Early and frequent use of cannabis is associated with major depressive disorder (MDD) as well as suicidal thoughts and behaviors, a large twin study suggests.
Investigators led by Arpana Agrawal, PhD, associate professor of psychiatry, Washington University in St. Louis, found that among monozygotic twins, those who used cannabis were more than 100 times more likely to meet criteria for MDD and report suicidal ideation than their genetically identical twin who had never used cannabis or who had used it less frequently.
This finding held true when the researchers adjusted for covariates. However, occasional use of cannabis was not associated with MDD and suicidal thoughts or behaviors.
"We need to carefully evaluate the relationship between various levels of cannabis use, from casual to heavy and problematic, and serious mental health outcomes, like depression and suicidal thoughts and behaviors," Dr Agrawal told Medscape Medical News.
"We also need to examine all possible pathways that might lead to this association, such as shared genetic factors, and exclude them before ascribing causal effects," she said.
The findings were published online July 24 in Lancet Psychiatry.
Role of Monozygous Twins
Previous research linked cannabis use and MDD and suicidal thoughts and behaviors. Daily cannabis use — especially during adolescence — has been associated with 6.8 odds of attempted suicide, the authors note.
Studying monozygous twins reared together is a useful avenue of exploration because cannabis use and suicidal thoughts and behaviors have been shown to be highly heritable. Because monozygotic twins share genetic and, typically, early familial influence, it follows that if a twin who uses cannabis shows an increased likelihood of MDD or suicidal thoughts and behaviors compared with their twin who does not use cannabis, "this residual association might be viewed as evidence supporting person-specific factors and causal mechanisms.
"Although prior research suggested that heavy cannabis use can increase likelihood of depression and suicidal thoughts, results were mixed, with some studies suggesting other factors, such as childhood neglect, that could explain the association," Dr Agrawal said.
"We also know that genetics are an important factor that contributes to heavy cannabis use, depression, and suicidal ideation. We wanted to examine whether the association between heavy and early cannabis use and these mental health conditions would remain when we examined pairs of individuals who had the same genetic background — ie, identical twins — but with different levels of cannabis use," she explained.
To investigate these questions, the researchers conducted a retrospective study that drew on data from three studies that recruited twins from the Australian Twin Registry.
Sample 1 (n = 5846) included monozygotic and dizygotic twins (aged 24 to 90 years) who were born between 1902 and 1964. Those born between 1902 and 1940 were excluded because the use of cannabis was low in that age group. The cohort was invited to participate in a short telephone in Between 1992 and 1993.
Sample 2 (n = 6255) included twins aged 24 to 36 years who were born from 1964 to 1971 and were interviewed by telephone from 1996 to 2000. Sample 3 (n = 3299) included twins aged 27 to 32 years (born from 1972 to 1979) who were first interviewed from 2005 to 2009.
Respondents in all three studies were assessed using the Australian Semi-Structured Assessment for the Genetics of Alcoholism. All were interviewed about cannabis use and suicidal thoughts and behaviors, as well as MDD and all covariates.
Respondents who reported lifetime use of cannabis were asked about the age at first use and how many times they had used cannabis during their lifetimes. Use of cannabis before age 18 years (for sample 1) and before 17 years (samples 2 and 3) was defined as "early." Those who used cannabis ≥100 times were designated as "frequent" users.
The researchers analyzed early and frequent use both within the pool of individuals who reported a lifetime history of cannabis use and within the full sample. Participants were also asked about suicidal ideation and suicide attempts.
Participants were regarded as experiencing the onset of MDD if they reported experiencing either recurring episodes of dysphoria or anhedonia. Cases involving MDD or suicidality that occurred prior to cannabis use were excluded from analysis.
The researchers studied 13,986 twin individuals (6181 monozygotic and 7805 dizygotic, including opposite-sex). Monozygotic and same-sex dizygotic twin pairs were selected from this sample.
Mean age at onset of cannabis use was higher in sample 1 and was similar in samples 2 and 3 (21.1 years vs 18.9 years and 17.9 years, respectively). Early and frequent use were correlated (r = 0·46), with 44% of early users of cannabis also reporting frequent use, and 49% of frequent users also reporting use from a young age.
After temporal ordering, the researchers found that cannabis use was associated with both MDD and suicidal thoughts and behaviors, although these associations were no longer significant after accounting for covariates. For this reason, the researchers did not examine cannabis use in discordant twin models.
By contrast, both early and frequent cannabis use were "robustly associated" with MDD as well as suicidal thoughts and behaviors, with adjusted odds ratios (ORs) ranging from 1.28 to 2.38, after adjustment for covariates.
These significant associations persisted, even when the researchers excluded lifetime never-users of cannabis from the analysis. Frequent users were twice as likely to report suicidal ideation and attempt than were lifetime but less frequent users.
In analyses with and without never users, within-pair associations between early cannabis use, MDD, and suicidal thoughts and behaviors were significant within dizygotic twins but not monozygotic twins (OR 2.23 - 6.50 vs OR 1.17 - 2.00). This pattern of results is "consistent with shared genetic influences contributing to the association," the authors suggest.
Within both dizygotic and monozygotic pairs, the associations between frequent cannabis use and MDD, suicidal ideation, and persistent ideation were significant.
Compared with their genetically identical twin who did not use cannabis as frequently, a monozygotic twin who reported frequent use was more likely to meet criteria for MDD and report suicidal ideation and persistent ideation (OR, 1.72, 2.71, and 3.14, respectively).
An OR of ≥1 in a monozygotic twin "suggests that factors other than those shared by members of identical twin pairs contribute to the association," the authors state.
After accounting for covariates, twins who frequently used cannabis were at 2.35 to 2.47 odds of reporting suicidal ideation, as compared with their genetically identical twin who did not use cannabis as frequently or who had never used it at all. For users, the odds of MDD remained at 1.98 as compared with their identical twin who used cannabis less frequently.
"These results indicated that individual-specific factors other than these covariates contribute to the association between frequent cannabis use and MDD and suicidal ideation (but not persistent ideation)," the authors comment.
Compared to concordant unexposed twins, the prevalence of MDD and suicidal ideation in concordant exposed twins was greater, "suggesting a strong, main effect of frequent cannabis use on suicidal ideation." In discordant twins, the exposed twins were more likely to report suicidal ideation and MDD than their identical but unexposed twin.
"Importantly, although there was minimal effect of the co-twin's exposure status on an individual twin's report of suicidal ideation, the rate of MDD was slightly higher in unexposed twins from discordant than concordant pairs," the authors note.
"We speculate that familial factors may play a more important role in the relationship between depression and heavy cannabis use than for suicidal ideation because individuals who did not use cannabis heavily themselves, but their identical twin did, were slightly more likely to report depression than individuals who did not use cannabis heavily and also did not have a twin who did," said Dr Arpana.
It appears that "having an identical twin increases one's own chance of depression, even when one does not use cannabis heavily, possibly due to factors shared with that twin," she added.
The authors note that when the associations between early and frequent cannabis use and MDD and suicidal thoughts and behaviors were examined within identical twin pairs, frequent use remained associated with MDD and suicidal ideation, "suggesting that factors beyond those shared by identical twins might contribute to the association."
A Constellation of Factors
Commenting on the study for Medscape Medical News, Laura Huckins, PhD, postdoctoral fellow, Icahn School of Medicine at Mount Sinai, New York City, called the study "a very well-written paper in that the authors take into consideration that there are a whole constellation of mechanisms linking cannabis use to suicidal thoughts and behaviors."
She was "pleased" that "all avenues were investigated thoroughly."
Genetic, environmental, and neurobiological effects all play a role in the constellation of mechanisms, and "we always expect study findings to say 'yes to all' of these, as was found in this study," said Dr Huckins, author of an accompanying editorial. "The risk is multifactorial."
It is possible that the connection between frequent cannabis use and suicide risk is mediated by poor societal outcomes, and that removing stigma and criminality from cannabis smoking might improve these outcomes, she suggested.
"Societies where cannabis is legal see better mental health outcomes for those individuals and have lower levels of alcohol use, violent crime, and suicide rates for those who use cannabis." Further research is needed to elucidate this mechanism.
Dr Agrawal added that the study findings have important implications for public health policy.
"The role of heavy cannabis use in potential mental health outcomes with serious morbidity, such as depression, should be carefully evaluated, as the results might inform how we frame future policies regarding cannabis use."
The study was funded by the National Institute on Drug Abuse, the National Institutes of Health (NIH), and the Australian National Health and Medical Research Council. Dr Agrawal and a coauthor have received NIH funding and compensation for grant reviews for NIH outside the submitted work. Dr Huckins has disclosed no relevant financial relationships.
Medscape Medical News © 2017
Cite this: Heavy Cannabis Use Associated With Depression, Suicidality - Medscape - Jul 31, 2017.