Penn State TCORS, VCU CSTP2, Rutgers-RWJMS2 Nicotine Dependence and Mental HHeterogeneity in acute nicotine absorption from electronic and traditional cigarettes ealth: Research at Penn State Hershey Jonathan Foulds, Jessica M. Yingst, Susan Veldheer, Shari Hrabovsky, Neil Trushin, Tom Eissenberg2, John Richie, Jill Williams3, Travis T Nichols, Stephen Wilson Penn State TCORS, VCU CSTP2, Rutgers-RWJMS2 jfoulds@psu.edu

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Penn State TCORS trial training with George Washington and Harvard teams Mass. General site visit: Dr Evins’ Team

Human Lab E-cig Sudies at PS TCORS

MRI and bench chemical analysis

Fig. 2. Overall weighted scores for each of the products Fig. 2. Overall weighted scores for each of the products. Cigarettes, with an overall harm score of 99.6, are judged to be most harmful, and followed by small cigars at 67. The heights of the colored portions indicate the part scores on each of the criteria. Product-related mortality, the upper dark red sections, are substantial contributors to those two products, and they also contribute moderately to cigars, pipes, water pipes, and smokeless unrefined. The numbers in the legend show the normalized weights on the criteria. Higher weights mean larger differences that matter between most and least harmful products on each criterion. Nutt DJ, Phillips LD, Balfour D, Curran HV, Dockrell M, Foulds J, Fagerstrom K, Letlape K, Milton A, Polosa R, Ramsey J, Sweanor D. Estimating the harms of nicotine-containing products using the MCDA approach. European Addiction Research. 2014 April; 20:218-225 link: http://www.karger.com/Article/FullText/360220

Penn State Electronic Cigarette Dependence Index 1.How many times per day do you usually use your electronic cigarette? (assume one “time” consists of around 15 puffs, or lasts around 10 minutes) __________ times per day (Scoring: 0-4 times/day = 0, 5-9 = 1, 10-14 = 2, 15-19 = 3, 20-29 = 4, 30+ = 5) 2. On days that you can use your electronic cigarette freely, how soon after you wake up do you first use your electronic cigarette? _______ minutes (Scoring: 0-5 minutes = 5, 6-15 = 4, 16-30 = 3, 31-60 = 2, 61-120 = 1, 121+ = 0) 3. Do you sometimes awaken at night to use your electronic cigarette? Yes No (Scoring: Yes = 1, No = 0) 4. If yes, how many nights per week do you typically awaken to use your electronic cigarette? _______ nights (Scoring: 0-1 nights = 0, 2-3 nights = 1, 4+ nights = 2)

7. Over the past week, how strong have the urges to use an electronic cigarette been? (check one) (Scoring: None/Slight = 0, Moderate/Strong= 1, Very Strong/Extremely Strong = 2) No urges Slight Moderate Strong Very strong Extremely strong 8. Is it hard to keep from using an electronic cigarette in places where you are not supposed to? Yes /No (Scoring: Yes = 1, No = 0) When you haven’t used an electronic cigarette for a while… OR when you tried to stop using… 9. Did you feel more irritable because you couldn’t use an electronic cigarette? Yes/No (Scoring: Yes = 1, No = 0) 10. Did you feel nervous, restless or anxious because you couldn’t use an electronic cigarette? Yes/No 11. What concentration of nicotine is in the liquid you typically use with your e-cig? ____mg/ml.

Foulds J, Veldheer S, Yingst J, Hrabovsky S, Sciamanna C, Cheng G, Maccani J, Berg A. The effect of motivational lung age feedback on short term quit rates in smokers seeking intensive group treatment: a randomized controlled trial. Drug Alcohol Dependence 2015, 153: 271-7. doi:10.1016/j.drugalcdep.2015.05.007 .

Relationship between nicotine concentration and dependence Foulds J, Veldheer S, Yingst J, Hrabovsky S, Wilson S, Nichols T, Eissenberg T. Development of a questionnaire to assess dependence on electronic cigarettes in a large sample of ex-smoker e-cig users. Nicotine and Tobacco Research 2015, February; 17(2): 186-192

Mean data for nicotine blood plasma (A) and heart rate (B) as a function of condition and time. Mean data for nicotine blood plasma (A) and heart rate (B) as a function of condition and time. X-axes, time in minutes relative to product administration; arrows, first and second product administrations. Y-axes, A, nicotine blood plasma concentration (ng/mL); B, heart rate (beats per minute); filled symbols, significant difference from baseline. An “a,” “b,” or “c” indicates that own brand was significantly different from sham, Hydro EC, or NPRO EC at that time point. A “d” indicates that Hydro EC was significantly different from sham at that time point. An “e” indicates that NPRO EC was significantly different from sham at that time point (Tukey's HSD, P < 0.05). Unidirectional error bars, 1 SE. Vansickel A R et al. Cancer Epidemiol Biomarkers Prev 2010;19:1945-1953 ©2010 by American Association for Cancer Research

Plasma nicotine concentration versus time as a function of electronic cigarette (ECIG) nicotine concentration. Plasma nicotine concentration versus time as a function of electronic cigarette (ECIG) nicotine concentration. Mean (±SEM) plasma nicotine values for 16 experienced ECIG users using ECIGs that varied by liquid nicotine concentration. Bouts consisting of ECIG use for 10 puffs with a 30 s inter-puff interval are denoted by arrows. Filled symbols indicate a significant (p<0.05) difference from 0 mg/mL ECIG liquid at that time point. Carolina P Ramôa et al. Tob Control 2016;25:e6-e9 ©2016 by BMJ Publishing Group Ltd

Plasma nicotine concentrations after 5min of ad lib electronic cigarette use at baseline and at 4-week follow-up. . Plasma nicotine concentrations after 5min of ad lib electronic cigarette use at baseline and at 4-week follow-up. Peter Hajek et al. Nicotine Tob Res 2015;17:175-179 © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

This study measured acute nicotine absorption in current e-cig users using their own device and compared it with absorption in a prior laboratory study using similar methods in traditional cigarette smokers.

There are hundreds of different types of electronic cigarettes There are hundreds of different types of electronic cigarettes. They vary by size, battery power, atomizer resistance, number of coils, liquid nicotine strength, liquid flavor, liquid type (PPG/VG) etc etc. Two broad categories are (a) First Generation/cigalikes (bottom) and Second Generation/Advanced (top)

Methods 14 current e-cig users (10 using advanced e-cigs, 4 using cigalikes) completed the acute pharmacokinetic study and are compared with 9 traditional cigarette smokers. E-cig users were required to abstain from smoked tobacco for 4 days and from all sources of nicotine for 14 hours prior to the laboratory visit and required to have an exhaled baseline CO below 8 ppm. They were instructed to take a puff on their e-cig once every 20 seconds for 10 minutes (i.e. 30 puffs). Blood samples were taken at baseline and then 1,2,4,6,8,10,12 and 15 minutes after initiation of puffing. Procedures were similar for smokers, except they smoked a cigarette as they wanted (mean 12 puffs in 5m).

Participant and Product Characteristics and main results Cigarette Smokers N= 10 E-cigarette users N=14 Cigalike Users N=4 Advanced Users N=10 p-value between advanced and cigalike users Mean Age (SD) 45.8 (11.1) 34.3 (11.5) 34.3 (11.9) 34.3 (12.0) .9945 % Male 70.0 57.1 75.0 50.0 .3932 % White 80.0 92.9 100.0 .1008 % Current Occasional Smoker - 21.4 25.0 20.0 .8368 Mean Cigarettes per day (SD) 21.5 (3.4) Mean Baseline Expired CO (in ppm) (SD) 6.0 (1.8) 3.1 (1.7) 3.0 (2.9) 3.1 (1.2) .9512 Mean number of months using e-cig (SD) 9.1 (6.7) 6.5 (0.6) 10.1 (7.8) .1800 Mean Penn State Electronic Cigarette Dependence Index Score (PSECDI) (SD) 7.4 (3.6) 8.0 (5.5) 7.2 (2.9) .7206 Mean Nicotine Concentration in E-liquid (in mg/mL) 15.9 (3.7) 17.3 (5.1) 15.4 (3.1) .4185 Mean Baseline Nicotine Level (SD) 4.9 (6.0) .81 (1.3) 1.0 (1.9) 0.7 (1.1) .7359 Mean Baseline Cotinine Level (SD) 205.4 (60.9) 142.2(103.2) 125.0 (109.9) 149.1 (105.8) .7099 Mean time smoking cigarette from first to last puff (in minutes) 5.2 (1.1) Tmax (in minutes) (SD) 6.4 (3.0) 11.5 (2.6) 10.0 (2.8) 12.1 (2.4) .1808 Cmax (in ng/mL) (SD) 25.9 (16.7) 9.0 (9.2) 2.8 (2.1) 11.5 (9.8) .0231 Mean Nicotine Boost (in ng/mL) (SD) 21.0 (13.9) 8.2 (9.2) 1.8 (0.9) 10.8 (9.8) .0177

Characteristics of E-cig devices E-cig type PID Nicotine Concentration (in mg/mL) E-liquid Brand E-liquid Flavor Composition of E-liquid Nicotine Boost Obtained 1 Advanced Joyetech eVic 12 . 50 PG/50 VG 5.9 2 Provari Provape D and D Vapor Fruit 20 PG/80 VG 18.8 3 Innokin iTaste MP 2.0 18 60 PG/40 VG 9.9 4 Aspire CF VW+ 16 Ovale Flavors Coffee 35.5 5 Vision Spinner Hostile Vapes Cinnamon Roll 25 PG/75 VG 5.5 6 SMOK T-Dux30 20 Sabor Vapors Raspberry 70 PG/30 VG 8.1 7 Vision Spinner 2 Hawaiian Punch 6.2 8 Vision XFir Namber Juice Glacier Banana 2.0 9 Cigalike Blu Vanilla 100 VG 1.4 10 Innokin iTaste MVP 2.0 Flavr Juice Blueberry 5.6 11 24 Menthol 1.8 15 iTaste VV 30 PG/70 VG 10.3 Greensmoke 100 PG 3.1 17 V2 Cig 1.0

Subjective Measures for e-cigarette users Post – Pre Score Measure Pre-Vape Mean Score Post-Vape Mean Score Post-Pre Mean Change Score p-value (difference between pre and post) Withdrawal Score 19.0 10.0 -9.0 .0319 Nervous 19.3 3.6 -15.6 .0353 Anxious 18.8 4.6 -14.2 .0368 Difficulty Concentrating 21 5.9 -15.1 .0150 Restlessness 17.7 6 -11.7 .0742 Hunger 35.2 43.1 7.9 .2171 Impatient 16.1 5.6 -10.6 .0438 Depression 4.9 1.2 -3.7 .1950 Nicotine Side Effects Score 8.0 10.6 2.6 .5390 Nauseous 5.7 7.7 2 .7349 Dizzy 16.7 9 .1344 Lightheaded 14.6 22.9 8.3 .3310 Sweaty 2.9 6.8 3.9 .5377 Headache 11.7 8.6 -3.1 .5577 Heart Pounding -4.4 .2481 Salivation 7.5 1.1 -6.4 .2049 Constipation -3.9 .1440 Craving 57.4 27.2 -30.2 .0126 Drowsiness 31.3 19.7 -11.6 .1466 Craving for sweets 13.6 -5.2 .3937

Fig. 1. Depiction of e-cigarette video (left) and electronic toothbrush video (right). Travis T. Nichols, Jonathan Foulds, Jessica M. Yingst, Susan Veldheer, Shari Hrabovsky, John Richie, Thomas Eissenberg, Stephen J. Wilson Cue-reactivity in experienced electronic cigarette users: Novel stimulus videos and a pilot fMRI study Brain Research Bulletin, 2015, Available online 23 October 2015 http://dx.doi.org/10.1016/j.brainresbull.2015.10.003

Fig. 2. Brain regions exhibiting a significant session X video condition interaction. The numbers above each brain slice denote the distance (millimeters) from the anterior commissure–posterior commissure plane in Talairach atlas space. Travis T. Nichols, Jonathan Foulds, Jessica M. Yingst, Susan Veldheer, Shari Hrabovsky, John Richie, Thomas Eissenberg, Stephen J. Wilson Cue-reactivity in experienced electronic cigarette users: Novel stimulus videos and a pilot fMRI study Brain Research Bulletin, 2015, Available online 23 October 2015 http://dx.doi.org/10.1016/j.brainresbull.2015.10.003

Conclusion: While experienced users of advanced e-cigs can obtain a rate of nicotine absorption similar to that of traditional cigarettes, most obtained lower absorption, and users of cigalike models appear to absorb very little nicotine, even when using a relatively aggressive puffing schedule. Potential regulation of e-cigs and interpretation of e-cig research should take into account the marked differences in nicotine delivery from different products.

There is no such thing as “an e-cig”. There are many different e-cigs Examples of electronic cigarette devices currently available on the market (Farsalinos and Polosa, 2014)

Acknowledgments This project was supported by the Penn State Clinical & Translational Research Institute, Pennsylvania State University CTSA (NIH/NCATS Grant Number UL1 TR000127). Additional support was provided by the Penn State Hershey Cancer Institute, the Penn State Social Science Research Institute, and the Penn State Clinical Translational Science Institute (NIH/NCRR Grant Number UL1RR033184). JF, SV, JY & SH are primarily funded by the National Institute on Drug Abuse of the National Institutes of Health and the Center for Tobacco Products of the U.S. Food and Drug Administration (under Award Numbers P50-DA- 036107-01, P50-DA-036105).   Dr. Eissenberg's effort was supported by the National Institute on Drug Abuse of the National Institutes of Health under Award Number P50DA036105 and the Center for Tobacco Products of the U.S. Food and Drug Administration. The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH, FDA, or any other funding agency.

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