Among the risk factors precipitating the onset of psychosis and worsening its outcome in adolescence and youth, substance use certainly plays a major role, and is observed to be highly prevalent both in young people with first episode of psychosis (FEP) and in subjects to be considered at clinical high risk. Cannabis is the most used recreational substance worldwide among adolescents and can produce detrimental effects on brain maturation in the pubertal period, a crucial phase for sensitization of the dopaminergic system [3]. As such, high levels of Δ-9-tetrahydrocannabinol (THC) through cannabis use increase susceptibility to impaired learning and memory recall [4], negative and positive psychotic symptoms [5], as well as the risk of developing full-blown psychosis [6]. Early, more frequent, and/or continuous high-potency cannabis exposures are associated with an augmented likelihood of developing subtle psychotic symptoms or FEP, with lifetime cannabis use being associated with poorer outcomes [7]. Additionally, smoking mixtures containing synthetic cannabinoids (SCs) have flooded the market for the last 15 years, becoming increasingly popular among people willing to experience a cannabis-like high (e.g., Spice, K2, Yucatan Fire). It soon became clear that even moderate doses of SCs may produce significant severe psychotomimetic adverse events [8]. Possible explanations for the relationship between cannabis use and psychosis have been debated for a long time, with more solid evidence of a direct effect of cannabis use in leading to the onset of psychosis and impacting on its progression, and more nuanced evidence of an inverse effect where psychosis would make the person more prone to use cannabis in an attempt to self-medicate [9].

Intriguingly, a unifying hypothesis suggests that cannabis use and psychiatric disorders, especially psychosis, notably share common neurobiological underpinnings [10]. Interestingly, schizophrenia may be preceded by neurocognitive and developmental difficulties in early childhood, and common psychotic symptoms may be phenotypically similar to manifestations occurring in autism spectrum disorders (ASDs), such as impaired social–communicative skills, repetitive stereotyped behaviors, and perceptual abnormalities [11]. In turn, autism has been widely described as a lifelong developmental disorder, whose many fundamental deficits exhibited during toddlerhood tend to improve over time, especially in less verbally compromised individuals; however, this does not indicate an evolution towards milder forms of autism, but rather a qualitative shift in the pattern of traits displayed [12]. To this end, neurodevelopmental disorders (NDDs) might be considered as part of an evolutionary trajectory that embraces, at its extreme, mental health disorders arising in late adolescence and young adulthood, such as affective and non-affective psychoses [13].

To further explore the above-mentioned neurodevelopmental continuum paradigm, we recently conducted a systematic review aimed at investigating the puzzling connection between autism and psychosis through the contribution of endocannabinoid (eCB) system modulation [14]. Overall, evidence from preclinical and clinical studies included in the systematic analysis converges on an overlapping relationship between autism and psychosis [15,16], with a potential developmental trajectory from autism to psychosis as a function of the eCB system disruption. Little evidence emerged of a diametral association between autism and psychosis, as originally stated in the 1980s [17,18]. Instead, correction of eCB system alterations was demonstrated to be crucial to mitigate several autism and schizophrenia features, thus suggesting that its modulation may provide interesting opportunities for novel treatment strategies and corroborate the possibility of a dimensional therapeutic approach for both conditions [18]. Additionally, the effects of endocannabinoid-based treatments appeared to rely on epigenetic changes across genes known to be involved in key mechanisms underlying both autism and schizophrenia [19], as well as to the shared genetic vulnerability between autism, schizophrenia, and cannabis use [20,21]. Regarding the latter, autism-related genes have been suggested to increase the liability for lifetime cannabis use [20], which in turns fuels the developmental cascade to psychosis [9]. Additionally, psychotic experiences among the general population have been reported to be sustained by genetic vulnerability for ASD, and are also more distressing in the context of a genetically perturbed eCB system [22]. Most importantly, despite some inconsistent animal and human evidence that higher-dose THC exposure may be ameliorative for behavioral disturbances in autism, the overwhelming majority of data highlight how THC/cannabis use deeply affects brain functioning and alters autism- and schizophrenia-related pathways genes [23], leading to schizophrenia-like phenotypes [18,24] and related biological alterations [25,26] in ASD individuals, possibly transitioning through an ARMS [24]. Specifically, THC exposure produces disruptive methylation effects involving several neurodevelopment- and autism-related genes [25,26], with two main implications. Firstly, the altered methylation pattern is shown to be intergenerationally inherited in brain areas, such as the nucleus accumbens, which plays a critical role in schizophrenia pathophysiology [25]. Secondly, autism candidate genes present with bivalent chromatin markings because of THC-induced methylation effects, and are more prone to subsequent disruption, possibly leading to psychosis onset later in life [26]. In other words, autistic individuals seem to show remarkable vulnerability to the pro-psychotic effects of cannabinoid exposure, which may, in addition, be transmitted to their progeny, further supporting the validity of overlapping and developmental trajectory models between autism and psychosis, as per the eCB system modulation.