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Aimee L. McRae-Clark,
PharmD, BCPP

Clinical Neuroscience Division
Associate Professor, Departments of
Psychiatry and Neurosciences


Clinical Neuroscience Division

Recent Publications

Laboratory-induced cue reactivity among individuals with prescription opioid dependence.
Back SE, Gros DF, McCauley JL, Flanagan JC, Cox E, Barth KS, Brady KT.
Addict Behav. 2014 Aug;39(8):1217-23. doi: 10.1016/j.addbeh.2014.04.007. Epub 2014 Apr 12.

Prescription opioid (PO) dependence is a critical health problem. Although examination of drug cue reactivity paradigms has advanced the understanding of risk factors for relapse for a variety of substances (e.g., cocaine, alcohol, nicotine), no PO specific drug cue paradigm has been developed. The current study addressed this gap in the literature and evaluated the ability of a newly developed PO drug cue paradigm to elicit subjective, physiological, and neuroendocrine changes among PO-dependent participants (n=20) as compared to controls (n=17). The drug cue paradigm included an induction script, viewing and handling paraphernalia (e.g., bottle of oxycontin pills, pill crusher) and watching a video depicting people using POs as well as places related to POs (e.g., pharmacies). Consistent with hypotheses, the PO group demonstrated significant pre- to post-cue increases on subjective ratings of craving, difficulty resisting POs, stress, and anger. The control group did not demonstrate significant changes on any of the subjective measures. Both the PO group and the control group evidenced significant pre- to post-cue increases in physiological responses (e.g., blood pressure, skin conductance), as expected given the arousing nature of the drug cue stimuli. The PO group, but not the control group, evidenced a significant pre- to post-cue increase in heart rate and salivary cortisol levels. The development and validation of a drug cue paradigm for POs may help inform future research and treatment development efforts for patients with PO dependence.

The relationship between years of cocaine use and brain activation to cocaine and response inhibition cues.Prisciandaro JJ, Joseph JE, Myrick H, McRae-Clark AL, Henderson S, Pfeifer J, Brady KT.Addiction. 2014 Jun 17. doi: 10.1111/add.12666. [Epub ahead of print]

AIMS: Functional magnetic resonance imaging research has attempted to elucidate the neurobehavioral underpinnings of cocaine dependence by evaluating differences in brain activation to cocaine and response inhibition cues between cocaine-dependent individuals and controls. This study investigated associations between task-related brain activation and cocaine use characteristics.  DESIGN: Cross-sectional.  SETTING: The Center for Biomedical Imaging at the Medical University of South Carolina, USA.  PARTICIPANTS: Fifty-one cocaine users (41 dependent).  MEASUREMENTS: Brain activation to cocaine-cue exposure and Go No-Go tasks in six a priori selected brain regions of interest and cocaine use characteristics (i.e. cocaine dependence status, years of cocaine use, cocaine use in the past 90 days) assessed via standardized interviews.  FINDINGS: Participants demonstrated elevated activation to cocaine (bilateral ventral striatum, dorsal caudate, amygdala) and response inhibition (bilateral anterior cingulate, insula, inferior frontal gyrus) cues in all hypothesized brain regions. Years of cocaine use was associated with task-related brain activation, with more years of cocaine use associated with greater activation to cocaine cues in right (F = 7.97, P = 0.01) and left (F = 5.47, P = 0.02) ventral striatum and greater activation to response inhibition cues in left insula (F = 5.10, P = 0.03) and inferior frontal gyrus (F = 4.12, P = 0.05) controlling for age, cocaine dependence status and cocaine use in the past 90 days.  CONCLUSIONS: Years of cocaine use may be more centrally related to cocaine cue and response inhibition brain activation than cocaine dependence diagnosis or amount of recent use.

An open-label pilot trial of N-acetylcysteine and varenicline in adult cigarette smokers.
McClure EA, Baker NL, Gipson CD, Carpenter MJ, Roper AP, Froeliger BE, Kalivas PW, Gray KM.
Am J Drug Alcohol Abuse. 2014 Jul 25:1-5. [Epub ahead of print]

Background: Varenicline (VAR) has demonstrated superior efficacy over other smoking cessation pharmacotherapies, though 50-60% of those treated do maintain abstinence. Some preclinical findings suggest that new nicotine dependence pharmacotherapies should target the glutamatergic system, given its demonstrated role in addiction. Attention has been given to N-acetylcysteine (NAC), which appears to restore normal glutamate signaling in animal models. It is possible that NAC and VAR may work in concert to promote abstinence at higher rates than with either medication alone. Objective: To demonstrate the feasibility and safety of co-administering NAC and VAR in nicotine-dependent participants. Methods: Participants (n = 19) were daily cigarette smokers, and did not need to be seeking treatment. They received 4 weeks of open-label treatment with NAC (1200 mg twice daily) and VAR (1 mg twice daily, following titration) and were assessed weekly for adverse events (AEs), smoking, craving and withdrawal. Results: Sixteen participants reported a total of 40 AEs, and most were mild (88%). The most commonly reported AE was nausea (15%). Medication adherence, assessed via self-reports and pill counts, was excellent (98%). Exploratory analyses showed reductions in cigarettes per day, though point prevalence abstinence at the end of the study was low. Conclusions: These preliminary data provide the first demonstration of safety and feasibility of the co-administration of NAC and VAR in cigarette smokers. AEs were consistent with those typically reported for VAR and NAC. These data support future efficacy research on NAC and VAR for smoking cessation.

Cigarette smoking during an N-acetylcysteine-assisted cannabis cessation trial in adolescents.
McClure EA, Baker NL, Gray KM.
Am J Drug Alcohol Abuse. 2014 Jul;40(4):285-91. doi: 10.3109/00952990.2013.878718. Epub 2014 Apr 10.

Background and objectives: Tobacco and cannabis use are both highly prevalent worldwide. Their co-use is also common in adults and adolescents. Despite this frequent co-occurrence, cessation from both substances is rarely addressed in randomized clinical trials. Given evidence that tobacco use may increase during cannabis cessation attempts, and additionally that tobacco users have poorer cannabis cessation outcomes, we explored tobacco outcomes, specifically cigarette smoking, from an adolescent cannabis cessation trial that tested the efficacy of N-acetylesteine (NAC). Methods: Cannabis-dependent adolescents (ages 15-21; n = 116) interested in cannabis treatment were randomized to NAC (1200 mg bid) or matched placebo for 8 weeks. Participants did not need to be cigarette smokers or be interested in smoking cessation to qualify for inclusion. Results: Approximately 59% of enrolled participants were daily and non-daily cigarette smokers, and only differed from non-smoking participants on the compulsion sub-scale of the Marijuana Craving Questionnaire. Among cigarette smokers who were retained in the study, there was no change in cigarettes per day for either NAC or placebo groups during the eight-week treatment phase. Being a cigarette smoker did not appear to influence the effects of NAC on cannabis abstinence, though there was a trend in the placebo group of poorer cannabis outcomes for cigarette smokers vs. non-smokers. Conclusions: No evidence was found of compensatory cigarette smoking during this cannabis cessation trial in adolescents. Further work assessing interventions to reduce both cannabis and tobacco use in this population is greatly needed.

Pain management perceptions among prescription opioid dependent individuals.
McCauley JL, Mercer MA, Barth KS, Brady KT, Back SE.
Drug Alcohol Depend. 2014 Jun 25. pii: S0376-8716(14)00946-6. doi: 10.1016/j.drugalcdep.2014.06.024. [Epub ahead of print]

BACKGROUND: Nearly two-thirds of prescription opioid dependent individuals report chronic pain conditions as both an initial and current motivation for prescription opioid use. However, to date, limited information exists regarding perceptions of the adequacy of pain management and pain management behaviors among prescription opioid dependent individuals with a history of treatment for chronic pain.
METHODS: The current study examined perceptions of the medical management of chronic pain among community-recruited individuals (N=39) who met DSM-IV-TR criteria for current prescription opioid dependence and reported a history of treatment for chronic pain. Prescription opioid dependence, symptoms of depression, and pain management perceptions were assessed using the Structured Clinical Interview for DSM disorders, Beck Depression Inventory, and the Pain Management Questionnaire, respectively.
RESULTS: Reports of insufficient pain management were common (46.2%), as was utilization of emergency room services for pain management (56.4%). Nearly half reported a physician as their initial source (46.2%) and pain management as their primary initial reason for prescription opioid use (53.8%), whereas 35.9% reported pain relief as their primary reason for current prescription opioid use. Symptoms of depression were common (51.3%), as was comorbid abuse of other substances and history of treatment for substance abuse.
CONCLUSIONS: Results highlight the complicated clinical presentation and prevalent perception of the under-treatment of pain among this population. Findings underscore the importance of interdisciplinary approaches to managing the complex presentation of chronic pain patients with comorbid prescription opioid dependence. Implications for future research are discussed.

Brain activation to cocaine cues and motivation/treatment status.Prisciandaro JJ, McRae-Clark AL, Myrick H, Henderson S, Brady KT.Addict Biol. 2014 Mar;19(2):240-9. PMCID: PMC3390439

Motivation to change is believed to be a key factor in therapeutic success in substance use disorders; however, the neurobiological mechanisms through which motivation to change impacts decreased substance use remain unclear. Existing research is conflicting, with some investigations supporting decreased and others reporting increased frontal activation to drug cues in individuals seeking treatment for substance use disorders. The present study investigated the relationship between motivation to change cocaine use and cue-elicited brain activity in cocaine-dependent individuals using two conceptualizations of 'motivation to change': (1) current treatment status (i.e. currently receiving versus not receiving outpatient treatment for cocaine dependence) and (2) self-reported motivation to change substance use, using the Stages of Change Readiness and Treatment Eagerness Scale. Thirty-eight cocaine-dependent individuals (14 currently in treatment) completed a diagnostic assessment and an fMRI cocaine cue-reactivity task. Whole-brain analyses demonstrated that both treatment-seeking and motivated participants had lower activation to cocaine cues in a wide variety of brain regions in the frontal, occipital, temporal and cingulate cortices relative to non-treatment-seeking and less motivated participants. Future research is needed to explain the mechanism by which treatment and/or motivation impacts neural cue reactivity, as such work could potentially aid in the development of more effective therapeutic techniques for substance-dependent patients.

Cannabis use disorders are comparatively prevalent among nonwhite racial/ethnic groups and adolescents: a national study.
Wu LT, Brady KT, Mannelli P, Killeen TK; NIDA AAPI Workgroup.
J Psychiatr Res. 2014 Mar;50:26-35. PMCID: PMC3941308

The racial/ethnic composition of the US population is shifting, with the nonwhite population growing faster than whites. We examined cannabis use disorder (CUD) prevalences and correlates in seven racial/ethnic groups. We included cannabis use (CU) prevalence as a comparison. Data were from the 2005-2011 National Surveys on Drug Use and Health (N = 394,400). Substance use among respondents aged ≥12 years was assessed by computer-assisted, self-interviewing methods. The following were included as control variables: age, sex, family income, government assistance, county type, residential stability, major depressive episode history, arrest history, nicotine dependence, alcohol disorder, and survey year. Past-year CU prevalence increased significantly from 10.45% in 2005 to 11.41-11.54% during 2009-2011. Compared with whites, mixed-race individuals had higher odds of CU; Asian Americans and Hispanics had lower odds of CU. There were no significant yearly changes in CUD prevalence in the sample during 2005-2011 (1.58-1.73%). Compared with whites, individuals who were mixed-race, black, and Native American had higher odds of CUD; Asian Americans had lower odds. In aggregate, 15.35% of past-year cannabis users met criteria for a CUD in the 12-month period. Past-year cannabis users who were black, Native American, Hispanic, or Asian American had higher odds of CUD than white users. In each racial/ethnic group, adolescent cannabis users generally showed greater odds of CUD than adult users. Behavioral health indicators (major depressive episode, arrest history, nicotine dependence, alcohol disorder) were associated with CU and CUD. In conclusion, CUD disproportionally affects nonwhite groups and youth.

Yohimbine administration and cue-reactivity in cocaine-dependent individuals.
Moran-Santa Maria MM, McRae-Clark A, Baker NL, Ramakrishnan V, Brady KT.
Psychopharmacology (Berl). 2014 Apr 8. [Epub ahead of print]. NIHMSID: NIHMS583711

Rationale: Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations. Objectives: The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women. Methods: In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n = 32), cocaine-dependent women (n = 30), control men (n = 32), and control women (n = 25) received either yohimbine or placebo prior to two cocaine cue exposure sessions. Results: Yohimbine increased ratings of anxiety both before (p < 0.001) and after (p = 0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p = 0.001). Yohimbine also significantly increased craving, compared with placebo (p < 0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p = 0.006). Yohimbine also increased salivary cortisol (p < 0.001) and dehydroepiandrosterone (p = 0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p < 0.001). Conclusions: Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.

Right anterior insula connectivity is important for cue-induced craving in nicotine-dependent smokers.
Moran-Santa Maria MM, Hartwell KJ, Hanlon CA, Canterberry M, Lematty T, Owens M, Brady KT, George MS.
Addict Biol. 2014 Feb 13. doi: 10.1111/adb.12124. [Epub ahead of print]. NIHMSID: NIHMS583705

The insula has been implicated in cue-induced craving and relapse in nicotine-dependent tobacco cigarette smokers. The aims of the present study were to identify brain regions that exhibit greater functional connectivity with the right anterior insula in response to smoking cues than to neutral cues and the role of functional connectivity between these regions in mediating cue-induced craving in healthy (free of axis I psychiatric disorders) nicotine-dependent tobacco cigarette smokers. Functional magnetic resonance imaging data were collected from 63 healthy nicotine-dependent smokers viewing blocks of smoking and neutral cues. Craving ratings were obtained after each block. A psychophysiologic interaction approach was used to identify regions that exhibited significantly greater functional connectivity with the right anterior insula (seed) during the smoking cues than during the neutral (corrected cluster thresholding, Z > 2.3, P = 0.05). Parameter estimates of the interaction effects from each region were regressed against the mean cue-induced craving scores. Significant task by seed interactions were observed in two clusters centered in the bilateral precuneus and left angular gyrus. The strength of connectivity between the right anterior insula and the precuneus, which is involved interoceptive processing and self-awareness, was positively correlated with the magnitude of the craving response to the smoking cues (r2  = 0.15; P < 0.01). These data suggest that among smokers, cue-induced craving may be a function of connectivity between two regions involved in interoception and self-awareness. Moreover, treatment strategies that incorporate mindful attention may be effective in attenuating cue-induced craving and relapse in nicotine-dependent smokers.

Substance use disorders and PTSD: an exploratory study of treatment preferences among military veterans.
Back SE, Killeen TK, Teer AP, Hartwell EE, Federline A, Beylotte F, Cox E.
Addict Behav. 2014 Feb;39(2):369-73. PMCID: PMC3855915

Background: Substance use disorders (SUDs) and Post Traumatic Stress Disorder (PTSD) frequently co-occur among Veterans and are associated with poor treatment outcomes. Historically, treatments for SUDs and PTSD have been delivered sequentially and independently. More recently, however, integrated treatments have shown promise. This study investigated Veterans' perceptions of the interrelationship between SUDs and PTSD, as well as treatment preferences. Methods: Participants were 35 Veterans of recent military conflicts in Iraq and Afghanistan, and prior operations, who completed the Treatment Preferences Questionnaire as well as an in-depth interview. Results: The majority (94.3%) perceived a relationship between their SUD and PTSD symptoms. Veterans reported that PTSD symptom exacerbation was typically (85.3%) associated with an increase in substance use, and PTSD symptom improvement was typically (61.8%) followed by a decrease in substance use (p<.01). Approximately 66% preferred an integrated treatment approach. Conclusions: Although preliminary, the findings provide clinically-relevant information that can be used to enhance the development and provision of care for Veterans with SUDs and PTSD.

Potential role of N-acetylcysteine in the management of substance use disorders.
McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM.
CNS Drugs. 2014 Feb;28(2):95-106. doi: 10.1007/s40263-014-0142-x. PMCID: PMC4009342

There is a clear and pressing need to expand pharmacotherapy options for substance use disorders (SUDs) in order to improve sustained abstinence outcomes. Preclinical literature has demonstrated the role of glutamate in addiction, suggesting that new targets for pharmacotherapy should focus on the restoration of glutamatergic function. Glutamatergic agents for SUDs may span multiple addictive behaviors and help demonstrate potentially overlapping mechanisms in addiction. The current review will focus specifically on N-acetylcysteine (NAC), a safe and well-tolerated glutamatergic agent, as a promising potential pharmacotherapy for the treatment of SUDs across several substances of abuse. Building on recently published reviews of the clinical efficacy of NAC across a broad range of conditions, this review will more specifically discuss NAC as a pharmacotherapy for SUDs, devoting particular attention to the safety and tolerability profile of NAC, the wealth of preclinical evidence that has demonstrated the role of glutamate dysregulation in addiction, and the limited but growing clinical literature that has assessed the efficacy of NAC across multiple substances of abuse. Preliminary clinical studies show the promise of NAC in terms of safety, tolerability, and potential efficacy for promoting abstinence from cocaine, nicotine, and cannabis. Results from randomized clinical trials have been mixed, but several mechanistic and methodological factors are discussed to refine the use of NAC in promoting abstinence and relapse prevention across several substances of abuse. Further preclinical and clinical investigation into the use of NAC for SUDs will be vital in addressing current deficits in the treatment of SUDs.

Craving, cue reactivity, and stimulus control among early-stage young smokers: effects of smoking intensity and gender.
Carpenter MJ, Saladin ME, Larowe SD, McClure EA, Simonian S, Upadhyaya HP, Gray KM.
Nicotine Tob Res. 2014 Feb;16(2):208-15. PMCID: PMC3880235

Introduction: Smoking initiation usually begins in adolescence, but how and for whom nicotine dependence emerges during this period is unclear. The cue-reactivity paradigm is well suited to examine one marker of dependence: craving-related stimulus control, i.e., the ability of environmental cues to elicit craving to smoke. This study examined the effects of both level of smoking involvement (daily vs. occasional smoking) and gender on reactivity to both smoking and alcohol cues. Methods: Young (age range 16-20; 42% female) daily (n = 55) and occasional (n = 52) smokers were exposed to each of three counterbalanced cues: (a) in vivo smoking (e.g., sight, smell, lighting of cigarette), (b) alcohol (e.g., opening, pouring, and smell of preferred beverage), and (c) neutral cue. Results: Daily smokers exhibited higher levels of tonic (i.e., noncue-elicited) craving than did occasional smokers. Both groups showed significant increases in craving in response to cues (i.e., cue-elicited craving), with little evidence that cue-elicited craving differed between groups. Females were more cue reactive to both the alcohol and smoking cues than males, particularly for the positively reinforced aspects of smoking (i.e., hedonic craving). There were no gender × group interaction effects in response to either the alcohol or the smoking cue. Conclusions: Findings show the presence of cue-elicited craving even among occasional smokers and are consistent with literature demonstrating heightened sensitivity to environmental cues among females. Cue-elicited craving may be one mechanism that contributes to the maintenance of smoking behavior and perhaps to the development of nicotine dependence within early stage smokers.

Smoking topography and abstinence in adult female smokers.
McClure EA, Saladin ME, Baker NL, Carpenter MJ, Gray KM.
Addict Behav. 2013 Dec;38(12):2833-6. PMCID: PMC3805754

Preliminary evidence, within both adults and adolescents, suggests that the intensity with which cigarettes are smoked (i.e., smoking topography) is predictive of success during a cessation attempt. These reports have also shown topography to be superior compared to other variables, such as cigarettes per day, in the prediction of abstinence. The possibility that gender may influence this predictive relationship has not been evaluated but may be clinically useful in tailoring gender-specific interventions. Within the context of a clinical trial for smoking cessation among women, adult daily smokers completed a laboratory session that included a 1-hour ad libitum smoking period in which measures of topography were collected (N=135). Participants were then randomized to active medication (nicotine patch vs. varenicline) and abstinence was monitored for 4 weeks. Among all smoking topography measures and all abstinence outcomes, a moderate association was found between longer puff duration and greater puff volume and continued smoking during the active 4-week treatment phase, but only within the nicotine patch group. Based on the weak topography-abstinence relationship among female smokers found in the current study, future studies should focus on explicit gender comparisons to examine if these associations are specific to or more robust in male smokers.

Sustained reduction of nicotine craving with real-time neurofeedback: exploring the role of severity of dependence.
Canterberry M, Hanlon CA, Hartwell KJ, Li X, Owens M, LeMatty T, Prisciandaro JJ, Borckardt J, Saladin ME, Brady KT, George MS.
Nicotine Tob Res. 2013 Dec;15(12):2120-4. PMCID: PMC3819983

Background: Neurofeedback delivered via real-time functional magnetic resonance imaging (rtfMRI) is a promising therapeutic technique being explored to facilitate self-regulation of craving in nicotine-dependent cigarette smokers. The current study examined the role of nicotine-dependence severity and the efficacy of multiple visits of neurofeedback from a single region of interest (ROI) in the anterior cingulate cortex (ACC) on craving reduction. Methods: Nine nicotine-dependent cigarette smokers participated in three rtfMRI visits that examined cue-induced craving and brain activation. Severity of nicotine dependence was assessed with the Fagerström Test for Nicotine Dependence. When viewing smoking-related images with instructions to "crave," patient-tailored ROIs were generated in the vicinity of the ACC. Activity levels from the ROI were fed back while participants viewed smoking cues with the instruction to reduce craving. Results: Neurofeedback from a single ROI in the ACC led to consistent decreases in self-reported craving and activation in the ACC across the three visits. Dependence severity predicted response to neurofeedback at Visit 3. Conclusions: This study builds upon previous rtfMRI studies on the regulation of nicotine craving in demonstrating that feedback from the ACC can reduce activation to smoking cues across three separate visits. Individuals with lower nicotine-dependence severity were more successful in reducing ACC activation over time. These data highlight the need to consider dependence severity in developing more individualized neurofeedback methods.

Effect of oxytocin on craving and stress response in marijuana-dependent individuals: a pilot study.
McRae-Clark AL, Baker NL, Maria MM, Brady KT.
Psychopharmacology (Berl). 2013 Aug;228(4):623-31. PMCID: PMC3729589

Rationale: Stress has been shown to be a significant factor in the maintenance of marijuana use. Oxytocin is a hypothalamic neuropeptide that has been shown to moderate behavioral responding to stress as well as play a role in the neuroadaptations that occur as a consequence of long-term drug use. Objectives: The current study evaluated the impact of oxytocin pretreatment on craving, stress, and anxiety responses following a psychosocial stress task in marijuana-dependent individuals. Methods: In a laboratory setting, baseline measurements of craving (assessed using the Marijuana Craving Questionnaire; MCQ), salivary cortisol and dehydroepiandrosterone (DHEA), stress, and anxiety were collected in 16 participants (age 19-40) meeting DSM-IV criteria for marijuana dependence. Participants were then administered either oxytocin 40 IU (n = 8) or placebo (n = 8) nasal spray prior to completion of the Trier Social Stress Task (TSST). Measurements were repeated pre-TSST, immediately post-TSST, and 5-, 35-, and 60-min post-TSST. ResultsL Oxytocin reduced both MCQ total score and DHEA levels from before to after the TSST. It also decreased anxiety, but not subjective stress ratings. Conclusions: Although preliminary, these results suggest that oxytocin may play a role in the amelioration of stress-induced reactivity and craving in marijuana-dependent individuals.

Updated August 2014