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DARK Classics in Chemical Neuroscience: Methamphetamine

Thomas J Abbruscato, and Paul C. Trippier
ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00123 • Publication Date (Web): 30 Mar 2018
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DARK Classics in Chemical Neuroscience: Methamphetamine

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2 Thomas J. Abbruscato* and Paul C. Trippier*
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School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States
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ABSTRACT
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2 Methamphetamine has the second highest prevalence of drug abuse after cannabis, with estimates of
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35 million users worldwide. The (S)-(+)-enantiomer is the illicit drug, active neurostimulant and eutomer, while
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7 the (R)-(-)-enantiomer is contained in over the counter decongestants. While designated a schedule II drug in
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9 1970, (S)-(+)-methamphetamine is available by prescription for the treatment of attention-deficit disorder and
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11 obesity. The illicit use of (S)-(+)-methamphetamine results in the sudden ‘rush’ of stimulation to the motivation,
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13 movement, pleasure and reward centers in the brain, caused by rapid release of dopamine. In this review, we
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15 will provide an overview of the synthesis, pharmacology, adverse effects and drug metabolism of this widely
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17 abused psychostimulant that distinguish it as a DARK classic in Chemical Neuroscience.
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21 Keywords: Methamphetamine, stimulant, drug of abuse, psychoactive
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INTRODUCTION
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2 Methamphetamine (1), a schedule II drug in the U.S., is an illicit recreational drug due to the strong
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central nervous system (CNS) stimulant properties of the (S)-(+) or D-stereoisomer form. The abuse of
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7 methamphetamine represents a significant public health problem throughout much of the world.1, 2 The (R)-(-)
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9 or L-isomer however, is readily available in several over-the-counter decongestant products.3, 4
(S)-(+)-
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11 Methamphetamine acts to increase concentrations of the natural neurotransmitters dopamine, serotonin and
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13 norepinephrine in the brain, by increasing their release from storage vesicles,5 and interfering with transporter
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15 action.6 This results in stimulation of motivation, movement, pleasure and reward centers.7 The release of
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17 dopamine is often rapid and leads to the sudden ‘rush’ that many users experience upon inhaling vaporized
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19 methampehtamine.8 Oral administration of methamphetamine is approved by the U.S. Federal Drug
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21 Administration (FDA) as a prescription-only medication for the treatment of attention-deficit disorder in
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children,9 and for the short-term treatment of obesity, where it acts as an appetite suppressant.10
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26 Methamphetamine and amphetamine-type stimulants (ATS) were widely prescribed to treat both of these
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28 conditions in the 1950s and 1960s, with the number of prescriptions peaking in 1967 at 31 million.11 The
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30 number of prescriptions fell sharply after methamphetamine was designated a schedule II drug in the
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32 Comprehensive Drug Abuse Prevention and Control Act of 1970.12 This lead to the growth of illicit manufacture
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34 of methamphetamine, based on phenyl-2-propanone (P2P), ephedrine and pseudoephedrine starting
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36 materials. The P2P precursor was rescheduled as a schedule II drug in 1980 with pseudoephedrine being
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38 restricted for public purchase in 2005.13, 14
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40 The U.S. National Survey on Drug Use and Health conducted in 2006, estimated that 5.8% of the
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population had used methamphetamine at some point in their life with, 259,000 recent new users.15 These
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figures appear to have remained largely consistent; in the 2012 U.S. National Survey on Drug Use and Health,
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47 4.7% of responders (>12 million people) indicated they had used methamphetamine at least once in their life,
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49 with 440,000 people indicating use within the last month, an increase on the 2006 survey.14 The World Health
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51 Organization estimates that 35 million people globally regularly use methamphetamine.16 These figures make
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53 methamphetamine and amphetamine abuse the most commonly used illicit drug after cannabis.1, 17
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55 Methamphetamine approved for clinical use is a powder that is pressed into tablets. Recrystallization of
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57 methamphetamine hydrochloride yields colorless crystals which vaporize without change to their structure and
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thus can be inhaled.18, 19 The crystal structure of this purified form of methamphetamine lends itself to the street
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2 names ‘crystal meth’, ‘glass’ and ‘ice’, with other common names including ‘Tina’, ‘Christine’, ‘yaba’ and ‘crazy
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medicine’.19 In this review, we will highlight the significance of methamphetamine abuse in neuroscience,
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7 examining the synthesis, metabolism and pharmacology of this commonly used illicit street drug.
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10 CHEMICAL PROPERTIES AND SYNTHESIS
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12 Methamphetamine, 1 (CAS no. 537-46-2, IUPAC name (2S)-N-methyl-1-phenylpropan-2-amine) is a
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14 monoamine possessing one chiral center, most often encountered on the street as the racemate. However, the
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16 (S)-(+)-enantiomer is the more active stimulant (the eutomer) and illegal street drug, while the (R)-(-)-
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18 enantiomer is a legal decongestant found in several over-the-counter products.4 The molecular weight of (S)-
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20 (+)-methamphetamine is 149.24 and it possesses a CLogP of 2.1. It has a pKa of 9.87 and a topological polar
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surface area of 12 Å2. It is a white crystalline powder in the hydrochloride salt form, recrystallization of
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methamphetamine hydrochloride yields colorless crystals, hence the name ‘crystal meth’. The molecule has
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27 one hydrogen bond donor and one hydrogen bond acceptor (the secondary amine acting in both roles).
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29 The three most commonly encountered synthetic routes in the U.S. in 1989 used either (-)-ephedrine
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31 (2), (+)-pseudoephedrine (3) or P2P (4) as starting material.20 The chemistry has not changed to this date.
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33 These synthetic routes include the palladium catalyzed reduction of the chlorine derivative of 2, produced by
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35 reacting 2 with SOCl2, PCl5, POCl3 or PCl3,21 to methamphetamine (1) and the hydroiodic acid and red
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37 phosphorous reduction of 2 to 1. Numerous other reductive methods are known to have been employed,
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39 including Nagai, Moscow, Rosenmund, Hypo and Birch reductions, due to detection of impurities in seized
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41 products (Scheme 1).22, 23
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Scheme 1. Synthesis of methamphetamine by reduction of ephedrine or pseudoephedrine.
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57 (+)-Pseudoephedrine, a common ingredient in over-the-counter decongestants, is commonly used as a
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59 replacement for 2.24 A modified Birch reduction beginning with 3, obtained from over the counter
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decongestants, known as the ‘shake and bake’ method has become a popular synthetic route to obtain 1.25 As
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2 such, congress passed the Combat Methamphetamine Epidemic Act in 2005 imposing restrictions on the
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amount of products containing (+)-pseudoephedrine an individual can purchase in one day. A number of states
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7 in the U.S. have made 3 a prescription-only medication. Due to these restrictions, the use of 4 as the starting
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9 material is common. The reductive amination of 4 with methylamine, proceeding via the (E)-N-methyl-1-
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11 phenylpropan-2-imine (5) intermediate, using aluminum foil and anhydrous ammonia as a source of hydrogen
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13 has been known since the 1990’s (Scheme 2).
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22 Scheme 2. Synthesis of racemic methamphetamine from phenyl-2-propanone precursor.
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26 The other major route to access methamphetamine from 4, the Leuckart method, proceeds by the
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28 intermediate amide (6) (Scheme 3).23 The routes employing 4 as starting material, form racemic 1, while use of
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30 2 or 3 provide access to the enantiomerically pure (S)-(+)-methamphetamine that provides greater potency and
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hence greater stimulant effect.
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43 Scheme 3. Synthesis of racemic methamphetamine by the Leuckart method.
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47 PHARMACOKINETICS AND METABOLISM
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49 Intranasal delivery or inhalation of methamphetamine results in good absorption with bioavailabilities of
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51 79% and 67% in humans respectively.26 Oral consumption results in similar bioavailability of 67%.27
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53 Intramuscular and intravenous administration of 1 in pigeons reaches 100% bioavailability by both routes.28
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55 Peak plasma level by intranasal delivery is obtained after four hours in humans.29 Distribution to most organs
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occurs with high accumulation in the liver (23%) and lungs (22%), with only intermediate accumulation in the
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Racemic compound 1 in humans is metabolized primarily by CYP2D6 resulting in aromatic
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7 hydroxylation and N-demethylation to provide two major metabolites; para-hydroxymethamphetamine (pOH-
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9 MA) and amphetamine (AMP). Amphetamine undergoes further metabolic changes resulting in the production
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11 of para-hydroxyamphetamine (p-OH-AMP), 4 (phenylacetone), N-hydroxyamphetamine and norephedrine
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56 Figure 1. Metabolic pathway of methamphetamine in humans.
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Methamphetamine has an elimination half-life of between 8-13 hours with its effects typically lasting for
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2 a similar time.32 Approximately 43% of methamphetamine is excreted in the urine unchanged while 4-7% is
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excreted as amphetamine.33-35 High urine acidity is associated with higher methamphetamine levels.36
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7 Stereoselectivity has been observed in the metabolism of methamphetamine with the pOH-MA
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9 metabolite least affected by stereochemistry of the administered compound. The area under the plasma
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11 concentration-time curve from time zero to infinity (AUC0-∞) was found to be 1996.5 ng/h/mL for the S-(+)-1
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13 enantiomer with a higher value of 2367 ng/h/mL for the R-(-)-1 enantiomer at equal 0.5 mg/kg dose. (Table 1).
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15 A slightly lower total clearance (CL) value for R-(-)-1 was observed compared to S-(+)-1 but was within the
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17 margin of error while renal clearance (CLR) was identical. Interestingly, the percentage of amphetamine and its
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19 para-hydroxy metabolite recovered in the urine seemed to be stereospecific with 6.4% of AMP and 11.5% of
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21 pOH-AMP recovered from i.v. delivery of S-(+)-1 compared with 2.1% of AMP and 7.1% of pOH-AMP
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recovered from i.v. delivery of R-(-)-1 (Table 1). Thus suggesting pOH-MA, the metabolite least affected by
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26 stereochemistry of the parent compound, as a better biomarker for detection of methamphetamine abuse.31
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30 Table 1. In vivo pharmacokinetics of methamphetamine enantiomers in i.v. methamphetamine users.
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32 Property S-(+)-1 R-(-)-1
33 0.5 mg/kg 0.5 mg/kg
34 AUC0-∞ (ng/h/mL) 1996.5 ± 373.1 2367.2 ± 522.3
35 CL (L/h/kg) 0.257 ± 0.038 0.221 ± 0.048
36 CLR (L/h/kg) 0.113 ± 0.034 0.118 ± 0.042
37 1 % recovered in urine 43.2 ± 14.8 49.1 ± 12.8
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pOH-AMP % recovered in urine 11.5 ± 6.0 7.1 ± 4.4
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AMP % recovered in urine 6.4 ± 2.3 2.1 ± 0.8
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pOH-MA % recovered in urine 0.34 ± 0.16 0.27 ± 0.22
42 Adapted from reference.31
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47 PHARMACOLOGY
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49 Methamphetamine acts as a psychostimulant drug that has immediate behavioral effects that include
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51 feelings of alertness, increased energy, well-being and euphoria which are both cardiovascular and centrally
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53 mediated. The cardiovascular effects of methamphetamine are mostly explained by the release of
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55 norepinephrine from sympathetic nerve endings.37 The CNS effects of methamphetamine are mainly through
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the monoamine neurotransmitter system (dopamine, serotonin, and norepinephrine). Methamphetamine
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release of catecholamines is reported to be through a non-exocytotic mechanism.6 This non-exocytotic

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2 mechanism is proposed to occur predominantly through two mechanisms; redistribution of catecholamines
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from synaptic vesicles to the cytosol and activation of putative reverse transport mechanisms of plasma
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7 membrane uptake carriers. Two ideas have been proposed to support the premise that methamphetamine
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9 redistributes vesicular catecholamines to the cytosol, 1) a weak base hypothesis and 2) vesicular monoamine
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11 transporter (VMAT) substrate actions.38
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13 Methamphetamine is capable of accepting protons acting as a weak base with a pKA of 9.87. The
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15 strong acidic pH of secretory vesicles provides the energy to concentrate neurotransmitters, and
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17 sympathomimetics, against a concentration gradient. Catecholamines have been shown to reach levels of 10
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19 µM within chromaffin vesicles.39 The hypothesis is that vesicular monoamines (amphetamine and
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21 methamphetamine) cause a vesicular pH gradient collapse and loss of vesicular neurotransmitter into the
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cytosol. VMAT also serves as a principle target for methamphetamine. Specifically, methamphetamine
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26 interacts with VMAT2 as a competitive antagonist and prevents the ability of cells to utilize VMAT for vesicular
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28 concentration.40, 41 This antagonist activity has profound effects on dopamine distribution in the cell creating, in
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30 some cases, a neurotoxic increase in intracellular dopamine. With this large cytoplasmic accumulation of
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32 neurotransmitter, methamphetamine has also been postulated to activate a reverse membrane transport
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34 mechanism to transport accumulated monoamines (dopamine, serotonin, or norepinephrine) to the
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36 extracellular space.38 Additional mechanisms by which methamphetamine is reported to increase monoamine
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38 levels include both increasing dopamine synthesis through tyrosine hydroxylase42 and inhibition of monoamine
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40 oxidase, and the degradation of dopamine.43 Overall, the multimodal effects of methamphetamine on synaptic
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dopamine accumulation is believed to play a key role in the intense transition from “drug-liking” to “drug-
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craving” upon methamphetamine use, and dopamine is involved in this “pathological learning” process.44
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49 ADVERSE EFFECTS
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51 The primary adverse effects of methamphetamine abuse are, perhaps not surprisingly,
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53 neuropsychiatric.45 Acute use of methamphetamine in high doses can produce symptoms reminiscent of
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55 psychiatric disorders such as anxiety, paranoia, hallucinations, delirium and related mood disorders due to
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57 increased levels of neurotransmitter release in the brain.46 Such symptoms are more pronounced in long-term
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intravenous users of methamphetamine.47, 48

A number of studies report conflicting data as to the effects of
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2 acute methamphetamine use on cognition. While some show an improvement in cognitive performance in both
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non-drug using volunteers49 and methamphetamine-dependent populations,50 yet others show cognitive
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7 deficits.51
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9 Chronic use of methamphetamine can induce myocardial infarction,52 increase the risk of stroke,53, 54 or
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11 acute aortic dissection and aneurysms,55 and result in pulmonary hypertension, possibly related to the large
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13 accumulation of methamphetamine in the lungs.56 Other adverse effects upon chronic use, include the mental
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15 health consequences previously discussed and rapid tooth decay, a stereotypical condition of meth abusers
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17 colloquially termed ‘meth mouth’.57-59 Chronic users often experience psychotic disorders including both
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19 positive and negative symptoms,60 wherein incidence is higher in intravenous users.61
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21 As a lipophilic drug that can cross the placenta, methamphetamine use in pregnant women has been
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documented to lead to growth restriction and lower the birth weight of infants carried to term.62, 63 A number of
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26 instances have been reported where methamphetamine abuse by the mother was correlated to an increased
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28 risk of stillbirth.64 Cessation of methamphetamine use at any time during pregnancy has been shown to
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30 improve birth outcomes.65 Studies in prenatal rat pups exposed to methamphetamine show cognitive and
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32 learning deficits.66-68 Placental insufficiency and abruption has been reported that resulted in maternal death.64
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34 Unlike many drugs of abuse, withdrawal symptoms from methamphetamine dependence are relatively
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36 mild. Such symptoms include dysphoria, irritability, anxiety, lack of concentration, depression, fatigue and
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However, these are relatively rare, with increases in sleep and appetite the major withdrawal
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40 symptoms. The neuropsychiatric symptoms of methamphetamine abuse were reported to be reduced by the
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first week of abstinence, with the sleep and appetite symptoms continuing through weeks two and three post
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cessation of use.70
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49 HISTORY AND IMPORTANCE IN NEUROSCIENCE
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51 It is apparent that the street drug forms of methamphetamine have high abuse potential and profound
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53 rewarding effects through long term modulation of dopamine release. The molecule was first synthesized from
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55 ephedrine in 1893 by a Japanese scientist and later in 1919, Akira Ogata synthesized crystallized
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57 methamphetamine by reducing ephedrine using red phosphorous and iodine, providing the basis for drug
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production on a larger scale.71 Crystallized methamphetamine HCl, “crystal meth” or “ice” can be conveniently
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2 vaporized and used for recreational purposes. In 1971, methamphetamine use was restricted by US law,
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although, one must appreciate that oral formulations continue to have a secondary therapeutic utility in the
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7 U.S., mostly for attention deficit disorder with hyperactivity and exogenous obesity.
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9 A major contributor to the high abuse potential for methamphetamine is the fact that a large amount of
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11 the drug becomes CNS available within minutes of inhalation, due to its high lipophilicity.30, 72
As described
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13 above, acute exposures can induce a system imbalance with regard to release and reuptake of dopamine,
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15 norepinephrine and epinephrine, resulting in intense feelings of euphoria, excitation and alertness, yet the
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17 chronic effects of high doses have been shown to damage brain dopamine neurons in preclinical studies.73
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19 Data from animal studies show that a high dose of methamphetamine causes damage to striatal dopamine
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21 nerve terminals.74 Whether this causes a localized pattern of brain abnormality in methamphetamine users is
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still a matter of debate. Some epidemiologic studies suggest that an increased relative risk exists for the
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26 development of Parkinson’s disease in patients hospitalized for methamphetamine use disorder.75 Recent
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28 studies have also suggested that high dose methamphetamine use can also disrupt the blood-brain barrier
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30 (BBB)76, 77 and contribute to vasogenic brain edema; causing water, protein and ionic movement into the brain
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32 extracellular fluid. These BBB specific effects of methamphetamine have been postulated to be by direct
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34 activation of metalloproteinases (MMP-2 and MMP-9) and opening of tight junctions between endothelial cells
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36 of the BBB and/or the increased production of reactive oxygen species. This disruption in the physical and
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38 dynamic separation between the blood and central nervous system is a hallmark feature of a number of
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40 neurodegenerative diseases and could be another contributor to both the acute and chronic methamphetamine
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induced brain abnormalities. Future areas of research should include both animal and clinical studies to
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determine the neuroanatomical regions of brain damage from methamphetamine abuse and the extent of
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47 recovery from the brain altering effects of chronic, high dose methamphetamine abuse. Additionally, future
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49 treatments are needed to offset the various stages of the addiction cycle that are pathologically altered by
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51 methamphetamine abuse including the quick movements from “binge and intoxication” to “withdrawal and
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53 negative affect” to “preoccupation and anticipation”.78
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55 In summary, methamphetamine is the most commonly used drug of abuse after cannabis marking its
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57 place as a DARK classic in chemical neuroscience. Despite decades of use in humans as both a prescription
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and illicit drug, the full neuropharmacological effects of methamphetamine are still poorly understood. The
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2 psychiatric side effects of methamphetamine abuse, due to perturbation of neurotransmitter systems, provide
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further insights and yet ask more questions of the monoamine hypothesis of depression, the prevalence of
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7 hallucinations in schizophrenia and Parkinson’s disease (PD) and the link between PD and anxiety, among
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9 others. Studies on the neurochemistry of methamphetamine users may yield insights into these and other
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17 AUTHOR INFORMATION
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19 Corresponding Author
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21 Email: thomas.abbruscato@ttuhsc.edu, paul.trippier@ttuhsc.edu
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ORCID
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26 Paul C. Trippier: 0000-0002-4947-5782
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30 CONFLICT OF INTEREST
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32 The authors declare no conflicts of interest.
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36 AUTHOR CONTRIBUTIONS
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38 Both authors contributed equally to this manuscript.
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FUNDING SOURCES
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We thank Texas Tech University Health Sciences Center and the numerous organizations that have provided
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47 funding to our labs for studies in chemical neuroscience.
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