Bipolar disorder and the endocannabinoid system

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. Summations 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. Perspectives 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.