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Variation at a single nucleotide polymorphism in the μ-opioid receptor gene (OPRM1), A118G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and A118G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and A118G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and A118G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the A118G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or A118G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX-treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT1 variation also moderated medication/A118G effects. There was a three-way interaction between medication and A118G and DAT1 genotypes on VS activation, such that, among G-allele carriers who received NTX, DAT1 10-repeat-allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, 10R homozygotes who received NTX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM1 and DAT1 should be considered in future studies of NTX, particularly regarding its effects on reward processing.

A comprehensive understanding of the neurobiology of alcohol cue reactivity is critical in identifying the neuropathology of alcohol use disorders (AUD) and developing treatments that may attenuate alcohol craving and reduce relapse risk. Functional neuroimaging studies have identified many brain areas in which alcohol cues elicit activation. However, extant studies have included relatively small numbers of cases, with AUD of varying severity, and have employed many different cue paradigms. We used activation likelihood estimation, a quantitative, coordinate-based meta-analytic method, to analyze the brain areas activated by alcohol-related cues across studies, and to examine whether these areas were differentially activated between cases and controls. Secondarily, we reviewed correlations between behavioral measures and cue-elicited activation, as well as treatment effects on such activation. Data analyzed were from 28 studies of 679 cases and 174 controls. Among cases, alcohol cues elicited robust activation of limbic and prefrontal regions, including ventral striatum, anterior cingulate and ventromedial prefrontal cortex. As compared to controls, cases demonstrated greater activation of parietal and temporal regions, including posterior cingulate, precuneus and superior temporal gyrus. Cue-elicited activation of ventral striatum was most frequently correlated with behavioral measures and most frequently reduced by treatment, but these results were often derived from region-of-interest analyses that interrogated only limbic regions. These findings support long-standing theories of mesolimbic involvement in alcohol cue processing, but suggest that cue-elicited activation of other brain areas may more clearly differentiate cases from controls. Prevention and treatment for AUD should consider interventions that may reduce cue-elicited activation of these areas., (© 2012 The Authors. Addiction Biology © 2012 Society for the Study of Addiction.)

Background: Naltrexone is moderately effective for the treatment of alcohol dependence, but there is great individual variability. The opioid receptor (OPRM1) single nucleotide polymorphism (SNP) asn40asp has been shown to alter alcohol and naltrexone response in animals and humans. In addition, the brain opioid and dopamine systems interact and might underlie drinking and craving. This study investigated the effects of the OPRM1 SNP and dopamine transporter (DAT) variable number of tandem repeat (VNTR) genetic differences on drinking, alcohol effects, and naltrexone response under controlled conditions in nontreatment-seeking alcoholics., Methods: Two hundred and sixty-five nontreatment-seeking individuals with alcohol dependence were genotyped a priori for the OPRM1 asn40asp SNP and post hoc for DAT (SLC6A3) 9 and 10 VNTRs. Asp40 carriers (n = 43) and matched asn40 homozygotes (n = 40) were randomized to naltrexone or placebo for 7 days before receiving a priming drink and limited-access alcohol consumption in a bar-lab setting. Effects of genotypes on natural drinking as well as drinking, alcohol effects, and response to naltrexone in the bar-lab setting were examined by genotype., Results: There were no significant main effects of naltrexone or OPRM1 genotype, or any medication by OPRM1 interaction, on drinking variables. However, in individuals who had at least one DAT 9 VNTR, and who were also OPRM1 asn40 homozygotes, naltrexone reduced drinks/d consumed under natural conditions (p = 0.006), but not in the bar-lab. OPRM1 asn40 homozygotes (p = 0.028) and DAT 9 VNTR carriers (p = 0.032) had more stimulation to alcohol after the priming drink., Conclusions: This study does not support a salient role for the OPRM1 asp40 alone in predicting drinking or naltrexone effects. However, although exploratory and in need of replication, it introduces the possibility that epistasis between the OPRM1 gene and DAT gene might need to be taken into account when examining differential genetic response to alcohol or medication treatment, especially in early-stage alcoholics., (Copyright © 2012 by the Research Society on Alcoholism.)

Introduction: Many veterans live in rural areas distant from Veterans Affairs Medical Centers (VAMCs) and receive primary medical care from community-based outpatient clinics (CBOCs). These veterans often must travel great distances to the nearest VAMC for neuropsychological evaluations, resulting in poor access to care, travel reimbursement costs, fee-basis evaluations of uncontrolled quality, and driving safety concerns. Return trips for feedback compound complications. Accordingly, we initiated a pilot trial of neuropsychological evaluation and feedback via telemedicine (i.e., clinical videoconferencing)., Subjects and Methods: Participants were veterans referred for neuropsychological evaluation from a rural CBOC 115 miles from the regional VAMC. All veterans were given the choice to undergo evaluation at the CBOC via telemedicine or in-person at the VAMC. Telemedicine equipment allowed presentation of digitized material with simultaneous patient observation. Testing materials were organized in numbered folders and given to veterans by CBOC clerks immediately prior to evaluation. Clerks returned completed materials via facsimile., Results: Fifteen veterans from the rural CBOC were seen for neuropsychological evaluation. Eight chose telemedicine evaluation. Groups based on evaluation modality appeared similar on demographics, referral basis, resulting neuropsychiatric diagnoses, and follow-through on recommendations. No significant technical or clinical difficulties were encountered, and veterans reported satisfaction with telemedicine. All veterans requested feedback via telemedicine., Conclusions: Neuropsychological evaluation via telemedicine is feasible and appears comparable to in-person evaluation. Experiences are encouraging and consistent with the broader literature on the acceptance of and satisfaction with clinical videoconferencing. Future studies will assess possible psychometric issues in clinical populations.

Divalproex, a GABA agonist, may be a useful agent in the treatment of tobacco dependence. Cue reactivity assessment paradigms are ideally suited to explore basic mechanisms underlying the pharmacological effects of medications that purport to have efficacy for smoking cessation. Our primary goal in the current study was to examine the effects of divalproex on in-treatment reactivity to smoking-relevant and affective cues, and to determine if these reactions were predictive of posttreatment smoking behavior. There were 120 nicotine dependent smokers enrolled in an 8-week double-blind clinical trial and randomly assigned to either divalproex or placebo conditions. Of these, 72 smokers (60% female) who achieved a minimal level of abstinence underwent an in-treatment cue reactivity assessment. Contrary to expectations, divalproex was associated with greater craving and arousal during smoking cue presentation. Divalproex also inhibited cardiovascular response to pleasant cues. Although no significant differences in cessation-related outcomes between divalproex- and placebo-treated participants were observed, cue-elicited craving to smoke predicted end-of-treatment and posttreatment smoking rates. These findings suggest that in-treatment cue reactivity assessment may proactively and dynamically inform ongoing treatment as well as provide a tool for screening potential medications for smoking cessation.

There is significant support for exposure therapy as an effective treatment for posttraumatic stress disorder (PTSD) across a variety of populations, including veterans; however, there is little empirical information regarding how veterans of different war theaters respond to exposure therapy. Accordingly, questions remain regarding therapy effectiveness for treatment of PTSD for veterans of different eras. Such questions have important implications for the dissemination of evidence based treatments, treatment development, and policy. The current study compared treatment outcomes across 112 veterans of the Vietnam War, the first Persian Gulf War, and the wars in Afghanistan and Iraq. All subjects were diagnosed with PTSD and enrolled in prolonged exposure (PE) treatment. Veterans from all three groups showed significant improvement in PTSD symptoms, with veterans from Vietnam and Afghanistan/Iraq responding similarly to treatment. Persian Gulf veterans did not respond to treatment at the same rate or to the same degree as veterans from the other two eras. Questions and issues regarding the effectiveness of evidence based treatment for veterans from different eras are discussed.

Background: Among some alcohol-dependent individuals, early alcohol abstinence is marked by alcohol withdrawal (AW), a phenomenon mediated by GABA and glutamate signaling. We previously reported that a combination of 2 medications that affect GABA and glutamate tone, gabapentin and flumazenil, more effectively reduced drinking among individuals with higher pretreatment AW (Anton et al., 2009). This study evaluated whether this finding is related to changes in neurocognitive performance, which is also affected by cortical GABA and glutamate tone., Methods: Neurocognitive performance was assessed at baseline and twice during the first week of treatment among 60 alcohol-dependent participants in the previously published clinical trial., Results: AW was associated with poorer baseline performance on 4 of 8 measures, and individuals with higher baseline AW who received the gabapentin and flumazenil combination demonstrated greater improvement on a measure of response inhibition than those with lower AW or those who received a combination of placebos. Improvement in response inhibition during the first week and medication group interacted in their effect on subsequent drinking, such that improvement predicted greater abstinence only among individuals who received gabapentin and flumazenil. Improvement on other neurocognitive measures was neither differentially impacted by medication or baseline AW nor related to subsequent drinking., Conclusions: Taken together, these data suggest that acute AW accounts for a small proportion of variance in neurocognitive performance, that gabapentin and flumazenil slightly improve response inhibition during early abstinence, and that such improvement may somewhat reduce later drinking. However, these medications may not affect other neurocognitive domains., (Copyright © 2011 by the Research Society on Alcoholism.)

Craving is a significant factor which can lead to relapse during smoking quit attempts. Attempts to resist urges to smoke during cue-elicited craving have been shown to activate regions in the brain associated with decision-making, anxiety regulation and visual processing. In this study, 32 treatment-seeking, nicotine-dependent smokers viewed blocks of smoking and neutral cues alternating with rest periods during magnetic resonance imaging scanning in a 3T Siemens scanner (Siemens AG, Erlangen, Bavaria, Germany). While viewing cues or control images, participants were instructed either to 'allow yourself to crave' or 'resist craving.' Data were analyzed with FSL 4.1.5, focused on the smoking cues versus neutral cues contrast, using cluster thresholding (Z > 2.3 and corrected cluster threshold of P = 0.05) at the individual and group levels. During the Crave condition, activation was seen on the left anterior cingulated cortex (LACC), medial prefrontal cortex, left middle cingulate gyrus, bilateral posterior cingulated gyrus and bilateral precuneus, areas associated with attention, decision-making and episodic memory. The LACC and areas of the prefrontal cortex associated with higher executive functioning were activated during the Resist condition. No clear distinctions between group crave and resist analyses as a whole were seen without taking into account specific strategies used to resist the urge to smoke, supporting the idea that craving is associated with some degree of resisting the urge to smoke, and trying to resist is almost always accompanied by some degree of craving. Different strategies for resisting, such as distraction, activated different regions. Understanding the underlying neurobiology of resisting craving to smoke may identify new foci for treatments., (© 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.)

Objective: Naltrexone, an efficacious medication for alcohol dependence, does not work for everyone. Symptoms such as insomnia and mood instability that are most evident during early abstinence might respond better to a different pharmacotherapy. Gabapentin may reduce these symptoms and help prevent early relapse. This clinical trial evaluated whether the combination of naltrexone and gabapentin was better than naltrexone alone and/or placebo during the early drinking cessation phase (first 6 weeks), and if so, whether this effect persisted., Method: A total of 150 alcohol-dependent individuals were randomly assigned to a 16-week course of naltrexone alone (50 mg/day [N=50]), naltrexone (50 mg/day) with gabapentin (up to 1,200 mg/day [N=50]) added for the first 6 weeks, or double placebo (N=50). All participants received medical management., Results: During the first 6 weeks, the naltrexone-gabapentin group had a longer interval to heavy drinking than the naltrexone-alone group, which had an interval similar to that of the placebo group; had fewer heavy drinking days than the naltrexone-alone group, which in turn had more than the placebo group; and had fewer drinks per drinking day than the naltrexone-alone group and the placebo group. These differences faded over the remaining weeks of the study. Poor sleep was associated with more drinking in the naltrexone-alone group but not in the naltrexone-gabapentin group, while a history of alcohol withdrawal was associated with better response in the naltrexone-gabapentin group., Conclusions: The addition of gabapentin to naltrexone improved drinking outcomes over naltrexone alone during the first 6 weeks after cessation of drinking. This effect did not endure after gabapentin was discontinued.

In functional magnetic resonance imaging (fMRI) studies of alcohol-dependent individuals, alcohol cues elicit activation of the ventral and dorsal aspects of the striatum (VS and DS), which are believed to underlie aspects of reward learning critical to the initiation and maintenance of alcohol dependence. Cue-elicited striatal activation may represent a biological substrate through which treatment efficacy may be measured. However, to be useful for this purpose, VS or DS activation must first demonstrate stability across time. Using hierarchical linear modeling (HLM), this study tested the stability of cue-elicited activation in anatomically and functionally defined regions of interest in bilateral VS and DS. Nine non-treatment-seeking alcohol-dependent participants twice completed an alcohol cue reactivity task during two fMRI scans separated by 14 days. HLM analyses demonstrated that, across all participants, alcohol cues elicited significant activation in each of the regions of interest. At the group level, these activations attenuated slightly between scans, but session-wise differences were not significant. Within-participants stability was best in the anatomically defined right VS and DS and in a functionally defined region that encompassed right caudate and putamen (intraclass correlation coefficients of .75, .81, and .76, respectively). Thus, within this small sample, alcohol cue-elicited fMRI activation had good reliability in the right striatum, though a larger sample is necessary to ensure generalizability and further evaluate stability. This study also demonstrates the utility of HLM analytic techniques for serial fMRI studies, in which separating within-participants variance (individual changes in activation) from between-participants factors (time or treatment) is critical., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The Veteran's Health Administration (VHA) has launched a large-scale initiative to promote prolonged exposure (PE) therapy, an evidence-based treatment for PTSD. While existing randomized controlled trials (RCTs) unambiguously support the efficacy of PE in civilian and some military populations, there is a need to better understand the course of treatment for combat Veterans of the current wars receiving PE in normative mental healthcare settings. The current study investigates 65 Veterans receiving care at an urban VA medical center. All Veterans were diagnosed with PTSD via a structured interview and treated with PE. Measures of PTSD and depression were collected pre- and post-treatment and every two sessions during treatment. Dependent means t-tests were used to estimate pre- and post-treatment d-type effect sizes. Additionally, hierarchical linear models (HLM) were used to investigate treatment effects over time, relationships between patient characteristics and outcomes, and to provide estimates of R(2)-type effect sizes. Results indicate that PE in regular VA mental healthcare contexts can be as effective as when implemented in carefully conducted RCTs., (Published by Elsevier Ltd.)

Because the effects of alcohol and its environmental cues on brain dopamine have been implicated in the maintenance of heavy drinking, drugs that modify dopamine might be useful in reducing drinking or promoting abstinence. The goal of the current study was to use an established brain imaging paradigm to explore the effect of aripiprazole (final dose 15 mg over a 14-day period), a dopamine stabilizer medication, on alcohol cue-induced brain activation and drinking in alcoholics. Non-treatment-seeking alcoholics were randomly assigned aripiprazole (n = 14) or identical placebo (n = 16) and reported their alcohol use while taking study medication for 14 days before an alcohol cue-induced brain functional magnetic resonance imaging study. In a Philips 3.0-T magnetic resonance imaging scanner, subjects were given a sip of alcohol before viewing a randomized presentation alcoholic- and nonalcoholic-beverage photographs while subjects rated their urge to drink. During photograph presentation, changes in regional brain activity were measured, and differences between viewing alcoholic beverage and nonalcoholic beverages were compared within and between groups. Brain activity analysis revealed increased activation for placebo-treated subjects in the right ventral striatum (P < 0.005; threshold 15 voxels), while there was a blunting of activation in this area in the aripiprazole-treated subjects. Aripiprazole-treated subjects, compared with placebo-treated subjects, also had significantly less heavy drinking during the 14-day medication period. The study provides both novel and valuable information regarding the effect of aripiprazole on cue-induced brain activation and voluntary drinking during treatment.

Introduction: Some anticonvulsants ameliorate signs and symptoms of alcohol withdrawal, but have an unacceptable side effect burden. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol that could increase psychomotor deficits, increase cognitive impairment, or increase intoxication. The aim of this study was to evaluate alcohol use and symptom reduction of gabapentin when compared with lorazepam in the treatment of alcohol withdrawal in a double-blinded randomized clinical trial., Methods: One hundred individuals seeking outpatient treatment of alcohol withdrawal with Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) ratings > or =10 were randomized to double-blind treatment with 2 doses of gabapentin (900 mg tapering to 600 mg or 1200 tapering to 800 mg) or lorazepam (6 mg tapering to 4 mg) for 4 days. Severity of alcohol withdrawal was measured by the CIWA-Ar on days 1 to 4 of treatment and on days 5, 7, and 12 post-treatment and alcohol use monitored by verbal report and breath alcohol levels., Results: CIWA-Ar scores decreased over time in all groups; high-dose gabapentin was statistically superior but clinically similar to lorazepam (p = 0.009). During treatment, lorazepam-treated participants had higher probabilities of drinking on the first day of dose decrease (day 2) and the second day off medication (day 6) compared to gabapentin-treated participants (p = 0.0002). Post-treatment, gabapentin-treated participants had less probability of drinking during the follow-up post-treatment period (p = 0.2 for 900 mg and p = 0.3 for 1200 mg) compared to the lorazepam-treated participants (p = 0.55). The gabapentin groups also had less craving, anxiety, and sedation compared to lorazepam., Conclusions: Gabapentin was well tolerated and effectively diminished the symptoms of alcohol withdrawal in our population especially at the higher target dose (1200 mg) used in this study. Gabapentin reduced the probability of drinking during alcohol withdrawal and in the immediate postwithdrawal week compared to lorazepam.

Improved treatment of alcohol dependence is a high priority, including defining subtypes that might respond differently. We evaluated a medication combination of intravenous flumazenil (FMZ) and oral gabapentin (GBP) in alcoholics who did and did not exhibit pretreatment alcohol withdrawal (AW) symptoms. Sixty alcohol-dependent individuals (44 with low AW and 16 with high AW) were randomized to receive FMZ (2 mg of incremental bolus for 20 minutes for 2 consecutive days) and GBP (up to 1200 mg nightly for 39 days) or their inactive placebos. Alcohol withdrawal was measured for the first 2 days, and drinking, sleep parameters, and adverse events were monitored during weekly evaluations, along with behavioral counseling sessions. Percent days abstinent (PDA) during treatment and time to first heavy drinking (TFHD) day were primary outcome variables. There was an interaction between the pretreatment AW status and the medication group on PDA (P = 0.0006) and TFHD (P = 0.06). Those in the high AW group had more PDA and more TFHD if treated with active medications, whereas those in the low AW group had more PDA and more TFHD if treated with placebo. This interaction remained for those totally abstinent (P = 0.03) and was confirmed by percent carbohydrate-deficient transferrin values. In addition, the pattern of response remained up to 8 weeks after treatment. In addition, in those with high AW, greater improvement in AW symptoms was observed in the active medication group compared with the placebo group. These results suggest a differential response to FMZ/GBP treatment, depending on pretreatment AW status that should be taken into account during future treatment trials.

Context: Medication for the treatment of alcoholism is currently not particularly robust. Neuroimaging techniques might predict which medications could be useful in the treatment of alcohol dependence., Objective: To explore the effect of naltrexone, ondansetron hydrochloride, or the combination of these medications on cue-induced craving and ventral striatum activation., Design: Functional brain imaging was conducted during alcohol cue presentation., Setting: Participants were recruited from the general community following media advertisement. Experimental procedures were performed in the magnetic resonance imaging suite of a major training hospital and medical research institute., Patients: Ninety non-treatment-seeking alcohol-dependent (by DSM-IV criteria) and 17 social drinking (< 14 drinks per week) paid volunteers recruited through advertisements at an academic center., Interventions: A taste of alcohol and a series of alcohol-related pictures, neutral beverage pictures, and visual control images were provided to volunteers after 7 days of double-blind randomly assigned daily dosing with 50 mg of naltrexone (n = 23), 0.50 mg of ondansetron hydrochloride (n = 23), the combination of the 2 medications (n = 20), or matching placebos (n = 24)., Main Outcome Measures: Difference in brain blood oxygen level-dependent magnetic resonance when viewing alcohol pictures vs neutral beverage pictures with a particular focus on ventral striatum activity comparison across medication groups. Self-ratings of alcohol craving., Results: The combination treatment decreased craving for alcohol. Naltrexone with (P = .02) or without (P = .049) ondansetron decreased alcohol cue-induced activation of the ventral striatum. Ondansetron by itself was similar to naltrexone and the combination in the overall analysis but intermediate in a region-specific analysis., Conclusions: Consistent with animal data that suggest that both naltrexone and ondansetron reduce alcohol-stimulated dopamine output in the ventral striatum, the current study found evidence that these medications, alone or in combination, could decrease alcohol cue-induced activation of the ventral striatum, consistent with their putative treatment efficacy.

Objective: Animal models suggest that N-acetylcysteine inhibits cocaine-seeking. The present pilot study evaluated whether N-acetylcysteine would suppress reactivity to cocaine-related cues in cocaine-dependent humans., Method: In this double-blind, placebo-controlled trial, 15 participants received N-acetylcysteine or placebo during a 3-day hospitalization. Participants were crossed over to receive the opposite condition on a second, identical 3-day stay occurring 4 days later. During each hospital stay, participants completed a cue-reactivity procedure that involved collecting psychophysical and subjective data in response to slides depicting cocaine and cocaine use., Results: While taking N-acetylcysteine, participants reported less desire to use and less interest in response to cocaine slides and watched cocaine slides for less time., Conclusions: The inhibition of cocaine cue reactivity is consistent with existing preclinical data and supports the use of N-acetylcysteine as a treatment for cocaine dependence.

Previous work has shown that multiple medication-treated alcohol detoxifications are associated with poorer treatment outcomes during subsequent detoxifications. Little is known about the impact of nonmedicated attempts to stop drinking outside the realm of these medically supervised detoxifications on acute detoxification outcomes. This study included 58 subjects enrolled in an outpatient detoxification study. Subjects were asked why and how often they quit alcohol for 3 days or longer during their drinking lifetime using concepts derived from the Cognitive Lifetime Drinking History. The effect of previous attempts at abstinence (both medicated and nonmedicated) on time to relapse during an index detoxification was examined. After the index detoxification, older individuals relapsed later than younger individuals and the number of previous medicated detoxifications rather than total lifetime quit attempts per se was related to quicker relapse. Contrary to expectation, those who reported fewer previous nonmedicated quit attempts tended to relapse sooner than those who reported more past quit attempts. This study supports and extends previous work that suggests that the number of previous medicated detoxifications, rather than the total number of past attempts at abstinence, predicts higher and sooner risk for early relapse drinking during outpatient alcohol detoxification.

Introduction: There has been increasing interest in the use of anticonvulsant agents in the treatment of alcoholism. Anticonvulsant agents have mostly been evaluated as an alternative to benzodiazepines in the treatment of alcohol withdrawal. Among the advantages of using anticonvulsant agents in this capacity is their purported lack of interaction with alcohol (i.e., interactions that could increase psychomotor deficits, cognitive impairment, and increase intoxication). This is particularly important in the treatment of alcohol withdrawal and relapse prevention in outpatients. Unfortunately, these untoward clinical interactions between anticonvulsants and alcohol in alcoholic patients have not been thoroughly assessed. The current clinical laboratory study was conducted to evaluate the safety and tolerability of the anticonvulsant gabapentin in alcoholic subjects. In addition, the ability of gabapentin to reduce alcohol craving and consumption was evaluated., Methods: Thirty-five non-treatment-seeking alcoholic subjects were enrolled in a subacute human laboratory study and received double-blind treatment with up to 1,200 mg of gabapentin (n=18) or placebo (n=17) for 8 days. The safety and tolerability of gabapentin were monitored in the natural environment during the first 5 days of medication treatment and during a free-choice limited access consumption paradigm following an initial drink of alcohol in a bar-lab setting on Day 7., Results: There was no overall effect of gabapentin on drinking or craving; however, it was tolerated (e.g., mood and sedation) as well as placebo over 5 days of natural drinking. During the bar-lab drinking session, there were no differences in subjective high or intoxication between subjects treated with gabapentin or placebo., Discussion: This study provides initial evidence that the anticonvulsant gabapentin is safe if used in conjunction with alcohol consumption in alcoholic individuals. Further study is needed with this and other lab models to determine the utility and safety of gabapentin in the treatment of alcoholism.

Acamprosate, a medication that has been used in Europe for years, is the newest drug to be approved by the US Federal Drug Administration for the treatment of alcohol dependence. It has been shown to assist in the maintenance of abstinence in recently detoxified alcohol-dependent individuals. The following review delineates the proposed mechanism of action and pharmacokinetics of the drug. Findings of clinical trials are outlined and topics such as cost effectiveness, comparison with other medications used for the treatment of alcohol dependences as well as combination pharmacotherapy are discussed. In combination with psychosocial treatment, acamprosate is a promising tool for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal. This review also illustrates the continued need to search for more effective treatments, as the overall effectiveness of our currently available pharmacotherapies remains limited in the long-term maintenance of recovery from alcohol dependence.

Aims: Pregabalin has been shown to possess anticonvulsant, analgesic, and anxiolytic properties in a variety of testing situations. This study was designed to evaluate the ability of pregabalin to exert its anticonvulsant effects against behavioral and electrographic measures of CNS hyperexcitability associated with alcohol withdrawal in a mouse model of ethanol dependence., Methods: Adult mice were chronically exposed to ethanol and, upon withdrawal, were tested for behavioral signs of seizure activity (handling-induced convulsions) or abnormalities in spontaneous EEG activity recorded from cortical and subcortical sites., Results: Pregabalin (50-200 mg/kg) administered 1 and 4 h into withdrawal dose dependently reduced severity of handling-induced convulsions in comparison to vehicle-treated mice. Similarly, pregabalin reduced the frequency in which EEG activity was interrupted by trains of high-voltage synchronous activity in a dose-related fashion. Finally, pregabalin treatment of repeated withdrawals was effective in blocking the development of withdrawal sensitization observed in vehicle-treated mice., Conclusions: Collectively, these results suggest that pregabalin may be an effective therapeutic agent for medical management of alcohol detoxification.

A retrospective chart review was performed within an inpatient VA hospital setting in an attempt to identify risk factors for delirium tremens (DTs). Cases of delirium tremens were compared to cases where patients' alcohol withdrawal during hospitalization did not progress to DTs. Significant differences were found in regard to prior histories of DTs and laboratory values at admission. The amount and duration of benzodiazepine use during hospitalization, antipsychotic use during hospitalization, and length of hospitalization were also statistically different between the groups. While not reaching statistical significance, there were differences in reason for admission and relapse rate upon follow-up between the groups.

A double-blind placebo-controlled crossover Phase I trial was conducted to assess the safety and tolerability of N-Acetylcysteine (NAC) in healthy, cocaine-dependent humans. Thirteen participants attended a three-day hospitalization in which they received placebo or NAC. Subjects were crossed over to receive the opposite medication condition during a second three-day hospitalization, which occurred the following week. Across placebo and NAC conditions, only mild side effects were noted, and the number of subjects reporting side effects did not differ. There were trends for a greater reduction in withdrawal symptoms and craving within the NAC condition. These preliminary results suggest that NAC is well tolerated in healthy, cocaine-dependent individuals and may reduce cocaine-related withdrawal symptoms and craving.

Although benzodiazepines are the standard of care in the treatment of alcohol withdrawal, several studies have suggested that anticonvulsants may be equally effective at alleviating alcohol withdrawal symptoms and may pose less of a risk of causing rebound of symptoms which could contribute to relapse. This report compares treatment outcomes for patients (N=13) treated for alcohol withdrawal with either the anticonvulsant tiagabine or the benzodiazepines oxazepam and lorazepam. The Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-Ar) was utilized to gauge alcohol withdrawal symptoms over the course of the study. When possible, follow-up data was obtained on alcohol use post-treatment. Both benzodiazepines and tiagabine appeared to reduce CIWA-Ar scores at about the same magnitude. There was a trend for tiagabine patients to have less post-detoxification drinking (Fisher exact test, p = 0.12). The reduction in alcohol withdrawal symptoms and decreased tendency to relapse observed in patients treated with the anticonvulsant tiagabine suggests that a double-blind, placebo controlled trial may be warranted.

Objective: The aim of the current study was to evaluate the role of beliefs about alcohol use and craving on predicting relapse as stated in Beck's cognitive theory of alcoholism in detoxified alcohol-dependent patients., Method: Seventy male participants who were alcohol dependent according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), and who were admitted to an inpatient unit for alcohol detoxification were studied at baseline and at 6 months follow-up. Participants were administered the Structured Clinical Interviews for DSM-IV axis I and DSM-III-R axis II Disorders (SCID-I and SCID-II, respectively), the Beck Anxiety Inventory and the revised Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). Beliefs about alcohol use were assessed with the Beliefs About Substance Use Inventory and the Craving Beliefs Questionnaire (CBQ)., Results: The relapse rate of the study group was 84.1% (58 patients). The age of onset of alcohol dependence and age at first hospitalization were lower in patients who relapsed. The severity of physical dependence and presence of comorbid antisocial personality disorder were higher in the relapse group. In addition, patients who relapsed had higher scores in the CBQ. According to logistic regression analysis, craving beliefs and the degree of physical dependence were predictors of relapse in alcoholic patients., Conclusions: Our findings suggest that beliefs about craving and the severity of physical dependence may play an important role in relapse of male alcoholic patients. These factors could have a direct clinical application for predicting relapse to drinking in male alcohol-dependent patients.

Although naltrexone has been shown to be effective in the treatment of alcohol dependence, less is known about its efficacy when combined with different behavioral therapies. Previous work has suggested that naltrexone works best when combined with weekly cognitive behavioral therapy (CBT). This study examined the efficacy of naltrexone when combined with CBT or a motivational enhancement therapy involving less patient contact. Outpatient alcoholics (N = 160) were randomly assigned to either naltrexone (50 mg/d) or placebo and either CBT (12 sessions) or motivational enhancement therapy (4 sessions), in a 4-cell design, and treated over a 12-week period. Subjects were evaluated periodically for alcohol consumption, craving, and biologic markers of drinking (carbohydrate-deficient transferrin and gamma-glutamyltransferase). There was high retention and adherence to therapy and medication in the trial with no significant difference across the treatment groups. Naltrexone, independent of therapy assignment, increased the time to first relapse. However, the CBT-naltrexone group did better than the other groups on a variety of outcome measures. Fewer CBT-naltrexone-treated subjects relapsed, and those that did had both fewer, and more time between, subsequent relapses. This randomized controlled trial is consistent with previous reports about the utility of combining naltrexone with CBT. Despite being more efficient to administer, the combination of motivational enhancement therapy and naltrexone is less effective than CBT and naltrexone. Because CBT and naltrexone share common mechanisms of action, such as craving reduction and relapse prevention, these therapies are likely to be well suited to use in combination.

Aims: The opioid antagonist naltrexone may reduce ethanol reward, but the underlying neurochemical mechanisms has yet to be clarified. The afferent projections to the nucleus accumbens from the ventral tegmental area (VTA) provide a potential substrate by which endogenous opioids may modulate the dopaminergic rewarding effects of ethanol. We assessed mRNA levels of tyrosine hydroxylase (TH), a major regulatory enzyme in the dopamine synthesis and levels of dopamine and its metabolites after chronic ethanol administration with and without concomitant naltrexone., Methods: Sprague-Dawley rats were exposed to chronic ethanol consumption (5%, 4 weeks) with and without concomitant naltrexone administration. Levels of TH mRNA in the VTA and substantia nigra (SN) and dopamine and its metabolites in the striatum of the rats were measured by in situ hybridization and by high performance liquid chromatography, respectively., Results: Chronic ethanol consumption increased TH mRNA levels in the VTA, but did not cause any significant change in the SN. With naltrexone treatment, ethanol-induced increase in the TH mRNA level was reduced in the VTA. Chronic ethanol consumption did not cause any change in the levels of dopamine and its metabolites in most brain regions. Only in the striatum, ethanol consumption with naltrexone treatment significantly increases the dopamine level., Conclusion: This finding supports the presence of interactions of opioid and dopaminergic systems in the VTA in mediating ethanol reward, and thus naltrexone attenuates the rewarding properties of ethanol by interfering with the ethanol-induced stimulation of the mesolimbic dopaminergic pathway.

Recent research has used functional magnetic resonance imaging (fMRI) to examine brain regions related to specific subcomponent cognitive processes of verbal working memory, which include initial encoding of material, maintenance of the information over a brief delay interval, and later retrieval of the information. The present study examined each of these subcomponents in 14 healthy adults using a Sternberg verbal working memory task and fMRI. Group analysis revealed several brain regions active during all subcomponent processes, which included dorsolateral and ventrolateral prefrontal, parietal, hippocampal, and premotor cortex. Several other brain regions showed activation limited to specific subcomponent processes.

There have been many recent developments in the pharmacological management of alcohol withdrawal and alcohol dependence. Although previous treatments had included benzodiazepines as their mainstay, the use of these agents in the alcoholic population is problematic. Benzodiazepines are themselves addictive and they may increase the risk of alcohol relapse. Non-benzodiazepine anticonvulsants such as carbamazepine, valproic acid, gabapentin, vigabatrin and topiramate have been shown to be excellent treatments of both alcohol withdrawal and the prevention of alcohol relapse. Although none of these agents have yet been approved by the FDA, there is growing evidence in the literature to support their use.

Objective: This study tested the hypothesis that patients with comorbid bipolar and substance use disorders use health services to a greater extent than patients with either bipolar or substance use disorder alone., Methods: A retrospective chart review was conducted among patients who used health services at the Ralph H. Johnson Department of Veterans Affairs medical center in Charleston, South Carolina, and had bipolar disorder alone, substance use disorder alone, and comorbid bipolar and substance use disorders. Patients with a psychiatric admission between 1999 and 2003 were included in the study. Information was collected on the use of health services one year before and including the index admission., Results: The records of 106 eligible patients were examined for this study: 18 had bipolar disorder alone, 39 had substance use disorder alone, and 49 had both bipolar and substance use disorders. Compared with the other two groups, the group with comorbid bipolar and substance use disorders was significantly more likely to be suicidal. Compared with the group with bipolar disorder alone, the group with comorbid disorders had significantly fewer outpatient psychiatric visits and tended to have shorter psychiatric hospitalizations. Among patients with an alcohol use disorder, those who also had bipolar disorder were significantly less likely than those with an alcohol use disorder alone to have had an alcohol-related seizure. Patients with comorbid bipolar and substance use disorders were significantly less likely than those with substance use disorder alone to be referred for intensive substance abuse treatment, even though both groups were equally likely to enter and complete treatment when they were referred., Conclusions: Despite significant functional impairment among patients with comorbid bipolar and substance use disorders, they had significantly fewer psychiatric outpatient visits than those with bipolar disorder alone and were referred for intensive substance abuse treatment significantly less often than those with substance use disorder alone.

Videoconferencing at a bandwidth of 384 kbit/s was used in open sessions for subjects with alcohol use disorders (AUD). Study participants received eight sessions of group therapy over a four-week period from an accredited addictions counsellor. Outcome assessment included self-report measures, a qualitative interview and a chart review. Of the 18 subjects who started the study, 14 attended at least four sessions of therapy, completed self-report assessments and the thematic interview. The participants reported high levels of satisfaction with telepsychiatry, found the intervention to be highly credible, had good session attendance and attrition comparable to that expected with conventional same-room treatment. In all, 82% of subjects reported that they would recommend the service to a friend or family member. The results demonstrate the feasibility of using videoconferencing for service delivery to adults with AUD, and encourage the future performance of randomized controlled trials.

Aims: Ghrelin is a peptide hormone that antagonizes the action of leptin and is thereby thought to regulate feeding behaviour. The actions of ghrelin and leptin appear to be mediated by the neuropeptide Y (NPY) and Agouti-related protein (AGRP) system. Recent studies have suggested that leptin and NPY play significant roles in the pathophysiology of alcoholism. The aim of this study was to determine whether ghrelin is associated with the state and duration of abstinence in individuals with alcohol dependence., Methods: Fasting plasma ghrelin levels were compared between 47 individuals with chronic alcoholism during a period of abstinence and 50 control subjects., Results: Fasting plasma ghrelin levels were higher in alcohol abstainers than those in controls. Furthermore, a positive correlation was observed between ghrelin levels and the duration of abstinence. In addition, daily alcohol intake prior to abstinence was inversely related to ghrelin levels., Conclusions: These findings suggest that ghrelin plays a role in the pathogenesis of alcohol dependence, particularly during the abstinence period, in individuals with chronic alcoholism.

There is growing interest in the co-occurrence of mood and substance use disorders. It is clear that co-occurrence of these disorders is common and has an impact on prognosis and course of both disorders. The diagnostic issues at the interface of substance or alcohol use disorders and affective illnesses are particularly difficult because of the substantial symptom overlap between substance intoxication and withdrawal and symptoms of affective disorders. Over the past few years, advances have been made in the treatment of co-occurring disorders. Further investigation of specifically tailored treatments for patients with co-occurring substance use and other mood disorders is underway. Because many advances have been made in pharmacotherapy of mood disorders in the past 10 years, this progress will impact individuals with co-occurring disorders, because newer agents with less toxicity and fewer adverse effects and interactions with substances of abuse will be evaluated for treating the comorbid condition. Specific considerations in choosing a pharmacologic agent for use in patients with substance use disorders include safety, toxicity, and abuse liability. Although there are few studies specifically targeting pharmacotherapy for co-occurring disorders, those that have been conducted indicate that similar pharmacotherapeutic agents work for mood disorders with or without substance use disorders. In conclusion, although the co-occurrence of substance abuse and mood disorders is an important area in which recent developments provide cause for considerable optimism, much work remains to be done.

Alcoholism is a devastating illness that leads to great societal losses. Despite significant health consequences, there are few medically based treatments for alcoholism. During the past decade, a better understanding of the neuroscientific underpinnings of addiction has led to the use of novel pharmacotherapeutic treatments for alcoholism. In particular, there have been new developments in the understanding of the involvement of the dopamine, opiate, serotonin, gamma-aminobutyric acid, and glutamate neurotransmitter systems in the pathophysiology of alcohol withdrawal, alcohol dependence, and in subtypes of individuals with alcoholism. In this article, new developments in the pharmacotherapy of alcohol dependence will be reviewed. In particular, the use of anticonvulsants in alcohol withdrawal and protracted abstinence syndromes will be discussed. Data on naltrexone, acamprosate, and topiramate will be highlighted. In addition, data concerning the use of serotonin reuptake inhibitors in subtypes of alcoholism and the use of combination pharmacotherapy will be reviewed.

Modafinil is an agent that is frequently used in the treatment of narcolepsy. More recently it has been used in the treatment of a variety of psychiatric, neurological, and medical illnesses. Due to its ability to improve wakefulness, modafinil has been viewed as a stimulant. Based on the potential for modafinil to become widely used in a variety of syndromes and settings, evidence from preclinical in vitro and in vivo studies, human laboratory studies, and post-marketing experiences examining the potential abuse liability of modafinil were reviewed. Initial evidence suggests that modafinil has limited potential for large-scale abuse.

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.

Background: An understanding of the neurophysiological mechanisms underlying alcohol craving is important in the effective treatment of alcohol dependence. The aim of this study was to examine the utility of the electroencephalogram (EEG) to measure the changes in electrical brain activity of alcoholics when exposed to alcohol-specific cues., Methods: Fifteen adult alcoholic subjects (four women) with a mean age of 35 (SD = 4.5) and 10 healthy social drinking controls (three women) with a mean age of 34 (SD = 5.6) were recruited. Subjects were serially rated for alcohol craving after presentations of pictures of control nonalcoholic and alcohol beverages. After the picture presentation, the EEG was recorded (16,384 data points for each epoch) with eyes closed. The dimensional complexity (D2) was estimated as a measure of complexity of the EEG., Results: Alcoholic subjects exhibited a significant increase in the D2 values of the EEG in frontal (F3, F4), right posterior temporal (T6), and occipital (O1, O2) regions after viewing alcohol cues compared with viewing other beverage cues. These results indicate that more complex (or higher) cortical activity is induced over specific brain regions of alcoholic subjects by alcohol-specific cues. Changes in subscale of alcohol craving between nonalcoholic and alcohol pictures were correlated with changes in D2 values in the left frontal (F3) region in alcoholic subjects., Conclusions: These findings suggest that, when subjects are exposed to alcohol cues, changes in the EEG complexity are induced in frontal, right posterior temporal, and occipital areas, which may be key brain structures for alcohol craving. In addition, nonlinear measures like the D2 are useful in evaluating alcohol cue-induced brain activity from the EEG.

To date, few medications have shown efficacy in the treatment of addictive disorders. The lack of effective treatments has led to the evaluation of a variety of pharmacotherapies to reduce alcohol or illicit drug use. The anticonvulsant agents are a class of medications that may represent novel treatments for addictive disorders. One of the most studied anticonvulsant agents in the treatment of addictive disorders has been valproate. This article will review the literature regarding the use of valproate in treating alcohol withdrawal symptoms and in reducing the use of alcohol and cocaine.

To explore the concordance between urine drug screen (UDS) results and self-report of cocaine use, results in a pharmacologic treatment trial for cocaine dependence were evaluated. Subjects with at least two occurrences of a positive UDS for cocaine were characterized as either an under-reporter (UR, n = 43) or a truthful reporter (TR, n = 32). Interestingly, URs attended more study sessions and were more likely to complete the study. Significant differences were found in cocaine use patterns and the prevalence of Axis I and Axis II disorders. This information may be important in guiding the judicious use of UDS in clinical and research settings.

A double-blind, randomized controlled trial of patients (n = 136) meeting DSM-IV criteria for alcohol withdrawal and stratified based on detoxification history were treated with carbamazepine or lorazepam for 5 days on a fixed dose tapering schedule. Mood symptoms improved for all subjects regardless of medication or detoxification history. There was a significant main effect favoring carbamazepine in reducing anxiety (p = 0.0007). Anxiety was highest in those individuals who had multiple previous detoxifications (p = 0.02). Visual analog measures of sleep quality indicated a statistically significant main effect of medication on sleep that again favored carbamazepine (p = 0.0186). Visual analog rating of perceived ability to return to work was decreased in individuals who had multiple previous detoxifications (p = 0.025). In this study of outpatients with mild to moderate alcohol withdrawal, carbamazepine was superior to lorazepam in reducing anxiety and improving sleep.

The current pilot project was designed to evaluate the safety and tolerability of a loading dose of divalproex (DVPX) in subjects with cocaine dependence. Seventeen cocaine-dependent subjects were enrolled in an eight-week, open-label trial of 20 mg/kg/day DVPX. Subjects were seen weekly and urine drug screens were obtained at each visit. Over the eight-week trial, craving intensity and frequency as well as reported time using cocaine decreased significantly. Retention in the current study was 79% at week four and 50% at week eight. The medication and dosing strategy was well tolerated. This pilot study indicates that DVPX loading is well tolerated and may be efficacious in the treatment of cocaine dependence. A placebo-controlled trial would be of interest.

Neuroscientific underpinnings and pharmacotherapeutic treatments of substance use disorders are rapidly developing areas of study. In particular, there have been exciting new developments in our understanding of the involvement of excitatory amino acid neurotransmitter systems and the opiate and serotonin systems in the pathophysiology of alcohol withdrawal, alcohol dependence, and in subtypes of individuals with alcoholism. In this article, new developments in the pharmacotherapy of alcohol dependence will be reviewed. In particular, the use of anticonvulsants in alcohol withdrawal and protracted abstinence syndromes will be discussed. New data on opiate antagonists and acamprosate, an agent that exerts actions through excitatory amino acid systems in relapse prevention, will be reviewed. Finally, there will be a review of new data concerning the use of serotonin reuptake inhibitors in subtypes of alcoholism and the use of combination pharmacotherapy.

Some anticonvulsants have been shown to be as effective as some benzodiazepines for the treatment of alcohol withdrawal. Anticonvulsants may offer advantages over benzodiazepines in the outpatient treatment of alcohol withdrawal: they lack abuse potential, have minimal interactions with alcohol, and may be more effective in ameliorating psychiatric symptoms of alcohol withdrawal. Carbamazepine appears to be as effective as lorazepam and oxazepam in ameliorating the symptoms of alcohol withdrawal. In addition, a recent study indicates that carbamazepine may suppress post-withdrawal alcohol use. Divalproex may also reduce symptoms of alcohol withdrawal, based on several open-label studies. However, both carbamazepine and divalproex have limited usefulness in alcoholics with severe hepatic or hematologic complications. Newer anticonvulsants, such as gabapentin and vigabatrin, also appear to reduce alcohol withdrawal symptoms in preclinical and open-label clinical trials while lacking the toxicities of carbamazepine and divalproex. Controlled trials are underway exploring the efficacy and safety of newer anticonvulsants for the treatment of alcohol withdrawal.

Background: Although multiple medications have been studied for the treatment of cocaine dependence, no medication has been shown to have a robust effect on craving and use. This pilot project was designed to evaluate the safety and tolerability of gabapentin in subjects with cocaine dependence., Method: Thirty cocaine-dependent subjects (DSM-IV criteria) were enrolled in an 8-week, open-label trial of 1,200 mg/day of gabapentin in divided doses. Urine drug screens, subjective measures of craving, and cocaine use interviews were conducted at each weekly visit., Results: Baseline rating of amount and frequency of craving decreased significantly by week 8 (78% vs. 25% for amount, p = .000; 74% vs. 23% for frequency, p = .004). Positive urine drug screens for cocaine decreased from 86% at baseline to 29% at weeks 4 and 8. There were no reports of significant side effects or adverse events., Conclusion: This pilot study indicates that gabapentin is safe and well tolerated and may be beneficial in the treatment of cocaine dependence. A placebo-controlled trial would be of interest.

It has been well known for a number of years that abrupt withdrawal from alcohol following chronic use is associated with adverse consequences, ranging from mild tremors to withdrawal seizures. The overall purposes of treating alcohol withdrawal (AW) are to relieve patient discomfort, to prevent the development of more serious withdrawal symptoms, and to initiate long-term alcohol rehabilitation. Several areas of controversy exist in the clinical management of AW, including the optimal treatment setting, the need for pharmacologic management, and the most appropriate agent to prescribe when medication is deemed necessary. This article reviews the clinical features, general management, and treatment of AW.

Priapism is a urologic disorder and medical emergency with a variety of known etiologies including the use of psychotropic medications. The antidepressant trazodone is the agent most frequently implicated in the precipitation of priapism. Additionally, a number of drugs of abuse including marijuana, ethanol, and cocaine have been known to cause the disorder. It is unknown if drugs may act in an additive or a synergistic manner to cause priapism. We report a case of priapism which occurred following trazodone overdose in an individual actively using cocaine. This case suggests that combined trazodone and cocaine use may pose an additional risk of priapism. Since trazodone is commonly employed as a hypnotic and often chosen for polysubstance abusers due to its low abuse potential, clinicians should be aware of the possible additive risk of priapism in this patient population.

The authors examine the relationship between substance use disorders, impulse control disorders (ICDs), and pathological aggression. Phenomenologic evidence, neurobiologic evidence, and comorbidity data, as well as evidence from the pharmacotherapy of aggression and impulse control and substance use disorders, suggest links between substance use, impulsivity, and pathologic aggression. There also is evidence suggesting that dysfunction in common neurotransmitter systems, particularly the serotonin and GABAergic systems, may be involved in both disorders. Serotonergic agents have been explored in the treatment of ICDs, pathological aggression, and substance use disorders. Mood-stabilizing anticonvulsant have GABAergic activity, have received preliminary exploration in the treatment of ICDs and aggression in a number of psychiatric disorders. There is also evidence that these agents may be useful in subgroups of individuals with substance use disorders.