Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana’s psychoactive principle Δ(9)-tetrahydro-cannabinol), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoyl-glycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time- and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizophrenia.

Keywords : 9-tetrahydrocannabinol, animal models, antipsychotics, cannabidiol, cannabis, CB receptors, endocannabinoid system, schizophrenia.

1. INTRODUCTION

1.1. Current Pharmacological Approach for the Treatment of Schizophrenia

Schizophrenia (SCZ) is a chronic mental disorder affecting about 1 % of the population worldwide. It is characterized by three broad clusters of symptoms which result in enormous personal suffering, as well as social and economic burden. These symptom domains include positive symptoms such as delusions, hallucinations, disorganized speech and behaviour; negative symptoms including anhedonia and social
withdrawal; and cognitive impairments in sensory information processing, attention, working memory and executive functions [1]. They occur in different combinations, differing degrees of severity and in a changing pattern over time in each patient. Thus, SCZ is regarded as a complex and highly heterogeneous disorder. Hyperfunction of dopaminergic (DAergic) system in the mesolimbic pathway was the original tenet of the theory underlying the basis of SCZ because antipsychotic drugs blocked dopamine D2 receptors (D2Rs) and amphetamine which indirectly increases the release of dopamine (DA) exacerbated positive symptoms and thus led to the dopamine hypothesis of schizophrenia [2]. The treatment of SCZ was revolutionized more than 50 years ago with the discovery – by serendipity
rather than design – that chlorpromazine and haloperidol (called today typical neuroleptics or the first generation antipsychotics) alleviate the psychotic manifestations such as hallucinations and delusions by blocking the D2Rs. From the 1970’s the second generation or atypical antipsychotics (including clozapine, olanzapine, risperidone and aripiprazole) were developed. These drugs still act mainly by DA antagonism in the central nervous system (CNS) but their effects are mediated by serotonin receptor subtypes (5-HT2A/5- HT2c), D3R and/or D4R in addition to D2Rs. This class is also known as Multi-acting Receptor Targeted Antipsychotics (MARTA) and has less tendency to produce unwanted
extrapyramidal side effects and hyperprolactinemia [3]. Although current pharmacological armamentarium is generally effective treating positive symptoms, it is less effective in treating the negative and cognitive symptoms. In addition, it can induce several side effects resembling Parkinson’s disease (known as extrapyramidal side effects) and metabolic syndrome. Furthermore, a significant proportion of patients are refractory to the available drugs. Thus, there is a need to develop new approaches for treating SCZ and appropriate animal models for preclinical testing [4, 5]. It is well accepted that the pathophysiological mechanisms underlying SCZ cannot be explained by simple changes in monoamine signalling such as DA and 5-HT but involves more complex alterations in brain circuits including glutamate, GABA and acetylcholine [6]. Thus, all these neurotransmitters could
represent potential targets for pharmacological intervention [4]. In accordance, a driven focus on rational discovery of highly selective drugs with new mechanisms such as the glutamatergic, cholinergic neurotransmission or neuropeptidergic signalling affecting intracellular signal transduction pathways appeared in the past decade. Unfortunately, none of these drugs have reached the market yet [7]. Therefore, the partial efficacy of current pharmacological armamentarium, since approximately one third of psychotic patients are non-responders raises the central question to be addressed in this review: Should the pharmacological exploitation of the endocannabinoid system (ECS) be a promising
therapeutic approach for treatment of the behavioural dimensions which are dysregulated in SCZ?

1.2. Cannabis and Schizophrenia : Clinical Evidence

Cannabis (or marijuana) is the most frequently abused illicit “recreational” substance in the Western society. Its popularity is due to its capacity to alter sensory perception, to induce euphoria and to increase sociability. Although the association between Cannabis sativa and psychopathologic conditions had been known for thousands of years, only in the last 50 years the identification of the chemical structure of marijuana components, cloning of specific cannabinoid receptors and discovery of the ECS in the brain has triggered an exponential growth of studies to explore its real effects on mental health [8, 9]. The Cannabis plant contains over 100 terpenophenolic pharmacologically active compounds,
known as cannabinoids. Of these, 9-tetrahydrocannabinol (THC), characterized in 1964 [10], was identified as the main psychoactive component of Cannabis and later shown to act as a direct agonist on cannabinoid CB1 and CB2 receptors. Other cannabinoids include cannabidiol (CBD), cannabichromene and cannabigerol which do not induce any THC-like psychoactivity. They act via several mechanisms,
including modulation of endocannabinoid system tone [11- 13], interaction with transient receptor potential vanilloid 1 (TRPV1) channels [11] and serotonin 5-HT1A receptors [14], and enhancement of adenosine signalling [15, 16]. As recently reviewed, the above mentioned mechanisms could underlie the positive effects induced by CBD treatment in preclinical and clinical studies of several disorders [17, 18].

In addition, accumulating evidence suggests that the recreational use of Cannabis during adolescence increases the relative risk for psychotic disorders. However, it is still unknown whether Cannabis use is an independent risk factor for SCZ or simply that the high prevalence of Cannabis use in SCZ patients as an attempt of self-medication due to Cannabis’s euphoric effects and increased sociability to relieve
negative symptoms [19, 20]. Furthermore its use may instead contribute as an environmental risk factor in vulnerable individuals with genetic mutation of COMT (Catechol-Omethyltransferase) enzymes [21] given that the majority of Cannabis users do not develop SCZ. Multiple lines of evidence have shown that frequent Cannabis consumption could down regulate anandamide (AEA) signalling in schizophrenic but not in healthy individuals. Also, it is associated to brain abnormalities in regions which are known to be rich in CB1 receptors such as the anterior and posterior cingulated cortex, as suggested by magnetic resonance imaging studies [22-25]. Although the exact relationship between Cannabis and SCZ is not fully elucidated, alterations of ECS elements as receptors and their endogenous activators seem to be involved in pathophysiology of SCZ. More specifically, previous studies have reported an increase in CB1 receptor binding in prefrontal area of brains from schizophrenic patients [26-31]. However, other studies failed to demonstrate any alteration [32] or reduction of CB1 density on the neuronal surface [33] and CB1 mRNA expression [34]. This contradiction might result from other neuroplastic alterations which further complicate the situation as another study detected lower CB1 receptor density but no differences on the level of CB1 mRNA expression [35]. Although several confounding factors such as Cannabis consumption, treatment with antipsychotics or different biochemical techniques used for the determination of CB1 receptors density and proteosynthesis might explain the apparent opposite results;
in general, the presence of a dysfunction in CB1 receptors in selected brain regions of patients is supported. Furthermore, polymorphisms in the CB1 receptor gene CNR1, which could be correlated with an increased probability to develop psychosis, have also been described. Yet, the data are still controversial [23, 36-39].

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