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A randomised, open-label, cross-over clinical study to evaluate the pharmacokinetic profiles of cigarettes and e-cigarettes with nicotine salt formulations in US adult smokers


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E-cigarettes containing ‘nicotine salts’ aim to increase smoker’s satisfaction by improving blood nicotine delivery and other sensory properties. Here, we evaluated the pharmacokinetic profiles and subjective effects of nicotine from two e-cigarette device platforms with varying concentrations of nicotine lactate (nicotine salt) e-liquid relative to conventional cigarettes. A randomised, open-label, cross-over clinical study was conducted in 15 healthy US adult smokers. Five different e-cigarette products were evaluated consecutively on different days after use of own brand conventional cigarette. Plasma nicotine pharmacokinetics, subjective effects, and tolerability were assessed following controlled use of the products. The rate of nicotine absorption into the bloodstream was comparable from all e-cigarettes tested and was as rapid as that for conventional cigarette. However, in all cases, nicotine delivery did not exceed that of the conventional cigarette. The pharmacokinetic profiles of nicotine salt emissions were also dependent upon the properties of the e-cigarette device. Subjective scores were numerically highest after smoking a conventional cigarette followed by the myblu 40-mg nicotine salt formulation. The rise in nicotine blood levels following use of all the tested e-cigarettes was quantified as ‘a little’ to ‘modestly’ satisfying at relieving the desire to smoke. All products were well tolerated with no notable adverse events reported. These results demonstrate that, while delivering less nicotine than a conventional cigarette, the use of nicotine salts in e-cigarettes enables cigarette-like pulmonary delivery of nicotine that reduces desire to smoke.
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Internal and Emergency Medicine
A randomised, open‑label, cross‑over clinical study toevaluate
thepharmacokinetic proles ofcigarettes ande‑cigarettes
withnicotine salt formulations inUS adult smokers
GrantO’Connell1· JohnD.Pritchard1· ChrisPrue1· JosephThompson1· ThomasVerron1· DonaldGra2·
Received: 4 October 2018 / Accepted: 2 January 2019
© The Author(s) 2019
E-cigarettes containing ‘nicotine salts’ aim to increase smoker’s satisfaction by improving blood nicotine delivery and other
sensory properties. Here, we evaluated the pharmacokinetic profiles and subjective effects of nicotine from two e-cigarette
device platforms with varying concentrations of nicotine lactate (nicotine salt) e-liquid relative to conventional cigarettes. A
randomised, open-label, cross-over clinical study was conducted in 15 healthy US adult smokers. Five different e-cigarette
products were evaluated consecutively on different days after use of own brand conventional cigarette. Plasma nicotine phar-
macokinetics, subjective effects, and tolerability were assessed following controlled use of the products. The rate of nicotine
absorption into the bloodstream was comparable from all e-cigarettes tested and was as rapid as that for conventional cigarette.
However, in all cases, nicotine delivery did not exceed that of the conventional cigarette. The pharmacokinetic profiles of
nicotine salt emissions were also dependent upon the properties of the e-cigarette device. Subjective scores were numerically
highest after smoking a conventional cigarette followed by the myblu 40-mg nicotine salt formulation. The rise in nicotine
blood levels following use of all the tested e-cigarettes was quantified as ‘a little’ to ‘modestly’ satisfying at relieving the
desire to smoke. All products were well tolerated with no notable adverse events reported. These results demonstrate that,
while delivering less nicotine than a conventional cigarette, the use of nicotine salts in e-cigarettes enables cigarette-like
pulmonary delivery of nicotine that reduces desire to smoke.
Keywords Conventional cigarette· Electronic cigarette· E-cigarette· Pharmacokinetics· Nicotine delivery· Nicotine salt·
Nicotine lactate
According to Public Health England and the Royal College
of Physicians, electronic cigarettes (e-cigarettes) are likely to
be at least 95% less harmful than conventional cigarettes [1,
2]. This view was recently reaffirmed, with a further com-
ment from Public Health England that e-cigarettes pose only
a fraction of the harms that smoking does, and that smokers
should be encouraged to switch [3]. Continuing to recognise
that complete cessation of all tobacco and nicotine use as
the best action smokers can take to improve their health,
Public Health England and the Royal College of Physicians
are clear that encouraging and assisting smokers who are
neither interested nor willing to quit smoking to switch to
using nicotine products that are substantially less harmful
than inhaled tobacco smoke is the next best option to help
stop smoking [2, 3].
A growing body of evidence suggests that e-cigarettes
can be an effective tool in helping smokers to quit smoking
[36]. E-cigarettes have become the most common quitting
aid for smokers in England, a finding supported by recent
data, suggesting that 38.2% of smokers in the last quarter
of 2017 reported using an e-cigarette in their recent quit
attempt compared with 18% using nicotine replacement
therapy (NRT) and 2.8% using Varenicline [3]. Studies
* Grant O’Connell
* Tanvir Walele
1 Imperial Brands plc, 121 Winterstoke Road,
BristolBS32LL, UK
2 Celerion Inc., 621 Rose Street, Lincoln, NE68502, USA
Internal and Emergency Medicine
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investigating abstinence rates have found that e-cigarettes
are helpful in enabling smokers to switch and subsequently
remain smoke free. For example, a 2016 report estimated
that 2.5% of smokers in England who used an e-cigarette
in their quit attempt (22,000 people) succeeded where they
would have failed if they had used nothing or a licensed
nicotine product purchased over the counter [7]. An analy-
sis of the data from the Eurobarometer 429 cross-sectional
survey, performed in a representative sample of the Euro-
pean Union 28 Member States in 2014, found that smoking
cessation with daily use of e-cigarettes was over 47% [8].
A recent study by Manzoli and colleagues followed up 236
e-cigarette users (all of whom were ex-smokers), 491 smok-
ers, and 232 dual users for 12months. They reported that
61.9% of the vapers were still abstinent from tobacco smok-
ing after 12months, compared with just 20.6% of the smok-
ers and 22.0% of the dual users, suggesting that e-cigarettes
can be effective in helping smokers abstain [9]. Research
undertaken by Polosa and colleagues has also shown that the
provision of e-cigarettes to smokers that have expressed no
prior commitment to stopping smoking is associated with a
significant reduction in smoking prevalence [10].
While there is a growing consensus that e-cigarettes
are substantially less harmful than smoking and have the
potential to generate substantial public health benefits at a
population level if significant numbers of smokers switch
from smoking to e-cigarette use [2, 3, 11, 12]; at this time,
only minority of smokers have fully switched to vaping.
For example, in the UK, there are an estimated 7.4 mil-
lion adults who continue to smoke [13]. Whilst inaccurate
beliefs on the relative harmfulness of e-cigarettes may be
deterring many smokers from even trying an e-cigarette [3],
it also suggests that currently available e-cigarettes do not
provide smokers with the sensory experience they require
from their conventional cigarettes [14]. Given the US Food
and Drug Administration (FDA) have highlighted the role of
nicotine in tobacco products, we hypothesise that the nico-
tine delivery profile of e-cigarettes may play a major role in
consumer-reported satisfaction [15].
Adapting the speed of nicotine delivery from e-ciga-
rettes may assist smokers in fully switching [16]. Nico-
tine replacement therapies (NRT) such as nicotine gums,
patches and inhalators, deliver nicotine much more slowly
and at lower doses than conventional cigarettes [3, 15, 17].
In addition to the absence of the behavioural and sensorial
aspects of the smoking experience using such products,
this may explain the limited success rate of NRT in smok-
ing cessation. Smoking abstinence using NRTs is report-
edly less than 7% after 12months [17]. There have been
number of attempts to develop an inhaled product which
would deliver nicotine through the lung and mimic the
physiological response from smoking. However, many of
them produced intolerable aversive reactions or delivered
an ineffective dose of nicotine [18]. By contrast, as e-cig-
arettes have evolved through several technical innovations,
their nicotine delivery has also improved, although it has
been shown to vary considerably across e-cigarette prod-
ucts [1921]. Under the same puffing regime, experienced
e-cigarette users can achieve greater increases in blood
nicotine levels than naïve users, albeit at a much slower
rate than achieved by smoking a conventional cigarette
[20, 22]. E-cigarette nicotine intake and delivery have also
been shown to be related to, and influenced by, user puff-
ing topographies [1, 2, 23, 24], which differ significantly
from puffing behaviours associated with smoking [25,
26]. When focussing on experienced e-cigarette users, it
has been shown that comparable or higher blood nicotine
levels can be obtained compared to smoking [27, 28]. A
recent pharmacokinetic study also found that similar doses
and speed of nicotine delivery to conventional cigarettes
can be achieved among users of more modern advanced
tank e-cigarette devices [29].
The form of nicotine ordinarily used in e-liquids is termed
as ‘freebase’ nicotine. Freebase nicotine is volatile. As a
result, when an e-cigarette aerosol is inhaled by a user, the
nicotine is more likely to off-gas from the aerosol droplets
and deposit in the mouth/upper respiratory tract, where it is
absorbed into the blood. Absorption in the oral cavity/upper
respiratory tract is slower than that with conventional ciga-
rette with pharmacokinetic studies indicating a profile which
more closely resembles NRT than a conventional cigarette
[18]. The need for more effective and appealing e-cigarette
products to provide satisfying alternatives to smoking has
led to the recent development and marketing of e-liquids
containing ‘nicotine salts’. Nicotine salts are formed by the
reaction of nicotine with a suitable acid and are less volatile
than freebase nicotine [15]. As a result, a greater fraction of
the nicotine in the salt form would be expected to remain in
inhaled aerosol droplets until the aerosol reaches the alveoli
for pulmonary absorption. For pulmonary absorption, once
deposited, nicotine salts must first dissociate into freebase
and acid, to enable the non-polar, lipid-soluble freebase
nicotine to gain cellular entry at the alveoli [15]. If nicotine
salts can more closely replicate cigarette-like nicotine deliv-
ery in the lung, they should enable switching to e-cigarettes,
therefore helping to further realise the harm reduction poten-
tial of these products.
Currently, there are limited data in the published litera-
ture available on the pharmacokinetic profiles of e-cigarettes
containing nicotine salts. Here we performed a randomised,
open-label, six-period cross-over clinical study to evaluate
the nicotine uptake from two e-cigarette device platforms
with varying concentrations of nicotine lactate (nicotine salt)
or freebase nicotine e-liquids relative to conventional ciga-
rettes in US adult smokers. In addition, subjective effects
and tolerability of the tested products were also assessed.
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Study design
This randomised, open-label, six-period crossover study
(; NCT03822546) was approved by the
Institutional Review Board of Chesapeake Research Review
(Maryland, USA) and was conducted in accordance with the
International Conference on Harmonisation (ICH) Harmo-
nised Tripartite Guideline for Good Clinical Practice (GCP)
and the Declaration of Helsinki. Up to 15 adult subjects (at
least six subjects of each sex) participated in this study which
was performed at a single clinical site (Celerion, Nebraska,
USA) in a confined setting over 6days in April 2018. All sub-
jects provided written informed consent prior to the study start.
Fifteen healthy American smokers aged 21–65years were
eligible for the study if they had smoked 10 manufactured
cigarettes (no restrictions on brand type) per day for at least
the last year. Women of child-bearing potential were eligible
only if they were using an accepted method of contraception.
All subjects had an expired carbon monoxide level of > 10ppm
at screening and tested positive for urinary cotinine (≥ 500ng/
mL). Subjects could try each product after check-in on Day 1
to ensure that they would be willing to use the products during
the pharmacokinetic evaluations. In total, subjects abstained
from using any tobacco or nicotine-containing product for at
least 18h prior to use on Day 1 (conventional cigarettes), and
thereafter were provided products at 24-h intervals.
Participants were excluded if they had a known or suspected
hypersensitivity to any component of the e-liquid formula-
tions; were taking or receiving prescription smoking cessa-
tion medicines; were willing or considering to stop smoking;
had a history or presence of clinically significant pulmonary,
cardiovascular, renal, hepatic, neurological, haematological,
endocrine, oncological, immunological or psychiatric condi-
tion that could place them at risk or interfere with the inter-
pretation of the study data; were a self-reported ‘puffer’, i.e.,
smokers who draw smoke into their mouth and throat but do
not inhale; or had a body mass index (BMI) of less than 18kg/
m2 or greater than 40kg/m2. Women who were breastfeeding
were excluded from the study.
No subjects reported previous e-cigarette use prior to
screening for the study and, thus, are considered naïve users.
Investigational products
The five e-cigarette products tested were (1) myblu pod-system
containing 25-mg nicotine (‘freebase’) tobacco flavour; (2)
myblu pod-system containing 16-mg nicotine lactate tobacco
flavour; (3) myblu pod-system containing 25-mg nicotine lac-
tate tobacco flavour; (4) myblu pod-system containing 40-mg
nicotine lactate tobacco flavour; and (5) blu PRO open system
containing 48-mg nicotine lactate tobacco flavour. The refer-
ence cigarettes, provided by the subjects, were their preferred
brand of commercially available conventional cigarette.
The e-cigarette products assessed in this study were
obtained from the US market and are manufactured by Fon-
tem Ventures B.V. (The Netherlands). The myblu device is
a rechargeable, closed pod-system e-cigarette, consisting
of two segments. A rechargeable battery section (battery
capacity, 350 mAh) and a replaceable e-liquid containing
pod (volume, 1.5mL; coil resistance, 1.3 Ω). The myblu
device delivers on average 7–8mg of aerosol per puff under
machine vaping conditions [30]. The blu PRO device is a
rechargeable, open-system e-cigarette, consisting of two
segments. A rechargeable battery section (battery capacity,
1100 mAh) and a refillable clearomiser (volume, 2.0mL;
coil resistance, 1.8 Ω). The blu PRO device delivers on aver-
age 2–3mg of aerosol per puff.
Subjects visited the study site for a screening visit within
28days prior to baseline Day 1. Screening evaluations
included physical examination, vital signs, ECG, clinical
laboratory tests (clinical chemistry, haematology, urinaly-
sis, and serology), urine drug, cotinine, and alcohol screen,
and serum pregnancy tests for females only. On Day 1,
subjects completed a trial of all investigational products
and completed the Fagerström Test for Cigarette Depend-
ence (FTCD). On Days 1–6, after overnight smoking and
nicotine abstinence, participants used the assigned product
under controlled conditions according to their randomisa-
tion sequence. On Day 1, all participants smoked a single
preferred brand of conventional cigarette (not randomised)
with puffs taken at 30-s intervals. On each of Days 2–6,
participants received their randomised assigned e-cigarette
with a fully charged battery and fresh pre-filled pod (myblu)
or clearomiser (blu PRO) and used the product for 10 inhala-
tions every 30s for 3s in duration. All product use sessions
were directly monitored by the clinic staff, who indicated to
the subjects when to start and stop puffing. All e-cigarette
products were weighed before and after use to determine the
quantity of e-liquid consumed.
Study assessments
Pharmacokinetic analysis
Plasma nicotine pharmacokinetic assessment was the pri-
mary outcome measure for this study. On each study day
(Days 1–6), 4mL of whole blood was collected 5min prior
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to and at 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, and 30min fol-
lowing the start of product use. Plasma was separated by
centrifugation within 60min of collection, aliquoted and
stored at − 20°C. The determination of plasma nicotine con-
centrations was carried out using a validated LC–MS/MS
method, over a calibration range spanning from the lower
limit of quantification of 0.200–25.0ng/mL.
The pharmacokinetic parameters determined were the
mean maximum plasma nicotine concentration (Cmax), the
median time to maximum plasma nicotine concentration
(Tmax), and the mean area under the plasma nicotine con-
centration–time curve, from time 0 to 30min (AUC
Pharmacokinetic analyses were performed using Phoe-
nix™ WinNonlin® Version 7.0.
Subjective eects
To assess the impact of the investigational products on desire
to smoke, their effects on aspects of nicotine satisfaction
and other subjective measures, responses were elicited on a
Likert-type scale with responses ranging from 1 (not at all)
to 7 (extremely). The following questions were compiled by
the clinical research organisation and were based on previ-
ous questionnaires designed to assess the effects of tobacco
product use [31, 32]: Did it make you dizzy? Did it make
you nauseous? Did you enjoy it? Did it relieve the urge to
smoke? Was it enough nicotine? Was it too much nicotine?
This assessment was made 20min after the start of product
Safety andtolerability
Safety and tolerability were assessed by the study investiga-
tor. The incidence and nature of any adverse events (AEs)
and concomitant medications throughout the study were
recorded by assessment of reported events, physical exami-
nation, monitoring of vital signs (respiratory rate, heart
rate, blood pressure, ECG, and temperature) and clinical
biochemistry tests (clinical chemistry, haematology and
Statistical analyses
Statistical summarizations were performed using SAS® Ver-
sion 9.3.
The sample size was determined adequate for nicotine
bioavailability comparisons and was selected based on simi-
lar pharmacokinetic studies on e-cigarette products [2022,
Participants were included in the pharmacokinetic pop-
ulation if they completed use of the tested investigational
product and evaluable data for the specified endpoints were
obtained. Baseline adjustments were performed. For the
subjective effects, descriptive statistics were calculated.
For AEs, investigational product use-emergent AEs are sum-
marised; an investigational product use-emergent AE was
defined as an AE that started or worsened at the time of, or
after, the first investigational product is used.
To determine whether pharmacokinetic parameters fol-
lowing use of the e-cigarette products were significantly
different from those of the conventional cigarette, a multi-
ple test comparison with a P value adjustment based on the
Westfall–Young approach was used. If the P value was less
than 0.05, the difference was considered to be statistically
significant where *P < 0.05, **P < 0.01 and ***P < 0.001.
Individual participants’ subjective scores to each investi-
gational product type were analysed by means of a non-para-
metric randomised block analysis of variance Friedman test.
Where a significant difference was observed (*P < 0.05),
post hoc comparisons were performed using a Nemenyi
test, with differences considered as statistically significant
for *P < 0.05.
Study population
Fifteen subjects were enrolled to test each investigational
product. There was one non-completer for the myblu 25mg
(freebase) and blu PRO 48mg (nicotine lactate) and two
for the myblu 25mg (nicotine lactate) which did not result
from product-related AEs. The baseline characteristics of
the subjects are summarised in Table1. No subjects reported
previous e-cigarette use prior to screening for the study.
Study product use
The mean number of puffs taken during each product use
session and the change in e-cigarette mass are reported
in Table2. Ten puffs were taken from each of the myblu
products containing nicotine lactate during each use ses-
sion, while one puff from the myblu 25mg (freebase), blu
PRO 48mg (nicotine lactate), and conventional cigarette
was missed by two subjects. All conventional cigarettes were
consumed in 9 or 10 puffs. Mean product mass changes from
pre- to post-use was greatest for the myblu 16-mg (nicotine
lactate) product, followed by the myblu 40mg (nicotine lac-
tate), myblu 25mg (nicotine lactate), myblu 25mg (free-
base), and blu PRO 48mg (nicotine lactate), respectively.
Pharmacokinetic analysis
The mean plasma nicotine concentration profiles of the con-
ventional cigarettes and the investigational e-cigarette prod-
ucts are shown in Fig.1 and the pharmacokinetic parameters
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for each product are reported in Table3. The myblu 40mg
(nicotine lactate) product had the closest set of pharmacoki-
netic parameters to that of the conventional cigarette.
All e-cigarette products had a median Tmax that was in the
range of the conventional cigarette indicating aerosol deposi-
tion in the deep lung facilitating rapid nicotine absorption
from all tested e-cigarettes.
The Cmax for all the e-cigarette products was significantly
lower (P < 0.05) than that of the conventional cigarette,
except for the myblu 40-mg (nicotine lactate) product which
was not significantly different. An increase in the nicotine
lactate concentration in the myblu device also resulted in an
increased Cmax, with a trend toward dose proportionality.
Of note, the Cmax was significantly higher (P < 0.05) for the
myblu 40-mg (nicotine lactate) product than the blu PRO
48-mg (nicotine lactate) open-system device which is likely
to be reflective of the technological improvements of the
newer myblu device.
For all e-cigarette products, the extent of nicotine absorp-
tion (AUC
0–30) was significantly less (P < 0.05) than that of
the conventional cigarette, except for the myblu 40-mg (nico-
tine lactate) product which was not significantly different.
With increasing nicotine lactate concentrations in the myblu
device, the AUC
0–30 increased, with a trend toward dose pro-
portionality. The blu 48-mg (nicotine lactate) product had
an AUC
0–30 significantly less than that of the myblu 40-mg
(nicotine lactate) product again indicating the improved
aerosol generation properties and nicotine delivery of the
myblu device vs the blu PRO device, which uses an older
aerosol generation technology.
Subjective eects
Subjective effect scores are reported in Table4. Subjective
scores were numerically highest for all questions after use of
the conventional cigarette followed by the myblu 40-mg (nic-
otine lactate) product. For three questions (Did it make you
dizzy? Did it relieve the urge to smoke? and Was it enough
nicotine?), a significant difference was observed between the
six investigational products (P < 0.05). In general, a rapid
absorption of nicotine with a higher Cmax appears to produce
greater relief in desire to smoke which may be important for
facilitating smoker switching and preventing relapse. The
other subjective measures appear to be numerically compa-
rable and not significantly different across all formulations
irrespective of nicotine delivery, indicating that in addition
to nicotine, other behavioural and sensorial elements that
e-cigarettes provide play a role in satisfaction.
Safety andtolerability
There were no serious adverse events reported during the
study. Product-use AEs were infrequent with four subjects
reporting 10 AEs in this study, none of which led to discon-
tinuation. Vessel puncture site pain was the most frequently
reported AE, experienced by two subjects. All remaining
Table 1 Demographic and baseline characteristics of the pharmacoki-
netic population
BMI body mass index; FTCD Fagerström Test for Cigarette Depend-
ence Questionnaire; SD standard deviation
a 15 enrolled, 1 participant did not use myblu 25 mg (freebase) and
blu PRO 48mg (nicotine lactate) and 2 participants did not use myblu
25mg (nicotine lactate)
Variable Characteristics
Number of subjects, n15a
Smoker type 10 ‘full flavour’
cigarettes; 5 ‘light’
1 menthol
14 non-menthol
Age (years)
Mean (SD) 42.3 (12.41)
Range 24–62
Sex, n (%)
Male 9 (60%)
Female 6 (40%)
BMI (kg/m2)
Mean (SD) 28.137 (5.1412)
Range 20.20–39.49
FTCD (total score)
Mean (SD) 5.5
Range 3–9
Table 2 Summary of product use by investigational product type
All values are arithmetic mean and standard deviation (SD)
NA not applicable
myblu 40mg (nico-
tine lactate)
myblu 25mg (nico-
tine lactate)
myblu 16mg (nico-
tine lactate)
blu PRO 48mg
(nicotine lactate)
myblu 25mg
Number of puffs 9.9 (0.35) 10.0 (0.00) 10.0 (0.00) 10.0 (0.00) 9.9 (0.27) 9.9 (0.27)
Product mass
change (g)
NA 0.04853 (0.022660) 0.04425 (0.018735) 0.06526 (0.028930) 0.01791 (0.013702) 0.04396 (0.019524)
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Fig. 1 Pharmacokinetic profiles:
mean plasma nicotine concen-
tration by investigational prod-
uct (linear scale) over 30 min
Table 3 Summary of pharmacokinetic parameters by investigational product type
All values are geometric mean and geometric coefficient of variation (CV%) unless stated otherwise
Cmax maximum plasma nicotine concentration; Tmax time to maximum nicotine concentration; AUC
0–30 area under the concentration–time curve
from time zero to the last quantifiable concentration (30min)
*Significant difference compared to conventional cigarette (**P < 0.01 and ***P < 0.001)
Significant difference between myblu 40mg (nicotine lactate) and blu PRO 48mg (nicotine lactate) (P < 0.05; ††P < 0.01)
myblu 40mg
myblu 25mg
(nicotine lactate)
myblu 16mg (nico-
tine lactate)
blu PRO 48mg
(nicotine lactate)
myblu 25mg
Cmax, ng/mL 17.81 (49.6) 10.27 (83.6) 7.58 (80.6)** 6.51 (76.5)*** 4.85 (108.3)***, † 5.048 (49.9)***
Tmax, median
(range), min
8.05 (5.00–15.13) 7.9 (1.97–15.0) 6.03 (4.58–16.77) 6.967 (3.98–15.05) 6.908 (2.35–15.03) 8.034 (2.28–15.10)
0–30, ng*min/
324.9 (35.8) 190.7 (71.8) 125.2 (53.4)*** 118.5 (60.8)*** 84.84 (89.8)***, †† 98.99 (35.8)***
Table 4 Summary of subjective evaluations of each investigational product type
Scale: 1, not at all; 2, very little; 3, a little; 4, modestly; 5, a lot; 6, quite a lot; 7, extremely
All values are mean and standard deviation (SD)
* Significant difference between the six investigational products (*P < 0.05)
myblu 40mg
(nicotine lactate)
myblu 25mg
(nicotine lactate)
myblu 16mg
(nicotine lactate)
blu PRO 48mg
(nicotine lactate)
myblu 25mg
Did it make you dizzy?* 3.7 (1.80) 2.8 (1.78) 2.1 (1.32) 1.5 (0.74) 1.7 (0.99) 1.9 (1.73)
Did it make you nauseous? 1.9 (1.44) 1.4 (0.91) 1.2 (0.44) 1.1 (0.26) 1.4 (0.84) 1.3 (0.83)
Did you enjoy it? 4.9 (1.44) 4.0 (1.36) 3.5 (1.98) 3.5 (1.46) 3.2 (1.81) 3.5 (1.87)
Did it relieve the urge to smoke?* 5.5 (1.60) 4.1 (1.79) 3.5 (1.98) 3.3 (1.91) 3.1 (2.11) 3.6 (2.10)
Was it enough nicotine?* 5.4 (1.55) 4.3 (1.79) 3.1 (1.93) 3.3 (1.99) 3.2 (2.08) 4.0 (1.96)
Was it too much nicotine? 2.4 (1.55) 2.2 (1.66) 1.5 (0.97) 1.7 (1.11) 1.4 (0.63) 2.5 (2.21)
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AEs were experienced by one subject each. All AEs were
mild in severity, apart from moderate insomnia with the
blu PRO 48mg (nicotine lactate). The principal investiga-
tor considered one AE of headache with the myblu 25mg
(freebase) to be possibly related to study product and the
remaining nine events unlikely or unrelated.
The use of the e-cigarette products under the study con-
ditions appeared to be well tolerated by the healthy adult
smokers in this study.
This study provides new insights into e-cigarette products
that contain nicotine lactate when used by adult smokers
under controlled conditions. The data indicate that nicotine
in lactate salt formulation is rapidly delivered into the sys-
temic circulation following inhalation using nicotine lactate
e-cigarette products with plasma pharmacokinetic profiles
consistent with pulmonary absorption; however, with nico-
tine doses less than that of a conventional cigarette. Com-
pared to conventional cigarettes, exposure to nicotine was
41% lower following use of myblu 40mg (nicotine lactate),
60% lower following use of myblu 25mg (nicotine lactate),
63% lower following use of myblu 16mg (nicotine lactate),
and 70% lower following use of myblu 25mg (freebase).
The blu PRO 48-mg (nicotine lactate) product delivered
approximately 73% less nicotine compared to conventional
As might be expected, variations in the concentration
of nicotine content of the e-liquid also had an impact on
nicotine delivery. Indeed, the pharmacokinetic profile of the
40-mg nicotine lactate e-cigarette product was approach-
ing that of a conventional cigarette; whereas, the 16-mg
comparator was significantly different. The subjective data
also show that the 40-mg nicotine lactate product reduced
the desire to smoke numerically more than the 16-mg nico-
tine lactate product; this may be consistent with an efficient
transfer of more nicotine to the lungs and a rapid rise of
nicotine absorption in the plasma. These initial findings sug-
gest that e-cigarettes with a higher concentration of nicotine
in nicotine lactate form may be more effective and more
appealing products for adult smokers switching from ciga-
rettes to vapour products. This is in line with public health
recommendations in the UK and elsewhere, e.g. [3, 12, 35].
From smoking a conventional cigarette, a plasma nico-
tine concentration of around 4ng/mL has been reported to
occupy up to 90% of available α4β2* nicotinic acetylcholine
receptors in the brain and significantly reducing desire to
smoke [36]. By contrast, following use of a licensed nicotine
inhaler, a peak receptor occupancy of 60% is only reached
after 3h which was insufficient to reduce desire to smoke
[37]. Thus, it appears that a shorter Tmax is important to
activate most nicotine receptors and provide smoker satisfac-
tion from alternative products. In our study, the Tmax values
for all e-cigarettes were in a range which is comparable to
published conventional cigarette data [38]. A study is under-
way to assess smoking reduction and switch rates associ-
ated with nicotine lactate e-cigarette adlibitum use in the
real-world with medicinal nicotine replacement product and
freebase e-cigarette comparators.
The European Union Tobacco Products Directive
(EUTPD) mandates that the maximum nicotine content of
an e-liquid cannot exceed 20mg/mL. Recent research has
shown that the use of lower nicotine concentration e-liq-
uids may be associated with ‘compensatory behaviour’ as
e-cigarette users puff more deeply, more frequently and for
longer to obtain a level of nicotine that reduces desire to
smoke [39]. In the present study, the myblu 40-mg nico-
tine lactate product had the closest nicotine uptake profile
to the conventional cigarette with the greatest relief in desire
to smoke. However, this product would not be permitted
in the European Union. Both Public Health England and
the Royal College of Physicians have stated that the cap on
nicotine concentrations imposed by the EUTPD may limit
the effectiveness of e-cigarettes as a smoking substitute,
particularly for heavier smokers [1, 2]. Based on our initial
data presented here, and other research insights [40], the
EUTPD nicotine concentration limit should be reviewed in
line with the scientific literature to ensure that adult smokers
have ready access to better alternatives that reduce desire to
smoke. Higher nicotine strength liquids with nicotine lactate
formulations and suitable flavour options that can be mar-
keted to smokers may maximise the public health potential
of e-cigarettes.
This was a small, short-duration study that was not
designed to fully evaluate safety. However, reports of AEs
were recorded, and the study was conducted to GCP. Use
of the nicotine lactate e-cigarettes was well tolerated by the
participants with no severe or serious AEs and no partici-
pants discontinued the study owing to an AE.
The main limitation of this study is that the e-cigarette
puff profile was fixed (use was not adlibitum) to obtain
clear pharmacokinetic profiles and blood sampling was
collected for only 30min. A more robust pharmacokinetic
assessment is planned in future studies. It is likely that
smokers using the e-cigarette devices in the ‘real world’
would change their behaviour to adapt to the new products
and own preference. To assess the amount of nicotine and
smoker satisfaction that nicotine lactate e-cigarettes pro-
vide under real-world conditions, it would be beneficial
to conduct a long-term study that allows subjects to adapt
their behaviour to product use. Another limitation is that
study participants were not experienced e-cigarette users.
However, prior to study start, subjects could use each of
the products, although their preferences on the products
Internal and Emergency Medicine
1 3
ahead of the study start were not known. This may have
influenced the reporting of subjective effects. The e-ciga-
rette products may not have been used in an optimal way
or in the same way they would have been used had the
participants been familiar with the product; a longer famil-
iarisation training period would be beneficial in future
studies. Furthermore, only tobacco-flavoured e-cigarettes
were assessed in this study; had the participants the oppor-
tunity to vary the flavour it may have influenced product
use and satisfaction. In the present study, only nicotine
lactate salt formulations were assessed; further research is
also warranted to determine the pharmacokinetic profiles
and efficacy of other nicotine salt formulations.
In summary, the results of this study indicate that the use
of nicotine lactate in e-cigarettes has promise as an effec-
tive form of nicotine replacement. The pharmacokinetic
and subjective data demonstrate that nicotine lactate can
be used to deliver nicotine via the pulmonary route for
increased speed of absorption, albeit with a maximum nic-
otine level that did not exceed the conventional cigarette,
coupled with acceptable subjective satisfaction and relief
of desire to smoke. Further studies are warranted to fully
assess the efficacy of nicotine lactate in aiding smokers to
fully switch to e-cigarettes in the real-world, as well as the
research on the role of flavours and other innovations that
can maximise the public health potential of alternatives to
cigarettes for adult smokers.
Acknowledgements The authors thank Celerion who conducted the
study and analysed the data.
Funding This study was supported by Imperial Brands plc. Fontem
Ventures B.V., the manufacturer of the investigational e-cigarettes used
in this study, is a wholly owned subsidiary of Imperial Brands plc.
Compliance with ethical standards
Conflict of interest GOC, JDP, CP, JT, TV and TW are full time em-
ployees of the Imperial Brands Group. Celerion has received funding
from several e-cigarette/tobacco manufacturers to conduct pharma-
cokinetic/pharmacodynamic studies of their products with smokers
and vapers, as well as biomarker studies on smokers who switch to
Ethics approval The study is registered at
(NCT03822546) and a favourable ethical opinion of this study was
given by the Institutional Review Board of Chesapeake Research
Review (Maryland, USA).
Informed consent Participants were presented with an Informed Con-
sent Form and gave written consent to participate at the start of the
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creat iveco
mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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... To this end, a recent tobacco harm reduction innovation is the use of nicotine salts, such as nicotine lactate, in e-cigarette devices. Blood nicotine pharmacokinetic studies show how nicotine salts seem to better mimic the nicotine profile obtained during smoking of a combustible cigarette compared to freebase nicotine which may be important in helping more adult smokers to move away from combustible cigarette smoking [16,[20][21][22][23]. ...
... This deposition pattern is consistent with two modes of inhalation of [ 11 C]nicotine reported following the use of a nicotine inhaler [26]. Reminiscent of the blood nicotine pharmacokinetic profiles reported by O'Connell et al., 2019 [16], freebase nicotine tended to deposit more in the oral cavity and respiratory pathways than for the nicotine lactate formulation. In the current study, the [ 11 C]nicotine uptake in the mouth and pharynx and the respiratory pathways was fast and measurable. ...
... The nicotine lactate formulation exhibited a faster distribution to the lungs and a higher deposition than freebase. This finding is in line with the observations from O'Connell et al. 2019 [16] that showed how nicotine lactate had a cigarette-like pulmonary blood nicotine delivery profile. In the lungs, the peak SUV and highest deposition were reached at 15 s for [ 11 C]nicotine lactate and 35 s for [ 11 C]nicotine freebase . ...
Full-text available
Smoking is a cause of serious disease in smokers. Electronic cigarettes, delivering aerosolized nicotine, offer adult smokers a potentially less harmful alternative to combustible cigarettes. This explorative PET/CT study investigated the distribution and deposition of inhaled [11C]nicotine using the mybluTM e-cigarette with two nicotine formulations, freebase and lactate salt. Fifteen healthy adult smokers participated in the two-part study to assess the distribution and accumulation of [11C]nicotine in the respiratory pathways and brain. Time-activity data for the respiratory pathways, lungs, oesophagus and brain were derived. 31–36% of both inhaled tracer formulations accumulated in the lung within 15–35 s. [11C]Nicotinefreebase exhibited higher uptake and deposition in the upper respiratory pathways. For [11C]nicotinelactate, brain deposition peaked at 4–5%, with an earlier peak and a steeper decline. A different kinetic profile was obtained for [11C]nicotinelactate with lower tracer uptake and accumulation in the upper respiratory pathways and an earlier peak and a steeper decline in lung and brain. Using nicotine lactate formulations in e-cigarettes may thus contribute to greater adult smoker acceptance and satisfaction compared to freebase formulations, potentially aiding a transition from combustible cigarettes and an acceleration of tobacco harm reduction initiatives.
... Results of this partial single-blind, randomized, 7-way crossover study suggest that, among current AS and MST users, the abuse potential of NPs tested is not likely to be higher than cigarette or MST. The study results and literature reported PK values for cigarettes (D'Ruiz et al. 2015;Goldenson et al. 2020;O'Connell et al. 2019;Phillips-Waller et al. 2021;Picavet et al. 2016;Rensch et al. 2021;Stiles et al. 2018;Voos et al. 2019;Yuki et al. 2017) and MST (Benowitz et al. 1988;Digard et al. 2013;Fant et al. 1999;Kotlyar et al. 2007;Lunell et al. 2020;Pickworth et al. 2014) indicate that the nicotine delivery and subjective effects of NPs tested are not likely to be greater than cigarette or MST. NPs may be potentially acceptable switching products for AS and adult MST users. ...
... While we observed a higher C max for the 8 mg NPs compared to OBC and OBMST used in this study, the mean nicotine C max measured during use of the 8 mg NP (15.4 ng/ mL) was within the range reported in published literature (Benowitz et al. 1988;D'Ruiz et al. 2015;Digard et al. 2013;Fant et al. 1999;Goldenson et al. 2020;Kotlyar et al. 2007; Lunell and Curvall 2011;Lunell et al. 2020;O'Connell et al. 2019;Phillips-Waller et al. 2021;Picavet et al. 2016;Pickworth et al. 2014;Stiles et al. 2018;Voos et al. 2019;Yuki et al. 2017) for cigarettes (11.8 to 23 ng/mL; Fig. 3a) and MST products (10.6 to 21.4 ng/ml; Fig. 3b). Also, in a previous study, we observed a higher mean C max for OBCs was 17.7 ng/mL (Rensch et al. 2021), than that observed in this study (12.2 ng/mL). ...
Full-text available
Rationale Oral tobacco–derived nicotine products include on!® nicotine pouches (NPs) which are tobacco-leaf free and available in multiple flavors and nicotine levels. Switching completely to NPs from cigarettes and moist smokeless tobacco (MST) has the potential to reduce harm for adult tobacco consumers. However, the dependence potential of NPs is not established. Therefore, we characterized the abuse potential of NPs with different nicotine levels compared to cigarettes and MST. Objectives To evaluate nicotine pharmacokinetics (PK) and subjective effects of NPs (ranging from 1.5 to 8 mg nicotine) compared to own brand cigarettes (OBCs) and MST (OBMST). Methods We used a randomized, in-clinic, partial single-blind, 7-way crossover design to assess nicotine PK and subjective effects in dual users of cigarettes and MST. Results The mean nicotine C max for NPs increased with nicotine level, ranging from 3.5 ng/mL (1.5 mg NP) to 15.4 ng/mL (8 mg NP), compared with 12.2 ng/mL for OBCs and 9.8 ng/mL for OBMST. Nicotine t max was much longer for all NPs and OBMST (32.5–34.4 min) compared to OBCs (8.5 min). Reductions in urges to smoke after use of the 2 mg, 3.5 mg, and 8 mg NPs were not statistically different ( p > 0.05) relative to OBC. Also, NPs resulted in lower ratings of positive subjective effects relative to OBCs and OBMST. Conclusions Overall, based on the study results and literature reported nicotine PK values for cigarettes and MST, the abuse potential of NPs is not likely to be higher than OBCs and OBMST. NPs may be potentially acceptable switching products for users of cigarettes and MST products.
... There is evidence that the degree of nicotine absorption and the level of nicotine concentration might be different between the use of r-cigs and e-cigs (Farsalinos et al., 2015;O'connell et al., 2019;Yingst et al., 2019). In our study, all the participants completed the physiological and behavioral tests after smoking r-cigs or vaping e-cigs, which took approximately 10 min from the start of r-cigs smoking or e-cigs vaping to the start of the fMRI run in the SAT state. ...
... Thus, the fMRI run in the SAT state for the e-cigs vaping condition may have been acquired before the nicotine was sufficiently absorbed. Further research is thus warranted to consider the quantitative measurement of the absorbed nicotine level such as from the blood sample (Farsalinos et al., 2015;Devito and Krishnan-Sarin, 2018;O'connell et al., 2019;Yingst et al., 2019). ...
Full-text available
Background Electronic cigarettes (e-cigs) as substitute devices for regular tobacco cigarettes (r-cigs) have been increasing in recent times. We investigated neuronal substrates of vaping e-cigs and smoking r-cigs from r-cig smokers.Methods Twenty-two r-cig smokers made two visits following overnight smoking cessation. Functional magnetic resonance imaging (fMRI) data were acquired while participants watched smoking images. Participants were then allowed to smoke either an e-cig or r-cig until satiated and fMRI data were acquired. Their craving levels and performance on the Montreal Imaging Stress Task and a 3-back alphabet/digit recognition task were obtained and analyzed using two-way repeated-measures analysis of variance. Regions-of-interest (ROIs) were identified by comparing the abstained and satiated conditions. Neuronal activation within ROIs was regressed on the craving and behavioral data separately.ResultsCraving was more substantially reduced by smoking r-cigs than by vaping e-cigs. The response time (RT) for the 3-back task was significantly shorter following smoking r-cigs than following vaping e-cigs (interaction: F (1, 17) = 5.3, p = 0.035). Neuronal activations of the right vermis (r = 0.43, p = 0.037, CI = [-0.05, 0.74]), right caudate (r = 0.51, p = 0.015, CI = [0.05, 0.79]), and right superior frontal gyrus (r = −0.70, p = 0.001, CI = [−0.88, −0.34]) were significantly correlated with the RT for the 3-back task only for smoking r-cigs.Conclusion Our findings suggest that insufficient satiety from vaping e-cigs for r-cigs smokers may be insignificant effect on working memory function.
... Another cardiovascular toxicity-related assay within the framework is the scratch wound assay, which looks at the rate of repair of human umbilical endothelial cell layers after a "wound" is cut, and can indicate wound healing rates following exposure to NGP samples relative to combustible cigarette smoke extracts (Simms and Trelles, 2019;Chapman et al., 2021). Results need to be confirmed with human clinical studies, which include assessment of short term safety following use of the test products, including cardiovascular parameters (O'Connell et al., 2019;Chapman et al., 2021;Morris, 2021 under review). Looking at the data from such pre-clinical and clinical assessments in combination can provide weight of evidence, which can be further compared to the scientific literature, to draw conclusions on the potential effects of NGPs relative to combustible cigarette smoking. ...
Full-text available
Combustible cigarette smoking is an established risk factor for cardiovascular disease. By contrast, the cardiotoxicity potential of non-combustible next generation nicotine products (NGPs), which includes heated tobacco products (HTPs) and electronic vaping products (EVPs), and how this compares relative to combustible cigarettes is currently an area of scientific exploration. As such, there is a need for a rapid screening assay to assess this endpoint. The Cardio quick Predict is a metabolomics biomarker-based assay that uses human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to screen for potential structural and functional cardiac toxicants based on the changes of four metabolites, lactic acid, arachidonic acid, thymidine, and 2′-deoxycytidine. The study aims were to investigate the cardiotoxicity potential of NGPs compared to cigarettes, in addition to nicotine. To accomplish this, hiPSC-CM were exposed to smoke or aerosol bubbled PBS samples: reference cigarette (1R6F); three variants of HTP; and three EVP variants. The 1R6F bPBS was the most active, having cardiotoxic potential at 0.3–0.6% bPBS (0.4–0.9 μg/mL nicotine), followed by HTP, which displayed cardiotoxic potential at a 10 times higher concentration, 3.3% bPBS (4.1 μg/mL nicotine). Both 1R6F and HTP bPBS (at 10-fold higher concentration than 1R6F) affected all four predictive metabolites, whereas none of the EVP bPBS samples were active in the assay up to the maximal concentration tested (10% bPBS). Nicotine tested on its own was predicted to have cardiotoxic potential at concentrations greater than 80 μg/mL, which is higher than expected physiological levels associated with combustible cigarette smoking. The application of this rapid screening assay to NGP research and the associated findings adds to the weight-of-evidence indicating that NGPs have a tobacco harm reduction potential when compared to combustible cigarettes. Additionally, this technique was shown to be sensitive and robust for the assessment of different NGPs and may be considered as part of a larger overall scientific framework for NGP assessments.
Objective To report on longitudinal tobacco product cessation rates, by product type, among adults (ages 18+ years) in the USA between 2013 and 2019. Methods The Population Assessment of Tobacco and Health Study, a nationally representative, longitudinal cohort study was used to report on annual and biennial rates of the following three cessation behaviours across 2013–2019: (1) discontinuing tobacco product use (ie, transition from past 30-day use to no past 30-day use), (2) attempting to quit tobacco product use and (3) quitting tobacco product use among those who attempted to quit. Each cessation behaviour was evaluated separately for cigarettes, electronic nicotine delivery systems (ENDS), cigars, hookah and smokeless tobacco. Generalised estimating equations were used to evaluate linear and nonlinear trends in cessation rates across the study period. Results Between 2013 and 2019, rates of discontinuing cigarette smoking among adults in the USA statistically increased from 16% to 18%, though these were consistently lower than rates of discontinuing use of other tobacco products. Similarly, quit attempt rates and rates of quitting among attempters increased for cigarette smokers. However, rates of discontinuing ENDS use sharply declined across the study period, from 62% to 44%. Conclusions Findings show that tobacco product cessation rates have been changing in recent years in the USA alongside the changing tobacco product marketplace and regulatory environment, though rates of discontinuing cigarette smoking remain relatively low. Findings can serve as a benchmark against which future cessation rates can be compared with evaluate the impacts of future tobacco regulatory policies.
Given that nicotine salts are a growing market, methods are needed to characterize nicotine forms in e-cigarette vaping products. By lowering the free-base nicotine fraction (αfb) in favor of protonated forms, the addition of organic acids to the e-liquid mix greatly modulates nicotine pharmacokinetics and improves vapers' craving. This research investigated (1) the performance of pH measurement, liquid-liquid extraction (LLE), and acid/nicotine molar ratio calculation methods for αfb estimation in 6 nicotine benzoate and nicotine salicylate e-liquids and (2) nicotine protonation in the aerosol post vaporization. Aerosols were generated with a JUUL device and another mod-pod on a vaping machine to assess device effects. E-liquid and aerosol samples were then analyzed after further analytical optimization of previous methods and careful consideration of biases. Globally, performances were comparable between methods. αfb accounted for less than 5% of nicotine content regardless of experimental conditions. αfb were consistent between e-liquids and aerosols irrespective of e-cigarette devices. Hence, e-liquids are adequate surrogates for aerosols, facilitating the establishment of regulations. pH measurement is one of the most used methods and enables the establishment of relative scales for e-liquid classification but lacks automation possibility. Until now, the extent of sample dilution remained arbitrary. The dilution factor was fixed at 10, as usually achieved, since no effect of dilution was noted. pH values ranged from 5.3 to 6.3 in accordance with the literature. By contrast, LLE relies on the specificity of organic solvent for free-base nicotine extraction, causing discrepancies in previous studies. Here, the results were similar to αfb values from pH determination. Yet, LLE presented the highest variability and was the most time-consuming protocol. Finally, αfb calculation from molar ratio was the most robust and versatile method. Estimations can be made in silico from reported composition data and/or after liquid chromatography routine analysis.
Introduction There is mixed evidence as to whether nicotine vaping products (NVPs) can help adults who smoke transition away from cigarettes. This study investigated if self-reported attempts to quit smoking and smoking cessation, over a period of either 18 or 24 months, differed between respondents who initiated nicotine vaping versus those who did not. Outcome comparisons were made between those who: (1) initiated vaping vs. those who did not; (2) initiated daily or non-daily vaping vs. those who did not; and (3) initiated daily or non-daily vaping between surveys and continued to vape at follow-up (daily or non-daily) vs. those who did not initiate vaping. Methods This cohort study included 3516 respondents from the ITC Four Country Smoking and Vaping Surveys (Australia, Canada, England, United Sates), recruited at Wave 1 (2016) or 2 (2018) and followed up at Wave 2 (18 months) and/or 3 (2020, 24 months). Adults who smoked daily at baseline and did not have a history of regular vaping were included. Initiation of vaping was defined as beginning to vape at least monthly between surveys. Respondents indicated whether they made an attempt to quit smoking between surveys. Smoking cessation was defined as those who self-reported no longer smoking cigarettes at follow-up. Results Relative to those who did not initiate vaping, initiation of any daily vaping between surveys was associated with a greater likelihood of smokers making a cigarette quit attempt (p < 0.001) and quitting smoking (p < 0.001). Among smokers who attempted to quit smoking, initiation of daily vaping was associated with a greater likelihood of being abstinent from smoking at follow-up (p = 0.001). Respondents who initiated vaping between surveys and were vaping daily at follow up were significantly more likely to have attempted to quit smoking (p < 0.001) and to have quit smoking (p < 0.001) than those who did not initiate vaping. Respondents who initiated non-daily vaping did not differ significantly from those who did not initiate vaping on any of the outcome measures. Conclusions Daily NVP use was associated with increased attempts to quit smoking and abstinence from smoking cigarettes. These findings are consistent with the concept that complete cigarette substitution may be more likely to be achieved when smokers vape nicotine daily.
Nicotine 2,6-dihydroxybenzoate is a nicotine salt that can be used as the nicotine source in tobacco products. X-ray powder diffraction data, unit-cell parameters, and space group for nicotine 2,6-dihydroxybenzoate, C 10 H 15 N 2 ⋅C 7 H 5 O 4 , are reported [ a = 7.726(8) Å, b = 11.724(3) Å, c = 9.437(1) Å, α = 90°, β = 109.081(3)°, γ = 90°, unit-cell volume V = 802.902 Å ³ , Z = 2, ρ cal = 1.309 g cm ⁻³ , and space group P 2 1 ] at room temperature. All measured lines were indexed and were consistent with the P 2 1 space group.
Introduction: Many adult cigarette smokers use electronic cigarettes (e-cigarettes) to cut down on or quit smoking cigarettes. E-cigarettes with higher abuse potential and appeal might facilitate complete switching. E-liquid nicotine concentration and flavor are two of the characteristics that may affect the abuse potential and appeal of e-cigarettes. The objective of this systematic review was to compile results from survey, animal, human laboratory, and clinical studies to understand the possible effects of nicotine concentration and flavor on abuse potential and appeal of e-cigarettes in adult current and former cigarette and e-cigarette users. Methods: A comprehensive literature search was conducted in Ovid Medline and PsycINFO followed by citation tracking in Web of Science Core Collection. Peer-reviewed studies published in English between 2007 and August 2020 were selected that analyzed differences between e-liquid nicotine concentration and/or flavors, had outcome measures related to abuse potential and/or appeal, and included adult humans (18+) or animals. 1624 studies were identified and screened. A qualitative synthesis of results was performed. Results: Results from 104 studies included in this review suggest that higher nicotine concentration and access to a variety of flavors are likely to be associated with higher abuse potential and appeal of e-cigarettes for adult current and former cigarette and e-cigarette users. Conclusions: Higher nicotine concentrations and the availability of a variety of flavors in e-cigarettes might facilitate complete substitution for cigarettes. Future e-cigarette regulations should take into account their impact on smokers, for whom e-cigarettes may be a cessation tool or reduced-harm alternative. Implications: E-cigarettes may provide a reduced-harm alternative to cigarettes for smokers unwilling/unable to quit or serve as a path for quitting all nicotine products. Higher nicotine concentrations and flavor variety are associated with higher abuse potential and appeal of e-cigarettes. Higher abuse potential and appeal products may help facilitate complete switching from cigarettes to e-cigarettes. Regulation of nicotine concentration and flavors aimed at decreasing naïve uptake may inadvertently decrease uptake and complete switching among smokers, reducing the harm reduction potential of e-cigarettes. Evidence-based effects of regulating nicotine concentration and flavors must be considered for the population as a whole, including smokers.
Cigarette smoking is the world’s leading cause of preventable death and disease. Alternative nicotine products such as e‐cigarettes are suggested to have tobacco harm reduction potential, by providing smokers with an alternative form of nicotine delivery but with either the reduced presence or absence of the numerous harmful chemicals found in cigarette smoke. One aspect of importance in determining the potential of e‐cigarettes to provide a viable alternative to combustible cigarettes for smokers is their ability to cause dependence, also known as their abuse liability. E‐cigarettes with little or no abuse liability would be unlikely to be used as a substitute for cigarettes, whereas at least some degree of abuse liability is acknowledged as supportive to both aiding cigarette substitution or complete cessation, and to preventing relapse. Given this link between abuse liability and efficacy, human studies assessing the abuse liability of e‐cigarettes are important to determine their true harm reduction potential. In this review, the concept of tobacco product abuse liability is discussed, along with the primary elements – pharmacokinetics and pharmacodynamics (subjective effects) – that need to be assessed to determine abuse liability. The review also presents a number of human abuse liability study design considerations and discusses what existing studies in the literature tell us about the abuse liability and harm reduction potential of e‐cigarettes.
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The issue of electronic cigarettes is one of the most controversial topics in public health. There is intense debate and dividing opinions about their use patterns, health effects and association with smoking. This is expected since they were only recently introduced to the market and they refer to a harm-reduction approach and strategy that is not universally accepted for smoking and tobacco use in the public health community. Three main factors determine the public health impact of electronic cigarettes: (1) their safety/risk profile, both relative to smoking and in absolute terms; (2) their effectiveness for smoking reduction and cessation; (3) the patterns of use by different population subgroups, especially never-smokers, and adoption of use by youth. This analysis presents a brief overview of currently available evidence and gaps in research covering these three factors.
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Introduction: Novel nicotine delivery systems represent an evolving part of the tobacco harm reduction strategy. The pharmacokinetic (PK) profile of nicotine delivered by P3L, a pulmonary nicotine delivery system, and its effects on smoking urges and craving relief in relation to Nicorette® inhalator were evaluated. Methods: This open-label, ascending nicotine levels study was conducted in 16 healthy smokers. Three different nicotine delivery levels, 50, 80, and 150 µg/puff delivered by the P3L system were evaluated consecutively on different days, after the use of the Nicorette® inhalator. Venous nicotine PK, subjective effects and tolerability were assessed. Results: Geometric Least-Squares means for maximum plasma nicotine concentration (Cmax), generated by the mixed-effect model for exposure comparison, were 9.7, 11.2, and 9.8 ng/mL for the 50, 80, and 150 µg/puff P3L variants, respectively, compared to 6.1 ng/mL after Nicorette® inhalator use. Median time from product use start to Cmax was 7.0 minutes for all P3L, compared to 30.0 minutes for the Nicorette® inhalator. Craving reduction was slightly faster than with the Nicorette® inhalator as assessed with the VAS craving score. The mean QSU-brief total scores did not differ for both products. P3L was well tolerated. Conclusions: At all three nicotine levels tested, the inhalation of the nicotine lactate aerosol delivered with the P3L provided plasma nicotine concentrations higher and faster compared to the Nicorette® inhalator. The plasma nicotine concentration-time profile supports a pulmonary route of absorption for P3L compared to the oromucosal absorption of the Nicorette® inhalator. Implications: The combination of nicotine and lactic acid with the P3L device shows potential over existing nicotine delivery systems by delivering nicotine with kinetics close to published data on conventional cigarettes and without exogenous carrier substances as used in current electronic nicotine delivery systems (ENDS). Altogether, the PK profile, subjective effects and safety profile obtained in this study suggest P3L is an innovative nicotine delivery product that will be acceptable to adult smokers as an alternative to cigarettes.
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Background: Delivering nicotine in the way smokers seek is likely to be the key factor in e-cigarette (EC) success in replacing cigarettes. We examined to what degree different types of EC mimic nicotine intake from cigarettes. Methods: Twelve participants ('dual users' of EC and cigarettes) used their own brand cigarette and nine different EC brands. Blood samples were taken at baseline and at 2-min intervals for 10 min and again at 30 min. Results: Eleven smokers provided usable data. None of the EC matched cigarettes in nicotine delivery (C max = 17.9 ng/ml, T max = 4 min and AUC0->30 = 315 ng/ml/min). The EC with 48 mg/ml nicotine generated the closest PK profile (C max = 13.6 ng/ml, T max = 4 min, AUC0->30 = 245 ng/ml/min), followed by a third generation EC using 20 mg/ml nicotine (C max = 11.9 ng/ml, T max = 6 min, AUC0->30 = 232 ng/ml/min), followed by the tank system using 20 mg/ml nicotine (C max = 9.9 ng/ml, T max = 6 min, AUC0->30 = 201 ng/ml/min). Cig-a-like PK values were similar, ranging from C max 7.5 to 9.7 ng/ml, T max 4-6 min, and AUC0->30 144 to 173 ng/ml/min. Moderate differences in e-liquid nicotine concentrations had little effect on nicotine delivery, e.g. the EC with 24 mg/ml cartridge had the same PK profile as ECs with 16 mg/ml cartridges. Using similar strength e-liquid, the tank EC provided significantly more nicotine than cig-a-like ECs. Conclusions: EC brands we tested do not deliver nicotine as efficiently as cigarettes, but newer EC products deliver nicotine more efficiently than cig-a-like brands. Moderate variations in nicotine content of e-liquid have little effect on nicotine delivery. Smokers who are finding cig-a-like EC unsatisfactory should be advised to try more advanced systems.
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Context: Rapid developments in e-cigarettes, or electronic nicotine delivery systems (ENDS), and the evolution of the overall tobacco product marketplace warrant frequent evaluation of the published literature. The purpose of this article is to report updated findings from a comprehensive review of the published scientific literature on ENDS. Evidence acquisition: The authors conducted a systematic review of published empirical research literature on ENDS through May 31, 2016, using a detailed search strategy in the PubMed electronic database, expert review, and additional targeted searches. Included studies presented empirical findings and were coded to at least one of nine topics: (1) Product Features; (2) Health Effects; (3) Consumer Perceptions; (4) Patterns of Use; (5) Potential to Induce Dependence; (6) Smoking Cessation; (7) Marketing and Communication; (8) Sales; and (9) Policies; reviews and commentaries were excluded. Data from included studies were extracted by multiple coders (October 2015 to August 2016) into a standardized form and synthesized qualitatively by topic. Evidence synthesis: There were 687 articles included in this systematic review. The majority of studies assessed patterns of ENDS use and consumer perceptions of ENDS, followed by studies examining health effects of vaping and product features. Conclusions: Studies indicate that ENDS are increasing in use, particularly among current smokers, pose substantially less harm to smokers than cigarettes, are being used to reduce/quit smoking, and are widely available. More longitudinal studies and controlled trials are needed to evaluate the impact of ENDS on population-level tobacco use and determine the health effects of longer-term vaping.
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Objective: To characterize vaping behavior and nicotine intake during ad libitum e-cigarette access. Methods: Thirteen adult e-cigarette users had 90 minutes of videotaped ad libitum access to their usual e-cigarette. Plasma nicotine was measured before and every 15 minutes after the first puff; subjective effects were measured before and after the session. Results: Average puff duration and interpuff interval were 3.5±1.4 seconds (±SD) and 118±141 seconds, respectively. 12% of puffs were unclustered puffs while 43%, 28%, and 17% were clustered in groups of 2-5, 6-10, and >10 puffs, respectively. On average, 4.0±3.3 mg of nicotine was inhaled; the maximum plasma nicotine concentration (Cmax) was 12.8±8.5 ng/mL. Among the 8 tank users, number of puffs was positively correlated with amount of nicotine inhaled, Cmax, and area under the plasma nicotine concentration-time curve (AUC0→90min) while interpuff interval was negatively correlated with Cmax and AUC0→90. Conclusion: Vaping patterns differ from cigarette smoking. Plasma nicotine levels were consistent with intermittent dosing of nicotine from e-cigarettes compared to the more bolus dosing from cigarettes. Differences in delivery patterns and peak levels of nicotine achieved could influence the addictiveness of e-cigarettes compared to conventional cigarettes.
Introduction Article 20 of the Tobacco Products Directive (EU-TPD) specifies that e-liquids should not contain nicotine in excess of 20 mg/mL, thus many vapers may be compelled to switch to lower concentrations and in so doing, may engage in more intensive puffing. This study aimed to establish whether more intensive puffing produces higher levels of carbonyl compounds in e-cigarette aerosols. Methods Using the HPLC-UV diode array method, four carbonyl compounds (formaldehyde, acetaldehyde, acetone and acrolein) were measured in liquids and aerosols from nicotine solutions of 24 and 6 mg/mL. Aerosols were generated using a smoking machine configured to replicate puffing topography data previously obtained from 12 experienced e-cigarette users. Results Carbonyl levels in aerosols from the puffing regimen of 6 mg/mL were significantly higher (p<0.05 using independent samples t-tests) compared with those of 24 mg/mL nicotine. For the 6 and 24 mg/mL nicotine aerosols respectively, means ±SD for formaldehyde levels were 3.41±0.94, and 1.49±0.30 µg per hour (µg/h) of e-cigarette use. Means ±SD for acetaldehyde levels were 2.17±0.36 and 1.04±0.13 µg/h. Means ±SD for acetone levels were 0.73±0.20 and 0.28±0.14 µg/h. Acrolein was not detected. Conclusions Higher levels of carbonyls associated with more intensive puffing suggest that vapers switching to lower nicotine concentrations (either due to the EU-TPD implementation or personal choice), may increase their exposure to these compounds. Based on real human puffing topography data, this study suggests that limiting nicotine concentrations to 20 mg/mL may not result in the desired harm minimalization effect.
Objectives To describe the effect of e-liquid flavors on nicotine intake and pharmacology of e-cigarettes. Methods 11 males and 3 females participated in a 3-day inpatient crossover study with strawberry, tobacco, and their usual flavor e-liquid. Nicotine levels were nominally 18 mg/ml in the strawberry (pH 8.29) and tobacco (pH 9.10) e-liquids and ranged between 3–18 mg/ml in the usual brands (mean pH 6.80). Each day consisted of a 15-puff session followed by 4 hours of abstinence, then 90 minutes of ad libitum use. Subjects used a KangerTech mini ProTank 3. Results After 15 puffs, the amount of nicotine inhaled and systemically retained were not significantly different between the strawberry and tobacco e-liquids but plasma AUC(0 → 180) was significantly higher with the strawberry e-liquid. While not significantly different, Cmax was 22% higher and various early time point AUCs to measure rate of rise of nicotine in blood ranged between 17-23% higher with the strawberry e-liquid compared to the tobacco e-liquid. During ad libitum use, systemic exposure to nicotine (AUC(0 → 90)) was the same for the tobacco and usual brand e-liquids but were both significantly lower than after using the strawberry e-liquid. The usual flavors were more liked and satisfying than the strawberry and tobacco e-liquids. Conclusion Flavors influence nicotine exposure through flavor liking, may affect rate of nicotine absorption possibly through pH effects, and contribute to heart rate acceleration and subjective effects of e-cigarettes. E-cigarette users titrate their nicotine exposure but the extent of titration may vary across flavors.
The study purpose was to analyze current daily and current daily nicotine-containing electronic cigarette (EC) use in the European Union (EU). Special Eurobarometer 429, a cross-sectional survey performed in a representative sample of 28 member states of the EU in November and December of 2014, was analyzed. The prevalence of current daily and current daily nicotine-containing EC use was 1.08% (95% CI 0.95–1.20%) and 1.00% (95% CI 0.88–1.12%), respectively, and was mainly observed in current and former smokers. Minimal current daily (0.08%, 95% CI 0.03–0.12%) and current daily nicotine-containing EC use (0.04%, 95% CI 0.01–0.08%) was observed among never smokers. Smoking cessation with the help of ECs was reported by 47.12% (95% CI 41.28–52.96%) of current daily and 49.14% (95% CI 43.12–55.17%) of current daily nicotine-containing EC users. Additionally, 33.18% (95% CI 27.67–38.69%) and 31.40% (95% CI 25.80–36.99%) reported reduction in smoking consumption, respectively. The strongest correlates of daily EC use were being current and former smokers. In the EU in late 2014, current daily EC use was predominantly observed in current and former smokers and was associated with high self-reported rates of smoking cessation and reduction. Current daily EC use by never smokers was extremely infrequent.
Introduction Electronic cigarettes’ (e-cigarettes) viability as a public health strategy to end smoking will likely be determined by their ability to mimic the pharmacokinetic profile of a cigarette while also exposing users to significantly lower levels of harmful/potentially harmful constituents (HPHCs). The present study examined the nicotine delivery profile of third- (G3) versus second-generation (G2) e-cigarette devices and their users' exposure to nicotine and select HPHCs compared with cigarette smokers. Methods 30 participants (10 smokers, 9 G2 and 11 G3 users) completed baseline questionnaires and provided exhaled carbon monoxide (eCO), saliva and urine samples. Following a 12-hour nicotine abstinence, G2 and G3 users completed a 2-hour vaping session (ie, 5 min, 10-puff bout followed by ad libitum puffing for 115 min). Blood samples, subjective effects, device characteristics and e-liquid consumption were assessed. Results Smokers, G2 and G3 users had similar baseline levels of cotinine, but smokers had 4 and 7 times higher levels of eCO (p<0.0001) and total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (i.e., NNAL, p<0.01), respectively, than G2 or G3 users. Compared with G2s, G3 devices delivered significantly higher power to the atomiser, but G3 users vaped e-cigarette liquids with significantly lower nicotine concentrations. During the vaping session, G3 users achieved significantly higher plasma nicotine concentrations than G2 users following the first 10 puffs (17.5 vs 7.3 ng/mL, respectively) and at 25 and 40 min of ad libitum use. G3 users consumed significantly more e-liquid than G2 users. Vaping urges/withdrawal were reduced following 10 puffs, with no significant differences between device groups. Discussion Under normal use conditions, both G2 and G3 devices deliver cigarette-like amounts of nicotine, but G3 devices matched the amount and speed of nicotine delivery of a conventional cigarette. Compared with cigarettes, G2 and G3 e-cigarettes resulted in significantly lower levels of exposure to a potent lung carcinogen and cardiovascular toxicant. These findings have significant implications for understanding the addiction potential of these devices and their viability/suitability as aids to smoking cessation.
Background: Electronic cigarettes (ECs) are electronic devices that heat a liquid into an aerosol for inhalation. The liquid usually comprises propylene glycol and glycerol, with or without nicotine and flavours, and stored in disposable or refillable cartridges or a reservoir. Since ECs appeared on the market in 2006 there has been a steady growth in sales. Smokers report using ECs to reduce risks of smoking, but some healthcare organizations, tobacco control advocacy groups and policy makers have been reluctant to encourage smokers to switch to ECs, citing lack of evidence of efficacy and safety. Smokers, healthcare providers and regulators are interested to know if these devices can help smokers quit and if they are safe to use for this purpose. This review is an update of a review first published in 2014. Objectives: To evaluate the safety and effect of using ECs to help people who smoke achieve long-term smoking abstinence. Search methods: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO for relevant records from 2004 to January 2016, together with reference checking and contact with study authors. Selection criteria: We included randomized controlled trials (RCTs) in which current smokers (motivated or unmotivated to quit) were randomized to EC or a control condition, and which measured abstinence rates at six months or longer. As the field of EC research is new, we also included cohort follow-up studies with at least six months follow-up. We included randomized cross-over trials, RCTs and cohort follow-up studies that included at least one week of EC use for assessment of adverse events (AEs). Data collection and analysis: We followed standard Cochrane methods for screening and data extraction. Our main outcome measure was abstinence from smoking after at least six months follow-up, and we used the most rigorous definition available (continuous, biochemically validated, longest follow-up). We used a fixed-effect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for each study, and where appropriate we pooled data from these studies in meta-analyses. Main results: Our searches identified over 1700 records, from which we include 24 completed studies (three RCTs, two of which were eligible for our cessation meta-analysis, and 21 cohort studies). Eleven of these studies are new for this version of the review. We identified 27 ongoing studies. Two RCTs compared EC with placebo (non-nicotine) EC, with a combined sample size of 662 participants. One trial included minimal telephone support and one recruited smokers not intending to quit, and both used early EC models with low nicotine content and poor battery life. We judged the RCTs to be at low risk of bias, but under the GRADE system we rated the overall quality of the evidence for our outcomes as 'low' or 'very low', because of imprecision due to the small number of trials. A 'low' grade means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. A 'very low' grade means we are very uncertain about the estimate. Participants using an EC were more likely to have abstained from smoking for at least six months compared with participants using placebo EC (RR 2.29, 95% CI 1.05 to 4.96; placebo 4% versus EC 9%; 2 studies; 662 participants. GRADE: low). The one study that compared EC to nicotine patch found no significant difference in six-month abstinence rates, but the confidence intervals do not rule out a clinically important difference (RR 1.26, 95% CI 0.68 to 2.34; 584 participants. GRADE: very low).Of the included studies, none reported serious adverse events considered related to EC use. The most frequently reported AEs were mouth and throat irritation, most commonly dissipating over time. One RCT provided data on the proportion of participants experiencing any adverse events. The proportion of participants in the study arms experiencing adverse events was similar (ECs vs placebo EC: RR 0.97, 95% CI 0.71 to 1.34 (298 participants); ECs vs patch: RR 0.99, 95% CI 0.81 to 1.22 (456 participants)). The second RCT reported no statistically significant difference in the frequency of AEs at three- or 12-month follow-up between the EC and placebo EC groups, and showed that in all groups the frequency of AEs (with the exception of throat irritation) decreased significantly over time. Authors' conclusions: There is evidence from two trials that ECs help smokers to stop smoking in the long term compared with placebo ECs. However, the small number of trials, low event rates and wide confidence intervals around the estimates mean that our confidence in the result is rated 'low' by GRADE standards. The lack of difference between the effect of ECs compared with nicotine patches found in one trial is uncertain for similar reasons. None of the included studies (short- to mid-term, up to two years) detected serious adverse events considered possibly related to EC use. The most commonly reported adverse effects were irritation of the mouth and throat. The long-term safety of ECs is unknown. In this update, we found a further 15 ongoing RCTs which appear eligible for this review.