Brief history of the medical and non-medical use of amphetamine-like psychostimulants.

The alkaloid ephedrine derived from Ephedra vulgaris is at the origin of psychostimulant-drugs as amphetamine. These drugs have been principally utilized for medical treatments in the past, while their utilization has been largely reduced from the 1970s when the high risk of addiction and abuse has been recognized. The first reported treatments were as anti-asthmatics and to contrast narcolepsy until their recreational stimulant and anorexic effects were reported. Benzedrine and Pervitin use were of great importance during the Second World War due to their abundant utilization among military troops. Nowadays the use of selective amphetamine-like drugs is limited to ADHD treatment.

DARK Classics in Chemical Neuroscience: Aminorex Analogues.

Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as "designer drugs" in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4'-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this Review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogues. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This Review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e., deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency, or the identity of the active ingredients remains obscure to NPS users.

Modafinil: its discovery, the early European and North American experience in the treatment of narcolepsy and idiopathic hypersomnia, and its subsequent use in other medical conditions.

Adrafinil, a new molecule identified by a French drug company, L. Lafon Ltd, in 1974, was found to cause a significant dose-dependent increase in motor activity in mice, without exerting peripheral sympathomimetic effects. As early as 1977-78, Michel Jouvet prescribed adrafinil to narcoleptic patients, but without consistent results. Meanwhile the kinetics of adrafinil led to the identification of an active metabolite, modafinil. In 1983, Jouvet and Bastuji prescribed modafinil to narcoleptic and idiopathic hypersomnia patients and obtained a significant decrease of excessive daytime sleepiness and sleep attacks in a majority of patients. L. Lafon Ltd was initially not interested in developing this molecule for market however, thanks to Jouvet's insistance, it decided to start clinical trials in both healthy volunteers and narcoleptic patients as well as conduct animal studies. Results were excellent and led to the use of modafinil by the French army during the Gulf War in January-February 1991, as well as to the official registration of the drug in France in 1992. Subsequent multicenter controlled clinical trials in North America confirmed the findings in Europe. Modafinil was later used to treat sleepiness, somnolence and fatigue in a large number of medical conditions.

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.

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.

Attention-Deficit/Hyperactivity Disorder: A Historical Review (1775 to Present).

As a new school year approaches, nurses will find themselves faced with students with symptoms of attention-deficit/hyperactivity disorder (ADHD). Navigating the diagnostic label changes and numerous psychopharmacological treatment options can prove time-consuming and confusing. The current article explores the early years of symptom identification, various diagnostic labels, and subsequent psychopharmacological treatments from psychostimulants to non-stimulant alternatives (including a prescription medical food). The current article also serves as a discussion guide for nurses and clinicians when providing education to patients and their loved ones, teachers, coaches, and others who may question the diagnosis and treatment of ADHD. This disorder can have a significant impact on one's ability to function within family, school, work, and social settings. A historical context is provided for the evolution of today's diagnostic criteria and the pharmacotherapy used in the treatment of ADHD. [Journal of Psychosocial Nursing and Mental Health Services, 55(9), 10-16.].

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.

History full circle: 'Novel' sympathomimetics in supplements.

Since the banning of ephedrine in over-the-counter nutritional supplements a decade ago, a plethora of untested and/or unsafe sympathomimetic stimulants have taken its place. This paper argues that these 'novel' stimulants in supplements recapitulate the work of synthetic chemists at commercial pharmaceutical firms during the 1930s and 1940s, all seeking substitutes for recently successful products based on ephedrine and amphetamine. Copyright © 2015 John Wiley & Sons, Ltd.

The Story of "Speed" from "Cloud Nine" to Brain Gain.

The substituted amphetamines have had a checkered medical history intertwined with a sensational cultural history. Mankind's insatiable fascination with speed has led to widespread misuse sometimes with disastrous neurological and psychiatric consequences that may cause a permanent harm but their potential to enhance cognition should not be dismissed or forgotten. Further, smarter research could perhaps still lead to an expanded beneficial role for stimulant use in modern society.

Amphetamine-Type Stimulants: The Early History of Their Medical and Non-Medical Uses.

Amphetamine was discovered as a drug in the late 1920s, and its pharmacological effects on attention and cognition, emotions, and appetite were explored thoroughly in the 1930s and 1940s. By the late 1940s, it had achieved medical and market success as an antidepressant and was quickly gaining such success as a diet medication. In contrast, both careful testing and extensive military experience had left the impression that the drugs' benefits for attention and cognition were more subjective than real and that any objective benefits were explained mainly by the drug's mood-elevating effects. Because of its unpatentable status, methamphetamine had been introduced for all the same uses by drug firms competing with the holder of the amphetamine patent. The drugs were being widely used nonmedically and their abuse potential was becoming recognized by medicine, eventually leading to their strict control internationally around 1970.

Psychostimulants and Artistic, Musical, and Literary Creativity.

This chapter explores links between psychostimulants and creativity in the arts. These links are set in the context of an overview of the association between mind-altering drugs in general and specific branches of the arts, particularly literature. The economic impact of the psychostimulants both historically and in today's world has been substantial and this is mirrored in the culture of the countries involved with the trade in these special commodities. As with other families of addictive drugs, the psychostimulants are sought out more frequently than is the norm by creative individuals who then may represent the drugs in their art or associate the drugs with their creativity. The creative process is outlined and it is noted that if a drug helps at all with creativity then the specific properties of the drug may link it to a particular stage of the creative process. Stimulants are particularly associated with the evaluation and elaboration stage of the creative process and in particular nicotine and caffeine have been used in this way by writers when putting words on paper. The ability of psychostimulants to boost convergent thinking is the main mechanism at work but this is at a cost as divergent thinking is diminished. The other findings of note in this review are that particular venues based around the consumption of a psychostimulants can act as a creative hub-café culture in Paris and Vienna and early modern Europe-and that particular drugs can come to define an artistic grouping as with the Beats and the group around Warhol who had a preference for amphetamine.

Regulatory status of caffeine in the United States.

This article summarizes the history of the regulation of caffeine, a key component of caffeine-containing energy drinks and other caffeine-containing energy products, in the United States. Caffeine as an ingredient in food has been regulated by the US Food and Drug Administration (FDA) since 1958, when the Food Additives Amendment to the Federal Food, Drug and Cosmetic Act was enacted. It is listed as a substance that is generally recognized as safe by experts for its intended use in cola-type beverages at levels not to exceed 200 parts per million. Here, the history of FDA evaluations of the safe use of, as well as consumer exposure to, caffeine in food in the United States is outlined. Finally, the FDA's current concerns about caffeine and caffeine-containing energy products are reported, along with the current activities to address those concerns.

The early history of the neuroscience of attention-deficit/hyperactivity disorder.

Research on the neurobiology and pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD) has grown exponentially since 1980. A reasonable question is whether this research has improved our understanding and treatment of ADHD. This article describes relevant developments that took place roughly between 1900 and 1970. During this time, the efficacy of stimulant therapy for the disorder was established and the symptoms of ADHD were linked to many possible nervous system disorders including in the brain-stem, reticular formation, diencephalon, basal ganglia, frontal lobes, and cortex. In 1970, the catecholamine hypothesis of ADHD was proposed. It is concluded that early theories about the neurobiologic basis of ADHD anticipated core ideas of modern theory.

The end of drugging children: toward the genealogy of the ADHD subject.

This genealogy of the ADHD subject will demonstrate that over the course of the twentieth century a new relation between power, knowledge, the body, and ethical practices of self-formation emerged around the ADHD-type in ways that are not captured by the received critical perspective. By examining the history of knowledge and practices surrounding the ADHD-type, this work will argue that the deviant subject that was located relative to external institutional moral/juridical values or standards is replaced over the course of the century by a new intelligibility of rational self-management. A further analysis of this emergent intelligibility attempts to advance the critical understanding of the increasingly prevalent ADHD phenomenon by showing how novel drug and brain imaging technologies work to link behaviors to identity, establishing new relations of power to the subject not captured by the received medicalization perspective. This work will be of interest to anybody interested in the relations among knowledge, drugs, power, and the ADHD subject.

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.

Thrills, spills and pills: Bond, Benzedrine and the pharmacology of peace.

This paper examines the conjunction of pharmacological science and espionage fiction of the post-war era. This paper argues that, during the 1950s, the relatively new science of pharmacology propounded the possibility that illness and human deficiency could be treated in a way that better reflected the post-war zeitgeist. The use of pharmacological medicine, perceived as cleaner and quicker than more 'bodily' forms of treatment, represented progress in contemporary medical science. It is argued that this philosophy extended to more overt means of pharmacological application, directly related to the geopolitical concerns of the 'Cold War'. A growing form of popular literature in this period was the espionage novel. This paper argues that the benefits proffered by pharmacology were incorporated into the fabric of espionage fiction, specifically the James Bond novels of Ian Fleming. Here, it is demonstrated how Fleming used pharmacological knowledge of Benzedrine throughout his novels. His works illustrate a belief that the augmentation of the spy's natural ability with pharmacological science would award decisive advantage in the Cold War conflict played out in spy fiction. However, the relationship between public use of Benzedrine and awareness of its side effects changed during the period of Fleming's publications, moving from a position of casual availability to one of controlled prescription. It is argued that the recognition of the dangers associated with the drug were over-ruled in favour of the benefits its use presented to the state. The continued use of the drug by Bond illustrates how the concerns of the nation are given priority over the health, and life, of the individual.