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Biological roots of addiction are
seen in the phenomenon of adapta-
tion in nature and in genetic coding.
ONE way of improving our under-
standing of alcoholism is to look
at its place in a wider framework. I
propose to look at alcoholism as a
specific case of drug addiction.
Alcohol is a drug like morphine or
cocaine, peculiar in some ways, simi-
lar in others. Alcoholism shows all
the characteristic properties of drug
addiction. One can learn about it by
reviewing the strange phenomenon
that a human being can become de-
pendent on the intake of a chemical
substance, can commit an anti-social,
criminal act to obtain the substance,
can regard the drug as the most im-
portant part of his life, both an angel
and a devil, to be praised and cursed,
BY PETER N. WITT, M.D.
BIOLOGIC AND ADDICTIVE
ASPECTS OF ALCOHOLISM
but hardly able to exist without.
Man and his reaction to drugs can
be regarded from many different
angles. For the purpose of under-
standing, one has to look at these
angles separately—look at man as a
biochemical machine, a physiological
organism, an individual who behaves
in reaction to surroundings according
to inherited and acquired guidelines,
a social and a religious one. In stres-
sing the biological angle of man’s
This article was a distinguished lecture
of the fifth annual John W. Umstead
Series of Distinguished Lectures held in
Raleigh in February of 1968. Dr. Witt j
is director of the Division on Research
of the N. C. Department of Mental
Health.
addiction, it is assumed that every-
body realizes that this is only one of
many viewpoints.
One of the puzzling aspects of ad-
diction is its compulsive nature: the
addict has to take the drug again
and again, increasingly threatened by
the appearance of frightening with-
drawal symptoms as soon as he is
without drugs. Addicts frequently
compare the way they feel in the ab-
sence of the drug with hunger; it
feels “as if something were missing.”
“I feel normal after my injection,
sick only without it,” can be heard
frequently. Sudden withholding of
the drug can cause severe circulatory
Vol. 19, No. 1, 1969-1970
13
and autonomic nervous symptons,
fall of blood pressure, change of
heart rate, shallow respiration, goose
pimples, diarrhea, etc. The with-
drawn addict lies for several days
moaning under his blanket, unhappy,
depressed, weak.
On the other hand, the achieve-
ment of “normality” under drugs fre-
quently requires the taking of in-
creasing doses. De Quincy in “Con-
fession of an Opium Eater” tells us
that he finally had to take 133
drachms (about 300 times the ther-
apeutic dose). In order to feel “nor-
mal” and comfortable an addict has
to take an amount of the substance
that would kill the unaccustomed. Do
we know something more about this?
Can we understand it better as a gen-
eral biological phenomenon, or is this
only the manifestation of an individ-
ual^ mad search for pleasure?
A look at the phenomenon of a-
daptation in nature appears to be
helpful. Adaptation is built into all
living beings. It can be studied at
any level of organization and is eas-
iest to study at the level of animals
with one cell.
Dr. Phillip B. Dunham, a biochem-
ically oriented zoologist at Syracuse
University, New York, observed such
mono-cellular organisms in their nor-
mal surroundings, namely in tap
water. The animals swam around,
ate, propagated, and showed all the
signs of healthy behavior. He then
added some sodium chloride to the
water in increasing amounts every
day. As long as he kept the daily
increase small, these animals lived
“happily” in a 200 mm sodium chlo-
ride solution, the same solution
which would have killed them if
they had been put into it at the be-
ginning. Another experiment show-
ed that the little animals were no
longer the same; when he transfer-
red some individuals back into clear
water they burst immediately and
died. Only a gradual, slow reversion
to original living conditions permit-
ted the animals to survive.
Dr. Dunham, in trying to find out
what the difference between the
adapted and unadapted animals was,
went a step further in his investiga-
tion. The normal animal of this kind
tries to preserve a steady concentra-
tion of 12 mg per cent sodium on the
inside. It achieves this with the help
of a pumping mechanism with which
it eliminates excess sodium or lets
sodium in from the environment. The
cells brought into the high sodium
concentration at first accumulated
much more sodium inside—105 mg
per cent instead of 12 mg per cent.
But soon their pump began to work
faster, and the sodium concentration
was brought back near control levels
(to 21 mg per cent). This new level
of pump activity could no longer be
reduced on short notice, and the cell
brought into the original medium
died from lack of sodium inside.
Only gradual reduction of sodium
concentration outside permitted the
pump to reduce its speed. The cell
had adjusted to cope with the high
sodium outside in the course of sever-
al weeks, and was unable to stand
sudden reduction. I leave it to you
to draw a parallel between these ob-
servations and the phenomena of tol-
erance and withdrawal symptoms in
the addict who is, after all, another
biological system in a chemically
changed environment.
From the first model, the compul-
siveness of the process becomes un-
derstandable. Whether there is much
pleasure involved in obtaining the
effect of the drug seems, at least at
the later stage of addiction and after
the development of tolerance, quite
irrevelant. The fact that some drugs
which cause a most interesting and
frequently enjoyable experience like
14
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mescaline (from cacti) or psilocy-
bin (from mushrooms) are not liable
to produce addiction while others
show a high addiction liability should
have already made us cautious
toward the conclusion that the in-
dividual seeks pleasure through re-
peated drug administration. It can
be experimentally established that
some drugs possess a priori a high
addiction liability and others do not.
What makes a drug this way is not
known. Could it be that addicting
drugs stimulate a certain area in the
central nervous system, and that this
area has to be stimulated again and
again to obtain satisfaction, estab-
lishing a vicious circle, once the
process has started? Experiments of
James and Marianne Olds in Mich-
igan seem to pinpoint such a center.
Experiments Conducted
These experiments managed to
implant in a number of rats two elec-
trodes in different areas of the brain.
Each pair of electrodes was connect-
ed by means of wires to an electronic
stimulation device above the cage,
the wires being designed in a way
which did not restrain the animals
in their movements. The Olds’ built
a lever into the circuit which could
be pressed by the rat; each pressing
would release a series of small elec-
tric stimuli of one half second dura-
tion. If the lever was held down, or
if it was released and not pressed
again, no stimulation would occur.
The experimenters wanted to find
out whether such stimuli would be
perceived and manipulated by rats
in a way that would reduce stimulus
frequency to a low level. A recording
device indicated the amount of stimu-
lation that the rat had produced over
a certain period of time.
The surprising discovery, which
has since been confirmed by many
investigators, was that when the
electrodes were placed in such a way
that certain areas in the forebrain
system were stimulated, the animal
quickly learned to press the lever
very frequently. Rates (in eight
minutes) ranged from 600 up to 1200
responses and higher. All other areas
showed the rats either carefully
avoiding restimulation after one ef-
fort, or the animals were indifferent.
To clarify further the nature of
this effect, Olds and Olds compared
the rewarding nature of the stimuli
with those of eating in hungry ani-
mals. Instead of food as reward, self-
stimulation was used to cause or-
ganization of a complicated response
pattern like learning to run through
a maze. When two groups of rats
were compared, one receiving food
as reward for crossing the maze and
the other receiving self-stimulation,
both learned equally fast ter reduce
mistakes. However, the stimulation
group ran faster for the reward than
the hunger group. When, after four
days of training, the stimulation re-
ward was withdrawn, extinction of
the acquired response appeared with
the same speed for both groups in
about four days. These observations
appear particularly interesting in the
light of the frequently quoted remark
by addicts that drug withdrawal is
like getting hungry, and the drug
makes them feel satiated. But notice
that in these experiments no drugs
were involved.
Let us return to drugs, but stay
with our animal models for the pur-
pose of obtaining further insight into
the self medication and regulation of
dosage. The experiments to be de-
scribed in the following were car-
ried out by J. R. Weeks in rats and
monkeys. They chose settings in
which rats could take the drug at
will, regarding this as a model re-
latively close to the human addict.
(Continued on page 18)
Vol. 19, No. 1, 1969-1970
15
BIOLOGIC AND ADDICTIVE
CONTINUED FROM PAGE 15
For the purpose of their investiga-
tion a tube was positioned in the
rat’s heart and connected to a sy-
ringe. The syringe, outside the cage,
was pushed forward by a motor to
inject a measured standard amount
of fluid as soon as the rat pressed
the lever. In the beginning of the
experiment, the rat received a shot
of morphine every hour for two days,
starting with 2 mg and building up
to 40 mg per kg. At the end of the
second day the mechanism was ad-
justed so that the rat could inject
itself with a 10 mg dose of morphine
each time it pressed the switch. Most
rats stabilized thereafter at one in-
jection every two hours—some a
little more frequently, some less.
They were apparently able to gauge
the desired dose.
The next step in the experiment
was taken to find out how well the
rat would be able to adjust the dose
if conditions were changed. Instead
of 10 mg/kg morphine per injection,
the solution was diluted to deliver
3.2 mg/kg each time the lever was
pressed. In a few trials the rats
established a new rhythm, injecting
themselves now about twice as fre-
quently as before. If morphine was
further reduced, injections grew even
more frequent. And leaving out mor-
phine from the solution altogether,
a high frequency injection pattern
was followed by slowing down to al-
most cessation of lever pressing. All
abstinence symptoms could be ob-
served in the rats, and the symptoms
could be promptly relieved by a
single injection of morphine.
The mechanism could be program-
med to inject a single dose of mor-
phine only after ten lever pressings.
The rats reacted with keeping quies-
cent in the intervals and pressing 10
times in a row at the end of two
hours, so that the original dose per
time was received—indicating again
the ability to titrate the optimal
amount. Replacement of morphine
with other addicting drugs showed
the same pattern of response.
A last set of animal experiments
should be discussed now because
they shed light on the role of dif-
ferences in different individuals. On
closer observation it becomes ap-
parent that some persons do not be-
come addicted to drugs in spite of
extensive exposure, while others
seem to seek out the places and sur-
roundings where drugs can be ob-
tained and are used. It is very dif-
ficult to separate the role of the
early experience of a person from
that of his inherited traits. Though
it seems likely that addiction in
parents makes children more suscep-
tible to similar behavior, we hardly
know how much of this is due to
early influences and how much is
inescapably anchored in the genes.
Another question that the following
experiments try to answer is that of
the choice of drugs. Can a certain
person or personality become addict-
ed only to a certain drug, or is drug
selection a question of more or less
accidental exposure?
Just last year two investigators,
Nichols and Hsiao, published the re-
sults of a series of experiments in
Science which, I believe, shed some
light on these questions. They caged
rats individually and offered two
calibrated 100 ml drinking tubes—
one with tap water and one with 0.5
mg morphine per ml water. Rats au-
tomatically preferred the water and
never touched thé morphine solu-
tion, even after they had been in-
jected with morphine once per day
in the amount of 10 mg/kg for 17
successive days. However, if the rats
were deprived of water for 24 hours,
18
INVENTORY
then received only morphine solution
to drink for 24 hours, then they got
tap water for another 24 hours, and
if this was repeated 5 times for al-
together 15 days, they preferred the
morphine solution to water. When
the morphine solution was with-
drawn, three days of severe with-
drawal symptoms appeared; 12 days
later animals were close to normal
and no longer showed signs of phy-
sical dependence. At this time rats
were brought into the original situa-
tion in single cages with tubes of
100 ml drinking water and 100 ml
morphine solution to choose from.
Soon some animals now drank reg-
ularly large amounts of morphine
solution, while others drank little
and preferred water.
After morphine preference had
been established as a stable trait in
certain individuals, the rats were sep-
arated into two groups—those that
would prefer morphine over water
and those that would rather drink
large amounts of water. Animals in
the middle range—which drank
equally from both solutions—were
eliminated. The morphine-drinking
rats were now bred to each other and
the water drinkers were also bred to
each other. The morphine preference
of the offspring was then tested.
This procedure was followed through
four generations. It could be estab-
lished that the morphine preference
increased from generation to genera-
tion in the one group and decreased
in the other. The difference from gen-
eration to generation was increasing
significantly below the 0.005 prob-
ability level.
After having established this pre-
ference pattern in the animals, the
authors asked the question whether
the preference of morphine over
water was specific for morphine in
each strain or whether it was a
rather general drug preference.
Again two strains of rats were used
which had now been bred for four
generations and they were tested for
their preference for alcohol in water
or clear water. It was again neces-
sary to proceed through five periods
of alcohol exposure in the way de-
scribed above; one day of complete
withdrawal of drink, one day of ex-
clusive exposure to alcohol water,
and one day exposure to tap water.
At the end of this period the rats
were again given a choice between
the alcohol 4- water and clear water.
It may be useful to remember at this
point that previously rats would not
have drunk water with alcohol at all;
they apparently found this quite dis-
tasteful. It became quite clear that
the morphine rats now became ad-
dicted to alcohol. After successful
withdrawal, the morphine susceptible
strain of rats drank twice as much
alcohol as the other strain (24 vs 12
ml), and this difference was signi-
ficant at the 0.005 probability level.
Non-addictive drugs were not found
to be preferred over water by any of
the animals.
It is time to summarize what we
have learned from the animal experi-
ments. Let me repeat that we have
only touched on a small sector of
the problems which are related to
drug addiction. No mention has
been made of the preference for cer-
tain drugs in certain parts of the
world: alcohol in the West and
opium in the East. Little has been
said about personality traits of the
addict, his early experience, the ex-
posure and opportunity to obtain the
drug, his mental and physical health.
We have also taken the liberty of
lumping drug addiction together in-
to one big category in spite of the
fact that we know very well that one
drug may stimulate the addict, an-
other may make him sleepy, another
—like alcohol—acts first one way
Vol. 19, No. 1, 1969-1970
19
and then the other. This was done to
draw a more general picture of the
biological roots of addiction, cer-
tainly a simplified one, but one
which is important and impressive.
All experiments have clearly in-
dicated the compulsive nature of
drug addiction at the cellular level,
in brain stimulation, or in self medi-
cation. Once started, the deviation,
or adaptation, grows according to its
own laws. The development of toler-
ance, or adaptation, and the causally
related withdrawal symptoms force
the addict to continue drug self medi-
cation with increasing doses. For
some unknown reason tolerance to
the undesirable effects of the drug
frequently develops not at the same
rate as tolerance to its desired effect,
and the addict gets increasingly un-
comfortable. Once “hooked,” he looks
no longer for a pleasurable experi-
ence or “the shortest way to paradise
on earth,” he just wants to feel—in
his own words—“normal.” Indepen-
dent of whether we attribute freedom
of will and moral responsibility to
man, the observation that an animal
can be bred to high or low drug pre-
ference is a biological argument in
favor of regarding the addict as a
person severely afflicted, rather than
as somebody with evil designs.
But in reading newspaper articles
and even some of the professional
journals, one cannot help getting the
impression that addicts are some-
times considered as people who have
only to be severely reprimanded or
even threatened with punishment
and they will pull themselves to-
gether and break the habit. The deep
roots of addiction in biological pro-
perties of adaptation and in genetic
coding contradicts the reasonableness
of such an attitude.
The results of the experiments
just quoted together with much
other evidence seem to me to teach
us another lesson: to put all the
blame on the drug appears to be too
easy a way out. Remember the rats
which became “addicted” to an elec-
trical stimulus in the brain and pre-
ferred this as a reward over food?
Remember the animals which show-
ed high morphine preference but
then manifested a similar preference
for alcohol? I propose that we regard
the drug as only an instrument; it
can be used in many ways, skillful or
clumsy, for good or bad, depending
on the hands of the user. The instru-
ment can easily be exchanged, but
it is the guiding hand that makes it
useful or damaging. Biological think-
ing warns us not to get too satisfied
with pointing to alcohol, morphine,
or LSD as the source of trouble. We
should rather treat sick individuals
and a sick society if they are found
to misuse a drug.
SOUTH CENTRAL REGION
CONTINUED FROM PAGE 17
tractual basis and is under the direc-
tion of Harold Holder, Ph.D. from
the Department of Mental Health.
The program planning and imple-
mentation will be determined by a
regional team, consisting of repre-
sentatives from each of the nine
mental health areas, the regional di-
rector and staff from Dorothea Dix
Hospital, with consultation from the
Department of Mental Health and the
above resource persons.
As a summary, the South Central
Regional Alcoholism Program,
through an application of systems
analysis, is to look at alcoholism and
alcohol related problems of the
region to determine if existing meth-
ods are inadequate. If so, what alter-
natives are there, how can they best
be implemented, and what would
they cost, and what are their predic-
table consequences.
20
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