The “probable” role of Sativex in the occurrence of the psychotic symptoms presented by our patient is demonstrated by the fact that symptoms appeared after Nabiximol was introduced, and disappeared after Sativex discontinuation. A total score of 5 (probable) was obtained on the Naranjo causality scale. The CNS side effects of Nabiximols are generally mild to moderate, are usually well tolerated, and tend to disappear with continued therapy, or with reduction of initial dosage. Nevertheless, hallucinations, delusional beliefs or transient psychotic reactions have also been reported. The brain endocannabinoid (eCB) system modulates several neurobiological processes and its dysfunction is suggested to be involved in the pathophysiology of mood and drug use disorders. The psychiatric disorders related to cannabis use are mainly anxiety and depressive mood, although cannabis use has been linked with the neurobiology of schizophrenia. Indeed, the CB1 receptor-mediated signaling has been shown to play a critical role in the neural circuitry mediating mood, motivation, and emotional behaviors. Moreover, an increase in CB1 receptor levels is associated with suicide.

Although data on the role of eCB system in the pathophysiology of major depression and suicide have been reported, it remains to be clearly understood whether alterations in the CB1 receptor-mediated signaling in selective brain regions are linked to neurobehavioral disorders, including depressive mood [5].

Moreover, a possible role of the GABA transmission in the pathophysiology of mood disorders may also be hypothesizable, since Sativex also act on GABA-B receptors, which in turn have been demonstrated to modulate serotoninergic neurotransmission.

However, we are not completely able to state if Sativex alone was responsible for our patient’s psychiatric symptoms, as they could be also related to the concomitant use of baclofen and methylprednisolone. Indeed, baclofen could have a complex and indefinite action on the dopaminergic or serotoninergic system, through which mania may be induced in vulnerable subjects. Notably, many other agents, including corticosteroids, have the potential for inducing behavioral side effects.

Emerging evidence have also demonstrated a genetic contributions to the depressive disorders through family studies and molecular genetics, with specific additional events (as a new drug introduction) precipitating depressive illness in such predisposed individuals [6].

In conclusion, physicians should pay more attention when prescribing drugs to MS patients affected by spasticity, including Sativex, since neurobehavioral side effects may emerge especially in predisposed individuals.