The National Methamphetamine
Treatment: Effects On the Brain and Body
Alan I. Leshner, Ph. D., Director
National Institute On Drug Abuse
The fundamental problem in dealing with any drug is to understand the target. The advances in science over the last 20 years have revolutionized our basic understanding of the nature of drug abuse and the nature of addiction. Research has taught us a tremendous amount, particularly about methamphetamine as an unusual stimulant with some unique effects. In order to understand what drugs are doing and why a drug is a problem, one must understand why people use drugs.
Most who talk about drug use have a tendency to discuss a wide variety of societal and risk factors for drug abuse and addiction. In fact, there are 72 risk factors for drug abuse and addiction, the same risk factors as for anything else bad that can happen: Poverty, racism, social dysfunction, weak families, poor peer groups. However, those risk factors only influence the possibility an individual might or might not use drugs. When we look at the individual case and ask why someone is using a drug, we need to understand he is using the drug simply because he wants to feel good, and this "feel good" effect has to do with how the drug affects the brain. My presentation outlines this phenomenon.
People take drugs because they like what it does to their brains; drugs modify mood, perception, and emotional state. To better understand this effect, we have to understand some basic neuroscience about how the brain works. First, the brain is organized into lobes, which are specific areas responsible for specialized functions like cognitive and sensory processes and motor coordination. The brain is also organized into far more complex units called circuits that involve direct connections among the billions of nerve cells that various drugs of abuse affect. Next, we must focus on the limbic reward system from the VTA (ventral tegmental area) to the nucleus accumbens. This little circuit is probably the essence of addiction. Every abusable substance—alcohol, cocaine, marijuana, nicotine, heroin—all have an effect on that system, and substances cause a change in the nucleus accumbens and cause the secretion of a chemical substance named dopamine.
Upon examining the brain, the connection between individual nerve cells and the neurons is important. The action of drugs occurs at a connection between two neurons called the synapse; what happens in this connection is the essence of what drugs do to the brain. An electrical signal comes from the axon to the first neuron and causes the release of a chemical substance called the neurotransmitter into the synapse. The neurotransmitter dopamine then moves to the next neuron where it is taken up by a receptor, or it is brought back by the dopamine reuptake transporter. This is very important because the transporter causes these chemical substances to be brought back into the brain.
Drugs of abuse modify the way in which those chemical substances are released into the space synapse and modify the activity of the receptors on one end or the other. Methamphetamine causes a tremendous release of dopamine into the synapse and causes displacement in little sacs of the dopamine transmitters. For the lay person, Time Magazine published an excellent description of what drugs do to the brain, and I commend the article for your reading.
Dr. Alan Leshner, director of the National Institute on Drug Abuse (NIDA), speaks about the dangerous effects of methamphetamine on the brain and body.
Various drugs of abuse modify dopamine neurotransmission. Methamphetamine produces a "spike" (an increase) in dopamine in the nucleus accumbens. Drug abusers love that spike; the more drug they take, the bigger the spike, and so the purpose of taking methamphetamine is, literally, to produce that spike. Studies at Brookhaven National Laboratories show the duration and intensity of the dopamine spike is directly related to the intensity of the high. This is a very important finding because it shows methamphetamine is different from other stimulants. Though stimulants might all produce a spike, methamphetamine has a gradual falloff in dopamine while cocaine has a more rapid falloff. Drug users binge crack cocaine to keep pushing their dopamine levels up, whereas the methamphetamine addict does not have to binge as much to keep a high.
Use is not just a chemical event. Dopamine is a neurotransmitter substance involving all pleasurable experiences and has a very widespread effect, even though its activity is in a relatively limited circuit in the brain. Some of the effects on the brain and on the behavior produced by acute methamphetamine use include: Increase in tension, decrease in fatigue, decrease in appetite, euphoria and rush, obvious increase in heart rate, and very complicated effects on motor functions. Methamphetamine is one of the most powerful acute stimulants available.
Methamphetamine use can not only modify behavior in an acute state, but, after taking it for a long time, the drug literally changes the brain in fundamental and long-lasting ways. This change in the brain is the problem with methamphetamine addiction—not physical dependence or the withdrawal symptoms one acquires after one stops taking a drug—and it is a very dramatic and more long-lasting change. We know a tremendous amount about how chronic methamphetamine use affects the secretion of various neurotransmitter substances, particularly dopamine and serotonin.
In the March issue of Behavioral Brain Research, William Melega and Mike Phelps from UCLA discuss a study performed on rhesus monkeys about amphetamine effects on the brain. PET (positron emission tomography) scans demonstrate that pre-amphetamine control is a measure of the ability to produce dopamine, and FDOPA dopamine is an indication of the ability to produce the chemical dopamine. Before a monkey was injected with amphetamine, there was an effective ability to produce dopamine in the area of the nucleus accumbens. The monkey then got two shots of amphetamine a day for 10 days. Four weeks after the injections had stopped, there was a tremendous decrease in the ability to produce dopamine. This problem persisted six months later. At one year, the brain was 90% functional, and, by two years later, the brain returned to normal dopamine production.
Prolonged use of amphetamine or heavy use of amphetamines produces a very dramatic change in the brain's ability to manufacture a chemical substance essential for the normal experience of pleasure and for normal psychological functioning. Chronic use has decreased the ability to produce that substance, and this effect may persist for up to a year after the individual has stopped taking the drug. We believe those changes in dopamine and the damage produced to dopamine and serotonin neurons are responsible for the much more dramatic chronic effects of methamphetamine use than the acute effects. Anyone who treats methamphetamine-addicted individuals or heavy users knows there are a wide array of behavior changes that are very dramatic, very persistent and very resistant to any kind of rational discourse. These behaviors are a direct result of what the drug is doing to the brain.
Source: C. Edgar Cook, NIDA Research Monograph 115: 6-23, 1991
It is also no surprise that use of the drug produces dependence and addiction. Methamphetamine is among the most addictive substances ever known to humankind. It is also dangerous because it can cause stroke or create methamphetamine psychosis, a mental disorder that may be pure paranoid psychosis or may mimic schizophrenia. It is difficult to define, but it is important for the lay person to understand these people act in a bizarre way, and they act this way because their brains are altered. The truth is that prolonged use of methamphetamine modifies the brain's systematic waves. This is a dangerous consequence, and the public must be educated about it.
What is particularly frightening about methamphetamine, more so than crack cocaine, is methamphetamine produces neurotoxicity. In animal models, and there is some evidence in humans as well, methamphetamine produces nerve toxicity to dopamine and serotonin neurons. To understand this fact is important, because antipsychotic medications work by changing the activities of the dopamine and serotonin neurons. We treat schizophrenics and psychotic individuals with drugs to reverse or return their brain function to normal. There have been a few studies investigating antipsychotic medications in the treatment of methamphetamine.
So we do understand there are very dramatic brain changes, and the changes persist long after a user stops taking the drug. We know brains in addicts are different from brains of nonaddicts, and those differences are an essential element of addiction. We are beginning to understand there are common brain changes characteristic to every addicting substance. Some of these changes are at a molecular level. After prolonged drug use, the individual moves from a state of drug use into a qualitatively different state of addiction because of what has happened in the brain. Drug use is voluntary behavior; addiction is not.
Addiction is a state of compulsive, uncontrollable drug use—the person is literally in a different brain state. Fundamentally and at its core, addiction is actually a brain disease. It is not a brain disease in which one develops a magic bullet to solve the problem; addiction is much more complex. The final common path to the brain that is influenced by the individual's physiological state, his or her genetics, environmental and societal situation, and how he or she is embedded into society comes together in the end. Addiction is a brain disease that has literally-embedded behavioral and social context aspects.
Perhaps the most important message I could leave is this: We need to face the fact that, when we are dealing with methamphetamine addicts, we are dealing with people whose brains have been changed by drugs and who are literally in a different brain state. Law enforcement officers on the street understand this problem from experience, but we all must understand this fact at a core level if we are to solve the problem. This educational shortfall can be overcome; we learned from Alzheimer's disease and schizophrenia. When I was a graduate student, schizophrenia was believed to be caused by "refrigerator" parents. In 1988, we decided to educate the public that schizophrenia was a brain disease, and we succeeded. We need to do the same with methamphetamine. We need to understand these brains are different, and we need to fix them. That is what treatment is for, and that is what treatment is about—either to change the brain back or to somehow compensate for that brain change.
Addiction is a psychobiological phenomenon of brain disease with behavioral and social context aspects. That tells us the most effective treatments will deal with all of those aspects: Biological, behavioral, environmental and social. Combined treatments that bring all of those together do well. The problem is that we have virtually no biological treatments for methamphetamine addiction. This is a terrible problem. The absence of medications for stimulant addiction is probably at the core of our inability to get a handle on this issue in this country, and I have declared the development of anti-stimulant addiction medications in my institution as a top priority.
On the other hand, we have tremendously effective behavioral techniques, and I hope at the workshops you will have the opportunity to talk about them. We have in our toolbox more clinical trial case treatments for drug addiction than we do for virtually any other mental or addictive state. We have some effective treatments, if used and applied in a systematic way. The Center for Substance Abuse Treatment (CSAT) recently published a very important study about the efficacy of treatment. Science is providing molecular targets at which to direct our efforts. These advances are helping us in our goal of developing medications.
We at NIDA are making progress. We have declared a methamphetamine research initiative to try to answer questions about this drug and its effects. We are committed to doing our part in the scientific community to increase our understanding of the phenomenon. Let me close with this core message: To a very large degree, the use of this drug is about its effect on the brain. To fix the problem, we will have to address those brain changes, and we will have to do so in systematic and fundamental ways. Thank you very much.
Q: You mentioned research on an anti-serum and anti-addiction-type serum. Where are we on this research, and what timeline do you see for research development?
A: This is what I call a multiple-strategy approach to an anti-addiction medication. We actually have 26 compounds in various stages of clinical trials at the moment. We are making progress; we certainly have more and more compounds that are candidates. Some of these clinical trials are giving us positive results, but the typical time it takes the pharmaceutical industry to develop a medication is 5 to 10 years. I cannot give an exact date of completion, but I certainly hope to move faster.
Q: What about ultra-rapid opioid detoxification (UROD)?
A: Literal detoxification is not drug treatment. Literal detoxification addresses the minimal physical dependence aspects of only those substances that cause physical dependence accompanied by dramatic withdrawal symptoms. It is necessary to detoxify people. But after they are detoxified, they must complete drug treatment, or they will not return to functional status in society, which is the goal.
Q: How many months or years must a person be in treatment to guarantee some success in the drug court system?
A: Addiction is a chronic, relapsing disorder. It is not like breaking a bone. It is more like diabetes and chronic hypertension where there will be or is a high risk of occasional relapse. Addicts must be followed for a very long period and must have access to needed resources if they are to recover. They can become productive members of the community, but that does not negate a booster session some time later. Most people need help managing this disorder for a long time.