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{{Short description|Medication and stimulant}}
{{Distinguish|ephedra|ephedrone|epinephrine}}
{{cs1 config|name-list-style=vanc}}
{{Infobox drug
| Verifiedfields = verified
| Watchedfields = verified
| verifiedrevid = 464189705
| image = Ephedrine v2.svg
| image_class = skin-invert-image
| width = 200px
| alt = Chemical structure of the (1''R'',2''S'')-ephedrine molecule
| image2 = (1R,2S)-Ephedrine molecule from xtal ball.png
| width2 = 225px
| alt2 = Ball-and-stick model of the (1''R'',2''S'')-ephedrine molecule
| caption = (−)-(1''R'',2''S'')-ephedrine chemical structure (top) and ball-and-stick model (bottom)
<!-- Clinical data -->| pronounce = {{IPAc-en|audio=En-us-ephedrine.ogg|ᵻ|ˈ|f|ɛ|d|r|ɪ|n}} or {{IPAc-en|ˈ|ɛ|f|ᵻ|d|r|iː|n}}
| tradename = Akovaz, Corphedra, Emerphed, others
| Drugs.com = Ephedrine: {{drugs.com|monograph|ephedrine}}<br />HCl: {{drugs.com|monograph|ephedrine-hydrochloride}}<br />Sulfate: {{drugs.com|monograph|ephedrine-sulfate}}
| pregnancy_AU = A
| pregnancy_AU_comment =
| pregnancy_category =
| ATC_prefix = C01
| ATC_suffix = CA26
| ATC_supplemental = {{ATC|R01|AA03}}, {{ATC|R01|AB05}} (combinations), {{ATC|R03|CA02}}, {{ATC|S01|FB02}}, {{ATCvet|G04|BX90}}
| legal_AU = S4
| legal_BR = D1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-15 |publisher=[[Diário Oficial da União]] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_CA = Schedule VI
| legal_UK = POM
| legal_UK_comment = /{{nbsp}}P<ref>{{cite web | title=Ephedrine Hydrochloride 15mg Tablets Summary of Product Characteristics (SmPC) | website=emc | url=https://www.medicines.org.uk/emc/product/2577/smpc | access-date=8 October 2020}}</ref><ref>{{cite web | title=Ephedrine Nasal Drops 1.0% Summary of Product Characteristics (SmPC) | website=emc | date=11 March 2015 | url=https://www.medicines.org.uk/emc/product/4840/smpc | access-date=8 October 2020 | archive-date=24 October 2020 | archive-url=https://web.archive.org/web/20201024054433/https://www.medicines.org.uk/emc/product/4840/smpc | url-status=dead }}</ref>
| legal_US = Rx-only
| legal_US_comment = /{{nbsp}}OTC<ref>{{cite web | title=Akovaz- ephedrine sulfate injection | website=DailyMed | date=16 April 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=25828db2-4942-4f7c-a0d5-dc66f82cfb71 | access-date=8 October 2020}}</ref><ref>{{cite web | url=https://ecfr.federalregister.gov/current/title-21/chapter-I/subchapter-D/part-341/subpart-C/section-341.80 | title=Title 21: Food And Drugs Part 341—Cold, Cough, Allergy, Bronchodilator, And Antiasthmatic Drug Products For Over-The-Counter Human Use | website=Electronic Code of Federal Regulations | access-date=8 October 2020}}</ref>
| routes_of_administration = [[Oral administration|By mouth]], [[intravenous]] (IV), [[intramuscular]] (IM), [[subcutaneous injection|subcutaneous]] (SC)
<!-- Pharmacokinetic data -->| bioavailability = 88%<ref name="DrugBank" />
| protein_bound = ~24–29% (5–10% to [[human serum albumin|albumin]])<ref name="VolppHolzgrabe2019">{{cite journal | vauthors = Volpp M, Holzgrabe U | title = Determination of plasma protein binding for sympathomimetic drugs by means of ultrafiltration | journal = Eur J Pharm Sci | volume = 127 | issue = | pages = 175–184 | date = January 2019 | pmid = 30391401 | doi = 10.1016/j.ejps.2018.10.027 | url = }}</ref><ref name="Schmidt2023">{{cite thesis | vauthors = Schmidt S | title=Lang-etablierte Arzneistoffe genauer unter die Lupe genommen: Enantioselektive Proteinbindung und Stabilitätsstudien | trans-title = A closer look at long-established drugs: enantioselective protein binding and stability studies | language = de | publisher= Universität Würzburg | date=2023 | doi=10.25972/opus-34594 | page= | doi-broken-date=15 August 2025 }}</ref><ref name="GadAzabKhattab2021">{{cite journal | vauthors = Gad MZ, Azab SS, Khattab AR, Farag MA | title = Over a century since ephedrine discovery: an updated revisit to its pharmacological aspects, functionality and toxicity in comparison to its herbal extracts | journal = Food Funct | volume = 12 | issue = 20 | pages = 9563–9582 | date = October 2021 | pmid = 34533553 | doi = 10.1039/d1fo02093e | url = }}</ref>
| metabolism = Largely unmetabolized<ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" />
| metabolites = • [[Norephedrine]]<ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989">{{cite journal | vauthors = Chua SS, Benrimoj SI, Triggs EJ | title = Pharmacokinetics of non-prescription sympathomimetic agents | journal = Biopharm Drug Dispos | volume = 10 | issue = 1 | pages = 1–14 | date = 1989 | pmid = 2647163 | doi = 10.1002/bdd.2510100102 | url = }}</ref>
| onset = [[Oral administration|Oral]]: 15–60 minutes<ref name="AHFS2016" /><br />{{Abbrlink|IM|Intramuscular injection}}: 10–20 minutes<ref name="AHFS2016" /><br />{{Abbrlink|IV|Intravenous administration}}: Rapid<ref name="AHFS2016" />
| elimination_half-life = 6{{nbsp}}hours<ref name="DrugBank">{{cite web | title=Ephedrine: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=29 April 2016 | url=https://go.drugbank.com/drugs/DB01364 | access-date=14 July 2024}}</ref>
| duration_of_action = [[Oral administration|Oral]]: 2–4{{nbsp}}hours<br />IV/IM: 60{{nbsp}}minutes
| excretion = Mainly [[urine]] (60% unchanged)<ref name="DrugBank" />
<!-- Identifiers -->| index2_label = as sulfate
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 299-42-3
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number2 = 134-72-5
| CAS_supplemental = <br />[https://commonchemistry.cas.org/detail?cas_rn=50-98-6 50-98-6] ([[hydrochloride]])
| PubChem = 9294
| IUPHAR_ligand = 556
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01364
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 8935
| ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID2 = 4514262
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = GN83C131XS
| UNII2 = U6X61U5ZEG
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00124
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D04018
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 15407
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 211456
| ChEMBL2_Ref = {{ebicite|correct|EBI}}
| ChEMBL2 = 1523964
| synonyms = (−)-Ephedrine; (1''R'',2''S'')-Ephedrine; (1''R'',2''S'')-β-Hydroxy-''N''-methylamphetamine; (1''R'',2''S'')-β-Hydroxy-''N''-methyl-α-methyl-β-phenethylamine
<!-- Chemical data -->| IUPAC_name = (1''R'',2''S'')-2-(methylamino)-1-phenylpropan-1-ol
| C = 10
| H = 15
| N = 1
| O = 1
| SMILES = C[C@@H]([C@@H](C1=CC=CC=C1)O)NC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10-12H,1-2H3/t8-,10-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KWGRBVOPPLSCSI-WPRPVWTQSA-N
}}
<!-- Definition and medical uses -->
'''Ephedrine''' is a [[central nervous system]] (CNS) [[stimulant]] and [[sympathomimetic agent]] that is often used to prevent [[hypotension|low blood pressure]] during [[anesthesia]].<ref name=AHFS2016>{{cite web|title=Ephedrine|url=https://www.drugs.com/monograph/ephedrine.html|publisher=The American Society of Health-System Pharmacists|access-date= 8 September 2017 |url-status=live|archive-url=https://web.archive.org/web/20170909053108/https://www.drugs.com/monograph/ephedrine.html|archive-date=2017-09-09}}</ref> It has also been used for [[asthma]], [[narcolepsy]], and [[obesity]] but is not the preferred treatment.<ref name=AHFS2016/> It is of unclear benefit in [[nasal congestion]].<ref name=AHFS2016/> It can be taken [[oral administration|by mouth]] or by [[intramuscular|injection into a muscle]], [[intravenous|vein]], or [[subcutaneous injection|just under the skin]].<ref name=AHFS2016/> Onset with intravenous use is fast, while injection into a muscle can take 20{{nbsp}}minutes, and by mouth can take an hour for effect.<ref name=AHFS2016/> When given by injection, it lasts about an hour, and when taken by mouth, it can last up to four hours.<ref name=AHFS2016/>
<!-- Side effects and mechanism of action -->
Common [[side effect]]s include [[insomnia|trouble sleeping]], [[anxiety]], [[headache]], [[hallucination]]s, [[hypertension|high blood pressure]], [[tachycardia|fast heart rate]], [[decreased appetite|loss of appetite]], and [[urinary retention]].<ref name=AHFS2016/> Serious side effects include [[stroke]] and [[myocardial infarction|heart attack]].<ref name=AHFS2016/> While probably safe in [[pregnancy]], its use in this population is poorly studied.<ref>{{cite book| vauthors = Briggs GG, Freeman RK, Yaffe SJ |title=Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk|date=2011|publisher=Lippincott Williams & Wilkins|___location=Philadelphia|isbn=9781608317080|page=495|edition=9th|url=https://books.google.com/books?id=OIgTE4aynrMC&pg=PA495|url-status=live|archive-url= https://web.archive.org/web/20170908191457/https://books.google.com/books?id=OIgTE4aynrMC&pg=PA495 |archive-date=2017-09-08}}</ref><ref name=PB2016>{{cite web|title=Ephedrine Pregnancy and Breastfeeding Warnings|url=https://www.drugs.com/pregnancy/ephedrine.html|access-date=8 October 2017|url-status=live|archive-url=https://web.archive.org/web/20170805145931/https://www.drugs.com/pregnancy/ephedrine.html|archive-date=5 August 2017}}</ref> Use during [[breastfeeding]] is not recommended.<ref name=PB2016/> Ephedrine works by [[norepinephrine releasing agent|inducing the release of norepinephrine]] and hence indirectly activating the [[α-adrenergic receptor|α-]] and [[β-adrenergic receptor]]s.<ref name=AHFS2016/> Chemically, ephedrine is a [[substituted amphetamine]] and is the (1''R'',2''S'')-[[enantiomer]] of [[hydroxymethylamphetamine|β-hydroxy-''N''-methylamphetamine]].<ref name="PubChem" />
<!-- History, society, and culture -->
Ephedrine was first [[chemical isolate|isolated]] in 1885 and came into commercial use in 1926.<ref>{{cite book | vauthors = Soni MG, Shelke K, Amin R, Talati | chapter = A Lessons from the Use of Ephedra Products as a Dietary Supplement | veditors = Bagchi D, Preuss HG |title=Obesity epidemiology, pathophysiology, and prevention|date=2013|publisher=CRC Press|___location=Boca Raton, Florida|isbn=9781439854266|page=692|edition=2nd|chapter-url=https://books.google.com/books?id=6oHRBQAAQBAJ&pg=PA692|url-status=live|archive-url=https://web.archive.org/web/20170908191457/https://books.google.com/books?id=6oHRBQAAQBAJ&pg=PA692|archive-date=2017-09-08}}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=541 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA541 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | ___location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2016/> It can normally be found in plants of the ''[[Ephedra (plant)|Ephedra]]'' genus.<ref name="AHFS2016" /><ref name="AbourashedEl-AlfyKhan2003">{{cite journal | vauthors = Abourashed EA, El-Alfy AT, Khan IA, Walker L | s2cid = 41083359 | title = Ephedra in perspective—a current review | journal = Phytotherapy Research | volume = 17 | issue = 7 | pages = 703–712 | date = August 2003 | pmid = 12916063 | doi = 10.1002/ptr.1337 }}</ref> [[Over-the-counter drug|Over-the-counter]] [[dietary supplement]]s containing ephedrine are illegal in the United States,<ref name="AHFS2016" /> with the exception of those used in [[traditional Chinese medicine]], where its presence is noted by [[Ephedra (plant)|''má huáng'']].<ref name=AHFS2016/><ref name="AbourashedEl-AlfyKhan2003" />
==Medical uses==
[[Image:EphedrineInBottles.jpg|thumb|right|Ephedrine Sulphate (1932), Ephedrine Compound (1932), and Swan-Myers Ephedrine Inhalant No. 66 (''circa'' 1940).]]
Ephedrine is a non-[[catecholamine]] [[sympathomimetic]] with cardiovascular effects similar to those of [[adrenaline]] (epinephrine): increased blood pressure, heart rate, and contractility. Like [[pseudoephedrine]], it is a [[bronchodilator]], with pseudoephedrine having considerably less effect.<ref name=Butterworth2022>{{cite book | vauthors = Butterworth IV JF, Mackey DC, Wasnick JD | chapter = Chapter 14. Adrenergic Agonists & Antagonists. | title = Morgan & Mikhail's Clinical Anesthesiology | edition = 7th | date = 2022 | publisher = McGraw-Hill Education | chapter-url = https://accessanesthesiology.mhmedical.com/content.aspx?bookid=3194§ionid=266518784 | isbn = 978-1-260-47379-7 }}</ref><ref name='drew'>{{cite journal | vauthors = Drew CD, Knight GT, Hughes DT, Bush M | title = Comparison of the effects of D-(-)-ephedrine and L-(+)-pseudoephedrine on the cardiovascular and respiratory systems in man | journal = British Journal of Clinical Pharmacology | volume = 6 | issue = 3 | pages = 221–5 | date = September 1978 | pmid = 687500 | pmc = 1429447 | doi = 10.1111/j.1365-2125.1978.tb04588.x }}</ref>
Ephedrine may decrease [[motion sickness]], but it has mainly been used to decrease the sedating effects of other medications used for motion sickness.<ref>{{cite book | vauthors = Buckey Jr JC |title=Space Physiology |date=2006 |publisher=Oxford University Press |isbn= 978-0-1997-4790-0 |page=201 |url= https://books.google.com/books?id=Jn_i6KbutXYC&pg=PA201 }}</ref><ref>{{cite book | vauthors = Sanford CA, Jong EC |title=The Travel and Tropical Medicine Manual E-Book |date=2008 |publisher=Elsevier Health Sciences |isbn=978-1437710694 |page=139 |url= https://books.google.com/books?id=gAz-_hBG90sC&pg=PA139 }}</ref>
Ephedrine is also found to have quick and long-lasting responsiveness in [[congenital myasthenic syndrome]] in early childhood and also even in adults with a novel [[COLQ]] mutation.<ref>{{Cite journal| vauthors = Higashida K, Yamada M, Shimohata T |date=2021-04-13|title=Quick and long-lasting responsiveness by ephedrine in an adult woman with congenital myasthenic syndrome associated with a novel COLQ mutation. (2928) |url= https://n.neurology.org/content/96/15_Supplement/2928 |journal=Neurology|volume=96|issue=15 Supplement|article-number=2928 |doi=10.1212/WNL.96.15_supplement.2928 |s2cid=266124150 |issn=0028-3878|url-access=subscription}}</ref>
Ephedrine is administered by intravenous boluses. Redosing usually requires increased doses to offset the development of [[tachyphylaxis]], which is attributed to the depletion of catecholamine stores.<ref name=Butterworth2022/>
===Weight loss===
Ephedrine promotes modest short-term [[weight loss]],<ref>{{cite journal | vauthors = Shekelle PG, Hardy ML, Morton SC, Maglione M, Mojica WA, Suttorp MJ, Rhodes SL, Jungvig L, Gagné J | display-authors = 6 | title = Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis | journal = JAMA | volume = 289 | issue = 12 | pages = 1537–45 | date = March 2003 | pmid = 12672771 | doi = 10.1001/jama.289.12.1470 }}</ref> specifically fat loss, but its long-term effects are unknown.<ref>{{cite journal | vauthors = Dwyer JT, Allison DB, Coates PM | title = Dietary supplements in weight reduction | journal = Journal of the American Dietetic Association | volume = 105 | issue = 5 Suppl 1 | pages = S80-6 | date = May 2005 | pmid = 15867902 | doi = 10.1016/j.jada.2005.02.028 | url = https://zenodo.org/record/1259087 }}</ref> In mice, ephedrine is known to stimulate [[thermogenesis]] in the [[brown adipose tissue]], but because adult humans have only small amounts of brown fat, thermogenesis is assumed to take place mostly in the [[skeletal muscle]]. Ephedrine also decreases [[gastric emptying]]. [[Methylxanthine]]s such as [[caffeine]] and [[theophylline]] have a synergistic effect with ephedrine for weight loss. This led to the creation and marketing of compound products.<ref name="BrayBouchard2004">{{cite book | vauthors = Bray GA, Bouchard C |title=Handbook of obesity |url= https://books.google.com/books?id=YVQPOfKYJhUC&pg=PA494 |year=2004 |publisher= CRC Press |isbn=978-0-8247-4773-2 |pages=494–496 |url-status=live |archive-url= https://web.archive.org/web/20140626190101/http://books.google.com/books?id=YVQPOfKYJhUC&pg=PA494 |archive-date= 2014-06-26}}</ref> One of them, known as the [[ECA stack]], contains ephedrine with caffeine and aspirin. It is a popular supplement taken by [[bodybuilding|bodybuilders]] seeking to cut body fat before a competition.<ref>{{cite journal | vauthors = Magkos F, Kavouras SA | title = Caffeine and ephedrine: physiological, metabolic and performance-enhancing effects | journal = Sports Medicine | volume = 34 | issue = 13 | pages = 871–89 | year = 2004 | pmid = 15487903 | doi = 10.2165/00007256-200434130-00002 | s2cid = 1966020 }}</ref>
A 2021 systematic review found that ephedrine led to a {{convert|2|kg}} weight loss greater than placebo, raised [[heart rate]], and reduced [[LDL]] and raised [[High-density lipoprotein|HDL]], with no statistically significant difference in [[blood pressure]].<ref>{{cite journal | vauthors = Yoo HJ, Yoon HY, Yee J, Gwak HS | title = Effects of Ephedrine-Containing Products on Weight Loss and Lipid Profiles: A Systematic Review and Meta-Analysis of Randomized Controlled Trials | journal = Pharmaceuticals | volume = 14 | issue = 11 | pages = 1198 | date = November 2021 | pmid = 34832979 | pmc = 8618781 | doi = 10.3390/ph14111198 | doi-access = free }}</ref>
===Available forms===
{{See also|Theophylline/ephedrine}}
Ephedrine is available as a [[prescription drug|prescription-only]] [[pharmaceutical drug]] in the form of an [[intravenous]] [[Solution (chemistry)|solution]], under brand names including Akovaz, Corphedra, Emerphed, and Rezipres as well as in [[generic drug|generic form]]s, in the United States.<ref name="Drugs@FDA">{{cite web | title=Drugs@FDA: FDA-Approved Drugs | publisher = Food and Drug Administration | website=accessdata.fda.gov | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | access-date=14 July 2024}}</ref><ref name="DailyMed">{{cite web | title=Search Results for ephedrine | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=ephedrine&searchdb=all&labeltype=all&sortby=rel&audience=professional&page=1&pagesize=200 | access-date=14 July 2024}}</ref> It is also available [[over-the-counter drug|over-the-counter]] in the form of 12.5 and 25{{nbsp}}mg [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s for use as a [[bronchodilator]] and as a 0.5% concentration [[nasal spray]] for use as a [[decongestant]].<ref name="DailyMed" /> The drug is additionally available in [[combination drug|combination]] with [[guaifenesin]] in the form of oral tablets and liquids.<ref name="DailyMed" /> Ephedrine is provided as the [[hydrochloride]] or [[sulfate]] [[salt (chemistry)|salt]] in pharmaceutical formulations.<ref name="Drugs@FDA" /><ref name="DailyMed" />
==Contraindications==
Ephedrine should not be used in conjunction with certain [[Antidepressant|antidepressants]], namely [[Norepinephrine–dopamine reuptake inhibitor|norepinephrine–dopamine reuptake inhibitors]] (NDRIs), as this increases the risk of symptoms due to excessive serum levels of norepinephrine.{{Citation needed|date=March 2025}}
[[Bupropion]] is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is an NDRI. Its action bears more resemblance to amphetamine than to [[fluoxetine]] in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some [[serotonin]] from presynaptic clefts. It should not be used with ephedrine, as it may increase the likelihood of side effects.{{Citation needed|date=March 2025}}
Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function, [[Hypoxia (medical)|hypoxia]], [[hypercapnia]], [[acidosis]], [[hypertension]], [[hyperthyroidism]], [[prostatic hypertrophy]], [[diabetes mellitus]], [[cardiovascular]] disease, during delivery if maternal blood pressure is >130/80 mmHg, and during lactation.<ref name =Mayne>Mayne Pharma. Ephedrine sulfate injection DBL (Approved Product Information). Melbourne: Mayne Pharma; 2004</ref>
[[Contraindications]] for the use of ephedrine include: [[glaucoma|closed-angle glaucoma]], [[phaeochromocytoma]], [[Hypertrophic cardiomyopathy#Obstructive and non-obstructive|asymmetric septal hypertrophy]] (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) [[monoamine oxidase inhibitor]] (MAOI) therapy, general [[anesthesia]] with halogenated hydrocarbons (particularly [[halothane]]), tachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants.{{citation needed|date=March 2023}}
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.<ref name =Mayne />
==Side effects==
Ephedrine is a potentially dangerous natural compound; {{as of|2004|lc=yes}} the US [[Food and Drug Administration]] (FDA) had received over 18,000 reports of adverse effects in people using it.<ref name="Palamar2011" />
[[Adverse drug reaction]]s (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include <ref name=JFC>Joint Formulary Committee. [[British National Formulary]], 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004. {{ISBN|0-85369-587-3}}</ref>
* Cardiovascular: [[tachycardia]], cardiac [[Heart arrhythmia|arrhythmia]]s, [[angina pectoris]], [[vasoconstriction]] with [[hypertension]]
* [[Dermatology|Dermatological]]: flushing, sweating, [[acne vulgaris]]
* [[Gastrointestinal tract|Gastrointestinal]]: nausea
* [[Genitourinary system|Genitourinary]]: decreased urination due to vasoconstriction of renal arteries, difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation
* [[Nervous system]]: restlessness, [[confusion]], [[insomnia]], mild euphoria, [[mania]]/[[hallucinations]] (rare except in previously existing psychiatric conditions), [[delusions]], [[formication]] (may be possible, but lacks documented evidence) [[paranoia]], [[hostility]], [[panic]], [[Psychomotor agitation|agitation]]
* [[Respiratory system|Respiratory]]: [[dyspnea]], pulmonary edema
* Miscellaneous: dizziness, headache, tremor, [[hyperglycemia|hyperglycemic]] reactions, dry mouth
==Overdose==
[[Overdose]] of ephedrine may result in [[sympathomimetic]] [[symptom]]s like [[tachycardia]] and [[hypertension]].{{Citation needed|date=August 2024}}
==Interactions==
Ephedrine with [[monoamine oxidase inhibitor]]s (MAOIs) like [[phenelzine]] and [[tranylcypromine]] can result in [[hypertensive crisis]].{{Citation needed|date=August 2024}}
==Pharmacology==
===Pharmacodynamics===
{| class="wikitable sortable floatright" style="font-size:small;"
|+ Monoamine release by ephedrine and related agents ({{Abbrlink|EC<sub>50</sub>|half maximal effective concentration}}, nM)<ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = Eur. J. Pharmacol. | volume = 479 | issue = 1–3 | pages = 23–40 | year = 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054}}</ref><ref name="RothmanBaumann2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Curr Top Med Chem | volume = 6 | issue = 17 | pages = 1845–1859 | date = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 | url = }}</ref>
|-
! Compound !! data-sort-type="number" | {{abbrlink|NE|Norepinephrine}} !! data-sort-type="number" | {{abbrlink|DA|Dopamine}} !! data-sort-type="number" | {{abbrlink|5-HT|Serotonin}} !! Ref
|-
| [[Dextroamphetamine]] (''S''(+)-amphetamine) || 6.6–7.2 || 5.8–24.8 || 698–1765 || <ref name="RothmanBaumannDersch2001">{{cite journal | vauthors = Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS | title = Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | journal = Synapse | volume = 39 | issue = 1 | pages = 32–41 | date = January 2001 | pmid = 11071707 | doi = 10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3 | url = }}</ref><ref name="BaumannPartillaLehner2013">{{cite journal | vauthors = Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW | title = Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products | journal = Neuropsychopharmacology | volume = 38 | issue = 4 | pages = 552–562 | year = 2013 | pmid = 23072836 | pmc = 3572453 | doi = 10.1038/npp.2012.204 }}</ref>
|-
| [[Cathinone|''S''(–)-Cathinone]] || 12.4 || 18.5 || 2366 || <ref name="RothmanVuPartilla2003">{{cite journal | vauthors = Rothman RB, Vu N, Partilla JS, Roth BL, Hufeisen SJ, Compton-Toth BA, Birkes J, Young R, Glennon RA | title = In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates | journal = J Pharmacol Exp Ther | volume = 307 | issue = 1 | pages = 138–145 | date = October 2003 | pmid = 12954796 | doi = 10.1124/jpet.103.053975 | url = }}</ref>
|-
| Ephedrine ((–)-ephedrine) || 43.1–72.4 || 236–1350 || >10000 || <ref name="RothmanBaumannDersch2001" />
|-
| (+)-Ephedrine || 218 || 2104 || >10000 || <ref name="RothmanBaumannDersch2001" /><ref name="RothmanVuPartilla2003" />
|-
| [[Dextromethamphetamine]] (''S''(+)-methamphetamine) || 12.3–13.8 || 8.5–24.5 || 736–1291.7 || <ref name="RothmanBaumannDersch2001" /><ref name="BaumannAyestasPartilla2012">{{cite journal | vauthors = Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, Brandt SD, Rothman RB, Ruoho AE, Cozzi NV | title = The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue | journal = Neuropsychopharmacology | volume = 37 | issue = 5 | pages = 1192–203 | date = April 2012 | pmid = 22169943 | pmc = 3306880 | doi = 10.1038/npp.2011.304 | url = }}</ref>
|-
| [[Levomethamphetamine]] (''R''(–)-methamphetamine) || 28.5 || 416 || 4640 || <ref name="RothmanBaumannDersch2001" />
|-
| [[Phenylpropanolamine|(+)-Phenylpropanolamine]] ((+)-norephedrine) || 42.1 || 302 || >10000 || <ref name="RothmanVuPartilla2003" />
|-
| [[Phenylpropanolamine|(–)-Phenylpropanolamine]] ((–)-norephedrine) || 137 || 1371 || >10000 || <ref name="RothmanVuPartilla2003" />
|-
| [[Cathine]] ((+)-norpseudoephedrine) || 15.0 || 68.3 || >10000 || <ref name="RothmanVuPartilla2003" />
|-
| [[L-Norpseudoephedrine|(–)-Norpseudoephedrine]] || 30.1 || 294 || >10000 || <ref name="RothmanVuPartilla2003" />
|-
| (–)-Pseudoephedrine || 4092 || 9125 || >10000 || <ref name="RothmanVuPartilla2003" />
|-
| [[Pseudoephedrine]] ((+)-pseudoephedrine) || 224 || 1988 || >10000 || <ref name="RothmanVuPartilla2003" />
|-
| colspan="7" style="width: 1px; background-color:#eaecf0; text-align: center;" | '''Notes:''' The smaller the value, the more strongly the substance releases the neurotransmitter. See also [[Monoamine releasing agent#Activity profiles|Monoamine releasing agent § Activity profiles]] for a larger table with more compounds.
|-
|}
Ephedrine, a [[sympathomimetic amine]], acts on part of the [[sympathetic nervous system]] (SNS). The principal mechanism of action relies on its indirect stimulation of the [[adrenergic receptor]] system by increasing activation of [[α-adrenergic receptor|α-]] and [[β-adrenergic receptor]]s via [[norepinephrine releasing agent|induction of norepinephrine release]].<ref name=merck>{{cite web | url = http://www.merckmanuals.com/professional/lexicomp/ephedrine.html | date = January 2010 | work = Merck Manuals | title = EPHEDrine | archive-url = https://web.archive.org/web/20110324031411/http://www.merckmanuals.com/professional/lexicomp/ephedrine.html | archive-date = 24 March 2011 }}</ref> The presence of direct interactions with α-adrenergic receptors is unlikely but still controversial.<ref name="Docherty2008" /><ref name='drew'/><ref name="Ma_2007">{{cite journal | vauthors = Ma G, Bavadekar SA, Davis YM, Lalchandani SG, Nagmani R, Schaneberg BT, Khan IA, Feller DR | display-authors = 6 | title = Pharmacological effects of ephedrine alkaloids on human alpha(1)- and alpha(2)-adrenergic receptor subtypes | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 1 | pages = 214–221 | date = July 2007 | pmid = 17405867 | doi = 10.1124/jpet.107.120709 | s2cid = 86429875 }}</ref><ref name="pmid14570629">{{cite journal | vauthors = Kobayashi S, Endou M, Sakuraya F, Matsuda N, Zhang XH, Azuma M, Echigo N, Kemmotsu O, Hattori Y, Gando S | display-authors = 6 | title = The sympathomimetic actions of l-ephedrine and d-pseudoephedrine: direct receptor activation or norepinephrine release? | journal = Anesthesia and Analgesia | volume = 97 | issue = 5 | pages = 1239–1245 | date = November 2003 | pmid = 14570629 | doi = 10.1213/01.ANE.0000092917.96558.3C | doi-access = free }}</ref> <small>L</small>-ephedrine, and particularly its stereoisomer [[norpseudoephedrine]] (which is also present in ''[[Catha edulis]]'') has indirect [[sympathomimetic]] effects and due to its ability to cross the [[blood–brain barrier]], it is a [[Central nervous system|CNS]] [[stimulant]] similar to [[amphetamine]]s, but less pronounced, as it releases norepinephrine and [[dopamine]] in the [[brain]].<ref>{{cite journal | vauthors = Munhall AC, Johnson SW | title = Dopamine-mediated actions of ephedrine in the rat substantia nigra | journal = Brain Research | volume = 1069 | issue = 1 | pages = 96–103 | date = January 2006 | pmid = 16386715 | doi = 10.1016/j.brainres.2005.11.044 | s2cid = 40626692 }}</ref>
===Pharmacokinetics===
====Absorption====
The [[oral administration|oral]] [[bioavailability]] of ephedrine is 88%.<ref name="DrugBank" /> The [[onset of action]] of ephedrine orally is 15 to 60{{nbsp}}minutes, via [[intramuscular injection]] is 10 to 20{{nbsp}}minutes, and via [[intravenous infusion]] is within seconds.<ref name="AHFS2016" />
====Distribution====
Its [[plasma protein binding]] is approximately 24 to 29%, with 5 to 10% bound to [[human serum albumin|albumin]].<ref name="VolppHolzgrabe2019" /><ref name="Schmidt2023" /><ref name="GadAzabKhattab2021" />
====Metabolism====
Ephedrine is largely not [[drug metabolism|metabolized]].<ref name="DrugBank" /> [[Norephedrine]] (phenylpropanolamine) is an [[active metabolite]] of ephedrine formed via ''N''-[[demethylation]].<ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" /> About 8 to 20% of an oral dose of ephedrine is demethylated into norephedrine, about 4 to 13% is [[oxidation|oxidatively]] [[deamination|deaminated]] into [[benzoic acid]], and a small fraction is converted into 1,2-dihydroxy-1-phenylpropane.<ref name="ChuaBenrimojTriggs1989" />
====Elimination====
Ephedrine is [[elimination (pharmacology)|eliminated]] mainly in [[urine]], with 60% (range 53–79%) [[excretion|excreted]] unchanged.<ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" />
The [[elimination half-life]] of ephedrine is 6{{nbsp}}hours.<ref name="DrugBank" /> Its [[duration of action]] orally is 2 to 4{{nbsp}}hours and via intravenous or intramuscular injection is 60{{nbsp}}minutes.{{Citation needed|date=August 2024}}
The elimination of ephedrine is dependent on urinary [[pH]].<ref name="ChuaBenrimojTriggs1989" />
==Chemistry==
Ephedrine, or (−)-(1''R'',2''S'')-ephedrine, also known as (1''R'',2''S'')-β-hydroxy-''N''-methyl-α-methyl-β-phenethylamine or as (1''R'',2''S'')-β-hydroxy-''N''-methylamphetamine, is a [[substituted phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical derivative|derivative]]. It is similar in [[chemical structure]] to [[phenylpropanolamine]], [[methamphetamine]], and [[epinephrine]] (adrenaline). It differs from methamphetamine only by the presence of a [[hydroxyl]] group (–OH). Chemically, ephedrine is an [[alkaloid]] with a [[phenethylamine]] skeleton found in various plants in the genus ''[[Ephedra (genus)|Ephedra]]'' (family [[Ephedraceae]]). It is most usually marketed as the [[hydrochloride]] or [[sulfate]] [[salt (chemistry)|salt]].<ref name="IndexNominum2004" />
It has an experimental [[partition coefficient|log P]] of 1.13, while its predicted log P values range from 0.9 to 1.32.<ref name="PubChem">{{cite web | title=Ephedrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/9294 | access-date=30 August 2024}}</ref><ref name="DrugBank" /><ref name="ChemSpider">{{cite web | title=L-(−)-Ephedrine | website=ChemSpider | date=30 August 2024 | url=https://www.chemspider.com/Chemical-Structure.8935.html | access-date=30 August 2024}}</ref> The [[lipophilicity]] of amphetamines is closely related to their [[blood–brain barrier|brain permeability]].<ref name="BharateMignaniWishwakarma2018">{{cite journal | vauthors = Bharate SS, Mignani S, Vishwakarma RA | title = Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis | journal = J Med Chem | volume = 61 | issue = 23 | pages = 10345–10374 | date = December 2018 | pmid = 29989814 | doi = 10.1021/acs.jmedchem.7b01922 | url = }}</ref> For comparison to ephedrine, the experimental log P of [[methamphetamine]] is 2.1,<ref name="SchepSlaughterBeasley2010">{{cite journal | vauthors = Schep LJ, Slaughter RJ, Beasley DM | title = The clinical toxicology of metamfetamine | journal = Clin Toxicol (Phila) | volume = 48 | issue = 7 | pages = 675–694 | date = August 2010 | pmid = 20849327 | doi = 10.3109/15563650.2010.516752 | url = | quote = Metamfetamine acts in a manner similar to amfetamine, but with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with 1.76 for amfetamine),<sup>4</sup> thereby enabling rapid and extensive transport across the blood–brain barrier.<sup>19</sup>}}</ref> of [[amphetamine]] is 1.8,<ref name="PubChem-Amphetamine">{{cite web | title=Amphetamine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/3007 | access-date=26 July 2024}}</ref><ref name="SchepSlaughterBeasley2010" /> of [[pseudoephedrine]] is 0.89,<ref name="PubChem-Pseudoephedrine">{{cite web | title=Pseudoephedrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/7028 | access-date=25 July 2024}}</ref> of [[phenylpropanolamine]] is 0.7,<ref name="PubChem-Phenylpropanolamine">{{cite web | title=Norephedrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/26934 | access-date=26 July 2024}}</ref> of [[phenylephrine]] is -0.3,<ref name="PubChem-Phenylephrine">{{cite web | title=Phenylephrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/6041 | access-date=21 July 2024}}</ref> and of [[norepinephrine (medication)|norepinephrine]] is -1.2.<ref name="PubChem-Norepinephrine">{{cite web | title=Norepinephrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/439260 | access-date=26 July 2024}}</ref> Methamphetamine has high brain permeability,<ref name="SchepSlaughterBeasley2010" /> whereas phenylephrine and norepinephrine are [[peripherally selective drug]]s.<ref name="Eccles2007">{{cite journal | vauthors = Eccles R | title = Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse | journal = British Journal of Clinical Pharmacology | volume = 63 | issue = 1 | pages = 10–14 | date = January 2007 | pmid = 17116124 | pmc = 2000711 | doi = 10.1111/j.1365-2125.2006.02833.x }}</ref><ref name="FroeseDianGomez2020">{{cite journal | vauthors = Froese L, Dian J, Gomez A, Unger B, Zeiler FA | title = The cerebrovascular response to norepinephrine: A scoping systematic review of the animal and human literature | journal = Pharmacol Res Perspect | volume = 8 | issue = 5 | article-number = e00655 | date = October 2020 | pmid = 32965778 | doi = 10.1002/prp2.655 | pmc = 7510331 | url = }}</ref> The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).<ref name="PajouheshLenz2005">{{cite journal | vauthors = Pajouhesh H, Lenz GR | title = Medicinal chemical properties of successful central nervous system drugs | journal = NeuroRx | volume = 2 | issue = 4 | pages = 541–553 | date = October 2005 | pmid = 16489364 | pmc = 1201314 | doi = 10.1602/neurorx.2.4.541 | url = | quote = Lipophilicity was the first of the descriptors to be identified as important for CNS penetration. Hansch and Leo54 reasoned that highly lipophilic molecules will be partitioned into the lipid interior of membranes and will be retained there. However, ClogP correlates nicely with LogBBB with increasing lipophilicity and increasing brain penetration. For several classes of CNS active substances, Hansch and Leo54 found that blood-brain barrier penetration is optimal when the LogP values are in the range of 1.5-2.7, with a mean value of 2.1. An analysis of small drug-like molecules suggested that for better brain permeation46 and for good intestinal permeability55 the LogD values need to be greater than 0 and less than 3. In comparison, the mean value for ClogP for the marketed CNS drugs is 2.5, which is in good agreement with the range found by Hansch et al.22}}</ref>
Ephedrine hydrochloride has a melting point of 187−188{{nbsp}}°C.<ref name=Budavari>{{cite book | veditors = Budavari S | title = The Merck Index: An encyclopedia of chemicals, drugs, and biologicals | edition = 12th | ___location = Whitehouse Station | publisher = Merck }}</ref>
The [[racemic mixture|racemic]] form of ephedrine is [[racephedrine]] ((±)-ephedrine; ''dl''-ephedrine; (1''RS'',2''SR'')-ephedrine).<ref name="Elks2014" /> A [[stereoisomer]] of ephedrine is [[pseudoephedrine]].<ref name="Elks2014" /> [[Chemical derivative|Derivative]]s of ephedrine include [[methylephedrine]] (''N''-methylephedrine), [[etafedrine]] (''N''-ethylephedrine), [[cinnamedrine]] (''N''-cinnamylephedrine), and [[oxilofrine]] (4-hydroxyephedrine).<ref name="Elks2014" /> [[Structural analog|Analogue]]s of ephedrine include [[phenylpropanolamine]] (norephedrine) and [[metaraminol]] (3-hydroxynorephedrine).<ref name="Elks2014" />
The presence of an ''N''-[[methyl group]] decreases binding affinities at α-adrenergic receptors, compared with norephedrine. Ephedrine, though, binds better than [[N-Methylephedrine|''N''-methylephedrine]], which has an additional methyl group at the nitrogen atom. Also, the [[Stereochemistry|steric]] orientation of the hydroxyl group is important for receptor binding and functional activity.<ref name="Ma_2007" />
===Nomenclature===
[[File:Ephedrine and pseudoephedrine isomers.svg|class=skin-invert-image|thumb|400px|The four stereoisomers of ephedrine.]]
Ephedrine exhibits [[optical isomer]]ism and has two [[chirality (chemistry)|chiral]] centres, giving rise to four [[stereoisomer]]s. By convention, the pair of [[enantiomer]]s with the stereochemistry (1''R'',2''S'') and (1''S'',2''R'') is designated ephedrine, while the pair of enantiomers with the stereochemistry (1''R'',2''R'') and (1''S'',2''S'') is called pseudoephedrine.
The isomer which is marketed is (−)-(1''R'',2''S'')-ephedrine.<ref name=Reynolds>{{cite book | editor=Reynolds JEF | title=Martindale: The complete drug reference | edition=29th | year=1989 | publisher=Pharmaceutical Press | ___location=London | isbn= 978-0-85369-210-2 | vauthors = Reynolds J | title-link=Martindale: The complete drug reference }}</ref>
In the outdated [[Chirality (chemistry)#By configuration: D- and L-|<small>D</small>/<small>L</small> system]] (+)-ephedrine is also referred to as <small>D</small>-ephedrine and (−)-ephedrine as <small>L</small>-ephedrine (in which case, in the [[Fischer projection]], the [[Phenyl group|phenyl ring]] is drawn at the bottom).<ref name="Reynolds"/><ref>{{cite journal | vauthors = Patil PN, Tye A, Lapidus JB | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 148 | issue = 2 | pages = 158–68 | date = May 1965 | pmid = 14301006 | url = http://jpet.aspetjournals.org/content/148/2/158.full.pdf | title = A Pharmacological Study of the Ephedrine Isomers | doi = 10.1016/S0022-3565(25)27031-8 }}</ref>
Often, the <small>D</small>/<small>L</small> system (with [[small caps]]) and the d/l system (with [[lower-case]]) are confused. The result is that the levorotary l-ephedrine is wrongly named <small>L</small>-ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly <small>D</small>-pseudoephedrine.
The [[IUPAC name]]s of the two enantiomers are (1''R'',2''S'')- respectively (1''S'',2''R'')-2-methylamino-1-phenylpropan-1-ol. A synonym is ''erythro''-ephedrine.
===Detection in body fluids===
Ephedrine may be quantified in blood, plasma, or urine to monitor possible abuse by athletes, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial [[immunoassay]] screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic techniques can easily distinguish ephedrine from other phenethylamine derivatives. Blood or plasma ephedrine concentrations are typically in the 20–200{{nbsp}}μg/L range in persons taking the drug therapeutically, 300–3000{{nbsp}}μg/L in abusers or poisoned patients, and 3–20{{nbsp}}mg/L in cases of acute fatal overdosage. The current [[World Anti-Doping Agency]] (WADA) limit for ephedrine in an athlete's urine is 10{{nbsp}}μg/mL.<ref>{{cite web |url= http://list.wada-ama.org/list/s6-stimulants |title=S6. Stimulants | List of Prohibited Substances and Methods |access-date= 2015-10-19 |url-status=dead |archive-url= https://web.archive.org/web/20151023042222/http://list.wada-ama.org/list/s6-stimulants/ |archive-date=2015-10-23 }}</ref><ref>{{cite journal | vauthors = Schier JG, Traub SJ, Hoffman RS, Nelson LS | title = Ephedrine-induced cardiac ischemia: exposure confirmed with a serum level | journal = Journal of Toxicology. Clinical Toxicology | volume = 41 | issue = 6 | pages = 849–53 | year = 2003 | pmid = 14677795 | doi = 10.1081/clt-120025350 | s2cid = 23359388 }}</ref><ref>WADA. ''The World Anti-Doping Code'', World Anti-Doping Agency, Montreal, Canada, 2010. [http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/WADA_Prohibited_List_2010_EN.pdf url] {{webarchive|url=https://web.archive.org/web/20130911050811/http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/WADA_Prohibited_List_2010_EN.pdf |date=2013-09-11 }}</ref><ref>{{cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | ___location = Foster City, CA | date = 2008 | pages = 542–544 }}</ref>
==History==
===Asia===
Ephedrine in its natural form, known as [[Ephedra (plant)|''máhuáng'']] (麻黄) in [[traditional Chinese medicine]], has been documented in China since the [[Han dynasty]] (206 BC – 220 AD) as an [[Asthma|antiasthmatic]] and stimulant.<ref name="principles">{{cite book| vauthors = Levy WO, Kalidas K | veditors = Miller NS |title=Principles of Addictions and the Law: Applications in Forensic, Mental Health, and Medical Practice|date=26 February 2010|publisher=Academic Press|isbn=978-0-12-496736-6|pages=307–308}}</ref> In traditional Chinese medicine, ''máhuáng'' has been used as a treatment for asthma and bronchitis for centuries.<ref name=Ford>{{cite book | veditors = Ford MD, Delaney KA, Ling LJ, Erickson T | title = Clinical Toxicology | ___location = Philadelphia | publisher = WB Saunders | date = 2001 | isbn = 0-7216-5485-1}}</ref>
In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese [[organic chemist]] [[Nagai Nagayoshi]] based on his research on [[Japanese traditional medicine|traditional Japanese]] and [[Chinese herbology|Chinese herbal medicines]].
The industrial manufacture of ephedrine in China began in the 1920s, when [[Merck & Co.|Merck]] began marketing and selling the drug as ephetonin. Ephedrine exports from China to the West grew from 4 to 216 tonnes between 1926 and 1928.<ref name="Dikotter">{{cite book | vauthors = Dikotter F, Laamann LP |title= Narcotic Culture: A History of Drugs in China |date=16 April 2004 |publisher=University of Chicago Press |isbn=978-0-226-14905-9 |page= 199 }}</ref>
===Western medicine===
Ephedrine was first introduced for medical use in the [[United States]] in 1926.<ref name="Palamar2011">{{cite journal | vauthors = Palamar J | title = How ephedrine escaped regulation in the United States: a historical review of misuse and associated policy | journal = Health Policy | volume = 99 | issue = 1 | pages = 1–9 | date = January 2011 | pmid = 20685002 | doi = 10.1016/j.healthpol.2010.07.007 | url = }}</ref>
It was introduced in 1948 in [[Vicks]] Vatronol nose drops (now discontinued) which contained ephedrine sulfate as the active ingredient for rapid nasal decongestion.
==Society and culture==
===Names===
''Ephedrine'' is the [[generic term|generic name]] of the drug and its {{Abbrlink|BAN|British Approved Name}}.<ref name="Elks2014">{{cite book | last=Elks | first=J. | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA793 | access-date=30 August 2024 | page=793}}</ref><ref name="IndexNominum2004">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2004 | isbn=978-3-88763-101-7 | url=https://books.google.com/books?id=EgeuA47Ocm4C&pg=PA450 | access-date=30 August 2024 | page=450}}</ref><ref name="Drugs.com-International">{{cite web | title=Ephedrine (International database) | website=Drugs.com | date=5 August 2024 | url=https://www.drugs.com/international/ephedrine.html | access-date=30 August 2024}}</ref> Its {{Abbrlink|DCF|Dénomination Commune Française}} is ''ephédrine'' while its {{Abbrlink|DCIT|Denominazione Comune Italiana}} is ''efedrina''.<ref name="IndexNominum2004" /><ref name="Drugs.com-International" /> In the case of the [[hydrochloride]] [[salt (chemistry)|salt]], its generic name is ''ephedrine hydrochloride'' and this is its {{Abbrlink|USAN|United States Adopted Name}}, {{Abbrlink|BANM|British Approved Name}}, and {{Abbrlink|JAN|Japanese Accepted Name}}.<ref name="Elks2014" /><ref name="IndexNominum2004" /><ref name="Drugs.com-International" /> In the case of the [[sulfate]] salt, its generic name is ''ephedrine sulfate'' or ''ephedrine sulphate'' and the former is its {{Abbrlink|USAN|United States Adopted Name}} while the latter is its {{Abbrlink|BANM|British Approved Name}}.<ref name="Elks2014" /><ref name="IndexNominum2004" /><ref name="Drugs.com-International" /> A synonym of ephedrine sulfate is ''isofedrol''.<ref name="Elks2014" /> These names all refer to the (1''R'',2''R'')-[[enantiomer]] of ephedrine.<ref name="Elks2014" /><ref name="IndexNominum2004" /> The [[racemic mixture|racemic]] form of ephedrine is known as ''[[racephedrine]]'' and this is its {{Abbrlink|INN|International Nonproprietary Name}} and {{Abbrlink|BAN|British Approved Name}}, while the hydrochloride salt of the racemic form is ''racephedrine hydrochloride'' and this is its {{Abbrlink|USAN|United States Adopted Name}}.<ref name="IndexNominum2000">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum 2000: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2000 | isbn=978-3-88763-075-1 | url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA390 | access-date=30 August 2024 | page=390}}</ref>
===Recreational use===
[[Image:Ephedrine - 10 x 30mg.jpg|thumb|right|Ephedrine tablets.]]
As a [[substituted phenethylamine|phenethylamine]], ephedrine has a similar chemical structure to [[substituted amphetamine|amphetamines]] and is a [[methamphetamine]] [[Structural analog|analog]] having the methamphetamine structure with a [[hydroxyl]] group at the [[Phenylethylamine#Substituted phenethylamines|β position]]. Because of ephedrine's structural similarity to methamphetamine, it can be used to create methamphetamine using [[Redox|chemical reduction]] in which ephedrine's hydroxyl group is removed; this has made ephedrine a highly sought-after chemical precursor in the [[Clandestine chemistry|illicit manufacture]] of [[methamphetamine]].
The most popular method for reducing ephedrine to methamphetamine is similar to the [[Birch reduction]], in that it uses [[anhydrous ammonia]] and [[lithium]] metal in the reaction. The second-most popular method uses red [[phosphorus]] and [[iodine]] in the reaction with ephedrine. Moreover, ephedrine can be synthesized into [[methcathinone]] via simple [[oxidation]]. As such, ephedrine is listed as a table-I precursor under the ''[[United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances]]''.<ref name=UN>[http://www.incb.org/pdf/e/list/red.pdf Microsoft Word – RedListE2007.doc<!-- Bot generated title -->] {{webarchive |url= https://web.archive.org/web/20080227224025/http://www.incb.org/pdf/e/list/red.pdf |date=February 27, 2008 }}</ref>
===Use in exercise and sports===
Ephedrine has been used as a [[performance-enhancing drug]] in [[exercise]] and [[sports]].<ref name="Docherty2008">{{cite journal | vauthors = Docherty JR | title = Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA) | journal = Br J Pharmacol | volume = 154 | issue = 3 | pages = 606–622 | date = June 2008 | pmid = 18500382 | pmc = 2439527 | doi = 10.1038/bjp.2008.124 | url = }}</ref><ref name="Lieberman2001">{{cite journal | vauthors = Lieberman HR | title = The effects of ginseng, ephedrine, and caffeine on cognitive performance, mood and energy | journal = Nutr Rev | volume = 59 | issue = 4 | pages = 91–102 | date = April 2001 | pmid = 11368507 | doi = 10.1111/j.1753-4887.2001.tb06995.x | url = }}</ref><ref name="MagkosKayouras2004">{{cite journal | vauthors = Magkos F, Kavouras SA | title = Caffeine and ephedrine: physiological, metabolic and performance-enhancing effects | journal = Sports Med | volume = 34 | issue = 13 | pages = 871–889 | date = 2004 | pmid = 15487903 | doi = 10.2165/00007256-200434130-00002 | url = }}</ref><ref name="Graham2001">{{cite journal | vauthors = Graham TE | title = Caffeine, coffee and ephedrine: impact on exercise performance and metabolism | journal = Can J Appl Physiol | volume = 26 Suppl | issue = | pages = S103–S119 | date = 2001 | pmid = 11897887 | doi = | url = }}</ref> It can increase [[heart rate]], [[blood pressure]], and [[cardiac contractility]] as well as act as a [[psychostimulant]].<ref name="Docherty2008" /> Ephedrine is often used in combination with [[caffeine]] for performance-enhancing purposes.<ref name="MagkosKayouras2004" /><ref name="Graham2001" />
===Other uses===
In [[chemical synthesis]], ephedrine is used in bulk quantities as a [[chiral auxiliary]] group.<ref>{{cite journal | vauthors = Borsato G, Linden A, Lucchi OD, Lucchini V, Wolstenholme D, Zambon A | title = Chiral polycyclic ketones via desymmetrization of dihaloolefins | journal = The Journal of Organic Chemistry | volume = 72 | issue = 11 | pages = 4272–5 | date = May 2007 | pmid = 17474779 | doi = 10.1021/jo070222g | hdl = 11380/1138891 | url = https://figshare.com/articles/Chiral_Polycyclic_Ketones_via_Desymmetrization_of_Dihaloolefins/3005413 | url-access = subscription }}</ref>
:[[Image:EphedrineChiralAuxiliary.svg|class=skin-invert-image|600px|Ephedrine as chiral auxiliary]]
In [[saquinavir]] synthesis, the half-acid is resolved as its salt with l-ephedrine.
===Legal status===
====Canada====
In January 2002, [[Health Canada]] issued a voluntary recall of all ephedrine products containing more than 8{{nbsp}}mg per dose, all combinations of ephedrine with other stimulants such as caffeine, and all ephedrine products marketed for weight-loss or bodybuilding indications, citing a serious risk to health.<ref name="health-canada">{{cite web |url = http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2002/2002_01_e.html |title= Health Canada requests recall of certain products containing Ephedra/ephedrine |publisher=[[Health Canada]] |date= January 9, 2002 |access-date= July 7, 2009 |archive-url= https://web.archive.org/web/20070206073244/http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/2002/2002_01_e.html |archive-date= February 6, 2007}}</ref> Ephedrine is still sold as an oral nasal decongestant<ref name= "LaccourreyeWerner2015">{{cite journal | vauthors = Laccourreye O, Werner A, Giroud JP, Couloigner V, Bonfils P, Bondon-Guitton E | title = Benefits, limits and danger of ephedrine and pseudoephedrine as nasal decongestants | journal = European Annals of Otorhinolaryngology, Head and Neck Diseases | volume = 132 | issue = 1 | pages = 31–4 | date = February 2015 | pmid = 25532441 | doi = 10.1016/j.anorl.2014.11.001 | doi-access = free }}</ref> in 8{{nbsp}}mg pills as a natural health product, with a limit of 0.4{{spaces}}g (400{{spaces}}mg) per package, the limit established by the Controlled Drugs and Substances Act as it is considered as Class A Precursor.<ref>{{Cite web|author=Legislative Services Branch|date=2021-03-18|title=Consolidated federal laws of canada, Controlled Drugs and Substances Act|url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-18.html|access-date=2021-07-30|website=laws-lois.justice.gc.ca|archive-date=2021-07-30|archive-url=https://web.archive.org/web/20210730190944/https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-18.html|url-status=dead}}</ref>
====United States====
In 1997, the [[Food and Drug Administration|FDA]] proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8{{nbsp}}mg (of active ephedrine) with no more than 24{{nbsp}}mg per day.<ref>[https://web.archive.org/web/20080102053737/http://www.cfsan.fda.gov/~lrd/fr97064a.html Federal Register: June 4, 1997 (Volume 62, Number 107): Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule]</ref> This proposed rule was withdrawn, in part, in 2000 because of "concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products."<ref>[https://web.archive.org/web/20080126192127/http://www.cfsan.fda.gov/~lrd/fr00043a.html Federal Register: April 3, 2000 (Volume 65, Number 64): Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part]</ref> In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use.<ref>[https://web.archive.org/web/20070929121300/http://www.cfsan.fda.gov/~lrd/fr040211.html Federal Register: February 11, 2004 (Volume 69, Number 28): Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk; Final Rule]</ref> On April 14, 2005, the [[United States District Court for the District of Utah|U.S. District Court for the District of Utah]] ruled the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe,<ref>{{cite web |url= http://www.ephedrinehydrochloride.com/204cv409-28.pdf |title=Nutraceutical Corporation; Solaray, Inc., Plaintiffs-appellees, v. Andrew Von Eschenbach, Acting Commissioner, U.S. Food and Drug Administration; United States Food and Drug Administration; Michael O. Leavitt, Secretary of the Department of Health and Human Services; Department of Health and Human Services; United States of America | quote = Defendants-appellants, 459 F.3d 1033 (10th Cir. 2006) |access-date= 2010-07-01 |url-status=usurped |archive-url= https://web.archive.org/web/20110710194438/http://www.ephedrinehydrochloride.com/204cv409-28.pdf |archive-date= 2011-07-10 }}</ref> but on August 17, 2006, the [[United States Court of Appeals for the Tenth Circuit|U.S. Court of Appeals for the Tenth Circuit]] in Denver upheld the FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States.<ref>{{cite court |litigants= Nutraceutical Corporation; Solaray, Inc. Plaintiffs-Appellees vs. Andrew Von Eschenbach, Acting Commissioner, US.. Food and Drug Administration; United States Food and Drug Administration; Michael O. Leavitt, Secretary of the Department of Health and Human Services; Department of Health and Human Services; United States of America |opinion= We find that the FDA correctly followed the congressional directive to analyze the risks and benefits of EDS in determining that there is no dosage level of EDS acceptable for the market. |court= United States Court of Appeals Tenth Circuit |date= August 17, 2006 |access-date= 2007-02-16 |url= http://www.ck10.uscourts.gov/opinions/05/05-4151.pdf |archive-url= https://web.archive.org/web/20080921084346/http://www.ck10.uscourts.gov/opinions/05/05-4151.pdf |url-status= dead }}</ref> Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA.<ref>{{cite web |url= http://www.drugfreesport.com/drug-resources/faq.asp |title=Sport Drug Testing – Drug Programs & Policy – Athletics |access-date= 2011-03-21 |url-status=dead |archive-url=https://web.archive.org/web/20110210135236/http://www.drugfreesport.com/drug-resources/faq.asp |archive-date=2011-02-10 }}</ref> Ephedrine is, however, still legal in many applications outside of dietary supplements. Purchasing is currently limited and monitored, with specifics varying from state to state.
The [[United States House of Representatives|House]] passed the [[Combat Methamphetamine Epidemic Act of 2005]] as an amendment to the renewal of the [[USA PATRIOT Act]]. Signed into law by President [[George W. Bush]] on March 6, 2006, the act amended the [[US Code]] (21 USC 830) concerning the sale of products containing ephedrine and the closely related drug [[pseudoephedrine]]. Both substances are used as [[Drug precursors|precursors]] in the [[Clandestine chemistry|illicit production]] of [[methamphetamine]], and to discourage that use the federal statute included the following requirements for merchants who sell these products:
* A retrievable record of all purchases identifying the name and address of each party to be kept for two years
* Required verification of proof of identity of all purchasers
* Required protection and disclosure methods in the collection of personal information
* Reports to the [[United States Attorney General|Attorney General]] of any suspicious payments or disappearances of the regulated products
* Non-liquid dose form of regulated product may only be sold in unit-dose blister packs
* Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access
* Daily sales of regulated products not to exceed 3.6{{nbsp}}g to a single purchaser, without regard to the number of transactions
* Monthly sales to a single purchaser not to exceed 9{{nbsp}}g of pseudoephedrine base in regulated products
The law gives similar regulations to mail-order purchases, except the monthly sales limit is 7.5{{nbsp}}g.
As a pure herb or tea, ''má huáng'', containing ephedrine, is still sold legally in the US. The law restricts/prohibits its being sold as a dietary supplement (pill) or as an ingredient/additive to other products, like diet pills.
====Australia====
Ephedrine and all ''Ephedra'' species that contain it are considered Schedule 4 substances under the [[Standard for the Uniform Scheduling of Medicines and Poisons|Poisons Standard]]. A Schedule 4 drug is considered a Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription under the [[Standard for the Uniform Scheduling of Medicines and Poisons|Poisons Standard]].
====South Africa====
In South Africa, ephedrine was moved to schedule 6 on 27 May 2008,<ref>{{cite web |url=http://www.doh.gov.za/docs/pr/2008/pr0527.html |title=Rescheduling of Medicines that Contain Ephedrine |access-date=2009-04-18 |url-status=dead |archive-url= https://web.archive.org/web/20090628091843/http://www.doh.gov.za/docs/pr/2008/pr0527.html |archive-date=2009-06-28 }}</ref> which makes pure ephedrine tablets prescription only. Pills containing ephedrine up to 30 mg per tablet in combination with other medications are still available OTC, schedule 1 and 2, for sinus, head colds, and influenza.
====Germany====
Ephedrine was freely available in pharmacies in Germany until 2001. Afterward, access was restricted since it was mostly bought for unindicated uses. Similarly, ephedra can only be bought with a prescription. Since April 2006, all products, including plant parts, that contain ephedrine are only available with a prescription.<ref>[http://www.buzer.de/gesetz/7048/index.htm ''Verordnung zur Neuordnung der Verschreibungspflicht von Arzneimitteln (AMVVNV).''] {{webarchive |url= https://web.archive.org/web/20140517122414/http://www.buzer.de/gesetz/7048/index.htm |date=2014-05-17 }} V. v. 21. Dezember 2005 BGBl. I S. 3632; Geltung ab 1. Januar 2006.</ref>
==Sources==
===Agricultural===
Ephedrine is obtained from the plant ''[[Ephedra sinica]]'' and other members of the genus ''[[Ephedra (plant)|Ephedra]],'' from which the name of the substance is derived. Raw materials for the manufacture of ephedrine and traditional Chinese medicines are produced in China on a large scale. As of 2007, companies produced for export US$13 million worth of ephedrine from 30,000 tons of ephedra annually, or about ten times the amount used in traditional Chinese medicine.<ref name=Chen>{{cite web | vauthors = Long C |url= http://www.chinadialogue.net/article/show/single/en/692-Chinese-medicine-s-great-waste-of-resources |title=Chinese medicine's great waste of resources |date= 15 January 2007 |access-date= 9 May 2016 |url-status=live |archive-url=https://web.archive.org/web/20160530231517/https://www.chinadialogue.net/article/show/single/en/692-Chinese-medicine-s-great-waste-of-resources |archive-date= 30 May 2016 }}</ref>
===Synthetic===
Most of the l-ephedrine produced today for official medical use is made synthetically as the extraction and isolation process from ''E. sinica'' is tedious and no longer cost-effective.<ref>{{cite news |url= http://english.peopledaily.com.cn/english/200111/05/eng20011105_83931.html |title=Chemically Synthesized Ephedrine Put into Mass Production in China |date=November 5, 2001 |url-status=live |archive-url= https://web.archive.org/web/20110629175239/http://english.peopledaily.com.cn/english/200111/05/eng20011105_83931.html |archive-date=June 29, 2011 }}</ref>{{unreliable source?|date=May 2016}}
===Biosynthetic===
[[File:Ephedrine biosynthesis.svg|class=skin-invert-image|thumb|400px|right|Proposed biosynthetic pathway of ephedrine from <small>L</small>-phenylalanine and pyruvic acid.<ref name="Hertweck">{{cite journal | vauthors = Hertweck C, Jarvis AP, Xiang L, Moore BS, Oldham NJ | title = A mechanism of benzoic acid biosynthesis in plants and bacteria that mirrors fatty acid beta-oxidation | journal = ChemBioChem | volume = 2 | issue = 10 | pages = 784–6 | date = October 2001 | pmid = 11948863 | doi = 10.1002/1439-7633(20011001)2:10<784::AID-CBIC784>3.0.CO;2-K | s2cid = 28159196 }}<!--|access-date = 2015-06-10--></ref><ref name="Grue-Sorensen 3714–3715">{{Cite journal |title= Biosynthesis of ephedrine |journal= Journal of the American Chemical Society |date= May 1, 1988 |issn= 0002-7863 |pages= 3714–3715 |volume= 110 |issue= 11 |doi= 10.1021/ja00219a086 | vauthors = Grue-Sorensen G, Spenser ID |bibcode= 1988JAChS.110.3714G }}</ref>]]
Ephedrine was long thought to come from modifying the amino acid <small>L</small>-phenylalanine.<ref name="sciencedirect.com">{{cite journal |title= Participation of C6-C1 unit in the biosynthesis of ephedrine in Ephedra |doi= 10.1016/0031-9422(73)80499-6 |volume=12 |issue=12 |journal= Phytochemistry |pages= 2877–2882 |year= 1973 | vauthors = Yamasaki K, Tamaki T, Uzawa S, Sankawa U, Shibata S |bibcode= 1973PChem..12.2877Y }}</ref> <small>L</small>-Phenylalanine would be decarboxylated and subsequently attacked with ω-aminoacetophenone. Methylation of this product would then produce ephedrine. This pathway has since been disproven.<ref name="sciencedirect.com"/> A new pathway proposed suggests that phenylalanine first forms [[cinnamoyl-CoA]] via the enzymes [[phenylalanine ammonia-lyase]] and acyl CoA ligase.<ref name="Hertweck"/> The cinnamoyl-CoA is then reacted with a hydratase to attach the alcohol functional group. The product is then reacted with a retro-aldolase, forming [[benzaldehyde]]. Benzaldehyde reacts with [[pyruvic acid]] to attach a 2-carbon unit. This product then undergoes transamination and methylation to form ephedrine and its stereoisomer, pseudoephedrine.<ref name="Grue-Sorensen 3714–3715"/>
==References==
{{Reflist}}
==External links==
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