DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants.

Cathinone is a plant alkaloid found in khat leaves of perennial shrubs grown in East Africa. Similar to cocaine, cathinone elicits psychostimulant effects which are in part attributed to its amphetamine-like structure. Around 2010, home laboratories began altering the parent structure of cathinone to synthesize derivatives with mechanisms of action, potencies, and pharmacokinetics permitting high abuse potential and toxicity. These "synthetic cathinones" include 4-methylmethcathinone (mephedrone), 3,4-methylenedioxypyrovalerone (MDPV), and the empathogenic agent 3,4-methylenedioxymethcathinone (methylone) which collectively gained international popularity following aggressive online marketing as well as availability in various retail outlets. Case reports made clear the health risks associated with these agents and, in 2012, the Drug Enforcement Agency of the United States placed a series of synthetic cathinones on Schedule I under emergency order. Mechanistically, cathinone and synthetic derivatives work by augmenting monoamine transmission through release facilitation and/or presynaptic transport inhibition. Animal studies confirm the rewarding and reinforcing properties of synthetic cathinones by utilizing self-administration, place conditioning, and intracranial self-stimulation assays and additionally show persistent neuropathological features which demonstrate a clear need to better understand this class of drugs. This Review will thus detail (i) historical context of cathinone use and the rise of "dark" synthetic derivatives, (ii) structural features and mechanisms of synthetic cathinones, (iii) behavioral effects observed clinically and in animals under controlled laboratory conditions, and (iv) neurotransmitters and circuits that may be targeted to manage synthetic cathinone abuse in humans.

DARK Classics in Chemical Neuroscience: Methamphetamine.

Methamphetamine has the second highest prevalence of drug abuse after cannabis, with estimates of 35 million users worldwide. The ( S)-(+)-enantiomer is the illicit drug, active neurostimulant, and eutomer, while the ( R)-(-)-enantiomer is contained in over the counter decongestants. While designated a schedule II drug in 1970, ( S)-(+)-methamphetamine is available by prescription for the treatment of attention-deficit disorder and obesity. The illicit use of ( S)-(+)-methamphetamine results in the sudden "rush" of stimulation to the motivation, movement, pleasure, and reward centers in the brain, caused by rapid release of dopamine. In this review, we will provide an overview of the synthesis, pharmacology, adverse effects, and drug metabolism of this widely abused psychostimulant that distinguish it as a DARK classic in Chemical Neuroscience.

Methamphetamine and psychiatry: A story of the colourless substance of abuse.

OBJECTIVE: The current paper aims to provide an overview of methamphetamine in its historical context, integrated with a current understanding derived from animal studies and clinical experience. CONCLUSION: Despite over a century of clinical experience, methamphetamine remains a troublesome substance. There remains an urgent need at multiple levels from various sectors to combat this ongoing problem, and psychiatry has an essential role in this endeavour.

Japan's hiropon panic: resident non-Japanese and the 1950s meth crisis.

BACKGROUND: This qualitative historical policy analysis explores Japan's early postwar market for hiropon (methamphetamine/meth) and the impact of its anti-hiropon campaigns. The paper traces the origins of medical methamphetamine production in prewar Japan; known at that time by its former brand-name, 'Philopon' (pronounced hiropon), and argues that the anti-meth 'shock-horror' campaigns of the 1950s were exacerbated by long-simmering animosity toward non-Japanese residents - especially Koreans and Taiwanese. METHODS: Through an analysis of both English- and Japanese-language source materials, the paper explores the gritty, frightening themes of Japan's 1950s-era anti-meth propaganda campaigns and the parallel effort by police to arrest, prosecute, and deport members of the resident Korean and Taiwanese communities. RESULTS: The author demonstrates that by incorporating a wider variety of contemporary Japanese-language sources such as news reports and anti-drug propaganda materials about the postwar hiropon trade, we may more fully appreciate the historic, underlying social tensions behind the swift and targeted public response. CONCLUSION: The author concludes that Japan's postwar federal and municipal governments, together with police and media agencies, cultivated a sensational 'drug panic' designed both to dissuade citizens from using hiropon and to fuel a concerted police campaign against non-Japanese involved in the meth trade.

An evolving problem: methamphetamine production and trafficking in the United States.

BACKGROUND: Methamphetamine is a serious illicit drug problem in the United States and globally. For decades, methamphetamine has been supplied to the illicit market through local clandestine manufacturing and trafficking. In the early stages, illicit methamphetamine was produced and trafficked by motorcycle gangs and Mexican criminal groups. Over time, local clandestine manufacturing increasingly contributed to the illicit supply and broader methamphetamine problem. This review examines the evolution of the illicit methamphetamine supply in the U.S. METHODS: A review of the literature on methamphetamine production and trafficking was conducted. Information was obtained from numerous sources including governmental reports, books and academic articles. RESULTS: Attempts to control the supply of methamphetamine have only led to short term disruptions in availability. Clandestine manufacturing and trafficking have undergone significant changes over the past several decades. Shifts in local production have regularly been counterbalanced by changes in production and trafficking from criminal organizations in Mexico. Transnational criminal organizations now control much of the methamphetamine supply in the U.S. and methamphetamine remains widely available. CONCLUSIONS: The supply of methamphetamine in the United States is dynamic. Producers and traffickers have adapted to control efforts and the problem continues. Control efforts focused on eliminating supply are limited at best.

Methamphetamine: here we go again?

Following more than two decades of generally increasing trends in the use and abuse of methamphetamine in certain parts of the country, prevalence indicators for the drug began to decrease in the mid-2000's-but was this decrease signaling the end of the "meth problem"? This paper has compiled historical and recent data from supply and demand indicators to provide a broader context within which to consider the changes in trends over the past half decade. Data suggest supply-side accommodation to changes in precursor chemical restrictions, with prevalence indicators beginning to attenuate in the mid-2000's and then increasing again by 2009-2010. Results support the need for continuing attention to control and interdiction efforts appropriate to the changing supply context and to continuing prevention efforts and increased number of treatment programs.

The history of Ephedra (ma-huang).

Ephedra is a Chinese shrub which has been used in China for medicinal purposes for several thousand years. The pure alkaloid ephedrine was first isolated and characterised by Nagai in 1885. It was then forgotten until it was rediscovered by Chen and Schmidt in the early 1920s. Its actions on the adrenoceptors could be classified into separate alpha and beta effects--a defining moment in the history of autonomic pharmacology. Ephedrine became a highly popular and effective treatment for asthma, particularly because, unlike adrenaline (until then the standard therapy), it can be given by mouth. Ephedrine as a treatment for asthma reached its zenith in the late 1950s, since when there has been a gradual and inevitable decline in its therapeutic use. From mainstream medicine, ephedrine moved into the twilight zone of street drugs and nutritional supplements. Ephedra and ephedrine products are now banned in many countries, as they are a major source for the production of the addictive compound methamphetamine (crystal meth).

The history and current state of drug abuse in Japan.

Drug abuse in Japan began after World War II and has been characterized by three epidemics of methamphetamine abuse; in addition, solvent abuse has been prominent for a long time. Since 1995, with the beginning of the third epidemic of methamphetamine abuse, drug abuse or dependence in Japan changed, with a marked decrease in solvent abuse, stabilization of methamphetamine abuse, an increase in the abuse of such drugs as cannabis or 3,4-methylenedioxymethamphetamine (which do not have high potential of causing drug-induced psychosis), and the emergence of designer drugs. Furthermore, the abuse of medical drugs such as Ritalin became a major issue in 2007. These changes reveal an increase in the abuse of drugs that do not as easily produce a psychotic state, underlain with a shift from personal conduct that leads to arrest to conduct that does not. Japan, therefore, needs to deal with drug abuse and dependence using not only a medical model, but also a criminal model as well.

Methamphetamine for Hitler's Germany: 1937 to 1945.

Methamphetamine was synthesized in Germany in 1937 and commercially released in 1938. It became a popular stimulant for tired night workers and a recreational drug for young people until mid-1941 when it became a controlled substance. It was abused by the armed forces during World War II when it was distributed by some commanding officers (occasionally over the objections of the units' physicians) to prevent or treat the fatigue of exhausted troops and thus allow them to survive, despite the strict restrictions issued by the Army Inspectorate. There is no evidence for the claim that the use of Pervitin was encouraged by the Nazi government to create a "superman." In fact the Health Leader L. Conti strongly discouraged its use.

[Fritz hauschild (1908-1974) and drug research in the 'German Democratic Republic' (GDR)]. / "Man sollte die Entwicklung nicht hemmen"--Fritz Hauschild (1908-1974) und die Arzneimittelforschung der DDR.

The chemist and pharmacologist Fritz Hauschild developed the sympathomimetic agent Pervitin (metamphetamin) in the 1930s. Not only because of the abuse of the stimulant during the Second World War ("pilot's chocolate") it is one of the most controversial substances in drug history. Nearly forgotten are Hauschild's contributions to build up the drug system in the GDR. Although he was a convinced communist, the skilful pharmacologist gave very early warning of the imminent lack of innovation in the GDR pharmaceutical industry. A letter which he addressed to the Minister of Health, Max Sefrin (born 1913), did not lack explicitness.

Methamphetamine use dates to post-WWII era. Drug little-known risk factor in early AIDS days.

Originally manufactured by the Germans in the 1880s and later used by the Japanese as a means of keeping military personnel awake on long shifts, methamphetamine first was a significant presence in the Western United States in the late 1940s. For decades, methamphetamine use was limited to the West Coast and Hawaii, becoming popular at various times in a multitude of groups, including Hells Angels.

History of the methamphetamine problem.

Methamphetamine, called meth, crystal, or speed, is a central nervous system stimulant that can be injected, smoked, snorted, or ingested orally; prolonged use at high levels results in dependence. Methamphetamine (MA) is a derivative of amphetamine, which was widely prescribed in the 1950s and 1960s as a medication for depression and obesity, reaching a peak of 31 million prescriptions in the United States in 1967. Until the late 1980s, illicit use and manufacture of MA was endemic to California, but the MA user population has recently broadened in nature and in regional distribution, with increased use occurring in midwestern states. An estimated 4.7 million Americans (2.1% of the U.S. population) have tried MA at some time in their lives. Short- and long-term health effects of MA use include stroke, cardiac arrhythmia, stomach cramps, shaking, anxiety, insomnia, paranoia, hallucinations, and structural changes to the brain. Children of MA abusers are at risk of neglect and abuse, and the use of MA by pregnant women can cause growth retardation, premature birth, and developmental disorders in neonates and enduring cognitive deficits in children. MA-related deaths and admissions to hospital emergency rooms are increasing. Although inpatient hospitalization may be indicated to treat severe cases of long-term MA dependence, optimum treatment for MA abusers relies on an intensive outpatient setting with three to five visits per week of comprehensive counseling for at least the first three months. The burgeoning problems of increased MA use must be addressed by adequate treatment programs suitable for a variety of user types.