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An extensive study utilizing the UK Biobank explores the impact of lifetime cannabis use on brain structure and function, suggesting significant changes but not necessarily causal relationships according to genetic analysis.
With increasing global legalization, understanding these effects is crucial, especially given the observed sex-based differences and lack of evidence supporting a safe usage threshold.
Lifetime cannabis use is linked to several changes in brain structure and function in later life, according to an observational study published in BMJ Mental Health. However, a genetic analysis of the same data suggests these associations may not be causal.
Researchers believe that other, unidentified factors may explain the observed differences, though they emphasize the need for further research to understand the full effects of heavy cannabis use and high potency on the brain.
Worldwide cannabis use has increased due to its legalization for medical and recreational purposes, but this has occurred without a thorough understanding of its potential long-term effects on the brain.
Evidence From Genetic Analysis
Cannabis use has been associated with negative impacts on neurocognitive performance, brain structure, and function, and researchers are uncertain if a safe threshold of use exists. Previous observational studies have not confirmed that cannabis directly causes the observed brain changes, and few studies have focused on older users.
In a bid to strengthen the evidence base, the researchers used Mendelian randomization, a technique that uses genetic variants as proxies for a particular risk factor—in this case cannabis use or dependence—to obtain genetic evidence in support of a particular outcome—in this study brain structure among older lifetime users.
Study Population and Methodology
They drew on 15,896 cannabis users participating in the UK Biobank for whom genetic profiling (2012-13) and brain imaging (MRI scans) (2014-19) data were available.
Participants reported if they had ‘ever taken cannabis’, with response options ranging from once or twice to more than 100 times.
All participants who responded ‘yes’ were categorized as lifetime cannabis users (3641; average age 61), with ‘no’ responders categorized as the comparison group (12,225; average age 64).
Cannabis users were further divided into low frequency users, defined as lifetime cannabis use of up to 10 times, and high frequency users defined as lifetime use of 11–100+ times. Participants also reported how old they were when they last used the drug.
The researchers accounted for a range of potentially influential factors, including: age at first scan (in years), sex, and age-by-sex interaction; level of deprivation; employment status; qualifications; smoking and alcohol consumption; blood pressure; weight (BMI); mental state; and 613 brain imaging-related variables.
Findings on Brain Structure and Function
After adjusting for these factors, cannabis use was associated with multiple measures of changes in brain structure and function.
Participants who had ever used cannabis had poorer white matter integrity, a constituent of the brain that is important for cognitive function. And this was particularly evident in the corpus callosum, the main route of communication between the left and right sides of the brain.
Cannabis users also had weaker resting state neuronal connectivity in brain regions which make up underlying the default mode network, thought to be active during mind wandering or daydreaming.
These areas of the brain are densely packed with cannabinoid receptors, the researchers point out.
Variations in Cannabis Impact by Sex
Neither the duration of cannabis abstinence nor the frequency of cannabis use were strongly associated with any of the observed findings in brain structure and function.
But there were some notable differences between the sexes: while significant associations were observed in six specific brain regions among the men, the observations seen in women were spread across 24 brain structures and functional regions.
Most associations were observed in functional connectivity among the men; in women, associations were primarily seen in white matter integrity, suggesting that cannabis use affects the sexes differently, say the researchers.
Genetic Findings and Their Implications
When Mendelian randomization was applied to the findings, no significant associations emerged between genetically predicted cannabis dependence/abuse or lifetime cannabis use.
“To the best of our knowledge, this is the largest observational study of relationships between cannabis use and brain structure and function to date, and the first Mendelian randomization investigation,” say the researchers.
“Cannabis users had significant differences in brain structure and function, most markedly for markers of lower white matter microstructure integrity. Genetic analyses found no support for causal relationships underlying these observed associations,” they add.
The Discrepancy Between Observations and Genetics
There are several possible explanations for the differences between the observational and Mendelian randomization findings, they suggest.
An unmeasured variable, such as family history, dietary intake, or use of certain medications, might have influenced the observational findings. And the Mendelian randomization analyses might have had less statistical power to detect small effects.
Mendelian randomization also assesses the lifelong impact of cannabis use, while changes in observational studies might be due to factors occurring at different points in a person’s life rather than cumulative impact across the life course, suggest the researchers.
They also acknowledge the limitations of using the UK Biobank, which is made up of predominantly healthy White participants. And few of those included in this study had cannabis use disorders.
Conclusion and Future Research
The researchers were also unable to look at the time points during life that might be critical for cannabis effects, and the study relied on participants’ recall concerning the amount or frequency of cannabis use during their lifetime, which may have been inaccurate.
They caution: “Our results need to be interpreted with careful consideration. Additional research is needed to understand the effects of heavy cannabis use in this population, including considerations of potency and related information to inform public policy.”
Reference: “Association between cannabis use and brain structure and function: an observational and Mendelian randomisation study” by Saba Ishrat, Daniel F Levey, Joel Gelernter, Klaus Ebmeier and Anya Topiwala, 30 October 2024, BMJ Ment Health.
DOI: 10.1136/bmjment-2024-301065
