Cannabis use and the course and outcome of major depressive disorder: A population based longitudinal study

Author’s Accepted Manuscript Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study Daniel Feingold, Jürgen Rehm, Shaul Lev-Ran www.elsevier.com/locate/psychres

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S0165-1781(16)31187-8 http://dx.doi.org/10.1016/j.psychres.2017.02.027 PSY10321

To appear in: Psychiatry Research Received date: 17 July 2016 Revised date: 8 December 2016 Accepted date: 11 February 2017 Cite this article as: Daniel Feingold, Jürgen Rehm and Shaul Lev-Ran, Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2017.02.027 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cannabis Use and the Course and Outcome of Major Depressive Disorder: a Population Based Longitudinal Study

Daniel Feingolda,b,*, Jürgen Rehmc,d,e and Shaul Lev-Ranb,c,f a

Ariel University, Ariel, Israel.

b2

Lev-Hasharon Medical Center, Pardesiya, Israel.

c

Social and Epidemiological Research Department, Centre for Addiction and Mental Health,

Toronto, Ontario, Canadad d

Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

e

Technische Universität Dresden, Klinische Psychologie & Psychotherapie, Dresden, Germany

f

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

* Corresponding author at Lev-Hasharon Medical Center, Pardesiya, Israel. Mail address: Pardesiya, PO box 90000, Israel. Telephone: 972-(0)98981111 Email: [email protected]

Abstract Cannabis use has been reported to affect the course of various psychiatric disorders, however its effect on the course of major depressive disorder (MDD) is not yet clear. We used data from Wave 1 and Wave 2 of the National Epidemiologic survey on Alcohol and Related Conditions (NESARC). Individuals with baseline MDD (N=2,348) were included in the study. Cannabis

users without a Cannabis Use Disorder (CUDs) and individuals with a CUD were compared to nonusers using linear and logistic regression analyses controlling for sociodemographics, psychiatric disorders and substance use disorders at baseline. No differences were found in rates of remission between the groups. Level of cannabis use was associated with significantly more depressive symptoms at follow-up, particularly anhedonia, changes in body weight, insomnia or hypersomnia and psychomotor problems. After adjusting for baseline confounding factors, no associations were found between cannabis use and suicidality, functionality and quality of life. We conclude that many of the associations between cannabis use and a more severe course of MDD do not seem to be attributed to cannabis use itself but to associated sociodemographic and clinical factors. Further longitudinal studies using depression severity indices are required.

Keywords: Marijuana; Cannabis use Disorder; Depression; Course of illness; Suicidality; Symptoms; Quality of life

1. Introduction Following tobacco and alcohol, cannabis is the most widely used drug in the world (United Nations Office on Drugs and Crime, 2012) with an estimated 5% prevalence of past-year use, representing up to 200 million annual users worldwide (Degenhardt et al., 2011). Research in the past decade has pointed to the contribution of the human endo-cannabinoid system to the onset and course of various psychiatric disorders (Carvalho and Van Bockstaele, 2012). Extensive epidemiological research has supported the notion that cannabis use, and especially heavy use, may be associated with an increased risk for developing a psychotic disorder including schizophrenia (Moore et al., 2007; WHO, 2016). Moreover, it has been reported that

cannabis use may affect the course of such disorders, leading to earlier onset, higher severity and longer persistence of psychotic disorders as well as more frequent psychotic relapses over time (Foti et al., 2010; Grech et al., 2005; Linszen et al., 1994; Whiteford et al., 2013). Cannabis use may also alter the course of additional psychiatric disorders. Individuals who used cannabis were more prone to have earlier onset of panic attacks (Zvolensky et al., 2006), elevated intensity of anxiety symptoms during panic attacks (Szuster et al., 1988) and increased sensitivity to anxiety symptoms (Buckner et al., 2009). A meta-analysis suggested that among individuals diagnosed with bipolar disorder, cannabis users were approximately threetimes more prone to experience a recurring manic episode compared to nonusers (Gibbs et al., 2014). Furthermore, individuals diagnosed with bipolar disorder and co-occurring cannabis use were reported to have more depressive and manic/hypomanic episodes per year (Lev-Ran et al., 2013a), longer duration of mixed and manic episodes (Strakowski et al., 2007) and poorer life functioning (Agrawal et al., 2011) compared to nonusers. However, the effect of cannabis use on the course and outcome of depression is less clear. Major depressive disorder (MDD) is a common psychiatric disorder which contributes significantly to the global burden of disease (Whiteford et al., 2013). Several cross-sectional studies revealed strong co-occurrence between cannabis use and psychopathology (such as posttraumatic stress disorder (Kevorkian et al., 2015)), and specifically between cannabis use and depression, indicating high prevalence of cannabis use among individuals with depression and vice-versa (Chen et al., 2002; Grant, 1995). Longitudinal studies have reported conflicting results; while several longitudinal studies reported that cannabis users were more prone to develop depression at follow-up compared to nonusers (Bovasso, 2001; Gage et al., 2015; Pacek et al., 2013), others reported no significant association (Danielsson et al., 2015). An integrative

study conducted by Horwood et al. (2012) explored the extent to which cannabis use consistently predicts the onset of depressive symptoms in four Australian cohorts. Controlling for possible confounding effects, analyses revealed a significant dose-response effect between cannabis use and latter onset of depressive symptoms, with evidence indicating that this effect may be strongest in mid-adolescence and weaker in mature adulthood. In a meta-analysis conducted by Lev-Ran et al. (2013) the authors concluded that cannabis use, and particularly heavy use, may be associated with moderate yet significant increased risk for developing depression. It has been argued that the discrepancy in longitudinal evidence concerning cannabis use and depression is caused by inconsistent measuring of cannabis use and depression as well as lack of sufficient control for confounding factors (Lev-Ran et al., 2013c). In addition, CUDs may be associated with MDD in a substantially different way than cannabis use per se, as Substance Use Disorders (SUDs) and MDD presumably share common mechanisms and manifestations, including clinical similarities and neurobiological pathways and abnormalities (Brady and Sinha, 2005). Recently Feingold et al. (2015) reported that after controlling for various confounding factors, including sociodemographic variables and additional psychiatric and substance use disorders among individuals without lifetime MDD, baseline cannabis use, even daily use, was not associated with increased risk for onset of MDD at follow-up compared to nonusers. Inversely, after controlling for confounding variables among lifetime cannabis abstainers, individuals with baseline MDD were at a significantly increased risk to initiate cannabis use at follow-up (Feingold. et al., 2015). However specific effects of cannabis use on the outcome of MDD are not clear. It has been reported that among individuals with MDD cannabis use may be associated with a significantly elevated feeling of dysphoria (Ablon and Goodwin, 1974) and an incline in

number of depressive symptoms (Otten and Engels, 2013). There is evidence suggesting that cannabis use, and particularly frequent use, may reduce the efficiency of pharmacological treatment for depressive symptoms (Bricker et al., 2007). Additional cross-sectional research indicates potentially lower self-reported quality of life (QoL) among individuals with MDD who use cannabis frequently, compared to nonusers (Aspis et al., 2015). Nevertheless, longitudinal data on the effect of cannabis use on the severity and course of depression is lacking. In this study we sought to explore the effect of cannabis use and Cannabis Use Disorders (CUDs) on the course and outcome of MDD over a three-year period. Course of illness and outcome were assessed using rates of remission, depressive symptomology, suicidality measures, treatment utilization, measures of impairment in social, occupational and educational functioning and self-reported mental QoL. We hypothesized that cannabis use and CUD are associated with poorer outcome of MDD, as manifested by increased depressive symptoms, more significant impairment and lower QoL.

2. Methods 2.1. Participants We used data from the National Epidemiologic survey on Alcohol and Related Conditions (NESARC), a national representative survey designed by the National Institute on Alcohol Abuse and Alcoholism (Grant et al., 2008). The NESARC is a longitudinal survey which targeted non-institutionalized adults living in the United States, including military personnel living off-base and those in group housing (e.g. college dormitories, shelters). Wave 1 of the NESARC was conducted at 2001-2002 including a sample of 43,093 participants 18 years of age and over (Grant et al., 2003b). Wave 2 was conducted at 2003-2004 comprising 34,653 of

the Wave 1 respondents, which represent a response rate of 86.7% of eligible respondents (Grant and Kaplan, 2005). The NESARC protocol was approved by the US Census Bureau and the US Office of Budget and Management, and this study was approved by the institutional IRB. More comprehensive accounts of the NESARC database can be found elsewhere (Grant and Kaplan, 2005; Grant et al., 2003b). We selected a subgroup of individuals who qualified for a past-year diagnosis of MDD at Wave 1 and also participated in Wave 2 (N=2,348).

2.2. Measures Substance use and substance use disorders, as well as additional psychiatric disorders, were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule — DSM-IV Version (AUDADIS-IV) (Grant et al., 2003a). The AUDADIS-IV includes a list of symptom questions that operationalizes DSM-IV criteria for SUDs and additional axis I and axis II diagnoses. It has been reported to have excellent reliability and validity in the United States (Cottler et al., 1997; Grant et al., 2003a; Hasin et al., 1997; Pull et al., 1997) and internationally (Chatterji et al., 1997; Vrasti et al., 1998), test-retest reliability of the AUDADIS-IV has previously ranked excellent for alcohol (k=0.74) and drug (k=0.79) use disorders (Grant et al., 2005) and good for MDD (k=0.64) (Grant et al., 2004). 2.2.1. Major Depressive Disorder Past-year MDD at Wave 1 and Wave 2 were defined as presence of at least five out of nine symptoms during the same two-week period in the last 12 months, as diagnosed according to DSM-IV-TR criteria (American Psychiatric Association, 2000). MDD symptoms included the following: depressed mood, anhedonia, significant change in body weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of

worthlessness or guilt, diminished ability to think or concentrate and recurrent thoughts of death. In this study only primary psychiatric disorders were included and all cases of substance-induced mental disorders were excluded (Grant et al., 2004). 2.2.2. Cannabis use and CUDs Respondents were asked about cannabis use in the time period between Wave 1 and Wave 2. In this study cannabis users were defined as those who reported using cannabis during this time period but did not qualify for a diagnosis of a CUD ("users, no CUD"). Individuals were designated as having a CUD if they qualified for a diagnosis of a CUD (abuse or dependence), as defined according to DSM-IV in the time period between Wave 1 and Wave 2. In all analyses, each of these two groups (users, no CUD and CUD) was compared to individuals reporting no use of cannabis throughout this time period (‘nonusers’). Frequency of use was based on self-report ranging from "every day" to "once a year".

2.2.3. Outcome Measures Course of illness and outcome in depression can be defined using various factors including recurrence, persistence, suicidality and various self-reported severity scales (Elhai et al., 2013; Nanni et al., 2012). In this study course of illness was assessed using measures of recurrence vs. remission, number of depressive symptoms, measures of suicidality, measures indicating impairment in social, occupational and educational functioning (being fired from work, having trouble with boss or coworker, getting divorced or separated, quitting school more than once), treatment utilization rates and self-reported mental QoL. The NESARC study does not include the DSM-IV severity specifier for MDD (American Psychiatric Association, 2000), therefore in line with other formal severity scales we used the number of depressive symptoms as

a severity measure (Hamilton, 1960; Kroenke et al., 2001). Remission from MDD was defined as not meeting criteria of MDD diagnosis in the twelve months prior to Wave 2 among individuals who met the diagnostic criteria at Wave 1. Number of depressive symptoms and prevalence of specific symptoms in the twelve months prior to Wave 2 were assessed and compared between groups. Health related QoL was assessed using the Short-Form 12-Item Health Survey, version 2 (SF-12), a short and efficient format of the SF Health Survey. This is a self-reported questionnaire addressing various aspects of QoL including emotional, physical, social and work related issues which has been shown to be particularly valid and useful in large sample studies (Ware et al., 1996) and described in detail elsewhere (Aspis et al., 2015).

2.2.4. Confounding factors As baseline differences between groups may affect the course of MDD, the following baseline confounding factors were controlled for in the analyses: sociodemographic variables (Piccinelli and Wilkinson, 2000), additional past-year occurrence (i.e. any occurrence in the 12 months prior to Wave 1) of psychiatric disorders (Penninx et al., 2011) and past-year occurrence of SUDs (excluding CUD) (Sullivan et al., 2005; Swendsen and Merikangas, 2000). Additionally, in each analysis outcome variable present at baseline (i.e., in the twelve months prior to Wave 1) were controlled for in order to take into account possible preliminary differences that may increase the risk for consequent recurrence (Suominen et al., 2004).

2.3. Analytic Strategy

Cross-tabulations were conducted in order to explore baseline socio-demographic and clinical characteristics of respondents in the different categories (nonusers, users, CUD) and chisquare analyses were performed in order to explore differences in these characteristic, comparing cannabis users and individuals with CUDs to nonusers. In cases of continuous outcome measures (number of depressive symptoms, QoL) we used linear regression analyses in order to explore the association between level of cannabis use (no use, use,no CUD, CUD) and specific outcome measures. In cases of binary outcome measure (presence of specific depressive symptoms, suicidality measures, measures indicating impairment in social, occupational and educational functioning and treatment utilization) multivariate logistic regression analyses were used. In all analyses, progressive models of adjustment were used in order to compare cannabis users and individuals with CUDs to nonusers. Independent sample t-tests (two-tailed) we used for comparison of baseline QoL measures between groups. Bonferroni correction was used according to clusters of analyses and p<0.007 (0.05/7) values have been considered statistically significant (Bland and Altman, 1995).

3. Results Among individuals with baseline MDD, 7.5% reported using cannabis throughout the study period without qualifying for a CUD, and 4.7% qualified for a diagnosis of a CUD throughout the same time-frame ("CUD"). In the twelve months prior to Wave 1, daily or almost daily use of cannabis was reported by 16.3% and 39.9% of cannabis users and individuals with CUD, respectively.. Compared to nonusers, both groups of cannabis users differed significantly in several sociodemographic variables (Table 1) and baseline prevalence of several psychiatric disorders (Table 2). The average age of onset of MDD among non cannabis users ( ̅ =29.7)

differed significantly compared to users without a CUD ( ̅ =23.73, t(2,2575)=4.29, p<0.001) and individuals with CUD ( ̅ =20.3, t(2,2575)=10.71, p<0.0001) Mean number of lifetime depressive episodes among nonusers ( ̅ =7.7) did not differ significantly compared to cannabis users without a CUD ( ̅ =8.4, t(2,2575)=0.5, p=0.646) or individuals with a CUD ( ̅ =7.5, t(2,2575)=0.1, p=0.914). Among individuals with baseline MDD, 82.6% of non cannabis users did not meet criteria for a diagnosis of MDD at follow-up compared to 88.7% of users without a CUD (χ2=3.23, p=0.0771) and 76.8% of individuals with CUD (χ2=1.78, p=0.187). After controlling for baseline confounders, including baseline number of depressive symptoms, a significant association has been found between level of cannabis use and number of depressive symptoms at follow-up (β= 0.62, S.E.=0.07, p=0.0019). Exploring specific MDD symptoms, after controlling for confounding factors, individuals with a CUD had significantly greater odds to report anhedonia (Adjusted Odds Ratio (AOR)= 2.62; 95% Confidence Interval (CI)=1.36-5.08; p=0.0048), change in body weight (AOR=2.30; 95% CI=1.33-3.99; p=0.0036), insomnia or hypersomnia (AOR=2.30; 95% CI=1.29-4.12; p= 0.0055) and psychomotor problems (AOR=3.51; 95% CI=1.95-6.3; p=0.0001) at follow-up compared to nonusers (Table 3).

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Considering measures associated with suicidality at baseline, though cannabis users and individuals with CUDs differed significantly from nonusers in prevalence rates of having thoughts about committing suicide (Table 4a), these findings did not retain significance after adjusting for baseline confounding factors (Table 4b). Similarly, after controlling for baseline confounders cannabis users and individuals with CUDs were not significantly more prone to report being fired from work, having trouble with boss or coworker, getting divorced or separated and quitting school more than once at follow-up compared to nonusers. No differences were found in rates of treatment utilization among cannabis users and individuals with CUD compared to non-users. At follow-up, mean scores in the QoL mental summary scale were seemingly lower among cannabis users ( ̅ =42.78, S.D=1.11) and individuals with CUD ( ̅ =40.8, S.D=1.49) compared to nonusers ( ̅ =44.6 S.D=0.22). No significant differences were found between cannabis users and non-users in baseline QoL scores (Table 5a), and no significant association was found between level of cannabis use and QoL scores at follow-up. (Table 5b).

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4. Discussion In this study we explored the effect of cannabis use and CUDs on the course and outcome of MDD over a three-year period. Results indicate that cannabis users and individuals with CUDs did not differ from nonusers in rates of remission from MDD. Levels of cannabis use (no use, users without a CUD and those with a CUD) were associated with increased number of

depressive symptoms at follow-up, particularly differences in prevalence ofanhedonia, change in body weight, insomnia or hypersomnia and psychomotor problems at follow-up compared to nonusers. After adjusting for confounding factors, no significant differences were found between cannabis users without a CUD and individuals with a CUD compared to non-users in suicidality and functioning-related factors. No significant differences were found in utilization of treatment or QoL measures when comparing the groups. Results indicate high rates of CUDs (nearly 39%) among individuals who reported using cannabis. Even though this is substantially higher compared to the reported rates of lifetime occurrence of CUDs within cannabis users among the general population (Hasin et al., 2015), this is in line with higher rates of comorbid SUDs, and particularly CUDs, among individuals with depression (Grant et al., 2004). In addition, even though the average age of MDD onset was younger among non cannabis users compared to users and individuals with CUD, there was no significant difference in number of lifetime episodes of MDD between the groups. These findings may imply that cannabis may have antidepressant activity (which has been shown to be the case for specific cannabinoids (El-Alfy et al., 2010), though this clearly cannot be inferred from this study. Our results do not support a clear negative impact of cannabis use and CUDs on MDD. Nevertheless, results indicate that cannabis use may be associated with reporting specific depressive symptoms among individuals with MDD compared to nonusers. The present results suggest that among individuals with MDD cannabis use is associated with a significant increase in rates of anhedonia (DSM-IV criteria A(2)), change in body weight (implying a significant weight loss or weight gain, e.g., DSM-IV criteria A(3)), insomnia or hypersomnia (DSM-IV criteria A(4)) and psychomotor agitation or retardation (DSM-IV criteria A(5)). These findings

are in line with previous reports which indicated increased incidence of anhedonia symptoms among cannabis users (Bovasso, 2001). In addition, in a recent review Volkow et al. (Volkow et al., 2016) point to emerging evidence indicating that cannabis use may be associated with diminished motivation and interest in everyday activities, thus it may well be that this effect is enhanced among individuals with MDD who use cannabis. Evidence concerning the association between cannabis use and body weight is conflicting, with research pointing both positive (Mittleman et al., 2001), negative (Le Strat and Le Foll, 2011) and no association (Rodondi et al., 2006) between cannabis use and Body Mass Index (BMI) within the general population. Further research is required to explore whether individuals with MDD who use cannabis report an increase or decrease in body weight. In addition, cannabis use has been associated with sleep disorders, with evidence indicating that cannabis use may lead to poorer sleep and inversely that sleep disorders may lead to initiation of cannabis use as means of self-medication (Roane and Taylor, 2008; Schierenbeck et al., 2008). Our study indicates that CUDs may contribute to the onset of sleep disorders among individuals with MDD. Similarly, cannabis has been previously shown to produce a dose-related impairment in psychomotor functioning (Hall and Degenhardt, 2009), which may explain the high prevalence of motor symptoms among cannabis users with MDD. This study also included outcome variables which evaluate clinical distress and impairment in social, occupational and educational functioning (DSM-IV criteria B). After adjusting for confounding factors at baseline cannabis users were not prone to report suicide attempt and ideation at follow-up compared to nonusers. A recent meta-analysis by Borges et al. (2016) concluded that cannabis use may be associated with an increased risk for suicide ideation and attempts within the general population, yet not all of the studies included were longitudinal

and none controlled for suicide attempts or ideation at baseline. Our findings imply that among individual with MDD the association between cannabis use and suicidality may be accounted for by baseline differences in suicidality. Similarly, cannabis users reported higher rates of impaired functioning compared to nonusers at follow-up, yet these failed to sustain after controlling for baseline differences in similar measures. Even though cannabis use has been previously reported to predict poorer psychosocial functioning, including education (Degenhardt et al., 2010) and income (Danielsson et al., 2014), our result imply that in contrary to our initial hypothesis, among individuals with MDD previous impairments in functioning, and not cannabis use per se, predict poorer functioning at later stages. Concerning change in mental QoL over time, previous studies have reported that mental QoL was significantly lower among cannabis users compared to nonusers within the general population (Lev-Ran et al., 2012a) and those suffering from anxiety disorders (Lev-Ran et al., 2012b) and MDD (Aspis et al., 2015); to the best of our knowledge this study is the first to compare cannabis users and nonusers in the degree to which mental QoL change over time. After controlling for baseline differences, no significant association was found between level of cannabis use and QoL scores over a three-year followup period. These findings together do not support our initial hypothesis associating cannabis use and worse course of illness and outcome among individuals with MDD. Several limitations should be taken into consideration when interpreting our results. First, the NESARC sample does not include participants under the age of 18 (Stetser et al., 2002), who are more highly prone to suffer from co-occurring cannabis use and psychiatric disorders (Horwood et al., 2012), including depression (Hibell et al., 2011; Merikangas et al., 2010). Second, rates of cannabis use in the NESARC sample are lower compared to those reported in parallel surveys from North America, Europe and Australia (SAMHSA, 2014). This may be

attributed to methodological differences, such as the exclusion of younger participants (Lev-Ran et al., 2013b) as well as matters of privacy and anonymity in the NESARC sample which may lead to an under-report of socially undesirable behaviors (Grucza et al., 2007). These limitations decrease the generalizability of our study and therefore caution should be taken when considering the results. Furthermore though our findings indicate significant differences in the prevalence of weight changes (as a DSM criterion of MDD), NESARC data does not allow exploring whether this refers to weight gain or weight loss. The similar limitation is applied to the psychomotor criterion as well. Finally, research has pointed out that MDD may be characterized by reoccurring periods of depression (Solomon et al., 2000). The NESARC data currently encompasses a relatively short period of time thus limiting our ability to explore the long-term effect of cannabis use on the reoccurrence of MDD. Finally, the NESARC data do not include common specific scales for assessing severity of depression. Despite these limitations our findings are important taking into account the high prevalence of cannabis use among individuals with MDD and concerns regarding potentially harmful effects of cannabis use on the course of MDD. Though individuals with MDD who are cannabis users may be more inclined to suffer from negative outcomes, based on our analyses aside from few specific depressive symptoms, these do not seem to be attributed to cannabis use itself, rather to additional associated sociodemographic and clinical factors (e.g., comorbid psychiatric disorders). Alongside the lack of evidence concerning a clear harmful effect of cannabis use on course of illness of MDD, it is also important to note no positive effect of cannabis on the course and outcome of MDD, possibly indicating that cannabis use does not serve as a particularly effective method of "self-medication" among individuals with MDD

(Whiting et al., 2015). These should all be further explored in longitudinal research using validated scales directly measuring severity of depression.

Conflict of interest The Authors have declared that there are no conflicts of interest in relation to the subject of this study.

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Table 1. Socio-demographic data of individuals with Major Depressive Disorder (MDD) in the year prior to Wave 1, comparing cannabis users and individuals with Cannabis Use Disorder (CUD) to nonusers during in the time period between Wave 1 and Wave 2.

Sex Male Female Race White Black American Indian / Alaska Native Asian / Native Hawaiian / Pacific Islander Hispanic / Latino Educational Level Less than highschool Highschool graduate Some college or higher Household Income $0 - $19,999 $20,000 - $34,999 $35,000 - $69,999 $70,000 or greater Marital Status Married Widowed/Divorced/Separated Never Married Age 18-29 30-44 45-64 65+ Region Northeast Midwest South West

Group A Non Cannabis Users N %

Individuals with MDD (N=2,348) Group B Group C Cannabis Use, no CUDa CUD N % N %

604 1679

30.44 69.56

78 95

50.83 49.17

56 65

1419 356 63 41 404

75.91 9.01 3.5 2.78 8.8

123 21 8 1 20

77.28 8.83 7.19 0.3 6.4

383 598 1302

15.48 26.01 58.51

26 43 104

702 452 674 455

25.98 18.44 31.29 24.3

937 739 607

χ2 / P-Value A vs. B

A vs. C

42.57 57.43

13.75/0.0004

5.26/0.025

69 22 3 3 24

72.19 13.02 2.88 2.77 9.15

3.25/0.0172

0.44/0.7765

17.62 24.41 57.97

18 33 70

12.99 27.19 59.82 0.14/0.8676

0.25/0.7826

51 44 52 26

33.04 23.7 28.57 14.68

40 28 33 20

28.6 27.42 29.9 14.08

2.53/0.0651

2.05/0.1151

51.62 24.41 23.97

36 59 78

24.93 28.12 46.95

32 27 62

31.6 19.55 48.85

15.71/<0.0001

8.05/0.0008

586 783 736 178

27.04 33.73 32.99 6.23

77 62 34 0

46.78 30.97 22.25 0

76 32 13 0

65.9 25.61 8.49 0

22.02/<0.0001

15.85/<0.0001

411 409 892 571

18.90 17.48 39.28 24.34

42 30 60 41

20.6 19.6 33.43 26.37

11 23 55 32

10.66 16.08 46.03 27.24

0.61/0.6090

1.66/0.1834

Table 2. Prevalence of psychiatric disorders among individuals with Major Depressive Disorder (MDD) in the year prior to Wave 1, comparing cannabis users and individuals with Cannabis Use Disorder (CUD) to nonusers in the time period between Wave 1 and Wave 2.

Group A Non Cannabis Users N % Any psychiatric disorder explored Yes No Any mood disorder Yes No Dysthymia Yes No Manic episode Yes No Hypomanic episode Yes No

Individuals with MDD (N=2,348) Group B Group C Cannabis Use, no CUD CUD N % N %

χ2 / P-Value A vs. B

A vs. C

1517 776

67.7 32.3

143 31

81.26 18.74

104 17

83.27 16.73

4.44/0.039

5.23/0.0255

669 1614

29.02 70.98

66 107

38.65 61.35

48 73

41.54 58.46

4.89/0.0305

5.69/0.02

362 1921

15.27 84.73

34 139

19.95 80.05

24 97

19 81

1.98/0.1642

0.75/0.389

271 2012

11.9 88.1

26 147

13.81 86.19

23 98

19.49 80.51

0.41/0.5223

3.51/0.0654

94 2189

4.08 95.92

18 155

11.05 98.95

10 111

9.13 90.87

5.36/0.0237

2.12/0.1499

Any anxiety disorder Yes No Panic disorder Yes No Specific phobia Yes No Social phobia Yes No GAD Yes No Any personality disorder Yes No Avoidant personality disorder Yes No Dependent personality disorder Yes No Paranoid personality disorder Yes No Schizoid personality disorder Yes No Histrionic personality disorder Yes No Antisocial personality disorder Yes No Any Substance Use Disorder Yes No

875 1408

40.85 59.15

61 112

34.07 65.93

46 75

42.98 57.02

0.24/0.6356

1.53/0.2205

282 2001

12.66 87.34

25 148

11.57 88.43

21 100

18.41 81.59

0.13/0.7199

1.68/0.2001

419 1864

19.12 80.88

31 142

19.85 80.15

30 91

28.05 71.95

0.03/0.8628

2.86/0.0954

282 2001

13.49 86.51

31 142

19.85 80.15

30 91

28.05 71.95

0.03/0.8628

2.86/0.0954

351 1932

16.57 83.43

31 142

14.39 85.61

18 103

18.77 81.23

0.52/0.4733

0.25/6182

803 1480

36.34 63.66

83 90

47.1 52.9

69 52

55.49 44.51

5.61/0.0208

9.91/0.0025

293 1990

13.23 86.77

31 142

17.73 82.63

22 99

17.58 82.42

1.24/0.2673

0.99/0.3241

58 2225

2.62 97.38

5 168

4.91 95.09

7 114

5.54 54.46

0.65/0.4205

1.82/0.1817

470 1813

20.08 79.92

44 129

24.04 75.96

39 82

26.27 73.73

0.8491/0.3602

1.94/0.1674

293 1990

12.33 87.67

19 154

10.9 89.1

25 96

20.44 97.56

0.02/0.654

3.36/0.0713

153 2130

6.95 93.05

26 147

16.13 83.87

17 104

12.83 87.17

5.38/0.0235

2.7/0.1047

180 2103

9.14 90.86

46 127

28.9 71.1

32 89

26.61 73.39

16.61/0.0001

11.43/0.0012

324 1959

14.29 85.71

72 101

43.14 56.86

74 47

59.54 40.46

28.5/<0.0001

26.39/<0.0001

Table 3. Depressive symptoms in the year prior to Wave 2 among individuals diagnosed with MDD in the year prior comparing cannabis users and individuals with CUD to nonusers. Individuals with MDD (N=2,348) Cannabis Use, no CUDa (N=173) CUDa (N=121) Odds Ratio (95% P-Value Odds Ratio (95% confidence confidence interval) interval) Symptom 1: depressed mood most of the day, nearly every day, as indicated by either subjective report or observation made by N=91 N=78 others. b Model 1 0.99 (0.66-1.49) 0.9629 1.75 (1.06-2.89) Model 2c 1.02( 0.67-1.65) 0.9377 1.71 (1.01-2.89) Model 3d 1.04 (0.65-1.67) 0.859 1.77 (1.02-3.07) e Model 4 1.22 (0.75-1.99) 0.4188 1.50 (0.80-2.79) Symptom 2: markedly diminished interest or pleasure in all, or N=81 N=75 almost all, activities most of the day, nearly every day Model 1 1.08 (0.73-1.62) 0.69 2.35 (1.42-3.87) Model 2 1.05(0.68-1.62) 0.0.8134 2.52 (1.43-4.44) Model 3 1.06 (0.67-1.68) 0.8062 2.85 (1.58-5.12) Model 4 1.26 (0.78-2.04) 0.346 2.62 (1.36-5.08) Symptom 3: significant weight loss when not dieting or weight N=62 N=68 gain, or decrease or increase in appetite nearly every day Model 1 0.99 (0.66-1.49) 0.9763 2.34 (1.51-3.63) Model 2 0.9 (0.59-1.37) 0.6115 2.62 (1.6-4.3) Model 3 0.92 (0.58-1.48) 0.7344 2.87 (1.72-4.79) Model 4 1.15 (0.71-1.88) 0.5615 2.30 (1.33-3.99)

to w1,

P-Value

0.029 0.0443 0.0427 0.201

0,0011 0.0018 0.0007 0.0048

0.0003 0.0002 0.0001 0.0036

Symptom 4: insomnia or hypersomnia nearly every day N=77 Model 1 0.9 (0.59-1.38) Model 2 0.92 (0.59-1.41) Model 3 0.96 (0.59-1.56) Model 4 0.99 (0.59-1.65) Symptom 5: psychomotor agitation or retardation nearly every N=48 day Model 1 0.79 (0.51-1.22) Model 2 0.86 (0.52-1.44) Model 3 1 (0.57- 1.75) Model 4 1.10 (0.59-2.03) Symptom 6: fatigue or loss of energy nearly every day N=67 Model 1 0.72 (0.48-1.08) Model 2 0.83 (0.52-1.32) Model 3 0.85 (0.52-1.39) Model 4 0.90 (0.53-1.54) Symptom 7: feelings of worthlessness or excessive or N=66 inappropriate guilt (which may be delusional) nearly every day Model 1 1.09 (0.73-1.64) Model 2 0.87 (0.56-1.35) Model 3 0.87 (0.53-1.43) Model 4 0.90 (0.53-1.52) Symptom 8: diminished ability to think or concentrate, or indecisiveness, nearly every day. N=74 Model 1 0.95 (0.63-1.45) Model 2 0.96 (0.62-1.49) Model 3 1.01 (0.63- 1.6) Model 4 1.02 (0.61-1.68) Symptom 9: recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. N=52 Model 1 1.16 (0.75-1.78) Model 2 0.99 (0.61-1.62) Model 3 1.00 (0.59 -1.69) Model 4 0.96 (0.55-1.70) c. Adjustments for matching suicidality measure at baseline. d. Additional adjustments for sociodemographic variables. e. Additional adjustment for psychiatric disorders and substance use disorders amphetamines, crack/cocaine, hallucinogens, inhalants, heroin, other drug and alcohol).

0.6372 0.6851 0.8603 0.9675

0.2809 0.5677 1 0.7609 0.1132 0.4309 0.5171 0.6911

N=73 2.4 (1.49-3.88) 2.38 (1.44-3.93) 2.62 (1.57-4.37) 2.30 (1.29-4.12) N=61 2.94 (1.79-4.82) 3.13 (1.87-5.25) 3.72 (2.16-6.41) 3.51 (1.95-6.3) N=67 2.16 (1.32-3.52) 2.14 (1.26-3.62) 2.31 (1.34-4) 2.03 (1.11-3.72)

0.0005 0.001 0.0004 0.0055

<0.0001 <0.0001 <0.0001 0.0001 0.0027 0.0053 0.0033 0.0231

N=66 0.6555 0.5244 0.0147 0.6782

2.43 (1.5-3.93) 2.65 (1.5-4.7) 2.92 (1.6-5.33) 2.30 (1.16-4.56)

0.0005 0.0011 0.0007 0.0175

0.8133 0.866 0.9805 0.9488

N=70 2.26 (1.4-3.76 2.18 (1.31-3.62) 2.29 (1.36-3.86) 2.09 (1.16-3.78)

0.0013 0.0031 0.0023 0.0155

0.5040 0.9723 0.9863 0.8965

N=62 2.59 (1.61-4.15) 2.35 (1.35-4.08) 2.54 (1.39-4.63) 1.78 (0.96-3.33)

0.0002 0.0029 0.0028 0.068

(including sedatives, tranquilizers, opioids,

Table 4a. Suicidality measures in the twelve months prior to Wave 1 among individuals diagnosed with Major Depressive Disorder (MDD) in this time period, comparing cannabis users and nonusers during the time period between Wave 1 and Wave 2. Individuals with MDD (N=2,348) Group A Group B Group C χ2 / P-Value Non Cannabis Users Cannabis Use, no CUDa CUD N % N % N % A vs. B A vs. C Did you attempt suicide? Yes 302 12.57 30 22.28 31 21.91 No 1974 87.43 143 77.72 90 78.09 3.93/0.0515 3.97/0.0506 Did you think about committing suicide? Yes 895 39.22 87 52.8 69 58.39 No 1379 60.78 86 47.2 52 41.61 7.54/0.0078 7.44/0.0082 Did you feel like you wanted to die? Yes 1169 51.33 97 54.48 83 67.9 No 1099 48.67 76 45.52 38 32.1 0.43/0.5155 7.23/0.0091 Did you think a lot about your own death? Yes 887 37.68 77 44.62 60 47.47 No 1382 62.32 96 55.38 60 52.53 2.25/0.1385 3.61/0.062 a. CUD= Cannabis Use Disorder

Table 4b. Differences in suicidality measures in the year prior to Wave 2 among individuals diagnosed with major depressive disorder (MDD) in the year prior to Wave 1, comparing cannabis users and nonusers during both the year prior to Wave 1 and the time period between Wave 1 and Wave 2. Individuals with MDD (N=2,348) Cannabis Use, no CUDa (N=173) CUDa (N=121) Odds Ratio (95% confidence P-Value Odds Ratio (95% confidence P-Value interval) interval) Did you attempt suicide? N=8 N=17 Model 1b 1.46 (0.54-3.93) 0.4479 3.94 (1.83-8.48) 0.0007 c Model 2 0.89 (0.26-3.1) 0.8560 3.25 (1.2-8.8) 0.0212 Model 3d 1.06 (0.27-4.2) 0.9335 3.11 (1.15-8.45) 0.0266 Model 4e 1.09 (0.23-5.15) 0.9135 3.23 (1.09-9.6) 0.0349 Did you think about committing suicide? N=37 N=41 Model 1 1.64 (0.97-2.79) 0.0664 2.13 (1.27-3.55) 0.0046 Model 2 1.32 (0.71-2.44) 0.3778 1.55 (0.84-2.86) 0.1548 Model 3 1.27 (0.22-2.26) 0.4011 1.53 (0.83-2.84) 0.1681 Model 4 1.19 (0.62-2.29) 0.597 1.28 (0.65-2.5) 0.4696 Did you feel like you wanted to die? N=48 N=51 Model 1 1.65 (0.94-2.88) 0.0794 2.29 (1.29-4.04) 0.0051 Model 2 1.61 (0.79-3.27) 0.1847 1.76 (0.95-3.24) 0.0696 Model 3 1.79 (0.88-3.65) 0.1085 1.18 (0.93-3.53) 0.0804 Model 4 1.59 (0.61-3.28) 0.2942 1.29 (0.65-2.59) 0.4599 Did you think a lot about your own death? N=32 N=41 Model 1 1.27 (0.75-2.13) 0.3661 1.41 (0.84-3.24) 0.1877 Model 2 1.25 (0.73-2.15) 0.4031 1.22 (0.7-2.15) 0.4768 Model 3 1.26 (0.72-2.22) 0.4123 1.32 (0.73-2.39) 0.3528 Model 4 1.2 (0.62-1.29) 0.585 1.19 (0.63-2.25) 0.5877 a. CUD: Cannabis Use Disorder b. Unadjusted analysis c. Adjustments for matching suicidality measure at baseline. d. Additional adjustments for sociodemographic variables. e. Additional adjustment for psychiatric disorders and substance use disorders (including sedatives, tranquilizers, opioids, amphetamines, crack/cocaine, hallucinogens, inhalants, heroin, other drug and alcohol).

Table 5a. SF-12 mental disability summary scale and subscales means scores (indicating self-reported Quality of Life) at Wave 1 for individuals diagnosed with MDD in the year prior to w1, comparing cannabis users and individuals with cannabis use disorder to nonusers during the time period between Wave 1 and Wave 2. Individuals with MDD (N=2,577) Group A Group B Group C t / P-Value Non Cannabis Cannabis Use, no CUD Users CUDa Mean S.E Mean S.E Mean S.E A vs. B A vs. C SF-12 mental disability summary scale 41.7 0.32 39.86 0.97 40.95 1.24 1.81/0.0755 0.58/0.5620 SF-12 subscales Vitality (VT) 47.5 0.27 48.37 1.06 48 1.04 -0.83/0.4092 -0.54/0.5922 Social Functioning (SF) 44.11 0.35 43.36 1.11 44.69 1.31 0.64/0.5252 -0.42/0.6755 Role Emotional (RE) 43.24 0.34 40.7 1.39 43.17 1.4 1.78/0.0798 0.04/0.965 Mental Health (MH) 41.48 0.3 39.89 1.12 42.13 1.24 1.37/0.1754 -0.51/0.6107 a. CUD= Cannabis Use Disorder

Table 5b. Association between level of cannabis use(no use, use without a CUD and CUD) between Wave 1 and Wave 2 and SF-12 mental disability summary scale and subscales (indicating self-reported Quality of Life) mean score at Wave 2 among individuals diagnosed with Major Depressive Disorder (MDD) in the year prior to Wave 1. Individuals with MDD (N=2,577)

Level of cannabis use SF-12 mental summary scale Model 1b

β (S.E.)

P-Value

-1.86 (0.68)

0.0081

disability

Model 2c Model 3d Model 4e SF-12 subscales Vitality (VT) Model 1 Model 2 Model 3 Model 4 Social Functioning (SF) Model 1 Model 2 Model 3 Model 4 Role Emotional (RE) Model 1 Model 2 Model 3 Model 4 Mental Health (MH) Model 1 Model 2 Model 3 Model 4

-1.5 (0.66) -1.71 (0.68) -1.87 (0.71)

0.0258 0.0148 0.0105

-0.36 (0.56) -0.5 (0.54) -1.12 (0.55) -0.95 (0.57)

0.5259 0.3494 0.045 0.0982

-1.35 (0.63) -1.26 -1.7 (0.67) -1.82 (0.71)

0.0358 0.0518 0.0132 0.0126

-1.39 (0.77) -1.16 (0.72) -1.85 (0.73) -1.86 (0.73)

0.0746 0.112 0.0141 0.0132

-1.2 (0.66) -1.02 (0.6) -1.37 (0.63) -1.6 (0.65)

0.0749 0.0943 0.034 0.017

Highlights ● Individuals with baseline major depressive disorder were followed over a three-year time period ● Cannabis users and individuals with cannabis use disorders were compared to nonusers ● No differences were found in rates of remission between the groups ● Level of cannabis use was associated with significantly more depressive symptoms at follow-up ● These findings did not retain significance after adjusting for baseline confounding factors