Abstracts: Substance-Related and Addictive Disorders

Volkow ND, Baler RD.

Neuropharmacology 2014; 76(Pt B):235–249

Until very recently addiction-research was limited by existing tools and strategies that were inadequate for studying the inherent complexity at each of the different phenomenological levels. However, powerful new tools (e.g. optogenetics and designer drug receptors) and high throughput protocols are starting to give researchers the potential to systematically interrogate “all” genes, epigenetic marks, and neuronal circuits. These advances, combined with imaging technologies (both for preclinical and clinical studies) and a paradigm shift toward open access, have spurred an unlimited growth of datasets transforming the way we investigate the neurobiology of substance use disorders (SUD) and the factors that modulate risk and resilience. This article is part of a Special Issue entitled “NIDA 40th Anniversary Issue.”

Reprinted with permission from Elsevier.

Wise RA, Koob GF.

Neuropsychopharmacology 2014; 39:254–262

What is the defining property of addiction? We dust off a several-decades-long debate about the relative importance of two forms of reinforcement—positive reinforcement, subjectively linked to drug-induced euphoria, and negative reinforcement, subjectively linked to the alleviation of pain—both of which figure importantly in addiction theory; each of these forms has dominated addiction theory in its time. We agree that addiction begins with the formation of habits through positive reinforcement and that drug-opposite physiological responses often establish the conditions for negative reinforcement to come into play at a time when tolerance, in the form of increasing reward thresholds, appears to develop into positive reinforcement. Wise’s work has tended to focus on positive-reinforcement mechanisms that are important for establishing drug-seeking habits and reinstating them quickly after periods of abstinence, whereas Koob’s work has tended to focus on the negative-reinforcement mechanisms that become most obvious in the late stages of sustained addiction. While we tend to agree with each other about the early and late stages of addiction, we hold different views as to (i) the point between early and late at which the diagnosis of “addiction” should be invoked, (ii) the relative importance of positive and negative reinforcement leading up to this transition, and (iii) the degree to which the specifics of negative reinforcement can be generalized across the range of addictive agents.

Reprinted with permission of Nature Publishing Group/Macmillan.

Chiesa A, Serretti A.

Subst Use Misuse 2014; 49:492–512

Mindfulness-based interventions (MBIs) are increasingly suggested as therapeutic approaches for effecting substance use and misuse (SUM). The aim of this article is to review current evidence on the therapeutic efficacy of MBIs for SUM. A literature search was undertaken using four electronic databases and references of retrieved articles. The search included articles written in English published up to December 2011. Quality of included trials was assessed. In total, 24 studies were included, three of which were based on secondary analyses of previously investigated samples. Current evidence suggests that MBIs can reduce the consumption of several substances including alcohol, cocaine, amphetamines, marijuana, cigarettes, and opiates to a significantly greater extent than waitlist controls, nonspecific educational support groups, and some specific control groups. Some preliminary evidence also suggests that MBIs are associated with a reduction in craving as well as increased mindfulness. The limited generalizability of the reviewed findings is noted (i.e. small sample size, lack of methodological details, and the lack of consistently replicated findings). More rigorous and larger randomized controlled studies are warranted.

Reprinted with permission from Informa Healthcare.

Psychiatr Serv 2014; 65:146–157

Objective: Detoxification followed by abstinence has shown little success in reducing illicit opioid use. Methadone maintenance treatment (MMT) helps individuals with an opioid use disorder abstain from or decrease use of illegal or nonmedical opiates. This review examined evidence for MMT’s effectiveness. Methods: Authors reviewed meta-analyses, systematic reviews, and individual studies of MMT from 1995 through 2012. Databases searched were PubMed, PsycINFO, Applied Social Sciences Index and Abstracts, Sociological Abstracts, Social Services Abstracts, and Published International Literature on Traumatic Stress. The authors rated the level of evidence (high, moderate, and low) based on benchmarks for the number of studies and quality of their methodology. They also described the evidence of service effectiveness and examined maternal and fetal results of MMT for pregnant women. Results: The review included seven randomized controlled trials and two quasi-experimental studies of MMT, indicating a high level of evidence for the positive impact of MMT on treatment retention and illicit opioid use, particularly at doses greater than 60 mg. Evidence suggests positive impacts on drug-related HIV risk behaviors, mortality, and criminality. Meta-analyses were difficult to perform or yielded nonsignificant results. Studies found little association between MMT and sex-related HIV risk behaviors. MMT in pregnancy was associated with improved maternal and fetal outcomes, and rates of neonatal abstinence syndrome were similar for mothers receiving different doses. Reports of adverse events were also found. Conclusions: MMT is associated with improved outcomes for individuals and pregnant women with opioid use disorders. MMT should be a covered service available to all individuals.

Biol Psychiatry 2014; 76:603–615

Background: Attention-deficit/hyperactivity disorder (ADHD) is associated with a broad range of neuropsychological impairments. The relationship between these neuropsychological deficits and the defining symptoms of ADHD seems more complex than originally thought. Methylphenidate (MPH) is an effective treatment for ADHD symptoms, but its impact on cognition is less clearly understood. Methods: With a common systematic search strategy and a rigorous coding and data extraction strategy across domains, we searched electronic databases to identify published placebo controlled trials that compared MPH and placebo on executive and nonexecutive memory, reaction time, reaction time variability and response inhibition in children and adolescents (5–18 years) with a formal diagnosis of ADHD. Results: Sixty studies were included in the review, of which 36 contained sufficient data for meta-analysis. Methylphenidate was superior to placebo in all five meta-analyses: executive memory, standardized mean difference (SMD) 0.26, 95% confidence interval (CI): −0.39 to −0.13; nonexecutive memory, SMD 0.60, 95% CI: −0.79 to −0.41; reaction time, SMD 0.24, 95% CI: −0.33 to −0.15; reaction time variability, SMD 0.62, 95% CI: −0.90 to −0.34; response inhibition, SMD 0.41, 95% CI: −0.55 to −0.27. Conclusions: These data support the potentially important effects of MPH on various aspects of cognition known to be associated with ADHD. Consideration should be given to adding cognitive outcomes to the assessment of treatment outcome in ADHD, considering the complexity of the relationship between ADHD symptoms and cognition.

Reprinted with permission from Elsevier.

Mol Psychiatry 2014; 19:41–49

We report a GWAS of alcohol dependence (AD) in European-American (EA) and African-American (AA) populations, with replication in independent samples of EAs, AAs and Germans. Our sample for discovery and replication was 16 087 subjects, the largest sample for AD GWAS to date. Numerous genome-wide significant (GWS) associations were identified, many novel. Most associations were population specific, but in several cases were GWS in EAs and AAs for different SNPs at the same locus, showing biological convergence across populations. We confirmed well-known risk loci mapped to alcohol-metabolizing enzyme genes, notably ADH1B (EAs: Arg48His, p=1.17×10(−31); AAs: Arg369Cys, p=6.33×10(−17)) and ADH1C in AAs (Thr151Thr, p=4.94×10(−10)), and identified novel risk loci mapping to the ADH gene cluster on chromosome 4 and extending centromerically beyond it to include GWS associations at LOC100507053 in AAs (p=2.63×10(−11)), PDLIM5 in EAs (p=2.01×10(−8)), and METAP in AAs (p=3.35×10(−8)). We also identified a novel GWS association (1.17×10(−10)) mapped to chromosome 2 at rs1437396, between MTIF2 and CCDC88A, across all of the EA and AA cohorts, with supportive gene expression evidence, and population-specific GWS for markers on chromosomes 5, 9 and 19. Several of the novel associations implicate direct involvement of, or interaction with, genes previously identified as schizophrenia risk loci. Confirmation of known AD risk loci supports the overall validity of the study; the novel loci are worthy of genetic and biological follow-up. The findings support a convergence of risk genes (but not necessarily risk alleles) between populations, and, to a lesser extent, between psychiatric traits.

Reprinted with permission from Macmillan.

Comparative Effectiveness Review No. 134. AHRQ Publication No. 14-EHC029-EF. Rockville, MD, Agency for Healthcare Research and Quality, 2014 (Available at effectivehealthcare.ahrq.gov/ehc/products/477/1908/alcohol-misuse-drug-therapy-report-140513.pdf)

Objectives: To conduct a systematic review and meta-analysis of the efficacy, comparative effectiveness, and harms of medications (both FDA approved and others) for adults with alcohol-use disorders, and to evaluate the evidence from primary care settings. Data Sources: PubMed®, Cochrane Library, PsycINFO®, CINAHL®, Embase®, U.S. Food and Drug Administration Web site, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (January 1, 1970, to October 11, 2013). Review Methods: Two investigators independently selected, extracted data from, and rated risk of bias of studies. We conducted meta-analyses using random-effects models. We graded strength of evidence (SOE) based on established guidance. Results: We included 135 studies. Most patients met criteria for alcohol dependence; mean ages were in the 40s. Studies typically included psychosocial cointerventions; effect sizes reflect the added benefits of medications. For acamprosate and oral naltrexone (50 mg per day), numbers needed to treat (NNTs) to prevent 1 person from returning to any drinking were 12 and 20, respectively (moderate SOE); NNT to prevent 1 person from returning to heavy drinking was 12 for oral naltrexone (50 mg per day) (moderate SOE). Our meta-analyses of four head-to-head trials found no statistically significant difference between the two medications for consumption outcomes (moderate SOE). For injectable naltrexone, meta-analyses found no significant benefit for return to any or heavy drinking, but found a reduction in heavy drinking days (low SOE). Evidence from well-controlled trials does not support efficacy of disulfiram, except possibly for patients with excellent adherence. Among medications used off label, moderate evidence supports the efficacy of nalmefene and topiramate for improving some consumption outcomes, and limited evidence supports the efficacy of valproic acid. Evidence from primary care settings was scant. We found insufficient direct evidence to conclude whether medications for alcohol-use disorders are effective for improving health outcomes. Compared with placebo, patients treated with acamprosate had a higher risk of anxiety, diarrhea, and vomiting; those treated with naltrexone had a higher risk of dizziness, nausea, and vomiting. In head-to-head studies, the risks of headache and vomiting were slightly higher for naltrexone than for acamprosate. Individual trials of topiramate reported a significantly increased risk of paresthesias, anorexia, difficulty concentrating, dizziness, psychomotor slowing, and other adverse effects. Our meta-analyses for variation in naltrexone response related to OPRM1 polymorphisms found no statistically significant difference between A-allele homozygotes and those with at least one G allele, but confidence intervals were wide and additional studies are needed. Conclusions: Acamprosate and oral naltrexone have the best evidence for improving alcohol consumption outcomes for patients with alcohol-use disorders. Head-to-head trials have not consistently established the superiority of one medication. Thus, other factors may guide medication choices, such as frequency of administration, potential adverse events, coexisting symptoms, and availability of treatments.

Addiction 2013; 108:275–293

Aims: Although debates over the efficacy of oral naltrexone and acamprosate in treating alcohol use disorders tend to focus on their global efficacy relative to placebo or their efficacy relative to each other, the underlying reality may be more nuanced. This meta-analysis examined when naltrexone and acamprosate are most helpful by testing: (i) the relative efficacy of each medication given its presumed mechanism of action (reducing heavy drinking versus fostering abstinence) and (ii) whether different ways of implementing each medication (required abstinence before treatment, detoxification before treatment, goal of treatment, length of treatment, dosage) moderate its effects. Methods: A systematic literature search identified 64 randomized, placebo-controlled, English-language clinical trials completed between 1970 and 2009 focused on acamprosate or naltrexone. Results: Acamprosate had a significantly larger effect size than naltrexone on the maintenance of abstinence, and naltrexone had a larger effect size than acamprosate on the reduction of heavy drinking and craving. For naltrexone, requiring abstinence before the trial was associated with larger effect sizes for abstinence maintenance and reduced heavy drinking compared with placebo. For acamprosate, detoxification before medication administration was associated with better abstinence outcomes compared with placebo. Conclusions: In treatment for alcohol use disorders, acamprosate has been found to be slightly more efficacious in promoting abstinence and naltrexone slightly more efficacious in reducing heavy drinking and craving. Detoxification before treatment or a longer period of required abstinence before treatment is associated with larger medication effects for acamprosate and naltrexone respectively.

Koob GF, Volkow ND.

Neuropsychopharmacology 2010; 35:217–238

Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: “binge/intoxication,” “withdrawal/negative affect,” and “preoccupation/anticipation” (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex-dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.

Reprinted with permission of Nature Publishing Group/Macmillan.

Nicotine Tob Res 2008; 10:1691–1715

The National Institute of Mental Health (NIMH) convened a meeting in September 2005 to review tobacco use and dependence and smoking cessation among those with mental disorders, especially individuals with anxiety disorders, depression, or schizophrenia. Smoking rates are exceptionally high among these individuals and contribute to the high rates of medical morbidity and mortality in these individuals. Numerous biological, psychological, and social factors may explain these high smoking rates, including the lack of smoking cessation treatment in mental health settings. Historically, “self-medication” and “individual rights” have been concerns used to rationalize allowing ongoing tobacco use and limited smoking cessation efforts in many mental health treatment settings. Although research has shown that tobacco use can reduce or ameliorate certain psychiatric symptoms, overreliance on the self-medication hypothesis to explain the high rates of tobacco use in psychiatric populations may result in inadequate attention to other potential explanations for this addictive behavior among those with mental disorders. A more complete understanding of nicotine and tobacco use in psychiatric patients also can lead to new psychiatric treatments and a better understanding of mental illness. Greater collaboration between mental health researchers and nicotine and tobacco researchers is needed to better understand and develop new treatments for co-occurring nicotine dependence and mental illness. Despite an accumulating literature for some specific psychiatric disorders and tobacco use and cessation, many unstudied research questions remain and are a focus and an emphasis of this review.

Reprinted with permission of Oxford University Press.