Behavioral and Accumbal Responses During an Affective Go/No-Go Task Predict Adherence to Injectable Naltrexone Treatment in Opioid Use Disorder.

Adherence is a major factor in the effectiveness of the injectable extended-release naltrexone as a relapse prevention treatment in opioid use disorder. We examined the value of a variant of the Go/No-go paradigm in predicting extended-release naltrexone adherence in 27 detoxified opioid use disorder patients who were offered up to 3 monthly extended-release naltrexone injections. Before extended-release naltrexone, participants performed a Go/No-go task that comprised positively valenced Go trials and negatively valenced No-go trials during a functional magnetic resonance imaging scan. Errors of commission and neural responses to the No-go vs Go trials were independent variables. Adherence, operationalized as the completion of all 3 extended-release naltrexone injections, was the outcome variable. Fewer errors of commission and greater left accumbal response during the No-go vs Go trials predicted better adherence. These findings support the clinical potential of the behavioral and neurophysiological correlates of response inhibition in the prediction of extended-release naltrexone treatment outcomes in opioid use disorder.

Unseen scars: Cocaine patients with prior trauma evidence heightened resting state functional connectivity (RSFC) between the amygdala and limbic-striatal regions.

BACKGROUND: Substance use disorder (SUD) patients with a history of trauma exhibit poorer treatment outcome, greater functional impairment and higher risk for relapse. Endorsement of prior trauma has, in several SUD populations, been linked to abnormal functional connectivity (FC) during task-based studies. We examined amygdala FC in the resting state (RS), testing for differences between cocaine patients with and without prior trauma. METHODS: Patients with cocaine use disorder (CUD; n=34) were stabilized in an inpatient setting prior to a BOLD fMRI scan. Responses to Addiction Severity Index and the Mini-International Neuropsychiatric Interview were used to characterize the No-Trauma (n=16) and Trauma (n=18) groups. Seed-based RSFC was conducted using the right and left amygdala as regions of interest. Examination of amygdala RSFC was restricted to an a priori anatomical mask that incorporated nodes of the limbic-striatal motivational network. RESULTS: RSFC was compared for the Trauma versus No-Trauma groups. The Trauma group evidenced greater connectivity between the amygdala and the a priori limbic-striatal mask. Peaks within the statistically significant limbic-striatal mask included the amygdala, putamen, pallidum, caudate, thalamus, insula, hippocampus/parahippocampus, and brain stem. CONCLUSIONS: Results suggest that cocaine patients with prior trauma (versus without) have heightened communication within nodes of the motivational network, even at rest. To our knowledge, this is the first fMRI study to examine amygdala RSFC among those with CUD and trauma history. Heightened RSFC intralimbic connectivity for the Trauma group may reflect a relapse-relevant brain vulnerability and a novel treatment target for this clinically-challenging population.

Emotional, physical and sexual abuse are associated with a heightened limbic response to cocaine cues.

Drug-reward cues trigger motivational circuitry, a response linked to drug-seeking in animals and in humans. Adverse life events have been reported to increase sensitivity to drug rewards and to bolster drug reward signaling. Therefore, we hypothesized that cocaine-dependent individuals with prior emotional, physical and sexual abuse might have a heightened mesolimbic brain response to cues for drug reward in a new brief-cue probe. Cocaine-dependent human individuals (N = 68) were stabilized in an inpatient setting and then completed an event-related blood-oxygen-level dependent functional magnetic resonance imaging task featuring 500-ms evocative (cocaine, sexual, aversive) and comparator (neutral) cues. Responses to three questions about emotional, physical and sexual abuse from the Addiction Severity Index were used to divide the patients into subgroups (history of Abuse [n = 40] versus No Abuse [n = 28]). When subjects were grouped by the historical presence or absence of emotional, physical or sexual abuse, the Abuse group showed a heightened midbrain, thalamic, caudate, and caudal orbitofrontal cortex response to cocaine cues; a similar result was found in other evocative cues, as well. These findings are the first reported for a 500-ms cocaine-cue probe, and they highlight the ability of very brief evocative cues to activate the brain's motivational circuitry. Although all participants had severe cocaine use disorders, individuals reporting prior abuse had a heightened mesolimbic response to evocative cues. To our knowledge, this is the first study in humans linking a history of abuse to a brain vulnerability (heightened mesolimbic response to drug cues) previously shown to contribute to drug-seeking.

A hypo-status in drug-dependent brain revealed by multi-modal MRI.

Drug addiction is a chronic brain disorder with no proven effective cure. Assessing both structural and functional brain alterations by using multi-modal, rather than purely unimodal imaging techniques, may provide a more comprehensive understanding of the brain mechanisms underlying addiction, which in turn may facilitate future treatment strategies. However, this type of research remains scarce in the literature. We acquired multi-modal magnetic resonance imaging from 20 cocaine-addicted individuals and 19 age-matched controls. Compared with controls, cocaine addicts showed a multi-modal hypo-status with (1) decreased brain tissue volume in the medial and lateral orbitofrontal cortex (OFC); (2) hypo-perfusion in the prefrontal cortex, anterior cingulate cortex, insula, right temporal cortex and dorsolateral prefrontal cortex and (3) reduced irregularity of resting state activity in the OFC and limbic areas, as well as the cingulate, visual and parietal cortices. In the cocaine-addicted brain, larger tissue volume in the medial OFC, anterior cingulate cortex and ventral striatum and smaller insular tissue volume were associated with higher cocaine dependence levels. Decreased perfusion in the amygdala and insula was also correlated with higher cocaine dependence levels. Tissue volume, perfusion, and brain entropy in the insula and prefrontal cortex, all showed a trend of negative correlation with drug craving scores. The three modalities showed voxel-wise correlation in various brain regions, and combining them improved patient versus control brain classification accuracy. These results, for the first time, demonstrate a comprehensive cocaine-dependence and craving-related hypo-status regarding the tissue volume, perfusion and resting brain irregularity in the cocaine-addicted brain.

A hyper-connected but less efficient small-world network in the substance-dependent brain.

BACKGROUND: The functional interconnections of the addicted brain may differ from the non-addicted population in important ways, but prioranalytic approaches were usually limited to the study of connections between a few number of selected brain regions. Recent approaches enable examination of the vast functional interactions within the entire brain, the functional connectome (FCM). The purpose of this study was to characterize FCM alterations in addiction using resting state functional Magnetic Resonance Imaging (rsfMRI) and to assess their relations to addiction-related symptoms. METHODS: rsfMRI data were acquired from 20 chronic polydrug users whose primary diagnosis was cocaine dependence (DRUG) and 19 age-matched non-drug using healthy controls (CTL). FCM was assessed using graph theoretical analysis. RESULTS: Among the assessed 90 brain subdivisions, DRUG showed stronger functional connectivity. After controlling functional connectivity difference and the resultant network density, DRUG showed reduced communication efficiency and reduced small-worldness. CONCLUSIONS: The increased connection strength in drug users' brain suggests an elevated dynamic resting state that may enable a rapid, semi-automatic, execution of behaviors directed toward drug-related goals.The reduced FCM communication efficiency and reduced small-worldness suggest a loss of normal inter-regional communications and topology features that makes it difficult to inhibit the drug seeking behavior.

Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues.

Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen-a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals-could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing-that which occurs outside of awareness-before it evolves into a less manageable state.

Neural responses to subliminally presented cannabis and other emotionally evocative cues in cannabis-dependent individuals.

RATIONALE: Addiction theories posit that drug-related cues maintain and contribute to drug use and relapse. Indeed, our recent study in cocaine-dependent patients demonstrated that subliminally presented cocaine-related stimuli activate reward neurocircuitry without being consciously perceived. Activation of reward neurocircuitry may provoke craving and perhaps prime an individual for subsequent drug-seeking behaviors. OBJECTIVES: Using an equivalent paradigm, we tested whether cannabis cues activate reward neurocircuitry in treatment-seeking, cannabis-dependent individuals and whether activation was associated with relevant behavioral anchors: baseline cannabis craving (drug-seeking behavior) and duration of use (degree of conditioning). METHODS: Twenty treatment-seeking, cannabis-dependent individuals (12 males) underwent event-related blood oxygen level-dependent functional magnetic resonance imaging during exposure to 33-ms cannabis, sexual, and aversive cues presented in a backward-masking paradigm. Drug use history and cannabis craving were assessed prior to imaging. RESULTS: Participants showed increased activity to backward-masked cannabis cues in regions supporting reward detection and interoception, including the left anterior insula, left ventral striatum/amygdala, and right ventral striatum. Cannabis cue-related activity in the bilateral insula and perigenual anterior cingulate cortex was positively associated with baseline cannabis craving, and cannabis cue-related activity in the medial orbitofrontal cortex was positively correlated with years of cannabis use. Neural responses to backward-masked sexual cues were similar to those observed during cannabis cue exposure, while activation to aversive cues was observed only in the left anterior insula and perigenual anterior cingulate cortex. CONCLUSIONS: These data highlight the sensitivity of the brain to subliminal reward signals and support hypotheses promoting a common pathway of appetitive motivation.

A VBM study demonstrating 'apparent' effects of a single dose of medication on T1-weighted MRIs.

Voxel-based morphometry (VBM) studies have interpreted longitudinal medication- or behaviorally induced changes observed on T1-weighted magnetic resonance images (MRIs) as changes in neuronal structure. Although neurogenesis or atrophy certainly occurs, the use of T1-weighted scans to identify change in brain structure in vivo in humans has vulnerability: the T1 relaxation time for arterial blood and gray matter are not clearly distinguishable and therefore, apparent reported structural findings might be at least partially related to changes in blood flow or other physiological signals. To examine the hypothesis that apparent structural modifications may reflect changes introduced by additional mechanisms irrespective of potential neuronal growth/atrophy, we acquired a high-resolution T1-weighted structural scan and a 5-min perfusion fMRI scan (a measurement of blood flow), before and after administration of an acute pharmacological manipulation. In a within-subject design, 15 subjects were either un-medicated or were administered a 20 mg dose of baclofen (an FDA-approved anti-spastic) approximately 110 min before acquiring a T1-weighted scan and a pseudo continuous arterial spin labeled perfusion fMRI scan. Using diffeomorphic anatomical registration through exponentiated lie algebra within SPM7, we observed macroscopic, and therefore implausible, baclofen-induced decreases in VBM 'gray matter' signal in the dorsal rostral anterior cingulate (family wise error corrected at p<0.04, T = 6.54, extent: 1,460 voxels) that overlapped with changes in blood flow. Given that gray matter reductions are unlikely following a single dose of medication these findings suggest that changes in blood flow are masquerading as reductions in gray matter on the T1-weighted scan irrespective of the temporal interval between baseline measures and longitudinal manipulations. These results underscore the crucial and immediate need to develop in vivo neuroimaging biomarkers for humans that can uniquely capture changes in neuronal structure dissociable from those related to blood flow or other physiological signals.

Reward-related brain response and craving correlates of marijuana cue exposure: a preliminary study in treatment-seeking marijuana-dependent subjects.

OBJECTIVE: : Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry (eg, amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex) triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brain's response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects. METHODS: : Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire-Short Form. Subsequently, blood oxygen level dependent functional magnetic resonance imaging data were acquired during exposure to alternating 20-second blocks of marijuana-related versus matched nondrug visual cues. RESULTS: : Brain activation during marijuana cue exposure was significantly greater in the bilateral amygdala and the hippocampus. Significant positive correlations between craving scores and brain activation were found in the ventral striatum and the medial and lateral orbitofrontal cortex (P < 0.0001). CONCLUSIONS: : This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving and extends the current literature on marijuana cue reactivity. Furthermore, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.

Acute baclofen diminishes resting baseline blood flow to limbic structures: a perfusion fMRI study.

BACKGROUND: Preclinical and clinical evidence show that the GABA B agonist, baclofen is a promising treatment for addictive disorders; however, until recently its mechanism of action in the human brain was unknown. In previous work we utilized a laboratory model that included a medication versus placebo regimen to examine baclofen's actions on brain circuitry. Perfusion fMRI [measure of cerebral blood flow (CBF)] data acquired 'at rest' before and on the last day of the 21-day medication regimen showed that baclofen diminished CBF bilaterally in the VS, insula and medial orbitofrontal cortex (mOFC). In the present study, we hypothesized that a single dose of baclofen would have effects similar to repeated dosing. METHODS: To test our hypothesis, in a crossover design, CBF data were acquired using pseudo continuous arterial spin labeled (pCASL) perfusion fMRI. Subjects were either un-medicated or were administered a 20mg dose of baclofen approximately 110 min prior to scanning. RESULTS: Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p=0.001). CONCLUSIONS: Results demonstrate that similar to repeated dosing, an acute dose of baclofen blunts the 'limbic' substrate that is hyper-responsive to drugs and drug cues. Smokers often manage their craving and can remain abstinent for extended periods after quitting, however the risk of eventual relapse approaches 90%. Given that chronic medication may not be a practical solution to the long-term risk of relapse, acute baclofen may be useful on an 'as-needed' basis to block craving during 'at risk' situations.

Expanding the single-case study: a proposed psychoanalytic research program.

This paper offers a proposed program of research using single-case time-series methods that can be used by practicing clinicians. The paper is written for psychodynamically oriented clinicians who want to get involved in psychotherapy research and make contributions to the scientific literature. How to measure treatment outcomes and psychodynamic constructs are discussed. With few exceptions, conducting single-case time-series research using psychodynamic psychotherapy has far more advantages than disadvantages.

Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort.

Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9-repeat allele (9-repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10-repeat allele (10/10-repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N=26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t=3.77). Contrasts between allelic groups revealed that 9-repeat carriers had a greater response to SCs in the VS (t=3.12) and mOFC (t=3.19). In separate groups, 9-repeat carriers showed increased activity in the VS (t=5.47) and mOFC (T=4.96), while no increases were observed in 10-repeats. Subjective reports of craving correlated with increased activity in reward-related structures including the extended amygdala, insula and post-central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT-genotype dependent (r=0.63-0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC-induced perfusion in 10/10-repeats in the insula, mOFC, medial temporal and superior frontal gyri (r=0.50-0.82), while correlations were absent in 9-repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs.

Effects of varenicline on smoking cue­triggered neural and craving responses.

CONTEXT: Varenicline, an effective smoking cessation medication, functions as an α4ß2 nicotinic acetylcholine receptor partial agonist. It indirectly affects the dopaminergic reward system by reducing withdrawal symptoms during abstinence and by decreasing the reinforcement received from nicotine while smoking. We hypothesize that varenicline would have a third mechanism to blunt responses to smoking cues in the reward-related ventral striatum and medial orbitofrontal cortex and would be associated with a reduction in smoking cue­elicited craving. DESIGN: A laboratory model of conditioned responding and arterial spin-labeled perfusion functional magnetic resonance imaging, a biomarker of regional brain activity, was used to test our hypothesis. Perfusion functional magnetic resonance imaging is quantitative and stable across time, facilitating the measurement of medication-induced neural modifications in the brain in response to a challenge (smoking cue exposure) and in the brain in the resting condition (without provocation). Smokers were imaged during rest and during smoking cue exposure before and after a 3-week randomized placebo-controlled medication regimen. Subjects were nonabstinent to explicitly examine the effects of varenicline on cue reactivity independent of withdrawal. SETTING: Center for the Study of Addictions, University of Pennsylvania, Philadelphia. Subjects Subjects were nicotine-dependent smokers who responded to advertisements placed on local radio and Listservs to participate in a medication-related research study that specifically stated "this is not a Quit Smoking Study" and "smokers may be contemplating but not currently considering quitting." RESULTS: Prerandomization smoking cues vs nonsmoking cues activated the ventral striatum and medial orbitofrontal cortex (t = 3.77) and elicited subjective reports of craving (P = .006). Craving reports correlated with increased activity in the posterior cingulate (t = 4.11). Administration of varenicline diminished smoking cue­elicited ventral striatum and medial orbitofrontal cortex responses (t values from ­3.75 to ­5.63) and reduced self-reported smoking cue­elicited craving, whereas placebo-treated subjects exhibited responses similar to those observed prior to randomization. Varenicline-induced activation of lateral orbitofrontal cortex in the brain at rest (t = 5.63) predicted blunting of smoking cue responses in the medial orbitofrontal cortex (r = ­0.74). CONCLUSIONS: Varenicline's reciprocal actions in the reward-activated medial orbitofrontal cortex and in the reward-evaluating lateral orbitofrontal cortex underlie a diminished smoking cue response, revealing a distinctive new action that likely contributes to its clinical efficacy.

Identifying risk factors for marijuana use among veterans affairs patients.

OBJECTIVES: Cannabis is the most widely used drug in the United States, and its use carries negative health consequences; however, universal screening for cannabis use is cumbersome. If data commonly collected in the primary care setting (eg, use of alcohol, smoking status, and depression symptoms) could predict cannabis use, then providers can implement targeted marijuana screening in high-risk groups. METHODS: We reviewed Behavioral Health Laboratory data collected between 2003 and 2006 from 5512 patients referred by Veterans Affairs primary care clinics for potential mental health needs. Logistic regression was used to determine the predictors of past year marijuana use. RESULTS: A total of 11.5% of the sample reported using marijuana in the past year. Age, gender, other drug use, presence of alcohol use disorders, smoking status, depressive disorders, posttraumatic stress disorder, anxiety disorders, and psychotic symptoms, individually, were associated with the patients' use of marijuana during the past year. When controlling for age, race, and gender in a logistic regression analyses, only other drug use, alcohol use disorder, and smoking status were linked to past year marijuana use. Patients were 5.4 (95% confidence interval [CI] 4.3-6.7) times more likely to have used marijuana during the past year if they used another illicit drug during the past year. Those with alcohol use disorder diagnosis or current smokers were 2.3 (95% CI 1.9-2.8) and 1.5 times (95% CI 1.3-1.7), respectively, more likely to have used marijuana during the past year. Receiver operating characteristic curve (area under curve = 0.79) represents good sensitivity and specificity of the model, correctly classifying 88.4% of the past year marijuana users. CONCLUSION: Identifying patients at high risk for cannabis use may facilitate targeted screening and provision of interventions in primary care. Patients who screen positive for cigarette use, alcohol abuse or dependence, or have evidence of other illicit drug use could be considered for cannabis screening.

Low prefrontal perfusion linked to depression symptoms in methadone-maintained opiate-dependent patients.

BACKGROUND: Clinically depressed patients without substance use disorders, compared to controls, exhibit significantly lower resting regional cerebral blood flow (rCBF) in the prefrontal cortex (PFC). In this study, we examined the link between resting rCBF in the PFC and current depressive symptoms in methadone-maintained opiate-dependent (MM) patients with or without major depression. METHODS: Arterial spin labeled perfusion fMRI at 3 Tesla was used to measure resting rCBF in 21 MM patients. Perfusion data were analyzed using SPM2. The relationship between Beck Depression Inventory (BDI) score and resting rCBF was examined in a single regression analysis. RESULTS: The BDI scores ranged between 0 and 18 (m=7.0, S.D.=4.8), and 30% of the sample had mild to moderate depression symptoms according to BDI scores. A negative correlation was observed between BDI scores and relative rCBF in the bilateral ventrolateral prefrontal cortex, and middle frontal gyri. CONCLUSIONS: The inverse relationship between prefrontal paralimbic rCBF and depression scores suggests a link between reduced fronto-limbic activity and depressive symptoms in MM patients. A significant subgroup of opiate-dependent patients has clinical or sub-clinical depression that is often undetected; our data identify brain substrates of depression symptoms that may also be a potential marker of relapse in this population. Treatment strategies targeting these brain regions may improve outcomes in depressed substance abusers.

Gender differences in predictors of treatment attrition with high dose naltrexone in cocaine and alcohol dependence.

Recently, we reported that naltrexone at 150 mg/day significantly decreased cocaine and alcohol use for men but not women with co-occurring cocaine and alcohol dependence. The present study is an exploratory investigation of predictors that explain the different gender responses to naltrexone, with a particular focus on differential predictors of treatment attrition. No significant predictors were associated with treatment discontinuation in men. Women, however, were more likely to discontinue treatment when reporting severe pre-treatment psychiatric problems or nausea while in treatment. Further research on the impact of pre-treatment and in-treatment gender differences with naltrexone is warranted.

Prelude to passion: limbic activation by "unseen" drug and sexual cues.

BACKGROUND: The human brain responds to recognizable signals for sex and for rewarding drugs of abuse by activation of limbic reward circuitry. Does the brain respond in similar way to such reward signals even when they are "unseen", i.e., presented in a way that prevents their conscious recognition? Can the brain response to "unseen" reward cues predict the future affective response to recognizable versions of such cues, revealing a link between affective/motivational processes inside and outside awareness? METHODOLOGY/PRINCIPAL FINDINGS: We exploited the fast temporal resolution of event-related functional magnetic resonance imaging (fMRI) to test the brain response to "unseen" (backward-masked) cocaine, sexual, aversive and neutral cues of 33 milliseconds duration in male cocaine patients (n = 22). Two days after scanning, the affective valence for visible versions of each cue type was determined using an affective bias (priming) task. We demonstrate, for the first time, limbic brain activation by "unseen" drug and sexual cues of only 33 msec duration. Importantly, increased activity in an large interconnected ventral pallidum/amygdala cluster to the "unseen" cocaine cues strongly predicted future positive affect to visible versions of the same cues in subsequent off-magnet testing, pointing both to the functional significance of the rapid brain response, and to shared brain substrates for appetitive motivation within and outside awareness. CONCLUSIONS/SIGNIFICANCE: These findings represent the first evidence that brain reward circuitry responds to drug and sexual cues presented outside awareness. The results underscore the sensitivity of the brain to "unseen" reward signals and may represent the brain's primordial signature for desire. The limbic brain response to reward cues outside awareness may represent a potential vulnerability in disorders (e.g., the addictions) for whom poorly-controlled appetitive motivation is a central feature.

Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence.

This is a randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy of a higher-than-typical daily dose of naltrexone (150 mg/day), taken for 12 weeks, in 164 patients (n = 116 men and n = 48 women) with co-occurring cocaine and alcohol dependence. Patients were stratified by gender and then randomly assigned to either naltrexone or placebo, and to either cognitive-behavioral therapy or a type of medical management. The two primary outcomes were cocaine use and alcohol use. Significant Gender x Medication interactions were found for cocaine use via urine drug screens (three way, with time) and self-reports (two way) for drug severity (two way) and alcohol use (two way). The type of psychosocial treatment did not affect outcomes. Thus, 150 mg/day naltrexone added to a psychosocial treatment resulted in reductions in cocaine and alcohol use and drug severity in men, compared to higher rates of cocaine and alcohol use and drug severity in women.

Risperidone in cocaine-dependent patients with comorbid psychiatric disorders.

BACKGROUND: : A high percentage of individuals with cocaine dependence have a comorbid psychiatric illness, which complicates treatment of the substance abuse. This report will describe clinical experience using risperidone in cocaine-dependent patients with psychiatric disorders. METHOD: : Sixteen male patients with cocaine dependence and comorbid psychiatric disorder (DSM-III-R) diagnoses, who were admitted to a voluntary, post-detoxification, intermediate-care inpatient substance abuse program, were started on risperidone (mean starting dose 2.3 mg/day) in an open-label, naturalistic trial. Patients were assessed weekly using the Clinical Global Impressions scale to assess overall functioning, a Likert scale for craving, the Abnormal Involuntary Movement Scale, interviews with substance abuse counselors and patients, and laboratory tests. All patients had at least one other substance use diagnosis besides cocaine dependence, and 13 patients were taking another psychiatric medication. RESULTS: : Of the 16 patients, 13 (81%) were rated improved or much improved on the CGI scale, and all patients reported mild or no craving at the last assessment (after a mean of 32.6 days of risperidone treatment). No patient developed extrapyramidal symptoms or hypomania. Compared to a 32% historical completion rate for patients receiving treatment as usual, fourteen (88%) of these patients completed the program, and 9 moved on to the next level of care. CONCLUSION: : The results of this naturalistic trial suggest that risperidone is safe and well tolerated in patients with cocaine dependence and comorbid psychiatric illness. In the short term, risperidone may also be effective in reducing cocaine craving and use and may increase the likelihood of completing substance abuse treatment.