psychosis and cannabis use have been linked for a long time in the scientific literature. However, this relationship is not easy to understand due to the complexity of the disease itself and the existing limitations of the scientific methodology to study such a relationship. Cannabis has been proposed as the cause of psychosis, but at the same time, psychosis has been proposed as the cause of cannabis use. Also, the relationship between both traits could be bidirectional as suggested by Degenhardt et al. (2018). Currently, there are three main hypothesis trying to explain this relationship (Gage et al., 2015).
The first hypothesis supports the idea of cannabis being a factor for Schizophrenia development in subjects with genetic vulnerability for the disease (Caspi and Moffitt, 2006; Caspi et al., 2005; Gleason et al., 2012; Henquet et al., 2006; O’Tuathaigh et al., 2010). Studies have shown that cannabis use can lead to psychotic symptoms and its use during adolescence has also been related to psychotic disorder development (Bossong and Niesink, 2010; Le Bec et al., 2009; Rehman and Farooq, 2007).
Shahzade et al. (2018) suggest that the type of use of cannabis in genetic vulnerable subjects to psychosis could predict their disease outcome. Frequency of cannabis use is also considered one of the factors of Schizophrenia development and is related to an early age of onset of the disease on high frequency users (Arranz et al., 2018; Compton et al., 2009; Henquet et al., 2005; Mustonen et al., 2018). Gender could also moderate the relationship between cannabis use and the onset of psychosis (Albertella et al., 2017; Setién-Suero et al., 2017)
Use of cannabis after the first episode of psychosis has been related with a poorer prognosis of the disease (Shah et al., 2017)
Schizophrenia patients with high cannabis use before Schizophrenia onset showed higher predisposition to Schizophrenia than non users (Aas et al., 2018)
The use of cannabis before the onset of Schizophrenia has been associated with cortical thinning in the caudal middle frontal gyrus (Hartberg et al., 2018)
COMT Val158Met genotype could modulate the age of onset of psychosis in cannabis users (Lodhi et al., 2017)
Patients with cannabis-induced psychotic disorders showed similar prepulse inhibition deficits when compared to patients with Schizophrenia and cannabis abuse (Morales-Muñoz et al., 2017)
Note that since cannabis use does not affect disease rate in a population level, there is no evidence to say that cannabis is the cause of Schizophrenia in healthy subjects (Hill, 2015).
The second hypothesis supports the idea of Schizophrenia being one of the causes of cannabis use. Cannabis would be used as self-medication in Schizophrenia patients, maybe due to the antipsychotic effects of CBD and THCV or maybe due to other mechanisms related to THC (Arnold et al., 2012; Cascio et al., 2015; Zuardi et al., 2012, 2006).
In fact, cannabis use (commonly high THC) could counteract some markers and/or cognitive deficits related to Schizophrenia, while it could also increase those in healthy controls (Rentzsch et al., 2017; Roser et al., 2018).
Schizophrenia has been previously related to impaired fronto-striatal connectivity. Oral administration of CBD (600 mg) showed improved connectivity of these areas (Grimm et al., 2018)
Cannabis use has been associated with lower reduction of total gray matter density compared to non users in a group of psychotic individuals (Abush et al., 2018).
Acute effects of cannabis use in cannabis users with high risk of psychosis showed higher psychotic effects and lower neurocognitive performance than cannabis users with lower risk of psychosis (Vadhan et al., 2017)
Moderate use of cannabis is related with lower cognitive impairment compared to low and high use of cannabis in a group of patients with Schizophrenia (Schnakenberg Martin et al., 2016)
Patients who show psychotic symptoms under the effects of cannabis need shorter interventions and/or hospitalizations than patients who did not use cannabis (Rylander et al., 2018)
However, a recent meta-analyses points in the opposite direction, showing worse cognitive functioning in patients with Schizophrenia who used cannabis compared to non-users (Bogaty et al., 2018)
The third hypothesis focuses on the possibility of shared comorbidity between Schizophrenia and cannabis use, either this comorbidity is genetic, environmental or mixed (French et al., 2015; Giordano et al., 2014; Power et al., 2014). In fact, in the last study from Pasman et al. (2018), causality from cannabis use to Schizophrenia was tested with weak evidence, in contrast to the causality from Schizophrenia to cannabis use, which had stronger evidence, suggesting that subjects with Schizophrenia have higher chances to use cannabis.
Regarding the molecular mechanisms of the comorbidity between cannabis and Schizophrenia, the endocannabinoid system has been already linked to the disease. endocannabinoids like Anandamide and 2-AG could play an important role on psychosis (Manseau and Goff, 2015).
Cannabis use has been associated with low glutamate leves in the prefrontal cortex while this has been shown also in patients with Schizophrenia (Rigucci et al., 2018)
Some studies point to an Anandamide imbalance associated to psychosis (Leweke, 2012).
In unmedicated patients with acute psychosis one of the body’s main endocannabinoids, Anandamide, is elevated 8-fold. This elevation is absent in patients on anti-psychotics and is inversely correlated with psychotic symptoms, suggesting Anandamide actually functions to suppress psychotic behavior (Giuffrida et al., 2004).
There is controversy regarding the role of the endocannabinoid receptor CB1 density, with studies showing lower density in Schizophrenia patients than in controls and vice versa. CB1 density could also be affected by antipsychotic treatment (Dean et al., 2001; Ranganathan et al., 2015).
PPAR-γ receptor has also been related to Schizophrenia (Costa et al., 2013; Liu et al., 2014).
CB1 receptor agonist THC has been reported to mimic psychotic symptoms in healthy volunteers, supporting the argument of a role of the endocannabinoid system in Schizophrenia (Bossong et al., 2014).
Long term THC exposure can sensitize 5HT2A receptors, which are related to hallucinations linked to Schizophrenia and psychosis (Ibarra-Lecue et al., 2018).
Some studies suggest that THC is the responsible of the psychosis symptoms while CBD would act as antipsychotic and anxiolytic. These effects of CBD would point to the hypothesis of self-medication as the cause of cannabis use in Schizophrenia subjects (Arnold et al., 2012; Bossong et al., 2014; Iseger and Bossong, 2015; Martin-Santos et al., 2012; Silva et al., 2015).
In an animal study, THCV was found to have anti-psychotic effects through activation of the 5-HT1A receptor (Cascio et al., 2014).
CBD acts as inverse agonist in CB1 receptor and THCV acts as an antagonist of CB1 receptor. These properties would counteract the psychotic symptoms of THC (Iseger and Bossong, 2015; Pertwee, 2005).
Cannabis use has been associated with higher cortisol levels in patients with ultra high risk of psychosis (Carol et al., 2017)
Also, activated microglia are present in Schizophrenia patients within the first 5 years of disease onset (van Berckel et al., 2008). Effects of CBD on activated microglia through PPAR-γ receptor could have also a role in Schizophrenia.
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