In this study, the prevalence of NSS was 83.6%, given the threshold score of 9.5 suggested by the NSS scale authors [43]. Studies that evaluated patients with first-episode psychosis reported a high prevalence of NSS, ranging from 20% for the Scottish Schizophrenia Research Group [9] to 97.1% for Browne et al. [4] (Table 6).

In this study, we examined the relationship between cannabis use and NSS in FEP patients; cannabis users had significantly fewer NSS than patients without a history of cannabis use. This findings were similar to those reported by Ruiz-Veguilla et al. [36] who studied cannabis use and NSS among 92 patients with FEP (64% males, mean age: 26.9 ± 10.1 years old). The authors found that heavy cannabis users (55% of the sample of the study) had significantly less NSS assesses with the Neurological Evaluation Scale independent of potential confounders, such as sex, age, family history of psychosis, and negative symptoms [36]. A similar association was also found by Stirling et al. [37] in a sample of 112 non-depressed FEP patients (56.2% males, mean age: 26.3 years old) with 38% of cannabis users. Other studies demonstrated a lower NSS scores for patients with chronic schizophrenia and a history of cannabis use than for those without cannabis use. For example, Bersani et al. [45] investigated NSS in 25 male cannabis-consuming and 25 male non-consuming schizophrenia patients, using the Neurological Evaluation Scale and concluded that non-consuming patients showed a higher incidence of NSS. Joyal et al. [35], in a study of 16 men with and 14 men without a dual diagnosis of drug abuse and schizophrenia, reported that drug abuse was associated to fewer frontal soft signs.

Three possible explanations are suggested for this seemingly paradoxical relationship between cannabis use and NSS in FEP. First, some cannabis components may have neuroprotective effects by inhibiting the glutamatergic excitotoxicity system [46, 47]. Second, this association could be explained by the fact that cannabis would act more directly on the onset of psychosis in genetically less vulnerable individuals [19, 48] since NSS are shown to reflect a genetic liability to psychosis. In this context, cannabis use may be the environmental factor that reveals or potentiates the vulnerability to psychosis. Accordingly, it is likely that cannabis could increase the effects of genetic risk factors for psychosis. Thus, cannabis users may follow a different pathway (with less neurobiological vulnerability factors) in developing psychotic disorders compared to patients without a history of cannabis use [36, 48]. Third, the inverse association between NSS and cannabis use could be explained by a relationship between severe NSS with other clinical characteristics that would limit a subject’s personal access to cannabis [47]. In fact, most studies that examined NSS in FEP, in concordance with the results of this study, concluded that NSS were associated with more negative symptoms [2, 49, 50], disorganization symptoms [2, 49, 50] and illness severity [2]. These illness dimensions can limit the patients’ social interaction abilities and diminish their motivation or ability to obtain cannabis.

This study also showed an inverse, but not significant relationship between the use of cannabis and both “motor coordination” (p = 0.06) and “involuntary movements” (p = 0.07) sub-scores. To our knowledge, no other study explored the interaction between cannabis use and the different sub-groups of NSS in FEP patients. The available data about this topic are restricted to studies with non-psychotic populations that showed greater impairment of motor functioning in patients with cannabis use. Dervaux et al. [51] compared the impact of cannabis use on NSS among patients with cannabis dependence and healthy controls and demonstrated that higher NSS scores were associated especially with motor coordination difficulties in cannabis users. Roser et al. [52] reported impairment in motor speed after cannabis use. These results could be explained by the important role of the endocannabinoid system in the control of movements. In fact, a prominent distribution of the cannabinoid 1 (CB1) receptors in the basal ganglia has been described in patients with movements disorders [53, 54], and cannabis, when interacting with CB1 receptors, induces dopamine release and an increase in motor response [55]. Heavy cannabis consumption may also lead to deterioration in the control system balance and thereby contribute to motor inhibition [56]. The dose-dependent response of motor coordination to cannabis may be due to the involvement of GABAergic and glutamatergic systems as a target of cannabis and its psychoactive component Delta-(9)-tetrahydrocannabinol (THC) [56], or the development of sensitization and adaptive process, which leads to dopamine decrease in prefrontal regions after repeated use [57, 58]. This finding may explain the impairment of motor skills reported over non-psychotic patients.

Conversely, however, higher cannabis consumption may produce a different response, which consists of a motor stimulation instead of inhibition depending on the adaptive mechanism put in place [47]. It is possible that this stimulatory effect could explain the inverse relation between motor coordination and cannabis in this study. Additionally, we investigated in-patients without any access to cannabis at the time of investigation. Hence, acute cannabis effects would not have been influenced our results and we assessed cannabis use more as a trait marker or risk factor for FEP. The fact that we found less motor coordination in patients with cannabis use and FEP strengthens our hypothesis that cannabis use might bring out psychosis risk in those individuals with less other neurobiological risk factors, as motor dysfunction, together with low intellectual quotient, was identified as one of the two strongest biological markers for schizophrenia risk in a recent meta-analysis [15].

There are several limitations to this study. First, the study was not based on a sample size calculation; the sample size, especially of the cannabis users, is small, although it lies within the range of similar FEP studies on this topic. Second, we did not confirm absence of cannabis use by urine screening and we did not have data regarding the exact time between the NSS evaluation and last cannabis consumption. Third, in view of the need for urgent treatment, it hasn’t been always possible to assess NSS before antipsychotic administration, which would have been better for NSS evaluation. Finally, we did not collect data on the amount of cannabis use.

This study demonstrated a negative association between cannabis use and NSS, especially regarding motor coordination. This finding supports the hypothesis that a strong environmental risk factor, such as cannabis, may contribute to the onset of psychosis even in the presence of lower biological and genetic vulnerability, as reflected indirectly by lower NSS scores. Nevertheless, due to the limitations of our study and its exploratory nature, this question remains open, and additional studies are needed to explore this interaction further. Such studies should have sufficiently large samples of cannabis users and non-users and consider cannabis and NSS in the context of additional neurobiological and environmental risk factors.