Ilaria Stirpe
Bruno E. Rossi
FENETHYLLINE
Fenethylline, also known as amphetaminoethyltheophylline or amfetyline, branded under the name of Captagon, is a psychostimulant synthetic drug derived by a linkage of amphetamine and theophylline obtained via an alkyle chain.
- Amphetamine, along with its derivatives, is a psychoactive substance that belongs to a larger class of substances, named phenetylamines. It has an half-life of approximatively 12 hours and performs as an indirect agonist towards the catecolaminergic system, mostly with a central action, being it a substrate to the dopamine active transporter (DAT) with whom it competes for the tranfer from synaptic space to cytosol. Moreover, it inhibits the vescicular monoamine transporter (VMAT), preventing the filling of synaptic vescicules. This causes a raise in cytoplasmatic concentration of dopamine and an inversion of orientation in DAT, with a consequent release of dopamine, noradrenaline and serotonine. This mechanism explains its narcotic, stimulant and anorectic effect.
- Theophylline (also known as dimetilxantine) is a chemical compound, part of the family of alkaloids; more specifically, it's a metilxantine. It takes part between basic azotate compounds produced by certain vegetal species and it is a xantine with a big structural and pharmacological similarity with caffeine and theobromine. In nature it's contained in tea leaves, though in a significantly lower dose than terapeutical. Theophylline has an half-life of about 5-8 hours and has stimulant effects on CNS.
HISTORY
Fenethylline was synthetized for the first time in 1961, while working on a project centered on the effects of theophylline derivatives on cardiovascular, lung and central nervous systems. That study was led by the research department of the german pharmaceutical company Degussa AG, known mostly for manufacturing and distributing the lethal gas Zyklon B, used during the Holocaust.
The drug was used mainly for treatment of ADHD; it was also used to treat DD, narcolepsy, lack of drive and absences.
It was distributed as an OTC medication until 1964, when prescription became mandatory. In 1981, FDA listed it as a schedule I controlled substance in the US. In 1986, it became illegal in most countries, after being listed by the World Health Organization for international scheduling under the Convention on Psychotropic Substances, suggesting a restrictive regulation or the inclusion between illegal substances.
After banishment, SU imported the formula from West Germany and started a local production, settled mainly in Bulgary. The substance was illegaly exported in western countries and the profits that derived from such traffic were finalized to the economic support of soviet communist regime. After the fall of the Berlin Wall, in 1989, with the end of the Soviet regime, production was yield by gangsters located in Eastern Europe. The traffic was gradually moved from western countries to Middle East, where small centers of production were born. In 2007, after the entrance of Bulgary in EU, a wider supervision was held, forcing the suspenction of the activity in Bulgary, shifting it in favour of middle-eastern centers, particularly Turkey and Lebanon. Since 2011, Syria has held the majority of the production, to this day it owns 90% of the production.
ABSORPTION AND METABOLIC FATE
The drug is taken orally. Animal testing proved that Fenethylline injected intravenously or intracerebroventricularly causes convulsions. Fenethylline is rapidly absorbed and reaches plasmatic peak after about an hour. It has an half-life of approximatively 1,3 hours. After the assumption, Captagon is converted in vivo in d-amphetamine and theophylline. These two compounds are transferred into the blood stream and can cross the brain blood barrier, becoming active at a central level.
Fenethylline metabolism follows two pathways.
# The first (and main) one concludes with the formation of amphetamine and derivatives (phenylacetone and p-hydroxy amphetamine).
# From the second pathway we obtain the metabolites of theophylline, the main of which is charbossimetyl-theophylline, produced via oxidation of an intermediate aldeide called formilmetyltheophylline. Other metabolites, in fewer percentages, are 7-acetaminoetyltheophylline, 7-hydroxyetyltheophylline and 7-aminoetyltheophylline.
The second pathway is based upon two types of N-acetyltransferases, which catalyses the acetilation of theophylline. The first one is located in hepatocytes' cytosol and catalyses the acetylation of primary ammines like sulphametazine, hysoniazide and hydralazine. The second one is a mycrosomial enzyme that takes place in liver and kidneys, which acetylates the amino groups of conjugate cysteine to obtain mercapturic acid.
The excretion of said metabolites is urinary: the main urinary metabolites are amphetamine and charbossimetyl-theophylline, respectively 27% and 41%.
The measurement of the last one is used to determine a distinction between amphetamine and Fenethylline abusers.
THERAPEUTIC INDICATION AND EFFECTS
Captagon was administered in tablets of 50 mg; long-term treatment wasn't advised, moreover a period treatment-free was required. The manifacturer house delared that Fenethylline effects were quantitatively and qualitatively different from amphetamine ones, declining the ranking of it as a "Pro-drug". Different studies of comparison made in 23 years in mice between amphetamino-likes, theophylline and fenethylline, defined such effects.
The therapeutical effects declared were, after an hour of administration: improvement of physical and motory performances, mood, ability of concentration and productivity, combined with a lack of parossistic crisis in epileptic and narcolectic patients. At a lower dosage was reported an improvement in precise motility and a reduction of tremors. Subjects after administration referred a well-balanced state. The company declined the possibility of side effects on liver, kidneys and cardiovascular system, also excluding a possible raise in aggressivity or euphoria. Side effects declared were piloerection, lowering of pressure, stereotyped movement, bland anorectic effects, restlessness, sleep disorders, tachicardy, dizziness, dry mouth, gastrointestinal symptoms, minor or aspecific sympaticomimetic effects, usually increased by caffeine assumption. Further studies shows severer cases, including psychosis, retinal vein occlusion and coma dépassé.
ADDICTION AND ABUSE
Degussa declared a minor addictive risk compared to amphetamines, though the substance was labeled as highly addictive from several national and international companies. Dealing and consumption with recreative purpose has always had, compared with other psychoactive substances, a minor relevance. Its use was mainly limited to German and US territory, and later it expanded towards the Middle East and Eastern Europe. Since 1964, with the introduction of obligatory prescription, the reports of overdose underwent a serious reduction. New cases were due mainly to dosage mistakes, or were caused by other drug abuers to reduce hangover and fatigue. There were fewer cases of non-medical uses, because the psychoemotional experience was generally well-balanced and controlled, compared with the desired euphoric state, explaining why drugs with more intense effects, like hallucinogenics and amphetamines, were used.
CAPTAGON 2.0
Fenethylline came back again in the news during the half of the 10s, thanks to the spread of a new drug, improperly labeled as Captagon, which was used by middle-eastern warriors who took part in several wars forming part of the so-called "Arab Spring". Such product, different in composition to the original drug, is a cocktail of substances used as an anesthetic-dissociative drug by ISIS jihadists and guerrilla fighters of Al-Nursa and FSA. This drug is a blending of stimulants, antibiotics and vasodilators, consisting in a combination of methamphetamine, ephedrine, metronidazole, caffeine, theophylline, chlorphenamine, procaine, trimethoprim, chloroquine and quinine. The physical effects produced are: increase in heart rate, body temperature, respiration rate and blood pressure. From the psychological point of view those included euphoria, alienation, loss of the sense of hunger, sleep and fatigue. These effects, which are sought by the guerrillas to fight, present dangerous side effects in the long term, which include lethargy, depression, insomnia, malnutrition and severe vascular toxicity, with ischemic and hemorrhagic consequences.
BIBLIOGRAPHY
"Fenetylline: therapeutic use, misuse and or abuse" - Kristen G. et al.(Drug and Alcohol Dependence, 17-1976)
"Fenethylline: New results on pharmacology" - Nickel B. et al. (Drug and Alcohol Dependence, 17-1976)
“Metabolic fate of fenethylline in rat and man”- Yoshimura H. et al. (Xenobiotica, 18-1988)
“Fenethyllin psychosis: description of two cases” - Shufman E., Dickman M. (The Israel journal of psychiatry and related sciences,36-1999)
“Fenethylline as a possible etiology for retinal vein occlusion” - Al-Ghadyan A. et al.( Annals of Ophthalmology, FW-2009)
“Chemical characterization of counterfeit captagon tablets seized in Jordan” - Alabdalla M. (Forensic Sciences International , 152 -2005)
“World Drugs Report” - UNODC (United Nations Office on Drugs and Crime), New York- 2008.
“Acute myocardial infarction associated with Captagon use” - Uluçay A. et al (the Anatolian journal of cardiology, 12- 2012)
“Syria’s Breaking Bad: Are Amphetamines Funding the War?” - Baker A. (Time, 2013)
“Amphetamine abuse: a growing reality in Saudi emergency departments” – Khattab e. (Emergency physicians international journal, 2013)
“Captagon: the amphetamine fuelling Syria's civil war” – Henley J. (The Guardian, 2014)
