Review Cite This: ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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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
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INTRODUCTION Methamphetamine (1), a schedule II drug in the United States, is an illicit recreational drug due to the strong central nervous system (CNS) stimulant properties of the (S)-(+) or Dstereoisomer form. The abuse of methamphetamine represents a significant public health problem throughout much of the world.1,2 The (R)-(−) or L-isomer, however, is readily available in several over-the-counter decongestant products.3,4 (S)(+)-Methamphetamine acts to increase concentrations of the natural neurotransmitters dopamine, serotonin, and norepinephrine in the brain by increasing their release from storage vesicles5 and interfering with transporter action.6 This results in stimulation of motivation, movement, pleasure, and reward centers.7 The release of dopamine is often rapid and leads to the sudden “rush” that many users experience upon inhaling vaporized methamphetamine.8 Oral administration of methamphetamine is approved by the United States Food and Drug Administration (FDA) as a prescription-only medication for the 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 these conditions in the 1950s and 1960s, with the number of prescriptions peaking in 1967 at 31 million.11 The number of prescriptions fell sharply after methamphetamine was designated a schedule II drug in the Comprehensive Drug Abuse Prevention and Control Act of 1970.12 This lead to the growth of illicit manufacture of methamphetamine based on phenyl-2propanone (P2P), ephedrine, and pseudoephedrine starting materials. The P2P precursor was rescheduled as a schedule II drug in 1980 with pseudoephedrine being restricted for public purchase in 2005.13,14 The United States National Survey on Drug Use and Health conducted in 2006 estimated that 5.8% of the population had used methamphetamine at some point in their life with 259 000 recent new users.15 These figures appear to have remained largely consistent; in the 2012 United States National Survey © XXXX American Chemical Society
on Drug Use and Health, 4.7% of responders (>12 million people) indicated they had used methamphetamine at least once in their life with 440 000 people indicating use within the last month, an increase from the 2006 survey.14 The World Health Organization estimates that 35 million people globally regularly use methamphetamine. 16 These figures make methamphetamine and amphetamine abuse the most commonly used illicit drug after cannabis.1,17 Methamphetamine approved for clinical use is a powder that is pressed into tablets. Recrystallization of methamphetamine hydrochloride yields colorless crystals which vaporize without change to their structure and thus can be inhaled.18,19 The crystal structure of this purified form of methamphetamine lends itself to the street names “crystal meth”, “glass”, and “ice”, with other common names including “Tina”, “Christine”, “yaba”, and “crazy medicine”.19 In this review, we highlight the significance of methamphetamine abuse in neuroscience, examining the synthesis, metabolism, and pharmacology of this commonly used illicit street drug.
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CHEMICAL PROPERTIES AND SYNTHESIS Methamphetamine, 1 (CAS no. 537-46-2, IUPAC name (2S)N-methyl-1-phenylpropan-2-amine) is a monoamine possessing one chiral center, most often encountered on the street as the racemate. However, the (S)-(+)-enantiomer is the more active stimulant (the eutomer) and illegal street drug, while the (R)(−)-enantiomer is a legal decongestant found in several overthe-counter products.4 The molecular weight of (S)-(+)-methamphetamine is 149.24, and it possesses a CLogP of 2.1. It has a pKa of 9.87 and a topological polar surface area of 12 Å2. It is a white crystalline powder in the hydrochloride salt form; Special Issue: DARK Classics in Chemical Neuroscience Received: March 15, 2018 Accepted: March 30, 2018 Published: March 30, 2018 A
DOI: 10.1021/acschemneuro.8b00123 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
enantiomerically pure (S)-(+)-methamphetamine that provides greater potency and hence greater stimulant effect.
recrystallization of methamphetamine hydrochloride yields colorless crystals, hence the name crystal meth. The molecule has one hydrogen bond donor and one hydrogen bond acceptor (the secondary amine acting in both roles). The three most commonly encountered synthetic routes in the United States in 1989 used either (−)-ephedrine (2), (+)-pseudoephedrine (3), or P2P (4) as starting material.20 The chemistry has not changed to this date. These synthetic routes include the palladium catalyzed reduction of the chlorine derivative of 2, produced by reacting 2 with SOCl2, PCl5, POCl3, or PCl321 to methamphetamine (1) and the hydroiodic acid and red phosphorus reduction of 2 to 1. Numerous other reductive methods are known to have been employed, including Nagai, Moscow, Rosenmund, Hypo, and Birch reductions due to detection of impurities in seized products (Scheme 1).22,23
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PHARMACOKINETICS AND METABOLISM Intranasal delivery or inhalation of methamphetamine results in good absorption with bioavailabilities of 79 and 67% in humans, respectively.26 Oral consumption results in similar bioavailability of 67%.27 Intramuscular and intravenous (i.v.) administration of 1 in pigeons reaches 100% bioavailability by both routes.28 Peak plasma level by intranasal delivery is obtained after 4 h in humans.29 Distribution to most organs occurs with high accumulation in the liver (23%) and lungs (22%), with only intermediate accumulation in the brain (10%).30 Racemic compound 1 in humans is metabolized primarily by CYP2D6, resulting in aromatic hydroxylation and Ndemethylation to provide two major metabolites: parahydroxymethamphetamine (pOH-MA) and amphetamine (AMP). Amphetamine undergoes further metabolic changes, resulting in the production of para-hydroxyamphetamine (pOH-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 High urine acidity is associated with higher methamphetamine levels.36 Stereoselectivity has been observed in the metabolism of methamphetamine with the pOH-MA metabolite least affected by stereochemistry of the administered compound. The area under the plasma concentration−time curve from time zero to infinity (AUC0−∞) was found to be 1996.5 ng/h/mL for the S(+)-1 enantiomer with a higher value of 2367 ng/h/mL for the R-(−)-1 enantiomer at equal 0.5 mg/kg dose (Table 1). A slightly lower total clearance (CL) value for R-(−)-1 was observed compared to S-(+)-1 but was within the margin of error, while renal clearance (CLR) was identical. Interestingly, the percentage of amphetamine and its para-hydroxy metabolite recovered in the urine seemed to be stereospecific 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 pOH-AMP recovered from i.v. delivery of R-(−)-1 (Table 1). 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
Scheme 1. Synthesis of Methamphetamine by Reduction of Ephedrine or Pseudoephedrine
(+)-Pseudoephedrine, a common ingredient in over-thecounter decongestants, is commonly used as a replacement for 2.24 A modified Birch reduction beginning with 3, obtained from over the counter decongestants, known as the “shake and bake” method has become a popular synthetic route to obtain 1.25 As such, congress passed the Combat Methamphetamine Epidemic Act in 2005, imposing restrictions on the amount of products containing (+)-pseudoephedrine an individual can purchase in one day. A number of states in the United States have made 3 a prescription-only medication. Due to these restrictions, the use of 4 as the starting material is common. The reductive amination of 4 with methylamine, proceeding via the (E)-N-methyl-1-phenylpropan-2-imine (5) intermediate using aluminum foil and anhydrous ammonia as a source of hydrogen has been known since the 1990s (Scheme 2). Scheme 2. Synthesis of Racemic Methamphetamine from Phenyl-2-Propanone Precursor
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PHARMACOLOGY Methamphetamine acts as a psychostimulant drug that has immediate behavioral effects that include feelings of alertness, increased energy, well-being, and euphoria, which are both cardiovascular and centrally mediated. The cardiovascular effects of methamphetamine are mostly explained by the release of norepinephrine from sympathetic nerve endings.37 The CNS effects of methamphetamine are mainly through the monoamine neurotransmitter system (dopamine, serotonin, and norepinephrine). Methamphetamine release of catecholamines is reported to be through a nonexocytotic mechanism.6 This nonexocytotic mechanism is proposed to occur predominantly through two mechanisms: redistribution of catecholamines from synaptic vesicles to the cytosol and activation of putative reverse transport mechanisms of plasma membrane
The other major route to access methamphetamine from 4, the Leuckart method, proceeds by the intermediate amide (6) (Scheme 3).23 The routes employing 4 as starting material, form racemic 1, while use of 2 or 3 provide access to the Scheme 3. Synthesis of Racemic Methamphetamine by the Leuckart Method
B
DOI: 10.1021/acschemneuro.8b00123 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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Figure 1. Metabolic pathway of methamphetamine in humans.
neurotoxic increase in intracellular dopamine. With this large cytoplasmic accumulation of neurotransmitter, methamphetamine has also been postulated to activate a reverse membrane transport mechanism to transport accumulated monoamines (dopamine, serotonin, or norepinephrine) to the extracellular space.38 Additional mechanisms by which methamphetamine is reported to increase monoamine levels include both increasing dopamine synthesis through tyrosine hydroxylase42 and inhibition of monoamine oxidase and the degradation of dopamine.43 Overall, the multimodal effects of methamphetamine on synaptic dopamine accumulation is believed to play a key role in the intense transition from drug-liking to drugcraving upon methamphetamine use, and dopamine is involved in this pathological learning process.44
Table 1. In Vivo Pharmacokinetics of Methamphetamine Enantiomers in i.v. Methamphetamine Usersa property AUC0−∞ (ng/h/mL) CL (L/h/kg) CLR (L/h/kg) 1 % recovered in urine pOH-AMP % recovered in urine AMP % recovered in urine pOH-MA % recovered in urine a
S-(+)-1 0.5 mg/kg R-(−)-1 0.5 mg/kg 1996.5 ± 373.1 0.257 ± 0.038 0.113 ± 0.034 43.2 ± 14.8 11.5 ± 6.0 6.4 ± 2.3 0.34 ± 0.16
2367.2 ± 522.3 0.221 ± 0.048 0.118 ± 0.042 49.1 ± 12.8 7.1 ± 4.4 2.1 ± 0.8 0.27 ± 0.22
Adapted from reference 31.
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uptake carriers. Two ideas have been proposed to support the premise that methamphetamine redistributes vesicular catecholamines to the cytosol: (1) a weak base hypothesis and (2) vesicular monoamine transporter (VMAT) substrate actions.38 Methamphetamine is capable of accepting protons acting as a weak base with a pKA of 9.87. The strong acidic pH of secretory vesicles provides the energy to concentrate neurotransmitters and sympathomimetics against a concentration gradient. Catecholamines have been shown to reach levels of 10 μM within chromaffin vesicles.39 The hypothesis is that vesicular monoamines (amphetamine and methamphetamine) cause a vesicular pH gradient collapse and loss of vesicular neurotransmitter into the cytosol. VMAT also serves as a principle target for methamphetamine. Specifically, methamphetamine interacts with VMAT2 as a competitive antagonist and prevents the ability of cells to utilize VMAT for vesicular concentration.40,41 This antagonist activity has profound effects on dopamine distribution in the cell, creating, in some cases, a
ADVERSE EFFECTS The primary adverse effects of methamphetamine abuse are, perhaps not surprisingly, neuropsychiatric.45 Acute use of methamphetamine in high doses can produce symptoms reminiscent of psychiatric disorders such as anxiety, paranoia, hallucinations, delirium, and related mood disorders due to increased levels of neurotransmitter release in the brain.46 Such symptoms are more pronounced in long-term intravenous users of methamphetamine.47,48 A number of studies report conflicting data as to the effects of acute methamphetamine use on cognition. While some show an improvement in cognitive performance in both nondrug using volunteers49 and methamphetamine-dependent populations,50 yet others show cognitive deficits.51 Chronic use of methamphetamine can induce myocardial infarction,52 increase the risk of stroke53,54 or acute aortic C
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ACS Chemical Neuroscience dissection and aneurysms,55 and result in pulmonary hypertension, possibly related to the large accumulation of methamphetamine in the lungs.56 Other adverse effects upon chronic use include the mental health consequences previously discussed and rapid tooth decay, a stereotypical condition of meth abusers colloquially termed “meth mouth”.57−59 Chronic users often experience psychotic disorders including both positive and negative symptoms,60 wherein incidence is higher in intravenous users.61 As a lipophilic drug that can cross the placenta, methamphetamine use in pregnant women has been documented to lead to growth restriction and lower the birth weight of infants carried to term.62,63 A number of instances have been reported where methamphetamine abuse by the mother was correlated to an increased risk of stillbirth.64 Cessation of methamphetamine use at any time during pregnancy has been shown to improve birth outcomes.65 Studies in prenatal rat pups exposed to methamphetamine show cognitive and learning deficits.66−68 Placental insufficiency and abruption has been reported that resulted in maternal death.64 Unlike many drugs of abuse, withdrawal symptoms from methamphetamine dependence are relatively mild. Such symptoms include dysphoria, irritability, anxiety, lack of concentration, depression, fatigue, and paranoia.47,69 However, these are relatively rare, with increases in sleep and appetite the major withdrawal symptoms. The neuropsychiatric symptoms of methamphetamine abuse were reported to be reduced by the first week of abstinence with the sleep and appetite symptoms continuing through weeks two and three post cessation of use.70
use can also disrupt the blood−brain barrier (BBB)76,77 and contribute to vasogenic brain edema, causing water, protein, and ionic movement into the brain extracellular fluid. These BBB specific effects of methamphetamine have been postulated to be by direct activation of metalloproteinases (MMP-2 and MMP-9) and opening of tight junctions between endothelial cells of the BBB and/or the increased production of reactive oxygen species. This disruption in the physical and dynamic separation between the blood and central nervous system is a hallmark feature of a number of neurodegenerative diseases and could be another contributor to both the acute and chronic methamphetamine induced brain abnormalities. Future areas of research should include both animal and clinical studies to determine the neuroanatomical regions of brain damage from methamphetamine abuse and the extent of recovery from the brain altering effects of chronic, high dose methamphetamine abuse. Additionally, future treatments are needed to offset the various stages of the addiction cycle that are pathologically altered by methamphetamine abuse, including the quick movements from binge and intoxication to withdrawal and negative affect to preoccupation and anticipation.78 In summary, methamphetamine is the most commonly used drug of abuse after cannabis, marking its place as a DARK classic in chemical neuroscience. Despite decades of use in humans as both a prescription and illicit drug, the full neuropharmacological effects of methamphetamine are still poorly understood. The psychiatric side effects of methamphetamine abuse, due to perturbation of neurotransmitter systems, provide further insights and yet produce more questions of the monoamine hypothesis of depression, the prevalence of 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.
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HISTORY AND IMPORTANCE IN NEUROSCIENCE It is apparent that the street drug forms of methamphetamine 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 Japanese scientist and later in 1919, Akira Ogata synthesized crystallized methamphetamine by reducing ephedrine using red phosphorus and iodine, providing the basis for drug production on a larger scale.71 Crystallized methamphetamine HCl, crystal meth, or ice, can be conveniently vaporized and used for recreational purposes. In 1971, methamphetamine use was restricted by United States law, although one must appreciate that oral formulations continue to have a secondary therapeutic utility in the United States, mostly for attention deficit disorder with hyperactivity and exogenous obesity. A major contributor to the high abuse potential for methamphetamine is the fact that a large amount of the drug becomes CNS available within minutes of inhalation due to its high lipophilicity.30,72 As described above, acute exposures can 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 chronic effects of high doses have been shown to damage brain dopamine neurons in preclinical studies.73 Data from animal studies show that a high dose of methamphetamine causes damage to striatal dopamine nerve terminals.74 Whether this causes a localized pattern of brain abnormality in methamphetamine users is still a matter of debate. Some epidemiologic studies suggest that an increased relative risk exists for the development of Parkinson’s disease (PD) in patients hospitalized for methamphetamine use disorder.75 Recent studies have also suggested that high dose methamphetamine
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Paul C. Trippier: 0000-0002-4947-5782 Author Contributions
Both authors contributed equally to this manuscript. Funding
We thank Texas Tech University Health Sciences Center and the numerous organizations that have provided funding to our laboratories for studies in chemical neuroscience. Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acschemneuro.8b00123 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
