The Pathophysiology and Clinical Course of
Nicotine Addiction
Joseph R DiFranza MD
University of Massachusetts Medical School
Nicotine Addiction- Case histories

We asked smokers what does it feel like to
need a cigarette?
Wanting

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“Wanting” is the first symptom of nicotine
withdrawal.
Wanting is a mild transient desire to smoke
that is easily ignored.
Craving



Craving is more intense than wanting and
intrudes upon the person’s thoughts.
It is more persistent and difficult to ignore.
“I feel like someone inside of me is really
telling me to smoke.”
Craving


Craving a cigarette “just, like, pops in your
head, like someone is sending you a
message.”
Craving is like “being hungry, but instead of
your stomach saying it, it’s your brain…it’s
just hungry, except for a cigarette.”
Needing



Needing is an intense and urgent desire to
smoke that is impossible to ignore. The
individual must smoke to restore a normal
mental or physical state.
“You really want one. You know you need it.
You know you’ll feel normal after smoking,
and you have to smoke to feel normal again.”
“Pretty urgent… you need it and you can’t get
your mind off it.”
Withdrawal recurs after each cigarette


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Wanting
then Craving
then Needing
Addiction develops in the same sequence in
all smokers



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No withdrawal symptoms
Wanting
Wanting and Craving
Wanting, Craving and Needing
Clinical Staging of Nicotine Addiction




Stage 1. Can remain abstinent indefinitely without
withdrawal symptoms
Stage 2. Wanting “If I go too long without smoking, the
first thing I will notice is a mild desire to smoke that I can
ignore.”
Stage 3. Craving “If I go too long without smoking, the
desire for a cigarette becomes so strong that it is hard to
ignore and it interrupts my thinking.”
Stage 4. Needing “If I go too long without smoking, I
just can’t function right, and I know I will have to smoke
just to feel normal again.”
Mean Adult FTND Scores by Stage
5
4.5
4
Score
3.5
3
2.5
2
1.5
1
0.5
0
Stage 1
Stage 2
Stage 3
Stage 4
Mean Adolescent HONC Scores by Stage
10
9
8
Score
7
6
5
4
3
2
1
0
Stage 1
Stage 2
Stage 3
Stage 4
Mean Adult HONC Scores by Stage
10
9
8
Score
7
6
5
4
3
2
1
0
Stage 1
Stage 2
Stage 3
Stage 4
The Latency to Withdrawal


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“A little light bulb goes off and it’s like, alright,
time [to smoke].”
The latency is the interval between smoking
one cigarette and wanting, craving, or
needing another.
Latency-to-wanting
Latency-to-craving
Latency-to-needing
The Latency to Withdrawal



At the onset of addiction the latency-to-wanting
may be longer than a month.
Repeated tobacco use causes the latencies to
shrink.
The shortening of the latency drives the
escalation in smoking.
The Latency to Withdrawal

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After smoking for 6 weeks, a 16-year-old girl
noticed a latency-to-craving of 2 days
which shortened to 4 hours by age 161/2,
…to 2 hours by age 17,
…to 1.5 hours by age 18,
…to 1 hour by age 19,
…and to 30-45 minutes by age 21.
The Latency to Withdrawal-Factors of 2
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
1 week (1 cig/wk)
3.5 days (2 cig/wk)
42 hours
21 hours
11.5 hours
5.6 hours
2.8 hours
1.4 hours
42 minutes (1 ppd)
21 minutes (2 ppd)

In adolescents, smoking 2 cigs/wk
increases the risk for heavy adult
smoking 174 fold.
Smokers have Latencies of days or weeks

With a half life of 2 hours, how can nicotine
have such a prolonged impact?
The neuroscience shows…


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One dose of nicotine increases noradrenaline synthesis
in the hippocampus for at least a month.
One dose lowers neural activation thresholds for a
month.
One dose affects tyrosine hydroxylase activity for a
month.
One dose in adolescent rats affects behavior during
adulthood.
The neuroscience shows…

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Nicotine changes the
transcription of hundreds
of genes in the brain.
Nicotine triggers a series
of events that cannot be
stopped by removing it.
What could change in the brain that
would cause addiction after one dose?
Homeostasis
The brain seeks balance.
Homeostasis
Nicotine disturbs the balance.
Homeostasis
The brain compensates to regain balance.
Homeostasis
Without nicotine the brain is disturbed.
Insular cortex activity during withdrawal –
“A little light bulb goes off, time to smoke.”
Nonsmokers
Smokers
Homeostasis
Nicotine is needed to restore balance.
Homeostasis
Craving occurs whenever the effect of nicotine wears off.
Homeostasis
Now you have to smoke just to feel normal.
Homeostasis

The Latency to Withdrawal determines how
long it is before the effect of each dose of
nicotine wears off.
The Latency to Withdrawal
The Latency to Withdrawal
The Latency to Withdrawal

Do the Stages of Nicotine Addiction coincide
with actual physical changes in the brain?
Fractional Anisotropy is an MRI measure
of structural complexity.
Low FA
High FA
Our data show smokers have higher FA than
nonsmokers in the dorsal anterior cingulate
bundle (p=0.05).
Smoking during adolescence
increases FA.
Smokers generally have higher
FA than nonsmokers.
Yet FA decreases as addiction
increases.
FA correlates inversely with the
FTND score: r = -.52, r = -.58,
and r = -.64.
FA decreases with advancing
Stage of Addiction: r= -.85
FA decreases with advancing
addiction as measured by the
Hooked on Nicotine Checklist :
r = -.96
The dorsal anterior cingulate gyrus- the location of maximal
correlation between FA and Stage of Addiction (top), and FA and
FTND (bottom)
The dorsal anterior cingulate gyrus- The location of
maximum correlation between FA and HONC
Interpretation

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Increasing FA in new smokers represents the
adaptations that cause wanting, craving and
needing.
Decreasing FA in adult smokers represents
the adaptations that cause the Latency to
Withdrawal to grow shorter.
Smokers have more structural connection between the dorsal
anterior cingulate and the prefrontal cortex than nonsmokers.
Structural connectivity increases between the dorsal anterior
cingulate and prefrontal cortex with advancing Stage of Addiction.
During withdrawal the anterior cingulate
shows greater functional connectivity
with…
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Superior medial
frontal cortex
Inferior parietal
Precuneus
Middle Cingulate
Middle temporal
Correlations between Functional
Connectivity and Withdrawal Craving
Correlated Circuitry
Peak
Correlation
Coefficient
ACC - Superior Frontal
0.74
ACC - R Precuneus
0.76
ACC - L Precuneus
0.75
ACC - L Putamen
0.77
ACC - Inf. Parietal
0.77
Summary
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Advancing stages of addiction are associated
with decreased organizational complexity in the
anterior cingulate white matter and increased
structural connectivity between it and the frontal
cortex.
These structural changes appear to be involved
with craving as withdrawal craving correlates
well with activity in this circuit.
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How quickly does addiction develop?
Percent with Diminished Autonomy
Endorsement of HONC symptoms of addiction by 10th Year NZ Youth
100
90
80
70
60
Girls
50
Boys
40
30
20
10
0
1
2
3-4
5-9
10 - 19 20 - 99
Lifetime Cigarette Consumption
≥ 100
The clinical data indicate that…

One cigarette must rapidly change the brain.
The neuroscience shows…

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The nicotine from one cigarette occupies
88% of the brain’s nicotinic receptors.
One dose stimulates an increase in the
number of brain nicotine receptors over night.
One dose initiates drug sensitization.
% Change in Distance Travelled
(% of Day 1)
Nicotine-Induced Behavioral Sensitization
900
850
800
750
700
Average of Nicotine animals (n=4)
Average of Control animals (n=4)
650
600
550
500
450
400
350
300
250
200
150
100
50
1
2
3
Day
4
5
6
A
1
1
5
B
2
2
2
3
3
4
4
7
5
7
6
6
5
PFC
2 Acg
3 Acc
4 VP
7
5
HP
6 VTA
7
VC
5%
4%
3%
2%
1%
0
C
-1%
-2%
-3%
-4%
-5%
Conclusion

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Nicotine hard-wires addiction into the brain.
This process begins with the first cigarette.
Addiction develops through 4 stages.
The shortening of the latency to withdrawal
drives the progression to daily smoking.
Is addiction reversible?

If the brain erases all trace of the addiction,
after a long abstinence, people should again
have the very long latencies of novice
smokers.
How much do people need to smoke
after a relapse?

The latency doubles in
length over three months.
After that it barely
changes.
100
90
Mean Pre-quit Ratio on Day 1 or 2 After Relapse

80
70
60
50
40
30
20
10
0
0
4
8
12
16
20
24
28
32
36
Duration of Abstinence in Months
40
44
48
52
The neuroscience shows…

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New adaptations develop in the brains of
rats weeks after nicotine is stopped.
In humans, smoking cessation triggers an
increase in nerve growth factor.
Recommended reading

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A sensitization-homeostasis model of nicotine
craving, withdrawal, and tolerance:
Integrating the clinical and basic science
literature. DiFranza and Wellman. Nicotine &
Tobacco Research. 2005; vol 7: 9-26.
The natural history and diagnosis of nicotine
addiction. DiFranza et al. Current Pediatric
Reviews, 2011; vol 7: 88-96.