the use of apomorphine, both from the associations of its name and doctors being reluctant to give hypodermic injections to alcoholics. in the us, the harrison narcotics tax act made working with any morphine derivatives extremely hard, despite apomorphine itself not being an opiate. in the 1950s the neurotransmitter dopamine was discovered in the brain by katharine montagu, and characterised as a neurotransmitter a year later by arvid carlsson, for which he would be awarded the nobel prize. a. n. ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors. this, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. a series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results. however, there was little clinical consequence. parkinson's disease the use of apomorphine to treat "the shakes" was first suggested by weil in france in 1884, although seemingly not pursued until 1951. its clinical use was first reported in 1970 by cotzias et al., although its emetic properties and short half-life made oral use impractical. a later study found that combining the drug with the antiemetic domperidone improved results significantly. the commercialization of apomorphine for parkinson's disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions. aversion therapy aversion therapy in alcoholism had its roots in russia in the early 1930s, with early papers by pavlov, galant and sluchevsky and friken, and would remain a strain in the soviet treatment of alcoholism well into the 1980s. in the us a particularly notable devotee was dr voegtlin, who attempted aversion therapy using apomorphine in the mid to late 1930s. however, he found apomorphine less able to induce negative feelings in his subjects than the stronger and more unpleasant emetic emetine. in the uk, however, the publication of j y dent's (who later went on to treat burroughs) 1934 paper "apomorphine in the treatment of anxiety states" laid out the main method by which apomorphine would be used to treat alcoholism in britain. his method in that paper is clearly influenced by the then-novel idea of aversion:he is given his favourite drink, and his favourite brand of that drink... he takes it stronger than is usual to him... the small dose of apomorphine, one-twentieth of a grain , is now given subcutaneously into his thigh, and he is told that he will be sick in a quarter of an hour. a glass of whisky and water and a bottle of whisky are left by his bedside. at six o'clock (four hours later) he is again visited and the same treatment is again administered... the nurse is told in confidence that if he does not drink, one-fortieth of a grain of apomorphine should be injected during the night at nine o'clock, one o'clock, and five o'clock, but that if he drinks the injection should be given soon after the drink and may be increased to two hourly intervals. in the morning at about ten he is again given one or two glasses of whisky and water... and again one-twentieth of a grain of apomorphine is injected... the next day he is allowed to eat what he likes, he may drink as much tea as he likes... he will be strong enough to get up and two days later he leaves the home.however, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex – "though vomiting is one of the ways that apomorphine relives the patient, i do not believe it to be its main therapeutic effect." – and by 1948 he wrote:it is now twenty-five years since i began treating cases of anxiety and alcoholism with apomorphine, and i read my first paper before this society fourteen years ago. up till then i had thought, and, unfortunately, i said in my paper, that the virtue of the treatment lay in the conditioned reflex of aversion produced in the patient. this statement is not even a half truth… i have been forced to the conclusion that apomorphine has some further action than the production of a vomit.this led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in switzerland by dr harry feldmann and later scientific testing in the 1970s, some time after his death. however, the use of apomorphine in aversion therapy had escaped alcoholism, with its use to treat homosexuality leading to the death of a british army captain billy clegg hill in 1962, helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies. opioid addiction in his deposition: testimony concerning a sickness in the introduction to later editions of naked lunch (first published in 1959), william s. burroughs wrote that apomorphine treatment was the only effective cure to opioid addiction he has encountered: the apomorphine cure is qualitatively different from other methods of cure. i have tried them all. short reduction, slow reduction, cortisone, antihistamines, tranquilizers, sleeping cures, tolserol, reserpine. none of these cures lasted beyond the first opportunity to relapse. i can say that i was never metabolically cured until i took the apomorphine cure... the doctor, john yerbury dent, explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme stream of addiction is destroyed over a period of four to five days. once the back brain is regulated apomorphine can be discontinued and only used in case of relapse. he goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting. despite his claims throughout his life, burroughs never really cured his addiction and was back to using opiates within years of his apomorphine "cure". however, he insisted on apomorphine's effectiveness in several works and interviews. society and culture apomorphine has a vital part in agatha christie's detective story sad cypress. the 1965 tuli kupferberg song "hallucination horrors" recommends apomorphine at the end of each verse as a cure for hallucinations brought on by a humorous variety of intoxicants; the song was recorded by the fugs and appears on the album virgin fugs. research there is renewed interest in the use of apomorphine to treat addiction, in both smoking cessation and alcoholism. as the drug is known to be reasonably safe for use in humans, it is a viable target for repurposing. flow chart depicting the role of apomorphine in alzheimer's disease. apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though its efficacy has been limited. nonetheless, it was under development as a treatment for erectile dysfunction by tap pharmaceuticals under the brand name uprima. in 2000, tap withdrew its new drug application after an fda review panel raised questions about the drug's safety, due to many clinical trial subjects fainting after taking the drug. alzheimer's disease apomorphine is reported to be an inhibitor of amyloid beta protein fiber formation, whose presence is a hallmark of alzheimer's disease, and a potential therapeutic under the amyloid hypothesis. alternative administration routes two routes of administration are currently clinically utilized: subcutaneous (either as intermittent injections or continuous infusion) and sublingual. other non-invasive administration routes were investigated as a substitute for parenteral administration, reaching different preclinical and clinical stages. these include: peroral, nasal, pulmonary, transdermal, rectal, and buccal, as well as iontophoresis methods. veterinary use apomorphine is used to inducing vomiting in dogs after ingestion of various toxins or foreign bodies. it can be given subcutaneously, intramuscularly, intravenously, or, when a tablet is crushed, in the conjunctiva of the eye. the oral route is ineffective, as apomorphine cannot cross the blood–brain barrier fast enough, and blood levels don't reach a high enough concentration to stimulate the chemoreceptor trigger zone. it can remove around 40–60% of the contents in the stomach. one of the reasons apomorphine is a preferred drug is its reversibility: in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the phenothiazines (for example, acepromazine). giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorphine's target receptors are already occupied. an animal who undergoes severe respiratory depression due to apomorphine can be treated with naloxone. apomorphine does not work in cats, who have too few dopamine receptors.