Early Marijuana Use: A More Harmful Impact on Brain Structure

Deborah Brauser

November 11, 2014

The link between long-term marijuana use and altered brain structure may depend on the age at first use and duration of use, new imaging research suggests.

Dr Francesca Filbey

A study of 110 adult participants show that long-term marijuana users have reduced gray matter volume and increased structural and functional connectivity in the orbitofrontal cortex (OFC), a brain region responsible for decision making, compared with nonusers. The findings also suggest that early onset of regular marijuana use may be associated with increased functional connectivity in white matter, whereas long duration of marijuana use might be tied to decreased structural connectivity.

"This was a much more comprehensive approach than has been done in the past," lead author Francesca M. Filbey, PhD, associate professor in the School of Behavioral and Brain Sciences at the University of Texas (UT) at Dallas and director of cognitive neuroscience research in addictive disorders at UT's Center for BrainHealth, told Medscape Medical News.

Dr Filbey noted that the findings show that clinicians should be aware of these long-term effects, as well as the fact that "the picture is very complex."

"Another important point from the paper is that there was a direct relationship with age of onset. So those who began regular use at adolescence seemed to have the greater effects on these brain measures, including greater volume reduction," she said.

The study was published online November 10 in the Proceedings of the National Academy of Sciences of the United States of America.

Inconsistent Findings

"We still know very little about the long-term effects of marijuana on the brain," said Dr Filbey, adding that although past studies have examined long-term marijuana use and brain alterations, the findings "remain inconclusive."

"Although functional changes have been widely reported across cognitive domains in both adult and adolescent cannabis users, structural changes...have not been consistent," write the investigators.

For the current study, the researchers sought to examine effects on the brain from delta-9-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, using three different magnetic resonance imaging (MRI) techniques.

They used whole brain MRI to measure gray matter volume in 48 adult marijuana users (59% men; mean age, 28.3 years) and 62 matched nonusers (63% men; mean age, 30 years) from the Albuquerque, New Mexico, metropolitan area.

The cannabis users reported using the substance at least four times per week during the previous 6 months. Current use was confirmed through positive urinalysis.

Resting state functional MRI scans were used to measure functional connectivity of the brain, and a diffusion tensor imaging (DTI) scan was used to assess structural connectivity between brain regions through white matter tracts. Fractional anisotropy (FA) was used as a value scale to describe the DTI process.

Results showed that the marijuana users had significantly lower gray matter volume in the right middle orbitofrontal and left superior orbitofrontal gyri than the nonusers (P < .01), as well as higher resting functional connectivity in the left and right OFC (P < .005 and < .05, respectively) and the left and right temporal gyri (P < .01 and < .05, respectively).

"This increased functional connectivity in users may suggest a compensatory mechanism whereby greater network recruitment is engaged to compensate for OFC liability," explain the investigators.

The cannabis group also showed higher structural connectivity through FA of the forceps minor (anterior forceps) tract, which connects orbitofrontal regions (P = .003 when using automatic measuring methods, P < .001 when using manual methods).

"Possible explanations for these findings...include differential effects of cannabis depending on the specific fiber tract," write the researchers.

"Specifically...it is possible that there are unique neural adaptations to the forceps minor that are unlike other white matter tracts in the brain (eg, corpus callosum)," they write, adding that anti-inflammatory effects of cannabis could also have led to greater FA.

Earlier age at first use was also associated with higher OFC functional connectivity (P < .05).

Impaired Decision Making

Interestingly, an observed trend showed initial increases in the FA and radial diffusivity (RD) of the forceps minor tract when the participants began heavy use of marijuana ― but this decreased with long-term regular use.

In 27 marijuana users who did not use any other substances, additional analyses showed a significant correlation between use duration and FA (P = .05) and RD (P = .016) of the forceps minor tract.

Finally, there was a significant inverse relationship between bilateral OFC gray matter volume and psychological and social problems in these "exclusive users" of marijuana. Lower volumes were associated with higher total scores on the Marijuana Problem Survey.

The overall findings suggest "differential effects of initial and chronic marijuana use that may reflect complex neuroadaptive processes," write the investigators.

"This is important for clinicians because this area of the brain is important," added Dr Filbey. "The OFC helps us to make informed decisions. It helps us with environmental cues and how we respond to them. So it's likely that any impairment in this region could lead to deficits in decision making."

However, the investigators note that more research is needed to determine causality and whether the brain changes can be reversed if marijuana use is discontinued.

Dr Filbey said that next steps include trying to understand whether the effects reflected preexisting brain conditions or whether they were a direct result of marijuana use by looking at genetic mechanisms. Plus, they hope to use a longitudinal approach in the future "to really determine which came first."

The study authors have reported no relevant financial relationships.

Proc Natl Acad Sci. Published online November 10, 2014. Abstract

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