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Research on

Methamphetamine
Research on

Methamphetamine

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ii

Introduction

The National Institute on Drug Abuse (NIDA) supports most of the world’s research on drug abuse and addiction.

NIDA-funded research enables scientists to apply the most advanced techniques available to the study of every aspect of

drug abuse, including:

• genetic and social determinants of vulnerability and response to drugs;

• short- and long-term effects of drugs on the brain, including addiction;

• other health and social impacts of drug abuse, including infectious diseases and economic costs;

• development and testing of medication and behavioral treatments for abuse and addiction; and

• development and evaluation of effective messages to deter young people, in particular, from abusing drugs.

Included in this document are selections of topic-specific articles reprinted from NIDA’s research newsletter, 

NIDA NOTES. Six times per year, NIDA NOTES reports on important highlights from NIDA-sponsored research, 

in a format that specialists and lay readers alike can read and put to use. Selections like the current one are intended 

to remind regular NIDA NOTES readers and inform other readers of important research discoveries during the periods

they cover.

We hope the information contained here answers your needs and interests. To subscribe to NIDA NOTES and for further

information on NIDA’s drug abuse and addiction research, please visit our Web site at www.drugabuse.gov.
iii

Table of Contents

Long-Term Abstinence Brings Partial 

Recovery From Methamphetamine Damage 

(V19-4; December 2004) . . . . . . . . . . . . . . . . . . . . . . .1

Mood Disorders in Methamphetamine Abusers 

Linked to Changes in Brain Metabolism 

(V19-4; December 2004) . . . . . . . . . . . . . . . . . . . . . . .3

Methamphetamine Abuse Linked to Impaired Cognitive

and Motor Skills Despite Recovery of Dopamine

Transporters (V17-1; April 2002) . . . . . . . . . . . . . . . . .4

Methamphetamine, Cocaine Abusers Have Different

Patterns of Drug Use, Suffer Different Cognitive

Impairments (V16-5; December 2001) . . . . . . . . . . . . .6

Methamphetamine Brain Damage in Mice More

Extensive Than Previously Thought 

(V15-4; September 2000) . . . . . . . . . . . . . . . . . . . . . . .8

NIDA Pursues Many Approaches to Reversing

Methamphetamine’s Neurotoxic Effects 

(V15-4; September 2000) . . . . . . . . . . . . . . . . . . . . . .10

Cocaine, Marijuana, and Heroin Abuse Up,

Methamphetamine Abuse Down 

(V15-3; August 2000) . . . . . . . . . . . . . . . . . . . . . . . . .12

Brain Imaging Studies Show Long-Term Damage From

Methamphetamine Abuse (V15-3; August 2000) . . . .13

Methamphetamine Abuse Alert 

(V13-6; March 1999) . . . . . . . . . . . . . . . . . . . . . . . . .15

NIDA Initiative Tackles Methamphetamine Use 

(V13-1; June 1998) . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Response to Escalating Methamphetamine 

Abuse Builds on NIDA-Funded Research 

(V11-5; November/December 1996) . . . . . . . . . . . . . .20

Facts About Methamphetamine 

(V11-5; November/December 1996) . . . . . . . . . . . . .23
Long-Term Abstinence Brings Partial Recovery From

Methamphetamine Damage

By Patrick Zickler, NIDA NOTES Staff Writer 

Research Findings

Volume 19, Number 4 (December 2004)

Methamphetamine abusers who remain abstinent for 9

months or longer show modest improvement in performance on some tests of motor skill and memory. They

also appear to recover from some of the drug's damaging

effects on metabolism in the thalamus, a brain region

involved in relaying and filtering sensory, motor, and emotional signals between the cerebral cortex and other brain

structures. Drug-related deficits appear to persist longer,

however, in another brain region, the striatum, which

plays a role in reward-linked motivation, planning, and

impulse control.

Dr. Gene-Jack Wang and colleagues at the Brookhaven

National Laboratory in Upton, New York, evaluated

metabolism and neuropsychological function in a small

group of methamphetamine abusers (three women and

two men; average age, 29) who entered treatment as part

of a California drug court rehabilitation program. In tests

following an abstinence of 2 months or less, the methamphetamine abusers scored lower than nonabusers, though

within normal ranges, on tests of gross motor function

(timed while walking in a straight line for a defined distance), fine motor coordination (inserting pegs into small

angled holes), memory (learning and recalling lists of

unrelated words immediately, after a delay, and after a distraction), and attention (identifying numbers previously

associated with symbols). When tested again after an additional 9 months of abstinence (average total abstinence

was 17 months), these methamphetamine abusers had

improved performance on three of five neuropsychological

measures: the timed gait test, symbol-digit association,

and delayed word recall. The changes in test scores correlated with improvement in thalamic metabolism.

The researchers used positron emission tomography (PET)

to evaluate methamphetamine's effect on metabolism in

the thalamus and striatum. This technique involves injection of a radioactively labeled form of glucose, the body's

basic metabolic fuel. Differences in activity among brain

regions are reflected by different rates of glucose consumption. PET imaging captures the signals emitted by the

radioactive glucose molecules; the strength of the signal

indicates the intensity of metabolic activity. The methamphetamine abusers had lower metabolism in the thalamus

than did nonabusers when evaluated after the short abstinence. However, the abusers' thalamic metabolism was

not significantly different from the nonabusers' after the

longer drug-free period, suggesting that drug damage in

this brain region is reversed with abstinence. “The correlation between increased thalamic metabolism and the tendency to better scores on some tasks suggests that the thalamic changes are functionally significant,” Dr. Wang says.

After a short abstinence, metabolism in another brain

region, the striatum, also was lower in methamphetamine

abusers than in participants who had never used the drug.

In contrast to the findings with thalamic metabolism,

however, abusers did not show recovery of striatal metabolism after the longer abstinence.

1

Thalamus Striatum

1.35

1.00

1.05

1.10

1.15

1.20

1.25

1.30

Relative Metabolism

Abstinence Interval

Short Protracted Short Protracted

Some Methamphetamine-Related Deficits Recover

After Protracted Abstinence

Relative metabolic activity (regional metabolic rate compared with

rate for entire brain) was reduced in the striatum and thalamus of

five methamphetamine abusers, compared with nonusers, after

short abstinence. After protracted (more than 9 months) abstinence,

thalamic metabolism returned to normal levels (blue line indicates

median level for healthy comparison subjects). Striatal metabolism

showed no recovery after abstinence.
The emerging pattern of these studies offers encouraging evidence that

some of the

destructive effects

of methamphetamine abuse may be

reversible. The

brain may respond

to damage by

rerouting some

connections.

Earlier work made

it clear that

methamphetamine causes damage to brain circuits that

rely on the neurotransmitter dopamine. “Recovery of thalamic metabolism could indicate in part a compensatory

adaptation to the loss of these dopamine cells by increased

activity in other brain cells that extend from the striatum

into the thalamus,” says Dr. Joseph Frascella of NIDA's

Division of Clinical Neuroscience, Development, and

Behavioral Treatments. “But there is a troubling indication

that some of the drug's damage is longer lasting. The 

persistent reduction in striatal metabolism seems to reflect

the drug's toxicity to dopamine terminals in that region.”

This lasting deficit in striatal metabolism may hold a clue

to the cause of other methamphetamine-related effects. In

some followup studies, methamphetamine abusers report

lack of motivation and anhedonia—an absence of pleasure

in response to acts that had previously been pleasurable—

as long as 2 years after their last use of methamphetamine.

Motivation and pleasurable response are both governed in

part by activities in one specific region of the striatum, the

nucleus accumbens, Dr. Wang explains.

“The anhedonia and decreased motivation reported by

some abstinent abusers may be the result of reduced activity—indicated in this study by reduced metabolism—in

the nucleus accumbens, which has a high density of

dopamine cells,” says Dr. Wang.

Source

Wang, G.-J., et al. Partial recovery of brain metabolism in

methamphetamine abusers after protracted abstinence.

American Journal of Psychiatry 161(2):242-248, 2004. 

2

The emerging pattern of

these studies offers

encouraging evidence

that some of the

destructive effects of

methamphetamine

abuse may be

reversible.
Mood Disorders in Methamphetamine Abusers Linked to Changes

in Brain Metabolism

Research Findings

Volume 19, Number 4 (December 2004)

Impaired metabolism in one part of the brain, the striatum, may be the culprit in methamphetamine-linked

mood disturbances. In a study similar to the one reported

in the accompanying article (see “Long-Term Abstinence

Brings Partial Recovery From Methamphetamine

Damage”), 17 chronic abusers of methamphetamine

underwent positron emission tomography (PET) brain

scans in the first week of rehabilitative treatment, a time

when many patients report high levels of depression and

anxiety. The scans revealed that metabolic activity in the

striatum varied with the severity of the patients' affective

symptoms.

The patients in the study (11 men and 6 women, with an

average age of 34.5 years) had used methamphetamine, on

average, for about 10 years. PET studies also were conducted on a comparison group of 18 volunteers who had

never taken the drug but had comparable histories of marijuana and alcohol abuse. The lead investigator on the

NIDA-funded study was Dr. Edythe London of the

University of California, Los Angeles.

All participants completed research questionnaires

designed to assess levels of depression and of generalized

(trait) and transitory (state) anxiety. For methamphetamine abusers, the average depression inventory score was

9.8 (scores between 9 and 15 are considered minimal to

mild depression) compared with an average score of 1.1

for the comparison group. On a 1-to-4 scale of anxiety,

abusers scored an average 1.9 for state anxiety and 2.2 for

trait anxiety (compared with 1.4 and 1.5, respectively, for

the comparison group). The higher measures of mood disturbances among methamphetamine abusers corresponded

to differences, relative to the comparison group, in regional brain metabolism.

“It appears that, at least in early abstinence, methamphetamine abusers who report negative mood states have dysfunctions in these brain regions,” says Dr. London. “The

abnormalities in metabolism that we see involve brain

regions that other investigations have implicated in mood

regulation.”

There is no pharmacological treatment for methamphetamine abuse, and negative moods can hinder behavioral

therapy, which relies on patients' voluntary participation.

“Early abstinence is the toughest stage of treatment for

methamphetamine abuse,” says Dr. Joseph Frascella of

NIDA's Division of Clinical Neuroscience, Development,

and Behavioral Treatments. “It's in the early stage that

mood disturbances may derail or complicate the most

effective treatment, cognitive behavioral therapy.

Methamphetamine abuse and addiction do not exist in

isolation, and this study suggests that associated depression and anxiety also must be addressed in treatment.”

Source

London, E.D., et al. Mood disturbances and regional 

cerebral metabolic abnormalities in recently abstinent

methamphetamine abusers. Archives of General Psychiatry

61(1):73-84, 2004. 

3
4

Research Findings

Methamphetamine Abuse Linked to Impaired Cognitive and Motor

Skills Despite Recovery of Dopamine Transporters

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 17, Number 1 (April 2002)

Animal studies have demonstrated that methamphetamine, a highly addictive stimulant, damages brain cells

involved in transport of the chemical messenger

dopamine. Now, NIDA-supported researchers have found

that long-term methamphetamine abuse by humans is

associated with a reduction in dopamine transporters after

2 months’ abstinence from methamphetamine and that

this damage appears to be linked to slowed motor skills

and weakened memory. Methamphetamine abusers who

were retested after remaining abstinent for at least 9

months showed substantial recovery from damage to the

dopamine transporters but not from impairments in

motor skills and memory.

Dopamine Transporter Damage After Brief Abstinence

Dr. Nora Volkow and colleagues at the Brookhaven

National Laboratory in Upton, New York, and at the

University of California, Los Angeles, used brain imaging

studies and tests of motor skills and memory to investigate

the effects of methamphetamine in 15 former methamphetamine abusers. The participants (nine women and six

men, average age 32 years) had used the drug at least 5

days per week for at least 2 years, and had been abstinent

from methamphetamine for at least 2 months.

The researchers used

positron emission tomography (PET) to measure

levels of dopamine transporters in the brain. PET

imaging detects signals

from chemical “tracers”

that are injected into the

bloodstream and carried to

the brain, where they bind

to dopamine transporters.

The strength of the signals

indicates the number of

transporters. Compared

with participants who

never used the drug,

methamphetamine abusers

had an average reduction

of 24 percent in levels of

dopamine transporters

(DAT) in the striatum, a part of the brain associated with

control of movement, attention, motivation, and reward.

Participants also took a series of tests to assess brain functions associated with the striatum: fine motor skills

(inserting pegs into angled holes as quickly as possible),

gross motor skills (walking as rapidly as possible in a

straight line), and memory (learning and recalling a list of

unrelated words immediately, after a delay, and after a distraction). “The abstinent methamphetamine abusers

showed impaired memory and slowed motor skills that

were directly proportional to the deficits in DAT. The

lower the levels of DAT, the worse their performance,” 

Dr. Volkow says.

“The reduction of dopamine transporters was seen in all

of the abusers,” Dr. Volkow says. “DAT loss also occurs

with age at a rate of 6 to 7 percent per decade, so the

DAT losses in methamphetamine abusers are roughly

equivalent to 40 years of aging.” Furthermore, she says,

DAT reduction in the range of 40 to 90 percent is one

characteristic of Parkinson’s disease, a progressive neurodegenerative disorder that causes tremor, weakness, and—in

some patients—cognitive impairment. “There is a concern

that methamphetamine abusers may be at increased risk

for neurodegenerative disease as they age. This will depend

Brain images of a person who has never used methamphetamine (left) and of a methamphetamine user

after 1 month of abstinence (center). Lighter colors show distribution of dopamine transporters (DAT) in

the striatum. DAT distribution is reduced in striatum of methamphetamine user. Brain image of a

methamphetamine user after 14 months’ abstinence (right) shows substantial recovery of DAT in striatum.

Low levels of DAT in methamphetamine users were associated with poorer performance on tests of memory

and motor skills, which did not improve with DAT after lengthy abstinence.
5

in part on the reversibility of DAT losses induced by

methamphetamine abuse.”

Dopamine Transporter Recovery

To assess the persistence of methamphetamine-related

DAT loss and impairments, the researchers reevaluated

five study participants (three women and two men, average age 29 years) after they had abstained from taking the

drug for at least 9 months. While these participants’ DAT

levels had increased to roughly equal those of never-users

of methamphetamine, they performed no better than

before on tests of gross and fine motor skills and memory.

Additional evaluations of five other former methamphetamine abusers with 9 months or more of abstinence (four

women and one man, average age 35 years) produced similar findings: normal DAT levels but reduced motor and

cognitive skills.

“This study documents significant recovery of DAT with

protracted abstinence from methamphetamine,” Dr.

Volkow says. “Moreover, for those evaluated twice, the

longer the interval between the first and second evaluations, the larger the increases in DAT. This suggests that

recovery is related to the length of time that methamphetamine abusers can stay off the drug. But, although there is

a recovery in DAT levels, there is no parallel improvement

in function.”

The relationship between impaired function and DAT loss

and recovery is unclear. It is possible that the DAT recovery is due to increased branching of dopamine terminals

rather than increased numbers of terminals, Dr. Volkow

says. “This may be insufficient to compensate for lost terminals. It is also possible that the neuropsychological

functions require other brain systems that recover slowly

or not at all from the effects of methamphetamine. Or the

failure to find an unambiguous association between DAT

recovery and improved function might reflect the small

number of participants who were able to stay drug free.

We will need longer term studies to see if increases in

DAT over longer periods of time are sufficient for complete recovery of function.”

Sources

• Volkow, N.D., et al. Association of dopamine transporter reduction with psychomotor impairment in

methamphetamine abusers. American Journal of

Psychiatry 158(3):377-382, 2001.

• Volkow, N.D., et al. Loss of dopamine transporters in

methamphetamine abusers recovers with protracted

abstinence. Journal of Neuroscience 21(23):9414-9418,

2001. 

Methamphetamine abusers may be at

increased risk for neurodegenerative

disease as they age. 
Research Findings

6

Methamphetamine, Cocaine Abusers Have Different Patterns of

Drug Use, Suffer Different Cognitive Impairments

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 16, Number 5 (December 2001)

NIDA-supported research has found that methamphetamine abusers typically use the drug throughout the day in

a pattern that resembles taking medication, while cocaine

abusers often exhibit a binge pattern, using the drug continuously over a period of several evening and nighttime

hours. And, according to the researchers at the University

of California, Los Angeles (UCLA), the drugs appear to

cause different types of deficits in reasoning and concentration.

Patterns of Use

Dr. Sara Simon and her UCLA colleagues interviewed 120

methamphetamine abusers and 63 cocaine abusers to

determine patterns of drug use. Ninety-seven of the

methamphetamine abusers and 56 cocaine abusers were

recruited from treatment programs; the others were currently using the drug and not seeking treatment.

Continuous use—more than 20 times per month—was

more common for both cocaine abusers (52 percent) and

methamphetamine abusers (70 percent) than was any

other pattern of drug use. Among those who used either

drug fewer than 20 times per month, methamphetamine

abusers were 4 times as likely as cocaine abusers (48 percent compared with 12 percent) to use the drug at least

once per week in a regular cycle.

“The typical methamphetamine abuser reported using the

drug when he or she first got up in the morning, then

using approximately every 2 to 4 hours during their waking day. Most of the descriptions of use more closely

resembled taking a medication than using a drug for pleasure,” Dr. Simon says. “Cocaine abusers reported patterns

that fit a picture of recreational use: They began in the

evening and continued until all the cocaine on hand had

been used.” 

The different patterns of use may in part be a result of the

drugs’ different effects in the body, the researchers say:

Methamphetamine triggers the release of large amounts of

the neurotransmitter dopamine into areas of the brain that

regulate feelings of pleasure, whereas cocaine blocks the

removal of dopamine, resulting in an accumulation that

causes continuous pleasurable stimulation of brain cells.

The effects of methamphetamine typically last more than

10 hours, and the half-life (the time it takes for the body

to remove 50 percent of the drug) of methamphetamine is

12 hours. Cocaine’s half-life is roughly 1 hour, and the

drug’s high lasts about 20 to 30 minutes.

Understanding the patterns of use for methamphetamine

and cocaine will help treatment providers and drug users

identify circumstances that may lead to relapse to drug

use. “Differences in use patterns indicate different triggers

and different times and places when the recovering abuser

is particularly vulnerable,” says Dr. Simon.

Effects on Reasoning and Memory

In another study, Dr. Simon and her colleagues evaluated

the effects of methamphetamine and cocaine on learning

and memory in 40 methamphetamine abusers and 40

cocaine abusers who were not in treatment and 80 individuals who had never used either stimulant drug. The

researchers administered tests to evaluate memory, perceptual speed and ability to manipulate information, ability

to ignore irrelevant information, general intelligence, verbal fluency, and executive function (abstract reasoning,

reactive flexibility, and ability to use feedback).

Methamphetamine abusers performed more poorly than

nonusers of stimulants in tests of word recall, perceptual

speed, ability to manipulate information, and abstract

thinking. Cocaine abusers scored more poorly than

nonusers of stimulants in tests measuring ability to recall

words and pictures and working memory.

“Methamphetamine abusers displayed impairments on the

tests of perceptual speed and manipulation of information
7

that were not seen in the cocaine group. Moreover, in tests

that require both speed and manipulation, there was even

more difference between the groups than on tests of either

skill separately,” Dr. Simon says.

“Overall, both drugs are associated with similar cognitive

deficits,” Dr. Simon says. “The most striking difference is

that methamphetamine abusers have more trouble than

cocaine abusers at tasks requiring attention and the ability

to organize information.”

Sources

• Simon, S.L., et al. A comparison of patterns of

methamphetamine and cocaine use. Journal of

Addictive Diseases, in press.

• Simon, S.L., et al. Cognitive performance of current

methamphetamine and cocaine users. Journal of

Addictive Diseases, in press. 
Research Findings

8

Methamphetamine Brain Damage in Mice More Extensive Than

Previously Thought

By Robert Mathias, NIDA NOTES Staff Writer 

Volume 15, Number 4 (September, 2000)

NIDA researchers have found that, when it comes to

brain cells, “speed” actually does kill. “Speed” is a street

name for methamphetamine, a powerfully addictive stimulant. Previous research had shown that methamphetamine damages but does not kill certain nerve cells in brain

structures that control movement. The new research, conducted in mice, indicates that methamphetamine-induced

damage prompts other nerve cells in brain regions

involved in cognition as well as movement to self-destruct.

The new findings raise concerns that methamphetamine

may have significantly more harmful long-term consequences than previously thought, the researchers say.

Previous research showed that methamphetamine damages

the nerve endings of brain cells containing dopamine, a

chemical messenger that plays a role in movement and

pleasure. Animal studies indicate that a gradual, partial

recovery occurs in the dopamine system when methamphetamine exposure is stopped. For example, a recent

imaging and postmortem study of the brains of monkeys

found substantial recovery in dopamine function over an

18-month period following the animals’ last exposure to

the drug. However, human brain imaging studies suggest

that significant damage to nerve endings of dopaminecontaining cells persists in the brains of chronic methamphetamine abusers for at least 3 years after they have

stopped using the drug. The damage, which affects

dopamine nerve endings located in the brain structures

that make up the striatum, is similar to but less extensive

than that caused by Parkinson’s disease.

“People used to think that the most serious methamphetamine-induced damage was to dopamine nerve terminals

because it put people at risk for developing Parkinson’s

disease as they got older,” says Dr. Jean Lud Cadet, clinical director of NIDA’s Intramural Research Program

(IRP). “We’ve now shown in our lab that methamphetamine is much more toxic than previously thought. It does

not just destroy the endings of dopamine-containing nerve

cells, it also kills other nerve cells that produce other neurotransmitters in additional brain pathways,” he says.

IRP researchers led by Dr. Cadet first linked this widespread loss of brain cells to a natural mechanism called

apoptosis, through which the body programs unhealthy

cells to kill themselves. In a study in cell cultures, they

showed that treating rat brain cells with methamphetamine caused cell death marked by apoptotic patterns, such

as DNA fragmentation and disintegration of cell bodies.

Previous research showed that methamphetamine damages the

nerve terminals of dopamine-producing brain cells. The new

research shows methamphetamine also triggers a natural mechanism called apoptosis that prompts the complete disintegration and

death of additional nerve cells in other brain regions. 

Methamphetamine-induced damage to nerve terminals of

dopamine-producing cells occurs primarily in a brain region

called the striatum. Methamphetamine-induced apoptosis killed

off different types of nerve cells in the frontal cortex, the 

hippocampus, and the striatum in mice. 
9

Subsequent studies in genetically engineered mice that

lacked specific genes known to promote or suppress programmed cell death suggested that at least part of the

nerve damage caused by methamphetamine may result

from activation of the molecular machinery that is

involved in apoptosis. The strongest evidence that

methamphetamine unleashes widespread apoptosis in animals came in a recent study that showed the drug caused

DNA fragmentation and loss of nerve cell bodies in the

striatum, the hippocampus, and the frontal cortex of mice

brains.

“Although these findings are in mice, if methamphetamine

kills nerve cells in the same brain regions of humans who

abuse the drug, the functional consequences could be significant,” Dr. Cadet says. Loss of cells in the hippocampus

and cortex could damage memory, cognitive function, and

decision-making capacity, he says. Loss of striatal cells

could lead to serious movement disorders that resemble

tardive dyskinesia and Huntington’s chorea.

Recent brain imaging studies in former methamphetamine

abusers conducted by Dr. Richard Ernst and Dr. Linda

Chang at the Harbor-UCLA Medical Center in Torrance,

California, provide additional support for the finding that

methamphetamine abuse causes brain cell death, says Dr.

Cadet. The California researchers found alterations in

brain chemistry in long-term methamphetamine abusers

indicative of nerve cell loss or damage similar to that

found in people suffering from strokes or Alzheimer’s disease (see “Brain Imaging Studies Show Long-Term

Damage From Methamphetamine Abuse”).

If methamphetamine kills brain cells in humans, it may

cause cognitive impairments that will have to be addressed

when treating methamphetamine abusers, Dr. Cadet says.

Although impaired people can do well in treatment, it is

possible that developing medications to repair the brain

could help such patients to do even better, he says. (See

“NIDA Pursues Many Approaches to Reversing

Methamphetamine’s Neurotoxic Effects”)

Sources

• Cadet, J.L.; Ordonez, S.V.; and Ordonez, J.V.

Methamphetamine induces apoptosis in immortalized

neural cells: Protection by the proto-oncogene, bcl-2.

Synapse 25:176-184, 1997.

• Deng, X; Ladenheim,B.; Tsao, L.I.; and Cadet, J.L.

Null mutation of c-fos exacerbation of methamphetamine-induced neurotoxicity. Journal of Neuroscience

19(22):10107-10115, 1999.

• Melega, W.P. Recovery from methamphetamine

induced long-term nigrostriatal dopaminergic deficits

without substantia nigra cell loss, Brain Research, in

press.

• McCann, U.D.; Wong, D.F.; Yokoi, F.; Villemagne,

V.; Dannals, R.F.; and Ricaurte, G.A. Reduced striatal

dopamine transporter density in abstinent methamphetamine and methcathinone users: Evidence from

positron emission tomography studies with

[11C]WIN-35,428. Journal of Neuroscience

18(20):8417-8422, 1998. 
Research Findings

10

NIDA Pursues Many Approaches to Reversing Methamphetamine’s

Neurotoxic Effects

By Robert Mathias, NIDA NOTES Staff Writer 

Volume 15, Number 4 (September, 2000)

NIDA-supported scientists are pursuing a number of

promising approaches to blocking or reversing some of the

brain damage wreaked by chronic abuse of methamphetamine. Research has shown that methamphetamine can

damage blood vessels and nerve endings in the brain and

cause changes in brain chemicals. These effects put chronic methamphetamine abusers at risk for cognitive impairment and early onset of movement disorders associated

with aging. (See “Methamphetamine Brain Damage in

Mice More Extensive Than Previously Thought”)

In January, NIDA’s Division of Treatment Research and

Development (DTR&D) convened a “Methamphetamine

Addiction Treatment Think Tank.” The meeting brought

together preclinical and clinical researchers to set up a new

program within NIDA’s Medications Development

Program to develop methamphetamine medications. The

program now is selecting and setting up five sites to conduct clinical pharmacology and outpatient studies of medications proposed to treat different aspects of methamphetamine abuse, beginning with methamphetamine

addiction. Overdose, neurodegeneration and cognitive

impairment, psychoses, and movement disorders will be

secondary targets.

“The first priority of the methamphetamine medications

development program is to develop medications to treat

methamphetamine addiction,” says Dr. Ahmed Elkashef

of DTR&D, who heads the program. Such medications

are aimed at stopping or reducing methamphetamine

abuse and not at directly reversing cognitive impairment

or other clinical manifestations of methamphetamine’s

neurotoxic effects when they already have occurred in

drug abuse treatment patients, Dr. Elkashef says. However,

by reducing drug use, this approach could stop additional

neurotoxic damage that might occur with continuing drug

use, he says.

In addition to preventing new brain damage, addiction

treatment medications may also help treat some of the

clinical manifestations of methamphetamine neurotoxicity.

“We will assess cognitively impaired patients to see if medications that stop or reduce methamphetamine abuse also

improve cognitive functioning,” Dr. Elkashef says.

Program scientists also plan to test a long list of promising

medications that may be able to reverse cognitive impairment caused by methamphetamine abuse, Dr. Elkashef

says.

One of the first compounds the program will test—

selegiline—is a medication that has the potential to treat

both methamphetamine addiction

and its associated cognitive

impairment. NIDA has been testing selegiline, an approved treatment for some symptoms of

Parkinson’s disease, as a cocaine

treatment medication. Selegiline’s

neuroprotective effects counter

several possible mechanisms of

methamphetamine neurotoxicity,

Dr. Elkashef says. “This medication has been shown to reduce

cognitive impairments among

HIV-positive patients, and we

expect it to help treat that aspect

of methamphetamine abuse,” 

he says. 

Methamphetamine may damage the brain in many ways,

including impairment of blood flow, production of harmful free radicals, and killing of brain cells. Thus, the

methamphetamine medications development program also

is considering using medications that have the potential to

improve cognitive function by countering these effects.

These PET images show brain activity of a chemical messenger called dopamine (shown by dark

color) in a monkey that was pretreated with glial-derived neurotrophic factor (GDNF) 1 week

before being administered a neurotoxic dose of methamphetamine. Later images showed that the

treated monkey had significantly greater recovery of dopamine function than an untreated monkey, at all time points following methamphetamine administration. (Brain images by Dr.

William P. Melega.) 
11

Potential cognitive enhancers, such as Hydergine, are

thought to improve overall brain function by increasing

blood flow and brain metabolism. Free radical scavengers,

such as vitamin E, boost natural protective chemicals and

processes that reduce brain damage caused by free radicals.

Hydergine has shown modest success in improving alertness and short-term memory in stroke patients and individuals with Alzheimer’s disease. Vitamin E administered

with selegiline has slowed progression of Parkinson’s disease and reduced severity of abnormal movements in tardive dyskinesia patients.

One possible strategy to address cognitive impairment in

methamphetamine-addicted patients would be to add

potential cognitive enhancers to drug addiction treatment

medications, Dr. Elkashef says. However, the first step

with each potential medication will be to assess whether

clinical pharmacology interaction studies are needed to

make sure it is safe to give it to outpatients who may continue to abuse methamphetamine, he stresses.

Developing Future Treatments

At a much earlier stage of treatment development, NIDAsupported researchers are conducting preclinical studies

that could lead to the development of more sophisticated

approaches to repairing methamphetamine-induced brain

damage. Among the approaches that have shown promising results in animal studies are:

• DADLE ([D-Ala2,D-Leu5] enkephalin), a synthetic

brain chemical and known tissue-protective agent.

DADLE has been shown to block and reverse one

type of methamphetamine-induced brain damage in

mice; 

• Neurotrophic factors, proteins produced by the body

that nourish and maintain nerve cells. One of these

factors, glial-derived neurotrophic factor, has been

shown to reduce methamphetamine’s neurotoxic

effects in monkeys; 

• Genetic factors and natural anti-oxidants that promote cell survival. Boosting production of these genes

and antioxidants in the brains of mice has been

shown to prevent or moderate methamphetamine’s

neurotoxic effects. 

Much additional research is needed to design safe and

effective formulations of these treatments and ways to get

them into the brain before researchers can begin testing in

humans. However, these basic studies are increasing

understanding of toxic reactions and protective mechanisms in the brain. This understanding should lead to the

development of new medications that advance the goals of

enabling patients to stop abusing methamphetamine and

recover from at least some of the brain damage caused by

the drug. 
Research Findings

12

Cocaine, Marijuana, and Heroin Abuse Up, Methamphetamine

Abuse Down

By Robert Mathias, NIDA NOTES Staff Writer 

Volume 15, Number 3 (August, 2000)

Cocaine abuse indicators increased in many U.S. metropolitan areas during 1998 and the first half of 1999,

according to a NIDA-supported network of drug abuse

researchers who regularly report data on drug abuse in the

United States. The rise follows several years of stable or

declining use, the researchers reported at the December

1999 meeting of the Community Epidemiology Work

Group (CEWG).

CEWG researchers meet twice a year to report on such

drug abuse indicators as drug-related deaths, hospital

emergency department (ED) visits, and treatment admissions. Data from 20 cities presented at the December

meeting indicate that marijuana and heroin abuse also

continued to increase in most areas of the country.

However, methamphetamine abuse declined in most

cities, including some areas that have been hardest hit by

the problem. Highlights from the meeting’s advance

report are:

Cocaine. Indicators of cocaine abuse increased in half of

the 20 CEWG cities, remained stable or mixed in 8, and

decreased in 2. Five cities reported significant increases in

cocaine-related ED incidents and 9 cities reported large

increases in the number of cocaine-related deaths.

Heroin. Heroin abuse indicators increased in 10 CEWG

cities, were stable or mixed in 9, and decreased in 1.

Heroin abuse and snorting of the drug continued to

increase among younger populations, such as college students. These trends were particularly apparent in East

Coast cities where pure forms of white powder heroin,

which can be snorted, are most available. Heroin-related

deaths also increased in many areas of the country.

Marijuana. Seventeen CEWG cities reported increases in

problems associated with marijuana abuse. The percentage

of drug abusers whose primary drug of abuse was marijuana continued to increase in many cities. Rates of marijuana-related ED visits also continued the consistent, often

dramatic, increases shown over the last 6 years. Increases

in marijuana-related problems may be tied to increased

availability, higher potency, and lower prices for the drug

along with perceptions that marijuana abuse is less risky

than abuse of other drugs, the report indicates.

Methamphetamine. Indicators of methamphetamine

abuse decreased in West Coast and Southwest areas where

abuse of the drug has been a major problem for years.

Sharp declines in methamphetamine-related ED visits were

reported in 1998 in six CEWG

areas. Several areas also reported that methamphetamine

treatment admissions, hospital

mentions, and deaths continued to decline in the first half

of 1999. Researchers cited several possible reasons for these

decreases, including initiation

of national and community

methamphetamine abuse prevention programs and enactment of laws that make it more

difficult to obtain the chemicals needed to produce the

drug.

Club Drugs. Thirteen cities reported problems with

MDMA (ecstasy) abuse. The drug is available at raves and

nightclubs in most areas. Ecstasy abuse also is increasing

in other settings, such as college campuses. Nine areas

reported GHB (gamma-hydroxybutyrate) abuse at raves

and clubs. Numerous medical emergencies and several

deaths were associated with GHB abuse.

For More Information

The CEWG “Advance Report, Epidemiologic Trends in

Drug Abuse, December 1999,” is available from NIDA’s

Web site, www.drugabuse.gov. 

Many CEWG cities reported statistically significant increases from

1997 to 1998 in hospital emergency department (ED) visits due

to cocaine, heroin, and marijuana

use. However, methamphetaminerelated ED visits declined sharply

in most cities where rates had previously been highest. Source:

Substance Abuse and Mental

Health Services Administration,

Drug Abuse Warning Network,

1998 (July 1999 Update). 
Research Findings

13

Brain Imaging Studies Show Long-Term Damage From

Methamphetamine Abuse

By Patrick Zickler, NIDA NOTES Staff Writer 

Volume 15, Number 3 (August, 2000)

Methamphetamine—commonly known

as “speed,” “meth,” “ice,” or “crystal”—

is a powerfully addictive stimulant that

acts on the central nervous system to

produce increased wakefulness and

physical activity as well as irritability,

insomnia, confusion, tremors, convulsions, anxiety, paranoia, and aggressiveness. The drug increases heart rate and

blood pressure and can irreversibly damage blood vessels in the brain. Now,

NIDA-supported research has demonstrated that methamphetamine abusers

risk long-term brain damage.

Dr. Thomas Ernst and Dr. Linda Chang

at the Harbor-UCLA Medical Center in

Torrance, California, used a noninvasive

brain imaging technique called magnetic

resonance spectroscopy (MRS) to measure levels of brain chemicals that indicate whether brain cells are healthy or

are diseased or damaged. “We found abnormal brain

chemistry in methamphetamine users in all the brain

regions we studied. In one of the regions, the amount of

damage was also related to the history of drug use-those

abusers who had the greatest cumulative lifetime methamphetamine use had the strongest indications of cell damage,” Dr. Chang says.

In each of the participants, the researchers examined a

midfrontal region consisting largely of “gray matter”—

nerve cell bodies and short extensions called dendrites that

communicate with neighboring neurons—and an area in

the basal ganglia, a neuron-dense region at the top of the

brain stem. They also examined a right frontal area 

composed largely of “white matter,” or long nerve cell

extensions called axons that communicate with more 

distant regions of the brain. These brain regions were

selected because they are areas of high activity of

dopamine, a neurotransmitter involved in the “rush” and

pleasure associated with addictive drugs.

The researchers measured levels of N-acetyl-aspartate

(NAA), a metabolite produced only in neurons. “NAA

levels are a measure of the viability and density of neurons,” Dr. Ernst says. “Many diseases associated with brain

cell loss or damage, such as Alzheimer’s disease, stroke,

and epilepsy, are also associated with reduced NAA.”

The scientists also measured levels of two other chemical

markers—choline-containing compounds and myo-inositol (MI)—associated mostly with specialized cells called

glial cells. “The primary role of glial cells is to maintain

normal function of neurons, including repair of injury to

the cells. Increases in glial markers suggest proliferation of

these support cells in response to neuronal damage,” 

Dr. Ernst explains.

Dr. Chang and Dr. Ernst measured levels of the chemical

markers in 26 participants who had a history of methamphetamine abuse but had not used the drug for periods

ranging from 2 weeks to 21 months with a median of

4.25 months since last use. They compared the results to

measurements of 24 participants who had no history of

methamphetamine use.

Among the methamphetamine abusers, NAA levels were

reduced by 5 percent in the frontal white matter and 6

percent in the basal ganglia compared with levels among

nonusers. “The reduced concentrations of NAA in the

drug users’ brains suggest that long-term methamphetamine abuse results in loss of or damage to neurons,” Dr.

Ernst says. Methamphetamine abusers also showed

Neurons in three areas of the brain show changes in levels of brain chemicals that serve

as indicators of health of brain cells. Levels of choline-containing compounds and myoinositol are elevated and levels of N-acetyl-aspartate are reduced in methamphetamine

abusers who have not used the drug for at least 2 weeks and up to 21 months. The

changes in concentrations of these chemical markers suggest that methamphetamine use

may result in long-term damage to brain cells used in thinking. 
14

increases of 11 percent in levels of MI and 13 percent in

levels of choline-containing compounds in the frontal gray

matter compared with nonusers. “This suggests an

increased number or size of glial cells as a reaction to the

injurious effects of the drug,” he adds.

“Methamphetamine may be substantially toxic to the cells

we use in thinking,” Dr. Ernst says. “This long-term, and

perhaps permanent, alteration in basic brain chemistry is

additional evidence that methamphetamine abuse, like

abuse of other drugs, should be considered a brain disease

and treated accordingly.”

Sources

• Ernst, T.; Chang, L.; Leonido-Lee, M.; and Speck, O.

Evidence for long-term neurotoxicity associated with

methamphetamine abuse: a 1H MRS study.

Neurology 54(6):1344-1349, 2000. 
Research Findings

15

Methamphetamine Abuse Alert

Volume 13, Number 6 (March, 1999)

In response to indicators that show methamphetamine

abuse increasing across the Nation, NIDA sent a bulletin

containing current, science-based information on

methamphetamine to more than 200,000 drug abuse

treatment providers, hospital emergency room workers,

and other health services practitioners. 

The four-page Community Drug Alert Bulletin on

Methamphetamine arms health care providers with important information they can use to mount effective prevention and treatment responses to methamphetamine’s threat

to the public health. Highlights are below. 

What Methamphetamine Is

Methamphetamine is a powerfully addictive stimulant that

dramatically affects many areas of the central nervous system. The drug has a high potential for widespread abuse

because it can easily be made in clandestine laboratories

from relatively inexpensive over-the-counter ingredients. 

Methamphetamine can be purchased at a low cost, is

available in many forms, and can be smoked, snorted,

injected, or orally ingested. 

Methamphetamine is sometimes called “speed,” “meth,”

and “chalk.” In its smoked form, the drug is often called

“ice,” “crystal,” “crank,” “fire,” and “glass.” 

Who Uses Methamphetamine

Traditionally associated with white male blue-collar workers, methamphetamine reportedly is being used by diverse

groups in all regions of the country. 

Use is increasing among men who have sex with men and

use other drugs; young adults who attend “raves” or go to

private clubs; homeless and runaway youth; commercial

sex workers; members of motorcycle gangs; and people in

occupations that demand long hours, mental alertness,

and physical endurance. 

New Trends and Patterns of Use

Emerging evidence indicates that users increasingly are

administering methamphetamine intravenously. Injecting

the drug puts the user at increased risk of contracting

HIV/AIDS, hepatitis, and other infectious diseases. 

Often, methamphetamine is used in dangerous combination with other substances, including cocaine and “crack”

cocaine, marijuana, heroin, and alcohol. 

Methamphetamine is not usually sold and bought on the

street. Users report that they obtain the drug from friends

and acquaintances. 

Methamphetamine, used primarily in urban areas of

California, has become a substantial drug problem in

other sections of the West and Southwest as well as rural

and urban areas of the South and Midwest. Its use also is

emerging in urban areas in the East. 

Signs of Methamphetamine Use 

Some common signs of methamphetamine use include: 

• agitation, excited speech, decreased appetite, increased

physical activity, dilated pupils, and nausea and vomiting; 

• occasional episodes of sudden and violent behavior,

intense paranoia, visual and auditory hallucinations,

and bouts of insomnia; and 

• a tendency to compulsively clean and groom and

repetitively disassemble and sort objects. 

Guidelines for Preventing Methamphetamine Use

Effective prevention of drug use begins with assessing the

specific nature of the drug problem within the local community and adapting prevention programs accordingly.

Prevention programs should start early, be comprehensive,

and stress key points repeatedly. Family-focused prevention efforts have a greater impact than strategies that focus

on parents only or children and adolescents only. 

Guidelines for Treating Methamphetamine Addiction

Cognitive behavioral interventions that help modify a

patient’s thinking and harmful behaviors and teach skills

to cope with stressful situations have been effective. 

Currently no medications are available to treat methamphetamine addiction or overdose. However, antidepressant

medications can be prescribed which can serve to combat

the depressive symptoms frequently experienced during

methamphetamine withdrawal. 
16

For More Information

NIDA’s Community Drug Alert Bulletin on

Methamphetamine and the NIDA Research Report,

Methamphetamine Abuse and Addiction (NCADI publication #PHD756) can be obtained from the National

Clearinghouse for Alcohol and Drug Information, P.O.

Box 2345, Rockville, MD 20847, 1-800-729-6686. These

publications and additional information about methamphetamine can be found on the NIDA home page on the

World Wide Web at www.nida.nih.gov. Fact sheets and

recorded messages about methamphetamine abuse and

addiction can also be found on Infofax, NIDA’s automated information retrieval system, at (888) 644-6432. 
Research Findings

17

NIDA Initiative Tackles Methamphetamine Use

By Robert Mathias, NIDA NOTES Staff Writer

Volume 13, Number 1 (June, 1998)

In response to an upsurge in heroin use among America’s

young people in recent years, NIDA convened a national

research-based conference on Heroin Use and Addiction

in Washington, D.C., this past September. The wellattended conference drew more than 600 participants who

examined all aspects of the changing nature of heroin use

in the United States and shared scientific information and

approaches to preventing and treating heroin abuse and

addiction. Representatives of national drug abuse organizations, scientists, prevention and treatment practitioners,

and criminal justice personnel took part in the conference. 

NIDA has launched an Institute-wide initiative to expand

scientific research on methamphetamine and apply the

findings to the prevention and treatment of methamphetamine abuse. The Methamphetamine Initiative is aimed at

increasing scientific knowledge about methamphetamine

and providing the public and health care practitioners

with the latest available information about the drug’s use,

consequences, prevention, and treatment. 

Methamphetamine, also called “meth,” is a potent, highly

addictive form of amphetamine. Use of the drug has been

a major problem in western areas of the United States

since the mid- to late 1980s and has been increasing in

other areas of the country, such as the South and

Midwest, since the early 1990s, according to reports from

NIDA’s Community Epidemiology Work Group

(CEWG). Traditionally, methamphetamine use has been

centered among white working class males and men who

have sex with men. However, recent CEWG reports and

drug use surveys indicate that use of the drug also may be

increasing among other groups such as Hispanics in Los

Angeles and adolescents in rural areas. 

“We know from research that methamphetamine is a powerfully addictive stimulant associated with serious health

conditions including brain damage, memory loss, psychotic-like behavior, heart damage, hepatitis, and HIV transmission,” NIDA Director Dr. Alan I. Leshner said in discussing the Initiative’s opening thrust—a NIDA-sponsored western regional methamphetamine symposium held

in San Francisco in December 1996. 

At that meeting, scientists, civic leaders, policymakers,

public officials, and drug abuse prevention and treatment

professionals discussed ways to improve State and local

prevention and treatment responses to methamphetamine

abuse. 

Last year, NIDA received $4.2 million in supplemental

funding from the White House Office of National Drug

Control Policy to expand the Institute’s program of

methamphetamine research. This year, the Director’s

Office of the National Institutes of Health awarded an

additional $2 million in special funds to NIDA for

methamphetamine research. NIDA is using these monies

to broaden the Initiative’s methamphetamine research in

the following areas: basic and clinical neurobiology, longterm effects of abuse, epidemiology and prevention, drug

abuse treatment and health services, and medications

development. 

The Initiative’s basic and clinical neurobiology research is

aimed at better understanding the mechanisms that

underlie methamphetamine’s addictive potential and the

adverse consequences of its chronic abuse. Previous

research has shown that methamphetamine, like cocaine,

achieves its euphoric effect by increasing the extracellular

concentration of the neurotransmitter dopamine in the

brain. However, methamphetamine and cocaine achieve

their dopamine-enhancing effects through different cellular mechanisms. In addition, methamphetamine remains

The numbers on the map represent the number of patients in

these metropolitan areas who sought hospital emergency department treatment due to methamphetamine use. 

Source: Year-End Preliminary Estimates from the 1996 Drug

Abuse Warning Network, Substance Abuse and Mental Health

Services Administration. 
18

in the brain much longer than cocaine does and damages

brain cells of animals that have been chronically exposed

to the drug.

Researchers supported by NIDA’s Division of Basic

Research (DBR) under the Initiative, such as Dr. Paul

Vezina at the University of Chicago, now are trying to

unravel the underlying mechanisms through which animals chronically exposed to methamphetamine become

more sensitive, or respond more strongly, to the drug.

“The hypothesis in the field is that sensitization is linked

to addiction,” explains DBR’s Dr. Jerry Frankenheim.

Therefore, another basic research study, by Dr. Stephen

Strakowski of the University of Cincinnati College of

Medicine, is studying the process of stimulant sensitization in humans using amphetamine, which is closely related chemically to methamphetamine. The study is examining whether there is a link between stimulant sensitization

in humans and their liking the drug and craving it later

on. In other research, Dr. William Melega at the

University of California at Los Angeles is examining how

methamphetamine-induced neurotoxicity affects the

behavior of animals. 

“This basic research is key to understanding the differences between cocaine and methamphetamine,” says Dr.

Frankenheim. “The results of this research will help us

determine if we need somewhat different approaches to

preventing and treating methamphetamine and cocaine

abuse,” he says. 

The Initiative also is trying to determine whether the

methamphetamine-induced neurotoxicity that studies

have shown in animals also occurs in humans. For example, Dr. George A. Ricaurte of The Johns Hopkins

Medical Institutions in Baltimore is conducting brain

imaging studies with long-term methamphetamine users

to assess how chronic methamphetamine use affects the

human brain, cognition, and other physiological functions. In addition, postmortem studies of the brains of

chronic methamphetamine abusers are being conducted

by Dr. Stephen Kish of the Clarke Institute of Psychiatry

in Toronto, Canada. The studies will provide additional

information about the long-term effects of methamphetamine abuse on human brain structure. In living humans,

these effects on brain structure could affect brain function. 

The Methamphetamine Initiative also is expanding

NIDA’s research on preventing methamphetamine abuse

and addiction. For example, Dr. Steve Sussman of the

University of Southern California has been developing a

promising drug abuse prevention intervention for students

in continuation or alternative public high schools in

southern California. More than 10 percent of students

participating in Dr. Sussman’s ongoing prevention study

are known to have used methamphetamine in the past.

Now, Dr. Sussman is expanding his research to examine

current methamphetamine use among these youths and to

assess whether the two experimental drug abuse prevention programs he has been developing can prevent

methamphetamine use in this population. (For more

information on Dr. Sussman’s research, see “Specialized

High School Prevention Programs Target At-Risk

Adolescents,” NIDA NOTES, May/June 1997) 

The Initiative also is aiming to resolve puzzling patterns of

methamphetamine abuse in the United States. “Why has

methamphetamine use occurred predominantly in the

western United States and Hawaii?” asks Dr. Zili Sloboda,

who directs NIDA’s Division of Epidemiology and

Prevention Research (DEPR). To answer this and other

questions about shifting patterns of methamphetamine

use, DEPR is launching a study in five cities where

methamphetamine use is high or where a methamphetamine problem may be emerging. This study will identify

characteristics of methamphetamine users, patterns of initiation and use, and consequences of use, says Dr.

Sloboda. Ultimately, the findings of this research will be

used to develop more effective methamphetamine prevention programs, she says. 

Development of behavioral treatments tailored to the specific needs of methamphetamine-abusing populations also

is being emphasized under the Initiative. For example,

men who have sex with men represent a significant target

group for methamphetamine treatment interventions.

Previous research shows that methamphetamine use is

high in this population and is linked to high-risk sexual

behaviors and the transmission of HIV. NIDA’s Division

of Clinical and Services Research (DCSR) has funded a

new behavioral treatment research study among gay and

bisexual male methamphetamine users in Los Angeles.

This study, which is being conducted by Dr. Steven

Shoptaw of the Los Angeles Treatment Research Center,

will compare the relative effectiveness of contingency

management, relapse prevention, and enhanced HIV

counseling methods in reducing methamphetamine use

and related high-HIV-risk sexual behaviors. DCSR also is

expanding several studies that have been testing other

promising behavioral treatments with cocaine-abusing

populations. The goal is to see whether these treatments

are appropriate and can be adapted to treat methamphetamine abuse and associated behaviors effectively, says the

Division’s Dr. Dorynne Czechowicz. 

The development of medications to reduce methamphetamine abuse and craving and to repair brain systems damaged by chronic methamphetamine use is another major

Initiative priority. In seeking potential treatment compounds to reduce methamphetamine abuse, NIDA’s

Medications Development Division (MDD) is capitalizing

on the substantial research that has been done to develop
19

cocaine treatment medications. Though the initial 

mechanisms of action for cocaine and methamphetamine

differ, ultimately they both greatly increase the levels of

dopamine between brain cells, points out Dr. Betty Tai of

MDD. “From that point, the cascade of events from the

cellular all the way to behavioral is quite similar,” she says.

Therefore, any compound that has shown promise for

treating cocaine abuse by producing a milder dopamine

effect could be tested as a potential methamphetamine

treatment medication, Dr. Tai says. 
Research Findings

20

Response to Escalating Methamphetamine Abuse Builds on 

NIDA-Funded Research

By Neil Swan, NIDA NOTES Staff Writer 

Volume 11, Number 5 (November/December 1996)

NIDA-funded scientists are providing research crucial to

the Nation’s response to increasing methamphetamine

abuse and addiction. Methamphetamine, also called

“meth,” is a potent form of amphetamine. It is a synthetic,

highly addictive stimulant that is cheaper and longer lasting than cocaine.

Methamphetamine comes in many forms and can be

smoked, snorted, orally ingested, or injected. The drug is

a white, odorless, bitter-tasting crystalline powder that can

be dissolved in water or alcohol. When made in clandestine labs, it is often in the form of a coarse powder or

chunks that are off-white to yellow. Other nicknames

include “speed,” “crank,” and “zip.” The smokable form of

the drug may be called “ice” or “crystal.” The drug is

addictive, and users can escalate quickly to larger and

more frequent doses. Chronic abuse can lead to violent

behavior. (For more information, see Facts About

Methamphetamine)

The growing abuse of the drug is linked to its increasing

availability and the fact that it can be easily manufactured

from readily available chemical ingredients. Congress last

summer passed the Comprehensive Methamphetamine

Control Act establishing new controls over volume sales of

the chemical ingredients used to produce the drug.

NIDA’s Community Epidemiology Work Group

(CEWG), a network of epidemiologists and researchers

from 20 major U.S. metropolitan areas that provides

frontline surveillance of the nature and extent of drug

abuse, confirms that methamphetamine use has been

prevalent in west coast cities and in western and southwestern communities, including many rural areas. Abuse

of the drug now is being reported in urban settings in

widening areas of the West, Midwest, and elsewhere.

Methamphetamine is the dominant illicit drug problem in

San Diego, according to CEWG data that include records

of hospital emergency room admissions, drug-related

deaths, and police drug seizures; and local observations of

street buys and drug-trafficking patterns. Honolulu and

San Francisco also have substantial methamphetamineusing populations, according to CEWG data. Recent

reports indicate increasing patterns of methamphetamine

use in Denver, Los Angeles, Minneapolis, Phoenix, Seattle,

and Tucson as well.

Until recently, the drug’s manufacture generally was dispersed so that small quantities were produced in rural

areas. There are indications that methamphetamine now is

being manufactured on a larger scale by organized groups

operating out of Mexico and southern California.

Methamphetamine of Mexican origin is now found along

newly extended trafficking routes in several States, including Arizona, Colorado, Iowa, Missouri, Nebraska, and

Texas, according to CEWG. Clandestine labs have produced the drug in rural and desert areas where the telltale

odors of the production process are less likely to be detected. Mobile labs in campers and vans have been reported in

Washington.

A NIDA-funded study in Seattle confirmed that methamphetamine use was widespread among the city’s homosexual and bisexual populations. Members of these groups

using methamphetamine reported they practice sexual and

needle-use behaviors that place them at heightened risk of

contracting and transmitting HIV, the virus that causes

AIDS. NIDA also supports basic research examining the

neurobiological mechanisms involved in methamphetamine’s action in the brain, seeking knowledge necessary

for long-term solutions to abuse of the drug. Research has

shown that methamphetamine releases high levels of the

neurotransmitter dopamine, which stimulates brain cells,

causing enhanced mood and increased body movement.

Another major research focus is on methamphetamine’s

neurotoxicity, specifically its action in damaging brain

cells that contain dopamine and serotonin, another neurotransmitter. Scientists think that methamphetamine abuse

over time may cause reduced levels of dopamine, which

Animal studies show that high doses

of methamphetamine damage nerve

cells. In rats, one high dose of

methamphetamine is enough to 

cause damage. Prolonged dosage

seems to make it worse.
21

can cause symptoms like those of Parkinson’s disease, a

severe movement disorder.

Animal studies going back more than 20 years show that

high doses of methamphetamine damage neuron cell-endings, says Dr. Lewis S. Seiden of the University of

Chicago, a NIDA-funded researcher who has studied

methamphetamine for many years. “The damage is essentially permanent, although there may be some regrowth.

The damage occurs in rats, guinea pigs, pigs, cats, and

nonhuman primates. In rats, one high dose of methamphetamine is enough to cause damage. Prolonged dosage

seems to make it worse,” he says. Recent NIDA-funded

studies by Dr. George A. Ricaurte at Johns Hopkins

Medical Institutions in Baltimore and by other scientists

indicate that neurotoxic effects are more pronounced in

nonhuman primates than in rodents.

Dopamine- and serotonin-containing neurons do not die

after methamphetamine use, but their nerve endings or

terminals are cut back or “pruned” by use of the drug, Dr.

Ricaurte says. “The question is, does the same thing occur

in humans?” he asks. “To answer that question we have

recently developed brain imaging techniques to study

these effects in humans who have previously used

methamphetamine.” (See NIDA-Supported Researchers

Use Brain Imaging to Deepen Understanding of

Addiction.)

Another NIDA-funded researcher, Dr. Glen R. Hanson at

the University of Utah, found evidence that dopaminegenerated compounds called free radicals that appear following methamphetamine use can affect serotonin production in contrasting ways. He also reports that several

neuropeptide systems linked to dopamine brain pathways

are profoundly altered by administration of low to high

doses of methamphetamine.

“Our results suggest that high and low doses of methamphetamine affect a peptide called neurotensin in very different ways,” says Dr. Hanson. High doses of methamphetamine limit neurotensin’s function, perhaps resulting

in exaggerated dopamine responses to the stimulant. Low

doses of methamphetamine increase neurotensin levels

and function, which in turn appear to counteract behavioral response to the drug. These findings suggest that

neurotensin perhaps could be used to prevent excessive

and damaging dopamine responses to methamphetamine,

he adds.

NIDA is also supporting research into treatment for

methamphetamine abuse. Dr. Richard A. Rawson of the

Matrix Institute in Beverly Hills, California, is conducting

two outpatient studies with patients using both cocaine

and methamphetamine.

One study concerns a small group of gay, methamphetamine-using males in Hollywood, California, where use of

the drug is closely related to high-risk sexual behavior.

Methamphetamine is the “drug of choice” among these

homosexual men whether it is snorted, injected, or

smoked, says Dr. Rawson. “They all talk about the interconnectedness of their sexual behavior and methamphetamine use.”

Another study concerns 600 heterosexual methamphetamine abusers seeking treatment at a facility in a rural area

of San Bernardino County, California. Methamphetamine

abuse has been a problem in this area since the late 1980s.

Users typically have also used cocaine but find methamphetamine longer lasting and more easily available; many

of those in treatment say they can readily get the drug,

even at their work sites or public places like truck stops,

says Dr. Rawson.

“Treatment response was somewhat poorer among

methamphetamine abusers than among cocaine abusers—

fewer meth abusers could remain drug free,” he says. “The

methamphetamine abusers are twice as likely as cocaine

abusers to require some kind of medical treatment,” he

says. “Methamphetamine abusers are more debilitated and

show paranoia and hallucinations. There is more violence

associated with methamphetamine abuse, according to the

treatment staff.”

Concern that methamphetamine abuse is a growing problem affecting many population groups has prompted the

White House to launch a policy and planning approach

called the President’s National Strategy for Combating

Methamphetamine Abuse. The White House Office of

National Drug Control Policy sponsored a Western

Regional Methamphetamine Conference last January in

San Francisco and will sponsor a national methamphetamine conference in May in Omaha, Nebraska.

The Substance Abuse and Mental Health Services

Administration, in collaboration with NIDA, in June

sponsored a satellite meeting on methamphetamine abuse

at the annual meeting of the College on Problems of Drug

Dependence in Puerto Rico. This meeting involved more

than 30 experts, many of them NIDA staffers and NIDAfunded researchers. (See Recommendations to Advance

Understanding of Methamphetamine, for a report on the

meeting’s recommendations.)

NIDA also sponsored a symposium, “Methamphetamine

Abuse, Treatment, and Prevention,” in San Francisco in

December 1996 focusing on national and regional issues

relating to methamphetamine abuse.

Sources

• Community Epidemiologic Work Group,

Epidemiologic Trends in Drug Abuse, National

Institute on Drug Abuse, Vol. 1. NIH, Publication

No. 96-4126; Vol. 2, NIH Publication No. 96-4127,

June 1996.
22

• Richards, J.B.; Baggot, M.J.; Sabol, K.E.; and Seiden,

L.S. A high-dose methamphetamine regimen results

in long-lasting deficits on performance of a reactiontime task. Brain Research 627:254-260, 1993.

• Wagstaff, J.D.; Gibb, J.W.; and Hanson, G.R.

Microdialysis assessment of methamphetamineinduced changes in extracellular neurotensin in the

striatum and nucleus accumbens. Journal of

Pharmacology and Experimental Therapeutics

278(2):1-8, 1996.

• McCann, U., and Ricaurte, G. Strategies for detecting

subclinical monoamine depletion in humans. In: L.

Erinoff, ed., Assessing Neurotoxicity of Drugs of

Abuse. NIDA Research Monograph 136, NIH

Publication No. 93-3644, Washington, DC: GPO,

1993. 
Research Findings

23

Facts About Methamphetamine

Volume 11, Number 5 (November/December 1996)

Methamphetamine is a central nervous system stimulant

with a high potential abuse and dependence. A synthetic

drug, methamphetamine is closely related chemically to

amphetamine, but produces greater effects on the central

nervous system. The drug’s euphoric effects are similar to

but longer lasting than those of cocaine. 

Methamphetamine takes the form of a white, odorless,

and bitter-tasting crystalline powder, readily soluble in

water or alcohol. Street methamphetamine is referred to

by many names including “meth,” “speed,” “zip,” “gofast,” “cristy,” “chalk,” and “crank.” Pure methamphetamine hydrochloride, the smokable form of the drug, is

called “L.A.” or—because of its clear, chunky crystals—

“ice” “crystal,” “glass,” or “quartz.” 

Methods and Effects of Use

Methamphetamine can be smoked, injected intravenously,

snorted, or ingested orally. The drug alters mood in different ways, depending on how it is taken. Immediately after

smoking or intravenous injection, the user experiences an

intense “rush” or “flash” that lasts only a few minutes and

is described as extremely pleasurable. Smoking or injecting

produces effects fastest, within 5 to 10 seconds. Snorting

or ingesting orally produces euphoria—a high but not an

intense rush. Snorting produces effects within 3 to 5 minutes, and ingesting orally produces effects within 15 to 20

minutes. 

Even small amounts of methamphetamine can produce

euphoria, enhanced wakefulness, increased physical activity, decreased appetite, and increased respiration. Other

central nervous system effects include athetosis (writhing,

jerky, or flailing movements), irritability, insomnia, confusion, tremors, anxiety, aggression, hyperthermia, and convulsions. Hyperthermia and convulsions sometimes can

result in death. 

Cardiovascular side effects include chest pain and hypertension and sometimes can result in cardiovascular collapse and death. In addition, methamphetamine causes

increased heart rate and blood pressure and sometimes can

cause irreversible damage to blood vessels in the brain,

producing strokes. Methamphetamine abuse during pregnancy may result in prenatal complications, increased rates

of premature delivery, and altered neonatal behavioral patterns. 

Psychological symptoms of prolonged methamphetamine

abuse can resemble those of schizophrenia and are characterized by paranoia, hallucinations, repetitive behavior patterns, and formication (delusions of parasites or insects on

the skin). Methamphetamine-induced paranoia can result

in homicidal or suicidal thoughts. Although no characteristic physical signs of withdrawal are associated with

methamphetamine abuse, users report drug craving,

depressed mood, sleepiness, and hunger. 

Extent of Use

NIDA’s 1996 Monitoring the Future study, which assessed

the extent of drug use among 8th-, 10th-, and 12thgraders across the country, reports that: 

• When high school seniors were asked if they had used

crystal methamphetamine at least once in their lifetimes, 4.4 percent said they had—an increase from

2.7 percent in 1990; 

• In that same year, when high school seniors were

asked if they had used crystal methamphetamine in

the 12 months prior to the survey, 2.8 percent said

they had-an increase from 1.3 percent in 1990. 

The Substance Abuse and Mental Health Services

Administration’s Drug Abuse Warning Network reports

that from 1991 to 1994, the number of methamphetamine-related visits to hospital emergency departments

more than tripled, from 4,887 to 17,397. 

More Information

For more information about methamphetamine, contact

the National Clearinghouse for Alcohol and Drug

Information (NCADI), P.O. Box 2345, Rockville, MD

20847, at 1-800-729-6686. Information is also available

at the NCADI Web site at http://www.health.org or at the

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Printed September 2005