Review

Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX pubs.acs.org/chemneuro

DARK Classics in Chemical Neuroscience: Methamphetamine

Thomas J. Abbruscato* and Paul C. Trippier*
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106,
United States

ABSTRACT: Methamphetamine has the second highest prevalence of drug abuse after cannabis, with
estimates of 35 million users worldwide. The (S)-(+)-enantiomer is the illicit drug, active
neurostimulant, and eutomer, while the (R)-(−)-enantiomer is contained in over the counter
decongestants. While designated a schedule II drug in 1970, (S)-(+)-methamphetamine is available by
prescription for the treatment of attention-deficit disorder and obesity. The illicit use of (S)-
(+)-methamphetamine results in the sudden “rush” of stimulation to the motivation, movement, pleasure, and reward centers in
the brain, caused by rapid release of dopamine. In this review, we will provide an overview of the synthesis, pharmacology,
adverse effects, and drug metabolism of this widely abused psychostimulant that distinguish it as a DARK classic in Chemical
Neuroscience.
KEYWORDS: Methamphetamine, stimulant, drug of abuse, psychoactive

■ INTRODUCTION
Methamphetamine (1), a schedule II drug in the United States,
on Drug Use and Health, 4.7% of responders (>12 million
people) indicated they had used methamphetamine at least
is an illicit recreational drug due to the strong central nervous once in their life with 440 000 people indicating use within the
system (CNS) stimulant properties of the (S)-(+) or D- last month, an increase from the 2006 survey.14 The World
stereoisomer form. The abuse of methamphetamine represents Health Organization estimates that 35 million people globally
a significant public health problem throughout much of the regularly use methamphetamine. 16 These figures make
world.1,2 The (R)-(−) or L-isomer, however, is readily available methamphetamine and amphetamine abuse the most com-
in several over-the-counter decongestant products.3,4 (S)- monly used illicit drug after cannabis.1,17
(+)-Methamphetamine acts to increase concentrations of the Methamphetamine approved for clinical use is a powder that
is pressed into tablets. Recrystallization of methamphetamine
natural neurotransmitters dopamine, serotonin, and norepi-
hydrochloride yields colorless crystals which vaporize without
nephrine in the brain by increasing their release from storage
change to their structure and thus can be inhaled.18,19 The
vesicles5 and interfering with transporter action.6 This results in
crystal structure of this purified form of methamphetamine
stimulation of motivation, movement, pleasure, and reward
lends itself to the street names “crystal meth”, “glass”, and “ice”,
centers.7 The release of dopamine is often rapid and leads to
with other common names including “Tina”, “Christine”,
the sudden “rush” that many users experience upon inhaling
“yaba”, and “crazy medicine”.19 In this review, we highlight
vaporized methamphetamine.8 Oral administration of meth-
the significance of methamphetamine abuse in neuroscience,
amphetamine is approved by the United States Food and Drug
examining the synthesis, metabolism, and pharmacology of this
Administration (FDA) as a prescription-only medication for the
commonly used illicit street drug.
treatment of attention-deficit disorder in children9 and for the
short-term treatment of obesity, where it acts as an appetite
suppressant.10 Methamphetamine and amphetamine-type
stimulants (ATS) were widely prescribed to treat both of
■ CHEMICAL PROPERTIES AND SYNTHESIS
Methamphetamine, 1 (CAS no. 537-46-2, IUPAC name (2S)-
these conditions in the 1950s and 1960s, with the number of N-methyl-1-phenylpropan-2-amine) is a monoamine possessing
prescriptions peaking in 1967 at 31 million.11 The number of one chiral center, most often encountered on the street as the
prescriptions fell sharply after methamphetamine was desig- racemate. However, the (S)-(+)-enantiomer is the more active
nated a schedule II drug in the Comprehensive Drug Abuse stimulant (the eutomer) and illegal street drug, while the (R)-
Prevention and Control Act of 1970.12 This lead to the growth (−)-enantiomer is a legal decongestant found in several over-
of illicit manufacture of methamphetamine based on phenyl-2- the-counter products.4 The molecular weight of (S)-(+)-meth-
propanone (P2P), ephedrine, and pseudoephedrine starting amphetamine is 149.24, and it possesses a CLogP of 2.1. It has a
materials. The P2P precursor was rescheduled as a schedule II pKa of 9.87 and a topological polar surface area of 12 Å2. It is a
drug in 1980 with pseudoephedrine being restricted for public white crystalline powder in the hydrochloride salt form;
purchase in 2005.13,14
The United States National Survey on Drug Use and Health
Special Issue: DARK Classics in Chemical Neuroscience
conducted in 2006 estimated that 5.8% of the population had
used methamphetamine at some point in their life with 259 000 Received: March 15, 2018
recent new users.15 These figures appear to have remained Accepted: March 30, 2018
largely consistent; in the 2012 United States National Survey Published: March 30, 2018

© XXXX American Chemical Society A DOI: 10.1021/acschemneuro.8b00123

ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
ACS Chemical Neuroscience Review

recrystallization of methamphetamine hydrochloride yields enantiomerically pure (S)-(+)-methamphetamine that provides

colorless crystals, hence the name crystal meth. The molecule greater potency and hence greater stimulant effect.

■
has one hydrogen bond donor and one hydrogen bond
acceptor (the secondary amine acting in both roles). PHARMACOKINETICS AND METABOLISM
The three most commonly encountered synthetic routes in
the United States in 1989 used either (−)-ephedrine (2), Intranasal delivery or inhalation of methamphetamine results in
(+)-pseudoephedrine (3), or P2P (4) as starting material.20 good absorption with bioavailabilities of 79 and 67% in humans,
The chemistry has not changed to this date. These synthetic respectively.26 Oral consumption results in similar bioavail-
ability of 67%.27 Intramuscular and intravenous (i.v.)
routes include the palladium catalyzed reduction of the chlorine
administration of 1 in pigeons reaches 100% bioavailability by
derivative of 2, produced by reacting 2 with SOCl2, PCl5,
both routes.28 Peak plasma level by intranasal delivery is
POCl3, or PCl321 to methamphetamine (1) and the hydroiodic
obtained after 4 h in humans.29 Distribution to most organs
acid and red phosphorus reduction of 2 to 1. Numerous other
occurs with high accumulation in the liver (23%) and lungs
reductive methods are known to have been employed,
(22%), with only intermediate accumulation in the brain
including Nagai, Moscow, Rosenmund, Hypo, and Birch
(10%).30
reductions due to detection of impurities in seized products
Racemic compound 1 in humans is metabolized primarily by
(Scheme 1).22,23 CYP2D6, resulting in aromatic hydroxylation and N-
demethylation to provide two major metabolites: para-
Scheme 1. Synthesis of Methamphetamine by Reduction of hydroxymethamphetamine (pOH-MA) and amphetamine
Ephedrine or Pseudoephedrine (AMP). Amphetamine undergoes further metabolic changes,
resulting in the production of para-hydroxyamphetamine (p-
OH-AMP), 4 (phenylacetone), N-hydroxyamphetamine, and
norephedrine (Figure 1).31
Methamphetamine has an elimination half-life of between 8
and 13 h with its effects typically lasting for a similar time.32
Approximately 43% of methamphetamine is excreted in the
urine unchanged, while 4−7% is excreted as amphetamine.33−35
(+)-Pseudoephedrine, a common ingredient in over-the-
High urine acidity is associated with higher methamphetamine
counter decongestants, is commonly used as a replacement for
levels.36
2.24 A modified Birch reduction beginning with 3, obtained
Stereoselectivity has been observed in the metabolism of
from over the counter decongestants, known as the “shake and
methamphetamine with the pOH-MA metabolite least affected
bake” method has become a popular synthetic route to obtain
by stereochemistry of the administered compound. The area
1.25 As such, congress passed the Combat Methamphetamine
under the plasma concentration−time curve from time zero to
Epidemic Act in 2005, imposing restrictions on the amount of
infinity (AUC0−∞) was found to be 1996.5 ng/h/mL for the S-
products containing (+)-pseudoephedrine an individual can
(+)-1 enantiomer with a higher value of 2367 ng/h/mL for the
purchase in one day. A number of states in the United States
R-(−)-1 enantiomer at equal 0.5 mg/kg dose (Table 1). A
have made 3 a prescription-only medication. Due to these
slightly lower total clearance (CL) value for R-(−)-1 was
restrictions, the use of 4 as the starting material is common.
observed compared to S-(+)-1 but was within the margin of
The reductive amination of 4 with methylamine, proceeding via
error, while renal clearance (CLR) was identical. Interestingly,
the (E)-N-methyl-1-phenylpropan-2-imine (5) intermediate
the percentage of amphetamine and its para-hydroxy
using aluminum foil and anhydrous ammonia as a source of
metabolite recovered in the urine seemed to be stereospecific
hydrogen has been known since the 1990s (Scheme 2).
with 6.4% of AMP and 11.5% of pOH-AMP recovered from i.v.
delivery of S-(+)-1 compared with 2.1% of AMP and 7.1% of
Scheme 2. Synthesis of Racemic Methamphetamine from pOH-AMP recovered from i.v. delivery of R-(−)-1 (Table 1).
Phenyl-2-Propanone Precursor Thus, this suggests that pOH-MA, the metabolite least affected
by stereochemistry of the parent compound, is a better
biomarker for detection of methamphetamine abuse.31

■ PHARMACOLOGY
Methamphetamine acts as a psychostimulant drug that has
The other major route to access methamphetamine from 4, immediate behavioral effects that include feelings of alertness,
the Leuckart method, proceeds by the intermediate amide (6) increased energy, well-being, and euphoria, which are both
(Scheme 3).23 The routes employing 4 as starting material, cardiovascular and centrally mediated. The cardiovascular
form racemic 1, while use of 2 or 3 provide access to the effects of methamphetamine are mostly explained by the
release of norepinephrine from sympathetic nerve endings.37
Scheme 3. Synthesis of Racemic Methamphetamine by the The CNS effects of methamphetamine are mainly through the
Leuckart Method monoamine neurotransmitter system (dopamine, serotonin,
and norepinephrine). Methamphetamine release of catechol-
amines is reported to be through a nonexocytotic mechanism.6
This nonexocytotic mechanism is proposed to occur predom-
inantly through two mechanisms: redistribution of catechol-
amines from synaptic vesicles to the cytosol and activation of
putative reverse transport mechanisms of plasma membrane
B DOI: 10.1021/acschemneuro.8b00123
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Figure 1. Metabolic pathway of methamphetamine in humans.

Table 1. In Vivo Pharmacokinetics of Methamphetamine neurotoxic increase in intracellular dopamine. With this large
Enantiomers in i.v. Methamphetamine Usersa cytoplasmic accumulation of neurotransmitter, methamphet-
amine has also been postulated to activate a reverse membrane
property S-(+)-1 0.5 mg/kg R-(−)-1 0.5 mg/kg
transport mechanism to transport accumulated monoamines
AUC0−∞ (ng/h/mL) 1996.5 ± 373.1 2367.2 ± 522.3 (dopamine, serotonin, or norepinephrine) to the extracellular
CL (L/h/kg) 0.257 ± 0.038 0.221 ± 0.048 space.38 Additional mechanisms by which methamphetamine is
CLR (L/h/kg) 0.113 ± 0.034 0.118 ± 0.042 reported to increase monoamine levels include both increasing
1 % recovered in urine 43.2 ± 14.8 49.1 ± 12.8 dopamine synthesis through tyrosine hydroxylase42 and
pOH-AMP % recovered in urine 11.5 ± 6.0 7.1 ± 4.4 inhibition of monoamine oxidase and the degradation of
AMP % recovered in urine 6.4 ± 2.3 2.1 ± 0.8 dopamine.43 Overall, the multimodal effects of methamphet-
pOH-MA % recovered in urine 0.34 ± 0.16 0.27 ± 0.22 amine on synaptic dopamine accumulation is believed to play a
a
Adapted from reference 31. key role in the intense transition from drug-liking to drug-
craving upon methamphetamine use, and dopamine is involved
in this pathological learning process.44

■
uptake carriers. Two ideas have been proposed to support the
premise that methamphetamine redistributes vesicular catechol-
amines to the cytosol: (1) a weak base hypothesis and (2) ADVERSE EFFECTS
vesicular monoamine transporter (VMAT) substrate actions.38 The primary adverse effects of methamphetamine abuse are,
Methamphetamine is capable of accepting protons acting as a perhaps not surprisingly, neuropsychiatric.45 Acute use of
weak base with a pKA of 9.87. The strong acidic pH of methamphetamine in high doses can produce symptoms
secretory vesicles provides the energy to concentrate neuro- reminiscent of psychiatric disorders such as anxiety, paranoia,
transmitters and sympathomimetics against a concentration hallucinations, delirium, and related mood disorders due to
gradient. Catecholamines have been shown to reach levels of 10 increased levels of neurotransmitter release in the brain.46 Such
μM within chromaffin vesicles.39 The hypothesis is that symptoms are more pronounced in long-term intravenous users
vesicular monoamines (amphetamine and methamphetamine) of methamphetamine.47,48 A number of studies report
cause a vesicular pH gradient collapse and loss of vesicular conflicting data as to the effects of acute methamphetamine
neurotransmitter into the cytosol. VMAT also serves as a use on cognition. While some show an improvement in
principle target for methamphetamine. Specifically, metham- cognitive performance in both nondrug using volunteers49 and
phetamine interacts with VMAT2 as a competitive antagonist methamphetamine-dependent populations,50 yet others show
and prevents the ability of cells to utilize VMAT for vesicular cognitive deficits.51
concentration.40,41 This antagonist activity has profound effects Chronic use of methamphetamine can induce myocardial
on dopamine distribution in the cell, creating, in some cases, a infarction,52 increase the risk of stroke53,54 or acute aortic
C DOI: 10.1021/acschemneuro.8b00123
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ACS Chemical Neuroscience Review

dissection and aneurysms,55 and result in pulmonary hyper- use can also disrupt the blood−brain barrier (BBB)76,77 and
tension, possibly related to the large accumulation of contribute to vasogenic brain edema, causing water, protein,
methamphetamine in the lungs.56 Other adverse effects upon and ionic movement into the brain extracellular fluid. These
chronic use include the mental health consequences previously BBB specific effects of methamphetamine have been postulated
discussed and rapid tooth decay, a stereotypical condition of to be by direct activation of metalloproteinases (MMP-2 and
meth abusers colloquially termed “meth mouth”.57−59 Chronic MMP-9) and opening of tight junctions between endothelial
users often experience psychotic disorders including both cells of the BBB and/or the increased production of reactive
positive and negative symptoms,60 wherein incidence is higher oxygen species. This disruption in the physical and dynamic
in intravenous users.61 separation between the blood and central nervous system is a
As a lipophilic drug that can cross the placenta, methamphet- hallmark feature of a number of neurodegenerative diseases and
amine use in pregnant women has been documented to lead to could be another contributor to both the acute and chronic
growth restriction and lower the birth weight of infants carried methamphetamine induced brain abnormalities. Future areas of
to term.62,63 A number of instances have been reported where research should include both animal and clinical studies to
methamphetamine abuse by the mother was correlated to an determine the neuroanatomical regions of brain damage from
increased risk of stillbirth.64 Cessation of methamphetamine methamphetamine abuse and the extent of recovery from the
use at any time during pregnancy has been shown to improve brain altering effects of chronic, high dose methamphetamine
birth outcomes.65 Studies in prenatal rat pups exposed to abuse. Additionally, future treatments are needed to offset the
methamphetamine show cognitive and learning deficits.66−68 various stages of the addiction cycle that are pathologically
Placental insufficiency and abruption has been reported that altered by methamphetamine abuse, including the quick
resulted in maternal death.64 movements from binge and intoxication to withdrawal and
Unlike many drugs of abuse, withdrawal symptoms from negative affect to preoccupation and anticipation.78
methamphetamine dependence are relatively mild. Such In summary, methamphetamine is the most commonly used
symptoms include dysphoria, irritability, anxiety, lack of drug of abuse after cannabis, marking its place as a DARK
concentration, depression, fatigue, and paranoia.47,69 However, classic in chemical neuroscience. Despite decades of use in
these are relatively rare, with increases in sleep and appetite the humans as both a prescription and illicit drug, the full
major withdrawal symptoms. The neuropsychiatric symptoms neuropharmacological effects of methamphetamine are still
of methamphetamine abuse were reported to be reduced by the poorly understood. The psychiatric side effects of methamphet-
first week of abstinence with the sleep and appetite symptoms amine abuse, due to perturbation of neurotransmitter systems,
continuing through weeks two and three post cessation of provide further insights and yet produce more questions of the
use.70 monoamine hypothesis of depression, the prevalence of

■ HISTORY AND IMPORTANCE IN NEUROSCIENCE

It is apparent that the street drug forms of methamphetamine
hallucinations in schizophrenia and PD, and the link between
PD and anxiety, among others. Studies on the neurochemistry
of methamphetamine users may yield insights into these and
other neurological conditions.

■
have high abuse potential and profound rewarding effects
through long-term modulation of dopamine release. The
molecule was first synthesized from ephedrine in 1893 by a AUTHOR INFORMATION
Japanese scientist and later in 1919, Akira Ogata synthesized Corresponding Authors
crystallized methamphetamine by reducing ephedrine using red *E-mail: [email protected].
phosphorus and iodine, providing the basis for drug production *E-mail: [email protected].
on a larger scale.71 Crystallized methamphetamine HCl, crystal ORCID
meth, or ice, can be conveniently vaporized and used for Paul C. Trippier: 0000-0002-4947-5782
recreational purposes. In 1971, methamphetamine use was Author Contributions
restricted by United States law, although one must appreciate Both authors contributed equally to this manuscript.
that oral formulations continue to have a secondary therapeutic
utility in the United States, mostly for attention deficit disorder Funding
with hyperactivity and exogenous obesity. We thank Texas Tech University Health Sciences Center and
A major contributor to the high abuse potential for the numerous organizations that have provided funding to our
methamphetamine is the fact that a large amount of the drug laboratories for studies in chemical neuroscience.
becomes CNS available within minutes of inhalation due to its Notes
high lipophilicity.30,72 As described above, acute exposures can The authors declare no competing financial interest.
induce a system imbalance with regard to release and reuptake
of dopamine, norepinephrine, and epinephrine, resulting in
intense feelings of euphoria, excitation, and alertness, yet the
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F DOI: 10.1021/acschemneuro.8b00123
ACS Chem. Neurosci. XXXX, XXX, XXX−XXX