Introduction

Cannabis is one of the oldest widespread illicit drugs among people worldwide. Cannabis counts for approximately 50% of the cases associated with psychosis, schizophrenia and schizophreniform psychosis (Shrivastava 2014). Although studies demonstrate early adolescent – onset cannabis users most vulnerable in development of later schizophrenia, however the great number of young people, who use cannabis are not associated with high risk of psychosis, indicating the hypothesis where some individuals might be genetically susceptible to its effects (Caspi 2005). Twin studies have demonstrated that cannabis use disorders are highly heritable. Nowadays there are several strategies underway that scan the genome for specific regions, genes and gene variants that affect liability to develop cannabis disorders (Agrawal and Lynskey 2009).

Tetrahydrocannabinol

The genome wide linkage studies have identified novel candidate genes, such as cannabinoid receptor 1 (CNR1) gene, which is known for its biological relevance in cannabis use disorders (Agrawal, Lynskey 2009).The biochemical mechanism by which cannabis exerts its effects on physiology and behaviour have not been understood until the constituents of cannabis were examined (Shrivastava 2014). Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) were identified as two major components of marijuana, the common name for cannabis sativa, but the principle psychoactive substance in cannabis was found to be THC (Cousijn 2011). This exogenous molecule acts as a ligand, binds to endogenous cannabinoid receptor – 1 in the brain (Figure 1) and inhibits release of glutamate into gamma–aminobutyric acidergic neurons that are involved in protection of nucleus accumbens to the ventral tegmental area. The inhibitory effects of these neurons increase release of dopamine in the striatum, which showed to be involved in the pathogenesis of psychotic symptoms (Forti 2012).Cannabinoid -1 receptors are major target of THC, which present around the body and mainly in the brain, especially in brain structures such as cerebellum, prefrontal cortex, cingulate cortex, striatum, amygdala and hippocampus (Cousijn 2011). Presence of CB2 receptors in the brain has been also demonstrated, although in the smaller proportion than CB1, but mainly found throughout the periphery of the nervous system, in t

Figure 1 The neuromodulatory mechanism of THC and endocannabinoids. THC acts at pre-synaptic CB1 receptors and inhibits calcium-gated channels, thereby inhibiting release of neurotransmitters or facilitates potassium channels, thereby facilitating the release of neurotransmitters (Marzo and Petrocellis 1997).

(Marzo and Petrocellis 1997)

he spleen and immune cells (Suarez-Pinilla 2014).

Endogenous ligands

Natural lipid-derived compounds, N –arachidonyl-ethanolamine (anandamide) and 2-archidonyl-glycerol (2-AG) among others play a major role in endocannabinoid system as physiological ligands for cannabinoid receptors. These endocannabinoids are not stored, but generated on demand and released through activation of voltage-gated calcium channels (Suarez-Pinilla 2014). The endogenous ligands have demonstrated distinct biochemical mechanisms of regulation and have found to differentiate in receptor-ligand recognition properties. Endocannabinoid system plays a critical role in maintenance of synaptic plasticity by control mechanisms of neurotransmitter release. (Malone 2010).