The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

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.

Purity, adulteration and price of drugs bought on-line versus off-line in the Netherlands.

BACKGROUND AND AIMS: On-line drug markets flourish and consumers have high expectations of on-line quality and drug value. The aim of this study was to (i) describe on-line drug purchases and (ii) compare on-line with off-line purchased drugs regarding purity, adulteration and price. DESIGN: Comparison of laboratory analyses of 32 663 drug consumer samples (stimulants and hallucinogens) purchased between January 2013 and January 2016, 928 of which were bought on-line. SETTING: The Netherlands. MEASUREMENTS: Primary outcome measures were (i) the percentage of samples purchased on-line and (ii) the chemical purity of powders (or dosage per tablet); adulteration; and the price per gram, blotter or tablet of drugs bought on-line compared with drugs bought off-line. FINDINGS: The proportion of drug samples purchased on-line increased from 1.4% in 2013 to 4.1% in 2015. The frequency varied widely, from a maximum of 6% for controlled, traditional substances [ecstasy tablets, 3,4-methylenedioxy-methamphetamine (MDMA) powder, amphetamine powder, cocaine powder, 4-bromo-2,5-dimethoxyphenethylamine (2C-B) and lysergic acid diethylamide (LSD)] to more than a third for new psychoactive substances (NPS) [4-fluoroamphetamine (4-FA), 5/6-(2-aminopropyl)benzofuran (5/6-APB) and methoxetamine (MXE)]. There were no large differences in drug purity, yet small but statistically significant differences were found for 4-FA (on-line 59% versus off-line 52% purity for 4-FA on average, P = 0.001), MDMA powders (45 versus 61% purity for MDMA, P = 0.02), 2C-B tablets (21 versus 10 mg 2C-B/tablet dosage, P = 0.49) and ecstasy tablets (131 versus 121 mg MDMA/tablet dosage, P = 0.05). The proportion of adulterated samples purchased on-line and off-line did not differ, except for 4-FA powder, being less adulterated on-line (χ2  = 8.3; P < 0.02). Drug prices were mainly higher on-line, ranging for various drugs from 10 to 23% higher than that of drugs purchased off-line (six of 10 substances: P < 0.05). CONCLUSIONS: Dutch drug users increasingly purchase drugs on-line: new psychoactive substances in particular. Purity and adulteration do not vary considerably between drugs purchased on-line and off-line for most substances, while on-line prices are mostly higher than off-line prices.

Occurrence of drugs of abuse in surface water from four Spanish river basins: Spatial and temporal variations and environmental risk assessment.

The present work investigates the occurrence of 22 drugs of abuse (DAs) and metabolites in surface water from four Spanish River basins: Llobregat, Ebro, Jucar and Guadalquivir. To this end, samples were collected from 77 selected sites in two sampling campaigns conducted in 2010 and 2011. Analyses were performed by means of on-line solid phase extraction-liquid chromatography-electrospray-tandem mass spectrometry (on-line SPE-LC-ESI-MS/MS). Cocaine, its metabolite benzoylecgonine, ephedrine, MDMA (ecstasy), and methadone and its metabolite EDDP were the most ubiquitous compounds, being present in more than 50% of the samples. Overall, DAs were present at low ng/L levels, showing comparatively higher concentrations in small tributary rivers impacted by wastewater treatment plant effluents. The results obtained did not show a clear relationship between the concentrations of DAs and the hydrological conditions of the river basins. Differences in the occurrence of DAs between river basins were observed, but only for MDMA this finding could be confirmed in both sampling campaigns. These results overall suggest similar drugs consumption in the studied areas. Estimation of potential ecotoxicological effects using Hazard Quotient (HQ) ratios and a concentration addition model showed that in four samples the presence of DAs could represent certain risk to aquatic organisms.

Rediscovering MDMA (ecstasy): the role of the American chemist Alexander T. Shulgin.

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.

Diazatetraester 1H-pyrazole crowns as fluorescent chemosensors for AMPH, METH, MDMA (ecstasy), and dopamine.

The synthesis and steady-state fluorescence studies on the interaction with AMPH, METH, MDMA, and DA of two diazatetraester pyrazole crowns containing appended N-(9H-fluoren-9-yl) and N-(naphth-2-ylmethyl) functions, in a water/ethanol 70:30 mixture at physiological pH, are described.

Monitoring synthetic drug markets, trends, and public health.

The Drugs Information and Monitoring System (DIMS) in The Netherlands is a toxicoepidemiologic monitor of drug markets that was established in 1992. Its main focuses are to identify the compounds of synthetic drugs, describe prevalence and trends, and identify health risks. Here we discuss the insights gained in the Ecstasy market, based on the weekly testing of more than 100 drug samples, and key information of synthetic drug users delivering drug samples and personnel participating in the DIMS network. Pills used as Ecstasy may contain a wide variety of compounds. The percentage of samples containing MDMA increased slowly reaching almost 75% in 1996, but decreasing sharply in 1997. Amphetamines ("speed" and "ice") and experimental varieties were found in at least one third of the pills. Origins and effects of this development are discussed, as well as the risk assessment. In 1998 the percentage of MDMA pills increased more than ever before, indicating among other things that consumers prefer the conventional product. However, the use of "speed" and other drugs may also be stimulated by the decrease in 1997 of the percentage of MDMA pills. With more new types of drugs likely in the next century, a monitor such as DIMS provides important surveillance and data for public health and preventive aims.