76: Amphetamines

HISTORY AND EPIDEMIOLOGY

Amphetamine is the acronym for racemic β-phenylisopropylamine or α-methylphenylethylamine. Amphetamine is representative of a broader group of compounds with a shared structure known as phenylethylamines, which is a more precise term. Numerous substitutions are possible on the phenylethylamine structure, resulting in a variety of compounds, some with unique properties. For the purposes of this chapter, all phenylethylamines that are not actually amphetamine will be called amphetamines, and the name amphetamine specifically refers to β-phenylisopropylamine.

Amphetamine was first synthesized in 1887, but was essentially lost until the 1920s, when there were concerns about the supply of ephedrine for asthma therapy.⁷¹ The attempt to synthesize ephedrine lead to the rediscovery of dextroamphetamine in the United States and methamphetamine (d-phenylisopropylmethylamine hydrochloride) in Japan.⁷¹ Amphetamine was first marketed by Smith, Kline, and French in 1932 as the nasal decongestant Benzedrine.¹⁵ Amphetamine tablets were later available in 1935 for the treatment of narcolepsy and were advocated as anorectants in 1938.⁷⁶

Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war in World War II. The stimulant and euphoric effects of amphetamine were recognized, with abuse reported as early as 1936.¹³⁷ As a result, Benzedrine inhalers were banned by the US Food and Drug Administration (FDA) in 1959. From 1950 to the 1970s, there were sporadic periods of widespread amphetamine use and abuse in the United States. In the 1960s, various amphetamines such as methylenedioxyamphetamine (MDA), para-methoxyamphetamine (PMA), and para-methoxymethamphetamine (PMMA) were popularized as hallucinogens.³⁴ The Controlled Substance Act of 1970 placed amphetamines in Schedule II to prevent the diversion of pharmaceutical amphetamines for nonmedicinal uses.⁵ Amphetamine abuse subsequently declined.⁹³

In the 1980s, use of methylenedioxy derivatives of amphetamine and methamphetamine surfaced and were able to circumvent existing regulations. The best known of these derivatives were 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethamphetamine (MDEA).⁴⁶ Since the late 1980s, a dramatic resurgence of methamphetamine abuse has spread throughout much of the United States. A high purity preparation of methamphetamine hydrochloride was marketed in a large crystalline form termed “ice” by abusers.^7,49 From 1991 to 1994, the number of methamphetamine-related deaths in the United States reported by medical examiners tripled from 151 to 433, with a disproportional distribution from the Los Angeles, San Diego, San Francisco, and Phoenix metropolitan areas. Methamphetamine use is particularly prevalent among men who have sex with men in New York City.⁷⁴ Because of the ease and low cost of methamphetamine synthesis and the local production, methamphetamine is the most common illicit drug produced by clandestine laboratories in the United States.^28,31 Since the mid-1990s, MDMA has become widely used by college students and teenagers in large gatherings, known as “rave” or “techno” parties in England, Australia, and the United States.^135,136 Methcathinone (a khat-derived substance) use in ...