Fourteen states and the District of Columbia have legalized the use of cannabis for medical purposes. A small, high-quality literature supports the efficacy of medical cannabis for the treatment of neuropathic pain. The smoked botanical product, however, is associated with a number of adverse medical and psychiatric consequences. Furthermore, experimental data indicate that acute use of cannabis results in impairment of every important metric related to the safe operation of a motor vehicle. Epidemiological data show associations between recent cannabis use and both psychomotor impairment and motor vehicle crashes, associations that are strengthened by the concomitant use of alcohol and other central nervous system depressants. Finally, data from pain clinics reveals an unusually high prevalence of cannabis use in nearly all age groups and an association between cannabis use and opioid and other substance misuse. Based on available data and expert opinion, concomitant use of cannabis and opioids is an absolute contraindication to the operation of a motor vehicle. In patients who use cannabis and are prescribed opioids, heightened vigilance for opioid- and other substance-related problems is warranted. It is appropriate to refrain from prescribing opioids to individuals using medical cannabis if there is reasonable suspicion that the combination will pose a risk to the patient or others.