A person’s genetic risk for developing a cannabis addiction is associated with structural brain differences during adolescence, even in individuals who have never struggled with substance abuse. The finding indicates that some brain variations previously attributed to marijuana use might partly originate from an inherited biological predisposition. The study was published in the Journal of Psychopharmacology.
Bipolar disorder is a severe mental health condition characterized by dramatic shifts in mood, energy, and activity levels. People with the condition experience intense emotional states known as mood episodes, which can include periods of extreme elation or irritability, known as mania, and periods of deep sadness, known as depression. The condition often emerges during the teenage years and is a leading cause of functional disability among youth globally.
Teenagers with bipolar disorder frequently face additional psychiatric challenges throughout their schooling and home lives. Research shows that about 30 percent of youth diagnosed with bipolar disorder also have a co-occurring substance use disorder. Cannabis use disorder ranks as the most common addiction in this specific clinical group. Youth with bipolar disorder use cannabis at higher rates than the general population and face an elevated risk of developing a long-term dependency on the drug.
Heavy cannabis use has been repeatedly linked to worse outcomes for individuals with bipolar disorder. These negative impacts include a higher risk of suicide, a delayed recovery process, and an increased likelihood of experiencing psychosis. Past brain imaging studies have also noted structural differences in the brains of teenagers who regularly consume cannabis, both with and without mood disorders. The exact nature of these differences has varied across different observational reports.
Some research points to larger gray matter volume in certain brain regions among users, while other reports document smaller volumes in those same areas. Because most of these studies observe people at a single point in time, it is difficult to determine whether cannabis changes the brain or if people with preexisting brain differences are simply more likely to use the drug. To separate cause from effect in these brain measurements, scientists sometimes examine genetics. Addiction involves inherited physical traits, and modern genetic testing allows researchers to measure a person’s underlying vulnerability to an addiction before it ever develops.
Scientists do this using an advanced mathematical tool called a polygenic risk score. Unlike older tests that look for a single faulty gene, a polygenic risk score tallies up thousands of tiny genetic variations across a person’s entire DNA sequence. By comparing these variations against data from people who have a condition, researchers can calculate a customized score that estimates an individual’s overall genetic likelihood of developing that specific problem. Alysha Sultan, a researcher at the Centre for Addiction and Mental Health in Toronto, recognized an opportunity to apply this genetics tool to brain imaging.
Sultan and her colleagues set out to discover if a high polygenic risk score for cannabis use disorder correlated with brain structure in youths, regardless of their developmental history of drug use. The researchers recruited 114 teenagers and young adults between the ages of 13 and 20. The sample included 67 youths who had been diagnosed with bipolar disorder at a specialty psychiatric clinic. The remaining 47 participants were healthy controls randomly recruited from the community who had no personal or family history of major psychiatric disorders.
The team asked all participants to provide a saliva sample. From this saliva, the scientists extracted DNA and scanned the genetic sequences to calculate a specific polygenic risk score for cannabis use disorder for every participant. To create the scoring baseline, they relied on data from a preexisting study of adults that mapped the genetic profiles of tens of thousands of people with a diagnosed cannabis dependency.
After collecting the genetic data, the researchers brought the participants in for brain imaging. They used a magnetic resonance imaging machine, commonly known as an MRI, to capture high-resolution pictures of the participants’ brains. The team focused on the cerebral cortex, the folded outer layer of the brain that manages complex thought, memory, and perception.
The researchers measured three specific physical traits of the cerebral cortex: volume, surface area, and thickness. Volume refers to the total amount of space a specific brain region takes up, while surface area measures the expanse of the folded outer layer. Thickness gauges the physical depth of the gray matter on that layer. The scientists wrote statistical models to compare these structural measurements against the participants’ genetic risk scores, accounting for variables like age, sex, and overall head size.
The neuroimaging data revealed a consistent physical pattern. Across the entire group of youths, a higher genetic risk score for cannabis use disorder matched up with localized reductions in brain size. The researchers observed lower total volume and lower surface area in a brain region called the right superior frontal gyrus. Located near the very top and front of the brain, the superior frontal gyrus is involved in higher cognitive functions such as spatial processing and working memory, which is the ability to hold and manipulate information in the mind over short periods.
The researchers also noticed a smaller surface area in a region called the left paracentral lobule. This area rests near the top center of the brain and helps process sensory information from the body. These results were evident regardless of whether the youths had bipolar disorder or whether they had ever tried cannabis. The researchers ran specialized tests that completely excluded the participants who currently or previously had a cannabis use disorder, and the structural differences remained.
When the team split the participants by diagnosis, they found similar patterns among the healthy volunteers. Healthy teenagers with a higher genetic risk for the addiction exhibited lower brain volume and surface area in both the left and the right superior frontal gyrus.
The results among the participants diagnosed with bipolar disorder were not statistically significant when analyzed on their own. The researchers suspect this outcome relates to the vast biological complexities associated with bipolar disorder itself. The youths with the condition had high rates of anxiety and attention difficulties, took various psychiatric medications, and reported different medical histories. These competing factors may alter brain structure in their own localized ways, creating statistical noise in the data that masks the subtler differences linked strictly to the cannabis risk genes.
Sultan and her colleagues pointed out a few constraints to their investigation. Addiction involves similar genetic pathways across different types of substances, meaning people with a genetic liability for cannabis use disorder often share a generalized genetic vulnerability to alcohol or nicotine. The risk scores used in the study might reflect a broader tendency toward behavioral disinhibition rather than a strict vulnerability to cannabis alone. The genetic baselines used in the study also relied on data from individuals of European ancestry, meaning the relationships might differ for people of other ethnic backgrounds.
The initial findings offer a new way to interpret past neuroimaging research. Because a genetic predisposition alone corresponds with smaller frontal brain regions, some of the brain differences previously blamed on teen marijuana use might have existed before the drug use began. The scientists suggest that longer studies following the same teenagers into adulthood could help explain how inherited vulnerabilities shape the growing brain over time.
The study, “Association of polygenic risk for cannabis use disorder with brain structure among youth with and without bipolar disorder,” was authored by Alysha A. Sultan, Clement C. Zai, Kody G. Kennedy, L. Trevor Young, Bradley J. MacIntosh, and Benjamin I. Goldstein.