Faculty Bibliography

Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms may be specific. This study examined the association of 98 single nucleotide polymorphisms in 13 dopamine-related genes with heroin addiction (OD) and/or cocaine addiction (CD) in a sample of 801 African Americans (315 subjects with OD +/- CD, 279 subjects with CD, and 207 controls). Single-marker analyses provided nominally significant evidence for associations of 24 SNPs) in DRD1, ANKK1/DRD2, DRD3, DRD5, DBH, DDC, COMT and CSNK1E. A DRD2 7-SNPs haplotype that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the functional COMT Val158Met was associated with protection from OD. None of the signals remained significant after correction for multiple testing. The study results are in accordance with the results of previous studies, including our report of association of DRD1 SNP rs5326 with OD. The findings suggest the presence of an overlap in genetic susceptibility for OD and CD, as well as shared and distinct susceptibility for OD in subjects of African and European descent.

RATIONALE: It is well established that the rewarding effects of alcohol are modulated by the mesolimbic dopaminergic system. Olanzapine, a D2 dopamine antagonist, has been shown to reduce alcohol craving and consumption. OBJECTIVE: To clarify whether olanzapine has clinical utility in the treatment of alcohol dependence, a 12-week, double-blind, and randomized clinical trial was conducted. METHODS: One hundred twenty-nine treatment-seeking alcohol-dependent adults were randomly assigned to 12 weeks of olanzapine (5 vs. 2.5 mg) or placebo. Outcomes examined were average drinks per drinking day (DDD), proportion of drinking days (PDD) to total days in treatment, alcohol craving, and impaired control over alcohol use. Mixed models were used to examine medication effects during the course of treatment on specified outcomes. RESULTS: All of the analyses indicated a main effect for time, such that there were reductions in alcohol use and craving and an increase in control over alcohol use across treatment conditions. Dose-response analyses indicated that, in comparison to placebo, participants in the 5 mg group experienced reduced craving for alcohol and participants in the 2.5 mg group decreased in PDD and increased in their control over alcohol use. Better control over alcohol use remained significant 6 months post-treatment for the 2.5 mg group. Subjective experiences of the medication suggest that 2.5 and 5 mg were equally well tolerated. CONCLUSIONS: Results provide some support for the notion that dosage is an important consideration in relation to effectiveness; however, the cost-benefit balance does not support the clinical utility of olanzapine in treating alcohol dependence.

We assess the geographic coverage and spatial clustering of drug users recruited through respondent-driven sampling (RDS) and discuss the potential for biased RDS prevalence estimates. Illicit drug users aged 18-40 were recruited through RDS (N = 401) and targeted street outreach (TSO) (N = 210) in New York City. Using the Google Maps API, we calculated travel distances and times using public transportation between each participant's recruitment location and the study office and between RDS recruiter-recruit pairs. We used K function analysis to evaluate and compare spatial clustering of (1) RDS vs. TSO respondents and (2) RDS seeds vs. RDS peer recruits. All participant recruitment locations clustered around the study office; however, RDS participants were significantly more likely to be recruited within walking distance of the study office than TSO participants. The TSO sample was also less spatially clustered than the RDS sample, which likely reflects (1) the van's ability to increase the sample's geographic heterogeneity and (2) that more TSO than RDS participants were enrolled on the van. Among RDS participants, individuals recruited spatially proximal peers, geographic coverage did not increase as recruitment waves progressed, and peer recruits were not less spatially clustered than seeds. Using a mobile van to recruit participants had a greater impact on the geographic coverage and spatial dependence of the TSO than the RDS sample. Future studies should consider and evaluate the impact of the recruitment approach on the geographic/spatial representativeness of the sample and how spatial biases, including the preferential recruitment of proximal peers, could impact the precision and accuracy of estimates.

Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. TRIAL REGISTRATION: NCT02061293.

Aims: ED-based SBIRT for alcohol and drug use has the potential to impact public health greatly. Time and resource constraints limit implementation. Targeted intervention may be more efficient and practical. We hypothesized that we could use chief complaints to identify patients at highest risk of positive drug or alcohol use assessments. Methods: Using baseline data from NIDA CTN0047: SMARTED, free text chief complaints of 14,972 subjects from six sites were coded using a tested algorithm (Thompson, 2006). Multiple team members manually reviewed and further collapsed the chief complaint categorization to ensure agreement. We excluded subjects having missing data or complaints related to substance use and chief complaints stated by <15 subjects. Positive screens were defined as AUDIT-C > 4 for men and >3 for women (alcohol) and DAST > 2 (drugs). We ranked-ordered the chief complaints by their sensitivity and positive predictive value to (1) minimize the number of chief complaints and (2) assess the fewest number of ED patients. Our goal was to identify 75% of ED patients having positive assessments using these strategies. Results: The screening assessments were positive in 5805/14,561 (39.9%) for alcohol and 2454/14,494 (16.9%) for drugs. We collapsed the free-text chief complaints into 50 usable categories. To identify 75% of all ED patients having positive assessments using the first strategy would require including 19 chief complaints for alcohol screening and 20 chief complaints for drug screening. Adapting the second strategy, we would need to screen at least 71% and 68% of all ED patients for alcohol and drugs respectively to identify 75% of those having positive assessments. Conclusions: Based on this large, multicenter study, chief complaints provide little assistance in targeting SBIRT for alcohol or drug use in the ED

Aims: To determine if specific single-nucleotide polymorphisms (SNPs) in stress-related genes are associated with heroin addiction. Methods: Case-control hypothesis-driven association study of 112 SNPs from 26 stress-related genes. The sample consists of 852 case subjects and 238 controls. The case subjects are former heroin addicts with a history of at least 1 year of daily multiple uses of heroin, treated at a MMTP. European ancestry was verified by ancestry informative markers (AIMs). Association analysis was performed by logistic regression. Results: Nineteen SNPs in 9 genes (AVP, CRHR1, CRHR2, FKBP5, NR3C2, AVPR1A, GAL, GLRA1 and NPY1R) showed nominally significant association (p < 0.05) with heroin addiction. Two tightly linked FKBP5 SNPs, rs1360780 and rs3800373, from intron 2 and the 3' UTR, respectively, remained significant after correction for multiple testing (experiment-wise p = 3.0E-04;OR= 2.35; 95% CI, 1.5-3.7 and p = 1.6E-05; OR= 2.85; 95% CI, 1.8-4.6, respectively). Conclusions: The study provides evidence for the association of FKBP5 SNPs with heroin addiction. These SNPs were previously associated with diverse affective disorders and showed functional differences in gene expression and stress response. The FKBP5 gene encodes a co-chaperone that regulates glucocorticoid sensitivity. The modulation of the stress response by FKBP5 may contribute to the development of opiate dependence and in turn FKBP5 may also mediate the abuse potential of opioids. The study also corroborates our and others previous reports of association of GAL SNP rs694066 and AVPR1A SNPs rs11174811, rs1587097 and rs10784339 with specific general drug addictions and suggests several new associations

Aims: Implementation of substance use screening in general medical settings is hindered by the lack of a brief yet precise and comprehensive screening tool that is compatible with clinical workflows. To address this need, we developed the Substance Use Brief Screen (SUBS); a 4-item screener for tobacco, alcohol, and drug use (illicit and prescription) that is self-administered and may be easily integrated with electronic health records. Methods: Adult patients were recruited consecutively in the waiting area of an urban safety net primary care clinic. The SUBS was self-administered in English on touchscreen tablet computers. Reference standard measures of unhealthy substance use and substance use disorders were then administered, including self reported measures and saliva drug tests. The SUBS was compared against the reference standards to determine its sensitivity, specificity, and area under the curve (AUC) for each substance class. Results: Among the 390 participants, rates of past year use reported on the SUBS were 37% tobacco, 43% alcohol (4+ drinks/day), 20% illicit drugs, and 12% prescription drugs. Sensitivity and specificity of the SUBS for detecting past year unhealthy use were: tobacco 99% and 91% (AUC = .95); alcohol 94% and 68% (AUC = .81); drugs (illicit or prescription) 84% and 89% (AUC = .86). Sensitivity was lower for prescription drugs (57%) than for illicit drugs (78%). For detecting a substance use disorder, sensitivity and specificity were: tobacco 100% and 73% (AUC = .87); alcohol 93% and 64% (AUC = .79); drugs 85% and 82% (AUC = .84). Conclusions: The SUBS accurately identified unhealthy tobacco, alcohol, and drug use in this primary care sample, and had high sensitivity but lower specificity for identifying substance use disorders. Individuals screening positive on the SUBS should receive further assessment. Our findings support use of the SUBS for substance use screening in primary care, but additional tools may be needed for prescription drugs

Ketamine is known within the medical field for its anesthetic properties, yet its unique psychedelic and antidepressant properties are being increasingly recognized. We document the case of a patient with bipolar I disorder and an extensive history of substance dependence who used large doses of ketamine (1-3 g) on a daily basis over a period of 5 years, and described acute antidepressant effects as well as diminished cravings for alcohol. While his use was untenable and ultimately led to an inpatient admission, it is notable that he did not experience a withdrawal syndrome nor did he have any observable cognitive deficits upon cessation of use. Such a unique drug profile suggests that further exploration of its risks and therapeutic potential in treating mood and addiction disorders is warranted. (Am J Addict 2015;24:7-9).

Individuals with alcohol use disorders (AUDs) have deficits in cognitive control, but how they change with treatment is unclear. Seven patients with AUD and anxiety from an open-label trial of disulfiram plus lorazepam performed a multisensory Stroop task during fMRI (both pre and post initiation of treatment), and were compared to nine healthy controls (HCs) (n = 16; Albuquerque, NM; years 2009-2012). Evoked BOLD signal and resting state functional connectivity were compared (HC vs. AUD; Scan 1 vs. Scan 2). AUD demonstrated hyperactivity and altered connectivity in the cognitive control network compared to HC, but treatment did not normalize function.