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MiniReview
Abstract: Fenethylline is a theophylline derivative of amphetamine having stimulant effects similar to those of other ampheta-
mine-type derivatives. Fenethylline was used as medicament for hyperactivity disorders in children, narcolepsy and depression,
but it has also been used as a drug of abuse under the common name of ‘captagon’. Unlike other drugs of abuse, the clandestine
synthesis of fenethylline is simple, using inexpensive laboratory instrumentation and raw materials legal to obtain. A review of
all the existing knowledge of fenethylline is reported, concerning its chemistry, synthesis, pharmacology and toxicology, legisla-
tion, its prevalence and use as drug of abuse, as well as its analysis in biological or seized samples. Published or reported cap-
tagon-related cases and seizures are also presented. All the reviewed information was gathered through a detailed search of
PubMed and the Internet. The primary drug market for fenethylline (as captagon) has traditionally been countries located on the
Arabian Peninsula but also North Africa since 2013. In Arab countries, millions of captagon tablets are seized every year which
represents one-third of global amphetamines seizures within a year. Furthermore, three of four patients treated for drug problems
in Saudi Arabia are addicted to amphetamines, almost exclusively in the form of captagon. Significant information on fenethyl-
line is provided for pharmacologists, toxicologists and forensic pathologists. Fenethylline, although old, has recently been intro-
duced to the drug market, especially in Arab countries. Continuous community alertness is needed to tackle this current growing
phenomenon.
The increasing number of new psychoactive substances or the used in lack of drive, particularly in elderly patients due to
re-appearance of older ones, when the newer ones are not avail- organic diseases (e.g. Parkinsonism) or other causes, as well
able, on the drug market is a major public health concern today. as after severe illness or injury (e.g. head injuries). In cases of
These designer drugs are being used to substitute or mimic the narcolepsy and epileptic absences, fenethylline improved vigi-
effects of traditional controlled drugs, when in shortage [1–3]. lance and reduced paroxysms. However, the above indications
Fenethylline was first synthesized by Chemiewerk Hom- for fenethylline were never approved in the United States, as
burg, a subsidiary of specialty chemicals company German no investigational new drug application was submitted to the
Degussa AG in 1961 as a part of an investigational pro- Food and Drug Administration [4,6,9].
gramme on side effects of theophylline derivatives and partic- Fenethylline has raised concern in West Asian and Arab
ularly on cardiovascular, pulmonary and central nervous countries in recent years, where it is clandestinely synthesized,
system [4–7]. It was used in Europe for over two decades as a using simple and inexpensive chemistry techniques and raw
milder alternative to amphetamine and related compounds and materials, and extensively used. Although illegal, it continues
as a non-prescription psychostimulant and analeptic agent mar- to be available among militant groups especially in Syria.
keted under the brand names Captagon, Fitton and Biocapton Fenethylline was found to be among the active ingredients of
[5,8]. Fenethylline was introduced into the Federal Republic a significant number of seized tablets trafficked as Captagon
of Germany by Degussa as a 50-mg tablet in 1961, while [2,3,9–11].
3 years later, a strict prescription status was requested; thus, The aim of this article was to review all the available infor-
its disposal was controlled, and the drug was used only under mation on chemistry, synthesis, pharmacology and toxicology
medical supervision [4]. The patent for its production dates to of fenethylline, its prevalence and use as drug of abuse, as
1962 [5]. Thus, it was used for many years in the treatment of well as the methods for its determination in biological or
attention-deficit–hyperactivity disorder, and in a lower extent, seized samples. Published or reported captagon-related cases,
in narcolepsy, epileptic absences and depression. It was also reported seizures and the legal status of fenethylline are also
presented. All the reviewed information was gathered through
Author for correspondence: Panagiota Nikolaou, Department of Foren- a detailed search of PubMed and the Internet using the terms
sic Medicine and Toxicology, Faculty of Medicine, National and of ‘fenethylline’ or ‘captagon’ and ‘pharmacology’, ‘toxicol-
Kapodistrian University of Athens, 75 Mikras Asias, Athens 115 27,
ogy’, ‘seizures’ and ‘legislation’.
Greece (fax +302107716098; e-mail pan_nik@hotmail.com).
© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
134 MARIA KATSELOU ET AL. MiniReview
© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview FENETHYLLINE (CAPTAGON) ABUSE 135
tic agent to lose weight. On the other hand, captagon is product (oxyethyltheophylline) is biotransformed to theo-
abused among wealthy people in the Middle East [5]. Accord- phylline. The final major metabolites are 1,3-dimethyluric
ing to the United Nations and the National Committee for acid, 1-methyluric acid and 3-methylxanthine. Only a small
Narcotics Control and Anti-Drug and Preventative Affairs, amount of theophylline is excreted unchanged. The intermedi-
captagon is the primary amphetamine-type stimulant consumed ate formation of amphetamine and theophylline contributes to
on the Arabian Peninsula counting the 40% of drug abusers in the pharmacodynamic action of fenethylline [12]. According
Saudi Arabia. Authorities in Saudi Arabia, Kuwait and Qatar to the second suggested pathway, metabolism of fenethylline
have reported a prevalent ‘captagon’ use among their younger can lead to the formation of 7-aminoethyltheophylline and
(between 12 and 22) affluent citizens [17,26]. The routes of phenylacetone [12,27]. The metabolic products are hippuric
administration are various, including ingestion, subcutaneous, acid and possibly theophylline which is further metabolized
intravenous and intraperitoneal [8]. [12].
Captagon is reported to be used by soldiers as it allows Later, Yoshimura et al. [28] showed that after oral adminis-
them to fight for extended period of time on little sleep with- tration of fenethylline in rats and human volunteers, six
out fatigue and without significant decrease in alertness or per- metabolites are produced. More specifically amphetamine,
formance. Thus, militants fight longer and harder with less p-hydroxyamphetamine, acetylaminoethyl theophylline, 7-ami-
concern for their own health and well-being, while resisting or noethyltheophylline, hydroxyethyl theophylline and car-
ignoring higher levels of pain [6]. boxymethyl theophylline were detected in their urine. They
It is also believed to be used by Islamic State fighters concluded that fenethylline metabolism proceeds via oxidative
(jihadist fighters), alone or along with other hallucinogenic cleavage at two different sites and produced aminoethyl theo-
pills, in order to boost their fervour and go to the battle without phylline and amphetamine. The major metabolites of fenethyl-
caring whether to live or die [10]. As captagon gives a ‘sense line were considered to be carboxymethyl theophylline and
of well-being, extra energy and euphoria’ [10,11,19], militants amphetamine [28]. It is possible that carboxymethyl theo-
and jihadist fighters ‘can stay awake for days at a time’, ‘keep phylline can be produced by oxidation of oxyethyltheophylline
up their motivation’ and ‘allow them to withstand the pain of which was suggested as a primary metabolite by Ellison et al.
being shot by bullets on the battlefield’ and feel ‘they are [12]. Carboxymethyl theophylline proved to disappear earlier
invincible and nothing can harm them’ [7,10,19,23]. ‘You than amphetamine from human urine and only trace levels of
can’t sleep or even close your eyes. . .and whatever you take to it can be detected in urine after 24–48 hr, whereas ampheta-
stop it, nothing can stop it’, said a Lebanese user, while mine was detectable at higher levels over the same time inter-
another user experienced, ‘I felt like I own the world high’ or val [28,30].
‘. . .there was no fear anymore after I took captagon’ [19]. The existence of the above metabolites was also confirmed
A drug control officer in the central city of Homs, western by R€ ucker et al. [29]. All the suggested metabolic pathways
Syria, described protesters’ and fighters’ behaviour under the are presented in fig. 2.
influence of captagon: ‘. . .we would beat them, and they
wouldn’t feel the pain. . . many of them would laugh while we
Pharmacology and Toxicology
were dealing them heavy blows. . .’ [11,22].
Since the late 1980s, counterfeit captagon tablets, which Literature reviewed showed that there is no extended scientific
contained mixtures of drugs with pharmacological effects simi- research on fenethylline regarding its pharmacology and toxi-
lar to those of fenethylline, have been reported in the Saudi cology.
Arabian drug market, while they have also appeared in Europe Results from early metabolic studies had led to speculation
and Turkey. Thus, examples of seized counterfeit tablets that fenethylline could be a pro-drug for amphetamine and/or
marked with the captagon logo have been reported in Serbia- theophylline [9,12,13]. The 13.7% and 24.5% of an oral dose
Montenegro, Former Yugoslavia, Turkey and Arab countries is apparently cleaved metabolically in human beings into theo-
[1,17]. The analysis of those counterfeit captagon tablets has phylline (weak stimulant chemically and pharmacologically
demonstrated the presence of amphetamine and/or ampheta- related to caffeine) and amphetamine (active stimulant),
mine-type derivatives, caffeine, theophylline, quinine, ephe- respectively [9,31,32]. So, the final pharmacological effect is
drine, acetaminophen, diphenhydramine, lactose and other the result of the combined action of these two stimulant agents
substances, while fenethylline was absent [17,18,20]. [25]. Fenethylline seems to display also its own stimulatory
effect to the same extent and at a similar time course as its
precursors, amphetamine and theophylline [33].
Metabolism of Fenethylline
Fenethylline stimulates the central nervous system, increas-
Only a few studies have been performed concerning the meta- ing alertness, concentration ability and physical performance,
bolism of fenethylline in animals or human beings [12,27–30]. while providing a feeling of well-being and appetite suppres-
The first metabolism study performed in human beings sion, due to its amphetaminic structure and its chemical resem-
using 3H-fenethylline suggested that the molecule can follow blance to natural neurotransmitters, like dopamine and
two possible metabolic pathways. According to the first path- adrenaline [5,17,34]. It causes dilation of bronchial vessels,
way, fenethylline is primarily hydroxylated (oxidized actually) and elevation of heart rate, body temperature, respiration and
to oxyethyltheophylline and amphetamine. The hydroxylated blood pressure in small to moderate doses. However, it does
© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
136 MARIA KATSELOU ET AL. MiniReview
not increase blood pressure to the same extent as ampheta- anorectic action than amphetamine and another stimulant used
mine; thus, it could be used by people with cardiovascular as anorectic agent, mazindol [13,36,37]. In contrast to amphe-
problems [9]. These moderate effects on blood pressure are tamine, fenethylline does not influence appetite and does not
due to the fact that theophylline is a vasodilator and ampheta- interfere with fine motor activity, but improves motor perfor-
mine is vasoconstrictor [7]. Fenethylline was also considered mance. It is also better tolerated than amphetamine and other
to have fewer side effects and less potential for abuse than central nervous system stimulants [4].
amphetamine [7,9]. Fenethylline is much more lipophilic than both ampheta-
The first psychological and psychomotor tests conducted by mine and theophylline; it accesses faster the brain and may
Janke and Boss [35] showed that 50 mg of fenethylline remain longer at receptors responsible for its activity. It also
improved mental and psychomotor performance 1 hr after oral decreased the acute toxicity of amphetamine and ampheta-
administration; thus, it increased productivity and ability to mine’s enhancement of ethanol and hexobarbital-induced loss
concentrate. The participants of the study were described to be of righting reflex [13].
in a well-balanced emotional state after the use of fenethylline, Intravenous or intracerebroventricular administration of
although the typical euphoria that is associated with ampheta- fenethylline produced convulsions in animals, whereas
mine-type substances did not occur with it [35]. amphetamine induced catalepsy [13,38]. Convulsions due to
Results of later pharmacological animal studies revealed that the administration of fenethylline were also reported by van
fenethylline increased motor activity in mice after oral admin- Meter et al. [39]; caffeine and theophylline exhibited weaker
istration with an onset of action between 90 and 120 min. activity in this regard, while amphetamine demonstrated no
similar to that seen with ()-amphetamine. The effects lasted convulsive activity under the same experimental conditions
approximately up to 180 min., although the respective dura- [39].
tion of action in case of ()-amphetamine persisted for up to The LD50 values of fenethylline after intravenous, intraperi-
240 min., as in case of theophylline. Thus, these results are toneal, subcutaneous and oral administration in mice and rats
not consistent to the hypothesis that fenethylline acts as a pro- vary from 55 to 347 mg/kg [8]. It has been proved to be much
drug for amphetamine and suggest that it acts as a different less toxic than amphetamine in terms of acute toxicity and
entity [13]. In the same study, fenethylline exhibited a lower developed no tolerance compared to its precursor [13].
© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
MiniReview FENETHYLLINE (CAPTAGON) ABUSE 137
Fenethylline demonstrated diuretic and positive nootropic Captagon was put under tight control in Austria since 1979,
effects similar to those observed after theophylline administra- a fact that dried up the respective sources. During the 1980s,
tion but different than those associated with amphetamine seizures of captagon were made while tablets were transferred
administration [40,41]. to the Arabian Peninsula [16].
The long-term use of fenethylline leads to remarkable side In March 2002, 107.5 kg of fenethylline was seized in Tur-
effects. The most common of them are extreme depression, key, while 6 months later more than 1.4 million captagon
lethargy, sleep deprivation (insomnia), occasional palpitation, tablets were seized in Syria while being shipped to Saudi Ara-
heart and blood vessel toxicity and malnutrition [4,17,34]. bia. Two more seizures of 75.03 and 39.7 kg of fenethylline
Other side effects that have been experienced by regular users were also reported in Bulgaria in March 2003 [17]. In 2003,
include blurred vision, vertigo, mouth dryness, breathing diffi- the Saudi authorities seized 291 kg of fenethylline, while
culties, irregular heartbeat, gastrointestinal symptoms, muscle 3 years later the respective seized quantity 12.3 tons, which
and/or joint pain, muscle cramping anxiety, mood swings, con- indicates an increase of stimulants consumption in the Saudi
fusion, feelings of anger or rage, irritability and impatience [6]. Arabia within the first decade of the 21st century [49].
The chronic use of fenethylline was supposed to have led to Between 2011 and 2012, there were 25 captagon-related
haemorrhagic central retina vein occlusion in three reported reports of narcotic crimes (among a total of 383) in Hatay
cases. In one of them, the haemorrhage, the oedema and the (southern Turkey); 21 of these captagon tablets (84%) were
engorged veins were remarkably improved after discontinua- seized in 2012. During the toxicological analyses of the seized
tion of the drug and laser treatment [42]. tablets, it was determined that most of the seizures concerned
The abuse of captagon tablets has been also correlated with counterfeit captagon tablets containing amphetamines, theo-
acute myocardial infarction. Particularly, a 21-year-old male phylline and caffeine. During the last 8 years, the seized
was admitted to the emergency department local State Hospital amount of captagon tablets at Hatay Province has increased
in Turkey with chest pain, confusion and aggressive behaviour dramatically [50,51]. More specifically, captagon seizures
after having ingested a captagon pill. He collapsed during the increased from 144,121 tablets in 2012 to 4,483,632 tablets in
initial examination and cardiac monitoring showed ventricular 2013. In 2014, a more dramatic increase in Turkish captagon
fibrillation. Coronary angiography was also performed reveal- seizures was observed [20]. In a single seizure (May 2014),
ing narrowing in the proximal portion of the left anterior Turkish authorities seized 7 million tablets en route to Saudi
descending artery [43]. Arabia. It was reported that the tablets were produced in Syria
It has to be stated here that similar symptoms can be devel- with raw materials from Lebanon [21,22].
oped after the consumption of counterfeit captagon pills that It was officially reported that in 2013, Lebanon authorities
usually contain amphetamines (where fenethylline is some- seized more than 12.3 million captagon tablets [22]. In April
times absent) and ephedrine, theophylline, caffeine, acetamino- 2014, Beirut security forces seized 15 million of captagon cap-
phen and/or other substances has been also incriminated sules hidden in shipping containers full of corn from Beirut’s
for cardiac symptoms, as well as for premature atherosclero- port [52].
sis [43]. It well known that the most common effects Recently, on 26 October 2015, prince of Saudi Arabia,
of usage of amphetamines are hypertension and tachycardia, Abdel Mohsen Bin Walid Bin Abdulaziz, and four others were
when ephedrine also causes positive chronotropic and detained in Beirut on charges of drug trafficking when two
inotropic effects, arterial vasoconstriction and hypertension tons of captagon tablets and cocaine were seized on a private
[44–47]. jet by airport security before departure for the Saudi capital of
The use of captagon tablets among young users has been Riyadh [52]. In November 2015, Agence France Press
also connected with heart failure and cardiomyopathy, reported that the Turkish authorities had seized 2 tons of cap-
although no published data in the literature exist. According to tagon on the Syrian border. The seized tablets (approximately
collected data from September 2010 to December 2012 in the 11 million) that had been produced in Syria were being
Persian Gulf region, 40 of 280 cardiomyopathy patients were shipped to countries in the Arab states of the Persian Gulf. It
captagon users; the majority of them were males (98%), alco- has been reported that 7.3 million captagon tablets were seized
hol consumers (28%) and smokers (92%). However, further ‘in one raid and were set to be shipped to Gulf countries by
studies with bigger sample size are needed to prove this sea hidden in 1300 oil filters’, while the rest 3.6 million
hypothesis [48]. tablets were seized in a depot [53].
In July 1981, 962,000 captagon tablets, which were ordered
by a Lebanese employee of a Beirut company, were seized by
Seizures
German authorities and proved to be counterfeit. Two years
Over the past years, a significant number of seizures of clan- later, 400,000 counterfeit boxes of captagon tablets along with
destine laboratories in several countries, such as Bulgaria, 4.5 million counterfeit captagon tablets were also confiscated
Slovenia Serbia-Montenegro and Turkey, have been reported by German police before they were to be shipped to the Near
by Interpol and International Narcotics Control Board. These East. Captagon was not commercially available in Italy, so it
laboratories varied in production capacity as far as the equip- was imported from Belgium, France and Germany through the
ment and the produced quantity are concerned [17,21]. black market [16].
© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
138 MARIA KATSELOU ET AL. MiniReview
In the same year, three clandestine laboratories that pro- Toxicological analyses of clandestine manufactured cap-
duced counterfeit captagon tablets were seized in the territory tagon tablets seized in Saudi Arabia showed that fenethylline
of the Republic of Serbia, while one of them was among the was not their major constituent or it was absent. The main
largest discovered in Europe producing several tons of amphe- active constituent of the investigated tablets was amphetamine
tamine salts. All the seized tablets (in a total weight of (38.8%), while approximately the half of the examined tablets
106.16 kg) were marked with the characteristic captagon logo. contained no amphetamines at all, and 12.2% of the investi-
Analysis of those tablets, using GC-MS, showed that fenethyl- gated tablets contained only a trace amount of the active
line was absent, while amphetamine salts, such as sulphate, amphetamines. The adulteration in captagon tablets varied
tartrate and phosphate, were the main constituents, followed from 40 to 47%, including caffeine (in 96% of the investi-
by caffeine, quinine, ranitidine, aminopyrine, as well as dilu- gated tablets), theophylline (93.9%), paracetamol (57.1%) and
ents, like lactose, microcrystalline cellulose, etc. [18]. allopurinol (59.2%) to dilute the concentration of manufac-
A seizure of captagon tablets was also reported in Dubai in tured amphetamines, enhance the excitatory effects and
2013, where an Arab was charged with consumption of psy- increase the amount of manufactured tablet, while two heavy
chotropic substances and possession of 4.2 million counterfeit metals (zinc and nickel) were also detected in the investigated
captagon tablets and other psychotropic substances with the tablets at toxic levels [56].
intention to sell them on the street. This was one of the most
significant seizures of amphetamines before the seized materi-
Legal Status
als were transferred to Saudi Arabia, according to the Dubai
Police [22,49]. Fenethylline has been a controlled substance on Schedule I of
the Controlled Substances Act since 1981 in the United States,
where it is no approved for medical use or distribution [9,17].
Determination of Fenethylline in Biological Fluids and
Although the actual incidence of fenethylline was quite low
Seized Samples
worldwide, it became illegal in most countries in 1986 after
Kikura and Nakahara [30] developed a GC-MS method being listed by the World Health Organization for international
for the determination of fenethylline, amphetamine and scheduling under the Convention on Psychotropic Substances
their metabolites in rat and human plasma, urine and hair [9]. In Canada and Germany, fenethylline is a Schedule III
after appropriate pre-treatment, liquid–liquid extraction with drug. The Drug Control Department of the Public Security
methylene chloride and derivatization of the analytes with tri- Directorate of Jordan has set fenethylline under control in
fluoroacetic anhydride. Fenethylline was orally and intraperi- 1988 [25].
toneally administered in human beings and rats, respectively.
Results revealed fenethylline concentrations were 1.2–2.7
Conclusion
times higher than those of amphetamine in human hair sam-
ples; however, the former rapidly disappeared from urine com- Fenethylline has been traditionally abused on the Arabian
pared to the latter. These findings suggested that hair can be a Peninsula as captagon with Syria being the major manufac-
useful specimen of disclosure for drug history of fenethylline turer, consumer and exporter, due to its strategic position at a
and for the discrimination between fenethylline and its precur- crossroads in the Middle East. The scheduling of amphetami-
sor, amphetamine [30]. nes and the fact that fenethylline synthesis requires cheap and
Early methods developed for the determination of the major legal raw materials, as well as no sophisticated instrumenta-
active ingredients in seized counterfeit captagon tablets used tion, also led to its production in clandestine laboratories and
UV, infrared spectroscopy (IR), as well as TLC [54,55]. abuse in Middle East, Turkey, Europe and North Africa. It is
For the identification and determination of fenethylline or likely to remain popular among the young affluent populations
other active substances in 124 illicit counterfeit captagon in the Arabian Peninsula States, as well as among militants
tablets seized by the Drug Control Authorities in Jordan, a and jihadist fighters. During the last years, the introduction of
GC-MS method was used by Alabdalla in 2005; the chemical counterfeit captagon tablets has been observed. In most of the
composition of each tablet was compared with the respective cases, these tablets contain no fenethylline, but amphetamine
legal reference standards available. Analysis of samples was or amphetamine analogues, which possess pharmacological
performed after appropriate pre-treatment of captagon tablets activities similar to fenethylline, in combination with other
via solid-phase extraction after alkalinization (pH 9), applica- drugs that may contribute to the causes of health risks. The
tion on C18 columns and elution with 2% ammoniacal ethyl captagon abuse potential led to its scheduling worldwide.
acetate solution. Analytical data revealed the presence of Despite that, an increase of its trafficking and abuse has been
amphetamine and caffeine in the majority of tablets, as the observed during the last years. Moreover, the extensive circu-
major constituents responsible for the stimulation effect expe- lation of counterfeit captagon tablets shows the popularity that
rienced by abusers, while ephedrine, metronidazole, theo- the name ‘captagon’ holds among them.
phylline, chlorpheniramine, procaine, trimethoprim,
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