1. Self-titration by experienced e- cigarette users: Blood nicotine delivery and subjective effects Lynne Dawkins (LSBU), Catherine Kimber (UEL), Mira Doig (ABS labs), Colin Feyerabend (ABS labs) and Olivia Corcoran (UEL)

2. Declarations Conducted research for e-cigarette companies (2010-2013) Consultant for pharmaceutical industry (2014) Expert witness in e-cigarette patent infringement case (2014) No funding from tobacco industry

3. Blood nicotine delivery: cigarette smoking Smoking one cigarette (5 mins): Cmax 15-30ng/mL Tmax: 5-8 mins Hukkanen, Jacob & Benowitz, (2005), Pharmacological Reviews

4. Self-Titration Hypothesis Smokers adjust their nicotine intake to maintain a personal optimal level. % difference from usual brand In cigsIn blood High nicotine cig30-40%10% Low nicotine cig50%15% Smokers compensated for about 2/3 of the difference in nicotine yields (Ashton et al., 1979, BMJ)

5. Compensatory Puffing Usual brand Low Yield Switch at Trial 3 Hammond et al. (2005) Cancer Epidemiol Biomarkers Prev 40% 12%

6. Smokers can achieve approx. 60-80% of the nicotine yield via compensatory puffing behaviour (Scherer & Lee, 2014) Mainly via taking longer, harder drags and more frequent puffs Switching to ‘light’ or reduced nicotine containing cigs doesn’t appear to reduce toxicant exposure and may even increase it.

7. E-cigs and nicotine delivery Bullen et al. (2010) Eissenberg (2010) ProductMean tmax (min) (95% CI) Mean Cmax (ng/mL) (95% CI) Usual cigarette14.3 (8.8 – 19.9)13.4 (6.5 – 20.3) 16mg e-cig19.6 (4.9 – 34.2)1.3 (0.0 – 2.6) Nicorette inhalator32.0 (18.7 – 45.3)2.1 (1.0 – 3.1) Product Mean (SEM) plasma nicotine (ng/mL) 5 mins Mean (SEM) plasma nicotine (ng/mL) 15 mins Own brand16.8 (3.4)11.2 (1.6) Hydro e-cig2.5 (0.2)2.3 (0.2) NPRO e-cig3.5 (0.5)2.8 (0.3)

8. E-cigs and nicotine delivery Nicotine boost of 4.7ng/mL after 10 mins (10 puffs). Cmax = 13.9ng/mL at 60 mins. Dawkins & Corcoran (2014) Error bars = 1SE

9. Individual nicotine levels

10. TPD Article 20 Limit on nicotine concentrations > 20mg/mL 9% use above 20mg/mL (ASH, 2016) 1/5 th of e-cig users initiated vaping with >20mg/mL nicotine concentration (Farsalinos et al., 2013)

11. Aims To explore: 1.the extent to which e-cigarette users self- titrate when given a lower nicotine concentration liquid 2.subjective effects (craving, withdrawal symptoms, positive and negative effects) and plasma nicotine concentrations between conditions (high vs. low nicotine concentration liquid)

12. Methods Participants: 11 male experienced e-cig users E-cigarette: eVic Supreme (Joyetech) with Aspire tank (Nautilus) E-liquid: 6 & 24mg/mL tobacco flavour (Halo Smokers’ Angels) Double-blind, counterbalanced

13. Measures Puffing topography: puff number, puff duration, mL consumed Mood & Physical Symptoms & Urge to Vape (West & Hajek, 2004) Positive Effects (e.g. hit, satisfaction on VAS) Negative Effects (e.g. nausea, dry mouth on VAS)

14. Procedure Blood Craving Withdrawal symptoms Blood Craving Withdrawal symptoms Puffing topography Blood Craving Withdrawal symptoms Puffing topography Blood Craving Withdrawal symptoms Puffing topography Positive & negative effects Overnight abstinence baseline 10 mins 30 mins 60 mins Pre-study Screening Salivary cotinine > 100ng/mL Ad lib vaping Repeated under high and low nicotine concentration conditions

15. Puffing topography More puffs, longer puffs and more liquid consumed in the low (6mg/mL condition (p < 0.05)

16. Blood nicotine delivery Incomplete self-titration from compensatory puffing

17. Blood nicotine/puffing topography correlations High: r = 0.85**; Low: r = 0.75** High: r = 0.56*; Low: r = 0.22 ** p < 0.01; * p < 0.05

18. Subjective effects No significant differences between conditions in urge to vape or withdrawal symptoms

19. Positive Effects Trend for higher ratings of hit and satisfaction in the high nicotine condition (p = 0.11 & p = 0.09)

20. Negative Effects ItemHigh mean (SD)Low mean (SD) Confused12.41 (14.66)7.32 (5.79) Dizzy14.91 (14.91)7.89 (6.70) Headache6.95 (7.05)7.32 (5.82) Pounding Heart6.77 (7.50)11.02 (11.85) Light Headed17.00 (16.67)12.64 (12.56) Nausea15.59 (18.13)9.14 (9.71) Vomiting5.86 (6.96)6.09 (5.55) Mouth Irritation17.81 (33.44)17.75 (23.04) Throat Irritation19.27 (27.82)14.36 (20.02) Stomach Ache8.25 (8.18)6.27 (5.75) Heartburn6.18 (7.03)6.41 (5.77) Total10.91 (8.60)8.89 (5.65) Rated on percentage scale: 0-100%; All ps > 0.09

21. Conclusions Clear evidence of compensatory puffing with lower nicotine concentration e-liquid Self-titration was partially effective… … equivalent reduction in urge to vape and withdrawal symptoms across conditions… …but significantly higher levels of blood nicotine in the high condition Very high levels of nicotine can be achieved very quickly (equivalent to smoking) under certain conditions

22. Implications Self-titration – another attractive feature of vaping? More e-liquid consumed = higher cost (Kimber et al., 2016) Advise smokers to use a higher nicotine strength liquid? Limiting nicotine concentrations in e-liquid (TPD; May 2016) not necessarily the best option. Blood nicotine levels akin to smoking may improve smoking cessation rates but prolong nicotine addiction

23. Acknowledgements Catherine Kimber Olivia Corcoran Mira Doig Colin Feyerabend Sarah Jakes Pooja Shah Neil Chauhan Lowell Edio Paul Boakes Rory Butterworth Participants