MICOTIZZ AID TER SNOXER
D.M. Warburton, Ph. r.
Department of PsycholoEy,
Reading University,
Reading, FG6 2AL,
UNITED KINGDOF
RESURCI HUM
Received
15 OCT 1984
C7-
BATCo document for Province of BritiSh Columbia 6
November 1999


ABSTRACT
In spite of the considerable publicity about the
health hazards of
smoking, people continue to smoke and so smokers
must consider that
the risks are outweighed by smoking's benefits.
This' highly selected
review of nicotine and the smoking habit reveals
that nicotine does (~d
have positive effects. Vicotine releases hormones
which reduce
fatigue and actE on the central nervous system to
produce more
efficient processing of information. The increased
efficiency
produced by nicotine enables both smokers and
nonsmokers to perform
better in work situations. In addition, nicotine
has a sedative
action reducing anxiety and anger. Smokers titrate
their nicotine
intake so that they obtain the appropriate dose of
nicotine for these
kinds of effects. The pharmacokinetic properties
of nicotine make
smoking doses remarkably safe for norm 'al healthy
adults in comparison
with other available stimulant and sedative
substances and BO there is
a high benefit-risk ratio for nicotine versus
other comparable agents.
If the other components of cigarette smoke could
be made less active,
the unique pharmacological properties of nicotine
make it an ideal
substance for self-medication by inhalation.
C:=)
C=)
CD
CYI-
BATCo document for Province of BritiSh Columbia 6
November 1999


INTRODUCTION
Smoking has been indicted by health authorities
around the world as a
habit which impairs health and shortens life.
According to
epidemiologists, smoking causes ill health and
premature death through
cancers of the upper respiratory tract and lung,
chronic bronchitis,
emphysema, and coronary heart disease (USPHS,
1979). It is felt by
many that, even if it does not always cause death
or disablement,
there is hypermorbidity for these diseases among
smokers. Joseph
Califano, former Secretary of the US Department of
Health, Education
and Welfare described smoking as "Preventable
Public Health Enemy
Number One" which has been convicted, "beyond
reaaonable doubt, of
crimes against the public health" (Califano,
1980).
In this climate of political and medical opinion,
it is not surprising
that researchers are reluctant to state publicly
that smoking can have
any positive effects for the smoker, and yet
common sense argues that
it must have. Smokers are exposed to considerable
publicity about the
health risks and so every smoker must have made
some judgement about
be additional risk to health of continuing to
smoke. Since
t
cigarettes continue to be purchased, we can only
cobclude that smokers
consider that the risks are outweighed by
smoking's positive effects.
TbiE belief of smokers about the beneficial
effects of smoking is
substantiated by this selective but balanced
review of the literature
on nicotine and the smoking habit.
II NICOTINE PHARMACOKIKETICS
A~
A 1.2 mg cigarette will give a mouth level of
150-250 ug of nicot'ine
(Armitage, 1973). The PH of the mainstream smoke
ranges between 5.5
and 6.2 for flue.cured cigarettes and between 6.5
and 8.8 for cigar
and pipe smoke. The level of alkalinity is crucial
in determining the
site and amount of nicotine absorption from the
smoke aerosol.
A. Absorption
Nicotine from tobacco smoke is absorbed from the
mouth, nose, and
lungs and digestive tract with the alkalinity
determining the amount
absorbed.
I. Oral Absorption
Nicotine base is readily absorbed by the buccal
membrane. However,
the amount of free base depends on PH, so that
when the pF is 5-35,
about 0.4 per cent of the nicotine is present as
the free base, while
at PH 8.5 (alkaline), e5 per cent of the nicotine
is present as the
free base. Beckett and Triggs (1967) found that
people take about 6%
from a 1.2 mg nicotine solution at PF 5.5 and 25%
at PH
8.5. Unpublished work by Dr M A H Russell and Dr Y
Wesnes showed that
cra2 absorption fro= tablete containing 1.5 mE
nicotine gave venous
levels ot*6.0 ng/ml at pF 6 and 10-15 ng/ml at PH
9. Thus, as little 0
as 30' of the zLicotine is absorbed orally from
cieerette smoke (pF 5.5
tc 6.2), although much more is taken uF fror-
cigar smoke (Arr-itaLve,
1973). As a consequence of the poor oral
absorption, a crucial part (D
cf cigarette smoking is further sooke manipulation
by inhaliLLr it an,~
ther ezTelling it throuEh the nose and mouth., or
ever just throur'-, th;
BATCo document for Province of British Columbia 5
November 1999


nose -
2. Nasal Absorption
The habit of snuff taking is found in many
cultures and it has been
8 uggested that nicotine is absorbed by th a nasal
mucosa. Recently,
Russell described the time course of plasma
nicotine after snuff
taking (Russell, Jarvis and Feyerabend, 1980)..
Uptake of nicotine
was extremely rapid and concentrations of over 20
ng/ml were found in
blood samples from a forearm vein. Thus some
nicotine must be
absorbed from the nose but it is a small amount in
comparison with the
uptake from inhalation.
3- Inhalation
The major site of nicotine absorption for the
majority of smokers is
the lungs. During inhalation, the smoke aerosol
passes down the
broncbii into the alveoli and absorption occurs
through the thin
alveolar membrane into the pulmonary capillaries.
Hicotine diffuses
so rapidly across the alveolar membrane and the
velocity of blood flow
through the capillaries is so slow that
equilibrium is probably
reached between alveolar nicotine and capillary
nicotine. On the
basis of the previous estimates of a 50 to 250 ug
mouth level of
nicotine from each puff, over 100 ug would be
taken up during each
inhalation from a medium delivery cigarette
(Armitage, 1973) giving
over 1.0 mg of nicotine per cigarette. The time
course of nicotine in
human plasma has been studied most extensively by
Russell (19-76).
Smokers puffed ten times on a cigarette and there
was a rapid increase
in plasma nicotine in the forearm vein with each
puff with
irregularities in the ascent profile from the puff
by puff boli of
nicotine. Peak venous nicotine levels of 15.5 to
3E.4 nE/m: were
reached at the end of the cigarette, about one
fifth or one sixth of
the carotid artery levels. The estimated overall
half-life in humans
is round 20 mins after finishing the cigarette
falling to baseline
levels of about 7 ng/ml in 40 mins.
4. Gastric Absorption
Gastric absorption only plays a small part in
nicotine uptake frcr
cigarette smoking in normal circumstances. Travell
(1967) showed that
nicotine was rapidly absorbed from a cat's stomach
when the solution
pY was alkaline but not when the solution was
acidic, the normal
gastrid pH.
5. Summary
The complicated practice of puffing on burning
tobacco leaves,
inhaling the smoke and blowing it out through the
nose and mouth
enables the efficient transfer of nicotine from
the tobacco to the
smoker's bloodstream.
B. Distribution
After absorption into the pulmonary capillaries,
the nicotire-losded
'~Icc-_~ leaves the lungs via the pulmonary veins
into the heari- From
there, the rLizotine is pumped out into the aorta
fror- which tLe large
arzeri eE branch off. The significant branch for
the smckine hstit is C)
CZ:>
tte c&rctid artery which leads directly to the
brain. Abou t a fi fth (=>
c:1 the b2ocd from the heart ascendF_ ir the
carotid arter7 F--- that a
fifth cf the absorbed nicotine passes to the brain
witLfm IC Eecs.
BATCo document for Province of BritiSh Columbia 5
November 1999


Lj
V ~r,
(Oldendorf, 1977) i.e. a dose of roundC250
u~g)from a medium delivery
cigarette on the basis of the earlier asauxptions.
In order to acton the brain, a substance must
penetrate the lipid
blood-brain barrier to the brain extracellular
fluid. Nicotine is
oluble in lipids and so passes passes through this
barrier. Rat
tudies have compared the percentage of nicotine
remaining in the
:
brain 15 seconds after a rapid intracarotid
injection with tritiated
water an a standard. Ninety per cent of the
tritiated water in taken
up on the first pass through the brain, and
nicotine uptake is 131% 0
that of tritiated water. (Oldendorf, Hyman, Brown
and Oldendorf, 1972) 7:~ y.
11
i.e. virtually all the nicotine that is delivered
to the brain leaves
the blood i.e. about 250 ug nicotine per
cigarette. As a result of
this efficient uptake of nicotine, doses affecting
the brain can be
obtained with relatively low blood levels which
minimises the risk of I-idollzt,
toxicity to other organs. Microautoradiograms
after 14 C-nicotine and
H-nicotine show radioactivity in cortical cells,
high levels in the
3
hippocampus, the cerebellum, and nuclei of the
hypothalamus and brain y.-
atem (Sebmiterlov, Hanson, Applegren and Hoffman,
1967). This pattern 1_,
of nicotine distribution throughout the bralin
allows wide scope for
pharxacodynamic interaction. The brain does not
metaboliae nicotiDe
but it washes out quickly from the brain which
gives a short duration
of action. Thus nicotine in a drug which is
rapidly absorbed -into the
brain, widely distributed and then quickly
removed; the ideal 11
specifications for a substance that is required
for a short duration
of action.
Nicotine's metabolism and excretion have been
discussed in numerous
publications (Russell, 1976). However there are
tvo aspects of major
importance to the smoking habit. First, it is
clear from the time
course that nicotine is metabolised very
efficiently by the liver,
which limits nicotine's duration of action in the
body. Second, the
metabolites e.g. cotinine, nornicotine, etc.
appear to be virtually
inactive and so the pbarmacodynamic effects are
determined almost
completely by the action of nicotine alone.
C. Conclusion
Studies of -nicotine pharmacokinetics have
revealed that it is a
substance which is absorbed very efficiently,
readily enters and is
quickly eliminated from the brain, and is rapidly
metabolised to
relatively inactive metabolites. This
pharmacokinetic pattern allows
a brief duration of action and the possibility of
central nervous
action with minimum side effects from actions on
the rest of the
body. The realization of this possibility depends
on the smoker's
ability to control nicotine intake.
III NICOTINE COYMOL
A major argument. for the relevance of nicotine to
the scoking habit
comes from eviden ce that people smoke to obtain
nicotine and ever.
regulate nicotine intake to obtain specific levels
of nicotine in
their bloodstrean. The implication of titration is
that smokers have
a need for nicotine and possess a mechanism in the
body which is
sensitive to nicotine so enabling then to control
the dose. E-vidence
for nicotine need and control has come fro=
surveys cf cigarette
C)
5
BATCo document for Province of BritiSh Columbia 5
November 1999


preference, studies of inhalation, studies of
daily smoking patterns,
the titration of individual cigarettes, nicotine
preloading and a
nicotine antagonist studies.
A. Preferred Cigarette Brands
In 1957, only one per cent of the cigarettes in
the United States were
filter tip and the average cigarette delivered 2.5
mg of nicotine and
round 36 mLq of tar. After the adverse publicity
from the Surgeon
General's report (USPHS, 1964), and the report of
the Royal College
of Physicians (RCP, 1964) in Britain, the average
levels of nicotine
in the USA, as determined by smoking machine
analyses had dropped to
1.3 mg in 1964. It might have been expected that
the combinatior- of
government publicity and company promotion would
have produced an even
more remarkable switch in brands to lower nicotine
and ter yields in
the following ten years, and the sales-weighted
average nicotine per
cigarette would have decreased a further 1.0 mg.
In fact, cigarettes
with a nicotine content of 0.3 mg and
correspondingly low levels of
particulate matter are not popular, and the
salea-weighted average
level of nicotine in UY cigarettes has been 1.3 -
1.4 mc per cigarette
for the past 8 years. Nicotine-free cigarettes
have been a total
disaster, even though many people have tried them.
It could be argued that cigarette preferences do
not provide
convincing evidence for the importance of nicotine
because nicotine
usually covaries with tar. However, one controlled
study has tested
ciLearettes with independently varied nicotine and
tar levels.
(Goldfarb, Jarvik and Click, 1970). Smokers were
allowed te smoke as
many as they wished of these cigarettes and this
number corre2ated
with nicotine content but not tar content.
Nevertheless, it is
interesting that non-nicotine cigarettes were
smoked tc some extent
over the three weeks of the test when there were
no other
alternatives. Although low and zero nicotine
cigarettes allow the
smoker to go through the rituals of lighting,
manipulating, and
puffing the cigarette as well as inhaling the
smoke, the lack of
nicotine results in- lower consumption. However,
it cannot be
concluded that flavour from the tar of tobacco
smoke plays no part in
cigarette acceptability. Nevertheless, the
inference from this work
is that nicotine is an essential ingredient of the
cigarette for the
smoker and this conclusion becomes even clearer
when a more complete
measure of smoking behaviour, than number of
cigarettes smoked, is
used.
B. Inhalation
Smoke inhalation results in very efficient
absorption of nicotine (See
Section II) and the large percentage of smokers
who do inhale provideF
evidence that an aim of smoking is to obtain
nicotine. Doll and Hi!2
(1964) found that 80 - 90% of cigarette smokers
reporting inhaline,
and Hacmond (1966) found that 96.4 per cent
thought that they VEr6
moderate to deep inhalers.
C. SM-Okinr PEttEM
C=)
CT_
BATCo document for Province of BritiSh Columbia 5
November 1999


The hypothesis that smokers attempt to maintain
minimum, or above,
levels of nicotine is supported by studies of
plasma levels of
nicotine throughout the day (Russell, Wilson,
Patel, Cole and
Feyerabend, 1973; Russell, Wilson, Patel,
Feyerabend and Cole, 1975).
The half-life of nicotine in plasma (see Section
II) is about 20 mine
and habitual smokers consume 15 to 30 cigarettes
per day, i.e. a
cigarette every 30 -to 50 minutes, excluding.
meals and sleep.
Russell's studies demonstrated that the
zid-morning levels of plasma
nicotine were remarkable consistent within
subjects across days,
although individual levels varied widely. Five
hours later in the
afternoon, these levels were either virtually the
same or higher.
D. Nicotine Titration
In this part, I will consider the direct evidence
for smokers
controlling their nicotine intake in terms of
cigarette consumption,
smoke generation and smoke manipulation.
1. Cigarette Consumption
The number smoked is the most obvious way for
smokers to control their
nicotine intake and it is the easiest to study.
The first studies
examined changes in cigarette brand and
consumption.
a. Cigarette Switching: The findings Of RUSBell et
al (1975), which
strongly hinted that smokers control their
nicotine intake were
explored further by switching the subjects from
their usual brand (1-5
mg average) to either a 3.2 mg or a 0-3 mr
nicotine cigarettes on
different days. The number smoked was recorded for
five hours. For
the high nicotine cigarette, consumption dropped
significantly by 37
per cent and increased by 17 per cent when they
changed to a low
nicotine cigarette, which was not significant.
However, su1jects
would have needed to smoke five times as many to
compensate if they
did not change any other aspects of their smoking
behaviour. In a two
hour experiment, smokers were switched to
cigarettes which were either
a 0.2 mg nicotine delivery or a 2.0 mg nicotine
delivery (Jarvik,
Popek, Schneider, Baer-Weiss and Gritz, 1978),
with identical tar
levels so that the taste difference was small.
Subjects smoked
significantly more of the lower delivery than the
higher delivery
cigarette which gives persuasive support for
nicotine regulation.
In a study Of smoking in real life, smokers were
given a 1.4 mg.
nicotine cigarette for the first week, a 0.8 mg
cigarette in the
second week, and a 0.3 mg. cigarette in the third
week (Turner,
Sillett and Ball, 1974). The subjects compensated
by smoking
significantly more cigarettes when they switched
from the 1.4 mg. to
the 0.8 mg cigarettes, but there was little chanEe
after the second
switch from 0.8 mg to the 0.3 mE of nicotine
product. A. longer study
(Freedman and Fletcher, 1976) examined the changes
in consumption over
a 20 month period when smokers were switched from
a conventional 1-39
mg nicotine cigarette to a 1.01 mg cigarette which
contained 30 per
cent tobacco substitute. The average number of
cigarettes evoked
stayed constant.for the first 15 months, but
increased slightly in the
last 5 months. A reanalysis od this data by
Rewbone (1976) showed a
significantly higher ratio of observed to expected
nicotine when the CD
smokerE were smoking the lower delivery product
(group i P<0.001;
group 2 P<0.005)which indicates co=pensation in
relaticz tu the higher
BATCo document for Province of BritiSh Columbia 5
November 1999


delivery product.
A sophisticated study of cigarette switching
(Yagerstrom, 1982)
studied the titration of smokers given either
their own brand, average
yield of 1.1 mg of nicotine, or one of two
experimental cigarettes,
one was a 0.53 mg. nicotine cigarette while the
other bad identical
composition but was 'sprayed with nicotine to
deliver 1.1 ME. The
subjects could differentiate them by taste bui not
by any other
characteristics. Some evidence of increased
consumption of the lower
delivery product was seen but the change was not
large. In an earlier
similar study by Finnegan, Larson and Haag (1945)
used tobacco leaf
with a naturally low nicotine content made into a
0-34 mg nicotine
cigarette or the same leaves sprayed with nicotine
to give a 1.96 mg
cigarette with the same pressure drop and tar
level,' although the
nicotine- would give a slightly different taste.
Subjects were given
the high nicotine product followed by a month on
the low nicotine
brand and then switched back to the high nicotine
cigarette. There
was no correlation between the number of
cigarettes smoked and the
nicotine level, but an interesting picture emerged
when Russell (1976)
examined the data on withdrawal symptoms in the
Finnegan, et al study;
subjects who did not increase their consumption on
the low nicotine
cigarette experienced lack of satisfaction,
irritability and poorer
concentration.
Further evidence for abstinence symptoms in the
absence of
compensation was found in a comparison of an heavy
smoker group (at
least 20 cigarettes a day) and a light smoker
group. Schechter (1977)
found that, as a group, the heavy smokers smoked
24 per cent more of a
0.3 mg nicotine cigarette than a 1.3 Mg. nicotine
brand, while the
light smokers used 16 per cent more of the low
nicotine compared with
the high nicotine cigarette. Schachter noted that
three heavy
smokers, who experienced severe abstinence
ByMptOMS, bad only
increased their consumption by. 14.3 per cent
compared with 33.6 per
cent for the restof the group. Thus the last two
studies suggest that
smokers who do not regulate their nicotine intake,
Buffer deprivation
symptoms.
b. Ventilated Holder: Another method of varying
smoke delivery to the
smoker is to use a normal cigarette but smoked
through a ventilated
cigarette holder. Two holders producing nicotine
dilutions of 2 per
cent and 58 per cent were used to study titration
(Sutton, Russell,
Feyerabend and Saloojee, 1978). Consumption
remained constant
throughout the week of Btudy. However, as We Will
see later,
compensation was achieved by increasing the amount
of smoke inhaled.
c. Partial Cigarettes: The number smoked in a week
has been examined
when subjects were only allowed to smoke part of a
cigarette.
Goldfarb and Jarvik (1972) gave smokers cigarettes
which were either
cut in half or 'hid a line drawn around them
halfway down, and the
nucber of smoked cigarettes was counted. Smoking
increased with the
lined cigarette.,and the cut cigarette, but during
the fourth week or
their own brand smoking was alac higher. The data
give lixited
support for titration because 12 subjects did
increase by an averaEe
of five a day on the lined ciEerettes and by an
average of seven a day ON
r*,-)
on the cut cigarettes. A more extensive study
(Tiussel2, Suttc-r--, NJ
e
BATCo document for Province of BritiSh Columbia 5
November 1999


Feyerabend and Cole, 1978) tested a full length
1.08 mg nicotine
cigarette, a threequarter length 0.83 mg nicotine
cigarette and a half
length 0.67 mg cigarette in the laboratory. There
was a clear and
significant increase in consumption with
decreasing delivery.
d. Nicotine Preload: A fourth approach has been to
preload smokers
with nicotine. JohnBton (1942) injected 20 mg of
nicotine
intravenously and reported that zmokers did not
want to smoke for some
time afterwards. Do details were given of number
consumed. In a
follow-up study (Lucchesi, Schuster and Emley,
1967), subjects were
given intravenous infusions of nicotine and their
cigarette
consumption examined. Low doses of nicotine had no
effect, but 4 mg
per hour very significantly reduced consumption
cigarettes of
unspecified delivery by 27 per cent. Nevertheless,
this decrease in
numbers is small in comparison with the amount of
nicotine given.
Similarly daily doses of five tablets of 1.0 Mg of
nicotine reduced
the number of cigarettes used by only eight per
cent although the
decrease was significant (Jarvik, Glick and
Nakamura, 1970). Nicotine
chewing gum is used as a stopping-smoking aid, and
in a test of it
(Russell, Wilson, Feyerabend and Cole, 1976),
subjects were given
either alkaline gum with nicotine (a high pH
increases buccal and
gastric absorption), or a placebo, both highly
spiced to hide the
taste. Subjects reduced their smoking on both gums
but significantly
more with the nicotine gum. Plasma nicotine
determinations showed
that nicotine war. absorbed from the nicotine gum
although blood
levels were lover than after smoking. Clearly, in
spite of a placebo
effect, there was reduction of consumption by the
absorbed nicotine.
e' Modified Excretion: A fifth type of study
manipulated nicotine
body levels by changing urine acidity. If the
urine is alkaline then
less than one per cent of the nicotine is excreted
unchanged and if
the urine is acid then 35 per cent is excreted
unchanged (Beckett and
Triggs, 1967). Thus, Schachter predicted that
increasing acidity
should increase smoking (Schachter, Kozlowski and
Silverstein, 19T7).
Ascorbic acid or glutamic acid hydrochloride were-
given to smokers to
increase excretion and there were increases in
consumption of 15.6 per
cent and 21.6 per cent respectively. Once again
there was some
evidence for control of nicotine intake by
changing consumption.
f. Nicotine Antagonists: A complementary study to
those on nicotine
loadinjused mecamylamine, which blocks nicotinic
synapses in the
brain (Stolerman, Goldfarb, Fink and Jarvik,
1973). Smokers were
given this mecamylamine or pentolinium, a
nicotinic blocker which does
not enter the brain, and asked to record the
number that they smoked
of their usual cigarettes. Yecamylamine, increased
cigarette
consumption by as much as 30 per cent, as smokers
smoked more to
overcome the partial nicotine blockade in the
brain. Pentoliniun:
produced no change which ruled out any peripheral
effects of nicotine
on consumption. Clearly smokers were using
cigarettes to obtaln
p2 asme levels of nicotine sufficient to affect
the train.
E. 5uircarv: Mise studies show that scae sut.iects
t:4tratc nicct'ne bT
changing the nurber of cigarettes that they c=oke.
Some Emcker., -hL,
do not corpensate, suffered abstinence Lsymptor-E
from the effects of
nicctine de;rivation- Fowever, negative stud-_~es
may be explained in
BATCo document for Province of BritiSh Columbia 5
November 1999


terms of changes in either puffing or inhalation.
Data, that show
these factors play a part, come from an experiment
by Gritz, Baer-
Weiss and Jarvik (1976) in which subjects were
given an equal number
of full length cigarettes and half length
cigarettes to smoke in a
week. Urinary nicotine measures showed that
subjects were able to
obtain considerably more nicotine than expected
from the half length
cigarettes, and indeed almost as much as from the
full cigarettes.
2. Smoke Ceneration
In the last section, cigarette consumption was
related to the nicotine
content of the cigarettes. These nicotine levels
were calculated on
the basis of nicotine deliveries that were
obtained from standard
smoking machines. These machines enable
comparisons of cigarettes,
but only produce an approximation of human
smoking. In an innovative
series of studies, Creighton and Lewis (1978 a and
b) recorded the
pattern of smoking in terms of number of puffs,
puff interval, puff
volume and puff shape. They found that there were
marked
interindividual differences and clear, but
smaller, intraindividual
variations, so that it was inevitable that an
individual's pattern of
generation rarely matched the smoking machine's
standard parameterB-
This same equipment was Used to study smokers.
smoking their own brand
twice in the laboratory (Battig, Buzzi and Nil,
1982) and they found
that smokers bad a consistent individual pattern
of puffing cigarettes
and that women took larger smoke volumes than men
which could have
been due to them smoking lower delivery brands.
The practical consequence of these variations in
smoking pattern, in
terms of nicotine deliveries, was examined using a
puff duplicator
(Creighton and Lewis, 1978 a). The divergence of
the smoking machine
yields from the actual values delivered can be
seen by comparing the
average amount of nicotine generated after
duplicating the smoking
patterns for a cigarette having a machine
estimated yield of 1.4 mg of
nicotine. Smokers derived 2.25 mg of nicotine for
males and 2.0 mg of
nicotine for females. Clearly. the machine
estimated delivery is a
limited index of the nicotine dose entering a
smokers routb.
Some of the previous studies of nicotine
regulation recorded puff
variables as well as numbers of cigarettes
consumed. Lucchesi et al
(1967) found that intravenous nicotine reduced the
number of puffs and
the subjects discarded their cigarette earlier.
However, a similar
study by Kumar (Kumar, Cooke, Lader and Russell,
1977) found no
changes in puff number, interpuff interval, puff
duration or puff
volume on a 1.3 mg cigarette after 10 injections
of nicotine at one
minute intervals in order to simulate 10 puffs on
a 0.8c'; ing or a 1.17
mg cigarette. A companion study, with controlled
smoking of either a
herbal cigarette, a 1.3 mg nicotine cigarette or
two 1.~ ME MiCOtinE
cigarettes did reduce the number of puffs taken
from the cigarette in
a dose dependent fashion. Thus smokers can control
their nicotine
intake by changing their smoke generation. Direct
studies of this
behaviour have employed cigarette switching and
partial cigarettes.
a. Cigarette S.vitching: Estimates of nicotine
entering the Br-oker*E
mouth have bee n made fro= the nicotine deposited
in the ciEarette CD
filter and the tip's filtration efficiency. One of
the first studies
on butt nicotine allowed smokers to smoke either a
1.0 mg cr 2.1 zg
C711
10
BATCo document for Province of BritiSh Columbia 5
November 1999


nicotine cigarette (Ashton and Watson. 1970).
Depth of inhalation was
unchanged but puff number was larger on the medium
delivery cigarette
and 'butt nicotine data showed that about the same
amount of nicotine
was delivered to the mouth from both cigarettes.
Titration had
occurred by amok:Lng the lower delivery cigarette
more intensely and
puffing the higher delivery product less
intensely. In our own
studies (Warburton and Wesnes, 1978) we found
similar changes.
Smokers smoked both a 0-3 mg nicotine cigarette
ind a 0.7 mg nicotine
cigarette more intensely but smoked a 1.64
nicotine cigarette,
slightly less intensely.
In a longer study by Freedman and Fletcher (1976),
in which there were
only small changes in the numbers smoked when
subjects switched from a
1.39 mg nicotine cigarette to a 1.01 mg product,
butt nicotine levels
also showed more intense smoking of the lover
brand in comparision
with the higher delivery cigarette. As part of
their studies using
the puff recorder and puff duplicator, Creighton
and Lewis (1978 a)
studied cigarette switching. Smokers smoked a 1.4
mg cigarette for
one month, a 1.8 mg nicotine cigarette for the
second month and the
1.4 mg cigarette again for the third month. The
estimated account of
nicotine that was delivered to the mouth of the
smoker was assessed,
The level of nicotine delivered to the mouth
stayed constant because
subjects reduced their puffing intensity when they
switched from
medium delivery to high delivery cigarettes and
increased their
smoking intensity for the opposite switch.
Clearly, smokers changed
their smoking intensity in the direction of
equalisiDg nicotine
deliveries. There was no evidence, in this study,
that smokers
modified the number smoked each day.
In another aeries of recordings of smoke
generation, Adams (197e)
measured puff number, puff volume and puff
duration, as well a butt
nicotine. He also found that smokers behaved
differently with a 0.8 mg
nicotine cigarette in comparison with a 1.4 mg
delivery cigarette;
they puffed harder on the lover delivery product
and left a shorter
butt. Butt nicotine analysis confirmed that more
intense smoking
resulted in proportionally more nicotine being
taken into the mouths
of smokers from the low nicotine brand. A similar
switching
experiment (Ravbone, Murphy, Tate and Kane, 1978)
studied smokers
before and after they switched from their own
brands (average 1.22 =g
of nicotine) to an undefined "low" delivery
product. Subjects did not
increase consumption, but smoked harder on the
lower delivery
cigarette, obtaining 0-83 ing for low against 0.96
mg for their own
medium delivery brands as a result of increased
puff volume. A
eimilar finding was obtained in a study that
tested smokers with
either a 2.5 mg, 1.2 mg, or a 0.4 mg nicotine with
similar tar levels
(Herning, Jones, Bachman and Mines, 1981). Puff
volumes were measured
and smokers took larger puffs with cigarettes
delivering less nicotine
than their usual product. In another precisely
controlled study,
Stepney (1981) switched smokers from their own
brands (1-55 mg
nicotine and 19 mg tar) to either a 1.1 mg or 0.7
mg nicotine product CD
with similar tar levels for three weeks. At weekly
intervals, the
cigarettes wer'e' smoked in the laboratcry and the
puffing recorded CD
using a puff recorder and again puff volumes
increased. Puff c:::)
duplication of the test brands showed that mouth
level of nicctinE- was CD
greater than would have been predicted by stanaard
smoldnE machine are 0"
BATCO document for Province of British Columbia 5
November 1999


closer to that-obtained from their usual brand. As
a consequence,
their exposure to tar was greater than predicted
and so smokers were
not getting the health benefit expected from the
reduced delivery.
b. Partial Cigarette: In a partial cigarette study
(Ashton, Stepney
and Thompson, 1978) subjects were tested with two
versions of their
usual cigarette:- a full length and a two-thirds
length, which was
calculated for each individual. The amount of the
cigarette normally
smoked was measured and then a mark was made on
the paper at two
thirds of this length. The subjects were issued
with the same number
of marked cigarettes as they smoked normally, so
that they were
deprived to the same degree but not by the same
absolute amount. Puff
duration increased and puff interval decreased
with the two thirds
cigarette showing more intensive smoking. However,
the butt nicotine
estimates showed that subjects did not obtain
their usual amount of
nicotine, as smokers had done in the study of
Gritz et al (1976),
because about 61 per cent of nicotine in the smoke
aerosol comes from
the half of the cigarette nearer the filter, and
only 39 per cent from
the other half (Gritz et al, 1976).
c. Summary: Estimations of the nicotine delivered
to the mouth of
smokers shows that there are many different ways
of smoking. Subjects
tend to smoke low delivery cigarettes more
intensively and smoke high
delivery brands less intensively, even allowing
for uncertainties of
the filter tip analysis (Creighton and Lewis, 1978
a). However,
estimations of mouth nicotine do not represent the
effective dose
because nicotine is not readily absorbed by the
mouth and cigarette
smoke must be manipulated for maximum absorption
of nicotine.
3- Smoke Manipulation
One index of manipulation is the amount of carbon
monoxide exhaled
after a cigarette compared with before smoking.
Carbon monoxide is
absorbed into the bloodstream from the lungs and
not the mouth. Vben
the residual smoke has been expelled from the
lungs after smoking,
carbon monoxide exchange from the blood to the
lungs will occur so
that the level of exhaled, end-tidal carbon
monoxide provides an index
of lung uptake.
a. Cigarette Switching: In a study referred to
twice before, switching
from 1.4 mg nicotine cigarettes to either 3.2 mg
nicotine or low 0.3
mg nicotine cigarettes was cozpared by measuring
exhaled carbon
monoxide (Russell et al, 1973). Exhaled carbon
monoxide for both
switches declined and Russell argued post hoc that
the decrease with
the high cigarettes represented less inhalation
while the decrease
with low cigarettes was attributable to the lower
carbon monoxide
yield of that product. Plasma nicotine measures
showed clear
titration in half of the subjects when switched to
the high nicotine
cigarette while there was some evidence of
titration for the group as CD
-
a whole when switched to the low nicotine
cigarette. Strong evidence CD
was obtained from subjects who switched from a 1.7
mg nicotine CD
cigarette with 17.2 mg of carbon monoxide to a
0-71 mg nicotine CD
cigarette with only 11.4 mg of carbon monoxide for
five weeks CFN
(Guillerm, Kasurel, Brouasole, Hyacinths, Simon,
and Hee, 1974). r")
Consumption increased slightly but carbon monoxide
levels increased 0__
fror 5.7L' per cent to 7.41, per cent even though
the inachine estimated
12
BATCo document for Province of British Columbia 5
November 1999


delivery of carbon monoxide from the lov-medium
nicotine cigarette was
lower -
Two of the studies which recorded smoke generation
with varying
nicotine, similar tar also measured smoke
manipulation (Stepney, 1981;
Fagerstrom, 1982). Carbon monoxide levels were
higher for the lower
nicotine product indicating more inhalation and
plasma nicotine and
cotinine levels in the Fagerstrom study
revealed'that similar amounts
of nicotine were absorbed from the two products.
Additional evidence
comes from an eleven week study (Ashton, Stepney
and Thompson, 1978)
in which smokers switched from their usual 1.4 mg
nicotine brand to
either a 1.84 mg nicotine cigarettes i.e. an
increase of 31 per cent
in delivery or 0.6 mg cigarettes i.e. a decrease
of 57 per cent in
delivery. The exhaled carbon monoxide levels
shoved an increase of
only 10 per cent on the 1.84 mg nicotine
cigarette, and were only 15
per cent lower on the 0.6 mg cigarette. Plasma
nicotine levels showed
a similar pattern indicating that considerable
post puffing titration
had occurred. Urinary nicotine excretion on the
high nicotine
cigarette gave no support for titration when the
machine delivery of
31 per cent was higher than the usual brand.
However with the low
nicotine cigarette, the 24 hour excretion was 94
per cent. Altogether
these studies give strong support for nicotine
titration by smoke
manipulation.
b. Partial Cigarettes: The experiment with half
and three-quarter
length cigarettes of Russell at al (1978) also
included determinations
of exhaled carbon monoxide and plasma nicotine.
Although smokers used
a greater number of the partial cigarettes, the
carbon monoxide and
plasma nicotine levels were as expected,
suggesting no titration. We
will return to this contradictory result in the
next sub-section.
c. Ventilated Holder: The ventilated bolder study
(Sutton et al,
1978) gave no support for titration in terms of
the number smoked, but
a comparison of the observed r.eduction of carbon
monoxide by the more
ventilated holder at two days and seven days with
the expected
reduction shoved partial but significant
compensation which was
maintained throughout the test week. There seemed
to be no
compensation with the less ventilated holder. The
outcome, in terms
of plasma nicotine, was a reduction of only 40 per
cent instead of the
expected 58 per cent which confirms the
effectiveness of smoke
manipulation as a titration mechanism. This clear
finding contrasted
with the partial cigarette study of Russell et al
(1978; Russell,
1980) in which smokers consummed more cigarettes,
but their exhaled
carbon monoxide and plasma nicotine levels were
the same as those
predicted if no titration had occurred. This study
implies that smoke
concentration is the cue for smoke manipulation
because total Emoke
inhaled increased for smoke diluted bv ventilation
but not vheL the
smoke concentration was the same as in the partial
c.-LEarettes
(Russell, 1980).
d. Nicotine Preloading: As one of F_ series of
titration studies we
administered an oral 1.0 mg dose of nicotine to
smokers prior to CZ)
smoking a 0.6 *mg nicotine cigarette (iesnes,
Pitkethly and Warburton, C:)
in preparation). The subjects thought they were
participating in a Cr*I
study of s=oking and the pure nicotine oL hand
trexcr. PuffinE NJ
behaviour, butt nicotine and exhaled carbor.
monoxide were reaEured.
I -"
BATCo document for Province of BritiSh Columbia 5
November 1999


Wo differences were seen in puffing or butt
nicotine levels for
nicotine and placebo conditions. However, there
was a significant
reduction of exhaled carbon monoxide after the
subjects had received a
nicotine tablet indicating reduced inhalation.
Clearly the smokers
were titrating their nicotine dose by smoke
manipulation according to
some internal mechanism sensitive to plasma
nicotine levels.
e. Sumzary: Nicotine intake can be controlled by
the amount of smoke
inhaled as well as by cigarette consumption and by
smoke generation.
Rawbone et al (1978) found no correlation of
carbon monoxide levels
with smoke generation measures. Thus, the
mechanisms are not
necessarily interdependent. As far as nicotine
absorption is
concerned, inhalation is the final control on
intake.
4. Conclusion
The experiments in this section show that nicotine
intake is titrated
to obtain more Picotine from lower delivery
cigarettes and less
nicotine from higher delivery brands.
Unfortunately, most studies
have only studied one titration method and found
that some subjects do
titrate, some titrate partially and some may not
titrate at all by
that method. Indeed it may be impossible to
titrate completely with
some low delivery brands. Evidence for control
over the nicotine dose
is important; it argues not only for nicotine
being a necessary
condition for smoking but also that smokers are
trying to obtain a
dose which will produced desired or needed
effects.
IV. NICOTINE PHA.RMACODYNAFICS
In this section, I will discuss nicotine's action
on the nervous
system and on behaviour which may be used to
account for the smoking
habit. With such a vast literature, on2y
illustrative experiments can
be cited.
A. Veurocbemical Action of.Nicotine
Ricotine could modify neural-transmission by
interfering with one or
more of the processes that are responsible for the
regulation of
transmitters i.e. (1) transmitter synthesis; (2)
Presynaptic storage;
(3) Transmitter inactivation (Warburton, 1975)-
There is evidence from in vivo animal studies that
nicotine produces
changes in the brain T-evels of catecbolamines,
indoleamines and
acetylcholine. The crucial questions are bow can
these changes in
levels be related to the dynamics of transmitter
systems and whether
these changes can be extrapolated meaningfully to
explain the human
smoking habit. A major problem, with the majority
of these animal
studies, is the unrealistically high doses of
nicotine that have been
tested. A 75 kg person, who takes between 0.75 and
3-0 mg of nicotine
from a cigarette into his mouth, will receive a
dose of between 10 and
40 ug I)tr.kg- -- There will obviously be
differences because of the
route of administration and the metabolic rates of
different species,
but it is safe to conclude that in mice, rats or
cats, over 10 timeE
"his does (0-4, mg/kg) is well outside the
"smoking' dose range.
Catecholamines
StudieE or, the cEtecholami-nes, have been carried
out by Licbtensteiger cc
14
BATCo document for Province of British Columbia 5
November 1999


and his co-varkers; (Lichtensteiger, 1979), by
Fuxe and his colleagues
(Fuxe, Agnati, Eneroth, Gustafson, Hokfelt,
Lofetrom, Skett and Skett,
1977) and Westfall's laboratory (Westfall, 1974).
These studies have
given the same answer in spite of wide differences
in nicotine done
levels, which ranged from 0-33 mg/kg in one of
Lichtensteiger's
tudieB to four doses of 3 mg/kg at 30 min
intervals in one of the
xperi ments of Fuxe's group. Lichtensteiger
repprted that increased
:
fluorescence intensity of catecbolamine neurones
in the substantia
nigra nuclei, zona compacts and tons incerta with
doses of 0-33 mg/kg
of nicotine, suggesting increased activity in
these neurones. This
conclusion was supported by recording from the
neurones and
biochemical analysis which showed some depletion
of both transmitters.
Nicotine produced a 25 per cent depletion of
catecbolamine levels in
the median palisade zone of the median eminence of
male rats (Fuxe et
al, 1977) but hexamethonium, a cbolinergic
blocker, prevented
depletion. No changes were found in dopamine or
noradrenalin receptor
activity in in vitro studies so the chang are
secondary to effects
on cholinerg-i7-c neurones. oc~t IV CC, a4f. ) -
r.
2. Indoleamines
Changes in the concentration and turnover of
eerotonin have been found
after doses of nicotine. A dose of 1 mg/kg of
nicotine,
intraperitoneally injected into mice, markedly
increased the levels of
serotonin in the mesencephalon and diencephalon
within 15 mins but not
in the cortex (Essman,1971). In the same study
serotonin's major
metabolite, 5-bydroryindoleacetic acid, was also
increased but there
was a decreased serotonin turnover rate of 20 per
cent and increased
serotonin turnover time C-300 per cent). It is not
clear whether the
changes in serotonin in rats after a large dose of
nicotine are
important for human smoking.
3- Acetylcholine
Nicotine depletes whole brain acetylcholine in the
mouse (Essman,
1971) in doses of I mg/kg. Depletion of
transmitter could be a
consequence of decreases synthesis, increased
release from storaEe,
increased release into the synaptic cleft or more
effective enzymatic
activation. There is no evidence that nicotine
modifies acetylcholine
synthesis (Hrdina, 1974) and the enzymatic
inactivation of
acetylcholine is extremely effective, which argues
for a change in
either storage or release. There is also for
increased free
acetylcholine at the cortex after a "smoking" dose
in the cet
(Armitage, Hall, Sellers, 1969) which is
consistent with both ideas.
The question of nicotine-i-nduced changes in
acetylcholine atoraEe
pools was tackled by Essman (1971). He found
evidence of a decrease
of acetylcholine in synaptic vesicles and in bound
acetylcbcl4-re at
the neocortex which suggests that acetylcholine
wac- beinLr released
from storage by nicotine. However there was mc
Increase i- the free
acetylcholine pool concentration which argues for
increased :-cleEse of
the unbound trans=itter and E u t se q uEnt irEc
t- va t; on by
scetylcholinestF_rase- The phenomenon of
incre!Ezed release at the
cortex would be' explained if nicotine enhanced
presynaptic release but 0
there is no in vitro evidence of enhancerent
(Erdina, 1974). Thus we
are left with the bypothesie that it is increased
activity in the
cholinerEic neurones to the cortex which produces
the in vivo
15
BATCo document for Province of British Columbia 5
November 1999


depletion.
4. Conclusion
There is evidence that moderate to enormous doses
of nicotine change
levels of catecholamines and indoleamines although
the catecholamine
changes were mediated by cholinergic pathways. The
major effect of
"Smoking" doses has been increased cortical
release of acetylcholine
but there is no evidence that it is due to a
direct effect on cortical
neurones, but must be due to indirect activation
of the cortical
neurones and this is discussed next.
B. Feurophysiological Action of Eicotine
The action of many pharmacologicg~li- agents has
been explored by usinLr
neurones in the peripheral nervous system which
are more accessible
than those in the central nervous system. Although
cautiOL must be
exercised when using this data to explain central
nervous system
phenomena, in general, the principles that have
been derived from such
studies have proved useful in understanding
nicotine's action on the
brain. Thus the first studies will describe
nicotine's action on
these neural junctions.
I. Peripheral Nervous System
The action of nicotine on the nervous system has
been known since
1914. Dale (1914) established that nicotine
mimicked acetylcholine at
autonomic ganglia and neuromuscular junctions. The
effects of dcses
of nicotine on cell membrane depolarization and
subsequent action
potentials was examined by Paton and Perry (1953)
using the cervical
ganglion preparation of the cat. When 0.2 ml of
the solution
containing 50 ug of nicotine tartrate was injected
into the external
carotid artery there was depolarization of the
membrane and some
reduction of the subsequent action potentials, a
change which was
similar to, but more transient than, the effecte
of a small dose of
acetylcholine. Six times the above dose, 0-3 mg of
nicotine, produced
prolonged depolarization and the-action potentials
were abolished i.e.
ganglionic block:ing. A challenge with a second
dose of nicotine after
the original depolarization, but before recovery
of the action
potentials, produced less depolariEation which
demonstrated that
nicotine was producing a competitive block of
cholinergic receptors.
Exactly the same phenomenon was observed with high
doses of
acetylcholine at the motor end-plate BO that once
again nicotine is
mimicking acetylcholine. However it seems unlikely
that blood
concentrations some 100,000 timer. that found in
the human forearm vein
ever occur in the smoker's brain and hence
unlikely that e
depolariration block occurs in brain neuronec-
after nicotine(thE
biphasic effect). In summary, "smoking" doses of
nicotine precisely
mimic acetylcholine and produce the same neural
changes that would
occur after natural activation of that synapse.
The reason for the
exact mimicking of acetylcholine by nicotine at
some cholinergic
synapses is -the -remarkable similarity -between
the structures of -the
two molecules.
2 Adren&l I~edulle
One preE&ngl4.or_iL Derve Eoes tc the adrenal
medulla and i-nitiates the C=)
release of cateciolanines intc the bloodstrea=.
E=ckinc a sinr2e CD
c'garette ;:roducess hii-her 3evelc cf
ncredrenelir than rsstinE sur-ire. CDI_
U-4
CD
BATCo document for Province of British Columbia 5
November 1999


but less than quiet standing and mild exercise and
certainly less than
moderate and vigorous exercise. Adrenalin levels
after one cigarette
are about the same as after moderate exercise and
greater than resting
supine, quiet standing and mild exercise, but
about a quarter of the
levels seen after heavy exercise (Cryer, 1980).
These small increases
in plasma catecbolamines just exceed the threshold
for cardiovascular
and some metabolic effects, such as increased
heart rate, systolic
pressor effects and lipolysio but not for
byperglycemia, ketogenesis,
glycolysia and suppression of insulin secretion.
It should be noted that "not only are noradrenalin
and adrena2in
rapidly cleared but they also accelerate their own
metabolic
clearance" (Cryer, 1980, p438) so that only very
heavy smoking could
produce accumulations of adrenalin and measurable
metabolic effects.
Thus, in order to demonstrate that cigarette
smoking could produce an
increase in plasma free fatty acids and so might
contribute to
coronary heart disease, atherogenesiB, and
atherosclerosis, Kershbaum
and Ballet (1968) had to give three cigarettes in
20 min. The lack of
realism of this dose can be seen from the fact
that a 40 a day Bmoker
smokes a cigarette every 20 mins. For average
smokers the effect of
nicotine on the adrenal medulla is no more than
taking moderate
exercise. The fatigue alleviation that would
result from the
metabolic changes will be discussed in the next
Bub-section.
3. Adrenal Cortex
Unlike the adrenal medulla, release from the
adrenal cortex into the
circulation is controlled from the brain, via the
anterior pituitary.
The glucocorticoids like the catecholazines have
marked metabolic
effects but small or no haemodynamic action. As
well as conversion of
amino acids to glucose, they also speed up
extensive mobilization of
depot lipid reserves, inhibit lipid synthesis and
reduce glucose
catabolism. Together these effectB elevate plasma
concentrations of
glucose. Thus,the two sets of hormones mobilize
energy sources and
prepare the person for action and reduce fatigue.
Adrenocortical
secretion does increase after smoking although it
does not seem to
occur after one cigarette; Habitual smokers had to
chain smoke four
unspecified cigarqttes in thirty minutes to
elevate the plasma
corticosteroid levels (Kershbaum, Pappajohn,
Bellet, Hirabayashi and
Shafiiha, 1968.
In a second study (Winternitz and Quillen, 1977),
habitual smokerE
were given eight 2.5 mg nicotine cigarette to
smoke in two hours
(equivalent to over 100 cigarettes per day). Their
graph shows that
cortisol levels are the same or lower after the
second cigarette and
it iE after the third cigarette in half ar hour
tbEt cortisol had
increased. The best conclusion that can be drawn
from these studies
is that high nicotine doses from extreme smoking
rates can elevate
plasma glucocorticoide. An alternative
interpretation is that the
rapid smokine was aversive and stressed the
subjects. If we accept
the most charitable interpretation that srokinE
produces some release
of glucocorticoide tber- combined wit!
catecbolamine release, they will C__
make evailabl-L enerry sources. Tbese would be
available for use by
the brain and the rest of the body (Astrand and
Rodahl, 1970) and,
thie way, smoking would alleviate rental and
muscle fatigue. c-._::
0 _%
7
BATCO document for Province of BritiSh Columbia 5
November 1999


4. Central Nervous System
Studies with iontophoretically applied
acetylcholine have revealed
that acetylcholine excites brain
neurones.(Pbillis, 1970) including
the medullary and mesencepbalic reticular
formation, lateral and
medial geniculate, caudate, ventrobasal complex of
the thalamus,
hippocampus, cerebellum, inferior colliculus and
the Betz cells of the
cerebral cortex. Cortical cells and caudate cells
clearly have
muscarinic receptors vhich were relatively
insensitive to nicotine
while acetylcholine receptors in the geniculate,
ventrobasal thalamus,
hippocampus and reticular formation nuclei were
sensitive to both
nicotinic and muscarinic compounds.
In spite of the clear evidence that the
cbolinerEic neuioz)es at the
cortex are predominantly musearinic, .smoking"
doses of nicotine (eg
20 ug/kg in the cat) produce excitation of
cortical cells (eg Kawamura
and Domino, 1969; Armitage, Hall and Sellers,
1969) and release of
acetylcholine at the cortex (Armitage et al,
1969). Cortical
acetylcholine release and cortical excitation can
be produced by
stimulation of the mesencephalic reticular
formation and this
phenomenon can be reduced in one hemisphere by
unilateral destruction
of this region ipsilaterally (Celesia and Jasper,
1966). In an
analysis of the effects of' "smoking" doses of
nicotine after
destruction of the midbrain (Kawamura and Domino,
1969), nicotine
produced cortical desynchronization and
hippocampal synchronization in
cats with a caudal midbrain transection at the
junction of the pone in
exactly the same way as intact animals given
nicotine. After
bilateral lesions in the tegmental reggion of the
midbrain, nicotine in
doses up to five times the "amoking"dose did not
activate the cortex.
Clearly, nicotine's action on the cortex depends
on an intact
tegmental region.
The ventral tegmental region of the mesencephalic
reticular formation
is the origin of a cholinergic pathway which
projects to the cortex
(Shute and Lewis, 1967). It terminates on the Betz
cells of the
sensory cortex and produces electrocartical
arousal (see review by
Warburton, 1981). The most parsimonious conclusion
is that "smokine .
doses of nicotine ascend in the carotid artery and
excite nicotinic
receptors on the tegmental-neocortical cholinergic
pathway in the
midbrain. Ricotine does not act directly on the
cortex but the
outcome of activation of the pathway at the
midbrain is release of
acetylcholine at the cortex and cortical
desynchronization.
C. Nicotine and Human Psychopbysiology
In this section we will consider the action of
nicotine on the human
cortex in the context of psychophysiology, the
correlation of
neurophysiological events with human behaviour.
(See extensive reviev
in Edwards and 'Warburton, 19L'3).
1. Cortical Desynchronization
Yany human studies have shown that emoking
increases th,- ar-ount of
cortical deEyncbronitation in the fcrr of a--
upward Ehift in dor-inart
a2 mha freauency.(eg Hauser, Schwartz, Rotl and
Eickford, 105E), leES
tctal a1pbE activitT and more bete activit, 'rker
Ynott, 1979; Yurphree,
1979). Thus these bu=Em studies shoy tha-,
FroLing- Troduces cortical'
desynchronizetior jjE', as nicotine dces in
F-r-i=E-l EtudieS. In a Etudy C7D
1--D
C" ,
1 E
BATCo document for Province of BritiSh Columbia 5
November 1999


correlating performance with electrocortical
activity, Warburton and
Vesnes (1979) found that both cigarettes and
nicotine tablets
increased the dominant alpha frequency and beta
activity, the alert
pattern similar to that found when a person is
concentrating. In the
same study, concentration performance was improved
by these
treatments. It is significant that Murphree (1979)
was unable to
distinguish the cortical arousal changes produced
in smokers and non-
smokers by 1-86 mg of nicotine intravenously i.e.
there was no
evidence of tolerance. This lack of tolerance
explains why smokers do
not increase their smoking over the years. These
results make sense
because of the molecular similarity of nicotine
and acetylcholine
because the brain cannot become tolerant to its
own transmitters.
In summary, the shifts in cortical activity are
within normal limits
and are indistinguishable from that Been when a
person is concentrating
hard. There is certainly no evidence of the EEG
abnormalities.
Smokers claim that they smoke to help them think
and concentrate and
nicotine's action an cortical desynchronization
produces the neural
state for satisfying this need. Evidence that
smokers can control
their nicotine intake to produce a specific brain
state has come from
contingent negative variation studies.
2. Contingent Regative Variation
The contingent negative variation (C19V) appears
as a slow negative
shift of cortical potential during the period
between a warning signal
and an imperative stimulus which requires a motor
response or a
decision i.e. planned action. Significant
correlations have been
reported between CNV amplitude and measures said
to represent many
psychological processes, but selective attention
or concentration is
the most commonly cited concept.
Experiments on the CHV and smoking (Ashton, MarBh,
Millman, Rawlins,
Telford and Thompeon,1978) have correlated CNV
with subjective reports
of feeling either "relaxed" or "stimulated
following smoking. Ashton
collected personality information and estimated
the amount of nicotine
taken into each subject's mouth from the cigarette
butts. After
smoking CNV amplitude increased in seven subjects,
decreased in eleven
and four Bbowed a bi-directional response (ABhton
et al, 1974).
Puffing an unlit cigarette by three other subjects
resulted in no CYV
amplitude changes. Repetition of the smoking
sessions for 11 of the
22 subjects produced the same directional changes
in the CNV in these
individuals.
Ashton assumed that there is a positive
relationship between CNV
magnitude and the individual's level of activity
in the neural
systems. Accordingly, they related individual
differences in CNV
personality and smoking behaviour by dividing
their group at the
extraversion mean. They found that the eight more
extraverted
subjects took a smaller oral dose-of nicotine-and
showed a mean
increase in CKV magnitude after smoking, while the
eight more
introverted eAjectr showed the reverBe. There was
some evidence from
subjects that self-report of a "sedative" effect
of smoking was C=:)
associated with a fall in CNV whereas
"stimulation" was associated
witb a rise in CKV.
BATCo document for Province of BritiSh Columbia 5
November 1999


Ashton and her co-yorkers 0978) also examined the
effects of a dose
of nicotine similar to that obtained by an
inhaling smoker from a I -
2 mg nicotine cigarette. The same direction of
change in CYV occurred
in individuals who took part in both the smoking
and nicotine
sessions. Then Ashton et al (1978) examined
whether the CKV changes
are dependent an the dose of nicotine
or,.a2ternatively, on both the
characteristics of the smoker and dose. Over a
range of doses there
was an inverted U relation between CKV magnitude
and dose for all
seven subjects, although the precise dose-response
relation was not
the same for each of them.
In summary, nicotine increased or decreased the
CKV amplitude
depending on the dose and subjects seemed to
control their smoking
behaviour in order to obtain a particular dose.
These findings were
combined by Ashton to give the hypothesis that
individuals adjust
their smoking behaviour to the amount of nicotine
for a particular
brain state and so control their psychological
state. Extending this
concept the desired state will depend on the
outcome of interaction
between the individual and the situation and, by
adjusting the
nicotine dose, the same individual may use a
cigarette to provide a
.stimulant" effect on one occasion and a
"sedative" effect on another.
3. Event-Related Potentials (ERP)
Event-Related Potentials, sometimes known as
Averaged Evoked
Potentials, are the complex electrical changes
recorded at the sane
time as a physical or mental event and represent
the activitv of
groups of neurones in the brain. The obvious
advantage of the EPP
technique is that it provides a continuous record
of evente occurring
in the brain during psychological processes. Vitb
repetitive
stimulation, the waveform between 0 to 250 mBec
post-stimulus consists
of components which are essentially constant for a
given stimulus.
These exogenous components occur irrespective of
the person's state.
Of particular interest are tb6 later so-called
endogenous cooponents
which are elicited or emitted in the absence of
stimulation, and whose
characteristics are partially independent of the
stimulus
characteristics. The major endogenous component
which has been
identified is the F3~or P300 whose latency ranges
from 275 - 600 msec.
The P300 is particularly sensitive to the
subject's prior experience,
intentions and decisions and varies according Zo
the task requirements
and instructions.
In an analysis of the effects of smoking on the
EF.Ps to correct target
detections in a rapid information processing task
(Edwards, Wesnes,
Warburton and Cale, in preparation), subjects were
instructed to
detect and respond to triplets of three odd or
even digits in a
sequence of single numbers that were presented on
a TV screen at the
rate of 100 per minute. Good performance depended
on subjects
maintaining Abeir concentration throughout the 20
minute session.
Smoking produced large decreases in the latency of
P300 (20-30 msec
decrease) and small decreases in the arplitude of
F300. A reduction
in P300 latendy is interpreted as a decrease Jn
tbe-time taken tc
evaluate or categorise a stimulus while a decreaL
-e ir F-31DO artlitudE
is thought to mean that the subject is usinE lesff
neural "resources"
in proceeFILE. Sr:oking also increased the targets
detected ard
20
BATCO document for Province of BritiSh Columbia 5
November 1999


decreased reaction time (see sub-section IV 1)).
This improvement of
performance fits neatly with the P300 changes
which are indicative of
more efficient neural processing of the input.
D. Psychopharmacology of Nicotine
In this section evidence will be presented on the
implications for
human behaviour of the neural states that are
induced by nicotine. As
we have seen, nicotine stimulates and produces
increased neural
changes that have been interpreted as F_ sedation
effect.
Questionnaire surveys (eg McKennell, 1970; Thomas,
1973; Russell, Peto
and Patel, 1974) have shown that desires for
stimulation and for
sedation are major smoking motives. Thus, this
section will
concentrate on the evidence for more efficient
performance after
nicotine and the effects of nicotine on mood
states.
1. Performance
This section discusses (1) sensation (the input of
information); (2)
attention (selection of information); (3)
processing of information;
(4) learning and memory (storage of information);
and (5) motor output
(the response). An extensive review of the effects
of smoking and
nicotine on performance has been published (Wesnes
and Warburton,
1983a) and so this section will be very selective.
a. Sensation: There is little evidence from
subjective reports of
smokers that smoking has any effect on sensation,
except perhaps for a
possible blunting of taste and smell. Some
research baE suggested
that smoking raises sensory thresholds slightly
i.e. the smokers are
less sensitive to stimuli (Larson, Haag and
Silvette, 1961) but there
are also reports that smoking doses of carbon
monoxide increase
thresholds (Halperin, McFarland, Niven and
Rougbton, 1959) which would
explain these changes. Even for taste and smell
the evidence for
changes after smoking are not clear cut. Pangborn
and Trabue (1973)
reviewed 16 experimental studies between 1937 and
1970 of which 11
reported impaired taste and, or, smell with heavy
smoking and five
which found no difference. The effects of nicotine
alone on sensory
thresholds have not been studied. A second test,
which has been used
to assess the effects of smoking on sensation, is
the critics.2 flicker
lusion test. Briefly, this task requires the
subject to discriminate
between -intermittent photic stimulation which
either appears to
flicker or appears to be a steady light. The
dependent variable is
the frequency at which the change in appearance
occurs so that a rise
in threshold could indicate better senscry
processing. Smoking
increased the threshold slightly (Larson, Finnegan
and Haag, 1950) and
a later study using an oral dose of 0.1 mg of
nicotine (Warwick and
Eysenck, 1963) found an elevation of the fusion
threshold by about
seven per cent. It is believed that the mechanism
for critical
flicker fusion is at the cortex and so Warwick and
Eysenck claim that
nicotine is improv-ing cortical reactivity rather
than sensory
processinE. In the next section we will be
considering the process of
attertion whicb,is also related to cortical
arousal.
L. Attention: Smoking motive questionnairee (e.g.
Russell, et &I, C=)
1974) indicate clearly that smokers believe that
amokdng helFE tbez tc. C:D
think and to ccncez-6.-rate. The first
expericental evidence tc surE!ez': CD
C71
21
BATCo document for Province of BritiSh Columbia 5
November 1999


that this experience of enhanced concentration was
due to nicotine
came from a complex vigilance study with a main
guiding task slid a
subsidiary visual monitoring (Tarriere and
Hartemann 1964). They
counted correct detections of peripheral signals.
false detections and
guidance errors and measured plasma nicotine,
beart rate and EEC. The
test groups were non-smokers, smokers deprived for
20 hours and
smokers allowed to smoke unspecified cigarettes
whenever they wished.
They do not give the plasma nicotine levels or EEG
data but an
elevation of heart rate, after smoking, indicates
some nicotine
absorption. Vigilance performance (per cent
omissions) declined in
non-smokers and deprived smokers during the test
but nicotine
maintained detection performance throughout the
session. Ao other
behavioural data were given on detection errors ox
guidance errors,
presumably because they did not change.
Frankenhaeuser and her colleagues (Frankenhaeuser,
Myraten, Post and
Johanaeon, 1971) also found that smoking during an
80 min. reaction
time task enabled subjects to maintain their
performance. All
subjects were deprived of cigarettes for 10 hours
prior to testing.
Half of them remained deprived throughout the test
while the other
half were allowed a 1.4 mg nicotine cigarette
after 20 mins, 40 mins
and 60 mins of testing. Heart rate increased which
suggested that
nicotine had been absorbed. The reaction times for
the deprived
smokers increased during the session while smoking
maintained the
reaction time. The smokers also reported that they
felt more alert
and more relaxed when amok:Lng.
Essentially, the same findings were obtained when
the study was
repeated using either a similar prolonged test or
this test with the
added stress of two other tasks to be performed at
the same time - a
high arousal test ()Iyroten, Post, Frankenbaeuser
and Johansson, 1972b;
14 yrsten, Andersson, Frankenhaeuser and Mardh,
1972a). The smokers
were sub-divided into.smokers who smoked more
often in low arousal
situations and those who smoked more often in high
arousal situations.
Reaction times were better for low arousal Emokers
Who smoked during
the low arousal test than when they were deprived
but emoizLn_c was not
beneficial during the high arousal test. The
opposite finding was
obtained for the high arousal smokers. These two
studies were the
first to reveal that performance was the outcome
of a smoking x
individual x situation interaction.
Veones and Warburton (1978) tested smokers
deprived for 12 hours and
non-smokers on a visual vigilance task which
consisted of detecting I
brief pauses in the minute hand of a clock.
Detection performance
declined over the 80 minute test in all subjects
who did not emcke but
deprived smokers who smoked a 1.4 mg cigarette at
20 vins, 40 minr and
60 mins (as in the Frankenbaeuaer studies) showed
no decrement in
performance. CigaretteE had helped smokers to
maintain better
detection perforzance than either deprived smokers
or non-smokers.
The two non-smoking groups did not differ
siErificantly sc there vas
no support for the hypothesis that cigarette
deprivaticm ves an
important factor.
Evidence that thin effect was due to ricetine came
from amcthsr
(Vesnes, Warburton and Matz, 1983) with thin tank
us~-_[- C, I and 2 ME
C=)
CD
22 CD
Cr,
BATCo document for Province of British Columbia 5
November 1999


nicotine on alkaline tablets held in the mouth at
the same 20 minute
intervals as before. During the first 20 minutes,
performance in the
three conditions was matched to give a baseline
and a comparison of
the three conditions shoved a clear dose related
improvement after the
first and second tablets at 20 mins and 40 mins.
However, after the
third tablet at 60 mina, performance was worse in
the 2 mg group than
the I mg group, probably due to the adverse
effects of a cumulative
dose of 6 mg of nicotine in an hour.
In a third study, cigarettes yielding 0-31, 0.71
and 1.65 mg of
nicotine were compared using a version of the
vigilance ask, with well
defined detection intervals and the same
experimental deEign ae
before. (Weanes and Warburton, 1978). The
cigarette butte were
analysed to estimate the amount of nicotine which
was generated by the
amoker. The best group performance during the
first 20 IminuteB after
a cigarette was obtained after smoking the 0.71 mg
nicotine cigarette
rather than after smoking the 0.31 mg nicotine
cigarette. However,
the butt analyses showed that smokers obtained
estimated mouth levels
of 0.63 mg of nicotine from the 0-31 mg nicotine
cigarette, 1.3 mg
nicotine from the 0.71 mg nicotine cigarette and
1.5 mg nicotine from
the 1.65 mg nicotine cigarette giving evidence of
titration. Analyses
of individual differences gave clear evidence that
subjects who scored
high on neuroticism smoked harder at the beginning
of the session than
low neuroticism subjects while there was some
evidence that subjects
who scored high on extraversion smoked more
intensely at the end of
the session than the more introverted subjects.
These studies suggest
that subjects bad a need for nicotine to help them
perform which
determined the smoking behaviour so that
performance was the outcome
of the interaction of the situation, the
individual and smoking.
As well as examining the effects of nicotine and
smoking in a long
boring task ve have also examined sustained
attention in a shorter 20
min rapid information processing test, that was
described in Secticr.
IV C3- In a set of eight studies (see Wesnes and
Warburton, 1978;
19 F-3; 1984a and b) we have tested cigarettes
with nicotine deliveries
ranging from 0 mg (herbal cigarette) to 2 mg as
vell as nicotine
tablets. Each subject was tested for 10 minutes
before a further 20
minutes after a cigarette or tablet. Performance
was compared with
both the pre-treatment baseline and the no
smoking, herbal cigarette
or placebo tablet conditions. The overall pattern
of findings shoved
that performance declined over the session in
exactly the same way for
herbal cigarettes and no smoking , showing that
the smoking act
itself bad no influence on performance. Smokinv
not only improved
performance relative to not smoking but produced
an absolute
enhancement of 11 - 15 per cent relative to the
pre-nicotine baseline
in the first 10 minutes in 68 - 76 per cent of the
subjects for each
cigarette in each study. In general, greater
improvement was seen
after high delivery cigarettes than low delivery
products but there
was overla_p between cigarettes of similar
delivery probably due to
nicotine titration by the subjects.
Conclusive evidence that the better detection
performance was due to
nicotine came from a study with non smokerE using
alkaline tablets
ccnte.ininE nicctine (Vesnes and Warburton,
1954a). Doses of 0.5, 1X
and 1.5 mE cf nicot--ne significantly reduced the
decrement tha't
27
CZ)
C:D
ON
BATCo document for Province of BritiSh Columbia 6
November 1999


occurred in the placebo condition and the 1.5 mg
done produced a
significant absolute improvement relative to the
pre-treatment
baseline. In this task the stimuli were well above
threshold, the
memory component was small and the motor response
was a simple button
press so it can be concluded that nicotine was
enhancing either the
attentional process, information processing, or
both processes.
Support for enhancement of the attentional
probessing came from a
study of nicotine tablets and the Stroop effect
(Yesnes, and
Warburton, 1984a). In the Stroop test, subjects
name the colourE of
either a set of colour spots or a set of colour
words printed in
another colour. There is a difference between the
time taken to read
the two sets, because of the distraction produced
ty the incongruity
between print colour and the word. ]Ricotine doses
of 1 mg and 2 mE
reduced the magnitude of the Stroop effect in both
smokers and non-
smokers and there was no difference in the size of
the effect in
smokers and non-smokers. This evidence argues
strongly for the
hypothesis that nicotine helps a subject to ignore
distracting
information and concentrate on relevant
information.
In summary, these data support the subjective
experience of smokere
that smoking helps them to concentrate. Nicotine
increases
electrocortical arousal and so this work fits
neatly vitb research
demonstrating that compounds which modify
electrocortical arousal
change attentional performance (See review
Warburton, 1981).
c. Information Processing: The studies of smokinC
and nicotine tablets
and rapid information processing (Wesnes and
Warburton, 1933b; 1984a
and b) provide unequivocal evidence for more
efficient processing in
terms of improved detection of triplets of three
odd or three even
digits in a string of single numbers flashed on a
computer screen.
However, nicotine from cigarettes and tablets also
reduced reaction
time. This improvement was around seven per cent
and between 65 and
77 per cent of the subjects were' improved
depending on the cigarette'L-
nicotine delivery. This finding is very important
because it shove
that there is no speed and accuracy trade-off and
so there was an
overall improvement in processing efficiency. This
behavioural data
fits with the study of Edwards et al (in press)
which showed that
smoking decreased the latency of the P300 wave in
the rapid
information processing task (Sub-section IV C3).
Thus both
behavioural and electrocortical measures indicate
that nicotine is
enabling more efficient processing of information
in the brain.
d. Learning and Memory: The effects of nicotine on
learning have been
investigated extensively by Karin Andereson. The
first study,
(Andersson and Post, 1974) compared the effect of
two nicotine-free
cigarettes and two 2.1 mE nicotine cigarettes on
light smokers (less
than five per day) who were deprived for 12 hours
prior to the
testing, when learning a nonsense syllable list.
Significant C=)
increases in heart rate indicated that nicotine
waE abscrbe~ frcz the
nicotine cigarettes. The first cigarette war-
Eiver. after the firEt CZ)
ter, trials of'I,earning the list and a second
cigarette, r,.' tbe c-azc- CD
kind waE given after 20 trials given every two
=-4rui.es. Tbe lesym4=C
curves were idemtical for the two conditions rrior
tc eroking, hut
after nicotine the nu=ber correct decreased and
t-,f
CO
2 L
BATCo document for Province of British Columbia 5
November 1999


scores in the nicotine-free condition suggesting
impaired short term
memory although the learning curves were parallel.
After the second nicotine cigarette, the number of
correct syllables
increased significantly to the same level of
acquisition performance
as in the nicotine-free cigarette condition. Thus,
relative to the
previous performance, nicotine bad improved recall
of the syllables.
The difficulty of interpreting the effects of
nicotine in this study
is that learning and recall are occurring over a
20 minute period
while plasma and brain levels of nicotine were
falling to half of
their peak levels. These date give no evidence of
nicotine impairing
acquisition because the learning curves are
parallel after the
nicotine cigarette. However, it appeared that
after the first
nicotine cigarette, the information stored in the
non-nicotine state
van less available in the nicotine state, a
phenomenon known as state-
dependent learning, perbaps due to the different
selection of
information in the two states.
Another study by Andersson (Andersson and Hockey,
1977) used a memory
task of relevant and irrelevant information which
enables a test of
this selectional interpretation. A list of eight
adjectives were
presented, one at a time, in one of the four
corners of a screen and
the subjects were asked to remember the vords in
presentation order
and by implication location was irrelevant. Two
groups of deprived
smokers received either a 2.3 mg nicotine
cigarette or remained
deprived. There were no differences between the
nicotine and no
nicotine groups for percentage of words that were
recalled in the
correct order, or for the percentage of words that
were recalled
correctly regardless of word order which
contradicts Andersson's
previous evidence on recall. The most interesting
finding was that
position on the screen was recalled significantly
less well with
nicotine. In a second test in which subjects were
asked to remember
words, word order and screen position, the groups
did not differ
significantly in their recall although there was a
trend for location
to be recalled better after nicotine than when
deprived. These data
on recall also contradict the previous findings.
This study suggests
that nicotine can enable more selective processing
of information but
only when the information is thought to be
irrelevant by the subjects
i.e. nicotine is not acting via a passive
processing system.
The possibility of nicotine producing state
dependent learning in
huran subjects was mentioned earlier and numerous
animal studies have
given evidence of state dependency with
cholinergic agents (see review
in Warburton, 10,77). 133 a state dependent
desiEr, one group of
subjects learns after a dose of compound while a
second group learns
after a placebo or nothing. For the recall test
both grcups are
divided, one half of each group are tested with
the agent of learning
and half are switched to the other condition. If
the recall scores
Ere better for those groups which learned In the
same chezical state,
then state dependent learning is said to have
occurred. This state <=)
dependency hypothesis with nicotine has been
investigated ir several
studies. CD
In the first published study (Houston, Schneider
and Jsrvik, 197E) 23
heE,,T smokers, deprived of cigarettes for three
hours, read a Lisa 1 011
c.
BATCo document for Province of BritiSh Columbia 5
November 1999


words and were matched an a free recall test prior
to smoking. One
group smoked a 1.5 mg nicotine cigarette and the
other group smoked
a non-nicotine cigarette and then the subjects
were given three lists
with free recall tests after each one. The
immediate recall scores
showed that the nicotine group bad significantly
poorer recall than
the placebo group, matching the findings of
Anderason and Post
(1974). Forty-eigbt hours later, only eight' of
the subjects from each
condition returned for retesting and these were
syb-divided into four
groups of four subjects. The recall scores of the
subjects, who
smoked a nicotine cigarette at the time of
learning, were
significantly worse than those who smoked a
non-nicotine cigarette
which was not consistent with the findings of
Andereson and Post
(1974). No evidence of state dependent learning
was obtained which is
not surprising with such small groups.
In contrast to the last study, three studies have
found evidence for
state dependent learning with nicotine (Peters and
McGee, 1982;
Warburton, Vesnes and Shergold, 1982). The first
experiment used the
state dependent design to test nicotine's effect
on recall and
recognition memory. After smoking a 1.4 mg
cigarette, the subjects
were shown a list of nouns and immediately. asked
to write down as many
as they could. There was no evidence of any
difference on immediate
recall in agreement with AndersBon and Hockey
(1977) and Houston et al
(1978). However the recognition test on the next
day showed a clear
state dependent effect but no difference between
the same state
groups. In another recognition study (Warburton at
al, 1982), smokers
who were deprived of cigarettes for 10 hours were
giverl a 1.4 mg
nicotine cigarette or nothing immediately before
serial presentation
of a set of Chinese radicals. They were divided
into four groups -
no smoking prior to learning and racall; no
smoking prior to learning
but a cigarette prior to recall; a cigarette prior
to learning end
recall; and a cigarette prior to learning but none
prior to recall.
Subjects who received nicotine prior to learning
had significantly
better recognition scores than the subjects who
did not smoke in the
first part of the experiment. There was no effect
of nicotine on
recall performance. A significant interaction term
indicated that
changing the chemical state interfered with
recognition.
A more elaborate study examined the effect of a
dose of nicotine on
both short-term and long-term recall, using a
state dependent design.
Subjects,- who were smokers deprived of cigarettes
for ten hours, held
a 1.5 mg alkaline nicotine tablet, or a placebc
tablet in their mouths
for five minutes to allow nicotine absorption,
before swallowing.
After the tablet the subjectE listened to a list
of words and ther,
did successive subtractions for one mi-nute to
prevent rehearsal. A
free recall test was given and then the subjects
were told that they
would be called in one hour for a second
unspecified test. ]--:ring
the hour they worked and were then recalled, given
either nicotine or
placebo tablets, depending on their group and
asked to recall as many
of the words a tbe-r could in another 10 rinutes
free recall test. The
short tera: recall date revealed a very
significant superiority of the
nicotine group,,over the rlacebo group. Long terr
recall war a2so
siEnificantly better when subjects had taken
nicotine prior to
.earning but not when taken prior to recall. The
very significer-t CD
_~-teraction term, again Leave evidence for a
state dependent effect of
CD
26
BATCO document for Province of British Columbia 5
November 1999


nicotine and showed that nicotine was facilitating
the input of
information to storage but had no direct effect on
storage but had no
direct effect on storage or retrieval.
These last findings are consistent with previous
results which
showed that nicotine' facilitated information
processing. However, the
state dependency effect in these studies and those
of Anderason and
Post (1974) and Peters and McGee(1982) resulted-in
a poorer recall
when subjects either learned with nicotine but
recalled without
nicotine or vice versa. A state dependent effect
is not surprising
because of the differences in the processing of
information by
nicotine's action on electrocortical arousal.
e. Motor Output: There is no evidence of gross
changes in motor output
after smoking doses of nicotine or nicotine
tablets and the only
change is a reliable increase in hand tremor after
smoking (Larson et
al, 1950). This fine tremor has no practical
significance.
2. Yood States
The illustrative studies in this section have
provided no evidence of
nicotine absorption from cigarettes, and so it is
not usually possible
to separate the pharmacological effects of
nicotine from those of the
smoking ritual.
a. Anxiety: Evidence for a tranquillicing action
of smoking comes from
questionnaire studies, stress studies, personality
tests of smokers
and non-smokers, smoking abstinence studies and
situations affecting
smoking behaviour.
In a factor analysis of smoking motives, YcKennell
(1970) ertracted a
factor, "nervous irritation" smoking, which
included "smokes when
anxious or worried" and "smokes when nervous . and
also "Emokes when
angry". When cigarette consum~)tion was equated,
female smokers had
higher scores for "nervous irritation" smoking. A
factor amEl.--is of
smoking situations (Frith, 1971) found a similar
factor which be
called high arousal smoking, 8 strong desire for a
cigarette in
stressful situations, and women were more likely
than men to smoke in
these situations. Using a Smoking Motives
Questionnaire, Russell et
al (1974) found that 93 per cent of smokers who
attended a smoking
clinic, 74 per cent of non-clinic smokers said
that they smoked when
worried while and Warburton and Weenes (1978)
found that M per cent
of students answered in the same way. Altogether,
this evidence shows
that smokers believe that smoking is beneficial
when they are anxious.
Nesbitt (1973) tested heavy smokerE (20 or nore
ciEaretteE a day) and
non-smokers, using willingness to accept electric
sbocks as a measure
of anxiety. Both smokers and non-smokers were
asked to puff and
inhale fror either a 1.6 irg, or 0-11 mE nicotine
cigarette, or puff on
a= unlighted cigarette. Smokers tclerstee zuch
stronger shocks aft er
cmoking and this effect was dose dependent. On the
other band, the CD
ncr-smckerE t6lerated r-crE shcck in tbe nc
Emoking condition and CD
rligbtly less after the higb ricotire ciLearette.
CD
if it is accezted that ehocl: to2erance ie e
reasure cf a=iet-y ,ans: it
2 _11
BATCo document for Province of BritiSh Columbia 5
November 1999


is a big IF) and that non-smokers can tolerate
smoking (another big
IF), the simple explanation that smoking reduces
anxiety does not fit
this data because the absence of nicotine in
smokers could have
resulted in more anxiety than non-smokers. Smokers
who puffed an
unlighted cigarette tolerated less shock than
non-smokerB in the same
condition which suggests that nicotine -from the
smoke is more
important than the smoking ritual for an effect on
anxiety of this
sort. These findings could mean either that a
nic6tine deficit in the
smokers resulted in abstinence symptoms due to
physiological
dependence on nicotine or that smokers are
constitutionally more
AnTious.
The latter possibility can be examined from
studies of the neuroticism
level of smokers, which correlates highly with
anxiety. Eyeenck's
studies of 6,000 men gave no evidence for a
significant correlation
(Fysenck, 1963) and Rae's (1975) survey of 253
female students
revealed no differences in the degree of
neuroticism between non-
smokers, ex-smokers, light smokers or medium
smokers (less than 15 per
day). However, at least seven studies have
suggested a positive
relationship of smoking with neuroticism and this
association is
particularly strong for women smokers (Guilford,
1966; Meares, et al,
1971; Vaters, 1971; Dunnell and Cartwright, 1972;
Shiffman, 1979b;
Varburton, Wesnes and Revell, 1983).
Although this evidence suggests that smokers are
constitutionally more
Anxious, it might still be argued that repeated
exposure to nicotine
had caused s=iety and a higher neuroticism score.
Evidence against
this argument comes from a crucial study done by
Cherry and Kiernan
(1976; 1978) which have followed a cohort of 2,853
young people for 25
years. When they were 16 years old they completed
the Maudeley
Personality Inventory before most of them had
begun to smoke. At 20
years and 25 years of age they completed a smcking
habits
questionnaire and it was foundthat the cigarette
smokers, as a group,
scored more highly on extraversion and
neuroticism. Statistical
analyses revealed that the two personality
dimensions were independent
and additive in their effect on the likelihood of
becoming a habitual
smoker and suggests that constitutional factors
underlying anxiety
results in some people smoking and not the other
way round.
Given ampkers can titrate for nicotine (Section
IIID), it would be
predicted that the situational demands would
modify titration if
nicotine reduces anxiety. Schachter (1978) gave
smokers electric
shocks ostensibly to determine their tactile
sensitivity. In the Ic w
stress condition, they only received a tingling
shock whille the high
stress group were occasionally given a painful
shock. Schachter
ccunted the number of cigarettes smoked between
tests in the
laboratory and found more cigarettes were smoked
in the interval after
the high stress condition when they were anxiously
anticipating the
next test series. Unfortunately, he did not
collect any information
about smoke generation and smoke manipulation.
ir- a recent study (Varburion et al, 1933),
undergraduates filled in a
detailed diary on their smoking habits during a
first year examinaticr
period and again 6 weeks later, after the
ezamination results had come CD
01 ~t. From the ciEarette totalE for the
afternocns and eveniar_5 it was CD
26
BATCo document for Province of BritiSh Columbia 5
November 1999


obvious that subjects smoked significantly more
cigarettes at all
times during the examination period than six weeks
later. Subjects
also gave a subjective evaluation of their degree
of inhalation and
there were highly significant increases in degree
of inhalation during
the examinations with respect to the
post-examinaticn period. Thus
the students smoked more when faced with
examinations and the
concomitant stress.
The situation x individual x smoking interaction
was examined by
studying the amount of nicotine taken by subjects
in the vigilance
test mentioned earlier (Warburton and Weenes,
1978). A positive
correlation was found between neuroticiam and the
difference in smoke
generation between the first and last cigarette
for both the low
nicotine cigarette and the high nicotine
cigarette, indicating that
the more neurotic subjects smoke more intensely at
the beginning of
the session than at the end of the test. This
result provides further
evidence that one aspect of smoking behaviour is
the outcome of the
interaction of the situation and the individual
and increases in
stressful situations; smokers use more cigarettes,
smoke them more
intensely and inhale the smoke more deeply with
those who are more
anxious and susceptible to stress showing the most
marked effects.
An interesting question is whether smoking does
help to cope vitb
streSE and improve behavioural efficiency? We have
analysed
performance increments as a function of
neuroticism. and found that
there was a direct association between the degree
of neuroticism and
the amount of performance improvement after
smokirg (WerburtoL and
Wesnes, 197e). The latter association iE
consistent with data
obtained by Kucek (1975) In an experiment where
subjects were teeted
under conditions of information overload. A
comparison of neurotic
smokers, who were allowed to smoke, and neurotic
smokerE who were
deprived of smoking showed that smoking had a
beneficial effect on the
performance of neurotic subjects allowed to smoke.
Ficotine is the most likely constituent of
cigarettes for producing
this improvement in performance, and we found that
for both females
and males the performance improvements after
nicotine tablet were
directly correlated with neuroticiam scores
(Warburton and Wesnes,
1978). This significant association with
neuroticism gives some
evidence. for the hypothesis that nicotine is the
tranquillizing
ingredient of cigarette smoke.
inferences about the properties of a
pharmacological agent can often
be made from the symptoms that occur when
medication is terminated.
Studies of withdrawal symptoms that follow
cessation of smoking show
that one of the major symptoms is anxiety
(Fesbitt, 1973; shiffma-- &Ld
Jarvik, 1976) and it is more likely to occur in
women amcng who= there
is a greater proportion of neurotic smokers
(Guilfcrd, 1966; Shiffcez,
1979 b). An -analysis of -the -situations which
resulted in a returL tc
scokinE by Marlatt (1979) and Shiffman (1979 a)
indicated that K -r~er
cent of these. Pituations fell into three
cate~corieE: copingr with C=)
anxiety and other negative emotional states (43%),
Eocial pressure C::)
(25%) and co;-JnE with social stress (12%). Few of
Yarlatt*E and C:)
Shifft:En's relapsed smokers reported that
pbysica2 sy-=ptc=r- triggeree 0-1
the r-ela;:se which argues aEainst the physical
dependence hy-potheEis- -=~-
Lf-J
29
BATCo document for Province of BritiSh Columbia 5
November 1999


In the Shiffzan (1979 a) study, tvc, th.--rdE of
the Fultiects -.-Fre
ctress at the time of relapse aL-d arx:ety was
particularly COL.-:c:.
cmonE ez-snokerE who relapsed at work, which
siogfest& that
related r-nxietv was a contributcry "actor.
Neurotics are mcre
arxiety-prcne and so it is not surprising that
they find it difficult
tC, EtOj- er-okinE or relapse if they abstEin
.(Cherry and K--;rzr-.aL, 1978).
These data on smok.-nC to cope with stress fit
meetly witl , studies
showinLr that de;rived smokers are more lil-e2F*to
feel anxiCUF in
rtreerful r-ituptionE (FrankenhaeuEer, et a!,
1971; YTrSteL. et &I,
1972a; Schachter, 1978).
A large epidemicicrical study has given some
evidence -.11:2crl LF7
indice,e there are adverse consequencer Of ErckinE
censEticr (lee,
1979). E.-it-ish doctors have reduced their
cigarette um,,~hing over 2L'
yearE, and there has been some of the eipected f--
;:rcvfrer, --'r-
mcrtality rate froz "e=oke-related" diseases, but
tht.- over~lj dEE41t.
rate did not fall as much &E would have beer,
predicted fron cther
Lgrou;2 of eimilar socioeconomic status. Mortality
froz other ca--,sfE
ha~"- Increased and, in partict:2ar,
etrces-:-elated deathr LF-,-;
relative to other prcfeEsiona in the ect: valent
eoci&2 c--&FE; mc-c
doctors had died from accidents, poiscninr--,
suicide, ano _c:.rrzC-5-,E C-
the liver. Lee concludes that "the relative
vorserinLr in E: C r-,L
from strasr-related diseases may have been due
partly to F- yc~F.,t-e
adverse effect Of giviDE UP ecckirE if smoking had
acted tc red-jc-E
stresr" (p 1538). This CODCIUEiOD rust be treated
vith cLuzzcz
bect-.;se 4-t is &Iwr:yE very hazardous to arrue
fror ccrrelraticr 1c:
caus. l-JtT but, Levertheless, it is consistent
with the FrevicuF dE-:L.
In summary, a larEe body of evidence indicates
thst ecc+err Emck-- -J--
order to reduce anxiety and smoke more and
preEurably ts:le rcr(
nicotine wheL under stress. Certainly,
&--iiety-pronf SLIJ-ctr -r:;-~
mcre intenselT and experiments show that nicotine
hc----T-s -E-
better. Ex-smokers report that en i-e-ty is One of
the n. i,_:- rr.'t ". E :7 c
of cessation and that streas' can lead tc relerse.
:;here F-c:-
sugEestict that those smokers who do elctair zzr;y
be r-crE i:c:t
stresE~-related discrders. It must be noted that
nicctine hzs rc-.
estal.'ished as the crucial aE-ent for aniietv
reduction, trErf- FrE a
nur-be: of otber Y)ossitls chemicals in c~ FarEtte
emoke anc
of Erzcke inLrredients that could be invo2ved iL
trF-LCU--*22i--&t;.Cz.-
lievertheless, nicotine is the most Pct~~nt
FFTchc&ct~-VE Srent :L
tol'acco Emoke.
b. Jmger- Another item that made uT, the
*'nc---~-ouE --;rritF-ticr'* factcr
sr-L-king in the 1-cKennell (1970)
q-,;est-,ornEire wF-E ezger- -n~z&r
reported that ciLrerette smcker-- a--d fcr=cr
2 evele of irritability arad Enrer, iL
ccm;.F-risor Vitf-
smckers. When the amchers VEre diviced irtc licht
(-'-css thai. I- F
6&y) and beEvy groups, the beavy archers showed
greater anfer
stress than ;
,be light E=okErE. SrckizC vhen
arEry was c r c- :~ & ", , - CZ)
reas= rivez for s~-ckirr !,-7 em,-J-err a
~
I
~
Z EtCZ CI:L ::
' F C---,
t':.
:.c.--C
ir-c --=okerr (1-75~,, &n
E:: -5
L L
&r-~L :-tC.: ar i C-SL e Z,
En-,E i; d es r-' &m(.-cr ar, d u -L c c z c
S F C ' C E:..- t rE::-,S C:. a,-' P. % C e 7. :r
r-; 7
BATCo document for Province of BritiSh Columbia 6
November 1999


done. Schachter (1978) reports a study by Perlick
which compared
irritability in "unrestrained" smokers and
restrained" smokers who
were trying to cut down their smoking. Each group
rated the annoyance
caused by aircraft noise, after smoking either a
1-3 mg nicotine
cigarette, a 0.3 mg nicotine cigarette or not
smoking. Unrestrained
smokers, when deprived or smoking the 0.3 mg
nicotine cigarette, were
more annoyed than when smoking the 1*.3 mg
cigarette. However,
unrestrained smokers, when smoking the 1.3 mg
cigarette, were no
better than non-smokers. The restrained group were
just as irritated
in all three conditions as the deprived or low
nicotine, unrestrained
smokers. There are at least two explanations for
these results;
either irritability is an abstinence symptom which
is the consequence
.f nicotine dependence, or smokers are
constitutionally more irritable
and nicotine from smoking helps to reduce this
feeling.
Studies of abstinence have shown hostility and
aggression increase
markedly during abstinence (Schachter and Pend,
1974; Shiffman and
Jarvik, 1976). Anger commonly triggers relapse
among ex-smckers, and
these relapses occurred in the absence of
smoking-related cues such as
.people around were smoking". (Shiffman, 1979 a).
Clearly, the
smoker who is deprived of nicotine is less calm.
Evidence from a
study by Thomas (1973), which showed similar
scores for anEer wher,
11 tressed for smokers and ex-emokers, suggests
that smokers are
constitutionally more angry and irritable.
In summary, smoking, and by inference nicotine,
seems to have anti-
anger effects as well as am anti-anxiety action.
3. Conclusion
Ficotine seems to be a unique substance because it
combines both
performance enhancement with anti-anxiety and
anti-arrer actior, or, the
basis of the present evidence. This finding alone
is interesting, tut
it is even more significant when it is considered
in the liCht of the
smoker*s precise personal control over nicotine
intake. Tie datrz iL
the preceding sections can be combined to argue
that cigcarette swokine
can be regarded as self-medication for certain
groups. Ftudies of
self-zedication suggest that people use those
classes of aEent which
fulfil their own i-ndividual needs (Warburton,
1978) and the research
presented here argues persuasively that people
titrate nicotine to
obtain- a specific dose to fit their needs.
Lepending on the situation, smokers will adjust
their evoking
behaviour in terms of the number of ciEaretteE
sr-oked, smoke
grenerstion and amount of smoke inbaled to control
the nicotine levels
reaching their brain and in this way their
psychological state.
Deprivation of cigarettes resultE in abstinence
syr-pto=s which arc
man-ifested as a less efficient function in
certain Eituations, and so
relapse is likely to occur.
Consequently, the behaviour of a smoker is the
outco=e of a cor7ler
sc-t of inte-ractions. It is deterEined, not
or-27, tT the
characteriStiCE of the r=i1':ustioz:, but the
perr-cnE24_-.-z cf th~-
individual. Personality characteristics 'will
deterrine the vET
pretE i fc.-r t t '--. i t h
vhich the individua2 selects and inter n & -
C~D
C-7)
CD
C'
(JI
BATCo document for Province of BritiSh Columbia 5
November 1999


situation ie there is an interaction going on
between individual
factors and situational factors. If it is assumed
that individual
differences have a constitutional basis (ie
differences in the
neurochemical pathways in the brain) then another
complex interaction
occurs when a pharmacological agent is given to a
person. These
agents do not affect human performance directly,
but they produce
changes in behaviour as a consequence of their
interaction with
endogenous chemicals within the body. Changed in
neurocherical
activity in the brain alter the way in which a
person interacts with
his environment and so performance reflects both
the nature of the
chemical agent and the biochemical state of the
person.
In this Sections, I have discussed the
"stimulation" smoker and the
.sedative" smoker as if they were separate
homogeneous groups who
smoked for the same reason all the time. However,
there must be
differences in smoking behaviour as a function of
the intensity of the
individual- situation interaction, its duration
and more probably its
density (the product of intensity and duration).
In other cases
smoking may not even be initiated until the
intensity, duration or
density of the interaction is at a critical level.
Clearly, lighting
a cigarette and the pattern of smoking behaviour
controlling nicotine
intake depends on the individual-situation
interaction.
Interestingly, some smokers smoke in anticipation
of a future need,
before the situation has occurred or the critical
stress level has
been reached and they are still coping. Here the
smoking behaviour is
very clearly a response to the individual's
interpretation of the
situation, ~is expectations about when may occur,
rather than the
objective characteristics of the situation.
Smokers have learned that
to control their mood by smoking will enable them
to function more
efficientli on some tasks and will help then avoid
the undesired
consequences of other situations and so
anticipatory smoking can be
seen as a rational coping strategy on the basis of
their past
experience.
Advocates of abstinence and the operators of stop
smoking clinics have
not considered the smoking habit from the point of
view of the
smoker's decision making. Smoking and absorbing
nicotine will enable
more efficient function now, but future health is
at risk. With
abstinence the multiple benefits of nicotine are
lost but there may be
better health in the future. Many smokers choose
to continue smoking
and abstaining smokers relapse indicating the
importance of the
perceived benefits of nicotine to the smoker. In
the next section we
will consider nicotine in the context of some
other substances which
are used to control mood or to perform better.
V. NICOTINE USE IF PERSPECTIVE
1. Introduction
'VheE evaluating nicotine use and the smoking
habit, it is interesting
tc cczrare nicotine with carDounds which produce
similar effects. CD
CorzzarisonE wi.;th reference substances are an
essential part cf the CD
assessment of any therapeutic agent so that the
relative ccstL- an-: CD
heneFits caL be estimated and decisions made about
the F-rent's C7111
Ur-efuluess. im the case of nicotine, the selected
re-ference F-E&I IF -r--
BATCo document for Province of BritiSh Columbia 5
November 1999


are two psychostimulanta (amphetamine and
caffeine), two aedatives (
diazepam, Valium, and alcohol) and marijuana
(active ingredient is
-tetrahydrocannabinol or THC), which is inhaled
for its pleasurable
effects.
The comparison takes the form of an analysie of
both the
pharmacokinetic and pharmacodynamic features which
could constitute
risk to the use i.e. absorption, user control of
dose, duration of
action, side effects that impair functioning
(acute toxicity), chronic
toxicity and abuse potential.
2. Absorption
As we have seen, nicotine inhaled into the lungs,
is readily absorbed
and travels to the brain within ten seconds
reaching peak
concentration immediately after the last puff of
the cigarette, ie
about seven minutes after lighting up (see Section
II). An oral dose
of alcohol must travel through the stomach to the
major site of rapid
absorption in the small intestine. Gastric
emptying time and thus
the onset of absorption results in a variable rate
of uptake so that
peak plasma and brain concentrations of alcohol
are reached between 40
and 120 minutes (Lemberger and Rubin, 1976).
Diatepar is also
absorbed from the gastrointestinal tract and
several hourE are needed
to achieve peak blood and brain levels
(Kornestaky, 1976).
Amphetamine and caffeine are absorbed from the
stomach and peak
concentrations in plasma and brain are reached
after about 30 minutes
for caffeine (Marks and Kelly, 1973) and between
one and three hours
for amphetamine (Beckett, 1970). Amphetamine is
also taken
intravenously and peak doses in the brain can be
achieved within five
minutes (Lemberger and Rubin, 1976). The
absorption of TBC into the
bloodstream is rapid when inhaled but uptake into
the brain is slow so
that only one per cent appears in rat brain at 10
minutes (Lemberger
and Rubin, 1976). Obviously, nicotine reaches
potential active sites
in the brain very quickly in comparison with these
reference
substances.
Absorption time is significant for personal
control of effect and
prevention of over-dosiag; a fast absorption time
enables the user to
adjust his dose to his requirements and so control
the magnitude of
effect. An ideal agent for self-medication would
enable the person to
fit the dose to his needs. Smokers have puff by
puff control with
brain effects occurring within 10 seconds while a
drinker musi choose
an "appropriate" dose for effects in an hour or
so. Thus ir terms of
personal control the experienced smoker has
precise control over
nicotine's psychoactive effects whereas most
drinkers have very
haphazard control. Precision Of COLtrol is alsc
particularly
importamt when considering toxicity because the
risk of exceedi-ng the
optimal dose is minimised.
3. Duration of Action
CD
A second aspecf of pharmacck:iLe-.ics, which is
also related to peracnal CD
control of a person's psychological EtFate, is
duration Of aCtiOL.
Ferchclogica2l needs vary and zort peecple want
coping techr-Jaues for
specific occasions rather thar for chronic states.
-Thus stirulatior.
BATCo document for Province of BritiSh Columbia 5
November 1999


may be needed for an arduous task but not some
hours later at bedtime.
Nicotine has a half-life of only 20 minutes and is
cleared from the
body in about 40 minutes (see Section II). In
comparison, alcohol
(Beckett, 1970) and caffeine (Marks and Kelly,
1973) have half-lives
in the range of 3-4 hours and both may remain in
the body for e-12
hours (Gilbert, 1976). Although these values are
several orders of
magnitude more than for nicotine they are
insignificant in comparison
with the 20-50 hours for the elimination half-life
of diazepam
(Breizer, 1979) and 56 hours for THC (Lemberger
and Rubin, 1976). in
addition, diazepam and THC have active metabolites
that further
prolong their action while cotinine the major
metabolite of nicotine
seems to be virtually inactive. Clearly nicotine
fits the
specifications of a corpound which a person can
use to exert fine
control over his psychological state on an hour by
hour basis.
4. Specificity of Action
One of the important pharmacodynamic criteria for
a therapeutically
useful agent is that it is relatively specific in
its site and mode of
action. The acetylcholine, dopamine, noradrenalin
and serotonin
systems are all modified directly by alcohol
(Warburton, 1975),
caffeine (Gilbert, 1976), diazepam (Warburton,
1975) and THC (Harris,
1978). In contrast, amphetamine which only acts on
the dopamine and
noradrenalin systems, is relatively specific
(Lemberger and Rubin,
1976). From the balance of evidence available,
smoking doses of
nicotine only act directly on some of the
acetylcholine systems im the
body (the so called "nicotinic" pathways). This
specificity of action
decreases the likelihood that a compound will
produce unwanted "side
effects", which will be discussed next.
5. Toxicity
Almost all substances have toxic effects if taken
in large doses for a
sufficiently long time. In this' section we will
consider the acute,
unwanted effects of the reference compounds and
the chronic
consequences of normally-uBed doses taken over a
long period of time.
Although amphetamine can improve performance in
laboratory tests, it
also distorts judgement. Amphetamine also acts as
a sleep and
appetite suppressant, and chronic use of this
agent imvariably leads
to loss o~ weight. Frequent small doses of
amphetamines produce
psychotic episodes in normal subjects (Kornetsky,
1976) and repeated
use of high doses result in severe psychosis.
Caffeine is a much less
harmful than amphetamine but is not without toxic
effects. An average
adult consuming over 600 mg of caffeine a dEV vill
be more like2y to
experience headaches, insomnia, anxiety and
derression or waking.
Repeated use increases the 2ikelibood of
myocardial infarction,
stomach ulcers, duodenal ulcere, and carcinoma of
the kidneys and
urinary tract. ~Gilbert, 1976). TbUE, although
caffeine is not
harmless, it is a zuch safer but lesr pctent
corpcund than
araph e tam i ne
In view of alcohol'r- non-specific biache=ical
action it is nct
surprirzinLr that moderate doses of alcohol hEve e
varietr of acute
UnW&LtEd conseauences, including inpairmen-, cf
thouEht, rEzor-.,
-z4
I
CO
BATCo document for Province of BritiSh Columbia 5
November 1999


concentration, fine movement, and motor control.
As a consequence,
anxiolytic doses are incompatible with most types
of work. Moderate
drinking probably cause very little chronic
toxicity but repeated use
results in larger and larger doses being required
for anti-anxiety
effects. Long term use of larger amounts leads to
deterioration of
the brain, liver and other organs (Wallgren and
Barry, 1971)-
The most common side effects of diatepam is some
drowsiness and
impairment of concentration which are hazardous in
a tired person or
someone who has taken a small amount of alcohol.
It should also be
remembered that alcohol persists in the body for
days and so the
alcohol interaction could occur long after taking
a dose. The
evidence for chronic toxicity with diazepax
escalation of doses that
can occur with alcohol (Marks, 1978). From the
point of view of acute
and chronic toxicity, diazepam is a much safer
anxiolytic than
alcohol.
Alcohol use is often compared unfavourably with
marijuana use, but the
problem with this toxicity comparison is that we
know so little about
-tetrahydrocannabinol (THC) and its active
metabolites. Performance
testing has revealed that impaired cognitive
ability (see review in
Varburton, 1975). There is no evidence that
repeated casual use has
adverse consequences but an &motivational syndrome
after frequent
marijuana use has been reported (Warburton, 1975).
A typical list of the toxic effects of nicotine
includes evesting,
tremor, nausea, vomiting, abdominal pain,
diarrhoea, palpitation,
fatigue and headache (Cohen and Roe, 1981) but, of
these symptoms,
only tremor occurs in experienced smokers which
suggests tnat either
tolerance to these effects has occurred or the
smoker titretes hiE
dose to avoid adverse effects. There is no
evidence of intellectual
impairment during use and, on the contrary,
nicotine improves
psychological performance (see Section IV D). This
benign action
could be due to the similarity between nicotine
and acetylcholine, so
that nicotine acts in a natural way on neurones
and only produces
changes in the brain which occur normally in
states of alertness. As
a consequence of its similarity to acetylcholine,
tolerance to its
action on electrocortical arousal does not occur
(Furphree, 1979).
This lack of tolerance is not surprising because
neuronez cannot
become tolerant to their own chemicals otherwise
they would cease to
function.
Without tolerance to the desired effects, smokers
do not have to keep
on increasing the dose to achieve the desired
amounts of sedation or
stimulation- Evidence for chronic toxicity due to
nicotine alone,
rather than cigarette smoke, is sparse and there
is little convincing
evidence of intellectual impairment even after a
lifetime of use.
Chronic nicotine use has sometimes been linked to
gastrointestinal
disturbance and cardiovascular disorders but no
studies have
controlled for raffeine and alcohol consumption.
Thus, nicotine, in
Emoking doses, has little known toxicity itself
and the health hazard
to the smoker is in the other smoke constituents.
6. Abuse Potential
CZ)
CZD
cy-
BATCo document for Province of BritiSh Columbia 5
November 1999


Use of any substance can only be evaluated with
respect to the
situation of use, the manner of use as well as the
consequences of use
(Balter, 1974). Normal use can be defined as
COMBUMptiOn for an
innocuous or constructive purpose in moderate
amounts and in the
ppropriate context in terms of place and culture.
Abuse focuses on
erse consequences of use in terms of
pb.7aiological or psychological
M
ffects The consequences of abuse are organ damage
and impairment of
:ocial-and persona.2 functioning. Indirectly abuse
refers to the
manner of use by the person (pattern and amount
taken). The problem
of abuse is in the person's interaction with the
compound and is not a
fault of the compound itself. However, some
substances are more
likely to lead to abuse than others and this
aspect is referred to as
abuse potential. The abuse potential of a
substance can be defined in
terms of its intrinsic attractiveness, the number
of users and the
number of users who become abusers of the
substances.
a. Intrinsic Attractiveness: Attractiveness refers
to the extent to
which moat users find the immediate effect of a
substance
instrinsically pleasing. It in independent of
cultural factors and
can be assessed from self- administration studies
with animals. While
animals will rapidly self-administer amphetamines
shoving the high
intrinsic attractivene3s of this compound, animals
self-administer
alcohol and THC to a much lesser extent. There is
no evidence that
animals will self administer diazepam or caffeine,
indicating
negligible intrinsic attractiveness. Attempts to
train animals to
self inject nicotine or "to smoke" have been
rather unsuccessful, which
suggests very low intrinsic attractiveness------
These laboratory studies fit with human
comparisons of the compounds
which indicate that the production of euphoria
seems to be essential
for high intrinsic attractiveness and for strong
habit formation.
Intravenous amphetamine produces pleasure like a
"pharmacogenic
orgasm", alcohol and THC produce moderate
euphoria, while caffeine
produces stimulation but no euphoria and diazepam
is pleasurably
relaxing but does not produce euphoria. Nicotine
can be either mildly
stimulating or pleasurably relaxing depending on
the situation, but is
not a eupboriant.
b. Percentage of Abusers: An abuser is a person
who is consuming a
chemical iM sufficient quantities to produce
damage to health. A
comparison of the number of users and abusers is
difficult because
nicotine, caffeine and alcohol are readily
available while amphetamine
and diazepam are controlled and mariJuans (THC) is
illegal. When
amphetamines were freely available on prescription
in Britain about
20% of the users were abusing the corpound (Kilob
and Brandon, 1962).
Alcohol and caffeine are socially acceptable
subEtances in most
Western cultures, and, in these, about 5-7% abuse
a1cchc] (YiEsin,
1972) and about 3% are caffeine abusers (Gilbert,
1976). It is
estimated that 5-7% of THC users are abusers
(KissiL, 1973). Abusers
of diarepar. are rare and current estimates are
less thar 11d, (Yarks,
1978). Strictly- &peaking, the number of abusers
of nicotine is zerc.
since few individuals take nicotine alone am--:
nicctine is not known tc
contribute to the smoke-related disorders (Cohen
and Roe, 19F-1
Abuse potential has been defined ir terms of
difficulty of stcppirE
C'.4 ILI,
CD
C:)
BATCo document for Province of BritiSh Columbia 6
November 1999


use, but comparable data are only available on
alcohol and smoking,
Hunt and Bespalec (1974) compared the relapse
rates for alcoholics and
smokers with heroin (an agent with very high
intrinsic attractiveness',
and found that the relapse curves were
very.similar. However, as
Jaffe and Jarvik (1978) point out, that while one
may wonder what
drives a heroin abuser to relapse in the face' of
the social
disapproval, the physical hazards and legal risks
of heroin use, it is
not surprising that ex-emokers relapse given the
multiple motives foi
smoking.
9. Conclusions
Nicotine, as used by the smoker. is a low risk
substance in terms of
acute and chronic toxicity and the smoke-related
diseases are due to
the other smoke constituents. Its rapid uptake
into the brain allows
personal control of their psychological state at
will so that smokers
can obtain either stimulation or sedation to help
them to cope with
situations. Ficotine acts on the brain producing
changes which are
within normal limits and so produces stimulation
and sedation.
Sicotine has low abuse potential but smoking is a
strong habit because
it enables smokers to have exquisite personal
control over their
psychological functioning.
VI. CONCLUDING COMMENTS
Smokers puff a rod of burning tobacco and the
majority of them i7ahale
the smoke. As a conBequence of smoke intake, a
number of smoke
constituents including nicotine are absorbed. It
is absorbed very
efficiently, enters the brain very quickly and is
metabolised quickly
giving a brief duration of action. Smokers are
sensitive to their
plasma nicotine levels and can control their
intake of nicotine.
Smokers control nicotine by varying their
cigarette consumption, their
strength of puffing and their inhalation. This
control is more then
avoidance of high toxic doses of nicotine but is
an attempt to titrate
for a specific nicotine dose. The smoker's aim in
titrating is
obtaining an optimal dose of nicotine which will
act on the body and
satisfy some need.
Experiments have revealed that nicotine has many
actions on the body
but the most consistent effect with smokinE doses
of nicotine is
stimulation of a subset of the cholinergic
neurones (ie the
"nicotinic" pathways), including the autonomic
nervous system and
pathways to the cortex and limbic system. The
outcome of these
actions iE an increase in blood levelr of
catecholamines and
glucocorticoids and greater amounts of cortical
desynchronization,
which are within the normal limits of the average
person. Smokers
believe that cigarettes alleviate mental and
muscular fatigue and
these effects can be attributed, in part, to the
mobilization of
energy reserves Py the catecbolamines and
glucocorticoids.
Smokers also claim that smoking helps them think
and concentrate and
experimental studies have shown that smoking can
produce absolute
enhancements in performance aE well as preventing
the performance
decrements. Enhanced performance of the same
maEnitude was foune vhen
nicotine tablets were given to non-smokers. A.
third important effect
37
C
C-D
BATCo document for Province of BritiSh Columbia 6
November 1999


of nicotine is its sedative action which has been
supported by
questionnaire and experimental studies of smoking.
Measures of
smoking behaviour during performance and while
subjects are under
tress show that smokers vary their nicotine intake
according to the
ituation. In this way they obtain the required
nicotine dose for
:
stimul:tion or sedation depending on the situation
and nicotine's
pharma okinetics make it suitable for hour-by-bour
control of a
person's psychological state Nicotine taken in
smoking doses seems to
be relatively safe for healthy adults to use and
stands in marked
contrast to the deleterious short term and long
term consequences of
the socially acceptable substance, alcohol.
A number of important and controversial
implications follow from these
facts about nicotine. If smokers derive beneficial
effects from
nicotine and cigarettes are the most effective
method of administerine
nicotine, then cigarettes should be designed to
deliver nicotine and
its beneficial effects with minimum risk from
smoke-related diseases.
The current trend of continuing to reduce nicotine
as well as tar and
carbon monoxide cannot have the expected health
benefits because
smokers are compensating by puffing harder and
inhaling more smoke.
It has been argued that because compensation can
only be partial with
low delivery brands, intake of tar and carbon
monoxide is still less
than when high delivery brands were smoked and so
these products have
less risk (Ravbone, 1979).
This argument would be true if cigarette
consumption did not increase.
However a recent paper (Wald et al, 1981) reported
that from 1949-1974
the sales-weighted average nicotine monotonically
decreased in the
U.K. by 3-0% per annum. Over these 25 years,
cigarette consumption
for male smokers (ESL, 1981) increased by 50%, an
average annual
change of 2.0%, reflecting two-thirds compensation
by corsumption
alone. The increase in consumption for women was
even greater, as it
became fashionable for them to smoke.
A more effective approach for mizimising risk and
maximising benefit
would be a produce with medium nicotine delivery
but a reduction of
some smoke components. For this strategy to be
successful, it is
obviously crucial that this cigarette has
sufficient flavour. It is
therefore essential that the product would not
need to be smoked more
intensively, or require more smoke to be inhaled,
in order to satisfy
taste, or to deliver the desired amount of
nicotine to the smoker.
Unfortunately, we have only a limited amount of
toxicological
information on a few of the 4000 identified
compounds in tobacco and
tobacco smoke on which to base a selective
reduction strategy. It is
said that tobacco smoke is a relatively mild
carcinogen (Tso, 1980)
which means either that the hazardoue compound or
compounds are only
weak carcinogens or the toxic compound is present
in very small
quantities. In the latter case the task of
identification of the
constituents to be reduced will be formidable.
T-he tobacco industry
h&E methods for modifying smoke delivery in crder
to Fartially
CD
diEscciate nicotine from tar. Some of the mc-re
drastic e=ckrz CD
reductior procedures change the chemical nature of
the Encke (Guerin, CD
1980) and the toxicological i=rlicatior of these
shif-rs 2.s unkncwn. Cr__
Fussell (1979) has briefly reporte6 some tests of
re4_uced tar, ree_~u= L-P
BATCo document for Province of BritiSh Columbia 5
November 1999


nicotine cigarettes but his comments imply that
they were less
acceptable. Thus the manipulations of smoke
delivery have been
unsatisfactory so far, not only because they may
leave harmful smoke
compounds but because they remove important
flavours. -Clearly, future
progress must be in the direction of reduction of
specific smoke
constitutents to reduce risk but maintain flavour
by adding flavouring
in order to preserve the characteristic full
flavour impact for the
smoker.
T
The way to a better cigarette is not an easy one,
but the development
of a medium nicotine cigarette, with reduction of
some smoke
components, and added flavour, could well
represent an important
milestone along this path. The end of the road
could not only be F_
safer cigarette but also with important benefits
to the smoker.
REFERENCES
ADAYS P I: The influence of cigarette smoke yields
on smok:ing habits.
In Smoking Behaviour, ed by R E Thornton, pp
349-360, Churchill-
Livingstone, Edinburgh, 1978.
ANDERSSON K: Effects of cigarette smoking on
learninE and retention.
Psychopharmacologia 41: 1-5, 1975a.
ANDERSSON K & HOCKEY G R J: Effects of cigarette
smoking on incidental
memory. Psycbopharmacologia 52: 223-226, 1977.
ANDERSSON K & POST B: Effects of cigarette smokinE
on verbal rote
learning and physiological arousal. Scand J
Psychol 15: 263-267,
1974.
ARMITAGE A K: Some recent observations relating to
the absorption of
nicotine from tobacco smoke. In Smoking Behaviour,
ed by W L Dunn, pp
e3-91, Winston (J Wiley), Washington DC, 1973.
ARMITAGE I K, HALL G H and SELLERS C Y: Effects of
nicotine on
electrocortical activity and acetylcholine release
from the cat
cerebral cortex. Brit J Pharmacol 35: 152-15C,
1969.
ASHTON Ji, MARSH V R, YILLYAN J E, RAWLINS Y r,
TELF0Fr F., THCEPS01, J
V: The 'use of even-related slow potentials of the
brain as a means to
analyse the effects of cigarette smoking and
nicotine in humans. In
Smoking Behaviour, ed by R E Thornton, PP 54-68,
Churchill-
Livingstone, Edinburgh, 1978.
ASHTON H, STEPNM R. and THOMPSON J V: Smoking
behaviour and nicotine
intake in smokers presented with a 'two-thirds'
cigarette. In Smoking
Behaviour ed by R E Thornton, pp 315-329,
Churchill-Livingstone,
Edinburgh, 1978.
ASHT01; E, STEPTEY R and THOFPSCN J W: Self
titration by cigarette
hc1ders. Erit- Yed J 2: 357-36C, 1979.
AERT'.1; H and 'WATSCI; r W: PuffinE frequency and
nicotine irtake: in
cigarette smokers. Brit Yed j 11: 679-681, 197C.
9
BATCo document for Province of BritiSh Columbia 5
November 1999


ASTRkND P 0 and RODAHL K: Textbook of 'Work
Physiology. McGraw-Hill,
Dew York, 1970.
BALTER M B: Drug abuse: a conceptual analysis and
overview of the
current situation. In Drug Use, ed by E Josephson
and E F Carroll,
PP3-22, Hemisphere Press (J Wiley), Washington DC,
1974.
BATTIG K BUZZI R A NIL R: Smoke yield of
cigariettes and puffing
behavior in men and women. Psychopharmacology 76:
139-148, 1982.
BECKETT A H: Effects of drug-drug and drug-food
interactions on drug
levels and performance in man. In Chemical
Influences on Behaviour,
ed by R Porter and J Birch, pp 89-106, Churchill,
Edinburgh, 1970.
BECKETT A 1i and TRIGGS E J: Buccal absorption of
basic drugs and its
application as an in vivo model of passive drug
transfer through lipid
membranes. J Pharm. Pharmacol 19: Suppl: 315-415,
1967.
BREIMER P D: Clinical pharmacokinetic and
biopharmaceutical aspects of
hypnotic drug therapy. In Sleep Research, ed by R
G Priest, A
Pletscber and J Ward, pp 63-81, MTP Press,
Lancaster UY 1979.
CALIFAVO J A: Remarks to the Fourth World Congress
on Smoking and
Health. In The Smoking Epidemic, ed by L Yj
Famstrom, pp 118-122,
Almquist and Viksell, Stockholm, 1980.
CASTEDEK D Y and COLE P V: Inhalation of tobaccc
smoke by pipe and
cigar smokers. Lancet 2 (7819): 21-22, 1973.
CELESIA G G and JASPER H H: Acetylcholine released
fron the cE;rebra2
cortex in relation to state of activation.
Neurology 16: 10573-100,
1966.
CHERRY N and KIERNAN K: Personality scores and
smoking behaviour - a
longitudinal study. Brit J Prevent hed 30:
123-131, 1976.
CHERRY V and KIERRAV K: A longitudinal study of
smoking and
personality. In Smoking Behaviour, ed by R E
Thornton, pp 12-16,
Cburchill-Livingstone, Edinburgh, 1978.
COHEN A J and ROE F J C: Monograph on the
Pharmacology and TcxicoloEy
of Nicotine. Tobacco Advisory Council, London,
19B1.
CREIGHTOF DF and LEWIS P H: The effect cf smckinC
patterr- oz srcke
deliveries. In SmokinE Behaviour, ed by F E
Thorntor, pp 3CI-314,
Churchill-Livingstone, Edinburgh, 1976a.
CEEIGHTON r E and LEiIS P H: The effect of
differert cirere~tes On
human smoking pEtterns. in Smoking Eebaviour, e,-'
bF. F E Thcr-.tcn, ;7
2 e9-30C. Churchtl2-LivinEstone, Edinhurgh,
107E'~.
CEYEE F F: PhyeaoloEy and pathcr,..ysJ_c1cj::7 of
the h,.;=a-- E---rTathoF,_~rena-'
neuroendocrine s-rEteiL. Kew Enng2 j Fe--f ICI:
Z--_4ZL,
BATCo document for Province of BritiSh Columbia 5
November 1999


DALE H H: The action of certain eaters and ethers
of choline, and
their relation to muscarine. J Pharm Exp Therap 6:
147-190, 1914.
DOLL R and HILL A B: Mortality in relation to
smoking: Ten years'
observations of British doctors. Brit Med J 1:
1399-1410 and 1460-
1467, 1964.
DUNNELL K and CARTWRIGHT A: Medicine Takers,
Prescribers and Hoarders.
Routledge I Kegan Paul, London, 1972.
EDWARDS J and WARBURTON P M: Smoking, nicotine and
electrocortical
activity. Pharmacol. Therap., in press, 1963.
EDWARDS J, WESNES K, WARBURTON 3) M and GALE A:
Event-Related
potentials and smoking. In preparation.
ESSXAF W B: Metabolic and behavioral consequences
of nicotine. In
Drugs and Cerebral Function, ed by W L Smith, pp
46-84, Charles C
Thomas, Springfield US, 1971.
EYSENCK H J: Personality and cigarette smoking.
Life Sci 3: 777-792,
1963-
EYSERCK H J and FYSENCK S B G: Manual of the
Eysenck Personality
Inventory. University of London Press, London,
1964.
FAGERSTROK K-0: Effects of a nicotine-enriched
cigarette or. nicotine
titration, daily cigarette consumption, and levels
of carbon monoxide,
cotinine, and nicotine. Psychopharmacology 77:
164-167, 1982.
FINNEGAN J K, LARSON P S and HAAG H B: The role of
nicotine in the
cigarette habit. Science 102:. 94-96, 1945.
FR,kNKENHAEUSER M, KYRSTEN A L, POST B and JOWSSOE
G: Behavioural and
physiological effe