Bipolar disorder and the endocannabinoid system, Shokouh Arjmand et al., 2019

Bipolar disorder and the endocannabinoid system

Shokouh Arjmand, Mina Behzadi, Kristi A. Kohlmeier, Shahrzad Mazhari, Abdolreza Sabahi and Mohammad Shabani

Acta Neuropsychiatrica, 2019, 1-9.



Objective : Bipolar disorder (BD) is a debilitating, lifelong neuropsychiatric illness characterised by unsteady mood states which vacillate from (hypo)mania to depression. Despite the availability of pharmaceutical agents which can be effective in ameliorating the acute affective symptoms and prevent episodic relapse, BD is inadequately treated in a subset of patients. The endocannabinoid system (ECS) is known to exert neuromodulatory effects on other neurotransmitter systems critical in governing emotions. Several studies ranging from clinical to molecular, as well as anecdotal evidence, have placed a spotlight on the potential role of the ECS in the pathophysiology of BD. In this perspective, we present advantages and disadvantages of cannabis use in the management of illness course of BD and provide mechanistic insights into how this system might contribute to the pathophysiology of BD.

Results : We highlight the putative role of selective cannabinoid receptor 2 (CB2) agonists in BD and briefly discuss findings which provide a rationale for targeting the ECS to assuage the symptoms of BD. Further, data encourage basic and clinical studies to determine how cannabis and cannabinoids (CBs) can affect mood and to investigate emerging CB-based options as probable treatment approaches.

Conclusion : The probable role of the ECS has been almost neglected in BD; however, from data available which suggest a role of ECS in mood control, it is justified to support conducting comprehensive studies to determine whether ECS manipulation could positively affect BD. Based on the limited available data, we suggest that activation of CB2 may stabilise mood in this disorder.

Key words : bipolar disorder; cannabis; cannabinoid receptors; inflammation


• Bipolar disorder (BD) may be a disorder of the entire body and not just the brain.
• Cannabis can affect age of onset of BD, severity, and the number of affective episodes. Both arachidonic acid (AA) and inflammatory mediators can play a part in the pathophysiology of BD.
• A proposed new treatment strategy of selective activation of cannabinoid receptor 2 (CB2) and antagonism of cannabinoid receptor 1 (CB1) may alleviate the symptoms of BD and should be rigorously explored.


1. The role of endocannabinoid system (ECS) in mood control and BD is suggested based on scant available data; however, data from these studies warrant more comprehensive studies, which are essential to empirically test whether ECS is involved in mood and to determine the mechanisms of action for ECS in regulation of affect. Although there is a surge in research on CBs, the possible role of the ECS in neuropsychiatric disorders, especially BD, has almost been neglected. Thus, there is an unmet need for conducting more clinical investigations of agents which affect the ECS in bipolar patients in order to pursue other treatment strategies than those currently available to normalise mood.

2. The lipophilic nature of the CB ligands, as well as their long biological half-life, confers the ability to cross the blood–brain barrier easily. Further, their high therapeutic index reduces the risk of overdose in BD patients which is highly relevant in the management of the BD population.

3. Selective activation of CB2 could provide mood stabilisation by suppressing AA turn over, which is a mechanism common to various types of currently available mood stabilisers.


Bipolar disorder (BD) is a debilitating lifelong neuropsychiatric disorder that is characterised by unstable high and low episodes of moods which swing between the extremes of (hypo)mania and depression. Extremes in the mood state tend to alternate in a cycle and are usually punctuated by periods of remission (Oswald et al., 2007; Fagiolini et al., 2013; Arjmand et al., 2017). BD takes a heavy toll and influences most aspects of the life of those who suffer from this disease with negative effects on their personal relationships, their social interactions, their performance in the workplace, and their ability to pursue educational goals (Leclerc et al., 2013).

Lithium is a commonly used approach in the pharmacological toolbox for the management of BD, which remains popular some 70 years after its introduction. Along with this gold standard treatment approach, other mood stabilisers including sodium valproate, carbamazepine, lamotrigine, and atypical antipsychotics, such as quetiapine and olanzapine, have been broadly used to alleviate the symptoms of both (hypo)mania and depression (Ashton et al., 2005; Shorter, 2009; Rapoport, 2014; Sportiche et al., 2016). Despite possessing a wide range of compounds with diverse mechanisms of action with which to ameliorate the acute affective symptoms and preclude episodic relapse, BD is sometimes inadequately treated (Ashton et al., 2005).

Both serotonergic (Burokas et al., 2014) and dopaminergic transmissions play a prominent role in the pathophysiology of neuropsychiatric disorders, and the fact that these systems are modulated by the endocannabinoid system (ECS) suggests examination of this system to potentially facilitate developing a new target to better control mental illnesses including BD (Van Der Stelt & Di Marzo, 2003; Arjmand et al., 2017; Ashok et al., 2017).

The ECS is comprised of cannabinoid (CB) receptors, endogenous lipid ligands, as well as enzymes which are in charge of both endocannabinoid synthesis and degradation that together play a neuromodulatory role in the central nervous system (CNS) (Arjmand et al., 2015; Lu & Mackie, 2016). CB receptors are in a class of G protein-coupled receptors and are divided into two main subtypes, CB receptor types 1 and 2 (CB1 and CB2, respectively) (Arjmand et al., 2015; Lu & Mackie, 2016). CB1 receptors are ubiquitous in the CNS and are located pre- and postsynaptically on neurons, whereas CB2 receptors were originally thought to occur only in the periphery and to be located on monocytes, macrophages, B cells, and T cells, where they played a role in immune system functions (Arjmand et al., 2015; Lu & Mackie, 2016). However, recent evidence indicates that CB2 receptors are present in the brain, albeit to a lesser extent than the CB1 receptors (Atwood & Mackie, 2010). These receptors have been detected in microglia and therefore play a role in the brain’s immune system, and there are reports showing that in pathological conditions their presence is enhanced (Viscomi et al., 2009; Lu & Mackie, 2016).

The ECS and signaling pathways to which the system is coupled have emerged to be of key importance in the regulation of processes underlying executive function, including emotion, reward, learning, and memory (Vinod & Hungund, 2006; Roche & Finn, 2010; Haghani et al., 2012; Wei & Piomelli, 2015; Abbassian et al., 2016). The ubiquitous neural presence ofCB receptors, particularly CB1 receptors, means they are present in brain areas which are involved in mood disorders such as the hippocampus, cerebellum, basal ganglia, and cortex. The localisation of the ECS system, when coupled with the well-known psychoactive properties of Cannabis sativa, has encouraged a dramatic peak of research to truly understand the role this intricate system plays in mental illnesses (Vinod & Hungund, 2005, 2006; Carvalho & Van Bockstaele, 2012; Esteban & García-Sevilla, 2012; Hillard et al., 2012).