Memantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism

Rationale

Individuals with a family history of alcoholism (family history positive [FHP]) show higher alcoholism rates and are more impulsive than those without such a family history (family history negative [FHN]), possibly due to altered N-methyl-d-aspartate (NMDA) receptor function.

Objectives

We investigated whether memantine, an NMDA receptor antagonist, differentially influences impulsivity measures and Go/No-Go behavior and fMRI activity in matched FHP and FHN individuals.

Methods

On separate days, participants received a single dose of 40?mg memantine or identical-appearing placebo.

Results

No group performance differences were observed on placebo for Go correct hit or No-Go false alarm reaction time on the Go/No-Go task. During fMRI, right cingulate activation differed for FHP vs. FHN subjects during No-Go correct rejects. Memantine had attenuated effects in FHP vs. FHN subjects: For No-Go false alarms, memantine was associated with limited reduction in subcortical, cingulate, and temporal regions in FHP subjects and reduced activity in fronto-striatal?Cparietal networks in FHN subjects. For No-Go correct rejects, memantine (relative to placebo) reduced activity in left cingulate and caudate in FHP but not FHN subjects.

Conclusions

Lower sensitivity to the effects of memantine in FHP subjects is consistent with greater NMDA receptor function in this group.     

Ketamine’s Antidepressant Efficacy is Extended for at Least Four Weeks in Subjects with a Family History of an Alcohol Use Disorder

Background:

A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine’s antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine’s antidepressant efficacy.

Methods:

Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100–200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17).

Results:

FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9).

Conclusions:

Ketamine’s extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials.     

Detecting impairment associated with cannabis with and without alcohol on the Standardized Field Sobriety Tests

Rationale

Cannabis and alcohol are the most popular drugs amongst recreational users and most prevalent in injured and deceased drivers. The Standardized Field Sobriety Tests (SFST) are commonly used to establish impairment due to drugs and alcohol, but limited empirical evidence exists concerning the combined effects of these drugs on SFST performance.

Methods

The sample comprised 80 individuals (31 females; 49 males). Age ranged between 21 and 35?years (M?=?26.5, SD?=?5). Forty participants (15 females; 25 males) took part in the low alcohol condition (BAC, <0.05?%), and 40 participants (16 females; 24 males), took part in the high alcohol condition (BAC, >0.05?%). For each part of the study, two levels of ?9-tetrahydrocannabinol (THC) were administered (1.8 and 3?% THC) or a matching placebo cigarette (0?% THC) in combination with alcohol. Performance on the SFST was assessed 30?min post-dosing.

Results

A number of significant differences in SFST performance were identified with 28?% of the sample failing the test (when the head movement and jerks sign was included) when low alcohol and low THC were administered together. When a higher dose of alcohol was administered with a low dose of THC, 38?% of the sample failed the test, and 35?% also failed when the high dose of alcohol was combined with a higher dose of THC.

Conclusions

The current results highlight the limited ability of the SFST to identify drug consumption in the absence of any evidence of driving impairment or physiological indicators.     

Tolerance and cross-tolerance to neurocognitive effects of THC and alcohol in heavy cannabis users

Introduction

Previous research has shown that heavy cannabis users develop tolerance to the impairing effects of ??9-tetrahydrocannabinol (THC) on neurocognitive functions. Animal studies suggest that chronic cannabis consumption may also produce cross-tolerance for the impairing effects of alcohol, but supportive data in humans is scarce.

Purpose

The present study was designed to assess tolerance and cross-tolerance to the neurocognitive effects of THC and alcohol in heavy cannabis users.

Methods

Twenty-one heavy cannabis users participated in a double-blind, placebo-controlled, three-way study. Subjects underwent three alcohol-dosing conditions that were designed to achieve a steady blood alcohol concentration of about 0, 0.5, and 0.7?mg/ml during a 5-h time window. In addition, subjects smoked a THC cigarette (400???g/kg) at 3?h post-onset of alcohol dosing during every alcohol condition. Performance tests were conducted repeatedly between 0 and 7?h after onset of drinking and included measures of perceptual motor control (critical tracking task), dual task processing (divided-attention task), motor inhibition (stop-signal task), and cognition (Tower of London).

Results

Alcohol significantly impaired critical tracking, divided attention, and stop-signal performance. THC generally did not affect task performance. However, combined effects of THC and alcohol on divided attention were bigger than those by alcohol alone.

Conclusion

In conclusion, the present study generally confirms that heavy cannabis users develop tolerance to the impairing effects of THC on neurocognitive task performance. Yet, heavy cannabis users did not develop cross-tolerance to the impairing effects of alcohol, and the presence of the latter even selectively potentiated THC effects on measures of divided attention.     

Alcohol affects the emotional modulation of cognitive control: an event-related brain potential study

Objective

The present study aimed to determine whether alcohol affects the emotional modulation of cognitive control and its underlying neural mechanisms, which is pivotal to an understanding of the socially maladaptive behaviors frequently seen in alcohol-intoxicated individuals.

Method

Event-related potentials (ERPs) were recorded in male participants receiving either a moderate dose of alcohol (0.65?g/kg alcohol; n?=?32) or a non-alcoholic placebo beverage (n?=?32) while performing an emotional Go/No-Go task that required response execution (Go trials) to pictures of a ??target?? emotional facial expression (angry, happy, neutral) and response inhibition (No-Go trials) to a different ??non-target?? expression.

Results

Overall, N200 and P300 amplitudes were more enhanced during No-Go than Go trials. Interestingly, alcohol-intoxicated individuals displayed larger No-Go N200 amplitudes across all emotional conditions than controls, accompanied by decreased task performance (i.e., more errors), particularly in response to angry faces. P300 amplitude in the alcohol group was significantly reduced for both Go and No-Go trials, but only following angry and happy emotional expressions.

Conclusions

These results suggest that alcohol-intoxicated individuals need to effortfully activate more cognitive resources during the early inhibition process in order to regulate a response than controls. Moreover, alcohol affected the emotional modulation of both response inhibition and execution in the later stages of cognitive control. Alcohol dampened emotional responsiveness, which may restrict the availability of attentional resources for cognitive control. Yet, these findings may underlie the lack of control in alcohol-intoxicated individuals when faced with emotionally or socially challenging situations.     

Stress and consumption of alcohol in humans with a Type 1 family history of alcoholism in an experimental laboratory setting

Background

This paper investigates how stress interacts with alcohol consumption in subjects with a family history of alcoholism. One mechanism for increases in alcohol intake may be that stress alters the subjective effects produced by the drug.

Methods

58 healthy volunteers, divided into two groups of family history positive (FHP) and two groups of family history negative (FHN) participated in two laboratory sessions, in which they performed in one out of two sessions a stress task. Then subjects were allowed to choose up to six additional drinks of ethanol or placebo depending on which session they were randomly assigned to start with.

Results

It was found that FHP subjects increased their consumption of alcohol after stress.

Conclusions

It is possible that both stress and alcohol specifically exaggerate the feelings of the reward in the FHP individuals in such way that it may increase the likelihood of consuming more alcohol.     

Higher levels of trait impulsiveness and a less effective response inhibition are linked to more intense cue-elicited craving for alcohol in alcohol-dependent patients

Rationale

Cue-elicited craving is a well-researched phenomenon in alcohol literature. However, not all alcohol-dependent people display the same reactivity to alcohol cues. Personality factors such as multiple impulsivity traits may be responsible for individual differences in cue reactivity by modulating its intensity. Nevertheless, there has been a scarcity of empirical studies testing this assumption in alcohol literature.

Objectives

The aim of the present study was to investigate the effects of response inhibition and trait impulsiveness on cue-elicited craving for alcohol in alcohol-dependent drinkers.

Methods

Participants (n?=?41) were inpatients of the private clinic U-Center, Netherlands. Alcohol exposure took place in a real bar–restaurant close to the premises of the clinic, and participants were exposed to real alcohol cues. Response inhibition was assessed with the stop-signal task and trait impulsiveness with the Barratt impulsivity scale version 11.

Results

The cue exposure was successful as alcohol-dependent patients experienced higher craving for alcohol when exposed to alcohol rather than to neutral cues. Additionally, both response inhibition and trait impulsiveness predicted cue-elicited craving for alcohol. Trait impulsiveness predicted both the absolute craving in the bar–restaurant and the increase in cue-elicited craving during the whole alcohol cue exposure, while response inhibition predicted only the former.

Conclusions

The results clearly implicate both trait impulsiveness and response inhibition in the modulation of cue-elicited craving in alcohol dependence. Theoretical and methodological issues in the findings and their clinical implications in alcohol treatment and relapse are discussed.     

Effects of caffeine on alcohol-related changes in behavioural control and perceived intoxication in light caffeine consumers

Rationale

Caffeinated alcoholic beverages have been associated with increased risk of alcohol-related harms. However, few studies have examined these combined effects on behavioural control, which is believed to underlie many of the negative effects of alcohol consumption. In addition, studies have often omitted subjective measures, and none have directly assessed the role of caffeine consumer history.

Objectives

To examine the combined effects of alcohol and caffeine on measures of behavioural control and perceived intoxication in abstinent, light caffeine consumers.

Methods

Participants (n?=?28; 50% male) attended four sessions at which they consumed one of the following beverages in a randomised order: placebo, alcohol alone (0.6?g/kg), caffeine alone (2.0?mg/kg), and alcohol/caffeine. They completed measures of mood, intoxication, anxiety and alcohol craving before and after a task battery comprising measures of behavioural control and reaction time performance.

Results

Caffeine attenuated alcohol-related performance deficits on stop-signal accuracy, had no effect on go–no-go performance deficits, and worsened accuracy on the Stroop task. Caffeine did not influence absolute changes in perceived intoxication but there was suggestion that caffeine may have changed the nature of intoxication with increases in stimulation.

Conclusions

Caffeine appears to have mixed effects on alcohol intoxication that are task-dependent. We found increased stimulation in the alcohol/caffeine condition, supporting the contention that caffeinated alcoholic beverages enable an individual to drink for longer. Future research should model real world drinking behaviour by examining how these effects change across multiple drink administrations.     

Implicit and explicit alcohol-related motivations among college binge drinkers

Rationale

Positive alcohol outcome expectancies and behavioral economic indices of alcohol consumption are related to binge drinking among college students and may reflect explicit and implicit motivations that are differentially associated with this behavior.

Objectives

The present study hypothesized that implicit (alcohol purchase task) and explicit (positive expectancy for alcohol’s effects) motivations for drinking would not be correlated. It was also hypothesized that greater implicit and explicit motivations would predict alcohol-related risk.

Methods

Participants were 297 college student binge drinkers (54% female; 88% European-American; Alcohol Use Disorders Identification Test: M?=?9.53, SD?=?5.04). Three indices from the alcohol purchase task (APT) were modeled as a latent implicit alcohol-related motivations variable. Explicit alcohol-related motivations were measured using a global positive expectancy subscale from the Comprehensive Effects of Alcohol Questionnaire. Alcohol Use Disorders Identification Test total, Rutgers Alcohol Problem Index total, and age of drinking onset were modeled as a latent alcohol-related risk variable. Structural equation modeling was used to examine associations amongst implicit motivations, explicit motivations, and alcohol-related risk.

Results

Implicit and explicit motivations were not correlated. Partially consistent with the second hypothesis, greater implicit motivations were associated with greater alcohol-related risk. Relations between explicit motivations and alcohol-related risk were marginally significant.

Conclusions

Implicit and explicit drinking motivations are differentially associated with problem drinking behaviors. Future research should examine the underlying neurobiological mechanisms associated with these factors.     

Varenicline effects on drinking,craving and neural reward processing among non-treatment-seeking alcohol-dependent individuals

Rationale

The α4β2 nicotinic acetylcholine receptor partial agonist varenicline has been reported to reduce drinking among both heavy-drinking smokers and primary alcoholics, and this effect may be related to varenicline-mediated reduction of alcohol craving. Among smokers, varenicline has been reported to modulate cigarette cue-elicited brain activation in several reward-related areas.

Objectives

This pilot study tested varenicline’s effects on drinking, alcohol craving, and alcohol cue-elicited activation of reward-related brain areas among non-treatment-seeking alcohol-dependent individuals.

Methods

Thirty-five such individuals (mean age?=?30, 57 % male, 76 % heavy drinking days in the past month, 15 smokers) were randomized to either varenicline (titrated to 2 mg) or placebo for 14 days, and were administered an alcohol cue reactivity fMRI task on day 14. A priori regions of interest (ROIs) were bilateral and medial orbitofrontal cortex (OFC), right ventral striatum (VS), and medial prefrontal cortex (mPFC).

Results

Despite good medication adherence, varenicline did not reduce heavy drinking days or other drinking parameters. It did, however, increase self-reported control over alcohol-related thoughts and reduced cue-elicited activation bilaterally in the OFC, but not in other brain areas.

Conclusions

These data indicate that varenicline reduces alcohol craving and some of the neural substrates of alcohol cue reactivity. However, varenicline effects on drinking mediated by cue-elicited brain activation and craving might be best observed among treatment-seekers motivated to reduce their alcohol consumption.     

Varenicline decreases alcohol consumption in heavy-drinking smokers

Rationale

Emerging evidence suggests that the ??4??2 form of the nicotinic acetylcholine receptor (nAChR) modulates the rewarding effects of alcohol. The nAChR ??4??2 subunit partial agonist varenicline (Chantix?), which is approved by the Food and Drug Administration for smoking cessation, also decreases ethanol consumption in rodents (Steensland et al., Proc Natl Acad Sci U S A 104:12518?C12523, 2007) and in human laboratory and open-label studies (Fucito et al., Psychopharmacology (Berl) 215:655?C663, 2011; McKee et al., Biol Psychiatry 66:185?C190 2009).

Objectives

We present a randomized, double-blind, 16-week study in heavy-drinking smokers (n?=?64 randomized to treatment) who were seeking treatment for their smoking. The study was designed to determine the effects of varenicline on alcohol craving and consumption. Outcome measures included number of alcoholic drinks per week, cigarettes per week, amount of alcohol craving per week, cumulative cigarettes and alcoholic drinks consumed during the treatment period, number of abstinent days, and weekly percentage of positive ethyl glucuronide and cotinine screens.

Results

Varenicline significantly decreases alcohol consumption (?? ²?=?35.32, p?Conclusions Varenicline can produce a sustained decrease in alcohol consumption in individuals who also smoke. Further studies are warranted to assess varenicline efficacy in treatment-seeking alcohol abusers who do not smoke and to ascertain the relationship between varenicline effects on smoking and drinking.     

Higher striatal dopamine transporter density in PTSD: an in vivo SPECT study with [99mTc]TRODAT-1

Rationale

Some evidence suggests a hyperdopaminergic state in posttraumatic stress disorder (PTSD). The 9-repetition allele (9R) located in the 3?? untranslated region of the dopamine transporter (DAT) gene (SLC6A3) is more frequent among PTSD patients. In vivo molecular imaging studies have shown that healthy 9R carriers have increased striatal DAT binding. However, no prior study evaluated in vivo striatal DAT density in PTSD.

Objectives

The objective of this study was to evaluate in vivo striatal DAT density in PTSD.

Methods

Twenty-one PTSD subjects and 21 control subjects, who were traumatized but asymptomatic, closely matched comparison subjects evaluated with the Clinician-Administered PTSD Scale underwent a single-photon emission computed tomography scan with [^99mTC]-TRODAT-1. DAT binding potential (DAT-BP) was calculated using the striatum as the region of the interest and the occipital cortex as a reference region.

Results

PTSD patients had greater bilateral striatal DAT-BP (mean?±?SD; left, 1.80?±?0.42; right, 1.78?±?0.40) than traumatized control subjects (left, 1.62?±?0.32; right, 1.61?±?0.31; p?=?0.039 for the left striatum and p?=?0.032 for the right striatum).

Conclusions

These results provide the first in vivo evidence for increased DAT density in PTSD. Increases in DAT density may reflect higher dopamine turnover in PTSD, which could contribute to the perpetuation and potentiation of exaggerated fear responses to a given event associated with the traumatic experience. Situations that resemble the traumatic event turn to be interpreted as highly salient (driving attention, arousal, and motivation) in detriment of other daily situations.     

Treatment of methamphetamine-induced psychosis: a double-blind randomized controlled trial comparing haloperidol and quetiapine

Rationale

To our knowledge, only a few double-blind randomized controlled trials with antipsychotic drugs have been conducted to examine the treatment of methamphetamine-induced psychosis (MAP).

Objectives

The aims of this study are to compare the antipsychotic and adverse events of quetiapine, an atypical antipsychotic drug, to haloperidol, a standard treatment for primary psychotic disorder, in individuals with MAP.

Methods

Eighty individuals with MAP were randomly assigned into two groups, i.e. treatment with quetiapine (n?=?36) and haloperidol (n?=?44). Sixty-eight patients (85 %) completed the study protocol, i.e. treatment with quetiapine at least 100 mg per day or haloperidol at least 2 mg per day orally once a day for 4 weeks. The doses were increased every 5 days until no psychotic symptom was observed from the Positive and Negative Syndrome Scale (PANSS). Data were analysed by survival analysis with Cox’s proportional regression analysis, general estimating equations and log-rank tests.

Results

Thirty-two (89 %) subjects from the quetiapine group and 37 subjects (84 %) from the haloperidol group met the remission criteria at the end of the study. Baseline PANSS total scores of quetiapine and haloperidol groups were 82.4?±?16.6 and 90.0?±?18.4, respectively (mean?±?SD; p?=?0.06). The change-from-baseline scores were ?47.8 for the quetiapine group and ?53.2 for the haloperidol group. There were no significant differences between the antipsychotic effects (coefficient value?=??2.6, p?=?0.32, 95%CI?=??7.6, 2.5) and the adverse effects of quetiapine and haloperidol.

Conclusions

Quetiapine may be used as an antipsychotic treatment for MAP with comparable therapeutic effects and adverse events to treatment with classical antipsychotic drugs.     

Effects of dexamphetamine with and without alcohol on simulated driving

Rationale

In party circuits dexamphetamine is frequently used in combination with alcohol. It is hypothesized that co-administration of dexamphetamine to alcohol might reduce the sedative effects of alcohol, but may potentiate risk-taking behaviour.

Objectives

The study was aimed at assessing the effects of alcohol, dexamphetamine and the combination of both on simulated driving and cognitive performance.

Method

Eighteen subjects participated in a randomized, crossover, placebo-controlled study employing four conditions: 10?mg dexamphetamine, 0.8?g/kg alcohol, 10?mg dexamphetamine + 0.8?g/kg alcohol, and placebo. Fundamental driving skills and risk-taking behaviour were assessed in a driving simulator. Subjects also completed vigilance and divided attention tasks, and subjective ratings.

Results

Mean BAC levels during simulated driving were between 0.91?? and 0.64??. Subjects using alcohol showed a significantly larger mean standard deviation of lateral position and shorter accepted gap time and distance. Use of alcohol or dexamphetamine + alcohol was associated with a higher frequency of red light running and collisions than the dexamphetamine or placebo conditions. Performance of vigilance and divided attention tasks was significantly impaired in the alcohol condition and, to a lesser degree, in the dexamphetamine + alcohol condition.

Conclusion

Single doses of 0.8?g/kg alcohol increased risk-taking behaviours and impaired tracking, attention and reaction time during a 3-h period after drinking when BACs declined from 0.9 to 0.2?mg/ml. The stimulatory effects of co-administration of dexamphetamine 10?mg were not sufficient to overcome the impairing effects of alcohol on skills related to driving.     

Fronto-temporal-mesolimbic gene expression and heritable differences in amphetamine-disrupted sensorimotor gating in rats

Rationale

Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague?CDawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia.

Objectives

After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH).

Methods

Startle and PPI were assessed in SD and LE rats administered d-amphetamine (0 vs. 4.5?mg/kg, sc). Two weeks later, brain tissue was processed for comt, nrg1, grid2, and csnk1e expression; blood comt expression was also tested.

Results

Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE?>?SD expression in most genes and regions, and female?>?male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120?ms correlated significantly with NAC nrg1 expression, while amphetamine sensitivity for 30?ms PPI and startle magnitude correlated significantly with VH nrg1 and blood comt expression.

Conclusions

Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia.     

Production of Inhalation Phage Powders Using Spray Freeze Drying and Spray Drying Techniques for Treatment of Respiratory Infections

Purpose

The potential of aerosol phage therapy for treating lung infections has been demonstrated in animal models and clinical studies. This work compared the performance of two dry powder formation techniques, spray freeze drying (SFD) and spray drying (SD), in producing inhalable phage powders.

Method

A Pseudomonas podoviridae phage, PEV2, was incorporated into multi-component formulation systems consisting of trehalose, mannitol and L-leucine (F1?=?60:20:20 and F2?=?40:40:20). The phage titer loss after the SFD and SD processes and in vitro aerosol performance of the produced powders were assessed.

Results

A significant titer loss (~2 log) was noted for droplet generation using an ultrasonic nozzle employed in the SFD method, but the conventional two-fluid nozzle used in the SD method was less destructive for the phage (~0.75 log loss). The phage were more vulnerable during the evaporative drying process (~0.75 log further loss) compared with the freeze drying step, which caused negligible phage loss. In vitro aerosol performance showed that the SFD powders (~80% phage recovery) provided better phage protection than the SD powders (~20% phage recovery) during the aerosolization process. Despite this, higher total lung doses were obtained for the SD formulations (SD-F1?=?13.1?±?1.7?×?10⁴ pfu and SD-F2?=?11.0?±?1.4?×?10⁴ pfu) than from their counterpart SFD formulations (SFD-F1?=?8.3?±?1.8?×?10⁴ pfu and SFD-F2?=?2.1?±?0.3?×?10⁴ pfu).

Conclusion

Overall, the SD method caused less phage reduction during the powder formation process and the resulted powders achieved better aerosol performance for PEV2.

     

Varenicline,low dose naltrexone,and their combination for heavy-drinking smokers: human laboratory findings

Rationale

Heavy-drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available.

Objectives

The present study used a double-blind, randomized, 2?×?2 medication design, testing varenicline alone (VAR; 1 mg twice daily), low dose naltrexone alone (L-NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on cigarette craving and subjective response to alcohol and cigarettes in a sample (n?=?130) of heavy-drinking daily smokers (≥10 cigarettes/day).

Methods

All participants were tested after a 9-day titration period designed to reach a steady state on the target medication. Testing was completed at 12 h of nicotine abstinence, after consuming a standard dose of alcohol (target breath alcohol concentration?=?0.06 g/dl) and after smoking the first cigarette of the day.

Results

The combination of VAR?+?L-NTX was superior to placebo, and at times superior to monotherapy, in attenuating cigarette craving, cigarette and alcohol “high,” and in reducing ad-lib consumption of both cigarettes and alcohol during the 9-day medication titration period.

Conclusions

These preliminary findings indicate that clinical studies of the combination of VAR?+?L-NTX for heavy drinkers trying to quit smoking are warranted and may ultimately improve clinical care for this sizeable and treatment-resistant subgroup of smokers.     

Working memory, executive processes and the effects of alcohol on Go/No-Go learning: testing a model of behavioral regulation and impulsivity

Rationale: Impulsivity is associated with increased risk for alcoholism. Alcohol also may increase impulsive behavior, although little is known about the processes underlying this effect. Objectives: This study tested a model proposing that the executive processes of working memory (WM) and conditional associative learning (CAL) modulate behavioral inhibition. Subjects had either a positive (FHP) or a negative (FHN) family history of alcoholism. Hypotheses were that alcohol would increase Go/No-Go impulsive responding but only in subjects with low working memory capacity (low-WM), low-CAL ability, or FHP for alcoholism. The model also predicted that WM and CAL modulate inhibitory responses to contingency reversal on a Go/No-Go task. Methods: A Go/No-Go learning task with a midway contingency reversal was administered to 71 FHP and 78 FHN subjects when sober and after drinking one of two moderate doses of alcohol. WM (digits backward) and CAL (conditional spatial association task) were also assessed when sober. Results: Alcohol resulted in more false alarms but only in low-WM subjects. Both WM and CAL modulated learning to inhibit behavior after contingency reversal, suggesting separate modulation mechanisms for WM and CAL. Subjects with low- capacity WM and subjects with low-capacity CAL ability had more difficulty learning response inhibition after contingency reversal. FHPs and FHNs did not differ in their response to alcohol. Conclusions: The results support our model of the modulatory role of WM and CAL in the ongoing regulation of behavioral inhibitory systems. The results also suggest that individuals with low capacity WM are more susceptible to alcohol’s effect of increasing impulsive behavior, suggesting that alcohol reduces the capacity of working memory to modulate response inhibition. Received: 3 March 1999 / Final version: 28 May 1999     

Responses to alcohol and cigarette use during ecologically assessed drinking episodes

Rationale

Tobacco and alcohol are frequently used together, and this may be partly explained by a distinct profile of subjective effects associated with co-administration. Ecological momentary assessment studies have examined effects of naturally occurring co-use, but, to date, have not assessed differing effects as alcohol levels rise and fall.

Objectives

The objective of the study was to describe subjective states and appraisals of cigarette and alcohol effects reported during the entirety of real-world drinking episodes.

Methods

Currently-smoking frequent drinkers (N?=?255) carried electronic diaries for 21?days. Analyses focused on reports made during 2,046 drinking episodes. Signaled prompts intensively oversampled moments in the hours following consumption of the first drink in an episode. Multilevel regression analyses were used to predict ratings of buzz, dizziness, excitement, and sluggishness as a function of person-level and contextual covariates, estimated blood alcohol concentration (eBAC) level, ascending vs. descending eBAC, smoking, and their interactions. Appraisals of cigarette and alcohol effects were also examined within this framework.

Results

Buzz, excitement, and pleasure from alcohol and cigarettes were prominent features of real-world drinking episodes. Smoking was associated with enhanced buzz and excitement when eBAC was high and descending. Smoking slightly accentuated the relation between eBAC and ratings of drinking pleasure among women, but this relation was somewhat weakened by smoking among men.

Conclusions

Smoking during drinking episodes may be partly explained by a persistence of stimulant alcohol effects beyond the blood alcohol concentration peak. Acute effects of nicotine and tobacco use on the descending limb deserve further scrutiny in experimental alcohol challenge research.     

The effect of acute tryptophan depletion on mood and impulsivity in polydrug ecstasy users

Rationale

Several studies suggest users of 3,4-methylenedioxymethamphetamine (ecstasy) have low levels of serotonin. Low serotonin may make them susceptible to lowered mood.

Objective

This work aims to study the acute effects on mood and impulsivity of lowering serotonin levels with acute tryptophan depletion in polydrug ecstasy users and to determine whether effects were different in men and women.

Methods

In a double-blind cross-over study, participants who had used ecstasy at least 25 times (n?=?13) and nonuser controls (n?=?17) received a tryptophan-deficient amino acid mixture and a control amino acid mixture containing tryptophan, at least 1 week apart. Mood was measured using the profile of mood states, and impulsivity was measured with the Go/No-Go task.

Results

The main result shows that a lowering of mood after acute tryptophan depletion occurred only in female polydrug ecstasy users (n?=?7), relative to controls (n?=?9). Results from the Go/No-Go task suggested that impulsivity was not increased by acute tryptophan depletion in polydrug ecstasy users.

Limitation

The group sizes were small, when males and females were considered separately.

Conclusions

Women polydrug ecstasy users appear to be more susceptible than men to the effects of lowered serotonin levels. If use of ecstasy alone or in conjunction with other drugs causes progressive damage of serotonin neurons, women polydrug ecstasy users may become susceptible to clinical depression.