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1.  A Randomized Trial Comparing the Effect of Nicotine Versus Placebo Electronic Cigarettes on Smoking Reduction Among Young Adult Smokers 
Nicotine & Tobacco Research  2016;18(10):1937-1943.
Introduction:
Electronic cigarette (EC) use is growing dramatically with use highest among young adults and current smokers. One of the most common reasons for using ECs is interest in quitting or reducing cigarettes per day (CPD); however there are few randomized controlled trials (RCT) on the effect of ECs on smoking abstinence and reduction.
Methods:
We conducted a two-arm; double-blind RCT. Subjects were randomized to receive 3-weeks of either disposable 4.5% nicotine EC (intervention) or placebo EC. The primary outcome was self-reported reduction of at least 50% in the number of CPDs smoked at week 3 (end of treatment) compared to baseline. Study subjects (n = 99) were young adult (21–35), current smokers (smoked ≥ 10 CPDs) living in NYC.
Results:
Compared with baseline, a significant reduction in CPDs was observed at both study time periods (1 and 3 weeks) for intervention (P < .001) and placebo (P < .001) groups. Between-group analyses showed significantly fewer CPDs in the intervention group compared to the placebo group at week 3 (P = .03), but not at any other follow-up periods. The logistic regression analysis showed that using a greater number of ECs, treatment condition and higher baseline readiness to quit were significantly associated with achieving at least 50% reduction in CPDs at the end of treatment.
Conclusion:
A diverse young adult sample of current everyday smokers, who were not ready to quit, was able to reduce smoking with the help of ECs. Further study is needed to establish the role of both placebo and nicotine containing ECs in increasing both reduction and subsequent cessation.
Implications:
Despite the critical need for well-designed clinical trials on the effect of ECs on cessation and cigarette reduction, the majority of studies have been observational or noncomparative intervention designs. Only three RCTs studying ECs as a cessation or reduction intervention have been published, and none were conducted in the United States. The current study adds knowledge to current literature on the feasibility of using ECs to aid smoking reduction among young smokers in US urban populations.
doi:10.1093/ntr/ntw017
PMCID: PMC5016841  PMID: 26783292
2.  Proceedings of the 14th annual conference of INEBRIA 
Holloway, Aisha S. | Ferguson, Jennifer | Landale, Sarah | Cariola, Laura | Newbury-Birch, Dorothy | Flynn, Amy | Knight, John R. | Sherritt, Lon | Harris, Sion K. | O’Donnell, Amy J. | Kaner, Eileen | Hanratty, Barbara | Loree, Amy M. | Yonkers, Kimberly A. | Ondersma, Steven J. | Gilstead-Hayden, Kate | Martino, Steve | Adam, Angeline | Schwartz, Robert P. | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | McNeely, Jennifer | Berman, Anne H. | Kolaas, Karoline | Petersén, Elisabeth | Bendtsen, Preben | Hedman, Erik | Linderoth, Catharina | Müssener, Ulrika | Sinadinovic, Kristina | Spak, Fredrik | Gremyr, Ida | Thurang, Anna | Mitchell, Ann M. | Finnell, Deborah | Savage, Christine L. | Mahmoud, Khadejah F. | Riordan, Benjamin C. | Conner, Tamlin S. | Flett, Jayde A. M. | Scarf, Damian | McRee, Bonnie | Vendetti, Janice | Gallucci, Karen Steinberg | Robaina, Kate | Clark, Brendan J. | Jones, Jacqueline | Reed, Kathryne D. | Hodapp, Rachel M. | Douglas, Ivor | Burnham, Ellen L. | Aagaard, Laura | Cook, Paul F. | Harris, Brett R. | Yu, Jiang | Wolff, Margaret | Rogers, Meighan | Barbosa, Carolina | Wedehase, Brendan J. | Dunlap, Laura J. | Mitchell, Shannon G. | Dusek, Kristi A. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla T. | Hosler, Colleen | O’Grady, Kevin E. | Brown, Barry S. | Angus, Colin | Sherborne, Sidney | Gillespie, Duncan | Meier, Petra | Brennan, Alan | de Vargas, Divane | Soares, Janaina | Castelblanco, Donna | Doran, Kelly M. | Wittman, Ian | Shelley, Donna | Rotrosen, John | Gelberg, Lillian | Edelman, E. Jennifer | Maisto, Stephen A. | Hansen, Nathan B. | Cutter, Christopher J. | Deng, Yanhong | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Bedimo, Roger | Gibert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria C. | Simberkoff, Michael S. | Justice, Amy C. | Bryant, Kendall J. | Fiellin, David A. | Giles, Emma L. | Coulton, Simon | Deluca, Paolo | Drummond, Colin | Howel, Denise | McColl, Elaine | McGovern, Ruth | Scott, Stephanie | Stamp, Elaine | Sumnall, Harry | Vale, Luke | Alabani, Viviana | Atkinson, Amanda | Boniface, Sadie | Frankham, Jo | Gilvarry, Eilish | Hendrie, Nadine | Howe, Nicola | McGeechan, Grant J. | Ramsey, Amy | Stanley, Grant | Clephane, Justine | Gardiner, David | Holmes, John | Martin, Neil | Shevills, Colin | Soutar, Melanie | Chi, Felicia W. | Weisner, Constance | Ross, Thekla B. | Mertens, Jennifer | Sterling, Stacy A. | Shorter, Gillian W. | Heather, Nick | Bray, Jeremy | Cohen, Hildie A. | McPherson, Tracy L. | Adam, Cyrille | López-Pelayo, Hugo | Gual, Antoni | Segura-Garcia, Lidia | Colom, Joan | Ornelas, India J. | Doyle, Suzanne | Donovan, Dennis | Duran, Bonnie | Torres, Vanessa | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Paroz, Sophie | Bertholet, Nicolas | Daeppen, Jean-Bernard | Satterfield, Jason M. | Gregorich, Steven | Alvarado, Nicholas J. | Muñoz, Ricardo | Kulieva, Gozel | Vijayaraghavan, Maya | Adam, Angéline | Cunningham, John A. | Díaz, Estela | Palacio-Vieira, Jorge | Godinho, Alexandra | Kushir, Vladyslav | O’Brien, Kimberly H. M. | Aguinaldo, Laika D. | Sellers, Christina M. | Spirito, Anthony | Chang, Grace | Blake-Lamb, Tiffany | LaFave, Lea R. Ayers | Thies, Kathleen M. | Pepin, Amy L. | Sprangers, Kara E. | Bradley, Martha | Jorgensen, Shasta | Catano, Nico A. | Murray, Adelaide R. | Schachter, Deborah | Andersen, Ronald M. | Rey, Guillermina Natera | Vahidi, Mani | Rico, Melvin W. | Baumeister, Sebastian E. | Johansson, Magnus | Sinadinovic, Christina | Hermansson, Ulric | Andreasson, Sven | O’Grady, Megan A. | Kapoor, Sandeep | Akkari, Cherine | Bernal, Camila | Pappacena, Kristen | Morley, Jeanne | Auerbach, Mark | Neighbors, Charles J. | Kwon, Nancy | Conigliaro, Joseph | Morgenstern, Jon | Magill, Molly | Apodaca, Timothy R. | Borsari, Brian | Hoadley, Ariel | Scott Tonigan, J. | Moyers, Theresa | Fitzgerald, Niamh M. | Schölin, Lisa | Barticevic, Nicolas | Zuzulich, Soledad | Poblete, Fernando | Norambuena, Pablo | Sacco, Paul | Ting, Laura | Beaulieu, Michele | Wallace, Paul George | Andrews, Matthew | Daley, Kate | Shenker, Don | Gallagher, Louise | Watson, Rod | Weaver, Tim | Bruguera, Pol | Oliveras, Clara | Gavotti, Carolina | Barrio, Pablo | Braddick, Fleur | Miquel, Laia | Suárez, Montse | Bruguera, Carla | Brown, Richard L. | Capell, Julie Whelan | Paul Moberg, D. | Maslowsky, Julie | Saunders, Laura A. | McCormack, Ryan P. | Scheidell, Joy | Gonzalez, Mirelis | Bauroth, Sabrina | Liu, Weiwei | Lindsay, Dawn L. | Lincoln, Piper | Hagle, Holly | Wallhed Finn, Sara | Hammarberg, Anders | Andréasson, Sven | King, Sarah E. | Vargo, Rachael | Kameg, Brayden N. | Acquavita, Shauna P. | Van Loon, Ruth Anne | Smith, Rachel | Brehm, Bonnie J. | Diers, Tiffiny | Kim, Karissa | Barker, Andrea | Jones, Ashley L. | Skinner, Asheley C. | Hinman, Agatha | Svikis, Dace S. | Thacker, Casey L. | Resnicow, Ken | Beatty, Jessica R. | Janisse, James | Puder, Karoline | Bakshi, Ann-Sofie | Milward, Joanna M. | Kimergard, Andreas | Garnett, Claire V. | Crane, David | Brown, Jamie | West, Robert | Michie, Susan | Rosendahl, Ingvar | Andersson, Claes | Gajecki, Mikael | Blankers, Matthijs | Donoghue, Kim | Lynch, Ellen | Maconochie, Ian | Phillips, Ceri | Pockett, Rhys | Phillips, Tom | Patton, R. | Russell, Ian | Strang, John | Stewart, Maureen T. | Quinn, Amity E. | Brolin, Mary | Evans, Brooke | Horgan, Constance M. | Liu, Junqing | McCree, Fern | Kanovsky, Doug | Oberlander, Tyler | Zhang, Huan | Hamlin, Ben | Saunders, Robert | Barton, Mary B. | Scholle, Sarah H. | Santora, Patricia | Bhatt, Chirag | Ahmed, Kazi | Hodgkin, Dominic | Gao, Wenwu | Merrick, Elizabeth L. | Drebing, Charles E. | Larson, Mary Jo | Sharma, Monica | Petry, Nancy M. | Saitz, Richard | Weisner, Constance M. | Young-Wolff, Kelly C. | Lu, Wendy Y. | Blosnich, John R. | Lehavot, Keren | Glass, Joseph E. | Williams, Emily C. | Bensley, Kara M. | Chan, Gary | Dombrowski, Julie | Fortney, John | Rubinsky, Anna D. | Lapham, Gwen T. | Forray, Ariadna | Olmstead, Todd A. | Gilstad-Hayden, Kathryn | Kershaw, Trace | Dillon, Pamela | Weaver, Michael F. | Grekin, Emily R. | Ellis, Jennifer D. | McGoron, Lucy | McGoron, Lucy
doi:10.1186/s13722-017-0087-8
PMCID: PMC5606215
3.  NIDA Clinical Trials Network CTN-0051, Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment (X:BOT): Study Design and Rationale 
Contemporary clinical trials  2016;50:253-264.
Introduction
For opioid-dependent patients in the US and elsewhere, detoxification and counseling-only aftercare are treatment mainstays. Long-term abstinence is rarely achieved; many patients relapse and overdose after detoxification. Methadone, buprenorphine-naloxone (BUP-NX) and extended-release naltrexone (XR-NTX) can prevent opioid relapse but are underutilized. This study is intended to develop an evidence-base to help patients and providers make informed choices and to foster wider adoption of relapse-prevention pharmacotherapies.
Methods
The National Institute on Drug Abuse's Clinical Trials Network (CTN) study CTN-0051, X:BOT, is a comparative effectiveness study of treatment for 24 weeks with XR-NTX, an opioid antagonist, versus BUP-NX, a high affinity partial opioid agonist, for opioid dependent patients initiating treatment at 8 short-term residential (detoxification) units and continuing care as outpatients. Up to 600 participants are randomized (1:1) to XR-NTX or BUP-NX.
Results
The primary outcome is time to opioid relapse (i.e., loss of persistent abstinence) across the 24-week treatment phase. Differences between arms in the distribution of time-to-relapse will be compared (construction of the asymptotic 95% CI for the hazard ratio of the difference between arms). Secondary outcomes include proportions retained in treatment, rates of opioid abstinence, adverse events, cigarette, alcohol, and other drug use, and HIV risk behaviors; opioid cravings, quality of life, cognitive function, genetic moderators, and cost effectiveness.
Conclusions
XR-NTX and BUP-NX differ considerably in their characteristics and clinical management; no studies to date have compared XR-NTX with buprenorphine maintenance. Study design choices and compromises inherent to a comparative effectiveness trial of distinct treatment regimens are reviewed.
doi:10.1016/j.cct.2016.08.004
PMCID: PMC5416469  PMID: 27521809
extended-release naltrexone; buprenorphine-naloxone; opioid dependence; medication assisted therapy; methods or experimental design; Clinical Trials Network
4.  Ethical and Clinical Safety Considerations in the Design of an Effectiveness Trial: A Comparison of Buprenorphine versus Naltrexone Treatment for Opioid Dependence 
We examine ethical challenges encountered in the design of an effectiveness trial (CTN-0051; X:BOT), comparing sublingual buprenorphine-naloxone (BUP-NX), an established treatment for opioid dependence, to the newer extended-release injectable naltrexone (XR-NTX). Ethical issues surrounded: 1) Known poor effectiveness of one possible, commonly used Treatment as Usual control condition—detoxification followed by counseling without medication; 2) The role of patients' preferences for treatments, given that treatments were clinically approved and available to the population; 3) Differences between the optimal “usual treatment” clinical settings for different treatments making it challenging to design a fair comparison; 4) Vested interest groups favoring different treatments exerting potential influence on the design process; 5) Potentially vulnerable populations of substance users and prisoners; 6) Potential therapeutic misconception in the implementation of safety procedures; and 7) High cost of a large trial limiting questions that could be addressed. We examine how the design features underlying these ethical issues are characteristic of effectiveness trials, which are often large trials that compare treatments with varying degrees of existing effectiveness data and familiarity to patients and clinicians, in community-based treatment settings, with minimal exclusion criteria that could involve vulnerable populations. Hence, investigators designing effectiveness trials may wish to remain alert to the possibility of similar ethical issues.
doi:10.1016/j.cct.2016.09.006
PMCID: PMC5466164  PMID: 27687743
ethics; effectiveness; clinical trial; opioid dependence; buprenorphine; naltrexone
5.  Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders 
The New England journal of medicine  2016;374(13):1232-1242.
BACKGROUND
Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited.
METHODS
In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78.
RESULTS
A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P = 0.91). The rates of other prespecified secondary outcome measures — self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration — were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P = 0.02).
CONCLUSIONS
In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation.
doi:10.1056/NEJMoa1505409
PMCID: PMC5454800  PMID: 27028913
6.  Extended-release naltrexone opioid treatment at jail reentry (XOR) 
Background
Extended-release naltrexone (XR-NTX) is an injectable monthly sustained-release mu opioid receptor antagonist, which blocks the typical effects of heroin and other opioid agonists. Use of XR-NTX among opioid dependent persons leaving jails and prisons is increasing despite scant high-quality evidence regarding XR-NTX’s effectiveness at re-entry.
Methods
This 24-week, open-label randomized controlled trial examines the effectiveness of XR-NTX as opioid relapse prevention at release from jail (N = 85) compared to enhanced treatment as usual (ETAU, N = 85). A third, non-randomized, quasi-experimental naturalistic arm of participants who have newly initiated a jail-to-community methadone treatment program (MTP, N = 85) allows for comparisons to a methadone standard-of-care.
Results
We describe the rationale, design, and primary and secondary outcomes of the study. The primary outcome is an opioid relapse event; the primary contrast is a time-to-relapse comparison of XR-NTX and ETAU over a 24-week treatment phase. Secondary outcomes are rates of: (a) post-release opioid treatment participation, (b) opioid, alcohol, and cocaine use, (c) injection drug use and HIV sexual risk behaviors, (d) overdose (fatal and non-fatal) and all-cause mortality, and, (e) re-incarceration.
Conclusions
XR-NTX is a potentially important, effective treatment and relapse prevention option for a large US population of persons with opioid use disorders leaving jails. This study will estimate XR-NTX’s effectiveness relative to existing standards of care, including counseling-only treatment-as-usual and methadone maintenance.
doi:10.1016/j.cct.2016.05.002
PMCID: PMC5455014  PMID: 27178765
Naltrexone; Extended-release naltrexone; Criminal justice; Opioid relapse prevention; Jail
7.  African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction 
Pharmacogenomics  2016;17(9):995-1003.
Aim:
This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence.
Patients & methods:
The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed.
Results:
Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing (Pcorrected = 0.047). CHRM4 is located in a region of strong linkage disequilibrium on chromosome 11 that includes genes associated with schizophrenia. CHRM4 SNP rs2229163 is in strong linkage disequilibrium with several African-specific SNPs in DGKZ and AMBRA1.
Conclusion:
Cholinergic receptors’ variants may contribute to drug addiction and have a potential role as pharmacogenetic markers.
doi:10.2217/pgs-2016-0028
PMCID: PMC4996315  PMID: 27269905
African ancestry; cholinergic receptors; CHRM4; cocaine addiction; opioid addiction
8.  VALIDATION OF AN AUDIO COMPUTER ASSISTED SELF INTERVIEW (ACASI) VERSION OF THE ALCOHOL, SMOKING AND SUBSTANCE INVOLVEMENT SCREENING TEST (ASSIST) IN PRIMARY CARE PATIENTS 
Addiction (Abingdon, England)  2015;111(2):233-244.
Aims
To address barriers to implementing the “Alcohol, Smoking and Substance Involvement Screening Test (ASSIST)” in medical settings, we adapted the traditional interviewer-administered (IA) ASSIST to an audio-guided computer assisted self-interview (ACASI) format. This study sought to validate the ACASI ASSIST by estimating the concordance, correlation, and agreement of scores generated using the ACASI versus the reference standard IA ASSIST. Secondary aims were to assess feasibility and compare ASSIST self-report to drug testing results.
Design
Participants completed the ACASI and IA ASSIST in a randomly assigned order, followed by drug testing.
Setting
Urban safety-net primary care clinic.
Participants
A total of 393 adult patients.
Measurements
Scores generated by the ACASI and IA ASSIST; drug testing results from saliva and hair samples.
Findings
Concordance between the ACASI and IA ASSIST in identifying moderate-high risk use was 92–99% for each substance class. Correlation was excellent for global scores (ICC=0.94, CI 0.92–0.95) and for substance-specific scores for tobacco (ICC=0.93, CI 0.91–0.94), alcohol (ICC=0.91, CI 0.89–0.93) and illicit drugs (ICC=0.85, CI 0.85–0.90), and good for prescription drugs (ICC=0.68, CI 0.61–0.73). Ninety-four percent of differences in global scores fell within anticipated limits of agreement. Among participants with a positive saliva test, 74% self-reported use on the ACASI ASSIST. The ACASI ASSIST required a median time of 3.7 minutes (range 0.7–15.4), and 21 (5.3%) participants requested assistance.
Conclusions
The computer self-administered Alcohol, Smoking and Substance Involvement Screening Test appears to be a valid alternative to the interviewer-administered approach for identifying substance use in primary care patients.
doi:10.1111/add.13165
PMCID: PMC4899945  PMID: 26360315
Drugs; alcohol; tobacco; substance abuse; screening; ACASI
9.  Glutamatergic and GABAergic susceptibility loci for heroin and cocaine addiction in subjects of African and European ancestry 
Background
Drug addiction, a leading health problem, is a chronic brain disease with a significant genetic component. Animal models and clinical studies established the involvement of glutamate and GABA neurotransmission in drug addiction. This study was designed to assess if 258 variants in 27 genes of these systems contribute to the vulnerability to develop drug addiction.
Methods
Four independent analyses were conducted in a sample of 1860 subjects divided according to drug of abuse (heroin or cocaine) and ancestry (African and European).
Results
A total of 11 SNPs in eight genes showed nominally significant associations (P < 0.01) with heroin and/or cocaine addiction in one or both ancestral groups but the associations did not survive correction for multiple testing. Of these SNPs, the GAD1 upstream SNP rs1978340 is potentially functional as it was shown to affect GABA concentrations in the cingulate cortex. In addition, SNPs GABRB3 rs7165224; DBI rs12613135; GAD1 SNPs rs2058725, rs1978340, rs2241164; and GRIN2A rs1650420 were previously reported in associations with drug addiction or related phenotypes.
Conclusions
The study supports the involvement of genetic variation in the glutamatergic and GABAergic systems in drug addiction with partial overlap in susceptibility loci between cocaine and heroin addiction.
doi:10.1016/j.pnpbp.2015.08.003
PMCID: PMC4564302  PMID: 26277529
GAD1; glutamate; GABA; heroin; cocaine; addiction; African Americans
10.  Validation of Self-Administered Single-Item Screening Questions (SISQs) for Unhealthy Alcohol and Drug Use in Primary Care Patients 
Journal of General Internal Medicine  2015;30(12):1757-1764.
Background
Very brief single-item screening questions (SISQs) for alcohol and other drug use can facilitate screening in health care settings, but are not widely used. Self-administered versions of the SISQs could ease barriers to their implementation.
Objective
We sought to validate SISQs for self-administration in primary care patients.
Design
Participants completed SISQs for alcohol and drugs (illicit and prescription misuse) on touchscreen tablet computers. Self-reported reference standard measures of unhealthy use, and more specifically of risky consumption, problem use, and substance use disorders, were then administered by an interviewer, and saliva drug tests were collected.
Participants
Adult patients aged 21–65 years were consecutively enrolled from two urban safety-net primary care clinics.
Main Measures
The SISQs were compared against reference standards to determine sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) for alcohol and drug use.
Key Results
Among the 459 participants, 22 % reported unhealthy alcohol use and 25 % reported drug use in the past year. The SISQ-alcohol had sensitivity of 73.3 % (95 % CI 65.3–80.3) and specificity of 84.7 % (95 % CI 80.2–88.5), AUC = 0.79 (95 % CI 0.75–0.83), for detecting unhealthy alcohol use, and sensitivity of 86.7 % (95 % CI 75.4–94.1) and specificity of 74.2 % (95 % CI 69.6–78.4), AUC = 0.80 (95 % CI 0.76–0.85), for alcohol use disorder. The SISQ-drug had sensitivity of 71.3 % (95 % CI 62.4–79.1) and specificity of 94.3 % (95 % CI 91.3–96.6), AUC = 0.83 (95 % CI 0.79–0.87), for detecting unhealthy drug use, and sensitivity of 85.1 (95 % CI 75.0–92.3) and specificity of 88.6 % (95 % CI 85.0–91.6), AUC = 0.87 (95 % CI 0.83–0.91), for drug use disorder.
Conclusions
The self-administered SISQs are a valid approach to detecting unhealthy alcohol and other drug use in primary care patients. Although self-administered SISQs may be less accurate than the previously validated interviewer-administered versions, they are potentially easier to implement and more likely to retain their fidelity in real-world practice settings.
doi:10.1007/s11606-015-3391-6
PMCID: PMC4636560  PMID: 25986138
Screening; Substance use; Validation; Alcohol; Illicit drugs
11.  Synaptic plasticity and signal transduction gene polymorphisms and vulnerability to drug addictions in populations of European or African ancestry 
CNS neuroscience & therapeutics  2015;21(11):898-904.
Summary
Aim
Drug addiction is characterized, in part, by deregulation of synaptic plasticity in circuits involved in reward, stress, cue learning and memory. This study was designed to assess if 185 variants in 32 genes central to synaptic plasticity and signal transduction contribute to vulnerability to develop heroin and/or cocaine addiction.
Methods
Analyses were conducted in a sample of 1860 subjects divided according to ancestry (African and European) and drug of abuse (heroin or cocaine).
Results
Eighteen SNPs in 11 genes (CDK5R1, EPHA4, EPHA6, FOSL2, MAPK3, MBP, MPDZ, NFKB1, NTRK2, NTSR1, and PRKCE) showed significant associations (P < 0.01) but the signals did not survive correction for multiple testing. SNP rs230530 in the NFKB1 gene, encoding the transcription regulator NF-kappa-B, was the only SNP indicated in both ancestry groups and both addictions. This SNP was previously identified in association with alcohol addiction. SNP rs3915568 in NTSR1, which encodes neurotensin receptor, and SNP rs1389752 in MPDZ, which encodes the multiple PDZ domain protein, were previously associated with heroin addiction or alcohol addiction, respectively.
Conclusions
The study supports the involvement of genetic variation in signal transduction pathways in heroin and cocaine addiction and provides preliminary evidence suggesting several new risk or protective loci that may be relevant for diagnosis and treatment success.
doi:10.1111/cns.12450
PMCID: PMC4619135  PMID: 26384852
African Americans; cocaine addiction; heroin addiction; signal transduction; synaptic plasticity
12.  A brief patient self-administered substance use screening tool for primary care: two-site validation study of the Substance Use Brief Screen (SUBS) 
The American journal of medicine  2015;128(7):784.e9-784.e19.
Background
Substance use screening is widely encouraged in healthcare settings, but the lack of a screening approach that fits easily into clinical workflows has restricted its broad implementation. The Substance Use Brief Screen (SUBS) was developed as a brief, self-administered instrument to identify unhealthy use of tobacco, alcohol, illicit drugs, and prescription drugs. We evaluated the validity and test-retest reliability of the SUBS in adult primary care patients.
Methods
Adults age 18-65 were enrolled from urban safety net primary care clinics to self-administer the SUBS using touch-screen tablet computers for a test-retest reliability study (n=54) and a two-site validation study (n=586). In the test-retest reliability study, the SUBS was administered twice within a 2-week period. In the validation study, the SUBS was compared to reference standard measures, including self-reported measures and saliva drug tests. We measured test-retest reliability and diagnostic accuracy of the SUBS for detection of unhealthy use and substance use disorder for tobacco, alcohol, and drugs (illicit and prescription drug misuse).
Results
Test-retest reliability was good or excellent for each substance class. For detection of unhealthy use, the SUBS had sensitivity and specificity of 97.8% (95% CI 93.7 to 99.5) and 95.7% (95% CI 92.4 to 97.8), respectively, for tobacco; and 85.2% (95% CI 79.3 to 89.9) and 77.0% (95% CI 72.6 to 81.1) for alcohol. For unhealthy use of illicit or prescription drugs, sensitivity was 82.5% (95% CI 75.7 to 88.0) and specificity 91.1% (95% CI 87.9 to 93.6). With respect to identifying a substance use disorder, the SUBS had sensitivity and specificity of 100.0% (95% CI 92.7 to 100.0) and 72.1% (95% CI 67.1 to 76.8) for tobacco; 93.5% (95% CI 85.5 to 97.9) and 64.6% (95% CI 60.2 to 68.7) for alcohol; and 85.7% (95% CI 77.2 to 92.0) and 82.0% (95% CI 78.2 to 85.3) for drugs. Analyses of area under the receiver operating curve (AUC) indicated good discrimination (AUC 0.74-0.97) for all substance classes. Assistance in completing the SUBS was requested by 11% of participants.
Conclusions
The SUBS was feasible for self-administration and generated valid results in a diverse primary care patient population. The 4-item SUBS can be recommended for primary care settings that are seeking to implement substance use screening.
doi:10.1016/j.amjmed.2015.02.007
PMCID: PMC4475501  PMID: 25770031
screening; substance use; validation; alcohol; illicit drugs; tobacco
13.  Susceptibility loci for heroin and cocaine addiction in the serotonergic and adrenergic pathways in populations of different ancestry 
Pharmacogenomics  2015;16(12):1329-1342.
Background
Drug addiction is influenced by genetic factors.
Aim
To determine if genetic variants in the serotonergic and adrenergic pathways are associated with heroin and/or cocaine addiction.
Subjects & methods
The study examined 140 polymorphisms in 19 genes in 1855 subjects with predominantly European or African ancestries.
Results
A total of 38 polymorphisms (13 genes) showed nominal associations, including novel associations in S100A10 (p11) and SLC18A2 (VMAT2). The association of HTR3B SNP rs11606194 with heroin addiction in the European ancestry subgroup remained significant after correction for multiple testing (pcorrected = 0.04).
Conclusion
The study strengthens our previous findings of association of polymorphisms in HTR3A, HTR3B and ADRA1A. The study suggests partial overlap in genetic susceptibility between populations of different ancestry and between heroin and cocaine addiction.
doi:10.2217/pgs.15.86
PMCID: PMC4896084  PMID: 26227246
ADRA1A; adrenergic pathway; African–American; association study; cocaine addiction; genetic variants; heroin addiction; HTR3A; HTR3B; S100A10; serotonergic pathway; SLC18A2; SLC6A4; stress
14.  Overlapping Dopaminergic Pathway Genetic Susceptibility for Heroin and Cocaine Addictions in African Americans 
Annals of human genetics  2015;79(3):188-198.
Summary
Drugs of abuse activate the mesolimbic dopaminergic pathway. Genetic variations in the dopaminergic system may contribute to vulnerability to drug addiction. Several processes are shared between cocaine and heroin addictions but some neurobiological mechanisms and environmental influence may be specific. This study examined the association of 98 single nucleotide polymorphisms (SNPs) in 13 dopamine pathway-related genes with heroin and/or cocaine addiction in a sample of 801 African Americans (315 subjects with heroin addiction (OD), with or without cocaine (CD) or alcohol addiction (AD), 279 subjects with CD, with or without AD, 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 with OD and/or CD. A DRD2 7-SNPs haplotype block that includes SNPs rs1075650 and rs2283265, which were shown to alter D2S/D2L splicing, was indicated in both addictions. The Met allele of the COMT Val158Met functional variant 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 several previous studies, including our report of association of DRD1 SNP rs5326 with OD in a smaller sample from this cohort. The findings suggest the presence of an overlap in the genetic liability for heroin and cocaine addictions, as well as shared and distinct liability for OD in subjects of African and European descent.
doi:10.1111/ahg.12104
PMCID: PMC4399004  PMID: 25875614
dopaminergic pathway; polymorphism; heroin addiction; cocaine addiction; African Americans; DRD1, DRD2, COMT Val158Met, rs5326, rs1075650, rs2283265
15.  Predicting Outcome of Substance Abuse Treatment in a Feedback Study: Can Recovery Curves be Improved Upon? 
Objective
The goal of the study was to evaluate whether enhanced normative feedback recovery curves are needed for treatment of substance use problems.
Method
Patient predictors of outcome were examined using data from 4 substance abuse treatment clinics.
Results
Baseline severity of symptoms/functioning, employment, and craving were found to be associated with rate of change in symptoms/functioning. Several other variables were associated with rate of change in alcohol use, although in the opposite direction than found in efficacy trials.
Conclusions
The results point to the complexity of designing feedback systems using normative recovery curves for those with substance use problems, and highlight the important differences between real-world treatment of those with substance use problems compared to data from efficacy trials.
doi:10.1080/10503307.2014.994146
PMCID: PMC4551657  PMID: 25588189
substance abuse; alcohol; feedback; Outcome Questionnaire-45; recovery curve
16.  Dopaminergic pathway polymorphisms and heroin addiction: further support for association of CSNK1E variants 
Pharmacogenomics  2014;15(16):2001-2009.
Background & aim
The dopaminergic pathways have been implicated in the etiology of drug addictions. The aim of this study was to determine if variants in dopaminergic genes are associated with heroin addiction.
Materials & methods
The study includes 828 former heroin addicts and 232 healthy controls, of predominantly European ancestry. Ninety seven SNPs (13 genes) were analyzed.
Results
Nine nominally significant associations were observed at CSNK1E, ANKK1, DRD2 and DRD3.
Conclusion
The results support our previous report of association of CSNK1E SNP rs1534891 with protection from heroin addiction. CSNK1E interacts with circadian rhythms and DARPP-32 and has been implicated in negative regulation of sensitivity to opioids in rodents. It may be a target for drug addiction treatment.
doi:10.2217/pgs.14.145
PMCID: PMC4288976  PMID: 25521358
casein kinase 1ε; circadian rhythms; dopaminergic reward pathways; heroin addiction; SNP rs1534891
17.  Effects of Regulation on Methadone and Buprenorphine Provision in the Wake of Hurricane Sandy 
Hurricane Sandy led to the closing of many major New York City public hospitals including their substance abuse clinics and methadone programs, and the displacement or relocation of thousands of opioid-dependent patients from treatment. The disaster provided a natural experiment that revealed the relative strengths and weaknesses of methadone treatment in comparison to physician office-based buprenorphine treatment for opioid dependence, two modalities of opioid maintenance with markedly different regulatory requirements and institutional procedures. To assess these two modalities of treatment under emergency conditions, semi-structured interviews about barriers to and facilitators of continuity of care for methadone and buprenorphine patients were conducted with 50 providers of opioid maintenance treatment. Major findings included that methadone programs presented more regulatory barriers for providers, difficulty with dose verification due to impaired communication, and an over reliance on emergency room dosing leading to unsafe or suboptimal dosing. Buprenorphine treatment presented fewer regulatory barriers, but buprenorphine providers had little to no cross-coverage options compared to methadone providers, who could refer to alternate methadone programs. The findings point to the need for well-defined emergency procedures with flexibility around regulations, the need for a central registry with patient dose information, as well as stronger professional networks and cross-coverage procedures. These interventions would improve day-to-day services for opioid-maintained patients as well as services under emergency conditions.
doi:10.1007/s11524-014-9904-5
PMCID: PMC4199439  PMID: 25163931
Hurricane Sandy; Opioid maintenance treatment; Emergency planning; Continuity of care
18.  Test-retest reliability of a self-administered Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in primary care patients 
The time required to conduct drug and alcohol screening has been a major barrier to its implementation in mainstream healthcare settings. Because patient self-administered tools are potentially more efficient, we translated the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) into an audio guided computer assisted self interview (ACASI) format. This study reports on the test-retest reliability of the ACASI ASSIST in an adult primary care population. Adult primary care patients completed the ACASI ASSIST, in English or Spanish, twice within a 1–4 week period. Among the 101 participants, there were no significant differences between test administrations in detecting moderate to high risk use for tobacco, alcohol, or any other drug class. Substance risk scores from the two administrations had excellent concordance (90–98%) and high correlation (ICC 0.90–0.97) for tobacco, alcohol, and drugs. The ACASI ASSIST has good test-retest reliability, and warrants additional study to evaluate its validity for detecting unhealthy substance use.
doi:10.1016/j.jsat.2014.01.007
PMCID: PMC4035183  PMID: 24629887
Screening; Substance use; Addiction; Alcohol use; Primary care
19.  Vaccine for Cocaine Dependence: A Randomized Double-Blind Placebo-Controlled Efficacy Trial 
Drug and alcohol dependence  2014;140:42-47.
Aims
We evaluated the immunogenicity, efficacy, and safety of succinylnorcocaine conjugated to cholera toxin B protein as a vaccine for cocaine dependence.
Methods
This 6-site, 24 week Phase III randomized double-blind placebo-controlled trial assessed efficacy during weeks 8 to 16. We measured urine cocaine metabolites thrice weekly as the main outcome.
Results
The 300 subjects (76% male, 72% African-American, mean age 46 years) had smoked cocaine on average for 13 days monthly at baseline. We hypothesized that retention might be better and positive urines lower for subjects with anti-cocaine IgG levels of ≥ 42 μg/mL (high IgG), which was attained by 67% of the 130 vaccine subjects receiving five vaccinations. Almost 3-times fewer high than low IgG subjects dropped out (7% vs 20%). Although for the full 16 weeks cocaine positive urine rates showed no significant difference between the three groups (placebo, high, low IgG), after week 8, more vaccinated than placebo subjects attained abstinence for at least two weeks of the trial (24% vs 18%), and the high IgG group had the most cocaine-free urines for the last 2 weeks of treatment (OR=3.02), but neither were significant. Injection site reactions of induration and tenderness differed between placebo and active vaccine, and the 29 serious adverse events did not lead to treatment related withdrawals, or deaths.
Conclusions
The vaccine was safe, but it only partially replicated the efficacy found in the previous study based on retention and attaining abstinence.
doi:10.1016/j.drugalcdep.2014.04.003
PMCID: PMC4073297  PMID: 24793366
cocaine; vaccine; clinical trial; immunotherapy
20.  Drug Addiction and Stress-Response Genetic Variability: Association Study in African Americans 
Annals of human genetics  2014;78(4):290-298.
Summary
Stress is a significant risk factor in the development of drug addictions and in addiction relapse susceptibility. This hypothesis-driven study was designed to determine if specific SNPs in genes related to stress response are associated with heroin and/or cocaine addiction in African Americans. The analysis included 27 genes (124 SNPs) and was performed independently for each addiction. The sample consisted of former heroin addicts in methadone maintenance treatment (n = 314), cocaine addicts (n = 281), and controls (n = 208). Fourteen SNPs showed nominally significant association with heroin addiction (p < 0.05), including the African-specific, missense SNP rs5376 (Asn334Ser) in the galanin receptor type 1 gene (GALR1) and the functional FKBP5 intronic SNP rs1360780. Thirteen SNPs showed association with cocaine addiction, including the synonymous SNPs rs237902, in the oxytocin receptor gene (OXTR), and rs5374 in GALR1. No signal remained significant after correction for multiple testing. Four additional SNPs (GALR1 rs2717162, AVP rs2282018, CRHBP rs1875999, and NR3C2 rs1040288) were associated with both addictions and may indicate common liability. The study provides preliminary evidence for novel association of variants in several stress related genes with heroin and/or cocaine addictions and may enhance the understanding of the interaction between stress and addictions.
doi:10.1111/ahg.12064
PMCID: PMC4065216  PMID: 24766650
heroin addiction; cocaine addiction; African Americans; stress; HPA axis; GALR1; FKBP5; NR3C2; OXTR; AVP
21.  Psychiatric Comorbidity, Red Flag Behaviors, and Associated Outcomes among Office-Based Buprenorphine Patients Following Hurricane Sandy 
In October 2012, Bellevue Hospital Center (Bellevue) in New York City was temporarily closed as a result of Hurricane Sandy, the largest hurricane in US history. Bellevue’s primary care office-based buprenorphine program was temporarily closed and later relocated to an affiliate public hospital. Previous research indicates that the relationships between disaster exposure, substance use patterns, psychiatric symptoms, and mental health services utilization is complex, with often conflicting findings regarding post-event outcomes (on the individual and community level) and antecedent risk factors. In general, increased use of tobacco, alcohol, and illicit drugs is associated with both greater disaster exposure and the development or exacerbation of other psychiatric symptoms and need for treatment. To date, there is limited published information regarding post-disaster outcomes among patients enrolled in office-based buprenorphine treatment, as the treatment modality has only been relatively approved recently. Patients enrolled in the buprenorphine program at the time of the storm were surveyed for self-reported buprenorphine adherence and illicit substance and alcohol use, as well as disaster-related personal consequences and psychiatric sequelae post-storm. Baseline demographic characteristics and insurance status were available from the medical record. Analysis was descriptive (counts and proportions) and qualitative, coding open-ended responses for emergent themes. There were 132 patients enrolled in the program at the time of the storm; of those, 91 were contacted and 89 completed the survey. Almost half of respondents reported disruption of their buprenorphine supply. Unexpectedly, patients with psychiatric comorbidity were no more likely to report increased use/relapse as a result. Rather, major risk factors associated with increased use or relapse post-storm were: (1) shorter length of time in treatment, (2) exposure to storm losses such as buprenorphine supply disruption, (3) a pre-storm history of red flag behaviors (in particular, repeat opioid-positive urines), and (4) new-onset post-storm psychiatric symptoms. Our findings highlight the relative resilience of buprenorphine as an office-based treatment modality for patients encountering a disaster with associated unanticipated service disruption. In responding to future disasters, triaging patient contact and priority based on a history of red-flag behaviors, rather than a history of psychiatric comorbidity, will likely optimize resource allocation, especially among recently enrolled patients. Additionally, patients endorsing new-onset psychiatric manifestations following disasters may be an especially high-risk group for poor outcomes, warranting further study.
doi:10.1007/s11524-014-9866-7
PMCID: PMC3978155  PMID: 24619775
Buprenorphine; Opioid dependence; Psychiatric comorbidity; Risk factors; Disasters; Substance use disorders; Cross-sectional studies
25.  SUBSTANCE USE SCREENING AND INTERVENTIONS IN DENTAL CLINICS: SURVEY OF PRACTICE-BASED RESEARCH NETWORK DENTISTS ON CURRENT PRACTICES, POLICIES, AND BARRIERS 
Background
Dental visits represent an opportunity to identify and assist patients with substance use, but little is known about how dentists are addressing tobacco, alcohol and illicit drugs. We surveyed dentists to learn about the role their practices might play in providing substance use screening and interventions.
Methods
A 41-item, web-based survey was distributed to all 210 dentists active in the PEARL dental practice-based research network. The questionnaire assessed clinic policies and current practices, attitudes, and perceived barriers to providing services for tobacco, alcohol, and illicit drug use.
Results
143 dentists completed the survey (68% response rate). While screening was common, fewer were providing follow-up counseling or referrals for substance use. Insufficient knowledge/training was the most frequently cited barrier to intervention. Many dentists said they would offer assistance for tobacco (67%) or alcohol or illicit drugs (52%) if reimbursed; an affirmative response was more likely among those who saw publicly insured patients.
Conclusions
Dentists recognize the importance of screening for substance use, but lack clinical training and systems that could facilitate intervention.
Practice Implications
If barriers were reduced through changes in reimbursement, education, and systems-level support, our findings indicate that dentists may be willing to address substance use, including use of alcohol and illicit drugs as well as tobacco.
PMCID: PMC3699308  PMID: 23729460
Substance use; tobacco cessation; dental tobacco interventions; dental practice; dental clinics; PEARL Network

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