ABSTRACT
Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.
Subject(s)
Central Nervous System Stimulants/chemical synthesis , Hallucinogens/chemical synthesis , Opiate Alkaloids/chemical synthesis , Psychotropic Drugs/chemical synthesis , Amphetamines/chemical synthesis , Amphetamines/chemistry , Amphetamines/history , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Benzodiazepines/history , Central Nervous System Stimulants/chemistry , Central Nervous System Stimulants/history , Cocaine/chemical synthesis , Cocaine/chemistry , Cocaine/history , Crack Cocaine/chemical synthesis , Crack Cocaine/chemistry , Crack Cocaine/history , Drug Industry , Drug Overdose/epidemiology , Drug Tolerance , Epidemics , Hallucinogens/chemistry , Hallucinogens/history , History, 19th Century , History, 20th Century , History, 21st Century , History, Ancient , Humans , N-Methyl-3,4-methylenedioxyamphetamine/chemical synthesis , N-Methyl-3,4-methylenedioxyamphetamine/chemistry , N-Methyl-3,4-methylenedioxyamphetamine/history , Opiate Alkaloids/chemistry , Opiate Alkaloids/history , Opium/history , Oxycodone/chemical synthesis , Oxycodone/chemistry , Oxycodone/history , Psychotropic Drugs/chemistry , Psychotropic Drugs/history , Substance-Related Disorders/epidemiology , Synthetic Drugs/chemical synthesis , Synthetic Drugs/chemistry , Synthetic Drugs/history , United States/epidemiologyABSTRACT
AIMS: Alexander T. Shulgin is widely thought of as the 'father' of +/-3,4-methylenedioxymethamphetamine (MDMA). This paper re-assesses his role in the modern history of this drug. METHODS: We analysed systematically Shulgin's original publications on MDMA, his publications on the history of MDMA and his laboratory notebook. RESULTS: According to Shulgin's book PIHKAL (1991), he synthesized MDMA in 1965, but did not try it. In the 1960s Shulgin also synthesized MDMA-related compounds such as 3,4-methylenedioxyamphetamine (MDA), 3-methoxy-4,5-methylenedioxyamphetamine (MMDA) and 3,4-methylenedioxyethylamphetamine (MDE), but this had no impact on his rediscovery of MDMA. In the mid-1970s Shulgin learned of a 'special effect' caused by MDMA, whereupon he re-synthesized it and tried it himself in September 1976, as confirmed by his laboratory notebook. In 1977 he gave MDMA to Leo Zeff PhD, who used it as an adjunct to psychotherapy and introduced it to other psychotherapists. CONCLUSION: Shulgin was not the first to synthesize MDMA, but he played an important role in its history. It seems plausible that he was so impressed by its effects that he introduced it to psychotherapist Zeff in 1977. This, and the fact that in 1978 he published with David Nichols the first paper on the pharmacological action of MDMA in humans, explains why Shulgin is sometimes (erroneously) called the 'father' of MDMA.