12

Mental Health

The relationship between substance use and mental health has been a long-standing and complex public health issue. In 2014, a national survey from the Substance Abuse and Mental Health Services Administration found that 20.2 million adults had a substance use disorder, and of these

individuals, 7.9 million had both a mental health disorder and a substance use disorder (SAMSHA, 2015). These statistics emphasize the importance of conducting cross-disciplinary research in order to appropriately inform public health decisions and ultimately improve population health. In this chapter, the committee reviews the current evidence on the association between cannabis use and prioritized mental health outcomes.

The mental health outcomes selected for review in this report were derived from the committee’s statement of task and the sponsors’ expressed interest and based on committee consensus. Specifically, mental health outcomes with high prevalence (e.g., depression and anxiety disorders) were included, as were outcomes with significant public health implications such as suicide. Studies on the association between cannabis use and schizophrenia and psychosis were included based on the large volume of literature on the subject, and in an effort to evaluate cannabis effects across the mental health diagnostic spectrum, studies on the association between cannabis use and bipolar disorder were reviewed as well.

Concerning each disorder, the committee focused on two key questions: What is the effect of cannabis use on the risk of developing the disorder? And in patients with the disorder, what are the effects of cannabis use on the symptoms or course of the disorder? An initial search of the primary literature (see Appendix B) produced a substantial number of primary articles (e.g., cross-sectional studies, case-control studies, cohort studies, randomized controlled trials [RCTs], or nonsystematic literature reviews) 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, for the health endpoints discussed below, literature searches were limited to articles that included the following search terms: longitudinal, prospective, and case-control.¹ The committee’s review of the literature focused on identifying studies relevant to answering these specific questions. In this chapter the committee will discuss the findings from 14 of the most recent, good- to fair-quality systematic reviews and from 31 primary literature articles that best address the committee’s research questions of interest.

It is important to note that the present review does not include findings from controlled laboratory studies. These studies have been used to assess the effect of cannabis on behavior, to understand how cannabis interacts with alcohol and other drugs to influence behavior, and to characterize the dose-dependent effects of cannabis as they relate to its

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¹ The initial search of the primary literature produced a relatively small literature base for the posttraumatic stress disorder section, and as such, the additional search restrictions were not applied.

potential for addiction. Evidence from this body of research—though illuminating at the mechanistic level—does not provide information on the mental health effects of cannabis use in real-world conditions, and was excluded for this reason.

SCHIZOPHRENIA AND OTHER PSYCHOSES

Schizophrenia spectrum disorders and other psychotic disorders are mental health disorders characterized by three different classes of symptoms: positive symptoms (e.g., delusions, hallucinations, or disorganized or abnormal motor behavior), negative symptoms (e.g., diminished emotional expression, lack of interest or motivation to engage in social settings, speech disturbance, or anhedonia), and impaired cognition (APA, 2013, p. 87; NIMH, 2015). Evidence suggests that the prevalence of cannabis use among people with schizophrenia is generally higher than among the general population (McLoughlin et al., 2014). In most of the studies reviewed below, schizophrenia, schizophreniform disorder, schizoaffective disorder, and psychotic disorders are used as aggregate endpoints. Therefore, conclusions regarding the association between cannabis use and psychosis are in general not diagnosis specific.

Is There an Association Between Cannabis Use and the Development of Schizophrenia or Other Psychoses?

Systematic Reviews

Five systematic reviews of fair or higher quality were identified that addressed the committee’s research question (Large et al., 2011, Marconi et al., 2016, Moore et al., 2007, Myles et al., 2012, van der Meer et al., 2012). While the systematic review by Marconi et al. was the most recent, it excluded studies that did not consider at least three levels of cannabis exposure because the researchers’ main purpose was to address dose–response relationships. In addition to reporting on the systematic review by Marconi et al., the systematic review conducted by Moore et al. is also discussed.This study addressed the broad question of cannabis use and psychotic outcome and included meta-analysis results. The remaining systematic reviews, which are not reported on here, focused on the time to onset of psychosis (or the age of onset of psychosis), the role of concomitant tobacco use, and psychotic symptomatology in patients at high risk of psychosis.

The systematic review by Marconi et al. (2016) included a search of the literature through December 31, 2013, and selected 10 studies for inclusion in the meta-analysis. A key feature of the researchers’ inclusion criteria

was the requirement that studies assess cannabis use with a dose criterion and classify cannabis use into at least three exposure groups. Thus, high-quality studies with cannabis assessed as a dichotomous variable were excluded from the analysis. Studies that reported psychotic symptoms on a continuous, rather than categorical, scale were also excluded from the analysis. The 10 studies reviewed were conducted in Australia, Europe, New Zealand, and the United States and reported results for 66,816 individuals. The age and sex of the subjects were not reported. Cannabis use was classified based on lifetime frequency, the frequency of use at baseline, the duration/frequency of current use, and frequency within the last year. The authors did not assess the quality of the papers included in the meta-analysis, but they did conduct analyses to assess publication bias and heterogeneity. They considered the publication bias to be low and acknowledged the existence of heterogeneity within their sample of studies. Marconi et al., (2016) found an association between cannabis use and psychosis (odds ratio [OR], 3.9; 95% confidence interval [CI] = 2.84–5.34) among the most severe cannabis users, as compared to the nonusers. The investigators also report a dose–response relationship with an OR of 1.97 (95% CI = 1.68–2.31) for those at the median of any cannabis use and an OR of 3.40 (95% CI = 2.55–4.54) for those in the top 20 percent of cannabis use. In addition, they reported associations of cannabis use with the presence of psychotic symptoms (pooled odds ratio [pOR], 3.59: 95% CI = 2.42–5.32), as well as with a diagnosis of schizophrenia or psychotic disorder (pOR, 5.07; 95% CI = 3.62–7.09). Subgroup analysis stratified by study design revealed a pOR of 3.99 (95% CI = 2.50–6.37) for cross-sectional studies and 3.83 (95% CI = 2.34–6.29) for cohort studies.

Moore et al. (2007) searched multiple databases from their inception through September 2006 and included only studies that were longitudinal, population-based, or case-control studies nested within longitudinal designs. They assessed study quality by recording information on sampling strategy, response rates, missing data, attrition, attempts to address reverse causation, intoxication effects, and other potential confounders. Their search identified 32 studies, with 11 studies reporting the incidence of psychosis from 7 cohort studies, 5 of which were adult population–based cohorts and 2 of which were birth cohorts. They found no evidence of the presence of publication bias using Egger’s test (p = 0.48). The authors noted that some individual studies adjusted for psychotic symptoms at previous assessments or baseline and excluded people with psychotic symptoms or diagnosis at baseline to help clarify the temporal order of events. The authors also noted that individual studies excluded psychotic symptoms that arose solely from drug use by using scales to measure drug intoxication. In addition, this group of studies collectively adjusted for approximately 60 different potential confounders, including

other substance use, personality traits, sociodemographic markers, intellectual ability, and other mental health problems. In a pooled analysis, the authors found that in individuals who have ever used cannabis, there was an associated increased risk of a psychotic outcome (adjusted odds ratio [aOR], 1.41; 95% CI = 1.20–1.65). When the analysis was restricted to studies examining the effects of frequent cannabis use, the investigators found a stronger association (aOR, 2.09; 95% CI = 1.54–2.84), suggesting a dose–response relationship between cannabis use and the risk of a psychotic outcome.

Primary Literature

Auther et al. (2015) used the North American Prodrome Longitudinal Study² phase 1 sample to examine the impact of the level of cannabis use on conversion to psychosis.³ From the subjects who contributed to the data, 370 were determined to be at a high risk for developing a psychotic disorder. After excluding subjects who were missing necessary outcome data—or who met criteria for attenuated positive symptom syndrome, brief intermittent psychotic syndrome, genetic high risk, and deterioration syndrome—a total of 283 subjects (mean age = 18.3 years) were included in the study’s analysis. Using the subjects’ reported level of lifetime use, subjects were divided into three subgroups: no use, use without impairment, and abuse and dependence. The primary outcome, conversion to psychosis, was determined by meeting the full criteria for Presence of Psychotic Syndrome on the Structured Interview for Prodromal Syndrome. In a follow-up assessment (approximately 17 months after the initial baseline assessment), the researchers found that cannabis abuse/ dependence was associated with a greater risk of conversion to psychosis within the chronic high-risk population; however, when alcohol use was incorporated into the Cox regression model, cannabis abuse/dependence was no longer significantly related to conversion (hazard ratio [HR], 1.875; 95% CI = 0.963–3.651). Similar research conclusions were reached in a longitudinal study by Valmaggia et al. (2014), where they examined the association between lifetime cannabis use and the development of psychosis. Valmaggia et al. (2014) followed 182 individuals at ultra-high risk for psychosis disorder for 2 years and found that varying degrees of cannabis use (i.e., frequent use, early-onset use, and continued use

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² The North American Prodrome Longitudinal Study is a collaborative database formed in 2007. The database contains data on various clinical, cognitive, and functioning variables collected from eight independent research centers.

³Auther et al. (2015) defined this outcome as having a psychotic level positive symptom that is either seriously disorganizing or dangerous, or that occurs for at least 1 hour per day for an average of 4 days in the past month.

after presentation) among lifetime cannabis users is associated with an increased transition to psychosis. It is of note, however, that within this specific ultra-high risk population, cannabis users were no more likely to develop psychosis than were those who had never tried cannabis.

Using a case-control design of 410 patients with first episode psychosis and 370 population controls, Di Forti et al. (2015) showed that first-episode psychosis patients were more likely to have lifetime cannabis use, more likely to use cannabis every day, and to mostly use high- potency cannabis as compared to the controls. The cases were also more likely to have used cannabis before the age of 15. Duration of use did not differ between patients and controls, nor did other drug use. After adjusting for a variety of confounders, including use of other drugs and alcohol, the researchers found an increased risk of developing psychosis in subjects who used cannabis daily (OR, 3.04; 95% CI = 1.91–7.76) and in subjects who used high-potency cannabis (OR, 2.91; 95% CI = 1.52–3.60). In a cross-sectional study of subjects with first-episode psychosis, Colizzi et al. (2015) examined the association between cannabis use, the risk of psychosis, and the dopamine receptor type 2 (DRD2) polymorphism rs1076560. Researchers found, after adjusting for confounders (e.g., gender, age, ethnicity, polysubstance use), a significant interaction between lifetime frequency of cannabis use and DRD2 polymorphism rs1076560 on psychosis risk. Moreover, a lifetime history of cannabis use was associated with an increased risk of having psychotic disorder in T-carrying subjects, relative to GG carrying subjects (OR, 3.07; 95% CI = 1.22–7.63).⁴

Discussion of Findings

The association between cannabis use and the development of a psychotic disorder is supported by data synthesized in several good-quality systematic reviews. The magnitude of this association is moderate to large and appears to be dose-dependent, and it may be moderated by genetic factors. Factors contributing to the strength of the evidence derived from the cited systematic reviews include large sample sizes, the relative homogeneity of the findings, the presence of relationships between the dose/ exposure and the risk, the studies having been controlled for confounders, and the systematic reviews having assessed for publication bias. The primary literature reviewed by the committee confirms the conclusions of the systematic reviews, including the association between cannabis use

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⁴ T-carrying subjects have at least one allele with the polymorphism. G-carrying subjects do not express the polymorphism. Genotype results of the subjects included homozygote G/G, heterozygote G/T, and homozygote T/T genotype classes. Due to the low number of TT subjects, GT and T/TT subjects were combined and compared to GG carriers.

and psychotic outcome and the dose-dependency of the effects, further bolstering the overall strength of evidence for our conclusions.

The limitations of the summarized studies include their reliance of self-report for cannabis use, issues with study designs (e.g., a lack of randomization), a lack of information on the frequency of use, patterns of long-term use, and possible confounding polysubstance effects. In addition, for the primary studies cited, some are also limited in terms of their sample sizes and controlling for confounders. Overall, the accumulated evidence is suggestive that cannabis use is associated with an increase in psychosis-related outcomes, as made evident in the discussion of Auther et al. (2015) and Valmaggia et al. (2014) above.

As noted in Box 12-1, the relationship between cannabis use and cannabis use disorder, and psychoses may be multidirectional and complex. The committee found this to be consistent with their review of the summarized data demonstrating a strong and consistent association between cannabis use and the subsequent development of psychosis and psychotic disorders. In addition, it is noteworthy to state that in certain societies, the incidence of schizophrenia has remained stable over the past 50 years despite the introduction of cannabis into those settings (Kirkbride et al., 2012); however, the committee did not examine ecologic data (studies of concomitant time trends) to evaluate trends in cannabis consumption and diagnosis of psychosis over time. Multiple factors (including measurement of dose and frequency of cannabis consumption over decades, and patterns of diagnosis of psychosis) limit our ability to draw conclusions from such findings. Of note, future analysis of rates of psychosis in states with increased access to cannabis could be tracked to provide valuable information regarding potential causal relationships between cannabis use and psychosis.

Is There an Association Between Cannabis Use and the Course or Symptoms of Schizophrenia or Other Psychoses?

Systematic Reviews

Positive Symptoms One systematic review was identified that assessed the effects of cannabis use on positive symptoms⁵ in patients with psychotic disorders, but the researchers did not conduct a quantitative synthesis of the findings (Zammit et al., 2008). An additional systematic review (Szoke et al., 2014) addressed the effects of cannabis on schizotypal symptom dimensions; however, the committee will report only on the conclusions reported by Zammit et al. (2008) because they provide information about patients with psychotic disorders rather than schizotypy.

After their assessment of the literature, Zammit et al. (2008) found mixed evidence for the effects of cannabis use on positive symptoms in patients with psychotic disorders, with studies reporting statistically significant but small associations between cannabis use and the severity of positive symptoms. The authors searched multiple databases through November 2006, screened 15,303 references, and identified 13 cohort studies (n = 1,413) for their review. Studies were included if they were longitudinal or were case-control studies nested in longitudinal designs to assure that cannabis use was measured before outcome ascertainment. The authors excluded cohorts of individuals with dual diagnoses (psychosis and cannabis misuse or dependence) because of the limitations on comparisons to control groups. The authors assessed the quality of the studies by comparing the response rate at baseline, loss to follow-up, masking of outcome assessment, adjustment for baseline severity, adjustment for alcohol and other substances, and adjustment for confounders. Their quality assessment is reported in a summary table, and the authors noted that the most likely source of confounding would be the lack of adjustment for baseline severity and a lack of adjustment for alcohol and other substances in several of the studies. The authors did not report sample sizes, the age or sex of the study participants, or the definitions of cannabis use. The authors noted that several of the reviewed studies varied in their consideration of confounders, such as the use of other substances and baseline symptom severity, and that the lack of an association may be explained by a random misclassification of exposure data, particularly self-reports of cannabis use.

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⁵ Positive symptoms of schizophrenia may include delusions, hallucinations, or abnormal motor behavior.

Negative Symptoms In the systematic review described above, Zammit et al. (2008) identified 4 studies (from the 13 cohort studies identified in the larger systematic review) that assessed the effects of cannabis use on negative symptoms⁶ in patients with psychotic disorders. Zammit et al. (2008) did not conduct a quantitative analysis of findings; in their review however, they found that cannabis use was not associated with negative symptom scores in three studies, but it was associated with reduced negative symptom scores in a fourth study. It should be noted that the fourth study did not control for confounders or baseline differences in symptoms.

Cognition Three systematic reviews were identified that assessed the relationship between cannabis abuse and dependence and cognition effects (e.g., disorganized thinking) in patients with psychotic disorders (Donoghue and Doody, 2012; Rabin et al., 2011; Yucel et al., 2012). A distinctive feature of this group of studies is the varying approaches to separating cannabis use from other substances. While the systematic review by Donoghue and Doody (2012) reported on all types of illegal substance abuse, it identified a subgroup of three studies focusing on cannabis use. This is in contrast to the work of Yucel and colleagues (2012) who included studies with patient groups who abused substances other than cannabis, and by Rabin et al. (2011), who considered cannabis use without other substance use but relied on cross-sectional studies only.

Donoghue and Doody (2012) conducted a search for relevant studies published between 1980 and October 2010, and from an initial pool of 7,075 studies, the authors selected 19 studies for further review. Three of the 19 studies focused on cannabis use. The three studies (n = 551) used the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria to define cannabis abuse or dependence, and DSM-IV criteria to define schizophrenia or schizoaffective disorders. All three studies included inpatients and outpatients, as well as patients with a dual diagnosis. In their review of these studies, the authors found that cannabis users performed better on various measures of cognition, including verbal learning and memory, attention and psychomotor, and global cognitive factor tests, than did non-cannabis users. The authors conducted a meta-analysis of the three studies and reported statistically significant associations between cannabis use and verbal learning and memory (Hedges g⁷ = 0.351, 95% CI = 0.179–0.523), attention and psychomotor

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⁶ Negative symptoms of schizophrenia may include diminished emotional expression, lack of interest or motivation to engage in social settings, speech disturbance, or anhedonia.

⁷ Hedges g reports the unbiased estimate of the effect size (the standardized difference between two means). It is commonly used for small sample sizes.

speed (Hedges g = 0.316, 95% CI = 0.144–0.488), and global cognitive factor (Hedges g = 0.237, 95% CI = 0.083–0.390). Tests of association with working memory and executive function were not statistically significant.

Rabin et al. (2011) conducted a meta-analysis on 8 cross-sectional studies, published between 2005 and 2010, with a total of 942 patients with schizophrenia. The 356 cannabis users among those patients had a mean age of 28.7 years, a mean education of 11.4 years, and 81.9 percent were male. Of the 942 patients, 586 were nonusers of cannabis and had a mean age of 32.4 years, a mean education of 12.2 years, and 65.8 percent were male. Limited information was provided about the statistical analysis, and the authors reported moderate associations with cannabis users performing better on general cognitive ability and intelligence; selective, sustained and divided attention; and visual-spatial and constructional abilities.

Yucel et al. (2012) searched the literature for the period between 1987 and March 2010 and included studies where cannabis was the predominant substance used by patients. They identified 10 studies involving 572 patients with schizophrenia; the studies were stratified by lifetime versus current or recent use. From their review, Yucel et al. (2012) found that patients with established schizophrenia and a history of cannabis use showed better performance on tests assessing cognitive abilities than did patients who did not use cannabis. For example, the meta-analysis conducted on 10 studies to assess global cognition resulted in a Cohen’s d⁸ of 0.35 (95% CI = 0.09–0.61; p = 0.009), showing small to moderate increases in performance in cannabis users compared to nonusers. Other small to moderate statistically significant effects were observed, again showing better performance by cannabis users compared to nonusers for processing speed, visual memory, and planning, despite the smaller number of studies available for these comparisons. The authors stated that tests for publication bias or heterogeneity were conducted, but these were only partially reported. No differences were reported for assessments of attention, verbal memory, or working memory.

Primary Literature

Positive Symptoms In a 2004 case-control study with schizophrenic patients, Rehman and Farooq (2007) determined that patients with cannabis abuse had higher rates of positive symptoms than nonusers. Seddon et al. (2016), in a case-control study examining cannabis use in the first year following a first-episode psychosis, found that cannabis use at baseline

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⁸ Cohen’s d is an estimate of the effect size (the standardized difference between two means).

or the 1-year assessment was associated with greater severity of positive symptoms (as measured by the Positive and Negative Syndrome Scale [PANSS], 2.14; 95% CI = 1.41–2.88) and a decrease in global functioning (as measured by the Global Assessment of Functioning symptom scale [–3.27; 95% CI = -–6.04 to –0.49]). In contrast, Barrowclough et al. (2013) found no association between cannabis use and positive symptoms in patients with non-affective psychotic disorders, as assessed by PANSS (adjusted coefficient = 0.07; 95% CI = –0.21–0.34). Moreover, using a longitudinal analysis over 24 months, the researchers found that changes in cannabis dose did not predict changes in positive symptoms severity, even when patients became abstinent. In their study, the researchers conducted a cross sectional analysis of 160 patients with a clinical diagnosis of non-affective psychotic disorder and a DSM-IV diagnosis of drug and/ or alcohol dependence or abuse. Notable strengths of this study are its dose–response analysis and its detailed quantification of cannabis use, with mean use in the sample being 4 days per week and an average of 2.4 grams per day. However, the results were not adjusted for confounders, including other drug use.

Another study, Dubertret et al. (2006) conducted a cross-sectional analysis on 205 patients with schizophrenia (n = 121 with no substance abuse; n = 38 cannabis users) and found that after controlling for other substance use, no association between cannabis use and positive symptoms was evident. A cross-sectional analysis by Tosato et al. (2013) (n = 311 patients) found no association between cannabis use and the severity of positive symptoms in a population of first-episode psychosis patients. Similarly, in a prospective, longitudinal cross-sectional study by Barrowclough et al. (2015), the authors found no specific association between cannabis dose and positive symptoms (n = 102; adjusted coefficient, 0.01; 95% CI = −0.24–0.25), and reductions in cannabis use during follow-up (longitudinal analysis up to 18 months) were not associated with improvements in positive PANSS symptoms in cannabis-using subjects after adjusting for confounders, including other drug use (n = 65; adjusted coefficient, –0.12; 95% CI = −0.45–0.22). After adjustment for confounders, abstinence from cannabis (90 days preceding the assessment) was found to be related to improved global functioning (adjusted coefficient, 4.95; 95% CI = 0.46–9.44). After controlling for confounders, van Dijk et al. (2012) found no difference between cannabis users (n = 68) and nonusers (n = 77) with schizophrenia with regard to the severity of baseline schizophrenia symptoms (p = 0.61; assessed by the Clinical Global Impression scale). The researchers also found no relationship between amount of cannabis used and the level of psychopathology (p = 0.676; as measured by PANSS).

Negative Symptoms Dubertret et al. (2006), using a cross-sectional analysis, found that after controlling for other drug substances, cannabis use was strongly associated with fewer negative symptoms of avolition—apathy (p = 0.0001)—as compared to non-cannabis users. Barrowclough et al. (2013), also using a cross-sectional analysis, found that previous 90-day cannabis use was not significantly associated with the severity of negative symptoms (adjusted coefficient, 0.12; 95% CI = –0.05–0.29). The longitudinal analysis of data from this cohort (up to 24 months) revealed no association between cannabis dose and negative symptom severity (adjusted coefficient, 0.18; 95% CI = –0.14–0.51). Similarly, a prospective longitudinal study by Barrowclough et al. (2015) found no association between cannabis dose and negative symptoms after adjustment for confounders, including other drug use (adjusted coefficient, 0.28; 95% CI = –0.04–0.61). Seddon et al. (2016) found that cannabis use at baseline or the 1-year assessment was not associated with differences in negative symptoms relative to nonusers (as measured by PANSS; –0.07; 95% CI = –1.11–0.97).

Cognition Power et al. (2015) found no association between lifetime cannabis use or cannabis dependence and cognitive function after controlling for confounding variables, including the onset of illness and comorbid cognitive functioning in Australian patients with an established International Classification of Diseases-10 (ICD-10) diagnosis of psychotic disorder. Sanchez-Torres et al. (2013) used a longitudinal study to examine the impact of lifetime and current cannabis use on cognition in 42 patients with schizophrenia and found a negative effect of longitudinal cannabis use specifically in the social cognition domain (Pearson correlation, –0.34; p <0.05). van Winkle et al. (2011) found that cannabis use before the onset of psychosis interacted significantly with the rs2494732 single nucleotide polymorphism of the AKT1 gene to affect patient reaction time and accuracy as measured by the Continuous Performance Test. Cannabis-using patients with the a priori vulnerability (i.e., homozygous for the polymorphism) were slower and less accurate on the CPT than nonusers.

Discussion of Findings

With regard to the effects of cannabis use on positive symptoms, the data are considered mixed. Studies report both worsening and no effect of cannabis use on positive symptoms in schizophrenia. The limitations observed in the reviewed studies included variable adjustment for other drug use and baseline symptom severity; issues with study design (observational); a reliance on self-reports; and variable analyses of cannabis use (i.e., dose/amount/frequency, current versus lifetime). However, these

studies, combined with human experimental studies demonstrating that cannabis can worsen positive symptoms in patients with schizophrenia, were also considered when determining the strength of evidence. With regard to negative symptoms, the data reviewed were generally more homogenous, with most studies reporting either an absence of association between cannabis use and negative symptoms or else reduced negative symptoms in cannabis users. Variable adjustments for other drug use and baseline symptom severity were noted as limitations in some studies. Overall, the data provide support for the conclusion that cannabis use does not worsen negative symptoms in patients with psychotic disorders. With regard to cognition in patients with psychotic disorders, the data reviewed in the systematic reviews suggest better cognitive performance in some cognitive domains in patients with psychotic disorders and cannabis use disorders, and in patients with a history of cannabis use, as compared to patients with psychotic disorders and no cannabis use disorder diagnosis. The limitations of two of the systematic reviews—Yucel et al. (2012) and Rabin et al. (2011)—include their study design (cross-sectional only); variable adjustments made for confounders, including other drug use; and variable definitions and inclusion criteria for cannabis using and non-using control groups. This study found better cognitive performance only in subjects with a lifetime history of cannabis use, but not recent cannabis use. The systematic review by Donoghue and Doody (2012) focused on longitudinal studies in schizophrenic subjects with and without comorbid cannabis use and found that cannabis users performed better on some measures of cognition, including verbal learning and memory, attention and psychomotor speed, and global cognitive factor tests, than non-cannabis users. The three reviewed studies showed similar effects; however, the largest study was more precise and had narrower confidence intervals. Estimates for the size of the effect are small to moderate. The primary articles reviewed indicate more mixed results than the systematic reviews.

Overall, the totality of data favor the conclusion that a history of, but not recent, cannabis use is associated with statistically significant performance improvement on measures of cognitive function in patients with psychotic disorders. It is not clear how the difference in scores might translate with respect to overall improved outcomes in functioning beyond the test setting. Furthermore, other data do not support the notion that acute cannabis exposure improves cognitive performance in patients with psychotic disorders, as acute intoxication is associated with impaired cognitive performance in cognitive domains of memory, learning, and attention (see Chapter 11). Among the multiple potential explanations of the data indicating better performance on certain measures of cognition in patients using cannabis are that these patients represent a higher-functioning sub-

group of psychotic patients or that cannabis users who achieve abstinence have better premorbid cognitive status. Additionally, it has been proposed that a history of cannabis use may have exerted neuroprotective effects in patients with psychotic disorders. Finally, we find insufficient data from which to draw conclusions regarding the effects of cannabis on risk for suicide in patients with psychotic disorders.

BIPOLAR DISORDER

Bipolar and related disorders are categorized by episodes and/or symptoms of mania, hypomania, and depression (APA, 2013). The risk factors for developing bipolar disorder are not clear; however, research suggests that brain structure, genetics, and family history may contribute to its onset (NIMH, 2016). Given that cannabis is reportedly the most commonly used illicit drug by individuals with bipolar disorders (Zorrilla et al., 2015), it is worthwhile for this report to explore the potential association between cannabis use and the development and course of bipolar disorder.

Is There an Association Between Cannabis Use and the Development of Bipolar Disorder or Mania?

Systematic Reviews

The committee identified one systematic review, Gibbs et al. (2015), that assessed the association between cannabis use and bipolar disor-

der or mania. The authors searched multiple databases for English language studies published through 2014 and included studies that were experimental, prospective, cohort, or longitudinal. The overall search strategy yielded six studies with a total of 14,918 participants who met the inclusion criteria. Two of these studies, published in 2006 (n = 4815) and 2010 (n = 705), were used in the analysis. The meta-analysis showed an association between cannabis use and new onset of manic symptoms in individuals without preexisting bipolar disorder (OR, 2.97; 95% CI = 1.80–4.90). However, the researchers did not report information about the patient characteristics, the total number of subjects, age, gender, cannabis form, the ascertainment of mania symptoms, or other features of the two studies. Furthermore, due to the low number of studies that contributed to their research findings, the authors describe their conclusions as prelimnary and tentative.

Primary Literature

Data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)⁹ (Feingold et al., 2014) found that any past-year use of cannabis was associated with the onset of bipolar disorder (OR, 2.24; 95% CI = 1.44–3.51) in unadjusted analyses. However, after adjusting for sociodemographic and clinical variables, the association was attenuated and no longer statistically significant (aOR, 1.17; 95% CI = 0.65–2.11).

Using the same NESARC dataset as Feingold, Cougle and colleagues (2015)¹⁰ found that the risk of a past-year bipolar disorder diagnosis was elevated in regular (e.g., weekly use) cannabis users at Wave 2 follow-up: (OR, 1.37; 95% CI = 1.11–1.69). Cougle and collaborators (2015) reminded readers about the correlational nature of the study design and noted that causality could not be inferred from their conclusions. They also cautioned that the increased risk in bipolar disorders might be due to augmenting the psychotic features in frequent cannabis users (i.e., manic symptoms) that need further investigation. Also, Cougle and collaborators (2015) warned that in adjusting for other psychiatric comorbidities they only adjusted for those that fulfilled diagnostic thresholds, not other psychiatric symptoms that could explain the relationships of interest.

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⁹ The NESARC is a longitudinal and nationally representative survey. Data on psychiatric disorders and quality of life were assessed from two waves of subjects. Wave 1: 2001–2002, n = 43,093; Wave 2: 2004–2005, n = 34,653.

¹⁰Cougle et al. (2015) and Feingold et al. (2014) used the same dataset, but they chose to use different outcome variables: one analyzed past-year cannabis use, while the other examined past-year weekly cannabis use.

Discussion of Findings

Overall there is some evidence to support the association between cannabis use and the increased incidence of bipolar disorders. Although there is support for this association, more information is needed on the potential mediators that could explain the relationship as well as whether the risk is likely to occur only in conjunction with the use of other substances such as alcohol or nicotine. For example, panel studies that have evaluated the relationship found the magnitude of the relationship to be similar, but once alcohol or other substances were adjusted for in the statistical models, the associations diminished or became insignificant. This suggests that the constellation of behaviors that includes the use of cannabis, alcohol, and other substances might all play roles in the risk for bipolar disorders, with those different roles being difficult to disentangle. See Box 12-1 for additional discussion on the complex relationship between substance use and mental health disorders.

Is There an Association Between Cannabis Use and the Course or Symptoms of Bipolar Disorder?

Systematic Reviews

The committee identified Gibbs et al. (2015) as a systematic review that assessed the relationship between cannabis use and the course, symptoms, or other endpoints in individuals with bipolar disorder. Gibbs et al. (2015) concluded, based on their narratives of three studies, that cannabis use may worsen the course of bipolar disorder by increasing the likelihood, severity, or duration of manic phases. Their narrative summarizes the findings of the three studies: the duration of active cannabis use was associated with duration of mania syndrome/symptoms; cannabis use within a quarter (3-month time period) was associated with manic symptoms or episodes; and a report of “any cannabis use” was associated with mania symptoms over 1 year in a sample of 3,426 inpatients and outpatients. The three studies were published in 2000, 2008, and 2009. The studies used clinical samples of 50 new-onset bipolar patients ages 16 to 54, 166 first-episode DSM-IV bipolar I patients ages 18 to 72, and 3,426 bipolar inpatients and outpatients (age not reported). No other information (gender, country, etc.) about the study populations was reported.

Primary Literature

Zorrilla and colleagues (2015), using the European Mania in Bipolar Longitudinal Evaluation of Medication study (n = 1,922 patients), showed that previous users of cannabis had similar outcomes to never users (all p >0.05) in terms of bipolar disorders, whereas current users had lower rates of recovery (p = 0.004) and remission (p = 0.014) and higher rates of recurrence of bipolar disorder (p = 0.014). They also demonstrated that the median time to remission was longer in the current cannabis use group (571 days, 95% CI = 539–588) compared with the other two groups (never users: 236 days, 95% CI = 209–345; previous users: 189 days, 95% CI = 1.5–357), while the times to relapse and recurrence were shorter in current use group. Using Cox regression models, Zorrilla and colleagues (2015) found that cannabis use (versus no use) was associated with time to recovery (HR, 0.53; 95% CI = 0.298–0.959), relapse (HR, 1.61; 95% CI = 1.116–2.316), and recurrence (HR, 1.67; 95% CI = 1.206–2.320). However, when alcohol and other substance use variables were included in the model as confounders, only the time to recurrence remained significantly associated with cannabis use (HR, 1.47; 95% CI = 1.030–2.092).

Using the NESARC data with two waves, Feingold et al. (2014) examined the relationship between weekly cannabis use and almost daily cannabis use and found a steady association with the incidence of mania/ hypomania symptoms in all adjusted models (OR, 2.47; 95% CI = 1.03–5.92). In contrast, daily cannabis use was not associated with mania/ hypomania symptoms (OR, 0.52, 95% CI = 0.17–1.55).

Discussion of Findings

The evidence on the association between cannabis use and the course and symptoms in patients with bipolar disorder is modest, but it is suggestive that cannabis use moderates the course of bipolar disorder by increasing the time to recovery, relapse, and recurrence of manic phases. As discussed in the section above, when adjustments for alcohol and other substance use variables are included in the model as confounders, only the time to recurrence remains as significantly associated to cannabis use. There is also moderate evidence that weekly cannabis use to almost daily cannabis use can lead to the onset of mania/hypomania symptoms in adjusted models, but there is less evidence of this association for daily users of cannabis. The authors report that, given the inconclusive nature of the relationship between very frequent cannabis use (daily/ almost daily) or less than weekly cannabis use and the onset of mania/ hypomania symptoms in adjusted models (i.e., dose–response), other factors that have not been identified might mediate the relationship. The authors suggest that part of the problem of being able to find a conclusive

relationship between the frequency of cannabis use and mania or hypomania symptoms might be due to the resemblance of mania and hypomania symptoms to psychotic symptoms, making it difficult to discriminate between these types of symptoms. It should also be noted that in some of the studies reviewed above, the analyzed patient populations were undergoing treatment for bipolar disorder, adding an additional layer of limitations to the research findings.

In reviewing the literature on the relationship between cannabis use and bipolar disorder, the committee identified various limitations in the studies discussed above, including a lack of biogenetic covariates that could relate to both cannabis use and bipolar disorders, as well as other psychological symptoms that are not adjusted in these studies. Many of these studies do not take into account the variance among the subtypes of cannabis or in the potency or route of administration, all of which could lead to difference in results. Also, the lack of precision in measuring the frequency of cannabis use at baseline and in measuring follow-up data remains a problem.

DEPRESSION

Depression is one of the nation’s most common mental health disorders (ADAA, 2016). Across the many depressive disorders that exist (e.g., persistent depressive disorder, major depressive disorder, premenstrual dysphoric disorder) there are common symptomatic features of feelings of sadness, emptiness, or irritable mood, accompanied by somatic and cognitive changes that affect the individual’s capacity to function (APA, 2013, p. 155). The endocannabinoid system is known to play a role in mood regulation (NIDA, 2015); therefore, the committee decided to explore the association between cannabis use and depressive disorders or symptoms.

Is There an Association Between Cannabis Use and the Development of Depressive Disorders or Symptoms?

Systematic Reviews

The committee identified two systematic reviews that assessed the association between cannabis use and the risk of developing depressive

disorders or symptoms: Lev-Ran et al. (2013) and Moore et al. (2007). The most recent systematic review is discussed.

Lev-Ran et al. (2013) searched the published literature through 2012 and included studies with: population-based data that were collected longitudinally and prospectively; an exposure variable referring specifically to cannabis use (not “substance use”); outcome measures that referred specifically to depression—and not, for example, mixed anxiety–depressive symptoms; the outcome variable (depression) controlled for at baseline, or individuals with baseline depression being excluded; and data either presented as odds of developing depression following cannabis use or that allowed the OR to be calculated. When the authors identified multiple studies reporting on the same population cohort at different time points, only one study (the most recent) reporting on the respective cohort was included. The authors identified 14 studies published between 1977 and 2012. Seven were conducted in the United States, and one each were conducted in Australia, Canada, Colombia, the Netherlands, New Zealand, Norway, and Sweden. Sample sizes ranged from 736 to 45,087, with 10 of the samples having 1,000 or more participants. The ages of patients at cannabis assessment included high school age, subjects ages 12 to 17 or 12 to 16, and older groups ages 18 to 64. A wide range of measures were used to assess cannabis use: namely, any cannabis use in the previous 30 days; any previous cannabis use; cannabis use disorder; cannabis use one or more times per month; any cannabis use in the previous year or heavy use (at least once per week in the previous month); at least five previous occasions of cannabis use or heavy use (at least weekly); any use in the previous 6 months; or more than 4 occasions of use per month in a 5-year period. Studies also varied in the definition of comparison groups, with some studies contrasting any cannabis use to no cannabis use, and other studies comparing “heavy cannabis use” to a group with some or no cannabis use. Thus, the comparison group (lower level of exposure to cannabis) in the latter studies included nonusers, as well as individuals using cannabis less than weekly, or individuals not having a cannabis use disorder. Studies varied in their approaches to adjust for confounding factors, ranging from none to adjustment for more than 20 variables. One half of the studies accounted for other types of substance use and/or mental health issues as potential confounders. The analysis showed that cannabis use was associated with a small increase in risk for depressive outcome (pOR, 1.17; 95% CI = 1.05–1.30). The analysis further revealed a dose–response relationship, with a slightly higher OR observed in seven studies comparing heavy cannabis use to non-cannabis users (pOR, 1.62; 95% CI = 1.21–2.16).

Primary Literature

Although several primary research studies found a positive association, the confounding factors of polydrug use or unspecified cannabis use made it difficult for the committee to make conclusions on the overall findings (Brook et al., 2016; Nkansah-Amankra and Minelli, 2016; Rasic et al., 2013). Additional studies reviewed provided mixed findings on the association between cannabis use and depression or depressive symptoms (Crane et al., 2015; Gage et al., 2015; Silins et al., 2014; Wilkinson et al., 2016). A consideration of the confounding factors led to several of these mixed findings. For example, Sillins et al. (2014) published an analysis of interview data from three longitundal studies from Australia and New Zealand. The investigators sought to determine the association between the maximum frequency of cannabis use before age 17 and seven developmental outcomes, including depression. The number of participants varied by the outcome assessed but ranged from n = 2,537 to 3,765. Because this was an integrated study, the outcomes of depression were assessed by different measures (i.e., Composite International Diagnostic Interview, Clinical Interview Schedule, and short-form Depression Anxiety Stress Scale) and at different ages across the three studies. The investigators of this study created a dichotomous measure of moderate or severe depression in the past week to the past month between ages 17 and 25 years. Using combined data adjusted for study-specific effects, the investigators found a significant asssociation between adolescent cannabis use and the study’s measure of depression (less than monthly use, OR, 1.12; 95% CI = 1.01–1.25; monthly or more, OR, 1.26; 95% CI = 1.02–1.56; weekly or more, OR, 1.42; 95% CI = 1.03–1.94; daily use OR, 1.59; 95% CI = 1.04–2.42), as well as an apparent potential dose–response relationship. However, after adjusting for relevant covariates in the analysis, this association became insignificant and negligible in size (less than monthly use, aOR, 1.01; 95% CI = 0.85–1.19; monthly or more, aOR, 1.01; 95% CI = 0.72–1.42; weekly or more, aOR, 1.02; 95% CI = 0.61–1.69; daily use, aOR, 1.02; 95% CI = 0.52–2.01). The authors noted that the confounding factors spanning the individual’s background and functioning as well as parental and peer factors likely affected the change in the research findings.

Discussion of Findings

The evidence reported suggests that cannabis use, and particularly heavy cannabis use, is associated with a small increase in the risk of developing depressive disorders. This evidence is supported by a good-quality recent systematic review that included 10 longitudinal studies with sample sizes between 700 and 45,000. Although the supplemental studies from the primary literature reported mixed findings, the commit-

tee concludes that there is a strong enough evidence base to support the conclusion that there is an association between cannabis use and a small increased risk (pOR of 1.17; Lev-Ran et al., 2013) of developing depressive disorders, which increases with increased frequency of use (OR of 1.62; Lev-Ran et al., 2013). The possible relationship between heavy cannabis use and the development of depressive disorders or symptoms needs to be further explored.

Given that these relationships are associational and not necessarily causal, it is important to note possible alternative explanations for the mixed findings. For example, within the literature, a reverse association between cannabis use and depressive disorders has been documented, and the relationship may be bidirectional (Horwood et al., 2012; Wilkinson et al., 2016). This complex scenario is consistent both with the known protective roles of the endocannabinoid system in the control of mood and affect and with the propensity of cannabinoid receptors to undergo desensitization following prolonged activation. See Box 12-1 for an additional discussion on this topic.

To review the research on the potential therapeutic effects of cannabis or cannabinoids on major depression disorder, please refer to Chapter 4 (Therapeutic Effects of Cannabis and Cannabinoids).

Is There an Association Between Cannabis Use and the Course or Symptoms of Depressive Disorder?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and the course, symptoms, or other endpoints in individuals with a depressive disorder.

Primary Literature

The committee did not identify any good-quality primary literature that reported on the association between cannabis use and the course, symptoms, or other endpoints in individuals with a depressive disorder 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.

SUICIDE

Suicide is the act of purposely taking one’s own life. It is the 10th most common cause of death in the United States, with an estimated 13 suicidal deaths per 100,000 individuals; it is often related to mental illness, substance abuse, or a major stressful event (CDC, 2014; MedlinePlus, 2016). Cannabis is widely used for both medical and recreational purposes (Azofeifa et al., 2016), and therefore, there is a public health interest to evaluate the possible association between cannabis use and suicide, suicidal attempts, and suicide ideation.

Is There an Association Between Cannabis Use and Suicidal Ideation, Suicide Attempts, and Suicide?

Systematic Reviews

Two systematic reviews were identified that assessed the association between cannabis use and suicidal ideation, attempts, and suicide (Borges et al., 2016; Moore et al., 2007). We report here on the most recent one. Borges et al. (2016) conducted a systematic review to address multiple questions concerning acute and chronic cannabis use, suicidal ideation, suicide attempts, and suicide. The authors reported the databases searched and their search terms, but they did not report the number of citations screened or the reasons for exclusions. The term “any cannabis use” was defined as: life-time use, use before or at age 15, ever used, any use in past 30 days, or any use in the last year. “Chronic use” was referred to as: cannabis use patterns, symptoms of cannabis use disorder, and heavy cannabis use. “Heavy cannabis use” was defined as: used 40 or more times, DSM-IIIR abuse/dependence, ≥6 times per month, >11 times in past year, >10 times, or daily.

The authors reviewed 12 studies that were relevant to the committee’s research question. Their meta-analysis of six studies showed that any cannabis use was associated with an increased risk of suicidal ideation (pOR, 1.43; 95% CI = 1.13–1.83). Similarly, a review of five studies showed that heavy cannabis use was also associated with a larger increase of suicidal ideation (pOR, 2.53; 95% CI = 1.00–6.39). The six studies included in the meta-analysis of any cannabis use and suicide ideation were published between 1997 and 2014 and conducted in Canada, New Zealand, Norway, and the United States (four studies) in populations of male and

female young adults or adolescents. The five studies included in the meta-analysis of heavy cannabis use and suicidal ideation were published between 1997 and 2013 and conducted in Canada, New Zealand, Norway, and the United States (two studies) in male and female populations of all age groups.

The authors also assessed another subset of six studies to determine the association between any cannabis use and suicide attempts, reporting a pOR of 2.23 (95% CI = 1.24–4.00). The studies used reported on male and female adolescents or young adults in Canada, Ireland, and the United States (four studies). A review of a third subset of six studies found a higher risk of suicide attempt associated with heavy cannabis use (pOR, 3.20; 95% CI = 1.72–5.94). These six studies reported on male and female adolescents, young adults, or adults in Canada, New Zealand/Australia (two studies), Norway, and the United States (two studies).

The researchers reported that any cannabis use was associated with an increased risk of death by suicide (pOR, 2.56; 95% CI = 1.25–5.27), based on a meta-analysis of four nonoverlapping studies. The studies included two case-control studies and two longitudinal studies published between 2003 and 2012, which were conducted in Colombia, Denmark, Sweden, and the United States; the studies were carried out in young adults and in all age groups, in males and females, and in male-only study groups. Interestingly, the one study restricted to males only showed no association of cannabis with suicide, but the other studies that used mixed groups of males and females did show an association of cannabis with suicide.

Primary Literature

The committee identified one recent primary article published in 2016 (Shalit et al., 2016) that reported on the association between cannabis use and the risk of suicidality (suicidal ideation and suicide attempt). Shalit and collaborators presented their results using a general population sample of the NESARC (n = 34,653; 963 cannabis users versus 30,586 nonusers). They found that in the general population, any cannabis use in Wave 1 (baseline) was not statistically significantly associated with increased risk for developing suicidality in Wave 2 (follow-up) (aOR, 1.56; 95% CI = 0.98–2.46). However, when the results were stratified by gender, the researchers found significant differences in risk for suicidality. Among men, any cannabis use was significantly associated with the incidence of suicidality in fully adjusted models (aOR, 1.91; 95% CI = 1.02–3.56), but not for women (aOR, 1.19; 95% CI = 0.64–2.20). The magnitude of the relationship with the 3-year incidence of suicide ideation is larger in men (aOR, 4.28; 95% CI = 1.32–13.82) who are daily cannabis users, but this pattern is not observed for women (aOR, 0.75; 95% CI = 0.28–2.05).

However, in adjusted models neither cannabis use (aOR, –1.91; 95% CI = 0.85–4.28) nor daily cannabis use (aOR, 1.13; 95% CI = 0.42–3.05) was statistically significantly associated with the incidence of suicide attempts. Another finding of importance was that sex moderated the association between cannabis use, particularly daily use, and suicide attempts, with a significantly increased dose–response relationship in men (any cannabis use OR, 3.35; 95% CI = 1.07–10.47; daily cannabis use OR, 32.31; 95% CI = 2.59–402.88). However, there are several limitations, including that suicidality was only assessed in participants who reported a 2-week period of depressed mood or anhedonia, so the results might underestimate the effect for those that have suicidal ideation or suicide attempts without these symptoms. Other limitations include the use of dichotomous response categories for suicidality when there is some evidence that additional changes to the measures are needed; the lack of adjustment for some early traumatic life events associated with suicidality; and the lack of adjustments for psychotic disorders.

Discussion of Findings

The evidence reported suggests that any cannabis use is related with increased suicidal ideation, augmented suicide attempts, and greater risk of death by suicide. The studies presented demonstrate evidence of a dose–response effect, with heavy cannabis use being associated with a higher risk of suicidal ideation and suicidal attempts. Additionally, sex differences emerged from the research findings related to suicidality (Shalit et al., 2016) and death by suicide (Borges et al., 2016). These sex differences may have occurred due to differences in where the study samples were recruited (e.g., Australia, Canada, Denmark, New Zealand, Norway, Sweden, United States, etc.) or how the data were assessed. This might suggest that sample composition, gender, and the type of assessment could matter when examining these associations between cannabis use and suicidality and suicide completion.

Although the evidence seems to support a relationship between cannabis use and suicidality, particularly heavy cannabis use and suicidality, the limitations of the literature temper such findings. Several limitations should be noted, including the lack of homogeneity in the measurement of cannabis exposure, the lack of systematic controls for known risk factors, the short period of observation for suicidality, the variability in the covariates used to adjust for confounders, the differences in the dose–response analyses, and problems of small sample size. Additionally, as reported by the authors, some studies adjust for alcohol and other comorbidities, while in other studies there is no report of such adjustments. There is a strong need for new studies that discriminate between the acute and the

chronic use of cannabis and between suicidal ideation, suicide attempts, and completed suicides.

ANXIETY

Anxiety disorders share features of excessive fear and anxiety, which induce psychological and physical symptoms that can cause significant distress or interfere with social, occupational, and other areas of functioning (APA, 2013). In a given year, an estimated 18 percent of the U.S. adult population will suffer from symptoms associated with an anxiety disorder (NIMH, n.d.). Given the role of the endocannabinoid system in mood regulation, it is worthwhile for this report to explore the relationship between anxiety and cannabis.

Is There an Association Between Cannabis Use and the Development of Anxiety Disorders?

Systematic Reviews

One systematic review was identified that assessed the relationship between cannabis use and anxiety disorders (Kedzior and Laeber, 2014). The authors searched two databases for articles published through 2013 to identify studies that had been conducted in noninstitutionalized populations, with anxiety diagnoses based on DSM/ICD criteria, with odds ratios or data sufficient for the calculation of effects, and with comparison data from healthy nonusers. They then identified five studies that examined cannabis use at baseline and anxiety at follow-up. The five studies were all longitudinal, published between 1996 and 2013, and conducted in Australia, Colombia, the Netherlands, New Zealand, and the United States. Sample sizes were more than 2,000 or greater in four studies and more than 12,000 in the fifth study. Four studies were of adolescents and a fifth studied the general population (age unspecified). The five studies

adjusted for confounders such as demographics, prior anxiety disorder diagnosis, alcohol and tobacco use, and other mental health problems at age 15. In their review of the five studies, Kedzior and Laeber (2014) found that cannabis use at baseline was associated with the developmment of symptoms of anxiety at follow-up (OR, 1.28; 95% CI = 1.06–1.54) after adjusting for confounders (e.g., other substance use, psychiatric comorbidity, certain demographics).

Primary Literature

In a longitudinal U.S. study of a nationally representative sample of adults 18 years or older (NESARC; n = 34,653), Blanco and colleagues (2016) investigated the prospective associations of cannabis use in the past 12 months (Wave 1; years 2001–2002); with anxiety disorders 3 years later (Wave 2; years 2004–2005); and adjusted for sociodemographic characteristics, family history of substance use disorder, disturbed family environment, childhood parental loss, low self-esteem, social deviance, education, recent trauma, past and present psychiatric disorders, and respondent’s history of divorce. The researchers found that cannabis use in the 12 months preceding the survey was not associated with an increased prevalence of anxiety disorders (OR, 1.0; 95% CI = 0.8–1.2) after adjustments for covariates. The researchers also reported no significant relationship of cannabis use (Wave 1) with the prevalence of panic disorder (OR, 0.8; 95% CI = 0.5–1.2), social anxiety disorder (OR, 1.2; 95% CI = 0.8–1.8), specific phobia (OR, 0.9; 95% CI = 0.7–1.2), or generalized anxiety disorder (OR, 1.0; 95% CI = 0.7–1.4) assessed 3 years later (Wave 2). The researchers also found no significant relationship between cannabis use and incident anxiety disorders (aOR, 0.9; 95% CI = 0.7–1.1). However, they did find that an increased frequency of cannabis use was related with significantly increased odds of incident social anxiety disorder (OR, 1.8; 95% CI = 1.1–2.8). Some of the limitations of this study are that cannabis use was ascertained by self-report, causality could not be established because of the possibility of residual confounding, and the follow-up period was limited to 3 years.

Feingold and colleagues (2016) used the same dataset as Blanco et al. (2016), NESARC, and also found no association of cannabis use with the increased incidence of any anxiety disorder (aOR, 1.12; 95% CI = 0.63–0.98) after adjusting for covariates. However, they did find a statistically nonsignificant association between daily or almost daily use of cannabis at Wave 1 (baseline) with the incidence of social anxiety at follow-up 3 years later (aOR, 1.98; 95% CI = 0.99–6.98). This relationship was found to be significant in older adults (aOR, 2.83; 95% CI = 1.26–6.35) but not for younger adults (aOR, 1.76; 95% CI = 0.44–6.98). They also found a

significant relationship between cannabis use disorder at baseline and incident social anxiety disorder among young adults (aOR, 2.45; 95% CI = 1.19–5.06) but not older adults (aOR, 1.38; 95% CI = 0.58–3.25). No other associations between cannabis use disorder and other anxiety disorders proved to be significant after adjustment for covariates.

Cougle et al. (2015) also used the NESARC to examine past-year regular cannabis use (defined as at least weekly use) and current and prospective presence of anxiety disorders 3 years later. These authors found no association (OR, 1.09; 95% CI = 0.90–1.32) in the prospective analyses that adjusted for psychiatric comorbidity and sociodemographic factors. However, when looking at specific anxiety disorders, Cougle and colleagues (2015) report finding a relationship between regular cannabis use and an increased risk of developing panic disorder with agoraphobia (OR, 1.56; 95% CI = 1.11–2.19) and social phobia (OR, 1.89; 95% CI = 1.54–2.32). As with other studies using the NESARC, the authors emphasize the nonrandomized nature of the study design, the possibility that the study was underpowered to find certain relationships, and the relatively short time period of observation.

Bechtold and colleagues (2015), using data from the oldest cohort of the Pittsburgh Youth Study, found that there were no differences among cannabis trajectory groups (categorized as low/nonusers, adolescence-limited users, increasing users, and early onset chronic users) related to a lifetime diagnosis of anxiety disorders for black or white men after controlling for confounders (e.g., socioeconomic status, co-occurring use of other substances, physical and mental health problems that predated cannabis use, and access to medical care). In this study cannabis use was evaluated with the Substance Use Questionnaire, with respondents (who were ages 15 to 26) initially indicating the number of days they had used cannabis in the previous 6 months and then, in each of the subsequent 10 annual follow-ups, reporting their use in the previous year. At age 36, respondents were assessed with the Diagnostic Interview Schedule to determine whether they had ever met the criteria for an anxiety disorder, and an analysis shows that the patterns of cannabis use from adolescence to young adulthood were not related to anxiety disorders. However, the authors mentioned several limitations, including the possibility of selection effects; the fact that cannabis use was determined by self-report; and the use of a limited sample that used cannabis from one geographic area and included only white and black men, implying that the results might not be generalizable to the general population. A recent study by Gage and colleagues (2015) found similar results. Using data from the Avon Longitudinal Study of Parents and Children (a UK birth cohort study), they found no evidence of an association between cannabis use at age 16 and anxiety disorder at age 18 (aOR, 0.96; 95% CI = 0.75–1.24) after

adjusting for pre-birth and childhood confounders (family history of depression, maternal education, urban living, IQ, borderline personality traits, victimization, peer problems, conduct disorder, and other substance use). The authors cite as limitations of their study the use of self-reported data, poor follow-up rates, and a limited power to detect small effects.

Brook and colleagues (2014), using the Harlem Longitudinal Developmental Study, assessed urban African American and Puerto Rican participants (n = 816) with four waves of data. In this study, Brook et al. (2014) found that participants with joint chronic cannabis, tobacco, and alcohol use were at an increased risk for generalized anxiety disorder in adulthood when compared to those with occasional alcohol use and no smoking and no cannabis use (OR, 4.35; 95% CI = 1.63–11.63). Again, this study’s limitations, such as the use of self-reports, the use of proxies to determine earlier generalized anxiety disorder (depression in Time 1), and omitted variables (such as family substance use), could have explained such relationships.

Additional work by Brook and colleagues (2016) reported on a large community-based sample (the Children and Adults in Community study, n = 973 at Time 1), examining comorbid trajectories of substance use which included conjoint chronic cannabis with chronic alcohol and cigarette use as predictors of generalized anxiety disorder. According to their multivariate logistic regression analyses, the Bayesian posterior probability (BPP) of members who were chronic or moderate to heavy users of cannabis, alcohol, and cigarettes—when compared to the patterns of those with occasional alcohol use and no smoking and no cannabis—had an aOR of 6.39 (95% CI = 2.62–15.56). This suggests that the conjoint use of cannabis with alcohol and cigarettes could have biological or psychosocial effects that increased the risk for generalized anxiety disorder. However, the study had several limitations in the present study, including having a mostly white sample from upstate New York and not including environmental or social variables that could explain the relationship under study, such as family substance use or childhood psychiatric disorders.

Discussion of Findings

Studies examining the relationship between cannabis use and anxiety disorder show mixed results depending on whether they assessed the development of anxiety symptoms or the incidence of anxiety disorders; whether the explanatory variable was any cannabis use or cannabis use disorder; and whether there were adjustments for psychiatric comorbidity and sociodemographic factors. For example, Kedzior and Laeber (2014) found that cannabis use at baseline was associated with the development of symptoms of anxiety at follow-up. In contrast, the 2016 report

by Blanco and colleagues, the 2015 report by Cougle et al., and the 2015 report by Gage and colleagues all found no association between cannabis use and an increased prevalence of anxiety disorders in adjusted models. However, both Feingold et al.’s and Blanco et al.’s studies did find an association of daily or almost daily use of cannabis at Wave 1 with the incidence of social anxiety disorder at follow-up 3 years later. Age seemed to moderate this relationship since it was found to be significant in older adults but not in younger adults.

Some of the limitations of these studies are that cannabis use was ascertained by self-report; that causality cannot be established because of the possibility of residual confounding; that the follow-up period was limited to 3 years; and that there was a high loss in the follow-up and limited power to detect small effects. Further work needs to be done to examine why the outcomes differ depending on whether the assessment is done with anxiety symptoms or anxiety disorders and whether the explanatory variable is any cannabis use or cannabis use disorder. Morever, studies are needed to determine whether psychiatric comorbidity, sociodemographic factors, or the conjoint use of cannabis with alcohol and cigarettes have biological or psychosocial effects that increase the risk for generalized anxiety disorder.

To review the research on the potential therapeutic effects of cannabis or cannabinoids on anxiety, please refer to Chapter 4 (Therapeutic Effects of Cannabis and Cannabinoids).

Is There an Association Between Cannabis Use and the Course or Symptoms of Anxiety Disorders?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and the course, symptoms, and other endpoints of anxiety disorders.

Primary Literature

Recent work by Grunberg and collaborators (2015) conducted a prospective study to examine whether cannabis use (i.e., use during the past 30 days using the Time-Line Follow Back¹¹) moderates the effects of temperament on the level of anxiety symptoms (measured with Achenbach’s System of Empirically Based Assessment) within late adolescence and early adulthood (n = 338; 18- to 21-year-olds). While there was no association between cannabis use groups and anxiety symptoms among the college students in this prospective study, the researchers conducted simple slope analyses investigating the relationship between harm avoidance (characterized by heightened apprehension, shyness, pessimism, and inhibition of behaviors) and prospective anxiety symptoms for those subjects who rated low (zero days of use out of 30 days) and high (approximately 26 days of use out of 30 days) on cannabis use. The researchers found that harm avoidance measured at baseline was associated with more symptoms of anxiety measured 1 year later—but only for those low in cannabis use (β = 0.15, t(329) = 2.69, p <0.01). When cannabis use was high, harm avoidance was unrelated to anxiety (β = − 0.14, t(329) = −1.40, p = 0.16). Study participants with higher cannabis use showed a positive association between novelty seeking and anxiety symptoms (β = 0.28, t(329) = 3.46, p = 0.001), while those lower in cannabis use showed no relation between novelty seeking and anxiety symptoms (β = −0.08, t(329) = −1.61, p = 0.11).

Discussion of Findings

Grunberg and collaborators (2015) warned, however, that the findings discussed above should be taken with caution since the mechanisms underlying these relations are still not clear. In addition, although this study uses a prospective design in which cannabis use and temperament are evalutated at baseline to predict anxiety symptoms 1 year later, it is limited to college students (ages 18–21) in only one assessment site. The authors emphasized that the reason the relationship between cannabis use and anxiety symptoms is inconsistent is that there was no consideration of cannabis effects on other factors that influence anxiety symptoms such as temperament (i.e., levels of harm avoidance and novelty seeking) within the sample. Some limitations of this study are the use of a college student sample, the use of self-report for all assessments, and the use of correlational data—although cannabis use and temperament were measured 1 year before anxiety symptoms. Given the limited evidence of studies that

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¹¹ Authors describe this as a calendar-assisted structured interview that allows participants to indicate the amount of cannabis used on each day over the past month.

address the relationship between cannabis use and anxiety symptoms, these findings need to be replicated in larger samples with appropriate controls.

POSTTRAUMATIC STRESS DISORDER

Posttraumatic stress disorder (PTSD) falls within the broader trauma- and stressor-related disorders categorized by the DSM-V. The diagnostic criteria of PTSD include an exposure to a traumatic event (e.g., the threat of death, serious injury, or sexual violence) and exhibiting psychological distress symptoms that occur as a result of that exposure (e.g., intrusion symptoms, such as distressing memories; avoidance of stimuli that are associated with the traumatic event; negative alterations in mood and cognition; alterations in arousal and reactivity associated with the traumatic event; functional impairment) (APA, 2013, pp. 271–272). Given the known psychoactive effects of cannabis, the committee chose to explore the association between PTSD and cannabis use in this review.

Is There an Association Between Cannabis Use and the Development of PTSD?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and the risk of developing PTSD.

Primary Literature

The committee did not identify any good-quality primary literature that reported on the association between cannabis use and the development of PTSD 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.

Is There an Association Between Cannabis Use and the Course or Symptoms of PTSD?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on the association between cannabis use and the course, symptoms, and other endpoints in PTSD.

Primary Literature

Gentes et al. (2016) found that past 6-month cannabis use was associated with increased PTSD severity (Clinician Administered PTSD Scale; global severity score; aOR, 1.30; 95% CI = 1.01–1.66), depressive symptoms (Beck Depression Inventory; aOR, 9.25; 95% CI = 1.13–1.75), and suicidality (Beck Depression Inventory Item 9; aOR, 4.63; 95% CI = 1.02–1.54) in a population of treatment-seeking veterans (n = 719). In this study, the odds ratios were adjusted for age, race, service era, and combat exposure, but not co-occurring substance use. Conversely, Manhapra et al. (2015) found improvements in PTSD symptoms (Mississippi Scale for Combat-Related Posttraumatic Stress Disorder), violence, and suicidality after 4 months of abstinence from cannabis relative to symptoms upon entry to the study in a large population of veterans admitted for an intensive PTSD program (n = 22,948). Villagonzalo et al. (2011), in a small study of patients (n = 80; mean age 35 years) participating in a methadone maintenance program, found that the severity of cannabis use was associated with the occurrence of certain PTSD symptoms, as measured by the Posttraumatic Stress Disorder Checklist–Civilian Version. Significant findings were identified for measures of reexperiencing (i.e., repeated disturbing dreams, χ²(2) = 6.351; p <0.05; physical reaction at reminder of event χ²(2) = 7.053; p <0.05; hyperarousal (i.e., difficulty concentrating, χ²(2) = 7.517; p <0.05; “super alert” χ²(2) = 6.778; p <0.05; easily startled χ²(2) = 9.645, p <0.01); and overall PTSD symptoms (1-way ANOVA, F(2,65) = 3.705; p <0.05).

Of interest, the committee also identified two large observational studies that compared the effects of cannabis to controls. Both studies enrolled predominately male veterans. A large cohort study (Wilkinson et al., 2015) examined outcomes for 2,276 veterans who received specialized intensive PTSD services between 1992 and 2011. Assessments for substance use and PTSD symptoms were taken at intake and at 4 months after discharge. Veterans who continued to use or started using cannabis after discharge had significantly worse PTSD symptoms and greater drug abuse than those who had never used or who had stopped cannabis use at 4 months after discharge (p <0.0001). Starters also had more violent behavior in the 4 months after enrollment compared to other groups

(p <0.0001). There were no significant differences among the groups on employment status. A second study (Johnson et al., 2016) was a matched, case-control cross-sectional study that was conducted in 700 veterans with probable PTSD, half of whom used cannabis and half who were nonusers. Cannabis users and nonusers did not differ on PTSD symptom severity (p = 0.91) or depression severity (p = 0.07) as measured by the PTSD Checklist–Civilian Version and the Patient Health Questionnaire, respectively. However, cannabis users were more likely to experience suicidal ideation (p = 0.04) and reported more alcohol use (p <0.001) as measured by the Paykel questionnaire, an Alcohol Timeline Followback assessment, and the Alcohol, Smoking, and Substance Involvement Screening Test.

Discussion of Findings

Notable in this section relative to the others in this chapter is the lack of data addressing the key questions posed by the committee. For example, using the committee’s specified search strategy, we found no relevant studies that directly addressed the question of whether cannabis use is associated with an increased risk of PTSD. Of the relevant studies reviewed, cannabis use appears to be associated with more severe symptoms, but limited sample sizes were an issue in certain studies; that issue, combined with the lack of adjustment for baseline symptom severity and other drug use and the examination of specialized patient populations, limits the strength of the conclusions that can be drawn. Overall, there is limited evidence for an association between cannabis use and increased PTSD symptom severity. The direction of the association is difficult to address, however. It has been argued that PTSD is a risk factor for cannabis use, and cannabis-using patients with PTSD often cite symptom-coping motives for cannabis use, which suggests that more severe PTSD may be driving patients to increase cannabis use in an effort to self-medicate.¹² In contrast, one study (Manhapra et al., 2015) found overall improvements in several symptom domains after 4 months of abstinence from cannabis, suggesting that cannabis use may be causally related to more severe PTSD symptoms. See Box 12-2 for a discussion on why it is often difficult to conclude causality in the associations between substance use and mental health.

To review the research on the potential therapeutic effects of cannabis or cannabinoids on PTSD, please refer to Chapter 4 (Therapeutic Effects of Cannabis and Cannabinoids).

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¹² Studies examining PTSD as a risk factor for cannabis use and cannabis use disorders were identified and are discussed in Chapter 13 of this report.

RESEARCH GAPS

As noted above, we found a paucity of studies relevant to our key questions. To address the research gaps relevant to PTSD, the committee suggests the following:

• More longitudinal studies to determine whether cannabis use is associated with an increased incidence of PTSD.
• In patients with PTSD, current data do not provide a very clear picture as to whether cannabis use affects PTSD symptoms. More longitudinal studies examining the effects of cannabis use on PTSD symptoms need to be conducted, with a specific emphasis placed on detailed measures of cannabis use (amounts, potency, routes of administration), controls for baseline symptom severity and the use of other substances, and temporality (excluding patients with cannabis use at study entry).
• From a cannabis therapeutics perspective, blinded, randomized, placebo-controlled studies in patients with PTSD need to be conducted to evaluate any potential therapeutic benefits of cannabis on PTSD symptoms and course.
• There is also a research need to investigate cannabis and cannabis constituents (tetrahydrocannabinol and cannabidiol) in animal models.

SUMMARY

This chapter outlines the committee’s efforts to review the current evidence base for the association of cannabis use with prioritized mental health conditions. The health conditions reviewed in this chapter include schizophrenia and other psychotic disorders, bipolar disorder, depression, suicide, anxiety, and PTSD. The committee formed a number of research conclusions related to these health endpoints; however, it is critically important that each of these conclusions be interpreted within the context of the limitations discussed in the Discussion of Findings sections. See Box 12-3 for a summary list of the chapter’s conclusions.

A conclusion weighted as substantial was reached for the research question addressing the statistical association between cannabis use and the development of schizophrenia or other psychoses. As noted in the

chapter’s Discussion of Findings sections, there are common trends in the types of study limitations found in this evidence base. The most common are limitations in the study design (e.g., a lack of appropriate control groups, a lack of long-term follow-ups) variable analysis of cannabis use (i.e., dose/amount/frequency current versus. lifetime); small

sample sizes; and research gaps in the studies of depression and PTSD. These limitations highlight the enormous amount of available opportunity to advance the current research agenda, in the hopes of providing comprehensive and conclusive conclusions on the potential harms and therapeutic benefits of cannabis or cannabinoid use.

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