1. health and fitness
2. addiction
3. smoking addiction

The Four Stages of Nicotine Addiction
Starship Children’s Hospital
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


“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 a cigarette “just, like, pops in your
head, like someone is sending you a
message.”
Craving

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.”
Craving and Needing can be accompanied by
the classic symptoms of nicotine withdrawal.
Restlessness
Anxiety
Irritability
Anger
Difficulty concentrating
Disturbed sleep
Withdrawal recurs after each cigarette



Wanting
then Craving
then Needing
When addiction first develops




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
Periodicity, a fundamental property of
nicotine addiction.





“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



At the onset of addiction the latency-towanting may be longer than a week.
Repeated tobacco use causes the latencies
to shrink.
The shortening of the latency drives the
escalation in smoking.
The Latency






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-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…




One dose of nicotine increases noradrenaline
synthesis in the hippocampus for at least a
month.
One dose lowers activation thresholds for a
month.
One dose affects tyrosine hydroxylase
activity for a month.
One dose in adolescence has measurable
effects on behavior during adulthood.
Why are early symptoms crucial?




It’s a vicious cycle
Initial tobacco use promotes the development
of wanting,craving,needing
The shortening of the latencies promote an
escalation in use
Escalated use promotes more symptoms and
shorter latencies
Homeostasis
The brain seeks balance
Homeostasis
Nicotine Throws off this Balance
Homeostasis
The brain compensates to regain balance.
Homeostasis
Without nicotine the brain generates craving.
Coordinated activity in the insular cortex of nonsmokers
at rest
Coordinated activity in the insular cortex of smokers in
withdrawal
Homeostasis
You need to smoke to regain balance
Homeostasis
Craving occurs whenever the effect of nicotine wears off
Homeostasis
Now you have to smoke just to feel normal.
Homeostasis

The latencies determine how long it is before
the effect of each dose of nicotine wears off.

Do the Stages of Nicotine Addiction coincide
with actual physical changes in the brain?
Fractional Anisotropy



This technique measures the ability of water
to diffuse through the white matter brain
tissue.
Tissue that is complexly organized has higher
FA.
Prior studies show that smokers generally
have higher FA than nonsmokers.
Our data show smokers trend toward higher FA than
nonsmokers in the dorsal anterior cingulate bundle (p=0.05)
Studies of FA and Addiction



In three studies FA has correlated with FTND
score: r = -.52, r = -.58, and r = -.64
Stage of Addiction correlates with FA: r= -.85
Hooked on Nicotine Checklist correlates with FA:
r = -.96
Location of maximal correlation between FA and
Stage of Addiction (top) and FTND (bottom)
Smokers show greater structural connectivity between the dorsal anterior
cingulate bundle and the prefrontal cortex than nonsmokers
With advancing Stage of Addiction structural connectivity increases
between the dorsal anterior cingulate bundle and prefrontal cortex.
Areas showing stronger functional connectivity with the anterior cingulate cortex
during withdrawal. These include the superior medial frontal cortex, the inferior
parietal cortex, the middle cingulate cortex and the precuneus.
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



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.
Withdrawal craving correlates well with
coordination of activity between the anterior
cingulate and several other brain structures.
Addiction is a result of structural changes in the
brain.

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…




The nicotine from one cigarette occupies
88% of the brain’s nicotinic receptors.
Nicotine changes the transcription of
hundreds of genes in the brain.
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%
Clinical Pearls



Nicotine literally rewires the brain to produce
addiction.
Neurological changes and addiction can begin
with the first dose of nicotine.
Nicotine addiction is a physical brain disease,
not a defect in will power.
Clinical Pearls



Nicotine addiction develops through 4 stages
with wanting, craving and needing.
The shortening of the latency to withdrawal
drives the progression to daily smoking.
Nondaily smokers relapse at the same rate as
daily smokers.
The Four Stages of Nicotine Addiction
Starship Children’s Hospital
Joseph R DiFranza MD
University of Massachusetts Medical School
Hooked on Nicotine Checklist
1) Have you ever tried to quit, but couldn’t?
2) Do you smoke now because it is really hard to
quit?
3) Have you ever felt like you were addicted to
tobacco?
4) Do you ever have strong cravings to smoke?
5) Have you ever felt like you really needed a
cigarette?
6) Is it hard to keep from smoking in places where
you are not supposed to?
Hooked on Nicotine Checklist
When you haven't smoked for a while do you…
7) find it hard to concentrate?
8) feel more irritable?
9) feel a strong need or urge to smoke?
10) feel nervous, restless or anxious?


A prior study showed that smoking during
adolescence increases FA.
Adult studies show that advancing addiction
is associated with decreasing FA.
Interpretation


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.