David J. Drobes

Differential brain activity in alcoholics and social drinkers to alcohol cues: relationship to craving

Using fMRI, our group previously found that after a sip of alcohol and exposure to alcohol beverage pictures, alcoholics compared to social drinkers had increased differential brain activity in the prefrontal cortex and anterior thalamus. This study extends this earlier work with several improvements including imaging the entire brain (rather than the anterior half previously) and recording craving, while the subjects viewed images within the scanner. In a Philips 1.5 T MRI scanner, 10 nontreatment-seeking alcoholics and 10 age-matched healthy social drinkers were given a sip of alcohol before viewing a 12 min randomized presentation of pictures of alcoholic beverages, nonalcoholic beverages, and two different visual control tasks. During picture presentation, changes in regional brain activity were measured in 15 transverse T2*-weighted blood oxygen level dependent slices. Subjects rated their urge to drink after each picture sequence. After a sip of alcohol, while viewing alcohol cues compared to viewing other beverage cues, the alcoholics, but not social drinkers, reported higher craving ratings and had increased activity in the prefrontal cortex and anterior limbic regions. Brain activity in the left nucleus accumbens, anterior cingulate, and left orbitofrontal cortex significantly correlated with subjective craving ratings in alcohol subjects but not in control subjects. This study suggests, as did our earlier study, that alcoholics and not social drinkers, when exposed to alcohol cues, have increased brain activity in areas that reportedly subserve craving for other addictive substances.

Imagery and smoking urges: The manipulation of affective content

This study investigated the impact of the affective content of imagery scripts used in an imagery paradigm designed to elicit smoking urges in a laboratory setting. Sixty cigarette smokers were instructed to vividly imagine 10 imagery scripts that described negative affect and explicit smoking urges, positive affect and explicit smoking urges, negative affect alone, positive affect alone, and neutral affect alone. Subjects ratings of the vividness of their images across the five script types did not differ but ratings of urges and cravings indicated that scripts containing descriptions of smoking urges elicited strong reports of smoking urges/cravings comparable in magnitude across positive and negative affective content. Among scripts that did not explicitly describe smoking urges, negative affect scripts were more effective in generating smoking urges/craving than positive affect scripts, although positive affect scripts did produce significantly stronger urges/cravings than neutral affect scripts. An analysis of subjects reports of the distribution of their strongest urges over imagery trials and regression analyses of the variables predictive of urge/craving report provided converging evidence that the content of the imagery scripts exerted considerable control over the generation of smoking urges in the imagery paradigm. The results indicated that the magnitude of urges and cravings produced by the imagery manipulation were clearly influenced by urge and affective content of the imagery scripts.

The early time course of smoking withdrawal effects

RationaleThere has been little study of the very early time course of the smoking withdrawal syndrome, despite its relevance to the maintenance of both smoking and postcessation abstinence. The literature contains a range of estimates about the early appearance of withdrawal symptoms, but without reference to empirical data.ObjectivesThe study aim was to conduct a comprehensive, multimodal assessment of the early time course of the symptoms associated with smoking withdrawal among cigarette smokers.MethodsParticipants were 50 smokers randomly assigned to either abstain or smoke at their own pace during 4xa0h in the laboratory. Dependent measures included resting heart rate, sustained attention (Rapid Visual Information Processing task; RVIP), selective attention to smoking stimuli (an emotional Stroop task), and self-report (Wisconsin Smoking Withdrawal Scale; WSWS). After baseline assessment, participants were assigned to the two conditions and the dependent measures were collected every 30xa0min.ResultsGeneralized estimating equations revealed that abstaining participants displayed greater withdrawal than smoking participants on all measures with the exception of the Stroop task. Statistically significant differences in withdrawal were found within 60xa0min on heart rate, within 30xa0min on the RVIP, and between 30 and 180xa0min postcessation on the various subscales of the WSWS.ConclusionsThese findings provide the first evidence of the early time course of smoking withdrawal symptoms, although further research is needed to distinguish withdrawal from drug offset effects. Implications for understanding the maintenance of daily smoking and for the treatment of tobacco dependence are discussed.

Nicotine self‐medication of cognitive‐attentional processing

This article selectively reviews research concerning nicotines effects on cognition, including the neurobiological mechanism for these effects, task and experimental features that may be important for elucidating these effects, and why these effects may have amplified motivational significance among smokers with cognitive deficit. Nicotine has effects on various cognitive processes, though most studies in humans have focused on the amelioration of cognitive deficits experienced during drug withdrawal. The direct cognitive‐enhancing effect of nicotine remains a controversial topic. The relationship between attentional and non‐attentional cognitive effects of nicotine is discussed in the context of cognitive self‐medication. Further research should include theory‐driven examination of cognitive effects of nicotine, and develop targeted smoking cessation programs based on an improved understanding of the role of cognitive self‐medication in high‐risk individuals.

Naltrexone effects on alcohol consumption in a clinical laboratory paradigm: temporal effects of drinking

BackgroundThis clinical laboratory study evaluated how the timing of drinking and subjective responses to alcohol are effected by the opioid antagonist naltrexone.MethodsForty non-treatment seeking alcoholics were randomly assigned to treatment with 50xa0mg naltrexone or matching placebo for 7 days. On day 7, they were administered an “initial drink” of alcohol (blood alcohol levels of between 20 and 30xa0mg%) in a bar-like setting. In a random fashion, half of the subjects in each group (naltrexone and placebo) had either immediate or delayed (40xa0min) access to up to 8 additional mini-drinks over a 2-h period. In the delayed group subjective reactions to alcohol were measured prior to access to more drinks.ResultsIn the immediate access condition, subjects had similar drinking patterns, irrespective of whether they were taking naltrexone or placebo. However, in the delayed condition, naltrexone-treated subjects consumed fewer drinks and had a slower progression of drinking. There was a positive relationship between alcohol-induced stimulation and the number of drinks consumed in the placebo subjects but a negative correlation in the naltrexone subjects.ConclusionsThese data suggest that the effectiveness of naltrexone on alcohol consumption may be somewhat dependent on pattern of consumption. Since naltrexone seems to disrupt the connection between alcohol-induced stimulation and further alcohol consumption, there may be a time-critical period between drinks necessary for alcoholics to benefit from its effects. These findings are consistent with clinical trial data that suggest a potential synergistic effect between relapse prevention therapies and opiate antagonist pharmacotherapy.

Randomized Trial of Reduced-Nicotine Standards for Cigarettes

BACKGROUNDnThe Food and Drug Administration can set standards that reduce the nicotine content of cigarettes.nnnMETHODSnWe conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking. Participants were randomly assigned to smoke for 6 weeks either their usual brand of cigarettes or one of six types of investigational cigarettes, provided free. The investigational cigarettes had nicotine content ranging from 15.8 mg per gram of tobacco (typical of commercial brands) to 0.4 mg per gram. The primary outcome was the number of cigarettes smoked per day during week 6.nnnRESULTSnA total of 840 participants underwent randomization, and 780 completed the 6-week study. During week 6, the average number of cigarettes smoked per day was lower for participants randomly assigned to cigarettes containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5, 16.3, and 14.9 cigarettes, respectively) than for participants randomly assigned to their usual brand or to cigarettes containing 15.8 mg per gram (22.2 and 21.3 cigarettes, respectively; P<0.001). Participants assigned to cigarettes with 5.2 mg per gram smoked an average of 20.8 cigarettes per day, which did not differ significantly from the average number among those who smoked control cigarettes. Cigarettes with lower nicotine content, as compared with control cigarettes, reduced exposure to and dependence on nicotine, as well as craving during abstinence from smoking, without significantly increasing the expired carbon monoxide level or total puff volume, suggesting minimal compensation. Adverse events were generally mild and similar among groups.nnnCONCLUSIONSnIn this 6-week study, reduced-nicotine cigarettes versus standard-nicotine cigarettes reduced nicotine exposure and dependence and the number of cigarettes smoked. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration Center for Tobacco Products; ClinicalTrials.gov number, NCT01681875.).

A clinical laboratory paradigm for evaluating medication effects on alcohol consumption: Naltrexone and nalmefene.

Opiate antagonist medications have been shown to improve alcoholism treatment, but few human laboratory-based studies investigating mechanisms for these effects have been conducted on alcohol dependent persons. The present study was designed to determine the impact of two opiate antagonists on alcohol consumption among nontreatment-seeking alcoholics (n=125) and social drinkers (n=90). Participants were randomly assigned to receive placebo, naltrexone (titrated to 50u2009mg/day), or nalmefene (titrated to 40u2009mg/day) for 8 days with an alcohol laboratory session on the final day. Alcohol consumption was monitored in the natural environment during the first 5 medication days, and during a choice consumption paradigm following a standard ‘priming’ alcohol dose in a bar–laboratory setting. Social drinkers consumed less alcohol than alcoholics during the prelab medication period and the laboratory choice consumption paradigm, and they attained lower blood alcohol levels than alcoholics following the priming drink. Both opiate antagonist medications equally reduced drinking amounts and frequency among alcoholics but not social drinkers, relative to placebo, during natural environment and bar–lab alcohol consumption evaluations. Greater medication side effects, mostly mild in nature, were observed in participants taking nalmefene. These findings demonstrate that both naltrexone and nalmefene can lead to reductions in alcohol consumption among alcoholics who are not attempting to reduce drinking. Similar laboratory paradigms may offer substantial advantages for observing these effects during evaluation of other medications as well.

Psychometric properties of the IES-R in traumatized substance dependent individuals with and without PTSD

Posttraumatic stress disorder (PTSD) is common among treatment-seeking substance abusers. Despite the high prevalence of these co-occurring conditions, few PTSD screening tools have been evaluated for their utility in identifying PTSD in substance use disorder (SUD) populations. The present study evaluated the psychometric properties of the Impact of Event Scale-Revised (IES-R) in a sample of 124 substance dependent individuals. All participants had a history of a DSM-IV Criterion A traumatic event, and 71 individuals met diagnostic criteria for PTSD. Participants with comorbid PTSD reported significantly more symptoms of anxiety, depression, and PTSD compared to substance dependent individuals without PTSD. Acceptable internal consistency and convergent validity of the IES-R were established among a substance dependent sample. Examination of diagnostic effectiveness suggested a cutoff value of 22 as optimal for a substance using population, resulting in adequate classification accuracy, sensitivity, and specificity.

Proof-of-concept human laboratory study for protracted abstinence in alcohol dependence: effects of gabapentin

There is a need for safe medications that can effectively support recovery by treating symptoms of protracted abstinence that may precipitate relapse in alcoholics, e.g. craving and disturbances in sleep and mood. This proof‐of‐concept study reports on the effectiveness of gabapentin 1200u2003mg for attenuating these symptoms in a non‐treatment‐seeking sample of cue‐reactive, alcohol‐dependent individuals. Subjects were 33 paid volunteers with current Diagnostic and Statistical Manual of Mental Disorders‐IV alcohol dependence and a strength of craving rating 1 SD or greater for alcohol than water cues. Subjects were randomly assigned to gabapentin or placebo for 1 week and then participated in a within‐subjects trial where each was exposed to standardized sets of pleasant, neutral and unpleasant visual stimuli followed by alcohol or water cues. Gabapentin was associated with significantly greater reductions than placebo on several measures of subjective craving for alcohol as well as for affectively evoked craving. Gabapentin was also associated with significant improvement on several measures of sleep quality. Side effects were minimal, and gabapentin effects were not found to resemble any major classes of abused drugs. Results suggest that gabapentin may be effective for treating the protracted abstinence phase in alcohol dependence and that a randomized clinical trial would be an appropriate next step. The study also suggests the value of cue‐reactivity studies as proof‐of‐concept screens for potential antirelapse drugs.

Varenicline effects on craving, cue reactivity, and smoking reward.

RationaleVarenicline is an α4β2 nicotinic acetylcholine receptor partial agonist that has been found to be effective for treating tobacco dependence. However, the subjective and behavioral mediators of its efficacy are not known.ObjectivesUsing multiple sessions of laboratory-based assessment, this double-blind, placebo-controlled experiment was designed to test if varenicline reduced both tonic and cue-provoked tobacco cravings, and if it attenuated perceived reward from smoking.MethodsParticipants in the present analysis include 100 smokers who were scheduled for three assessment sessions: at baseline, before receiving medication; at mid-run-in, 5–7xa0days after beginning medication; and after full dosage was reached, 12–15xa0days. Following overnight abstinence, each session included assessment of tonic craving, reactivity (including craving) to smoking cues, expected value of a cigarette, smoking behavior, and self-reported reward following smoking.ResultsVarenicline, compared to placebo, reduced tonic craving, cue-provoked craving by the final assessment, the expected value of cigarettes, number of puffs and time spent smoking, and self-reported reward (i.e., satisfaction) from smoking.ConclusionsResults showing that varenicline reduced tonic craving levels and perceived reward from smoking are consistent with reports from clinical trials, strengthening the evidence in support of these subjective mechanisms of action. This is the first placebo-controlled study to demonstrate that varenicline reduced cue-provoked cravings, thereby offering another potential mediator of its therapeutic effects. Findings may aid in the development of more targeted interventions for tobacco dependence.