Apomorphine

The use of apomorphine to treat "the shakes" was first suggested by Weil in France in 1884,{{cite journal | vauthors = Weil E |date=1884|title=De l'apomorphine dans certain troubles nerveux|trans-title=On apomorphine in certain nervous shakes|journal=Lyon Med|language=fr|volume=48|pages=411–419}} although seemingly not pursued until 1951.{{cite journal | vauthors = Schwab RS, Amador LV, Lettvin JY | title = Apomorphine in Parkinson's disease | journal = Transactions of the American Neurological Association | volume = 56 | pages = 251–253 | year = 1951 | pmid = 14913646 }} Its clinical use was first reported in 1970 by Cotzias et al.,{{cite journal | vauthors = Cotzias GC, Papavasiliou PS, Fehling C, Kaufman B, Mena I | title = Similarities between neurologic effects of L-dopa and of apomorphine | journal = The New England Journal of Medicine | volume = 282 | issue = 1 | pages = 31–33 | date = January 1970 | pmid = 4901383 | doi = 10.1056/NEJM197001012820107 }} 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.{{cite journal | vauthors = Corsini GU, Del Zompo M, Gessa GL, Mangoni A | title = Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson's disease | journal = Lancet | volume = 1 | issue = 8123 | pages = 954–956 | date = May 1979 | pmid = 87620 | doi = 10.1016/S0140-6736(79)91725-2 | s2cid = 43526111 }} 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.{{cite journal | vauthors = Stibe CM, Lees AJ, Kempster PA, Stern GM | title = Subcutaneous apomorphine in parkinsonian on-off oscillations | journal = Lancet | volume = 1 | issue = 8582 | pages = 403–406 | date = February 1988 | pmid = 2893200 | doi = 10.1016/S0140-6736(88)91193-2 | s2cid = 35208453 }}

Apomorphine is used in advanced Parkinson's disease intermittent hypomobility ("off" episodes), where a decreased response to an anti-Parkinson drug such as L-DOPA causes muscle stiffness and loss of muscle control.{{cite web|url=https://www.drugs.com/mtm/apomorphine.html|title=Apomorphine Uses, Side Effects & Warnings|work=Drugs.com|access-date=27 February 2018}}{{cite book|url=https://books.google.com/books?id=WxamCwAAQBAJ&pg=PA210|title=Basic Pharmacology for Nurses – E-Book| vauthors = Clayton BD, Willihnganz M |publisher=Elsevier Health Sciences|year=2016|isbn=978-0-323-37697-6|pages=210–211}} While apomorphine can be used in combination with L-DOPA, the intention is usually to reduce the L-DOPA dosing, as by this stage the patient often has many of dyskinesias caused by L-DOPA and hypermobility periods.{{cite web|url=https://www.drugs.com/monograph/apomorphine-hydrochloride.html|title=Apomorphine Hydrochloride Monograph for Professionals|work=Drugs.com|access-date=26 February 2018}}{{cite journal | vauthors = Chaudhuri KR, Clough C | title = Subcutaneous apomorphine in Parkinson's disease | journal = BMJ | volume = 316 | issue = 7132 | pages = 641 | date = February 1998 | pmid = 9522772 | pmc = 1112674 | doi = 10.1136/bmj.316.7132.641 }} When an episode sets in, the apomorphine is injected subcutaneously or applied sublingually,{{cite journal | vauthors = Paton DM | title = Apomorphine hydrochloride: a sublingual tablet for the OFF episodes in Parkinson's disease | journal = Drugs of Today | volume = 57 | issue = 1 | pages = 5–16 | date = January 2021 | pmid = 33594386 | doi = 10.1358/dot.2021.57.1.3211618 | s2cid = 231945531 }} and signs subside. It is used an average of three times a day. Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the "on" state and using apomorphine as an effective monotherapy.{{cite book|url=https://books.google.com/books?id=uAjdh9lvtYcC&pg=PA35 |title=Principles of Treatment in Parkinson's Disease| vauthors = Schapira AH, Olanow CW |publisher= Elsevier Health Sciences|year=2005|isbn=978-0-7506-5428-9|edition=illustrated|page=35}}

File:Apomorphine therapeutic scheme.png

Apomorphine is reported to be an inhibitor of amyloid beta protein fiber formation, whose presence is a hallmark of Alzheimer's disease. Thus apomorphine is a potential therapeutic under the amyloid hypothesis.{{cite journal | vauthors = Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ | title = New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 42881–42890 | date = November 2002 | pmid = 12167652 | doi = 10.1074/jbc.M206593200 | doi-access = free }}

While it promotes oligomerization of the Aβ40 group of molecules, it inhibits more advanced fibril formation; this is thought to be due to the autoxidation that occurs at the hydroxyl groups. Once this functional group was altered, the inhibitory effect could be seen to decrease, reducing either the indirect or direct interference of the fibril formation.

The protective effects of apomorphine were tested in mouse models with mutations in genes related to AD, such as the amyloid precursor protein gene. Apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze. The levels of the aberrant proteins that lead to neuronal disruption were also tested in the brains of mice. Treatment was seen to decrease the intraneuronal levels of the more aggressive Aβ42 molecule when compared to the control mice. This result is consistent with the finding that another protein linked to AD, tau protein, was seen to decrease with apomorphine treatment.{{cite journal | vauthors = Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J | title = Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation | journal = Annals of Neurology | volume = 69 | issue = 2 | pages = 248–56 | date = February 2011 | pmid = 21387370 | doi = 10.1002/ana.22319 | s2cid = 242138 }}

The main and absolute contraindication to using apomorphine is the concurrent use of adrenergic receptor antagonists; combined, they cause a severe drop in blood pressure and fainting. Alcohol causes an increased frequency of orthostatic hypotension (a sudden drop in blood pressure when getting up), and can also increase the chances of pneumonia and heart attacks. Dopamine antagonists, by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine.

IV administration of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot (thrombus) and block a pulmonary artery (pulmonary embolism).

Nausea and vomiting are common side effects when first beginning therapy with apomorphine;{{cite journal | vauthors = Dressler D | title = Apomorphin bei der Behandlung des Morbus Parkinson | trans-title = Apomorphine in the treatment of Parkinson's Disease | language = de | journal = Der Nervenarzt | volume = 76 | issue = 6 | pages = 681–689 | date = June 2005 | pmid = 15592807 | doi = 10.1007/s00115-004-1830-4 | s2cid = 19617827 }} antiemetics such as trimethobenzamide or domperidone, dopamine antagonists,{{cite conference |vauthors=Youdim MB, Gassen M, Gross A, Mandel S, Grünblatt E |title=Advances in Research on Neurodegeneration, vol. 7 |chapter=Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist; apomorphine |journal=Journal of Neural Transmission. Supplementum |issue=58 |pages=83–96 |year=2000 |pmid=11128615 |doi=10.1007/978-3-7091-6284-2_7 |isbn=978-3-211-83485-5 |publisher=Springer Science & Business Media |veditors= Mizuno Y, Calne DB, Horowski R, Poewe W, Riederer P, Youdim MB |conference=Seventh International Winter Conference on Neurodegeneration and Neuroinflammation. Karuizawa, Nagano, Japan. January 20–22, 1999 }} are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphine's emetic effects that they can discontinue the antiemetic.

Other side effects include orthostatic hypotension and resultant fainting, sleepiness, dizziness, runny nose, sweating, paleness, and flushing.{{cn|date=January 2025}} More serious side effects include dyskinesias (especially when taking L-DOPA), fluid accumulation in the limbs (edema), suddenly falling asleep, confusion and hallucinations, increased heart rate and heart palpitations, and persistent erections (priapism).{{cite web|url=https://medlineplus.gov/druginfo/meds/a604020.html|title=Apomorphine|date=15 June 2017|work=Medline Plus|publisher=US National Library of Medicine|access-date=26 February 2018}} The priapism is caused by apomorphine increasing arterial blood supply to the penis. This side effect has been exploited in studies attempting to treat erectile dysfunction.{{cite book|url=https://books.google.com/books?id=S4GJio79XOUC&pg=PA77|title=Standard Practice in Sexual Medicine| vauthors = Porst H, Buvat J |publisher=John Wiley & Sons|year=2008|isbn=978-1-4051-7872-3|page=77}}

Apomorphine's R-enantiomer is an agonist of both D₁ and D₂ dopamine receptors, with higher activity at D₂. The members of the D₂ subfamily, consisting of D₂, D₃, and D₄ receptors, are inhibitory G protein–coupled receptors. The D₄ receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders.{{cite journal | vauthors = Ptácek R, Kuzelová H, Stefano GB | title = Dopamine D₄ receptor gene DRD4 and its association with psychiatric disorders | journal = Medical Science Monitor | volume = 17 | issue = 9 | pages = RA215–RA220 | date = September 2011 | pmid = 21873960 | pmc = 3560519 | doi = 10.12659/MSM.881925 }} Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states.{{cite journal | vauthors = Stacy M, Silver D | title = Apomorphine for the acute treatment of "off" episodes in Parkinson's disease | journal = Parkinsonism & Related Disorders | volume = 14 | issue = 2 | pages = 85–92 | date = 2008 | pmid = 18083605 | doi = 10.1016/j.parkreldis.2007.07.016 }}

Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway, the limbic system, the hypothalamus, and the pituitary gland.{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/6005|title=Apomorphine| publisher = U.S. National Library of Medicine|work=PubChem|access-date=26 February 2018}} It also increases blood flow to the supplementary motor area and to the dorsolateral prefrontal cortex (stimulation of which has been found to reduce the tardive dyskinesia effects of L-DOPA).{{cite book|url=https://books.google.com/books?id=wOQf3XcExF8C&pg=PA22|title=Parkinson's Disease: The Treatment Options| vauthors = Lewitt P, Oertel WH |publisher=CRC Press|year=1999|isbn=978-1-85317-379-0|page=22}}{{cite journal | vauthors = Rektorová I, Sedláčková S, Telečka S, Hlubočky A, Rektor I | title = Dorsolateral prefrontal cortex: a possible target for modulating dyskinesias in Parkinson's disease by repetitive transcranial magnetic stimulation | journal = International Journal of Biomedical Imaging | volume = 2008 | pages = 372125 | date = 2008 | pmid = 18274665 | pmc = 2233877 | doi = 10.1155/2008/372125 | doi-access = free }} Parkinson's has also been found to have excess iron at the sites of neurodegeneration; both the (R)- and (S)-enantiomers of apomorphine are potent iron chelators and radical scavengers.{{cite book|url=https://books.google.com/books?id=w4PLOkTwKS8C&pg=PA195|title=Scientific Basis for the Treatment of Parkinson's Disease | edition = 2nd | vauthors = Galvez-Jimenez M |publisher=CRC Press|year=2013|isbn=978-0-203-33776-9|page=195}}

Apomorphine also decreases the breakdown of dopamine in the brain (though it inhibits its synthesis as well).{{cite book|url=https://books.google.com/books?id=zZsyBwAAQBAJ&pg=PT238|title=Biogenic Amine Receptors| vauthors = Iversen L |publisher=Springer Science & Business Media|year=2012|isbn=978-1-4684-8514-1|pages=238}}{{cite book|url=https://books.google.com/books?id=MyNwTA-iWvgC&pg=PA123|title=Advances in Pharmacology and Chemotherapy |volume=15 |publisher=Academic Press| vauthors = Garattini S, Goldin A, Hawking F, Kopin IJ |year=1978|isbn=978-0-08-058106-4|pages=27, 93, 96}} It is an upregulator of certain neural growth factors,{{cite journal | vauthors = Ohta M, Mizuta I, Ohta K, Nishimura M, Mizuta E, Hayashi K, Kuno S | title = Apomorphine up-regulates NGF and GDNF synthesis in cultured mouse astrocytes | journal = Biochemical and Biophysical Research Communications | volume = 272 | issue = 1 | pages = 18–22 | date = May 2000 | pmid = 10872797 | doi = 10.1006/bbrc.2000.2732 }} in particular NGF but not BDNF, epigenetic downregulation of which has been associated with addictive behaviour in rats.{{cite journal | vauthors = McGeary JE, Gurel V, Knopik VS, Spaulding J, McMichael J | title = Effects of nerve growth factor (NGF), fluoxetine, and amitriptyline on gene expression profiles in rat brain | journal = Neuropeptides | volume = 45 | issue = 5 | pages = 317–322 | date = October 2011 | pmid = 21820738 | doi = 10.1016/j.npep.2011.06.002 | s2cid = 38444849 }}{{cite journal | vauthors = Heberlein A, Muschler M, Frieling H, Behr M, Eberlein C, Wilhelm J, Gröschl M, Kornhuber J, Bleich S, Hillemacher T | title = Epigenetic down regulation of nerve growth factor during alcohol withdrawal | journal = Addiction Biology | volume = 18 | issue = 3 | pages = 508–510 | date = May 2013 | pmid = 21392176 | doi = 10.1111/j.1369-1600.2010.00307.x | s2cid = 20317993 }}

Apomorphine causes vomiting by acting on dopamine receptors in the chemoreceptor trigger zone of the medulla; this activates the nearby vomiting center.{{cite book|url=https://books.google.com/books?id=ievLulSqwBAC&pg=PA318|title=Veterinary Pharmacology and Therapeutics| vauthors = Riviere JE, Papich MG |publisher=John Wiley & Sons|year=2009|isbn=978-0-8138-2061-3|page=318}}

While apomorphine has lower bioavailability when taken orally, due to not being absorbed well in the GI tract and undergoing heavy first-pass metabolism, it has a bioavailability of 100% when given subcutaneously. It reaches peak plasma concentration in 10–60 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the cerebrospinal fluid. Its lipophilic structure allows it to cross the blood–brain barrier.

Apomorphine possesses affinity for the following receptors (note that a higher K_i indicates a lower affinity):{{cite web | url=https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=apomorphine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | title = PDSP K_i Database | vauthors = Roth BL, Driscol J |author1-link=Bryan Roth|date=12 January 2011|work=Psychoactive Drug Screening Program (PDSP)|publisher=University of North Carolina at Chapel Hill and the United States National Institute of Mental Health|access-date=1 July 2014}} Note: Values for humans are used. If there is more than one value listed for humans, their average is used.{{cite journal | vauthors = Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ | title = Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D₂-like receptor and α₁/α₂-adrenoceptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 303 | issue = 2 | pages = 805–814 | date = November 2002 | pmid = 12388667 | doi = 10.1124/jpet.102.039875 | s2cid = 35238120 }}{{cite journal | vauthors = Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ | title = Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT₁ and 5-HT₂, receptor subtypes | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 303 | issue = 2 | pages = 815–822 | date = November 2002 | pmid = 12388668 | doi = 10.1124/jpet.102.039883 | s2cid = 19260572 }}

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It has a K_i of over 10,000 nM (and thus negligible affinity) for β-adrenergic, H₁, and mACh.

Apomorphine has a high clearance rate (3–5 L/kg/hr) and is mainly metabolized and excreted by the liver. It is likely that while the cytochrome P450 system plays a minor role, most of apomorphine's metabolism happens via auto-oxidation, O-glucuronidation, O-methylation, N-demethylation, and sulfation. Only 3–4% of the apomorphine is excreted unchanged and into the urine. The half-life is 30–60 minutes, and the effects of the injection last for up to 90 minutes.

Toxicity depends on the route of administration; the LD₅₀s in mice were 300 mg/kg for the oral route, 160 mg/kg for intraperitoneal, and 56 mg/kg intravenous.{{cite book| vauthors = Lewis Sr RJ |title=Sax's Dangerous Properties of Industrial Materials|date=2004|publisher=Wiley, John & Sons, Incorporated|isbn=978-0471476627|page=287|edition=11}}

Apomorphine has a catechol structure similar to that of dopamine.

Several techniques exist for the creation of apomorphine from morphine. In the past, morphine had been combined with hydrochloric acid at high temperatures (around 150 °C) to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%.{{cite web| vauthors = Gurusamy N |title=Process for making apomorphine and apocodeine|url=https://patents.google.com/patent/EP2007730A1/en}}

More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type alkaloids, such as phosphoric acid. The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as phthalic anhydride or titanium chloride. The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%.File:Morphine to Apomorphine.png

The pharmacological effects of the naturally-occurring analog aporphine in the blue lotus (Nymphaea caerulea){{cite journal | vauthors = Poklis JL, Mulder HA, Halquist MS, Wolf CE, Poklis A, Peace MR | title = The Blue Lotus Flower (Nymphea caerulea) Resin Used in a New Type of Electronic Cigarette, the Re-Buildable Dripping Atomizer | journal = Journal of Psychoactive Drugs | volume = 49 | issue = 3 | pages = 175–181 | date = July 2017 | pmid = 28266899 | pmc = 5638439 | doi = 10.1080/02791072.2017.1290304 }} were known to the ancient Egyptians and Mayans,{{cite journal | vauthors = Bertol E, Fineschi V, Karch SB, Mari F, Riezzo I | title = Nymphaea cults in ancient Egypt and the New World: a lesson in empirical pharmacology | journal = Journal of the Royal Society of Medicine | volume = 97 | issue = 2 | pages = 84–85 | date = February 2004 | pmid = 14749409 | pmc = 1079300 | doi = 10.1177/014107680409700214 }} with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties.{{cn|date=January 2025}}

The modern medical history of apomorphine begins with its synthesis by Arppe in 1845{{cite journal | vauthors = Taba P, Lees A, Stern G | title = Erich Harnack (1852–1915) and a short history of apomorphine | journal = European Neurology | volume = 69 | issue = 6 | pages = 321–324 | date = 2013 | pmid = 23549143 | doi = 10.1159/000346762 | doi-access = free }} from morphine and sulfuric acid, although it was named sulphomorphide at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulfuric acid in the process, naming the resulting compound apomorphine. Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor Samuel Gee,{{cite journal| vauthors = Gee S |date=1869|title=On the action of a new organic base, apomorphia|journal=Transactions of the Clinical Society of London|volume=2|pages=166–169}} and for the treatment of stereotypies in farmyard animals.{{cite journal | vauthors = Feser J |date=1873|title=Die in neuester Zeit in Anwendung gekommen Arzneimittel: 1. Apomorphinum hydrochloratum|trans-title=The most recently used medicines: 1. Apomorphine hydrochloride|journal=Z Prakt Veterinairwiss|pages=302–306}} Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death.

Apomorphine was one of the earliest used pharmacotherapies for alcoholism. The Keeley Cure (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from James Tompkins{{cite journal| vauthors = Tompkins J |date=1899|title=Apomorphine in Acute Alcoholic Delirium|journal=Medical Record}} and Charles Douglas.{{cite journal | title = Apomorphine as a hypnotic | journal = The Lancet | volume = 155 | issue = 3998 | pages = 1083 | doi = 10.1016/s0140-6736(01)70565-x | date = April 1900 }}{{cite journal| vauthors = Douglas CJ |date=1899|title=The withdrawal of alcohol in delirium tremens|journal=The New York Medical Journal|pages=626}} Tompkins reported, after injection of 6.5 mg ("one tenth of a grain"):{{blockquote|In four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep.}}Douglas saw two purposes for apomorphine:{{blockquote|[it can be used to treat] a paroxysm of dipsomania [an episode of intense alcoholic craving]... in minute doses it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine… Four or even 3m [minim – roughly 60 microlitres] of the solution usually checks for some hours the incessant demands of the patient… when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. Accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. Such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient.}}This use of small, continuous doses (1/30th of a grain, or 2.16 mg by Douglas) of apomorphine to reduce alcoholic craving comes some time before Pavlov's discovery and publication of the idea of the "conditioned reflex" in 1903. This method was not limited to Douglas; the Irish doctor Francis Hare, who worked in a sanatorium outside London from 1905 onward, also used low-dose apomorphine as a treatment, describing it as "the most useful single drug in the therapeutics of inebriety".{{cite book|title=On alcoholism; its clinical aspects and treatment|url=https://archive.org/details/39002010600097.med.yale.edu| vauthors = Hare F |publisher= Churchill |year=1912 |location=London }} He wrote:{{blockquote|In (the) sanatorium it is used in three different sets of circumstances: (1) in maniacal or hysterical drunkenness: (2) during the paroxysm of dipsomania, in order to still the craving for alcohol; and (3) in essential insomnia of a special variety... [after giving apomorphine] the patient's mental condition is entirely altered. He may be sober: he is free from the time being from any craving from alcohol. The craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. These succeeding injections should be quite small, 3 to 6 min. being sufficient. Doses of this size are rarely emetic. There is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze.}}He also noted there appeared to be a significant prejudice against 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.{{cite journal | vauthors = Benes FM | title = Carlsson and the discovery of dopamine | journal = Trends in Pharmacological Sciences | volume = 22 | issue = 1 | pages = 46–47 | date = January 2001 | pmid = 11165672 | doi = 10.1016/S0165-6147(00)01607-2 }} A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors.{{cite journal | vauthors = Ernst AM | title = Relation between the action of dopamine and apomorphine and their O-methylated derivatives upon the CNS | journal = Psychopharmacologia | volume = 7 | issue = 6 | pages = 391–399 | date = May 1965 | pmid = 5831877 | doi = 10.1007/BF00402361 | s2cid = 7445311 }} 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.{{cite journal | vauthors = Moynihan NH | title = The Treatment of Alcoholism in General Practice | journal = The Practitioner | volume = 195 | pages = 223–227 | date = August 1965 | pmid = 14328866 }}{{cite journal | vauthors = Carlsson C, Johansson PR, Gullberg B | title = A double-blind cross-over study: apomorphine/placebo in chronic alcoholics | journal = International Journal of Clinical Pharmacology and Biopharmacy | volume = 15 | issue = 5 | pages = 211–213 | date = May 1977 | pmid = 326687 }}{{cite journal | vauthors = Halvorsen KA, Martensen-Larsen O | title = Apomorphine revived: fortified, prolonged, and improved therapeutical effect | journal = The International Journal of the Addictions | volume = 13 | issue = 3 | pages = 475–484 | date = April 1978 | pmid = 352969 | doi = 10.3109/10826087809045262 }}{{cite journal | vauthors = Jensen SB, Christoffersen CB, Nørregaard A | title = Apomorphine in outpatient treatment of alcohol intoxication and abstinence: a double-blind study | journal = The British Journal of Addiction to Alcohol and Other Drugs | volume = 72 | issue = 4 | pages = 325–330 | date = December 1977 | pmid = 341937 | doi = 10.1111/j.1360-0443.1977.tb00699.x }}{{cite journal | vauthors = Schlatter EK, Lal S | title = Treatment of alcoholism with Dent's oral apomorphine method | journal = Quarterly Journal of Studies on Alcohol | volume = 33 | issue = 2 | pages = 430–436 | date = June 1972 | pmid = 5033142 | doi = 10.15288/qjsa.1972.33.430 }} However, there was little clinical consequence.

Aversion therapy in alcoholism had its roots in Russia in the early 1930s,{{cite book| vauthors = Ban TA | title=Conditioning behavior and psychiatry|date=2008|publisher=AldineTransaction|location=New Brunswick [N.J.]|isbn=978-0-202-36235-9 |oclc=191318001 }} with early papers by Pavlov, Galant and Sluchevsky and Friken,{{cite book|title=Governing habits : treating alcoholism in the post-Soviet clinic | vauthors = Raikhel EA |isbn=9781501703133 |location=Ithaca | publisher = Cornell University Press |oclc=965905763 |year = 2016}} 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,{{cite journal | vauthors = Lemere F, Voegtlin WL | title = An evaluation of the aversion treatment of alcoholism | journal = Quarterly Journal of Studies on Alcohol | volume = 11 | issue = 2 | pages = 199–204 | date = June 1950 | pmid = 15424345 | doi = 10.15288/qjsa.1950.11.199 }} 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"{{cite journal| vauthors = Dent JY |date=1 October 1934|title=Apomorphine in the Treatment of Anxiety States, with Especial Reference to Alcoholism*|journal=British Journal of Inebriety |volume=32|issue=2|pages=65–88|doi=10.1111/j.1360-0443.1934.tb05016.x|issn=1360-0443}} 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:{{blockquote|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 [3.24 mg], 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 [1.62 mg] 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 [3.24 mg] 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:{{blockquote|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{{cite journal | vauthors = De Morsier G, Feldmann H | title = [Apomorphine therapy of alcoholism; report of 500 cases] | journal = Schweizer Archiv für Neurologie und Psychiatrie. Archives Suisses de Neurologie et de Psychiatrie. Archivio Svizzero di Neurologia e Psichiatria | volume = 70 | issue = 2 | pages = 434–440 | date = 1952 | pmid = 13075975 }} 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,{{cite news|url=http://news.bbc.co.uk/1/hi/uk/8251033.stm|title=Gay injustice 'was widespread'|date=12 September 2009|access-date=24 January 2018|language=en-GB}} helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies.

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:

{{Blockquote|text=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".{{cite web|url=http://realitystudio.org/bibliographic-bunker/william-burroughs-and-the-history-of-heroin/|title=William Burroughs and the History of Heroin| vauthors = Birmingham J |date=2 November 2009|work=RealityStudio}} However, he insisted on apomorphine's effectiveness in several works and interviews.{{citation needed|date=May 2018}}

There is renewed interest in the use of apomorphine to treat addiction, in both smoking cessation{{cite journal | vauthors = Morales Rosado JA, Cousin MA, Ebbert JO, Klee EW | title = A Critical Review of Repurposing Apomorphine for Smoking Cessation | journal = Assay and Drug Development Technologies | volume = 13 | issue = 10 | pages = 612–622 | date = December 2015 | pmid = 26690764 | doi = 10.1089/adt.2015.680 }} and alcoholism.{{cite web|url=http://apomorphine.info/|title=Apomorphine – A forgotten treatment for alcoholism|website=apomorphine.info|language=en-GB|access-date=24 January 2018}} As the drug is known to be reasonably safe for use in humans, it is a viable target for repurposing.

Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though its efficacy has been limited.{{cite book|url=https://books.google.com/books?id=ZyYmDwAAQBAJ&pg=PA388|title=The Textbook of Clinical Sexual Medicine| vauthors = Ishak WW |publisher=Springer|year=2017|isbn=978-3-319-52539-6|page=388}} 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.{{cite news|title=Abbott Withdraws Application for an Impotence Pill|url=https://www.nytimes.com/2000/07/01/business/company-news-abbott-withdraws-application-for-an-impotence-pill.html|work=Bloomberg News via The New York Times|date=1 July 2000}}

Two routes of administration are currently clinically utilized: subcutaneous (either as intermittent injections or continuous infusion) and sublingual.{{cn|date=January 2025}} Other non-invasive administration routes were investigated as a substitute for parenteral administration, reaching different preclinical and clinical stages. These include: peroral,{{cite journal | vauthors = Borkar N, Holm R, Yang M, Müllertz A, Mu H | title = In vivo evaluation of lipid-based formulations for oral delivery of apomorphine and its diester prodrugs | journal = International Journal of Pharmaceutics | volume = 513 | issue = 1–2 | pages = 211–217 | date = November 2016 | pmid = 27615708 | doi = 10.1016/j.ijpharm.2016.09.024 }} nasal,{{cite journal | vauthors = Netsomboon K, Partenhauser A, Rohrer J, Elli Sündermann N, Prüfert F, Suchaoin W, Laffleur F, Bernkop-Schnürch A | title = Preactivated thiomers for intranasal delivery of apomorphine: In vitro and in vivo evaluation | journal = European Journal of Pharmaceutics and Biopharmaceutics | volume = 109 | pages = 35–42 | date = December 2016 | pmid = 27615996 | doi = 10.1016/j.ejpb.2016.09.004 }}{{cite journal | vauthors = Kapoor R, Turjanski N, Frankel J, Kleedorfer B, Lees A, Stern G, Bovingdon M, Webster R | title = Intranasal apomorphine: a new treatment in Parkinson's disease | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 53 | issue = 11 | pages = 1015 | date = November 1990 | pmid = 2283516 | pmc = 488291 | doi = 10.1136/jnnp.53.11.1015 }}{{cite journal | vauthors = Sam E, Jeanjean AP, Maloteaux JM, Verbeke N | title = Apomorphine pharmacokinetics in parkinsonism after intranasal and subcutaneous application | journal = European Journal of Drug Metabolism and Pharmacokinetics | volume = 20 | issue = 1 | pages = 27–33 | date = March 1995 | pmid = 7588990 | doi = 10.1007/BF03192285 | s2cid = 7126130 }}{{cite journal | vauthors = Ikechukwu Ugwoke M, Kaufmann G, Verbeke N, Kinget R | title = Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems | journal = International Journal of Pharmaceutics | volume = 202 | issue = 1–2 | pages = 125–131 | date = July 2000 | pmid = 10915935 | doi = 10.1016/S0378-5173(00)00434-8 }} pulmonary,{{cite journal | vauthors = Grosset KA, Malek N, Morgan F, Grosset DG | title = Inhaled dry powder apomorphine (VR040) for 'off' periods in Parkinson's disease: an in-clinic double-blind dose ranging study | journal = Acta Neurologica Scandinavica | volume = 128 | issue = 3 | pages = 166–171 | date = September 2013 | pmid = 23527823 | doi = 10.1111/ane.12107 | s2cid = 22189634 | doi-access = free }} transdermal,{{cite journal | vauthors = Priano L, Albani G, Brioschi A, Calderoni S, Lopiano L, Rizzone M, Cavalli R, Gasco MR, Scaglione F, Fraschini F, Bergamasco B, Mauro A | title = Transdermal apomorphine permeation from microemulsions: a new treatment in Parkinson's disease | journal = Movement Disorders | volume = 19 | issue = 8 | pages = 937–942 | date = August 2004 | pmid = 15300660 | doi = 10.1002/mds.20054 | hdl = 2318/41858 | s2cid = 28397399 | hdl-access = free }} rectal,{{cite journal | vauthors = Van Laar T, Jansen EN, Essink AW, Rutten WJ, Neef C | title = Rectal apomorphine: a new treatment modality in Parkinson's disease | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 55 | issue = 8 | pages = 737–738 | date = August 1992 | pmid = 1527553 | pmc = 489221 | doi = 10.1136/jnnp.55.8.737-a }}{{cite journal | vauthors = van Laar T, Jansen EN, Neef C, Danhof M, Roos RA | title = Pharmacokinetics and clinical efficacy of rectal apomorphine in patients with Parkinson's disease: a study of five different suppositories | journal = Movement Disorders | volume = 10 | issue = 4 | pages = 433–439 | date = July 1995 | pmid = 7565822 | doi = 10.1002/mds.870100405 | s2cid = 30947265 }} and buccal,{{cite journal | vauthors = Itin C, Komargodski R, Barasch D, Domb AJ, Hoffman A | title = Prolonged Delivery of Apomorphine Through the Buccal Mucosa, Towards a Noninvasive Sustained Administration Method in Parkinson's Disease: In Vivo Investigations in Pigs | journal = Journal of Pharmaceutical Sciences | volume = 110 | issue = 4 | pages = 1824–1833 | date = April 2021 | pmid = 33333142 | doi = 10.1016/j.xphs.2020.12.010|issn=0022-3549 | s2cid = 229317834 | doi-access = free }}{{cite journal | vauthors = Itin C, Komargodski R, Domb AJ, Hoffman A | title = Controlled Delivery of Apomorphine Through Buccal Mucosa, Towards a Noninvasive Administration Method in Parkinson's Disease: A Preclinical Mechanistic Study | journal = Journal of Pharmaceutical Sciences | volume = 109 | issue = 9 | pages = 2729–2734 | date = September 2020 | pmid = 32497595 | doi = 10.1016/j.xphs.2020.05.017 | s2cid = 219331493 }} as well as iontophoresis methods.{{cite journal | vauthors = Li GL, de Vries JJ, van Steeg TJ, van den Bussche H, Maas HJ, Reeuwijk HJ, Danhof M, Bouwstra JA, van Laar T | title = Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment | journal = Journal of Controlled Release | volume = 101 | issue = 1–3 | pages = 199–208 | date = January 2005 | pmid = 15588905 | doi = 10.1016/j.jconrel.2004.09.011 }}

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.{{cite book|url=https://books.google.com/books?id=0Hf2DAAAQBAJ&pg=PA94|title=Clinical Pharmacology and Therapeutics for Veterinary Technicians – E-Book| vauthors = Bill RL |publisher=Elsevier Health Sciences|year=2016|isbn=978-0-323-44402-6|page=94}}{{cite book|url=https://books.google.com/books?id=8tu24Au35bkC&pg=PA310|title=Common Toxicologic Issues in Small Animals, an Issue of Veterinary Clinics: Small Animal Practice – E-Book| vauthors = Khan SN, Hooser SB |publisher=Elsevier Health Sciences|year=2012|isbn=978-1-4557-4325-4|page=310}} 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.{{cite book|title=Plumb's Veterinary Drug Handbook| vauthors = Plumb DC |publisher=Wiley|year=2011|isbn=978-0-470-95964-0|edition=7th|location=Stockholm, Wisconsin|pages=77–79|chapter=Apomorphine}}

One of the reasons apomorphine is a preferred drug is its reversibility:{{cite book|url=https://books.google.com/books?id=a36rGkkFo2IC&pg=PA131|title=Small Animal Toxicology| vauthors = Peterson ME, Talcott PA |publisher=Elsevier Health Sciences|year=2006|isbn=978-0-7216-0639-2|page=131}} 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.

• 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.

Mdo-npa, the methylenedioxy analog of apomorphine, has greater bioavailability and a longer duration of action.{{cn|date=January 2025}}

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