There have been a number of controversial studies that have linked long-term marijuana use with various forms of mental illness (including at least one we've covered). However, the effects of short-term use have generally seemed to be pretty minor. But a new study of Dutch teens suggests that cannabis use might be associated with the onset of symptoms associated with depression—but only if the teens carried a specific genetic predisposition.

There are a number of reasons to treat this result skeptically. The numbers are small, there are a lot of potential confounding factors, the statistical analysis used is fairly uncommon, and the particular genetic variant has a long history of controversial associations with various behavioral traits. But the authors validated their work on a second population, which at least suggests the study is worth following up on.

The authors of the new study indicate there's a history of research looking into the association between depressive behavior and the use of cannabis, but the record is very mixed. They then suggest a possible explanation for the confusion: cannabis can induce these symptoms, but only within those genetically predisposed to respond in that manner.

They then propose and test a very specific genetic factor: a variant form of the serotonin reuptake protein, which clears the neurotransmitter out of nerve synapses after signaling takes place. The gene is targeted by a variety of antidepressants, which does make it a reasonable candidate. Unfortunately, past attempts to tie this variant to depression have been just as mixed as the cannabis studies; some have found a link, others not, and a meta-analysis of multiple studies argues that there is no connection.

So this probably isn't the best gene to go fishing with if you're hoping for a new association. But the authors do so, with surprising confidence, writing, "It is likely that the link between cannabis use and depressive symptoms is conditional on the presence of the short allele of the 5-HTTLPR polymorphism of the serotonin transporter gene."

The typical approach at this point would be to aim for a large population and have a rigorous diagnosis of depression, scoring for the serotonin signaling genotype and surveying about cannabis use. Again, that's not quite what the authors did. Instead, they worked with a small population of Dutch families, did the genotyping, and tracked a cohort of teenagers over several years, doing surveys on frequency of marijuana use and general behavioral tendencies using a survey called the Quick Big Five. Other factors that were considered were alcohol and tobacco use, as well as parental education and skills.

Cannabis usage went up from 10 percent to just under 40 percent by the end of the study, with about 17 percent of the teens being weekly users by the end of the study. The authors had originally planned to do an analysis that included five categories of use, but the numbers in each category were too small, so they had to lump them into just three.

The next unusual feature of the study was its statistical analysis. Instead of simply testing for association, the authors performed what's called a parallel-process latent growth model, which is a method of testing whether the growth curves of two features follow similar trajectories. The authors describe the process as "regressing the intercept and the slope of depressive symptoms on the intercept of cannabis use and by regressing the intercept and the slope of depressive symptoms on the intercept of cannabis use simultaneously." This measures whether the two factors, cannabis use and depressive symptoms, show a similar growth during the study period.

On its own, marijuana use was not associated with depressive symptoms, nor with the specific serotonin signaling genotype at issue. (Both cannabis use and depressive symptoms were linked to other factors, like an openness to new experiences and a lower level of parental support, respectively.) But their parallel-process analysis showed a significant correlation between the onset of cannabis use and the trajectory of depressive symptoms specifically in the groups with the serotonin signaling variant. The same analysis in the control group showed no such link. The authors then performed the same analysis with the younger siblings in the same set of families, and came up with the same result.

The authors are appropriately cautious about claiming causation, using terms like "might" and noting that the environment during the teen years has a rather complex impact on emotional development, and so there could be a number of external factors that drive both trends. They also "stress the necessity for replication in larger samples to ensure the stability of such interaction." So they're not trying to oversell their results, and explicitly call for larger studies to confirm them.

That raises the obvious question of whether the results are likely to hold up. There are a lot of reasons to think they won't, the iffy history of this particular serotonin signaling gene being just one of them. The numbers are small, the statistical analysis a bit unusual, and the general scoring of depressive symptoms (instead of actual clinical symptoms) all seem to allow a lot of room for a few outliers to skew the results. In addition, the teen years are a rather complex time, and experimenting with cannabis is just one of a large number of things that might end up influencing a teen's mood.

I think it might be worth looking at in a larger population, but I wouldn't be surprised if nothing turns up when it's done.

Addiction Biology, 2011. DOI: 10.1111/j.1369-1600.2011.00380.x (About DOIs).