Amphetamine and fenproporex levels following multidose administration of fenproporex.

Drugs that are metabolized to amphetamine or methamphetamine are potentially of significant concern in the interpretation of positive drug-testing results for amphetamines. A number of different drugs have been reported to produce amphetamine in the urine of users. One of these compounds, fenproporex, has been shown to be metabolized to amphetamine, and previous reports indicated the parent compound could be detected at low levels for up to 48 h. Administration of fenproporex for seven days (one 10-mg dose per day) to five healthy volunteers resulted in amphetamine being detected in the urine of all subjects. Peak concentrations of amphetamine ranged from approximately 2850 to 4150 ng/mL. Amphetamine could be detected (> or = 5 ng/mL) in the urine for up to nearly 170 h after the last dose. Analysis of the metabolically produced amphetamine showed the presence of both enantiomers, which can be helpful in the differentiation of some illicit amphetamine use from the use of this precursor drug. In addition, evaluation of the enantiomeric composition of the metabolite (amphetamine) can be a valuable tool in the interpretation of time since last dose. More significantly, all samples that contained amphetamine at a concentration of > or = 500 ng/mL were shown to also contain detectable amounts of the parent compound.     

Self-reported psychopathology in polydrug users

There is a large body of work investigating concurrent associations between polysubstance use and psychopathology, but much of this work has either pre-dated or failed to account for the complex and culturally specific patterns of contemporary drug use. In particular, attendees of dance music events report a greater drug history than their peers and engage in a unique lifestyle. To further investigate the consequences of this type of drug use, 100 subjects who regularly attended dance music events were administered a battery of self-report psychiatric symptom scales. This battery contained the Anxiety Sensitivity Index, the Beck Anxiety Inventory (BAI), the Center for Epidemiologic Studies Depression scale (CES-D), the Dissociative Experiences Scale, the Padua Inventory Revised and additional questions about substance use. Our study population included abstainers and drug users with a wide history of use. We demonstrated strong associations between use of many different drugs, suggesting that polydrug use is the norm in this type of population. We found weak, but statistically significant, correlations between use of alcohol (p < 0.05), amphetamine (p < 0.01) and ecstasy (p < 0.01) with self-reported score on the BAI. There were also positive associations between dissociative symptomatology and the use of amphetamine (p < 0.05) and cocaine (p < 0.05). Furthermore, weekly unit intake of alcohol positively correlated with score on the CES-D (p < 0.05). As polydrug use was the norm in this sample, we performed regression analysis to investigate the contribution of multiple drug use on self-report. This showed that weekly use of alcohol, and frequency of use of amyl nitrate and cigarettes were significant predictors of BAI score. However, the majority of subjects reported being unworried by these symptoms, which may represent a lack of self-awareness, or acceptance of them as the subacute effects of substance use. It remains to be determined at what point adverse effects of drug use begin to interfere with day-to-day life.     

Risk factors for polydrug use in a Native American population

The Diagnostic Interview Schedule was used in 1993-1995 to collect information on the use of alcohol and other substances from 1,086 Navajo Indians living on or near their reservation in the southwestern United States. Bivariate and multivariate analyses are used to show that age of first alcohol use has declined over the past 50 years and is a significant risk factor for both alcohol dependence and polysubstance use. Limitations are noted.     

The prediction of neuropsychological impairment in polydrug abusers

Previous research has found a significant proportion of polydrug abusers to be neuropsychologically impaired and has implicated depressant and opiate use as contributing to the observed impairment. This investigation assessed the relative contribution of drug use, demographic, and personality variables to the prediction of impairment in polydrug users. Acknowledgment of drug use consequences and drug use style were found to be better predictors of neuropsychological impairment than amount of drug use or personality.     

Cognitive performance in recreational ecstasy polydrug users: a two-year follow-up study

There is important preclinical evidence of long lasting neurotoxic and selective effects of ecstasy MDMA on serotonin systems in non-human primates. In humans long-term recreational use of ecstasy has been mainly associated with learning and memory impairments. The aim of the present study was to investigate the neuropsychological profile associated with ecstasy use within recreational polydrug users, and describe the cognitive changes related to maintained or variable ecstasy use along a two years period. We administered cognitive measures of attention, executive functions, memory and learning to three groups of participants: 37 current polydrug users with regular consumption of ecstasy and cannabis, 23 current cannabis users and 34 non-users free of illicit drugs. Four cognitive assessments were conducted during two years. At baseline, ecstasy polydrug users showed significantly poorer performance than cannabis users and non-drug using controls in a measure of semantic word fluency. When ecstasy users were classified according to lifetime use of ecstasy, the more severe users (more than 100 tablets) showed additional deficits on episodic memory. After two years ecstasy users showed persistent deficits on verbal fluency, working memory and processing speed. These findings should be interpreted with caution, since the possibility of premorbid group differences cannot be entirely excluded. Our findings support that ecstasy use, or ecstasy/cannabis synergic effects, are responsible for the sub-clinical deficits observed in ecstasy polydrug users, and provides additional evidence for long-term cognitive impairment owing to ecstasy consumption in the context of polydrug use.     

Neuropsychological function in ecstasy users: a study controlling for polydrug use

Rationale

A number of studies have compared ecstasy users to control groups on various measures of neuropsychological function in order to determine whether ecstasy use results in lasting cognitive deficits. However, few of those studies controlled adequately for non-ecstasy illicit drug use.

Objective

The aim of this study was to investigate neuropsychological function in chronic ecstasy users while controlling for polydrug use.

Methods

Neuropsychological function was assessed in four groups—30 current 3,4-methylenedioxymethamphetamine (MDMA) users with a little history of illicit drug use other than ecstasy and cannabis, 30 polydrug controls, 30 drug-naïve controls and 20 ex-MDMA users—using a battery of well-validated, computerized neuropsychological tests. The battery focused on memory, executive function, impulsivity and risk-taking.

Results

Few differences were apparent between the groups, and on no measure were the current MDMA users impaired significantly relative to the polydrug controls. However, within the current MDMA users, questionnaire-measured impulsivity correlated with performance on a number of tests—a relationship that was not apparent in the controls.

Conclusions

These data highlight the complexity in understanding the current ecstasy literature and suggest that some individuals may be particularly vulnerable to cognitive impairment following chronic use. Although no differences were identified between the current MDMA users and the controls, trait impulsiveness was significantly correlated with impairment on a number of neuropsychological outcome measures in the MDMA users, but not in the controls. These data suggest that impulsive individuals may be those most at risk for the development of cognitive impairment following chronic ecstasy use.

     

Auditory verbal learning in drug-free Ecstasy polydrug users

Drug-free Ecstasy polydrug users have shown impairment on tasks of verbal working memory and memory span. Current research aims to investigate how these deficits may affect the learning of verbal material by administration of the Auditory Verbal Learning Task (AVLT) (Rey, 1964). The task provides a learning curve by assessing immediate memory span over multiple trials. Learning strategies are further analysed by tendencies to confabulate as well as demonstrate either proactive or retroactive interference elicited by a novel 'distractor' list. Three groups completed the task: two groups of 14 Ecstasy users (short- and long-term) and one group of 14 polydrug controls. Compared with controls both Ecstasy groups recalled significantly fewer words and made more confabulation errors on the initial three recall trials as well as a delayed recall trial. Long-term users demonstrated increased confabulation on the initial trials and the novel 'distractor7' trial, compared with short-term users. Only following repeated presentations were both short- and long-term users shown to perform at control levels. As such, deficits in verbal learning may be more related to storage and/or retrieval problems than problems associated with capacity per se. No interference errors were demonstrated by either of the Ecstasy groups. However, a high level of intrusion errors may indicate selective working memory problems associated with longer-term use of the drug. Copyright 2001 John Wiley & Sons, Ltd.     

A laboratory study of hydromorphone and cyclazocine on smoking behavior in residential polydrug users

The effects of cyclazocine and hydromorphone on spontaneous and laboratory cigarette smoking were compared in a double-blind, placebo-controlled, crossover study. Participants (seven men, one woman) received oral doses of placebo, cyclazocine (0.2, 0.4, and 0.8 mg) and hydromorphone (5 and 15 mg) in a randomized order on experimental days. Spontaneous smoking was recorded during two intervals on the experimental days: a 3-h period 5-8 h after drug administration (Interval 1), and the rest of the day (Interval 2). Measures of smoking topography and subjective and physiologic effects of a single cigarette were obtained on the experimental days. Neither hydromorphone nor cyclazocine significantly changed spontaneous smoking when compared to the placebo condition; however, compared to hydromorphone (5 mg), cyclazocine (0.4 and 0.8 mg) decreased spontaneous smoking during Interval 1. Hydromorphone (5 and 15 mg) and cyclazocine (0.4 and 0.8 mg) diminished smoking-induced increases in heart rate. Compared to the placebo condition, cyclazocine (0.2 and 0.4 mg) reduced exhaled carbon monoxide (CO) boost, a measure of smoke exposure. Further studies of the effects of kappa opioid agonists on smoking behavior may lead to a better understanding of the role of opiates in smoking behavior.     

Behavioral neurotoxicity in adolescent and adult mice exposed to fenproporex during pregnancy

We investigated the effects of gestational exposure to fenproporex, one of the most used anorectic drugs in Brazil, on the behavior of adolescent and adult pups (30 and 60 days of age, respectively). Pregnant Swiss mice were treated daily, by gavage, with 15 mg/kg of fenproporex chloride or water during the whole gestational period. Male pups were submitted to open-field, forced swimming test, tail suspension test and fenproporex-induced stereotyped behavior. The results demonstrated that gestational exposure to fenproporex induces antidepressant-like effect and decreases fenproporex-induced stereotyped behavior in both adolescent and adult pups. Moreover, fenproporex-exposed adolescent pups tended (P= 0.06) to be more active than control pups. Our data show, for the first time, that gestational exposure to fenproporex leads to long-lasting behavioral toxicity in male mice characteristic of altered dopaminergic transmission.     

Types of polydrug use among Spanish adolescents

Objective

This study examined the types of polydrug use among Spanish adolescents.

Method

1501 high school students (50.6% female) aged 12 to 17 years old (mean age = 14.03, SD = 1.28), from public schools in the city of Girona (Catalonia, Spain), completed the survey.

Results

In the previous six months 20.9% of the Spanish adolescents used alcohol, 18.8% tobacco, 10.5% cannabis and 0.7% cocaine. Specifically, 28.6% of the sample (n = 429; 29% males and 28.2% females) used at least one drug and 13.9% reported polydrug use (n = 208; 12.6% males and 15.1% females). The present research also found that the most critical ages for starting polydrug use were 14 and 15 years old. More than one quarter (27.9%) of the adolescent polydrug users were type A (tobacco and alcohol), 67.8% were type B (cannabis together with tobacco and/or alcohol) and 3.4% were type C (cannabis together with tobacco and/or alcohol, and cocaine).

Conclusions

These results suggest that Spanish adolescents, particularly males, commence polydrug use at an earlier age than other European adolescents. Early preventative strategies and a multisubstance perspective are greatly needed in Spain to avoid the initiation of polydrug use or to prevent progress onto heavier drugs.     

A reflection on the possibility of finding a good surrogate

Surrogate endpoints need to be statistically evaluated before they can be used as substitutes of true endpoints in clinical studies. However, even though several evaluation methods have been introduced over the last decades, the identification of good surrogate endpoints remains practically and conceptually challenging. In the present work, the question regarding the existence of a good surrogate is addressed using information-theoretic concepts, within a causal-inference framework. The methodology can help practitioners to assess, given a clinically relevant true endpoint and a treatment of interest, the chances of finding a good surrogate endpoint in the first place. The methodology focuses on binary outcomes and is illustrated using data from the Initial Glaucoma Treatment Study. Furthermore, a newly developed and user friendly R package Surrogate is provided to carry out the necessary calculations.     

ERP evidence suggests executive dysfunction in ecstasy polydrug users

Background

Deficits in executive functions such as access to semantic/long-term memory have been shown in ecstasy users in previous research. Equally, there have been many reports of equivocal findings in this area. The current study sought to further investigate behavioural and electro-physiological measures of this executive function in ecstasy users.

Method

Twenty ecstasy–polydrug users, 20 non-ecstasy–polydrug users and 20 drug-naïve controls were recruited. Participants completed background questionnaires about their drug use, sleep quality, fluid intelligence and mood state. Each individual also completed a semantic retrieval task whilst 64 channel Electroencephalography (EEG) measures were recorded.

Results

Analysis of Variance (ANOVA) revealed no between-group differences in behavioural performance on the task. Mixed ANOVA on event-related potential (ERP) components P2, N2 and P3 revealed significant between-group differences in the N2 component. Subsequent exploratory univariate ANOVAs on the N2 component revealed marginally significant between-group differences, generally showing greater negativity at occipito-parietal electrodes in ecstasy users compared to drug-naïve controls. Despite absence of behavioural differences, differences in N2 magnitude are evidence of abnormal executive functioning in ecstasy–polydrug users.     

Reasoning deficits in ecstasy (MDMA) polydrug users

RATIONALE/OBJECTIVES: Previous research has shown that ecstasy users are impaired in thinking and reasoning. The present study sought to explore the possibility that syllogistic reasoning errors in ecstasy users were due to an inability to construct a model of the premises due to working memory limitations. METHODS: Twenty-nine ecstasy users and 25 nonecstasy user controls completed abstract syllogistic reasoning problems varying in difficulty. Pairs of premises were provided, and participants were required to generate conclusions that followed necessarily from them. RESULTS: On the easier problems, both groups performed at well above chance although nonusers achieved significantly more correct responses. Consistent with existing research, on the more difficult problems, errors by nonusers were characterised by incorrect conclusions suggesting that while nonusers have the working memory capacity to construct a single model of the premises, this is not an exhaustive representation and usually results in an erroneous conclusion. On the other hand, for all problem types, ecstasy users, rather than produce incorrect responses, were more likely to fail to generate a conclusion. CONCLUSIONS: The present results are consistent with the possibility that ecstasy users with their reduced working memory capacity may experience difficulty in constructing even a single model of the premises. While this might be attributable to the effects of 3,4-methlylenedioxymethamphetamine neurotoxicity, many of the ecstasy users in the present study were polydrug users. Thus, the possibility that other drugs including cannabis and cocaine might contribute to the present results cannot be excluded.     

Patterns of polydrug use in Great Britain: Findings from a national household population survey

BackgroundPolydrug use potentially increases the likelihood of harm. As little is known about polydrug use patterns in the general population, it is difficult to determine patterns associated with highest likelihood.MethodsLatent class analysis was performed on nine illicit substance groups indicating past year use of cannabis, cocaine, amphetamines, ecstasy, LSD, mushrooms, amyl nitrate, tranquillisers and heroin or crack. Analyses were based on data from a large multi-stage probability sample of the population of Great Britain (n = 8538) collected in 2000. Multinomial logistic regression was performed highlighting associations between classes, and demographic and mental health variables.ResultsA three class solution best described patterns of polydrug use; wide range, moderate range, and no polydrug use. For males and young people, there was a significantly increased chance of being in the wide and moderate range polydrug use groups compared to the no polydrug use class. Hazardous drinking was more likely in the wide and moderate polydrug classes with odds ratios of 9.99 and 2.38 (respectively) compared to the no polydrug use class. Current smokers were more likely to be wide and moderate range polydrug users compared to the no polydrug use class with odds ratios of 4.53 and 5.85 respectively. A range of mental health variables were also related to class membership.ConclusionsPolydrug use in Great Britain can be expressed as three distinct classes. Hazardous alcohol use and tobacco use were strongly associated with illicit polydrug use, polydrug use appeared to be significantly associated with mental health, particularly lifetime suicide attempts.     

A behavioral economic analysis of polydrug abuse in alcoholics: asymmetrical substitution of alcohol and cocaine

Economic concepts can be used to assess how drug prices affect consumption patterns. Increases in price for a commodity typically result in reductions in consumption. Demand is considered elastic if decreases in consumption are proportionally greater than increases in price, and inelastic if they are proportionally smaller than rises in price. The price of one commodity can also affect consumption of others. Commodities can function as substitutes, complements or independents, and these concepts refer to increases, decreases, or no change in the consumption of one item as the price of another increases. This study evaluated the effects of drug prices on hypothetical drug-purchasing decisions in 53 alcohol abusers. Experiments 1, 2, and 3 examined how alcohol, cocaine, and Valium prices, respectively, influenced purchases of alcohol, cocaine, Valium, heroin, marijuana and nicotine. As price of alcohol rose in Experiment 1, alcohol purchases decreased and demand for alcohol was inelastic. Cocaine was a complement to alcohol, but other drugs purchases were independent of alcohol prices. In Experiment 2, demand for cocaine was elastic as its price increased. Alcohol was a substitute for cocaine, but other drug purchases did not change significantly. In Experiment 3, demand for Valium was elastic as its price rose, and all other drug purchases were independent of Valium prices. Hypothetical choices were reliable between and within subjects and associated with urinalysis results and lifetime histories of drug abuse. These results suggest that, among alcohol abusers, cocaine is a complement to alcohol, but alcohol is a substitute for cocaine.     

Childhood adversity and poor mothering: consequences of polydrug abuse use as a moderator

Drug abuse consequences have been typically examined as a direct or main effect on various later outcomes. Drug abuse may also serve as a consequence that alters (moderates) critical developmental trajectories. This study examined the relationship between childhood adversity factors (parent alcohol and drug-related problems, childhood maltreatment) and future parenting practices through an analysis of the moderating effects of polydrug problems. Data from a community sample of mothers was divided into two groups based on the median split level of polydrug problems (alcohol, marijuana, cocaine) that they reported (low, N=123; high, N=114). Confirmatory factor models (CFAs) were developed for the two groups and compared with multiple group analyses (MGAs). Results revealed that mothers who had parents with alcohol or drug-related problems were more likely to become poor parents, if they themselves used drugs and had problems related to drug use.