Patients who chronically use alcohol, marijuana or opioids, or suffer from post-traumatic stress disorder (PTSD), can be difficult to sedate with midazolam and fentanyl, and are often referred for monitored anesthesia care during endoscopy. Nurse-administered propofol continuous infusion sedation (NAPCIS), which confers the benefit of propofol-based sedation without the added expense of anesthesia, is effective and safe for sedation of healthy patients. We investigated whether NAPCIS is also effective for patients who are difficult to sedate.We performed a retrospective study of patients who underwent upper endoscopy or colonoscopy with NAPCIS at a single center from January 2018 through April 2018. We reviewed records from patients who were heavy users of alcohol (n=105), daily users of marijuana (n=267) or opioids (n=178), had a diagnosis of PTSD (n=91), or were none of these (controls, n=786). We compared mean fentanyl and propofol doses (adjusted for body weight), procedure and recovery times, procedure success rates, and adverse events.Compared with the controls, the marijuana group required higher mean adjusted sedative doses for colonoscopies (0.6 vs. 0.4 mcg/kg fentanyl and 5.0 vs. 4.7 mg/kg propofol, p≤0.025 for both) and upper endoscopies (0.8 vs. 0.3 mcg/kg fentanyl and 3.7 vs. 3.2 mg/kg propofol, p≤0.021 for both), the PTSD group required a higher dose of fentanyl for colonoscopies (0.6 vs. 0.4 mcg/kg, p=0.009), and the alcohol group required a higher dose of fentanyl for upper endoscopies (0.7 vs. 0.3 mcg/kg, p<0.001). Procedure success rates were high (95.1-100%) and did not differ significantly between the difficult to sedate groups and controls; procedure times (7.0-9.0 minutes for upper endoscopies, 21.1-22.9 minutes for colonoscopies) and recovery times (22.5-29.6 minutes) were also similar among groups. Upper endoscopies were associated with lower sedative doses and shorter procedure and recovery times than colonoscopies. Sedation-related adverse events were rare in all groups (only 26 cases total), and there were no serious complications or deaths.NAPCIS seems to be a safe and effective means of providing sedation for endoscopy to patients who may be difficult to sedate due to alcohol, marijuana or opioid use, or PTSD.