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Director's Report to the National Advisory Council on Drug Abuse - May, 2009

Research Findings - Research on Pharmacotherapies for Drug Abuse

Predictors of Treatment Outcome in Outpatient Cocaine and Alcohol Dependence Treatment

The investigators examined the ability of several baseline variables to predict treatment outcome in a pharmacotherapy trial that included 164 participants who were both cocaine- and alcohol-dependent and were selected for a randomized, double-blind, placebo-controlled study. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial Urine Drug Screen results, cocaine and alcohol craving and cocaine and alcohol withdrawal symptoms at the start of treatment. Successful treatment was defined as four continuous weeks of self-reported cocaine abstinence verified by urine drug screens. In respect to demographic characteristics, there were no significant differences between patients who achieved four weeks of abstinence from cocaine and those who did not. Baseline variables that most consistently predicted cocaine abstinence included initial urine drug screen (UDS) results, the initial Cocaine Selective Severity Assessment (CSSA) scores, and initial self-reported cocaine use in past 30 days, whereas cocaine craving, cocaine composite scores, alcohol craving, alcohol withdrawal symptoms, and alcohol composite scores did not. The results of this study suggest that cocaine dependence severity in general, and initial UDS results, the CSSA scores and frequency of recent cocaine use in particular, have a significant impact on treatment outcome in the treatment of cocaine-dependent patients with comorbid alcoholism. Initial UDS results and CSSA scores are very useful predictors of treatment outcome and could be used as stratifying variables in outpatient cocaine and alcohol medication trials. Ahmadi J, Kampman KM, Oslin DM, Pettinati HM, Dackis C, Sparkman T. Predictors of treatment outcome in outpatient cocaine and alcohol dependence treatment. Am J Addict. 2009;18(1):81-6.

Influence of Phase-related Variability in Premenstrual Symptomatology, Mood, Smoking Withdrawal, and Smoking Behavior during Ad Libitum Smoking, on Smoking Cessation Outcome

Emerging evidence suggests that women have a more difficult time quitting smoking than men-possibly due, in part, to sex hormones. The present study characterized mood, premenstrual symptomatology, and smoking withdrawal, as well as smoking behavior, in the follicular and luteal phases during ad libitum smoking in 25 women intending to quit. The investigators also investigated the possible influence of phase-related variability in these measures on likelihood of study adherence and smoking cessation. The investigators found that premenstrual symptomatology, as well as some measures of mood and smoking withdrawal, were significantly higher during the luteal phase than in the follicular phase. Cigarettes/day did not vary by menstrual cycle phase. Phase-related variability in premenstrual symptomatology [F(3, 20)=2.82, p=0.0650)] and urge to smoke [F(2, 21)=4.85, p=0.0186)] were associated with relapse. These data support the inference that sex hormones influence smoking cessation outcome. This knowledge may contribute to the development of more rational and effective smoking cessation interventions for women. Allen SS, Allen AM, Pomerleau CS. Influence of phase-related variability in premenstrual symptomatology, mood, smoking withdrawal, and smoking behavior during ad libitum smoking, on smoking cessation outcome. Addict Behav. 2009;34(1):107-11.

A Prospectively Measured Serum Biomarker for a Tobacco-Specific Carcinogen and Lung Cancer in Smokers

No prior studies have related a tobacco-specific carcinogen to the risk of lung cancer in smokers. Of the over 60 known carcinogens in cigarette smoke, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is specific to tobacco and causes lung cancer in laboratory animals. Its metabolites, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), have been studied as biomarkers of exposure to NNK. The investigators studied the relation of prospectively measured NNK biomarkers to lung cancer risk. In a case-control study nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the investigators randomly selected 100 lung cancer cases and 100 controls who smoked at baseline and analyzed their baseline serum for total NNAL, cotinine, and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a biomarker of polycyclic aromatic hydrocarbon exposure and metabolic activation. To examine the association of the biomarkers with all lung cancers and for histologic subtypes, computed odds ratios for total NNAL, PheT, and cotinine using logistic regression to adjust for potential confounders. Findings: Individual associations of age, smoking duration, and total NNAL with lung cancer risk were statistically significant. After adjustment, total NNAL was the only biomarker significantly associated with risk (odds ratio, 1.57 per unit SD increase; 95% confidence interval, 1.08-2.28). A similar statistically significant result was obtained for adenocarcinoma risk, but not for nonadenocarcinoma. This first reporting of the effect of the prospectively measured tobacco-specific biomarker total NNAL, on risk of lung cancer in smokers provides insight into the etiology of smoking-related lung cancer and reinforces targeting NNK for cancer prevention. Church TR, Anderson KE, Caporaso NE, Geisser MS, Le CT, Zhang Y, Benoit AR, Carmella SG, Hecht SS. A prospectively measured serum biomarker for a tobacco-specific carcinogen and lung cancer in smokers. Cancer Epidemiol Biomarkers Prev. 2009;18(1):260-6.

Self-Administration of Cocaine, Cannabis and Heroin in the Human Laboratory: Benefits and Pitfalls

The objective of this review is to describe self-administration procedures for modeling addiction to cocaine, cannabis and heroin in the human laboratory, the benefits and pitfalls of the approach, and the methodological issues unique to each drug. In addition, the predictive validity of the model for testing treatment medications will be addressed. The results show that all three drugs of abuse are reliably and robustly self-administered by non-treatment-seeking research volunteers. In terms of pharmacotherapies, cocaine use is extraordinarily difficult to disrupt either in the laboratory or in the clinic. A range of medications has been shown to significantly decrease cocaine's subjective effects and craving without decreasing either cocaine self-administration or cocaine abuse by patients. These negative data combined with recent positive findings with modafinil suggest that self-administration procedures are an important intermediary step between pre-clinical and clinical studies. In terms of cannabis, a recent study suggests that medications that improve sleep and mood during cannabis withdrawal decrease the resumption of marijuana self-administration in abstinent volunteers. Clinical data on patients seeking treatment for their marijuana use are needed to validate these laboratory findings. Finally, in contrast to cannabis or cocaine dependence, there are three efficacious Food and Drug Administration-approved medications to treat opioid dependence, all of which decrease both heroin self-administration and subjective effects in the human laboratory. In summary, self-administration procedures provide meaningful behavioral data in a small number of individuals. These studies contribute to our understanding of the variables maintaining cocaine, marijuana and heroin intake, and are important in guiding the development of more effective drug treatment programs. Haney M. Self-administration of cocaine, cannabis and heroin in the human laboratory: benefits and pitfalls. Addict Biol 2009;14(1):9-21.

Comorbidity in Pediatric Bipolar Disorder

The growing literature shows the pervasiveness and importance of comorbidity in youth with bipolar disorder (BPD). For instance, up to 90% of youth with BPD have been described to manifest comorbidity with attention-deficit hyperactivity disorder. Multiple anxiety, substance use, and disruptive behavior disorders are the other most commonly reported comorbidities with BPD. Moreover, important recent data highlight the importance of obsessive-compulsive and pervasive developmental illness in the context of BPD. Data suggest that not only special developmental relationships are operant in the context of comorbidity but also that the presence of comorbid disorders with BPD results in a more severe clinical condition. Moreover, the presence of comorbidity has therapeutic implications for the treatment response for both BPD and the associated comorbid disorder. Future longitudinal studies to address the relationship and the impact of comorbid disorders on course and therapeutic response over time are required in youth with BPD. Joshi G, Wilens T. Comorbidity in pediatric bipolar disorder. Child Adolesc Psychiatr Clin N Am. 2009;18(2):291-viii.

Perspective: Translational Studies on Glutamate and Dopamine Neurocircuitry in Addictions: Implications for Addiction Treatment

New research suggests that the modulation of dopamine neurocircuitry by glutamate plays a key role in the development of nicotine and other addictions. For example, manipulation of glutamatergic pathways can alter the mood-enhancing and reinforcing properties of nicotine. These glutamatergic pathways are also sensitive to manipulation by other drugs of abuse. The studies described in this special issue of Neuropsychopharmacology bring together rodent studies with translational work in humans to enhance our understanding of the cellular mechanisms underlying the subjective and objective effects of drugs of abuse. These studies suggest new therapeutic targets based on central glutamate systems that may lead to the development of novel and more effective treatments for addictive disorders. Lambe EK, George TP. Perspective: Translational studies on glutamate and dopamine neurocircuitry in addictions: implications for addiction treatment. Neuropsychopharmacology. 2009;34(2):255-6.

Provigil (Modafinil) Plus Cognitive Behavioral Therapy for Methamphetamine Use in HIV+ Gay Men: A Pilot Study

The objective of this study was to evaluate the efficacy of modafinil combined with cognitive behavioral therapy (CBT) for treatment of methamphetamine (MA) dependence among HIV+ gay men. In a single blind trial, modafinil was administered for 12 weeks, followed by a 4-week placebo phase. CBT was conducted for 18 sessions over the 16-week study. Primary outcome measures were self-reported use of days per week plus urine toxicology assays. Additional measures included the Beck Depression Inventory, Cravings Scale, and O/C Crystal Use Scale. Response was defined as > 50% decline in days used per week. Thirteen patients were enrolled over an 18-month period. Ten patients (77%) completed the trial, although two discontinued modafinil due to side effects. Six of the ten study completers reduced their MA use by > 50%. These preliminary results suggest good retention using combined medication and psychotherapy, and support further examination of modafinil and CBT in double-blind placebo controlled trials. McElhiney MC, Rabkin JG, Rabkin R, Nunes EV. Provigil (modafinil) plus cognitive behavioral therapy for methamphetamine use in HIV+ gay men: a pilot study. Am J Drug Alcohol Abuse. 2009;35(1):34-7.

Effects of Oral Methamphetamine on Cocaine Use: A Randomized, Double-Blind, Placebo-Controlled Trial

No medication is currently approved for the treatment of cocaine dependence, but several preclinical and clinical reports suggest agonist-like medications, e.g., amphetamine analogues, may be a productive strategy for medication development. This current proof-of-concept study sought to evaluate the safety, tolerability, and effectiveness of methamphetamine as a candidate treatment for cocaine dependence. A randomized, double-blind, placebo-controlled study served to evaluate three treatment conditions in 82 cocaine-dependent individuals: (1) placebo (0mg, 6x/day; n=27), (2) immediate release (IR) methamphetamine (5mg, 6x/day; n=30), (3) sustained release (SR) methamphetamine (30 mg first pill, 1x/day; 0mg 5x/day; n=25). The study employed a sequential, two-phase design (i.e., 4 weeks of medication and counseling followed by 4 weeks of medication/counseling plus a contingency management procedure). Both preparation forms of methamphetamine were well-tolerated, with similar retention to placebo (0mg, 33%; 30 mg IR, 30%, 30 mg SR, 32%). Methamphetamine SR was associated with decreased sleep and increased weight loss. Medication adherence rates were high for the first dose of the day (95%), while adherence for subsequent capsules was lower. Those in the SR condition exhibited consistently lower rates of cocaine-positive urine samples (0mg, 60%; 30 mg IR, 66%; 30 mg SR, 29%), p<0.0001, and reported the greatest reduction in craving for cocaine, p<0.05. SR methamphetamine significantly reduced cocaine use and craving. Additional research is warranted to develop and evaluate agonist-like medications that may effectively treat cocaine dependence. Mooney ME, Herin DV, Schmitz JM, Moukaddam N, Green CE, Grabowski J. Effects of oral methamphetamine on cocaine use: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 2009;101(1-2):34-41.

Mechanisms Underlying the Comorbidity Between Depressive and Addictive Disorders in Adolescents: Interactions Between Stress and HPA Activity

Depression may be a precursor to substance use disorder in some youngsters, and substance abuse might complicate the subsequent course of depression. This study examined whether hypothalamic-pituitary-adrenal (HPA) activity and stressful life experiences are related to the development of substance use disorder in depressed and nondepressed adolescents, and whether substance use disorder predicts a worsening course of depression. Urinary-free cortisol was measured for 3 nights in 151 adolescents with no prior history of substance use disorder (55 depressed, 48 at high risk for depression, and 48 normal subjects). Information was obtained on recent stressful life experiences. The participants were followed for up to 5 years to assess the onset of substance use disorder, course of depression, and stressful experiences. The relationships among depression, cortisol as a measure of HPA activity, stressful experiences, and substance use disorder were examined. Elevated cortisol was associated with onset of substance use disorder. Stressful life experiences moderated this relationship. Cortisol and stress accounted for the effects of a history or risk of depression on the development of substance use disorder. Substance use disorder was associated with higher frequency of subsequent depressive episodes. Higher cortisol prior to the onset of substance use disorder may indicate vulnerability to substance use disorder. Stressful experiences increase the risk for substance use disorder in such vulnerable youth. The high prevalence of substance use disorders in depressed individuals may be explained, in part, by high levels of stress and increased HPA activity. Rao U, Hammen CL, Poland RE. Mechanisms underlying the comorbidity between depressive and addictive disorders in adolescents: interactions between stress and HPA activity. Am J Psychiatry. 2009;166(3):361-9.

Caffeinated Energy Drinks--A Growing Problem

Since the introduction of Red Bull in Austria in 1987 and in the United States in 1997, the energy drink market has grown exponentially. Hundreds of different brands are now marketed, with caffeine content ranging from a modest 50 mg to an alarming 505 mg per can or bottle. Regulation of energy drinks, including content labeling and health warnings differs across countries, with some of the most lax regulatory requirements in the U.S. The absence of regulatory oversight has resulted in aggressive marketing of energy drinks, targeted primarily toward young males, for psychoactive, performance-enhancing and stimulant drug effects. There are increasing reports of caffeine intoxication from energy drinks, and it seems likely that problems with caffeine dependence and withdrawal will also increase. In children and adolescents who are not habitual caffeine users, vulnerability to caffeine intoxication may be markedly increased due to an absence of pharmacological tolerance. Genetic factors may also contribute to an individual's vulnerability to caffeine-related disorders including caffeine intoxication, dependence, and withdrawal. The combined use of caffeine and alcohol is increasing sharply, and studies suggest that such combined use may increase the rate of alcohol-related injury. Several studies suggest that energy drinks may serve as a gateway to other forms of drug dependence. Regulatory implications concerning labeling and advertising, and the clinical implications for children and adolescents are discussed. Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks--a growing problem. Drug Alcohol Depend. 2009;99(1-3):1-10.

Diurnal Variation in Cue-Induced Responses Among Protracted Abstinent Heroin Users

The physiological and psychological responses to drug cue exposure have been assessed in substance abusers. However, there is no study to demonstrate whether the responses to drug cue exposure are diurnal dependence. The present study was to examine whether there was a variation in drug-related cue reactivity across the diurnal cycle among recently abstinent opiate addicts. Four groups of 20 abstinent heroin dependent patients (n=80) were exposed to both neutral and drug-related videos at four separate times during the day: 8:00, 12:00, 16:00, and 20:00 h. Physiological and psychological responses, including heart rate, blood pressure, heroin craving, and subjective anxiety were assessed before and after each cue exposure. Drug cue significantly increased craving ratings compared to neutral cues across all the four separate times of day. Drug cue-induced craving was greater in the morning (8:00 am) than noon (12:00 pm), but was similar to evening assessments (8:00 pm). Drug cues also significantly increased anxiety, which positively correlated with cue-induced craving. Drug cues increased heart rate, systolic and diastolic blood pressures, which were not correlated with cue-induced craving or anxiety. However, no time effects were found on the three physiological measures. Cue-induced craving could be profoundly affected by the time points of cue exposure, using cue-reactivity paradigm. The relative sensitivity of morning and evening assessments of drug craving suggests a need for replication and further research on mechanisms contributing to these diurnal variations. Ren ZY, Zhang XL, Liu Y, Zhao LY, Shi J, Bao Y, Zhang XY, Kosten TR, Lu L. Diurnal variation in cue-induced responses among protracted abstinent heroin users. Pharmacol Biochem Behav. 2009; 91(3):468-72.

Cocaine Effects During D-amphetamine Maintenance: A Human Laboratory Analysis of Safety, Tolerability and Efficacy

Agonist replacement therapies are effective for managing substance abuse disorders including nicotine and opioid dependence. The results of preclinical laboratory studies and clinical trials indicate that agonist replacements like D-amphetamine may be a viable option for managing cocaine dependence. This experiment determined the physiological and behavioral effects of cocaine during D-amphetamine maintenance in seven cocaine-dependent participants. The investigators predicted cocaine would be well tolerated during D-amphetamine maintenance. The investigators also predicted D-amphetamine would attenuate the behavioral effects of cocaine. After 3-5 days of D-amphetamine maintenance (0, 15, and 30 mg/day), volunteers were administered ascending doses of cocaine (4, 30, 60 mg, i.n.) within a single session. Cocaine doses were separated by 90 min. Cocaine produced prototypical physiological (e.g., increased heart rate, blood pressure, and body temperature) and subject-rated (e.g., increased ratings of Good Effects) effects. During maintenance on the highest D-amphetamine dose, the heart rate increasing effects of cocaine were larger than observed during placebo maintenance. These effects were not clinically significant and no unexpected or serious adverse events were observed. D-amphetamine attenuated some of the subject-rated effects of cocaine. These results are concordant with those of previous preclinical studies, human laboratory experiments and clinical trials, further suggesting that agonist replacement therapy may be a viable strategy for managing cocaine abuse. Additional research in humans is needed to determine whether D-amphetamine attenuates the effects of cocaine under different experimental conditions (e.g., higher cocaine doses) and behavioral arrangements (e.g., drug self-administration or discrimination). Rush CR, Stoops WW, Hays LR. Cocaine effects during D-amphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacy. Drug Alcohol Depend. 2009;99(1-3):261-71.

Discriminative Stimulus and Subject-Rated Effects of Methamphetamine, D-amphetamine, Methylphenidate, and Triazolam in Methamphetamine-Trained Humans

Methamphetamine abuse is a significant public health concern. Although widely studied in laboratory animals, little is known about the abuse-related behavioral effects of methamphetamine relative to other abused stimulants in controlled laboratory settings in humans. The aim of this study was to examine the discriminative stimulus, subject-rated, performance, and cardiovascular effects of methamphetamine in humans. In the present study, subjects first learned to discriminate 10 mg of oral methamphetamine from placebo. After acquiring the discrimination (> or = 80% drug-appropriate responding on four consecutive sessions), a range of oral doses of methamphetamine (2.5-15 mg), d-amphetamine (2.5-15 mg), methylphenidate (5-30 mg), and triazolam (0.0625-0.375 mg) was tested. Methamphetamine functioned as a discriminative stimulus and produced prototypical stimulant-like subject-rated effects. D-amphetamine and methylphenidate produced dose-related increases in methamphetamine-appropriate responding, whereas triazolam did not. D-amphetamine and methylphenidate produced stimulant-like behavioral effects, whereas triazolam produced sedative-like effects. Methamphetamine, but no other drug, increased heart rate, systolic pressure, and diastolic pressure significantly above placebo levels. Performance in the Digit-Symbol Substitution Test was not affected by any of the drugs tested. Overall, these results demonstrate that the acute behavioral effects of methamphetamine, d-amphetamine, and methylphenidate overlap extensively in humans, which is concordant with findings from preclinical studies. Future studies should assess whether the similarity in the behavioral effects of methamphetamine and related stimulants can be extended to other behavioral assays, such as measures of reinforcement, in humans. Sevak RJ, Stoops WW, Hays LR, Rush CR. Discriminative stimulus and subject-rated effects of methamphetamine, d-amphetamine, methylphenidate, and triazolam in methamphetamine-trained humans. J Pharmacol Exp Ther. 2009;328(3):1007-18.

Modeling Stress and Drug Craving in the Laboratory: Implications for Addiction Treatment Development

Addition is a chronic relapsing illness affected by multiple social, individual and biological factors that significantly impact course and recovery of the illness. Stress interacts with these factors and increases addiction vulnerability and relapse risk, thereby playing a significant role in the course of the illness. This paper reviews the authors' efforts in developing and validating laboratory models of stress and drug cue-related provocation to assess stress responses and stress-related adaptation in addicted individuals compared with healthy controls. Empirical findings from human laboratory and brain imaging studies are presented to show the specific stress-related dysregulation that accompanies the drug-craving state in addicted individuals. In order to adequately validate the laboratory model, the investigators have also carefully examined relapse susceptibility in the addicted individuals and these data are reviewed. The overarching goal of these efforts is to develop a valid laboratory model to identify the stress-related pathophysiology in addiction with specific regard to persistent craving and compulsive seeking. Finally, the significant implications of these findings for the development of novel treatment interventions that target stress processes and drug craving to improve addiction relapse outcomes are discussed. Sinha R. Modeling stress and drug craving in the laboratory: implications for addiction treatment development. Addict Biol. 2009;14(1):84-98.

Posttraumatic Stress Disorder and Substance Use Disorder in Adolescent Bipolar Disorder

Anxiety disorders such as posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are increasingly recognized as comorbid disorders in children with bipolar disorder (BPD). This study explores the relationship between BPD, PTSD, and SUD in a cohort of BPD and non-BPD adolescents. The investigators studied 105 adolescents with BPD and 98 non-mood-disordered adolescent controls. Psychiatric assessments were made using the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiologic Version (KSADS-E), or Structured Clinical Interview for DSM-IV (SCID) if 18 years or older. SUD was assessed by KSADS Substance Use module for subjects under 18 years, or SCID module for SUD if age 18 or older. Nine (8%) BPD subjects endorsed PTSD and nine (8%) BPD subjects endorsed subthreshold PTSD compared to one (1%) control subject endorsing full PTSD and two (2%) controls endorsing subthreshold PTSD. Within BPD subjects endorsing PTSD, seven (39%) met criteria for SUD. Significantly more SUD was reported with full PTSD than with subthreshold PTSD (chi(2) = 5.58, p = 0.02) or no PTSD (chi(2) = 6.45, p = 0.01). Within SUD, the order of onset was BPD, PTSD, and SUD in three cases, while in two cases the order was PTSD, BPD, SUD. The remaining two cases experienced coincident onset of BPD and SUD, which then led to trauma, after which they developed PTSD and worsening SUD. An increased rate of PTSD was found in adolescents with BPD. Subjects with both PTSD and BPD developed significantly more subsequent SUD, with BPD, PTSD, then SUD being the most common order of onset. Follow-up studies need to be conducted to elucidate the course and causal relationship of BPD, PTSD and SUD. Steinbuchel PH, Wilens TE, Adamson JJ, Sgambati S: Posttraumatic stress disorder and substance use disorder in adolescent bipolar disorder. Bipolar Disord. 2009;11(2):198-204.

Clinical Characteristics of Treatment-Seeking Prescription Opioid vs. Heroin-Using Adolescents with Opioid Use Disorder

The objectives of this study were to compare the clinical characteristics of treatment-seeking prescription opioid-using adolescents with DSM-IV opioid use disorder (OUD) to those with heroin-using OUD adolescents. The investigators analyzed the data on OUD adolescents (94, ages 14-18 years) extracted from the parent study dataset comparing clinical characteristics of treatment-seeking OUD to non-OUD adolescents from a adolescent substance abuse treatment program in Baltimore, MD. The sample consisted of 41 non-heroin prescription opioid-using and 53 heroin-using OUD adolescents who were assessed cross-sectionally using standardized interviews and self-reports. Chi-square and t-tests were performed to determine group differences on demographic, substance use, psychiatric and HIV-risk behaviors. Both groups were older (mean 17 years), predominantly Caucasian, and had a suburban residence; they had high rates of co-occurring psychiatric disorders (83%) and they reported moderately high depression symptoms. The heroin-using sample was more likely to have dropped out of school, be dependent on opioids and inject drugs using needles. The prescription opioid-using OUD youth were more likely to meet criteria for multiple SUDs (including prescription sedatives and psychostimulants), current ADHD and report selling drugs; and more likely to be court ordered to current treatment and report prior psychiatric treatment. Both groups of treatment-seeking OUD adolescents had multiple comorbidities but there were substantial differences between prescription opioid-users and heroin-users. These differences may suggest different prognoses and treatment implications. Future research may shed light on the factors leading to differences in choice of opioids and their impact on treatment outcomes; and assess the role of agonist assisted treatments and integrated psychiatric care. Subramaniam GA, Stitzer MA. Clinical characteristics of treatment-seeking prescription opioid vs. heroin-using adolescents with opioid use disorder. Drug Alcohol Depend. 2009;101(1-2):13-19.

Clinical Characteristics of Treatment-Seeking Adolescents with Opioid Versus Cannabis/Alcohol Use Disorders

The objectives of this study were to assess the clinical characteristics of adolescents with DSM-IV opioid use disorder (OUD) and compare them to adolescents with cannabis/alcohol use disorders. Ninety-four adolescents (ages 14-18 years) with a current OUD and 74 adolescents with a current non-OUD cannabis/alcohol use disorder were recruited from admissions, predominantly residential, to a substance abuse treatment program in Baltimore, ML. Participants were assessed cross-sectionally using standardized interviews and self-reports. Chi-square, t-tests and ANCOVA (adjusting for age, gender and treatment setting, race and residence) were performed to determine group differences on demographic, substance use, psychiatric and HIV-risk behaviors; logistic regression analyses, both unadjusted and adjusted for the above five factors were conducted to assess the strength of associations. The OUD group was more likely to be Caucasian, to have dropped out of school and to live in the suburbs (trend). They also had greater substance use severity with higher proportion of current sedative and multiple substance use disorders (SUD). There were generally no differences in rates of criminal behaviors. Both groups had high rates of current psychiatric disorders (83% vs. 78%, n.s.) but the OUD adolescents reported higher depressive symptoms, mostly in the moderate range. Injection drug use (IDU) and needle sharing was almost exclusive to the OUD group, while both groups reported similar high rates of risky sexual behaviors. While there were similarities between the two groups, OUD adolescents evidenced greater impairment in academic, substance use, depressive symptom and IDU-related HIV-risk areas. Findings suggest poorer long-term prognosis and highlight the need for specialized interventions for treatment-seeking OUD adolescents. Subramaniam GA, Stitzer ML, Woody G, Fishman MJ, Kolodner K. Clinical characteristics of treatment-seeking adolescents with opioid versus cannabis/alcohol use disorders. Drug Alcohol Depend. 2009;99(1-3):141-149.

Low Prefrontal Perfusion Linked to Depression Symptoms in Methadone-Maintained Opiate-Dependent Patients

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, the investigators 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. 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. 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. 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. Suh JJ, Langleben DD, Ehrman RN, Hakun JG, Wang Z, Li Y, Busch SI, O'Brien CP, Childress AR. Low prefrontal perfusion linked to depression symptoms in methadone-maintained opiate-dependent patients. Drug Alcohol Depend. 2009;99(1-3):11-17.

Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice

There has been much interest in the relative importance of dopamine and serotonin transporters in the abuse-related-effects of cocaine. The investigators tested the hypotheses that mice lacking the dopamine transporter (DAT(-/-)), the serotonin transporter (SERT(-/-)), or both (DAT(-/-)SERT(-/-)) exhibit decreased reinforcing effects of cocaine. The investigators also assessed whether observed effects on self-administration are specific to cocaine or if operant behavior maintained by food or a direct dopamine agonist are similarly affected. The investigators used a broad range of experimental conditions that included acquisition without previous training, behavior established with food training and subsequent testing with food, cocaine or a direct dopamine agonist as reinforcers, fixed ratio and progressive ratio schedules of reinforcement, and a reversal procedure. Wild-type mice readily acquired cocaine self-administration and showed dose-response curves characteristic of the schedule of reinforcement that was used. While some DAT(-/-) mice appeared to acquire cocaine self-administration transiently, almost all DAT(-/-) mice failed to self-administer cocaine reliably. Food-maintained behaviors were not decreased by the DAT mutation, and IV self-administration of a direct dopamine agonist was robust in the DAT(-/-) mice. In contrast to those mice, cocaine's reinforcing effects were not diminished in SERT(-/-) mice under any of the conditions tested, except for impaired initial acquisition of both food- and cocaine-maintained behavior. These findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine. Thomsen M, Hall FS, Uhl GR, Caine SB. Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. J Neurosci. 2009;29(4):1087-92.

Does Conduct Disorder Mediate the Development of Substance Use Disorders in Adolescents With Bipolar Disorder?

Recent work has highlighted important relationships among conduct disorder (CD), substance use disorders (SUD), and bipolar disorder in youth. However, because bipolar disorder and CD are frequently comorbid in the young, the impact of CD in mediating SUD in bipolar disorder youth remains unclear. One hundred and five adolescents with DSM-IV bipolar disorder (mean +/- SD age = 13.6 +/- 2.50 years) and 98 controls (mean +/- SD age = 13.7 +/- 2.10 years) were comprehensively assessed with a structured psychiatric diagnostic interview for psychopathology and SUD. The study was conducted from January 2000 through December 2004. Among bipolar disorder youth, those with CD were more likely to report cigarette smoking and/or SUD than youth without CD. However, CD preceding SUD or cigarette smoking did not significantly increase the subsequent risk of SUD or cigarette smoking. Adolescents with bipolar disorder and CD were significantly more likely to manifest a combined alcohol plus drug use disorder compared to subjects with bipolar disorder without CD (chi(2) = 11.99, p < .001). While bipolar disorder is a risk factor for SUD and cigarette smoking in a sample of adolescents, comorbidity with preexisting CD does not increase the risk for SUD. Further follow-up of this sample through the full risk of SUD into adulthood is necessary to confirm these findings. Wilens TE, Martelon M, Kruesi MJ, Parcell T, Westerberg D, Schillinger M, Gignac M, Biederman J. Does conduct disorder mediate the development of substance use disorders in adolescents with bipolar disorder? A case-control family study. J Clin Psychiatry. 2009;70(2):259-65.

Opioid Detoxification Enhanced by Use of Low Dose Naltrexone

Although withdrawal severity and treatment completion are the initial focus of opioid detoxification, post-detoxification outcome better defines effective interventions. Very low dose naltrexone (VLNTX) in addition to methadone taper was recently associated with attenuated withdrawal intensity during detoxification. This article describes the results of a seven-day follow-up evaluation of 96 subjects who completed inpatient detoxification consisting of the addition of VLNTX (0.125 or 0.250 mg per day) or placebo to methadone taper in a double blind, randomized investigation. Individuals receiving VLNTX during detoxification reported reduced withdrawal and drug use during the first 24 hours after discharge. VLNTX addition was also associated with higher rates of negative drug tests for opioids and cannabis and increased engagement in outpatient treatment after one week. Further studies are needed to test the utility of this approach in easing the transition from detoxification to various follow-up treatment modalities designed to address opioid dependence. Mannelli P, Patkar AA, Peindl K, Gottheil, E, Wu LT, Gorelick, DA. Early outcomes following low dose naltrexone enhancement of opioid detoxification. Am J Addict. 2009;18(2):109-16.

Psychopharmacologic Management of Opioid-dependent Women During Pregnancy

Illicit drug use during pregnancy presents complex clinical challenges, including reducing drug use and treating psychiatric disorders. Pharmacologic treatment of psychiatric disorders in a pregnant woman requires an evaluation of the balance between potential clinical benefit and the risk of potential neonatal consequences. This study describes psychiatric symptoms in 111 opioid-dependent pregnant women and their prescribed psychotropic medications. Hypomania, generalized anxiety disorder and depression were the most common disorders for which psychiatric symptoms were endorsed. Over half of women studied were prescribed some form of psychoactive medication during pregnancy. Pharmacologic vs. non-pharmacologic treatment approaches in this patient population are discussed. Martin PR, Arria AM, Fischer G, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Selby P, Jones HE. Psychopharmacologic management of opioid-dependent women during pregnancy. Am J Addict. 2009;18(2):148-56.

Unrestricted Access to Methamphetamine or Cocaine in the Past is Associated With Increased Current Use

Laboratory animals allowed to self-administer stimulants for extended periods of time escalate drug intake compared to animals that self-administer under temporally limited conditions. Prior to this study, this phenomenon had not been systematically investigated in humans. Researchers interviewed 106 (77 male, 29 female) methamphetamine (Meth) and 96 (81 male, 15 female) cocaine (Coc) users to determine if they had experienced discrete period(s) of unrestricted access to unlimited quantities of Meth or Coc in the past. Fifty-eight Meth users and 53 Coc users reported having a discrete period of unrestricted access in the past, but not in the present. Meth-using participants with a prior history of unrestricted access reported significantly more current Meth use, compared to Meth users with no prior history of unrestricted access. Specifically, these participants reported more days used in the past 30 d, more days of use per week, greater use per day and greater total use per week (p<0.05 for each). Coc-using participants with a prior history of unrestricted access also reported significantly more current Coc use, compared to Coc users with no prior history of unrestricted access. This was true across all measures of current use for these participants, including more days used in the past 30 d, more days of use per week, greater use per day, and higher total use per week (p<0.02 for each). Taken together, these results suggest that a history of unrestricted access to stimulants is associated with long-lasting increases in stimulant use. Culbertson C, De La Garza R, Costello M, Newton TF. Unrestricted access to methamphetamine or cocaine in the past is associated with increased current use. Int J Neuropsychopharmacol. 2009;Feb 16:1-9.

Cocaine Dependence May Not be Associated With a Reduction in D1 Receptor Availability

The goal of this study was to determine D1 receptor availability in human cocaine dependent subjects and matched healthy controls. In addition, cocaine dependent subjects performed cocaine self-administration sessions to explore the association between D1 receptor availability and cocaine-seeking behavior. In this study, 25 cocaine dependent subjects and 23 matched healthy controls were scanned with PET and the radiotracer [11C]NNC 112. During the cocaine self-administration sessions, cocaine dependent volunteers were given the choice to self-administer cocaine (0, 6 and 12 mg) or to receive a monetary voucher worth $5. D1 receptor availability was measured in the limbic, associative, and sensori-motor striatum in addition to cortical brain regions. No difference in D1 receptor availability was seen between the two groups. A negative association was seen between D1 receptor BPND in the limbic striatum and the choice for the 6 mg dose of cocaine. These results do not support the hypothesis that cocaine dependence is associated with a reduction in D1 receptor availability in the striatum. However, within the cocaine dependent subjects group, low D1 receptor availability in the ventral striatum was associated with the choice to self-administer cocaine, suggesting that low D1 receptor availability may be associated with an increased risk of relapse in cocaine dependence. Martinez D, Slifstein M, Narendran R, Foltin RW, Broft A, Hwang DR, Perez A, Abi-Dargham A, Fischman MW, Kleber HD, Laruelle M. Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine. Neuropsychopharm. 2009;Jan 1-9, (Epub ahead of print).

D-Amphetamine Attenuated Some of the Subject-rated Effects of Cocaine

Agonist replacement therapies are effective for managing substance abuse disorders including nicotine and opioid dependence. The results of preclinical laboratory studies and clinical trials indicate that agonist replacements like D-amphetamine may be a viable option for managing cocaine dependence. This experiment determined the physiological and behavioral effects of cocaine during D-amphetamine maintenance in seven cocaine-dependent participants. Researchers predicted cocaine would be well tolerated during D-amphetamine maintenance. They also predicted D-amphetamine would attenuate the behavioral effects of cocaine. After 3-5 days of D-amphetamine maintenance (0, 15, and 30 mg/day), volunteers were administered ascending doses of cocaine (4, 30, 60 mg, i.n.) within a single session. Cocaine doses were separated by 90 min. Cocaine produced prototypical physiological (e.g., increased heart rate, blood pressure, and body temperature) and subject-rated (e.g., increased ratings of Good Effects) effects. During maintenance on the highest D-amphetamine dose, the heart rate increasing effects of cocaine were larger than observed during placebo maintenance. These effects were not clinically significant and no unexpected or serious adverse events were observed. D-amphetamine attenuated some of the subject-rated effects of cocaine. These results are concordant with those of previous preclinical studies, human laboratory experiments and clinical trials, further suggesting that agonist replacement therapy may be a viable strategy for managing cocaine abuse. Additional research in humans is needed to determine whether D-amphetamine attenuates the effects of cocaine under different experimental conditions (e.g., higher cocaine doses) and behavioral arrangements (e.g., drug self-administration or discrimination). Rush CR, Stoops WW, Hays LR. Cocaine effects during D-amphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacy. Drug Alcohol Depend. 2009;99(1-3):261-71.

Preclinical Data Support the Hypothesis that Chronic Cocaine Alters the Composition of White Matter in Corpus Callosum

Studies in cocaine-dependent human subjects have shown differences in white matter on diffusion tensor imaging (DTI) compared with non-drug-using controls. It is not known whether the differences in fractional anisotropy (FA) seen on DTI in white matter regions of cocaine-dependent humans result from a pre-existing predilection for drug use or purely from cocaine abuse. To study the effect of cocaine on brain white matter, DTI was performed on 24 rats after continuous infusion of cocaine or saline for 4 weeks, followed by brain histology. Voxel-based morphometry analysis showed an 18% FA decrease in the splenium of the corpus callosum (CC) in cocaine-treated animals relative to saline controls. On histology, significant increase in neurofilament expression (125%) and decrease in myelin basic protein (40%) were observed in the same region in cocaine-treated animals. This study supports the hypothesis that chronic cocaine use alters white matter integrity in human CC. Unlike humans, where the FA in the genu differed between cocaine users and non-users, the splenium was affected in rats. These differences between rodent and human findings could be due to several factors that include differences in the brain structure and function between species and/or the dose, timing, and duration of cocaine administration. Narayana PA, Ahobila-Vajjula P, Ramu J, Herrera J, Steinberg JL, Moeller FG. Diffusion tensor imaging of cocaine-treated rodents. Psychiatry Res. 2009;171(3):242-51.

Tolerance, Rather Than Sensitization, Appears to Result from Repeated Exposure to Smoked Cocaine

Studies using rodents have shown that behavioral responses to a stimulant are enhanced when the stimulant is given within the same context as previous stimulant administrations; this increase in effect related to context is often referred to as sensitization. The investigators examined the role of environmental stimuli in modulating the subjective and cardiovascular effects of cocaine in humans (1) within a daily "binge" and (2) after cocaine abstinence. Ten non-treatment seeking users of smoked cocaine were admitted to the hospital for 17 consecutive days. Participants smoked cocaine (25mg/dose) under two counterbalanced conditions: paired stimuli (same stimuli presented each session) and unpaired stimuli (varied stimuli presented each session). Under each stimulus condition, participants had cocaine test sessions for three consecutive days, no sessions for the next 3 days, then another cocaine test session on the following day, for a total of eight test days. Stimulus condition had no effect on cardiovascular or subjective effects so data were analyzed as a function of repeated cocaine administration over 2 weeks. Maximal ratings on "good drug" and "drug rating" subjective effects clusters decreased over days of repeated cocaine exposure. In contrast, baseline and peak heart rate and systolic pressure increased over days of repeated cocaine administration. Thus, repeated administration of smoked cocaine to experienced cocaine users resulted in increases in baseline blood pressure and heart rate and modest decreases in positive subjective effects. These data indicate modest tolerance rather than sensitization to the positive subjective effects of cocaine with repeated exposure. Reed SC, Haney M, Evans SM, Vadhan NP, Rubin E, Roltin RW. Cardiovascular and subjective effects of repeated smoked cocaine administration in experienced cocaine users. Drug Alcohol Depend. 2009; Mar 19. (Epub ahead of print).

Reinforcing and Subjective Effects of Methylphenidate in Adults With and Without ADHD

There has been controversy over the abuse potential of methylphenidate (MPH) in the context of treatment for attention deficit hyperactivity disorder (ADHD). The objective of this study was to compare the reinforcing and subjective effects of oral MPH in adults with and without ADHD. Following screening, 33 adults (n = 16 with ADHD; n = 17 free from psychiatric diagnoses) completed four pairs of experimental sessions, each of which included a sampling session and a self-administration session. During sampling sessions, subjects received in randomized order 0 (placebo), 20, 40, and 60 mg MPH. During self-administration sessions, subjects completed a progressive ratio (PR) task to earn portions of the dose received on the corresponding sampling session. Subjective effects were recorded throughout all sessions. The main outcome measure for the study was the number of ratios completed on the PR task. Secondary measures included peak subjective effects and area-under-the-curve values for subjective effects. Compared to the control group, the ADHD group completed more ratios on the PR task. Both groups showed robust effects of methylphenidate on subjective endpoints. Main effects of group were noted on subjective effects involving concentration and arousal. Compared to placebo, MPH produced reinforcing effects only for the ADHD group and not for the control group. Increases in stimulant-related subjective effects in non-ADHD subjects were not associated with drug reinforcement. Kollins SH, English J, Robinson R, Hallyburton M, Chrisman AK. Reinforcing and subjective effects of methylphenidate in adults with and without attention deficit hyperactivity disorder (ADHD). Psychopharmacology (Berl). 2008; Dec 23. (Epub ahead of print).

Drug Self-Administration Using a Progressive-Ratio Schedule in Humans Better Predicts Stimulant Drug Abuse and Dependence

Drug self-administration methodologies have been developed for use in humans to model naturalistic stimulant drug-taking behaviors. These methodologies use a number of schedules of reinforcement, including progressive-ratio schedules. As the name implies, in a progressive-ratio schedule, the response requirement for each subsequent delivery of drug increases, and the primary outcome variable is often the break point (i.e., the last ratio completed to receive a drug delivery). These schedules have been used in a number of human laboratory studies evaluating the reinforcing effects of stimulants. The results of these studies have demonstrated that progressive-ratio schedules are sensitive to manipulation of a pharmacological variable, dose, and to non-pharmacological variables contributing to stimulant drug effects. In addition, findings with progressive-ratio schedules are largely concordant with clinical findings, suggesting that drug self-administration under these schedules has predictive validity in terms of drug abuse and dependence. Future research is necessary, however, to understand better how pharmacological factors like route of administration, onset of effects, and pretreatment influence the reinforcing effects of stimulants under progressive-ratio schedules. Stoops WW. Reinforcing effects of stimulants in humans: sensitivity of progressive-ratio schedules. Exp Clin Psychopharmacol. 2008;16(6):503-12.

Bayesian Statistical Analysis May be a Better Means for Evaluating Salient Interactions in Pharmacotherapy Trials

Difficulty identifying effective pharmacotherapies for cocaine dependence has led to suggestions that subgroup differences may account for some of the heterogeneity in treatment response. Well-attested methodological difficulties associated with these analyses recommend the use of Bayesian statistical reasoning for evaluation of salient interaction effects. A secondary data analysis of a previously published, double-blind, randomized controlled trial examines the interaction of decision-making, as measured by the Iowa Gambling Task, and citalopram in increasing longest sustained abstinence from cocaine use. Bayesian analysis indicated that there was a 99% chance that improved decision-making enhances response to citalopram. Given the strong positive nature of this finding, a formal, quantitative Bayesian approach to evaluate the result from the perspective of a skeptic was applied. Bayesian statistical reasoning provides a formal means of weighing evidence for the presence of an interaction in scenarios where conventional, Frequentist analyses may be less informative. Green CE, Moeller FG, Schmitz JM, Lucke JF, Lane SD, Swann AC, Lasky RE, Carbonari JP. Evaluation of heterogeneity in pharmacotherapy trials for drug dependence: a Bayesian approach. Am J Drug Alcohol Abuse. 2009;35(2):95-102.

A Preliminary Trial of Nefazodone and SR Bupropion on Cannabis Use and Cannabis Withdrawal Symptoms

This study investigated the efficacy of nefazodone and bupropion-sustained release for treating cannabis dependence in a double-blind, placebo-controlled, 13 week outpatient study in 106 subjects. Subjects were randomized to one of three medication conditions: nefazodone, bupropion-sustained release, or placebo with a weekly therapy program. Results indicated an increased probability of achieving abstinence over the course of treatment and a decrease in the severity of cannabis dependence and the withdrawal symptom of irritability. There were no significant effects demonstrated for nefazodone and bupropion-sustained release on cannabis use or cannabis withdrawal symptoms. The results indicate that nefazodone and bupropion-sustained release may have limited efficacy in treating cannabis dependence. Carpenter KM, McDowell D, Brooks DJ, Cheng WY, Levin FR. A preliminary trail: double-blind comparison of nefazodone, bupropion-SR, and placebo in the treatment of cannabis dependence. Am J Addictions. 2009;18:53-64.

Preliminary Data Suggests Inhibition of Nitric Oxide (NO) Synthesis Reduces Craving for Cigarettes

In recent preclinical studies, the role of nitric oxide (NO) in nicotine dependence has become increasingly evident. Inhibition of NO synthesis blocks acquisition of conditioned place preference, and attenuates the nicotine abstinence syndrome in rodents. These findings have not been followed up in human studies. In order to obtain preliminary data on NO inhibition in human smokers, the investigators conducted a randomized, double-blind, crossover study (N=12) of minocycline, a tetracycline derivative antibiotic, that inhibits the neuronal nitric oxide (NO) synthase enzyme with resultant inhibition of NO production. Medication effects were assessed through a smoking choice procedure as well as subjective and physiological responses to nicotine administered via the intravenous route (IV). Minocycline treatment did not affect smoking self-administration in this choice procedure and did not affect most of the subjective responses to IV nicotine or sample smoking. Following IV nicotine administration, there was a greater reduction in craving for cigarettes under minocycline, compared to placebo. Similarly, smokers had greater reduction in their craving for cigarettes following sample smoking under minocycline treatment. These findings provide limited support for the potential use of minocycline as a treatment of nicotine dependence. Sofuoglu M, Waters AJ, Mooney M, O'Malley SS. Minocycline reduced craving for cigarettes but did not affect smoking or intravenous nicotine responses in humans. Pharmacol Biochem Behav. 2009;92(1):135-40.

Early Exposure to Nicotine May Facilitate the Subsequent Development of Stimulant Abuse

Stimulant users smoke cigarettes at high rates; however, little is known about the relationship between tobacco and stimulants. The authors' goal in this article is to synthesize a growing literature on the role of cigarette smoking in stimulant addiction. Early nicotine exposure may influence the development of stimulant addiction. Preclinical and clinical studies suggest a facilitatory role of nicotinic agonists for stimulant addiction. Smoking appears to be associated with more severe stimulant use and poorer treatment outcomes. It is important to assess smoking and smoking-related variables within stimulant research studies to more fully understand the comorbidity. Integrating smoking cessation into stimulant treatment may improve nicotine and stimulant treatment outcomes. Weinberger AH, Sofuoglu M. The impact of cigarette smoking on stimulant addiction. Am J Drug Alcohol Abuse. 2009;35(1):12-17.

Smoking Abstinence Does Not Increase Short-Term Weight Gain by Menstrual Phase

Prevention of early weight gain may be critical to avoid relapse among women with a fear of weight gain. Menstrual phase has physiological fluctuation of fluid resulting in short-term weight gain, suggesting menstrual phase of smoking cessation may impact short-term weight gain. This study examined the effect of smoking abstinence and menstrual cycle on short-term weight gain. Women were randomized to quit smoking during the follicular or luteal phase of their cycle and followed for four weeks. Weight, among other measures, was recorded at five post-quit date visits (days 2, 5, 9, 12 and week 4). Participants (n=152) were grouped based on randomized quit phase and smoking status after assigned quit date: 1) follicular (F), quit < 24 h, 2) F, quit > or = five days, 3) luteal (L), quit < 24 h, and 4) L, quit > or = five days. Participants who quit smoking experienced significantly more weight gain than those who quit for less than 24 h. There were no significant increases in short-term weight gain based on menstrual cycle phase during attempted smoking cessation. Allen SS, Allen AM, Mooney M, Bade T. Short-term weight gain by menstrual phase following smoking cessation in women. Eat Behav. 2009;10(1):52-5.

Cognitive Measures of Bitterness or Hostility, As Opposed to Aggressive Behaviors, Were Positively Correlated to Poor Smoking Cessation Outcomes and Greater Withdrawal Symptoms

Hostility is a multifaceted construct encompassing affective, behavioral, and cognitive aspects. There is preliminary evidence linking hostility to poorer outcomes in smoking cessation treatment; however, it is unclear which components of hostility are most important in cessation. In this study, the authors examined multiple aspects of trait hostility in 92 heavy social drinkers who were seeking smoking cessation treatment. Consistent with their hypothesis, the authors found that the cognitive component of hostility was most relevant to smoking cessation outcome. Specifically, those who expressed bitterness about their lives and tended to believe that they had poor luck and had gotten a raw deal out of life had poor smoking cessation outcomes. Cognitive measures of hostility also predicted greater nicotine withdrawal symptoms 1 week after quitting smoking. Other components of hostility including anger and both physical and verbal aggression did not significantly predict smoking outcome or nicotine withdrawal. Further examination of how a hostile worldview contributes to smoking cessation failure is warranted, as this facet of hostility may prove a valuable target for smoking cessation interventions. Kahler CW, Spillane NS, Leventhal AM, Strong DR, Brown RA, Monti PM. Hostility and smoking cessation treatment outcome in heavy social drinkers. Psychol Addict Behav. 2009;23(1):67-76.

Microneedles Permit Transdermal Delivery of a Skin-Impermeant Medication to Humans

Drugs with poor oral bioavailability usually are administered by hypodermic injection, which causes pain, poor patient compliance, the need for trained personnel, and risk of infectious disease transmission. Transdermal (TD) delivery provides an excellent alternative, but the barrier of skin's outer stratum corneum (SC) prevents delivery of most drugs. Micrometer-scale microneedles (MNs) have been used to pierce animal and human cadaver skin and thereby enable TD delivery of small molecules, proteins, DNA, and vaccines for systemic action. A clinical study of MN-enhanced drug delivery was carried out in humans. Naltrexone (NTX) is a potent mu-opioid receptor antagonist used to treat opiate and alcohol dependence. This hydrophilic and skin-impermeant molecule was delivered from a TD patch to healthy human subjects with and without pretreatment of the skin with MNs. Whereas delivery from a standard NTX TD patch over a 72-h period yielded undetectable drug plasma levels, pretreatment of skin with MNs achieved steady-state plasma concentrations within 2 h of patch application and were maintained for at least 48 h. The MNs and NTX patch were well tolerated with mild systemic and application site side effects. The MN arrays were painless upon administration and not damaged during skin insertion, and no MNs were broken off into the skin. This human proof-of-concept study demonstrates systemic administration of a hydrophilic medication by MN-enhanced TD delivery. These findings set the stage for future human studies of skin-impermeant medications and biopharmaceuticals for clinical applications. Wermeling DP, Banks SL, Hudson DA, Gill HS, Gupta J, Prausnitz MR, Stinchcomb AL. Proc Natl Acad Sci USA. 2008;105(6):2058-63.

Methadone Pharmacokinetics are Independent of Cytochrome P4503A (CYP3A) Activity and Gastrointestinal Drug Transport: Insights from Methadone Interactions with Ritonavir/Indinavir

This paper reports that inhibition of both hepatic and intestinal CYP3A activity is responsible for ritonavir/indinavir drug interactions. Methadone disposition was unchanged, despite profound inhibition of CYP3A activity, suggesting little or no role for CYP3A in clinical methadone metabolism and clearance. Methadone bioavailability was unchanged, despite inhibition of gastrointestinal P-glycoprotein activity, suggesting that this transporter does not limit methadone intestinal absorption. Kharasch ED, Hoffer C, Whittington D, Walker A, Bedynek PS. Anesthesiology. 2009;110(3):660-72.

Methadone Metabolism and Clearance are Induced by Nelfinavir Despite Inhibition of Cytochrome P4503A (CYP3A) Activity

This article reports that nelfinavir induces methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects. Kharasch ED, Walker A, Whittington D, Hoffer C, Bedynek PS. Drug Alcohol Depend. 2009;101(3):158-68.


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