Journal of Affective Disorders 165 (2014) 103–108
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Review
Cannabis use and first manic episode Nathalie Bally a, Daniele Zullino a, Jean-Michel Aubry b,n a
Division of Addiction Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Switzerland Mood Disorders Unit, Division of Psychiatric Specialties, Department of Mental Health and Psychiatry, Geneva University Hospitals, 20 Bis, Rue de Lausanne, CH-1201 Geneva, Switzerland
b
art ic l e i nf o
a b s t r a c t
Article history: Received 14 February 2014 Received in revised form 14 April 2014 Accepted 15 April 2014 Available online 24 April 2014
Background: Cannabis is the most commonly abused drug among patients with bipolar disorder. Available data has shown that the risk of psychotic disorders increases with the frequency and intensity of cannabis abuse. The present purpose was to review relevant studies to investigate whether cannabis use can be linked to the onset of mania in bipolar disorder. Methods: Articles published between 1972 and December 2013 were searched on Medline and PsychInfo using the following keywords: first manic episode, or onset mania, or bipolar disorder and cannabis. Relevant papers cited in the references of selected articles were further considered for inclusion into the review. Results: Lifetime use of cannabis among bipolar patients appears to be around 70% and approximately 30% of patients with a bipolar disorder present a comorbidity of cannabis abuse or dependence. Cannabis use is associated with younger age at onset of first mania and with more frequent depressive or manic episodes, although the evidence is somewhat inconsistent. Likewise cannabis consumption is related to poorer outcome and an increased risk of rapid cycling or mixed episodes. In contrast, neuro-cognitive functioning seems to be positively affected in patients with psychiatric comorbidity. While cannabis use often precedes first manic episodes, the causal direction remains to be determined. Limitations: Variations in definition of cannabis use/dependence. Lack of controlled studies limiting definite conclusions about a putative causal relationship between cannabis and onset of mania. Conclusions: Further investigations are needed to clarify the relationships between cannabis use and first manic episode. & 2014 Elsevier B.V. All rights reserved.
Keywords: Cannabis Marijuana Bipolar disorders Onset mania
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Cannabis use frequency in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Cannabis use or dependence?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Bipolar disorder outcome with co-occurring cannabis use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Cognitive and clinical observations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Psychotic symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Cannabis use as a cause of onset mania? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Corresponding author. Tel.: þ 41 22 305 45 38; fax: þ 41 22 305 45 80. E-mail address: [email protected] (J.-M. Aubry).
http://dx.doi.org/10.1016/j.jad.2014.04.038 0165-0327/& 2014 Elsevier B.V. All rights reserved.
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1. Introduction Cannabis is the most widely used illegal substance in western countries, with a lifetime use reported by almost half of young adults in the USA and Canada and 32% in the European Union (Arendt et al., 2013). In the 2013 world drug report from the UN (UNODC, 2013), the annual prevalence for the use of cannabis in 15–64 years old population was 7.6% for occidental and central Europe, 10.7% for North America and 10.9% for Oceania. In a recent study on systematic reviews of epidemiological data on cannabis dependence for 187 countries worldwide, Degenhardt et al. (2013) reported that prevalence was higher in males and peaked between 20 and 24 years and in high income regions. Accumulating epidemiological data has demonstrated that the risk of psychotic disorders increases with the frequency and intensity of cannabis use (Di Forti et al., 2014; Khan and Akella, 2009; Lange et al., 2014; Leweke and Koethe, 2008; Manrique-Garcia et al., 2012). Since in psychosis it may be difficult to identify precisely the age at onset, the term psychosis mentioned in the literature usually includes a broad definition of psychotic disorders. Bipolar disorder bears the highest rate of substance abuse among mood disorders. Indeed, about 50% of patients with bipolar disorder have a lifetime comorbidity of an alcohol use disorder (AUD) and 41% of any other substance use disorder (Regier et al., 1990; Strakowski et al., 2007), cannabis being the most commonly used illegal drug among patients with bipolar disorders (Leweke and Koethe, 2008). If cannabis use often starts at a young age, its role and impact as a trigger of a first manic episode remain to be determined. Thus, several studies have reported on the high use of cannabis among adolescents and young adults worldwide. For example, an average life-time use of 19% for cannabis was reported for adolescents aged 15–16 years in 35 countries around the world (Hibell et al., 2009). On one hand, there is very limited data on the neurobiological mechanisms underlying cannabis effect on psychiatric disorders. On the other hand, longitudinal data have consistently shown that substance use mostly precedes the onset of bipolar disorder. However, the causal direction of the relationship (cannabis use as a cause or a consequence of the psychiatric symptomatology) remains a matter of debate. Cannabis contains over 60 cannabinoids, including cannabidiol (CBD), cannabigerol (CBG) and cannabinol (CBN) (Greydanus et al., 2013). Cannabinoids bind to G-protein-coupled receptors, CB1 essentially, widely distributed in the brain. CB1 receptors are located on presynaptic terminals which release GABA, glutamate and other neurotransmitters (Howlett et al., 2002). Cannabinoids activating these receptors inhibit neurotransmitter release and synaptic transmission (Freund et al., 2003). In the human brain, endocannabinoids like anandamide and 2-arachidonylglycerol (2-AG) are the natural ligands for these receptors (Mechoulam and Parker, 2013). The short-term effects of delta-9-tetrahydrocannabinol (THC), the principal active compound of cannabis, include euphoria, disinhibition, altered perceptions, increased appetite, and cognitive deficits (Iversen, 2000). In healthy subjects, intravenous delta9-THC has been shown to induce psychotic symptoms such as paranoia, dysfunctional thinking and perceptual alterations including hallucinations (D’Souza et al., 2004). THC enhances mesolimbic dopaminergic activity, which is known to be correlated to its addiction promoting effects (Di Chiara, 1995; Oleson and Cheer, 2012). In addition, an hyperactivity of these pathways has been implicated in both psychosis and mania (Carlsson, 1988; Coque et al., 2011). Cortical glutamate levels, which also seem to play a significant role in acute mania, have also been found to be increased by THC (van Laar et al., 2007). Cannabidiol (CBD), a major cannabinoid present in cannabis plants, lacks the psychotomimetic effects of THC. Interestingly,
it can antagonize THC effects and several pre-clinical and clinical studies have reported anti-anxiety and antipsychotic properties (Ashton et al., 2005; Campos et al., 2013). The anxiolytic effect of CBD is milder than the one of diazepam (Mechoulam and Hanus, 2004) but can possibly be sufficient to explain the symptom relief referred by some patients using cannabis on a regular basis. One hypothesis states that cannabis effect on psychiatric symptoms can depend on the CBD/THC ratio (Di Forti et al., 2009). To date, there is good evidence based data, including longitudinal studies pointing to a causal relationship between cannabis use and onset of psychotic illness (Burns, 2013). For example, it was noticed that age at onset of positive symptoms in schizophrenia was younger for subjects using cannabis (Donoghue et al., 2014; Sevy et al., 2010). In contrast, information about a potential role and impact of cannabis on a first manic episode is still scarce, even if onset of manic symptoms seems to be associated with cannabis use in young patients (Sevy et al., 2010; Stone et al., 2014). So far, only a few longitudinal studies have associated cannabis use with the expression of manic symptoms, mostly among patients with an already established diagnosis of bipolar disorder. One such example is the study by Henquet et al. (2006) who interviewed and followed for 3 years 4815 subjects randomly selected in the general population and also assessed lifetime use of psychostimulants and alcohol use at baseline. However, based on clinical experience, beliefs and attitude of psychiatrists regarding the risk and consequences of cannabis consumption among psychiatric patients are mostly pessimistic. For example, in a survey on Swiss psychiatrists, 43% of respondents believed that cannabis could potentially induce manic episodes. 70% of them viewed cannabis as a trigger for psychotic episodes (Zullino et al., 2008). This review will examine available data regarding the role of cannabis abuse on the onset of a first manic episode and on triggering bipolar disorder.
2. Methods Articles and abstracts published in English were considered for selection. Based on titles and abstracts, potentially relevant studies were identified. Full texts of these articles were analyzed for final selection. Articles published between 1972 and December 2013 were searched on Medline and PsychInfo using the following keywords: first manic episode, or onset mania, or bipolar disorder and cannabis. Articles were selected considering their relevance for the questions (subtitles in the results section) addressed in our review. A total of 163 publications were identified through PubMed. Out of this first selection, 53 were considered to be relevant for our review (prospective and retrospective studies, survey, case reports and reviews). Relevant papers cited in the references of selected articles were further considered for inclusion into the review.
3. Results 3.1. Cannabis use frequency in bipolar disorder Among mood disorders, mania has the highest lifetime prevalence of comorbid substance use disorders (Sherwood Brown et al., 2001), with 40% prevalence of SUD among bipolar I and around 20% in bipolar II patients (Cerullo and Strakowski, 2007). Around 30% of bipolar patients have a diagnosis of cannabis abuse or dependence (Agrawal et al., 2011) and lifetime use of cannabis has
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been found in 70% of bipolar patients. Bipolar II disorder seems to be less studied and fewer results appear for it on articles observing comorbidity between bipolar disorders and substance abuse. Bipolar I and II disorders were often considered together in studies. Risks factors such as male sex (Cotton et al., 2013), poor education, or other comorbidity on Axis I (Sonne et al., 1994) have been reported for substance abuse in bipolar patients. We cannot exclude other risk factors such as a birth cohort effect. As pointed by da Silva Magalhaes et al. (2009), substance use disorders may be rising in bipolar disorder. However, some data also suggest that prevalence of cannabis dependence has not changed from 1990 until 2008 in a study by Degenhardt et al., 2013 3.2. Cannabis use or dependence? Determining the threshold between occasional substance use and dependence may be difficult. In most papers reviewed, no explicit precise criteria were given to clarify the extent of substance use or misuse. In the majority of studies selected for our review, the term abuse refers to DSM IV criteria. In most north American publications, the concept of cannabis abuse was applied, without any clear definitions using the term “substance use disorder” (Cerullo and Strakowski, 2007; Duffy et al., 2012) or substance use versus abuse/dependence (Merikangas et al., 2008). Furthermore, among all the articles included in our review, very different ways of classifying cannabis abuse severity were used. For example, in the Dutch study of Henquet et al. (2006), a difference was made between: less than once a month, 1–3 days/month, 1–2 days/week, 3–4 days/week, nearly everyday. Some studies recruited patients after assessment with SCID-I/P using the substance use disorders module and the Addiction severity index (ASI) (Baethge et al., 2005; Strakowski et al., 2007). The Canadian study of Lev-Ran et al. (2013a) counted the number of joints consumed with the number of days when cannabis was used in the last 12 months. Frequency was defined as ranging from “almost daily” to “once a year”. De Hert et al. (2011) used the CIDI for lifetime substance use and classified patients as “heavy users” when consumption was several times a day. In another Dutch study, Tijssen et al. (2010) considered only patients who reported cannabis use 5 times or more on a life-time in the cannabis use variable. In the study by Lagerberg et al. (2011), “excessive cannabis use” was considered by the Norwegian authors as soon as patients met the DSM-IV substance use disorders criteria or had predominant weekly use of non-alcoholic substance through at least 4 years on one of the following lifetime periods: 11–15 years, 16–20 years, 21–27 years, 28–44 years, 45–60 years, 60 years and more. 3.3. Bipolar disorder outcome with co-occurring cannabis use In bipolar disorders, it was noticed that the age at onset of first depressive or manic episode was younger when there was cooccuring cannabis abuse (Duffy et al., 2012; Lagerberg et al., 2011) or alcohol and other substance use disorder (da Silva Magalhaes et al., 2009) and the number of depressive or manic episodes was higher (De Hert et al., 2011; Lev-Ran et al., 2013a). A majority of studies have also shown that the course of illness was more severe and the treatment compliance poorer (Agrawal et al., 2011). In bipolar I disorder, it was shown that early onset was correlated with a higher frequency of substance abuse (Leboyer et al., 2005). However, earlier age at onset of mood symptoms and association with substance abuse was not supported by all studies (Strakowski et al., 1996). Regarding the rate of cannabis abuse comorbidity and the course of illness, no significant difference was found comparing
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type I and II bipolar disorders (Bega et al., 2012). A previous study reported that bipolar I disorder had a higher rate of substance abuse (61% prevalence) than bipolar II (48% prevalence). However, this study did not differentiate between cannabis use alone or cannabis plus other substances. A contrast between cannabis use and abuse was not done (Regier et al., 1990). A review about bipolar disorder and drug abuse could not find evidence differentiating diagnosis of primary bipolar disorder from substance-induced mood disorders (Sherwood Brown et al., 2001). It was pointed out that some behavioral changes induced by substance abuse could lead to misdiagnosis of bipolar disorder. Kessler et al. (1996) found that 56% of mood disorders patients experimented mood swings before the onset of substance dependence. More recently it was pointed out that diagnosing bipolar disorder in adolescents or young adults could be quite difficult because secondary behavioral and affective symptoms induced by substance abuse could be hard to distinguish from primary mood disorder symptoms (Black et al., 2012). In adults, van Laar et al. found that use of cannabis was correlated with a more than twofold increased risk of “any mood disorder” and that correlation was the strongest with bipolar disorder, with an odds ratio of 4.98 (van Laar et al., 2007). The outcome was considered poorer with greater functional impairment and the risk of rapid cycling disorders increased (Duffy et al., 2012; Strakowski et al., 2007). It was also reported that the risk of substance abuse comorbidity was higher for rapidcycling patients or mixed manic patients (Himmelhoch et al., 1976; McElroy et al., 1992; Sonne et al., 1994). However, Agrawal et al. (2011) did not find a statistically significant increase of the rapid cycling risk, but more frequent mixed episodes in patients with cannabis use disorders. Lev-Ran et al. (2013b) noticed a more severe course of illness in bipolar patients with a comorbidity of cannabis abuse and poorer treatment outcomes. In the University of Cincinnati First-Episode Mania Study, it appeared that duration of cannabis abuse was closely related with duration of manic episode (Cerullo and Strakowski, 2007). A cannabis “dose-response” relationship was suggested for at least weekly use of cannabis, where an increased risk of bipolar disorder was observed. However a daily consumption failed to be significant for any relationship in terms of risk level. Finally, a recent study showed that cannabis users who changed the frequency or stopped the use of cannabis after first hospitalization had a greater improvement in symptoms at one year follow-up compared to those who did not reduce their consumption (Stone et al., 2014). 3.4. Cognitive and clinical observations It was observed that cannabis was correlated with cognitive impairments in heavy users, but there is only few information about neurocognitive effects of cannabis in patients with bipolar disorder. A recent retrospective study found puzzling results, where a significant better neurocognitive functioning was observed among bipolar patients abusing cannabis. Measures such as attention, processing speed and working memories were significantly better than those in non-cannabis users (Braga et al., 2012). This was already suggested by a previous study, showing a better verbal fluency performance among bipolar patients with a comorbidity of cannabis abuse (Ringen et al., 2010). Thus, these findings suggest that cannabis might have a positive effect on cognitive function in patients with a psychiatric comorbidity. One hypothesis is that cannabis consumption needs some skills to be acquired and can select subjects with a certain level of cognition to maintain a regular consumption introducing a bias in the cohort (Braga et al., 2012). As dopamine has been correlated to salience attribution, cannabis effect on dopamine may improve related
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cognitive functions at least in a subgroup of patients. Another hypothesis can be that cannabis may trigger psychiatric symptoms in less severe psychiatric disorders. Braga et al. (2012) also found that patients with bipolar disorder and comorbidity of cannabis abuse present a higher rate of psychotic symptoms during acute episodes. Similar effects were described by van Rossum et al. (2009), in a prospective study showing that cannabis abuse by bipolar patients had a negative impact on treatment compliance, course of illness and symptoms severity. On the contrary, they found that engagement in social activities was not impaired by cannabis abuse. Very recently, it was observed that psychotic patients using cannabis had less neurodevelopmental impairment and a better cognitive function than other psychotic patients (Cunha et al., 2013). This study also showed that patients using cannabis had less brain abnormalities with lateral ventricle volume preservation and gray matter preservation. As with bipolar patients, they found that psychotic patients with cannabis use were performing better in attentional and executive skills. 3.5. Psychotic symptoms Duffy et al. showed that there was a higher risk of experimenting psychotic symptoms (26%) on a lifetime for people with substance use disorder (Duffy et al., 2012). They also noticed that minor mood disorders by teenagers and young adults predicted substance abuse disorders. In bipolar patients, it was observed that individuals using cannabis were more likely to experiment psychotic symptoms (van Rossum et al., 2009). In comparison, schizophrenia patients with cannabis abuse had been more studied. They have a poorer prognosis and a lower adhesion to treatment than non-substance using patients. Cannabis is associated with increased risks of repeated hospitalizations, violent behavior, severity of psychotic symptoms, infectious comorbidities and poorer social and living conditions of schizophrenic patients (De Hert et al., 2011). A recent meta-analysis has shown that cannabis use disorders were more common among younger male patients experiencing first psychotic episode (Koskinen et al., 2010). It was showed that cannabis use was associated with an earlier onset of psychosis (Large et al., 2011). 3.6. Cannabis use as a cause of onset mania? It has been suggested that cannabis and other substance of abuse trigger the onset of bipolar illness (De Hert et al., 2011; Strakowski et al., 1998) and more precisely mania (Daban et al., 2006; Strakowski et al., 2007). To test this hypothesis, French and American samples of patients were compared to study clinical expression of bipolar I disorder. It appeared that in the French sample, 14.1% of patients were abusing cannabis versus 38.1% for the American sample. In fact, age at onset was earlier in the American sample (18.9 years) than in the French one (25.1 years). This data thus corroborates the hypothesis of cannabis abuse contributing to lower age at onset (Etain et al., 2012). Other observations, however, contrast with this hypothesis (Escamilla et al., 2002; Strakowski et al., 1996). Agrawal et al. (2011) reported that for patients using cannabis after their first mood episode, age at onset of bipolar illness would be lower. It must be pointed out that in some of these studies, cannabis was not differentiated from other substance abuse, and abuse could include more than one substance. A prospective study of 166 first episodes bipolar I disorder with comorbidity of substance abuse, and followed for nearly 5 years, has suggested that there is a selective association of substance abuse with mood disorders. Cannabis was rather associated with
manic or hypomanic episodes and alcohol with depressive episodes. In this study, substance abuse preceded or coincided with the mood episode, but did not follow exacerbation phases which would support the causal hypothesis (Baethge et al., 2008). Other studies have considered comorbidity between cannabis abuse and bipolar disorder from a reverse point of view. It has been suggested that having any mental disorder originally is associated with increased rates of cannabis abuse (Wittchen et al., 2007). A prior notion of bipolar disorder was assumed to increase the risk of cannabis abuse disorder. For example, having experimented manic symptoms contributed to a higher risk for development of any future substance abuse (Merikangas et al., 2008). In adolescent patients, bipolar disorder represents a risk factor for later substance use disorder (Wilens et al., 1999). In a retrospective study, about half of bipolar patients related their mood disorders prior to cannabis use and it was more common to experiment a first hypomanic or manic episode before onset of cannabis use (Agrawal et al., 2011). A recent prospective study about cigarette smoking and its relationship to mood disorders has shown that 13% of adolescents developed a cannabis use disorder within 12 months following a first hospitalization for mixed or manic episodes. 89% of them had no past history of cannabis use before the considered hospitalization. The same trend was observed in adults bipolar patients (Heffner et al., 2012). The authors also concluded that smoking is associated with an increased risk of cannabis abuse disorder in adolescents with bipolar disorder, which should lead to prevention strategies and psychoeducation among bipolar adolescents. In contrast to these findings, it was suggested that substance abuse developed early in high risk subjects (e.g. having one parent with bipolar disorder), even before the first major manic episode (Duffy et al., 2012). In a naturalistic study with bipolar I and II patients, excessive cannabis use was associated with an earlier onset of bipolar disorder, whether cannabis consumption preceded or followed the mood disorder onset (Lagerberg et al., 2011). These results are in contrast to another study reporting a later onset of bipolar disorder secondary to cannabis (Strakowski et al., 2007). A direct causal relationship between cannabis use and first manic episode was not investigated in the study by Lagerberg et al., which has the limitation of retrospective gathering of substance use and illness characteristics. A potential bias to take into account when interpreting the results of the above mentioned studies is a cohort effect linked to the age at interview, since cannabis use is very frequent in adolescents and young adults in the general population. However, previously mentioned published data are controversial concerning this hypothesis (da Silva Magalhaes et al., 2009; Degenhardt et al., 2013). In summary, further investigations are needed to qualify the strength of the association between cannabis use and onset of bipolar disorder (van Laar et al., 2007). The only study which clearly associated cannabis use with onset of manic symptoms focused on risk factors predicting onset of bipolar disorder (Tijssen et al., 2010). Alcohol use was also assessed. The authors noticed that cannabis and novelty seeking were both involved in onset of manic symptoms. But novelty seeking was only predicting a transitory course, whereas cannabis was involved in an extended bipolar phenotype over time. One of the limitations of this study was the exclusion of subjects with manic or depressive symptoms at study baseline, which resulted in a loss of power.
4. Conclusion While the available literature concerning cannabis use and bipolar disorder is meager compared to data on psychosis and
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cannabis, it has lead to similar hypotheses and results. Cannabis use and abuse are undeniably correlated to different aspects of bipolar disorders but it remains difficult to draw a definite conclusion from all these studies and cannabis consumption appear to be both a cause and a consequence of early bipolar disorder onset. Indeed, the available data does not permit to decide between the various hypotheses suggested for possible causal relationships. The possible causal directions will be of some importance regarding potential preventive and/or therapeutic interventions. To confidently decide e.g. between (a) the hypothesis of cannabis triggering manic episodes and (b) cannabis being used by high-risk patients in order to attenuate prodromal symptoms, controlled exposition studies would be needed. As they are not feasible, for ethical and practical reasons, interventional trials are at least warranted in order to assess the preventive effect of cannabis smoking cessation on the supposed risks. Such data is still lacking.
Role of funding source There are no funding source.
Conflict of interest All authors declare that they have no conflict of interest.
Acknowledgment We thank Sandra Ter Pelle for her expert technical support in the preparation of this manuscript.
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Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Review
Cannabis use and first manic episode Nathalie Bally a, Daniele Zullino a, Jean-Michel Aubry b,n a
Division of Addiction Psychiatry, Department of Mental Health and Psychiatry, Geneva University Hospitals, Switzerland Mood Disorders Unit, Division of Psychiatric Specialties, Department of Mental Health and Psychiatry, Geneva University Hospitals, 20 Bis, Rue de Lausanne, CH-1201 Geneva, Switzerland
b
art ic l e i nf o
a b s t r a c t
Article history: Received 14 February 2014 Received in revised form 14 April 2014 Accepted 15 April 2014 Available online 24 April 2014
Background: Cannabis is the most commonly abused drug among patients with bipolar disorder. Available data has shown that the risk of psychotic disorders increases with the frequency and intensity of cannabis abuse. The present purpose was to review relevant studies to investigate whether cannabis use can be linked to the onset of mania in bipolar disorder. Methods: Articles published between 1972 and December 2013 were searched on Medline and PsychInfo using the following keywords: first manic episode, or onset mania, or bipolar disorder and cannabis. Relevant papers cited in the references of selected articles were further considered for inclusion into the review. Results: Lifetime use of cannabis among bipolar patients appears to be around 70% and approximately 30% of patients with a bipolar disorder present a comorbidity of cannabis abuse or dependence. Cannabis use is associated with younger age at onset of first mania and with more frequent depressive or manic episodes, although the evidence is somewhat inconsistent. Likewise cannabis consumption is related to poorer outcome and an increased risk of rapid cycling or mixed episodes. In contrast, neuro-cognitive functioning seems to be positively affected in patients with psychiatric comorbidity. While cannabis use often precedes first manic episodes, the causal direction remains to be determined. Limitations: Variations in definition of cannabis use/dependence. Lack of controlled studies limiting definite conclusions about a putative causal relationship between cannabis and onset of mania. Conclusions: Further investigations are needed to clarify the relationships between cannabis use and first manic episode. & 2014 Elsevier B.V. All rights reserved.
Keywords: Cannabis Marijuana Bipolar disorders Onset mania
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Cannabis use frequency in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Cannabis use or dependence?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Bipolar disorder outcome with co-occurring cannabis use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Cognitive and clinical observations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Psychotic symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Cannabis use as a cause of onset mania? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
n
Corresponding author. Tel.: þ 41 22 305 45 38; fax: þ 41 22 305 45 80. E-mail address: [email protected] (J.-M. Aubry).
http://dx.doi.org/10.1016/j.jad.2014.04.038 0165-0327/& 2014 Elsevier B.V. All rights reserved.
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1. Introduction Cannabis is the most widely used illegal substance in western countries, with a lifetime use reported by almost half of young adults in the USA and Canada and 32% in the European Union (Arendt et al., 2013). In the 2013 world drug report from the UN (UNODC, 2013), the annual prevalence for the use of cannabis in 15–64 years old population was 7.6% for occidental and central Europe, 10.7% for North America and 10.9% for Oceania. In a recent study on systematic reviews of epidemiological data on cannabis dependence for 187 countries worldwide, Degenhardt et al. (2013) reported that prevalence was higher in males and peaked between 20 and 24 years and in high income regions. Accumulating epidemiological data has demonstrated that the risk of psychotic disorders increases with the frequency and intensity of cannabis use (Di Forti et al., 2014; Khan and Akella, 2009; Lange et al., 2014; Leweke and Koethe, 2008; Manrique-Garcia et al., 2012). Since in psychosis it may be difficult to identify precisely the age at onset, the term psychosis mentioned in the literature usually includes a broad definition of psychotic disorders. Bipolar disorder bears the highest rate of substance abuse among mood disorders. Indeed, about 50% of patients with bipolar disorder have a lifetime comorbidity of an alcohol use disorder (AUD) and 41% of any other substance use disorder (Regier et al., 1990; Strakowski et al., 2007), cannabis being the most commonly used illegal drug among patients with bipolar disorders (Leweke and Koethe, 2008). If cannabis use often starts at a young age, its role and impact as a trigger of a first manic episode remain to be determined. Thus, several studies have reported on the high use of cannabis among adolescents and young adults worldwide. For example, an average life-time use of 19% for cannabis was reported for adolescents aged 15–16 years in 35 countries around the world (Hibell et al., 2009). On one hand, there is very limited data on the neurobiological mechanisms underlying cannabis effect on psychiatric disorders. On the other hand, longitudinal data have consistently shown that substance use mostly precedes the onset of bipolar disorder. However, the causal direction of the relationship (cannabis use as a cause or a consequence of the psychiatric symptomatology) remains a matter of debate. Cannabis contains over 60 cannabinoids, including cannabidiol (CBD), cannabigerol (CBG) and cannabinol (CBN) (Greydanus et al., 2013). Cannabinoids bind to G-protein-coupled receptors, CB1 essentially, widely distributed in the brain. CB1 receptors are located on presynaptic terminals which release GABA, glutamate and other neurotransmitters (Howlett et al., 2002). Cannabinoids activating these receptors inhibit neurotransmitter release and synaptic transmission (Freund et al., 2003). In the human brain, endocannabinoids like anandamide and 2-arachidonylglycerol (2-AG) are the natural ligands for these receptors (Mechoulam and Parker, 2013). The short-term effects of delta-9-tetrahydrocannabinol (THC), the principal active compound of cannabis, include euphoria, disinhibition, altered perceptions, increased appetite, and cognitive deficits (Iversen, 2000). In healthy subjects, intravenous delta9-THC has been shown to induce psychotic symptoms such as paranoia, dysfunctional thinking and perceptual alterations including hallucinations (D’Souza et al., 2004). THC enhances mesolimbic dopaminergic activity, which is known to be correlated to its addiction promoting effects (Di Chiara, 1995; Oleson and Cheer, 2012). In addition, an hyperactivity of these pathways has been implicated in both psychosis and mania (Carlsson, 1988; Coque et al., 2011). Cortical glutamate levels, which also seem to play a significant role in acute mania, have also been found to be increased by THC (van Laar et al., 2007). Cannabidiol (CBD), a major cannabinoid present in cannabis plants, lacks the psychotomimetic effects of THC. Interestingly,
it can antagonize THC effects and several pre-clinical and clinical studies have reported anti-anxiety and antipsychotic properties (Ashton et al., 2005; Campos et al., 2013). The anxiolytic effect of CBD is milder than the one of diazepam (Mechoulam and Hanus, 2004) but can possibly be sufficient to explain the symptom relief referred by some patients using cannabis on a regular basis. One hypothesis states that cannabis effect on psychiatric symptoms can depend on the CBD/THC ratio (Di Forti et al., 2009). To date, there is good evidence based data, including longitudinal studies pointing to a causal relationship between cannabis use and onset of psychotic illness (Burns, 2013). For example, it was noticed that age at onset of positive symptoms in schizophrenia was younger for subjects using cannabis (Donoghue et al., 2014; Sevy et al., 2010). In contrast, information about a potential role and impact of cannabis on a first manic episode is still scarce, even if onset of manic symptoms seems to be associated with cannabis use in young patients (Sevy et al., 2010; Stone et al., 2014). So far, only a few longitudinal studies have associated cannabis use with the expression of manic symptoms, mostly among patients with an already established diagnosis of bipolar disorder. One such example is the study by Henquet et al. (2006) who interviewed and followed for 3 years 4815 subjects randomly selected in the general population and also assessed lifetime use of psychostimulants and alcohol use at baseline. However, based on clinical experience, beliefs and attitude of psychiatrists regarding the risk and consequences of cannabis consumption among psychiatric patients are mostly pessimistic. For example, in a survey on Swiss psychiatrists, 43% of respondents believed that cannabis could potentially induce manic episodes. 70% of them viewed cannabis as a trigger for psychotic episodes (Zullino et al., 2008). This review will examine available data regarding the role of cannabis abuse on the onset of a first manic episode and on triggering bipolar disorder.
2. Methods Articles and abstracts published in English were considered for selection. Based on titles and abstracts, potentially relevant studies were identified. Full texts of these articles were analyzed for final selection. Articles published between 1972 and December 2013 were searched on Medline and PsychInfo using the following keywords: first manic episode, or onset mania, or bipolar disorder and cannabis. Articles were selected considering their relevance for the questions (subtitles in the results section) addressed in our review. A total of 163 publications were identified through PubMed. Out of this first selection, 53 were considered to be relevant for our review (prospective and retrospective studies, survey, case reports and reviews). Relevant papers cited in the references of selected articles were further considered for inclusion into the review.
3. Results 3.1. Cannabis use frequency in bipolar disorder Among mood disorders, mania has the highest lifetime prevalence of comorbid substance use disorders (Sherwood Brown et al., 2001), with 40% prevalence of SUD among bipolar I and around 20% in bipolar II patients (Cerullo and Strakowski, 2007). Around 30% of bipolar patients have a diagnosis of cannabis abuse or dependence (Agrawal et al., 2011) and lifetime use of cannabis has
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been found in 70% of bipolar patients. Bipolar II disorder seems to be less studied and fewer results appear for it on articles observing comorbidity between bipolar disorders and substance abuse. Bipolar I and II disorders were often considered together in studies. Risks factors such as male sex (Cotton et al., 2013), poor education, or other comorbidity on Axis I (Sonne et al., 1994) have been reported for substance abuse in bipolar patients. We cannot exclude other risk factors such as a birth cohort effect. As pointed by da Silva Magalhaes et al. (2009), substance use disorders may be rising in bipolar disorder. However, some data also suggest that prevalence of cannabis dependence has not changed from 1990 until 2008 in a study by Degenhardt et al., 2013 3.2. Cannabis use or dependence? Determining the threshold between occasional substance use and dependence may be difficult. In most papers reviewed, no explicit precise criteria were given to clarify the extent of substance use or misuse. In the majority of studies selected for our review, the term abuse refers to DSM IV criteria. In most north American publications, the concept of cannabis abuse was applied, without any clear definitions using the term “substance use disorder” (Cerullo and Strakowski, 2007; Duffy et al., 2012) or substance use versus abuse/dependence (Merikangas et al., 2008). Furthermore, among all the articles included in our review, very different ways of classifying cannabis abuse severity were used. For example, in the Dutch study of Henquet et al. (2006), a difference was made between: less than once a month, 1–3 days/month, 1–2 days/week, 3–4 days/week, nearly everyday. Some studies recruited patients after assessment with SCID-I/P using the substance use disorders module and the Addiction severity index (ASI) (Baethge et al., 2005; Strakowski et al., 2007). The Canadian study of Lev-Ran et al. (2013a) counted the number of joints consumed with the number of days when cannabis was used in the last 12 months. Frequency was defined as ranging from “almost daily” to “once a year”. De Hert et al. (2011) used the CIDI for lifetime substance use and classified patients as “heavy users” when consumption was several times a day. In another Dutch study, Tijssen et al. (2010) considered only patients who reported cannabis use 5 times or more on a life-time in the cannabis use variable. In the study by Lagerberg et al. (2011), “excessive cannabis use” was considered by the Norwegian authors as soon as patients met the DSM-IV substance use disorders criteria or had predominant weekly use of non-alcoholic substance through at least 4 years on one of the following lifetime periods: 11–15 years, 16–20 years, 21–27 years, 28–44 years, 45–60 years, 60 years and more. 3.3. Bipolar disorder outcome with co-occurring cannabis use In bipolar disorders, it was noticed that the age at onset of first depressive or manic episode was younger when there was cooccuring cannabis abuse (Duffy et al., 2012; Lagerberg et al., 2011) or alcohol and other substance use disorder (da Silva Magalhaes et al., 2009) and the number of depressive or manic episodes was higher (De Hert et al., 2011; Lev-Ran et al., 2013a). A majority of studies have also shown that the course of illness was more severe and the treatment compliance poorer (Agrawal et al., 2011). In bipolar I disorder, it was shown that early onset was correlated with a higher frequency of substance abuse (Leboyer et al., 2005). However, earlier age at onset of mood symptoms and association with substance abuse was not supported by all studies (Strakowski et al., 1996). Regarding the rate of cannabis abuse comorbidity and the course of illness, no significant difference was found comparing
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type I and II bipolar disorders (Bega et al., 2012). A previous study reported that bipolar I disorder had a higher rate of substance abuse (61% prevalence) than bipolar II (48% prevalence). However, this study did not differentiate between cannabis use alone or cannabis plus other substances. A contrast between cannabis use and abuse was not done (Regier et al., 1990). A review about bipolar disorder and drug abuse could not find evidence differentiating diagnosis of primary bipolar disorder from substance-induced mood disorders (Sherwood Brown et al., 2001). It was pointed out that some behavioral changes induced by substance abuse could lead to misdiagnosis of bipolar disorder. Kessler et al. (1996) found that 56% of mood disorders patients experimented mood swings before the onset of substance dependence. More recently it was pointed out that diagnosing bipolar disorder in adolescents or young adults could be quite difficult because secondary behavioral and affective symptoms induced by substance abuse could be hard to distinguish from primary mood disorder symptoms (Black et al., 2012). In adults, van Laar et al. found that use of cannabis was correlated with a more than twofold increased risk of “any mood disorder” and that correlation was the strongest with bipolar disorder, with an odds ratio of 4.98 (van Laar et al., 2007). The outcome was considered poorer with greater functional impairment and the risk of rapid cycling disorders increased (Duffy et al., 2012; Strakowski et al., 2007). It was also reported that the risk of substance abuse comorbidity was higher for rapidcycling patients or mixed manic patients (Himmelhoch et al., 1976; McElroy et al., 1992; Sonne et al., 1994). However, Agrawal et al. (2011) did not find a statistically significant increase of the rapid cycling risk, but more frequent mixed episodes in patients with cannabis use disorders. Lev-Ran et al. (2013b) noticed a more severe course of illness in bipolar patients with a comorbidity of cannabis abuse and poorer treatment outcomes. In the University of Cincinnati First-Episode Mania Study, it appeared that duration of cannabis abuse was closely related with duration of manic episode (Cerullo and Strakowski, 2007). A cannabis “dose-response” relationship was suggested for at least weekly use of cannabis, where an increased risk of bipolar disorder was observed. However a daily consumption failed to be significant for any relationship in terms of risk level. Finally, a recent study showed that cannabis users who changed the frequency or stopped the use of cannabis after first hospitalization had a greater improvement in symptoms at one year follow-up compared to those who did not reduce their consumption (Stone et al., 2014). 3.4. Cognitive and clinical observations It was observed that cannabis was correlated with cognitive impairments in heavy users, but there is only few information about neurocognitive effects of cannabis in patients with bipolar disorder. A recent retrospective study found puzzling results, where a significant better neurocognitive functioning was observed among bipolar patients abusing cannabis. Measures such as attention, processing speed and working memories were significantly better than those in non-cannabis users (Braga et al., 2012). This was already suggested by a previous study, showing a better verbal fluency performance among bipolar patients with a comorbidity of cannabis abuse (Ringen et al., 2010). Thus, these findings suggest that cannabis might have a positive effect on cognitive function in patients with a psychiatric comorbidity. One hypothesis is that cannabis consumption needs some skills to be acquired and can select subjects with a certain level of cognition to maintain a regular consumption introducing a bias in the cohort (Braga et al., 2012). As dopamine has been correlated to salience attribution, cannabis effect on dopamine may improve related
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cognitive functions at least in a subgroup of patients. Another hypothesis can be that cannabis may trigger psychiatric symptoms in less severe psychiatric disorders. Braga et al. (2012) also found that patients with bipolar disorder and comorbidity of cannabis abuse present a higher rate of psychotic symptoms during acute episodes. Similar effects were described by van Rossum et al. (2009), in a prospective study showing that cannabis abuse by bipolar patients had a negative impact on treatment compliance, course of illness and symptoms severity. On the contrary, they found that engagement in social activities was not impaired by cannabis abuse. Very recently, it was observed that psychotic patients using cannabis had less neurodevelopmental impairment and a better cognitive function than other psychotic patients (Cunha et al., 2013). This study also showed that patients using cannabis had less brain abnormalities with lateral ventricle volume preservation and gray matter preservation. As with bipolar patients, they found that psychotic patients with cannabis use were performing better in attentional and executive skills. 3.5. Psychotic symptoms Duffy et al. showed that there was a higher risk of experimenting psychotic symptoms (26%) on a lifetime for people with substance use disorder (Duffy et al., 2012). They also noticed that minor mood disorders by teenagers and young adults predicted substance abuse disorders. In bipolar patients, it was observed that individuals using cannabis were more likely to experiment psychotic symptoms (van Rossum et al., 2009). In comparison, schizophrenia patients with cannabis abuse had been more studied. They have a poorer prognosis and a lower adhesion to treatment than non-substance using patients. Cannabis is associated with increased risks of repeated hospitalizations, violent behavior, severity of psychotic symptoms, infectious comorbidities and poorer social and living conditions of schizophrenic patients (De Hert et al., 2011). A recent meta-analysis has shown that cannabis use disorders were more common among younger male patients experiencing first psychotic episode (Koskinen et al., 2010). It was showed that cannabis use was associated with an earlier onset of psychosis (Large et al., 2011). 3.6. Cannabis use as a cause of onset mania? It has been suggested that cannabis and other substance of abuse trigger the onset of bipolar illness (De Hert et al., 2011; Strakowski et al., 1998) and more precisely mania (Daban et al., 2006; Strakowski et al., 2007). To test this hypothesis, French and American samples of patients were compared to study clinical expression of bipolar I disorder. It appeared that in the French sample, 14.1% of patients were abusing cannabis versus 38.1% for the American sample. In fact, age at onset was earlier in the American sample (18.9 years) than in the French one (25.1 years). This data thus corroborates the hypothesis of cannabis abuse contributing to lower age at onset (Etain et al., 2012). Other observations, however, contrast with this hypothesis (Escamilla et al., 2002; Strakowski et al., 1996). Agrawal et al. (2011) reported that for patients using cannabis after their first mood episode, age at onset of bipolar illness would be lower. It must be pointed out that in some of these studies, cannabis was not differentiated from other substance abuse, and abuse could include more than one substance. A prospective study of 166 first episodes bipolar I disorder with comorbidity of substance abuse, and followed for nearly 5 years, has suggested that there is a selective association of substance abuse with mood disorders. Cannabis was rather associated with
manic or hypomanic episodes and alcohol with depressive episodes. In this study, substance abuse preceded or coincided with the mood episode, but did not follow exacerbation phases which would support the causal hypothesis (Baethge et al., 2008). Other studies have considered comorbidity between cannabis abuse and bipolar disorder from a reverse point of view. It has been suggested that having any mental disorder originally is associated with increased rates of cannabis abuse (Wittchen et al., 2007). A prior notion of bipolar disorder was assumed to increase the risk of cannabis abuse disorder. For example, having experimented manic symptoms contributed to a higher risk for development of any future substance abuse (Merikangas et al., 2008). In adolescent patients, bipolar disorder represents a risk factor for later substance use disorder (Wilens et al., 1999). In a retrospective study, about half of bipolar patients related their mood disorders prior to cannabis use and it was more common to experiment a first hypomanic or manic episode before onset of cannabis use (Agrawal et al., 2011). A recent prospective study about cigarette smoking and its relationship to mood disorders has shown that 13% of adolescents developed a cannabis use disorder within 12 months following a first hospitalization for mixed or manic episodes. 89% of them had no past history of cannabis use before the considered hospitalization. The same trend was observed in adults bipolar patients (Heffner et al., 2012). The authors also concluded that smoking is associated with an increased risk of cannabis abuse disorder in adolescents with bipolar disorder, which should lead to prevention strategies and psychoeducation among bipolar adolescents. In contrast to these findings, it was suggested that substance abuse developed early in high risk subjects (e.g. having one parent with bipolar disorder), even before the first major manic episode (Duffy et al., 2012). In a naturalistic study with bipolar I and II patients, excessive cannabis use was associated with an earlier onset of bipolar disorder, whether cannabis consumption preceded or followed the mood disorder onset (Lagerberg et al., 2011). These results are in contrast to another study reporting a later onset of bipolar disorder secondary to cannabis (Strakowski et al., 2007). A direct causal relationship between cannabis use and first manic episode was not investigated in the study by Lagerberg et al., which has the limitation of retrospective gathering of substance use and illness characteristics. A potential bias to take into account when interpreting the results of the above mentioned studies is a cohort effect linked to the age at interview, since cannabis use is very frequent in adolescents and young adults in the general population. However, previously mentioned published data are controversial concerning this hypothesis (da Silva Magalhaes et al., 2009; Degenhardt et al., 2013). In summary, further investigations are needed to qualify the strength of the association between cannabis use and onset of bipolar disorder (van Laar et al., 2007). The only study which clearly associated cannabis use with onset of manic symptoms focused on risk factors predicting onset of bipolar disorder (Tijssen et al., 2010). Alcohol use was also assessed. The authors noticed that cannabis and novelty seeking were both involved in onset of manic symptoms. But novelty seeking was only predicting a transitory course, whereas cannabis was involved in an extended bipolar phenotype over time. One of the limitations of this study was the exclusion of subjects with manic or depressive symptoms at study baseline, which resulted in a loss of power.
4. Conclusion While the available literature concerning cannabis use and bipolar disorder is meager compared to data on psychosis and
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cannabis, it has lead to similar hypotheses and results. Cannabis use and abuse are undeniably correlated to different aspects of bipolar disorders but it remains difficult to draw a definite conclusion from all these studies and cannabis consumption appear to be both a cause and a consequence of early bipolar disorder onset. Indeed, the available data does not permit to decide between the various hypotheses suggested for possible causal relationships. The possible causal directions will be of some importance regarding potential preventive and/or therapeutic interventions. To confidently decide e.g. between (a) the hypothesis of cannabis triggering manic episodes and (b) cannabis being used by high-risk patients in order to attenuate prodromal symptoms, controlled exposition studies would be needed. As they are not feasible, for ethical and practical reasons, interventional trials are at least warranted in order to assess the preventive effect of cannabis smoking cessation on the supposed risks. Such data is still lacking.
Role of funding source There are no funding source.
Conflict of interest All authors declare that they have no conflict of interest.
Acknowledgment We thank Sandra Ter Pelle for her expert technical support in the preparation of this manuscript.
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