Where methylene blue is concerned, thankfully the dye never went away completely. The phenothiazine nucleus, a three-ring molecule that sits at the centre of what was then a newly discovered blue dye, became the platform from which new drugs were developed well into the twentieth century, especially in France. That nucleus, it turned out, had antihistaminic effects, an area of focus for the drug company Rhône-Poulenc. It produced drowsiness and eradicated seasonal allergies, the drippy nose and weepy eyes irritated by pollen-packed air in the spring and summer. Rhône-Poulenc used the phenothiazine nucleus to create drugs we still take today, like Benadryl, as well as drugs that have fallen out of favour, like promethazine, a powerful antihistamine synthesised in 1947 and the direct precursor to chlorpromazine.
Henri Laborit
The French military doctor Henri Laborit, soon to be chlorpromazine’s earliest champion, was born in Hanoi, in 1914, and first served as a medic in Indochina. He was unusual in all sorts of ways. Laborit was passionate about science, but he was also deeply interdisciplinary, producing in his lifetime not only reams of scientific articles but also novels and plays and poems. He preferred his private research to federally funded projects, desiring the freedom to pursue the questions that most captivated him. A loner by nature, he cast his professional allegiance with no particular person or place and was thus uniquely positioned, as a free-spirited individual open to experimentation, to recognise the potential of chlorpromazine, a drug that, he believed, could be useful to a variety of medical disciplines.
During the Second World War, Laborit had served aboard the destroyer Sirocco, which was torpedoed by German S-boats in the battle of Dunkirk, suffering several explosions and promptly beginning to sink, tilting first with one side submerged before finally going under the choppy frozen sea, where several hundred sailors lost their lives. Laborit spoke little of this incident during his lifetime, little of the fact that the ship had taken him with it before he resurfaced and began to swim from the doomed vessel, spending hours in an icy ocean, his chin thrust just above the frosty froth, before he reached shore. Years later, during his tenure at the Val-de-Grâce military hospital in Paris, Laborit began to study what he termed ‘artificial hibernation’, inducing in his surgical patients a kind of hypothermia in the hopes of slowing the body’s response to the insult of the incision, the flood of histamines, the heaving of the heart. He would pack his patients in ice and cool their bodies, so that all the physical reactions to surgery went into a kind of suspended animation while he sawed and sutured. One wonders if Laborit’s hypothermic experience in the ocean inspired in him this idea to encase his patients in ice and bring their body temperatures so low that every system slowed to a creep, thereby stemming the stress response to his scalpel.
But before he ever tried artificial hibernation on patients, Laborit had been especially fond of the antihistamine promethazine during his surgery days in Tunisia, where he was stationed immediately after the war, at the naval hospital in Sidi Abdallah. The area was heavily mined with leftover explosives from the war, and many young soldiers suffered casualties in their efforts to clear them, often arriving at the hospital in a state of shock. Laborit operated on patients with missing limbs or with their chests blown open, the human heart visible, that vermilion pump. In these surgeries he began using promethazine, because he had observed that it instilled in his patients a ‘euphoric quietude’ – a unique kind of calm, or even indifference, that allowed him to slide his scalpel into skin and limbs with no cries of protest or pain. The antihistamine served as a ‘potentiator’ that permitted Laborit to use smaller doses of other dream-making drugs, like morphine and barbiturates, both of which, when given in large amounts, compromised the body’s metabolic systems even as they were decreasing pain. He was so taken with promethazine as an anaesthetic potentiator that, after arriving at Val-de-Grâce in 1951, he asked his colleagues to come watch him operate on some of his ‘tense and anxious Mediterranean types’, all of whom succumbed to promethazine’s blow, lying glassy-eyed and listless as Laborit carved and cut.
It is hard for the modern mind to grasp the hurdles our predecessors faced not even a hundred years ago. These days, a large percentage of surgeries are done laparoscopically, with minimal anaesthetic and with the patient sitting up and sliding off the table on to two stable feet once the procedure is complete. While every surgical patient still signs a consent form which says, in small print, that you might well expire from the endeavour, outpatient surgery today is almost as safe as driving your car to the corner shop. But in the 1930s, ’40s and ’50s, when Laborit was practising and morphine and barbiturates were the drugs of choice, many patients died not from their illnesses but from the stress, or shock, of surgery itself, a phenomenon called surgical shock, described by Philadelphia surgeon Virgil H. Moon in 1942:
The patient is profoundly depressed. Metabolic functional activities are low. The skin is pale and moist with cold perspiration. The eyes are sunken, the features drawn and anxious in expression . . . The flesh has a lifeless doughy feel and the superficial veins are collapsed and bloodless. There is a constant thirst but efforts to relieve it are ineffectual because of constant vomiting. The respirations are shallow and are interspersed with deep sighs. The pulse is rapid and weak . . . The patient is restless . . . and may become delirious. Death is preceded by stupor or coma.
It was this constellation of symptoms that so seized Laborit’s mind, that worried him and urged him on to find innovative ways to avoid surgical shock and the resultant deaths. Artificial hibernation – packing his patients in ice – was one method, and using promethazine as a potentiator another. But while each of these helped sometimes, Laborit wanted something better, quicker, cleaner, something that would once and for all eradicate the deadly condition that V. H. Moon had so aptly described, the pale and doughy flesh, the stuporous coma and deep delirium that always preceded the end.
Discovery
Rhône-Poulenc knew of Laborit’s use of their antihistamine promethazine and Laborit knew of Rhône-Poulenc’s ongoing interest in developing novel antihistamines with effects on the central nervous system. The great pharmaceutical house was especially interested in Laborit’s observation that promethazine, with or without cooling, seemed to dissociate the mind from pain. With that information in hand, the company set about trying to create a still more powerful antihistamine that would build on and exceed promethazine’s strength, an antihistamine that would so stabilise the body and so limit the stress response to the scalpel that surgical shock would, once and for all, become a thing of the past.
Thus it was that chemist Paul Charpentier, in 1950, began to further explore promethazine and its phenothiazine nucleus. The company’s main goal was to develop a drug capable of potentiating other narcotics. Rhône-Poulenc had no intention of creating a psychiatric drug, not because they thought a psychiatric drug might fare poorly in the marketplace, but because, as previously mentioned, the very idea of a drug to treat madness was marginal at best. What Rhône-Poulenc wanted, and what Laborit wanted, was something stronger than promethazine, a drug that would sever the mind from feelings of pain while allowing the patient to retain some modicum of consciousness and the surgeon to avoid the dangers and shortcomings of morphine and barbiturates.
Charpentier, along with his colleague Simone Courvoisier, began to toy with methylene blue’s phenothiazine nucleus during the autumn and winter of 1950. The two chemists chlorinated promazine, an antihistamine related to promethazine, thereby producing ‘a completely different molecule’, and creating, as a result, a more potent drug called chlorpromazine, a novel compound which in its US incarnation was eventually christened Thorazine, though it’s known as chlorpromazine in the UK.
Charpentier and Courvoisier were familiar with Pavlov’s work with dogs that had been conditioned to salivate when they heard the ringing of a bell. Pavlov’s dogs had learned that when the bell rang, they would get food; in time all it took to moisten their mouths was the ti
nny sound of the clapper. Pavlov demonstrated, through these experiments, that animals, including humans, could be trained to form strong associations and that these associations were, in many instances, the fundamental building blocks of learning and memory. With this in mind, Courvoisier set out to test chlorpromazine on rats trained to climb a rope in order to escape an electrical shock that was administered along with the sound of a buzzer. The scientist electrified the floors of the rats’ cages and hung a rope from the ceiling to the floor with a non-electrified platform, partway up, where the rats could rest in safety. Courvoisier then set about training the rats to climb the rope in order to escape the shock, something they all quickly learned to do.
Once her rodent subjects were trained, Courvoisier dosed them with the newly developed chlorpromazine, at that time simply called 4560RP (the RP standing for Rhône-Poulenc). The buzzers sounded. And something strange happened. Under the influence of 4560RP the rats did not climb the rope in order to flee the electrical surge. Instead they simply squatted in their cages, their tiny feet absorbing the jangling current, their eyes open and alert but oddly impassive. This new compound, unlike the antihistamines that had preceded it, was able to undo the associative learning that is the bedrock of classical conditioning. With a seemingly simple swipe, it was gone. Had the compound put the rats to sleep, their responses might have made more sense; the animals could have been so heavily sedated that they ceased to feel the surge of current in their bodies. But this was not the case. Every rat was awake, alert, but indifferent to the shocks and uninterested in the rope as a means of escape. This suggested to the chemists that 4560RP – descended from methylene blue – was more powerful than promethazine, so powerful it was able to alter deeply ingrained habits, responses, reactions and reflexes.
Throughout the winter of 1950, Courvoisier and Charpentier tested chlorpromazine on rats, rabbits and dogs. They discovered that the new drug could outperform promethazine in several areas. Its strong anti-emetic properties meant that it could eradicate nausea and the vomiting that often accompanied it. It was also anticholinergic, meaning it could suppress muscle spasms, while the drug’s obvious hypnotic and sedative effects were an advance beyond promethazine, in that they caused still more indifference in the patient.
Of all the research Courvoisier and Charpentier did with chlorpromazine, Rhône-Poulenc was most interested in the drug’s capacity to eradicate the conditioned reflex response. Although the lab rats’ muscular strength and agility were clearly unimpaired, under the influence of chlorpromazine they showed no interest in climbing the rope to escape the shocks coming from the electric grid of their floor. This suggested to the pharmaceutical company that this new drug was more than a simple sedative, and that it was acting on the central nervous system in profound ways.
Accordingly, in the spring of 1951, Rhône-Poulenc distributed eighteen ampules of their novel compound for clinical testing, which meant something very different in those days from what it does in ours. Doctors ‘tested’ a new drug in one of two ways: either by taking it first themselves and recording in a notebook their own responses, or by handing it to a small sample of patients and observing the effects. Researchers had only recently begun to conduct randomised double-blind, placebo-controlled trials, which have become the gold standard of drug testing in our day. (A double-blind trial is one in which neither the patient nor the researcher knows who is taking the actual medication and who is taking the placebo, and is meant to guard against biases on each side.) Pierre Koetschet of Rhône-Poulenc admitted: ‘We had no clear idea of what “chlorpromazine” would do in man. We had the strong impression that it was an interesting non-toxic product that would be useful.’ Rhône-Poulenc released the drug with the idea that it would act as an anaesthetic potentiator, not as a psychiatric drug. According to David Healy, ‘The idea of an antipsychotic was all but inconceivable at that time.’
Because Laborit and Rhône-Poulenc already had a close working relationship, and because of his enthusiasm for promethazine, Laborit was one of the first doctors to receive chlorpromazine. He received five samples and was quick to try them out on patients as part of what he called his ‘lytic cocktail’, an anaesthetic made up of different drugs that produced drowsiness and indifference. Now, with his five samples, Laborit substituted the new antihistamine, chlorpromazine, for promethazine. He also went so far as to recommend that chlorpromazine be included in soldiers’ battlefield kits, as a kind of first aid that could be self-administered in case of injury, to help manage stress responses and the flood of histamines into the body. Adhering to this recommendation, the US military did include chlorpromazine in the medical kits of its soldiers during the Korean War. So marked was the apathy caused by chlorpromazine that the soldiers who took it lay languidly on the battlefield, indifferent to their wounds and unworried about their situation, in some cases foregoing opportunities for rescue, to the point where some may have died as a consequence. Chlorpromazine as a battlefield staple was quickly discontinued.
Clearly this new drug altered one’s mental as well as physical state. Laborit’s clinical notes reveal from early on his awareness that chlorpromazine might have psychiatric relevance. There was potential, he believed, for ‘possible use of the product in psychiatry, its potentiating action permitting, among other things, a sleep treatment with barbiturates that has an improved margin of safety’.
Laborit went further than suggesting the use of chlorpromazine in psychiatry in his published papers. He also discussed it forcefully, if informally, over lunch in the canteen at Val-de-Grâce, urging his psychiatric colleagues to try this new compound, saying that if they did, they might not need to resort to the strait-jacket, the ice pick and the isolation. His colleagues, however, with hypnotics and barbiturates already at their disposal, showed little interest in experimenting on their raving charges. Their indifference did not dissuade Laborit. There is no record that he ever administered chlorpromazine to himself, but his next subject, rather than a patient, was a 28-year-old psychiatrist friend named Cornelia Quarti, who agreed to test the drug on herself. At 11 am on 9 November 1951, at the Villejuif psychiatric hospital, and with Laborit and three of her associates watching, Quarti submitted to an intravenous injection of chlorpromazine, after which she lurched to the lavatory and returned nearly fainting.
Laborit, along with colleague Léon Chertok, propped up their now dosed subject in bed with pillows and watched her closely. Despite her descent, Quarti was still game and she communicated to Laborit all the subjective states she was experiencing under the influence of chlorpromazine. About a week later, on the basis of Laborit’s tape recording of their session, Quarti wrote out how the drug had affected her:
No subjective change was felt until 12.00, when I began to have the impression that I was weaker, that I was dying. It was very painful and agonising . . .
At 1.00, an intense affective change appeared . . . the painful feeling of imminent death disappeared to make room for a euphoric relaxation. I had felt all along that I was going to die, but this new state left me indifferent. I began to talk more volubly, although my voice was still very weak, very faint. I tried to joke; I felt incapable of being angry about anything; irresistibly optimistic, and full of love for the whole world. Although very much in touch with my surroundings, I was more and more overcome by an extreme feeling of detachment from myself and from the others. My perceptions were normal, but their tone had changed; everything was filtered, muted . . .
The weakness and difficulty in speaking persisted for several days before gradually disappearing. The affective changes lasted for about a week, but became more complex than the simple dysfunction felt during and immediately after the experiment. Contrary to my customary manner, I felt very jovial, with a facility for puns . . . a complete detachment or neglect, and a certain lessening of self-control. The mood was of perfect euphoria, unaffected by all the little traumas of daily life.
More convinced than ever about the relevance of this ne
w drug for psychiatry, Laborit continued to make his case at the hospital canteen until finally, on 19 January 1952, Colonel Joseph Hamon, the hospital’s director of neuropsychiatry, and two of his associates gave the drug to 24-year-old Jacques Lh., afflicted with severe manic agitation, a ‘revolving door’ kind of patient who had been institutionalised at Val-de-Grâce several times in the past and had received, all told, fifteen electroconvulsive treatments and four treatments with the sedative thiopental for mania between 9 September and 10 October 1949, and then again, from 6 February to 6 April 1951, nine electroconvulsive treatments and fifteen insulin comas. Given that he was considered a hopeless case, perhaps the doctors at Val-de-Grâce thought they had little to lose in shooting him up with this largely mysterious compound. Jacques Lh. took his chlorpromazine intramuscularly, along with a strong dose of a drug called pethidine, a sedative, as he lay supine on his pillows. The needle sank into his skin. He lay very still, without moving. The doctors watched, wondering. They spoke to him and he responded. Then he stuck out his tongue and fell straight into a deep sleep.
For the next twelve days Jacques Lh. received the same cocktail, chlorpromazine and pethidine, every day, after which he slept. Hours later, as the sedative wore off, he would awaken and step out of bed and into a period of unusual calm that at first lasted no more than a few minutes before he returned to his typically psychotic behaviour, but that gradually, as the days went by, began to stretch out for longer and longer allotments of time. Eventually he ceased tearing his sheets and trying to burn his blankets. He no longer put flowerpots on his head. He lost interest in giving disjointed, impassioned speeches about the loss of liberty on the planet Pluto. The violence he was prone to packed up and went away. After twenty days, this supposedly hopeless case, having now received in total 855 milligrams of chlorpromazine, was judged by the Val-de-Grâce staff to be ‘adaptable à une vie normale’ (‘fit for a normal life’), and he was discharged and never heard from again. No one knows the long-term fate of Jacques Lh. No one knows if he returned home, or if he even had a home to return to. No one knows what happened to his dreams and his demons, although since he was not maintained on the drug, it is hard to believe that they didn’t return. We know only that he was not seen at Val-de-Grâce again.
The Drugs That Changed Our Minds Page 3
