This study is the first to directly explore self-titration by allowing experienced e-cigarette users, habitually using high nicotine strength liquid, to vape ad libitum in the lab. The findings provide direct empirical evidence of a clear attempt to self-titrate; when given lower nicotine strength liquid, users increased their puff frequency and duration and consumed more liquid. As with tobacco smoking, compensation was partially effective; users reported equivalent reduction in urge to vape and withdrawal symptoms between conditions although blood nicotine levels were significantly higher in the high nicotine condition.

Consumption of liquid was doubled in the low versus high nicotine condition; mean puff number increased from 48.36 to 70.73 and puff duration from 3.84 to 5.20 s. These findings support the notion that users attempt to self-titrate by adjusting puffing behaviour to maximise nicotine delivery from a lower nicotine strength liquid. Indeed, indices of puffing patterns correlated positively with blood nicotine levels (with the exception of puff duration in the low nicotine condition). The phenomena of self-titration via compensatory puffing are well documented in the tobacco literature. Smokers increase puff frequency, duration and volume when switching to a lower nicotine cigarette whilst maintaining blood nicotine levels (Sutton et al. 1982). Similarly, here, although there was a fourfold reduction in the nicotine strength of the low compared with the high liquid, corresponding plasma nicotine levels were only reduced by half at 30 and 60 min, but were at the expected level at 10 min (i.e. approximately one fourth that of the high condition). Thus, compensatory puffing can be effective in raising blood nicotine levels but can take up to 30 min (at least with the concentrations used here) and, as with tobacco-smoking, does not appear to be complete (Ashton, Stepney & Thompson 1979; Russell, Wilson, Patel, Feyerabend & Cole,1975). Incomplete self-titration may be due to a ‘saturation’ effect, that is a limit on the volume of liquid that an individual can comfortably consume within a given time period, or because a given level of compensatory puffing is sufficient to achieve subjective satisfaction and alleviation of craving and withdrawal symptoms.

Indeed, despite the difference in plasma nicotine concentrations, the magnitude of craving and withdrawal symptom reduction was similar across conditions suggesting effective compensatory puffing behaviour, at least in the short term. Hit and satisfaction were generally higher in the high nicotine condition but not significantly so. There was, however, considerable individual variation and the lack of a statistically significant effect may be related to the small sample size. Effects of puffing topography associated with different nicotine strength liquids on subjective effects certainly merit further exploration. Adverse effects were uncommon and only 2 % higher in the high nicotine condition.

Although our participants demonstrate clear evidence of compensatory puffing, self-titration was far from perfect with significantly higher plasma nicotine levels in the high nicotine condition. We observed a mean plasma nicotine boost of 33.77 ng/mL in 10 min with some individuals achieving considerably higher concentrations. This level exceeds those reported by other researchers using similar (Farsalinos et al. 2014; 2015) or higher nicotine e-liquid strength (Ramôa et al. 2015) and is equivalent to that observed in tobacco smokers (Russell 1980; Russell et al. 1975) within 5 min of finishing a cigarette. The high plasma nicotine levels are likely due to a combination of the device used, our ad libitum vaping design, 12-h nicotine abstinence requirement and the nature of our participants. The Aspire Nautilus tank used here is a more advanced system with more effective nicotine delivery to the aerosol (Farsalinos et al. 2016) compared to previous studies (Farsalinos et al. 2014; 2015; Ramôa et al. 2015). We also selected participants already familiar with using higher nicotine strength liquid and who had baseline salivary cotinine levels exceeding 100 ng/mL. In fact, baseline salivary cotinine levels were very high (M: 467) similar to (indeed higher than) those typically seen in heavy smokers (334.83 ng/mL) (Russell et al. 1981). Although all participants were ex-smokers, a full smoking history and pre-quit salivary cotinine levels were not obtained so we cannot conclude whether nicotine exposure matched, exceeded or fell short of their pre-quit levels.

Our study is one of the first (Farsalinos et al. 2015) to use inbuilt EC software to capture information on puffing topography, a straightforward and arguably more ecologically valid procedure than CReSS pocket devices. However, the eVic does not capture puff flow rate and, as a safety feature, stops functioning after a 10-s puff/button press. Nevertheless, recent findings suggest that puff velocity does not influence nicotine yield (Talih et al. 2014), >10-s puffs are rare (only 1.17 % of all puffs in our study) and the CReSS device shares similar recording issues with a limit of 43 puffs. Despite methodological differences, puff durations under high and low nicotine conditions observed here are similar to those previously reported in experienced users using newer generation devices (Farsalinos et al. 2014; Hua et al. 2013) but longer than those reported for cartomiser (first-generation) devices (Behar, Hua, & Talbot 2015) and tobacco cigarettes (Hua et al. 2013). Our study was conducted in a controlled laboratory environment which may not reflect real-world puffing behaviour (Robinson et al. 2015) possibly over-estimating puffing. Indeed, the self-reported daily millilitre usually consumed (mean 4.09 ± 1.79; see Table 1) supports this notion, although the 12-h abstinence period may have also contributed to the intense puffing patterns as participants strive to raise fallen nicotine levels. Similarly, the fixed device settings imposed here reflect standard second-generation devices and allow a high degree of experimental control, but may not reflect how experienced third-generation e-cigarette users behave.

To conclude, vapers may opt for, or switch to, lower nicotine strength liquid for a variety of reasons: the belief that it is healthier, weaning off nicotine or due to the implementation of the EU Tobacco Products Directive (TPD). Our data suggest that experienced users tend to adjust their puffing patterns when switching to a lower nicotine liquid, maintaining adequate subjective effects, satisfaction and hit. It also suggests that very high nicotine levels are not absolutely necessary for alleviation of craving or withdrawal at least in acute conditions in the laboratory. Compensatory puffing patterns, however, cannot fully compensate for the low nicotine delivery and increased puffing frequency results in increased costs and more frequent refills. Those currently using nicotine levels exceeding 20 mg/mL will be obliged to switch to lower nicotine strength liquids with the implementation of the TPD from May 2016. Our results suggest that such individuals will increase their liquid consumption. If health risk is related to dose and longer, more frequent puffing is associated with higher temperatures, this is likely to increase risk of exposure to potential toxins and carcinogens (Kośmider et al. 2014) although exposure is still likely to be considerably lower than from cigarette smoke. Electronic cigarettes have seen an unprecedented evolution in technology over the last 5 to 6 years. Here, using 24 mg/mL nicotine strength liquid, we observed high blood nicotine levels achieved very quickly, matching and even exceeding those reported in tobacco smokers. Although it may be at the detriment of continued nicotine dependence, such effective nicotine delivery may be important to increase the appeal of e-cigarettes and augment smoking cessation rates.