Publications by authors named "Nora D Volkow"

539 Publications

Methamphetamine Use, Methamphetamine Use Disorder, and Associated Overdose Deaths Among US Adults.

JAMA Psychiatry 2021 Sep 22. Epub 2021 Sep 22.

National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland.

Importance: Mortality associated with methamphetamine use has increased markedly in the US. Understanding patterns of methamphetamine use may help inform related prevention and treatment.

Objective: To assess the national trends in and correlates of past-year methamphetamine use, methamphetamine use disorder (MUD), injection, frequent use, and associated overdose mortality from 2015 to 2019.

Design, Setting, And Participants: This cross-sectional study analyzed methamphetamine use, MUD, injection, and frequent use data from participants in the 2015 to 2019 National Surveys on Drug Use and Health (NSDUH). Mortality data were obtained from the 2015 to 2019 National Vital Statistics System Multiple Cause of Death files.

Exposures: Methamphetamine use.

Main Outcomes And Measures: Methamphetamine use, MUD, injection, frequent use, and overdose deaths.

Results: Of 195 711 NSDUH respondents aged 18 to 64 years, 104 408 were women (weighted percentage, 50.9%), 35 686 were Hispanic individuals (weighted percentage, 18.0%), 25 389 were non-Hispanic Black (hereafter, Black) individuals (weighted percentage, 12.6%), and 114 248 were non-Hispanic White (hereafter, White) individuals (weighted percentage, 60.6%). From 2015 to 2019, overdose deaths involving psychostimulants other than cocaine (largely methamphetamine) increased 180% (from 5526 to 15 489; P for trend <.001); methamphetamine use increased 43% (from 1.4 million [95% CI, 1.2-1.6 million] to 2.0 million [95% CI, 1.7-2.3 million]; P for trend = .002); frequent methamphetamine use increased 66% (from 615 000 [95% CI, 512 000-717 000] to 1 021 000 [95% CI, 860 000-1 183 000]; P for trend = .002); methamphetamine and cocaine use increased 60% (from 402 000 [95% CI, 306 000-499 000] to 645 000 [95% CI, 477 000-813 000]; P for trend = .001); and MUD without injection increased 105% (from 397 000 [95% CI, 299 000-496 000] to 815 000 [95% CI, 598 000-1 033 000]; P for trend = .006). The prevalence of MUD or injection surpassed the prevalence of methamphetamine use without MUD or injection in each year from 2017 to 2019 (60% to 67% vs 37% to 40%; P for trend ≤.001). Adults with MUD or using injection were more likely to use methamphetamine frequently (52.68%-53.84% vs 32.59%; adjusted risk ratio, 1.62-1.65; 95% CI, 1.35-1.94). From 2015 to 2019, the adjusted prevalence of MUD without injection more than tripled among heterosexual women (from 0.24% to 0.74%; P < .001) and lesbian or bisexual women (from 0.21% to 0.71%; P < .001) and more than doubled among heterosexual men (from 0.29% to 0.79%; P < .001) and homosexual or bisexual men (from 0.29% to 0.80%; P = .007). It increased over 10-fold among Black individuals (from 0.06% to 0.64%; P < .001), nearly tripled among White individuals (from 0.28% to 0.78%; P < .001), and more than doubled among Hispanic individuals (from 0.39% to 0.82%; P < .001). Risk factors for methamphetamine use, MUD, injection, and frequent use included lower educational attainment, lower annual household income, lack of insurance, housing instability, criminal justice involvement, comorbidities (eg, HIV/AIDS, hepatitis B or C virus, depression), suicidal ideation, and polysubstance use.

Conclusions And Relevance: This cross-sectional study found consistent upward trends in overdose mortality, greater risk patterns of methamphetamine use, and populations at higher risk for MUD diversifying rapidly, particularly those with socioeconomic risk factors and comorbidities. Evidence-based prevention and treatment interventions are needed to address surges in methamphetamine use and MUD.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.2588DOI Listing
September 2021

Ca channel blockade reduces cocaine's vasoconstriction and neurotoxicity in the prefrontal cortex.

Transl Psychiatry 2021 Sep 6;11(1):459. Epub 2021 Sep 6.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, USA.

Cocaine profoundly affects both cerebral blood vessels and neuronal activity in the brain. The vasoconstrictive effects of cocaine, concurrently with its effects on neuronal [Ca] accumulation are likely to jeopardize neuronal tissue that in the prefrontal cortex (PFC) could contribute to impaired self-regulation and compulsive cocaine consumption. Here we used optical imaging to study the cerebrovascular and neuronal effects of acute cocaine (1 mg/kg i.v.) and to examine whether selective blockade of L-type Ca channels by Nifedipine (NIF) (0.5 mg/kg i.v.) would alleviate cocaine's effects on hemodynamics (measured with cerebral blood volume, HbT), oxygenation (measured with oxygenated hemoglobin, HbO) and neuronal [Ca], which were concomitantly measured in the PFC of naive rats. Our results show that in the PFC acute cocaine significantly reduced flow delivery (HbT), increased neuronal [Ca] accumulation and profoundly reduced tissue oxygenation (HbO) and these effects were significantly attenuated by NIF pretreatment. They also show that cocaine-induced vasoconstriction is distinct from its increase of neuronal [Ca] accumulation though both of them contribute to hypoxemia and both effects were attenuated by NIF. These results provide evidence that blockade of voltage-gated L-type Ca channels might be beneficial in preventing vasoconstriction and neurotoxic effects of cocaine and give support for further clinical investigations to determine their value in reducing cocaine's neurotoxicity in cocaine use disorders.
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http://dx.doi.org/10.1038/s41398-021-01573-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421405PMC
September 2021

Naloxone precipitated withdrawal increases dopamine release in the dorsal striatum of opioid dependent men.

Transl Psychiatry 2021 Sep 1;11(1):445. Epub 2021 Sep 1.

Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Dopamine (DA) neurotransmission is critical in the neurobiology of reward and aversion, but its contribution to the aversive state of opioid withdrawal remains unknown in humans. To address this, we used updated voxelwise methods and retrospectively analyzed a [C]raclopride-PET dataset to measure D receptor availability and relative cerebral blood flow (R1) in male opioid use disorder (OUD) participants (n = 10) during placebo and acute opioid withdrawal conditions. We found that acute withdrawal precipitated by the opioid antagonist naloxone significantly increased dorsal striatal DA release in OUD participants (p < 0.05). Net changes in striatal DA were significantly correlated with a subjective index of withdrawal aversion such that greater DA increases were associated with more aversive responses (r(8) = 0.82, p < 0.005). Withdrawal also affected brain function, as indexed by increases in relative cerebral blood flow in the insula and putamen (p < 0.05). Our findings are different from preclinical studies that have primarily reported decreases in ventral striatal DA during naloxone precipitated withdrawal, whereas this effect was not significant in OUD participants (p = 0.79). In sum, we provide evidence for the contribution of increases in dorsal striatal DA to the aversive state of naloxone precipitated withdrawal in humans.
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http://dx.doi.org/10.1038/s41398-021-01548-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410787PMC
September 2021

Discovery of Highly Potent Adenosine A Receptor Agonists: Targeting Positron Emission Tomography Probes.

ACS Chem Neurosci 2021 09 1;12(18):3410-3417. Epub 2021 Sep 1.

Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892-1013, United States.

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the biodistribution of ARs in the central nervous system (CNS), which is of therapeutic interest for various neuropsychiatric disorders. Additionally, radioligands that can image changes in endogenous adenosine levels in different physiological and pathological conditions are still lacking. The binding of known antagonist adenosine A receptor (AR) radiotracer, [C]MDPX, failed to be inhibited by elevated endogenous adenosine in a rodent PET study. Since most of the known AR PET radiotracers were antagonists, we propose that an AR agonist radioligand may possess higher sensitivity to measure changes in endogenous adenosine concentration. Herein, we report our latest findings toward the development of a full agonist adenosine A radioligand for PET. Based on a 3,5-dicyanopyridine template, 16 new derivatives were designed and synthesized to optimize both binding affinity and functional activity, resulting in two full agonists (compounds and ) with single-digit nanomolar affinities and good subtype selectivity (A/A selectivity of ∼1000-fold for compound and 29-fold for compound ). Rapid O-[C]methylation provided [C] and [C] in high radiochemical yields and radiochemical purity. However, subsequent brain PET imaging in rodents showed poor brain permeability for both radioligands. An PET study using knockout mice for MDR 1a/a, BCRP, and MRP1 indicated that these compounds might be substrates for brain efflux pumps. In addition, evaluation using multiparameter optimization identified high molecular weight and high polar surface area as the main molecular descriptors responsible for low brain penetration. These results will provide further insight toward development of full agonist adenosine A radioligands and also highly potent CNS AAR drugs.
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http://dx.doi.org/10.1021/acschemneuro.1c00397DOI Listing
September 2021

The Helping to End Addiction Long-term (HEAL) Initiative of the National Institutes of Health.

JAMA 2021 Sep;326(11):1005-1006

National Institute on Drug Abuse, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jama.2021.13300DOI Listing
September 2021

Addiction should be treated, not penalized.

Authors:
Nora D Volkow

Neuropsychopharmacology 2021 Aug 17. Epub 2021 Aug 17.

National Institute on Drug Abuse, Three White Flint North, North Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41386-021-01087-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369862PMC
August 2021

Sleep disturbances are associated with cortical and subcortical atrophy in alcohol use disorder.

Transl Psychiatry 2021 Aug 16;11(1):428. Epub 2021 Aug 16.

National Institute on Alcohol Abuse and Alcoholism, Laboratory of Neuroimaging, National Institutes of Health, Bethesda, MD, 20892-1013, USA.

Sleep disturbances are prominent in patients with alcohol use disorder (AUD) and predict relapse. So far, the mechanisms underlying sleep disruptions in AUD are poorly understood. Because sleep-related regions vastly overlap with regions, where patients with AUD showed pronounced grey matter (GM) reduction; we hypothesized that GM structure could contribute to sleep disturbances associated with chronic alcohol use. We combined sleep EEG recording and high-resolution structural brain imaging to examine the GM-sleep associations in 36 AUD vs. 26 healthy controls (HC). The patterns of GM-sleep associations differed for N3 vs. REM sleep and for AUD vs. HC. For cortical thickness (CT), CT-sleep associations were significant in AUD but not in HC and were lateralized such that lower CT in right hemisphere was associated with shorter N3, whereas in left hemisphere was associated with shorter REM sleep. For the GM density (GMD), we observed a more extensive positive GMD-N3 association in AUD (right orbitofrontal cortex, cerebellum, dorsal cingulate and occipital cortex) than in HC (right orbitofrontal cortex), and the GMD-REM association was positive in AUD (midline, motor and paralimbic regions) whereas negative in HC (the left supramarginal gyrus). GM structure mediated the effect of chronic alcohol use on the duration of N3 and the age by alcohol effect on REM sleep. Our findings provide evidence that sleep disturbances in AUD were associated with GM reductions. Targeting sleep-related regions might improve sleep in AUD and enhance sleep-induced benefits in cognition and emotional regulation for recovery.
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http://dx.doi.org/10.1038/s41398-021-01534-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368207PMC
August 2021

Relationship between BMI and alcohol consumption levels in decision making.

Int J Obes (Lond) 2021 Aug 6. Epub 2021 Aug 6.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.

Background: Decision-making deficits in obesity and alcohol use disorder (AUD) may contribute to the choice of immediate rewards despite their long-term deleterious consequences.

Methods: Gambling task functional MRI in Human connectome project (HCP) dataset was used to investigate neural activation differences associated with reward or punishment (a key component of decision-making behavior) in 418 individuals with obesity (high BMI) and without obesity (lean BMI) and either at high (HR) or low (LR) risk of AUD based on their alcohol drinking levels.

Results: Interaction between BMI and alcohol drinking was seen in regions of the default mode network (DMN) and those implicated in self-related processing, memory, and salience attribution. ObesityHR relative to obesityLR also recruited DMN along with primary motor and regions implicated in inattention, negative perception, and uncertain choices, which might facilitate impulsive choices in obesityHR. Furthermore, obesityHR compared to leanHR/leanLR also demonstrated heightened activation in DMN and regions implicated in uncertain decisions.

Conclusions: These results suggest that BMI is an independent variable from that of alcohol drinking levels in neural processing of gambling tasks. Moreover, leanLR relative to leanHR, showed increased activation in motor regions [precentral and superior frontal gyrus] suggestive of worse executive function from excessive alcohol use. Delayed discounting measures failed to distinguish between obesity and high alcohol drinking levels, which as for gambling task results suggests independent negative effects of obesity and chronic alcohol drinking on decision-making. These findings highlight distinct associations of obesity and high-risk alcohol drinking with two key constituents of decision-making behavior.
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http://dx.doi.org/10.1038/s41366-021-00919-xDOI Listing
August 2021

How Academic Medicine Can Help Confront the Opioid Crisis.

Acad Med 2021 Aug 3. Epub 2021 Aug 3.

N.D. Volkow is director, National Institute on Drug Abuse, Bethesda, Maryland. T. McLellan is founder and CEO, Treatment Research Institute, and professor of psychology, University of Pennsylvania, Philadelphia, Pennsylvania. C. Blanco is director, Division of Epidemiology, Services, and Prevention Research, National Institute on Drug Abuse, Bethesda, Maryland.

The United States is in the midst of a devastating overdose and addiction crisis involving opioids as well as other drugs. Yet, despite the existence of effective treatments for opioid use disorder, only a minority of people who need treatment for this or other substance use disorders receive it. Besides the terrible human and economic costs of overdose deaths and the other health consequences of addiction, untreated substance use has wide ranging impacts across health care. Academic medicine can help address this crisis by increasing the preparedness of the current and future clinical workforce to detect and treat substance misuse and addiction through increased attention to these topics in medical and nursing schools and in residency programs. In this commentary, the authors explore the barriers to treatment for substance misuse and addiction and the role of academic medicine in improving treatment outcomes through training, clinical care, health service delivery, and research.
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http://dx.doi.org/10.1097/ACM.0000000000004289DOI Listing
August 2021

Prenatal caffeine exposure: association with neurodevelopmental outcomes in 9- to 11-year-old children.

J Child Psychol Psychiatry 2021 Jul 27. Epub 2021 Jul 27.

Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

Background: Despite the widespread use of caffeine including consumption during pregnancy, the effect of prenatal caffeine exposure on child brain development and behavior is unclear.

Methods: To address this, we used data from the Adolescent Brain and Cognitive Development Study (n = 11,875 children aged 9-11 years from 22 sites across the United States). We explored the associations between prenatal caffeine exposure and various developmental outcomes including birth outcomes, physical health, behavior problems, cognition, substance use and brain structure in children, and evaluated dose effects.

Results: Among 9,978 children (4,745 females) who had valid data for prenatal caffeine exposure and whose mothers did not use drugs of abuse after knowing of pregnancy, 4,170 (41.79%) had no prenatal caffeine exposure, 2,292 (22.97%) had daily, 1,933 (19.37%) had weekly, and 1,583 (15.86%) had less than weekly exposures. Prenatal caffeine exposure including the widely recommended 'safe' dose was associated with greater externalizing problems, whereas greater BMI and soda consumption were only observed in children with high dose exposures (3+ per day). Notably, the effect size for association of externalizing problems with prenatal caffeine exposure was comparable with that reported for prenatal alcohol (The American Journal of Psychiatry, 177, 2020 and 1060) and prenatal cannabis (JAMA Psychiatry, 78, 2020 and 64) exposures from previous ABCD publications. Additionally, prenatal caffeine exposure was associated with brain structural changes that included greater posterior and lower frontal cortical thickness and altered parietooccipital sulcal depth.

Conclusions: The recommended 'safe' dose of caffeine during pregnancy should be carefully studied to assess whether the behavioral and brain correlates observed here are clinically relevant and determine whether it needs adjustment. Because of the high prevalence of caffeine use in the general population, studies on prenatal exposure to drugs of abuse should include prenatal caffeine use as a covariate.
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http://dx.doi.org/10.1111/jcpp.13495DOI Listing
July 2021

Choosing appropriate language to reduce the stigma around mental illness and substance use disorders.

Neuropsychopharmacology 2021 Jul 19. Epub 2021 Jul 19.

National Institute on Alcohol and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41386-021-01069-4DOI Listing
July 2021

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward.

J Clin Invest 2021 Sep;131(18)

National Institute on Alcohol Abuse and Alcoholism, Laboratory of Neuroimaging, and.

BACKGROUNDCertain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODSWe examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTSWe found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSIONThese findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATIONClinicalTrials.gov: NCT03190954.FUNDINGNational Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).
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http://dx.doi.org/10.1172/JCI149722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439593PMC
September 2021

Obese Individuals Show Disrupted Dynamic Functional Connectivity between Basal Ganglia and Salience Networks.

Cereb Cortex 2021 Jul 8. Epub 2021 Jul 8.

Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China.

Previous functional magnetic resonance imaging (fMRI) studies have showed obesity (OB)-related alterations in intrinsic functional connectivity (FC) within and between different resting-state networks (RSNs). However, few studies have examined dynamic functional connectivity (DFC). Thus, we employed resting-state fMRI with independent component analysis (ICA) and DFC analysis to investigate the alterations in FC within and between RSNs in 56 individuals with OB and 46 normal-weight (NW) controls. ICA identified six RSNs, including basal ganglia (BG), salience network (SN), right executive control network/left executive control network, and anterior default-mode network (aDMN)/posterior default-mode network. The DFC analysis identified four FC states. OB compared with NW had more occurrences and a longer mean dwell time (MDT) in state 2 (positive connectivity of BG with other RSN) and also had higher FC of BG-SN in other states. Body mass index was positively correlated with MDT and FCs of BG-aDMN (state 2) and BG-SN (state 4). DFC analysis within more refined nodes of RSNs showed that OB had more occurrences and a longer MDT in state 1 in which caudate had positive connections with the other network nodes. The findings suggest an association between caudate-related and BG-related positive FC in OB, which was not revealed by traditional FC analysis, highlighting the utility of adding DFC to the more conventional methods.
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http://dx.doi.org/10.1093/cercor/bhab190DOI Listing
July 2021

Obese Individuals Show Disrupted Dynamic Functional Connectivity between Basal Ganglia and Salience Networks.

Cereb Cortex 2021 Jul 8. Epub 2021 Jul 8.

Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China.

Previous functional magnetic resonance imaging (fMRI) studies have showed obesity (OB)-related alterations in intrinsic functional connectivity (FC) within and between different resting-state networks (RSNs). However, few studies have examined dynamic functional connectivity (DFC). Thus, we employed resting-state fMRI with independent component analysis (ICA) and DFC analysis to investigate the alterations in FC within and between RSNs in 56 individuals with OB and 46 normal-weight (NW) controls. ICA identified six RSNs, including basal ganglia (BG), salience network (SN), right executive control network/left executive control network, and anterior default-mode network (aDMN)/posterior default-mode network. The DFC analysis identified four FC states. OB compared with NW had more occurrences and a longer mean dwell time (MDT) in state 2 (positive connectivity of BG with other RSN) and also had higher FC of BG-SN in other states. Body mass index was positively correlated with MDT and FCs of BG-aDMN (state 2) and BG-SN (state 4). DFC analysis within more refined nodes of RSNs showed that OB had more occurrences and a longer MDT in state 1 in which caudate had positive connections with the other network nodes. The findings suggest an association between caudate-related and BG-related positive FC in OB, which was not revealed by traditional FC analysis, highlighting the utility of adding DFC to the more conventional methods.
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http://dx.doi.org/10.1093/cercor/bhab190DOI Listing
July 2021

Gene Variants Associated With a Higher Risk for Alcohol Dependence in Multiethnic Populations.

Front Psychiatry 2021 31;12:665257. Epub 2021 May 31.

Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Genetics influence the vulnerability to alcohol use disorders, and among the implicated genes, three previous studies have provided evidences for the involvement of in alcohol dependence (AD). expression is broadly dysregulated in postmortem brain from AD humans, as well as in the brain of mice with alcohol dependent-like behaviors and in a zebrafish model of alcohol preference. The aim of the present study was to evaluate the association of variants in the gene with AD in multiethnic populations from South and North America. Alcohol-screening questionnaires [such as CAGE and Alcohol Use Disorders Identification Test (AUDIT)] were used to determine individual risk of AD. Multivariate logistic regression analyses were done in three independent populations (898 individuals from Bambuí, Brazil; 3,015 individuals from Pelotas, Brazil; and 1,316 from the United States). Linkage disequilibrium and conditional analyses, as well as functional analyses, were also conducted. Four variants were significantly associated with AD in our discovery cohort (Bambuí): rs4768231, rs4767971, rs7307310, and rs1465527. Two of these variants (rs4768231 and rs4767971) were replicated in both Pelotas and US cohorts. The consistent association signal (at the locus) found in populations with different genetic backgrounds reinforces the relevance of our findings. Taken together, these results support the notion that genetic variants in the locus are risk factors for AD in humans.
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http://dx.doi.org/10.3389/fpsyt.2021.665257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202767PMC
May 2021

Research on substance use disorders during the COVID-19 pandemic.

J Subst Abuse Treat 2021 10 8;129:108385. Epub 2021 Apr 8.

National Institute on Drug Abuse, 6001 Executive Boulevard, Bethesda, MD 20852, United States of America. Electronic address:

The COVID-19 pandemic has triggered changes in the substance use disorder (SUD) treatment delivery system, in the availability of legal and illicit drugs, and in other social and economic factors. As such, these changes necessitate that the field re-evaluate research approaches to SUDs, including in epidemiology, clinical trials, health services, implementation and policy research, as well as basic and translational neuroscience. COVID-19 has reduced researchers' access to target populations and made it difficult for them to obtain timely data to monitor changes in patterns of drug use and overdoses. These changes have increased researchers' interest in virtual technologies to expand and accelerate access to populations; increased modifications in the design, conduct, and analysis of clinical trials; and increased emphasis on implementation. Similarly, as researchers better understand the biology of COVID-19, they will better understand potential effects of COVID-19 on neurotransmitter receptors and signaling pathways, mechanisms underlying COVID-19 associated neurological and psychiatric sequelae, and interactions between COVID-19 treatments and psychoactive substances. The pandemic has also revealed the need for research that addresses health disparities. Overall, the COVID-19 pandemic has challenged several aspects of current research on SUD. Responding to these challenges provides opportunities to develop robust research approaches that align with the goals of improving patient outcomes and public health and are resilient to the challenges of future crises.
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http://dx.doi.org/10.1016/j.jsat.2021.108385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028597PMC
October 2021

Cannabis Affects Cerebellar Volume and Sleep Differently in Men and Women.

Front Psychiatry 2021 13;12:643193. Epub 2021 May 13.

National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States.

There are known sex differences in behavioral and clinical outcomes associated with drugs of abuse, including cannabis. However, little is known about how chronic cannabis use and sex interact to affect brain structure, particularly in regions with high cannabinoid receptor expression, such as the cerebellum, amygdala, and hippocampus. Based on behavioral data suggesting that females may be particularly vulnerable to the effects of chronic cannabis use, we hypothesized lower volumes in these regions in female cannabis users. We also hypothesized poorer sleep quality among female cannabis users, given recent findings highlighting the importance of sleep for many outcomes related to cannabis use disorder. Using data from the Human Connectome Project, we examined 170 chronic cannabis users (>100 lifetime uses and/or a lifetime diagnosis of cannabis dependence) and 170 controls that we attempted to match on age, sex, BMI, race, tobacco use, and alcohol use. We performed group-by-sex ANOVAs, testing for an interaction in subcortical volumes, and in self-reported sleep quality (Pittsburgh Sleep Questionnaire Inventory). After controlling for total intracranial volume and past/current tobacco usage, we found that cannabis users relative to controls had smaller cerebellum volume and poorer sleep quality, and these effects were driven by the female cannabis users (i.e., a group-by-sex interaction). Among cannabis users, there was an age of first use-by-sex interaction in sleep quality, such that females with earlier age of first cannabis use tended to have more self-reported sleep issues, whereas this trend was not present among male cannabis users. The amygdala volume was smaller in cannabis users than in non-users but the group by sex interaction was not significant. These data corroborate prior findings that females may be more sensitive to the neural and behavioral effects of chronic cannabis use than males. Further work is needed to determine if reduced cerebellar and amygdala volumes contribute to sleep impairments in cannabis users.
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http://dx.doi.org/10.3389/fpsyt.2021.643193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155508PMC
May 2021

The epidemic of fentanyl misuse and overdoses: challenges and strategies.

Authors:
Nora D Volkow

World Psychiatry 2021 Jun;20(2):195-196

National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1002/wps.20846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129846PMC
June 2021

Remembering Mary Jeanne Kreek and her many contributions to addiction science.

Nat Neurosci 2021 07;24(7):899-900

National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.

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http://dx.doi.org/10.1038/s41593-021-00863-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249229PMC
July 2021

Associations of family income with cognition and brain structure in USA children: prevention implications.

Mol Psychiatry 2021 May 14. Epub 2021 May 14.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.

Poverty, as assessed by several socioeconomic (SES) factors, has been linked to worse cognitive performance and reduced cortical brain volumes in children. However, the relative contributions of the various SES factors on brain development and the mediating effects between cognition and brain morphometry have not been investigated. Here we used cross-sectional data from the ABCD Study to evaluate associations among various SES and demographic factors, brain morphometrics, and cognition and their reproducibility in two independent subsamples of 3892 children. Among the SES factors, family income (FI) best explained individual differences in cognitive test scores (stronger for crystallized than for fluid cognition), cortical volume (CV), and thickness (CT). Other SES factors that showed significant associations with cognition and brain morphometrics included parental education and neighborhood deprivation, but when controlling for FI, their effect sizes were negligible and their regional brain patterns were not reproducible. Mediation analyses showed that cognitive scores, which we used as surrogate markers of the children's level of cognitive stimulation, partially mediated the association of FI and CT, whereas the mediations of brain morphometrics on the association of FI and cognition were not significant. These results suggest that lack of supportive/educational stimulation in children from low-income families might drive the reduced CV and CT. Thus, strategies to enhance parental supportive stimulation and the quality of education for children in low-income families could help counteract the negative effects of poverty on children's brain development.
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http://dx.doi.org/10.1038/s41380-021-01130-0DOI Listing
May 2021

Extended-Release Buprenorphine and Its Evaluation With Patient-Reported Outcomes.

JAMA Netw Open 2021 May 3;4(5):e219708. Epub 2021 May 3.

National Institute on Drug Abuse, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.9708DOI Listing
May 2021

Cocaine Reduces the Neuronal Population While Upregulating Dopamine D2-Receptor-Expressing Neurons in Brain Reward Regions: Sex-Effects.

Front Pharmacol 2021 12;12:624127. Epub 2021 Apr 12.

Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, United States.

Addiction to cocaine is associated with dysfunction of the dopamine mesocortical system including impaired dopamine-2 receptor (D2r) signaling. However, the effects of chronic cocaine on neuronal adaptations in this system have not been systematically examined and data available is mostly from males. Here, we investigated changes in the total neuronal density and relative concentration of D2r-expressing neurons in the medial prefrontal cortex (mPFC), dorsal striatum (Dstr), nucleus accumbens (NAc), and ventral tegmental area (VTA) in both male and female mice passively exposed to cocaine for two weeks. In parallel experiments, we measured mRNA levels for and for opioid peptides (m and m). Through a combination of large field of view fluorescent imaging with BAC transgenic D2r-eGFP mice and immunostaining, we observed that cocaine exposed mice had a higher density of D2r-positive cells that was most prominent in mPFC and VTA and larger for females than for males. This occurred amidst an overall significant decrease in neuronal density (measured with NeuN) in both sexes. However, increases in mRNA levels with cocaine were only observed in mPFC and Dstr in females, which might reflect the limited sensitivity of the method. Our findings, which contrast with previous findings of cocaine-induced downregulation of D2r binding availability, could reflect a phenotypic shift in neurons that did not previously express and merits further investigation. Additionally, the neuronal loss particularly in mPFC with chronic cocaine might contribute to the cognitive impairments observed with cocaine use disorder.
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http://dx.doi.org/10.3389/fphar.2021.624127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072657PMC
April 2021

Ketogenic diet reduces alcohol withdrawal symptoms in humans and alcohol intake in rodents.

Sci Adv 2021 Apr 9;7(15). Epub 2021 Apr 9.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.

Individuals with alcohol use disorder (AUD) show elevated brain metabolism of acetate at the expense of glucose. We hypothesized that a shift in energy substrates during withdrawal may contribute to withdrawal severity and neurotoxicity in AUD and that a ketogenic diet (KD) may mitigate these effects. We found that inpatients with AUD randomized to receive KD ( = 19) required fewer benzodiazepines during the first week of detoxification, in comparison to those receiving a standard American (SA) diet ( = 14). Over a 3-week treatment, KD compared to SA showed lower "wanting" and increased dorsal anterior cingulate cortex (dACC) reactivity to alcohol cues and altered dACC bioenergetics (i.e., elevated ketones and glutamate and lower neuroinflammatory markers). In a rat model of alcohol dependence, a history of KD reduced alcohol consumption. We provide clinical and preclinical evidence for beneficial effects of KD on managing alcohol withdrawal and on reducing alcohol drinking.
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http://dx.doi.org/10.1126/sciadv.abf6780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034849PMC
April 2021

To end the opioid crisis, we must address painful social disparities.

Authors:
Nora D Volkow

Drug Alcohol Depend 2021 05 18;222:108678. Epub 2021 Mar 18.

National Institute on Drug Abuse, United States. Electronic address:

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http://dx.doi.org/10.1016/j.drugalcdep.2021.108678DOI Listing
May 2021

Accelerated Aging of the Amygdala in Alcohol Use Disorders: Relevance to the Dark Side of Addiction.

Cereb Cortex 2021 Jun;31(7):3254-3265

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA.

Here we assessed changes in subcortical volumes in alcohol use disorder (AUD). A simple morphometry-based classifier (MC) was developed to identify subcortical volumes that distinguished 32 healthy controls (HCs) from 33 AUD patients, who were scanned twice, during early and later withdrawal, to assess the effect of abstinence on MC-features (Discovery cohort). We validated the novel classifier in an independent Validation cohort (19 AUD patients and 20 HCs). MC-accuracy reached 80% (Discovery) and 72% (Validation). MC features included the hippocampus, amygdala, cerebellum, putamen, corpus callosum, and brain stem, which were smaller and showed stronger age-related decreases in AUD than HCs, and the ventricles and cerebrospinal fluid, which were larger in AUD and older participants. The volume of the amygdala showed a positive association with anxiety and negative urgency in AUD. Repeated imaging during the third week of detoxification revealed slightly larger subcortical volumes in AUD patients, consistent with partial recovery during abstinence. The steeper age-associated volumetric reductions in stress- and reward-related subcortical regions in AUD are consistent with accelerated aging, whereas the amygdalar associations with negative urgency and anxiety in AUD patients support its involvement in the "dark side of addiction".
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http://dx.doi.org/10.1093/cercor/bhab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196255PMC
June 2021

Sensory cue reactivity: Sensitization in alcohol use disorder and obesity.

Neurosci Biobehav Rev 2021 05 12;124:326-357. Epub 2021 Feb 12.

National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA; National Institute of Nursing Research, Bethesda, MD, USA. Electronic address:

Neuroimaging techniques to measure the function of the human brain such as electroencephalography (EEG), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI), are powerful tools for understanding the underlying neural circuitry associated with alcohol use disorder (AUD) and obesity. The sensory (visual, taste and smell) paradigms used in neuroimaging studies represent an ideal platform to investigate the connection between the different neural circuits subserving the reward/executive control systems in these disorders, which may offer a translational mechanism for novel intervention predictions. Thus, the current review provides an integrated summary of the recent neuroimaging studies that have applied cue-reactivity paradigms and neuromodulation strategies to explore underlying alterations in neural circuitry as well in treatment strategies in AUD and obesity. Finally, we discuss literature on mechanisms associated with increased alcohol sensitivity post-bariatric surgery (BS) which offers guidance for future research to use sensory percepts in elucidating the relation of reward signaling in AUD development post-BS.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.014DOI Listing
May 2021

Interventions to Address the Opioid Crisis-Modeling Predictions and Consequences of Inaction.

JAMA Netw Open 2021 02 1;4(2):e2037385. Epub 2021 Feb 1.

National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamanetworkopen.2020.37385DOI Listing
February 2021

Methamphetamine Overdose Deaths in the US by Sex and Race and Ethnicity.

JAMA Psychiatry 2021 May;78(5):564-567

National Institute on Drug Abuse, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamapsychiatry.2020.4321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100861PMC
May 2021

Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses.

Mol Psychiatry 2021 Jan 11. Epub 2021 Jan 11.

Center for Artificial Intelligence in Drug Discovery, Case Western Reserve University, Cleveland, OH, USA.

Morbidity and mortality from opioid use disorders (OUD) and other substance use disorders (SUD) is a major public health crisis, yet there are few medications to treat them. There is an urgency to accelerate SUD medication development. We present an integrated drug repurposing strategy that combines computational prediction, clinical corroboration using electronic health records (EHRs) of over 72.9 million patients and mechanisms of action analysis. Among top-ranked repurposed candidate drugs, tramadol, olanzapine, mirtazapine, bupropion, and atomoxetine were associated with increased odds of OUD remission (adjusted odds ratio: 1.51 [1.38-1.66], 1.90 [1.66-2.18], 1.38 [1.31-1.46], 1.37 [1.29-1.46], 1.48 [1.25-1.76], p value < 0.001, respectively). Genetic and functional analyses showed these five candidate drugs directly target multiple OUD-associated genes including BDNF, CYP2D6, OPRD1, OPRK1, OPRM1, HTR1B, POMC, SLC6A4 and OUD-associated pathways, including opioid signaling, G-protein activation, serotonin receptors, and GPCR signaling. In summary, we developed an integrated drug repurposing approach and identified five repurposed candidate drugs that might be of value for treating OUD patients, including those suffering from comorbid conditions.
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http://dx.doi.org/10.1038/s41380-020-01011-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797705PMC
January 2021
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