fenethylline

{{Infobox drug

|Verifiedfields = changed

|verifiedrevid = 461099552

|IUPAC_name = (RS)-1,3-dimethyl- 7-[2-(1-phenylpropan-2-ylamino)ethyl]purine- 2,6-dione

|image = Fenethylline.svg

|image_class = skin-invert-image

|alt = Skeletal formula

|width = 250px

|chirality = Racemic mixture

|image2 = Captagon molecule spacefill.png

|image_class2 = bg-transparent

|alt2 = Space-filling model of the captagon molecule

|INN = Fenetylline

|Drugs.com = {{drugs.com|international|fenethylline-hydrochloride}}

|legal_AU = S9

|legal_BR = A3

|legal_BR_comment = {{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=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}

|legal_CA = Schedule III

|legal_US = Schedule I

|legal_DE = Anlage III

|legal_UK = Class C

|routes_of_administration = Oral

|CAS_number_Ref = {{cascite|correct|CAS}}

|CAS_number = 3736-08-1

|ATC_prefix = N06

|ATC_suffix = BA10

|PubChem = 19527

|DrugBank_Ref = {{drugbankcite|correct|drugbank}}

|DrugBank = DB01482

|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

|ChemSpiderID = 18398

|UNII_Ref = {{fdacite|correct|FDA}}

|UNII = YZ0N7VL5R3

|KEGG_Ref = {{keggcite|correct|kegg}}

|KEGG = D07944

|ChEBI = 135451

|ChEMBL = 2111152

|C=18 | H=23 | N=5 | O=2

|smiles = O=C2N(c1ncn(c1C(=O)N2C)CCNC(C)Cc3ccccc3)C

|StdInChI_Ref = {{stdinchicite|correct|chemspider}}

|StdInChI = 1S/C18H23N5O2/c1-13(11-14-7-5-4-6-8-14)19-9-10-23-12-20-16-15(23)17(24)22(3)18(25)21(16)2/h4-8,12-13,19H,9-11H2,1-3H3

|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

|StdInChIKey = NMCHYWGKBADVMK-UHFFFAOYSA-N

}}

Fenethylline (BAN, USAN) or fenetylline (INN) is a codrug of amphetamine and theophylline and so a mutual prodrug of both. It is also spelled phenethylline; other names for it are amphetamin{{wbr}}oethyl{{wbr}}theophylline and amfetyline. The drug was marketed for use as a psychostimulant under the brand names Captagon, Biocapton, and Fitton.{{Cite book |title=Dictionary of Organic Compounds |url=https://books.google.com/books?id=x2Su3GKCvtsC&pg=PA3140 |publisher=CRC Press |year=1996 |pages=3140– |isbn=978-0-412-54090-5}}{{Cite book |title=Index Nominum 2000: International Drug Directory | year=2000 |url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA431 |publisher=Taylor & Francis |pages=431– |isbn=978-3-88763-075-1}} The brand name "Captagon" (or in lowercase as "captagon") is often used generically to describe illicitly produced fenethylline.

Fenethylline is now illegal in most countries. It is produced primarily for illicit use, which takes place mainly in the Middle East, with some evidence that it is used by Islamist militants and terrorists, as stimulants for gunmen. The illicit global market for the drug was estimated in 2023 to be worth approximately US$ 57 billion.{{cite web | title=Tackling the illicit drug trade fuelling Assad's war machine | website=GOV.UK|author=((Foreign, Commonwealth & Development Office and Lord (Tariq) Ahmad of Wimbledon))| date=28 March 2023 | url=https://www.gov.uk/government/news/tackling-the-illicit-drug-trade-fuelling-assads-war-machine}}

Smuggling of Captagon became Syria's principal export, exceeding the total of all other exports under the Assad regime, from 2011 to 2024 of the Syrian Civil War in which it ruled Syria. It was the world's largest producer of the drug, accounting for about 80% of the global supply.{{Cite news | vauthors = Alkhaldi C |date=11 April 2023 |title=A little-known drug brought billions to Syria's coffers. Now it's a bargaining chip |publisher=CNN |url=https://edition.cnn.com/2023/04/10/middleeast/syria-drugs-bargaining-chip-mime-intl/index.html |archive-url=https://web.archive.org/web/20230517053609/https://edition.cnn.com/2023/04/10/middleeast/syria-drugs-bargaining-chip-mime-intl/index.html |archive-date=17 May 2023}}{{Cite news |date=9 May 2023 |title=What is Captagon, the addictive drug mass-produced in Syria? |work=Al Jazeera News |url=https://www.aljazeera.com/news/2023/5/9/what-is-captagon-the-addictive-drug-mass-produced-in-syria |archive-url=https://web.archive.org/web/20230605043558/https://www.aljazeera.com/news/2023/5/9/what-is-captagon-the-addictive-drug-mass-produced-in-syria |archive-date=5 June 2023}} A huge quantity of "Captagon", ready for clandestine export, was captured by anti-Assad forces that took control of Damascus in December 2024.{{Cite news |date=12 December 2024 |title= Syrian rebels seize vast haul of banned drug captagon, country's largest export |work=The Guardian |agency=Agence France-Presse|location=Damascus |url=https://www.theguardian.com/world/2024/dec/13/syrian-rebels-captagon-drug-haul-exports-fenethylline|url-status=live|archive-url=https://web.archive.org/web/20241213025126/https://www.theguardian.com/world/2024/dec/13/syrian-rebels-captagon-drug-haul-exports-fenethylline |archive-date=13 December 2024}}

History

Fenethylline was first synthesized by the German pharmaceutical firm Degussa AG in 1961 and used for around 25 years as a milder alternative to amphetamine and related compounds.{{cite journal | vauthors = Kristen G, Schaefer A, von Schlichtegroll A | title = Fenetylline: therapeutic use, misuse and/or abuse | journal = Drug and Alcohol Dependence | volume = 17 | issue = 2–3 | pages = 259–271 | date = June 1986 | pmid = 3743408 | doi = 10.1016/0376-8716(86)90012-8 }} Although there are no FDA-approved indications for fenethylline, it was used in the treatment of "hyperkinetic children", in what would now be called attention deficit hyperactivity disorder, and, less commonly, for narcolepsy and depression. One of the main advantages of fenethylline was that it does not increase blood pressure to the same extent as an equivalent dose of amphetamine and so could be used in patients with cardiovascular conditions.{{cite journal | vauthors = Katselou M, Papoutsis I, Nikolaou P, Qammaz S, Spiliopoulou C, Athanaselis S | title = Fenethylline (Captagon) Abuse - Local Problems from an Old Drug Become Universal | journal = Basic & Clinical Pharmacology & Toxicology | volume = 119 | issue = 2 | pages = 133–140 | date = August 2016 | pmid = 27004621 | doi = 10.1111/bcpt.12584 | doi-access = free }}

Fenethylline was considered to have fewer side effects and less potential for abuse than amphetamine. However, because its chemical composition is similar to amphetamine's, fenethylline was listed in 1981 as a schedule I controlled substance in the United States, and it became illegal in most countries in 1986 after being listed by the World Health Organization for international scheduling under the Convention on Psychotropic Substances, even though the actual incidence of fenethylline abuse was quite low.

Pharmacology

The fenethylline molecule results when theophylline is covalently linked with amphetamine by an alkyl chain.{{cite journal | vauthors = Nickel B, Niebch G, Peter G, von Schlichtegroll A, Tibes U | title = Fenetylline: new results on pharmacology, metabolism and kinetics | journal = Drug and Alcohol Dependence | volume = 17 | issue = 2–3 | pages = 235–257 | date = June 1986 | pmid = 3743407 | doi = 10.1016/0376-8716(86)90011-6 }}

Fenethylline is metabolized by the body to form two drugs, amphetamine (24.5% of oral dose) and theophylline (13.7% of oral dose), both of which are active stimulants. The physiological effects of fenethylline therefore seem to result from a combination of these two compounds,{{cite journal | vauthors = Ellison T, Levy L, Bolger JW, Okun R | title = The metabolic fate of 3H-fenetylline in man | journal = European Journal of Pharmacology | volume = 13 | issue = 1 | pages = 123–128 | year = 1970 | pmid = 5496920 | doi = 10.1016/0014-2999(70)90192-5 }}{{cite journal | vauthors = Alabdalla MA | title = Chemical characterization of counterfeit captagon tablets seized in Jordan | journal = Forensic Science International | volume = 152 | issue = 2–3 | pages = 185–188 | date = September 2005 | pmid = 15978343 | doi = 10.1016/j.forsciint.2004.08.004 }}{{cite journal | vauthors = Wenthur CJ, Zhou B, Janda KD | title = Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity | journal = Nature | volume = 548 | issue = 7668 | pages = 476–479 | date = August 2017 | pmid = 28813419 | pmc = 5957549 | doi = 10.1038/nature23464 | bibcode = 2017Natur.548..476W }} although it is not entirely clear how, and seems to involve a synergistic effect between amphetamine and theophylline produced following metabolism.{{cite journal | vauthors = Wu N, Feng Z, He X, Kwon W, Wang J, Xie XQ | title = Insight of Captagon Abuse by Chemogenomics Knowledgebase-guided Systems Pharmacology Target Mapping Analyses | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 2268 | date = February 2019 | pmid = 30783122 | pmc = 6381188 | doi = 10.1038/s41598-018-35449-6 }} The pharmacological actions of fenethylline before cleavage also remain poorly established, though it appears to act directly at several serotonin receptors.{{cite journal | vauthors = Wang YQ, Lin WW, Wu N, Wang SY, Chen MZ, Lin ZH, Xie XQ, Feng ZW | title = Structural insight into the serotonin (5-HT) receptor family by molecular docking, molecular dynamics simulation and systems pharmacology analysis | journal = Acta Pharmacologica Sinica | volume = 40 | issue = 9 | pages = 1138–1156 | date = September 2019 | pmid = 30814658 | pmc = 6786385 | doi = 10.1038/s41401-019-0217-9 }}

Abuse and illegal trade

Abuse of fenethylline using the former brand name Captagon is common in the Middle East,{{Cite news | vauthors = Hubbard B, Saad H |title=On Syria's Ruins, a Drug Empire Flourishes |work=The New York Times |url= https://www.nytimes.com/2021/12/05/world/middleeast/syria-drugs-captagon-assad.html |url-access=limited |date=5 December 2021 |access-date=8 December 2021 |archive-url=https://ghostarchive.org/archive/20211228/https://www.nytimes.com/2021/12/05/world/middleeast/syria-drugs-captagon-assad.html |archive-date=28 December 2021 |issn=0362-4331}}{{cbignore}}{{Cite news|date=2023-07-01 |title=Middle East's drug of choice |url=https://mondediplo.com/2023/07/03captagon |access-date=2023-07-24 |website=Le Monde diplomatique |language=en}} and counterfeit versions of the drug continue to be available despite its illegality.{{Cite web |title=2011 Global Assessment of Amphetamine-Type Stimulants |url=http://www.unodc.org/documents/southeastasiaandpacific/2011/09/global-ats-2011/ATS_Global_Assessment_2011_web.pdf |publisher=United Nations Office on Drugs and Crime}}{{Cite web |date=2 July 2020 |title=Why would the Islamic State group try to smuggle the 'drug of the Jihad' into Europe? |url=https://www.abc.net.au/news/2020-07-02/italy-drug-bust-captagon-how-is-it-linked-to-islamic-state/12414804 |access-date=15 May 2021 |website=www.abc.net.au}} Fenethylline is much less common outside of the Middle East, to the point that police may not recognize the drug. Fenethylline production and export were a significant industry sponsored by Bashar Al-Assad's government, with revenue from its exports contributing more than 90% of its foreign currency.{{Cite news | vauthors = Wood P |title=How Syria became the world's most profitable narco state |url=https://www.spectator.co.uk/article/how-syria-became-the-worlds-most-profitable-narco-state/ |work=The Spectator |date=19 November 2022 |archive-url=https://web.archive.org/web/20230106175927/https://www.spectator.co.uk/article/how-syria-became-the-worlds-most-profitable-narco-state/ |archive-date=6 January 2023}} After the fall of Al-Assad's government in Syria, Captagon trade fell by around 90%.{{citation needed|date=December 2024}} The Assad regime's annual fenethylline revenues were estimated to have been worth US$57 billion in 2022, about three times the total trade of the entire Mexican illicit drug market.{{Cite news | vauthors = Jalabi R |date=28 March 2023 |title=Assad cousins hit with sanctions over amphetamine trade that funds regime |work=Financial Times |url=https://www.ft.com/content/de522480-4738-49fb-985e-c0e1538846ff |archive-url= https://web.archive.org/web/20230328175918/https://www.ft.com/content/de522480-4738-49fb-985e-c0e1538846ff |archive-date=28 March 2023}}{{Cite web |date=28 March 2023 |title=Tackling the illicit drug trade fuelling Assad's war machine |url=https://www.gov.uk/government/news/tackling-the-illicit-drug-trade-fuelling-assads-war-machine |archive-url=https://web.archive.org/web/20230404194305/https://www.gov.uk/government/news/tackling-the-illicit-drug-trade-fuelling-assads-war-machine |archive-date=4 April 2023 |website=Gov.uk}}

Many of these counterfeit "Captagon" tablets contain other amphetamine derivatives that are easier to produce, but are pressed and stamped to look like Captagon pills. Some counterfeit Captagon pills analysed do contain fenethylline, indicating that illicit production of the drug continues to take place.{{cite journal | vauthors = Alshehri AZ, Al Qahtani MS, Al Qahtani MA, Faeq AM, Aljohani J | title = Study of Adulterants and Diluents in Some Seized Captagon-Type Stimulants. | journal = Annals of Clinical Nutrition | date = 2020 | volume = 3 | issue = 1 | pages = 1017 | publisher = MedDocs Publishers | url = https://meddocsonline.org/annals-of-clinical-nutrition/study-of-adulterants-and-diluents-in-some-seized-captagon-type-stimulants.pdf }} These illicit pills often contain "a mix of amphetamines, caffeine and various fillers",{{Cite web | vauthors = Hubbard B, Saad H |date=2021-12-05 |title=On Syria's Ruins, a Drug Empire Flourishes |url=https://www.nytimes.com/2021/12/05/world/middleeast/syria-drugs-captagon-assad.html |access-date=2024-12-06 |website=New York Times}} which are sometimes referred to as "captagon" (with a lowercase "c").

Fenethylline is a popular drug in Western Asia, and American media outlet CNN reported in 2015 that it is allegedly used by militant groups in Syria. Later research demonstrated that it was the former Syrian government of Bashar al-Assad that has been financing production and sponsoring networks of its drug dealers in coordination with the former Assad regime aligned Syrian intelligence.{{Cite web |date=27 April 2021 |title=The Syrian Economy at War: Captagon, Hashish, and the Syrian Narco-State |url=https://coar-global.org/2021/04/27/the-syrian-economy-at-war-captagon-hashish-and-the-syrian-narco-state/ |archive-url=https://web.archive.org/web/20230519102454/https://coar-global.org/2021/04/27/the-syrian-economy-at-war-captagon-hashish-and-the-syrian-narco-state/ |archive-date=19 May 2023 |website=Center for Operational Analysis and Research |quote=Whereas attention has been lavished on drug use among combatants, little attention has been paid to the societal and individual costs of the pervasive spread of narcotics during the conflict. Even more neglected are the structural dynamics of drug trafficking and their impact on the trajectory of the conflict itself. As the Syrian state has re-consolidated control over much of the country since 2018, narcotics trafficking in Syria has become more expansive and widespread. In parallel, the decimation of conventional economic activities has increased the relative attractiveness of industrial-scale drug profiteering, which has been largely captured and controlled by narco-entrepreneurs linked to the regime of Syrian President Bashar al-Assad and the regime's foreign allies. Ironically, the armed group commonly thought to be most closely associated with the Captagon trade — Islamic State — is, in fact, among the few conflict actors that has had no demonstrable institutional connection to the trade of this drug. This association has persisted in large part because of sensational foreign media coverage. the narcotics trade was decisively reconfigured to the advantage of pro-Government forces. Increasingly prominent in this period are narco-entrepreneurs affiliated with the Assad regime. Record-setting foreign drug interceptions since 2018 evince the evolution of Syria's drug industry, with exports of Captagon and hashish suggesting new levels of mass production.}} It is manufactured locally by a cheap and simple process. In July 2019 in Lebanon, captagon was sold for $1.50 to $2.00 a pill.{{Cite news | vauthors = Holley P |title=The tiny pill fueling Syria's war and turning fighters into superhuman soldiers |newspaper=The Washington Post |url=https://www.washingtonpost.com/news/worldviews/wp/2015/11/19/the-tiny-pill-fueling-syrias-war-and-turning-fighters-into-super-human-soldiers/?tid=pm_pop_b |date=19 November 2015 |access-date=20 November 2015 }} In 2021 in Syria, low-quality pills were sold locally for less than $1, while high-quality pills are increasingly smuggled abroad and may cost upwards of $14 each in Saudi Arabia. {{needs update|date=December 2024}}

According to some leaks, militant groups export the drug in exchange for weapons and cash.{{Cite news |date=12 January 2014 |title=Syria's civil war being fought with fighters high on drugs |work=The Telegraph |url=https://www.telegraph.co.uk/news/worldnews/middleeast/syria/10567021/Syrias-civil-war-being-fought-with-fighters-high-on-drugs.html |access-date=13 January 2014 |vauthors=Freeman C}} According to Abdelelah Mohammed Al-Sharif, secretary general of the National Committee for Narcotics Control and assistant director of Anti-Drug and Preventative Affairs, forty percent of users between the ages of twelve and twenty-two in Saudi Arabia are addicted to fenethylline. In 2017, fenethylline was the most popular recreational drug in the Arabian Peninsula.{{Cite news |date=18 July 2017 |title=A new drug of choice in the Gulf |newspaper=The Economist |url=https://www.economist.com/news/middle-east-and-africa/21725167-dangerous-arrival-dangerous-region-new-drug-choice-gulf |access-date=19 July 2017}}

In October 2015, a member of the Saudi royal family, Prince Abdel Mohsen Bin Walid Bin Abdulaziz, and four others were detained in Beirut on charges of drug trafficking after airport security discovered two tons of fenethylline pills and some cocaine on a private jet scheduled to depart for Riyadh, the Saudi capital.{{Cite news |date=26 October 2015 |title=Saudi prince held after seizure of two tonnes of amphetamines at Beirut airport |work=The Daily Telegraph |url=https://www.telegraph.co.uk/news/worldnews/middleeast/lebanon/11955937/Saudi-prince-held-after-seizure-of-two-tons-of-amphetamines-at-Beirut-airport.html |access-date=20 November 2015 |vauthors=Spencer R}}{{Cite news |date=26 October 2015 |title=Saudi prince arrested in Lebanon trying to smuggle two tonnes of amphetamine pills out of the country by private jet |work=The Independent |url=https://www.independent.co.uk/news/world/middle-east/saudi-prince-arrested-in-lebanon-trying-to-smuggle-two-tonnes-of-amphetamine-pills-out-of-the-a6709546.html |access-date=20 November 2015 |vauthors=Baker G}}{{Cite news |date=26 October 2015 |title=Saudi Royal, Four Others Detained in Beirut Captagon Bust |publisher=NBC News |url=https://www.nbcnews.com/news/world/saudi-royal-four-others-detained-beirut-captagon-bust-n451486 |access-date=20 November 2015 |vauthors=Vinograd C, Kassem M}} The following month, Agence France-Presse reported that Turkish authorities had seized two tonnes of fenethylline—about eleven million pills—during raids in the Hatay region on the Syrian border. The pills had been produced in Syria and were being shipped to countries in the Arab states of the Persian Gulf.{{Cite news |author-link=Agence France-Presse |date=20 November 2015 |title=Turkey seizes 11 million pills of 'Syria war drug': Reports |work=Agence France-Presse |location=Istanbul |url=http://timesofindia.indiatimes.com/world/middle-east/Turkey-seizes-11-million-pills-of-Syria-war-drug-reports/articleshow/49860478.cms |access-date=20 November 2015 |archive-url=https://web.archive.org/web/20151125013845/https://timesofindia.indiatimes.com/world/middle-east/Turkey-seizes-11-million-pills-of-Syria-war-drug-reports/articleshow/49860478.cms |archive-date=25 November 2015 |via=The Times of India}}

In December 2015, the Lebanese Army announced that it had discovered two large-scale drug production workshops in the north of the country and seized large quantities of fenethylline pills. Two days earlier, three tons of fenethylline and hashish were seized at Beirut Airport, concealed in school desks being exported to Egypt.{{cite news|newspaper=The Daily Star|location=Beirut|date=December 30, 2015|url=http://www.dailystar.com.lb/News/Lebanon-News/2015/Dec-30/329610-tuesday-raids-in-east-lebanon-netted-800-kgs-of-hash-police.ashx|title=Tuesday raids in east Lebanon netted 800 kg of hash:police}}{{cite news|url=http://www.dailystar.com.lb/News/Lebanon-News/2015/Dec-30/329490-lebanese-army-busts-two-drug-factories.ashx|title=Lebanese Army busts two drug factories|newspaper=The Daily Star|location=Beirut|date=December 30, 2015}}

Traces of the drug were found on a mobile phone used by Mohamed Lahouaiej Bouhlel, a French-Tunisian who killed eighty-four civilians in Nice on Bastille Day 2016.{{Cite web |date=21 July 2016 |title=Attacker in Nice plotted for months with 'accomplices' |url=http://www.cnn.com/2016/07/21/europe/nice-france-attacker-plot-accomplices/index.html |access-date=2016-07-21 |publisher=CNN |vauthors=Sanchez R}}

In May 2017, French customs at Charles de Gaulle Airport seized 750,000 fenethylline pills being transported from Lebanon to Saudi Arabia.{{Cite news |date=30 May 2017 |title=In a first, authorities say they found 750,000 'Captagon' pills in France |newspaper=The Washington Post |url=https://www.washingtonpost.com/news/worldviews/wp/2017/05/30/in-a-first-authorities-say-they-found-750000-captagon-pills-in-france/ |vauthors=Taylor A}} In 2017, two other consignments of pills were found at Charles de Gaulle Airport: in January, heading for the Czech Republic, and in February, hidden in steel moulds.{{Cite web |date=30 May 2017 |title=Customs seize 135 kg of captagon for first time in France |url=http://www.rfi.fr/en/france/20170530-jihadist-drug-captagon-seized-first-time-france |website=rfi.fr}} Further investigation showed that the seized products mainly contained a mixture of amphetamine and theophylline.{{Cite news |date=2017 |title=Les 135 kilos de drogue saisis n'étaient pas du Captagon, "la drogue des djihadistes" |work=Le Parisien |url=https://www.leparisien.fr/faits-divers/les-135-kilos-de-drogue-saisis-n-etaient-pas-du-captagon-la-drogue-des-djihadistes-06-06-2017-7022343.php}}

In January 2018, Saudi Arabia seized 1.3 million fenethylline pills at the Al-Haditha crossing near the border with Jordan.{{Cite web |date=12 January 2018 |title=Saudi customs bust drug smugglers with haul of 1.3m pills |url=https://www.arabnews.com/node/1224416/saudi-arabia |website=Arab News}} In December 2018, Greece intercepted a Syrian ship sailing for Libya, carrying six tonnes of processed cannabis and three million fenethylline pills.{{Cite news |date=14 December 2018 |title=Greece seizes big drugs haul from Syrian freighter sailing for Libya |publisher=Reuters |location=London |url=https://www.reuters.com/article/us-greece-drugs/greece-seizes-big-drugs-haul-from-syrian-freighter-sailing-for-libya-idUSKBN1OD1RF |access-date=21 July 2020 |vauthors=Koutantou A, Kambas M, Stamp D}} In July 2019, a shipment of 33 million fenethylline pills, weighing 5.25 tonnes, was seized in Greece coming from Syria.{{Cite news |date=5 July 2019 |title=Greece seizes record amount of amphetamine Captagon shipped from Syria |publisher=Reuters |location=London |url=https://www.reuters.com/article/us-greece-drugs/greece-seizes-record-amount-of-amphetamine-captagon-shipped-from-syria-idUSKCN1U01IH |access-date=21 July 2020 |vauthors=Georgiopoulos G, Heinrich M}} In July 2019, 800,000 fenethylline pills were found on a boat in the United Arab Emirates.{{Cite web |date=24 July 2019 |title=Dogs help seize 800,000 Captagon pills worth Dh3 million |url=https://gulfnews.com/uae/dogs-help-seize-800000-captagon-pills-worth-dh3-million-1.65412113 |website=Gulf News}} In August 2019, Saudi customs at Al-Haditha seized over 2.5 million fenethylline pills found inside a truck and a private vehicle.{{Cite news |date=21 August 2019 |title=Saudi officials stop Captagon smuggling plots |url=https://www.arabianbusiness.com/culture-society/426154-saudi-officials-stop-captagon-smuggling-plots |website=Arabian Business}}

In February 2020, the UAE found 35 million fenethylline pills in a shipment of electric cables from Syria to Jebel Ali.{{Cite web |date=26 February 2020 |title=Video: Massive drug bust in Dubai, 5.6 tonnes of captagon seized |url=https://www.khaleejtimes.com/uae/dubai/video-massive-drug-bust-in-dubai-56-tonnes-of-captagon-seized |website=Khaleej Times}} In April 2020, Saudi Arabia seized 44.7 million fenethylline pills smuggled from Syria,{{Cite web |date=30 April 2020 |title=Saudi Arabia busts drug smuggling operation from Assad's Syria |url=https://www.middleeastmonitor.com/20200430-saudi-arabia-busts-drug-smuggling-operation-from-assads-syria/ |website=Middle East Monitor}} and citing drug smuggling concerns, imposed an import ban on fruits and vegetables from Lebanon, causing the price of Lebanese lettuce to plummet.{{cite news| title=Saudi Arabia bans fruit, vegetable imports from Lebanon| vauthors = Seifeddine WS, İbicioğlu S |publisher=Anadolu Ajansı | date=24 April 2021 | url=https://www.aa.com.tr/en/middle-east/saudi-arabia-bans-fruit-vegetable-imports-from-lebanon/2218829}}{{Cite web | vauthors = Kanaan A, El Dahan M, Blair E | veditors = Shirbon E |date=12 May 2021 |title=Lebanese fear fruit and vegetables going to waste with Saudi market shut |url=https://www.reuters.com/world/middle-east/lebanese-fear-fruit-vegetables-going-waste-with-saudi-market-shut-2021-05-12/ |access-date=8 June 2021 |publisher=Reuters}}

In July 2020, an anti-drug operation coordinated in Italy by the Italian Guardia di Finanza and Customs and Monopolies Agency seized fourteen tonnes of amphetamines, labeled as Captagon, smuggled from Syria and initially thought by the Italian authorities to have been produced by ISIS,{{Cite news |date=1 July 2020 |title=Salerno, sequestrate 84 milioni di pasticche di droga dell'Isis: le stesse usate dai terroristi del Bataclan |language=it |work=La Repubblica |location=Rome |url=https://napoli.repubblica.it/cronaca/2020/07/01/news/salerno_sequestrate_14_tonnellate_di_droga_dell_isis_valgono_un_miliardo-260651827/ |access-date=21 July 2020 |vauthors=Del Porto D, Foschini G}}; {{cite news |date=10 July 2020 | vauthors = Foschini G |url= https://rep.repubblica.it/pwa/generale/2020/07/10/news/la_droga_dell_isis_non_era_dell_isis_quelle_14_tonnellate_di_anfetamine_sequestrate_in_italia_e_il_legame_con_la_siria_di-261584585/ |title="La droga dell'Isis non-era dell'Isis": quelle 14 tonnellate di anfetamine sequestrate in Italia e il legame con la Siria di Assad |work=La Repubblica |location=Rome |language=it |access-date=21 July 2020}}{{Cite news |date=1 July 2020 |title=Italian police seize 14 tons of amphetamines with possible ISIS link |publisher=NBC News |location=London |url=https://www.nbcnews.com/news/world/italian-police-seize-14-tons-amphetamines-possible-isis-link-n1232633 |access-date=21 July 2020 |vauthors=Givetash L, Lavanga C}}{{Cite news |date=1 July 2020 |title=Italian Police on Amalfi Coast Seize 84 Million 'Captagon' Pills Shipped by ISIS From Syria |work=The Daily Beast |url=https://www.thedailybeast.com/italian-police-on-amalfi-coast-seize-84-million-captagon-pills-shipped-by-isis-from-syria |access-date=21 July 2020 |vauthors=Nadeau BL}} which were found in three shipping containers filled with around 84 million pills, in the southern port of Salerno.{{Cite news |title=Captagon: Italy seizes €1bn of amphetamines 'made to fund IS' |url=https://www.bbc.com/news/world-europe-53254879 |publisher=BBC News |date=1 July 2020 |access-date=21 July 2020}}

In November 2020, Egypt seized two shipments of fenethylline pills at Damietta port coming from Syria. The first had over 3.2 million tablets,{{Cite web |date=15 November 2020 |title=Egyptian police seize container with 1,858 Captagon drug packets |url=https://egyptindependent.com/managed-to-seize-a-container-police-seizes-container-containing-1858-packets-of-captagon-drug-hidden-in-canned-corn-shipmentcontaining-1858-packets-of-captagon-drug-hidden-in-canned-corn-shipment/ |website=Egypt Independent}} while the second contained 11 million.{{Cite web |date=30 November 2020 |title=Attempt to smuggle 11M drug tablets in container thwarted |url=https://www.egypttoday.com/Article/1/94822/Attempt-to-smuggle-11M-drug-tablets-in-container-thwarted |website=Egypt Today}} In December 2020, Italian authorities seized about 14 tonnes of fenethylline arriving from Latakia, Syria, and heading towards Libya, consisting of about 85 million pills, worth around $1 billion.{{Cite web | vauthors = Chaundy F, Miglierini J |title=Captagon: Destroying the frontline drug |url=https://www.bbc.com/news/av/world-55378461 |publisher=BBC News |date=21 December 2020 |access-date=12 June 2023}}

In January 2021, Egyptian authorities seized eight tons of fenethylline and another eight tons of hashish at Port Said, from a shipment that arrived from Lebanon.{{Cite web |date=6 January 2021 |title=Egypt busts massive drugs haul worth Dh143m |url=https://gulfnews.com/world/mena/egypt-busts-massive-drugs-haul-worth-dh143m-1.76292594 |website=Gulf News}} In February 2021, Lebanese customs seized at Beirut port a shipment of 5 million fenethylline pills hidden in a tile-making machine, intended for Greece and Saudi Arabia.{{Cite web |date=3 February 2021 |title=Lebanon seizes 5m captagon pills at Beirut port |url=https://www.arabnews.com/node/1803386/middle-east |website=Arab News}} In April 2021, Saudi authorities discovered 5.3 million fenethylline pills hidden in fruits imported from Lebanon.{{Cite web | vauthors = Houssari N |date=25 April 2021 |title=Lebanon vows to punish drug smugglers as Saudi import ban bites |url=https://www.arabnews.com/node/1848171/middle-east |website=Arab News}}

=Production in Syria=

File:Captagon.jpg before being destroyed in May 2018]]

The drug has played a role in the Syrian civil war.{{Cite web |date=20 November 2015 |title=Captagon, ISIS's favorite amphetamine, explained |url=https://www.vox.com/world/2015/11/20/9769264/captagon-isis-drug |website=Vox |vauthors=Lopez G}}{{Cite news |date=13 January 2014 |title=Captagon: the amphetamine fuelling Syria's civil war |work=The Guardian |url=https://www.theguardian.com/world/shortcuts/2014/jan/13/captagon-amphetamine-syria-war-middle-east |access-date=31 December 2015 |vauthors=Henley J}} The production and sale of fenethylline generates large revenues which are likely used to fund the purchase of weapons, and fenethylline is used as a stimulant by combatants.{{Cite news | vauthors = Kalin S |title=Insight – War turns Syria into major amphetamines producer, consumer |date=12 January 2014|publisher=Reuters |url=https://www.reuters.com/article/us-syria-crisis-drugs-insight-idUSBREA0B04H20140112/|url-status=live| archive-url = https://web.archive.org/web/20170202155617/http://uk.reuters.com/article/uk-syria-crisis-drugs-idUKBREA0B04K20140113 | archive-date = 2 February 2017}}{{Cite magazine |title=Syria's Breaking Bad: Are Amphetamines Funding the War? |magazine=Time |url=https://world.time.com/2013/10/28/syrias-breaking-bad-are-amphetamines-funding-the-war/ |access-date=2016-02-03 |issn=0040-781X |vauthors=Baker A}} Poverty and international sanctions that limit legal exports are contributing factors.{{Cite web |date=4 June 2022 |title=The Arab World's New Drug of Choice |url=https://www.bbc.co.uk/programmes/m00180hs |website=BBC Radio 4}}

In May 2021, The Guardian described the effects of fenethylline production in Syria on the economy as "a dirty business that is creating a near-narco-state". Drug money flowing into Syria is destabilizing legitimate businesses, positioning it as the global centre of fenethylline production, with increased industrialization, adaptation, and technical sophistication.{{Cite web | vauthors = Chulov M |date=7 May 2021 |title='A dirty business': how one drug is turning Syria into a narco-state |url=https://www.theguardian.com/world/2021/may/07/drug-captagon-turning-syria-into-narco-state |website=The Guardian}}

In June 2021, Saudi authorities at Jeddah port seized 14 million fenethylline tablets hidden inside a shipment of iron plates coming from Lebanon.{{Cite web |date=26 June 2021 |title=14 million Captagon amphetamine pills coming from Lebanon seized |url=https://saudigazette.com.sa/article/608191 |website=Saudi Gazette}} In the same month, Saudi authorities seized a shipment of 4.5 million fenethylline pills, smuggled inside several orange cartons, at Jeddah port.{{Cite web |date=30 June 2021 |title=Saudi Arabia seizes 4.5m amphetamine pills hidden in oranges |url=https://www.aljazeera.com/news/2021/6/30/saudi-arabia-seizes-4-5m-amphetamine-pills-hidden-in-oranges |website=Al Jazeera}} In July 2021, Saudi customs discovered 2.1 million fenethylline pills at Al-Haditha hidden in a tomato paste shipment.{{Cite web | vauthors = Al Sherbini R |date=24 July 2021 |title=Saudis bust bid to smuggle 2 million Captagon pills |url=https://gulfnews.com/world/gulf/saudi/saudis-bust-bid-to-smuggle-2-million-captagon-pills-1.80876785 |website=Gulf News}}

In December 2024, shortly after the Assad government collapsed, Syrian former-rebels found warehouses filled with Captagon alongside factory equipment to make it and also found some Captagon pills inside the copper coils of new voltage stabilisers, showing one way the former Syrian government used to smuggle Captagon out of the country. The Captagon was all destroyed by the new government; "Khattab", a pseudonym of one of the former rebels said "We destroyed and burned it because it's harmful to people. It harms nature and people and humans."

The New York Times reported in December 2021 that the Syrian Army's elite 4th Armoured Division, commanded by Maher al-Assad, the brother of Syrian President Bashar al-Assad, oversaw much of the production and distribution of fenethylline, among other drugs. The unit controlled manufacturing facilities, packing plants, and smuggling networks all across Syria, and had started to deal in crystal meth. The division's security bureau, headed by Maj. Gen. Ghassan Bilal, provided protection for factories and along smuggling routes to the port city Latakia and to border crossings with Jordan and Lebanon. Jihad Yazigi, editor of The Syria Report, reported that fenethylline had "probably become Syria's most important source of foreign currency."

= Military use =

Fenethylline is a major stimulant, sometimes dubbed the "jihad drug", used by some jihadist fighters. It quickly produces a euphoric intensity in users, allowing them to stay awake for a very long time, remaining more calm and focused under the effects of the drug, which allows the senses to stay at more operational levels. It also helps to subdue feelings of fear and hunger during lengthy operations.{{Cite web |date=2024-02-18 |title=Was Hamas drug crazed from Captagon during Oct. 7 attacks? |website=USA Today |url=https://www.usatoday.com/story/news/world/2023/11/02/hamas-captagon-drug-use-idf-claim/71288873007/ |access-date=2024-03-11 |archive-url=https://web.archive.org/web/20240218012646/https://www.usatoday.com/story/news/world/2023/11/02/hamas-captagon-drug-use-idf-claim/71288873007/ |archive-date=18 February 2024 }}{{Cite news |date=2023-12-11 |title=The drug that stimulates, and finances, terrorists |url=https://en.globes.co.il/en/article-the-drug-that-stimulates-and-finances-terrorists-1001462238 |access-date=2024-03-11 |work=Globes |language=en}}{{cite web | vauthors = Gotev G | date = 16 November 2023 | title = The brief – the captagon fighters | work = Euractive.com | url = https://www.euractiv.com/section/global-europe/opinion/the-brief-the-captagon-fighters/ }} Psychiatrist Robert Keisling said that the drug "gives you a sense of well-being and euphoria", along with the thought that "you're invincible and that nothing can harm you."{{Cite web | vauthors = McConnell D, Todd B | date = 20 November 2015 |title=Syria fighters may be fueled by amphetamines | work = CNN |url=https://www.cnn.com/2015/11/20/world/syria-fighters-amphetamine/index.html | archive-url = https://web.archive.org/web/20231104220157/https://edition.cnn.com/2015/11/20/world/syria-fighters-amphetamine/index.html| archive-date = 4 November 2023 }} Those who go on jihad missions take high doses to prepare, says a former fighter associated with the Muslim Brotherhood. He described the effect: "They go blank. Their heart rate spikes. They lose all connection to their emotions and thoughts." Some commented on this effect as a "zombie-like detachment".{{Cite web | vauthors = Anderson S |date=2015-12-09 |title=These Are the People Making Captagon, the Drug ISIS Fighters Take to Feel 'Invincible' |url=https://nymag.com/intelligencer/2015/12/men-making-captagon-the-drug-fueling-isis.html |access-date=2024-03-11 |website=Intelligencer |language=en}}{{cite report | vauthors = Rose C, Söderholm A | date = 2022 | title = The Captagon Threat A Profile of Illicit Trade, Consumption, and Regional Realities | location = Washington | publisher = New Lines Institute | pages = 14–15 | url = https://newlinesinstitute.org/wp-content/uploads/20220404-Captagon_Report-NLISAP-final-.pdf }}

An illegal Syrian manufacturer told New York Magazine in 2015 of the effect the drug had on fighters: "[If] someone takes many pills, like 30 or so, they become violent and crazy, paranoid, unafraid of anything. They'll have a thirst for fighting and killing and will shoot at whatever they see. They lose any feeling or empathy for the people in front of them and can kill them without caring at all."

According to some commentators, fighters taking the drug in Syria were better able to tolerate the pain of being shot. A drug control officer in the central city of Homs told Reuters that protestors and fighters were able to resist painful interrogations better while on fenethylline. Former fighters have told the media that the pills helped them overcome their fear. Doctors report that the drug has dangerous side effects, including psychosis and brain damage. According to former fighters, hundreds became addicted to the pills they were given by brigade leaders without knowing what they were taking.

Fenethylline use was associated with the rise of jihadist group ISIS. One 19-year-old fighter named Kareem, who said he fought alongside ISIS for more than a year, told CNN in 2014: "They gave us drugs, hallucinogenic pills that would make you go to battle not caring if you live or die."

In February 2023, Israel's Ministry of Defense claimed to have thwarted an attempt to smuggle thousands of fenethylline tablets from the West Bank into the Gaza Strip.{{cite web | vauthors = Ecanow N | date = 10 February 2023 | title = Captagon: Assad's deadly drug of choice expands to Israel | work = Foundation for Defense of Democracy | url = https://www.fdd.org/analysis/2023/02/10/captagon-assads-deadly-drug-expands-to-israel/ }} Hamas claimed it had seized 50,000 fenethylline pills on the border, and claimed Israel was attempting to dope Gaza.{{cite news | vauthors = Sally I | date = 21 February 2023 | title = Hamas seizes 50,000 captagon pills in Gaza, blaming Israel as source | work = The New Arab | url = https://www.newarab.com/news/hamas-seizes-50000-captagon-pills-blaming-israel-source }}

Israel has publicly stated that fenethylline was used during the October 7 attacks, but this has been doubted by Caroline Rose, director of New Lines Institute’s Strategic Blind Spots Portfolio.{{Cite web | vauthors = Gault M |date=2023-11-03 |title=U.S. and Israeli Officials Claim Hamas Was High During Oct. 7 Attack. Is It True? |url=https://www.vice.com/en/article/us-and-israeli-officials-claim-hamas-was-high-during-oct-7-attack-is-it-true/ |access-date=2024-04-30 |website=Vice |language=en}} Israeli forces said they had found fenethylline-containing tablets, powder, and liquid on the bodies of the attackers.{{cite news | vauthors = Lahav E | date = 29 October 2023 | title = Jihad on speed: captagon at the service of terror organization's | work = IDSF | url = https://idsf.org.il/en/opinion-en/jihad-on-speed-captagon-at-the-service-of-terror-organizations/ }}{{cite web | vauthors = Meyer J, Hjelmgaard K | date = 2 November 2023 | title = Were the Hamas attacks on Israel so brutal because the killers were high on the drug captagon? | work = USA Today | url = https://www.usatoday.com/story/news/world/2023/11/02/hamas-captagon-drug-use-idf-claim/71288873007/ | archive-url = https://web.archive.org/web/20240218012646/https://www.usatoday.com/story/news/world/2023/11/02/hamas-captagon-drug-use-idf-claim/71288873007/ | archive-date = 18 February 2024 }} Rose said that she had never seen fenethylline made in liquid form. While precursor chemicals for fenethylline tend to be in powdered form, she said, fenethylline itself is not commonly a powder. She concluded "I find it somewhat difficult to believe that, in a single raid, we find two new forms of Captagon."

Videos compiled by the Israeli government of the Hamas attack—cobbled together from cell phones, GoPros, as well as car and surveillance cameras—allege that at least some of the militants were under the influence of the drug.{{cite news | vauthors = Solomon J | date = 1 November 2023 | title = Some Hamas killers were high on amphetamine, officials say | work = Semafor | url = https://www.semafor.com/article/10/31/2023/hamas-killers-were-high-on-amphetamine-officials-say }}{{cite web | vauthors = Coleman T | date = 15 November 2023 | title = A drug called captagon may have helped fuel Hamas' attack on Israel | work = The Week | url = https://theweek.com/politics/drug-captagon-hamas-attack-israel }} Rose also said that 'Fighters might have taken cocaine right before, or captagon, or no substances at all. Some might have taken caffeine, some may be sleep deprived...but there's no way that captagon was a factor to blame in the violence and atrocities that we witnessed on October 7'.{{cite web | vauthors = Gault M | date = 3 November 2023 | title = U.S. and Israeli Officials Claim Hamas Was High During Oct. 7 Attack. Is It True? | work = Vice| url = https://www.vice.com/en/article/us-and-israeli-officials-claim-hamas-was-high-during-oct-7-attack-is-it-true/ }}

Synthesis

According to reviewers Pergolizzi Jr., et al., writing in 2024, the clandestine chemical synthesis of fenethylline is "straightforward and inexpensive".{{cite journal | vauthors = Pergolizzi J, LeQuang JA, Vortsman E, Magnusson P, El-Tallawy SN, Wagner M, Salah R, Varrassi G | title = The Emergence of the Old Drug Captagon as a New Illicit Drug: A Narrative Review | journal = Cureus | volume = 16 | issue = 2 | pages = e55053 | date = February 2024 | pmid = 38550445 | pmc = 10977473 | doi = 10.7759/cureus.55053 | doi-access = free }}

Small-scale synthesis in academic laboratories is equally straightforward:{{cite journal | vauthors = Rücker G, Neugebauer M, Neugebauer M, Heiden PG | title = [The chemical stability of fenethylline] | journal = Archiv Der Pharmazie | volume = 320 | issue = 12 | pages = 1272–1275 | date = December 1987 | pmid = 3439867 | doi = 10.1002/ardp.198700045 }}Gagauzov, I. et al, CA, 1984, 101, 130491 Kohlstaedt Dr Erwin, Klingler Dr Karl-Heinz, DE1123329 (1962 to Chemiewerk Homburg Zweignieder).File:Fenethylline synthesis.svg

The overall transformation is accomplished in two laboratory steps, each requiring extraction and purification. In the first step, theophylline (1) is alkylated in a substitution reaction using 1-bromo-2-chloroethane (2) to give 7-(β-chloroethyl)theophylline (Benaphyllin, Eupnophile; 3).{{cn|date = July 2024}} In the second step, the primary amine in amphetamine (4) displaces the terminal halide in 3 to give fenethylline (5).{{cn|date = July 2024}}

The synthesis can also be performed with analogous reagents and solvents.{{cite journal | vauthors = Rücker G, Neugebauer M, Neugebauer M, Heiden PG | title = Zur chemischen Stabilität des Fenetyllins | language = de | journal = Archiv der Pharmazie | volume = 320 | issue = 12 | pages = 1272–1275 | date = December 1987 | pmid = 3439867 | doi = 10.1002/ardp.198700045 | trans-title = The chemical stability of fenethylline | s2cid = 84235752 }}{{cite patent |country=DE |number=1123329 |inventor=Kohlstaedt E, Klingler KH |gdate=1962 |assign1=Chemiewerk Homburg Zweignieder |postscript=.}} and {{cite patent |country=GB |number=927288 |inventor=Kohlstaedt E, Klingler KH |gdate=1962 |assign1=Chemiewerk Homburg Zweignieder.}} "[Title] 1-and 7-(basically-substituted-alkyl) xanthine derivatives, a process for their manufacture and pharmaceutical compositions containing them. [Front page drawing] X—A—NH—CH(R₁)—CH₂—R₂ [Abstract] The invention comprises compounds of the general formula wherein X represents a 1-theobromine or 7-theophylline radical, A is a straight or branched chain alkylene radical, R1 is an alkyl radical of 1-3 carbon atoms and R2 is an aryl, e.g. phenyl radical, together with acid addition salts thereof, and comprises also the preparation of those compounds by reacting a haloalkyl-xanthine X-A-Halogen with an aralkylamine of the formula H2N-CH(R1)-CH2-R2, preferably at 70 DEG -170 DEG C. in an inert solvent such as toluene in the presence of an acid-binding agent such as potassium carbonate..." Use of tetradeutero-vic{{nbh}}dichloroethane instead of vic{{nbh}}chlorobromoethane yields reasonably a perdeuterated-bridge analogue.{{cite journal | vauthors = You ZY, Chen YJ, Wang YY, Chen C | title = Synthesis of Deuterium Labeled Standards of 1-Benzylpiperazine, Fenetylline, Nicocodeine and Nicomorphine. | journal = Journal of the Chinese Chemical Society | date = June 2008 | volume = 55 | issue = 3 | pages = 663–667 | doi = 10.1002/jccs.200800099 }}

Identification in biological samples

A gas chromatography-mass spectrometry (GC-MS) method for the determination of fenethylline and related substances in plasma, urine, and hair has been developed, suggesting that hair testing can be useful for determining a drug history of fenethylline, and discrimination between fenethylline and its precursor, amphetamine.{{cite journal | vauthors = Kikura R, Nakahara Y | title = Hair analysis for drugs of abuse. XVI. Disposition of fenethylline and its metabolite into hair and discrimination between fenethylline use and amphetamine use by hair analysis | journal = Journal of Analytical Toxicology | volume = 21 | issue = 4 | pages = 291–296 | date = 1997 | pmid = 9248947 | doi = 10.1093/jat/21.4.291 }}