The number of patients using cannabis for therapeutic purposes is growing worldwide. While research regarding the treatment of certain diseases/disorders with cannabis and cannabinoids is also expanding, only a few longitudinal studies have assessed the mid-term impacts of medical cannabis use on psychological variables and quality of life (QoL). The aim of the study was to assess the psychological safety and QoL of patients with chronic diseases who self-medicate with cannabis over time. We recruited patients with various chronic diseases who use cannabis and collected data regarding patterns of cannabis use as well as mental health, personality and QoL. Participants were followed-up at baseline, 4, 8 and 12 months. Hair analysis was conducted to confirm the presence of cannabinoids. Personality assessment showed a consistent decrease in self-transcendence and self-directedness scores. Neither cognitive nor psychopathological deterioration was found. There were also no variations in QoL. Mid-term use of medical cannabis seems to show adequate tolerability regarding cognitive and psychopathological abilities, and it may help patients with chronic diseases to maintain an acceptable QoL.