Cannabis use is associated with an increased risk of adverse psychosocial outcomes, depression and schizophrenia, and has been shown to alter human DNA methylation. Examining cannabis-only and cannabis + tobacco users from The Christchurch Health and Development Study, we found the most significantly differentially methylated sites in cannabis + tobacco users were in the AHRR and F2RL3 genes, replicating previous studies on the effects of tobacco. Cannabis-only users had no evidence of differential methylation in these genes (P=0.97), or at any other loci at the epigenome-wide significance level (P<10-8). However, there were 521 sites differentially methylated at P<0.001. The top cannabis-only loci are in, near or interact with genes whose function is consistent with the psychosocial outcomes associated with cannabis use. We conclude that the effects of cannabis use on the mature human methylome differ from the effects of tobacco use, with further research required to further identify specific loci.