H: SUBSTANCES OF ABUSE

Amphetamines

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

Amphetamine was first synthesized in 1887 but was essentially lost until the 1920s, when concerns arose regarding the supply of ephedrine for asthma therapy.⁶⁷ The attempt to synthesize ephedrine lead to the rediscovery of dextroamphetamine in the United States and methamphetamine (d-phenylisopropylmethylamine hydrochloride) in Japan. Amphetamine was first marketed by Smith, Kline, and French in 1932 as the nasal decongestant Benzedrine. Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war during World War II. Amphetamine tablets were later available in 1935 for the treatment of narcolepsy and were advocated as anorexiants in 1938.¹⁷

The stimulant and euphoric effects of amphetamine were immediately recognized, with abuse reported as early as 1940.⁷⁴ 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 and early 1970s, various amphetamines such as methylenedioxyamphetamine (MDA), para-methoxyamphetamine (PMA), and para-methoxymethamphetamine (PMMA) were popularized as hallucinogens.^97,127 The Controlled Substance Act of 1970 placed amphetamines in Schedule II to prevent the diversion of pharmaceutical amphetamines for nonmedicinal uses. Abuse of amphetamines subsequently declined.¹³⁶

In the 1980s, use of methylenedioxy derivatives of amphetamine and methamphetamine surfaced and circumvented existing regulations. The best known of these derivatives were 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyethamphetamine (MDEA).⁶ 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 illegally marketed in a large crystalline form termed “ice” by abusers.⁴⁶ Methamphetamine-related deaths in the United States increased through the 1990s, initially at several hundred per year. From 2010 to 2014, deaths involving methamphetamine doubled from 1,388 to 3,728 per year.¹⁷¹ Men who have sex with men in New York City (and perhaps elsewhere) remain a specific population at risk, with a persistently high prevalence of methamphetamine use.⁷² The ease and low cost of methamphetamine synthesis encourage establishment of illegal clandestine laboratories in the United States.⁷² Since the mid-1990s, MDMA has been widely used by college students and teenagers in large gatherings, known as “rave” or “techno” parties, in Europe and the United States.¹³⁴ Methcathinone (a khat-derived substance) and 4-bromo-2,5-methoxyphenylethylamine (2CB) were popular in dance clubs in the Midwestern United States in the 1990s, but use was not widespread.^59,62 Synthetic cathinones are currently sold as “bath salts” or “legal highs” to circumvent existing laws, resulting in serious toxicity and deaths.³¹ Recently, older amphetamines such as PMA and PMMA made a resurgence, with new reports of toxicity and deaths.¹⁰²

PHARMACOLOGY

Amphetamine is the acronym for racemic β-phenylisopropylamine. Amphetamine is representative of a ...