“Chemical Courage”: A Review on Pharmacotoxicological Aspects of Fenethylline (Captagon)

Chemistry and Dosage Form

Fenethylline [or phenethylline or amphetaminoethyltheophylline or amfetyline] with Chemical Abstract Service (CAS) name: (R,S)- 3,7-Dihydro- 1,3-dimethyl-7-[2-[(1-methyl-2-phenylethyl)amino]ethyl]- 1H-purine-2,6-dione, defines as a covalently linked of an amphetamine molecule with theophylline as an alkyl chain (Figure 1) [5, 6]. In 1961, German chemists at Degussa AG Pharmaceutical company first synthesized fenethylline from amphetamine and 7-(2-chloroethyl) theophylline. The company began to market its hydrochloride salt under the property name Captagon [6]. Fenethylline is a co-drug of amphetamine and theophylline and a prodrug to both [1, 6]. The physicochemical characteristics of fenethylline and its hydrochloride salt have shown in Table 1 [6, 7].

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Captagon is available in the form of oral tablets containing 50 mg of fenethylline hydrochloride (in standard dosage form) but tablets can be crushed, heated, and intravenously injected for more powerful and rapid effects in cases of abuse [1].

Analysis of many seized samples of illicit and counterfeit Captagon tablets have been shown the mixtures of amphetamine plus caffeine, rather than fenethylline hydrochloride. In some counterfeit Captagon samples, methamphetamine rather than amphetamine is found.

The most common adulterants which detected in street-level manufactured tablets includes amphetamine, methamphetamine, procaine, caffeine, quinine, chloroquine, ephedrine, metronidazole, theophylline, chlorpheniramine, acetaminophen and trimethoprim [1, 8, 9, 10, 11].

Metabolism

In in vivo situation, fenethylline metabolizes by oxidative enzymes to produce its original components, amphetamine and theophylline, each of them has its own undesirable characteristics when taken in large quantities [12]. Captagon metabolizes to amphetamine (24.5%) and theophylline (13.7%) per oral dose.

Theophylline, a xanthine derivatives, is a weaker CNS stimulant in comparison with caffeine with a narrow therapeutic index. In supratherapeutic doses, it is induced arrhythmias and gastrointestinal side effects [1]. Captagon has greater lipophilicity than either theophylline or amphetamine alone, allowing its more rapid absorption into the CNS, but amphetamine penetrates brain tissue more rapidly than Captagon [12]. Theophylline is metabolized via cytochrome P450-2D6 (CYP2D6) enzyme, while amphetamine inhibits CYP2D6. Therefore, amphetamine is eliminated more rapidly from the body than theophylline, but these two agents act synergistically with each other to enhance the individual drug stimulant effects [13].

Investigation on metabolic fate of fenethylline in an animal model (male Sprague-Dawley rats) and human volunteers showed that six metabolites were identified in the rat and human urine samples including amphetamine(AP), p-hydroxy-AP, acetylaminoethyl-theophylline(TP), aminoethyl-TP, hydroxyethyl-TP and carboxymethyl-TP. In human, carboxymethyl-TP(39-43% dose) and AP(23-33% dose) were the major metabolites in 0-48h urine [14].

Mechanism of Action and Pharmacology

Captagon has a strong CNS stimulating effect that its primary metabolite, amphetamine. However, multi-targets issues associated with the drug and metabolites as well as its underlying mechanisms have not been fully understood [1, 15].

Amphetamine acts as an agonist at the trace amine- associated receptor 1 (TAAR-1), which enhances dopamine signaling. This dopaminergic effects may induce behavioral changes such as irritability and aggression and can lead to dependence. Wu N, et al. [13] performed a drug abuse chemogenomics-knowledge base systems pharmacology approach to conduct targets/off-targets mapping investigation of Captagon and its metabolites. Theophylline as an antagonist of adenosine receptors (e.g. A2aR) in the brain responsible for restlessness and analgesia, may attenuate the behavioral sensitization caused by Amphetamine. Also, they found that the synergies between two metabolites cause Captagon’s psychoactive effects to act faster and more potently than those of Amphetamine alone. The researchers carried out molecular docking modeling and molecular dynamics simulation to explore the molecular interactions between Amphetamine and Theophylline and their important G protein-coupled receptors (GPCRs) targets, including TAAR1 and adenosine receptors [13].

Serotonin (5-HT) receptors are important role in various neurobiological processes, such as cognition, learning, memory, anxiety, appetite, mood, sleep, aggression, and thermoregulation. These receptors are commonly related to drug abuse and addiction as targets for various medicinal and recreational drugs.

Wang YQ, et al. [15] investigated on all type of 5-HT receptors based on the existing crystal structures of 5-HT1B, 5-HT2B, and 5-HT2C. Then, they performed molecular docking studies between 5-HT receptors agonists/inhibitors and 3D models. They performed molecular docking simulations for 12 5-HT receptors complexed with ligands. They showed that 5-HT2C, 5-HT5A, and 5-HT7 were the most promising targets for Captagon before metabolism [15].

Side Effects and Toxicology

The most common side effects of captagon include psychosis, hallucinations, visual abnormalities, acute heart failure, seizures, and acute myocardial infarction [1, 16]. The pathophysiology of amphetamine-induced myocardial infarction has not been elucidated but it is likely associated with vasoconstriction and instability of the thrombus due to the amphetamine [16]. Other side effects are tachycardia, hypertension, hyperthermia and tachypnea [1]. Captagon chronic use can result in insomnia, lethargy, and depression [1, 17].

Some long-term Captagon users may suffer from malnutrition, as the drug can induce anorexia and reduce interest in food [1, 2]. However, prolonged insomnia and reduced appetite may be beneficial for soldiers and combatants in times of war. Hallucinations and psychosis have been reported with Captagon use along with depression, irritability and aggression [1, 3, 18]. It is unclear whether Captagon or other amphetamines lead to psychosis in general or whether they provoke prolonged insomnia as the triggers the psychosis [1, 19].

While insomnia is a common side effect of chronic use of Captagon, the effect of Captagon on sleep conditions has not been well known. In a study of 78 male patients with diagnosed amphetamine induced psychosis, the majority of participants (92.9%) experienced insomnia while taking Captagon, but insomnia was often intermittent. The longest period of persistent wakefulness observed in this study was seven days and occurred in one participant [17]. Subjects in this study reported that psychotic symptoms and/or hallucinations were mitigated or ended completely when normal sleep was restored [17].

Delusions may also occur with prolonged captagon use. In a study from Saudi Arabia of 101 male patients between the ages of 19 and 46 years with the diagnosis of Captagon induced psychosis, 25.7% developed infidelity delusions. Compared to other patients, those with jealous delusions had a higher divorce rate. It has been suggested that morbid jealousy may be related to Captagon-induced disordered sleep [20].

In rare cases, Captagon may induced arrhythmias and acute coronary syndrome [21]. In a case report, two patients with Captagon abuse has induced visible changes on the electrocardiogram that appear similar to those of congenital Brugada syndrome [22]. Also, three cases of hemorrhagic central retina vein occlusion following continuous use of Captagon has been reported. In one of them, notable improvement in the hemorrhage, edema and the engorged veins after discontinuing the drug and laser supplement has been observed [23]. However, there are no known cases of direct mortality due to Captagon use [1].

Abuse and Addiction

Captagon is an addictive agent, although it is considered less addictive than amphetamine, perhaps because it penetrates the brain tissue more slowly than amphetamine [1, 6]. Captagon is often part of intentional and unintentional polysubstance drug abuse pattern when a user takes a contaminated product mixed with other drugs [1].

However, polysubstance abuse in the EMR is more likely to include Captagon in the mix than polysubstance cocktails in Western Europe and North America. Captagon plus an opioid such as methadone is a common combination [2, 3]. Other Captagon combinations are including alcohol and/or cannabis, crystal methamphetamine and tramadol [24].

In a study of Jordanian university students using captagon over several days, they experienced increased level of stress, felt disorganized in a way that they missed classes, and were being socially isolated. It was noted that even those who wanted to stop taking the substance hesitated to ask for help because of the shame attached to drug abuse. That most students took the drug to manage personal and academic pressures [25]. Most Captagon users are young men [1, 2, 3, 25].

Captagon and War

The use of drugs to propel demonstrations into street battles and terrorism has been termed “pharmaco- terrorism” and represents a potential threat across the world [1]. Captagon may represent an important evolution in pharmaco-terrorism [11].

Captagon has been named as: “Chemical courage”, “Jihadi pill”, “Jihad pill” or “Jihadist’s drug” by the Islamic State of Iraq and Syria (ISIS) (also known as the Islamic State of Iraq and the Levant (ISIL) and by its Arabic acronym Daesh) fighters in Syria and Iraq [26, 27, 28]. Captagon use in military and terroristic operations, where it can increase to be desirable characteristics (aggressiveness, euphoria, prolonged wakefulness, alertness, and fearlessness) in their operations. Captagon has been reported to suppress or reduce pain perception. Captagon is reported to be taken not only by soldiers, but also by civilians in war-torn areas to help them manage crucial and terrifying conditions [1, 5].

In the early 2000s, a shift toward clandestine manufacturing of Captagon was observed in Balkan and Anatolia region countries (Slovenia, Serbia-Montenegro, Bulgaria and Turkey) with stockpiling and trafficking of this new synthetic ATS through Turkey and Bulgaria into the Arabian Peninsula [11, 27, 28, 29].

At present, Captagon’s production, use, abuse, and trafficking remain concentrated in the Middle East. Syria is considered to be the world’s largest manufacturer of Captagon, accounting for about 80% of the global supply [11]. Since the Syrian civil war started in 2011, this country has changed from being a transit country to becoming a producer site for Captagon and this country has become an international hub for Captagon production. A main Captagon trafficking route runs from Syria to the Arabian peninsula via Jordan and Lebanon [29]. This has caused increasing domestic consumption of Captagon in Jordan [29].

Syria and Lebanon were the top countries for Captagon seizures in 2016, the trade being partly fueled by the Syrian conflict [28]. Captagon (or ‘Abu Hilalain’ its Arabic nickname due to stamped the Captagon white pills with two crescents) is a popular street –level stimulant in the Middle East [30]. Authorities in Arab countries seize millions of Captagon tablets every year [29]. Captagon is particularly popular in Saudi Arabia and the United Arab Emirates where it is used as a stimulant and appetite suppressant. Its street value varies widely, depending on supply factors and range from $10 to $25 per pill in Saudi Arabia [31]. Recently, Captagon mostly enters Jordan at the southern Syrian border, but shipments have also been confiscated at the port in Aqaba, as well as at the borders with Saudi-Arabia and Iraq [32]. More than 21 million tablets have been reported seized in Jordan (all originating from Syria) between 2015 and beginning 2022 [29]. Also, there are some evidences about the Paris attackers in 2015 that were involved of use of Captagon [33].