Coal tar, dyes, and the unlikely origins of psychotherapeutic drugs

While it may be difficult to imagine in a day and age when psychiatric medicines are advertised as a way to treat nearly every mental disorder, only 65 years ago targeted and effective psychiatric medicines were still just an unrealized aspiration. In fact, until the middle of the 20th century, the efficacy and safety of many common approaches to treating mental illness were highly questionable. For example, one method of treating schizophrenia that was common in the 1940s and 1950s, known as insulin coma therapy, involved the repeated administration of insulin to precipitate a coma---and then rousing the patient out of the coma with a sugar solution. Although in hindsight this was an ineffective and dangerous way of treating the disorder, that realization didn't spread throughout the medical community until the late 1950s (about 30 years after the introduction of the procedure). Other methods used at the time (e.g. lobotomy, electroconvulsive therapy) were applied in a similarly precarious fashion while providing little to no real improvement in symptomatology. Pharmacological approaches weren't much better, as the drugs used to treat psychiatric disorders tended to be very non-specific, and often dangerous. For example, agents like chloral hydrate or barbiturates might be used to calm a schizophrenic patient whose erratic symptoms made him difficult to pacify. These drugs, however, didn't target any pathology specific to schizophrenia; they simply caused massive sedation and in the process posed a variety of risks ranging from dependence to overdose.

In the 1950s, however, treatment of psychiatric disorders began to change. The decade saw the identification of the first true antipsychotic drugs to treat schizophrenia, the first antidepressants, and the first benzodiazepines to treat insomnia and anxiety. Indeed, the 1950s ushered in what many refer to as the "psychopharmacological revolution," an appellation that began to be used as the second half of the 20th century saw the development of an unprecedented number pharmacological treatments for psychiatric illnesses. Over this time, pharmacological treatments would surpass all other approaches as the most common ways to address psychiatric disorders. And many point to the first antipsychotic drug, chlorpromazine, as the drug that started it all. Considering the major impact it had on psychiatry, medicine, and society, it is perhaps surprising to consider the humble origins of chlorpromazine: the discovery of the drug can be traced back to a black sludge formed in the process of converting coal to fuel.

From coal tar to dyes

When coal is transformed into fuel, one of the byproducts left behind is a thick brown or black liquid known as coal tar. Coal tar smells strongly of naphthalene---one of its chemical constituents and the main ingredient in mothballs---and its appearance and odor probably wouldn't give anyone the impression that there was anything extraordinary about it. Coal tar, however, is made up of a very rich mixture of organic chemicals. Over the years, many of these chemicals---like naphthalene and benzene--were isolated from coal tar and found domestic or industrial uses either in their unaltered form or as starting points for other derivative chemicals. One such use was as synthetic dyes for clothing or other fabrics.

In the 1800s, dyes had to be obtained from natural sources; for example, blue or indigo dye was extracted from tropical plants of the Indigofera genus while yellow was obtained from the flowers of Crocus sativus, or the saffron plant. Relying solely on natural sources for dyes was expensive and resource dependent; the process of extracting dyes from natural sources also tended to be somewhat complicated. Thus, when chemists began to discover ways of creating synthetic dyes from cheap and readily-available substrates, synthetic dyes quickly supplanted natural dyes as the most common method for staining a variety of products ranging from clothing to upholstery. In the process, dye synthesis became the foundation on which a new industry that dealt in the production and use of chemicals was built. The growth of the chemical industry would not just change manufacturing and commerce, but also science---as for many it provided a necessary justification for the existence of chemistry as a scientific field in its own right.

The pioneering chemists in the work on dye synthesis had unintentionally found that aniline, one of the organic constituents of coal tar, could---with the appropriate reaction---produce dyes that were brilliantly purple, magenta, red, or really almost any color imaginable. Then it was discovered that many of the components of coal tar---like benzene, toluene, naphthalene, phenol, and anthracene---could be used to synthesize dyes as well. These discoveries made dyestuffs an extraordinarily lucrative industry in the second half of the twentieth century. The money made selling synthetic dyes helped several major firms like BASF, Bayer, and Sandoz become global powers; the fact that these companies (in some form---Sandoz is now Novartis) are still extremely influential in the chemical and/or pharmaceutical markets indicates that the impact of synthetic dye production can still be felt today.

From dyes to pharmaceuticals

The use of coal tar wasn't limited to dyes, however. Scientists found the rich organic makeup of coal tar could be exploited to produce a variety of substances ranging from paints to cosmetics. As they experimented with this bountiful substrate, researchers also began to find that some of the products they derived had potential as medicines. The first of these substances that were marketed for medicinal purposes were antipyretic, or fever-reducing drugs. The commercial success of some of these drugs led to it being commonplace to test dyes and related compounds for potential therapeutic effects.

At around the same time these antipyretic substances were discovered, chemists were working with another coal tar derivative dye called methylene blue. While examining the structure of methylene blue, the German chemist August Bernthsen discovered that it was a derivative of a previously unknown compound that would come to be called phenothiazine. Phenothiazine derivatives were subsequently found to have antiparasitic properties, and many were synthesized in the hopes of finding treatments for malaria. At the time quinine was the only available antimalarial treatment, and the need for an alternative was acutely felt when events like the World Wars limited access to the natural source of quinine, the tree quina cinchona.

Investigation of the phenothiazines led to some successes in malaria treatment. One in particular was the drug quinacrine, a methylene blue derivative that ended up being used to treat malaria as much as quinine itself. Many of the drugs that came out of these investigations, however, did not prove to be effective antimalarials. Instead of abandoning them altogether, though, researchers investigated their potential uses in treating other ailments. In the process, it was noted that some of the drugs had sedative properties, and one line of research explored their potential use in preventing surgical shock, a condition that can cause extremely low blood pressure during surgery and carries a significant risk of death. One hypothesis at the time, proposed by French surgeon Henri-Marie Laborit, was that surgical shock was precipitated by an excessive defensive reaction to stress, and that this exaggerated reaction might be inhibited through the use of sedatives. Laborit found that one of the phenothiazine derivatives, promethazine, was useful for this purpose when mixed with an opioid drug. Under the influence of this drug combination, patients were much calmer going into surgical procedures and the occurrence of shock was significantly reduced.

The success of promethazine in lowering the risk of surgical shock led to the investigation of other phenothiazine derivatives for their sedative effects. One of the resultant substances, a chlorinated derivative of promazine called chlorpromazine, seemed not only to be an ideal candidate for use in preventing surgical shock, but also to possess some other unique pharmacological characteristics. For example, while other drugs of a sedative nature (like barbiturates) inhibited all behavioral responses in experimental animals, chlorpromazine only inhibited certain learned responses. This suggested the drug was having a more targeted effect on the brain and thus that it might have a more specific mechanism than something like a barbiturate, which caused widespread central nervous system sedation.

As Laborit began to use chlorpromazine to prevent the occurrence of surgical shock, he was amazed at the degree of calmness and relaxation patients who were treated with it felt before, during, and after the surgery. These observations led Laborit to suggest the use of chlorpromazine be explored for the treatment of other psychiatric conditions that required sedation. It didn't take long before chlorpromazine was investigated as a potential treatment for psychosis.

Chlorpromazine as an antipsychotic

The symptoms schizophrenic patients present with are very diverse and vary from patient to patient. They can involve the loss of a normal function like speech, emotion, motivation, or the desire to interact with others; such symptoms that involve the deficit of a normal function are often referred to as negative symptoms. On the other hand, schizophrenic symptoms may involve the development of new thought patterns or behaviors. These symptoms, often called positive symptoms, can include delusions, hallucinations, and erratic behavior, and generally involve some loss of touch with reality---a phenomenon known as psychosis.

Positive symptoms can sometimes be difficult for caretakers to manage, as misguided efforts to calm agitated patients may actually cause patients to become more agitated. Thus, a tranquilizing medication that could help to calm agitated patients---but without some of the potentially severe side effects seen with the use of drugs like barbiturates or chloral hydrate---was welcomed by many practitioners of psychiatric medicine in the 1950s. And so the use of chlorpromazine to treat psychotic patients caught on quickly. Chlorpromazine had first been synthesized in 1950, but within five years its use had already spread through Europe and into the United States and Canada. It was introduced to the US market by Smith Kline & French Laboratories (which would later become GlaxoSmithKline) and sold under the trade name Thorazine. It would soon become a highly profitable drug for Smith Kline & French Laboratories, causing other pharmaceutical companies to rush to discover their own lucrative psychotherapeutic drugs.

From such humble beginnings

It wasn't all smooth sailing for chlorpromazine and the other antispychotic drugs that soon emerged in an attempt to replicate its success. It was quickly recognized that these first generation antipsychotics caused movement-related side effects that could be severe---and in some cases irreversible. Critics also argued that antipsychotic drugs still weren't targeting a mechanism specific to schizophrenia, and instead were just a safer way to sedate patients to make their symptoms more manageable. The success of chlorpromazine and other early antipsychotics, however, ushered in a new era of drug discovery that would change psychiatry and the way we think about mental disorders. The idea that medication could be be targeted to relieve the symptoms of a mental illness supported the perspective that disorders were caused by disruptions in neurobiology, and were better treated medically than through approaches like Freudian psychoanalysis (which was the preferred method of treatment until this time). A valid approach to treating psychiatric disorders like schizophrenia also provided options other than institutionalization, leading to improved treatment for schizophrenic patients and other patients with severe psychiatric disturbances.

Coal tar's major influence on psychiatry didn't end with chlorpromazine, as chlorpromazine would be modified to create imipramine, the first tricyclic antidepressant. Additionally, the success of chlorpromazine would cause increased interest in the therapeutic potential of dyestuffs, which would lead to the discovery of the first benzodiazepine (chlordiazepoxide) in the late 1950s. The discovery imipramine and chlordiazepoxide would also be significant moments in the early days of the psychopharmacological revolution. Due in part to the influence of the new drugs that began appearing in the 1950s, the appearance of psychiatric treatment looks nothing like it did 65 years ago. It is still imperfect, but significantly less barbaric and crude than it was at the middle of the 20th century. And, although such paradigm shifts inevitably involve the contribution of many factors, the role of smelly black sludge in this massive change in psychiatric therapy is impossible to deny.

López-Muñoz, F., Alamo, C., cuenca, E., Shen, W., Clervoy, P., & Rubio, G. (2005). History of the Discovery and Clinical Introduction of Chlorpromazine Annals of Clinical Psychiatry, 17 (3), 113-135 DOI: 10.1080/10401230591002002