An overview about what we know and what we have yet to discover about electronic cigarettes. The potential risks and current research.

1. Electronic Cigarettes & Nicotine
Addiction

2. Background
• Premature deaths from smoking related
diseases each year:
– 6 million deaths worldwide
– 435,000 in US
• Overall, cause of 1 in 5 deaths
• Approx. 50% probability that a lifelong smoker
will die prematurely from a complication of
smoking.

3. Nicotine
• Alkaloid found in tobacco
• Acts as an agonist of nicotinic acetylcholine
receptors (nAChRs) in the peripheral and
central nervous systems.
• Cigarettes typically contain 1 to 2 mg of
nicotine, but has substantial toxic effects at
higher doses.
• Estimated lethal dose for a child is 10 mg =
half a pack of cigarettes.

4. • Instant gratification makes cigarettes the most
addictive drug of abuse, with tobacco
eclipsing cocaine and heroin in terms of users’
reported difficulty in abstaining.

5. Statistics
• Currently, about 46 million Americans smoke
tobacco.
• 70% say they would like to quit.
• Every year 40% do quit for at least 1 day.
• 80% who attempt to quit on their own return
to smoking within a month.
• Only 3% of smokers quit successfully per year.

6. Associated risks
• Tobacco use is a major cause of death from:
– Cancer
– Cardiovascular disease
– Pulmonary disease
• Cigarette smoking is also a risk factor for:
– respiratory tract other infections
– Osteoporosis
– Reproductive disorders
– Adverse postoperative events
– Delayed wound healing
– Duodenal and gastric ulcers
– Diabetes

7. E-Cigarettes
• On April 25, 2011, FDA announced its intention of
regulating “electronic cigarettes” as tobacco
products, having failed in its initial attempt to
regulate them as drug-delivery devices.
• The misleading term “e-cigarette” refers to an
aerosolizing delivery device mated with a
disposable cartridge. The cartridge contains
nicotine in solution in a humectant, usually
propylene glycol.

10. • Despite being marketed as cigarettes, these
devices have more in common with pipes, multi-
dose inhalers, nebulizers, or other devices loaded
with a drug, whether regulated (albuterol) or
illicit (cocaine).
• Propylene glycol is the most common humectant.
• Manufacturers claim it is safe.
• However, the safety of inhaling it, particularly
over an extended period, has not been studied in
humans.

11. Something Old
Something New
• Historically, similar inhaler devices have used mechanical
heat —or have lacked a heat source, like the Favor inhaler
of the late 1980s, which therefore released no visible
aerosol.
• Favor reached the market briefly but was removed by the
FDA.
• The technology was sold to a pharmaceutical company, it
eventually earned FDA approval as a safe and effective
smoking-cessation aid and was rereleased as the Nicotrol
inhaler.
• Nothing limits the current generation of devices to
delivering nicotine: instructions for filling cartridges with
marijuana hash oil can be found on YouTube.

12. Pitfalls
• Testing of cartridges has revealed poor quality control
and marked inter- and intra-manufacturer variability in
nicotine content, as well as large deviations from the
content claimed on the label.
• Testing of the vapour from the devices has revealed
similar variability, including marked “puff-to-puff”
variation.
• Testing of users in laboratory settings revealed minimal
blood nicotine concentrations.
• Marketing claims aside, the devices tested did not
efficiently deliver nicotine, much less deliver it into the
arterial blood as tobacco smoke does.

13. ?Cause for concern
• Since evidence of both safety and cessation
benefit is lacking, there is cause for concern
that the devices will become “bridge
products” for use in places where smoking is
prohibited or as starter products that are
attractive to young people or former smokers.

14. A work in progress
• The ineffective nicotine delivery of today’s models
cannot be seen as a permanent limitation.
• Increasing the cartridges’ nicotine concentration may
increase deposition — marketers of refills advertise
their escalating concentrations, and some sell bottles
of solution containing enough nicotine to kill an adult if
ingested.
• Manipulating the fluid by altering its acid–base status
can increase bioavailability, since absorption in the
mouth and proximal airways depends on the pH.
• Various temperature and flow characteristics may alter
the particle size and absorption of the vapor.

15. • Shortly after the FDA’s announcement, both
Philip Morris and British American Tobacco
purchased nicotine-inhaler technologies that
promise pulmonary delivery — strategic
decisions that are unlikely to be coincidental
and almost surely presage future consumer
products.

16. “Vape”
shops

17. Clever marketing of E-cigarettes, currently there are no restrictions on E-cigarette marketing, many celebrities endorse
Certain brands. They are also widely advertised in NZ.

18. Differing Views
• Argument that strict regulation/withdrawal of the
devices would harm current users, forcing them
to return to smoking tobacco.
• Both smokers and e-cigarette users have many
alternatives: multiple nicotine products,
approved, regulated, and deemed to be safe and
effective by the FDA.
• Patients should be advised to stick to the FDA
regulated forms, such as patches, gum, lozenges,
nasal spray — or even, perhaps, the existing FDA
approved inhaler.

19. Nicotine Addiction
• Tobacco addiction (like all drug addictions)
involves the interplay of
– Pharmacology
– Learned/conditioned factors
– Genetics
– Social and environmental factors

20. Nicotinic Acetylcholine Receptors
• Smoking tobacco leads to nicotine deposition in
the alveoli, absorption into the arterial
circulation, and delivery to the brain within
seconds.
• Binds to nAChRs (ligand-gated ion channels that
normally bind acetylcholine).
• Binding of nicotine at interface between two
subunits of the receptor opens the channel,
• Allows the entry of sodium or calcium into
neuron.

21. Nicotine and Neurotransmitter
release
• Entry of cations further activates voltage-dependent
calcium channels, allowing more calcium to enter.
• Calcium in a neuron facilitates release of
neurotransmitters. E.g. dopamine
• Dopamine signals a pleasurable experience.
– Critical for reinforcing effects (effects that promote self-
administration) of nicotine & other drugs of abuse, as well
as compelling drives like eating.
• With long-term exposure to nicotine, some nAChRs
become desensitized.

22. Figure 2. Role of the Mesolimbic Dopamine System in Nicotine Activity.
Nicotine activates α4β2* receptors in the ventral tegmental area, resulting in dopamine release in the shell of the nucleus
accumbens.

23. Monamine Oxidase
• Other constituents also contribute to nicotine
addiction.
• Monoamine oxidases are enzymes that catalyze
the metabolism of dopamine, norepinephrine,
and serotonin.
• Condensation products of acetaldehyde in
cigarette smoke with biogenic amines inhibit the
activity of monoamine oxidase.
• Inhibition of monoamine oxidase reduces the
metabolism of dopamine, norepinephrine, and
serotonin, contributing to the addictiveness.

24. Neuroadaptation
• With repeated exposure to nicotine, neuroadaptation
(tolerance) of nicotine develops.
• The number of binding sites on the nAChRs in the
brain increases due to nicotine-mediated
desensitization.
• The symptoms of craving and withdrawal begin in
smokers when desensitized nAChRs become
responsive during periods of abstinence.
• Nicotine binding of these receptors during smoking
alleviates craving and withdrawal.

25. Smokers are attempting to avoid
withdrawal symptoms when
maintaining this desensitized
state by sustaining sufficient
levels of plasma nicotine to
prevent withdrawal symptoms.

26. Figure 4. The Tobacco Addiction Cycle.
The first cigarette of the day has a substantial pharmacologic effect, at the same time, tolerance to nicotine begins to develop.
A second cigarette is smoked later, at a time when the smoker has experienced some regression of tolerance. With subsequent smoking, there is an
accumulation of nicotine in the body, resulting in a greater level of tolerance, and withdrawal symptoms become more pronounced between
successive cigarettes.
The shaded area of the graph represents the affective neutral zone that exists between the threshold level of nicotine needed to produce pleasure
and arousal and the threshold level below which withdrawal symptoms will occur. Transiently high levels of nicotine in the brain after individual
cigarettes are smoked may partially overcome tolerance, but the primary (euphoric) effects of nicotine tend to lessen throughout the day. Abstinence
overnight allows considerable resensitization.

27. Psychoactive Effects of Nicotine
• Nicotine induces pleasure, reduces stress & anxiety.
• For some smoking improves concentration, reaction
time, and performance of certain tasks.
• Relief from withdrawal symptoms is the primary reason
for this enhanced performance and heightened mood.
• Cessation causes the emergence of withdrawal
symptoms: irritability, depressed mood, restlessness,
and anxiety.
• The intensity of these mood disturbances is similar to
that found in psychiatric outpatients.

28. Anhedonia
• The feeling that there is little pleasure in life
can also occur with withdrawal from nicotine,
and from other drugs of abuse.
• The basis of nicotine addiction is a
combination of positive reinforcements,
including enhancement of mood and
avoidance of withdrawal symptoms.

29. Conditioned Behaviour
• When a person who is addicted to nicotine stops smoking, the urge to
resume is recurrent and persists long after withdrawal symptoms
dissipate.
• Smokers may take a cigarette after a meal, with a cup of coffee, an
alcoholic drink, or with friends who smoke. When repeated many times,
such situations become a powerful cue for the urge to smoke.
• Aspects of smoking itself -manipulation of smoking materials, or the
taste, smell, or feel of smoke in the throat , also become associated with
the pleasurable effects of smoking.
• Unpleasant moods can become conditioned cues for smoking:
– a smoker may learn that not having a cigarette provokes irritability and that smoking one
provides relief.

30. Figure 3. Molecular and Behavioral Aspects of Nicotine Addiction.
Craving — induced by smoking cues, stressors, or a desire to relieve withdrawal symptoms — triggers the act of smoking a cigarette, which delivers a spike of nicotine to
the brain. Nicotinic cholinergic receptors (nAChRs) are activated, resulting in the release of dopamine and other neurotransmitters, which in turn cause pleasure,
stimulation, and mood modulation.
Receptor activation also results in the development of new neural circuits in association with environmental cues, and behavioural conditioning. After being activated by
nicotine, nAChRs ultimately become desensitized to it, which results in short-term tolerance of nicotine and reduced satisfaction from smoking. In the time between
smoking cigarettes, or after quitting tobacco use, brain nicotine levels decline, which leads to reduced levels of dopamine and other neurotransmitters and to
withdrawal symptoms, including craving. In the absence of nicotine, nAChRs regain their sensitivity to nicotine and become reactivated in response to a new dose.

31. Vulnerability to Addiction
• 80% of smokers begin smoking by 18 years of age.
• Two thirds of young people try cigarette smoking
• 20 - 25% of them become dependent daily smokers.
• Tobacco addiction is highly prevalent among persons
with mental illness or substance-abuse disorders.
• Association is likely due to shared genetic
predisposition, the capacity of nicotine to alleviate
some psychiatric symptoms, and the inhibitory effects
of tobacco smoke on monoamine oxidase.
• Rapid metabolism of nicotine is associated with more
severe withdrawal symptoms, greater intake and a
lower probability of success in quitting.

32. References

33. The End