Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins: a retrospective cohort study

doi:10.1016/S2215-0366(17)30280-8

The Lancet Psychiatry

Volume 4, Issue 9, September 2017, Pages 706-714

https://doi.org/10.1016/S2215-0366(17)30280-8 Get rights and content

Summary

Background

Early and frequent cannabis use are associated with an increased likelihood of major depressive disorder (MDD) as well as suicidal thoughts and behaviours. We identify associations between aspects of cannabis use, MDD, and suicidal thoughts and behaviours and examine whether such associations persist after accounting for those predisposing factors, including genetic liability and early family environment, that are shared by identical twins who are discordant for cannabis exposure. Any residual association in such identical pairs might be indicative of individual-specific pathways that might be of a causal nature.

Methods

We did a logistic regression analysis of cannabis use from retrospective data on same-sex male and female twin pairs drawn from 3 studies that had recruited twins from the Australian Twin Registry, 1992–93 (sample 1), 1996–2000 (sample 2), and 2005–09 (sample 3). We studied associations between early use and frequent use of cannabis and MDD, suicidal ideation (ever and persistent), and suicide plan and attempt in the full sample as well as in pairs of monozygotic and dizygotic twins that were discordant for each measure of cannabis involvement at a single timepoint. Significant monozygotic associations were further adjusted for covariates, such as early alcohol or nicotine use, early dysphoric or anhedonic mood, conduct disorder, and childhood sexual abuse. Interactions between each cannabis measure and sex, sample or study effects, and birth year category were also examined as covariates.

Findings

In 13 986 twins (6181 monozygotic and 7805 dizygotic), cannabis use ranged from 1345 (30·4%) of 4432 people in sample 1 to 2275 (69·0%) of 3299 in sample 3. Mean age of first cannabis use ranged from 17·9 years (SD 3·3) in sample 3 to 21·1 years (5·2) in sample 1, and frequent use (≥100 times) was reported by 214 (15·9%) of 1345 users in sample 1 and 499 (21·9%) of 2275 in sample 3. The prevalence of suicidal ideation ranged from 1102 (24·9%) of 4432 people in sample 1 to 1644 (26·3%) of 6255 people in sample 2 and 865 (26·2%) of 3299 people in sample 3. Prevalence of MDD ranged from 901 (20·3%) people in sample 1 to 1773 (28·3%) in sample 2. The monozygotic twin who used cannabis frequently was more likely to report MDD (odds ratio 1·98, 95% CI 1·11–3·53) and suicidal ideation (2·47, 1·19–5·10) compared with their identical twin who had used cannabis less frequently, even after adjustment for covariates. For early cannabis use, the monozygotic point estimate was not significant but could be equated to the significant dizygotic estimate, suggesting a possible association with suicidal ideation.

Interpretation

The increased likelihood of MDD and suicidal ideation in frequent cannabis users cannot be solely attributed to common predisposing factors.

Funding

National Institute on Drug Abuse, National Institutes of Health, Australian National Health and Medical Research Council.

Introduction

Cannabis use has been linked to both major depressive disorder (MDD) and suicidal thoughts and behaviours.1, 2, 3 Daily cannabis use, especially during adolescence, has been associated with a 6·8 odds of suicide attempt.⁴ In a 30-year longitudinal study, even weekly cannabis use has been linked to onset of suicidal ideation, particularly in men, and the association largely persisted after controlling for the confounding effects of various sociodemographic and mental health characteristics and familial risk factors.⁵ MDD is partly correlated with suicidal thoughts and behaviours. However, associations between cannabis use and MDD are weaker than those noted for suicidal thoughts and behaviours⁶ and often dissipate after covariate correction.⁴

One approach to understanding the nature of the association between cannabis use and MDD and suicidal thoughts and behaviours is to study monozygotic twins reared together who are discordant for cannabis use. Some studies have shown the high heritability of cannabis use (h²=50–60%), MDD (h²=30–40%), and suicidal thoughts and behaviours (h²=40–45%).7, 8, 9, 10, 11 Monozygotic twins typically share all their segregating loci and are also highly likely to share early familial influences. Therefore, if a twin who uses cannabis shows an increased likelihood of MDD or suicidal thoughts and behaviours compared with their twin who does not use cannabis, this residual association might be viewed as evidence supporting person-specific factors and causal mechanisms.¹² Although cross-sectional discordant twin data cannot prove causality, the absence of an association in discordant twin pairs might be viewed as evidence against causal mechanisms. In one such study,¹³ we have shown that, relative to their twin, the cannabis-dependent twin was 3·4 times more likely to report suicidal ideation and attempts. A similarly significant association was noted for suicide attempts when discordance for early cannabis use was examined.¹³ By contrast, increased likelihood of MDD was noted in the cannabis-dependent twin in dizygotic but not monozygotic twin pairs that were discordant for cannabis dependence, suggesting that common genetic influences could alone be implicated in this association.¹³

Research in context

Evidence before this study

We searched PubMed (Jan 1, 1990–Feb 15, 2017) using the search terms “cannabis”, “marijuana”, “depression”, “suicide”, and “twin” with no language restrictions. Although associations between early and heavy or frequent cannabis use and suicidal thoughts and behaviours are robust when adjusted for confounders, associations with major depressive disorder (MDD) are neither as strong nor as independent. Rodent models support the role of the endocannabinoid system in mood regulation. Cannabis involvement, MDD, and suicidal thoughts and behaviours are heritable. One previous study found that cannabis-dependent individuals were more likely to report suicidal thoughts and behaviours than their monozygotic and dizygotic twins who were not dependent on cannabis, although associations with MDD were significant only in dizygotic pairs. An association was also noted between suicide attempt and discordance in early cannabis use in dizygotic as well as monozygotic twins. These results suggested that early and heavy or frequent cannabis use, or use resulting in abuse and dependence, might be related to MDD via genetic pathways alone whereas associations with suicidal thoughts and behaviours might be attributable to non-genetic, individual-specific environmental factors, which could be of a causal nature.

Added value of this study

In this large retrospective study of cannabis, MDD, and suicidal thoughts and behaviours in twins (n=13 986), we found that even within monozygotic pairs, twins who used cannabis 100 times or more were significantly more likely to meet criteria for MDD and to report suicidal ideation than their genetically identical twin who had either never used cannabis or had used it less frequently, even after accounting for covariates. We have also shown that ever using cannabis is not as robustly associated with MDD and suicidal thoughts and behaviours as early or frequent use.

Implications of all available evidence

Given the well documented role of endocannabinoid signalling in mood regulation and the results from our study, a causal role of frequent cannabis use in MDD and suicidal ideation cannot be discounted. Preventing escalation in cannabis use might ameliorate a portion of the morbidity associated with these serious mental illnesses.

In this study, we incorporated data from additional twin datasets (n=13 986 for current study, vs 6257 for the previous study) and we examine additional aspects of cannabis use with suicidal thoughts and behaviours. The goals of the study were to examine whether: a lifetime history of cannabis use as well as early-onset use and frequent use were associated with MDD, suicidal ideation, persistent ideation, ideation with a plan, and suicide attempt; any significant associations that were observed in the full sample of twins persisted when twin pairs discordant for each cannabis measure were examined; and associations within pairs of twins persisted after accounting for additional covariates that might have contributed to discordance in cannabis use and subsequently to MDD and suicidal thoughts and behaviours.

Section snippets

Study design and participants

Data on same-sex male and female twin pairs were drawn from 3 studies that had recruited twins from the Australian Twin Registry.¹⁴ Three groups of samples formed the population for the retrospective analysis reported in this study. Sample 1 (n=5846) included monozygotic and dizygotic twins aged 24–90 years (born between 1902 and 1964) who had either participated in a previous alcohol challenge study¹⁵ or at least one twin had participated in a survey done in 1989.¹⁶ They were invited to

Results

After exclusions for missing data in all three sample sets, 13 986 twin individuals (6181 monozygotic and 7805 dizygotic, including opposite-sex) from Australian datasets acquired between 1992 and 2009 were available for analysis for cannabis use and MDD or suicidal thoughts and behaviours. Monozygotic and same-sex dizygotic twin pairs were selected from this sample. Cannabis use was higher in samples 2 (3741 [59·8%] of 6255) and 3 (2275 [69·0%] of 3299) than in sample 1 (1345 [30·4%] of 4432;

Discussion

In this large retrospective study using data from three samples taken from the Australian Twin Registry, we found that early and frequent cannabis use were associated with MDD and suicidal thoughts and behaviours, even after controlling for confounders. When these associations 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.

The similarity

References (32)

G Borges et al.
A literature review and meta-analyses of cannabis use and suicidality
J Affect Disord
(2016)
E Silins et al.
Young adult sequelae of adolescent cannabis use: an integrative analysis
Lancet Psychiatry
(2014)
JC van Ours et al.
Cannabis use and suicidal ideation
J Health Econ
(2013)
LJ Horwood et al.
Cannabis and depression: an integrative data analysis of four Australasian cohorts
Drug Alcohol Depend
(2012)
AL Glowinski et al.
Suicide attempts in an adolescent female twin sample
J Am Acad Child Adolesc Psychiatry
(2001)
J Flint et al.
The genetics of major depression
Neuron
(2014)
MJ Delforterie et al.
The relationship between cannabis involvement and suicidal thoughts and behaviors
Drug Alcohol Depend
(2015)
EJ Topol et al.
Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial
Lancet
(2010)
KB Werner et al.
The association of specific traumatic experiences with cannabis initiation and transition to problem use: differences between African-American and European-American women
Drug Alcohol Depend
(2016)
A Agrawal et al.
Reciprocal relationships between substance use and disorders and suicidal ideation and suicide attempts in the Collaborative Study of the Genetics of Alcoholism
J Affect Disord
(2017)

ND Volkow et al.

Adverse health effects of marijuana use

N Engl J Med

(2014)

C Price et al.

Cannabis and suicide: longitudinal study

Br J Psychiatry

(2009)

KJ Verweij et al.

Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies

Addiction

(2010)

DF Maciejewski et al.

Overlapping genetic and environmental influences on nonsuicidal self-injury and suicidal ideation: different outcomes, same etiology?

JAMA Psychiatry

(2014)

DJ Statham et al.

Suicidal behaviour: an epidemiological and genetic study

Psychol Med

(1998)

KS Kendler et al.

Smoking and major depression: a causal analysis

Arch Gen Psychiatry

(1993)

Cited by (57)

A cross-sectional study of the relationship between frequency of cannabis use and psychiatric symptoms among people seeking mental health and addiction services in Nova Scotia (2019–21)
2024, Journal of Psychiatric Research
Cannabis use may be a modifiable risk factor for mental health problems; however, the role of cannabis use frequency in population seeking mental health and addiction services remains unclear. This study aimed to: 1) compare the prevalence and functional impact of psychiatric symptoms among frequent, infrequent, and non-users of cannabis; and 2) evaluate the associations between cannabis use frequency and functional impact of psychiatric symptoms in help-seeking individuals.
Data from the Mental Health and Addictions (MHA) Central Intake system in Nova Scotia, Canada was used. Participants aged 19–64 who received MHA Intake assessments from September 2019 to December 2021 with complete information about substance use were included (N = 20,611). Cannabis use frequency over past 30 days was categorized into frequent (>4 times a month), infrequent (≤4 times a month), and non-use. Psychiatric symptomatology consists of five domains: mood, anxiety, psychosis, cognition, and externalizing behaviors. Multivariate ordinal logistic regression was used to examine the associations between cannabis use frequency and functional impact of psychiatric symptoms.
Frequent and infrequent cannabis users had a higher prevalence of psychiatric symptoms in each domain than non-users, while no significant differences were found between frequent and infrequent users. Frequent cannabis use was associated with greater functional impact of psychiatric symptoms in each domain compared to non-users, while infrequent use was only associated with greater functional impact of externalizing behaviors.
Frequent cannabis use is associated with increased prevalence and functional impact of psychiatric symptoms among adults seeking mental health services.
Cannabis smoking increases the risk of suicide ideation and suicide attempt in young individuals of 11–21 years: A systematic review and meta-analysis
2022, Journal of Psychiatric Research
Cannabis is the most frequently consumed drug around the world. Its use has been associated with increased suicide behaviors; nonetheless, the association of cannabis smoking and suicide behaviors in adolescents has not yet been established. The aim of this systematic review and meta-analysis was to evaluate the risk of suicide attempt, suicidal ideation or suicide planning in individuals of 11–21 years of age who smoke cannabis.
We performed an online searched using PubMed, EBSCO and Science Direct databases, up to July 2021. We calculated odds ratio with 95% confidence intervals to evaluate the association between suicide attempt, suicidal ideation or suicide planning and cannabis smoking in individuals of 11–21 years of age.
Twenty studies reported suicide attempts in 34,859 young individuals, suicidal ideation in 26, 937 individuals, and suicide planning in 9054 young individuals. We found an increased risk of suicide attempt in cannabis smokers than in non-cannabis users (OR: 2.33; 95% CI: 1.78–3.05; Z p value; <0.0001; I² = 97.12%), as well as a significant association between cannabis smoking and suicidal ideation (OR: 2.04; 95%CI: 1.64–2.53; Z p value: <0.001; I²: 94.88) and suicide planning (OR: 1.674; 95% CI: 1.554–1.804; Z p value: 0.000; I²: 92.609). Subgroup analyses showed that American teens have an increased risk of suicidal ideation; the meta-regression analysis revealed that age was negatively associated with the risk of suicide attempt.
This meta-analysis shows that cannabis smoking increased the risk of suicide attempt, suicidal ideation and suicide planning in young individuals of 11–21 years of age. The high risk of suicide behaviors could vary depending on the population studied; therefore, more studies are necessary to corroborate the risk of presenting suicide behaviors in individuals of 11–21 years of age who smoke cannabis.
Association between cannabis use and suicidal behavior: A systematic review of cohort studies
2022, Psychiatry Research
Citation Excerpt :
It is worth noting that the study also compared initiating cannabis use in participants with and without SI and/or SA, finding that SI in women increased the chances of starting to use cannabis (OR 2.34, 95% CI 1.42-3.87). Another study (Agrawal, Nelson, et al., 2017) compiled data from 3 samples that involved same-sex twins born in Australia between 1941 and 1979, a figure totalling almost 14,000 individuals. Analyses involved examining discordant twins, divided into dizygotic and monozygotic pairs, for cannabis exposure.
The use of cannabis is highly prevalent worldwide, with known short and long-term adverse effects. However, the relationship between cannabis use and suicidal behavior remains relatively unexplored and this paper aims to unify existing literature on the topic. A systematic review was conducted using MEDLINE, Embase, PsycINFO and LILACS databases with a supplementary search to identify cohort articles published up to January 2020, with no age delimitation for the samples. This review aimed to address the relationship between cannabis use and suicidal behavior, defined as suicidal ideation, attempted suicide or completed suicide. Twenty-two articles were identified, with no clear consensus, irrespective of the outcome being investigated. This was the case even when taking into consideration only those studies with a sound methodology (according to the Newcastle-Ottawa scale). Studies that identified an association explored the importance of the endocannabinoid system as well as the psychosocial context of the individual while developing suicidal behavior, with certain studies demonstrating that greater intensity or precocity of cannabis use increases the strength of this association. The relationship between cannabis use and suicidal behavior is complex, with no consensus in the literature. Further studies with standardized definitions for cannabis use, including frequency of use, along with improved controls for confounding variables are needed.
Lower-Risk Cannabis Use Guidelines (LRCUG) for reducing health harms from non-medical cannabis use: A comprehensive evidence and recommendations update
2022, International Journal of Drug Policy
Citation Excerpt :
A multi-country modelling study on first-episode psychosis (FEP) found a linear relationship between symptom dimensions (paranoia, hallucinations) and cannabis exposure, with the highest scores observed in individuals with daily use of high-potency cannabis (B=0.35; 95% CI 0.14–0.56) (Di Forti et al., 2019). In a retrospective cohort study of monozygotic twins, the twin who used cannabis more frequently was more likely to report a MDD (OR:1.98, 95%CI: 1.11–3.53) or suicidal ideation (OR:2.47, 95%CI: 1.19–5.10) (Agrawal et al., 2017). Among US adults (2008-2016), daily cannabis use was significantly more common among those with past-month serious psychological distress (SPD; 8.07%), compared to those without past-month SPD (2.66%) (Weinberger et al., 2019).
Cannabis use is common, especially among young people, and is associated with risks for various health harms. Some jurisdictions have recently moved to legalization/regulation pursuing public health goals. Evidence-based ‘Lower Risk Cannabis Use Guidelines’ (LRCUG) and recommendations were previously developed to reduce modifiable risk factors of cannabis-related adverse health outcomes; related evidence has evolved substantially since. We aimed to review new scientific evidence and to develop comprehensively up-to-date LRCUG, including their recommendations, on this evidence basis.
Targeted searches for literature (since 2016) on main risk factors for cannabis-related adverse health outcomes modifiable by the user-individual were conducted. Topical areas were informed by previous LRCUG content and expanded upon current evidence. Searches preferentially focused on systematic reviews, supplemented by key individual studies. The review results were evidence-graded, topically organized and narratively summarized; recommendations were developed through an iterative scientific expert consensus development process.
A substantial body of modifiable risk factors for cannabis use-related health harms were identified with varying evidence quality. Twelve substantive recommendation clusters and three precautionary statements were developed. In general, current evidence suggests that individuals can substantially reduce their risk for adverse health outcomes if they delay the onset of cannabis use until after adolescence, avoid the use of high-potency (THC) cannabis products and high-frequency/-intensity of use, and refrain from smoking-routes for administration. While young people are particularly vulnerable to cannabis-related harms, other sub-groups (e.g., pregnant women, drivers, older adults, those with co-morbidities) are advised to exercise particular caution with use-related risks. Legal/regulated cannabis products should be used where possible.
Cannabis use can result in adverse health outcomes, mostly among sub-groups with higher-risk use. Reducing the risk factors identified can help to reduce health harms from use. The LRCUG offer one targeted intervention component within a comprehensive public health approach for cannabis use. They require effective audience-tailoring and dissemination, regular updating as new evidence become available, and should be evaluated for their impact.
Cannabis vaping among adults in the United States: Prevalence, trends, and association with high-risk behaviors and adverse respiratory conditions
2021, Preventive Medicine
The e-cigarette or vaping product-use-associated lung injury outbreak in the United States has raised concerns about the potential health effects of cannabis vaping, a method of cannabis use that is becoming increasingly popular. We used 2017–2019 Behavioral Risk Factor Surveillance System data to estimate yearly prevalence and trends of past-30-day cannabis use and vaping among US adults. We used multivariable logistic regression to evaluate the associations of cannabis vaping with high-risk behaviors, asthma, and other respiratory symptoms.
Our sample size was 160,209 (53,945–2017; 55,475–2018; and 50,789–2019). Past-30-day cannabis use prevalence increased from 10.0% (95% CI, 9.4%–10.7%) in 2017 to 13.4% (12.8%–12.0%) in 2019. Similarly, past-30-day cannabis vaping prevalence increased from 1.0% (0.8%–1.2%) to 2.0% (1.7%–2.2%) over the same period, with the greatest increase, 1.2% to 3.9%, observed among young adults (18-24 years). Individuals who vaped cannabis were more likely to concurrently vape nicotine. Cannabis vaping was associated with increased odds of heavy alcohol use (aOR, 1.95; 95% CI, 1.45–2.63), binge drinking (aOR, 2.82; 95% CI, 2.25–3.54), and other high-risk behaviors (aOR, 2.47; 95% CI, 1.89–3.24). In analyses adjusting for sociodemographic characteristics and body mass index, cannabis vaping was not associated with asthma (aOR, 1.03; 95% CI, 0.64–1.64) or other respiratory symptoms (aOR, 1.08; 95% CI, 0.44–2.63). Adjusting for nicotine vaping did not substantively alter these associations.
The prevalence of past-30-day cannabis vaping has increased, particularly among young adults, and was associated with high-risk behaviors. Although there was no association between cannabis vaping and asthma or other respiratory symptoms, the increasing trends of cannabis vaping, particularly among young adults, raise concern and underscore the need for continued surveillance.
Frequent teenage cannabis use: Prevalence across adolescence and associations with young adult psychopathology and functional well-being in an urban cohort
2021, Drug and Alcohol Dependence
Citation Excerpt :
Cannabis use during later adolescence and young adulthood, especially frequent use, has been linked with later illicit and problematic drug use (Blanco et al., 2016; Boden et al., 2020; Volkow et al., 2014); certain psychiatric disorders such as psychosis (Arseneault et al., 2002; Bourque et al., 2018; Fergusson et al., 2005b; Volkow et al., 2014); poorer functional outcomes, including delinquency, financial and social problems into midlife (Boden et al., 2020; Cerda et al., 2016; Degenhardt et al., 2013; Fergusson et al., 2002; Green et al., 2017; Horwood et al., 2012; Horwood et al., 2010; Silins et al., 2014, 2015; Taylor et al., 2017), and reduced intellectual ability (Meier et al., 2012) and educational attainment (Horwood et al., 2010; Silins et al., 2014, 2015). Evidence for associations between adolescent/young adult cannabis use and other psychiatric outcomes (e.g., depression, anxiety) is less consistent (Agrawal et al., 2017; Boden et al., 2020; Borges et al., 2016; Degenhardt et al., 2003; Lev-Ran et al., 2014; Moore et al., 2007; Silins et al., 2014; Smolkina et al., 2017). For example, in a meta-analysis of prospective-longitudinal analyses, zero of three studies found an associations of cannabis use before age 18 with anxiety; three of seven studies, and also the overall meta-analysis, found a significant association with depression (Gobbi et al., 2019).
Amidst cannabis legalization efforts and laws, we do not fully understand how the youngest frequent cannabis users fare during young adulthood. This study aims to 1) examine the prevalence of cannabis use during adolescence, and 2) investigate links of frequent (i.e., weekly or daily) teenage cannabis use with psychopathology and functional well-being at age 20—compared to no or occasional use.
Data came from a prospective-longitudinal cohort study (assessments from 2004 to 2018, from ages 7–20) in an urban setting (N = 1482). Substance use was assessed with self-reports between ages 13 and 20. At age 20, participants reported on psychopathology (psychotic symptoms, problematic substance use, aggression, and internalizing symptoms) and functional well-being (delinquency, financial difficulties, social exclusion, general well-being, and not being in education, employment, or training). Covariates were based on self-, parent-, teacher-, and behavioral measures.
Almost one in five adolescents had used cannabis frequently between ages 13 and 17 (26.6% of males, 9.8% of females). Adjusting nearly 20 potential confounders, frequent teenage cannabis use was associated with age 20 problematic substance use and poorer functional well-being compared to the no cannabis use and the occasional use groups. Frequent teenage cannabis use was more consistently associated with age 20 functional outcomes compared to frequent teenage nicotine or alcohol use.
Frequent teenage cannabis use was common and associated with problematic substance use, more delinquency, and poorer functional well-being at age 20. Accordingly, frequent teenage cannabis users could experience increased difficulties in mastering the transitions of young adulthood.

View all citing articles on Scopus

View full text

ArticlesMajor depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins: a retrospective cohort study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

J Affect Disord

Lancet Psychiatry

J Health Econ

Drug Alcohol Depend

J Am Acad Child Adolesc Psychiatry

Neuron

Drug Alcohol Depend

Lancet

Drug Alcohol Depend

J Affect Disord

Adverse health effects of marijuana use

N Engl J Med

Cannabis and suicide: longitudinal study

Br J Psychiatry

Genetic and environmental influences on cannabis use initiation and problematic use: a meta-analysis of twin studies

Addiction

Overlapping genetic and environmental influences on nonsuicidal self-injury and suicidal ideation: different outcomes, same etiology?

JAMA Psychiatry

Suicidal behaviour: an epidemiological and genetic study

Psychol Med

Smoking and major depression: a causal analysis

Arch Gen Psychiatry

Articles
Major depressive disorder, suicidal thoughts and behaviours, and cannabis involvement in discordant twins: a retrospective cohort study