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.

[Should we continue to use benzodiazepines in clinical practice?]. / Dovremmo continuare a utilizzare le benzodiazepine nella pratica clinica?

The discovery of benzodiazepines has represented a milestone in the history of pharmacological treatments and in relation to the management of anxiety, sleep and other psychiatric disorders. After several decades, these agents still represent one of the largest and most widely prescribed groups of medications, not only in the psychiatric clinical practice, but also in the whole medical field. Over the last decade, however, multiple concerns have been raised on the risks related to the prescription of benzodiazepines, for their addictive potential and for cognitive side-effects. Therefore, benzodiazepines are today considered as a double-edge sword, which should be carefully handled and preferentially prescribed by specialists (or at least under their supervision), after an adequate training. Unfortunately, this is not the case in many situations, and the need to improve training on benzodiazepines management has been recently emphasized.

Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

AIM: Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. METHODS: Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. RESULTS: It took many years before the drug regulators acknowledged benzodiazepine dependence and SSRI withdrawal reactions and before the prescribers and the public were informed. Drug regulators relied mainly on the definitions of dependence and withdrawal reactions from the diagnostic psychiatric manuals, which contributed to the idea that SSRIs do not cause dependence, although it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug agencies have reacted in concordance with the slowly growing knowledge of adverse drug reactions and have sharpened the information to the prescribers and the public over time. However, solely relying on spontaneous reporting of adverse effects leads to underestimation and delayed information about the problems. CONCLUSION: Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted.

Is there a way to curb benzodiazepine addiction?

Benzodiazepines are widely prescribed drugs used to treat anxiety and insomnia, induce muscle relaxation, control epileptic seizures, promote anaesthesia or produce amnesia. Benzodiazepines are also abused for recreational purposes and the number of benzodiazepine abusers is unfortunately increasing. Within weeks of chronic use, tolerance to the pharmacological effects can develop and withdrawal becomes apparent once the drug is no longer available, which are both conditions indicative of benzodiazepine dependence. Diagnosis of addiction (i.e. compulsive use despite negative consequences) may follow in vulnerable individuals. Here, we review the historical and current use of benzodiazepines from their original synthesis, discovery and commercialisation to the recent identification of the molecular mechanism by which benzodiazepines induce addiction. These results have identified the mechanisms underlying the activation of midbrain dopamine neurons by benzodiazepines, and how these drugs can hijack the mesocorticolimbic reward system. Such knowledge calls for future developments of new receptor subtype specific benzodiazepines with a reduced addiction liability.

The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs.

The clinical introduction of chlordiazepoxide half a century ago was one of the major breakthroughs in the history of psychopharmacology, as it opened the door for the benzodiazepine saga, the pharmacological family par excellence in the treatment of anxiety disorders. This review analyses the discovery of this drug, which was filled with chance events, and numerous chemical and clinical errors of approach. Chlordiazepoxide, initially called methaminodiazepoxide, was patented in 1958 and introduced in clinical treatment in 1960 under the brand name Librium®. The benzodiazepines became the most widely prescribed drugs worldwide, provided truly effective treatment for "minor forms" (neuroses) of mental disorders for the first time, increased the quality of scientific methodology in clinical research, and enabled the development of new etiopathogenic theories for anxiety disorders, especially after the discovery in 1977 of their high-affinity receptor complex.

[From alcohol to liquid ecstasy (GHB)--a survey of old and modern knockout agents. Part 2: benzodiazepines and other sedatives/hypnotic drugs]. / Vom Alkohol zum Liquid Ecstasy (GHB)-- ein Uberblick über alte und moderne K.-o.-Mittel. Teil 2: Benzodiazepine und andere Sedativa/Hypnotika.

Owing to the rapid progress in the development of synthetic pharmaceuticals, the classical knockout drugs such as chloroform and diethyl ether have been superseded by highly effective sedative and hypnotic drugs (e. g. methyprylone, clozapine and especially benzodiazepines). These are frequently given to the victim unnoticed by adding them to an alcoholic drink. In this way, alcohol still plays an important role as an interaction partner. The article presents relevant case examples together with their criminalistic background.

The impact of diazepam's discovery on the treatment and understanding of status epilepticus.

The fortuitous discovery of the benzodiazepines and the subsequent application of these agents to the treatment of status epilepticus (SE) heralds in the modern age of treating this neurologic emergency. More than 50 years after their discovery, the benzodiazepines remain the drugs of first choice in the treatment of SE. However, the benzodiazepines can be ineffective, especially in those patients whose seizures are the most prolonged. The benzodiazepines act by increasing the affinity of gamma-aminobutyric acid (GABA) for GABAA receptors. A receptor's subunit composition affects its functional and pharmacologic properties, trafficking, and cellular localization. The GABAA receptors that mediate synaptic inhibition typically contain a gamma2 subunit and are diazepam-sensitive. Among the GABAA receptors that mediate tonic inhibition are the benzodiazepine-insensitive delta subunit-containing receptors. The initial studies investigating the pathogenesis of SE demonstrated that a reduction in GABA-mediated inhibition within the hippocampus was important in maintenance of SE, and this reduction correlated with a rapid modification in the postsynaptic GABAA receptor population expressed on the surface of the hippocampal principal neurons. Subsequent studies found that this rapid modification is, in part, mediated by an activity-dependent, subunit-specific trafficking of the receptors that resulted in the reduction in the surface expression of the benzodiazepine-sensitive gamma2 subunit-containing receptors and the preserved surface expression of the benzodiazepine-insensitive delta subunit-containing receptors. This improved understanding of the changes in the trafficking of GABAA receptors during SE partially accounts for the development of benzodiazepine-pharmacoresistance and has implications for the current and future treatment of benzodiazepine-refractory SE.

From King Kong pills to mother's little helpers--career cycles of two families of psychotropic drugs: the barbiturates and benzodiazepines.

This article compares the careers of two families of 20th-century psychotropic drugs, the barbiturates and the benzodiazepines, in five different countries. Both families of drugs were used as so-called hypnotics and sedatives, and later as minor tranquillizers. In addition these drugs were extensively used as self-medication. The careers show a cyclical temporal course and generally encompass three phases: first, an expanding use of the drugs, accompanied by high expectations; then, rising criticism and disappointment; and finally contracting use and limited application. These phases need not have been sequential: they often overlapped. The cycle sometimes ended by the disappearance of the drug from mental health care, only to be replaced by new drugs with a profile of promise and hope. These cycles, which we term Seige cycles, are generally typical for the careers of psychotropic drugs. The analytical concept of the Seige cycle facilitates a comparative perspective on the commonalities as well as the differences between the various drug careers under consideration.

[Leo Sternbach, an inventor of benzodiazepines].

A biography of Leo Sternbach, an inventor of benzodiazepine tranquillizers, is presented. It consists of (1) a societal desire for lifestyle pills, (2) Leo's birth in 1908 and youth, (3) education, (4) in Vienna, (5) in Zurich, (6) at Hoffmann-La Roche, Basel, (7) to the New World, (8) at Roche, Nutley NJ, (9) invention of the new drugs, (10) revolution of people's lifestyle, and (11) reward, retirement and obituary in 2005. This paper may be the first comprehensive biography of this remarkable chemist written in Japanese.

Attitudes toward benzodiazepines over the years.

Benzodiazepines have been used extensively for the treatment of anxiety and related disorders since the 1960s. Although they have been proven to be effective as first-line treatment for anxiety disorders, during the 1980s public perception and concern for abuse liability and physical dependence with long-term use gave rise to a great deal of controversy. Negative perceptions toward the use of benzodiazepines for treating anxiety not only caused severely ill patients to go untreated or under-treated but also called into question whether the illness itself was worthy of treatment. Although new pharmacologic and psychological treatments for anxiety are available, psychopharmacologists continue to endorse benzodiazepines as primary or adjunct treatment for anxiety disorders. The intent of this article is to provide a historic overview of these issues and to offer some general clinical principles to help minimize the risk of abuse and dependence with benzodiazepine use.

Breve história dos hipnoindutores: dos barbituratos aos hipnóticos de terceira geraçäo / Short history of hypnotics: from barbiturates to third-generation hypnotics

A Psicofarmacologia ainda busca hipnótico ideal. No entanto, observa-se evoluçäo desde os antigos babitúricos à nova geraçäo de hipnáticos. Entre esses dois tipos de substâncias se encontram as Benzodiazepinas (segunda geraçäo), compostos que servem de modelo farmacológico aos novos hipnóticos. Este artigo mostra algumas diferenças essenciais entre as Benzodiazepinas e hipnóticos de terceira geraçäo (Imidazopiridina e Ciclopirrolona). Os ensaios de laboratórios e clínico demonstram real avanço com os novos hipnóticos.

The early history of psychotherapeutic drugs.

The four most frequently used groups of drugs in psychiatric therapy are: neuroleptics, antidepressants, anxiolytics, and lithium salts. Their introduction came largely during the past 3 decades. This review summarizes the history of the research that led to their discovery and to the present concept of their modes of action.