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Seeking Input from the Research Community on the Upcoming Longitudinal Study of Adolescent Substance Use

July 04, 2014

By Nora Volkow (Director, NIDA), George Koob (Director, NIAAA), Alan Guttmacher (Director, NICHD), and Bob Croyle (Director, Division of Cancer Control and Population Sciences, NCI)

Photo of a group of teens

As we wrote in early May, the time is ripe for a large prospective cohort study that will comprehensively assess the effects of adolescent substance use on the developing brain. The proposed study will recruit a large sample of children prior to substance use initiation (around age 10) and follow them for a decade, throughout adolescence and into young adulthood, deploying a range of neuroimaging, behavioral, and other assessment tools to monitor individual trajectories of brain development and related outcomes. The necessary technology is now available, and given rapidly shifting policies and attitudes around substance use in our society, the need for answers is more and more pressing.

Planning has begun. An expert panel workshop convened in late May to start the process of developing recommendations for optimal large-scale project design and to discuss measures for assessing developmental effects of exposure to nicotine, alcohol, marijuana, and other drugs. A summary of that workshop is now available. In addition, we have just issued a formal request for information (RFI) to solicit advice for this project from the extramural research community and other stakeholders.  We invite you to weigh in on all aspects of the study—including optimal sample size and sampling strategies, approaches for replication of findings, and data-sharing arrangements that would balance Principal Investigators’ incentives with the need to keep the data open-access.

We believe that this study will be a major boon to investigators across a wide range of substance abuse and child development fields—not just those directly studying adolescent substance use and brain development.  In the process of gathering data to answer the primary research questions, the envisioned study will generate a very rich data set on normative brain development, diverse patterns of substance use, and on the full range of behaviors and symptoms of mental disorders. Thus, two ancillary benefits of this study include an infrastructure to further a wide range of research and the generation of extensive and comprehensive data for secondary analyses, including biospecimen collection for genetic and epigenetic analyses. It is even possible that sufficient information will be generated that new data-analytic methods will ultimately emerge.  Akin to other large, resource-intensive scientific projects, such as the Human Genome Project, the yield will far exceed the specific planned outcome, and thus the resources put into it will truly be an investment, in every possible sense.

We are extremely excited about the National Longitudinal Study of Neurodevelopmental Consequences of Substance Use, not only because it will clarify myriad unknowns about the effects of substance use on adolescent development and help answer the many questions currently being asked by health providers, policymakers, and the public, but also because it will contribute to answering new questions that researchers have not even begun to ask.

Responses to the RFI will be accepted until August 31, 2014. In addition, the NIH intends to host an open satellite event/meeting about this project at the Society for Neuroscience Annual Meeting in Washington DC, in November 2014. We anticipate that a Funding Opportunity Announcement (FOA) for the project will be issued jointly in 2015 by our institutes (the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, the National Cancer Institute, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development).

This page was last updated July 2014



Congratulations to you all for thinking big. I must read the background materials more carefully, but I can see five major challenges: (1) Ethics. I applaud consideration being given to ethics and responsible conduct of research, but is it going to be enough to screen and refer cases of 'problematic' alcohol, tobacco, and other drug use when we now have viable and apparently low toxicity interventions for early adolescents who have just started to use one or more of these drugs, and have not yet presented any of the prodromal or more advanced clinical features one might describe as a 'drug problem'? One viable approach is to offer, at random, an array of viable alternative early intervention maneuvers in order to try to dampen what otherwise might be an upward developmental trajectory toward the second trial use of the drug and acceleration beyond trial use toward drug problems of greater clinical significance. I would describe this solution as 'nesting the randomized intervention trial within the otherwise observational longitudinal design that, in retrospect, might look a lot like the Tuskegee syphilis studies. (2) Enviroment. The currently described array of measures looks a bit brain-heavy and "environment-lite" when the processes and sequences of primary interest most likely involve dynamic interplay of gene expression with potentially modulating environments. 'Academic performance' and 'IQ' are mentioned, but I'm not seeing any attention to environmental conditions that can be measured, and might well offset any drug-induced brain changes (e.g., frequency of playing chess, musical instruments, or even smartphone game apps, or frequency of listening to complex polyrhythmic music or reading more than a newspaper cartoon or a billboard). The environmental determinants of persistence of use also deserve more consideration. Peer drug use is mentioned, but there is more to it than that. For example, we've known for 20 years that boys have earlier and more chances to try drugs, as compared to age-matched girls, and the density of chances to try involves more than just peer drug use. In addition, partnering up with an abstinent partner and/or having babies come into play as well. Etc. etc. (3) Propensity scoring (i.e., high-end predictive models of the conditions and processes that precede early-onset of alcohol, tobacco, and other drug use so that the final analyses can clear away uncertainties of the following form: "You tell me that this brain deficit or below-normal reduced plasticity is due to early-onset drug use. Convince me that that same brain deficit or below-normal reduced plasticity is not explained by whatever it was that caused the early-onset users to become early-onset users." This is the Achilles heel of the discordant MZ co-twin design when it has been used to estimate effects of early-onset versus later-onset environmental exposures. It's necessary to account for why one MZ twin started early and the other MZ co-twin did not start early. The proposed design does not have the MZ design advantage of control over each co-twin's genetic similarity from the get-go at conception. (4) Migration. Take a look at the latest statistics on how highly mobile our American families have become during the past decade, and you'll discover a major challenge that will have to be faced as families of origin (at baseline) move from place to place and then the offspring begin departing from the family of origin and then begin their own migratory dances. (5) Instrumentation drift. Back in the 1980s Godfrey Pearlson and I started to design one of the first longitudinal studies of a community sample of adults, with structural MRI and neuropsychological testing at the core. This 'Aging Brain and Cognition (ABC)" study eventually was funded by NIH, but not until we had solved the problem of rapid technological changes in MRI instrumentation over the proposed five year longitudinal span. We had to contract with an imaging center that agreed not to upgrade to new machines. Forecast the additional challenge when the timeline for longitudinal followup stretches out beyond the five year horizon, and imagine what brain imaging technology will look like as today's 12 year olds mature out toward entry into early adulthood in 2024. We cooked up a solution called a 'sleeved design' that essentially requires two measurements at every time point of assessment, 't': one assessment at 't' with the imaging approach used in the prior wave of assessment at time t-1, and another assessment at 't' with the best imaging approach available at that 't'. It would be better to have three sequential assessments with the same imaging approach: 't' then 't+1' then 't+2', but when improvements in imaging approach are accelerating, this means three imaging sessions at each time point 't', and respondent burden might become overwhelming. Again, congratulations for thinking big. I'll look forward to the group's solutions to these challenges. Goodcheer! Jim

Prevención, ante todo.

Resultan muy interesantes estas investigaciones llevadas a cabo por el NIDA, sobre todo la de realización de un genotipo para poder determinar un programa individualizado para curar cada adicción o unificar dependencia a las drogas. Sobre todo me gusta el trabajo de difusión de los efectos en el cerebro de los diferentes tipos de drogas, porque la información adecuada es una herramienta básica para que los adolescentes se frenen antes de consumir. Felicidades por esta gran labor!!


I too would like to congratulate NIH for working together to advance studies of the neuroscience of addiction across the research institutes. However, like Jim Anthony I have some concerns about the "environment lite" approach. In this respect, I believe the greatest concern will be potential failures to address differential exposures of youthful drug users to other neurodevelopmental risks strongly correlated with drug use environments. The social and physical environments of users determine the conditions under which use is possible for any drug, the determinants of these conditions and the social and behavioral mechanisms by which they affect subsequent use and problems are coming to be better understood in the research community each year, and critically, use environments appear to determine much of the risks related to use among youth and adults. Substance use on its own terms is a marker for many developmental risks that can affect neurobiological outcomes (e.g., brain trauma related to violence) and some effects of substance use on the developing brain will likely be mediated through these, essentially environmental, mechanisms. Comprehensive assessments of developing risk environments will be essential to address this plausible set of confounding conditions. - Paul G

National Longitudinal Study of Neurodevelopmental Consequences..

I am curious to know if there will be an effort to identify and separate the understanding of the effects of specific substances, or will this be an all inclusive study of substance abuse in general?

Yes, an important aspect of

Yes, an important aspect of this study will be looking at all forms of substance use and patterns of co-use. The large sample size should enable us to tease apart the effects of different substances and also study their specific interactive effects in adolescents who use multiple substances.

quantifying change from repeated MRI measurements

The proposed study is ambitious, and potentially very exciting. Jim Anthony has identified a number of ethical, logistic, and substantive challenges that will need to be addressed in planning a longitudinal study of brain development and substance abuse in young people.

Let me add three items to Jim's list:
1. Although comparisons of repeated MRI measures of brain structure seem to be working out very well, it is not clear that tracking change in repeated measures of function in fMRI will work quite as well. A number of publications have documented that measurements from fMRI tasks typically show test-retest reliability only ~.50 over short durations (weeks, months). Variables with this limited level of measurement reliability are generally inadequate for tracking change over time, because most of the change observed in scores will necessarily be error. As a result, any longitudinal study of change in brain function associated with substance abuse will need quite a substantial amount of advanced focused effort on developing an fMRI protocol with statistical and psychometric properties strong enough for longitudinal work. This program of measurement development is sorely needed by the field, and it would be grand if the proposed study includes time and support for it.

2. MRI measures need a better nomological net of information about their consequences for human neuropsychological and personality function. Often we see comparisons of clinical group X versus healthy control group Y on a MRI measurement in a publication, but information as to whether this MRI difference is associated with any expected concomitant change in actual behavior is not provided. To insure such essential data are available, the proposed longitudinal study might include repeated neuropsychological testing and personality assessment, in parallel with each of the repeated MRI measurements. Of course this data collection adds time, cost, and subject burden, but without it, we may have evidence suggestive of anatomical change, but without any evidence of whether it matters.

3. A major stumbling block in recruiting a new cohort sample is non-response or refusal. Recent research by a National Academy panel pointed to only 50% participation rates in new cohorts and surveys in the USA in recent years. And of course, recruiting adolescents has its own special challenges. There are many ways of ensuring the hoped-for sample of pre-adolescents will represent the aimed-for population. But many of these ways require a lot of resources and strategic planning. Time and money will be needed for capturing the ideal sample as an initial basis for the longitudinal study.

This study will be great fun to plan. Terrie

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    NIDA. (2014, July 4). Seeking Input from the Research Community on the Upcoming Longitudinal Study of Adolescent Substance Use. Retrieved from https://www.drugabuse.gov/about-nida/noras-blog/2014/07/seeking-input-research-community-upcoming-longitudinal-study-adolescent-substance-use

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