Cocaine use and overdose mortality in the United States: Evidence from two national data sources, 2002–2018

Cano, Manuel; Oh, Sehun; Salas-Wright, Christopher P.; Vaughn, Michael G.

doi:10.1016/j.drugalcdep.2020.108148

Cited by 68 publications

(48 citation statements)

References 28 publications

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“…Until the COVID‐19 pandemic emerged, the opioid epidemic crisis had begun to plateau. Meanwhile, PUDs have quietly made a resurgence, with increased use and deaths 1,2 . Yet, despite an estimated 40%–50% heritability for PUDs, 3–5 genome‐wide association studies have identified few loci 6 .…”

Section: Introductionmentioning

confidence: 99%

A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity

Goldberg

Yao²,

Kelliher³

et al. 2021

Genes Brain and Behavior

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Psychostimulant (methamphetamine, cocaine) use disorders have a genetic component that remains mostly unknown. We conducted genome‐wide quantitative trait locus (QTL) analysis of methamphetamine stimulant sensitivity. To facilitate gene identification, we employed a Reduced Complexity Cross between closely related C57BL/6 mouse substrains and examined maximum speed and distance traveled over 30 min following methamphetamine (2 mg/kg, i.p.). For maximum methamphetamine‐induced speed following the second and third administration, we identified a single genome‐wide significant QTL on chromosome 11 that peaked near the Cyfip2 locus (LOD = 3.5, 4.2; peak = 21 cM [36 Mb]). For methamphetamine‐induced distance traveled following the first and second administration, we identified a genome‐wide significant QTL on chromosome 5 that peaked near a functional intronic indel in Gabra2 coding for the alpha‐2 subunit of the GABA‐A receptor (LOD = 3.6–5.2; peak = 34–35 cM [66–67 Mb]). Striatal cis‐expression QTL mapping corroborated Gabra2 as a functional candidate gene underlying methamphetamine‐induced distance traveled. CRISPR/Cas9‐mediated correction of the mutant intronic deletion on the C57BL/6J background to the wild‐type C57BL/6NJ allele was sufficient to reduce methamphetamine‐induced locomotor activity toward the wild‐type C57BL/6NJ‐like level, thus validating the quantitative trait variant (QTV). These studies show the power and efficiency of Reduced Complexity Crosses in identifying causal variants underlying complex traits. Functionally restoring Gabra2 expression decreased methamphetamine stimulant sensitivity and supports preclinical and human genetic studies implicating the GABA‐A receptor in psychostimulant addiction‐relevant traits. Importantly, our findings have major implications for studying psychostimulants in the C57BL/6J strain—the gold standard strain in biomedical research.

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Section: Introductionmentioning

confidence: 99%

A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity

Goldberg

Yao²,

Kelliher³

et al. 2021

Genes Brain and Behavior

View full text Add to dashboard Cite

show abstract

“…Until the COVID-19 pandemic emerged, the opioid epidemic crisis had begun to plateau. Meanwhile, PUDs have quietly made a resurgence, with increased use and deaths (Cano et al 2020;Maxwell 2020). Yet, despite an estimated 40-50% heritability for PUDs (Goldman et al 2005;Ho et al 2010;Ducci & Goldman 2012), genome-wide association studies have identified few loci (Jensen 2016).…”

Section: Introductionmentioning

confidence: 99%

A quantitative trait variant inGabra2underlies increased methamphetamine stimulant sensitivity

Goldberg

Yao

Kelliher

et al. 2021

Preprint

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Psychostimulant (methamphetamine, cocaine) use disorders have a genetic component that remains mostly unknown. Here, we conducted genome-wide quantitative trait locus (QTL) analysis of methamphetamine stimulant sensitivity. To facilitate gene identification, we employed a Reduced Complexity Cross between closely related C57BL/6 mouse substrains and examined maximum speed and distance traveled over 30 min following methamphetamine (2 mg/kg, i.p.). For maximum methamphetamine-induced speed following the second and third administration, we identified a single genome-wide significant QTL on chromosome 11 that peaked near the Cyfip2 locus [LOD = 3.5, 4.2; peak = 21 cM (36 Mb)]. For methamphetamine-induced distance traveled, we identified a single genome-wide significant QTL on chromosome 5 that peaked near a functional intronic indel in Gabra2 that codes for the alpha-2 subunit of the GABA-A receptor [LOD = 5.2; peak = 35 cM (67 Mb)]. Striatal cis-expression QTL mapping corroborated Gabra2 as a functional candidate gene underlying methamphetamine-induced distance traveled. CRISPR/Cas9-mediated correction of the mutant intronic deletion on the C57BL/6J background to the wild-type C57BL/6NJ allele was sufficient to reduce methamphetamine-induced locomotor activity toward the wild-type C57BL/6NJ-like level, thus validating the quantitative trait variant (QTV). These studies demonstrate the power and efficiency of Reduced Complexity Crosses in identifying causal genes and variants underlying complex traits. Functionally restoring Gabra2 expression decreased methamphetamine stimulant sensitivity and supports preclinical and human genetic studies implicating the GABA-A receptor in psychostimulant addiction-relevant traits. Importantly, our findings have major implications for investigators studying psychostimulants in the C57BL/6J strain - the gold standard strain in biomedical research.

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“…[12][13][14] Recent studies on drug overdoses call for improved efforts to screen for drug use and better understand the implications of screening results. 15 At present, it is unknown if results of biochemical drug testing can be used to predict mortality in teenagers. The aim of this study was to examine the association between testing positive for any illicit substance, for cocaine, and for tetrahydrocannabinol (THC) on a routine urinary drug screen (UDS) and early mortality from drug overdose, suicide, homicide, or accidents (subsequently referred to as "external mortality") in a geographically defined population-based cohort of youth, aged 13-18 years, who present for medical care.…”

mentioning

confidence: 99%

Positive Urine Drug Screens and External Mortality in Teenagers Who Present for Medical Care

Markota¹,

Croarkin²,

Bobo³

2022

J. Clin. Psychiatry

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Objective: To examine whether a positive urine drug of abuse screen in youth who receive medical care is associated with subsequent risk of external mortality (eg, overdose, suicide, homicide, accident). Methods: This was a population-based retrospective cohort study of all Olmsted County (Minnesota) residents who were 13-18 years of age at the time of urine drug screen (UDS) testing (January 1, 1999, to November 28, 2012. Cox regression models were used to examine the relationships between having a positive UDS and external mortality, adjusted for sex, race, age, alcohol exposure, psychiatric diagnoses as defined by the International Classification of Diseases (ICD-9/ICD-10), and medical setting of UDS testing. Separate analyses were done for (1) overall UDS results, (2) tetrahydrocannabinol (THC), and (3) cocaine.Results: Of the 2,772 teenagers included in this study (47.2% male), a total of 26 died of external causes during a median follow-up period of 11.8 years. Testing positive for any illicit substance was not associated with significantly increased risk of external mortality (hazard ratio [HR] = 1.9; 95% CI, 0.9-4.2). Testing positive for cocaine was associated with significantly increased risk of external mortality (HR = 7.0; 95% CI, 1.9-25.0). Testing positive for THC was associated with a marginally significantly increased risk of external mortality (HR = 2.1; 95% CI, 1.0-4.7); however, when cocaine was added as a covariate in the analysis, the relationship between THC-positive UDS and mortality was still elevated but was no longer statistically significant (HR = 1.8; 95% CI, 0.8-4.1). Conclusions: History of cocaine-positive UDS may help identify a population of young people who are at high risk of premature death.

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Cocaine use and overdose mortality in the United States: Evidence from two national data sources, 2002–2018

Cited by 68 publications

References 28 publications

A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity

A quantitative trait variant in Gabra2 underlies increased methamphetamine stimulant sensitivity

A quantitative trait variant inGabra2underlies increased methamphetamine stimulant sensitivity

Positive Urine Drug Screens and External Mortality in Teenagers Who Present for Medical Care

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