Mentored by a Madman

by A. J. Lees

  In the November 1989 edition of the Philadelphia Enquirer another participant, Dr Hurtig, said, ‘Doctors should consider giving the drug to all Parkinson’s disease patients.’

  8

  – Crushed Hopes –

  As a result of the preliminary findings of the DATATOP study, it became widely accepted that deprenil might be able to stop Parkinson’s disease spreading through the brain. Knoll’s self-experimentation had received scientific validation from a highly reputable group of investigators.

  Then, in 1993, further long-term analyses of the trial cast doubt on this understandable outburst of misplaced optimism. The new data clearly demonstrated that the disability scores had diminished in some of the deprenil treated patients. This raised an alternative possibility as to why the patients on deprenil had been able to delay starting L-DOPA. A modification of the original conclusions was necessary, with a more guarded interpretation of the findings. It seemed to me that the Parkinson Study Group’s careful and rigorous observations had finally undermined their own unbridled enthusiasm.

  In our 1977 Lancet paper we had drawn attention to improvement seen in some previously untreated patients with deprenil. If the North American DATATOP investigators had paid more attention to this report they may have at least considered an alternative trial design. My thoughts turned back to the numerous instances where respected American colleagues had refused to reference important science published outside their own back yard. If the findings hadn’t appeared in a journal published in the United States of America then they weren’t worth reading!

  When William Landau, a distinguished neurological elder, had the temerity to challenge the validity of the DATATOP conclusions, he was pilloried in the correspondence section of Neurology:

  Certainly, Landau is entitled to express his opinion, but he should not be exempt from peer review or contemporaneous response. Landau offered not a whit of novel, substantive criticism. Rather, he played to the crowd with innuendo, cute turns of phrase and, unfortunately, a large measure of either intentional obfuscation or lack of clear understanding. Landau’s article served only one useful function: it illustrates the need for proper editorial review.

  I largely agreed with Landau’s criticisms and envied ‘his cute turns of phrase’. Almost all the leading figures in American Parkinson’s disease research had taken part in the DATATOP study so it was left to a senior statesman of neurology to provide a salutary word of caution about the increasing unacceptable use of spin in medical research

  The United Kingdom Parkinson’s Disease Research Group reported its preliminary six-year findings in the British Medical Journal in 1995. Contrary to expectations, the group of patients who had received deprenil combined with L-DOPA had an increased mortality rate. This cast serious doubt on deprenil’s neurorestorative potential.

  By this time, I had been elected the convenor and Honorary Secretary for the Group and as spokesman for the trial found myself in the invidious position of being the first person to put a dint in the charmed reputation of a drug that had given so many patients hope.

  Neurologists and patients wanted to believe, and had clung to the notion that deprenil might slow the march of Parkinson’s disease even after the DATATOP volte-face. Deprenil was too alluring to abandon easily and had become a petrified truth. It was now also being promulgated as a possible treatment for Alzheimer’s disease, depression and fatigue. Professional boxers and body builders were taking it illicitly to enhance performance, and in Canada it had been added to dog food to promote canine vitality.

  In contrast to the DATATOP trial that had been widely defended as impeccable peer-reviewed scientific research conducted by a group of experienced and sophisticated clinical trialists, a torrent of criticism engulfed our findings. Particularly vituperative letters were received by the journal from medical statisticians and some members of the United States Parkinson’s Study Group who argued that our methodology and statistical analysis were both inherently flawed. In their view, the lack of a placebo arm for at least the first six months of the trial was a serious shortcoming. Doubt was also cast on the competence of specialists in geriatric medicine to adequately assess disability in Parkinson’s disease.

  Under threat of subpoena I was summoned to give telephone evidence to the United States Food and Drug Administration (FDA). A barrage of hostile questions from regulators and lawyers rained down. The FDA also requested permission and had legal authority to investigate all the paperwork relating to the trial. I felt relieved that our main end point depended on death certification rather than the unreliable clinical rating scales that are even today the only practical way to measure change in physical handicap in Parkinson’s disease. The French Government, on the other hand, wanted to ban deprenil rather than protect it and I was asked to provide a confidential report on the methods and results of our trial. I felt vulnerable and exposed and received no support from the General Medical Council, the Medical Defence Union or the University.

  The Parkinson’s Disease Research Group of the United Kingdom acted promptly and set up an independent data monitoring panel to look for an explanation for the cause of the increased and unexpected mortality seen on the L-DOPA/deprenil combination.

  The commonest cause of death in patients with Parkinson’s disease, as judged from death certification, is pneumonia, either from bacterial or viral infection or aspiration of food into the lungs, but there was extremely limited historical data available to inform the committee. A careful scrutiny of all the death certificates and the autopsy data from those few patients who had received post-mortems, failed to reveal a single explanation for the increased loss of life seen with the L-DOPA/ deprenil combination treatment. In our paper we speculated that the increased number of deaths might have occurred in a subgroup of elderly patients who were at risk of heart rhythm disturbances or drops in blood pressure as a consequence of cardiovascular co-morbidity that would have excluded them from drug company sponsored trials.

  The findings continued to generate debate and acrimony for years. Opponents tried to expunge our British Medical Journal paper from memory by performing half-baked meta-analyses and systematic reviews. Despite Orion Pharma’s attempts to limit the financial damage of the UK Parkinson’s Disease Research Group trial, our results had dented the deprenil business and the drug’s sales fell markedly and rapidly in the United Kingdom.

  Josef Knoll never forgave me and in his book How Deprenyl Slows Brain Aging, published in his 87th year in 2012, he wrote:

  An example of a multicentre clinical trial in which the improper combination of levodopa with deprenil led to confusion and misinterpretation is the one performed by the United Kingdom Parkinson’s Disease Group of the United Kingdom (UK-PDRG) (Lees 1995). Quite unexpectedly this group published an alarming paper claiming that parkinsonian patients treated with L-DOPA combined with deprenil show an increased mortality in comparison with the patients treated with L-DOPA alone. The finding was in striking contradiction to all other studies published in a variety of countries.

  I wished that I had had the opportunity to emphasise to him our very cautious interpretation of the interim results and the Group’s determination to continue the trial after re-randomising the deprenil patients to one of the other two arms. Several years later we were able to show that there was no lasting advantage to starting treatment with either deprenil or bromocriptine and that L-DOPA, contrary to popular opinion, was not toxic, a view that is now generally accepted by all national guidelines and evidence based reviews. Our trial had been conducted on a shoestring budget using the research resource of the National Health Service and neither the investigators nor patients received any form of remuneration. It was also one of the very first trials to emphasise the absolute necessity of increasing the length of follow up in Parkinson’s disease trials to a minimum of ten years.

  Up until his death, Knoll continued to believe and deny. He was a high priest in possession of a great power. I became his academic ene
my because our data had contradicted his starry-eyed view of deprenil. The most charitable explanation I could find for his behaviour was that he was protecting his commercial interest and that he had fallen out of love with the scientific process. His YouTube video, which provided an overview of his book, resembled a sales pitch. The idea of a midbrain enhancer delaying brain aging seemed even more way out now than it had done at the time when I still wanted to believe. I could now see all too clearly the detrimental effect of hype in medicine. The scientific hard sell inevitably underwrote an insecure investment.

  9

  – Rainforest Science –

  In the sixth form at school, I had been introduced to the work of Richard Spruce, a self-taught moss and liverwort collector. Notes of a Botanist on the Amazon and Andes, compiled by Alfred Russel Wallace from Spruce’s personal notebooks, letters and diaries, became my guiding light. Spruce had criss-crossed vast stretches of the Amazon jungle at the same time as Wallace and the entomologist Henry Bates and despite their fierce competitiveness and need to collect specimens to earn a living, these professional naturalists, all from humble backgrounds, had remained friends long after they had returned to England. All three had been forced to descend into a primal chaos to search for a liberating, rational truth.

  Spruce was a negligible interloper on a peculiar errand, but there were times when the portentousness of the Amazon basin had made him feel like a fallen comet, lost and scattered over the earth’s crust. In the upper Uaupés almost every plant he collected was an unrecorded species. He wrote to George Bentham at Kew:

  I well recollect how the banks of the river had become clad with flowers, as it were by some sudden magic, and how I said to myself as I scanned the lofty trees with wistful and disappointed eyes, ‘there goes a new Dipteryx – there goes a new Qualea – there goes a new the Lord knows what!’ until I could no longer bear the sight and covering up my face with my hands, I resigned myself to the sorrowful reflection that I must leave all these fine things to waste their sweetness on the jungle air.

  – Notes of a Botanist on the Amazon and Andes

  Some days he would spend hours rooted to a single spot admiring the arrangements of lichens. What seemed to the uncultured eye like a mind-numbing wilderness had provided him with an opportunity to write his name into history. On some evenings he carried out self-experimentation in an attempt to verify the medicinal and magical properties claimed by the Indians for the plants he had pressed.

  Spruce risked his life in order to discover and study new species of flora. Every lichen, with its millions of emerald ears and golden mouths, held secrets that challenged his erudition. The interrelationships of plants informed him about the world in which he lived. Spruce’s life goal was to expose the laws of nature. He considered plants to be sentient beings that beautified the earth. In a letter to his friend, Daniel Hanbury, he wrote:

  It is true that the Hepaticae have hardly as yet yielded any substance to man capable of stupefying him, or of forcing his stomach to empty its contents, nor are they good for food; but if man cannot torture them to his uses or abuse, they are infinitely useful where God has placed them […] and they are, at the least, useful to, and beautiful in, themselves – surely the primary motive for every individual existence.

  In this green Mars he saw things that he knew had never been seen before by the trained eye – sensational plant forms that he feared he would never behold again. His descriptions left me with an indelible impression of the convulsive beauty of the forest. There was an integrity and essential goodness about his life and a refreshing innocence. His work epitomised the romance and openness of science and brought biology alive.

  Spruce alerted me to how much of the unknown the darkness still held but this should not deter me in my attempts to observe more clearly. He taught me that science was precious and must be pure, that fieldwork had an important part to play in discovery and that unshakeable faith and tenacity were needed to make headway. Despite his abhorrence of any attempt to reduce the Amazon to a list of potential commodities he also hinted in his logbooks that the plants of the rainforest held most of the secrets to understanding and manipulating the chemical systems of the human brain.

  Long after I had given up all hopes of following Spruce into the rainforest, I ran into him for a second time in the course of researching the history of monoamine oxidase inhibitors for the introductory chapters of my doctoral thesis on deprenil. Nine years after his reluctant return from South America, Spruce wrote an article entitled ‘On Some Remarkable Narcotics of the Amazon Valley and Orinoco’ published in Ocean Highways, The Geographical Magazine in 1873. In the article, he related how in November 1852, while staying in the village of Panuré, situated at the base of two treacherous narrow channels on the Rio Uaupés, he had befriended some Tukano Indians and after he had gained their confidence through his fluency in their language, he was invited to attend their Feast of Gifts. He arrived at dusk in a place called Urubú-coará (The Vulture’s Nest) four miles above the rapids to be greeted by the doleful sound of trumpets. In the intermissions between the tribesmen’s communal dancing, an Indian carrying two calabashes of caapi would run from the thatched house murmuring ‘Mo-mo-mo-mo-mo-mo’, then squat to allow the Tukanos gathered in a semi-circle to imbibe the greenish yellow liquid. Within a few minutes of drinking the potion, Spruce recorded that the tribesmen turned pale, retched and began to shiver. Some broke into a sweat and bellowed out in anger, beating their weapons threateningly on the ground while shouting out the names of their enemies. Calmness then descended and some of the intoxicated men closed their glazed eyes briefly before the dancing resumed. Spruce noted that the women were not allowed to witness the feast and were forced to hide away inside the long ancestral house. He also observed that although five or six caapi rituals occurred throughout the night, it was extremely uncommon for any one Indian to drink the brew on more than one occasion.

  Spruce was offered a half measure of the bitter concoction, followed by liberal quantities of manioc beer and palm wine. He was also instructed to smoke a two-foot long tobacco cigar. The overall effect of this heady cocktail of alkaloids was sedation and a nauseous inebriation, forcing him to retire to his hammock.

  He made it his business to learn that the most important ingredient of caapi was a fast growing liana with a thick, double helical stem and an alternate pinnate leaf arrangement. The vine had an attractive inflorescence of tiny pinkish white flowers with five sepals and five petals. After the Tukanos had collected the climbing plant from the forest, the lower part of its stem was beaten in a mortar with some water and then concentrated by boiling. The mixture was then sieved to remove any fibre and stored in a sacred urn.

  Spruce collected some fresh specimens of the twiner that he had found growing in a manioc plot and dispatched them to the Royal Botanical Gardens at Kew for classification and analysis in March 1853. On their eventual arrival at Kew, George Bentham, the systematic botanist, was able to confirm Spruce’s opinion that these voucher samples were a hitherto unclassified species of Malpighiaceae and endorse his proposed provisional Latin name of Banisteria caapi.

  Banisteriopsis caapi, the source of yagé

  The following year Spruce again watched the ceremonial use of caapi, this time among the Guahibo Indians of the Upper Orinoco, and noted that they also chewed the dry stem. He was now convinced that the caapi brew contained a rapidly acting potent substance with divinatory properties quite distinct from opium, Indian hemp and coca and he expressed hope that the samples he had dispatched to Kew would be analysed.

  A few years after Notes of a Botanist had finally been published in 1908 and twenty years after Spruce’s death, the first chemical secrets of caapi were revealed to the world. Banisteria samples were sent by chemists at the University of Bogotá to E. Merck, a pharmaceutical company based in Germany, who had developed a major research interest in the medicinal potential of mind-bending molecules. The scientists working at Merck sent some of
the material to a freelance Berlin pharmacologist called Louis Lewin, who isolated a new alkaloid he called banisterine from the stems. A few years later the Merck chemists showed that banisterine and two other pharmacologically active extracts from the vine, tentatively labelled yageine and telepathine, were all chemically indistinguishable from a nitrogenous molecule called harmine.

  One evening in 1952, while waiting for a train at Grand Central Station in Manhattan, William Burroughs read about yagé (also known as caapi and ayahuasca) in a magazine. The article described how the ‘vine of the soul’ allowed the Indian shaman to foresee the future and communicate with the minds of his ancestors. It went on to describe how a medicine man from the Kofán tribe had been able to envision the city of Copenhagen including some of its street signs and describe them to a Danish explorer. After renouncing psychoanalysis, Burroughs had become increasingly interested in extrasensory perception and clairvoyance and was intrigued by the plant’s alleged pharmacological effects.

  He then carried out research into the plant in the New York Public Library. There he learned that Banisteriopsis caapi was a fast growing liana with a thick stem that could reach a length of sixty feet and that the inner bark was the main source of the hallucinating narcotic. He was disappointed by the dearth of first-hand accounts of yagé’s psychotropic effects and wrote to his former hypnotherapist Dr Wolberg in the hope of obtaining further information. In the letter Burroughs wrote, ‘I don’t know your opinion but I consider telepathy an established fact’. Wolberg informed Burroughs that yagé was under wraps because the US Army were conducting secret experiments with the plant.