and intoxicated conditions, methamphetamine-dependent men and women were more likely than cocaine-dependent men and women to report psychotic symptoms. Future studies will compare psychotic symptoms reported by non-dependent recreational stimulant users to stimulant-dependent individuals.

Predictors of cardiovascular response to methamphetamine administration in methamphetamine-dependent individuals.

The goal of the present investigation was to determine predictors of cardiovascular response to methamphetamine administrated in the laboratory. Heart rate (HR) and blood pressure (BP) were measured at baseline and at several time points following the administration of methamphetamine or saline placebo. One-way ANOVA was used to determine the differences between female and male subjects in their cardiovascular response. In male subjects, linear regression and one-way ANOVA were used to determine the influence of potential predictors on cardiovascular response, including age, weight, drug use indicators, concurrent use of other substances, route of administration, and race. Methamphetamine administration provoked significant increases in HR and BP, as compared to placebo. Female gender was associated with larger peak change in diastolic BP following administration. Baseline HR and BP were found to be strong predictors of cardiovascular response to methamphetamine administration in male subjects. Lifetime use and recent use of methamphetamine and nicotine did not predict cardiovascular response to methamphetamine. Recent alcohol use was associated with increased peak change in diastolic BP. Also, current use of cannabis was negatively correlated with peak HR change. Male cannabis users show lower peak change in HR as compared to non-cannabis users. As compared to methamphetamine smokers, intravenous users demonstrated higher peak change in diastolic BP following drug administration. Race did not have a significant effect on cardiovascular response. Taken together, these findings may help in the prevention and treatment of cardiovascular events in a population at high risk of premature morbidity and mortality.