Brain differences in childhood predict substance use in later life, study finds

A recent study published in JAMA Network Open has found that subtle differences in brain structure during late childhood are linked to whether young people start using substances like alcohol, nicotine, or cannabis in their early teens. Children who initiated substance use before the age of 15 tended to have slightly larger overall brain volumes and a thinner prefrontal cortex compared to their peers who did not use substances. Importantly, these brain characteristics were often detectable even before the young people had ever tried substances, suggesting they could be pre-existing factors that increase the likelihood of early substance use.

The widespread use of psychoactive substances and the serious problems that can arise from it, such as addiction and health issues, are a major concern for public health around the world. While the most severe consequences of substance use often become apparent in late adolescence or young adulthood, the path towards these problems frequently begins much earlier. It is well-established that starting to use substances at a young age is a strong predictor of developing substance use problems later in life. Therefore, understanding what puts some young people at risk of starting substance use early is a critical area of research.

Previous studies using brain imaging have shown that people with substance use problems often have differences in their brain structure compared to those without such problems. These differences have been observed as reductions in the amount of gray matter in the brain, a thinning of the outer layer of the brain called the cortex, and less integrity in the brain’s white matter, which is responsible for communication between brain regions.

While these brain changes are often seen across the entire brain, some areas, like the hippocampus (important for memory) and the prefrontal cortex (involved in decision-making and self-control), seem to be particularly affected. However, much of this previous research has looked at brain structure in people who already have substance use problems. This makes it difficult to determine whether these brain differences are a result of substance use itself, or if they were present beforehand.

Some research has started to suggest that these brain differences may not just be caused by substance use, but could also be pre-existing risk factors. For example, studies following children over time have found that children with smaller brain volumes and a thinner prefrontal cortex are more likely to start using alcohol later in adolescence. Furthermore, studies of families have shown that even children who do not drink heavily, but have siblings or parents with alcohol problems, also tend to have similar brain structure differences.

These findings suggest that brain structure might play a role in making some individuals more susceptible to substance use, possibly due to a combination of genetic predispositions and environmental influences. This idea aligns with broader theories about addiction, which propose that brain biology can be both a cause and a consequence of substance use. Developmental theories also highlight that the way the brain develops during adolescence, with an imbalance between emotional drive and cognitive control, might contribute to a greater vulnerability to substance use during this period.

To explore this further, researchers analyzed data from the Adolescent Brain and Cognitive Development (ABCD) Study. This large, ongoing study is following the development of over ten thousand children across the United States from childhood into young adulthood. The researchers wanted to see if differences in brain structure, measured when the children were around 9 or 10 years old and had not yet started using substances, could predict whether they would begin using substances in the following years. Specifically, they wanted to know if brain variations present in late childhood were associated with starting to use substances before the age of 15.

“A lot of existing research on brain structure associations with substance involvement has focused on the effect of substance use on the brain, typically in the context of substance use disorders, rather than the brain on substance use,” explained study author Alex P. Miller, an assistant professor of psychiatry at Indiana University School of Medicine, who conducted the research while a postdoctoral fellow at Washington University School of Medicine working with Arpana Agrawal and Ryan Bogdan.

“This study provided the opportunity to investigate this latter possibility and examine whether pre-existing brain structure differences in late childhood were associated with early substance use initiation in early adolescence in a large sample well-designed to examine this question.”

The researchers used data from nearly 10,000 children participating in the ABCD study. These children were initially between 9 and 11 years old when they joined the study. As part of the ABCD study, the children underwent brain scans using magnetic resonance imaging, a technique that provides detailed pictures of the brain’s structure. These scans were performed at the beginning of the study. The children and their parents also participated in regular interviews, both in person and over the phone, over the next three years. During these interviews, they were asked whether they had ever used alcohol, nicotine, cannabis, or other illicit substances.

The researchers defined “substance use initiation” as having used any of these substances at any point during the three-year follow-up period. They focused on early initiation, specifically before the age of 15. They considered the use of alcohol, nicotine, and cannabis separately, as well as any substance use in general. It is important to note that they excluded instances of alcohol or nicotine use that were solely within religious ceremonies, focusing on use in other contexts. Children who reported using any substance during this period were categorized as “initiators,” while those who reported no substance use were considered “non-initiators.”

From the brain scans, the researchers measured a wide range of brain structure features. These included overall measures like the total volume of the whole brain, the volume of the cortex, the volume of subcortical gray matter, the total surface area of the cortex, and the average thickness of the cortex. They also measured the volumes of specific subcortical structures, such as the hippocampus, amygdala, and caudate. Furthermore, they analyzed the volume, thickness, surface area, and depth of folds in 34 different regions of the cortex in both hemispheres of the brain. In total, they examined nearly 300 different brain structure measurements.

To analyze the data, the researchers used statistical methods to compare the brain measurements of children who initiated substance use with those who did not. They took into account factors that could influence brain development and substance use, such as the child’s age, sex, stage of puberty, whether they were a twin or sibling in the study, and the type of magnetic resonance imaging scanner used for their brain scan. By controlling for these factors, the researchers could isolate the relationship between brain structure and substance use initiation more clearly.

The study’s findings revealed several significant associations between brain structure and early substance use initiation. Children who went on to initiate substance use before age 15 showed, on average, larger overall brain volumes, including larger total brain volume, cortical volume, subcortical volume, and cortical surface area. Regionally, they found that those who initiated substance use had a thinner cortex in a specific area of the prefrontal cortex, called the right rostral middle frontal gyrus. However, in other regions of the brain, specifically in the temporal, occipital, and parietal lobes, they observed a thicker cortex in the substance-using group.

When they looked at specific substances, they found that alcohol use initiation largely mirrored the findings for any substance use, which is not surprising given that alcohol was the most commonly used substance in this age group. They found similar associations between larger brain volumes and thinner prefrontal cortex with alcohol initiation. Nicotine and cannabis use initiation showed some unique associations with brain structure as well, but these were less consistent and did not hold up to the strictest statistical tests applied in the study.

“The findings of the study suggest that early adolescent substance use is associated with differences in brain structure measured in late childhood and that some of this brain structure variability precedes initiation,” Miller told PsyPost. “Variability in brain structure may partially reflect predispositional risk for initiating substance use earlier in life which is, in turn, associated with greater risk of developing a substance use disorder later in life.”

“The fact that there are associations between brain structure and early substance use, some of which preceded substance exposure, to me, was not as surprising as the particular pattern of results. Namely, that substance use initiation was associated with larger global brain metrics, while later stages of substance involvement (substance use disorders) are typically associated with smaller global brain metrics.”

“Similarly, thinner prefrontal cortex being associated with early substance use initiation was largely consistent with our hypotheses and prior research; however, that this was paired with thicker cortical regions elsewhere was unexpected and suggests a possible pattern of differential brain development that will be interesting to follow up on in future studies.”

To ensure their findings were robust, the researchers conducted additional analyses. They repeated their analyses, excluding children who had already used substances before the baseline brain scan, to focus on brain features present before substance use began. The results remained largely consistent, suggesting that the observed brain structure differences were indeed present before substance use began for most of these children. They also considered the potential influence of prenatal substance exposure but found that this did not change their main findings.

But as with all research, there are some caveats. “Recent research suggests that many brain-behavior associations may be characterized by relatively small effects,” Miller noted. “Given the small effect sizes we are seeing and the level of exposure studied being the very earliest forms of substance involvement, the results of our study are not clinically meaningful or predictive of individual outcomes for substance use disorder treatment.”

“However, these findings do inform, and to some extent, challenge current theoretical models of addiction. As researchers continue to follow participants of the ABCD Study over time, the hope is that we will continue to learn more about how brain structure and brain activity influences and is influenced by substance use in ways that will someday improve precision healthcare approaches.”

“We are currently examining the degree to which these brain structure differences related to early substance use initiation might themselves be influenced by differences in both environmental and genetic factors as well as to what extent brain structure correlates of early substance use initiation might overlap with those related to impulsive personality traits,” Miller added.

The study, “Neuroanatomical Variability and Substance Use Initiation in Late Childhood and Early Adolescence,” was authored by Alex P. Miller, David A. A. Baranger, Sarah E. Paul, Hugh Garavan, Scott Mackey, Susan F. Tapert, Kimberly H. LeBlanc, Arpana Agrawal, and Ryan Bogdan.