by Avram Goldstein, M.D.
    Professor Emeritus of Pharmacology
    Stanford University

ADDICTION AND THE BRAIN

There 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).

Recent 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.

Every 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.

We 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.

An 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.

We 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.

Our 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

FIRST 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 heroin?

People 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.

All 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.

A 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.

Another 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.

Those 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.

Animal 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.

More 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.

SECOND KEY QUESTION: 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.

We 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 skin responses.

A 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.

I 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

So 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.

Whether 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.

Methadone 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.

The 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 behaviors.

When 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.

Methadone 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

1.	Dosage 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 doses.
2.	Duration 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.
3.	Patients 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.
4.	Urine 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.

Editors Note:

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.