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. Author manuscript; available in PMC: 2012 Feb 28.
Published in final edited form as: Psychiatry Res. 2010 Jul 31;185(3):459–461. doi: 10.1016/j.psychres.2010.07.007

Cannabis involvement in individuals with Bipolar Disorder

Arpana Agrawal a, John I Nurnberger Jr b; The Bipolar Genome Studyc, Michael T Lynskey a
PMCID: PMC2976789  NIHMSID: NIHMS223460  PMID: 20674039

Abstract

In a study of 471 BD cases and 1761 controls, individuals with BD were 6.8 times more likely to report a lifetime history of cannabis use. Rates of DSM-IV cannabis use disorders in those with BD were 29.4% and were independently and significantly associated with increased suicide attempts, experience mixed episodes and disability attributable to BD.

Keywords: cannabis, bipolar disorder, comorbidity

1. INTRODUCTION

Bipolar Disorder and disorders of the Bipolar Spectrum (BD) are, globally, the sixth leading cause of disability (Woods, 2000). 20-50% of BD subjects endorse some form of cannabis-related problems (Cerullo and Strakowski, 2007) with a recent study reporting higher severity of illness and greater treatment non-compliance in chronic cannabis users (van, I et al. 2009). While there has been a considerable amount of interest – and controversy – surrounding the associations between cannabis use and (variously defined) “psychosis” (Hall and Degenhardt 2000; Macleod et al., 2007), a recent study shows only a modest reduction in the association between cannabis use and mania when excluding psychotic features (Henquet et al., 2006). However, prior studies that have examined the association between cannabis-related behaviors and BD are characterized by several limitations including low sample size, limited assessments of BD and also limited data on comorbid conditions. We (a) report on the association between lifetime cannabis use and BD; (b) examine patterns of cannabis involvement in those with BD and (c) investigate BD-related outcomes in those with comorbid cannabis use disorders.

2. METHODS AND MATERIALS

2.1. Subjects

Extensive information on ascertainment of cases and controls is available in a related publication (Smith et al., 2009). Briefly, cases were unrelated subjects diagnosed with DSM-IV BD 1 as well as a small subset with BD spectrum disorders, using best estimate diagnosis. We used data collected using the DIGS 4.0 (Nurnberger, Jr. et al., 1994) from 321 European-American and 150 African-American individuals. Controls were drawn from a larger pool of subjects from across the U.S. who agreed to donate a blood sample for transformation into lymphoblastoid cell lines and to respond to a medical questionnaire. Only individuals with complete or near-complete psychiatric questionnaire data who did not fulfill diagnostic criteria for major depression, and did not report a history of schizophrenia, bipolar disorder or psychosis were retained – further matching for gender and ethnicity with BD cases allowed for inclusion of 1081 European-American and 680 African-American subjects.

2.2. Measures

All BD, cannabis involvement and psychpathology measures were collected using the semi-structured DIGS 4.0. Best estimate diagnosis of DSM-IV (American Psychiatric Association, 1994) BD and BD spectrum disorders were used. 89.8% of the 471 cases, were diagnosed with Bipolar I, 6.7% with Schizoaffective, Bipolar, and the remainder with Bipolar II (with recurrent depression) or Bipolar NOS. While no adjustments were made for confidence associated with diagnosis, 80% of the subjects were diagnosed with definite diagnostic confidence with the remainder being diagnosed with a high level of confidence (only missing supporting observations). Diagnoses for comorbid DSM-IV psychiatric and substance use disorders were also extracted from the best estimate diagnosis section. Clinical features of BD were rated by a clinician, based on responses to a variety of questions in the DIGS as well as interviewer narratives. For instance, BD-related disability was rated by a clinician as follows: 0=never ill, 1=no loss of employment or marital status, 2= loss of status but not disabled, 3=disabled but lives independently, 4=disabled and not living independently. This rating was based on multiple interview items rating general impact of illness on life functioning (e.g. did something happen as a result of illness (such as marital separation, absence from work or school, loss of job, or lower grades) as well as interviewer observations and clinical overview of the complete interview.

Data on lifetime cannabis use was available on cases and controls. In the cases, subjects who reported a lifetime history of 21 or more instances of cannabis use in a single year were queried about their age at first cannabis use as well DSM-IV abuse criteria. Those endorsing a single abuse criterion were subsequently queried for the 6 DSM-IV dependence criteria as well as cannabis withdrawal. Age at meeting criteria for, and recency of, DSM-IV cannabis abuse/dependence were also available.

2.3. Statistics

To examine the association between cannabis use and abuse/dependence and aspects of BD, chi-square analysis of contingency tables was used along with logistic regression controlling for sex, age, ethnicity, comorbid substance use disorders and DSM-IV psychopathology.

3. RESULTS

Compared with controls, BD cases were 6.8 times [95% C.I. 5.41-8.52] more likely to report a lifetime history of cannabis use – 71.3% of the cases, compared with 26.8% of the controls. This association was not modified by sex (p=0.22), however, the association was somewhat less strong in African-American (O.R. 0.48, 95% C.I. 0.29-0.76) subjects and in those aged 18-34 years (O.R. 0.58, 0.34-0.98). The association between BD and lifetime cannabis use persisted even after adjusting for other forms of substance use (alcohol, nicotine, cocaine and other illicit drugs).

Characteristics of cannabis-related behaviors in individuals with BD are presented in Table 1. Fifty seven percent of users reported using cannabis 21 or more times in a single year. Rates of DSM-IV abuse/dependence were high – 30% of individuals with BD (72% of those reporting lifetime use of 21 or more times in a single year) met criteria for DSM-IV cannabis use disorders. Fifty-three percent of the cases reported onset of a mood episode (depression, mania or hypomania) prior to their onset of cannabis use – the onset of a manic/hypomanic episode prior to onset of cannabis use was more common (43%) than onset of a depressive episode prior to cannabis use (21%). Of those who had used cannabis 21 or more times in a single year, 45% met criteria for cannabis use disorders prior to, or concurrent with the onset of BD – manic/hypomanic episodes were more likely than depressive episodes to precede onset of cannabis use disorders.

TABLE 1.

Prevalence of cannabis involvement and prevalence of, and association between, DSM-IV cannabis use disorders and clinical features of Bipolar Disorder (BD) in 471 GAIN cases interviewed using DIGS 4.0.

All cases
Lifetime use 71.3% (N=330)
21+ times in a single year 40% (N=186)
DSM-IV abuse/dependence 29.4% (N=138)
Mean age at 1st use 16.7
[7-45 years]
Mean age at DSM-IV cannabis use disorders 19.2
[12-36 years]
Mean age at recency of DSM-IV cannabis use
disorders		 29.8
[15-57 years]
% in those with
cannabis use
disorders
(N=138)		 % in those without
cannabis use disorders
(N=331)		 O.R.
[95% C.I.]		 Multivariate
O.R.*
[95 % C.I.]
Psychosis 62.3% (N=86) 64.7% (N=214) 0.90
[0.60-1.36]		 ns
Rapid Cycling 24.6% (N=34) 27.2% (N=90) 0.88
[0.55-1.38]		 ns
Mixed Episodes 53.6% (N=74) 43.2% (N=143) 1.52
[1.02-2.27]		 1.44
[0.93-2.24]
Incapacitation during depression 83.3% (N=115) 82.8% (N=274) 1.04
[0.61-1.77]		 ns
Incapacitation during mania 81.9% (N=113) 86.1% (N=285) 0.73
[0.43-1.24]		 ns
General disability associated with life functioning
(self-reported disabled, living independently or not)		 63.7% (N=86) 44.5% (N=145) 2.19
[1.45-3.31]		 1.81
[1.13-2.91]
Suicide attempt
(self-reported – acted with ambivalence/intent to die
with minimal/serious consequences)		 60.9% (N=84) 50.8% (N=168) 1.51
[1.01-2.26]		 1.33
[0.85-2.10]
Mean depression episodes 21.2 23.0 ns ns
Mean mania episodes 14.6 13.7 ns ns
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*

Only shown when univariate is significant. Covariates for multivariate analyses include age, sex, ethnicity, a variable representing DSM-IV abuse/dependence on alcohol or cocaine or sedatives, stimulants, opiates or other drugs or DSM-IV nicotine dependence and a variable representing meeting criteria for DSM-IV panic disorder with/without agoraphobia, agoraphobia without panic disorder, social phobia, specific phobia, obsessive compulsive disorder, anorexia nervosa, bulimia nervosa, pathological gambling, attention deficit hyperactivity disorder or antisocial personality disorder.

ns=not significant at p < .05

In this sample, 64% of individuals with BD reported affective psychosis (during mania, depression or both). Of those with psychosis, 79.2% had experienced psychotic features during 2 or more episodes of depression or mania. The association between cannabis use disorders and BD was not attributable to psychosis nor to chronicity. Presence of psychosis was also not associated with lifetime cannabis use or with using cannabis for the first time prior to age 14 (early use).

In these data, those who initiated using cannabis prior to their first manic/hypomanic/depressive episode had a significantly lower mean age at first use (15.1 vs. 17.7 yrs) while those who used cannabis after (or in tandem with) their onset of a manic/hypomanic/depressive episode had a lower age at onset of BD (17.5 vs. 21.5 yrs). Those who used cannabis prior to onset of a BD episode were 1.75 [95% C.I. 1.05-2.91] times more likely to report disability attributable to BD. Thus, earlier onset of cannabis use was associated with BD-related disability.

Those meeting lifetime criteria for DSM-IV cannabis use disorders experienced greater disability – 63.7% of those with cannabis use disorders reported disability while only 44.5% of those not meeting criteria reported disability. Those individuals with BD who reported comorbid cannabis use disorders were 2.2 times more likely to report disability in life-functioning attributable to BD and also a modest increased probability of attempting suicide. Mixed episodes were more common in those with a lifetime history of DSM-IV cannabis use disorders. Importantly, even after controlling for all sociodemographic, substance use and psychiatric covariates, those with DSM-IV cannabis use disorders were 1.8 times more likely to report disability due to BD than those without a history of cannabis use disorders.

4. DISCUSSION

Cannabis use and use disorders are more common in those with BD and their presence is independently associated with greater disability associated with BD. This exacerbation of BD-related life functioning in those with cannabis abuse/dependence is independent of psychosis and other co-occurring psychopathology and substance use disorders. For individuals presenting with BD, efforts should be made both to assess their extent of cannabis use and, for those presenting with problematic use, to reduce their levels of use. Whether such a reduction has a causal influence on the etiology of BD is speculative but evidence for better treatment outcomes in non-users does exist (Baethge et al., 2005).

Some caveats to this study are noteworthy. First, data on cannabis use disorders are not available in control subjects. Second, we elected to use data collected with the DIGS 4.0 as this provided the most comprehensive assessment and also excluded any heterogeneity attributable to assessment – thus, individuals assessed using prior versions of the DIGS were excluded. This did not influence the association between BD case status and cannabis use. Retaining only those subjects with a Bipolar I diagnosis also did not modify the association. Finally, the retrospective nature of the data precludes tests of causality.

In conclusion, there is ongoing debate on the efficacy of medication for BD in individuals afflicted with comorbid substance use disorders and on the modifying effects of antipsychotic medication on the endogenous cannabinoid system (Hamdani et al., 2008; Wiley et al., 2008; Leweke and Koethe, 2008). BD cases with comorbid cannabis use disorders are a vulnerable population and continued efforts to identify integrated treatments for dually diagnosed patients is vital.

ACKNOWLEDGEMENTS

Funding support for the Whole Genome Association Study of Bipolar Disorder was provided by the National Institute of Mental Health and genotyping of samples was provided through the Genetic Association Information Network (GAIN). The datasets used in this study were obtained from the database of Genotype and Phenotype (dbGAP) found at http://www.ncbi.nlm.nih.gov/gap through dbGAP accession number phs000017.v3.p1. These data were approved for use by AA and MTL for the research project ‘Substance involvement and Bipolar Disorder: Phenotypic and Genetic Analyses’ (approved 10/10/2009)

Data and biomaterials for the NIMH Bipolar Disorder sample were collected in four projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991–98, the Principal Investigators and Co-Investigators were: Indiana Univ., Indianapolis, IN, U01 MH46282, John Nurnberger, MD, PhD, Marvin Miller, MD, Howard J. Edenberg and Elizabeth Bowman, MD; Washington Univ., St. Louis, MO, U01 MH46280, Theodore Reich, MD, Alison Goate, PhD, and John Rice, PhD; Johns Hopkins Univ., Baltimore, MD U01 MH46274, J. Raymond DePaulo, Jr. MD, Sylvia Simpson, MD, MPH, and Colin Stine, PhD; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, MD, Elliot Gershon, MD, Diane Kazuba, BA, and Elizabeth Maxwell, M.S.W. Data and biomaterial were also collected as part of ten projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1999–2007, the Principal Investigators and Co-Investigators were: Indiana Univ., Indianapolis, IN, R01 MH59545, John Nurnberger, MD, PhD, Marvin J. Miller, MD, Elizabeth S. Bowman, MD, N. Leela Rau, MD, P. Ryan Moe, MD, Nalini Samavedy, MD, Rif El-Mallakh, MD (at Univ. of Louisville), Husseini Manji, MD (at Wayne State Univ.), Debra A. Glitz, MD (at Wayne State Univ.), Eric T. Meyer, M.S., Carrie Smiley, RN, Tatiana Foroud, PhD, Leah Flury, M.S., Danielle M. Dick, PhD, Howard Edenberg, PhD; Washington Univ., St. Louis, MO, R01 MH059534, John Rice, Ph.D, Theodore Reich, MD, Alison Goate, PhD, Laura Bierut, MD; Johns Hopkins Univ., Baltimore, MD, R01 MH59533, Melvin McInnis MD, J. Raymond DePaulo, Jr MD Dean F. MacKinnon, MD, Francis M. Mondimore, MD, James B. Potash, MD, Peter P. Zandi, Ph.D, Dimitrios Avramopoulos, and Jennifer Payne; Univ. of Pennsylvania, PA, R01 MH59553, Wade Berrettini MD, PhD; Univ. of California at Irvine, CA, R01 MH60068, William Byerley MD, and Mark Vawter MD; Univ. of Iowa, IA, R01 MH059548, William Coryell MD, and Raymond Crowe MD; Univ. of Chicago, IL, R01 MH59535, Elliot Gershon, MD, Judith Badner PhD, Francis McMahon MD, Chunyu Liu PhD, Alan Sanders MD, Maria Caserta, Steven Dinwiddie MD, Tu Nguyen, Donna Harakal; Univ. of California at San Diego, CA, R01 MH59567, John Kelsoe, MD, Rebecca McKinney, BA; Rush Univ., IL, R01 MH059556, William Scheftner MD, Howard M. Kravitz, D.O., MPH, Diana Marta, BA, Annette Vaughn-Brown, MSN, RN, and Laurie Bederow, MA; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, Francis J. McMahon, MD, Layla Kassem, PsyD, Sevilla Detera-Wadleigh, Ph.D, Lisa Austin, Ph.D, Dennis L. Murphy, MD.

The NIMH control subjects were collected by the NIMH Schizophrenia Genetics Initiative ‘Molecular Genetics of Schizophrenia II’ (MGS-2) collaboration. The investigators and coinvestigators are: ENH/Northwestern University, Evanston, IL, MH059571—Pablo V Gejman, MD (Collaboration Coordinator; PI), Alan R Sanders, MD; Emory University School of Medicine, Atlanta, GA, MH59587—Farooq Amin, MD (PI); Louisiana State University Health Sciences Center; New Orleans, LA, MH067257—Nancy Buccola APRN, BC, MSN (PI); University of California-Irvine, Irvine, CA, MH60870—William Byerley, MD (PI); Washington University, St Louis, MO, U01, MH060879—C Robert Cloninger, MD (PI); University of Iowa, Iowa, IA, MH59566—Raymond Crowe, MD (PI), Donald Black, MD; University of Colorado, Denver, CO, MH059565—Robert Freedman, MD (PI); University of Pennsylvania, Philadelphia, PA, MH061675—Douglas Levinson, MD (PI); University of Queensland, QLD, Australia, MH059588—Bryan Mowry, MD (PI); Mt Sinai School of Medicine, New York, NY, MH59586—Jeremy Silverman, PhD (PI).

Research on this project is also supported by DA23668 (to A.A.) and DA18660 and DA18267 (to M.T.L.).

Funding sources were not involved in any aspect of this study.

We thank Louis Fox and Sumitra Balasubramanian for assistance with data management for these analyses, and the staff and participants on all contributing studies for their generous contributions.

Footnotes

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Declaration of interest: None

Literature Cited

  1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 4th edition. American Psychiatric Association; Washington, DC: 1994. Revised edn. [Google Scholar]
  2. Baethge C, Baldessarini RJ, Khalsa HM, Hennen J, Salvatore P, Tohen M. Substance abuse in first-episode bipolar I disorder: indications for early intervention. American Journal of Psychiatry. 2005;162:1008–1010. doi: 10.1176/appi.ajp.162.5.1008. [DOI] [PubMed] [Google Scholar]
  3. Cerullo MA, Strakowski SM. The prevalence and significance of substance use disorders in bipolar type I and II disorder. Substance Abuse, Treatment, Prevention and Policy. 2007;2:29. doi: 10.1186/1747-597X-2-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Hall W, Degenhardt L. Cannabis use and psychosis: a review of clinical and epidemiological evidence. Australian and New Zealand Journal of Psychiatry. 2000;34:26–34. doi: 10.1046/j.1440-1614.2000.00685.x. [DOI] [PubMed] [Google Scholar]
  5. Hamdani N, Tabeze JP, Ramoz N, Ades J, Hamon M, Sarfati Y, Boni C, Gorwood P. The CNR1 gene as a pharmacogenetic factor for antipsychotics rather than a susceptibility gene for schizophrenia. European Neuropsychopharmacology. 2008;18:34–40. doi: 10.1016/j.euroneuro.2007.05.005. [DOI] [PubMed] [Google Scholar]
  6. Henquet C, Krabbendam L, de GR, ten HM, van OJ. Cannabis use and expression of mania in the general population. Journal of Affective Disorders. 2006;95:103–110. doi: 10.1016/j.jad.2006.05.002. [DOI] [PubMed] [Google Scholar]
  7. Leweke FM, Koethe D. Cannabis and psychiatric disorders: it is not only addiction. Addiction Biology. 2008;13:264–275. doi: 10.1111/j.1369-1600.2008.00106.x. [DOI] [PubMed] [Google Scholar]
  8. Macleod J, Davey SG, Hickman M, Egger M. Cannabis and psychosis. Lancet. 2007;370:1539–1540. doi: 10.1016/S0140-6736(07)61651-1. [DOI] [PubMed] [Google Scholar]
  9. Nurnberger JI, Jr., Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T. Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Archives of General Psychiatry. 1994;51:849–859. doi: 10.1001/archpsyc.1994.03950110009002. [DOI] [PubMed] [Google Scholar]
  10. Smith EN, Bloss CS, Badner JA, Barrett T, Belmonte PL, Berrettini W, Byerley W, Coryell W, Craig D, Edenberg HJ, Eskin E, Foroud T, Gershon E, Greenwood TA, Hipolito M, Koller DL, Lawson WB, Liu C, Lohoff F, McInnis MG, McMahon FJ, Mirel DB, Murray SS, Nievergelt C, Nurnberger J, Nwulia EA, Paschall J, Potash JB, Rice J, Schulze TG, Scheftner W, Panganiban C, Zaitlen N, Zandi PP, Zollner S, Schork NJ, Kelsoe JR. Genome-wide association study of bipolar disorder in European American and African American individuals. Molecular Psychiatry. 2009;14:755–763. doi: 10.1038/mp.2009.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. van R,I, Boomsma M, Tenback D, Reed C, van OJ. Does cannabis use affect treatment outcome in bipolar disorder? A longitudinal analysis. Journal of Nervous and Mental Disease. 2009;197:35–40. doi: 10.1097/NMD.0b013e31819292a6. [DOI] [PubMed] [Google Scholar]
  12. Wiley JL, Kendler SH, Burston JJ, Howard DR, Selley DE, Sim-Selley LJ. Antipsychotic-induced alterations in CB1 receptor-mediated G-protein signaling and in vivo pharmacology in rats. Neuropharmacology. 2008;55:1183–1190. doi: 10.1016/j.neuropharm.2008.07.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Woods SW. The economic burden of bipolar disease. Journal of Clinica; Psychiatry. 2000;61(Supp 13):38–41. [PubMed] [Google Scholar]

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