by A. J. Lees
A few months later, another of the volunteers from the bromocriptine trial returned to clinic complaining of burning in the fingers and toes and severe cramping in her calves when walking that forced her to pull up and rest after about a hundred metres. On examination she was disorientated, had deathly white hands and an ashen nose. The normal pulsations in the arteries of her feet were impalpable and her radial pulse was thready. Her symptoms resembled those first described in the seventeenth-century epidemics of St Anthony’s Fire, caused by eating rye bread contaminated with Claviceps purpurea fungus. No cases of ergotism caused by bromocriptine had been reported, but I felt nevertheless that this was the likely diagnosis. I stopped the trial drug at once and switched her over to L-DOPA; she recovered completely over the next four weeks and gangrene was avoided.
The following week I took a call from the worried son of Mrs N, an elderly lady who had worked as a cleaner all her life and been diagnosed three years earlier with Parkinson’s disease. He told me that his mother had started to compulsively squander all her pension money on bingo and he had begun to wonder whether the bromocriptine she was taking had anything to do with it. I told him I was not aware of any link between gambling and the new drug but to contact me again if things deteriorated. My own view was that his mother was probably very lonely and it was her way of trying to cheer herself up.
Things got much worse and Mrs N’s son made an emergency appointment for her to see me. He told me she was now visiting the bingo hall four days a week and had fallen behind with her rent. Although his mother vehemently denied intemperate gambling, he estimated that she had lost several thousand pounds in the last few months. It was hard to know who was telling the truth. After excusing myself, I stepped out of the clinic room and called the Medical Information Department at Sandoz, whereupon I was told that two cases of pathological gambling had already been reported with bromocriptine but a clear and definite cause and effect had not been established. To the son’s relief, I tapered down his mother’s bromocriptine and when she returned to clinic six weeks later, she told me that she had given up bingo altogether.
The most exciting finding to come out of my continuing work with bromocriptine was that when the drug was used alone to treat the symptoms of Parkinson’s disease, it provided sustained symptom relief without the volleys of jolting twitches and convulsive movements seen with L-DOPA. Considered at best a long shot, bromocriptine had far exceeded expectations and been shown to be a very effective treatment for Parkinson’s disease. However, it was also now clear the medicine carried a considerable risk, and doubts were being expressed on whether it was safe for routine use. This vicissitude in bromocriptine’s fortune replicated the twists and turns in the path to acceptance of most effective treatments. New drugs were often the subject of exaggeratedly enthusiastic accolades, followed by excessively critical reappraisal. Clinical experience usually showed that the truth lay somewhere in the middle and eventually, despite concerns about its unwanted psychiatric side effects, bromocriptine became a popular medicine with many experts recommending it as first line treatment in younger patients with Parkinson’s disease.
Albert Hofmann, a former director of medical research at Sandoz, had shown that all the naturally occurring alkaloids extracted from the rye fungus Claviceps purpurea were derived from a single building block. Substitutions in the tetracyclic indole ring of lysergic acid determined the type and action of each of the naturally occurring ergot alkaloids.
One day, Hofmann was dabbling with this basic structure in the hope of developing a new powerful analeptic when he isolated d-lysergic acid diethylamide (LSD). The drug did not seem a promising candidate for therapeutic trials as it caused unsteadiness and catatonia in animals. He put the unusually fragile molecule to one side. A few years later, he synthesised a new batch of LSD and decided to re-investigate its properties. During the course of one experiment, he was overcome by a pleasant and unexpected state of intoxication. On getting home, he closed his eyes and was treated to an uninterrupted, two-hour stream of extraordinary pictures and astonishing geometric shapes. He concluded correctly that he must have inhaled or ingested a very small dose of LSD. A few days later, he deliberately took what he imagined to be the tiny dose of 250 micrograms. He immediately felt terrified and giddy and asked his laboratory assistant to accompany him home by bicycle. On the way home, he noticed that the sound of cars was transformed into optical effects and colours changed rapidly from one radiant hue to another. All the effects wore off after six hours. Hoffmann had written himself into the annals of psychedelia by taking the first ever recorded acid trip.
Publication of his results caused a sensation. It was hoped that LSD-25, ‘the medicine of the soul’, could help shed light on the biology of schizophrenia and other serious mental disorders. Sandoz introduced the drug commercially in 1947. The CIA began a research programme that involved administering it without informed consent to military personnel, government agents and prostitutes. In the sixties, Timothy Leary, a Harvard academic, suggested the drug could induce a heavenly sunlit inner quietude and provide a better treatment for the mentally ill. Leary considered the brain to be a biochemical electrical network capable of creating a changing series of adaptive realities. He wrote that the language of God was not English or Latin but cellular and molecular.
Leary went to Tangier in July 1961 to meet Burroughs and invited him to visit his Centre for Research in Personality. In a letter written from Harvard the previous January, Leary had described the political situation as far as psychedelic drugs were concerned:
Medicine has already pre-empted LSD, marijuana is the football for two other powerful groups – Bohemia and the narcotics agents. Mescaline and psilocybin are still up for grabs and it is our hope to keep them ungrabbed, uncontrolled, available.
– Rub out the Words
On his return to the International Zone of Tangier, Burroughs told his literary friend, Paul Bowles, that ‘Doctor Tim’ had the most unscientific mind he had ever encountered and that he did not condone Leary’s proselytizing of psychedelic drugs for personal development. Despite his distaste for scientists, Burroughs never equated a scientific paper with a piece of imaginative poetry. After a rocky start, Burroughs and Leary got on fine and shared the view that the only hope for the world lay in exploration of the galaxies and the development of space colonies.
In England, during my medical student days, Timothy Leary was portrayed in the tabloid press as a disgraced lunatic, but for hippies during the Summer of Love he was considered a visionary. When asked about Burroughs in a 1989 interview for Pataphysics, Leary said:
He’s a very scientific person. The only psychedelic he likes is marijuana … Burroughs has forgotten more about drugs in his life than I’ve learned. Burroughs is in charge of his life. He knows what he’s doing … But Burroughs, he’s not the guy that goes around with a grin on his face saying peace and love. He’s a very crusty, introverted guy with a deep sense of humour. He’s one of the funniest persons alive – it’s a very laid-back kind of humor.
More than 30,000 mental patients, including some with alcoholism, were treated with LSD and more than a thousand peer review papers were published between 1957 and 1967. Psychiatrists considered its main value was in facilitating the psychoanalytical process and relieving anxiety. The response to a dose of the drug, however, was highly unpredictable and some acutely psychotic patients deteriorated after treatment, with their hallucinations acquiring a menacing and phantasmagorical quality. Reports of young people ‘flying’ to their death after taking LSD for recreational purposes and the Manson murders, led to mounting public concern. Richard Nixon stated that Timothy Leary was ‘the most dangerous man in America’ and put him in jail for drugs offences. Senator Robert Kennedy on the other hand, questioned this sudden shift of opinion: ‘Perhaps to some extent we have lost sight of the fact that (LSD) can be very, very helpful in our society if used properly.’ In response to its increasing use by leading lights in t
he countercultural movement, the United States made LSD-25 illegal in 1966.
The molecule’s hallucinogenic properties were thought to be due to its stimulant effects on the brain’s 5-hydroxytryptamine (serotonin) receptors but, like bromocriptine, it also stimulated dopamine receptors. When I compared the structural formula of the bromocriptine molecule with that of LSD-25, I understood why some of my patients had seen cinematic visions, misidentified shapes and people, and become convinced that mice were running across the floor.
I even thought about a trial of Hofmann’s ‘problem child’ LSD-25 in Parkinson’s disease but Burroughs’ warnings about ‘backbrain stimulants’ held me back. In a 1966 letter to the New Statesman, Burroughs had written:
I can speak from experience about the hallucinogenic drugs having experimented over a period of years with LSD, mescaline, psilocybin, dimethyltryptamine. I consider these drugs more dangerous than useful. They can produce states of acute pain and anxiety even death, as occurred last year in London to a doctor who had taken a ‘safe’ dose. Toxic effects are more liable to occur after several exposures than on first use – that is we are dealing with a phenomena of decreased tolerance or sensitisation.
– Rub out the Words
Fear of censorship by my peers also restrained me but the tie-up between psychedelic drugs and Parkinson’s disease was something I stored up in my brain attic for possible future scientific exploration. Medical history had taught me that something that was not specifically sought and owed nothing to hypothesis-driven research could culminate in an important discovery. I hoped that serendipity and random recombination could help me find a molecule that could permanently reset the catecholamine imbalance to the default position and loosen the rigid structures of the brain.
6
– The Speed Laboratory –
After two years in the hospital my clinical skills had improved sufficiently for me to embark on the next phase of my training. Although the chemical revolution had stalled and Parkinson’s disease remained incurable, clinical pharmacology was still an exciting field. There was growing optimism that the advances taking place in the life sciences would soon translate to new treatments and in 1978 I was excited to be given an opportunity to pitch for glory in the ‘serotonin lab’ of Gerald Curzon at the Institute of Neurology in Chenies Mews.
I found out quickly that neurological practice and research were two different worlds with very different methodologies and incommensurate languages. Science required an appreciation of balanced experimental design. Everything had to be quantified or calculated if it was to be believed. It spoke in jargon and impenetrable prose.
My project was to inject albino Sprague-Dawley rats with a high dose of d-amphetamine and then observe how drugs with different effects on the brain’s serotonin (5-hydroxytryptamine) pathways further modified the animals’ behaviour. Serotonin was believed to play an important role in the regulation of appetite and sleep and low brain levels had been linked to depression.
Amphetamines release dopamine from nerve terminals. They cause rodents to rear up, sniff and lick, weave their heads from side to side and run aggressively up and down in their cages. My experiments were designed to explore serotonin’s interaction with dopamine.
At a dose of 15 milligrams per kilogram of damphetamine, the rats circled and walked backwards. These peculiar behaviours were similar to those seen with hallucinogens including LSD-25 and mescaline in laboratory animals. They also resembled the repetitive rotations seen in caged zoo animals and the behavioural vices of disturbed farm animals. After I had quantified the individual behaviours using laboratory counters and rating scales, I would then inject one of a panel of drugs known to modify brain serotonin. One of the drugs I used was fluoxetine, which blocked the re-uptake of serotonin into the nerve terminals and would later be marketed as Prozac, the best-selling and controversial drug for depression.
At the end of each experiment, I would guillotine the rats, dissect their brain from the skull and freeze the tissue for neurochemical analysis. My naive idea of work in a laboratory had been based on the apparent infallibility of routine blood tests and the ease of ordering investigations on the wards. As I learned to centrifuge, homogenise, pipette, amplify and sacrifice in a vain attempt to acquire the tools of the trade, I realised that the skills I had learned in the hospital were of negligible use in the lab.
Although neurology training took many years and the prospect of obtaining a consultant post in a teaching hospital was small, the career path for the young doctoral scientists I now worked with was far more uncertain. Their shorter working day and relative freedom from responsibility hardly justified their risible pay scale. During my short stay in the laboratory some of my colleagues, trying to live on salaries barely above the minimum working wage, were forced to sell their souls to the pharmaceutical industry, join the brain drain or reluctantly abandon research altogether and take positions as laboratory managers or administrators. It was the Winter of Discontent and I came to see those who clung to their scientific principles as admirable idealists.
Amphetamines were first synthesised in the late nineteenth century but little interest was shown in them until the 1930s when the pharmaceutical company Smith, Kline and French introduced Benzedrine (dl-amphetamine) inhalers for the relief of hay fever and asthma. Amphetamines were also found to have mild benefits in Parkinson’s disease and became established as a treatment for depression, hyperactivity and poor attention in children. During World War II they were widely used by the Allies to combat fatigue and increase bravado but concerns about the increasingly widespread use of ‘Mother’s little helpers’ and ‘Purple Hearts’ in the 1960s led to their recreational (‘off-label’) use being outlawed in Europe and North America. It was hardly surprising that a class of drugs reported to give limitless energy, increase vigilance, aid weight loss and improve sexual performance, might prove attractive to human beings. Stockbrokers were able to stay up all night to play the international markets and be in the office the following morning fresh as daisies. Unscrupulous professional sportsmen got an edge on their adversaries, broke records and achieved a tarnished glory. Long distance truck drivers reached ever more demanding deadlines without falling asleep at the wheel. ‘Speed’, as it was known on the street, offered a short cut to prosperity and bliss and incited the capitalist dream. I thought of Jack Kerouac’s day and night typing of On the Road where he had used a continuous scroll of paper to allow him to record passively each and every event over a three-week Benzedrine jag:
Benny has made me see a lot. The process of intensifying awareness naturally leads to an overflow of old notions, and voila, new material wells up like water forming its proper level, and makes itself evident at the brim of consciousness.
Kerouac claimed that amphetamines had accelerated his thought processes and allowed him to write in ‘the now’. They helped him to find a new, spontaneous way of writing that banished convention and directly communicated raw physical and emotional experience. In contrast to Burroughs, who revised over and over again, Kerouac believed the first draft was always the best.
Most scientific papers were riddled with technical language and obscure acronyms and used specialised terms that made them incomprehensible to all but the cognoscenti. I learned about prejudices, conceit, jealousies, and pressure to publish and also how difficult it could be to reproduce the results even of one’s own experiments. Some of the referees of my first publications seemed positively vindictive. One night, after a long day with ‘the speed rats’ when I was supposed to be writing up my research at home, Burroughs spoke to me – I pulled out Junkie and read what it was like for him to be on ‘Bennys’:
I began talking very fast. My mouth was dry and my spit came out in round white balls-spitting cotton, it’s called. […] I was full of expansive benevolent feelings and suddenly wanted to call on people I hadn’t seen in months or even years, people I did not like and who did not like me.
Burroughs also wrote
that the suspiciousness of many amphetamine addicts was justified because their interminable, rambling, agitated monologues alienated even their friends. I then turned to his scientific analysis that had been published in the Appendix of Naked Lunch:
This is a cerebral stimulant like cocaine. Large doses cause prolonged sleeplessness with feelings of exhilaration. The period of euphoria is followed by a horrible depression. The drug tends to increase anxiety. It causes indigestion and loss of appetite.
His descriptions of ‘speed’ stuck in my head; those I had read in standard pharmacology textbooks did not. It was his mixing of registers that was so imprinting – one minute clean and clinical and the next throwing in an unruly, inappropriate phrase. Writing up my research demanded a dry, storyless discourse governed by abstract nouns, tangled clauses and passive verbs. I needed Burroughs’ colourful and authentic prose to revive me.
The circling and backward walking seen in the rats had been caused by a massive outpouring of dopamine and was increased further by serotonin release. These studies in the laboratory gave me the idea to investigate drugs that antagonised serotonin in the brain as potential treatments for the abnormal involuntary movements and visual illusions seen as complications of L-DOPA in Parkinson’s disease.
After several rejections, my printed communications were eventually published. These sanitised articles didn’t tell half the story but I was proud of them. My unembroidered scientific papers were a travesty in that the experiments had all been conceived with some unacknowledged expectation of outcome. They provided a misleading narrative of the process of thought and glossed over observations considered irrelevant by my superiors. They had been composed in such a way as to deny the importance of inspired guesses. I felt then – as I still do – that the discussion section of the paper should come at the beginning and not at the end.