["Addiction, EarlyView. ", "\nAbstract\n\nBackground and aims\nMandated reduction of the nicotine content of cigarettes to reduce addictiveness to minimal levels has the potential to substantially reduce combusted cigarette use and promote public health. This paper examined the hypothesis that when people who smoke cigarettes are switched to very low nicotine content (VLNC) cigarettes and provided with access to non‐combusted alternative nicotine delivery systems (ANDS), they will titrate nicotine to maintain baseline levels of nicotine intake with the use of ANDS.\n\n\nDesign\nThis is a secondary analysis of a recently published randomized clinical trial. Clinical trial number NCT03272685.\n\n\nSetting\nMulticenter clinical trial conducted in the United States.\n\n\nParticipants\n438 individuals who smoked 5 to 40 cigarettes per day, mean age 44 (range 20–73).\n\n\nIntervention\nSmokers were randomized 1:1 for 12 weeks of smoking Spectrum brand research cigarettes containing VLNC (0.4 mg nicotine/g tobacco) or normal nicotine content (15.8 mg nicotine/g, NNC). Participants purchased tobacco products from an experimental marketplace containing non‐combusted ANDS, including electronic cigarettes, nicotine replacement medications and oral nicotine products.\n\n\nMeasurements\nMeasures taken at baseline, 4, 8 and 12 weeks included cigarettes smoked per day (CPD) and measures of ANDS use, assessed using past 3‐day daily diary data, which would roughly account for nicotine intake as measured by urine total nicotine equivalents (TNE). Based on self‐report and biomarker data at weeks 4, 8 and 12, we characterized three product‐using groups of participants as cigarette‐only users, ANDS‐only users and dual users. Nicotine titration was assessed as the ratio of urine TNE at various research cigarette study weeks compared with baseline (smoking their own cigarettes). Combusted product abstinence was examined using expired carbon monoxide (CO) and adherence to smoking VLNC by urine anatabine.\n\n\nFindings\nMedian titration at 12 weeks in cigarette‐only participants was 0.84 (interquartile range 0.68–1.18) in the NNC group and 0.05 (0.01–0.12) in the VLNC group. Median titration at 12 weeks in ANDS‐only participants was 0.81 (0.69–1.16) in the NNC group and 0.89 (0.49–1.58) in the VLNC group. Median titration at 12 weeks in dual use participants was 1.0 (0.78–1.29) in the NNC group and 0.91 (0.61–1.25) in the VLNC group.\n\n\nConclusions\nMost adults who smoke, when switched to very low nicotine content cigarettes, will use available alternative nicotine delivery systems (ANDS) to supplement their intake of nicotine. Provision of ANDS appears to be associated with a high degree of nicotine titration. Making less harmful ANDS widely available may make a mandated nicotine reduction intervention more acceptable to people who smoke.\nClinical Trial Registration Details: NCT03272685.\n\n"]