Priority Focus Areas
The four main goals outline the broad scope of NIDA’s strategic objectives over the next 5 years. Across these goals and objectives, four priority focus areas have been identified that present unique opportunities to leverage over that time frame. These areas include:
- Understanding the complex interactions of factors influencing drug use trajectories
- Accelerating development of treatments
- Addressing real-world complexities
- Advancing bidirectional translation
Behaviors such as drug use and addiction are mediated by numerous biological, environmental, social, and developmental factors. Understanding the interactions among these factors and how they contribute to the risk for addiction and other negative consequences of drug use is critical for developing better prevention and treatment strategies. Basic and clinical addiction research have made significant progress in the identification of discrete genetic, epigenetic, neuro-circuitry, and behavioral factors that contribute to substance use disorders (SUDs).40 Moving forward, the integration of knowledge across scales and domains related to the complex expression of phenotypes will allow for a deeper and more clinically meaningful understanding of addiction, which, in turn, can translate into better prevention and treatment interventions.
Advances in informatics and information technology are enabling more sophisticated types of analyses than ever before. Effectively leveraging these advances will require coordinated efforts, including:
- infrastructure development
- multidisciplinary workforce training
- culture change related to data sharing
- consensus-based data standardization
- support for large-scale data collection, curation, and maintenance
To achieve real progress toward understanding the human brain and how it is affected by drugs, it is vital to develop more powerful analytical methods and visualization tools that can help capture the richness of data being generated from genetic, epigenetic, molecular, proteomic, metabolomic, brain imaging, behavioral, clinical, social, and environmental studies. Neuroscience is fast approaching a data analysis bottleneck.113 Dramatic advances in sequencing technologies, for example, have reached the point where it is now far cheaper to sequence whole genomes than to analyze the results. As a result, we are taking advantage of smaller and smaller fractions of the high density of data derived from various methodologies. A long-term effort is needed to develop the infrastructure necessary to analyze complex systems (drawing from mathematics, statistics, engineering, computer science, and bioinformatics) in ways that allow researchers to investigate behaviors of nonlinear, highly interacting systems. Such analytical and modeling tools are urgently required to take full advantage of the emerging data sets and to address multifaceted questions, such as how genes linked to addiction influence brain function and the response to drug use; how orchestrated genetic networks drive complex, adaptive brain functions; and how social and environmental stimuli can interact with those networks to perturb their balance.
Over the next 5 years, NIDA will capitalize on emerging technologies and discoveries to facilitate integration and analysis of diverse data sources, including genomic, epigenomic, behavioral, neurobiological, environmental, and other phenotypic data associated with the stages of drug use and addiction. These efforts will focus on developing data sets and tools with the power to reveal hidden associations across organizational, temporal, and spatial scales and yield critical insights about brain function and development, genetic influence on brain and behavior development, and the biological precursors to and correlates of SUDs. These efforts will include:
This landmark 10-year study led by NIDA in partnership with NIAAA; NCI; the Collaborative Research on Addiction at NIH, or CRAN; and other NIH partners (NICHD, NIMH, NIMHD, NINDS, and OBSSR) will establish a large cohort of youth to prospectively examine neurodevelopmental outcomes using brain imaging, genetics, and varied measures of physical health and development, psychosocial development, cognition (e.g., information processing, learning, memory, decision-making), academic achievement, motivation, and emotional regulation. Youth will be recruited at approximate ages 9 or 10 and followed into early adulthood, the period of highest risk for substance use and SUDs. Objectives of the study include:
- Identifying individual developmental trajectories (e.g., brain, cognitive, emotional, academic) and the factors that can affect them
- Developing national standards of normal brain development in youth
- Examining the role of genetic versus environmental factors on development, enriched by comparisons of twin participants (800 pairs are expected to be included in the study)
- Exploring the effects of physical activity and sleep, as well as sports injuries and other injuries on brain development and other outcomes
- Evaluating the onset and progression of mental disorders, factors that influence their course or severity, and the relationship between mental disorders and substance use
- Providing knowledge of how exposure to different substances such as alcohol, marijuana, nicotine, caffeine, and others, individually or in combination, affects various developmental outcomes (and vice versa)
- Providing rapid and open access to de-identified data to enable scientists to address unforeseen scientific questions over the course of the study, maximizing and extending the impact of this scientific investment
Findings from the ABCD study will greatly increase our understanding of environmental, social, and genetic factors relevant to brain and cognitive development and their role in the initiation of substance use and the progression to SUD, which can inform the development of substance use prevention and treatment strategies.
This initiative aims to integrate diverse data types to enable meaningful analyses, assimilating a diverse, interoperable collection of multiscale data sets that can be mined by the scientific community and visualized in a user-friendly framework to support discovery of novel relationships and scientific knowledge related to addiction. The Addictome will be a collection of numerous data types from diverse sources representing internal and external factors that contribute to an individual’s risk for addiction across the lifespan. It will provide the infrastructure tools necessary to enable investigation into how these diverse factors interact within and across individuals to influence drug experimentation, escalation, and diverse substance use trajectories. This project will be aligned with the Trans-NIH Big Data to Knowledge initiative.
It is also critical to ensure that, once created, these databases are effectively used. As a part of this effort, NIDA will work to:
- Develop standard data formats and common data elements for a user-friendly framework
- Ensure that addiction scientists are trained in the statistical and analytical methods needed to analyze these data sets
- Provide incentives for contributing data to this initiative
- Increase support for secondary data analyses
Understanding how environmental exposures impact genetic and epigenetic factors to influence the risk for developing SUDs across development is critical for creating and improving prevention and treatment strategies—especially for SUDs for which there are limited effective therapeutic interventions available. The primary challenge of GxExD research is to determine how small genetic effects across many genes combine to contribute to the overall risk for SUDs and how these genetic effects change with varying environmental exposures across human development.
A number of single-gene variants that contribute to SUD risk have been identified. In addition, research has successfully identified some environmental contributors to risk. For example, when a person experiences extreme or prolonged stress, changes in the epigenetic profile can make him or her more susceptible to drug taking and addiction.114 The nearly infinite biological complexity associated with individual genetics, variation in environmental exposures, and diversity in human behavioral responses make GxExD research particularly challenging. However, new advances in genetic and epigenetic technology coupled with increasing and evolving computational power are allowing such challenges to become increasingly tractable. Using these technologies to study complex GxExD interactions gives us the power to transform our fundamental understanding of how drug use and addiction evolve.
The SUD treatment field has seen some important successes, but significant challenges remain. There are currently three medications approved by the U.S. Food and Drug Administration (FDA) to treat opioid addiction: buprenorphine, methadone, and extended-release naltrexone.91 While these have represented meaningful advances in the ability to treat opioid use disorders, the efficacy of these medications is far from ideal. In addition, while there are evidence-based psychosocial treatments (e.g., cognitive-behavioral therapy, contingency management interventions, etc.) available for the treatment of cocaine, methamphetamine, or cannabis use disorders, there are no approved medications for these SUDs. Moreover, many larger pharmaceutical companies are reticent to enter the addiction market because of the perception of a small market size, the difficulties in executing clinical trials in patients with SUDs (who frequently suffer from multiple comorbidities and who often do not adhere to the treatment protocol), and the high regulatory bar required to obtain approval by the FDA (i.e., the focus on abstinence instead of harm reduction).99
To accelerate development of new medications for SUDs, NIDA supports a dual strategy. The first is a "repurposing" strategy that focuses on medications already approved for other indications that may also show potential benefit for treating or preventing SUDs. This approach aims to leverage existing safety profiles and pharmacology data to lower development costs and shorten the timeline for obtaining FDA approval. The second is to translate basic knowledge of the molecular pathways and brain circuits involved in SUDs to develop new approaches that modulate specific targets and networks. In this context, novel therapeutic approaches include pharmacotherapies as well as biologics (e.g., vaccines, immunotherapies, peptides) and nonpharmacological interventions such as transcranial magnetic stimulation, deep brain stimulation, and neurofeedback, which modify the activity of specific brain regions and, thus, may have fewer adverse effects.
NIDA will continue to prioritize efforts to de-risk medication development and foster strategic partnerships to accelerate the development of therapeutics for SUDs using the combined strengths and resources of NIDA and outside organizations, including academic institutions, pharmaceutical and biotechnology companies, private and public foundations, and small businesses. In addition, efforts will focus on defining alternative end points other than abstinence, such as decreased drug use, that can be linked to improved patient outcomes to reduce the regulatory bar to obtain approval of new therapeutics. For example, a recent publication found that reduced use of cocaine decreased endothelial dysfunction, a marker of heart disease risk that is characteristic of chronic cocaine use.115
Treating Addictions with Antibodies
Can we prevent a drug from affecting the brain of the person who takes it? One promising approach is to tap into the well-known ability of antibodies in the immune system to recognize, stop, and get rid of foreign agents. Anti-addiction vaccines aimed at eliciting antibodies that block the effects of a specific drug have great potential for treating SUDs, and researchers have been exploring the feasibility of this approach against drugs such as nicotine, cocaine, heroin, and methamphetamine for several years.
The biggest challenge thus far has been getting an immune response strong enough to effectively neutralize the drug in the bloodstream before it enters the brain. NIDA continues to invest in research to enhance the potency of these vaccines, but we are also investing in an alternative approach called passive immunization. This approach bypasses the person’s immune response by using a monoclonal antibody that is made in a lab. An anti-methamphetamine monoclonal antibody (ch-mAb7F9) is in development, and the results are promising. The first-ever Phase I, randomized clinical trial of this approach found that ch-mAb7F9 was safe and well-tolerated, and that it remained at high enough levels in the blood to be effective for an average of 3 weeks.116 While these preliminary results are encouraging, more studies are needed to further assess its safety and side effects in active methamphetamine users.
The concept of ch-mAb7F9 is exciting because it offers specific advantages for addiction therapy over other vaccines. For example, the user’s immune system does not need to be functioning, making this type of therapy uniquely suited to patients with HIV and other conditions that suppress the immune system. Also, compared with vaccines, monoclonal antibodies can easily reach very high concentrations that can last much longer, and the dosing can be more precisely controlled. When combined, these properties can provide around-the-clock protection from methamphetamine’s effects, making people much less vulnerable to relapse and thus more likely to succeed with recovery.
Methamphetamine use disorder causes serious medical, social, and economic harm, yet there are currently no FDA-approved medications for its treatment. If successful, therapies like ch-mAb7F9—either alone or in combination with other treatments—have the potential to revolutionize how we treat, and maybe even someday prevent, addiction to methamphetamine and other drugs of abuse.
The specific symptoms experienced by people with SUDs are shaped by complex, interacting factors that range from co-occurring physical and behavioral health conditions to social and environmental influences. In addition, while much of the research focuses on the effects of taking a single drug, we know that most drug use and SUDs involve polydrug use, including alcohol and tobacco use. Further, different stages of life, such as adolescence, pregnancy, and old age, confer unique risk factors and treatment needs. Finally, when effective evidence-based prevention and treatment strategies are developed, there is often a significant research-to-practice gap in the implementation of these interventions. A broadening of research focus is necessary to include the context of such interacting complexities to develop and effectively disseminate interventions that meet the diverse needs associated with this variability in substance-use-related phenotypes.
Substance use, including tobacco use, and SUDs frequently occur in people with psychiatric and physical health comorbidities. These conditions can often arise from shared causal factors, and these comorbidities can interact to affect symptom profiles, illness trajectory, and treatment outcomes.69,117 As the field moves toward an integrative view of SUDs, phenotypes should be defined in a way that captures these underlying causes. Rather than considering all SUDs together, varied SUD phenotypes should be separated based on functional domains that can be defined biologically. Indeed, defining the pathway from gene variation to molecular profile, to neuron function and brain circuit activity, and then to disordered behavior will enable a deeper understanding of addiction and reveal new targets for prevention and treatment intervention.
The severity of any co-occurring condition can influence the course of another, which highlights the importance of effectively integrating treatments. Psychiatric disorders frequently occur along with SUDs and, in the case of nicotine, contribute significantly to shorter life expectancies among this population. In addition, SUDs are associated with increased risk of physical health comorbidities, including HIV, cancer, chronic pain conditions, and cardiovascular and cardiopulmonary diseases.118 Recent health care reform efforts are prioritizing integrated medical care for people with SUDs, and more research is needed to inform the development of treatment delivery strategies that simultaneously address SUDs and co-occurring conditions.
The complexity of interacting biological, environmental, and social factors that contribute to and sustain SUDs presents significant opportunities for the application of precision medicine. An individual’s environment, experience, and biology combine to determine their risk for developing an SUD, the trajectory the SUD will take, and the interventions that will be most effective for treating it. This is the inspiration behind the President Obama’s Precision Medicine Initiative, which will provide a foundation for the development of personalized interventions addressing the multiplicity of individual phenotypes.
More focused research is also needed to help address the significant research-to-practice gap in the implementation of evidence-based prevention and treatment interventions. Closing the gap between research discovery and clinical and community practice is both a complex challenge and an absolute necessity if we are to ensure that all populations benefit from the Nation’s investments in scientific discoveries. Research is needed to better understand the barriers to successful and sustainable implementation of evidence-based practices and to develop implementation strategies that effectively overcome these barriers. Conversely, there is also a need for research that addresses how to reduce the use of strategies and procedures that are not evidence based that may be harmful or wasteful.
NIDA will prioritize research that focuses on addressing real-world complexities, such as:
- Understanding the common underlying substrates and biological mechanisms that contribute to common comorbidities
- Research that incorporates real-world complexities including common comorbidities, pregnancy, development and aging, environmental stress, polysubstance use, etc.
- Development of prevention and treatment interventions that account for individual differences in biological, environmental, and social factors that impact SUD trajectories and phenotypes (precision medicine)
- Development, validation, and use of animal models that address real-world complexities
- Strategies to improve the effective and sustainable implementation of evidence-based prevention and treatment interventions (implementation science)
One core component of NIDA’s mission is supporting research that will ultimately improve individual and public health. To support this goal, NIDA is fostering a strong bidirectional translational pipeline spanning basic neuroscience to clinical and applied research that is focused on the neurobiological substrates of addiction. Efforts are focused on integrating and coordinating human and basic research spanning all stages of drug use (i.e., initiation through recovery) and stages of development (i.e., from childhood through senescence), and across scales (i.e., molecular to societal).
Basic research should identify potential mechanisms and processes that may provide targets for intervention—including new molecular, brain circuit, and behavioral targets—which should then rapidly be tested in humans. Clinical research findings should be translated in applied, patient-oriented, and population-based research to facilitate broad implementation of best practices and improve public health. Importantly, insights from clinical and applied research should be modeled in basic research to identify and understand the biological mechanisms underlying the various phases of addiction.
Human and animal studies that use directly comparable outcome measures and testing conditions offer a powerful translational opportunity. A key integrative interface between clinical and basic studies is provided by human laboratory studies, including those with healthy volunteers. A recent reorganization of NIDA’s divisions and branches was undertaken to foster bidirectional communication and interaction between clinical, applied, and basic research efforts. NIDA’s ongoing efforts in this area will promote strong collaborations across basic and clinical researchers to advance this goal.