One Is Not Enough: Understanding and Modeling Polysubstance Use

Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.

The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems--so-called direct and indirect pathways--form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D(1) and D(2) DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.

Summary Background Alcohol and drug use can have negative consequences on the health, economy, productivity, and social aspects of communities. We aimed to use data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2016 to calculate global and regional estimates of the prevalence of alcohol, amphetamine, cannabis, cocaine, and opioid dependence, and to estimate global disease burden attributable to alcohol and drug use between 1990 and 2016, and for 195 countries and territories within 21 regions, and within seven super-regions. We also aimed to examine the association between disease burden and Socio-demographic Index (SDI) quintiles. Methods We searched PubMed, EMBASE, and PsycINFO databases for original epidemiological studies on alcohol and drug use published between Jan 1, 1980, and Sept 7, 2016, with out language restrictions, and used DisMod-MR 2.1, a Bayesian meta-regression tool, to estimate population-level prevalence of substance use disorders. We combined these estimates with disability weights to calculate years of life lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 1990–2016. We also used a comparative assessment approach to estimate burden attributable to alcohol and drug use as risk factors for other health outcomes. Findings Globally, alcohol use disorders were the most prevalent of all substance use disorders, with 100·4 million estimated cases in 2016 (age-standardised prevalence 1320·8 cases per 100 000 people, 95% uncertainty interval [95% UI] 1181·2–1468·0). The most common drug use disorders were cannabis dependence (22·1 million cases; age-standardised prevalence 289·7 cases per 100 000 people, 95% UI 248·9–339·1) and opioid dependence (26·8 million cases; age-standardised prevalence 353·0 cases per 100 000 people, 309·9–405·9). Globally, in 2016, 99·2 million DALYs (95% UI 88·3–111·2) and 4·2% of all DALYs (3·7–4·6) were attributable to alcohol use, and 31·8 million DALYs (27·4–36·6) and 1·3% of all DALYs (1·2–1·5) were attributable to drug use as a risk factor. The burden of disease attributable to alcohol and drug use varied substantially across geographical locations, and much of this burden was due to the effect of substance use on other health outcomes. Contrasting patterns were observed for the association between total alcohol and drug-attributable burden and SDI: alcohol-attributable burden was highest in countries with a low SDI and middle-high middle SDI, whereas the burden due to drugs increased with higher S DI level. Interpretation Alcohol and drug use are important contributors to global disease burden. Effective interventions should be scaled up to prevent and reduce substance use disease burden. Funding Bill & Melinda Gates Foundation and Australian National Health and Medical Research Council.