13

Problem Cannabis Use

A recent national survey reported that 22.2 million Americans (ages 12 or older) identify as current users of cannabis (CBHSQ, 2015). A subgroup of these users, 4.2 million Americans, reported experiencing symptoms in the previous year that would qualify them for cannabis use disorder (CUD) (CBHSQ, 2015). Unfortunately, the literature remains unclear on the association or developmental link between varying levels of cannabis use and the development of “problem” cannabis use or cannabis use disorder, particularly at different age groups (e.g., 12 years or older).

In this chapter, the committee reviews the current research evidence that most directly addresses prioritized research questions related to the association between cannabis use and the development of problem cannabis use and to the risk and protective factors involved in the development or exacerbation of problem use. An initial search of the primary literature (see Appendix B) produced a substantial number of primary articles for the committee to review. Due to the time constraints of the study, additional search constraints were added to zero in on the types of studies

that would likely produce the clearest research conclusions. For example, literature searches were limited to articles that included the following search terms: longitudinal, prospective, and case-control. The primary literature was further limited to studies that included a sample size of >500 participants and to studies that investigated problem cannabis use as a function of the most relevant risk factors, including mental health, the age of initiation of cannabis use, risk factors during adolescence, biological sex, and other drug use. Large population-based studies that explored multiple demographic variables were also included.

It is of note, however, that due to the specific search restrictions outlined above, controlled laboratory studies with cannabis were not included in the committee’s set of articles to review. There do, in fact, exist controlled lab studies that assess the direct effects of cannabis on behaviors relevant to cannabis use disorder and the dose-dependent effects of cannabis and that are related to its abuse liability. Unfortunately, because of the constraints of this study, these findings are not incorporated in the chapter’s discussion. Furthermore, the committee’s prioritized research questions did not examine the association between low-level cannabis use or infrequent cannabis use and the development of problem cannabis use.

To inform their research conclusions, the committee reviewed two of the most recent good- to fair-quality systematic reviews and 26 primary literature articles.

PROBLEM CANNABIS USE

As noted above, the literature is unclear on the association between cannabis use and the progression to the sort of cannabis use determined to be “problem” use. A major contributor to this issue is the lack of official distinction between “risky” or “problem” use of cannabis (Casajuana et al., 2016). In recent years, CUD¹ has been termed an official psychiatric disorder (APA, 2013; WHO, 2015). A current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) diagnosis of CUD replaces the previous diagnoses of cannabis abuse and cannabis dependence. Although some progress has been made in standardizing terminology, explicit characterizations of cannabis use patterns that precede abuse or dependence still remain unclear (Casajuana et al., 2016). Given this context, for the purposes of this chapter the committee will use the broad term “problem cannabis use disorder” to encompass various levels of

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¹ In brief, CUD is a diagnosable psychiatric disorder defined as a problematic pattern of cannabis use leading to clinically significant personal, social, physical, and/or psychological distress or impairment.

hazardous or potentially harmful cannabis use patterns, including those related to CUD, dependence, and abuse.

Which Characteristics of Cannabis Use Are Associated with the Progression to Developing Problem Cannabis Use?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and cannabis use disorder, dependence, abuse, or problem cannabis use.

Primary Literature

Several studies using large population-based surveys have explored the rates of cannabis use disorder and the variables that affect progression from the initiation of use to problem cannabis use. According to findings from Wave 1 (baseline; 2001–2002) and Wave 2 (follow-up; 2004–2005) of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a survey of a nationally representative sample of U.S. adults ages 18 years and older (n = 34,653 in Wave 2), cannabis use reported during the first wave was significantly associated with any cannabis use disorder during the second wave (adjusted odds ratio [aOR], 9.5; 95% confidence interval [CI] = 6.4–14.1); 14.1 percent of past-year cannabis users in Wave 1 met the criteria for cannabis abuse in Wave 2, and 5.1 percent met criteria for dependence, as compared with 0.7 percent of participants who reported no past-year cannabis use during Wave 1 who met the criteria for cannabis abuse and 0.2 percent who met the criteria for cannabis dependence (Blanco et al., 2016). This study accounted for multiple sociodemographic factors that may have affected the outcome.

The progression of cannabis use to developing cannabis use disorder as a function of the frequency of cannabis use was also explored using Waves 1 and 2 of the NESARC data (Cougle et al., 2016) Among the past-year weekly nondependent cannabis users in Wave 1 (n = 435), 9.7 percent progressed to cannabis dependence in Wave 2; however, an increased frequency of cannabis use per day only weakly predicted progression of cannabis use to CUD (odds ratio [OR], 1.08; CI = 1.04–1.13) in a prospective analysis. A cross-sectional analysis of Wave 1 data found that 8.0 percent of respondents who reported using cannabis at least once in the past year met the criteria for dependence, whereas among weekly and daily cannabis smokers, 17.0 percent and 18.8 percent, respectively, met the criteria for dependence.

Using data obtained from the U.S. National Household Survey on

Drug Abuse (NHSDA) conducted in 2001 with a representative sample of U.S. residents 12 years of age and older (n = 114,241), Chen and colleagues (2005) explored the rates of developing cannabis dependence syndrome after onset of use. Of the recent onset users (individuals that used cannabis within 24 months prior to assessment), an estimated 3.9 percent developed dependence during the interval since first use (median time = 1 year). Of those who initiated cannabis use more than 24 months before the assessment, and were also active cannabis users within the past year, 9.9 percent developed dependence (Chen et al., 2005).

Using data from two large U.S. surveys—the 1991 National Longitudinal Alcohol Epidemiologic Survey (NLAES) (n = 42,862) and the 2002 NESARC (n = 43,093)—Compton and colleagues (2004) assessed the rates of cannabis use disorder as a function of biological sex, ethnicity, and frequency of cannabis use. They found that the overall prevalence of DSM-IV cannabis abuse and dependence increased significantly from 1.2 percent to 1.5 percent between 1991 and 2001. The greatest increases in these rates were observed among young black men and women (p < 0.001), and young Hispanic men (p = 0.006). The increase in the rates of cannabis use disorder among cannabis users was observed in the absence of self-reported increases in frequency or quantity of use (p = 0.002); this suggests that the increases in cannabis use disorders may be due to the increased potency (percent tetrahydrocannabinol [THC]) of cannabis between 1991 and 2001.

Discussion of Findings

The limitations of these studies include the reliance on self-reported cannabis use, the fact that data were restricted to two time points of assessment separated by 3 years, and that the findings are based on epidemiological data obtained more than 10 years ago. A significant issue with relying on self-report methodologies to ascertain problem cannabis use is that this requires that the respondent have insight into the fact that cannabis is actually causing problems in order to meet criteria for cannabis abuse/dependence (as per the DSM-IV) or CUD (as per the DSM-V). Furthermore, while the primary literature indicates a weak association between the frequency of use and a greater risk of developing cannabis use disorder, it should be noted that the frequency of use in these studies was assessed in the absence of determining the amount of cannabis used per occasion, which is a primary variable hypothesized to affect the rates of developing problem cannabis use.

Cannabis use is increasing across the country and across age groups (Hasin et al., 2015); the strength of cannabis has increased (ElSohly et al., 2016); and different routes of cannabis administration have become popu-

lar, including vaping, dabs, and edibles (Daniulaityte et al., 2015; Kilmer et al., 2013; Pacula et al., 2016). These trends may reflect an increased vulnerability to developing problem cannabis use relative to what was estimated based on the Wave 1 and Wave 2 NESARC data collected in 2001–2001 and 2004–2005. Therefore, the estimated risk of developing problem cannabis use based on these data may not accurately reflect the risk now, given the current trends.

Are There Risk and Protective Factors for Developing Problem Cannabis Use?

Anxiety

Systematic Reviews Kedzior and Laeber (2014) searched two large databases for articles published from inception through 2013 to identify studies of cannabis use and anxiety. They included cross-sectional and longitudinal studies conducted in noninstitutionalized populations, with anxiety diagnoses based on DSM or International Classification of Diseases (ICD) criteria, odds ratios, or data sufficient for the calculation of a measure of effects, and they included comparison data from healthy nonusers. Their purpose was to examine both of the possible temporal relationships between cannabis use and anxiety (i.e., the effect of anxiety on cannabis use and the effect of cannabis use on anxiety). They identified 31 studies for their review. Five of these examined cannabis use at baseline and anxiety at follow-up, and the remainder considered the role of anxiety as a risk factor for cannabis use. Sample sizes were almost 2,000 or greater in four studies and more than 12,000 in a fifth study. After analyzing various subsets of the selected articles, the authors concluded that there was a small positive association between anxiety and CUD (OR, 1.68; 95% CI = 1.23–2.31, n = 13 studies). One study included in the analysis assessed anxiety at baseline and cannabis use at follow-up and did not find an association (OR, 0.94; 95% CI = 0.86–1.03), but it did not report on problem cannabis use at follow-up. The authors found little evidence of publication bias after their assessment, and they reported a moderate-high heterogeneity. They offered three possible explanations of this heterogeneity: differences in adjustment for confounding when calculating the OR, year of publication, and different methods for diagnosing anxiety. Based on this systematic review, it appears that while there is a small association between anxiety and CUD, anxiety does not seem to be a predisposing risk factor for developing CUD.

Primary Literature The committee did not identify any good-quality primary literature that reported on anxiety as a risk or a protective factor for developing problem cannabis use and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Stimulant Medication in Children Diagnosed with Attention Deficit Hyperactivity Disorder

Systematic Reviews Humphreys et al. (2013) conducted a systematic literature review and meta-analysis to assess the association between childhood treatment with stimulant medication and later substance use, abuse, or dependence. They searched the literature published between 1980 and 2012 and included published and unpublished studies with a longitudinal design, binary measures to identify children with attention deficit hyperactivity disorder (ADHD), binary substance use and abuse measures, and data allowing the calculation of odds ratios. Fifteen studies were included in the review; nine of these evaluated the association of stimulant medication with a lifetime history of ever using marijuana, and nine evaluated the association of stimulant medication with cannabis abuse or dependence. All study subjects were children at the time of enrollment, and the follow-up time ranged from 4 to 28 years in the group of 9 studies reviewed, with the mean age at follow-up ranging from 15 to 26 years. One of the studies in this systematic review included children as young as 4 years of age who would not be expected to develop CUD in the follow-up time period. The percentage of study subjects who were male ranged from 0 to 100, with the majority of the studies being more than 80 percent male. The researchers reported an OR of 1.01 (95% CI = 0.68–1.50) for the association between stimulant medication and marijuana abuse or dependence. Some suggestion of publication bias was noted, and heterogeneity was noted in the group of nine studies with data about marijuana abuse or dependence. These results suggest that medication for ADHD during childhood does not constitute a risk factor for developing problem cannabis use later in life.

Primary Literature The committee did not identify any good-quality primary literature that reported stimulant medication in children diagnosed with ADHD as a risk or a protective factor for developing problem cannabis use and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Psychopathology

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on psychopathology as a risk or a protective factor for developing problem cannabis use.

Primary Literature Data obtained from the 2001 and 2005 NESARC, a survey of a nationally representative sample of U.S. adults ages 18 years and older (n = 34,653 in Wave 2), explored anxiety as a risk factor for progression to cannabis use disorder. Using data from Wave 2 (comprised of 34, 653 participants from Wave 1), Feingold and colleagues (2016) found that anxiety disorders were not associated with an increased incidence of cannabis use disorders (aOR, 0.68; 95% CI = 0.41–1.14). Similarly, a prospective analysis using Wave 1 and Wave 2 NESARC data also found that anxiety disorders failed to predict progression from cannabis use to cannabis dependence in weekly cannabis users (Cougle et al., 2016).

Another analysis used these data to determine the association between baseline major depressive disorder (MDD) as a risk factor for cannabis use disorders (Pacek et al., 2013). A positive relationship was observed between baseline MDD and cannabis use disorders (OR, 2.01, 95% CI = 1.09–3.68); baseline MDD also increased the risk of co-occurring alcohol and cannabis use disorders (OR, 5.23; 95% CI = 1.28–21.34) when compared to individuals without baseline MDD. When adjusting the model to account for potential confounding variables, the association between baseline MDD and the development of cannabis use disorders alone, and co-occurring with alcohol use disorders was retained (aOR, 2.28; 95% CI = 1.28–4.05 for cannabis use disorders alone and aOR, 4.51, 95% CI = 1.31–15.60 for comorbid alcohol and cannabis use disorders). These findings support a strong association between MDD and the development of cannabis use disorders. According to a later prospective analysis (Cougle et al., 2016), among weekly, nondependent cannabis users in Wave 1, depressive disorders did not significantly predict progression to cannabis dependence in Wave 2 (OR, 0.89; 95% CI = 0.58–1.38) (Cougle et al., 2016). The discrepancy between these two findings may be due to the former study assessing respondents who met the criteria for MDD. Also, the pool of respondents in the earlier study was not limited to those who reported weekly cannabis use during Wave 1, as was the case with the later study.

Another study assessing the impact of baseline depressive symptoms on developing cannabis abuse used data from a longitudinal study involving 1,980 participants (the 1980 Baltimore Epidemiologic Catchment Area study). In this study, a subset of participants (n = 1,837) were assessed for cannabis use disorders 14 to 16 years after initial assessment (Bovasso, 2001). Depressive symptoms failed to predict cannabis abuse at follow-up assessments, which indicated that among the population

studied, depression was not a risk factor for later cannabis abuse. The long duration between the initial assessment and the follow-up and the presence of significant attrition were significant limitations to this study.

In order to determine the effects of psychotic disorders on the risk for heavy cannabis use, data obtained from the Genomic Psychiatric Cohort—a clinically assessed multiethnic sample of participants (n = 9,142) with a diagnosis of schizophrenia, bipolar disorder with psychotic features, or schizoaffective disorders—were compared to a control population (n = 10,195) (Hartz et al., 2014). Relative to the control population, individuals with chronic psychotic disorders were found to have an increased risk for heavy cannabis use, defined by the researchers as cannabis use more than 21 times per year (OR, 3.5; 95% CI = 3.2–3.7). It is important to note, however, that it remains difficult to determine how heavy cannabis use translates to problem cannabis use, cannabis dependence, or CUD.

A prospective analysis using data from Waves 1 and 2 of the NESARC found that personality disorders failed to predict a progression from past-year, weekly nondependent cannabis use in Wave 1 to cannabis dependence in Wave 2 (OR, 0.91; 95% CI = 0.62–1.34). This same analysis demonstrated that bipolar disorder was associated with a lower risk for developing CUD (OR, 0.43; 95% CI = 0.36–0.52) (Cougle et al., 2016).

Biological Sex

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on biological sex as a risk or a protective factor for developing problem cannabis use.

Primary Literature Data from the NLAES (n = 42,862) were analyzed in effort to determine the effect of biological sex on the risk of developing cannabis use disorders (Grant et al., 2006). Of the participants that reported cannabis use at least 12 times, women were less likely to be categorized with cannabis “abuse/moderate dependence” relative to men (8 percent versus 14 percent) or “severe abuse/dependence” (3 percent versus 6 percent). While men were consistently more likely to report hazardous cannabis use relative to women, women were more likely to report withdrawal and to have higher rates of four symptoms of dependence (i.e., emotional problems, giving up activities, using more cannabis than intended, withdrawal) in the “abuse/moderate dependence” category than men. These findings may suggest either that men and women differ in cannabis dependence symptomatology or that they differ in their willingness to self-report the symptoms.

Using data obtained from Wave IV of the National Longitudinal Study of Adolescent Health—a nationally representative population--

based survey of young adults ages 24 to 32 (n = 15,500; interviewed from 2008–2009)—lifetime prevalence rates of cannabis dependence were determined to be 8.3 percent, and they were higher among males than among females (Haberstick et al., 2014). However, a prospective analysis using data from Wave 1 and Wave 2 of the NESARC failed to find that biological sex predicted a progression from cannabis use to cannabis dependence in weekly nondependent cannabis users (OR, 1.17; 95% CI = 0.75–1.81) (Cougle et al., 2016).

Progression from the onset of cannabis use to the development of cannabis dependence as a function of biological sex was explored using data obtained from the NHSDA, which was conducted in 2001 with a representative sample of U.S. residents 12 years of age and older (n = 114,241) (Chen et al., 2005). The rate for developing cannabis dependence 24 months after onset of use was 3.9 percent for both men and women. However, it is not known if differences between men and women would have emerged if a shorter time frame from cannabis use onset had been explored.

Other Drug Use

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on other drug use as a risk or a protective factor for developing problem cannabis use.

Primary Literature To explore the impact of other drug use as a risk factor for developing problem cannabis use, data obtained from the NHSDA conducted in 2001 with a representative sample of U.S. residents 12 years of age and older (n = 114,241) were analyzed. The rate of developing cannabis dependence within 24 months of first cannabis use was doubled among respondents who had experience with three or more other drugs (tobacco, alcohol, and other drugs) prior to cannabis use (adjusted risk ratio [aRR] = 2.2; 95% CI = 1.1–4.3; p = 0.03) (Chen et al., 2005). However, a prospective analysis using data from Waves 1 and 2 of the NESARC failed to find that alcohol or nicotine dependence predicted progression from cannabis use to cannabis dependence (OR, 0.88; 95% CI = 0.58–1.32 and OR, 0.77; 95% CI = 0.52–1.13, respectively) (Cougle et al., 2016).

Age—Older Population

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on older age as a risk or a protective factor for developing problem cannabis use.

Primary Literature Based on the large population-based U.S. National Survey on Drug Use and Health, the prevalence of cannabis use in the United States was assessed in a population more than 50 years of age (n = 10,953; data from 2005 and 2006). Only 0.12 percent of the population met the criteria for cannabis abuse and dependence demonstrating that, at the time of this survey, this is an age group that is at low risk for developing CUD (Blazer and Wu, 2009).

Age of Initiation of Cannabis Use

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on the age of initiation of cannabis use as a risk or a protective factor for developing problem cannabis use.

Primary Literature The age of initiation of cannabis use as a risk factor for developing cannabis dependence has been explored in many studies. Chen et al. (2005) used data obtained from the NHSDA conducted in 2001 with a representative sample of U.S. residents 12 years of age and older (n = 114,241). Adolescent onset cannabis users were more likely to become dependent than respondents who had initiated cannabis use during adulthood. Using data obtained from adult onset users of cannabis (21 years of age and older) as a reference, Chen and colleagues found a strong association between an onset of cannabis use between 11 and 13 years of age and the relative risk of becoming dependent (aRR = 10.8; 95% CI = 2.5–47.1). The estimated risk ratio of developing cannabis dependence when initiating cannabis use at 14 to 15 years of age was 12.0 (95% CI = 2.9–50.3).

Another study exploring early, frequent cannabis use as a risk factor for developing cannabis use disorder used data from three long-running surveys in Australia and New Zealand² (Silins et al., 2014). Compared to individuals who had never used cannabis, those who were daily users before 17 years of age had significantly greater odds of later developing cannabis dependence (n = 2,675; aOR, 17.95; 95% CI = 9.44–34.12). This study controlled for 53 covariates, including socio-demographic factors and other potential antecedents to the development of problem cannabis use that may have affected the findings.

A longitudinal study of a community-based sample of adolescents and young adults surveyed between 14 and 24 years of age in Munich, Germany, with four waves of assessments over a 10-year period (n = 3,021 at baseline) ascertained the prevalence rates of DSM-IV cannabis

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² These surveys include the Australian Temperament Project, the Christchurch Health and Development Study, and the Victorian Adolescent Health Cohort Study.

dependence as a function of cannabis use (Perkonigg et al., 2008). During the first assessment (at baseline), 1.5 percent of the sample met the criteria for DSM-IV cannabis dependence. Among those who reported using cannabis at that time, 4.3 percent met the criteria for dependence. At the 10-year follow-up, 6.1 percent of those who reported using cannabis at baseline met the criteria for dependence. The authors concluded that the higher rates of cannabis dependence during the 10-year follow-up assessment suggested that cannabis use early in life may be indicative of increased vulnerability to developing CUD. However, there are other factors (as discussed below) that may explain why an increase in cannabis dependence was observed at the 10-year follow-up.

A later study using these data evaluated the probability and speed of going from first cannabis use to developing cannabis dependence as a function of the age of first use. The conditional probability of transition from cannabis use to dependence was estimated to be 6.2 percent (Behrendt et al., 2009). The authors also compared the time of transition from first substance use (nicotine, alcohol, or cannabis) to the development of the specific substance use disorder and found that the transition from first cannabis use to the development of CUD occurred at a faster rate than for those with alcohol or nicotine use disorders.

Other Variables Specific to Adolescents

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on variables that protect against or increase the risk of developing cannabis use disorders among adolescents.

Primary Literature Longitudinal data from the above-described community-based sample from Munich, Germany, were analyzed to determine whether the age of first alcohol and nicotine affects the risk of transition from cannabis use to cannabis dependence (Behrendt et al., 2012). This analysis took into account externalizing disorders (mental disorders characterized by disruptive behaviors that are directed toward an individual’s external environment) and parental substance use disorders as potential factors that may affect the trajectory to cannabis dependence. Using multiple models, the authors found that (1) a younger age of cannabis use (hazard ratio [HR], 0.77), (2) paternal alcohol dependence (HR, 1.47), and (3) externalizing disorders (HR, 1.69) were all associated with a higher risk of developing cannabis dependence. Externalizing disorders were associated with a slower transition from initial cannabis use to cannabis dependence (HR main effect, 1.14; HR interaction effect, 1.17; 95% CI = 1.03–1.33; p = 0.013). A younger age of first alcohol use was also associated with a higher risk for developing cannabis dependence (HR, 0.88).

In participants who used nicotine first, younger age of cannabis use and maternal alcohol dependence were associated with a higher risk of developing cannabis dependence. As such, the age of first alcohol and nicotine use interacted with other risk factors, including the age of first cannabis use, externalizing disorders, and parental alcohol use, in contributing to the risks of developing CUD.

In a population-based longitudinal study of children between the ages of 6 and 12 with yearly assessments, CUD was assessed at ages 19 to 21 (n = 1,803) to define the overall prevalence rates of the disorder (Pingault et al., 2013). The authors further determined whether childhood inattention and hyperactivity symptoms of ADHD, including oppositional behaviors (e.g., hostile, disobedient, or defiant behaviors), and anxiety and depressive behaviors served as risk factors for developing CUD. Overall, cannabis abuse or dependence (high, moderate, or severe) affected 9.1 percent of the participants during young adulthood. Only oppositional behaviors contributed to the risk of developing CUD (OR, 2.33; 95% CI = 1.4–3.87), whereas anxiety and depressive disorders did not.

To determine early life-course predictors of problem cannabis use in early adulthood, data obtained from a population-based birth cohort study of 2,493 young adults who had been included in the Mater Hospital and University of Queensland Study of Pregnancy (MUSP) were assessed (Hayatbakhsh et al., 2009). In this population, 21 percent of those who ever used cannabis were classified as having a CUD at the 21-year follow-up assessment. Males were 2.5 times more likely to have a CUD than females; children living in a family with the mother reporting more frequent changes in marital status had an increased risk of CUD (OR, 2.9; 95% CI = 1.7–5.0); aggressive and delinquent children were 5.4 times more likely to develop CUD; those with poor school performance at 14 years of age were more likely to have CUD (OR, 3.4; 95% CI = 2.3–4.9); and maternal smoking when the child was 14 years of age also increased risk of CUD (OR, 2.0; 95% CI = 1.6–2.5). Childhood anxiety and depression were not risk factors for developing CUD.

In an effort to determine the association between cannabis use by 18 years of age and risk for CUD at 24 years of age, the frequency of cannabis use was evaluated in a 10-year representative cohort study set in Australia (n = 1,520 participants included in the final assessment), which included six surveys during adolescence (15–17.5 years of age) and two follow-up assessments during young adulthood (at 21 and 24 years of age) (Swift et al., 2008). One-third of the population reported having used cannabis during adolescence, and 37 percent of the adolescent cannabis users were using at least weekly when interviewed at 24 years of age. After adjusting for potential confounding factors, problem cannabis use at 24 years of age was associated with adolescent cannabis use, tobacco

use, and persistent mental health problems. The frequency of cannabis use was evaluated in a follow-up analysis that sought to determine whether moderation of cannabis use among adolescent cannabis users protected against the risk of CUD in young adulthood (Swift et al., 2009). In this study, participants were grouped into one of six categories that reflected their maximum level of adolescent use (i.e., nonusers, occasional to abstinence, occasional persisting, weekly to abstinence, weekly to occasional, and weekly persisting). The study’s outcome measures were the level of cannabis use and DSM-IV cannabis dependence in youth adulthood. While 31 percent of the population reported having ever used cannabis, 71 percent of occasional users and 28 percent of weekly users were abstinent in young adulthood. Adolescent weekly or daily users who persisted with regular use (rather than decreased use or becoming abstinent) were at the greatest risk for developing CUD in young adulthood. Therefore, this suggests that moderating adolescent cannabis use can protect against the later problem use that is observed in persistent users. However, regardless of whether the adolescent users moderated their intake, the risk for developing CUD in young adulthood was still significantly greater for adolescent users than for those who never used cannabis.

The Christchurch Health and Development longitudinal birth cohort study (n = 1,265) from New Zealand assessed the probability of developing CUD by young adulthood as a function of various social and demographic factors (Boden et al., 2006). By 18 years of age, 4.7 percent of the population met criteria for cannabis dependence; that number increased to 12.5 percent by 25 years of age. The primary risk factors that predicted the development of CUD included being male and having poor academic performance. Respondents with four or more of the following risk factors had a 50 percent risk of developing cannabis dependence: (1) peer substance use, (2) parental history of a substance use disorder, (3) novelty seeking, (4) cigarette smoking, (5) childhood sexual abuse, and (6) conduct problems.

A longitudinal study of probands from the Oregon Adolescent Depression Project (final n = 816) assessed the prevalence and age of onset of CUD over four assessments between the ages of 16 and 30 (Farmer et al., 2015). The weighted lifetime prevalence of CUD before the age of 30 was estimated to be 19.1 percent; 81.8 of these participants achieved recovery from CUD, and the recurrence rate of CUD was 27.7 percent, which likely occurred within 36 months following the offset of the first CUD diagnosis. Males were more likely to have been diagnosed at some point during their lives than females.

The association between psychopathology and problem cannabis use was also assessed in a longitudinal prospective study of adolescents (n = 1,395) that were 14 to 17 years of age at baseline and who were assessed

at three different time points over the course of 10 years (Wittchen et al., 2007). A prospective analysis determined that mood disorders (OR, 2.5; 95% CI = 1.3–4.7), including bipolar disorder (hypomania and mania) (OR, 2.7; 95% CI = 1.1–6.2), but not including dysthymia (chronic depression) (OR, 2.3; 95% CI = 0.7–6.7), predicted progression to CUD. Generalized anxiety disorder and specific phobias were also associated with CUD (OR, 3.9; 95% CI = 1.1–13.8 and OR, 1.8; 95% CI = 1.1–3.0, respectively). Of note, ADHD, posttraumatic stress disorder (PTSD), and panic/anxiety all failed to predict the development of CUD.

Data from a longitudinal survey of a representative sample (n = 2,032) of secondary students in the Australian state of Victoria who were assessed for cannabis disorders six times between the ages of 14 and 17 from 1992–1995 and again at 20 years of age were evaluated to determine the adolescent precursors of young adult cannabis dependence (Coffey et al., 2003). Variables that independently predicted cannabis dependence in young adulthood included being male (OR = 2.6; p <0.01), regular cannabis use during adolescence (weekly use: OR = 4.9; daily use: OR = 4.6; p = 0.02), persistent antisocial behavior (linear effect p = 0.03), and persistent cigarette smoking (linear effect p = 0.02). Psychiatric comorbidity did not predict cannabis dependence (linear effect, p = 0.26). Regular cannabis use during adolescence only increased the risk for CUD in the absence of persistent problem alcohol use.

Discussion of Findings

Overall findings suggest that both biological sex and the age of initiation of cannabis use are positively associated with the development of problem cannabis use. There is also evidence that being male and smoking cigarettes are risk factors that contribute to the progression to problem cannabis use. Additional risk factors for the development of CUD during adolescence that are supported by moderate evidence include frequency of use, oppositional behaviors, younger age of first alcohol use, nicotine use, parental substance use, poor school performance, and childhood sexual abuse. The strength of association between the risk factors for developing problem cannabis use, including other drug use and psychopathology, differs between adult and adolescent onset of cannabis use. It is important to highlight that the studies reviewed above vary in their age grouping and generally include populations that cross from late adolescence into young adulthood. Therefore, the conclusions below pertain to a mixture of age subgroups, including older adolescents and young adults.

One significant limitation of any conclusions drawn from the current literature is that the data on cannabis use, other drug use, and the symptoms of problem cannabis use are derived from self-reports. Another

concern is that the structured interviews used to assess baseline dependent variables (i.e., mental health) and outcomes (i.e., problem cannabis use) vary between studies, and even for some longer longitudinal studies, within individual studies. Also, as mentioned in the first section, understanding the conclusions drawn from the currently available literature should take into account the fact that trends in cannabis use have evolved over the last 10 years and that the strength of cannabis has increased, which likely affects the strength of associations between risk factors and developing problem cannabis use. It is also important to note that there is biological plausibility for many of the risk factors noted above. Specifically, there is preclinical literature that speaks to the sex-dependent effects, exposure to nicotine as a risk factor for CUD, and the age of initiation of use affecting CUD.

Biological Sex

13-2(f) There is moderate evidence that being male is a risk factor for the development of problem cannabis use.

Other Drug Use

13-2(g) There is moderate evidence that exposure to the combined use of abused drugs is a risk factor for the development of problem cannabis use.

13-2(h) There is moderate evidence that neither alcohol nor nicotine dependence alone are risk factors for the progression from cannabis use to problem cannabis use.

13-2(i) There is substantial evidence that being male and smoking cigarettes are risk factors for the progression of cannabis use to problem cannabis use.

Age

13-2(j) There is substantial evidence that initiating cannabis use at an earlier age is a risk factor for the development of problem cannabis use.

13-2(k) There is moderate evidence that during adolescence the frequency of cannabis use, oppositional behaviors, a younger age of first alcohol use, nicotine use, parental substance use, poor school performance, antisocial behaviors, and childhood sexual abuse are risk factors for the development of problem cannabis use.

Are There Risk and Protective Factors for Severity or Persistence of Problem Cannabis Use?

Psychopathology

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on psychopathology as a risk or a protective factor for the severity or persistence of problem cannabis use.

Primary Literature A case-control study sought to determine the association between a history of psychiatric treatment and persistent cannabis

use disorder (Arendt et al., 2007). Data from the Danish Psychiatric Case Register (n = 3,114; mean age at start of treatment = 25.7 years) were compared to a representative control group that was randomly selected from the general population and matched to the patient population for age and biological sex (n = 15,570). The authors determined that a history of psychiatric treatment was associated with increased rates of reentry into substance abuse treatment for cannabis dependence (OR, 1.26; 95% CI = 1.07–1.48) relative to the control population.

In an Israeli population (n = 1,317; ages ranged from 21–45 years and older), Walsh et al. (2014) conducted in-person structured interviews to examine the association between traumatic exposure and substance dependence (alcohol, nicotine, and marijuana) and to assess whether PTSD accounted for this association. After controlling for alcohol and nicotine dependence, investigators found that PTSD symptoms were associated with increased odds of marijuana dependence (OR, 1.1; 95% CI = 1.04–1.24) and concluded that the severity of PTSD symptoms may increase the risk for substance dependence. It should be noted, however, that these are cross-sectional data and that the directionality and causality of these associations cannot be determined.

A study by Boden et al. (2013) was outside the scope of our primary literature search due to its small sample size, but it was included because of its potential relevance to the committee’s prioritized research question. In this study, researchers found that in a small population of cannabis-dependent military veterans (n = 37; mean age of starting sample = 51.3 years), a diagnosis of PTSD was significantly associated with the use of cannabis to cope with PTSD symptoms, the severity of cannabis withdrawal, and three factors of cannabis drug craving (i.e., compulsivity, emotionality, and anticipation) relative to a cannabis-dependent population without a diagnosis of PTSD (n = 57). Furthermore, the severity of PTSD symptoms was associated with an increased severity of cannabis withdrawal and factors of cannabis craving (i.e., compulsivity, emotionality, and anticipation).

Biological Sex

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on biological sex as a risk or a protective factor for the severity or persistence of problem cannabis use.

Primary Literature Data from the NLAES (n = 42,862) were analyzed in an effort to determine the effect of biological sex on the risk and severity of cannabis use disorders (Grant et al., 2006). Of the participants who reported cannabis use at least 12 times, women were less likely to be cat-

egorized with cannabis “abuse/moderate dependence” than men (8 percent versus 14 percent) or “severe abuse/dependence” (3 percent versus 6 percent). While men were consistently more likely than women to report hazardous cannabis use, women were more likely to report withdrawal and to have higher rates of four symptoms of dependence in the “abuse/ moderate dependence” category.

A longitudinal study of probands from the Oregon Adolescent Depression Project (final n = 816) assessed recovery from CUD as a function of biological sex (Farmer et al., 2015). Females achieved recovery from CUD at a significantly faster rate than males (females = 24.2 months, standard deviation [SD] = 24.8; males = 41.2 months, SD = 42.7; p = .006), although recurrence rates of CUD did not differ between males and females (30.0% of males, 25.4% of females, p = 0.564).

Discussion of Findings

In addition to the limitations cited for the first two sections such as issues with self-reported cannabis use, the respondents’ reporting of symptoms of problem cannabis use, and data restricted to trends of cannabis use and cannabis strength that do not accurately reflect current trends, the current findings are additionally restricted to limited followup with participants and to only a few of the risk factors highlighted in the second section, including biological sex. The impact of the primary risk factors for developing problem cannabis use identified in the second section of this chapter, including the age of initiation of use, biological sex, and other drug use, should be explored as risk factors for both the severity and the recurrence of problem cannabis use over extended periods of time.

13-3(c) There is moderate evidence of a statistical association between problem cannabis use and increased severity of posttraumatic stress disorder symptoms.

RESEARCH GAP

To address the research gaps relevant to problem cannabis use, the committee suggests the following:

• The impact of the primary risk factors for developing problem cannabis use needs to be explored as risk factors for both the severity and the recurrence of problem cannabis use over extended periods of time.

SUMMARY

This chapter outlines the committee’s efforts to review the current evidence base (1) to determine likelihood of developing problem cannabis use and (2) to identify the potential risk and protective factors involved in the development or exacerbation of problem use. The vast majority of the conclusions formed within this chapter were of moderate evidence; however, the conclusions that were determined to have substantial evidence were formed by research that examined the impact of biological sex, cannabis use at an early age, and past use of cannabis on problem cannabis use. Many of the chapter conclusions pertain to a mixture of age groups, including older adolescents and young adults. See Box 13-1 for a summary list of the chapter’s conclusions.

These research conclusions may have important public health implications; however, it is important that the conclusions be interpreted within the context of the limitations discussed in the Discussion of Findings sections above. It is also important to understand that the conclusions drawn from the currently available literature should take into account the fact that trends of cannabis use have evolved over the past 10 years and note that the strength of cannabis has increased, which likely has affected strength of associations between risk factors and developing problem cannabis use. Greater attention to the research limitations (e.g., reliance on self-reported cannabis use, limited detail on the amount of cannabis used per occasion, polydrug use, limited follow-up, and so on) and improvements to study design and methodological approach would bolster the evidence base and help ensure that substantial evidence concerning problem cannabis use is available.

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