Cannabis controversies: how genetics can inform the study of comorbidity.
- Authors
- Agrawal, Arpana; Lynskey, Michael T
- Year
- 2014
- Journal
- Addiction (Abingdon, England)
- PMID
- 24438181
- DOI
- 10.1111/add.12436
- PMCID
- PMC3943474
AIMS: To review three key and controversial comorbidities of cannabis use-other illicit drug use, psychosis and depression, as well as suicide, from a genetically informed perspective. DESIGN: Selective review. RESULTS: Genetic factors play a critical role in the association between cannabis use, particularly early-onset use and use of other illicit drugs, psychosis and depression, as well as suicide, albeit via differing mechanisms. For other illicit drugs, while there is strong evidence for shared genetic influences, residual association that is attributable to causal or person-specific environmental factors cannot be ruled out. For depression, common genetic influences are solely responsible for the association with cannabis use but for suicidal attempt, evidence for person-specific factors persists. Finally, even though rates of cannabis use are inordinately high in those with psychotic disorders, there is no evidence of shared genetic etiologies underlying this comorbidity. Instead, there is limited evidence that adolescent cannabis use might moderate the extent to which diathesis influences psychosis. CONCLUSIONS: Overlapping genetic influences underlie the association between early-onset cannabis use and other illicit drug use as well as depression and suicide. For psychosis, mechanisms other than shared genetic influences might be at play.
Multiple possible mechanisms that may link cannabis use and misuse to mental health outcomes, including other illicit drug use, depression and suicide as well as psychosis. Panel A: Cannabis use directly causes outcome; A1 depicts how this causal effect may be exerted via alterations in biological pathways (such as receptor cross-tolerance) while A2 demonstrates a similar causal effect mediated by environmental exposures (such as access to drug supplier). Panel B demonstrates reverse causation, such as self-medication. Panel C shows how cannabis use and outcomes might be related via common genetic and environmental underpinnings. Panel D illustrates stress-diathesis (or gene-environment interaction) – cannabis use modifies the extent to which diathesis (such as select genotypes in the catechol-o-methyltransferase gene) influences the outcomes.
The discordant twin design is illustrated. Pairs of twins (MZ=monozygotic/identical; DZ=dizygotic/fraternal) discordant for cannabis use are matched to varying degrees for genetic and environmental factors allowing for residual associations to be explained by unshared factors. Pairs of unrelated individuals are shown for comparison.
Hypothetical results expected from a discordant twin study, for discordant pairs of MZ, DZ and unrelated individuals, which can be used to infer the nature of the association between cannabis use and outcomes. If the association is entirely due to causal or individual-specific factors then the magnitude of association is invariant to degree of relatedness. In contrast, if genes or family environment play a role, then matching discordant pairs of individuals for these factors results in an attenuation of the association.
| Name | Type |
|---|---|
| academic performance | phenotype |
| adolescent cannabis use | phenotype |
| Adolescent onset local | phenotype |
| Adopted Offspring local | cohort |
| adult-onset cannabis use local | drug |
| Adverse neighborhoods local | phenotype |
| age at onset of psychotic disorder local | phenotype |
| Agrawal study local | cohort |
| alcohol | phenotype |
| alcohol dependence | phenotype |
| Alcohol Use | phenotype |
| ALDH2 | gene |
| anhedonia | phenotype |
| antisocial personality disorder | phenotype |
| Asian | cohort |
| Australasian datasets cohort local | cohort |
| Avon Longitudinal Study of Parents and Children | cohort |
| behavioral outcomes | phenotype |
| bipolar disorder | phenotype |
| cannabis dependence | phenotype |
| cannabis use | phenotype |
| cannabis use disorder | phenotype |
| Caspi et al study | cohort |
| childhood trauma | phenotype |
| Chrna7 | gene |
| Cnr1 | gene |
| CNR1 variant local | variant |
| cocaine | phenotype |
| cocaine use disorder | phenotype |
| cognition | phenotype |
| COMT | gene |
| COMT Met allele | gene |
| COMT Val allele | gene |
| COMT variant local | variant |
| conduct disorder | phenotype |
| Cross-sensitization local | phenotype |
| delusions | phenotype |
| depression | phenotype |
| discordant twin study local | cohort |
| dopamine | drug |
| DRD2 | gene |
| drug dependence | phenotype |
| Drug-using peers local | phenotype |
| Dutch sample | cohort |
| early alcohol use | phenotype |
| early cannabis use | phenotype |
| Early cannabis use (by age 15) local | phenotype |
| early consensual sex local | phenotype |
| early-onset of cannabis use local | phenotype |
| early substance use | phenotype |
| educational attainment | phenotype |
| endocannabinoids | drug |
| Epigenetic modifications | phenotype |
| externalizing disorders | phenotype |
| hallucinations | phenotype |
| hallucinogens | drug |
| hallucinogen use local | phenotype |
| hard drug dependence local | phenotype |
| hard drugs | drug |
| hard drug use local | phenotype |
| Hard drug use local | phenotype |
| Harder drugs local | drug |
| healthy controls | cohort |
| heavy drinking | phenotype |
| hippocampus | anatomy |
| humans | cohort |
| hypothalamic-pituitary-adrenal axis | anatomy |
| illicit drugs | phenotype |
| illicit drug use | phenotype |
| Illicit hard drug use local | phenotype |
| Individual-specific environments local | phenotype |
| longitudinal studies local | cohort |
| long-term depression | phenotype |
| low mood | phenotype |
| Lynskey et al. study local | cohort |
| Lynskey study local | cohort |
| major depressive disorder | phenotype |
| Met/Met genotype | variant |
| Non-adopted Offspring local | cohort |
| non-users | cohort |
| opiates | drug |
| opioid | drug |
| opioid use local | phenotype |
| other drug use | phenotype |
| other substances | phenotype |
| Parental Cannabis Use Disorder local | phenotype |
| party drugs local | drug |
| party drug use local | phenotype |
| physical abuse | phenotype |
| psychiatric disorders | phenotype |
| Psychiatric Genomics Consortium | cohort |
| psychiatric patient population local | cohort |
| psychosis | phenotype |
| psychosis outcomes local | phenotype |
| psychosis proneness local | phenotype |
| psychotic disorder patient cohort local | cohort |
| psychotic features local | phenotype |
| Receptor cross-sensitization local | phenotype |
| rimonabant | drug |
| rodents | cohort |
| Rodent study local | cohort |
| rs4680 | variant |
| rs671 | variant |
| schizophrenia | phenotype |
| schizophreniform disorder | phenotype |
| sedatives | drug |
| sedative use local | phenotype |
| social anxiety | phenotype |
| Socio-environmental factors local | phenotype |
| spatial working memory | phenotype |
| stress | phenotype |
| substance use | phenotype |
| suicide | phenotype |
| Swedish male conscripts cohort local | cohort |
| THC | drug |
| tobacco use | phenotype |
| Twin cohort | cohort |
| unrelated individuals | cohort |
| Val158Met | gene |
| Val allele | gene |
| Val/Met genotype local | variant |
| Val/Val genotype | gene |
| working memory | phenotype |
No uploaded files.
In this knowledge base
| Title | Year | PMID |
|---|---|---|
| Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia. | 2017 | 28739213 |
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Development of Substance Use Problems: The Role of Adolescent Cannabis Age of Onset, Frequency of Use and Childhood Risk Factors. | Hamaoui J et al. | — | 2026 | → |
| Absolute Risk Prediction for Cannabis Use Disorder in Adolescence and Early Adulthood Using Bayesian Machine Learning. | Wang T et al. | — | 2025 | → |
| Alternative hypotheses regarding the association between early engagement in gambling and gambling-like activities and later problem gambling - a commentary on Richard and King (2023). | Rhee SH et al. | — | 2023 | → |
| Hemp Seed Cake Flour as a Source of Proteins, Minerals and Polyphenols and Its Impact on the Nutritional, Sensorial and Technological Quality of Bread. | Capcanari T et al. | — | 2023 | → |
| Alcohol use and alcohol use disorder differ in their genetic relationships with PTSD: A genomic structural equation modelling approach. | Bountress KE et al. | — | 2022 | → |
| Cannabis use and posttraumatic stress disorder: prospective evidence from a longitudinal study of veterans. | Metrik J et al. | — | 2022 | → |
| Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis. | D'Souza DC et al. | — | 2022 | → |
| Examining Risk Factors in the Cannabis-Suicide Link: Considering Trauma and Impulsivity among University Students. | Daneshmend AZB et al. | — | 2022 | → |
| Risk of suicide ideation in comorbid substance use disorder and major depression. | Onaemo VN et al. | — | 2022 | → |
| Trauma exposure among cannabis use disorder individuals was associated with a craving-correlated non-habituating amygdala response to aversive cues. | Regier PS et al. | — | 2022 | → |
| Cannabinoid use and self-injurious behaviours: A systematic review and meta-analysis. | Escelsior A et al. | — | 2021 | → |
| Cannabis use and cannabis use disorder. | Connor JP et al. | — | 2021 | → |
| Cannabis use in adolescence and risk of psychosis: Are there factors that moderate this relationship? A systematic review and meta-analysis. | Kiburi SK et al. | — | 2021 | → |
| Down and High: Reflections Regarding Depression and Cannabis. | Langlois C et al. | — | 2021 | → |
| Prevalence, sociodemographic variables, mental health condition, and type of drug use associated with suicide behaviors among people with substance use disorders: a systematic review and meta-analysis. | Armoon B et al. | — | 2021 | → |
| Alcohol Use Disorder and the Persistence/Recurrence of Major Depression: Le trouble de l'usage de l'alcool et la persistance/récurrence de la dépression majeure. | Onaemo VN et al. | — | 2020 | → |
| Association between polygenic liability for schizophrenia and substance involvement: A nationwide population-based study in Taiwan. | Wang SH et al. | — | 2020 | → |
| Cannabis use, depression and suicidal ideation in adolescence: direction of associations in a population based cohort. | Bolanis D et al. | — | 2020 | → |
| Public Health Implications of Rising Marijuana Use in Pregnancy in an Age of Increasing Legalization-Reply. | Agrawal A et al. | — | 2019 | → |
| Cannabis use is associated with lower rates of initiation of injection drug use among street-involved youth: A longitudinal analysis. | Reddon H et al. | — | 2018 | → |
| US Epidemiology of Cannabis Use and Associated Problems. | Hasin DS | — | 2018 | → |
| Alcohol, cannabis and other drugs and subsequent suicide ideation and attempt among young Mexicans. | Borges G et al. | — | 2017 | → |
| Association between substance use disorder and polygenic liability to schizophrenia | Hartz SM et al. | — | 2017 | — |
| Association Between Substance Use Disorder and Polygenic Liability to Schizophrenia. | Hartz SM et al. | — | 2017 | → |
| Cannabis and Depression: A Twin Model Approach to Co-morbidity. | Smolkina M et al. | — | 2017 | → |
| A literature review and meta-analyses of cannabis use and suicidality. | Borges G et al. | — | 2016 | → |
| Associations between Polygenic Risk for Psychiatric Disorders and Substance Involvement. | Carey CE et al. | — | 2016 | → |
| Moderating effects of perceived social benefits on inhalant initiation among American Indian and White youth. | Swaim RC | — | 2016 | → |
| Predictors of comorbid polysubstance use and mental health disorders in young adults-a latent class analysis. | Salom CL et al. | — | 2016 | → |
| The association between cannabis use and suicidality among men and women: A population-based longitudinal study. | Shalit N et al. | — | 2016 | → |
| Cannabis: the never-ending, nefarious nepenthe of the 21st century: what should the clinician know? | Greydanus DE et al. | — | 2015 | → |
| Commentary on Kosty et al. (2015): Cannabis abuse from one generation to the next-a heightened vulnerability in women? | Melchior M | — | 2015 | → |
| Cannabis use in adolescence and risk of future disability pension: a 39-year longitudinal cohort study. | Danielsson AK et al. | — | 2014 | → |