NIDA’s investment in basic science is transforming our understanding of drug use and addiction. The fields of neuroscience, medicinal chemistry, pharmacology, genetics and epigenetics, behavioral science, and epidemiology have illuminated how the brain functions; how drugs interact with brain circuits; the factors that influence drug use; and how SUDs develop, manifest over time, and resolve. This research has led to the understanding that addiction is a medical condition that is strongly influenced by social circumstances, affects the brain, changes behavior, and negatively impacts health. It has also provided the foundational knowledge upon which effective interventions have been developed. While tremendous strides have been made, to address the evolving crises of drug use and addiction it is essential to develop a deeper understanding of the brain and how it is affected by substance use. This means further interrogating the molecular signals and neural circuits that are modified by drug use; finding gene-environment interactions that could guide the development of powerful new treatments; and developing new models to understand how biological mechanisms drive behavior across the continuum of addiction, from initial drug use to treatment and recovery. Creating a full picture of drug use and addiction also requires understanding the contextual landscape and trajectory of drug use in the United States, including how drugs are used and by whom, and how risk and protective factors interact over an individual’s lifespan to influence drug-related outcomes.
- Goal 1.1: Expand our understanding of the biological mechanisms underlying drug use, addiction, diverse treatment responses, and their impact on health and behavior throughout the lifespan
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A significant portion of NIDA’s research portfolio will continue to be dedicated to advancing our knowledge of the basic biological mechanisms that underlie drug use and addiction, and their effects on the body throughout the lifespan.
Although the protein targets and signal transduction pathways relevant to substances with addiction liability have been known for some time, NIDA-supported research is resolving the structure and dynamics of these proteins at an atomic level and identifying how the binding of specific drugs initiates the distinct signaling cascades that become the cellular basis of their physiological and behavioral effects. Recent studies using newly developed genetically encoded biosensors revealed that opioid receptors do not just function at the cell membrane as previously thought but can move into the cell and can be functional at different cellular locations, depending on the opioid type. This could be related to the distinct profiles of drugs in producing tolerance or dependence. Genetic screens in model organisms have identified an orphan receptor—a receptor for which the ligand or signaling molecule has not been identified—that has anti-opioid activity. This could be a target for treating the adverse consequences of opioids. These examples demonstrate how advances in our knowledge of opioid receptor signaling and function can lead to new approaches to treatments.
NIDA-supported research is leveraging cutting-edge tools developed through the NIH Brain Research Through Advancing Innovative Neurotechnologies® (NIH BRAIN Initiative®) and other efforts to accelerate our understanding of brain function and addiction at a multidimensional level. For example, single-cell transcriptional profiling approaches identified gene expression changes in specific brain cell types that occur in response to specific drugs. New approaches in neural circuit dissection are elucidating how the circuits engaged by different drugs underlie cognitive dimensions of addiction. In addition, new chemogenomic and chemoproteomic approaches are accelerating the discovery of targets that can be modified and used for therapeutic purposes.
Not everyone who uses substances goes on to develop an SUD. Addiction science has made strides in identifying biological risk factors for substance use, SUD, and related outcomes. Genetic studies—including GWAS—have identified genes that can protect or predispose an individual to developing addiction, including genes that modulate responses to adverse social environments. GWAS are also identifying genes relevant to addiction treatment, including genetic variants associated with heroin use outcomes and effective doses of methadone for different populations. Advances in brain imaging are beginning to delineate the role of genes in brain development and are helping researchers identify key periods of development during which exposure to socio-environmental factors can disrupt the trajectory of brain development and impact long-term outcomes, including substance use behaviors. Combined with the power of big data analytics and supercomputers that can integrate and predict causal relationships from genetic, molecular, cellular, systems, and behavioral data, these tools offer the promise of elucidating addiction biology at an unprecedented level of detail, ultimately guiding the development of improved prevention and treatment interventions.
Key Focus Areas
- Identify the genes and networks of genes that modulate drug responses, risk for addiction, and treatment responses.
- Characterize how the genetic, epigenetic, and molecular profiles of individual cells change in response to different substances across the trajectory of drug use by leveraging novel approaches for single-cell analysis.
- Identify novel targets for therapeutics through new knowledge of receptor structure combined with high-throughput screening studies and related approaches.
- Further elucidate the neural circuits and mechanisms underlying SUDs, including the progression from initial to compulsive substance use and the recovery process.
- Determine the complex relationship between neural activity and behavior using novel tools for cell manipulation and observation and computational modeling.
- Identify the biological bases for individual differences in substance use and SUD vulnerability and resilience.
- Characterize the chemistry, pharmacology, toxicology, and addictive potential of emerging drugs and drug combinations.
- Goal 1.2: Advance research on the social determinants of health related to brain development, substance use, and addiction
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Individual health is inextricably linked to one’s social environment and living conditions. NIDA-supported research has identified multiple social determinants of health—risk and resilience factors related to an individual’s life experiences—that contribute to substance use initiation and progression to addiction as well as to key comorbidities like other mental illnesses. Lack of strong relationships and community support—including adverse childhood experiences and exposure to drug use, violence, trauma, poverty, homelessness, incarceration, and racism—confer risk for drug use and addiction, comorbidities, and other adverse health outcomes. Conversely, strong family relationships, healthy role models, and a safe, supportive community are protective factors, especially in children. NIDA research is elucidating how these social determinants of health increase or decrease risk for addiction over the lifespan.
Understanding how risk and protective factors in one’s environment can influence individual drug use trajectories and comorbidities is essential for informing the development of interventions. NIDA is prioritizing studies to help us better understand how social determinants of health impact substance use, treatment utilization, outcomes, and recovery, as well as research on interventions targeting these determinants. Findings from NIDA-led prospective, longitudinal ABCD Study® and HBCD Study data will inform our understanding of healthy development—including brain and cognitive development—and how drugs and other exposures affect it (see callout box below, “Longitudinal Studies of Child Brain Development”). NIDA is exploring opportunities to leverage these data and to connect the fields of epidemiology, developmental neuroscience, and prevention to inform interventions for a wider range of youth.
Longitudinal Studies of Child Brain Development
The first few years of life are a period of exponential brain growth and development, and the long-term effects of early environmental exposures—including in utero drug exposures—on infant and child development are not well understood. The brain continues to develop during adolescence and young adulthood when risk-taking behaviors, such as drug use, can emerge. It is vital to understand the effects of drugs and other environmental exposures during these key developmental windows to ameliorate negative outcomes and promote resilience.
NIDA is leading two large trans-NIH research initiatives, the Adolescent Brain Cognitive Development (ABCD) Study® and the HEALthy Brain and Child Development (HBCD) Study, that aim to do just that. Launched in 2015, the ABCD Study® is the largest long-term study of brain development and child health ever conducted in the United States. Researchers are following nearly 12,000 children from ages 9 to 10, prior to substance use initiation, through adolescence into young adulthood, the period of highest risk. This study will identify risk and resilience factors for substance use and help us understand how substance exposures and other experiences shape brain, cognitive, social, and emotional development. ABCD Study® data are available to the broad scientific community, allowing researchers all over the world to ask questions and gain insights that may not have even been imagined at the study’s inception. Benefiting from open data sharing and sophisticated data analysis methods, the ABCD Study® has provided the world with a promising and highly productive research approach that has already resulted in numerous publications that span a wide array of topics, including substance use, psychiatric conditions, screen time, neighborhood disadvantage, obesity/weight gain, genetics, and their interactions with brain structure and function.
Using similar methods as the ABCD Study®, and with partial funding from the NIH Helping to End Addiction Long-Term® (HEAL) Initiative, the HBCD Study will follow approximately 7,500 children from the prenatal period through ages 9-10. Launched in 2021, this study will help us understand normative variation in brain development and how it contributes to cognitive, behavioral, social, and emotional functioning. The HBCD Study will also provide critical data on how exposure to drugs and other environmental influences affect development through early childhood.
The longitudinal design and scientific rigor of these studies will provide unprecedented opportunities to examine and draw causal inferences from a multitude of factors about how the relationships among them affect developmental outcomes. NIDA is also encouraging prevention, treatment, and implementation scientists to take advantage of these findings as they emerge to facilitate the translation of developmental neuroscience into interventions, policies, and practices to help youth reach their full potential.
Key Focus Areas
- Elucidate the social determinants of vulnerability to substance use and addiction, including the role of racism and other forms of discrimination.
- Examine the mechanisms whereby social determinants of health interact with biological factors, including genetics, to influence risk or resilience for substance use and SUDs, and other comorbid mental health conditions.
- Support longitudinal research on the impacts of substance use and other socio-environmental influences on development throughout the lifespan.
- Model how these complex factors interact to contribute to substance use and SUDs.
- Goal 1.3: Enhance our knowledge of the real-world landscape of drug use patterns and trends, and trajectories to addiction
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Epidemiological and policy research are essential for improving our understanding of the real-world landscape of drug use. This includes determining which drugs are used (alone and in combination) and by whom; the incidence and prevalence of drug use disorders, key comorbidities such as other mental illnesses, viral infections, and other conditions (see callout box below, “Collision of COVID-19 and Substance Use Disorders”), other precursors and consequences of drug use; and how these all shift over time.
NIDA has long supported epidemiological studies that monitor trends in drug use and related outcomes. The annual Monitoring the Future survey measures substance use and related attitudes among adolescent students, and the longitudinal Population Assessment of Tobacco and Health (PATH) Study—a collaboration with the U.S. Food and Drug Administration’s (FDA) Center for Tobacco Products—assesses how tobacco use affects behavior and health outcomes. Findings from these studies showed that flavored e-cigarette products particularly appeal to youth and helped inform a 2020 FDA guidance prioritizing enforcement against certain unauthorized flavored cartridge-based products that appeal to youth.8,9 In addition to annual studies like these, other approaches are needed to more rapidly detect trends related to drugs and drug use. NIDA’s National Drug Early Warning System provides near real-time data on indicators of emerging drug use, availability, and consequences by leveraging existing data from law enforcement, public health, and research sources, in combination with novel data available via the internet and media. NIDA is placing a high priority on innovative research that utilizes novel data collection and sophisticated analysis methods that integrate information from multiple sources and reduce lag times in data reporting.
NIDA also plays a key role in evaluating the effects of national and state-level drug policies aimed at reducing drug use and misuse. Such research has shown that higher taxes on cigarettes and smoke-free workplace laws result in significant reductions in smoking, and naloxone distribution programs prevent overdose, increase quality-adjusted life years, and are cost-effective. This research has bolstered support for these public health strategies. In the era of rapidly shifting state cannabis policies, it will be essential to research how increased availability and use of cannabis impacts educational outcomes, job productivity, health conditions, and other outcomes. As the COVID-19 pandemic brought about significant drug treatment policy changes that expanded telehealth and access to medications for opioid use disorder (MOUD), research is also needed on the impact of these changes and how they can be leveraged to further improve treatment access. NIDA-supported epidemiological and policy research will remain critical to inform addiction science broadly, along with evolving policy and practice.
Key Focus Areas
- Develop and test novel data collection and analysis methods to improve the timeliness of data on drug use, addiction, and related consequences.
- Encourage study designs, data formats, and measurements that directly address the needs of patients, providers, and policymakers.
- Evaluate the effects of local, state, and national drug policies on public health.
- Advance research on the impact of comorbid mental and physical conditions on substance use and addiction.
- Understand the social, behavioral, and economic effects of the COVID-19 pandemic on substance use and addiction.
- Examine the use of cannabis for medicinal purposes, including different products, reasons for use, timing, and outcomes on non-cannabis medication use.
Collision of COVID-19 and Substance Use Disorders
The addiction and overdose crisis has collided with the COVID-19 pandemic, each exacerbating the deleterious effects of the other. People who use drugs are more vulnerable to SARS-CoV-2 infection, more vulnerable to worse outcomes, and at higher risk for breakthrough infections in vaccinated individuals. Smoking or vaping drugs—including tobacco/nicotine, marijuana, heroin, or crack cocaine—worsens chronic lung conditions, which can make a person more likely to get severely ill from SARS-CoV-2. People with opioid use disorder (OUD) are also vulnerable because opioids act in the brainstem to slow breathing, increasing the risk for long-term damage to the lungs, heart, brain, and other organs that are also affected by SARS-CoV-2. In addition, the use of stimulants constricts the blood vessels and may increase the risk for stroke, heart attacks, abnormal heart rhythm, seizures, and other conditions that may lead to more severe consequences of SARS-CoV-2 infection.
Researchers have long recognized the strong correlation between stress and substance use, particularly in prompting relapse, and pandemic-related stress likely contributes to the dramatic increases in drug use and overdose. There have been increased reports of mental distress since the onset of the pandemic, including among individuals with no history of mental disorders, younger adults, essential workers, unpaid adult caregivers, and people from diverse racial and ethnic communities. Social isolation, as occurred with earlier COVID-19 mitigation policies, also made people with SUDs more vulnerable to negative outcomes because it interfered with many of the support systems that can help them to reach and sustain recovery.
Other contributing factors to mental distress include job loss, underemployment, and risk of COVID-19 exposure among low-income essential workers, who are more likely to be racial and ethnic minorities. In fact, Black Americans and other communities of color report greater mental distress and COVID-19-related discrimination than their white counterparts, and experience worse pandemic-related outcomes than white people. Moreover, children from communities of color bear the greatest burden of caregiver loss to COVID-19-related deaths. Indeed, the COVID-19 pandemic has exposed and exacerbated deep racial health inequities that are particularly stark in the field of addiction. As U.S. overdose death counts continue to skyrocket, overdose rates are increasing fastest among Black Americans and Native American/Alaska Native women, although overdose numbers remain highest among white people.
Shortly after COVID-19 mitigation guidelines were released, NIDA issued a Notice of Special Interest for research on the intersection of COVID-19 and SUDs and is funding research under this and other NIH funding opportunities. This includes basic research on SARS-CoV-2 transmission and infection; impacts of the COVID-19 pandemic on people who use drugs and on child and adolescent development; effects of pandemic-related policy changes on SUD treatment; research to expand COVID-19 testing and vaccine uptake among underserved populations, including those with SUDs; and research aimed at understanding and addressing vaccine hesitancy, comorbid and co-occurring medical and psychiatric conditions, and many others. Under an NIH-wide program, NIDA is also leading research to detect SARS-CoV-2 in wastewater, a project that takes advantage of NIDA expertise developed through research to detect the presence of drugs in wastewater.
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