Leslie H. Lundahl

Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers

Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 ± 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 ± 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 ± 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this drug.

Alcohol expectancies: Effects of gender, age, and family history of alcoholism

To explore the effects of gender, age, and positive (FH+) and negative (FH-) family history of alcoholism on alcohol-related expectancies, the Alcohol Expectancy Questionnaire (AEQ) was administered to 627 college students (female n = 430). In an attempt to control for consumption effects, only individuals who described themselves as heavy drinkers were included in the study. A 2 (Family History) x 2 (Gender) x 2 (Age Range) multivariate analysis of variance (MANOVA) was conducted on the six scales of the AEQ. Results indicated that FH+ females under the age of 20 years reported stronger expectancies of social and physical pleasure than did FH- females. Results also suggested that females over the age of 20 reported significantly lower expectancies of global, positive effects compared to all other subjects, regardless of family history of alcoholism. Finally, both male and female subjects under the age of 20 reported greater expectancies of global, positive effects, sexual enhancement, feelings of increased power and aggression, and social assertion compared to individuals over the age of 20. These results indicate that alcohol-related expectancies vary as a function of age, gender, and family history of alcoholism.

Impulsivity as a predictor of treatment outcome in substance use disorders: Review and synthesis

ISSUES Impulsivity is a widely studied personality trait and research construct that has been implicated as a risk factor for substance use, including initiating and continuing use. However, relatively few studies have examined impulsivity as a predictor of treatment outcome. Because impulsivity has been operationalised in many different ways, cross-comparisons of empirical studies have been difficult. APPROACH The PubMed database was searched in September 2013. Reference lists of papers retrieved from this search were also manually scanned for additional resources. Studies were included if they presented data that assessed impulsivity as a predictor of treatment outcomes. KEY FINDINGS The body of literature reviewed in this paper suggests that higher pretreatment impulsivity, regardless of how it is measured, usually is associated with poorer treatment outcomes. Recent data indicate that some psychosocial and pharmacological treatments may directly impact impulsivity and thus represent an interesting avenue for further research. CONCLUSIONS Impulsivity appears to be a key predictor of substance use treatment outcomes and warrants more attention in the improvement of treatment outcomes. Suggestions for future research on the role of impulsivity in substance use treatment are provided.

Sustained Release d -Amphetamine Reduces Cocaine but not ‘Speedball’-Seeking in Buprenorphine-Maintained Volunteers: A Test of Dual-Agonist Pharmacotherapy for Cocaine/Heroin Polydrug Abusers

The aim of this study was to determine whether oral sustained release d-amphetamine (SR-AMP) reduces cocaine and opioid/cocaine combination (‘speedball’-like) seeking in volunteers with current opioid dependence and cocaine dependence. Following outpatient buprenorphine (BUP) 8 mg/day stabilization without SR-AMP, eight participants completed a 3-week in-patient study with continued BUP 8 mg/day maintenance and double-blind ascending SR-AMP weekly doses of 0, 30, and 60 mg/day, respectively. After 3 days (Saturday–Monday) stabilization at each SR-AMP weekly dose (0, 15, or 30 mg administered at 0700 and 1225 each day), on Tuesday–Friday mornings (0900–1200 hours), participants sampled four drug combinations in randomized, counterbalanced order under double-blind, double-dummy (intranasal cocaine and intramuscular hydromorphone) conditions: cocaine (COC 100 mg+saline); hydromorphone (COC 4 mg+HYD 24 mg); ‘speedball’ (COC 100 mg+HYD 24 mg); and placebo (COC 4 mg+saline). Subjective and physiological effects of these drug combinations were measured. From 1230 to 1530 hours, participants could respond on a choice, 12-trial progressive ratio schedule to earn drug units (1/12th of total morning dose) or money units (US

Short-term treatment with citicoline (CDP-choline) attenuates some measures of craving in cocaine-dependent subjects: a preliminary report

2). SR-AMP significantly reduced COC, but not HYD or speedball, choices and breakpoints. SR-AMP also significantly reduced COC subjective (eg, abuse-related) effects and did not potentiate COC-induced cardiovascular responses. This study shows the ability of SR-AMP to attenuate COC self-administration, as well as its selectivity, in cocaine/heroin polydrug abusers. Further research is warranted to ascertain whether SR-AMP combined with BUP could be a useful dual-agonist pharmacotherapy.

Mecamylamine Blockade of Both Positive and Negative Effects of IV Nicotine in Human Volunteers

Abstract The administration of cytidine-5′-diphosphate choline (CDP-choline, citicoline) to animals increases the rate of membrane phospholipid synthesis and elevates brain dopamine levels. Because cocaine dependence has been associated with increases in brain phospholipid precursors, as well as depletion of dopamine within the central nervous system, the present outpatient study was conducted to assess the safety of citicoline (500 mg bid) and to determine if short-term treatment alters mood states and cocaine craving in subjects with a history of cocaine dependence. In addition, measures of drug craving and mood states after presentation of cocaine-related cues were collected on two occasions: before and after 14 days of double-blind treatment with either citicoline or placebo. Subjects did not experience any side effects and citicoline treatment was associated with decreases in self-reported mood states associated with cocaine craving. These preliminary data are encouraging and suggest that citicoline warrants further study as a promising potential treatment for cocaine abuse and dependence that is devoid of side effects.

Cue reactivity in cannabis-dependent adolescents.

The ganglionic blocker mecamylamine blocks the positive reinforcing effects of IV nicotine, but has been shown to increase cigarette smoking behavior under some conditions. The effects of mecamylamine on subjective and physiologic responses to IV nicotine were evaluated in seven healthy male volunteer cigarette smokers who provided informed consent and resided on a clinical pharmacology research unit. On four separate days, each subject was given a different oral dose of mecamylamine (placebo, 5, 10, or 20 mg). One hour later subjects received the first of four doses of IV nicotine (placebo, 0.75, 1.5, and 3.0 mg); the remaining injections were given at 1-h intervals. Both the positive effects following 0.75 mg and negative effects following 3.0 mg of nicotine were significantly reversed by mecamylamine. Thus, the mecamylamine-induced increase in smoking may be due both to competitive blockade of nicotinic receptors and nicotines reversal of aversive effects.

Cue-induced craving for marijuana in cannabis-dependent adults.

The authors measured event-related potentials with a craving manipulation to investigate the neural correlates of drug cue reactivity in 13 adolescents who are cannabis dependent (CD; ages 14-17). The P300 responses to marijuana (MJ) pictures (MJ-P300) and control pictures (C-P300) were assessed after handling neutral objects and again after handling MJ paraphernalia (MJP). Self-reported drug craving and heart rates also were measured. MJ-P300 were larger than C-P300 (p < .001), and both the MJ-P300 and craving increased significantly after handling MJP (p = .002 and p = .003, respectively), with no association between the magnitude of craving and MJ-P300. Heart rates were not affected by handling MJP. The results showed that adolescents who are CD have an attentional bias to MJ stimuli that increases after handling marijuana paraphernalia. Generally, the results are consistent with what has been reported for adult heavy chronic cannabis smokers, although there were some differences that require further investigation.

BDNF Val66Met genotype is associated with drug-seeking phenotypes in heroin-dependent individuals: A pilot study

Recent interest in the development of medications for treatment of cannabis-use disorders indicates the need for laboratory models to evaluate potential compounds prior to undertaking clinical trials. To investigate whether a cue-reactivity paradigm could induce marijuana craving in cannabis-dependent adults, 16 (eight female) cannabis-dependent and 16 (eight female) cannabis-naïve participants were exposed to neutral and marijuana-related cues, and subsequent changes in mood, self-reported craving, and physiologic function were assessed. Significant Group X cue interactions were found on all three VAS craving indices as well as on the Compulsivity scale of the Marijuana Craving Questionnaire-Brief Form (MCQ-BF). Cannabis-dependent individuals responded to marijuana-related cues with significantly increased reports of marijuana craving compared to neutral cue exposure, although there were no cue-induced changes in any of the physiological measures. There were no significant gender differences on any of the measures. These results indicate that marijuana craving can be induced and assessed in cannabis-dependent, healthy adults within a laboratory setting, and support the need for further research of the cue reactivity paradigm in the development of medications to treat cannabis-use disorders.

Progression to regular heroin use: Examination of patterns, predictors, and consequences

Brain‐derived neurotrophic factor (BDNF) Val66Met genotype has been associated with neurobehavioral deficits. To examine its relevance for addiction, we examined BDNF genotype differences in drug‐seeking behavior. Heroin‐dependent volunteers (n = 128) completed an interview that assessed past‐month naturalistic drug‐seeking/use behaviors. In African Americans (n = 74), the Met allele was uncommon (carrier frequency 6.8%); thus, analyses focused on European Americans (n = 54), in whom the Met allele was common (carrier frequency 37.0%). In their natural setting, Met carriers (n = 20) reported more time‐ and cost‐intensive heroin‐seeking and more cigarette use than Val homozygotes (n = 34). BDNF Val66Met genotype predicted 18.4% of variance in ‘weekly heroin investment’ (purchasing time × amount × frequency). These data suggest that the BDNF Met allele may confer a ‘preferred drug‐invested’ phenotype, resistant to moderating effects of higher drug prices and non‐drug reinforcement. These preliminary hypothesis‐generating findings require replication, but are consistent with pre‐clinical data that demonstrate neurotrophic influence in drug reinforcement. Whether this genotype is relevant to other abused substances besides opioids or nicotine, or treatment response, remains to be determined.