A person’s genetic risk of developing cannabis addiction, even in people who have never suffered from drug abuse, is linked to structural differences in the brain during adolescence. The findings indicate that some of the brain mutations previously thought to be caused by marijuana use may stem in part from genetic biological predispositions. The study was published in the Journal of Psychopharmacology.
Bipolar disorder is a severe mental health condition characterized by dramatic changes in mood, energy, and activity levels. People with this condition experience intense emotional states known as mood episodes. This may include periods of extreme elation or irritability, known as mania, or periods of deep sadness, known as depression. This condition often begins in the teenage years and is a leading cause of functional disability in young people around the world.
Teens with bipolar disorder often face additional psychiatric challenges throughout their school and home lives. Research shows that approximately 30% 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 particular clinical group. Young people with bipolar disorder use cannabis at higher rates than the general population and face an increased risk of developing long-term dependence on the drug.
Heavy cannabis use has been repeatedly associated with worse outcomes in patients with bipolar disorder. These negative effects include increased risk of suicide, delayed recovery process, and increased likelihood of experiencing psychosis. Previous brain imaging studies have also pointed to structural differences in the brains of teens who regularly consume cannabis, with and without mood disorders. The exact nature of these differences varies from observational report to observational report.
Some studies note that users have larger gray matter volumes in certain brain regions, while others report smaller gray matter volumes in the same regions. Most of these studies look at people at one point in time, so it’s difficult to determine whether cannabis causes changes in the brain, or whether people with pre-existing brain differences are simply more likely to use cannabis. To distinguish cause and effect in these brain measurements, scientists sometimes test genetics. Addiction involves genetic physical traits, and modern genetic testing allows researchers to measure a person’s potential vulnerability to addiction before it develops.
Scientists do this using a sophisticated mathematical tool called a polygenic risk score. Unlike older tests that look for a single faulty gene, polygenic risk scores aggregate thousands of small genetic variations across a person’s DNA sequence. By comparing these variations with data from people with the disease, researchers can calculate a customized score that estimates an individual’s overall genetic likelihood of developing a particular problem. Alisha Sultan, a researcher at Toronto’s Center for Addiction and Mental Health, recognized an opportunity to apply this genetic tool to brain imaging.
Sultan and her colleagues set out to discover whether high polygenic risk scores for cannabis use disorder correlated with brain structure in young people, regardless of their developmental history of drug use. Researchers recruited 114 teenagers and young adults between the ages of 13 and 20. The sample included 67 young people diagnosed with bipolar disorder in a specialized psychiatric clinic. The remaining 47 participants were healthy controls randomly recruited from the community with no personal or family history of major mental illness.
The team asked all participants to provide saliva samples. Scientists extracted DNA from this saliva, scanned it for genetic sequences, and calculated a specific polygenic risk score for cannabis use disorder for all participants. To create a baseline for scoring, they relied on data from an existing study of adults that mapped the genetic profiles of tens of thousands of people diagnosed with cannabis dependence.
After collecting the genetic data, the researchers took the participants for brain imaging tests. They used a magnetic resonance imaging machine, commonly known as an MRI, to take high-resolution pictures of the participants’ brains. The research team focused on the cerebral cortex, the folded outer layer of the brain that manages complex thinking, memory, and perception.
The researchers measured three specific physical characteristics of the cerebral cortex: volume, surface area, and thickness. Volume refers to the total amount of space occupied by a particular brain region, while surface area measures the extent of the folded outer layer. Thickness measures the physical depth of the gray matter above that layer. The scientists created a statistical model to compare these structural measurements to participants’ genetic risk scores, taking into account variables such as age, gender, and overall head size.
Neuroimaging data revealed a consistent body pattern. Across youth groups, higher genetic risk scores for cannabis use disorder were consistent with reduced regional brain size. The researchers observed a decrease in total volume and surface area in a brain region called the right superior frontal gyrus. The superior frontal gyrus is located near the top and front of the brain and 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 for short periods of time.
The researchers also noticed that a region called the left paracentral lobule had a smaller surface area. This area is located near the top center of the brain and helps process sensory information from the body. These results were evident regardless of whether the young people had bipolar disorder or had tried cannabis. Although the researchers conducted a special test that completely excluded participants who had a current or former cannabis use disorder, structural differences remained.
When the team divided participants by diagnosis, they found similar patterns among healthy volunteers. Healthy teens with a high genetic risk for addiction had smaller brain volumes and surface areas in both the left and right superior frontal gyri.
Results for participants diagnosed with bipolar disorder were not statistically significant when analyzed independently. Researchers believe this result may be related to the vast biological complexity associated with bipolar disorder itself. Youth with the disorder had higher rates of anxiety and decreased attention, were taking a variety of psychiatric medications, and reported a variety of medical histories. These competing factors can alter brain structure in unique, localized ways and generate statistical noise in the data that masks subtle differences strictly related to cannabis risk genes.
Sultan and colleagues noted that the study has several limitations. Addiction involves similar genetic pathways across different types of substances. This means that people with a genetic predisposition to cannabis use disorder often share a systemic genetic vulnerability to alcohol and nicotine. The risk score used in this study may reflect a broader trend toward behavioral disinhibition rather than a strict vulnerability to cannabis alone. The genetic baseline used in this study also relied on data from individuals of European descent, meaning the relationship may be different for people of other ethnic backgrounds.
The first findings provide a new way to interpret past neuroimaging studies. Because only genetic predisposition corresponds to smaller frontal brain regions, some of the brain differences traditionally attributed to teenage marijuana use may have existed before drug use began. Scientists suggest that long-term studies that follow the same teenagers into adulthood could help explain how genetic vulnerabilities shape the developing brain over time.
The study, “Polygenic risk and association with brain structure for cannabis use disorder in youth with and without bipolar disorder,” was authored by Alisha A. Sultan, Clement C. Zai, Cody G. Kennedy, L. Trevor Young, Bradley J. McIntosh, and Benjamin I. Goldstein.
