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  Fully acquainted with the scientific facts, I now supported Dent’s daughters’ campaign to get the medical establishment to re-investigate the apomorphine pump as a treatment for heroin and alcohol dependence, but my pleas fell on deaf ears. Big Pharma were not interested in drug addiction because of the inherent risks involved. One of the concerns was that even if a new treatment showed promising results an addict might simply override his treatment by overdosing on opiates, leading to bad publicity for their product. The addiction specialists I contacted either failed to respond or said they were too busy to consider setting up a trial. I got the feeling a self-perpetuating substance dependence industry had grown up with strong survival instincts and ambitions for further expansion.

  After our seminal publication in 1988, apomorphine’s use for the treatment of Parkinson’s disease had rapidly spread round the world yet despite its undisputed effectiveness it had not yet managed to clear the regulators in the United States. It had run into the same brick wall Dent had experienced thirty years earlier.

  Throughout the 1990s I carried out many clinical pharmacological experiments to better understand apomorphine’s mode of action and find ways of avoiding the need for injections. Large numbers of morphine derivatives were flooding the market and being dished out to excess in the treatment of chronic pain but the pharmaceutical industry showed no interest in clinical trials on the related aporphines for the management of neurological and psychiatric disorders. Apomorphine survived as an expensive and underused ‘orphan drug’ treatment. At times of disappointment, Burroughs’ writing spurred me on:

  No doubt substances fifty times stronger than apomorphine could be developed and the side effect of vomiting eliminated … I suggest that research with variations of apomorphine and synthesis of it will open a new frontier extending far beyond the problem of addiction.

  – Naked Lunch

  Groups of atoms with structures closely related to apomorphine had now been identified in the flowers and tubers of the Maya’s sacred water lilies and I felt that their study might offer an interesting alternative to Burroughs’ scientific suggestion of spinning the molecular roulette wheel. I was still drawn to the idea that the cure for Parkinson’s disease might lie hidden deep in the Amazon forest and that the chemical structures of lianas, roots and barks might serve as templates from which drug compounds could be created.

  12

  – Hooked on the Medicine –

  In 1999, completely out of the blue, the wife of one of my patients told me that apomorphine had turned her husband into a junky. Over the last year he had become infatuated with its ‘cloud nine’ effects and he had lost all interest in her and the rest of his family. He binged on food, spent money irresponsibly and acted out fantasies with a sex therapist. Sometimes he disappeared for hours and was brought home late at night by the police or paramedics who suspected he was ‘crack dancing’.

  Mr C denied most of his wife’s story but admitted that over the last year he had developed a deep fear of the doom he associated with medication ‘switch-offs’. He also conceded that after taking an L-DOPA capsule or an injection of apomorphine he sometimes felt like a world-beater. I explained to both of them that to my knowledge craving for apomorphine had never been reported in the medical literature. I instructed the patient to limit the number of ‘rescue’ shots he was giving himself to a maximum of six a day and to cut back a little on his L-DOPA.

  Not long after I had dismissed out of hand the possibility of addiction to apomorphine, a second, equally concerning story was drawn to my attention, (a train of events well recognised in medicine that frequently marks the first step in the delineation of a new syndrome). A commercial salesman whom I had been treating for four years told me that over the last few months he had felt an uncontrollable drive to take more and more L-DOPA even though he realised that he may be overdosing. In the space of a year he had doubled his dose and still was not satisfied with the effect. Later that afternoon, I re-read the chastening letter I had received from Mr C’s wife a week after the fraught consultation:

  Dear Dr Lees,

  My husband has changed fundamentally. He has become obsessed with his drugs, their administration, and particularly their effects on his physical condition. It is now like living with a horrible stranger. He has started to lie to me about everything. He never lied before. He has become financially extravagant, so much so that we are now in a great deal of debt. He was always careful and responsible about money. He is injecting himself 15 times a day over his prescribed dose and always has a pocket full of L-DOPA. As for our sexual partnership, that stopped when he discovered that ‘Planet Apomorphine’ was better than sex. I was secretly pleased, as I was so angry I wouldn’t have sex with him anyway. He is no longer the man I married. He has also recently developed ‘fantasy attachments’ to old girlfriends and to some of my female friends and has started to act out his fantasies either by harassing them, turning up at their door late at night in an agitated state or, more frequently, endlessly telephoning them. At the recent consultation, I felt as if I was seen as the ‘problem’ and that you did not believe me. I hope that after receiving this letter you will consider admitting my husband to hospital for a period of detoxification.

  I now understood that I had remained too focused on relieving the patient’s physical discomfort and been oblivious to the undesirable consequences of his medication. I questioned whether my keenness for apomorphine that had returned to neurological practice six years earlier, had clouded my judgement. I had been guilty of blinkered thinking but was still not sure that I needed to apologise. Abuse of medicines prescribed by doctors for pain and mental illness was well recognised but the notion that a highly effective treatment for a degenerative neurological disorder could cause a damaging chemical dependency still seemed implausible.

  Gavin Giovannoni, my senior registrar, and I subsequently identified a further thirteen individuals, all of whom complained that despite a massive escalation of their L-DOPA dose their medication was becoming less and less effective. These patients could sometimes be recognised in the outpatient waiting room because of their drug-fuelled gyrating whirls and pirouettes and their total inability to sit still. They stood out from the motionless silent majority by their restless pacing and fidgeting. When they entered the consulting room they complained bitterly of being ‘under pilled’. They had pressured speech, seemed to be distracted and were hard to engage in rational conversation. Some were drenched in sweat and unable to concentrate.

  One young man told me he had become a slave to his medication and had started to visit other doctors’ surgeries asking for supplies of L-DOPA. I thought of Burroughs’ advice to junkies, ‘You need a good bedside manner with doctors or you will get nowhere’. One of the patients who I had admitted to the hospital in an attempt to reduce his medication confided in me later that he had left his car close to the hospital in a long stay car park and had sneaked out regularly without the nurses’ knowledge to take extra L-DOPA from a cache stockpiled in the boot of his car.

  We soon realised that these ‘overusing’ patients frequently had very disturbed behaviour patterns that included morbid jealousy (the Othello syndrome), irresponsible ruinous internet and scratch card betting and hypersexuality. Unbeknown to his wife, one man had ordered twenty four pet Mexican turtles that arrived at his home by courier, while another man went to the supermarket for a loaf of bread and returned with ten romantic DVDs. One man in his fifties had been imprisoned for attempted rape and another had given away thousands of pounds to a stranger in a bout of reckless generosity. In some cases the seriousness of the medication dependency had only come to light during emergency hospital admissions when the nurses reported to the medical staff that the patient was constantly demanding extra pills. A sense of shame and profound embarrassment combined with a reluctance to associate the damaging behaviour to their medical lifeline had driven a grave problem under the surface. Two of the wives had filed for divorce because of th
eir husband’s insatiable sexual demands. During our investigations I received another desperate letter from a patient’s wife:

  I am pretty much at the end of the line now. My husband is acting so strangely, has cut himself off from me and his daughter who he adores and is almost paranoid that people are watching him. He is living in a complete bubble and honestly thinks that we will all be fine about his selfish actions. He is holding false beliefs which cannot be changed by fact. I literally can’t go on any more and for the psychiatrist to basically say he doesn’t think there is anything wrong with him is beyond me.

  House calls had become a vital part of our inquiries as it was only in the patients’ homes that we could appreciate the true extent of the mayhem. It was also as a result of these domiciliary visits that another hidden and equally disruptive behaviour came to light. We learned that some individuals were carrying out repetitive ritualistic behaviours for hours on end at the expense of everything else, including eating and drinking. A seamstress collected and endlessly sorted thousands of buttons, while another woman withdrew into herself and spent all night marking every object in her house with yellow sticky labels. A man circled London on the orbital bypass twenty or more times a night in his car, while a retired engineer had constructed a monstrous Heath-Robinson computer that grew and grew until it filled the whole of one bedroom. A former jeweller spent all his time purposelessly dismantling old watches and putting them back together again.

  These purposeless activities first reported in bikers using large amounts of intravenous amphetamine had been termed punding, a Swedish word meaning ‘blockhead’. During a ‘run’, some of the amphetamine addicts would pound up and down the same part of the street, or march in circles, often lifting their legs high. A visitor to the Burroughs’ household in New Orleans described how Joan Vollmer would spend all day washing the kitchen wall, mopping and scrubbing the floor of the children’s room and sweeping lizards off the dead tree in the yard while neglecting her own personal hygiene and that of her children – classical signs of Benzedrine-induced punding.

  After several rejections by high impact neurology journals it was evident that the anonymous peer reviewers were highly sceptical of our findings. Some of the comments were scathing and derogatory. One suggested that we had misinterpreted the patients’ stories. The anonymous peer review system that was held in such great esteem seemed to me archaic and dishonest. It was ponderous, prone to bias and abuse and a bit of a lottery. It was also ineffective at spotting errors and deceit. If a referee for a scientific journal had concerns or criticisms about my paper then they should be prepared to release their name.

  We had entitled our paper ‘Hedonistic homeostatic dysregulation’ – technical jargon we lifted from the substance dependence literature in the hope of reducing the risk of media sensationalism and the subsequent inevitable clamour of concern driven by ambulance chasers. ‘Addict’ carried moral connotations that suggested the individual was of weak will and low moral fibre. I did not want to cast doubt yet again on L-DOPA, the single most important therapeutic advance to have occurred in neurology in the previous fifty years.

  A sick joke now going around the pharmaceutical industry was that in the current safety-first society of Western Europe, the most profitable drug to licence and market was a placebo. More and more effort was going into the development of ‘harmless’ drugs with marginal benefits. An increasingly risk-averse society was stifling innovation and I didn’t want to give the lawyers any more ammunition. The Journal of Neurology, Neurosurgery and Psychiatry finally accepted our paper on 24 August 1999, after it had gone through two rounds of extensive but inconsequential revisions.

  The idea that patients could develop an addiction to L-DOPA or apomorphine was considered fanciful and greeted with incredulity by most neurologists. Some thought we were simply describing a pathological failure to resist harmful temptations that had recently been acknowledged as an uncommon complication of therapy with dopamine agonist drugs and which I had first witnessed in the lady on bromocriptine, gambling her money away at bingo in 1976.

  After I had presented our findings at an international Parkinson’s disease conference, one famous and well respected neurologist stood up and stated that he had treated thousands of patients with L-DOPA over thirty years and had never encountered a patient who had become addicted to the treatment. His intonation and manner suggested that I had a vivid imagination and was irresponsibly seeking publicity. He expressed surprise that the editors of a reputable journal had published our findings and went on to say that if by any remote chance our observations had validity then they could be adequately explained by a patient’s understandable attempt to avoid an aversive dysphoric dopamine withdrawal state.

  Experience had taught me to expect this negative reaction to our findings. In many ways it encouraged me because it indicated we had reported something that, despite its gravity, hadn’t been recognised by our colleagues. The reason the distinguished colleague who had cast doubt on our findings had not seen it could be explained by the fact that most of his patients came only once to his office and were then sent back to the referring physician. Despite the opposition within the neurological world I was now convinced of the importance of our naïve empiricism. I also now knew that I had heard similar stories several years earlier but had dismissed them out of hand.

  Just before the paper describing our shocking findings was published, Oliver Sacks, who had now become a friend and occasional visitor to my department, had been moved to congratulate the Editor of JAMA Neurology for permitting a healthy debate in its correspondence column in relation to the lingering suggestions that L-DOPA might actually accelerate dopamine nerve cell loss. He contrasted the journal’s democratic approach to the violent reaction he had faced thirty years earlier when he had drawn attention to the potential of L-DOPA to cause pathological sensitivities in postencephalitic patients. He then nailed his colours to the mast with respect to his own therapeutic preferences:

  I would certainly want to be put on L-DOPA myself, if I became parkinsonian, because nothing else can give comparable benefit. I would want this even knowing that its effects would sooner or later decline and be compromised, and that it might accelerate the disease process or cause neuronal death. The immediate benefit, for me, would outweigh the incalculable future. But others might feel very differently.

  Field work in which we had recorded the distressing stories of our patients’ families had taken us this far but if we were to convince our dubious critics we now needed help from psychiatrists working in the field of drug dependency. Jenny Bearn from the Bethlem Addictions Unit in South London agreed to collaborate, and her research fellow, Mike Kelleher, interviewed the ‘overusing’ patients to determine if they fulfilled established operational psychiatric criteria for addiction. Semi-structured questionnaires were administered in order to distinguish whether adaptive therapeutic dependence on L-DOPA and apomorphine or a pathological pattern of use was responsible. Compared with the matched control patients, the ‘DOPA dysregulators’ experienced more euphoria on medication and more dissatisfaction during the ‘switched off’ state. Dopamine replacement therapy was affecting their lives negatively. One of them had used amphetamine as a stimulant for several years during his teens and two were alcoholics.

  We concluded that a small sub-group of patients had become abnormally dependent on dopamine replacement therapy, a finding that not only had implications for treatment choice in Parkinson’s disease, but also provided further indirect evidence for the role of dopamine in the genesis of substance dependence.

  We next attempted to construct a profile of the dysregulating ‘addicts’ personality before the onset of their Parkinson’s disease from meetings with their family. The patients were asked to fill in some personality inventories with the instruction that they must try to recall what they had been like in the years before their illness had begun, rather than how they felt now. Most of the DOPA addicts were men who had been stru
ck down with Parkinson’s disease in their thirties, forties and fifties and they exhibited risk-taking novelty-seeking traits on the tests similar to those frequently reported in alcoholics and drug addicts. Their behaviour was the converse of that seen in the large majority of people with Parkinson’s disease, who tended to be introspective, cautious, anhedonic, non-smokers.

  Apart from our collaborators at the Bethlem Hospital there was little initial interest in our findings from addiction specialists who rarely read neurology journals and attend different medical meetings. My earlier attempts to kindle interest in further trials with apomorphine in substance-dependence had taught me that psychiatrists were greatly constrained by government policy in relation to what trials they could carry out and what they could safely say in public. After the farrago of misinformation with deprenil I was also determined to minimise any press coverage of our findings. Nevertheless, the dopamine dysregulators offered a perfect surrogate for research into addiction.

  I did receive one or two letters from psychiatrists who raised the very reasonable question that if taking L-DOPA was so rewarding why was it not being used more on the street like other dopamine drugs such as amphetamine and cocaine?

  Elucidation of this conundrum came when one of my patients introduced me to a demi-monde of blogs on the grey web where neophytes recounted a candy-land dream world of DOPA ‘highs.’ The mere contemplation of taking a tablet was a source of great joy for one man who had managed to buy L-DOPA on the Internet. Bodybuilders described using herbal sources of the amino acid (the beans of the cowhage plant) that they had bought to increase muscle bulk and experiencing libidinous and aggressive impulses similar to those they had felt with anabolic steroids. A young sybarite had left an account of a DOPA trip in which he had experienced enhanced colour vision and a ‘return to a childhood world of exceptional beauty and innocence’. On a patient chatline someone had written, ‘Had an insane high on 250 mg L-DOPA, felt like I was king of the earth, sex drive way above my normal levels and feels as if it is still increasing, sensations all take longer and the feel is multiplied, fantastic dreams that are so amazingly vivid that makes it feel as if I have another world to go to when I sleep.’ The patient then told me that his first ‘hit’ had caused a rush through the brain that had never been repeated. He extolled the virtues of Sinemet (one of the proprietary names for L-DOPA) in the following ode: