Context: Individual differences in cannabis sensitivity may be associated with genetic risk for psychotic disorder.
Objectives: To demonstrate and replicate, using 2 conceptually different genetic epidemiological designs, that (familial) liability to psychosis is associated with sensitivity to cannabis.
Design, setting, and participants: Sibling-control and cross-sibling comparisons using samples of patients with a psychotic disorder (n = 1120), their siblings (n = 1057), and community controls (n = 590) in the Netherlands and Flanders.
Main outcome measures: Positive and negative schizotypy using the Structured Interview for Schizotypy-Revised (for siblings and controls) and self-reported positive and negative psychotic experiences using the Community Assessment of Psychic Experiences (for siblings and patients). Cannabis use was assessed as current use (by urinalysis) and lifetime frequency of use (by Composite International Diagnostic Interview).
Results: In the sibling-control comparison, siblings displayed more than 15 times greater sensitivity to positive schizotypy associated with particularly current cannabis use by urinalysis (adjusted B = 0.197, P < .001) than controls (adjusted B = 0.013, P = .86) (P interaction = .04) and a similar difference in sensitivity to its effect on negative schizotypy (siblings: adjusted B = 0.120, P < .001; controls: B = -0.008, P = .87; P interaction = .03). Similarly, siblings exposed to cannabis resembled their patient relative nearly 10 times more closely in the positive psychotic dimension of the Community Assessment of Psychic Experiences (adjusted B = 0.278, P < .001) compared with nonexposed siblings (adjusted B = 0.025, P = .12) (P interaction < .001). No significant effect was apparent for the Community Assessment of Psychic Experiences negative domain, although the association was directionally similar (2 times more resemblance; P interaction = .17). Cross-sibling, cross-trait analyses suggested that the mechanism underlying these findings was moderation (familial risk increasing sensitivity to cannabis) rather than mediation (familial risk increasing use of cannabis).
Conclusions: Genetic risk for psychotic disorder may be expressed in part as sensitivity to the psychotomimetic effect of cannabis. Cannabis use may synergistically combine with preexisting psychosis liability to cause positive and negative symptoms of psychosis.