Narco-terrorism today: the role of fenethylline and tramadol Introduction The relationship between psychoactive substances and violent crimes such as war acts and terrorism dates long back in history. Viking warriors famously fought in a trance-like state, probably as a result of taking agaric "magic" mushrooms and bog myrtle (McCarthy, 2016). More recently, under the German Nazis’ Third Reich, methamphetamine gained an extreme popularity, despite an official “drug-free” propaganda. Under the trademark Pervitin, it could be sold without prescription until 1939, and it was not regulated by the Reich Opium Law of 1941. Pervitin was commonly used in recreational and working settings, and, of course, the stimulant was shipped to German soldiers when the troops invaded France, allowing them to march sleepless for 36 to 50 hours (Ohler, 2016). On the other side, Benzedrine, a racemic mixture of amphetamine initially developed as a bronchodilator, was the stimulant of choice of the Allied forces during World War II (McCarthy, 2016). Vietnam War (1955-1975) is considered to be the first “pharmacological war” of modern history, so called due to an unprecedented high level of consumption of psychoactive substances by military personnel (Kamienski, 2016). In 1971, a report by the House Select Committee on Crime revealed that from 1966 to 1969, the US armed forces had used 225 million tablets of stimulants, mostly Dexedrine (dextroamphetamine), an amphetamine derivative that is nearly twice as strong as the Benzedrine used in the Second World War (Kamienski, 2016). The use of illicit drugs such as stimulants or painkillers by terrorists or insurgents while undertaking their terrorist activities has been hypothesized but still needs further documentation. Moreover, besides being fuelled by psychoactive drugs, terrorism also needs to be funded, and drug trafficking makes a very profitable and secure business (EMCDDA, 2016). The Revolutionary Armed Forces of Colombia, known as FARC, is Latin America’s oldest guerrilla group: since the 1980s, it has been taxing cocaine producers and smugglers in rebel-controlled areas in order to finance their activities (Otis, 2014). In Afghanistan’s poppy-rich southern and southwestern regions, Taliban profit from opium traffickers who operate along the Pakistan border (Peters, 2009). The recent development of online drug markets in both surface and deep Web may also provide a further and safer opportunity for buying and selling psychoactive products (Orsolini et al., 2017). Chemical, pharmacological and metabolic characteristics Fenethylline Fenethylline, also spelled phenethylline or fenetylline, is a co-drug of amphetamine and theophylline. In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain; the drug exhibits effects qualitatively and quantitatively different from those of parent compounds, strongly suggesting that the compound exerts its own intrinsic activity (Nickel et al., 1986) (Fig.1). Fenethylline was originally synthesized by the German company Degussa AG in 1961 as part of an investigational program on theophylline derivatives, with an interest on its effects on cardiovascular, pulmonary and central nervous systems. One of the main advantages of fenethylline over other amphetamines is that it does not increase significantly blood pressure, so it can be used by patients suffering from cardiovascular conditions (Kikura and Nakahara, 1997). Fig.1 Chemical structure of fenethylline Source: https://pubchem.ncbi.nlm.nih.gov/compound/fenethylline#section=2D-Structure Fenethylline is a crystal solid with the molecular formula C18H23N5O2, and it is usually found as its hydrochloric salt (1892-80-4,cas lookchem). According to Yoshimura, who investigated the metabolism of fenethylline in male rats and in three male volunteers, six metabolites have been identified, and the two major are carboxymethyl theophylline and amphetamine (Yoshimura et al., 1988). The 13.7% and 24.5% of an oral dose is apparently cleaved metabolically in human beings into theophylline (weak stimulant, pharmacologically related to caffeine) and amphetamine (active stimulant), respectively (Shulgin, 1975; Kraemer and Maurer, 2002). Fenethylline was primarily proposed in the 1960s as a treatment for children with a diagnosis of attention deficit hyperactivity disorder, narcolepsy and depression. It was marketed under the brand names Captagon, Biocapton, and Fitton, initially as a non- prescription psychostimulant, but later on it could only be prescribed under medical supervision (Kristen, Schaefer and von Schlichtegroll, 1986). Fenethylline was never approved by the US Food and Drug Administration: it was later listed as a “Schedule I controlled” substance in the United States, and became illegal in most countries in 1986 (UNODC, 2014). Tramadol Tramadol is a central analgesic with low affinity for opioid receptors, structurally related to codeine and morphine (Grond and Sablotzki, 2004). It was first synthesized in 1962 by Grünenthal GmbH in Germany, and it exists as a racemic mixture of the right and left enantiomers (World Health Organization, 2014) (fig.2). In its hydrochloride form, it appears as a white crystalline powder with a bitter taste, and it is easily soluble in both water and methanol. The analgesic mechanism of action of tramadol includes both non- opioid components, (e.g., noradrenergic and serotonergic components, due to the effects of right and left enantiomers on neurotransmitters’ reuptake), and opioid components (due to the binding of the O-desmethyl metabolite to the µ receptors (Scott and Perry, 2000; Raffa et al., 2012). The fact that non-opioid mechanisms are involved in its analgesic effect is supported by the observation that naloxone only partially antagonizes tramadol-induced analgesia (World Health Organization, 2014). In conclusion, the analgesic effect of tramadol appears to be produced by a multimodal mechanism involving the μ-opioid system, the noradrenergic system, and the serotonergic system. Tramadol acts as a releaser and reuptake inhibitor of serotonin, and as a reuptake inhibitor of noradrenaline, and its metabolite is active as a μ-opioid receptor agonist. Noradrenaline and serotonin have long been considered to be involved in the regulation of nociceptive perceptions, and tramadol has been the first pharmacological product to employ this unique mechanism of action. Fig.2 Chemical structure of tramadol Source: https://pubchem.ncbi.nlm.nih.gov/compound/63013#section=2D-Structure Tramadol was initially approved for medical use in Germany in 1977, although it was not approved by the Food and Drugs Administration (FDA) until 1995. Tramadol has a potency similar to that of codeine, and its bioavailability is approximately 20% of oral morphine (Grond and Sablotzki, 2004). The efficacy and safety of tramadol in treating both acute and chronic moderate to severe pain has been demonstrated in extensive clinical studies. Tramadol has also shown efficacy as a treatment option for neuropathic pain, in which usually opioid drugs have limited effect; a further advantage of tramadol with respect to conventional opioids is that it presents less withdrawal symptoms and a lower risk for respiratory depression (Bravo, Mico and Berrocoso, 2017). Tramadol is marketed in a variety of pharmacological formulations (oral, sublingual, rectal, intravenous, intramuscular), and immediate- and extended-release versions are available too. The daily dose of the drug should not exceed 400 mg: most treatments range between 100 and 400 mg (Tramadol Uses, Side Effects, Dosage & Warnings - Drugs.com, 2017). Tramadol is listed as a prescription-only drug in most countries. It is under control in Bahrein, Mauritius, Australia, Iran, Sweden, Venezuela, Ukraine, Egypt Jordan, Saudi Arabia and the UK (World Health Organization, 2014). Misuse, toxicology and fatalities Fenethylline For low dosages, fenethylline adverse reactions are commonly limited to minor sympathomimetic effects (vertigo, dry mouth, palpitations) (Kristen, Schaefer and von Schlichtegroll, 1986). Higher fenethylline consumption has been linked to potential cardiac and vascular toxic effects (e.g., haemorrhagic central retina vein occlusion, acute myocardial infarction, acute heart failure) (Al-Ghadyan, Rushood and Alhumeidan, 2009; Ulucay, Arpacik and Aksoy, 2012; Elasfar, Eldein-Ahmad and Alsagha, 2014). With respect to psychiatric adverse consequences, the potential development of fenethylline- induced psychosis, presenting with symptoms such as aggression, agitation and paranoid delusions, is reported (Shufman and Dickman, 1999; Twark and Suzuki, 2016). Drug discontinuation usually determines a quick resolution of the symptomatology, but in some cases antipsychotic medications (e.g., haloperidol, olanzapine) may be needed (Leelahanaj, Kongsakon and Netrakom, 2005). Amphetamine-induced psychosis may be very similar in its clinical features to schizophrenia spectrum psychosis, and therefore it may be difficult for clinicians to distinguish the two in an acute setting. More pronounced grandiosity and visual hallucinations, together with a faster, although often incomplete, recovery, are considered to be more typical of induced psychosis with respect to schizophrenic psychosis; nevertheless, the two conditions share several susceptibility genes, suggesting a common vulnerability pathway (Bramness et al., 2012). Fenethylline appears to be a major substance of misuse in the Middle East, where it is most known under