Avram Goldstein, M.D.
Professor Emeritus of Pharmacology
ADDICTION AND THE BRAIN
are eight families of addictive drugs, which are different in many
ways, but similar in one important respect -- whether it is nicotine
or alcohol or cocaine or heroin, some people lose control and become
compulsive users. The hallmark of addiction is compulsive use. Addiction
is "a behavioral pattern of drug use, characterized by overwhelming
involvement with the use of a drug (compulsive use), the securing
of its supply, and a high tendency to relapse after withdrawal"
(J. H. Jaffe, 1985).
years have seen great advances in our understanding of this compulsive
behavior. As all behavior is rooted in the brain, our new knowledge
about addiction comes directly from basic brain research.
addictive drug used by people is also self-administered by rats
and monkeys. If we arrange matters so that when an animal presses
a lever, it gets a shot of heroin into a vein, that animal will
press the lever repeatedly, to the exclusion of other activities
(food, sex, etc.); it will become a heroin addict. A rat addicted
to heroin is not rebelling against society, is not a victim of socioeconomic
circumstances, is not a product of a dysfunctional family, and is
not a criminal. The rat's behavior is simply controlled by the action
of heroin (actually morphine, to which heroin is converted in the
body) on its brain.
are beginning to learn why a laboratory animal (or a person) uses
these drugs. A bundle of nerve cells (neurons) deep in the brain,
the so-called mesolimbic dopaminergic pathway, is the main site
of action of opiates like heroin -- and also, interestingly, of
all other addictive drugs. We call this the "reward pathway". It
mediates feelings of pleasure and satisfaction. Within the reward
pathway, opiates indirectly cause dopamine neurons to release their
dopamine. These dopamine neurons are held constantly in check by
inhibitory neurons. Opiates act on those inhibitory neurons, shutting
them down, removing the inhibition and thus allowing the dopamine
neurons to run wild. Inhibition of inhibition causes stimulation.
analogy may help. Dopamine, in that part of the brain, could be
called a "pleasure hormone"; its release causes feelings of satisfaction,
of euphoria. The dopamine neurons are held constantly in check by
another neurotransmitter released from inhibitory neurons. If a
dopamine neuron is like the accelerator pedal in a car, the inhibitory
neuron is like the brake pedal, keeping the car from going too fast.
Then endorphin neurons, in turn, hold the inhibitory neurons in
check, prevent too much braking action and tend to let the car speed
up. The net result is to keep the speed just right. A complicated
way to run a car, a complicated way to run a brain; but an efficient
way to maintain precise control. Thus, in short, opiates like heroin,
mimicking the endorphins, cause more dopamine release, cause euphoria;
but they do so in an uncontrolled way, overriding the natural controls.
have learned the structure of the mu opioid receptors, on which
the endorphins -- and also, of course, opiates like morphine (from
heroin) and methadone -- act. These receptors are the locks that
are unlocked by the endorphin (or opiate) keys. We know exactly
how each of the several hundred amino acids in the receptor protein
is positioned. Seven segments span the nerve cell membrane, back
and forth, forming the staves of a barrel. A molecule of an endorphin
(or morphine or methadone), passing from a blood capillary onto
a neuron, would drop into the pocket in the middle of the barrel.
When the molecular key drops into the lock, it changes the shape
of the receptor, and a "signal" is sent to the inside of the cell.
That "signal" triggers big chemical changes, which make that neuron
less active, so it releases less of its neurotransmitter. The neurons
containing mu opioid receptors, which are activated by endorphins
or opiates, are the ones that hold the dopamine neurons in check,
as already described, and the net result is to stimulate the release
of more dopamine.
normal feelings of satisfaction, our good moods, are controlled
by the regulation of dopamine release by endorphins acting on mu
opioid receptors, as described. Heroin is rapidly converted in the
body to morphine and 6-acetylmorphine, which act on these same receptors
in the brain. The brain responds with feelings of euphoria, but
the dopamine stimulation is excessive -- far greater than when under
the fine-tuned natural control of the endorphins. The brain adapts
to this changed condition. It becomes less sensitive to opioids
through several mechanisms I shall not discuss here. There are two
important consequences of this adaptation. First, more heroin is
now required to produce the desired "high"; and second, the system
has become less sensitive to the endorphins, so that without heroin,
there is insufficient dopamine release, and an uncomfortable feeling
we describe as "dysphoria" (and the addict calls "sick"). Thus,
after repetitive use of heroin, at increasing dosages, the addict
has become tolerant and dependent, and undergoes withdrawal disturbances
if the heroin is abruptly terminated.
TWO KEY QUESTIONS ABOUT ADDICTION
KEY QUESTION: Why
do some people become addicted in the first place, and others not?
Why do some people not even like the psychoactive effects of an
addictive drug and therefore never start using it? Why can some
people use such a drug in moderation and never go on to heavy use
and addiction? This extreme variability among people is typical
for every addictive drug, from nicotine and alcohol to cocaine and
heroin. Might there be some people whose reward pathway is defective
in some way from birth, who can only feel "normal" on an opiate,
for example, and who discover this the first time they encounter
sometimes argue that becoming addicted is a psychologic, not a biologic
problem. But behavior, the business of psychology, is also the business
of the brain. Until recently, there had been no way to map the living
functioning human brain; but now imaging techniques, such as magnetic
resonance imaging (MRI) and positron emission tomography (PET) have
begun to make that possible. Thus, we are actually learning, by
imaging techniques, which brain circuits mediate which behaviors.
of brain anatomy and chemistry is determined, at the outset, by
the blueprints in our DNA. Then, through our life experiences, both
anatomy (the brain circuitry) and chemistry (the neurotransmitters
and their receptors) become modified. Most behaviors are determined
by both genetics and environment, one or the other predominating
in a particular case.
researcher brought together for his studies seven pairs of identical
twins, boys and girls about four years old. On one occasion he had
them sit for a photograph, giving them no special instructions.
We have all seen pairs of identical twins, so as we look at this
photograph, we are not surprised to see how much alike each pair
looks. But there is something amazing. No instructions were given
about how to hold their hands, yet as we look more closely we see
that every twin pair holds their hands in an identical way. Some
twins clasp right hand over left, some clasp left over right, some
hold the hands in a closed fist, some rest their hands outstretched
on their laps, and so on. Each twin pair displays identical behavior
in this simple matter of hand position.
researcher brought together adult identical twins who had been reared
apart, so identical behavior could not be due to environmental influences.
Again, a photograph, and again we see in each twin pair an identical
positioning of hands and legs, identical tilt of the head, identical
facial expression. No such similarity is seen in fraternal (nonidentical)
twins. With respect to these behaviors, then, genetics seems to
count for everything.
who still doubt that genetics strongly influences behavior should
consider working dogs, which are specifically bred for certain behaviors,
such as retrieving, pointing, attacking, or herding. In our family
there is an Australian Shepherd dog who has never seen a sheep in
his life, who was separated from his mother before she could teach
him the trade. Yet this animal herds our family with great determination
whenever we go for a walk with our children and grandchildren; no
one is allowed to stray away from the group.
studies tell us that strains of mice and rats can be bred for willingness
or unwillingness to self-administer heroin, for ease or resistance
to becoming addicted. In the case of alcohol, we know that there
are indeed people who are predisposed (vulnerable) to becoming addicts.
That knowledge comes from family, twin, cross-adoption, and pharmacologic
studies. And the search is under way for the genes that contribute
to the predisposition.
research is needed to find out if genetic predisposition plays a
role in heroin addiction. This is an important issue because if
it is true that becoming an addict is not entirely a free choice,
but rather is driven by a disorder of brain chemistry, it would
validate the disease concept of heroin addiction. And that, in turn,
would go far toward removing stigma and legitimizing long-term treatment
with an opiate like methadone or LAAM in the eyes of the policy
makers, the public, and the addicts themselves.
Since withdrawal discomfort is now readily controlled with various
medications, so that an addict can be brought without difficulty
to an abstinent state, why doesn't that solve the problem? Why is
relapse so common? Is it because of innate deficiencies in the reward
pathway, or because chronic exposure to an opiate has caused irreversible
changes? In either case, there may be addicts who can not function
normally on their own supply of endorphins but require some opiate
(like methadone) to occupy the receptors.
need to know what triggers relapse in an abstinent ex-addict. Relapse
is preceded by craving -- an irresistible urge to use, often provoked
by an environmental cue related to previous use. A cue such as the
sight of injection paraphernalia or of a place to buy heroin on
the street can not only evoke craving, but can cause measurable
physiologic changes like altered pulse, blood pressure, and galvanic
recent study, by researchers at the National Institute on Drug Abuse,
concerns craving for cocaine in former cocaine abusers. The method
was PET scan, an imaging procedure that shows which areas in the
living human brain are activated by certain stimuli. There are two
groups of subjects -- people who had never used cocaine, and people
who had been cocaine abusers in the past but had not used any in
recent months. Two kinds of cue were presented on video tape --
a neutral one (such as a pastoral scene), and a cocaine-related
one (such as injection equipment). Subjects who had never used cocaine
showed no unusual brain activity when exposed to either kind of
cue. Subjects who had abused cocaine in the past were not affected
at all by a neutral cue; but they responded very differently to
a cocaine-related cue. Intense craving was provoked, and specific
brain areas lit up on the PET scan -- areas in parts of the brain
(frontal cortex and amygdala) that are known to be associated with
emotional memories and craving.
tell you about this experiment because it shows clearly that in
the subjects with previous heavy exposure to cocaine, certain brain
regions had been altered by the chronic use of the addictive drug.
And it also shows which brain areas are specifically involved in
the craving that leads to relapse. Most important for us, it points
the way to future similar research with heroin addicts, using brain
imaging techniques -- an exciting prospect that was only a dream
just a few years ago.
HOW METHADONE WORKS
what does all this have to do with methadone maintenance? None of
it was known 32 years ago when Dole and Nyswander conceived the
idea that a long-acting opiate might stabilize the neurochemistry
and behavior of heroin addicts. Now, every professional care-giver
who has treated heroin addicts properly with methadone knows how
effective this medication can be.
a heroin addict's reward pathway was defective to begin with, or
whether it was altered by the long-term insult of excessive dopamine
release, it seems to function normally only if an opiate continuously
occupies the mu opioid receptors. This continuous receptor occupancy
is the stabilizing factor that permits addicts on methadone to normalize
their behavior and to discontinue heroin use. It is, therefore,
not correct to think of methadone as a "substitute" for heroin;
its totally different pharmacokinetic properties make it, in effect,
a completely different drug. It is true that both heroin (morphine)
and methadone can occupy the mu opioid receptors. But the steady,
stable occupancy by methadone contrasts sharply with the repeated
excessive "highs" followed by excessive "lows" with heroin.
is not an experimental medication. It is more soundly based in biologic
science and has been proved in more clinical trials than many drugs
we use in modern medicine. It has helped hundreds of thousands of
heroin addicts all over the world. It is safe and efficacious. Taken
by mouth, it is well absorbed into the circulation, and it occupies
the mu opioid receptors in the brain for about 24 hours. Its stabilizing
action puts an end to the pattern of alternating "high" and "sick"
several times a day that is typical for heroin addicts.
effectiveness of methadone by mouth permits the addict to discontinue
intravenous drug use, thus reducing the risk of hepatitis, AIDS,
and other blood-borne infectious diseases. Quitting intravenous
drug use is also the first step away from a set of bizarre anti-social
used properly, methadone allows a heroin addict to stop using heroin.
It diminishes the craving for heroin, and by producing opioid tolerance
it blocks the heroin "high". Very important, if a patient on methadone
does occasionally use heroin, that event need not become a relapse
-- it can remain a single episode, without significant consequences.
In contrast, an abstinent ex-addict can almost never prevent a single
"taste" of heroin from leading to a total relapse.
itself is a therapeutic aid, not a panacea. No magical interventions
can stop a heroin addict from using, unless there is some motivation
to stop. Thus, methadone must be accompanied by skillful counseling
and rehabilitative aid, by psychotherapy as required (comorbidity
with other mental illnesses is common), by job training if needed,
by family involvement, and so on. Success requires a well-run program
with well-trained staff, who understand that heroin addiction is
a chronic relapsing disease, and who treat the addict with respect.
The primary criterion of success is cessation of heroin use and
of other drug abuse, as well as social rehabilitation. Giving up
methadone eventually is realistic for some patients, not for others;
it is certainly NOT a primary goal of treatment. As the underlying
defect in the reward pathway has not been cured, there may well
be addicts (we don't know how many) who will require lifelong maintenance,
much as diabetics requires insulin.
FOUR PRACTICAL GUIDELINES FOR TREATMENT
must be sufficient, typically in the 60-80 mg range, but some
patients require more. In no other branch of medicine can one
imagine guidelines -- much less regulations -- that insist on
the lowest possible dosage, even if that dosage is only marginally
effective in saturating the receptors. No medicine can work
unless given in adequate dosage, so low-dosage programs are
self-defeating. In the United States, the General Accounting
Office compared the effectiveness of methadone programs across
the country; the least successful were those with the lowest
of treatment must be adequate. In no other branch of medicine
would effective therapy for a chronic disease be terminated
after a fixed time. Imagine the outcry if physicians were forced
to discontinue steroids and nonsteroidal anti-inflammatory drugs
for rheumatoid arthritis, or digoxin for congestive heart failure.
Yet some jurisdictions have mandated a time limit on methadone
maintenance. Especially ironic is the view that when addicts
are doing WELL on methadone, they should be terminated; one
would think the opposite made more sense -- that patients doing
well on a drug should stay on that drug.
themselves are usually eager to quit methadone -- not only because
of the nuisance but also because societal attitudes make them
feel demeaned. Staff should DISCOURAGE terminating methadone
until fully satisfactory social rehabilitation has been achieved
and no heroin whatsoever has been used for at least a year.
However, if a patient does terminate prematurely and then relapses,
the door should be left open for immediate readmission and re-induction
without punitive attitudes on the part of treatment staff.
testing is essential -- on site, with immediate feedback of
results as an aid to the counseling process. Again, consider
the treatment of other diseases. Would we treat hypertension
without regularly checking the blood pressure? Or obesity without
regular weighings? Especially with a patient population not
famous for veracity, OBJECTIVE EVIDENCE provides the only sure
milestones for measuring progress or detecting relapses.
The News Report typically does not publish articles or speeches,
however, Dr. Goldstein's speech during the scientific plenary of
the 1997 National Methadone Conference stands as an exception. It
is increasingly important for treatment providers to understand
the neurobiology of addiction in order to effectively use the pharmacology
of methadone and other pharmacotherapies, such as LAAM and developing
treatment agents. The following article represents the major text
of Dr. Goldstein's plenary speech during the April, 1997 Conference.
It is being published here with his permission. It is our hope that
you will find the information useful in guiding you in treating
our patients more effectively.