Mentored by a Madman Read online

  Lack of trust and a culture of patient complaining encouraged by government and consumer organisations were further new serious roadblocks. Younger colleagues who were keen to do research were buckling under the sheer volume of inflexible rules, auditing and clinical guidelines. The regulations governing who paid for what in research in the National Health Service were a complex jumble, quite beyond the comprehension of most mortals. The Data Protection Act was another obstruction. After ethical approval, every study involving data from National Health Service records required an application to the Patient Information Advisory Group. If approval was granted the project then had to be reviewed annually to ensure the investigators were moving towards informed consent or anonymisation. Before 1998 I had tried to answer a few of the numerous clinical uncertainties that still existed in everyday neurological practice through ‘reviews of case notes’ at the National Hospital, seldom with permission from the patients but without a single complaint. This was now out of the question without going through months of cumbersome officialdom.

  Policing of research had become extraordinarily bureaucratic, expensive and confusing. Although ethics committees provided necessary protection against research subjects being harmed, the time researchers now had to spend to obtain approval even for minor amendments to their protocol was lengthy. University Research and Development departments, however well intentioned, had bogged down researchers with their unnecessary bean counting and legalistic red tape. They were a cancerous growth eating away at novelty. The big lie was that they were necessary to protect society from maverick physicians conducting poor research. The ‘little men’ like Patrick Steptoe (in vitro fertilisation pioneer) and John Charnley (the man who invented hip replacement) had been extinguished because they did not have the resources or desire to comply with this judgemental administration. A body that had been set up to support and assist researchers had worked against many of them. Blue sky innovation by individuals rather than corporations was stifled whereas derivative research that fitted a standard and recognised format was condoned. Compliance with the rules was now prohibitively expensive except for industry, meaning that the research agenda would be inevitably shaped by profit. The emphasis was on process and political correctness, not ethics or good science. What was even worse was the fact that these bodies within universities were colluding with funders, journals and science leaders to cover up malpractice.

  In some situations over-regulation had led to serious bias with wrong conclusions being drawn. For example if the individual’s right to opt out is extended too far then the collected data will come from a biased sample because those patients who agree to their data being used may be very different from those who don’t.

  Lobbying scientists, media professors and self-satisfied cliques of super-specialists who met periodically to pat themselves on the back and forecast the future were new forces purporting to represent science. Many of these people seemed to believe that research papers were literary products and science was a continuation of politics by another means. Others had grossly over optimistic expectations of the clinical benefits of basic biological research. Medical journals and researchers now counted any media coverage as a good thing and would overextend their results in press releases to sell it. It seemed to me that academic medicine had been hijacked by basic science and was not fit for purpose.

  Everything was now constrained, governed and directed by rules, nothing was possible. Exploitation, abuse and an oppressive bumbledom had not been included in my job plan but I felt acutely aware of all three now. I gave up on one academic clinical pharmacological study after a battle of more than a year, in which despite obtaining funding, ethical approval and free samples of the already licensed drug from the manufacturer, the Hospital Trust where I had worked for thirty years refused to accept indemnity. Some of the desperate patients whom I had told about the proposed study were disappointed when I informed them that unfortunately the trial was not to go ahead. Some offered to sign a consent form that would divorce the hospital from any indemnity for their well-being and safety. In my experience most patients understand that better clinical care depends on research. Many comment that in course of a trial they receive better follow-up, enjoy more time with the doctor, and are given better information about their illness. In a trial I had conducted many years ago, before the routine availability of brain scans, a research volunteer who was acting as a control was found to have a large ‘silent’ tumour, which if it had not been picked up and operated on may well have left him with serious neurological deficit.

  When I sought advice from The Medical Defence Union, the body I paid to provide me with legal support should my competence be questioned, I was advised that it would be unwise to proceed because it would be difficult to defend me if one of the consented patients went back on their word and sued. In other words the patient’s word was not worth the paper it was written on. In the end, my longstanding deep-seated fear of authority prevented me from pressing ahead. The officials and the apparatchiks had won the day while the ever longer delays in sanctioning fresh research were costing lives.

  Of greater concern than the lack of new treatments in Parkinson’s disease was the fact that some of the useful, cheap drugs that had been approved in the NICE National Guidelines for Parkinson’s disease, like amantidine, benzhexol and Sinemet, kept inexplicably disappearing from pharmacies all over the country, leaving patients and their doctors to manage potentially life-threatening, acute, unsupervised drug-withdrawals. The Government took no responsibility for guaranteeing drug supplies or curbing market forces, leading to a system that allowed retail warehouses to sell their stocks for more money to other European countries. Once a drug had become cheap and unprofitable, it was at risk of abandonment even when it was the best available remedy. In keeping with the lamentable reporting of important health issues in the British press, this scandal received scant and low-key coverage.

  In 1776, James Parkinson had been admitted as a pupil to my alma mater. As my career had advanced, his optimism expressed in An Essay on the Shaking Palsy had often spurred me on:

  On the contrary, there appears to be sufficient reason for hoping that some remedial process may ere long be discovered, by which, at least the progress of the disease may be stopped.

  I badly wanted to make up for lost time, overcome the challenges and make Parkinson’s prediction come true. Many important and tractable basic clinical questions had remained ignored and unanswered, to the disappointment of my patients. The solution was clear. I needed to forge alliance with groups representing patients with Parkinson’s disease in order to break free.

  In 1995, at a time when my research group had been investigating the therapeutic potential of a new reversible type A monoamine oxidase inhibitor called moclobemide, I had alighted upon a review article by Juan Sánchez-Ramos from the University of Miami. He described a fascinating bygone chapter in the history of neurological therapeutics that gave me hope that Burroughs had been right and that yagé, despite its inherent dangers, might yet be ‘the final fix’.

  Louis Lewin, the Berlin pharmacologist who had isolated harmine (banisterine) from the B. caapi stems, had described feelings of re-invigoration and faster reactions after self-experimentation. He had then administered the drug to an obese patient in the Neuekolin Hospital who described immediate lightness of her limbs and an improved speed of walking. Encouraged by the alkaloid’s effects on movement he suggested that banisterine might offer hope for sufferers with postencephalitic Parkinson’s syndrome (the sleepy sickness survivors). As he was approaching retirement, he recommended that two younger colleagues, Beringer and Willmans, should conduct the first trials in Heidelberg.

  Beringer, who had published papers on mescaline-induced visions and their relevance to schizophrenia, administered 100 mg of harmine to a volunteer colleague and noted ‘an uncontrollable tremor in the arms and legs, similar to what we see in parkinsonian patients’. Despite this setback he proceeded to treat f
ifteen postencephalitic patients and captured striking improvements in their mobility if not their tremor on a series of cinematographic recordings. One of the patients who had been incapacitated by stiffness and had a spasm of the jaw told him, ‘Doctor, I am healthy again’. Benefit from harmine was seen after about thirty minutes and in some cases lasted for many hours.

  Within a year of Beringer’s published findings in 1928, the Merck Company marketed harmine for the treatment of parkinsonism and made it available to doctors in capsules, suppository and injectable form. Nineteen pages of the Merck Jahrbuch were devoted to its potential as a neurotropic agent and the company’s literature particularly recommended it for younger patients with Parkinson’s disease who had no tremor. Beringer warned his medical colleagues of unrealistic expectations and cautioned that the ‘exaggerated and extravagant reports in the newspapers’ were ‘arousing hopes in the ill that could not be fulfilled’. He drew attention to the variability and unpredictability of harmine’s effect. While some patients had spectacularly improved, others had no benefit and in one or two, tremor had worsened. In 1930, a German physician named Halpern took a dose of 40 mg by mouth and wrote:

  The impression was felt as if consciousness was packed in ether. When lying on a sofa, the light-headedness increased to a feeling of floating and the weight of the body was subjectively less. These clinical observations should be compared to the state of levitation frequently reported to occur with the crude drug ayahuasca or caapi … With higher doses excitation was increased even in an aggressive way … the author who is normally not belligerent started a fight with a man in the street where he was the one who attacked even though according to the circumstances the prospect for the attacker was unfavourable.

  In the 1 March 1929 edition of the periodical Charon-nothefte; der kompass, harmine was heralded as a magic formula and its use spread rapidly throughout continental Western Europe. But by 1932 the high hopes for the drug had all but gone and harmine experienced a fall from grace almost as precipitous as had been its sensational uptake. It still had a few advocates and in 1945 Dr Morell asked Ludwig Stumpfegger to treat Adolf Hitler’s parkinsonism with Merck’s harmine.

  Many of the potions that were used to treat Parkinson’s disease in the nineteenth and first half of the twentieth century such as calabar beans, Raeff’s Bulgarian belladonna concoction, henbane, monkey glands, iron carbonate, and parathyroid extract had rightly been discarded. Only synthetic drugs like trihexiphenidyl (Artane) and orphenadrine (Disipal), whose introduction had hastened the demise of harmine survived and remain useful for the control of rigidity, trembling and spasms. Harmine had never been marketed for depression but the improvements we had seen with moclobemide, the new type A monoamine oxidase inhibitor, in both depression and motor handicap in Parkinson’s disease, kept the flame alive. I had also learned from this paper that yagé was used as a religious sacrament by two state-approved churches in Brazil (União do Vegetal and Santo Daime).

  I next came across another paper in a scarcely-read journal by Dr Marcos Serrano Dueñas, a neurologist working in Quito and Dr Sánchez-Ramos, the author of the banisterine review paper. They had carried out a trial in which thirty previously untreated patients with Parkinson’s disease had been randomised to receive either 200 ml of Banisteriopsis caapi extract or 200 ml of an equally bitter-tasting placebo drink. Highly significant improvements in speed of movement and reductions in stiffness had been seen in the active treatment arm, with feelings of sickness and diarrhoea as the only reported adverse effects. In common with Beringer’s earlier results a worsening of tremor occurred in one or two cases. The dosage the patients received was equivalent to the brew Schultes’ Desana Indian guide had provided Burroughs with and which he had found rather disappointing as a hallucinogen. No researchers or phytopharmaceutical companies pursued these findings and the article had plummeted into the annals of neglected medical literature. The only interest in the paper had come from the medical department of the União do Vegetal. Sanchez-Ramos was invited to present his results at their scientific meeting held in 1992 at the Hotel Gloria in Rio de Janeiro, where cultural and scientific ideas were exchanged relating to caapi as a promoter of health, serenity and wellbeing and its potential as a treatment for nervous ailments.

  The apomorphine saga had taught me that the excavation and re-investigation of remedies consigned to oblivion was an alternative to the ‘bench to bedside’ idyll of academic medicine. Colleagues I spoke to who were employed in the pharmaceutical industry informed me that there were hundreds of unremembered molecules of potential interest sitting on dusty shelves waiting for a plug. They also told me there were virtually no company-sponsored botanists going into the forests as Spruce and Schultes had done.

  I wanted to believe that these more striking results with the stems of the natural vine compared with Merck’s harmine were due to an ‘entourage effect’ in which whole plant extracts could produce better results than the purified alkaloid.

  At my request, Serrano-Dueñas posted several dried B. caapi stems and together with Peter Houghton and Peter Jenner at King’s College London we went on to demonstrate that both harmine and harmaline, identified in the plant material, could release dopamine as well as prevent the neurotransmitter’s breakdown by type A monoamine oxidase inhibition.

  By 2010, government funding had dwindled and the big pharmaceutical companies had all but baled out from drug development in Parkinson’s disease. The flow of new drugs had reduced to a trickle and the patients’ hopes for a fast cure now lay largely in the hands of venture capitalists, wealthy private benefactors and charitable foundations. Any treatment that came through had a new hurdle to overcome which had nothing to do with science. Payers employed by the Department of Health and private insurance companies were now a very important consideration in what had become a 3.5 billion dollar game.

  Drug company sponsored trials had become rewarding for NHS Trust hospitals but they were colossal and impersonal. Data collection from the patient volunteers involved a mechanical, tedious process of box-ticking dictated by the European Medicines Agency and the FDA rather than scientific rationale or even common sense. The Trust often delegated this time-consuming chore involving kilograms of paper to research nurses whose salaries were funded partly by the pharmaceutical company and who did not mind if their name was not included on the eventual publication. Clinical trials now took three times longer than in 1975 and were infinitely more expensive to conduct. Less than one in ten drugs in development made it all the way to the clinic. The heroic era of neuropharmacological research had long vanished and self-experimentation was denigrated for its danger and lack of objectivity. Burroughs’ dream that molecules more potent and less toxic than yagé could be synthesised and find wider medical application had been ignored. Parkinson’s disease research went round in circles with no beginnings and no end. Treatments came and went according to fashion.

  —

  In my sixty-sixth year I prepared myself for a new journey of radical empiricism. Although I had failed in my adolescent desire to follow in the footsteps of Richard Spruce, I had made many contacts with Brazilian neurologists and a meeting of the Brazilian Academy of Neurology to which I was invited in Belém in 2013 finally provided the excuse I had been waiting for. Hallucinogenic molecules could open up frightening new vistas of exploration and if Burroughs was right, my trip to the Amazon would lead me to unimagined cures. I wanted to see whether yagé could infuse my monochromatic research canvas and open up vivid new scientific perspectives.

  I arrive by boat at Tabatinga and climb up the jetty looking for a ride to Colombia. Surrounded on all sides by motorcycles, I bump across the coca frontiers on a tuk tuk past the Hotel Anaconda and the deafening screech of the roosting parakeets in Parque Santander. At Kilometros Seis we turn off Via Leticia and pass a barrier guarded by a languorous guard before entering the shadowy aldeia of the tree spirits.

  Dona Angélica Floréz is a slight, white-haired sto
ryteller with an interest in the unpredictable and a clairvoyant gift. She shares her name with a celestial tree with starburst flowers that is used to promote healing and remove curses. She was born north of the Putumayo in La Chorrera, a municipality notorious during the rubber boom for some of Casa Arana’s worst atrocities. Her family had moved to Leticia at the time of the hostilities between Colombia and Peru in 1932. Her abode is sparsely furnished with a firewood hearth and with a few fading magazine cuttings on the wall. At the back of the house, a door leads out to a patio where a liana with winged fruits coils up a wall and angel’s trumpet flowers open in anticipation of the early evening moths. Dona Angélica’s Indian eyes are like dark mysterious pools. I follow her through the small garden into a dark wooden cabin.

  She sits on the stone floor and puts on a white Arara headdress and beaded necklace. In front of her on a low circular table are four dirty plastic bottles, a heap of fresh leaves and some pieces of vine. I drink the sour dark liquid from a calabash. An intense nausea coming straight from the brain is my first reaction to the brew. The room is silent and soon the candle is extinguished. In the darkness the croak of the yellow dart frog, the sound of children playing in the street outside and the roar of a plane heading for Tabatinga, all seem abnormally penetrating. I feel cold and pensive. Angélica begins to intone in her quivering, sibilant voice. I close my eyes, hunch forward and begin to see preternatural apparitions just beneath my eyelids, a gallimaufry of ever changing faces, an unrecognizable metropolis and the buttresses of Gormenghast. As I travel through inner space, motion sickness comes in stomach-churning gusts. I feel near death. Angélica continues to calm me with her haunting singing. After a long time a curandero called Juan anoints my face and hands with camphor, brushes me with a knotted sprig of leaves and invokes the healing spirits of the trees and the waters.