Stimulants belong to a diverse group of psychoactive drugs whose function exerts a constant contribution to hyperactivity and impulse control. From caffeine and nicotine to cocaine and amphetamines, each vary widely in how amply they accelerate body functions, how they are used, and their legal status. Illegal stimulant derivatives including amphetamines, arylcyclohexylamines, cathinones, cocaine/tropanes, phenethylamines, and piperazines are among the most widely abused across the US and Europe. However, the popularity of each substance use, particularly in party culture settings, is frequently changing. Each has a storied beginning that ultimately led to epidemic abuse in some cases and inevitable classification as controlled substances. Starting with amphetamine, one of the most commonly abused drugs worldwide (second only to Cannabis products), this article series aims to provide an overview of the history, chemistry, pharmacology, and metabolism of the major classes of stimulants.

Series Part 1: Amphetamines

History

Amphetamine was first synthesized in 1887 by Romanian chemist Lazăr Edeleanu who was working on a treatment for asthma at the University of Berlin. As it was a methyl analog of the mammalian neurotransmitter phenethylamine, he named it phenylisopropylamine, but it sat uncharacterized until 1927 when University of California, Los Angeles researcher Gordon Alles resynthesized it and demonstrated its therapeutic value as a CNS and respiratory stimulant. It was commercialized as a powerful bronchodilator inhalant called Benzedrine and placed on the legal drug market to treat colds and asthma. It was also suggested to be useful in treating obesity, narcolepsy, hangovers from alcohol, depression, vomiting associated with pregnancy, and paradoxically attention-deficit/hyperactivity disorders (ADHD). Recreational Benzedrine use was popular during prohibition as a readily obtainable high. Benzedrine and Dexedrine (d-amphetamine) use by soldiers was encouraged during World War II to enhance endurance and alertness. Shire Pharmaceuticals rebranded the use of amphetamines in 1996 by introducing Adderall as a “patented blend” of four different types of racemic amphetamine salts to compete with other pharmaceuticals on the market targeted to treat ADHD and narcolepsy. Though the 3:1 enantiomeric mixture of d-amphetamine:l-amphetamine salts in Adderall was designed to increase focus and limit the initial euphoric rush, the mechanism of action also stimulates the brain’s pleasure and reward centers, rendering it highly addictive. Nonetheless, Adderall continues to be popular, especially in academic and military settings.

Methamphetamine, which was first synthesized in Japan in 1893 by Nagayoshi Nagai from the precursor chemical ephedrine, was also used by soldiers during the war as energy pills to ward off fatigue. After the war, surplus stores of amphetamines were made available over the counter in Japan and parts of Europe and abuse soon reached epidemic proportions. At first, the US government did not recognize the epidemic threat since a prescription was needed to access the drugs. US doctors continued to prescribe amphetamines for therapeutic purposes. Oral and injectable methamphetamine derivatives were also introduced and used in the treatment of heroin addiction. Abuse of methamphetamine increased by the 1960s when its rapid onset of euphoric effects with intravenous use was realized. Culmination of such abuse was hoped to be accomplished with the US restriction of amphetamine as a Schedule II controlled substance in 1971. Despite these efforts, production of methamphetamine in clandestine labs in the 1980s led to a new rise in abuse. To help counter this resurgence, the DEA regulated the precursors commonly used in the illicit production: ephedrine and pseudoephedrine. While these efforts led to substantial temporary reductions in methamphetamine-related problems, it inadvertently opened the market to foreign producers who now supply much of the US market.

MDMA (also known as Molly, Ecstasy, or X) was developed by the German pharmaceutical company Merck in 1912. Originally known as Methylsafrylaminc, it was intended as a parent compound to synthesize medications that control bleeding. Because it was not a key substrate, only a precursor, Merck’s scientists did not perform basic pharmacological tests with MDMA for economic reasons until the 1950s. Despite never undergoing formal clinical trials or receiving approval from the US Food and Drug Administration (FDA) for use in humans, MDMA gained a small following among psychiatrists in the late 1970s and early 1980s as an adjunct to psychotherapy. At the same time, MDMA started becoming more widely available on the street, often taken for the feelings of well-being, energy, and distortions in time and sensory perceptions that it produces. In 1985, the DEA declared an emergency ban on MDMA, placing it on the list of Schedule I drugs, defined as substances with no currently accepted medical use and a high potential for abuse. Despite this ban, MDMA has remained on the illegal drug market. Recent confiscated tablets of ecstasy have been found to be laced with dangerous combinations of methamphetamine, ketamine, caffeine, ephedrine, dextromethorphan, heroin, phencyclidine, and/or cocaine. Methylone and ethylone, synthetic stimulants commonly found in bath salts, have been identified in substances being branded as Molly. Such contaminations pose serious health risks, especially when stimulants are combined with opioids. Data from as recent as 2017 reveal increases in cocaine- and methamphetamine-related overdoses when opioid-naïve stimulant users are either knowingly or unknowingly exposed to fentanyls.

Chemistry

Amphetamine is a synthetic derivative of phenylethylamine (Figure 1), a naturally occurring substance found in chocolate, cheeses, and some wines, and looks similar in structure to dopamine. When consumed as a food stuff, phenylethylamine has little or no amphetamine-like effect because it is rapidly degraded by monoamine oxidases. However, the addition of a methyl group attached to the α-carbon of the phenylethylamine side chain protects amphetamine from degradation by monoamine oxidases, which enables the effects of amphetamine to persist. Methamphetamine differs from amphetamine by the addition of a methyl group at the basic nitrogen of the side chain (Figure 1). This addition creates biological actions that are even more potent than amphetamine. MDMA is a formed by the fusion of a methylenedioxy group to the C-3 and C-4 of the phenyl ring (Figure 1).

Figure 1. Amphetamine derivatives.

Amphetamine has a chiral center at the α-carbon, wherein its methyl group can be attached to the side chain in a left- or right-handed manner (Figure 2). The right-handed dextro isomer (aka d-amphetamine, (+)-S-amphetamine, dexamphetamine, Dexedrine) produces less of an initial euphoric norepinephrine rush compared to the left-handed levo isomer but increases the supply of dopamine and norepinephrine at synaptic clefts for many hours. The dextro isomer (d-methamphetamine) of methamphetamine is the more potent isomer compared to its levo counterpart and is the one most often distributed illicitly. While variations of the amphetamine scaffold have been developed by pharmaceutical companies for treatment of ADHD, appetite suppression, or to slow the progression of Parkinson’s disease (e.g., Adderall, phentermine, and selegiline), designer drug chemists attempting to skirt DEA regulations have also made modifications to the basic amphetamine structure. Some common substitutions are noted in Figure 2 below.

Figure 2. Common modifications of the amphetamine core.

The compounds created by these modifications span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens. Cues on where to modify the phenyl ring and/or the isopropyl amine backbone have been taken from other stimulant classes whose effect is wished to elicit. For example, trimethoxyamphetamines are modeled after the naturally occurring hallucinogenic phenethylamine mescaline. Cathinone, which will be covered in a future edition of this stimulant series, differs from many other amphetamines only by the addition of a carbonyl group in the β-position.

Pharmacology

Amphetamines are indirect monoamine agonists that produce the release of norepinephrine, dopamine, and serotonin in both the CNS and periphery. Because they appear similar to monoamines, amphetamines can enter presynaptic terminals of neurons via reuptake transporters or passive diffusion and force the release monoamine neurotransmitters from their storage vesicles (Figure 3). Reuptake transporters must work in reverse to facilitate the efflux of norepinephrine, dopamine, and serotonin into the synaptic cleft. Thereby, their reuptake function is inhibited.

Figure 3. The mechanism of action of amphetamine in a dopamine neuron. Amphetamines pass through dopamine transporters (or the neural membrane) and, when reach synaptic vesicles, force the dopamine molecules out of their storage vesicles and expel them into the synaptic cleft by making the dopamine transporters work in reverse, therefore inhibiting their reuptake function.

At high concentrations, amphetamines may also act as a direct agonist of central serotonin receptors, which are associated with a sense of euphoria, and may inhibit the activity of monoamine oxidases, which prolongs the availability of these neurotransmitters at synaptic clefts. Amphetamines may also stimulate dopaminergic neurons by removing the inhibiting effect of metabotropic glutamate receptors. By releasing this normal brake, amphetamines can make the dopaminergic neurons more readily excitable. Additionally, they may increase the activity and expression of the dopamine-synthesizing enzyme tyrosine hydroxylase. Dopamine released in the nucleus accumbens and other terminal areas also activates the behavior-reinforcing mesolimbic dopaminergic reward system, which leads to addiction. Amphetamines also augment the concentration of noradrenaline in the prefrontal cortex, which provides executive control over behaviors like reward seeking.

Metabolism

Amphetamine undergoes oxidation by the action of the cytochrome P450 enzyme 2D6 in humans, although CYP1A2, CYP3A4, and CYP2B6 may also influence the reaction. The main metabolic pathways occur through (1) oxidative deamination, N-oxidation, and conjugation of the nitrogen to form hippuric acid and benzoic acid, or (2) aromatic hydroxylation to form 4-hydroxyamphetamine (which is known to be a potent hallucinogen) (Figure 4). A significant part (~26%) of the parent compound remains unchanged. A minor metabolic pathway occurs through aliphatic hydroxylation, giving rise to norephedrine, which can be further oxidized to 4-hydroxynorephedrine (Figure 4). If the reactions give rise to a phenol group, this is further conjugated with sulfate or glucuronic acid.

Figure 4. The metabolic pathway of amphetamine.

N-alkylated or N,N-dialkylated amphetamine derivatives, including those with legitimate therapeutic value, are metabolically (bis)dealkylated to amphetamine or methamphetamine, making it quite difficult to differentiate from illicit amphetamine use during forensic toxicological evaluation. The corresponding hydroxy metabolites of these derivatives, which are specific to the taken drug, can be detected for a brief time. However, in late stages of excretion these hydroxy metabolites may not always be detectable in urine. Chiral analysis of the amphetamine or methamphetamine metabolically formed from amphetamine-type medications may possibly help differentiate from a drug of abuse, since some medications are prescribed as pure enantiomers and racemization does not occur during metabolism. These cases are most promising for pure levo isomers such as selegiline, since abuse of (+)-S-amphetamine is unlikely.

Available from Cayman

Cayman offers several analytical standards for the identification of amphetamines. If you are having trouble identifying or finding a compound of interest, please contact our technical support department. Cayman can also provide assistance in the identification of unknown compounds and provides other tools on our Forensic Science Products page such as our Spectral Library, GC-MS Search Tool, and GC-MS Interpretation Guide to help chemists identify novel analogs.

Other Articles in this Series

Cathinones

Future Articles in the Series

Arylcyclohexylamines

Cocaine & Tropanes

Phenethylamines

Piperazines

Suggested Reading

Bernschneider-Reif, S., Oxler, F., and Freudenmann, R.W. The origin of MDMA ("ecstasy")--separating the facts from the myth. Pharmazie. 61(11), 966-972 (2006).

Heal, D.J., Smith, S.L., Gosden, J., et al. Amphetamine, past and present – a pharmacological and clinical perspective. J. Psychopharmacol.27(6), 479–496 (2013).

Kraemer, T. and Maurer, H.H. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Ther. Drug Monit.24(2), 277-289 (2002).

LaRue, L., Twillman, R.K., Dawson, E., et al. Rate of Fentanyl Positivity Among Urine Drug Test Results Positive for Cocaine or Methamphetamine. JAMA Netw Open. 2(4), e192851 (2019).

Problem amphetamine and methamphetamine use in Europe. European Monitoring Centre for Drugs and Drug Addiction, Lisbon, November 2010.

Rasmussen, N. America’s first amphetamine epidemic 1929–1971. A quantitative and qualitative retrospective with implications for the present. Am. J. Public Health. 98(6), 974-985 (2008).

de la Torre, R., Farré, M., Navarro, M. et al. Clinical pharmacokinetics of amfetamine and related substances: monitoring in conventional and non-conventional matrices. Clin. Pharmacokinet.43(3), 157-185 (2004).

Uddin, M.S., Sufian, M.A., Kabir, M.T., et al. Amphetamines: Potent recreational drug of abuse. J. Addict. Res.Ther. 8:330 (2017)