Karen Hanson

Neurocognitive function in users of MDMA: the importance of clinically significant patterns of use.

BACKGROUNDnUse of MDMA (ecstasy), a serotonin neurotoxin, has been associated with memory impairment and psychological dysfunction. This study examined cognitive functioning in abstinent MDMA users and MDMA-naive controls.nnnMETHODnParticipants completed measures of intelligence, motor function, attention, memory span, verbal fluency, immediate and delayed verbal memory, and working memory. They were also assessed for the presence of psychopathology. In addition to comparing cognitive function in MDMA users relative to controls, the possibility that clinically dysfunctional MDMA use increases the risk of cognitive impairment was examined.nnnRESULTSnMDMA users exhibited relative deficits in mnemonic and executive functions. Additionally, users that met DSM-IV substance use disorder criteria for lifetime MDMA abuse or dependence exhibited a number of additional deficits relative to those who did not meet these criteria.nnnCONCLUSIONnThese findings suggest that clinically dysfunctional, rather than purely recreational, MDMA use is associated with cognitive impairment. Future research studies of diverse samples of users may shed light on the mechanisms that underlie these differences.

Effects of tryptophan loading on verbal, spatial and affective working memory functions in healthy adults

Serotonin (5-HT) appears to modulate affective behaviours by providing a homeostatic threshold around which other transmitters respond. This general principle of activity should hold for other types of behaviour, including cognition, but has not been extensively examined. We hypothesized, based on past findings, that increased 5-HT would constrain prefrontally guided working memory functions that are mediated by catecholamine neurotransmitters. Healthy adults ingested amino acid compounds designed to deplete and load systemic tryptophan levels in a repeated-measures crossover design. Outcome variables included total plasma tryptophan, serum prolactin levels and self-report measures of mood, as well as measures of motor skill, attention, memory span and working memory for verbal, spatial and affective stimuli. Our findings indicate decrements in working memory for verbal and affective stimuli following tryptophan loading versus depletion, as well as subtle changes in vigilant attention and motor coordination. Implications for the aetiology and treatment of affective disorders and psychosis are discussed.

The relative efficacy of fluoxetine and manual-based self-help in the treatment of outpatients with bulimia nervosa.

A randomized, placebo-controlled study was conducted examining the singular and combined effects of fluoxetine and a self-help manual on suppressing bulimic behaviors in women with bulimia nervosa. A total of 91 adult women with bulimia nervosa were randomly assigned to one of four conditions: placebo only, fluoxetine only, placebo and a self-help manual, or fluoxetine and a self-help manual. Subjects were treated for 16 weeks. Primary outcome measures included self-reports of bulimic behaviors. Fluoxetine and a self-help manual were found to be effective in reducing the frequency of vomiting episodes and in improving the response rates for vomiting and binge-eating episodes. Furthermore, both factors were shown to be acting additively on the primary and secondary efficacy measures in this study. Results are discussed in relation to previous research and the implications for treatment of bulimia nervosa.

Smoking topography in tobacco chippers and dependent smokers.

Although most cigarette smokers exhibit signs of tobacco dependence, a subset of this population, referred to as tobacco chippers, does not show characteristic signs of dependence. Few studies have attempted to characterize differences between these groups of smokers. The purpose of the present study was to examine smoking topography in chippers (CH) and dependent smokers (DS). Topographical variables including puff number and duration, and intercigarette interval were examined in seven CH and seven DS under both laboratory and naturalistic conditions. Saliva nicotine, cotinine, and thiocyanate, as well as expired air carbon monoxide (CO) levels were also measured. The results indicate that there were no differences in smoking topography between CH and DS, except those that would be expected based on selection criteria. Although there were differences between groups on pre- and postsmoking CO and saliva cotinine levels, there were no differences in change scores from pre- to postsmoking on these measures. Additional studies will need to be done in order to completely characterize differences between CH and DS.

Methodological issues in the administration of multiple doses of smoked cocaine-base in humans.

Many methodological issues exist in human laboratory research with smoked cocaine-base that include safety, precision of dose delivery of smoked cocaine, and the lack of an adequate placebo. All of these issues are particularly apparent with studies involving multiple doses of cocaine. Addressing these concerns is important in conducting parametric studies that require examining dose-response effects. The purposes of this study were to determine: 1) the safest interval between doses to deliver smoked cocaine; 2) the accuracy or reproducibility of administering precise and multiple doses of cocaine; 3) the potential for using a control dose of cocaine; and 4) the influence of multiple doses on these parameters. Six black males were given 10 doses of either 5 or 35 mg of cocaine-base at 15-, 30-, and 45-min intervals. The dependent measures included physiological, subjective, and performance responses. These measures were taken prior to dosing and at specific time intervals after each dose of smoked cocaine. The results showed: 1) dosing at 30-min intervals allowed sufficient time for recovery of blood pressure and heart rate to permit up to 10 doses to be safely administered; 2) reproducible blood cocaine levels were obtained with repeated dosing using a heated wire-coil device; 3) significant differences were observed between the 5- and 35-mg dose with 5 mg being a low enough dose to produce minimal effects; 4) acute tolerance was evidenced with multiple doses of cocaine for most of the measures; and 5) considerable between- and within-subject variability was observed in the pattern of responses to cocaine.

Clinical Trials Methods for Evaluation of Potential Reduced Exposure Products

Potential reduced exposure products (PREPs) to tobacco toxicants may have promise in reducing tobacco-related morbidity or mortality or may promote greater harm to individuals or the population. Critical to determining the risks or benefits from these products are valid human clinical trial PREP assessment methods. Such an assessment involves determining the effects of these products on biomarkers of exposure and effect, which serve as proxies for harm, and assessing the potential for consumer uptake and abuse of the product. This article identifies critical methodologic issues associated with PREP assessments, reviews the methods that have been used to assess PREPs, and describes the strengths and limitations of these methods. Additionally, recommendations are provided for clinical trial PREP assessment methods and future research directions in this area based on this review and on the deliberations from a National Cancer Institute sponsored Clinical Trials PREP Methods Workshop. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3143–95)

A preliminary report on dopamine system reactivity in PKU: acute effects of haloperidol on neuropsychological, physiological, and neuroendocrine functions

BackgroundClassic phenylketonuria (PKU) is due to an inborn error of metabolism resulting in an inability to metabolize the amino acid phenylalanine. To avoid mental retardation, affected individuals observe a phenylalanine-restricted diet. When dietary control is poor, deficits in prefrontally mediated cognitive functions have been observed. It has been suggested that these deficits are due to disruptions in the mesocortical dopamine system that projects to the prefrontal cortex.MethodsIn this study, dopamine system reactivity was examined in individuals with PKU, relative to age-matched controls, using the non-specific DA antagonist haloperidol, in a repeated measures placebo-controlled design. Outcome variables included neuroendocrine, physiological, and cognitive measures.ResultsRegardless of drug condition, PKU participants differed from control participants in their blood phenylalanine and tyrosine levels, and in their times to complete measures of attention and working memory. Also, relative to placebo, haloperidol influenced several variables irrespective of group status, including serum prolactin secretion, times to complete attention and working memory tasks, and accuracy of working memory performance. An interaction between group and drug condition was observed for the digit span task, where PKU participants exhibited greater relative impairments on haloperidol. When composite indices of impairment were derived, PKU participants demonstrated selective disruption in executive function on haloperidol relative to control subjects.ConclusionsFindings are consistent with the presence of frontostriatal dysfunction in PKU but are less consistent with the notion that PFC dopamine function is specifically affected.

Nicotine withdrawal and craving in adolescents: Effects of sex and hormonal contraceptive use

While sex differences in the nicotine withdrawal (NW) symptoms and craving (NC) have been extensively described in adult cigarette smokers, few studies have investigated these phenomena in adolescents. We investigated the effect of gender and hormonal contraception (HC) on NW and NC during the first 14 days of cessation in adolescent smokers using data from a randomized, placebo-controlled, double-blind trial of the transdermal nicotine replacement therapy for smoking cessation. Analyses showed similar levels of NW severity in males and females, regardless of HC use. However, significantly higher NC was observed in females compared to males, (2.22+/-0.12 vs. 1.65+/-1.14; p=0.003). Further, females not using HC reported the highest level of NC (2.38+/-0.16) followed by females using HC (2.08+/-0.25) and males (1.71+/-0.16; p=0.007). The current findings suggest that adolescent females experience similar NW severity to males, but have stronger NC. Further, the use of hormonal contraceptives may impact the severity of craving. Addressing these different symptoms in adolescents may be useful in increasing smoking cessation rates in this special population of smokers.

Cigarette reduction: An intervention for adolescent smokers

This observational study examined whether adolescents who were not interested in quitting could reduce cigarette smoking and if cigarette reduction led to a corresponding and significant reduction in biomarkers of exposure. The study design was a randomized, open-label trial of nicotine patch and nicotine gum with an added placebo control. Participants (n=103) attended 4 treatment visits over 4 weeks and follow-up visits at 3- and 6-months. Participants were told to reduce their smoking by 25% of baseline smoking during the 1st week and by 50% of baseline smoking during the subsequent 3 weeks. Of consented participants, 91.3% (n=94/103) completed the study until the end-of-treatment, 85.1% (n=80/94) completed the 3-month follow-up visit and 71.3% (n=67/94) completed the 6-month follow-up visit. Participants had a very high prevalence of co-morbidity. With regard to the percentage of participants who achieved a 50% reduction of baseline smoking, there were no significant differences among treatment groups (p=.89). At the end-of-treatment, 49.4% of participants (n=41) had reduced smoking by at least 50%. Additionally, there was no significant group, visit or interaction effect of a biomarker measure for carcinogen exposure (p>.05). The results suggest that reduction may be a potential aid to engage adolescents who are unable or unwilling to quit, but should not be an end goal. The effect of treatment methods on outcome measures did not differ significantly.

Measures for Assessing Subjective Effects of Potential Reduced-Exposure Products

Potential reduced-exposure products (PREP) may reduce toxicant exposure and thereby may possibly reduce health risks associated with conventional tobacco use. However, lessened health risk to the individual or harm to the population through the use of PREPs is unknown. Research is being conducted to evaluate the possible health effects associated with PREP use. As part of this evaluation, it is critical to provide sound measures of subjective responses to PREPs to determine the use and the abuse potential of a product, that is, the likelihood that the product will lead to addiction. The goal of this paper is to conduct a systematic review of scales that have been used to measure the subjective responses to PREPs and examine their characteristics. In this article, scales are identified and the items on the scales are described. Scales are also examined to determine whether they are sensitive in testing PREPs. Furthermore, scales to assess PREPs are recommended to investigators. Where no scales exist, items that may be critical for the development and validation of new scales are identified. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3209–24)