Gustavo A. Angarita

Sleep abnormalities associated with alcohol, cannabis, cocaine, and opiate use: a comprehensive review.

Sleep abnormalities are associated with acute and chronic use of addictive substances. Although sleep complaints associated with use and abstinence from addictive substances are widely recognized, familiarity with the underlying sleep abnormalities is often lacking, despite evidence that these sleep abnormalities may be recalcitrant and impede good outcomes. Substantial research has now characterized the abnormalities associated with acute and chronic use of alcohol, cannabis, cocaine, and opiates. This review summarizes this research and discusses the clinical implications of sleep abnormalities in the treatment of substance use disorders.

Detecting cocaine use with wearable electrocardiogram sensors

Ubiquitous physiological sensing has the potential to profoundly improve our understanding of human behavior, leading to more targeted treatments for a variety of disorders. The long term goal of this work is development of novel computational tools to support the study of addiction in the context of cocaine use. The current paper takes the first step in this important direction by posing a simple, but crucial question: Can cocaine use be reliably detected using wearable electrocardiogram (ECG) sensors? The main contributions in this paper include the presentation of a novel clinical study of cocaine use, the development of a computational pipeline for inferring morphological features from noisy ECG waveforms, and the evaluation of feature sets for cocaine use detection. Our results show that 32mg/70kg doses of cocaine can be detected with the area under the receiver operating characteristic curve levels above 0.9 both within and between-subjects.

Abstinence-related changes in sleep during treatment for cocaine dependence

BACKGROUND Former sleep studies among non-treatment seeking chronic cocaine users had captured polysomnographic changes for as long as three weeks of abstinence. METHODS 20 cocaine dependent participants, randomized to placebo in an ongoing clinical trial, received 12 days of inpatient substance abuse treatment followed by 6 weeks of outpatient cognitive behavioral therapy. Polysomnographic recording was performed on consecutive nights during the 1st and 2nd inpatient and 3rd and 6th outpatient weeks. Number of days abstinent was determined from thrice weekly urine toxicology and self-report. Polysomnographic sleep was compared between study week 1 and 2, using paired t-tests. Trajectory of total sleep time (TST) was modeled both as a linear and a quadratic function of days abstinent. RESULTS Despite reporting an improvement in overall sleep quality, polysomnographic sleep worsened from week 1 to 2. Among all participants, TST and stage 2 sleep time decreased, while REM sleep latency increased. Among participants who began the study with a positive urine test, there was also a decrease in REM and a trend for decreased slow wave sleep. TST compared to number of days abstinent (up to 54 days) was best fit with a quadratic model (p=0.002), suggesting the possibility of an improvement in total sleep time with extended abstinence. CONCLUSIONS This is the first polysomnographic characterization of sleep in a large sample of cocaine users in treatment. Present findings confirm earlier results of poor and deteriorating sleep early in abstinence, and raise the possibility of improvement after an extended abstinence.

No-Show for Treatment in Substance Abuse Patients with Comorbid Symptomatology: Validity Results from a Controlled Trial of the ASAM Patient Placement Criteria.

Purpose:Mismatched placement, according to the American Society of Addiction Medicines (ASAM) Patient Placement Criteria (PPC), promotes no-shows to treatment; however, little is known about the impact on patients with psychiatrically comorbid substance use disorder. Methods:In a multisite trial, public-sector treatment-seeking adults (N = 700), following a computer-assisted ASAM PPC-1 structured interview, were blindly scored and randomly assigned to Level-of-Care (LOC)-II (intensive outpatient) or LOC-III (residential) settings. Patients scored as needing LOC-II but assigned to LOC-III were, by definition, “overmatched.” Results:Among 143 overmatched patients, no-shows were significantly higher in comorbids versus noncomorbids (54% versus 28%; P < 0.01). Among overmatched comorbids, patients who no-showed compared with patients who showed were more likely to be females (70.4% versus 34.8%; P < 0.05), to have anxiety (63% versus 17.4%; P < 0.01), or have supportive family/social environments (81.5% versus 34.8%; P < 0.01). Conclusions:The data support the validity of the PPC for matching comorbid patients. Mismatching increases no-show rates in general with undermatching, but it does so in particular with overmatching in patients with comorbid psychiatric symptomatology. Comorbidity interacts with gender, overmatched status, presence of anxiety, and supportive environment as predictors of treatment no-shows (odds ratios = 2.69, P < 0.05; 3.27, P < 0.05; 5.32, P < 0.001; and 3.12, P < 0.05, respectively).

In vivo imaging of translocator protein, a marker of activated microglia, in alcohol dependence.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [11C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1–4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [11C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

Modafinil and sleep architecture in an inpatient–outpatient treatment study of cocaine dependence

OBJECTIVE To determine whether the increase in slow-wave sleep associated with modafinil treatment in chronic cocaine users mediates improved clinical outcomes. METHOD 57 cocaine dependent participants were randomized to receive modafinil 400mg or placebo daily during a period of inpatient treatment followed by six weeks of outpatient treatment. Participants underwent polysomnographic sleep recording during inpatient treatment prior to and after starting modafinil. Outpatient treatment consisted of weekly cognitive behavioral therapy. Contingency management was used to promote participation in treatment and research demands, including thrice weekly visits during the outpatient phase for urine toxicology screens and other assessments. The primary clinical outcome was the percent of urine toxicology screens that were negative for cocaine. RESULTS Modafinil treatment was associated with a higher mean percentage (52% vs. 26%) of cocaine-free urine screens (p=0.02) and an increase in N3 sleep time (p=0.002). The change in N3 sleep time mediated the higher rate of cocaine-free urine screens. Modafinil treatment was also associated with more consecutive days abstinent during outpatient treatment, greater survival of abstinence, higher daily rates of abstinence, and less sleep degradation typically associated with abstinence from chronic cocaine use. CONCLUSIONS Morning-dosed modafinil improves slow-wave sleep in abstinent cocaine users in the inpatient setting, and this effect is a statistical mediator of improved clinical outcomes associated with continued modafinil treatment. The high rates of abstinence achieved in this trial suggest that promoting healthy sleep physiology in an inpatient setting may be important in the effective treatment of cocaine dependence.

A preliminary study of dopamine D2/3 receptor availability and social status in healthy and cocaine dependent humans imaged with [11C](+)PHNO

BACKGROUND Previous work in healthy non-human primates and humans has shown that social status correlates positively with dopamine 2/3 receptor (D2/3R) availability imaged with antagonist radioligands and positron emission tomography (PET). Further work in non-human primates suggests that this relationship is disrupted by chronic cocaine administration. This exploratory study examined the relationship between social status and D2/3R availability in healthy (HH) and cocaine dependent (CD) humans using the D3-preferring, agonist radioligand, [(11)C](+)PHNO. METHODS Sixteen HH and sixteen CD individuals completed the Barratt Simplified Measure of Social Status (BSMSS) and underwent [(11)C](+)PHNO scanning to measure regional brain D2/3R binding potentials (BPND). Correlations between BPND and BSMSS scores were then assessed within each group. RESULTS Within HH and CD groups, inverse associations between BSMSS score and BPND were observed in the substantia nigra/ventral tegmental area (SN/VTA) and the ventral striatum, and for the CD group alone, the amygdala. After adjusting for body mass index and age, negative correlations remained significant in the SN/VTA for HH and in the amygdala for CD subjects. CONCLUSION These preliminary data utilizing a dopamine agonist tracer demonstrate, for the first time, an inverse association between social status and D2/3R availability in the D3R rich extrastriatal regions of HH and CD humans.

Correlates of polysomnographic sleep changes in cocaine dependence: Self-administration and clinical outcomes☆

BACKGROUND Abstinence from chronic cocaine use is associated with abnormal sleep architecture. As sleep abnormalities are associated with clinical outcome in alcohol dependence, we hypothesized a similar relationship in cocaine dependence. METHODS We report data from a cocaine self-administration study (N=12) and the placebo arm of a randomized clinical trial (N=20). Self-administration participants underwent three cocaine self-administration sessions during a three-week inpatient stay. Treatment participants underwent two weeks of inpatient followed by six weeks of outpatient treatment including once-weekly cognitive behavioral therapy. Measurements included polysomnography from early and late in abstinence during the inpatient stays. Clinical outcomes included amount of cocaine self-administered, urine tests, and self-reported use and withdrawal symptoms. RESULTS Change in slow-wave sleep from early to late abstinence (ΔSWS; p=0.05), late abstinence rapid eye movement sleep (REM; p=0.002), and late abstinence total sleep time (p=0.02) were negatively correlated with the amount of cocaine self-administered. Early abstinence REM was positively correlated with withdrawal symptoms (p=0.02). Late abstinence REM was positively correlated with percent negative urines and maximum consecutive number of days abstinent (both p<0.001). ΔSWS was positively correlated with percent negative urines (p=0.03) and participants with increased SWS had greater percent negative urines (p=0.008) and maximum consecutive number of days abstinent (p=0.009). CONCLUSIONS Correlations between sleep deficits and amount of cocaine self-administered, clinical outcomes, and severity of withdrawal symptoms underscore the relevance of sleep in clinical outcomes in the treatment of cocaine dependence.

Domain adaptation methods for improving lab-to-field generalization of cocaine detection using wearable ECG

Mobile health research on illicit drug use detection typically involves a two-stage study design where data to learn detectors is first collected in lab-based trials, followed by a deployment to subjects in a free-living environment to assess detector performance. While recent work has demonstrated the feasibility of wearable sensors for illicit drug use detection in the lab setting, several key problems can limit lab-to-field generalization performance. For example, lab-based data collection often has low ecological validity, the ground-truth event labels collected in the lab may not be available at the same level of temporal granularity in the field, and there can be significant variability between subjects. In this paper, we present domain adaptation methods for assessing and mitigating potential sources of performance loss in lab-to-field generalization and apply them to the problem of cocaine use detection from wearable electrocardiogram sensor data.

Regulation of cocaine self-administration in humans: Lack of evidence for loading and maintenance phases

BACKGROUND In rodents, cocaine self-administration under a fixed-ratio schedule and with timeout intervals limited to the duration of the infusions is characterized by an initial burst of drug intake (loading) followed by more stable infusion rates (maintenance). We sought to examine whether similar phases might characterize self-regulated cocaine use in humans. METHODS 31 Non-treatment seeking, cocaine dependent subjects participated in three (8, 16, and 32 mg/70 kg/infusion), self-regulated, 2-h cocaine self-administration sessions under a fixed-ratio 1, 5-min timeout schedule. Data were assessed for visual (e.g., by graphs of cumulative numbers of infusions) and statistical evidence of change in phase (by step-function analyses of individual infusion rates). RESULTS Graphs of cumulative infusions over time suggested a single, linear rate of self-administration over 2h at each cocaine dose. Statistical analyses of infusion data by generalized estimating equation (GEE) models also failed to support a loading/maintenance pattern (suggesting, if anything, the possibility of increasing infusion rates over time). CONCLUSIONS Our findings fail to support the existence of distinct loading and maintenance phases of self-regulated cocaine administration in humans at behaviorally relevant doses. Several factors may account for these observations including differences between humans and rodents in self-regulated drug intake.