Finally, a study conducted in Spain among 60 patient-sibling pairs, constituted by subjects with functional psychosis in the first five years of their illness matched with a non-psychotic sibling, demonstrated that after controlling for cannabis use and neuroticism, the odds of suffering psychosis for individuals who were afflicted with a childhood trauma were 7.3 times higher than the odds for persons who did not experience a childhood trauma . Researchers indicated that those effects were independent from confounding factors such as sex, age, socio-economic status, childhood trauma and use of other drugs. This incidence was not irrelevant, as the majority of subjects exposed to both urbanicity and cannabis developed the psychosis outcome because of their co-action . The findings indicate that the interaction between cannabis use and urbanicity may represent not only an underlying mechanism of moderation but also of mediation.

After observing that individuals living in the urban environment were more likely to use cannabis at baseline than subjects from the rural area, the authors suggested than an early exposure, i.e. between the ages of 5 and 15 years, to increased social fragmentation associated with an urban environment may constitute an environmental stressor that, through epigenetic mechanisms, induces a progressive behavioral sensitization which leads ultimately to permanent neurodevelopmental alterations. This in turn may contribute to an enhanced sensitivity,later in life, to the psychotomimetic effects of cannabis . The hypothesis that cannabidiol attenuates the psychotomimetic effects of THC was postulated for the first time in 1982 by Rottanburg et al. who found anincreased prevalence of psychotic symptoms among users of cannabis with a high THC concentration and lack of CBD . At the same period, Zuardi etal. observed that the co-administration of CBD and THC significantly reduced the psychotomimetic symptoms induced by THC .

Indeed, several studies have illustrated that the co-administration of CBD and THC may alter the pharmacological actions of the later, potentiating some beneficial effects, while mitigating some of its negative side effects.Other studies have demonstrated the antipsychotic properties of cannabidiol and suggested that it can antagonize the negative impact of THC on brain functions and have protective effects against psychosis .Different preclinical studies have provided evidence of the antipsychotic activity of cannabidiol,with a pharmacological profile resembling that of haloperidol . Indeed, the effects of CBD were similar to those produced by haloperidol in a rodent model predictive of antipsychotic activity, using different doses of drugs .Interestingly, contrary to haloperidol, CBD was devoid of extrapyramidal side effects, making it a potential candidate to treat different forms of psychosis in humans.Preliminary clinical case reports also suggested that cannabidiol might exertantipsychotic properties in schizophrenic patients.The analysis of hair samples of 140 cannabis smokers demonstrated that those with low CBD/THC ratios predicted high levels of schizophrenia-like symptoms. Similarly, an association was found between the use of cannabis with high THC and low CBD content and a higher risk of developing a first psychotic episode.

In a British study conducted on 120 current cannabis smokers, 66 daily users and 54 recreational users, investigators performed hair analysis to objectively quantify levels of THC and CBD. Researchers found lower psychosis-like symptoms in subjects whose hair had CBD compared with those without CBD. However,this was observed only in recreational users who had higher levels of THC in their hair .High THC recreational cannabis users with no CBD present in their hair showed much greater levels of psychosis proneness than all other groups. They were also associated with increased depression, anxiety and recall impairments.While analysing their results, researchers indicated that a growing body of evidence suggests that cannabidiol may modulate the psychotomimetic effects of THC not only acutely in laboratory settings giving CBD and THC to healthy volunteers but also chronically in cannabis users .Considering that CBD does not interact directly with the pharmacokinetics of THC, the authors suggested that the mechanism of CBD’s modulation of the effects of THC is that CBD chronically counteracts the induction of psychotic-like symptoms by THC .

It has been demonstrated that cannabidiol modulates powerfully theme solimbic dopamine system and normalizes both acute and neuro developmentally-induced dysregulation of dopaminergic activity states associated with both positive and negative schizophrenia-like psychopathology . This ability of CBD to reverse THC induced hyperactivity of mesolimbic dopaminergictransmission confers to CBD its promising antipsychotic properties .In fact, growing pre-clinical and clinical evidence supports the therapeutic efficacy of cannabidiol in a broad range of neuropsychiatric disorders. Indeed, CBD attenuates brain damage caused by ischemic and/or neurodegenerative conditions. It also facilitates neurogenesis by acting on synaptic plasticity.