Schizophrenia is a severe neuropsychiatric disorder with heterogeneous clinical outcomes.¹ It affects people differently, as the symptoms can vary from person to person, and there are several underlying causes, most of which are as yet unknown.² Approximately one-third of patients show scarce or no response to medicines.⁴ Continued research is thus absolutely critical to advance our understanding of treatment-resistant schizophrenia.
 
Prevalence of cannabis use in schizophrenic patients is high.⁵ While the relationship between schizophrenia and the use of cannabis is not entirely understood, it is well established that cannabis use increases the risk of psychosis and triggers schizophrenia relapse.⁶ Cannabis use has also been associated with poorer disease outcomes and treatment resistance⁷, but the underlying mechanism remains unclear.
 
In a 2019 study, Arsalan et al. investigated the impact of cannabis use on schizophrenia treatment outcomes in a Pakistani cohort, where cannabis production and trafficking were widespread.⁸ The study was conducted in 230 patients in a hospital setting, where a higher proportion of schizophrenia patients had developed resistance to common antipsychotics. The rate and predictors of treatment resistance of self-reported past or current cannabis use on drug treatment were examined. Patients were divided into two groups based on therapeutic response to different doses of antipsychotics; treatment responsive and treatment-resistant. Results supported the hypothesis that cannabis use is associated with reduced effectiveness of antipsychotics⁹, however the causal link between cannabis use and schizophrenia still remains a sharply debated issue.
 
The conclusion that cannabis is linked with a poor response to antipsychotics was explained by the need for higher medication doses to individuals who were using or had used cannabis, and the additional acute intoxicant effects following cannabis use in some patients.⁸ Based on the literature, a possible explanation could be that cannabis interacts with cannabinoid receptors, which may influence the effective dopamine blockade when activated, and further affect disease’s outcome.¹⁰ The “dopamine hypothesis of schizophrenia” states that schizophrenia correlates with an overactive dopamine system in the brain and, specifically, the overactivation of D2-dopaminergic receptors.¹⁵ There are several lines of evidence suggesting a complex interaction between the cannabinoid receptor system and the dopaminergic system.¹⁰ Therefore, when the former is activated by cannabis, the latter might be overactivated and cause or exacerbate psychosis.^10,12
 
Moreover, in the Arsalan study there were distinct subgroups in the treatment-resistant schizophrenia group, as in some individuals, resistance started at onset, while in others it started later.⁸ The authors investigated how the onset of illness and treatment response were affected by the duration of untreated psychosis, age and consanguinity, all of which have been previously assessed as risk factors, but were unable to find any association between them.^13,14 The limitations to the study were insufficient data on the duration of untreated psychosis, the small sample of patients, and the lack of diagnostic and statistical manual of mental disorders for cannabis use, which is used by clinicians and psychiatrists as a standard to diagnose psychiatric illnesses.¹⁵
 
Overall, further research on larger populations and different ethnicities is required to confirm these findings. If cannabis use is a cause for treatment resistance in schizophrenia, then it could potentially become a target for treatment strategies in the future.