Module 4
Sedatives, Hypnotics, Anxiolytics (SHAs) and Tobacco
A. The Nature and Neurophysiology of Anxiety
Anxiety is a normal part of life. The sense of apprehension or nervousness we
feel when getting ready for a first date, sitting in a job interview, preparing to write an
exam, or calculating whether there is enough money in the bank account to cover the
month’s rent— these anxieties are common and normal. But when anxiety is
unrelenting, unreasonably exaggerated given the circumstances, and interrupts one’s
ability to meet the everyday demands of life, that degree of anxiety is not normal.
Anxiety disorders are the most common of all psychiatric conditions, with a lifetime
prevalence estimated to be as high as 28.8% (Kessler, Berglund, et al., 2005). Women
are up to twice as likely as men to suffer from anxiety, and there appears to be a
genetic component, as anxiety disorders tend to run in families. The DSM-IV-TR
includes five classes of anxiety disorders, and research links them with abnormal
brain physiology, especially in the limbic system and in regions communicating with
it.
Social phobia or social anxiety disorder is the most frequently experienced
anxiety disorder. It is the fear of being scrutinized, rejected, or embarrassed in public.
Oftentimes, sufferers will avoid social interactions to prevent distress. Like those with
generalized anxiety disorder, social phobia is marked by hyperactivity of the
amygdala and also of the orbitofrontal cortex (Damsa et al., 2009). The category
specific phobia refers to the extreme anxiety that results when confronting or even
thinking about certain objects or situations. Some common phobias include fear of
specific animals (spiders, dogs), natural environments (heights, storms), blood–
injection–injury (needles, medical procedures), and situations (elevators, flying).
fMRI studies of people presented with or even anticipating a feared stimulus (such as
a spider) show heightened activity of many brain regions: visual areas, supplementary
motor regions, thalamus, amygdala, anterior cingulate cortex, and insular cortex.
Panic disorder is associated with panic attacks— seemingly unprovoked,
quickly mounting, full-blown alarm reactions marked by heightened sympathetic
nervous system activity. Racing heartbeat, sweating, trembling, chest pain, difficulty
breathing, nausea, and a sense of losing control or detachment from reality are all
features of panic attack. Sufferers may fear they are having a heart attack or a stroke,
or are dying. A specific phobia, called agoraphobia, often coincides with panic
disorder. This is the fear of being in a place or situation from which it would be
difficult to escape or get help if a panic attack were to occur, such as on an airplane or
in an empty parking garage. Although agoraphobia is not one of the five major classes
of anxiety disorders according to the DSM-IV-TR, it is proposed to become its own
diagnosable disorder in the DSM-5. MRI studies of individuals with panic disorder
show structural brain abnormalities, specifically a reduction in the volume of the
anterior cingulate cortex and an increase in gray matter within the insula, superior
temporal gyrus, midbrain, and pons.
The term anxiolytic (or, more historically, tranquilizer) is applied to drugs that
are used therapeutically to treat agitation and anxiety disorders. The term sedative-
hypnotic refers to drugs that are used to sedate and aid sleep (i.e., sleeping pills).
There are several categories of drugs that have anxiolytic and sedating effects. The
most common in use today is the benzodiazepines. Before that, the barbiturates were
widely used. A number of other substances that are neither barbiturates nor
benzodiazepines have also been used as sedative-hypnotics or anxiolytics. They
include older drugs like meprobamate (Miltown) and methaqualone (Quaalude),
which were widely used in the 1960s but are no longer used today. More newly
developed classes of drugs include the nonbenzodiazepines such as abecarnil and
alpidem (these have similar therapeutic and side effects as the benzodiazepines, but
have significantly different chemical structures) and a class of drugs introduced since
the late 1990s called the Z drugs, which include zolpidem, zopiclone, zaleplon, and
eszopiclone (these have increasingly become the accepted treatment for insomnia, as
they have a shorter duration of action and are associated with less risk of tolerance
and abuse.
Anxiolytics and sedative-hypnotics share some properties with alcohol (see
Chapter 6), with inhaled solvents, and with other substances generally called
depressants or general anesthetics. GHB ( gamma-hydroxybutyrate) is a peculiar
substance that occurs naturally in the body and shares many properties with the
sedative-hypnotics. It could well have been included in this chapter, but it also has
many unique properties that have caused some to suggest that it is a unique
pharmacological entity.
B. History of Anxiolytic and Sedative-Hypnotic Drug Development
Before the development of the barbiturates, physicians of the nineteenth
century had only a few substances that they could use to calm people or aid sleep.
These were alcohol (usually in the form of brandy), bromides, chloral hydrate
(otherwise known as chloral), and opium. For the most part, these were marginally
effective and had unwanted side effects. Barbiturates were first synthesized in 1864,
and, for over 100 years, they were one of the most useful drugs in the physician’s
black bag for the treatment of anxiety and insomnia, replacing brandy, bromides, and
opium as tranquillizers. Barbiturates were essentially the only drugs used as sedatives
and tranquillizers from the 1920s to mid-1950s.
During the twentieth century, more than 2,500 different barbiturates were
synthesized, and about 50Bhave been marketed and used clinically (examples of these
can be found in Table 7-1; some drugs may no longer be used or may not be approved
for use in parts of Europe or North America). Compounds containing barbiturates
have been recommended in the treatment of nearly 80 different disorders ranging
from arthritis to bed-wetting (Reinisch & Sanders, 1982). In 1936 in the United States
alone, 70 tons of barbiturate pills were sold, and dependence became widespread. By
the 1990s, however, benzodiazepines had largely replaced barbiturates in almost all
medical uses, mainly because of their improved therapeutic index. But barbiturate use
has not disappeared completely.
The long-acting drug phenobarbital is still prescribed to prevent epileptic
seizures and to antagonize adverse stimulating effects of some drugs such as
ephedrine, d-amphetamine, and theophylline. Butalbital is an intermediate-acting
barbiturate combined with drugs such as aspirin, caffeine, acetaminophen, and
codeine in analgesic preparations such as Fioronal and Fioricet for the treatment of
headaches. Some ultrashort-acting barbiturates, such as thiopental, are given
intravenously prior to surgery as anesthetic inducers. Since the 1970s, barbiturates
have been used to reduce intracranial pressure following traumatic brain injury.
Although not as commonly as before, amobarbital, aprobarbital, butabarbital,
pentobarbital, and secobarbital are all still prescribed for the treatment of insomnia.
The first synthesis of the benzodiazepines was a combination of good science
and good luck. In the 1930s, Leo Sternback synthesized several substances known as
heptoxdiazines while working on the chemistry of dyes in Krakow, Poland. But not
until the 1950s, when he was working at the Hoffman–La Roche laboratories in the
United States, did Sternback and his colleagues do further work with these
compounds. Their research was stimulated by an attempt to find a new, safe drug that
could be used as an anxiolytic. Their approach was simple; they would pick a class of
biologically active chemicals that was simple to make and easy to change and that no
one else had studied. They would then makeBand test as many derivatives as they
could, hoping to discover a useful drug by chance. The heptoxdiazines fitted this
description perfectly, so the researchers started to synthesize all sorts of new
variations and had them tested for their biological properties.
According to a study by the U.S. Drug Testing Advisory Board that compared
pharmacy dispensing of prescription anxiolytics and sedative-hypnotics in the decade
spanning 1997–2008, barbiturate prescriptions have decreased, by 22% (representing
820,000 fewer prescriptions) for phenobarbital and 61% (381,000 prescriptions) for
butalbital. During the same time period, the dispensing of prescription
benzodiazepines increased, by 114% for clonazepam (representing 10.9 million
additional prescriptions), 71% for alprazolam (17.6B million prescriptions), 30% for
temazepam (1.9Bmillion prescriptions), 24% for lorazepam (4.2Bmillion prescriptions),
and 17% for diazepam (2.1 million prescriptions). Since their introduction in the late
1990s, prescriptions for the Z drugs have also been increasing as these drugs are
slowly replacing the benzodiazepines in the treatment of insomnia, especially in North
America.
C. Neurophysiology
The neurophysiology of the barbiturates and benzodiazepines is fairly well
understood. Their effects are mediated primarily by their ability to modify
transmission of the inhibitory transmitter GABA, specifically at the GABAA receptor
(it might be helpful, at this point, to review the information related to GABA and its
receptor subtypes found in Chapters 4 and 6). A prototypical GABAA receptor
complex is illustrated in Figure 7-1. Although GABAA receptors exist in a variety of
forms, the most common type of subunit combination is c1d2i2, which comprise
approximately 60% of all GABAA receptors in the brain. GABA receptors are found
all throughout the central nervous system (CNS), both at synapses and elsewhere, and
seem to maintain a general level of activity that creates an inhibitory tone in the brain,
preventing excessive excitation that could result in seizures.
The barbiturates, benzodiazepines, and nonbenzodiazepines do not modify
GABAA receptor activity by altering levels of GABA or by interacting directly with
GABA’s receptor binding site. Instead, these drugs are positive allosteric modulators
—they have their own binding sites on the GABAA receptor complex that, when
occupied, enhances the effects of GABA binding. Some drugs, like abecarnil and
alpidem, have a low affinity for the benzodiazepine receptor binding site and have a
weak effect. Others, like diazepam, flunitrazepam, midazolam, and triazolam, have a
high affinity and a correspondingly greater effect. Some compounds that act as
allostatic modulators of the benzodiazapine binding site have been shown to alter
GABA activity dramatically, by more than 700%.
Even though many of the effects of the benzodiazepines and barbiturates can
be understood in terms of their ability to modulate GABA activity, their
neurophysiology is complex, and other transmitters and neuromodulators may also be
involved. For example, the benzodiazepines are known to enhance the effects of
adenosine, another inhibitory transmitter, by blocking its reuptake and permitting its
accumulation (Phillis & O’Regan, 1988), an effect directly opposite to that of
caffeine.
Benzodiazepines, though considered safer and less addicting than the
barbiturates, are known to have abuse potential. Dependence, defined by high-dose
use over a prolonged period, is not common among individuals who are prescribed
these medications, but abuse is prevalent among individuals who obtain the drugs
without prescription and who are also dependent upon alcohol and other drugs (Kan,
Breteler, van der Ven, Timmermans, & Zitman, 2001). Like all addictive drugs,
benzodiazepines influence the transmission of dopamine in the mesolimbic dopamine
pathway, which projects from the ventral tegmental area to the nucleus accumbens
and prefrontal cortex. If you refer to Figure 12-1 in Chapter 12, you will notice that
glutamate, dopamine, and GABA neurons all converge within the ventral tegmental
area. Benzodiazepines increase dopamine activity by binding to c1-containing
GABAA receptors and inhibiting GABAergic interneurons that synapse upon
dopamine cell bodies within the ventral tegmental area.
The net result is a reduction in GABA neuron firing and a disinhibition
(freeing) of dopamine neurons that are normally suppressed by GABA interneuron
activity. This disinhibition of dopamine activity leads to neuroplastic changes within
the mesocortical pathway, specifically in the firing of excitatory glutamatergic
neurons that synapse upon dopamine cell bodies in the ventral tegmental area.
Glutamate activity is amplified, driving dopamine cell firing even higher. In
laboratory research using mice, just a single administration of diazepam or zolpidem
resulted in neuroplastic changes in glutamate activity.
D. Effects on the Body
Apart from a depression in respiration and a slight drop in blood pressure,
barbiturates have few physiological effects at low doses. Unlike the barbiturates, the
benzodiazepines do not produce significant depression of respiration in healthy
individuals, even at high doses. They also have little effect on heart rate or blood
pressure. The benzodiazepines are also reported to increase appetite, and weight gain
is sometimes a consequence of continuous use.
The benzodiazepines are effective in treating insomnia; flurazepam is widely
used in the United States, and nitrazepam is used in Europe for this purpose.
Zolpidem is also one of the most widely used hypnotics. These drugs decrease latency
to fall asleep, decrease wakefulness during the night, and increase total sleeping time.
Unfortunately, benzodiazepines, like the barbiturates, decrease the percentage of time
spent in REM as well as in stage 3 and stage 4 sleep. This effect diminishes with
continued use, and when the drug is discontinued, after as little as 2 weeks, there is a
withdrawal rebound (Griffiths & Sannerud, 1987). With nitrazepam, this rebound
reaches a peak about 10 days after the drug is stopped and may last for several weeks.
With the increase in REM comes an increase in rebound insomnia, that is, bizarre
dreaming, restlessness, and wakefulness during the night (Oswald, Lewis, Tangey,
Firth, & Haider, 1973). The desire to resume taking the drug to get a good night’s
sleep increases accordingly.
Many (although not all) studies of the subjective effect of the benzodiazepines
have shown that subjects report euphoria and liking along with sedation and fatigue
(de Wit & Griffiths, 1991; Evans, Griffiths, & de Wit, 1996). In one experiment,
diazepam and a placebo were given to volunteers who were asked to fill out a Profile
of Mood States form at that time and at 1, 3, and 6 hours later. Compared with a
placebo, doses of 5 and 10 mg of diazepam caused a decrease in feelings of arousal
and vigor and an increase in fatigue and confusion. These effects were seen only at 1
hour with the low dose but were generally seen for up to 3 hours with the high dose.
These feelings were considered unpleasant by the participants, few of whom
voluntarily took the drug again when they were given the chance ( Johanson &
Uhlenhuth, 1980). Positive effects and increased liking scores for benzodiazepines are
more likely to be seen in people with a history of sedative or alcohol abuse, moderate
alcohol use, or opioid use, including those on methadone maintenance (Evans et al.,
1996). Flunitrazepam seems more likely than other benzodiazepines to increase
“liking” and “take again” scores in normal healthy volunteers and in people on
methadone maintenance.
The benzodiazepines and barbiturates increase the critical frequency of fusion
threshold, indicating a deficit in visual functioning. Some studies have also reported
that the auditory flicker fusion threshold is diminished by the benzodiazepines (Vogel,
1979). The benzodiazepines can have severe effects on memory; they cause
anterograde amnesia, a loss of memory for events that occurred while under the
influence of the drug (Lader, 2011). These problems occur at low doses that do not
cause sedation or impair alertness or motor functioning. Memory problems are
sometimes observed in patient populations taking benzodiazepines for anxiety or
insomnia. Benzodiazepine users consistently perform worse on verbal memory tasks
than nonusers.
Benzodiazepines are widely used at bedtime to induce sleep. Many have such
a long half-life that they are still in the body for some time the next day. Because
sleeping pill users may drive to work, operate equipment, and engage in other
activities that might be impaired by the drug, it is important to determine whether
these residual levels of the drug can affect performance the next day. Many, but not
all, studies show next-day residual effects of benzodiazepines. Not surprisingly,
higher doses are more likely to have residual effects than lower doses (Woods &
Winger, 1997). In an attempt to reduce these residual effects, the benzodiazepines and
nonbenzodiazepines with short-elimination half-lives are now being more widely used
as hypnotics.
One of the first effects noticed in the early screening tests of the
benzodiazepines was a taming effect. The research animals became more placid, and
fighting behavior induced by electric shocks was reduced. It has since been
demonstrated that chlordiazepoxide and diazepam are effective in reducing only
defensive aggression, that is, aggression induced by an attack or provoked by a
painful stimulus like a shock. Unprovoked aggression or attack behavior does not
seem to be altered at lower-than-toxic doses (DiMascio, 1973). It has been suggested
that this change in provoked aggression is a result of the ability of the
benzodiazepines to diminish anxiety. Defensive aggression is presumably a result of
anxiety or fear caused by being attacked. Attack itself is not motivated by anxiety.
E. Resistance and Detoxification
Tolerance to the effects of benzodiazepines can develop during a single
administration. Such tolerance seems to be limited in humans to the effect of
benzodiazepines on behavior such as digit symbol substitution and tracking and may
not be seen in physiological effects. It has also been shown that the acute tolerance
can develop to the motor-impairing effects of midazolam (Coldwell et al., 1998).
Similarly, studies have shown that phenobarbital has a more powerful effect at a given
concentration as the blood level is rising than when the blood level is descending.
Tolerance also develops slowly to the anticonvulsant effects of the
benzodiazepines as well as to the drowsiness that is seen sometimes at therapeutic
doses. Although there are some data to suggest that tolerance does not develop to the
hypnotic effects of benzodiazepines and to zolpidem in particular, other work has
shown that tolerance to the sleep-producing effects of these drugs develops after about
4 weeks (Rush, 1998). As mentioned earlier, there has been a tendency to prescribe
short-acting benzodiazepines and nonbenzodiazepines as sleeping pills to avoid next-
day residual effects, but it seems that these drugs have a tendency to develop tolerance
faster than the longer-acting benzodiazepines. In addition, they also seem to cause
more frequent and more intense rebound insomnia. Among the short- acting
hypnotics, however, there are differences. Triazolam appears to cause more rebound
insomnia than either midazolam or zolpidem.
There is cross-tolerance between the benzodiazepines and other depressant
drugs. The drowsiness sometimes produced by higher therapeutic doses of the
benzodiazepines is less often seen in people who have a recent history of barbiturate
and alcohol abuse (Greenblatt & Shader, 1974). One study has shown that tolerance
develops after only one exposure to the motor-impairing effect of alcohol,
barbiturates, and benzodiazepines in mice. Animals that are tolerant to the barbiturates
are cross-tolerant to alcohol and the benzodiazepines, and benzodiazepinetolerant
animals are tolerant to the effects of alcohol but show only weak or partial tolerance
to the barbiturates. This suggests that the tolerance to barbiturates and
benzodiazepines may arise from mechanisms that are similar but not identical.
In laboratory animals, it has been shown that many benzodiazepines will cause
physical dependence similar to barbiturates, and there is a cross-dependence between
phenobarbital and many benzodiazepines; that is, withdrawal from phenobarbital can
be blocked by benzodiazepines (Gerak et al., 2001). Nevertheless, the symptoms of
barbiturate withdrawal can be much more severe than those of benzodiazepine
withdrawal, as described later. In humans, barbiturate withdrawal was first described
in the medical literature in 1905, 2 years after the introduction of the first barbiturate
into medical practice. In spite of this early report, the medical literature on barbiturate
withdrawal was contradictory until the 1930s, when the weight of evidence could no
longer be denied.
The sedative-hypnotic type of withdrawal involves tremors, delirium, cramps,
and, possibly, convulsions. These are similar to the symptoms of barbiturate and
alcohol withdrawal (described in Chapter 6), and they are the symptoms described in
studies of the effects of high doses of benzodiazepines. Sedative-hypnotic withdrawal
can be expected in people who have taken the drug in higher-than-recommended
therapeutic doses for at least a month. Generally, the withdrawal symptoms start
within a few days of abstinence and are gone within about 10 days. These withdrawal
symptoms are more likely to be seen with benzodiazepines that have short half-lives
because blood levels of these drugs fall more rapidly than blood levels of the longer-
acting drugs.
Low-dose benzodiazepine withdrawal symptoms are seen in some individuals
after low therapeutic doses have been taken for longer than 6 months. They emerge
more slowly and include anxiety, panic, irregular heartbeat, increased blood pressure,
impairment of memory and concentration, feelings of unreality, muscle spasm, and a
sensitivity to lights and sounds. Patients consistently report feeling as though they are
walking on cotton wool, in a mist, or wearing a veil over their eyes. There are
frequent reports of perceptual difficulties, such as sloping walls or floors, and
distortion of reality and selfperception: “Everything feels unreal or distant”; “I feel
I’m not really me”; “My head feels like a huge balloon”
F. Human and Nonhumans self-application
In a study that used normal human participants and has been replicated several
times, Johanson and Uhlenhuth (1980) gave people a choice between capsules of
different colors. In an earlier part of the experiment, participants had been given each
of the capsules twice, so they knew what effect each colored capsule would have,
even though they did not know what each capsule contained. In this experiment, the
participants chose capsules containing amphetamine much more often than a placebo,
but they did not choose diazepam more often than a placebo (Griffiths et al., 1980). In
a similar procedure, lorazepam was not chosen more often than a placebo; in fact, at
higher doses, participants chose a placebo more frequently than lorazepam or
diazepam.
In a study conducted by Roland Griffiths and colleagues (Griffiths, Bigelow,
& Lieberson, 1979) at the Johns Hopkins University School of Medicine,
pentobarbital was made available to male volunteers in an experimental hospital ward
setting. The participants, all of whom had a history of sedative drug abuse, could earn
an administration of a drug by riding an exercise bicycle for 15 minutes. Five of the
seven participants continued to self-administer doses of 90 mg (a high level) of
pentobarbital over the 10 days of the experiment, indicating that the drug acted as a
positive reinforcer in humans. The same experiment also showed that participants
would not self-administer a placebo. Diazepam was self-administered by some
participants but not as frequently or as reliably as the barbiturate.
Outside the laboratory, humans show two patterns of benzodiazepine self-
administration apart from use for legitimate medical conditions. In the legal or
iatrogenic (physician-caused) pattern, the drug is prescribed for its effects as an aid to
sleep or anxiety problems and is then continued unnecessarily, or the dose is
escalated. In the street-use pattern, the drugs are obtained illegally and are taken at
high doses. Of these two patterns, the first is more common.
Benzodiazepines are widely prescribed for a variety of symptoms. In many
cases, the prescription and use are entirely consistent with appropriate treatment of
medical conditions; however, the use of these drugs often changes in nature and may
cause problems for the patient in a couple of different ways. As we have seen, if they
are prescribed at too high a dose or for too long, they can cause physical dependence
and require special treatment to avoid withdrawal when the drug is discontinued. In
addition, a patient may become motivated by the reinforcing effects of the drug and
may start exhibiting an inappropriate amount of behavior toward obtaining the drug in
increasing amounts. Such a patient may learn exactly how to tailor a medical history
so that a physician will predictably prescribe the desired drug or may go “doctor
shopping” to find a compliant physician. Some patients may refuse to stop taking a
drug and not consider alternative therapies, even though the drug is causing adverse
side effects or the doctor recommends stopping. Other signs include a tendency to
escalate doses, requests for early refills of the prescription because the prescription
was “lost,” and so on.
Like humans, rats and monkeys will readily work to give themselves infusions
of all types of barbiturates, although it appears that the short-acting barbiturates may
maintain higher rates of responding than the longer-acting barbiturates. Laboratory
animals will also self-administer benzodiazepines both intravenously and orally
(Rowlett, Platt, Lelas, Atack, & Dawson, 2005; Stewart, Lamaire, Roche, & Meisch,
1994). Currently, there are many demonstrations of self-administration of both short-
and long-acting benzodiazepines (Gerak et al., 2001; Griffiths, Lucas, Bradford,
Brady, & Snell, 1981), although short-acting benzodiazepines like triazolam maintain
higher rates of responding than long-acting benzodiazepines.
Subjective reports and epidemiological studies suggest that flunitrazepam may
have a higher potential for use than any other benzodiazepine because it is preferred
by many users, but self-administration and drug discrimination studies with laboratory
animals have been unable to find any difference between the effects of flunitrazepam
and other short-acting benzodiazepines like midazolam and triazolam (Gerak et al.,
2001). It has also been noted that people on methadone maintenance seem to use
benzodiazepines to “boost” methadone’s subjective effect. In one study using
baboons, self- administration of flunitrazepam was enhanced in animals who were
administered methadone concurrently.
G. Therapy
Anyone wishing to discontinue using the benzodiazepines after a long period
of use should not attempt it alone because the withdrawal can be severe and may
involve convulsions, which require medical treatment. Withdrawal should be done
under medical supervision with the aid of a physician who appreciates the problem.
Although withdrawal can usually be accomplished on an outpatient basis,
hospitalization may be necessary, especially for patients with a history of seizures,
psychotic episodes, or high doses of the drug.
The approach to detoxification from a benzodiazepine is similar to
detoxification from other sedative drugs and alcohol. The best way to proceed is to
gradually reduce the daily dose of the benzodiazepine, a technique called GDR,
gradual dose reduction. Withdrawal should be conducted over an 8 to 12 week period
and be completed in no more than 6 months (Lader, 2011). This is most successfully
done in conjunction with counseling, group therapy, or Cognitive Behavioral Therapy,
and careful monitoring of the patient’s withdrawal symptoms. It is important that the
patient be told exactly what symptoms to expect and how long they will last.
It is sometimes helpful to also seek social support from self-help groups and
members of the family. The patient should be taught various strategies for coping, not
only with the withdrawal but also with the reemergence of the symptoms for which
the benzodiazepine was prescribed in the first place (Colvin, 1983). The most intense
withdrawal and the greatest anxiety and panic are experienced while the last few
milligrams of the drug are being withdrawn (Lader, 2011; Smith & Wesson, 1983).
Treatment of iatrogenic physical dependence is usually successful: 88 to 100% of
patients stop their benzodiazepine use.
H. The Background of Tobacco and Nicotine
Tobacco is the only known natural source of nicotine, and it is now clear that
nicotine is the active ingredient in tobacco. The tobacco plant belongs to the
nightshade family of plants (Solanaceae). The genus Nicotiana, of which there are two
subgenera, rustica and tabacum, is used for its nicotine content. Both subgenera
contain many species and varieties that differ quite widely in physical characteristics.
By far, the principal source of tobacco today is N. tabacum, which is cultivated in
temperate climates all over the world. Species of N. rustica are not widely grown
commercially. While it has a higher nicotine content (up to 9%), it is reputedly harder
to cultivate. Wild N. rustica has been widely used as a medicine and for shamanistic
rituals by native peoples of North and South America. In addition to nicotine, it
contains other psychoactive substances such as the hallucinogen harmine (see Chapter
15). Cultivated strains of tobacco have much higher nicotine content than any wild
members of the same genus. The actual nicotine content of the cured tobacco leaf may
reach as high asB6.17%.
The leaves of the tobacco plant are cured and prepared in different ways,
depending on the intended use of the tobacco. The vast bulk of tobacco is consumed
as cigarettes or cigars and in pipes. After harvesting, tobacco for burning is usually
dried or cured and then fermented, a process that is not really fermentation as
described in Chapter 6, but oxidization. Drying and fermenting cause a change in the
chemistry of the plant and influence the taste and other characteristics of the tobacco.
Tobacco for chewing is specially processed and flavored. Traditional tobacco
snuff is made by drying the leaves, grinding them to a very fine powder, and mixing
the powder with various aromatic and flavoring agents. Dry snuff was usually snorted
into the nostrils in the form of a dry powder, but this practice is no longer used.
Modern snuff is sometimes called moist snuff. It is not inhaled, but placed in the
mouth and tucked under the tongue or between the lip and the gums. It is not chewed
and, unlike traditional chewing tobacco, does not require spitting. Sometimes
additives are used for flavor and to enhance absorption of the nicotine. Often tobacco
used as moist snuff is not fermented, but pasteurized, a process where the product is
steamed. There are numerous varieties of moist snuff including dipping tobacco and a
product from Sweden called snus.
Every early European explorer, from Columbus on, commented on one aspect
of the life of the native peoples of North America: their use of tobacco. At San
Salvador, the site of Columbus’s first landfall in 1492, the local inhabitants presented
him with some “dry leaves,” which Columbus concluded “must be a thing much
appreciated among them.” Later members of his expedition went ashore in search of
the Great Khan. They found no Khan, but they did observe the natives smoking
cigars, something that they did not appreciate or understand. They reported that the
natives were “perfuming themselves” and that they “drink smoke.” One of these men,
Rodrigo de Jerez, would later become all too familiar with the significance of the
activity; he took up smoking and was imprisoned by the court of the Inquisition for
this “devilish habit.”
Tobacco use spread as a wonder cure, but it did not take long to catch on as a
recreational activity, although many users were quick to point out that they were
really using it to prevent diseases, such as the Plague. When Samuel Pepys, the
British diarist, encountered houses where victims of the Great Plague had perished, he
felt “an ill conception of myself and my smell, so that I was forced to buy some roll-
tobacco to smell and to chew, which took away the apprehension” (Brooks, 1952, p.
40). This association of tobacco with healing lasted into the Victorian era.
The English were among the last Europeans to take up tobacco. In the late
sixteenth century, British sailors and sea captains, among them Hawkins, Drake, and
Raleigh, carried the habit home from the West Indies. Raleigh’s name has long been
associated with tobacco not only because he is credited with the introduction of
smoking to the English court but also because he founded the colony at Virginia that
was later to owe its survival and prosperity to tobacco cultivation. Although the
British were late to take to the drug, they made up for their tardiness in the popularity
tobacco acquired. By the end of the sixteenth century, the demand for the leaf was
beginning to cause concern in some quarters. In 1604, King James I published an
antitobacco essay titled A Counterblaste to Tobacco, in which he refuted all the
arguments claiming medical benefits from smoking. As a matter of fact, James I
anticipated most of the modern antismoking campaigns, even to claiming that
smoking affects “the inward parts of man, soiling and infecting them with a vicious
and oily kind of Soote, as hath been found in some great tobacco takers, that hath after
their death opened”.
The tobacco that the English were smoking all this time (and that so angered
the king) was imported from Spain at great expense, but the English colony at
Virginia was to change all that. The colonists, under John Rolfe, had gotten off to a
very bad start. They suffered shipwreck and starvation and were at the point of
quitting when Rolfe decided to try growing some Spanish tobacco seeds (Nicotiana
tabacum) in the soil of Virginia. The experiment was a great success. The plants
prospered, and in 1616 a shipload of Virginia tobacco was sent to Britain. At first, the
English were skeptical, but the quality of Virginia tobacco was obvious, and within a
decade it had replaced the Spanish imports. In spite of the king’s taxes and other
attempts to discourage the tobacco trade, the colony flourished and secured the
English colonial presence in North America.
I. The Use of Tobacco and Nicotine
Unlike cocaine from the coca leaf or morphine from opium, until recently
nicotine from tobacco was never self-administered in its pure form. Nicotine is a
highly toxic poison, and doses must be controlled precisely; too high a dose will have
quite unpleasant effects. Because of its diluted concentration in tobacco, precise
control of dosage can more easily be achieved when the nicotine is in its natural form.
Forms of tobacco delivery that have been developed more recently, such as the patch,
gum, and others, are constructed to deliver precise amounts and avoid toxic doses of
nicotine.
When tobacco is burned, nicotine vaporizes and can be found in the smoke
and particles of ash that dissolve in the mucous membranes on the inside surface of
the lungs. About 90% of inhaled nicotine is absorbed into the blood in this way
(Pierce, 1941). The amount of nicotine actually delivered to the smoker is determined
more by the way the cigarette is smoked than by the actual nicotine content of the
cigarette; the delivered amount can vary between 0.3 and 3.2 mg per cigarette
(Benowitz & Henningfield, 1994). The average cigarette contains 8 to 9 mg of
nicotine, of which a typical smoker absorbs about 1 mg in the course of taking 10
puffs per cigarette ( Jones, 1987). The major determinant of nicotine absorption is the
volume of smoke inhaled per puff. Increasing the duration of the inhalation does not
significantly increase nicotine absorption.
Nicotine from tobacco smoke may also be absorbed through membranes of the
mouth (buccal membranes), but because nicotine is a weak base with a pKa of about
8.0, absorption by this route is determined by changes in the pH of saliva. In general,
cigarettes are made from flue-cured tobacco, which has an acidic smoke. This lowers
the pH of saliva to about 5.3. In acidic saliva, nicotine is ionized and absorption
reduced. To be absorbed, the nicotine from cigarette smoke must be inhaled into the
lungs, which are so efficient that pH has no effect on absorption. By contrast, pipe and
cigar tobacco is usually air-cured, and this process results in a more basic or alkaline
smoke. This raises the pH of saliva to about 8.5, well within the range where
ionization of nicotine is less than 50%, and absorption is rapid (see Chapter 1).
Consequently, nicotine in the smoke from cigars and pipes can be absorbed from the
mouth, and inhalation is not necessary.
A long-standing theory is that the bolus causes a sudden delivery of
concentrated nicotine to the brain and that this is responsible for the strength of
nicotine addiction, but the presence of the bolus has largely been theoretical. Jed E.
Rose of Duke University Medical Center and his colleagues attempted to examine the
absorption kinetics of nicotine during cigarette smoking using PET imaging with a 3-
second temporal resolution and radiolabeled 11C-nicotine loaded into cigarettes. He
used both nicotine-dependent smokers (DS) and nondependent smokers (NDS) and
scanned them while they took 10Bpuffs on the cigarette with 48 seconds between each
puff.
Note that nicotine concentrations in the blood continue to accumulate after
each puff and do not fall back as would be expected by the nicotine bolus theory. This
finding was unexpected and means that the nicotine bolus theory needs to be
reconsidered. Tobacco taken in the form of traditional dry snuff is sniffed into the
nostrils. With this route of administration, most of the nicotine is absorbed through the
mucous membranes of the nasal cavity, although some tobacco eventually gets into
the stomach and lungs. Since dry snuff is not commonly used in modern times,
absorption from this route of administration has not been extensively studied.
When tobacco is chewed or taken in the form of moist snuff, the nicotine is
absorbed through the buccal membranes in the cheeks and under the tongue. With
traditional chewing tobacco, the tobacco juice is spit out, so chewing is not a form of
oral administration. However, with moist snuff where spitting is uncommon, nicotine
in saliva that is not absorbed through the membranes of the mouth is swallowed.
Nicotine is a weak base, so it will not have many lipid-soluble molecules when
dissolved in solutions with a pH lower than 6. Consequently, this nicotine is not
readily absorbed from the acidic digestive system. Swallowed nicotine has another
disadvantage because the blood from the capillaries of the digestive tract must pass
through the liver before it achieves general circulation throughout the body. Because
nicotine is metabolized rapidly in the liver, much of the nicotine that is swallowed is
metabolized during this first pass before it can get to the rest of the body. Although
nicotine is not normally self-administered orally, a large number of poisonings occur
each year among children who eat tobacco. Fortunately, the nicotine that gets into the
blood in high levels induces vomiting, and the swallowed tobacco is frequently
expelled before the nicotine reaches toxic levels.
Newer forms of nicotine administration have been developed for the purpose
of nicotine replacement therapy for people who have given up smoking. Nicotine
chewing gum was the first of these. The fact that nicotine can be absorbed
transdermally (through the skin) allowed for the development of the patch. Nicotine-
containing patches are placed on the skin, and they release nicotine in various
concentrations for a period of time. Nicotine nasal sprays and lozenges have also been
developed.
The patch causes a slow buildup of nicotine in the blood and maintains it at a
constant level for hours. The gum will cause rises and falls in blood nicotine levels in
response to its use; as a result, it causes patterns in blood nicotine that more closely
resemble those caused by smoking, although peak levels reach only one-third that of
smoking (Keenan, Henningfield, & Jarvik, 1995). The nasal spray causes the most
cigarette-like changes in blood levels. Within 2.5 minutes of administration, nicotine
reaches 85% of peak levels in the blood (Sutherland et al., 1992). Figure 8-3 shows
the blood level of nicotine for 1 hour after administration by these routes.
J. Tobacco and Nicotine Effects
In the PNS, nicotinic receptor sites are located in the neuromuscular junctions
of striated or voluntary muscles. The poisonous effects of curare result because the
drug blocks these junctions, and the muscles become paralyzed; the victim can no
longer breathe and dies of suffocation. Acetylcholine is important in the functioning
of both the sympathetic and parasympathetic divisions of the autonomic nervous
system. The preganglionic transmission in both systems depends on nicotinic
receptors so that stimulation and blocking of nAChRs can alter functioning of both
the sympathetic and parasympathetic divisions. The receptor subtypes found in
parasympathetic ganglia are largely alpha3 and beta4 subtypes.
In general, at doses encountered in tobacco smoking, nicotine produces
increases in heart rate and blood pressure and causes a constriction of blood vessels in
the skin. This constriction causes a drop in skin temperature and is probably
responsible for the cold touch that smokers have and the reason that the skin of
smokers tends to wrinkle and age faster than that of nonsmokers (Daniell, 1971). The
reduced blood flow to the skin also explains why smokers do not blush easily. This
lack of skin color prompted one judge in the 1930s to accuse cigarettes of “deadening
the sense of shame” and corrupting the morals of young people. Nicotine also inhibits
stomach secretions and stimulates the activity of the bowel. For this reason, especially
for someone with little tobacco tolerance, a cigarette can act as a laxative.
The effects of nicotine in the CNS are complicated. Apart from its direct
effects on synapses, nicotine also stimulates the release of epinephrine from various
sites in the PNS, including the adrenal glands, causing CNS arousal. Arousal is also
produced by direct stimulation of the reticular activating system. Respiration is
increased because of both direct and indirect stimulation of the respiration center in
the brainstem. Respiratory arrest caused by an overdose of nicotine results from a
block of these centers as well as of the neuromuscular junctions that control the
muscles used in breathing. Nicotine can cause muscular tremors. One British surgeon,
H. J. Johnson (1965), was motivated to quit smoking when he noticed that an extra
cigarette before surgery caused a fine hand tremor. In addition, there may be an
inhibition of some reflexes. There is a decrease in the patellar reflex (knee jerk) after a
cigarette. This effect, which is due to a lowering in the tone of voluntary muscles,
appears to be a direct result of stimulation of inhibitory cells in the motor pools in the
spinal cord.
Nicotine is known to increase dopamine activity in the nucleus accumbens.
This effect is caused by direct stimulation of dopamine neurons in the nucleus
accumbens and by the ability of nicotine to potentiate excitatory glutamatergic
connections to dopaminergic neurons in the ventral tegmental area and nucleus
accumbens. Nicotine increases the activity of glutamatergic neurons by boosting
glutamate release through presynaptic receptors and by increasing depolarization of
postsynaptic neurons (Dani & Balfour, 2011). It has been shown that nAChRs on
dopaminergic neurons projecting from the ventral tegmental area to the nucleus
accumbens contain the beta2 subunit. It is possible to breed mice that do not have a
particular gene that codes for this subunit. These are referred to as knockout (KO)
mice. Knockout mice that do not have the gene that contains instructions for making
beta2 subunits (beta2 KO mice) do not show a surge in dopamine in the nucleus
accumbens when the ventral tegmental area is stimulated and do not self-administer
nicotine.
Smoking is a pleasurable experience for many people (de Wit & Zacny, 1995).
In one study, nicotine was administered either by tobacco smoke inhalation or by
intravenous infusion to volunteers, and their subjective responses were measured
using the Addiction Research Center Inventory (ARCI). Smokers reported increased
liking scores and subjective effects similar to those caused by morphine and
amphetamine. These effects peaked about 1 minute after administration and were
gone within a few minutes. Nonsmokers, however, did not enjoy the experience
(Henningfield, Miyasato, & Jasinski, 1985; Jasinski, Johnson, & Henningfield, 1984).
These subjective effects were blocked by mecamylamine (Henningfield, Miyasato,
Johnson, & Jasinski, 1983). In another experiment, smokers were deprived of
smoking beginning in the evening and given cigarettes with different levels of
nicotine on the morning after. They were permitted to smoke the cigarettes themselves
and were asked to push a button when they experienced “a rush, a buzz, or a high.”
Nineteen of twenty-two subjects experienced at least one such sensation. Frequency
and duration of sensations were related to blood nicotine levels. These sensations
lasted for about 11 seconds and occurred with a delay of about 30 seconds after a puff.
A survey in the United Kingdom has shown that smokers have lower levels of
psychological well-being than nonsmokers and ex-smokers (West, 1993). In addition,
even though it is typically found that mood worsens when a person stops smoking, it
slowly returns to the normal smoking level after 3 or 4 weeks. What’s more, it then
continues to improve even further during the following 10 weeks, so the person’s
mood becomes even better than it was while he or she was smoking.
Over the years, a considerable amount of research has explored the effect of
nicotine on motor and cognitive performance; the results have been inconsistent. This
is partly because many experiments have not been well designed and have had
shortcomings that make the results difficult to interpret. For example, if an
improvement in performance is reported for participants who smoke, it is important to
be able to rule out the possibility that this was not a result of nicotine improving
performance that had been degraded by withdrawal. Thus, such research needs to be
conducted either on smokers who have not been deprived of nicotine or on
nonsmokers. A recent meta-analysis reported that 40% of studies published between
1994 and 2008 used participants who were smokers deprived of nicotine for more
than 4 hours.
Another common problem is that many studies do not use a placebo control
and do not have a double-blind design so that expectancy and placebo effects cannot
be ruled out. In a 1994 review, Heishman, Taylor, and Henningfield found that 74% of
studies did not use a placebo smoking condition. This situation seems to be
improving, however, because in 2010, Heishman and colleagues found that this
percentage had decreased to only 30% (Heishman et al., 2010). Another factor that
has allowed for improvement in the design of recent studies examining the effects of
nicotine on performance is that nicotine can now be administered in various forms,
such as in nicotine gum, whereas most studies conducted prior to 1994 used ad labium
smoking, which meant that the dose of nicotine was impossible to control.
Working memory is often tested by using the n-back test. In this test,
researchers present participants with a visual display of constantly changing letters in
which a target letter appears from time to time. When the target letter appears,
participants are asked to report which letter had been presented either immediately
before, two letters before, or three letters before the target letter. Increasing the
number of letters that must be remembered increases cognitive load by taxing
working memory. Nicotine had a negative effect on the accuracy of working memory,
but it was not significant. Response times, however, were improved by nicotine.
K. Drug State Discrimination
In a drug state discrimination task, nicotine is an effective cue in a dosage
range similar to that which alters operant behavior. It has been shown that 0.2 mg/kg
of nicotine can be used as a cue and will not generalize to various doses of
epinephrine, pentobarbital, physostigmine, chlordiazepoxide, or caffeine. The
stimulus properties of nicotine can be blocked by mecamylamine (Morrison &
Stephenson, 1969; Stolerman, Pratt, & Garcha, 1982). In experiments with rats, low
doses of ethanol can block nicotine discrimination (Korkosz et al., 2005), but alcohol
does not seem to affect nicotine discriminations in humans (Perkins, Fonte,
Blakesley-Ball, Stolinski, & Wilson, 2005). Caffeine is able to potentiate the
discrimination of nicotine in rats.
As mentioned earlier, humans sometimes describe the effect of intravenous
nicotine as being similar to that of cocaine. Similarly, nicotine will fully substitute for
cocaine in rats, but the effect is not bidirectional; cocaine will only partially substitute
for nicotine in trained animals. Desai, Barber, and Terry (2003) used various
antagonist drugs to further explore this relationship and concluded that nicotine’s
ability to mimic cocaine is due to its stimulation of dopamine release, an effect it
shares with cocaine. The subjective similarity is not because cocaine has an effect on
cholinergic systems that would also be affected by nicotine.
In an attempt to determine the locations in the brain responsible for nicotine’s
discriminative properties, Miyata, Ando, and Yanagita (2002) trained rats to
discriminate nicotine and then tested the generalization of the nicotine response when
nicotine was administered into various locations in the brain. They found that the
nicotine response generalized fully to nicotine administrations into the medial
prefrontal cortex and only partially to administrations into the nucleus accumbens and
the ventral tegmental area. Administrations into the dorsal hippocampus and the
medial habenular nucleus did not generalize at all, showing that the discriminative
stimulus properties of nicotine are primarily mediated by effects in the cortex and that
reinforcement systems are only partially involved.
It has been shown that humans can discriminate between identical cigarettes
that are different only in nicotine content (Kallman, Kallman, Harry, Woodson, &
Rosecrans, 1982), although it is not known whether this is done by taste or through a
central mechanism. Humans can easily detect nicotine in nasal spray. This effect is
centrally mediated because it is blocked by mecamylamine and cannot be blocked by
a PNS blocker of nAChRs. Men appear to be more sensitive to the stimulus properties
of nicotine than women.
L. Withdrawal Symptoms
When most tobacco users attempt to give up their habit, they experience
withdrawal symptoms in varying degrees of intensity. Withdrawal from nicotine is not
as physically severe as withdrawal from heroin, but it is just as stressful
psychologically (Sigmund Freud, during one of his many attempts to quit cigar
smoking, was described by his doctor as suffering “torture beyond human power to
bear”; Jones, 1953, p. 311). Indeed, many ex-heroin addicts who have also quit
smoking report that they found it harder to give up tobacco than heroin. While this
chapter has focused primarily on the effects of nicotine on dopamine, nicotinic
receptors are involved in the modulation of virtually every major neurotransmitter in
the brain. After chronic exposure to nicotine, all these systems show adaptation.
Smoking cessation disrupts this new equilibrium and leads to a constellation of
physiological changes in all parts of the brain as systems readjust to the absence of the
effects of nicotine. Nicotine withdrawal is the manifestation of all these changes.
Systematic studies of nicotine withdrawal in chronic smokers reliably show
the following symptoms: decreased heart rate; increased eating causing weight gain;
an inability to concentrate; increased awakenings from sleep; craving for cigarettes;
and mood changes including anxiety, anger, aggression, and depression (Hughes,
Gust, Skoog, Keenan, & Fenwick, 1991; Hughes, Higgins, & Bickel, 1994). Other
reported symptoms include nervousness, drowsiness, light-headedness, headaches,
dizziness, tremor, and nausea ( Jarvik, 1979). Nicotine-dependent individuals who
abstain from tobacco for 10Bto 24 hours show a slowing in brainwave activity to levels
normally seen during drowsiness or light sleep.
Withdrawal symptoms can be relieved by the administration of nicotine via
other sources such as gum and transdermal patches. Symptoms of nicotine withdrawal
can also be reduced, at least temporarily, by the taste and smell of tobacco or the act
of smoking itself. One study showed that tobacco withdrawal symptoms were relieved
if smokers were allowed to smoke a denicotinized cigarette that delivered no nicotine
at all to the smoker. Nicotine withdrawal can interfere with performance on various
cognitive and motor tasks. Functional magnetic resonance imaging (fMRI) studies
provide an illustration of the cognitive impairments caused in chronic smokers by
nicotine abstinence. Using BOLD imaging, researchers tested participants using the n-
back test described earlier and in Chapter 2. If the participants had smoked nicotine
within 1.5 hours prior to testing, activity in the dorsolateral prefrontal cortex was
significantly lower when reporting which letter had directly preceded the letter X
(one-back) compared to when reporting which letter had occurred two or three letters
before X (two-back and three-back). However, following 14 hours of nicotine
abstinence when participants were experiencing nicotine withdrawal, BOLD imaging
showed that participants exhibited high levels of activity in the dorsolateral prefrontal
cortex, regardless of which letter they were asked to report. In other words, during
nicotine withdrawal, the previously simple one-back task required as much brain
activity as the two- and three-back tasks. The researchers also found that participants
made more errors on all three tasks during nicotine withdrawal.
Unlike most other drugs that cause physical dependence, withdrawal severity
of nicotine does not seem to be related to dose; heavy and light smokers report
equally severe withdrawal. Nor is withdrawal severity related to length of time
smoking, previous attempts at quitting, sex, age, education, or alcohol and caffeine
use (Hughes et al., 1991). However, severity of withdrawal does seem to be related to
speed of nicotine metabolism. Fast metabolizers show more severe withdrawal than
slow metabolizers. Nicotine withdrawal has widespread effects on laboratory animals
on many tests of performance and emotionality. Nicotine withdrawal increases the
threshold for the rewarding effects of electrical brain stimulation, indicating a
depression of the reward system. Nicotine withdrawal will create a conditioned place
aversion in rats; that is, rats will avoid places where they have experienced nicotine
withdrawal. Fear is also enhanced; rats experiencing nicotine withdrawal avoid the
open arms of an elevated plus maze (see Chapter 2). Beta2 and alpha6 subunits appear
to be involved in these and other effects showing increased anxiety during
withdrawal.
M. Human and Nonhumans Self-Application
Because self-administration of nicotine in humans is so persistent and
widespread, it is surprising that laboratory animal self-administration is much less
robust and restricted to a limited set of conditions. There are some anecdotal accounts
of tame monkeys smoking. Indeed, Charles Darwin, in The Descent of Man (1882),
claimed to have seen monkeys “smoke tobacco with pleasure” (p.B7). Darwin used
these observations to support his contention that the sense of taste and the nervous
systems of humans and monkeys are similar. Surprisingly, however, early systematic
research from laboratories found monkeys to be reluctant smokers ( Jarvik, 1973).
Monkeys have been taught to inhale cigarette smoke, but the procedure involved a
period of forced consumption in which the thirsty monkeys were reinforced with
drinking water for sucking on a tube through which they received tobacco smoke.
After this training, some animals seemed to prefer sucking on a tube that delivered
tobacco smoke over one that delivered only air. It is doubtful whether this procedure
represents a situation similar to human tobacco use. Animals do not normally initiate
smoking on their own.
But even after appropriate doses were determined, selfadministration did not
appear to be as robust as it should have been, considering its persistence in humans. It
was noticed, however, that responding for nicotine was much more persistent if a
second-order schedule was used. For example, Goldberg, Spealman, and Goldberg
(1981) demonstrated reliable intravenous self-administration in monkeys using a
second-order schedule where the nicotine infusion was preceded by a colored light.
They found that monkeys would respond at a higher rate for the combination of light
and nicotine infusion than the nicotine infusion alone. They also showed that the
monkeys would persistently respond for the light alone, even if it was only
occasionally paired with the nicotine infusion.
It appears that the presence of conditioned reinforcement arising from stimuli
paired with nicotine infusions is very important in the reinforcing properties of
nicotine. Anthony Caggiula at the University of Pittsburgh, Eric Donny at Johns
Hopkins School of Medicine, and their colleagues have extensively explored this
effect. They designed a series of experiments where rats were trained to lever press
for a combination of a cue light and nicotine infusions, and then each of these
elements was removed and systematically replaced (Caggiula et al., 2001). They
trained rats to lever press on an FR5 schedule for an infusion of nicotine. Each
nicotine infusion was paired with a 1-second cue light and was followed by a 1-
minute time-out period where the house light (the overhead light in the chamber) was
turned off. After 20 days of training on the FR5 schedule there was a 12-day
extinction period. The extinction period was different for each of three groups of rats.
For one group (the “saline + cues” group), saline was substituted for the nicotine
infusion, but presentation of the cue light continued during the saline infusion. For
another group (the “nicotine + no cues” group), the nicotine infusion continued, but
there were no changes in the house light and cue light. For the third group of rats (the
“saline + no cues” group), both nicotine and the cue- and house-light changes were
discontinued.
There is little doubt that nicotine is a reinforcer in human smokers. In one
study, smokers were attached to an intravenous catheter and could self-administer
infusions of nicotine by pressing a lever on an FR10 schedule. Responding increased
on this lever when the nicotine was available and was extinguished when saline
infusions were substituted. It was also shown that when larger doses were used,
subjects administered fewer infusions, and they increased infusions when the dose
was decreased (Henningfield et al., 1987; Henningfield, Lucas, & Bigelow, 1986).
This research shows that humans are sensitive to changes in nicotine concentration
and are capable of adjusting doses, but the nature of the change in blood nicotine
levels that is responsible for these adjustments is not clear. One possibility is that
smokers are trying to maintain a constant level of nicotine in the blood; another is that
they are trying to achieve sudden high doses delivered to the brain.
One assumption often made about smoking behavior is that the smoker is
attempting to maintain a constant blood level of nicotine; that is, a dose high enough
to avoid withdrawal symptoms, but below a level that has toxic or aversive effects.
For some time, it had not been clearly established that nicotine is the ingredient in
tobacco that is responsible for tobacco consumption. To show that it is, researchers
used the strategy of changing the nicotine content of cigarettes and noting whether the
amount of smoking changed as a consequence. Would smokers adjust (titrate) their
consumption to achieve a constant nicotine blood level?
One of the predictions of the constant blood level theory is that the first few
puffs on a cigarette will be rapid and deep as the smoker tries to raise blood nicotine
levels that have fallen since the previous cigarette was smoked. As the nicotine level
increases, the puff rate will decrease, and few puffs will be taken near the end of the
cigarette. This change in puff rate has been reported by several researchers (Chait &
Griffiths, 1982). In addition, the theory predicts that people will be highly motivated
to smoke when their blood levels are low after a period without smoking. The lowest
levels occur after a night of sleeping. A British study showed that 14% of smokers
light up within 5 minutes of waking in the morning, and 50% do so within 30 minutes.
Even though human smokers attempt to prevent their nicotine blood level
from falling to the point where withdrawal symptoms occur and make adjustments for
the amount of nicotine delivered by their cigarette, they are unable to compensate
completely. Their blood levels then become higher than normal when nicotine content
is increased and lower than normal when it is decreased. In addition, nicotine
replacement therapy is not as effective as one might expect if maintaining constant
nicotine blood level and withdrawal avoidance were all that mattered. Factors other
than constant blood level must be controlling nicotine intake as well.
The nicotine bolus theory was proposed by M. A. H. Russell of the Maudsley
Hospital in London to explain some aspects of smoking behavior. Careful observation
of a cigarette smoker will show that when smoke is inhaled into the lungs, it is
frequently done with one rapid inhalation rather than gradually, as with a normal
breath. This sudden filling of the lungs with smoke tends to saturate the blood in the
capillaries of the lungs with nicotine at the moment of inhalation. This concentration
of nicotine in the blood, known as the nicotine bolus, stays together as the blood
returns to the heart and is pumped to the brain. This theory suggests that the sudden
high level of nicotine in the brain intensifies the pleasure and enhances its reinforcing
effect. This is what makes cigarette smoking so much more addicting than other,
slower routes of administration and keeps the smoker smoking (Russell, 1976). A
similar theory has been proposed to explain the addictive nature of intravenous
injections of heroin (Dole, 1980) and is consistent with the general finding that the
reinforcing properties of many drugs can be greatly enhanced by delivering them to
the brain rapidly and in high concentrations. When drug absorption in the brain is
slowed, the pleasurable effects are greatly blunted.
Careful examination of Figure 8-2 shows that this series of events cannot
happen because there is no spike. There is merely an increase in the concentration of
nicotine caused by the nicotine bolus, but the levels never drop before the next puff.
This does not mean that the nicotine bolus is not important; it only shows that the
mechanism of action cannot incorporate a decrease in desensitization of nAChRs. It is
still clear that after each pulse, nicotine concentrations rapidly increase, and rapid
increases in drug concentration usually have an intensified effect, although, in this
case, the mechanism for such an effect is not apparent from what we know about the
properties of nAChRs. Because a nicotine bolus can be achieved only by smoking,
this theory explains why the craving for the drug is worse in smokers than in those
who take tobacco by other means, but it cannot account for the great popularity of
tobacco in its other forms throughout history.
N. Negative Consequence
Smoking increases the risk of heart disease by two to four times that of a
nonsmoker and doubles the risk of stroke Heart disease caused by tobacco smoke
appears to be due largely to the combined action of nicotine and carbon monoxide.
Carbon monoxide is present in smoke, and, when breathed into the lungs, it binds
with hemoglobin in the blood, reducing the ability of the blood to carry oxygen and,
consequently, reducing oxygen supply to the heart itself. Nicotine increases the
workload of the heart by releasing catecholamines. These effects are further
complicated by the fact that other constituents in the smoke reduce the lungs’ ability
to absorb oxygen (see the next section on lung disease), so the heart must work even
harder to pump more blood through the lungs and satisfy the oxygen needs of the
body. In addition, there is a relationship between atherosclerosis and the number of
cigarettes smoked per day. Atherosclerosis is a disease wherein plaques, or deposits,
build up in blood vessels and eventually stop the circulation of blood. When the blood
flow to the heart itself is stopped in this manner, the heart muscle dies, and a heart
attack occurs.
When tobacco smoke is inhaled, the ash and tars are deposited on the moist
membranes on the inside surface of the lung, through which oxygen and carbon
dioxide must pass to and from the blood. Normally, particles are cleared from the
lungs by small hairs called cilia, which agitate and work the pollutants upward until
they are ejected by coughing. Another line of defence against inhaled particles is the
action of phagocytes. The phagocytes attack, surround, and destroy foreign matter in
the lungs. Smoking reduces the actions of both the cilia and the phagocytes, leaving
the lungs more vulnerable to the toxic effects of inhaled pollutants and infections by
bacteria and viruses. As a result, smokers are more susceptible to COPD.
According to the American Cancer Society, smoking is responsible for 30% of
all cancer deaths and 87% of all lung cancer deaths in the United States. The risk of
developing lung cancer in male smokers is 23 times higher than in nonsmokers, and,
in females, the risk is 13 times higher. Lung cancer is not the only cancer associated
with smoking. Smoking increases the risk of many other forms of cancer:
nasopharynx, nasal cavity and paranasal sinuses, lip, oral cavity (a form of cancer that
Freud suffered), pharynx, larynx, esophagus, pancreas, uterine cervix, kidney, bladder,
stomach, colorectum, and blood (leukemia) (American Cancer Society, 2011; Sasco,
Secretan, & Straif, 2004). It should be no surprise that smoking causes cancer because
tobacco smoke is known to contain many recognized carcinogens including arsenic,
benzene, beryllium, 1,3–Butadiene, cadmium, chromium, ethylene oxide, nickel,
Polonium-210, and vinyl chloride.
O. Intervention
Perhaps one of the most tragic examples of the strength of the tobacco habit is
that of the founder of psychoanalysis, Sigmund Freud. Freud smoked cigars (upward
of 20 per day) for most of his life, despite the fact that he suffered from heart pains
and cancer of the mouth as a direct result. Toward the end of his life, he was in
constant pain after undergoing 33 operations for his cancer yet was still unable to quit.
Freud died of cancer at the age of 83. He had tried to quit for 45 years but was unable
to do so for any more than a year or so.
Freud, of course, is not alone. In his Statement on Nicotine-Containing
Cigarettes in 1994 before the House Subcommittee on Health and the Environment,
David Kessler, the commissioner of the FDA, made the following points: (a) Two-
thirds of adults who smoke say that they wish they could quit, and (b) 17 million try
to quit each year in the United States, but fewer than 1 out of 10 succeed. Three out of
four adult smokers say they are addicted, and eight out of ten smokers say they wish
they had never started. As Freud’s case shows, tobacco smoking can be a difficult
habit to break, but his case is not typical. Perhaps he was a fast metabolizer of
nicotine or had a genetic abnormality of nAChR subunits, which amplified his
withdrawal from nicotine. A large British survey conducted in the late 1980s, before
there were many smoking cessation therapies and no pharmacotherapies, found that
quitting is not all that bad; 53% of ex-smokers reported that stopping was “not at all
difficult,” 27% said it was “fairly difficult,” and only 20% said it was “very difficult.”
Between two-thirds and three-quarters of ex-smokers were able to stop smoking
without the benefit of any treatment (Chapman & MacKenzie, 2010), but for those
who need help, a great variety of therapies is now available. One of the most common
and most effective is nicotine replacement therapy (NRT).
This treatment is the most commonly used smoking cessation strategy. It is
based on the same strategy as methadone maintenance with heroin addicts (see
Chapter 11). It substitutes a relatively safe source of the drug, such as a nicotine
patch, gum, nasal spray, lozenge, sublingual tablet, or nicotine inhaler, for the more
harmful source: tobacco smoke. In addition, it blunts the pleasurable effect of inhaled
nicotine. Most NRT vehicles create relatively low nicotine blood levels with slow
absorption (see Figure 8-3), but the nasal spray and inhaler are more rapidly absorbed
and more closely mimic tobacco smoke.
All forms of NRT have been shown to increase the chances of quitting to a
greater extent than a placebo. A meta-analysis of 110 studies has shown that the rate
of quitting at 6 months with a placebo is about 10%, but with NRT, the rate is 17%.
This gives an odds ratio of 1.7. Another meta-analysis of the different forms of NRT
showed that nicotine gum and the patch are the least effective, while the inhaler, the
lozenge/sublingual tablet, and the nasal spray are the most effective, doubling the
chances of abstinence over a placebo. Success rates have been further increased by
combining a constant rate delivery system, like the patch, with a rapid delivery system
like the nasal spray, which can be used to control breakthrough cravings.
Bupropion is another pharmacological treatment for smoking, but is not a
nicotine replacement therapy. Bupropion was originally developed as an
antidepressant and sold as Wellbutrin. It is considered a third-generation
antidepressant as it acts primarily as a reuptake inhibitor of norepinephrine and
dopamine (see Chapter 13). After being marketed as an antidepressant, it was shown
that bupropion seemed to be able to help people quit smoking. With further testing, it
was marketed as a smoking cessation aid and sold as Zyban. In addition to its ability
to act as a reuptake inhibitor of monoamines, bupropion is also an antagonist at
nAChRs that contain the alpha3, alpha4, alpha7, beta2, and beta4 subunits. Action at
alpha4, alpha6, alpha7, and beta2 receptors involves the release of dopamine, and, by
inhibiting these receptors, bupropion diminishes the primary reinforcing effect of
nicotine. Alpha3 and beta4 subunits are primarily located in the habenular nuclei,
which have antireward functions and cause unpleasant symptoms of nicotine
withdrawal. Thus, bupropion is capable of reducing both the rewarding effects of
nicotine and the aversive effects of nicotine withdrawal.
Varenicline was approved as a pharmacotherapy for smoking cessation in the
United States and the European Union in 2006. It is sold as Chantix in the United
States and Champix in Canada, Britain, and Europe. Varenicline was developed from
cytisine, an alkaloid found in the leaves and seeds of the golden rain tree ( Cytisus
laburnum), which were dried and smoked as a tobacco substitute during World War II.
Varenicline is a partial agonist at the alpha4beta2 nicotinic acetylcholine receptor.
That is, it partially stimulates the receptor and also, by occupying the receptor, blocks
other agonists such as nicotine from having any effect. This action partially mimics
that of nicotine, but blocks any effect of nicotine molecules if they are present. By
partially stimulating the alpha4beta2 nAChR, varenicline causes some of the primary
reinforcing effects of nicotine in the mesolimbic dopamine system and alleviates some
of the nicotine withdrawal effects. At the same time, it blocks any reinforcing effects
of nicotine delivered by smoking. Like many antidepressant drugs, varenicline is also
a serotonin reuptake blocker, but it is not known whether this action contributes in any
way to its smoking cessation properties.
All of these studies of pharmacotherapies have used participants who want to
stop smoking, but is there anything that can be done for those who are not ready to
quit? The Clinical Practice Guidelines of the U.S. Public Health Service recommend
that people who are not ready to quit be given a brief “motivational intervention.”
One such strategy might be an attempt to reduce smoking rather than stopping it
altogether, but there are concerns about such a strategy. These include (a) uncertainty
that smoking reduction has any health benefits, (b) concern that any smoking
reduction may only be temporary, and (c) concern that such attempts will undermine
future attempts to stop.
