While agonist replacement therapies are effective for managing opioid dependence, community treatment programs are increasingly choosing detoxification. Unfortunately, success rates for opioid detoxification are very low, in part, due to physical and psychological symptoms associated with opioid withdrawal. Few behavior therapies specifically address the distressing experiences specific to opioid withdrawal. A novel behavioral treatment, Acceptance and Commitment Therapy (ACT), works from the premise that the avoidance of unpleasant private experiences (thoughts, feelings, bodily sensations) is ubiquitous yet may be pathogenic, resulting in treatment drop-out and further drug use.
This Stage I pilot study developed and tested an ACT-based opioid detoxification behavioral therapy. Opioid dependent patients (N = 56) who were attending a licensed methadone clinic were randomized to receive either 24 individual therapy sessions of ACT or Drug Counseling (DC) in the context of a 6-month methadone dose reduction program.
While no difference was found on opioid use during treatment, 37% of participants in the ACT condition were successfully detoxified at the end of treatment compared to 19% of those who received DC. Fear of detoxification was also reduced across time in the ACT condition relative to DC.
This first study of ACT to assist opioid detoxification indicates promise. Research is needed to refine specific treatment strategies for this population to further strengthen effects.
opiate; opioid dependence; opioid detoxification; methadone; opioid withdrawal; Acceptance and Commitment Therapy; mindfulness; behavior therapy
Brain dysfunction in prefrontal cortex (PFC) and dorsal striatum (DS) contributes to habitual drug use. These regions are constituents of brain networks thought to be involved in drug addiction. To investigate whether networks containing these regions differ between nicotine dependent female smokers and age-matched female non-smokers, we employed functional MRI (fMRI) at rest.
Data were processed with independent component analysis (ICA) to identify resting state networks (RSNs). We identified a subcortical limbic network and three discrete PFC networks: a medial prefrontal cortex (mPFC) network and right and left lateralized fronto-parietal networks common to all subjects. We then compared these RSNs between smokers and non-smokers using a dual regression approach.
Smokers had greater coupling versus non-smokers between left fronto-parietal and mPFC networks. Smokers with the greatest mPFC-left fronto-parietal coupling had the most DS smoking cue reactivity as measured during an fMRI smoking cue reactivity paradigm. This may be important because the DS plays a critical role in maintaining drug-cue associations. Furthermore, subcortical limbic network amplitude was greater in smokers.
Our results suggest that prefrontal brain networks are more strongly coupled in smokers, which could facilitate drug-cue responding. Our data also are the first to document greater reward-related network fMRI amplitude in smokers. Our findings suggest that resting state PFC network interactions and limbic network amplitude can differentiate nicotine-dependent smokers from controls, and may serve as biomarkers for nicotine dependence severity and treatment efficacy.
Resting State; Functional Connectivity; Smoking; Limbic; Prefrontal Cortex
Despite the relatively high prevalence of marijuana use among college students, little information exists regarding health outcomes associated with different use patterns or trajectories.
Seven annual personal interviews (Years 1–7) were administered to 1,253 individuals, beginning in their first year in college. Growth mixture modeling was used to identify trajectories of marijuana, alcohol, and tobacco use frequency during Years 1–6. Logistic regression was used to evaluate the relationship between marijuana use trajectories and several Year 7 health outcomes, holding constant Year 1 health, demographics, and alcohol and tobacco use trajectories.
Six marijuana use trajectories were identified: Non-Use (71.5%wt of students), Low-Stable (10.0%wt), Late-Increase (4.7%wt), Early-Decline (4.3%wt), College-Peak (5.4%wt), and Chronic (4.2%wt). The six marijuana trajectory groups were not significantly different on Year 1 health-related variables, but differed on all ten Year 7 health outcomes tested, including functional impairment due to injury, illness, or emotional problems; general health rating; psychiatric symptoms; health-related quality of life; and service utilization for physical and mental health problems. Non-Users fared significantly better than most of the marijuana-using trajectory groups on every outcome tested. Chronic and Late-Increase users had the worst health outcomes.
Marijuana use patterns change considerably during college and the post-college period. Marijuana-using students appear to be at risk for adverse health outcomes, especially if they increase or sustain a frequent pattern of use.
Cannabis; health outcomes; physical and mental health; health care utilization; longitudinal studies
Adolescence is a period of development associated with a peak in an organism’s responsiveness to reward. Epidemiological data indicate that the initiation of smoking is high during adolescence and that earlier age of onset is associated with increased incidence of dependence as adults. In rats, nicotine is known to have primary reinforcing and reinforcement enhancing effects. Although the primary reinforcing effects of nicotine have been demonstrated in adolescent rats (self-administration), less is known about its reinforcement enhancing effects during this period. Moreover, the impact of adolescent nicotine exposure on its reinforcement enhancing effects during adulthood has not yet been examined. The objectives of this study were to assess whether 1) nicotine enhances operant responding for an unconditioned visual reinforcer (VS) in adolescent rats, and 2) exposure to nicotine during adolescence affects responsiveness to the VS in adulthood.
Rats were exposed to nicotine (0.32 mg/kg, subcutaneous injection) or saline during adolescence (Postnatal day 29–42) and adulthood. Nose-poking for the VS was assessed under fixed and progressive ratio schedules.
Nicotine increased responding for the VS during adolescence. Adolescent nicotine exposure failed to significantly affect adult responsiveness for the VS, regardless of adult nicotine exposure, but early exposure to the VS affected responsiveness to the VS in adulthood.
Nicotine exhibits reinforcement enhancing effects in adolescent rats. Long-term effects of adolescent nicotine on reinforcement enhancement are minimal, but the impact of early exposure to the VS and/or the primary reinforcing effects of nicotine requires further investigation.
Nicotine; Adolescent; Reinforcement; Reinforcement Enhancement; Rat; Nose-poke; Operant Behavior
Group differences in brain structure between methamphetamine-dependent and healthy research participants have been reported, but findings in the literature present discrepancies. Although most methamphetamine-abusing individuals also smoke cigarettes, the effects of smoking on brain structure have not been distinguished from those of methamphetamine. Changes with abstinence from methamphetamine have also been relatively unexplored. This study, therefore, attempted to account for effects of smoking and brief abstinence from methamphetamine on gray-matter measures in methamphetamine-dependent research participants.
Gray matter was measured using voxel-based morphometry in three groups: 18 Control Nonsmokers, 25 Control Smokers, and 39 Methamphetamine-dependent Smokers (methamphetamine-abstinent 4–7 days). Subgroups of methamphetamine-dependent and control participants (n = 12/group) were scanned twice to determine change in gray matter over the first month of methamphetamine abstinence.
Compared with Control Nonsmokers, Control Smokers and Methamphetamine-dependent Smokers had smaller gray-matter volume in the orbitofrontal cortex and caudate nucleus. Methamphetamine-dependent smokers also had smaller gray-matter volumes in frontal, parietal and temporal cortices than Control Nonsmokers or Smokers, and smaller gray-matter volume in insula than Control Nonsmokers. Longitudinal assessment revealed gray matter increases in cortical regions (inferior frontal, angular, and superior temporal gyri, precuneus, insula, occipital pole) in methamphetamine-dependent but not control participants; the cerebellum showed a decrease.
Gray-matter volume deficits in the orbitofronal cortex and caudate of methamphetamine-dependent individuals may be in part attributable to cigarette smoking or pre-morbid conditions. Increase in gray matter with methamphetamine abstinence suggests that some gray-matter deficits are partially attributable to methamphetamine abuse.
methamphetamine; cigarette smoking; longitudinal; voxel-based morphometry; prefrontal cortex; caudate nucleus
Determining time since last cannabis/Δ9-tetrahydrocannabinol (THC) exposure is important in clinical, workplace, and forensic settings. Mathematical models calculating time of last exposure from whole blood concentrations typically employ a theoretical 0.5 whole blood-to-plasma (WB/P) ratio. No studies previously evaluated predictive models utilizing empirically-derived WB/P ratios, or whole blood cannabinoid pharmacokinetics after subchronic THC dosing.
Ten male chronic, daily cannabis smokers received escalating around-the-clock oral THC (40-120 mg daily) for 8 days. Cannabinoids were quantified in whole blood and plasma by two-dimensional gas chromatography-mass spectrometry.
Maximum whole blood THC occurred 3.0 h after the first oral THC dose and 103.5 h (4.3 days) during multiple THC dosing. Median WB/P ratios were THC 0.63 (n=196), 11-hydroxy-THC 0.60 (n=189), and 11-nor-9-carboxy-THC (THCCOOH) 0.55 (n=200). Predictive models utilizing these WB/P ratios accurately estimated last cannabis exposure in 96% and 100% of specimens collected within 1-5 h after a single oral THC dose and throughout multiple dosing, respectively. Models were only 60% and 12.5% accurate 12.5 and 22.5 h after the last THC dose, respectively.
Predictive models estimating time since last cannabis intake from whole blood and plasma cannabinoid concentrations were inaccurate during abstinence, but highly accurate during active THC dosing. THC redistribution from large cannabinoid body stores and high circulating THCCOOH concentrations create different pharmacokinetic profiles than those in less than daily cannabis smokers that were used to derive the models. Thus, the models do not accurately predict time of last THC intake in individuals consuming THC daily.
Δ9-tetrahydrocannabinol; chronic; cannabis; predictive models; cannabinoids; marijuana
Personalized treatment for psychopathologies, in particular alcoholism, is highly dependent upon our ability to identify patterns of genetic and environmental effects that influence a person’s risk. Unfortunately, array-based whole genome investigations into heritable factors that explain why one person becomes dependent upon alcohol and another does not, have indicated that alcohol’s genetic architecture is highly complex. That said, uncovering and interpreting the missing heritability in alcohol genetics research has become all the more important, especially since the problem may extend to our inability to model the cumulative and combinatorial relationships between common and rare genetic variants. As numerous studies begin to illustrate the dependency of alcohol pharmacotherapies on an individual’s genotype, the field is further challenged to identify new ways to transcend agnostic genomewide association approaches. We discuss insights from genetic studies of alcohol related diseases, as well as issues surrounding alcohol’s genetic complexity and etiological heterogeneity. Finally, we describe the need for innovative systems-based approaches (Systems Genetics) that can provide additional statistical power that can enhance future gene-finding strategies and help to identify heretofore-unrealized mechanisms that may provide new targets for prevention/treatments efforts. Emerging evidence from early studies suggest that Systems Genetics has the potential to organize our neurological, pharmacological, and genetic understanding of alcohol dependence into a biologically plausible framework that represents how perturbations across evolutionarily robust biological systems determine susceptibility to alcohol dependence.
Genetics; Alcoholism; Alcohol Dependence; GWAS; Systems Genetics
Attenuation of cue-elicited craving with brain stimulation techniques is a growing area of attention in addiction research. This investigation aims to guide these studies by assessing individual variability in the location of peak cortical activity during cue-elicited craving.
Twenty-six nicotine-dependent individuals performed a cue-elicited craving task in a 3T MRI scanner while BOLD signal data was collected. The task included epochs of smoking cues, neutral cues, and rest. The location of peak activity during smoking cues relative to neutral cues (‘hot spot’) was isolated for each individual. The spatial dispersion of the 26 cue-elicited hot spots (1 per participant) was quantified via hierarchical clustering.
When viewing nicotine cues all 26 participants had at least one cluster of significant prefrontal cortex activity (p<0.05, cluster corrected). Only 62% had peak activity in the medial prefrontal cortex cluster (including 100% of the men). In 15% of the participants peak activity was located in either the left lateral prefrontal cortex or left insula cluster. Peak activity in the remaining 23% was dispersed throughout the prefrontal cortex.
There is considerable individual variability in the location of the cue-elicited ‘hot spot’ as measured by BOLD activity. Men appear to have a more uniform location of peak BOLD response to cues than women. Consequently, acquiring individual functional imaging data may be advantageous for either tailoring treatment to the individual or filtering participants before enrollment in treatment.
nicotine; craving; functional MRI; transcranial magnetic stimulation
To identify patterns and correlates of developmental trajectories of DSM-IV nicotine dependence criteria from adolescence to early adulthood.
The analytical sample of lifetime smokers (N = 877) is from a longitudinal cohort of 6th–10th graders drawn from an urban school system. Subjects were interviewed 5 times at 6-month intervals and once 4.5 years later. Growth mixture models were estimated to identify trajectories of DSM-IV nicotine dependence criteria over ages 12–23.
A four-class solution fitted the data best: No dependence criteria (Class 1, 32.0%); Early onset/Chronic course (Class 2, 26.1%); Early onset/Remission (Class 3, 15.4%); Late onset (Class 4, 26.5%). There appeared to be three critical periods. At ages 12–15, symptoms increased rapidly. As of age 16, the Early onset/Chronic class stabilized at high levels of symptoms, the Early onset/Remission class started its symptomatic decline, and the Late onset class experienced a sharp increase in symptoms. At age 20, there was a convergence in the prevalence of symptoms experienced at high (Classes 2 and 4) and low levels (Classes 1 and 3). Extensiveness of smoking and marijuana use were associated with higher baseline levels of nicotine dependence criteria. Anxiety disorders were associated with all three symptomatic trajectories. Parental smoking and nicotine dependence were associated specifically with the Early/Chronic class, while pleasant initial sensitivity and earlier onset ages of cigarette and marijuana use characterized the two early onset classes (2 and 3).
Trajectories of dependence criteria constitute an advantageous phenotype for research and intervention over static summaries of smoking behaviors.
Nicotine dependence criteria; Developmental trajectories; Growth mixture modeling; Adolescence
Methamphetamine use has become a growing problem in a number of countries over the past two decades, but has only recently emerged in South Africa. This study investigated the prevalence of methamphetamine use among high-school students in Cape Town and whether students reporting methamphetamine use were more likely to be at risk for mental health and aggressive behavior problems.
A cross-sectional survey of 15 randomly selected high-schools in Cape Town, of 1561 male and female grade 8–10 students (mean age 14.9), was conducted using the Problem Oriented Screening Instrument for Teenagers (POSIT) and the Beck Depression Inventory (BDI).
Findings indicated that 9% of the students had tried methamphetamine at least once. Ordinal logistic regression analyses showed that methamphetamine use in the past year was significantly associated with higher aggressive behavior scores (OR = 1.81, 95% CI: 1.04–3.15, p < 0.05), mental health risk scores (OR = 2.04, 95% CI: 1.26–3.31, p < 0.01) and depression scores (OR = 2.65, 95% CI: 1.64–4.28, p < 0.001).
Methamphetamine use has become a serious problem in Cape Town, particularly among adolescents. Screening adolescents in school settings for methamphetamine use and behavior problems may be useful in identifying youth at risk for substance misuse, providing an opportunity for early intervention. These findings have implications for other parts of the world where methamphetamine use may be occurring at younger ages and highlight the importance of looking at co-morbid issues related to methamphetamine use.
Adolescents; methamphetamine use; aggression; mental health; South Africa
Substance abuse treatment programs are often characterized by high rates of premature treatment dropout, which increases the likelihood of relapse to drug use. Negative reinforcement models of addiction emphasize an individual’s inability to tolerate stress as a key factor for understanding poor substance use treatment outcomes, and evidence indicates that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis contributes to an individual’s inability to respond adaptively to stress. The aim of the current study was to examine whether HPA axis response to stress is predictive of treatment retention among a sample of drug users in residential substance abuse treatment.
Prospective study assessing treatment retention among 102 individuals enrolled in residential substance abuse treatment. Participants completed two computerized stress tasks, and HPA axis response to stress was measured via salivary cortisol at five time points from baseline (pre-stress) to 30 min post-stress exposure.
The main outcome measures were treatment dropout (categorical) and total number of days in treatment (continuous). A significantly higher salivary cortisol response to stress was observed in treatment dropouts compared to treatment completers. Further, Cox proportional hazards survival analyses indicated that a higher peak cortisol response to stress was associated with a shorter number of days to treatment dropout.
Results indicate that a higher salivary cortisol level in response to stress is associated with an inability to remain in substance abuse treatment. These findings are the first to document a biological marker of stress as a predictor of substance abuse treatment dropout, and support the development and implementation of treatments targeting this vulnerability.
Endocrinology; Stress; Cortisol; HPA axis; Residential; Treatment
Ecstasy use is prevalent among young people and often co-occurs with other drug use, but little is known about the past 12-month and lifetime psychiatric comorbidity and specific additional drug abuse among young adult ecstasy users in the general population. To provide this information, we compared current ecstasy users to former users, other illicit drug users, and non-illicit drug users.
Data were gathered in a face-to-face survey of the United States conducted in the 2001–2002 (NESARC). Participants were household and group quarters residents aged 18–29 years (n = 8666). We measured current ecstasy use defined as any use in the past year; former ecstasy use as use prior to the past year only; other lifetime drug use included any drug other than ecstasy; lifetime non-illicit drug use as no illicit drug use. Associations were determined for nine other classes of illicit drugs, eight personality disorders, and seven mood and anxiety disorders.
Of current ecstasy users, 44% used >3 other classes of illicit drugs in the past year, compared to 1.6% of non-ecstasy drug users. Current ecstasy use was associated with current anxiety (OR = 3.7), specifically panic disorder (OR = 7.7) and specific phobia (OR = 4.1), also alcohol abuse (OR = 21.6) and dependence (OR = 4.1) and any personality disorder (OR = 5.1) compared to non-illicit drug users.
Results indicate important differences in comorbidities of current and former ecstasy users compared to other drug users and lifetime non-illicit drug users that may affect phenotype definitions and etiologic studies. Ecstasy use may represent a distinct population of drug users for which unique treatments may be necessary.
Ecstasy; MDMA; Epidemiology; Young adult; Poly-drug
This study examined intimate partner aggression in a sample of 489 participants enrolled in substance use disorder treatment, and expands on prior research by including measures of various forms of aggression, a mixed gender sample (76% men, 24% women), and measurement of several potential risk domains. Aggression measures included both participant-to-partner and partner-to-participant psychological aggression, physical aggression and injury. Analyses focused on the role of distal and proximal risk factors, including demographics, history of childhood physical and sexual abuse, and family history of problems with alcohol, drugs and depression, as well as recent substance use and symptoms of depression. Overall rates of participant-to-partner psychological aggression (77%), physical aggression (54%) and injuring partners (33%) were high, as were rates of partner-to-participant psychological aggression (73%), physical aggression (51%), and injury (33%). Several distal (family history variables, physical abuse) and proximal factors (binge drinking, several different drugs, depressive symptoms) were bivariately related to most of the aggression measures. However, according to multivariate analyses predicting aggression and injury measures, binge drinking and cocaine use were the drugs significantly associated with most measures, depression symptoms also were related to most aggression and injury measures, and a history of reported childhood physical abuse was related to all frequency of aggression and injury measures among those reporting such behaviors. Overall, the high rates of aggression among both men and women observed in this study further illustrate the need for interventions targeting substance use and aggression, and for further research regarding the inter-relationships among substance, aggression and depressive symptoms.
alcohol; drugs; violence; cocaine; depressive symptoms
Fear of weight gain is a significant obstacle to smoking cessation, preventing some smokers from attempting to quit. Several previous studies of naltrexone yielded promising results for minimization of post-quit weight gain. Given these encouraging findings, we endeavored to test whether minimization of weight gain might translate to better quit outcomes for a population that is particularly concerned about gaining weight upon quitting.
Smokers (N = 172) in this investigation were prospectively randomized to receive either 25 mg naltrexone or placebo for 27 weeks (1 week pre-, 26 weeks post-quit) for minimization of post-quit weight gain and smoking cessation. All participants received open label therapy with the nicotine patch for the first 8 weeks post-quit and behavioral counseling over the 27 week treatment. The 2 pre-specified primary outcomes were change in weight for continuously abstinent participants and biologically verified end-of-treatment 7-day point prevalence abstinence at 26 weeks after the quit date.
The difference in weight at 26 weeks post-quit between the naltrexone and placebo groups (naltrexone: 6.8 lbs ± 8.94 vs placebo: 9.7 lbs ± 9.19, p = .45) was not statistically different. Seven-day point prevalence smoking abstinence rates at 26 weeks post-quit was not significantly different between the 2 groups (naltrexone: 22% vs placebo: 27%, p = .43).
For smokers high in weight concern, the relatively small reduction in weight gain with low dose naltrexone is not worth the potential for somewhat lower rates of smoking abstinence.
Smoking cessation; tobacco; naltrexone; weight gain; nicotine patch
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.
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 20 mg dose of baclofen approximately 110 min prior to scanning.
Acute baclofen diminished mOFC, amygdala, and ventral anterior insula CBF without causing sedation (family-wise error corrected at p = 0.001).
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.
Addiction; fMRI; GABA B agonist; Cerebral blood flow; Smoking cessation; Treatment; Baclofe
Methamphetamine (METH) use has increased substantially in the last 10 years and poses a serious health concern, especially for young populations. Drug abuse primarily begins during adolescence, when uninhibited and excessive and drug intake is a common occurrence; thus, understanding the developmental patterns of addiction during this critical period is an essential step in its prevention. In the present study, the effect of age on the vulnerability to METH abuse was examined using a rat model of bingeing (i.e., escalation).
Adolescent and adult rats were compared during short (ShA, 2-h) and long-access (LgA, 6-h) to METH self-administration. On postnatal (PN) days 23 (adolescents) and 90 (adults), rats were implanted with i.v. catheters and trained to lever press for infusions of METH (0.05 mg/kg) during 2-h sessions. Once the rats reached a steady rate of METH self-administration, they were divided into ShA or LgA groups and allowed to self-administer METH for 15 additional days.
Results indicated that adolescent rats earned significantly more infusions than adults under the LgA condition, but the age groups did not differ during ShA. Adolescents, but not adults, also significantly increased (i.e., escalated) METH self-administration across the 15 days of testing under the LgA condition. Further analysis indicated excessive responding during infusions in the LgA METH-exposed adolescents compared to the other groups, suggesting elevated impulsivity or motivation for drug.
These results demonstrate that adolescents are more vulnerable to the escalation of METH than adults during LgA.
METH; Adolescence; Escalation; Bingeing; Rat
Questions relevant to DSM-V alcohol use disorders (AUD) include whether dimensional measures provide more information than categorical diagnoses, whether to combine abuse and dependence criteria, and whether to add a new diagnostic criterion, binge drinking. Binary and dimensional models of three versions of AUD criteria were investigated: (1) dependence criteria; (2) abuse and dependence criteria combined; and (3) abuse and dependence criteria combined with a binge drinking criterion added. In a national sample of lifetime drinkers (N = 27,324), these models of AUD criteria were investigated in relation to two well-established risk factors for AUD, family history and early drinking onset. Logistic or Poisson regression modeled the relationships between the validating variables and dependence in categorical, dimensional and hybrid forms; Wald tests were used to assess differences between the dimensional, categorical and hybrid models. Alcohol dependence criteria represented a single continuum (family history Wald = 9.93, p = 0.13; early drinking Wald = 7.62, p = 0.27) with no support for a categorical or hybrid version of alcohol dependence. Adding four abuse criteria produced similar results for family history (Wald = 15.4, p = 0.12) although with early drinking, this model showed a trend towards deviating from the data (Wald = 16.7, p = 0.08). No support was found for any diagnostic threshold at 3, 4, 5, 6, or 7 criteria when abuse and dependence were combined. Adding binge drinking resulted in a significant departure from linearity for family history (Wald = 21.8, p = 0.03) and early drinking (Wald = 23.9, p = 0.01). The number of alcohol dependence and abuse criteria met should be explored further as a useful AUD severity indicator or phenotype.
Alcohol use disorders; DSM-IV diagnoses; Dimensional and categorical diagnoses; NESARC
Nicotine is known to generate oxidative stress through cytochrome P450 2A6 (CYP2A6)-mediated metabolism in the liver and other organs, including macrophages. This study has been designed to examine the role of CYP2A6 in nicotine metabolism and oxidative stress in SVGA cells, an immortalized human astrocyte cell line.
SVGA astrocytes were treated with 1μM nicotine, followed by determination of mRNA and protein levels of several CYPs using quantitative RT-PCR and western blot analyses, respectively. Quantitation of nicotine and the nicotine metabolites, cotinine and nicotine-derived nitrosamine ketones (NNK), was performed using an LC-MS/MS method. The generation of reactive oxygen species (ROS) was measured using flow cytometry.
Nicotine significantly upregulated mRNA and protein expression of the most abundantly expressed CYPs in SVGA astrocytes, CYP2A6 and CYP1A1. To characterize the metabolism of nicotine in astrocytes, a highly sensitive LC-MS/MS method was developed which is capable of quantifying very low concentrations of nicotine (0.3ng/ml), cotinine and NNK (0.11ng/ml). The LCMS/MS results showed that nicotine is steadily metabolized to cotinine and NNK from 0.5–4h. Finally, we showed that nicotine initially causes an increase in ROS formation which is then gradually decreased, perhaps due to the increase in superoxide dismutase level. Nicotine metabolism and ROS formation by CYP2A6 were further confirmed by using tryptamine, a selective inhibitor of CYP2A6, which significantly lowered the levels of cotinine and NNK and inhibited ROS formation.
CYP2A6 plays a key role in nicotine metabolism and oxidative stress in astrocytes, and this has implications in nicotine-associated brain toxicity.
Nicotine; CYP2A6; astrocytes; LC-MS/MS; oxidative stress
Two clinical trials have shown efficacy for bupropion in treating methamphetamine (MA) dependence among those with moderate baseline MA use. However, treatment response is highly variable and it is unclear what duration of treatment is necessary to determine if maintaining the treatment course is indicated or if discontinuation or augmentation is appropriate. The present study assessed the relationship among early bupropion treatment response for moderate MA users and end-of-treatment (EOT) abstinence. These data provide estimates of the duration of treatment and the degree of responsiveness required to persist in bupropion treatment.
Participants with moderate baseline MA use in the bupropion condition of two randomized double-blind placebo controlled trials were included. The relationship between early treatment response and EOT outcomes was assessed with Receiver Operating Characteristic (ROC) curves.
With thrice weekly urine drug testing, excellent predictive power was established in the first two weeks of treatment. The inability to achieve at least three MA negative samples in the first two weeks is associated with greater than 90% likelihood of treatment failure. More closely approximating clinical settings, once-weekly testing featured reliable predictive power within three weeks, suggesting that the failure to produce at least two clean samples in the first three weekly visits confers high risk of treatment failure.
The findings provide preliminary evidence to guide clinical decisions for moderate MA users receiving bupropion. The results are consistent with data from the smoking cessation literature and may highlight the importance of early response in addiction treatment.
methamphetamine dependence; abstinence; early response; bupropion; treatment switching
1) To examine the impact of monthly Recovery Management Checkups (RMC) vs. control in the first 90 days post-release from jail on receipt of community-based substance abuse treatment, and 2) To explore the impact of RMC, treatment, and abstinence on HIV risk behaviors and recidivism.
Of the 480 women randomized, 100% completed the intake and release interviews, and over 90% completed the 30-, 60-, and 90-day post-release interviews. Of the 915 times women assigned to RMC were interviewed (at release, 30, 69 and 90 days post release), 885 (97%) times they attended linkage meetings, 429 (47%) times they were identified as in need of substance abuse treatment, 271 (30%) times they agreed to go to treatment, 149 (16%) times they showed to the treatment intake, and 48 (5%) times they stayed in treatment at least two weeks.
During the 90 days following release from jail, women in the RMC condition (vs. control) were significantly more likely to return to treatment sooner and to participate in substance abuse treatment. Women who received any treatment were significantly more likely than those who did not to be abstinent from any alcohol or other drugs. Those who were abstinent were significantly more likely to avoid HIV risk behaviors and recidivism.
These results demonstrate the feasibility of conducting monthly Recovery Management Checkups with women offenders post-release and provide support for the effectiveness of using RMC to successfully link women offenders to treatment.
Substance use disorder; recovery management checkups; women offenders; re-entry; HIV risk behavior; recidivism
While methamphetamine users report high rates of internalized or self-stigma, few studies have examined experiences of stigma (i.e., stigmatization by others) and its correlates.
This study identified correlates of stigma experiences in a sample of 438 HIV-positive men who have sex with men (MSM) who were enrolled in a sexual risk reduction intervention in San Diego, CA.
Approximately 96% of the sample reported experiences of stigma related to their use of methamphetamine. In multiple regression analysis, experiences of stigma were associated with binge use of methamphetamine, injection drug use, increased anger symptoms, reduced emotional support, and lifetime treatment for methamphetamine use.
These findings suggest that experiences of stigma are common among methamphetamine users and that interventions to address this type of stigma and its correlates may offer social, psychological, and health benefits to HIV-positive methamphetamine-using MSM.
Stigma experiences; Methamphetamine; Men who have sex with men; HIV
In opiate-dependent individuals, abstinence results in deficits in cognitive functioning, which may be exacerbated by medication-associated sleep disruption.
To assess cognitive function and the influence of sleep deprivation (SD), 14 healthy control (HC) and 22 methadone maintained (MM) participants completed the Continuous Performance Task (CPT) after a baseline night, a night of total SD, and two recovery sleep nights. The Digit Symbol Substitution Task (DSST) was administered at bedtime and in the morning. Secondary analyses separated MM participants into short- (<12 months; n=8) and long-term (≥12 months; n=14) treatment duration groups, and into low- (< 80 mg; n=9) and high-dose (≥ 80 mg; n=13) groups.
Linear mixed model ANOVAs revealed that there was no effect of SD. Across all days MM participants had more errors of omission, fewer correct responses, and slower reaction times (RTs) on the CPT, and fewer accurate substitutions on the evening and morning DSST. Short-term MM participants exhibited slower RTs on the CPT, and fewer correct substitutions on the evening DSST compared to long-term MM participants. Low-dose MM participants had slower RTs on the CPT than HCs and high-dose MM participants.
These data demonstrate that methadone-maintained individuals exhibit poorer performance on tasks of psychomotor speed and selective attention/impulsivity, but with longer-term treatment, performance appears to return toward control levels. Furthermore, while one day of SD was enough to alter subjective reports of sleep quality, cognitive function may be more resilient.
methadone maintained; sleep deprivation; psychomotor performance; impulsivity
Little is known about the effects of alcohol dependence on cortical concentrations of glutamate (Glu) or gamma aminobutyric acid (GABA). We used proton magnetic resonance spectroscopy (MRS) to study cross-sectionally and longitudinally the concentrations of these Glu and GABA in alcohol dependent individuals (ALC) during early abstinence from alcohol.
Twenty ALC were studied at about one week of abstinence from alcohol (baseline) and 36 ALC at five weeks of abstinence and compared to 16 light/non-drinking controls (LD). Eleven ALC were studied twice during abstinence. Participants underwent clinical interviewing, blood work, neuropsychological testing, structural imaging and single-volume proton MRS at 4 Tesla. Absolute concentrations of Glu, GABA and those of other 1H MRS-detectable metabolites were measured in the anterior cingulate (ACC), parieto-occipital cortex (POC) and dorso-lateral prefrontal cortex (DLPFC). Relationships of metabolite levels to drinking severity and neurocognition were also assessed.
ALC at baseline had lower concentrations of Glu, N-acetylaspartate (NAA), and choline- (Cho) and creatine-containing metabolites than LD in the ACC, but normal GABA and myo-inositol (mI) levels. At five weeks of abstinence, metabolite concentrations were not significantly different between groups. Between one and five weeks of abstinence, Glu, NAA and Cho levels in the ACC increased significantly. Higher cortical mI concentrations in ALC related to worse neurocognitive outcome.
These MRS data suggest compromised and regionally specific bioenergetics/metabolism in one-week-abstinent ALC that largely normalizes over four weeks of sustained abstinence. The correlation between mI levels and neurocognition affirms the functional relevance of this putative astrocyte marker.
anterior cingulate cortex; glutamate; GABA; abstinence from alcohol; MR spectroscopy
Cigarette smoking represents an enormous public health problem worldwide that leads to over 5 million deaths per year. The gradual reduction of the nicotine content of cigarettes below the threshold that is required to develop addiction is one strategy that might substantially reduce the number of addicted smokers and prevent adolescents from becoming addicted to nicotine (Benowitz and Henningfield 1994). While the potential public health benefits of this approach are enormous, the guiding concepts and relevant empirical evidence needed to support the implementation of a nicotine reduction policy require a critical examination.
The purpose of this paper is to briefly review the current concepts and research regarding nicotine reduction while also discussing the utility of the addictive threshold for nicotine in this approach. The accurate determination of the nicotine addiction threshold presents some conceptual challenges as there is a lack of consensus on how to best measure nicotine addiction. This difficulty can impede the progress for developing a science-based tobacco control policy. As an alternative, the nicotine reinforcement threshold is a relatively clear concept, and well-accepted methods and criteria are available to measure nicotine reinforcement.
However, there are many gaps in our current knowledge concerning the nicotine reinforcement threshold in humans. The threshold for nicotine reinforcement remains to be determined in controlled settings using different populations of current or potential tobacco users. In addition, the value of the nicotine reinforcement threshold in predicting tobacco use in real-world settings needs to be examined. The results of such studies will determine the potential utility of the estimated threshold for nicotine reinforcement in developing science-based tobacco control policies.
nicotine; tobacco addiction; reinforcement; adolescent smoking