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Neurology Today:
Special Report: Methamphetamine Abuse

INCREASING RATES OF METH ABUSE MEANS GREATER INVOLVEMENT FOR NEUROLOGISTS

Laino, Charlene

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As crystal methamphetamine continues its deadly march into rural and, now, urban areas, neurologists in some regions of the country may be called in for consults. But even clinicians who treated cocaine-related neurotoxicities during the crack epidemic of the late 1980s and early 1990s may need to prepare for a different pattern of spread and complications, experts say.

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LONGER ACTION, PROLONGED EFFECTS

In contrast to cocaine, which is quickly removed and almost completely metabolized in the body, methamphetamine (or “crystal meth,” as it is known on the streets) has a much longer duration of action, with a single administration lasting five to 12 hours, said Glen R. Hanson, DDS, PhD, Senior Advisor for the National Institute on Drug Abuse (NIDA) and Professor in the Department of Pharmacology and Toxicology at the University of Utah in Salt Lake City.

This can lead to prolonged stimulant effects and result in a slew of acute complications, including subarachnoid hemorrhage and hemorrhagic and occlusive strokes, said John C.M. Brust, MD, Director of Neurology at Harlem Hospital Center and Professor of Clinical Neurology at Columbia University College of Physicians and Surgeons in New York City.

In addition, Dr. Hanson said that patients may develop tachycardias, arrhythmias, hyperthermia, and convulsions. Chronic methamphetamine abuse can result in pericarditis, and among users who inject the drug, damaged blood vessels and skin abscesses.

Ingredients from which methamphetamine can be made – including battery acid, drain cleaner, lantern fuel, and antifreeze – further raise the risk of myocardial infarction, stroke, and serious brain damage, compared with other drugs. Behavioral problems are frequent, with methamphetamine abusers experiencing episodes of violent behavior, paranoia, anxiety, confusion, and insomnia.

Many methamphetamine addicts have been in fights during which they lose consciousness for long periods of time, “so you also have to consider all the complications of that,” added Thomas E. Nordahl, MD, PhD, Professor in the Department of Psychiatry and Behavioral Sciences at the University of California-Davis.

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CNS EFFECTS

Chemically related to amphetamine, methamphetamine has even greater effects on the CNS, he said. A powerful psychostimulator, methamphetamine causes some neurotransmitters, chiefly the catecholamines dopamine and norepinephrine, and the monoamine serotonin, to spill out of the appropriate neurons at high levels, he said.

“The receptor targets are dramatically activated so the litany of functions of these neurotransmitters are turned on at high rates – almost to the point of having a pathology,” Dr. Hanson said.

As dopamine begins to flow, for example, users feel the elevated mood and euphoria that characterizes the “meth” high. But in excess, dopamine can cause irritability, psycho-excitability, almost a Superman mentality. People begin to act irrationally and hyperactively. Thinking they are invincible, they begin to exhibit strange behavior.

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PSYCHOSIS DEVELOPS

Figure. Methamphetam...
Figure. Methamphetam...
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Chronic excess levels of dopamine can induce a psychosis that “looks a lot like schizophrenia,” Dr. Hanson said. “Users may feel paranoid and persecuted. They think law enforcement is out to get them. And they're suspicious that other people are trying to steal their girlfriend or boyfriend or get them fired.”

At some point, cognitive function is damaged: Memory is impaired and decision-making is compromised. “This is a problem for the both the person providing treatment and receiving treatment, as the patient's limbic system, or emotions, starts to drive decisions,” Dr. Hanson said. “Logic doesn't play much of a role. This means that trying to scare a patient with the consequences of his abuse, such as saying it raises the risk of HIV or infection, won't work. The immediate perceived need for the drug is what computes.”

TABLE. METHAMPHETAMI...
TABLE. METHAMPHETAMI...
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While studies into the CNS of long-term users are just starting to be done, Dr. Hanson said he believes that chronic use probably damages some of the brain's cognitive centers, such as the frontal cortex, the orbital cortex, and, maybe the sensory cortex.

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CAUSE OF BRAIN DAMAGE

Dr. Brust noted that animal studies suggest that methamphetamine is even more likely than cocaine – the drug of choice among his patients at Harlem Hospital – to cause brain damage. In animals, a single high dose of the drug has been shown to damage nerve terminals in the dopamine-containing regions of the brain.

While dopamine- and serotonin-containing neurons do not die after methamphetamine use, the nerve terminals are cut back, and regrowth appears to be limited. Over time, methamphetamine appears to cause reduced levels of dopamine, damaging the nigral-striatal dopamine pathway and causing a Parkinson-like disease, Dr. Hanson said. Meanwhile, the serotonin system, important for memory, mood, sleep, and cognitive function, is also damaged, he said. Mariana Cherner, PhD, Assistant Professor of Psychiatry at the HIV Neurobehavior Research Center at the University of California, San Diego, said that in addition to dopaminergic alterations, chronic methamphetamine use or acute use of large amounts can also affect levels of glutamate and GABA, which may further contribute to long-lasting damage to striatal and cortical monoaminergic nerve terminals. “Glutamate is probably a major culprit in neurodamage,” she said.

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ROLE FOR NEUROLOGISTS

So what should a neurologist called in for a consult be doing? Most importantly, work hand-in-hand with an addiction specialist, Dr. Hanson advised. “Especially in the early stages, patients can be most uncooperative. They lie, and you need to get independent verification for everything they say.”

Dr. Nordahl added: “For neurologists, the big issue may be the ability of these patients to stay focused on anything.”

The more profound effects of the drug don't clear up for at least six to eight months, Dr. Hanson said. “But somewhere around nine months, it's almost like a light turns on. Users stop denying the problem. It's almost like they can't believe who they were.”

Keep in mind that compliance is a big issue, Dr. Hanson added. “Patients are often not motivated to take all their meds and the neurologist may want to order blood tests to check on compliance.”

Also, about 60 percent of methamphetamine addicts suffer from alcohol abuse. “You need to get a really thorough history so you know what you are dealing with. If the patient has not been jettisoned by his or her family, recruit its support,” Dr. Hanson said.

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NEUROPSYCHOLOGICAL DEFICITS

Increased sexuality – a byproduct of methamphetamine abuse – and sharing contaminated needles can also lead to such comorbidities as HIV infection or hepatitis C. Dr. Cherner and colleagues have found that hepatitis C or HIV infection can also contribute to the neuropsychological deficits observed among methamphetamine-dependent persons (Neurology 2005;64:1343–1347).

For the study, neurocognitive functioning tests were given to 430 people who had hepatitis C infection, HIV infection, a history of methamphetamine dependence, combinations of these factors, or none of these factors.

Dr. Cherner said the study, which was part of a NIDA-funded program project on neuroAIDS, also showed that methamphetamine users were more likely than healthy non-users to show problems in most areas of cognitive functioning.

These problems are consistent with disturbances of the frontal striatal circuity of the brain. “In particular, people with a long history of methamphetamine use or who used heavy amounts had problems with learning and memory as well as motor deficits.”

“And those who were also infected with hepatitis C or HIV did worse,” she added. “The greater the number of risk factors, the worse they fared.”

But another study by Terry Jernigan, PhD, Director of the HIV Neurobehavioral Research Center at the University of California-San Diego, showed quite different results. The study, which appeared in the American Journal of Psychiatry (2005;162:1461–1472), concluded that methamphetamine abuse “was surprisingly associated” with increases in the volume of the brain's parietal cortex, the part of the brain responsible for understanding and attention. There were also increases in the volume of the basal ganglia, which are linked to motor function and motivation.

For the study, MRI was used to analyze structural volume changes in 103 adults divided into four groups: methamphetamine abusers who were HIV-positive; methamphetamine abusers who were HIV-negative; nonabusers who were HIV-positive; and nonabusers who were HIV-negative. The participants also underwent tests that examined speed of information processing, attention-working memory, learning and delayed recall, abstraction-executive functioning, verbal fluency, and motor functioning.

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Figure. Using magnet...
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Figure. Over time, m...
Figure. Over time, m...
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Figure. Dr. John C.M...
Figure. Dr. John C.M...
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Among the methamphetamine abusers in the study, the greater the increase in the volume in the parietal cortex, the worse the cognitive function, the study showed.

Although the results of the study provide little information about the specific mechanisms leading to the methamphetamine's unexpected effects on understanding and attention, they could be the result of inflammation in the brain or compensatory changes associated with methamphetamine toxicity, according to Dr. Jernigan.

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HOPE FOR NEURONAL RECOVERY

Dr. Nordahl said there is hope, with some studies, including his own, suggesting that there can be some neuronal recovery with prolonged abstinence. The study, which appeared in the Archives of General Psychiatry (2005;62:444–452), included eight methamphetamine users who had not used the drug for one to five years, 16 abstinent methamphetamine users who had not used the drug for one to six months, and 13 healthy, non-substance-using controls.

Using magnetic resonance spectroscopy, the researchers measured biomarkers in the anterior cingulum cortex, a region of the brain associated with selective attention. Levels of N-acetylaspartate (NAA), which is present only in neurons, were measured as a marker of the amount of neuronal loss. Levels of choline, which is generated by the creation of new membranes, were used to track changes consistent with neuronal recovery.

“When the terminal part of the dopamine and serotonin axons are damaged, choline is released. So we would expect levels to be elevated if damage was occurring,” Dr. Nordahl explained.

Levels of NAA were abnormally low in all the methamphetamine users, the researchers found. And while levels of choline were elevated in the short-term methamphetamine abstainers, they normalized in the longer abstainers.

While stressing the preliminary nature of the work, Dr. Nordahl said that sharing the results may help the patient who asks, ‘Why stop now?’

“Also, it appears the length of use correlates with the loss of viable neuronal tissue,” he said.

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EFFECT ON DEVELOPING FETUS

So what about the unborn: Can methamphetamine affect the developing fetus? While there is not much research in this area, a 2001 study suggested a possible abnormality in energy metabolism in the basal ganglia of children exposed to methamphetamine in utero.

As reported in Neurology (2001;57:255–260), the study of 12 children who had been exposed to methamphetamine in the womb and 12 age-matched unexposed children showed that the exposed youngsters had higher levels of total creatine in the striatum.

While there were no differences in reported behavior problems among the two groups, “the elevated creatine may represent either an abnormal response or an overcompensated effect in brain energy metabolism to the neurotoxicity of the drug.”

“Because executive functioning (or decision-making) is thought to be mediated in part by the frontal-striatal pathway, the findings of altered energy metabolism in the striatum may have important clinical implications,” concluded Lynne M. Smith, MD, of Harbor-UCLA Medical Center's Martin Research Center, who led the study.

Dr. Brust said that anecdotal evidence suggests high or chronic doses can cause behavioral changes, altered head circumference, and actual morphologic changes in the brain of the fetus. Also, animal studies suggest in-utero vascular changes.

“My guess,” Dr. Hanson said, is that methamphetamine has to affect the way the neurological system develops because its pharmacological effect is so profound. But what it will look like is anyone's guess.

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ARTICLE IN BRIEF

✓Given the CNS effects of methamphetamine abuse, the article focuses on the most current knowledge about the neurobiology of this form of addiction – and what neurologists can expect to see in affected patients.

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AREAS OF ABUSE FOR METHAMPHETAMINE ABUSE

Geographically, Hawaii is among the hardest hit for abuse of crystal methamphetamine, according to the National Institute on Drug Abuse (NIDA). Other hot spots of abuse include the West Coast, where Portland, Seattle, Los Angeles, and San Diego have been particularly hard hit; some of the mountain states, with Phoenix and Denver reporting substantial problems; and a lot of the Midwest states, including Iowa, Missouri, Kentucky, and Tennessee.

While the East has been relatively spared, Atlanta and Baltimore are starting to report a rise in use. And gay club-goers in New York City and other cities often use methamphetamine in an injectable form, a risky practice that increases the risk of transmission of HIV and hepatitis C, according to Glen R. Hanson, DDS, PhD, Senior Advisor for the NIDA and Professor in the Department of Pharmacology and Toxicology at the University of Utah in Salt Lake City.

Richard A. Rawson, PhD, of the Semel Institute for Neuroscience and Human Behavior at the University of California-Los Angeles, said surveys show that more people are seeking help, with admissions for methamphetamine abuse nationwide rising 10 percent from 2002 to 2003.

“The number of people using methamphetamine nationwide is actually stable, but more people are showing up for treatment. There is a huge increase in admissions in some states to the point that treatment centers are overwhelmed,” he said.

In the first six months of 2004, nearly 59 percent of substance abuse treatment admissions (excluding alcohol) in Hawaii were for primary methamphetamine abuse, according to the latest NIDA statistics. San Diego followed, at nearly 51 percent. Notable increases in methamphetamine treatment admissions occurred in Atlanta (10.6 percent in the first 6 months of 2004, compared with 2.5 percent in 2001) and Minneapolis-St. Paul (18.7 percent in the first 6 months of 2004, compared with 10.6 percent in 2001).

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REFERENCES

• Cherner M, Letendre S, HIV Neurobehavioral Research Center Group, et al. Hepatitis C augments cognitive deficits associated with HIV infection and methamphetamine. Neurology 2005;64:1343–1347.

• Jernigan TL, Gamst AC, Grant I. Effects of methamphetamine dependence and HIV infection on cerebral morphology. Am J Psychiatry 2005;162:1461–1472.

• Nordahl TE, Salo R, Buonocore MH, et al. Methamphetamine users in sustained abstinence: A proton magnetic resonance spectroscopy study. Arch Gen Psychiatry 2005;62:444–452.

©2005 American Academy of Neurology

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