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Research on

Methamphetamine
Research on

Methamphetamine

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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.
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Table of Contents

Low-Cost Incentives Improve Outcomes in Stimulant

Abuse Treatment (V21-1; October 2006) . . . . . . . . . . . 1

Methamphetamine Evokes and Subverts Brain Protective

Responses (V20-6; July 2006) . . . . . . . . . . . . . . . . . . . 3

Methamphetamine Increases, and HIV Decreases, Brain

Volumes (V20-6; July 2006) . . . . . . . . . . . . . . . . . . . . 6

Brain Activity Patterns Signal Risk Of Relapse to

Methamphetamine (V20-5; April 2006) . . . . . . . . . . . 8

Community-Based Treatment Benefits Methamphetamine

Abusers (V20-5; April 2006) . . . . . . . . . . . . . . . . . . . 10

Treatment Curbs Methamphetamine Abuse Among Gay

and Bisexual Men (V20-4; March 2006) . . . . . . . . . . 12

Long-Term Abstinence Brings Partial Recovery 

From Methamphetamine Damage 

(V19-4; December 2004) . . . . . . . . . . . . . . . . . . . . . . . . 15

Mood Disorders in Methamphetamine Abusers 

Linked to Changes in Brain Metabolism 

(V19-4; December 2004) . . . . . . . . . . . . . . . . . . . . . . 17

Methamphetamine Abuse Linked to Impaired Cognitive

and Motor Skills Despite Recovery of Dopamine

Transporters (V17-1; April 2002) . . . . . . . . . . . . . . . . 18

Methamphetamine, Cocaine Abusers Have Different

Patterns of Drug Use, Suffer Different Cognitive

Impairments (V16-5; December 2001) . . . . . . . . . . . 20

Methamphetamine Brain Damage in Mice More

Extensive Than Previously Thought 

(V15-4; September 2000) . . . . . . . . . . . . . . . . . . . . . . 22

NIDA Pursues Many Approaches to Reversing

Methamphetamine’s Neurotoxic Effects 

(V15-4; September 2000) . . . . . . . . . . . . . . . . . . . . . . 24

Cocaine, Marijuana, and Heroin Abuse Up,

Methamphetamine Abuse Down 

(V15-3; August 2000) . . . . . . . . . . . . . . . . . . . . . . . . 26

Brain Imaging Studies Show Long-Term Damage From

Methamphetamine Abuse (V15-3; August 2000) . . . . 27

Methamphetamine Abuse Alert 

(V13-6; March 1999) . . . . . . . . . . . . . . . . . . . . . . . . . 29

NIDA Initiative Tackles Methamphetamine Use 

(V13-1; June 1998) . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Response to Escalating Methamphetamine 

Abuse Builds on NIDA-Funded Research 

(V11-5; November/December 1996) . . . . . . . . . . . . . 34

Facts About Methamphetamine 

(V11-5; November/December 1996) . . . . . . . . . . . . 37
Low-Cost Incentives Improve Outcomes in Stimulant Abuse

Treatment

In community-based treatment programs, the intervention added $2.42 per patient per day to 

counseling costs.

By Lori Whitten, NIDA Notes Staff Writer

Research Findings

Volume 21, Number 1 (October 2006)

The opportunity to win rewards worth as little as $1 for

abstinence can help motivate outpatients to stay in behavioral therapy and remain drug-free, according to a NIDA

Clinical Trials Network (CTN) study. At eight community-based addiction treatment programs across the United

States, stimulant abusers who could earn a chance to win a

prize by providing drug-free urine samples were four times

as likely as peers who were not offered this incentive to

attain 12 weeks of continuous abstinence. Prizes for the

incentive intervention cost the programs about $200, or

$2.42 a day per participant.

“Many addiction treatment clinics face the challenge of

high patient dropout rates. Reinforcing abstinence helps

keep patients interested in attending treatment for longer

periods, which can facilitate behavioral changes to keep

them off drugs for the long haul,” says Dr. Nancy Petry of

the University of Connecticut School of Medicine,

coleader of the study. Prior research has found that, no

matter how it is achieved, duration of abstinence during

treatment is one of the best predictors of abstinence 1 year

later. “More patients achieve this therapeutic milestone

with a boost from incentive programs,” says the study’s

other coleader, Dr. Maxine Stitzer of The Johns Hopkins

University School of Medicine.

The CTN investigators randomly assigned 415 treatmentseeking stimulant abusers (see chart) to one of two conditions: usual care or usual care plus abstinence-based incentives for 12 weeks. Usual care typically consisted of group

counseling, although some patients received individual

and family therapy. Patients gave urine and breath samples

twice weekly. Research assistants tested the urine samples

for stimulants, opiates, and marijuana, and tested the

breath samples for alcohol. 

Each participant in the incentive condition received

immediate feedback on his or her samples. After submitting stimulant- and alcohol-negative samples, the patient

could draw from an opaque container with 500 chips,

each with words of encouragement or an assigned value:

Half of the chips simply said, “good job;” 209 could be

traded for $1 prizes, 40 for $20 prizes, and 1 for a $100

prize. Prizes were conferred immediately and included

many options, ranging from toiletries, snacks, and bus

tokens to kitchen items, telephones, and retail store certificates for televisions, music players, and DVD players.

The number of draws earned increased by one each week

in which all the patient’s samples were stimulant- and

alcohol-negative, but fell back to one following a positive

sample or an unexcused absence. When a participant first

achieved two consecutive weeks of abstinence, he or she

received a $20 prize. Participants who submitted stimulant- and alcohol-negative samples could earn two bonus

draws a week if their urine samples were also opioid- and

marijuana-negative.

More patients in the incentive program (49 percent) than

in usual care (35 percent) completed 12 weeks of counseling. Patients in the incentive group achieved an average

duration of sustained abstinence of 4.4 consecutive weeks,

compared with only 2.6 weeks among counseling-only

patients. Nineteen percent of patients receiving the incentive intervention attained 12 weeks of continuous abstinence compared with 5 percent of those in usual care.

Intervention patients also attended more counseling sessions (19 versus 16) and submitted more stimulant-negative urine samples during treatment than patients in usual

care (48 versus 36 percent). 

1
Incentives Accentuate the Positive

“Incentive programs, including lowcost ones, add excitement and additional reasons to attend substance

abuse treatment. Many substance

abusers are ambivalent about treatment, and rewards may help them

stay involved in counseling,” says 

Dr. Petry. Extending retention in

treatment may prolong abstinence, in

part, because it gives counselors more

time to help patients re-engage in a

drug-free lifestyle, says Dr. Stitzer.

Helping patients sustain abstinence

once they leave therapy is a challenge

for all treatments, including incentive

programs. 

Some previous clinical trials of voucher-based incentive programs showed

benefits of the treatment persisting for

1 to 2 years, but others found no

added value over the long term compared with usual care. Further

research will focus on followup with

patients to determine the conditions

under which incentive interventions,

particularly as applied by communitybased treatment programs, support

extended abstinence.

Other relatively small, often single-site

NIDA-funded clinical trials over the

past 15 years have demonstrated that

motivational incentives are an effective adjunct to standard therapy for

opiate-, marijuana-, alcohol-, and

cocaine-addicted patients. Patients in

most of those early studies always received vouchers

exchangeable for goods or services, rather than chances to

win prizes, for positive behaviors; costs typically ran to

about $1,000 per patient over 3 months, with the result

that few community programs adopted the motivational

incentive approach. Dr. Petry developed her prize-drawing

system to make incentives affordable for community 

programs. She has tested it successfully in several

Connecticut treatment programs, and now its effectiveness

is confirmed by the CTN trial. NIDA is collaborating

with the Substance Abuse and Mental Health Services

Administration’s Addiction Technology Transfer Center 

to promote awareness of the low-cost motivational 

incentive technique (see text box).

The CTN researchers note that some community-based

treatment providers resist the idea of motivational incentives based on a belief that clinicians should not reward

patients for behaviors “that they are supposed to do anyway.” In response, the researchers point out that groups

and individuals often use external incentives to motivate

others—from employees’ bonuses to children’s allowances

for household chores. Dr. Stitzer advocates a shift in perspective from punishing lapses to celebrating successes.

She observes that counselors have often changed their

views when they have seen incentives help revolving-door

patients stay in therapy. “Incentive programs—the idea of

catching people being good and rewarding the behavior—

can infuse addiction treatment with a positive outlook and

reinvigorate patients and counselors,” says Dr. Stitzer. 

Source

• Petry, N.M., et al. Effect of prize-based incentives on

outcomes in stimulant abusers in outpatient psychosocial treatment programs: A National Drug

Abuse Treatment Clinical Trials Network Study.

Archives of General Psychiatry 62(10):1148-1156,

2005. 

2
3

Methamphetamine Evokes and Subverts Brain Protective

Responses

Two new studies appear to highlight the role of glial cells—the nervous system’s equivalents to the body’s

immune cells—in methamphetamine abuse.

By Patrick Zickler, NIDA NOTES Contributing Writer

Research Findings

Volume 20, Number 6 (July 2006)

NIDA-supported researchers have produced brain images

demonstrating that structures in an area called the striatum expand in volume during early methamphetamine

abuse, then regress toward normal. The investigators

believe their findings likely are attributable to neuroprotective cells in the brain mounting an initial attempt to

counteract the drug’s toxic effects, which continued 

exposure subsequently overwhelms. In a related result, 

scientists working with mice have produced evidence 

that methamphetamine may prompt cells that normally

serve neuroprotective functions to instead attack healthy

brain cells.

Structural Fluctuation Suggests Glial Activation 

Dr. Linda Chang (now at the University of Hawaii) and

colleagues at the University of California, Los Angeles,

used magnetic resonance imaging to measure the volumes

of striatal brain structures, including the putamen and

globus pallidus, in a group of methamphetamine abusers.

The studied individuals, 26 women and 24 men (average

age 31 years), had abused methamphetamine (average 1.6

g/day on 6.3 days/week) for periods ranging from 4 to 15

years. All had been abstinent for periods ranging from 1

week to 4 years at the time of the study; 44 also took tests

of verbal memory and intelligence, gross and fine motor

function, mood, executive function, and other capacities

likely to be affected by striatal damage.

The researchers expected to find that the methamphetamine abusers’ striatal regions were smaller than those of a

comparison group of age- and gender-matched individuals

with no history of methamphetamine abuse. Such a finding would be consistent with previous research showing

that methamphetamine reduces the density of striatal

dopamine terminals. Instead, says Dr. Chang, “Contrary

to our hypothesis, striatal volumes were larger in the

methamphetamine abusers as a group.” The size difference

was greatest among individuals with less cumulative exposure to the drug, and smaller among those with more.

Those with the most exposure also performed slightly

worse on neuropsychological tests of verbal fluency and

visual-motor coordination.

Dr. Chang believes the surprising increase in striatal volumes of methamphetamine abusers may reflect the activity

of glia—cells that provide protective and reparative functions for the brain’s main functional cells, the neurons.

When molecules potentially harmful to neurons penetrate

the brain, glia mount a response resembling the inflammation and scar tissue formation associated with immune

responses in other parts of the body. Possibly, Dr. Chang

suggests, methamphetamine provokes glia to react in this

way, leading to an increase in regional volume analogous
4

to the swelling seen in bodily immune responses.

Subsequently, she speculates, the glial response may 

taper off as cumulative exposure to the drug—and neuron

damage—mount. Continued abuse results in damage that

is manifested in decreased cognitive performance.

“This work is consistent with an increasing body of

research that shows a relationship between methamphetamine exposure and structural changes in the brain,” 

says Dr. Steven Grant of NIDA’s Division of Clinical

Neuroscience and Behavioral Research. “It links methamphetamine abuse, structural change, and functional

deficits and suggests that the magnitude of these effects is

related to the degree of abuse. We don’t understand what

is happening at deeper levels, but the observations made

in this study suggest that the volume changes are related

to methamphetamine’s direct or indirect effect on glial

cells. We still need to understand how structural changes

result in functional deficits; how much, if any, of this

damage can be reversed; and how methamphetamine acts

at the cellular level.”

In Mice, Methamphetamine Misdirects Glia To Attack

Brain Cells

A study by Drs. Donald Kuhn and David Thomas and

colleagues at Wayne State University School of Medicine

indicates that methamphetamine’s toxic effects may

include subverting some glial cells to attack rather than

preserve neurons. Specifically, their results indicate that

the drug incites a subset of glia called microglia to mount

an immune response against dopamine neurons.

Normally, microglia protect neurons against toxic injury

by several mechanisms. They detect and bind to invading

molecules, including viruses or bacteria, making them 

easily accessible to destructive immune system cells 

such as lymphocytes. As well, they produce compounds,

some toxic, to help contain or eliminate the danger.

Methamphetamine, the new study suggests, causes

dopamine neurons to release a signal that decoys the

microglia into turning these normally protective responses

against the neurons themselves. When that happens, 

Dr. Kuhn says, “The microglia aren’t reacting to methamphetamine’s neural damage. Instead, they are active 

participants in the drug’s neurotoxicity.”

To begin their experiments, the researchers reasoned that

if microglia contribute to methamphetamine toxicity to

dopamine terminals, compounds that protect against 

such toxicity might do so, at least in part, by inhibiting

microglial activation. Their first hypothesis, accordingly,

was that the compound MK-801, which is known to be

protective, blunts microglial activation. The team showed

this to be the case by exposing cell cultures of mouse

microglia to two proteins known to precipitate damaging

microglial responses: lipopolysaccharide (LPS) and HIV

Tat, a derivative of the human immunodeficiency virus.

Compared with LPS and HIV Tat exposure without pretreatment, exposure following pretreatment with MK-801

significantly reduced the amount of two protein products

of microglial activation, called cyclooxygenase-2 (Cox-2)

and tumor necrosis factor-a (TNF-a). Dextromethorphan

(DXM), a compound biochemically similar to MK-801,

had the same effect.

“These results suggested that both MK-801 and dextromethorphan exert direct action on the microglial cells

in culture to block the activation process,” Dr. Kuhn says.

Having determined that the two compounds block

microglial activation in vitro, the researchers next hypothesized that they would also do so in living animals.

Drs. Kuhn and Thomas injected mice with either MK801 or DXM and then methamphetamine (5 mg/kg of

body weight) 15 minutes later, repeating this sequence

four times at 2-hour intervals. A control group of mice

received the same regimen, but with saline substituted for

methamphetamine. Forty-eight hours after the last injection, the researchers assayed the brains of the mice for

Cox-2 and TNF-a, the indicators of microglia activation,

and for striatal dopamine levels, a widely used index of

damage to dopamine neurons. Dr. Kuhn says, “We found

that both DXM and MK-801 significantly reduced the

markers of striatal microglial activation associated with

methamphetamine exposure and protected against
5

dopamine nerve terminal damage in the striatum. The

close association between the ability of MK-801 and

DXM to significantly lower both microglial activation and

neuronal damage suggests a causal link between the two.

It looks as though the damage associated with methamphetamine abuse is the result of microglial action.”

The apparent association of microglia and damage to

dopamine neurons has implications beyond what it may

reveal about methamphetamine abuse, says Dr. Jerry

Frankenheim of NIDA’s Division of Basic Neuroscience

and Behavioral Research. “Microglia are the primary

immune defense cells in the brain. They safeguard neural

functions, yet excessive activation can cause microglia to

harm neurons. Other research implicates microglial

involvement in a wide range of neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease,

and stroke. Understanding how methamphetamine is able

to decoy microglia into a destructive rather than reparative

role could also help explain the processes involved in these

other disorders.”

Sources

• Chang, L., et al. Enlarged striatum in abstinent

methamphetamine abusers: A possible compensatory

response. Biological Psychiatry 57(9):967–974, 2005.

• Thomas, D.M., and Kuhn, D.M. MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity.

Brain Research 1050(1-2):190–198, 2005. 
6

Methamphetamine Increases, and HIV Decreases, Brain Volumes 

HIV infection and methamphetamine addiction produce distinct, partly overlapping effects on 

brain structures.

By John S. DeMott, NIDA NOTES Contributing Writer

Research Findings

Volume 20, Number 6 (July 2006)

In a study that confirmed the association between HIV

infection and loss of brain volume, NIDA-funded investigators also found an association between methamphetamine addiction and increased regional brain volume. Each

type of volume change was associated with neurocognitive

impairments, but it was unclear whether the two together

caused any cognitive effects beyond the sum of what each

produced individually.

Using structural magnetic resonance imaging (MRI), Drs.

Terry L. Jernigan, Anthony C. Gamst, and colleagues at

the University of California, San Diego (UCSD) mapped

the major gray-matter brain structures of 103 people in

four age- and education-matched groups: HIV-infected;

methamphetamineaddicted; having both

conditions; and having

neither. The methamphetamine-addicted

individuals were in

recovery at UCSD’s

HIV Neurobehavioral

Research Center.

After accounting for

normal age-related

reductions in brain 

volume, the participants

with HIV had smaller

volumes of cortical, 

limbic, and striatal

structures, with the

associations being most

pronounced in the

frontal and temporal

lobes. Methamphetamine

addiction was linked

with increased volume

in the parietal cortex

and in all three segments of the basal ganglia—caudate nucleus,

lenticular nucleus, and

nucleus accumbens

(NAc). In the caudate,

volume reductions related to HIV and increases related to

methamphetamine overlapped, producing a net volume

approximating normal.

A further analysis of the volume data may reinforce existing evidence that drug abuse is especially damaging during

adolescence and young adulthood, when the brain is still

developing. The results showed that addicted individuals

who were younger had greater NAc volume differentials

compared with their non-drug-abusing age mates than did

older addicted individuals. One possible explanation for

this is that the drug interfered with the pruning of some

NAc connecting fibers that normally occurs in the transition to adulthood, producing a small but measurable

(See www.nida.gov/NIDA_notes/NNVol20N6/Increases.html for color image)
7

reduction in NAc volume. “While we can’t be certain of

the explanation, this finding highlights the concern that

exposure during adolescence may alter the course of ongoing brain maturation,” says Dr. Jernigan (see chart).

Although the study results provided little information

about specific drug mechanisms, the investigators note

that animal studies have shown methamphetamine can

incite inflammatory responses and abnormal growth of

nerve fibers, each of which can increase tissue volume.

“These findings emphasize that the brain’s response to

stimulant exposure, and indeed to HIV as well, is probably quite dynamic, characterized by overlapping responses

in different glial, as well as neuronal, cell populations,”

says Dr. Jernigan. “The findings raise interesting questions

for multiple-modality imaging studies, and underscore the

degree of neural plasticity, and thus the potential for targeted intervention.”

Dr. Jernigan says a finding of extensive change in the parietal cortex of methamphetamine abusers “helps to confirm

the importance of parietal lobe involvement and may help

correct a tendency in the field to neglect this region.”

Implications for Brain Function

The researchers looked for correlations between the brain

volume abnormalities and ratings of neuropsychological

impairment. At the outset of the study, all other groups

were significantly impaired relative to the HIV-negative

and methamphetamine-negative group, which had a rating

of 2.9 compared with 4.7 for those with both conditions,

4.2 for methamphetamine-addicted participants and 4.1

for HIV-positive individuals. Brain impairment was most

pronounced in the HIV-positive participants with the

most extensive loss of cortical volume and in the methamphetamine-addicted participants with the highest increase

in cortical volume. The investigators found only one significant correlation between brain volumes and impairment in addicted individuals with HIV, a finding they

believe probably reflects confounding by the opposed volume impacts of the two pathologies. The correlation was

between hippocampal volume—a structure that both factors may damage—and severity of cognitive impairment

in the dually diagnosed group.

“The fact that brain alterations in methamphetamine

dependence and HIV infection are distinct from each

other is a clue that may help us to sort out the origins of

different kinds of mental problems in these individuals,”

Dr. Jernigan says.” This is very exciting, because our

results raise a number of specific questions that may not

have been posed without these findings.”

Dr. Ro Nemeth-Coslett, a NIDA psychologist, agrees. “As

often happens in research, these results raise more questions than they answer. Dr. Jernigan’s findings of structural

inconsistencies in pathology are unaccounted for. Now we

need mechanistic studies to provide a clearer understanding of what aspects of microscopic cellular organization

actually drive the MRI measures.”

Source

• Jernigan, T. L., et al. Effects of methamphetamine

dependence and HIV infection on cerebral 

morphology. American Journal of Psychiatry

162(8):1461-1472, 2005.

“The fact that brain alterations 

in methamphetamine dependence

and HIV infection are distinct from

each other is a clue that may help us

to sort out the origins of different

kinds of mental problems in 

these individuals.”

The line shows the healthy comparison curve
Brain Activity Patterns Signal Risk Of Relapse to Methamphetamine

Methamphetamine abusers who relapse after treatment appear to make decisions using different brain

regions than do those who remain abstinent.

BY Patrick Zickler, NIDA NOTES Contributing Writer

Research Findings

Volume 20, Number 5 (April 2006)

NIDA-supported investigators have found that functional

magnetic resonance imaging (fMRI) of the brain, performed during a psychological test, can predict with high

accuracy whether an individual will relapse following

treatment for methamphetamine abuse. Their study

revealed a characteristic pattern of brain activity in

methamphetamine-abusing men who relapsed within 

1 to 3 years after completing treatment and a different

pattern in men who did not.

Dr. Martin Paulus and colleagues at the University of

California, San Diego, took the point of departure for

their work from previous research that showed methamphetamine abusers and nonabusers activating different

brain areas during psychological tests of decisionmaking.

These earlier studies showed that poor choices made by

drug abusers correlate to distinctive patterns of activity in

some areas of the brain. Dr. Paulus’s team hypothesized

that activity patterns in those regions might also be associated with relapse to drug abuse, which involves similarly

destructive decisions.

To test their hypothesis, the researchers recruited 46 men

who had voluntarily entered and completed a 28-day

inpatient drug treatment program after abusing methamphetamine for periods ranging from 3 to 34 years. When

each man had been abstinent for about 4 weeks, he participated in two psychological tests. During one, he was

asked to watch a computer screen and press a button every

time a symbol appeared. In the other, he was asked to try

to predict whether a flashing symbol would next occur on

the left side or right side of the computer screen. The difference between the two tasks was that, in the first, the

test-taker needed only to react upon seeing the symbol,

while in the second, he needed to decide which side to

choose. The researchers recorded the men’s brain activity

with fMRI throughout the tests.

A year or more (360 to 967 days) after the imaging sessions, Dr. Paulus’s team was able to locate and contact 40

of the 46 patients. Of these, 18 had relapsed to methamphetamine abuse (median time to relapse, 279 days; range,

36 to 820 days). Comparing their fMRI results with those

of the 22 nonrelapsers, the researchers noted nine regions

where the groups’ brain activity had differed during decisionmaking. The relapse group showed less activation of

the dorsolateral, prefrontal, parietal, and temporal cortices

and the insula—regions associated with evaluation and

choice among actions that may lead to either beneficial or

harmful outcomes. The patterns of brain activation predicted relapse in 17 of the 18 men who had resumed

methamphetamine abuse and predicted successful abstinence in 20 of the 22 patients who had not relapsed, Dr.

Paulus says. 

“The most striking aspect of this result is that the fMRI

pattern has 90 percent accuracy in predicting outcome,”

Dr. Paulus says. “The differences in brain activity are pronounced, with little overlap.” Differences in the right

insula, right posterior cingulate, and right middle temporal gyrus differentiated relapsers from nonrelapsers. Other

brain regions predicted the timing of relapse.

8
“Some of these predictive areas have not previously been

strongly associated with drug abuse,” observes Dr. Steven

Grant of NIDA’s Division of Clinical Neurosciences and

Behavioral Research. “For example, while other investigators have reported alterations in the parietal lobe related to

drug abuse, this is the first study to show the parietal cortex playing an important role. However, because so many

brain regions were related to relapse, we still do not have a

full understanding of what specific process might be dysfunctional in the relapse group.”

The potential clinical implications of the new finding are

promising, but uncertain. For example, no women were

included among the participants, who were enrolled from

treatment programs. “It’s important to confirm the findings in women, for whom social, demographic, and other

factors associated with relapse may differ,” Dr. Paulus

points out. Nonetheless, he says that, in principle, programs treating methamphetamine abuse might use the

fMRI protocol to assess patients, then assign those likelier

to relapse to higher levels of care. Dr. Paulus believes such

an approach might prove cost-effective, even with typical

fMRI charges of up to $700 per hour in academic imaging centers. “The human and social costs of relapse are

high,” Dr. Paulus says. “Using this imaging technique to

precisely allocate care to the patients who need it most

might well produce enough savings elsewhere to more

than offset its expense. An alternative, more practical

course of action might be to use these fMRI results as a

benchmark for development of other assessments that are

less costly, but have the same predictive strength.”

Source

• Paulus, M.P.; Tapert, S.F.; and Schuckit, M.A. Neural

activation patterns of methamphetamine-dependent

subjects during decision making predict relapse.

Archives of General Psychiatry 62(7):761-768, 2005.

9

“The most striking aspect of this

result is that the fMRI pattern has 90

percent accuracy in predicting outcome. The differences in brain activity

are pronounced, with little overlap.”
Community-Based Treatment Benefits Methamphetamine Abusers 

A large California study finds favorable effects for inpatients and outpatients; women’s gains are larger.

By Lori Whitten, NIDA NOTES Staff Writer

Research Findings

Volume 20, Number 5 (April 2006)

Methamphetamine abusers can achieve long-term abstinence with the help of standard community-based drug

abuse treatment. Nine months after beginning therapy, 

87 percent of patients treated for heavy or long-term

methamphetamine abuse in California outpatient and 

residential programs were abstinent from all drugs, according to a NIDA-supported analysis. “In the public dialogue, and even among professionals in

the field, one sometimes hears that

meth abuse is ‘not treatable.’ But that

view is not borne out by recent clinical

trials or our study, which shows that

community-based treatment reduces

drug abuse and other problems,” says

lead investigator Dr. Yih-Ing Hser.

Dr. Hser and colleagues at the

University of California, Los Angeles

analyzed data from the California

Treatment Outcome Project (CalTOP),

an ongoing study that has followed the progress of adult

substance abusers treated at 43 outpatient and residential

programs throughout the State since April 2000. The

researchers focused on 1,073 patients who reported that

methamphetamine abuse was their primary drug problem

(572) or that they had abused the stimulant regularly for

at least 1 year before beginning treatment (501). Most

were in their 30s or younger, White or Latino, unemployed, and on public assistance; most had an arrest history. They had abused methamphetamine for about 9 years,

on average, and nearly one-quarter (22 percent) reported

injecting drugs at least once. Although 64 percent had

children aged 18 or younger, one-third of parents did not

live with their children in the month before beginning

treatment. One parent in five reported that a child protection court had ordered that his or her children live with

someone else, and 6.3 percent had their parental rights

terminated by the State.

The patients received the addiction treatment services routinely provided by each program. These usually included

group therapy, with an average of 69 drug-related and 51

alcohol-related sessions during the first 3 months of treatment. On average, the patients also received 22 sessions

on dealing with mental health symptoms and 13 addressing psychosocial problems, including family, parenting,

and employment.

More than 60 percent of the patients completed 3 months

of treatment. Among all the patients in the study—those

who finished 3 months and those who did not—the 

average reported frequency of methamphetamine abuse

fell from 2.7 to 0.5 days per month from the start of 

treatment to 9 months later. The portion who were abstinent from all drugs rose from 55 percent to 87 percent 

in the same interval, and 68 percent were abstinent and

also not incarcerated. Patients improved in all areas—drug

and alcohol abuse; mental health symptoms; and employment, family, and legal problems—except one: men’s

medical problems. 

10

“Because methamphetamine abusers respond to

treatment, getting them into therapy is a top priority.

For women, there is added urgency to help them

avoid exposing the children they may bear to the

consequences of prenatal drug exposure.”
Dr. Thomas Hilton of NIDA’s

Division of Epidemiology, Services and

Prevention Research says these findings

should reassure professionals working

in the addiction, social services, and

criminal justice fields that current therapies work for these troubled patients.

“Dr. Hser’s findings suggest that treatments available in the community help

meth abusers reduce drug abuse and

start to get their lives back on track,

echoing prior research,” he says.

Women’s Experiences

Dr. Hser’s findings confirm gender differences seen in other studies: Women

began treatment with more severe psychosocial problems than men (see

chart, right) and benefited more.

Although treatment retention levels

were similar for the two sexes, the

women made greater gains in the areas

of family relationships and medical

problems, while achieving similar

improvements in all other areas at the

9-month followup. The women’s better

outcomes may have resulted in part

from more intensive services (see chart

below); as well, Dr. Hser says that

many women in the study had a powerful motivator—family. “Many were

trying to maintain or regain custody of

their children by demonstrating

improvement during treatment. Others had ‘hit bottom,’

saw how drug abuse was hurting their families, and decided to make a change,” she says.

“Because methamphetamine abusers respond to treatment,

getting them into therapy is a top priority. For women,

there is added urgency to help them avoid exposing the

children they

may bear to the

consequences of

prenatal drug

exposure,” says

Dr. Hser.

Dr. Hser and her

colleagues continue to analyze

CalTOP data,

aiming to determine the longerterm impact of

therapy and

identify ways

programs can

improve outcomes. “Enhancing psychiatric, parenting,

and employment services would better match patients’

needs, and my team plans to study the relationship

between help for these problems and longer-term 

outcomes,” says Dr. Hser. They also plan to investigate

whether women-only treatment is more effective for 

pregnant methamphetamine abusers than mixed-gender

programs.

“The field needs more research following meth abusers

over time to get a picture of the long-term outcomes of

treatment, relapse episodes, and whether these patients

require additional support to sustain gains made during

therapy,” says Dr. Hilton. “Because the availability of

community health and social services varies across 

States, we cannot generalize the findings from one State,

such as California. We need data from across the country,”

he adds. 

Source

• Hser, Y.-I.; Evans, E.; and Huang, Y.-C. Treatment

outcomes among women and men methamphetamine

abusers in California. Journal of Substance Abuse

Treatment 28(1):77-85, 2005. 

11
Treatment Curbs Methamphetamine Abuse Among Gay and

Bisexual Men

By Lori Whitten, NIDA NOTES Staff Writer

Research Findings

Volume 20, Number 4 (March 2006)

Behavioral therapy can help gay

and bisexual men (GBM)

reduce methamphetamine

abuse and risky sexual behaviors and sustain these gains for

1 year, NIDA-funded

researchers report. By the end

of a 16-week trial of four different behavioral therapies, study

participants’ stimulant-positive

urine samples fell 31 percent,

and their number of pastmonth sexual partners fell more

than 50 percent—outcomes

that regressed little at the followup visits. Symptoms of

depression also improved.

Dr. Steven Shoptaw and colleagues at the University of

California, Los Angeles and the

Friends Research Institute

recruited 263 methamphetamine-addicted GBM throughout

Los Angeles County, particularly

in Hollywood, where HIV prevalence is especially high. Of these,

162 completed the requirements for entering the treatment phase of the study, which were to attend six assessments and participate in at least two of four group sessions on abstinence skills during a 2-week “baseline period.” Men who met the requirements reported less severity

and shorter duration of methamphetamine abuse than

those who did not, despite having abused methamphetamine for 5 years and having spent $293 on the drug in

the past month, on average. Half had engaged in unprotected anal intercourse (UAI) with someone other than

their primary partner in the past month, and 84 percent

of these men linked the behavior to methamphetamine

abuse. Most participants (73 percent) reported symptoms

of depression, with about 30 percent describing these as

moderate to severe.

The researchers randomly assigned each patient to one of

four behavioral therapies: cognitive-behavioral therapy

(CBT), contingency management (CM), CBT+CM, or

Gay CBT (GCBT). In CBT, participants analyzed situations and emotions linked with relapse, practiced ways to

manage craving and thoughts about drug abuse, and discussed healthy behaviors in group sessions. In CM, participants received vouchers redeemable for groceries, transportation, and clothing if they submitted stimulant-negative urine samples. GCBT addressed standard CBT

issues—including relapse, craving, and healthy behaviors—using specific examples from gay cultural events and

environments. For example, they compared the experience

of owning up to a drug problem with the experience of

acknowledging sexual orientation by “coming out.” All

four interventions were offered three times a week for 4

months.

Multiple, Lasting Benefits

Participants reduced methamphetamine abuse and risky

sexual behaviors and experienced fewer depression symp12

Although all interventions were effective, participants who received contingency management

(CM), cognitive-behavioral therapy (CBT) and CM, or culturally tailored Gay CBT (GCBT)

submitted fewer stimulant-positive urine samples during treatment, compared with those in standard CBT.
toms in the last month of treatment compared with the

month before therapy, regardless of the therapeutic

approach. Overall, they decreased methamphetamine

abuse from 9.6 to 2.4 days a month and reduced the

number of past-month sexual partners from 9.8 to 4.3, on

average. The percentage who reported unprotected

insertive anal intercourse—a risk factor for HIV-infected

individuals to transmit the virus to partners—fell from

36.9 percent to 16.7 percent by the end of treatment.

Beck Depression Inventory (BDI) scores improved from

14.3 (in the “mild to moderate” range) at baseline to 5.4

(“minimal”) in the last week of treatment.

Although all therapies benefited participants, response to

the treatments differed. During the treatment period, participants in GCBT and the combined treatments attended

more weeks of therapy and submitted fewer stimulantpositive urine samples than those who received standard

CBT during treatment. Participants receiving GCBT

showed a faster decrease in unprotected receptive anal

intercourse—a risk factor for acquiring the virus from a

partner—compared with those in standard CBT. Most

participants (80 percent) took part in the 1-year followup.

Generally, they sustained the lower levels of methamphetamine abuse, risky sexual behaviors, and depression

observed at the end of treatment (see page 12, “Benefits of

Behavioral Therapy Persist Up to One Year”). 

“It is encouraging that several types of behavioral treatment reduced both drug abuse and risky sexual behaviors

among gay and bisexual men at high risk for contracting

or transmitting HIV,” says Ms. Debra Grossman of

NIDA’s Division of Neuroscience and Behavioral

Research. However, more studies are needed to determine

the components of treatment that affect risky sexual

behaviors and the link between methamphetamine abuse

and such behaviors in other populations, she adds.

Methamphetamine Treatment as HIV Prevention

For about a decade in California, the drug most tightly

linked with HIV infection in GBM has been methamphetamine. The drug conveys a sense of heightened sexuality in the short term and is associated with risky sexual

behaviors and extremely high rates of HIV infection in

those seeking treatment. Sixty percent of the participants

in Dr. Shoptaw’s study reported HIV-positive status, a

prevalence much higher than his group has observed

among GBM seeking treatment for cocaine (30 percent),

alcohol (15 percent), or heroin (5 percent) abuse. 

“The reductions in risky sexual behavior in this study

exceeded those observed in HIV prevention trials among

GBM. We conclude that treatment for meth abuse fits

into a comprehensive HIV prevention strategy,” says Dr.

Shoptaw. The findings have already made an impact:

These data helped policymakers at the California Office of

AIDS decide to allocate $3 million for programs that

address methamphetamine abuse among GBM. 

Methamphetamine and

the Blues

The researchers were not surprised by the high percentage

of their study participants

who reported depression

symptoms at the beginning 

of the study. GBM are three

times as likely as heterosexual

men to have clinical depression.

Methamphetamine abusers

often say they take the drug

to kick the blues, but results

from the current study suggest

that continuing abuse may

serve to relieve low moods

related to stimulant withdrawal rather than alleviate underlying chronic depression.

When they analyzed the temporal link between metham13

Participants demonstrated improvement in Beck Depression Inventory (BDI) scores, which dropped

sharply the first week of treatment and leveled off at week 4.
phetamine abuse and depression, Dr. Shoptaw and his colleagues found that a urine sample indicating abuse of the

drug within the past 5 days strongly predicted high BDI

scores and abstinence strongly predicted low scores. In

contrast, BDI scores did not predict episodes of future

methamphetamine abuse, which is what would be expected if the men were abusing the drug to alleviate depression. “Meth abusers probably remember feeling better

after taking the drug, but this perception may not match

the physiology of long-term stimulant abuse,” says Dr.

James Peck, a member of the research team who led the

analysis of the depression data.

Sources 

• Shoptaw, S., et al. Behavioral treatment approaches

for methamphetamine dependence and HIV-related

sexual risk behaviors among urban gay and bisexual

men. Drug and Alcohol Dependence 78(2):125-134,

2005.

• Peck, J.A., et al. Sustained reductions in drug use and

depression symptoms from treatment for drug abuse

in methamphetamine-dependent gay and bisexual

men. Journal of Urban Health 82(1):i100-i108, 2005.

14
15

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.

Thalamus Striatum

1.35

1.00

1.05

1.10

1.15

1.20

1.25

1.30

Relative Metab

olism

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. 

16

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 page 15, “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. 

17
18

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.
19

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

20

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
21

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

22

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. 
23

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 page 27, “Brain Imaging Studies Show LongTerm 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

page 24, “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

24

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 page 22, “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.) 
25

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

26

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

27

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 myoinositol

(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. 
28

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

29

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. 
30

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

31

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. 
32

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
33

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

34

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 page 37, “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

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

severe movement disorder.

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.
35

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,”

NIDA Notes, November/December 1996, Vol. 11, No.5)

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,” NIDA Notes,

November/December 1996, Vol 11, No 5 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.

• 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.
36

• 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

37

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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