Cho2001 Patterns of Methamphetamine Abuse

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Patterns of Methamphetamine
Abuse and Their Consequences
a a b
Arthur K. Cho PhD & William P. Melega PhD
a
Department of Molecular and Medical
Pharmacology, UCLA School of Medicine, Los
Angeles, CA, USA
b
UCLA School of Medicine Brain Research Institute,
USA
Published online: 12 Oct 2008.
To cite this article: Arthur K. Cho PhD & William P. Melega PhD (2001): Patterns of
Methamphetamine Abuse and Their Consequences, Journal of Addictive Diseases,
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Patterns of Methamphetamine Abuse
and Their Consequences
Arthur K. Cho, PhD

William P. Melega, PhD
ABSTRACT. The abuse of methamphetamine (METH) continues to in-

crease throughout all age groups in different regions of the United States.
“Ice,” the popularized jargon for (+) methamphetamine hydrochloride, is
the predominant drug form that is now consumed. “Ice” is effectively ab-
sorbed after either smoking or snorting and it is this rapid influx of drug
that produces effects similar to those after intravenous administration.
The intensity of METH actions in the central and peripheral nervous
system shows tolerance after chronic administration, indicating that neuro-
adaptations have occurred. Thus, the physiological processes and corre-
sponding biochemical mechanisms that regulate neuronal function have
been changed by METH exposure. These biological alterations contrib-
ute to the craving and dependence associated with METH abuse and the
withdrawal syndrome upon abstinence. However, these changes in be-
havior may also result from METH-induced neurotoxicity. This article
reviews aspects of METH pharmacokinetics and related molecular
pharmacodynamics that represent METH pharmacology and then relates
those actions to their potential to produce neurotoxicity in humans. [Ar-
ticle copies available for a fee from The Haworth Document Delivery Service:
1-800-342-9678. E-mail address: <getinfo@haworthpressinc.com> Website:
<http://www.HaworthPress.com> 2002 by The Haworth Press, Inc. All rights
reserved.]
Arthur K. Cho and William P. Melega are affiliated with the Department of Molec-
ular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA. Dr.
Melega is also affiliated with the UCLA School of Medicine Brain Research Institute.
Address correspondence to: William P. Melega, PhD, Department of Molecular and
Medical Pharmacology, 23-120 CHS, UCLA School of Medicine, Box 951735, Los
Angeles, CA 90095-1735 (E-mail: wmelega@mednet.ucla.edu).
The work from the authors’ laboratories has been supported, in part, by USPHS
grant DA-11237, the NIDA-MDD/VA intragency agreement 1 YO1 DA-50038 and
the U.S. Department of Energy Contract DE-FC03-87ER60615.
Journal of Addictive Diseases, Vol. 21(1) 2002
 2002 by The Haworth Press, Inc. All rights reserved. 21
22 JOURNAL OF ADDICTIVE DISEASES
KEYWORDS. Methamphetamine, neurotoxicity, neurodegeneration,

PET
INTRODUCTION
The recent increase in the abuse of methamphetamine (METH) and related

substances has raised public awareness of this class of drugs although in the
1940s and 1950s there were already reports on the abuse potential of the
desmethyl METH analog, amphetamine (AMPH).1 AMPH was originally in-
troduced as a nasal decongestant and it has been used clinically to treat atten-
tion disorder syndrome in children, to promote weight loss and to offset
fatigue. Although it is METH that is now predominantly abused, we will re-
view the pharmacology of both AMPH and METH since both drugs have
abuse potential and further, AMPH is the principal metabolite formed in vivo
from METH. Both compounds are indirectly acting sympathomimetic drugs
that primarily increase the actions of norepinephrine in the peripheral sympa-
thetic nervous system and the actions of dopamine, norepinephrine, and sero-
tonin in the central nervous system. The behavioral pathology associated with
the chronic use of AMPH and METH has been well-documented in animal2
and human studies.3 Here, we describe aspects of METH and AMPH chemis-
try and then review their pharmacological actions on the nigrostriatal dopa-
mine system that contain neuronal circuits (particularly to the nucleus accumbens)
that are critically related to drug dependence and reward-reinforcement.4 Re-
cent evidence is also presented for neurotoxicity initiated by METH-induced
excessive dopamine release that may lead to long term behavioral alterations.
CHEMISTRY OF AMPHETAMINES
Compounds that contain a phenylisopropyl amine structure but different

side groups are often collectively referred to as amphetamines. The term is also
used to characterize the actions of either METH or AMPH. Several examples
of amphetamine congeners are shown in Figure 1, together with close chemi-
cal relatives that are used for therapeutic and abuse purposes.
The phenylisopropyl amines have a chiral center at the α-carbon which is
recognized by their biological substrates. Consequently, the enantiomers of
these compounds have different biological potencies, with the S-(+) or d-con-
figuration having 5-10 times greater potency at the dopamine terminal than the
R-(⫺) or l-configuration.5 Enantiomeric purity is therefore an important as-
pect in the assessment of activity of a particular formulation. The racemic
(50% each of d- and l-) mixture is essentially one half as active as the pure d-
Arthur K. Cho and William P. Melega 23
FIGURE 1. Structure formulae of the psychomotor stimulants–amphetamine

and methamphetamine. The other compounds shown include the nasal decon-
gestants, ephedrine (with two chiral centers) and phenylpropanolamine, and
the weight loss drug, phentermine. The related substituted amphetamines–
methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine
(MDMA) are shown for comparison.

OH
H H
NH2 N N
CH3 CH3
CH3 CH3 CH3
Amphetamine Methamphetamine Ephedrine
OH
CH3
NH2 NH2
*Denotes chiral center
CH3
CH3
Phenylpropanolamine Phentermine
H
NH2 O N
O CH3
CH2 CH2
CH3 CH3
O O
Methylenedioxyamphetamine Methylenedioxymethamphetamine
(MDA) (MDMA)
form. The l-enantiomer, also called desoxyephedrine, is the active ingredient

in nasal decongestant inhalants. The other compounds shown in Figure 1 in-
clude the nasal decongestants, ephedrine (with two chiral centers) and phenylpro-
panolamine, and the weight loss drug, phentermine. Note that these compounds
are without substituents on the aromatic ring and it is that structural specificity
that contributes to their actions being selective for the dopamine system. In
contrast, compounds with substituents on the aromatic ring appear to exert pri-
mary effects on the serotonin system, e.g., methylenedioxyamphetamine (MDA)
and methylenedioxymethamphetamine (MDMA). Nonetheless, all of these
substances have CNS stimulatory effects that are related, in part, to actions
similar to those of AMPH and METH but with different potencies.
The differences in magnitude of effect for these compounds can be attrib-
uted to parameters that are pharmacodynamic (the type and extent of interac-
tion between the drug and tissue) and pharmacokinetic (the physical-chemical
properties of the compound that affect its movement across membranes and its
rate of metabolism). For example, the lower CNS potency of ephedrine rela-
tive to METH and AMPH is related, in part, to its pharmacokinetics because
ephedrine is more polar and consequently, does not diffuse as readily into the
brain.
AMPH and METH can be readily prepared from simple chemical precur-
sors unlike cocaine that is a plant-derived substance. However, the more re-
cently available METH form known as “ice” is prepared from the natural
product, ephedrine (see Figure 2). METH was initially synthesized in illicit
laboratories by the Leukart reaction in which phenylacetone is condensed with
methylamine in the presence of formic acid. The product is the racemic, d,l
mixture and can be contaminated with phenylacetone. More recently, d-METH
hydrochloride of greater purity has become readily available. This preparation
is biologically more potent and is called “ice” because of its resemblance to
that of ice crystals. “Ice” is prepared by the reduction of the β-hydroxyl group
on ephedrine (Figure 2) with a mixture of iodine and red phosphorous. The hy-
drochloride salt of METH remains volatile without decomposing upon heating
and it is this property that allows for abusers to inhale METH vapors from a
pipe. Recently, however, a potentially toxic impurity has been observed in
street samples of “ice.” This compound, an aziridine, (see Figure 2) is an inter-
FIGURE 2. Methamphetamine hydrochloride is called “ice” because its physi-

cal appearance resembles that of ice crystals. “Ice” is prepared by the reduc-
tion of the β-hydroxyl group on ephedrine with a mixture of iodine and red
phosphorous. A potentially toxic intermediate compound called an aziridine
can be formed in the conversion of ephedrine to methamphetamine. (See text
for details.)
Leukart Synthesis
H
O N
CH3
+ CH3NH2
CH3 HCOOH CH3
Phenylacetone Methamphetamine
Reduction of Ephedrine
CH3
OH
H N H
N N
CH3 CH3
CH3 CH3 CH3
Ephedrine an Aziridine Metamphetamine

mediate compound formed in the conversion of ephedrine to METH (unpub-

lished observations). Aziridine acts as an alkylating agent that can disrupt
functions of macromolecules in the cell and promote formation of antigenic
macromolecules with toxic consequences. However, the extent of its toxic ef-
fects in either humans or animal studies has not been systematically examined.
PHARMACOKINETICS OF METHAMPHETAMINE
The pharmacokinetics of METH as the predominant amphetamine has been

examined in humans after intravenous injection,6,7 inhalation (smoking) and
oral doses.8 Substantial proportions of administered METH (30-50%),7 and
AMPH (30%) are excreted in the urine, depending on urine pH.9 Both are rela-
tively strong bases (pKa = 9-10) and are ion-trapped in the more acidic urine.
These compounds are also metabolized by phase I (oxidation) and phase II
(conjugation) reactions. In phase 1 metabolism, METH and AMPH as substrates
for the cytochrome P450 systems undergo N-dealkylation and hydroxylation
reactions on the aromatic ring and the nitrogen.10,11 One of the cytochrome
P450 enzymes responsible for these reactions in humans is CYP2D6. This en-
zyme exhibits a genetic polymorphism,12 and about 10% of Caucasians are de-
ficient in this enzyme. These individuals may be more sensitive to METH and
AMPH than the general population because of their relative inability to metab-
olize the drugs efficiently. The two primary metabolites of METH are AMPH
and 4-hydroxy-METH13 (see Figure 3) but their contribution to the overall phar-
macology of METH may not become important until repeated doses are taken.
The drugs appear to enter tissues by a flow-limited process14 so that once in
the plasma, their movement into well-perfused organs, e.g., the heart and
FIGURE 3. Methamphetamine metabolism in humans: N-demethylation to am-

phetamine (major metabolite) and 4-hydroxylation to 4-hydroxymethamphet-
amine (minor metabolite) are both mediated by the cytochrome P450 system in
liver.
H
N
CH3
4-Hydroxylation CH3
N-demethylation
(CYP2D6)
Methamphetamine
H
N NH2
CH3
CH3 CH3
HO
4-Hydroxymethamphetamine Amphetamine
brain, is quite rapid. The plasma half-life of METH in humans is ~12 hours
(range: 9-13 hours), considerably longer than the 90 minutes reported for co-
caine.15 The steady state volume of distribution for METH is about 3-4
L/kg.7,8 We have found similar values in rodents (3.6 L/kg, unpublished data)
suggesting that both absorption and distribution properties of the drugs are
similar for both species. Consistent with this large volume of distribution,
studies with rats indicate that METH and AMPH accumulate in the brain, with
brain to plasma ratios of 10 to 1. This accumulation is reversible and its clear-
ance from the brain parallels that from the plasma.16 However, the high brain
to plasma ratio indicates that measured plasma levels significantly underesti-
mate concentrations of METH in the brain. Therefore, the rather protracted du-
ration of this accumulation effect may increase potential METH toxicity in the
brain.
Two distinct patterns of METH abuse are apparent in humans: (a) chronic,
periodic self-administration throughout the day, and (b) multiple dosing that
continues throughout several days and is labeled as a “binge” or “run.” The
chronic abuser takes regular “hits” or puffs of the vaporized compound from
pipes as often as every 30 minutes during the day but stops taking the drug late
in the day so as to sleep at night. Estimates of the total drug consumed in a day
are between 0.7 to 1 gram. We have estimated that during this abuse pattern,
plasma METH concentrations in the micromolar range are readily achieved,
indicating that brain levels may be ten times higher. In contrast, individuals
who “binge” on METH will continually self-administer the drug in increasing
doses over a period of 1-3 days after which they “rest.” The quantities of drug
consumed during a binge can be quite high and estimates of total drug con-
sumption are in the range of 2-4 grams. Both of these exposure processes allow
substantial concentrations of the drug to accumulate in the brain because of the
short dosage interval compared to the relatively longer plasma half-life of
METH (12 hours).
PHARMACODYNAMICS OF METHAMPHETAMINE
Briefly, the effects of METH can cause pleasurable feelings, anorexia, in-
creased motor activity as well as stereotypy, psychosis, and sympathomimetic
cardiovascular stimulation. With repeated use, tolerance to these effects oc-
curs and consequently, larger doses are taken by an abuser. After chronic use,
psychological dependence develops and upon abstinence, craving and with-
drawal symptoms are experienced. Although linkage between these behaviors
and specific biochemical mechanisms remains undefined, it is apparent that
the molecular actions of METH affect the complex neurochemical processes
regulating expression of these behaviors.
At the biochemical level, these actions of METH are mediated initially by

increasing the activity of the norepinephrine system in the periphery and of the
dopamine (DA) system in the central nervous system. METH causes the re-
lease of these neurotransmitters and the blockade of their reuptake into the
presynaptic nerve terminal. METH induces the release of large quantities of
catecholamines into the synapse by an exchange diffusion process that is inde-

pendent of neuron depolarization activity.17 The primary site of action is at the
dopamine transporter (DAT). This was recently demonstrated in experiments
with mice in which the complete deletion of DAT expression by genetic engi-
neering (DAT knockout) resulted in the absence of METH-induced effects.18,19
METH also acts on other sites of the presynaptic terminal that include storage
vesicles and monoamine oxidase.20,21 In vitro microdialysis studies in rodents
have shown that extracellular concentrations of dopamine after high doses of
METH can exceed 1 micromolar.14 Those effects may be further increased by
the METH inhibition of monoamine oxidase activity, an enzyme that normally
converts dopamine and norepinephrine to inactive metabolites. However, a
secondary consequence of METH’s prolonged actions at the synapse is the de-
pletion of available neurotransmitter for further release. Thus, METH’s ac-
tions become less potent after multiple administrations, an effect referred to as
short term tolerance or tachyphylaxis. These tolerance mechanisms explain, in
part, the need for the chronic abuser to escalate the quantity of METH per dose
during multiple self-administrations (binges).
Recently, evidence has been presented to show that the METH-induced re-
lease of high concentrations of DA into the extracellular space can result in the
formation of reactive oxygen species that inactivate the transporter. Evidence
for the formation of one of these reactive species, the ortho-quinone of DA,
was provided by Carlsson and his associates22-24 who found a DA-cysteine
adduct in the brain of several mammalian species. The DAT is a protein that is
susceptible to modification caused by agents that attach to protein thiol
functions25,26 and to oxidants that will convert the thiol function to a disulfide.27
Under conditions in which high DA concentrations are present, such as after
high doses of METH, formation of DA oxidized products may become phar-
macologically or toxicologically significant. That such oxidized products
form, in vivo, is evidenced by reports of the DA-cysteine adduct being de-
tected in the brains of guinea pigs22 and humans.24 Although a number of stud-
ies (see review in28) have demonstrated that DA oxidation-derived compounds
can be neurotoxic, a more selective effect–a suppression of DAT activity–is
possible under conditions of limited exposure.29 Depending on the nature of
the interaction, suppression of the DA transporter activity may result in short
term/reversible or long term/irreversible alterations in nerve terminal function.
A long term neuroadaptation at the DA nerve terminal could result in chronic
behavioral alterations that parallel those caused acutely by drugs of abuse,
since it has been well established that changes in DAT activity are temporally
associated with the expression of behavioral effects.
Presently, the in vitro evidence for increases in dopamine-derived oxidation
products after METH has not been related to precise chemical mechanisms
that inactivate transporter activity. It should be noted that there are other sec-
ondary changes induced by prolonged dopaminergic activity in vivo that in-

clude increases in extracellular concentrations of Ca2+, glutamate and endogenous
opioids as well as glial activation.30,31 Dysregulation of these processes likely
synergistically affects both expression of METH-induced behaviors and neuro-
toxic interactions. Recent reviews detail the multiple molecular actions in-
duced by METH and resultant potential neurotoxicity.32
NEUROTOXICITY OF METHAMPHETAMINE
Although METH abuse has become more widespread over the past decade,
only modest progress has been made elucidating the neurobiological mecha-
nisms associated with its long-term abuse. However, at the biochemical level,
the molecular mechanisms of METH have been further defined by recent ele-
gant in vitro and in vivo studies. For example, alterations in gene expression
related to the reinforcing effects of addictive substances have been demon-
strated, although the relationship of those actions to the addictive process has
not been clarified. Presently, these research areas are being intensively studied
and current reviews are presented elsewhere.33,34
In this review, we will address another aspect of METH pharmacology,
namely, the potential neurotoxicity associated with its abuse. Examples of
METH toxicity in rodents and non-human primates are followed by recent
data on the neurotoxicity of human METH exposure.
The term, neurotoxicity, is often used to indicate neurodegeneration related
to the irreversible loss of nerve terminals or neuron cell bodies. We will use a
more inclusive definition as formulated by The Interagency Committee on
Neurotoxicology: “Neurotoxicity is any adverse effect on the structure or func-
tion of the central and/or peripheral nervous system by a biological, chemical or
physical agent. Neurotoxic effects may be permanent or reversible, produced
by neuropharmacological or neurodegenerative properties of a neurotoxicant,
or the result of direct or indirect actions on the nervous system.”35 By these cri-
teria, a wide range of different neurotoxicity profiles has been characterized in
animal studies with various drug administration regimens. A complete review
and critique of those studies is beyond the scope of this review. Rather, the
neurotoxic effects of METH on the striatal DA system will be described, inso-
far as METH appears to interact primarily with the dopaminergic systems and
alterations in DA function are likely to critically affect behavior.
The neurotoxicity observed in the striatal DA system has been character-

ized in several animal models, most extensively in the rodent and less so in the
monkey.36-38 In rat studies, METH exposure can result in long-term decreases
in striatal DA uptake binding sites associated with the DAT,39 in DA concen-
trations, and of DA system-related proteins, DAT, tyrosine hydroxylase (TH),
and the vesicular monoamine transporter (VMAT).40,41 Additionally, after

“high dose” METH as well as with MDMA,42 alterations in the diameter and
density of neuronal fibers43,44 and nerve fiber/terminal degeneration have
been observed.42,45,46 Temperature-related factors have also been implicated
in METH neurotoxicity since hyperthermia has often been observed after
METH exposure in humans. The extant data from rodent studies have indicated
that hyperthermia is a necessary concomitant insofar as apparent neuroprotection
has resulted from either the lowering of ambient or body temperature29,47,48
(see Bowyer37 for recent review of hyperthermia effects). However, the rela-
tively high dosages required to produce these deficits have been distinguished
from lower dosage protocols that effect behavioral changes but not neuro-
toxicity (see Robinson49 for review of high-toxic vs. low-behavior dose am-
phetamine effects).
In non-human primates studies, extensive DA system deficits after METH
have been characterized by decreases in DAT, VMAT binding, dopamine syn-
thesis rates, and dopamine concentrations.50-52 However, long-term studies
have noted that these apparent neurotoxic effects are reversible to variable ex-
tents.53,54 Both the magnitude of the striatal neurotoxicity and its recovery over
time have been demonstrated in vivo with positron emission tomography (PET).53
However, in spite of many animal studies with a wide range of doses, vari-
able number of injections and different routes of administration, the extrapola-
tion of these results for interpretation of the functional consequences of human
drug use has remained tenuous for many years. The modeling of human
METH abuse patterns is complicated by the lack of accurate data, especially
when it is derived anecdotally from reports by drug abusers. Further, in hu-
mans the METH consumption is often supplemented by alcohol, nicotine or
other abused substances. However, a generic METH profile includes a transition
from a pattern of “recreational” use and frequency to one of incremental doses in
multiple “hits” over shorter periods of time, culminating in “binges.”3,55,56
Accordingly, the consequences of this gradual escalation in METH dosage and
frequency as observed in humans may be different from animal models that
employ acute, high-dose regimens that do not parallel the human pattern of
METH administration. Consequently, a human binge pattern may not result in
the kind or degree of toxic effects often observed in animal studies because, in
humans, tolerance is likely to have developed to many of METH’s actions.3,57-61
Nonetheless, several of those METH-induced deficits in striatal dopamine
function as characterized previously in animal studies have now been shown to
occur in human chronic METH users. Due to the limited data presently avail-
able, generalizations on neurotoxicity patterns in humans should remain tem-
pered by both the low number of human studies and small size of subject
groups. However, the initial results suggest that METH neurotoxicity in hu-
mans resembles aspects of those observed in animal models. Specifically,
decreases in binding of radioligands that have high selectivity for DAT (sug-
gestive of alterations in dopamine transporter function) and dopamine concen-
trations (suggestive of reduced dopamine synthesis capacity) were recently
reported in a post-mortem study of brains from human METH abusers.62 Yet,
those deficits were not attributed to nerve terminal loss because another index
of neuronal integrity, VMAT, was not correspondingly reduced, implying
preservation of neuronal vesicles and the terminals that contained them.63 This
was the first study on the effects of METH in humans and the results demon-
strated that, in this group of individuals, METH had produced alterations in
neuronal indices of striatal dopamine system integrity. It should be noted that
these results represent only one study on one subset of individuals who died
within 24 hours from the effects of METH or from other causes while on
METH. Still, the results have clearly shown that the human brain is sensitive to
METH-induced alterations in dopamine function.
More recently, PET imaging studies in human METH abusers have shown
20-30% decreases in the binding of a radioligand, [C-11]WIN 35,428, to the
dopamine transporter.64 The functional significance of these alterations re-
mains to be clarified; however, the results provide further evidence that
METH-induced neuroadaptations occur in humans.
Future studies of humans drug abusers with PET in which neurochemical
alterations in brain can be non-invasively imaged will contribute uniquely to
our understanding of the nexus between brain and behavior. Also, the potential
reversibility or permanent effects of METH can be determined by longitudinal
PET studies in individual subjects. With that database, more appropriate ani-
mal models can then be designed to mimic the human condition. In such models,
the molecular processes that govern the temporal development of addictive
processes may then be delineated. Also, in these animal models, pharma-
cotherapies can be evaluated for their potential to promote recovery from
METH-induced neuroadaptations that have been linked to associated behav-
ioral pathology.
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Arthur K. Cho, PhD

ABSTRACT. The abuse of methamphetamine (METH) continues to in-

KEYWORDS. Methamphetamine, neurotoxicity, neurodegeneration,

The recent increase in the abuse of methamphetamine (METH) and related

Compounds that contain a phenylisopropyl amine structure but different

FIGURE 1. Structure formulae of the psychomotor stimulants–amphetamine

(MDMA) are shown for comparison.

Amphetamine Methamphetamine Ephedrine

form. The l-enantiomer, also called desoxyephedrine, is the active ingredient

FIGURE 2. Methamphetamine hydrochloride is called “ice” because its physi-

Ephedrine an Aziridine Metamphetamine

mediate compound formed in the conversion of ephedrine to METH (unpub-

The pharmacokinetics of METH as the predominant amphetamine has been

FIGURE 3. Methamphetamine metabolism in humans: N-demethylation to am-

At the biochemical level, these actions of METH are mediated initially by

catecholamines into the synapse by an exchange diffusion process that is inde-

ondary changes induced by prolonged dopaminergic activity in vivo that in-

The neurotoxicity observed in the striatal DA system has been character-

and the vesicular monoamine transporter (VMAT).40,41 Additionally, after

3. Angrist B. Amphetamine psychosis: clinical variations of the syndrome. In:

5. Melega WP, Cho AK, Schmitz D, Kuczenski R, Segal DS. l-Methamphetamine

ence of a factor responsible for maintaining sequestration. J Neurochem. 1990; 54:

22. Fornstedt B, Carlsson A. A marked rise in 5-s-cysteinyl-dopamine levels in

38. Seiden L. Neurotoxicity of methamphetamine: mechanisms of action and is-

quantitative autoradiography. Synapse 1992; 11:287-293.

52. Villemagne V, Yuan J, Wong D, Dannals R, Hatzidimitriou G, Mathews W,

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