A study of 169 men found that medial prefrontal cortex volume loss was associated with the total number of substances used rather than any single drug, though tobacco and cocaine showed specific effects in other brain regions after controlling for polysubstance use.
Neuroscience researchers studying substance effects on brain structure; addiction researchers; anyone interpreting neuroimaging studies of cannabis users.
Prefrontal volume loss tracked with number of substances used, not any individual drug
What the researchers found
Researchers measured gray matter volume in 169 men across six groups ranging from non-users to heavy polysubstance users (alcohol, tobacco, cocaine, and cannabis).
The number of substances used was negatively associated with volume in the dorsal and ventral medial prefrontal cortex (mPFC). More substances used correlated with less volume in these regions.
Without controlling for other substances, alcohol, tobacco, and cocaine all showed negative associations with dorsal mPFC volume. But after controlling for polysubstance use, these associations disappeared for the mPFC.
Substance-specific effects did emerge in other regions: tobacco was specifically associated with reduced thalamic volume, and cocaine with reduced ventrolateral PFC volume, even after accounting for other substance use.
Cannabis did not show independent effects on gray matter volume after controlling for other substance use.
Why it matters
Most brain imaging studies of cannabis users do not adequately control for polysubstance use. This study demonstrates that brain volume differences often attributed to individual substances may actually reflect cumulative polysubstance exposure, which changes how we interpret neuroimaging findings.
The numbers in context
169 males: 15 non-users, 89 moderate drinkers, 27 drinkers + tobacco, 13 drinkers + tobacco + cocaine, 10 heavy drinkers + tobacco + cocaine, 15 heavy drinkers + tobacco + cannabis + cocaine. Dorsal and ventral mPFC volume negatively correlated with number of substances.
How the study worked
Cross-sectional neuroimaging study of 169 males in six substance use groups. Voxel-based morphometry for gray matter volume. Regression analyses with and without controlling for co-occurring substance use.
What this study cannot tell us
Cross-sectional design cannot establish causation. All-male sample limits generalizability. Cannabis users were only in the heaviest polysubstance group, making it hard to isolate cannabis-specific effects. No pre-substance-use baseline measurements.
How to read the evidence
Moderate. Well-designed neuroimaging study with appropriate controls for polysubstance use, but cross-sectional design and all-male sample limit causal inference.
When this study was published
Published in 2018. The importance of controlling for polysubstance use in neuroimaging research has been increasingly recognized.
The bigger picture
This challenges the common approach of studying single-substance effects on the brain without accounting for polysubstance use. The mPFC findings suggest a general "substance burden" effect, while specific substances may affect distinct brain regions beyond this general effect.
Questions still open
- Would cannabis show independent brain effects in a sample of cannabis-only users? Does the cumulative substance burden effect reverse with abstinence? Are the mPFC changes a cause or consequence of polysubstance use?
Common questions
Does this mean cannabis does not damage the brain?
Why does the number of substances matter more than which ones?
Read the original research
The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users.
Drug and alcohol dependence, 187, 186-194
Citation
Kaag, A M; Schulte, M H J; Jansen, J M; van Wingen, G; Homberg, J; van den Brink, W; Wiers, R W; Schmaal, L; Goudriaan, A E; Reneman, L. (2018). The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users.. Drug and alcohol dependence, 187, 186-194. https://doi.org/10.1016/j.drugalcdep.2018.03.010
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