Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are critically implicated in development and maintenance of function of neurons. Neurodevelopment is reported to be impaired in schizophrenia and vulnerable schizophrenic brains may be more sensitive to toxic influences. Thus, cannabis as a neurotoxin, may be more harmful to schizophrenic brains than to non-schizophrenic brains when used chronically. And neurotoxic events may promote disease-onset and lead to exaggerated release of neurotrophins. We investigated 157 drug-naive first-episode schizophrenic patients and found significantly elevated BDNF serum concentrations (by up to 34%) in patients with chronic cannabis abuse (n = 35, p < 0.001) or multiple substance abuse (n = 20, p < 0.001) prior to disease onset. Drug-naive schizophrenic patients without cannabis consumption showed similar results to normal controls and cannabis controls without schizophrenia. Thus, raised BDNF serum levels are not related to schizophrenia and/or substance abuse itself but may reflect a cannabis-related idiosyncratic damage of the schizophrenic brain. In line with this hypothesis, disease onset was 5.2 years earlier in the cannabis-consuming group (p = 0.0111).