EDITOR'S NOTE

Alcohol and Cannabis Use Disorders

Ned H. Kalin, M.D.

This issue of the Journal is focused on providing a deeper now exists in many states. However, it was not until 2012
understanding of the factors underlying alcohol and canna- when Washington and Colorado first legalized cannabis for
bis use and misuse in relation to the development of sub- recreational use. Therefore, the timing of the collection of
stance use disorders and interactions with other psychiatric the data used in this study is relevant to understanding risk-
illnesses. The prevalence of alcohol use disorder in the related factors prior to the legalization of selling cannabis
United States is high. Data from 2019 suggest that 14.5 mil- for recreational use. Data from 3,119 veterans were used to
lion individuals age 12 or older suffered with alcohol use understand the relation between the nonmedical use of can-
disorder (1). It is important to note that alcohol misuse sub- nabis and cannabis use disorder. The findings from this sam-
stantially contributes to premature death, which is largely ple of veterans demonstrated that the 12-month prevalence
due to alcohol-related accidents, suicides, and medical ill- of past cannabis use was 7.3% and of cannabis use disorder
nesses. According to the World Health Organization, 5.3% of was 1.8%, and the lifetime prevalence for cannabis use and
all deaths worldwide in 2016 were related to alcohol use (2). cannabis use disorder was 32.5% and 5.7%, respectively.When
Cannabis use in the United States is also very common and, selectively considering nonmedical cannabis users, the lifetime
notwithstanding federal regulations, numerous states have prevalence of cannabis use disorder was estimated to be 17.4%.
legalized its recreational and medical use. In 2018, it was Factors associated with greater prevalence of cannabis use
estimated that 11.8 million adolescents and young adults and cannabis use disorder included male gender, being sin-
used cannabis in the past year (3). Frequent, chronic, and gle, younger age, lower income, and living in a state in which
heavy cannabis use can lead to cannabis use disorder, which the medical use of cannabis was legalized. Other substance
can be associated with psychosocial dysfunction, effects on use disorders, as well
cognition and memory, reduced motivation, and alterations as psychiatric disor-
The papers in this issue
in mood and anxiety regulation. ders, were also associ-
of the Journal provide
The centerpiece of this issue is an overview on cannabis ated with increased
insights into the factors
use, authored by Dr. Margaret Haney from Columbia Uni- cannabis use and can-
versity, that reviews cannabinoid substances and the endog- nabis use disorder. In
underlying alcohol and
enous cannabinoid system in relation to cannabinoid abuse their editorial, Dr. cannabis use and misuse
and its treatment (4). This overview sets the stage for the Catherine Striley and and also address their
accompanying original research papers that examine canna- Carolin Hoeflich from interactions with other
bis use in U.S. veterans, the relation between cannabis use the University of Flo- psychiatric illnesses.
and psychotic disorders, and interactions between cannabis rida discuss this study
and alcohol use and eating disorders. In addition to the edi- in more detail and emphasize the findings linking canna-
torials commenting on these papers, we include a piece in bis use and cannabis use disorder to psychopathology,
which the Journal’s Editors highlight papers published in especially posttraumatic stress disorder and opioid use
2021 that they found to be particularly impactful (5). disorder (7).

Cannabis Use and Cannabis Use Disorders in Cannabis Use and Self-Reported Psychotic Disorders
U.S. Veterans
The goal of Livne et al. in their study (8) was to determine
With numerous states legalizing cannabis for medical and the relation between the nonmedical use of cannabis and
recreational use, cannabis use will almost certainly continue psychotic disorders. They also used NESARC-III data, in
to increase in the United States, which is why it is important this case from the general adult U.S. population, and analy-
to better understand the factors associated with the devel- ses were performed with data from two different time peri-
opment of cannabis use disorder. Browne et al. (6) focus on ods, 2001–2002 (N543,093) and 2012–2013 (N536,309).
cannabis use in U.S. veterans and, by using data from the This approach allowed for two separate assessments of the
2012–2013 National Epidemiologic Survey on Alcohol and relation between cannabis use and psychotic disorders, as
Related Conditions–III (NESARC-III), provide insights into well as an assessment of the possible change across these
the risk of developing cannabis use disorder. The medical periods in the relation between cannabis use and psychosis.
use of cannabis was first legalized in California in 1996 and When assessing the past-year prevalence of self-reported

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EDITOR'S NOTE

psychotic disorders, a significant increase was observed disorder. Eating disorder patients without a substance
from the 2001–2002 period (0.33%) to the 2012–2013 period use disorder had a 2.85 hazard ratio for all-cause mortal-
(0.80%). At both time points, the data revealed that psy- ity compared with controls. A marked increase in mor-
chotic disorders during the past 12 months were more likely tality was found for eating disorder patients with
to occur in past-year cannabis users (nonmedical) compared comorbid substance use disorders (e.g., a hazard ratio of
with nonusers. At the 2001–2003 time point, the prevalence 11.84 for alcohol use disorder comorbid with eating dis-
difference for psychotic disorders between nonmedical can- orders). For these individuals the hazard ratio for deaths
nabis users and nonusers was 1.38%, and at the 2012–2013 related to external causes was 13.87 and for internal
time point it was 1.21%. In relation to cannabis use disorder, causes was 11.87. The greatest risk for mortality was
at both time points it was established that individuals with observed in eating disorder patients who had all three
past-year cannabis use disorder, compared with individuals types of substance use disorders, with a mortality hazard
who were nonusers, were more likely to report a psychotic ratio of 22.99. More specifically, in relation to anorexia
disorder (2001–2002 prevalence difference: 2.28%; nervosa and bulimia nervosa, the hazard ratio for all-
2012–2013 prevalence difference: 2.70%). No significant dif- cause mortality with comorbid alcohol or cannabis use
ferences in the associations between cannabis use and psy- disorder was 11.28, and 5.86, respectively. Taken together,
chotic disorders were found when comparing data from the these findings underscore clinically important issues rel-
two time points. While these data link cannabis use to psy- evant to the assessment and treatment of patients with
chotic disorders, it is important to keep in mind that the eating disorders. In their editorial, Drs. Compton Wilson
reported findings are associational and do not provide direct and Beth Han from the National Institute on Drug Abuse
evidence for a causal relation between cannabis use or use comment on the significance of these findings, suggest
disorder and psychotic disorders. In their editorial, Drs. other questions that are raised by these data, and
Suhas Ganesh and Cyril D’Souza discuss this theme in emphasize that to achieve optimal outcomes in treating
depth, providing a basis for understanding how to think eating disorder patients it is critical to assess, and
about causality in relation to epidemiological, population equally value, the treatment of coexisting substance use
health, and genetic data (9). disorders (11).

Increased Mortality in Patients With Eating Disorders Large Genome-Wide Association Study (GWAS)
and Substance Abuse Relevant to Alcohol Consumption, Problems,
and Dependence
Eating disorders are associated with high levels of mor-
bidity and mortality, and anorexia nervosa is considered Numerous GWASs have attempted to uncover genes
to have the highest mortality risk of all psychiatric disor- associated with alcohol use and alcohol use disorder,
ders. Reduced life span in eating disorder patients is due with results pointing to specific genes. The study by
both to a high suicide rate and to the debilitating physio- Mallard et al. (12) represents the largest GWAS to date
logical consequences of dysregulated eating, poor nutri- and is also notable because it takes a dimensional
tion, and cachexia. Eating disorders are highly comorbid approach to understanding the genetics underlying alco-
with other psychiatric disorders, including anxiety disor- hol use. The authors also use the data to examine the
ders, depression, and substance use disorders. The data genetic relatedness of alcohol consumption with prob-
presented by Mellentin et al. (10) address the extent to lematic alcohol use. The study relies on the Alcohol Use
which comorbid substance use disorders further increase Disorders Identification Test (AUDIT) for phenotyping,
the risk of premature mortality in patients with eating a 10-item survey with two subscales that assess alcohol
disorders. Eating disorder patients (N520,7590) were consumption (AUDIT-C) and alcohol-related problems
retrospectively identified from a Danish nationwide reg- (AUDIT-P). The large sample used data from 160,824
istry, as were matched control subjects without eating individuals assembled from three different sources (UK
disorders (N583,036). At entry, 90% of participants were Biobank, Netherlands Twin Register, and Avon Longitu-
under 30 years of age, and participants were followed on dinal Study of Parents and Children), all of whom were
average for approximately 11 years; drugs of abuse were AUDIT phenotyped. The researchers also used a novel
classified into alcohol, cannabis, and hard drugs (e.g., analytic approach called genomic structural equation
opioids, sedative-hypnotics, cocaine, hallucinogens, vola- modeling. This statistical method enables an under-
tile solvents). Mortality was considered to be due to standing of the genetic architecture and shared genetic
either external causes (i.e., suicide, accident, or murder) underpinnings of complex phenotypic traits and also
or internal causes (i.e., related to substance use disorder, the involvement of specific single-nucleotide polymor-
eating disorder, other psychiatric disorder, or a somatic phisms (SNPs) in accounting for the variance shared
disorder). The authors found that eating disorder between related traits. Using a latent factor approach
patients, compared with control subjects, were approxi- with the AUDIT data, the authors identified a
mately 4 times more likely to have a substance use “consumption” factor and a “problems” factor that

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 EDITOR'S NOTE

together demonstrated a high degree of phenotypic and problems share genetic underpinnings with each other
genetic correlation. They also found that these two fac- and with alcohol dependence (distinct genes associated
tors were highly genetically correlated with alcohol with these different components of alcohol use were also
dependence and that the “problems” factor was more identified). The findings presented in this issue of the
robustly genetically correlated with psychopathology. Journal relevant to understanding the genetic and non-
When using polygenic risk scores (PGRs) in indepen- genetic factors associated with the development of alco-
dent analyses of the three different subsamples, the hol and cannabis use disorder are derived from human
authors found that the PGR for “consumption” was samples. At a preclinical level, considerable work using
associated with alcohol use disorder phenotypes. In animal models has elucidated neural circuits and molec-
relation to specific genes, some differences were uncov- ular mechanisms underlying the habitual use of these
ered for “consumption” compared with “problems.” For substances (14, 15). New treatment development will
example, the gene for corticotropin-releasing hormone benefit from translational cross-species efforts that con-
receptor 1 (CRHR1) was found to be selectively associ- tinue to advance the understanding of causal mecha-
ated with “consumption.” This is a potentially important nisms underlying alcohol and cannabis misuse.
finding because the CRH system plays a prominent role
in integrating the hormonal, autonomic, and behavioral
AUTHOR AND ARTICLE INFORMATION
responses to stress, and alterations in this system have
Department of Psychiatry, University of Wisconsin School of Medicine
been implicated in stress-related psychopathology.
and Public Health, Madison
Numerous other interesting SNP findings are detailed in
Send correspondence to Dr. Kalin ([email protected]).
the paper. Taken together, this work strongly supports
Disclosures of Editors’ financial relationships appear in the April 2021
AUDIT as a phenotypic measure of importance for link-
issue of the Journal.
ing genetic variation to alcohol use from both a dimen-
Am J Psychiatry 2022; 179:1–4; doi: 10.1176/appi.ajp.2021.21111134
sional and a disease-related perspective and sheds new
light on specific genes that may contribute to the risk
REFERENCES
for alcohol consumption and misuse. In their editorial, 1. SAMHSA Center for Behavioral Health Statistics and Quality:
Drs. Henry Kranzler, Hang Zhou, and Rachel Kember 2019 National Survey on Drug Use and Health, Table 5.4A: Alco-
review other GWASs related to alcohol use and discuss hol Use Disorder in Past Year Among Persons Aged 12 or Older,
in more detail the sociodemographic and medical fac- by Age Group and Demographic Characteristics: Numbers in
tors that may confound studies regarding GWAS find- Thousands, 2018 and 2019. https://www.samhsa.gov/data/sites/
default/files/reports/rpt29394/NSDUHD
ings in relation to alcohol-related phenotypes (13).
2. World Health Organization: Alcohol: fact sheet, 2018. https://
www.who.int/en/news-room/fact-sheets/detail/alcohol
3. NIDA: What is the scope of marijuana use in the United States?
Conclusions
National Institute on Drug Abuse, April 20, 2021 (https://www.
Alcohol and cannabis are among the most commonly drugabuse.gov/publications/research-reports/marijuana/what-
used psychoactive substances that, when misused, can scope-marijuana-use-in-united-states)
4. Haney M: Cannabis use and the endocannabinoid system: a clini-
lead to addiction, interference with functioning, disabil-
cal perspective. Am J Psychiatry 2022; 179:21–25
ity, and medical and psychiatric comorbidities. The 5. Kalin NH, Binder E, Brady KT, et al: 2021 articles of import and
habitual use of alcohol or cannabis during critical devel- impact. Am J Psychiatry 2022; 179:17–20
opmental phases such as adolescence can be particularly 6. Browne KC, Stohl M, Bohnert KM, et al: Prevalence and corre-
deleterious, interfering with developmental trajectories lates of cannabis use and cannabis use disorder among US veter-
underlying the maturation of cognitive, emotional, and ans: results from the National Epidemiologic Survey on Alcohol
and Related Conditions (NESARC-III). Am J Psychiatry 2022;
social capacities that are essential for success during 179:26–35
adulthood. The papers in this issue of the Journal pro- 7. Striley CW, Hoeflich CC: Intricacies of researching cannabis use
vide insights into the factors underlying alcohol and can- and use disorders among veterans in the United States. Am J
nabis use and misuse and also address their interactions Psychiatry 2022; 179:5–7
with other psychiatric illnesses. A summary of the find- 8. Livne O, Shmulewitz D, Sarvet AL, et al: Association of cannabis
use–related predictor variables and self-reported psychotic dis-
ings includes 1) the prevalence of cannabis use and
orders: US adults, 2001–2002 and 2012–2013. Am J Psychiatry
cannabis use disorder in veterans and the factors con- 2022; 179:36–45
tributing to use and misuse in this population; 2) an 9. Ganesh S, D’Souza DC: Cannabis and psychosis: recent epidemi-
association between cannabis use or cannabis use disor- ological findings continuing the “causality debate.” Am J Psychi-
der and self-reported psychotic disorders, as well as an atry 2022; 179:8–10
estimate of the magnitude of the increased prevalence of 10. Mellentin AI, Mejldal A, Guala MM, et al: The impact of alcohol
and other substance use disorders on mortality in patients with
psychotic disorders conferred by cannabis use; 3) a
eating disorders: a nationwide register-based retrospective
marked increase in premature mortality in patients with cohort study. Am J Psychiatry 2022; 179:46–57
eating disorders who also have substance use disorders; 11. Compton WM, Han B: Substance use disorders are deadly. Am J
and 4) how alcohol consumption and alcohol-related Psychiatry 2022; 179:11–13

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12. Mallard TT, Savage JE, Johnson EC, et al: Item-level genome-wide 14. Koob GF, Powell P, White A: Addiction as a coping response:
association study of the Alcohol Use Disorders Identification Test in hyperkatifeia, deaths of despair, and COVID-19. Am J Psychiatry
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13. Kranzler HR, Zhou H, Kember RL: Identifying and reducing 15. Spanagel R: Cannabinoids and the endocannabinoid system in
bias in genome-wide association studies of alcohol-related reward processing and addiction: from mechanisms to interven-
traits. Am J Psychiatry 2022; 179:14–16 tions. Dialogues Clin Neurosci 2020; 22:241–250.

The Journal Is Seeking Statistical Editors

The American Journal of Psychiatry is seeking individuals to serve as Statistical Editors in three areas:
• Neuroimaging (e.g., network connectivity modeling)
• OMICS (e.g., genomics, transcriptomics, and proteomics)
• Multivariate modeling in relation to psychiatric research
(e.g., clinical trials, biomarker investigations)
Individuals interested in the neuroimaging and genetic areas should have expertise in analytic strate-
gies related to large datasets as well as an understanding of machine learning. Regarding multivariate
modeling in relation to psychiatric research, expertise in applying these methods to clinical popula-
tions and biomarkers would be desirable.
Statistical Editors will review papers in their area of expertise that are on a potential path for publica-
tion, providing guidance to authors on matters regarding their analyses and how they are presented.
Estimated obligation < 10 hours per month.
Statistical Editors are featured on the masthead among editorial leadership, and each position comes
with an annual stipend.
Interested persons should indicate the statistical area for which they are applying and submit a CV and
cover letter to [email protected] with the subject line “Statistical Editor Application.”

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