There is increasing interest in investigating cannabis for behavioral symptoms in individuals with autism spectrum disorder (ASD). The potential role of dysregulated cannabinoid signaling contributing to the pathophysiology of ASD is an area of active investigation. Results from retrospective and uncontrolled trials of cannabis in subjects with ASD have been published, reporting both potential benefits and adverse effects. Here, we describe the clinical course of three young adult males with ASD who developed mania or psychosis after the consistent use of cannabidiol and delta-9-tetrahydrocannabinol. Caution should be utilized with cannabis use in individuals with ASD until large-scale, replicated randomized controlled trials demonstrating efficacy, safety and tolerability have been published.