Discriminating cocaine use from other sympathomimetics using wearable electrocardiographic (ECG) sensors.

BACKGROUND: Our group has established the feasibility of using on-body electrocardiographic (ECG) sensors to detect cocaine use in the human laboratory. The purpose of the current study was to test whether ECG sensors and features are capable of discriminating cocaine use from other non-cocaine sympathomimetics. METHODS: Eleven subjects with cocaine use disorder wore the Zephyr BioHarness™ 3 chest band under six experimental (drug and non-drug) conditions, including 1) laboratory, intravenous cocaine self-administration, 2) after a single oral dose of methylphenidate, 3) during aerobic exercise, 4) during tobacco use (N=7 who smoked tobacco), and 5) during routine activities of daily inpatient living (unit activity). Three ECG-derived feature sets served as primary outcome measures, including 1) the RR interval (i.e., heart rate), 2) a group of ECG interval proxies (i.e., PR, QS, QT and QTc intervals), and 3) the full ECG waveform. Discriminatory power between cocaine and non-cocaine conditions for each of the three outcomes measures was expressed as the area under the receiver operating characteristics (AUROC) curve. RESULTS: All three outcomes successfully discriminated cocaine use from unit activity, exercise, tobacco, and methylphenidate conditions with a mean AUROC values ranging from 0.66 to 0.99 and with least squares means values all statistically different/higher than 0.5 among all subjects [F(3, 99) = 3.38, p =0.02] and among those with tobacco use [F(4, 84) = 5.39, p = 0.0007]. CONCLUSIONS: These preliminary results support discriminatory power of wearable ECG sensors for detecting cocaine use.

Genome-wide meta-analysis of alcohol use disorder in East Asians.

Alcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified ~30 AUD risk genes in European populations, but many fewer in East Asians. We conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from five cohorts: (1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP) sample; (2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese-GSA (array) cohort; (3) AD in a Han Chinese-Cyto (array) cohort; and (4) two AD Thai cohorts. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4464 East Asians (Genetic Epidemiology Research in Adult Health and Aging (GERA)). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS. Two risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, SE = 0.067, p = 2.47 × 10-10) and nominally associated with pack years of smoking (beta = 0.09, SE = 0.05, p = 4.52 × 10-2) and ever vs. never smoking (beta = 0.06, SE = 0.02, p = 1.14 × 10-2). This is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.

Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder.

BACKGROUND: Preclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD). METHODS: Non-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin). RESULTS: Thirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001). CONCLUSIONS: We did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Sex Differences in Methamphetamine Use and Dependence in a Thai Treatment Center.

BACKGROUND AND OBJECTIVE: Males and females who use methamphetamine (MA) differ in sociodemographics, MA diagnoses, comorbidities, and brain activity. The objective of this study was to investigate sex differences in the characteristics of MA use and dependence in patients at a Thai substance treatment center. METHODS: Demographic, MA use, and diagnostic data for 782 MA users were obtained by using the Semi-Structured Assessment for Drug Dependence and Alcoholism-Thai version. Categorical comparisons of males (n = 413, 53%) and females (n = 369, 47%) were made by chi-square test. Factors significantly differentiating men and women with respect to MA-dependence were identified by logistic regression analysis controlling for demographic, diagnostic, and MA use variables. RESULTS: Males admitted to residential drug treatment for MA use had an earlier age of onset for both MA use (17.7 ±â€Š4.1 vs 19.7 ±â€Š6.2 years; t = -5.3, P < 0.001) and dependence (20.4 ±â€Š5.2 vs 22.2 ±â€Š6.4 years; t = -3.6, P < 0.001). Females were more likely than males to be MA-dependent (79% vs 60%; χ1 = 33.7, P < 0.001), and to experience MA withdrawal (65.3% vs 48.9%; χ1 = 21.4, P < 0.001), withdrawal-related hypersomnia (77.2% vs 64.8%; χ1 = 14.5, P < 0.001), fatigue (77.5% vs 70.3%; χ1 = 5.2, P = 0.02), and psychomotor retardation (64.5% vs 57.0%; χ1 = 4.5, P = 0.03). Similarly, females had heavier (eg, largest daily amount [χ1 = 12.4, P < 0.001), more frequent (χ1 = 5.1, P = 0.02]) and greater lifetime episodes of MA use (χ1 = 24.1, P < 0.001) than males. After controlling for such variables by logistic regression, being female remained a significant factor influencing the occurrence of MA-dependence (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.8-4.1, P < 0.001). Shared associated factors (or comorbidities) for MA-dependence in both sexes included nicotine dependence (in males: OR 4.1, 95% CI 2.4-7.0, P < 0.001; and in females: OR 2.4, 95% CI 1.3-4.4, P = 0.007), greater lifetime episodes of MA use (in males: OR 3.5, 95% CI 1.9-6.4, P < 0.001; and in females: OR 5.9, 95% CI 3.1-11.4, P < 0.001), and more frequent use (in males: OR 5.1, 95% CI 2.8-9.1, P < 0.001; and in females: OR 3.6, 95% CI 1.9-6.9, P < 0.001). Comorbid antisocial personality disorder predicted MA-dependence in males only (OR 3.7, 95% CI 1.6-8.6, P = 0.002). CONCLUSIONS: The current study highlights both common (eg, nicotine dependence and severity of MA use) and sex-specific differences (eg, MA use/dependence characteristics and comorbidities), including sex itself, with respect to MA-dependence in a Thai treatment cohort.

An exploratory examination of marijuana use, problem-gambling severity, and health correlates among adolescents.

BACKGROUND AND AIMS: Gambling is common in adolescents and at-risk and problem/pathological gambling (ARPG) is associated with adverse measures of health and functioning in this population. Although ARPG commonly co-occurs with marijuana use, little is known how marijuana use influences the relationship between problem-gambling severity and health- and gambling-related measures. METHODS: Survey data from 2,252 Connecticut high school students were analyzed using chi-square and logistic regression analyses. RESULTS: ARPG was found more frequently in adolescents with lifetime marijuana use than in adolescents denying marijuana use. Marijuana use was associated with more severe and a higher frequency of gambling-related behaviors and different motivations for gambling. Multiple health/functioning impairments were differentially associated with problem-gambling severity amongst adolescents with and without marijuana use. Significant marijuana-use-by-problem-gambling-severity-group interactions were observed for low-average grades (OR = 0.39, 95% CI = [0.20, 0.77]), cigarette smoking (OR = 0.38, 95% CI = [0.17, 0.83]), current alcohol use (OR = 0.36, 95% CI = [0.14, 0.91]), and gambling with friends (OR = 0.47, 95% CI = [0.28, 0.77]). In all cases, weaker associations between problem-gambling severity and health/functioning correlates were observed in the marijuana-use group as compared to the marijuana-non-use group. CONCLUSIONS: Some academic, substance use, and social factors related to problem-gambling severity may be partially accounted for by a relationship with marijuana use. Identifying specific factors that underlie the relationships between specific attitudes and behaviors with gambling problems and marijuana use may help improve intervention strategies.

Clinical features of methamphetamine-induced paranoia and preliminary genetic association with DBH-1021C→T in a Thai treatment cohort.

AIMS: To explore the clinical features of methamphetamine-induced paranoia (MIP) and associations between MIP and a genetic polymorphism in dopamine ß-hydroxylase (DBH-1021C→T). DESIGN: Retrospective analysis of clinical presentation and genetic association by χ(2) test and logistic regression analysis. SETTING: A Thai substance abuse treatment center. PARTICIPANTS: A total of 727 methamphetamine-dependent (MD) individuals. MEASUREMENTS: Clinical: Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) and the Methamphetamine Experience Questionnaire (MEQ). Genetic: DBH-1021C→T. FINDINGS: Forty per cent of individuals (289 of 727; 39.8%) with MD had MIP. Within-binge latency to MIP onset occurred more rapidly in the most recent compared with initial MIP episode (P = 0.02), despite unchanging intake (P = 0.89). Individuals with MIP were significantly less likely to carry lower (TT/CT) compared with higher (CC) activity genotypes (34.3 versus 43.3%; χ(2) 1 = 5, P = 0.03). DBH effects were confirmed [odds ratio (OR) = 0.7, P = 0.04] after controlling for associated clinical variables (MD severity, OR = 3.4, P < 0.001; antisocial personality disorder, OR = 2.2, P < 0.001; alcohol dependence, OR = 1.4, P = 0.05; and nicotine dependence, OR = 1.4, P = 0.06). TT/CT carriers were more likely to initiate cigarette smoking (OR = 3.9, P = 0.003) and probably less likely to be dependent on alcohol (OR = 0.6, P = 0.05). CONCLUSIONS: Among methamphetamine-dependent individuals, paranoia appears to occur increasingly rapidly in the course of a session of methamphetamine use. Severity of methamphetamine dependence and antisocial personality disorder predicts methamphetamine-induced paranoia. The genetic polymorphism in dopamine ß-hydroxylase is associated with methamphetamine-induced paranoia and influences smoking initiation.

Reductions in brain 5-HT1B receptor availability in primarily cocaine-dependent humans.

BACKGROUND: Preclinical evidence implicates the serotonin receptor 5-hydroxytryptamine 1B (5-HT1B) in the effects of cocaine. This study explores 5-HT1B in humans by examining receptor availability in vivo in subjects whose primary addiction is cocaine dependence (CD) using positron emission tomography. METHODS: Study participants included 14 medically healthy subjects with CD (mean age = 41 ± 6 years) who were compared with 14 age-matched healthy control subjects (mean age = 41 ± 8 years) with no past or current history of cocaine or other illicit substance abuse. Participants underwent magnetic resonance imaging followed by positron emission tomography with the highly selective 5-HT1B tracer, [(11)C]P943, for purposes of quantifying regional binding potential. Voxel-based morphometry and gray matter masking also were employed to control for potential partial volume effects. RESULTS: The [(11)C]P943 positron emission tomography imaging data in nine candidate regions (amygdala, anterior cingulate cortex, caudate, frontal cortex, hypothalamus, pallidum, putamen, thalamus, and ventral striatum) showed significant or nearly significant reductions of regional binding potential in subjects with CD in three regions: anterior cingulate (-16%, p < .01), hypothalamus (-16%, p = .03), and frontal cortex (-7%, p = .08). Voxel-based morphometry showed significant gray matter reductions in the frontal cortex of subjects with CD. After gray matter masking, statistically significant reductions in the [(11)C]P943 regional binding potential were either retained (anterior cingulate, -14%, p = .01; hypothalamus, -20%, p < .01) or achieved (frontal cortex, -14%, p < .01). Whole-brain voxel-wise parameter estimation confirmed these results. Secondary analyses were also significant in some regions for years of cocaine and daily tobacco use. CONCLUSIONS: The reductions found in this study suggest that 5-HT1B receptors may contribute to the etiology or expression of CD and potentially represent a target for medication development.

Inter-rater reliability and concurrent validity of DSM-IV opioid dependence in a Hmong isolate using the Thai version of the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA).

Because isolated populations offer relative genetic and environmental homogeneity, they are important resources for mapping genes for complex traits. Reliable and valid phenotypic characterization of the disease in the population studied is essential. We examined diagnostic reliability and concurrent validity of DSM-IV opioid dependence (OD) in a Hmong population in Thailand with historically high rates of opium (and heroin) use. 578 Thai-speaking Hmong individuals were assessed for lifetime OD, using Thai versions of both the Semi-Structured Assessment for Drug Dependence and Alcoholism (Thai SSADDA) and the Mini-Neuropsychiatric Interview (Thai MINI; adapted for lifetime diagnoses). In a subsample of 123 individuals, two raters interviewed each subject independently within a 2-week period. Chance-corrected agreement on the OD diagnosis was assessed between raters and instruments. Results showed excellent agreement for the DSM-IV diagnosis of OD both for the SSADDA (κ=0.97) and MINI (κ=1.00) and between the SSADDA and MINI (κ=0.97). Consistent with reliability assessments of English versions, our data demonstrate high reliability for Thai versions of the SSADDA and MINI in the diagnosis of OD. The high concordance between instruments supports the concurrent validity of the diagnosis. Either interview provides reliable, valid OD diagnoses in Thai-speaking Hmong individuals.

Cocaine users differ from normals on cognitive tasks which show poorer performance during drug abstinence.

Seventeen non-treatment seeking cocaine-dependent individuals participated in three-week longitudinal inpatient studies of cognitive changes during drug use and abstinence. Protocols included three days drug-free baseline, three days cocaine self-administration, and two weeks complete abstinence. A repeatable cognitive battery showed attention and delayed verbal recognition memory but not working memory to be impaired in cocaine users compared to age- and sex-matched normative values. Attention was significantly poorer during the first and second week of abstinence compared to days on which cocaine was used suggesting that certain cocaine-induced impairments may be acutely normalized by cocaine use, but resurface during abstinence.

Sleep, sleep-dependent procedural learning and vigilance in chronic cocaine users: Evidence for occult insomnia.

Sleep disturbance has been implicated in cocaine use; however, the nature of the disturbance and its potential effects on cognition and learning are largely unknown. Twelve chronic cocaine users completed a 23-day inpatient study that included randomized, placebo-controlled, cocaine self-administration sessions. Six subjects received cocaine on each of days 4-6 and placebo on days 18-20, the other six received cocaine on each of days 18-20 and placebo on days 4-6. Sleep was measured by polysomnography, the Nightcap sleep monitor, and self-reported measures. Simple and vigilance reaction times were measured daily; a motor-sequence test of procedural learning was administered four times. Electrophysiological measures of sleep showed a different pattern than self-reported sleep across cocaine administration and abstinence: total sleep time and sleep latency were at their worst by 14-17 days of abstinence while self-reported sleep was at its best. Vigilance correlated positively with electrophysiologically measured sleep and negatively with self-reported measures. Similarly, sleep-dependent procedural learning correlated with total sleep time and was impaired at 17 days abstinence relative to 2- and 3-days abstinence. Slow-wave activity was lowest at days 4-9 of abstinence and highest during use and days 10-17 of abstinence. With sustained abstinence, chronic cocaine users exhibit decreased sleep, impaired vigilance and sleep-dependent procedural learning, and spectral activity suggestive of chronic insomnia. However, they report subjectively improving sleep, indicating they are unaware of this "occult" insomnia. These results suggest the possibility of homeostatic sleep drive dysregulation in chronic cocaine users.

N-acetylcysteine augmentation in serotonin reuptake inhibitor refractory obsessive-compulsive disorder.

RATIONALE: Dysfunction of glutamatergic neurotransmission has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD) and recent clinical reports suggest that some glutamate modulating agents are efficacious in the treatment of this disorder. N-acetylcysteine (NAC) is a readily available amino acid compound that is thought to attenuate glutamatergic neurotransmission. NAC may be useful in treating psychiatric disorders involving glutamatergic dysfunction such as OCD. OBJECTIVES: To examine the efficacy of augmentation with NAC in a patient with serotonin reuptake inhibitor (SRI)-refractory OCD. METHODS: A patient with SRI-refractory OCD was treated with an off-label use of NAC augmentation of fluvoxamine over several weeks. RESULTS: NAC augmentation of fluvoxamine resulted in a marked decrease in Yale-Brown Obsessive Compulsive Scale (Y-BBOCS) score and a clinically significant improvement in OCD symptoms. CONCLUSIONS: NAC augmentation was effective in treating SRI-refractory OCD in this single case. Further research is warranted to investigate the use of NAC and other glutamate modulating agents in the treatment of OCD.

Cerebrospinal fluid interleukin (IL)-6 in unipolar major depression.

BACKGROUND: Previous studies have suggested that regulation of the proinflammatory cytokine interleukin (IL)-6 is abnormal in patients with major depression. This study was undertaken to determine whether IL-6 concentrations in cerebrospinal fluid (CSF) differ between depressed patients and healthy control subjects. METHODS: Lumbar puncture with a standardized procedure was performed on 18 drug-free patients meeting DSM-IV criteria for unipolar major depression and 26 age- and sex-matched healthy volunteers. CSF was assayed for IL-6 using a quantitative 'sandwich' enzyme immunoassay technique. RESULTS: Mean+/-S.D. CSF IL-6 levels did not differ between depressed (2.2+/-1.0 pg/ml) and healthy control (2.4+/-1.9 pg/ml) subjects. LIMITATIONS: This study had adequate power (0.8) to detect a large (d=0.88) effect size at alpha = 0.05. Although sample sizes were comparable to or larger than those of previous CSF studies, it is possible that a less robust difference between depressed and healthy subjects was not detected. CONCLUSIONS: These findings fail to support speculation that immune activation may be causally involved in the pathogenesis of depression.

Changes in human in vivo serotonin and dopamine transporter availabilities during chronic antidepressant administration.

Few studies have demonstrated in vivo alterations of human serotonin and dopamine transporters (SERTS and DATS) during antidepressant treatment. The current study measured these transporter availabilities with [(123)I]beta-CIT single photon emission computed tomography (SPECT) during administration of selective serotonin reuptake inhibitors (SSRIs) or a non-SSRI, bupropion. A total of 17 healthy human subjects were randomly assigned to two different treatment protocols: (1). citalopram (40 mg/day) followed by augmentation with bupropion (100 mg/day) or (2). bupropion (100-200 mg/day) for 16 days. Citalopram significantly inhibited [(123)I]beta-CIT binding to SERT in brainstem (51.4%) and diencephalon (39.4%) after 8 days of administration, which was similarly observed after 16 days. In contrast, citalopram significantly increased striatal DAT binding by 15-17% after 8 and 16 days of administration. Bupropion and its augmentation to citalopram did not have a significant effect on DAT or SERT. In 10 depressed patients who were treated with paroxetine (20 mg/day), a similar increase in DAT and inhibition of SERT were observed during 6 weeks treatment. The results demonstrated the inhibition of SERT by SSRI in human in vivo during the chronic treatment and, unexpectedly, an elevation of DAT. This apparent SSRI-induced modulation of the dopamine system may be associated with the side effects of these agents, including sexual dysfunction.