<<

Narco-terrorism today: the role of 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, gained an extreme popularity, despite an official “-free” propaganda. Under the trademark Pervitin, it could be sold without prescription until 1939, and it was not regulated by the Reich Law of 1941. Pervitin was commonly used in recreational and working settings, and, of course, the 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 of initially developed as a , 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 , mostly Dexedrine (), an amphetamine derivative that is nearly twice as strong as the Benzedrine used in the Second World War (Kamienski, 2016). The use of illicit 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 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 . 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 is that it does not increase significantly , 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 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 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 ) 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, and . 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 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 with low affinity for receptors, structurally related to and (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 and methanol. The analgesic of tramadol includes both non- opioid components, (e.g., noradrenergic and serotonergic components, due to the effects of right and left enantiomers on ’ 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 of , and as a reuptake inhibitor of noradrenaline, and its metabolite is active as a μ-opioid 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 similar to that of codeine, and its 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 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 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, , Venezuela, Ukraine, , 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, ) (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 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 , 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., , 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 , 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 , where it is most known under the Arabic name “Abu Hilalain”, “father of the two crescent moons.” The Arabic slang derives from the two letter C’s resembling crescent moons found on each Captagon tablet. Street names also include Abu mlaf, Lajah, Alabyad (white), Al qeshtah, Al asfaar (yellow) (Bamofleh et al., 2017). In Saudi Arabia, the popularity of the drug is rising among students, who may consider using the substance as a cognitive enhancer, to increase their ability to concentrate and perform better during examinations (Drug use on the rise among Saudi students | Arab News, 2013). Adolescents and young adults (15 to 25 years old) appear to be those more at risk to experiment with fenethylline (Bamofleh et al., 2017). Use of fenethylline as a pro- agent is also reported. According to the United Nations and the National Committee for Control and Anti-Drug and Preventative Affairs, fenethylline is the primary amphetamine-type stimulant consumed in the Arabian Peninsula, especially among young affluent citizens (Katselou et al., 2016). Despite being illegal, the drug is widely marketed in the Middle Eastern area (see paragraph Markets and ).

Tramadol

Tramadol is considered to be relatively safe with respect to other opioid analgesic drugs. When use at therapeutic doses, its most common side effects include nausea, vomiting, diarrhoea, and drowsiness, , , itching, sweating (Tramadol

Uses, Side Effects, Dosage & Warnings - Drugs.com, 2017). Two more relevant adverse reactions are seizures and serotonin syndrome, which are more likely to develop when tramadol is administered at high doses or in co-administration with (mainly tricyclic and selective serotonin reuptake inhibitors) (Sansone and Sansone, 2009). Tramadol has a potential for , but from both animal models and human data it appears to be low, unless the subject has a previous history of substance misuse or the drug is used for an extended period (Sarkar et al., 2012). Withdrawal symptoms are similar to those of other opioids: restlessness, agitation, , , , paraesthesia, and gastrointestinal symptoms are often present (Barsotti, Mycyk and Reyes, 2003). Tramadol abuse is more common among non-dependent opioids abusers and recreational drugs user (Zacny, 2005; Babalonis et al., 2013). Fatalities are mostly linked to substance nonmedical use or combination with other drugs (Iravani et al., 2010).

There is growing evidence of tramadol misuse in some African (Egypt, ) and Asian (Jordan, Saudi Arabia, ) countries (International Narcotics Control Board, 2012). In Egypt, tramadol has become ubiquitous, as it is used both recreationally and as an enhancer (A pill for work and play, 2015). In fact, the drug gained its popularity among youth and middle-aged users as a potential sexual enhancer, able to treat premature ejaculation and to improve performance and orgasm. The substance is also used to relieve the symptoms of psychosomatic stress (Fawzi, 2011). Apparently, tramadol has had a notable diffusion in the Gaza strip since 2007, especially among people living in refugee camps, in order to cope with feelings of hopelessness and anxiety (Eldar, 2016). According to the US and Mental Health Services Administration, the number of tramadol-related admissions involving misuse or abuse increased about 250 percent from 2005 to 2011, and in most cases the substance was mixed with or one or more other drugs, thus notably increasing the health risks (Bush, 2015).

Potential links with terrorism

Fenethylline

As mentioned in the previous paragraph, fenethylline is among the most abused stimulant psychoactive substances in Arab countries. Terrorist groups, including the Islamic State in Iraq and the Levant (ISIL, formerly known as ISIS) and other militant groups in are anecdotally reported to use fenethylline to increase aggression and (AL-Imam et al., 2016). Amphetamine use, in fact, has been associated with impulsive, aggressive, antisocial, and, rarely, homicidal behaviour (Sekine et al., 2006; Scott et al., 2007), especially when used in higher dosages and on the long run. According to eyewitnesses, the terrorist attackers who killed 130 people in Paris on November 13th, 2015 were acting “zombie-like” during the shootings, and were therefore supposed to be under the influence of a psychoactive substance, possibly fenethylline (Fond and Howes, 2016), but this has not been proven by toxicological findings (Paris attackers not on drugs, toxicology report finds - France 24, 2016). The terrorist who shot and killed 38 people on a Tunisian beach in summer 2015 may have been under the effects of fenethylline, too. According to reports, during the shooting, he was smiling and laughing, in a sort of emotional detachment (Fond and Howes, 2016). The use of psychoactive substances in terrorist acts can definitely represent a worsening and/or precipitating factor, as attackers with an altered mental state can be more hostile (e.g., paranoid delusion symptoms) and unpredictable (Khanra and Sen, 2016). Captagon-labelled tablets are also widely involved in the Syrian conflict, both marketed for funding the war, and used as a stimulant by fighters to induce greater fighting aggression, alertness, and for cognitive enhancement during long missions (Van Hout and Wells, 2016). Prior to the civil war, Syria had a significant pharmaceutical industry that supplied the region, and there is evidence that since the advent of the war, there has been an increase in production of Captagon or Captagon-like products inside the country (Global Islamic Terrorism Research & Analysis, 2017).

The use of psychoactive substances by Muslim terrorist groups is an extremely ambivalent phenomenon: for instance, Al-Qaeda strictly adheres to Islamic law (Sharia),

and forbids its members to alcohol and take substances other than prescription drugs (Mashayekhi, Sattari and Mashayekhi, 2012). On the other hand, ISIL appears to act more “flexibly”, somehow justifying psychoactives consumption for its means. It has to be noticed that Captagon was originally patented as a medication, and despite having been banned for medical purposes in most countries, it may still be considered as a medical product. Similarly, trafficking drugs for fundraising may be allowed by religious insurgent groups as well, often justified by the consideration that most drugs consumers are non- (Nichols and Kravitz, 2015).

Tramadol

As mentioned in the previous section, tramadol misuse has been increasing in a number of African and Asian countries, and in particular in Egypt and in the Gaza strip (Sweileh et al., 2014). Thousands of young Palestinian, mostly aged 14-30, allegedly use black market tramadol on a regular basis, and apparently at least 15,000 are addicted (O’Loughlin, 2008). Similarly to what we already mentioned for fenthylline, despite in most Arab countries the use of drugs and substance-related disorders are considered a deviation from the recommendation of the holy Quran, frequently misuse of prescription medication can somehow be justified. Using tramadol as a recreational drug may also be preferred because it is the only opioid that cannot be detected by the standard drug-tests. Dependence on tramadol has been reported to be a major social problem in some of the Persian language countries (Bigdeli et al., 2013). Tramadol is reportedly used by Daesh and other militias to numb pain and reduce fear (Baruah, 2017).

Markets and Seizures

Fenethylline

Until 2009, fenethylline was synthesized mainly in illicit laboratories located in South Eastern (Turkey, Bulgaria, Slovenia, Serbia, and Montenegro), and then trafficked towards Lebanon, Syria and the rest of the Arab Peninsula (Kravitz and Nichols, 2016). The International Narcotics Control Board reports an increasing fenethylline abuse in Lebanon since 2010, suggesting a possible shift from transit to production in the country (Kravitz and Nichols, 2016). Moving the production of the drug from Europe to Lebanon may determine a number of advantages, lowering the risks of seizures and reducing the distance from production to consumption sites. In 2015, authorities in Lebanon and Turkey reported seizures of more than 15 million tablets labelled as Captagon in each country (International Narcotics Control Board, 2017). According to the Turkish National Police, “Captagon” seizures in 2013 mostly occurred the Turkish provinces of Hatay and Gaziantep, located along the border with the Syrian Arab Republic, thus confirming the role of Turkey in the trafficking towards the Near and Middle East (United Nations Office on Drugs and Crime, 2017) (see fig.3)

Fig.3 Amphetamine-type stimulants flow of trafficking in Near and Middle East, 2014- 2015

Jordan still remains a transient country for fenethylline tablets (banned since 1988 in the country), due to its geographical location between drug-producing and drug- consuming countries (Alabdalla, 2005). Syria appears to be now among the premier producer and exporter of counterfeit forms of fenethylline, taking over from Lebanon

since 2013 (Van Hout and Wells, 2016). In 2013, 12.3 million pills labelled as Captagon were seized near the border between Lebanon and Syria (Henley, 2014). Lawless and war-torn Syria may currently be the centre of Captagon production, also considering it is the leading country for importation, which is a key ingredient for counterfeit stimulant pills (Nichols and Kravitz, 2015). Amphetamine-type stimulants have made a recent appearance in Iraq: tablets labelled “01 Pills” (local name for Captagon tablets) have been seized since 2009 (Al-Hemiary et al., 2014). Recently, a large of 635,000 Captagon tablets was carried out by Greek authorities in Attica. The drug is believed to be destined to Middle Eastern countries, including Syria. (Makris, 2017). Saudi Arabia is a notable market for Captagon recreational consumption: the typical user is described to be a Saudi male in his 20s-30s, from both lower and higher social classes, interested in partying and in a sort of “youthful rebellion” to the conservative society (Nichols and Kravitz, 2015).

Fig.4 Google Trends for Captagon search

Other areas of Europe besides South-Eastern countries appear to be involved in Captagon production/marketing, probably for local, more restricted use. In April 2017, Dutch police discovered an illicit drug laboratory in the area of Limburg, and seized counterfeit Captagon-labelled tablets (analysis revealed they contained a mixture of amphetamine and caffeine) (BBC News, 2017). The first Captagon seizure in France has been reported in January-February 2017 at Charles de Gaulle Airport: 135 kilograms of

drug tablets, worth 1.5 million euros and allegedly destined to (Première saisie en France de Captagon, la « drogue du conflit syrien », 2017).

It has to be considered that tablets reporting the Captagon logo are frequently counterfeit: they may contain less, or even no fenethylline as an active ingredient. Moreover, the adulterant materials may either be toxic undesirable contaminants (e.g., due to poor manufacturing/storage conditions) or chemicals added to increase/facilitate the pharmacological effects (Al-Mazroua, no date). According to reports from local Poison Centres, all Captagon-labelled tablets seized in Saudi Arabia from the black market did not actually contain fenethylline. The main active principle identified was amphetamine (about 40% of the sample), but other adulterants (caffeine, theophylline, , ) were also present. Finally, two heavy metals ( and nickel) with notable toxic and carcinogenic effects were highlighted in most tablets as well (Al- Mazroua, no date). chromatography-mass spectroscopy (GC-MS) analysis of 124 batches of illicit Captagon seized in Jordan revealed the presence of amphetamine, caffeine and several other substances, besides the absence of fenethylline (Alabdalla, 2005). This phenomenon is not recent: the presence of genuine fenethylline in seized Captagon tablets decreased from 61% to 31% over the period 1986-1993, while mixtures of caffeine, theophylline, , , paracetamol and amphetamines were revealed (Al Hussaini, 1996).

Tramadol

Most of the tramadol hitting the black markets in Africa and Asia appears to be manufactured in India. In 2014, more than 43,578 kg of tramadol were seized by three port control units Ghana. In February 2015, 13,612 kg of tramadol were seized, shipped from India and destined to Niger. Seizures of tramadol in Egypt declined significantly, from 435 million tablets in 2012 to 157 million tablets in 2014, to 90 million tablets in 2015. According to the Egyptian authorities, the decrease could be attributed to the fact that tramadol had been brought under national control in 2013 (International Narcotics Control Board, 2017). Increased misuse of tramadol was reportedly observed in the Sahel region, and seems to have increased in Libya, which is considered a major source

of tramadol trafficked to Egypt. The number of tramadol seizures by customs officials in the United States sharply decreased in 2014, by approximately 30 per cent in comparison to 2013 (World Customs Organisation, 2014). Nevertheless, the number of tramadol seizures by the Customs Enforcement Network increased globally, making it the second psychotropic substance by number of seizures worldwide in 2014 (World Customs Organisation, 2014). Tramadol is considered a noteworthy substance of abuse in Armenia, Jordan, Lebanon (mainly imported from Egypt), Oman (where it is reportedly imported from China and Egypt), Qatar, Saudi Arabia, Turkey and Turkmenistan. A seizure of 142,000 ampoules of tramadol was reported by authorities in Jordan in 2015. In March 2016, according to information available to the Board, 1 million tramadol pills originating in India were seized by customs authorities at Imam Khomeini International Airport, Tehran. The pills had been falsely declared as “advertising and exhibition substances” (International Narcotics Control Board, 2017). In May 2016, ’s Financial Crime Unit seized a cargo ship on its way to Syria, concealing 26 million tramadol tablets, with an estimated market value of 13 million $ (Baruah, 2017). In May 2017, the Italian seized three shipping containers in the port of Genoa, heading from India to Syria (or Libya, according to other sources). The cargos content was declared to be shampoos and fabrics, but it hid 37.5 million tramadol tablets. According to Italian intelligence, the proceeds from the sale of the drugs, were expected to be used to fund Islamic terrorism in the region (Santacroce et al., no date; Mills, 2017).

According to Google Trends, African and Asian countries are among the major potential markets for tramadol (see Fig.5). Ghana, Iran and Nigeria are respectively the second, third and fourth countries worldwide for tramadol search in Google search engine. Nonetheless, it has to be considered that the interest in tramadol appears to be notably more “global” when compared to fenethylline (see Fig.6)

Fig.5 Google Trends for Tramadol search

Fig.6 Google Trends comparison of worldwide interest (tramadol fenethylline)

There are also evidences of the marketing of counterfeit tramadol, but this issue appears to be less relevant in comparison to “fake fenethylline” tablets. Recipes for making tramadol are readily available to the general public online. Ingredients are usually simple over-the-counter drugs mixed with household chemicals, but the chemical reactions from the tramadol-making process can actually be dangerous (explosions, toxic fumes) and/or generate extremely potent or ineffective tramadol batches (Dangers of Counterfeit and Street Versions of Tramadol | Tramadol Addiction and Abuse Help, no date). Moreover, street tramadol and other painkillers sold without a medical

prescription may contain contaminants, e.g., the potentially lethal opioid fentanyl (Zalkind, 2016).

The role of Internet as a marketplace/source of information

Fenethylline

Al-Imam et al. analysed Captagon use and trade in Middle East countries carrying out a multilingual search of online sources, A list of specified keywords (Captagon, 01 pills, Fenethylline, Counterfeit Captagon, Counterfeit amphetamine, Inferior amphetamine, and Amphetamine) was applied across medical databases, web and Dark web, search engines, social communication media, electronic commerce websites, media networks, and the Global Public Health Intelligence Network (GPHIN) database. Information on Captagon could openly be retrieved from Google and AOL search engines, YouTube, and Amazon, where the substance was illicitly advertised and sold as a powerful psychostimulant in the form of tablets, pills, and powder. Moreover, the Dark net, and mostly AlphaBay Market, appears to be involved in Captagon commerce in two Middle East countries (Syria and ). Local e-commerce websites on the surface web (aliexpress.com, souq.com, araboo.com) also generated results when searched for the above-mentioned keywords (AL-Imam et al., 2016).

With regards to online drug fora, there are few threads about Captagon/fenethylline on English speaking websites, and most of the discussions are posted by individuals living in Middle Eastern countries (Question - - Captagon Use , Captagon , Fenethylinne | Drugs-Forum, no date, Captagon (Amphetamine compound) | Drugs-Forum, no date). Western users mainly compare fenethylline to ADHD prescription drugs, and enquire about its possible use as a cognitive enhancer (Anyone heard of a fenethylline analog? : researchchemicals, no date, Trying Captagon for studying? : DarkNetMarkets, no date).

A search on TOR Browser’s Grams search engine (Oct. 6th, 2017) for the keywords Captagon, Fenethylline and Fenetylline, yielded a total of two results (see Fig. 7). Both

results were related to the same vendor, advertising Captagon from India. The minimum dose on sale was 5 grams.

Fig.7 TOR Browser search for Captagon

Data from the EPS/NPS Project analysing Alphabay and EastIndia cryptomarkets in 2015 and 2016 highlighted only one vendor for fenethylline tablets in the first of the two markets. The vendor, nicknamed DoctorMario, advertised his products in the category “stimulants”; he was located in the United Arab Emirates, and promised to ship the goods worldwide.

Tramadol

Tramadol can be easily purchased online without a medical prescription, mostly from fake online pharmacies (e.g., www.freepharmacy.net, www.24-h-rx.net, www.tramadol.co, www.dokteronline.com ). Currently, no tramadol-containing products are sold online by generalist marketplaces (e.g., Amazon, Ebay).

Tramadol misuse is highly discussed in drugs fora message boards (Tramadol? : Drugs, no date, Erowid Tramadol (Ultram, Ultracet) , no date, Tramadol | Drugs-Forum,

no date). Users frequently ask for tramadol interactions with other drugs (e.g., , antipsychotics, antidepressants, ), routes of administration (e.g., , rectal), side effects and adverse reactions, intoxications and withdrawal syndromes.

With regards to DarkNet markets, tramadol search on Grams search engine (Oct. 10th, 2017) yields almost 400 results (see Fig.8). Tramadol is marketed at different doses, and vendors are located not only in India, but also in Europe (e.g., United Kindgdom, Germany), United States, South Africa and Australia.

Fig.8 TOR Browser search for tramadol

According to data from the EPS/NPS Project, tramadol was advertised on both Alphabay and EastIndia cryptomarkets in the years 2015 and 2016. On Alphabay, the drug was offered by 10 vendors, promoting the product either in the “opioids” or in the “prescription drugs” categories. Vendors were located in Europe, Asia and North America, and shipped their products worldwide, with only one exception (BluGecko, located in the United Kingdom, who would only ship to Belgium, France, Germany, Ireland and the UK). On EastIndia, four vendors advertised tramadol tablets in the

“opioids” section. Two of them only shipped to Europe, while the remaining would send the product worldwide.

References

1892-80-4,cas lookchem (no date). Available at: http://www.lookchem.com/cas_1892- 80-4_suppliers.html (Accessed: 19 September 2017).

A pill for work and play (2015) . Available at: https://www.economist.com/news/middle-east-and-africa/21648690-painkiller- becomes--favourite-recreational-drug-pill-work-and-play (Accessed: 22 September 2017).

Al-Ghadyan, A., Rushood, A. A. and Alhumeidan, A. A. (2009) ‘Fenethylline as a possible etiology for retinal vein occlusion.’, Annals of ophthalmology (Skokie, Ill.), 41(3–4), pp. 199–202. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20214057 (Accessed: 21 September 2017).

Al-Hemiary, N. J., Al-Diwan, J. K., Hasson, A. L. and Rawson, R. A. (2014) ‘Drug and alcohol use in Iraq: findings of the inaugural Iraqi Community Epidemiological Workgroup.’, Substance use & misuse. NIH Public Access, 49(13), pp. 1759–63. doi: 10.3109/10826084.2014.913633.

AL-Imam, A., Santacroce, R., Roman-Urrestarazu, A., Chilcott, R., Bersani, G., Martinotti, G. and Corazza, O. (2016) ‘Captagon: use and trade in the Middle East’, Human : Clinical and Experimental, (June), pp. 1–8. doi: 10.1002/hup.2548.

Al-Mazroua, M. (no date) Analysis of Captagon Tablets in Saudi Arabia.

Alabdalla, M. A. (2005) ‘Chemical characterization of counterfeit captagon tablets seized in Jordan’, Forensic Science International, 152(2–3), pp. 185–188. doi: 10.1016/j.forsciint.2004.08.004.

Anyone heard of a fenethylline analog? : researchchemicals (no date). Available at:

https://www.reddit.com/r/researchchemicals/comments/3tpgnp/anyone_heard_of_a _fenethylline_analog/ (Accessed: 6 October 2017).

Babalonis, S., Lofwall, M. R., Nuzzo, P. A., Siegel, A. J. and Walsh, S. L. (2013) ‘Abuse liability and reinforcing efficacy of oral tramadol in humans’, Drug and , 129(1–2), pp. 116–124. doi: 10.1016/j.drugalcdep.2012.09.018.

Bamofleh, E. A., Mohammed, J. A., Abdelrahim, M. E. A. and Gamal, M. (2017) ‘The Reasons Behind Prevalence of Captagon Addiction in and Community Awareness: A Questionnaire-Based Study.’, Scholars Report. Scholars Report, 2(1). Available at: http://www.scholarsreport.com/articles/vol_2/issue_1/Journal Scholars Report 000020.html (Accessed: 22 September 2017).

Barsotti, C. E., Mycyk, M. B. and Reyes, J. (2003) ‘Withdrawal syndrome from tramadol hydrochloride’, The American Journal of Emergency Medicine, 21(1), pp. 87–88. doi: 10.1053/ajem.2003.50039.

Baruah, S. (2017) PressReader.com - Connecting People Through News. Available at: https://www.pressreader.com/india/the-asian-age/20170319/283802853538232 (Accessed: 9 October 2017).

BBC News (2017) ‘Jihad pills’ found by Dutch and Italian police - BBC News. Available at: http://www.bbc.com/news/world-europe-39870180 (Accessed: 3 October 2017).

Bigdeli, I., Corazza, O., Aslanpour, Z. and Schifano, F. (2013) ‘Novel Psychoactive Substances (NPS): a Study on Persian Language Websites.’, Iranian journal of public health. Tehran University of Medical Sciences, 42(5), pp. 511–5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23802109 (Accessed: 9 October 2017).

Bramness, J. G., Gundersen, Ø. H., Guterstam, J., Rognli, E. B., Konstenius, M., Løberg, E.-M., Medhus, S., Tanum, L. and Franck, J. (2012) ‘Amphetamine-induced psychosis--a separate diagnostic entity or primary psychosis triggered in the vulnerable?’, BMC psychiatry. BioMed Central, 12, p. 221. doi: 10.1186/1471-244X-12-221.

Bravo, L., Mico, J. A. and Berrocoso, E. (2017) ‘Discovery and development of tramadol for the treatment of pain’, Expert Opinion on Drug Discovery, pp. 1–11. doi:

10.1080/17460441.2017.1377697.

Bush, D. M. (2015) ‘EMERGENCY DEPARTMENT VISITS FOR DRUG MISUSE OR ABUSE INVOLVING THE PAIN MEDICATION TRAMADOL AUTHORS’. Available at: https://www.samhsa.gov/data/sites/default/files/report_1966/ShortReport-1966.pdf (Accessed: 25 September 2017).

Captagon (Amphetamine compound) | Drugs-Forum (no date). Available at: https://drugs-forum.com/threads/captagon-amphetamine-compound.221698/ (Accessed: 6 October 2017).

Dangers of Counterfeit and Street Versions of Tramadol | Tramadol Addiction and Abuse Help (no date). Available at: http://www.tramadolabusehelp.com/dangers-of- counterfeit-and-street-versions-of-tramadol/ (Accessed: 10 October 2017).

Drug use on the rise among Saudi students | Arab News (2013). Available at: http://www.arabnews.com/news/452189 (Accessed: 22 September 2017).

Elasfar, A., Eldein-Ahmad, K. and Alsagha, W. (2014) ‘Clinical characteristics and outcome of heart failure and captagon amphetamine use: an observational prospective study.’, Eur Heart J, 66, pp. 1–35.

Eldar, S. (2016) Is Gaza facing an opioid epidemic? Available at: http://www.al- monitor.com/pulse/originals/2016/08/tramadol-gaza-strip-pain-killer-siege-israel- hamas.html (Accessed: 22 September 2017).

EMCDDA (2016) EU Drug Markets Report. Available at: http://www.emcdda.europa.eu/system/files/publications/2373/TD0216072ENN.PDF (Accessed: 3 August 2017).

Erowid Tramadol (Ultram, Ultracet) Vault (no date). Available at: https://erowid.org/pharms/tramadol/ (Accessed: 10 October 2017).

Fawzi, M. (2011) ‘Some medicolegal aspects concerning tramadol abuse: The new Middle East youth plague 2010. An Egyptian overview’, Egyptian Journal of Forensic Sciences. No longer published by Elsevier, 1(2), pp. 99–102. doi:

10.1016/J.EJFS.2011.04.016.

Fond, G. and Howes, O. (2016) ‘Pharmacoterrorism: the potential role of psychoactive drugs in the Paris and Tunisian attacks’, Psychopharmacology. Springer Berlin Heidelberg, 233(6), pp. 933–935. doi: 10.1007/s00213-016-4204-2.

Global Islamic Terrorism Research & Analysis (2017) ‘Captagon: the drug fuelling Syria’s civil war’.

Grond, S. and Sablotzki, A. (2004) ‘Clinical pharmacology of tramadol.’, Clinical , 43(13), pp. 879–923. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15509185 (Accessed: 19 September 2017).

Henley, J. (2014) Captagon: the amphetamine fuelling Syria’s civil war | World news | . Available at: https://www.theguardian.com/world/shortcuts/2014/jan/13/captagon-amphetamine- syria-war-middle-east (Accessed: 30 September 2017).

Van Hout, M. C. and Wells, J. (2016) ‘Is Captagon (fenethylline) helping to fuel the Syrian conflict?’, Addiction, 111(4), pp. 748–749. doi: 10.1111/add.13262.

Hughes, K., Bellis, M. A. and Chaudry, M. (2004) ‘Elevated substance use in casual labour at international nightlife resorts: A case control study’, International Journal of , 15(3). doi: 10.1016/j.drugpo.2004.01.004.

Al Hussaini, S. (1996) ‘Counterfeit Captagon: an analytical study’, Science and Justice, 36(3), pp. 139–142.

International Narcotics Control Board (2012) Report of the International Narcotics Control Board for 2012, New York: United Nations. Available at: http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:Report+of+the+Inter national+Narcotics+Control+Board+for+2012#2.

International Narcotics Control Board (2017) Report of the International Narcotics Control Board for 2016, New York: United Nations.

Iravani, F. S., Akhgari, M., Jokar, F. and Bahmanabadi, L. (2010) ‘Current Trends in

Tramadol-Related Fatalities, Tehran, Iran 2005–2008’, Substance Use & Misuse, 45(13), pp. 2162–2171. doi: 10.3109/10826081003692098.

Kamienski, L. (2016) During the Vietnam War, the U.S. Army Used Drugs to Build Super Soldiers - The Atlantic. Available at: https://www.theatlantic.com/health/archive/2016/04/the-drugs-that-built-a-super- soldier/477183/ (Accessed: 2 August 2017).

Katselou, M., Papoutsis, I., Nikolaou, P., Qammaz, S., Spiliopoulou, C. and Athanaselis, S. (2016) ‘Fenethylline (Captagon) Abuse – Local Problems from an Old Drug Become Universal’, Basic and Clinical Pharmacology and Toxicology, 119(2), pp. 133–140. doi: 10.1111/bcpt.12584.

Khanra, S. and Sen, S. (2016) ‘Pharmacoterrorism: We should be worried’, Asian Journal of Psychiatry. Elsevier B.V., 22(2016), p. 83. doi: 10.1016/j.ajp.2016.05.002.

Kikura, R. and Nakahara, Y. (1997) ‘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 of analytical toxicology, 21(4), pp. 291–6. doi: 10.1093/jat/21.4.291.

Kraemer, T. and Maurer, H. H. (2002) ‘Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives.’, Therapeutic drug monitoring, 24(2), pp. 277–89. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11897973 (Accessed: 19 September 2017).

Kravitz, M. and Nichols, W. (2016) ‘A Bitter Pill To Swallow: Connections Between Captagon, Syria, and The Gulf’, Journal of International Affairs, 70, pp. 1–16. Available at: https://jia.sipa.columbia.edu/bitter-pill-swallow-connections-captagon-syria-gulf.

Kristen, G., Schaefer, A. and von Schlichtegroll, A. (1986) ‘Fenetylline: therapeutic use, misuse and/or abuse.’, Drug and alcohol dependence, 17(2–3), pp. 259–71. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3743408 (Accessed: 19 September 2017).

Leelahanaj, T., Kongsakon, R. and Netrakom, P. (2005) ‘A 4-week, double-blind comparison of olanzapine with haloperidol in the treatment of amphetamine

psychosis.’, Journal of the Medical Association of Thailand = Chotmaihet thangphaet, 88 Suppl 3, pp. S43-52. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16858942 (Accessed: 22 September 2017).

Makris, A. (2017) Captagon Seized in Attica was Destined for Middle East and Linked to ISIS, Greek Authorities Say | GreekReporter.com. Available at: http://greece.greekreporter.com/2017/03/06/captagon-seized-in-attica-was-destined- for-middle-east-and-linked-to-isis-greek-authorities-say/ (Accessed: 3 October 2017).

Mashayekhi, S., Sattari, M. and Mashayekhi, S. (2012) ‘Islam and Addiction’, Pharmaceutical sciences, 18(3), pp. 151–158. Available at: http://pharm- sci.tbzmed.ac.ir (Accessed: 5 October 2017).

McCarthy, B. (2016) A brief history of war and drugs: From Vikings to Nazis - News from Al Jazeera. Available at: http://www.aljazeera.com/indepth/features/2016/10/history-war-drugs-vikings-nazis- 161005101505317.html (Accessed: 1 August 2017).

Mills, K.-A. (2017) 37.5 million tramadol tablets seized by customs en route to help fund Islamic terrorism - Mirror Online. Available at: http://www.mirror.co.uk/news/world- news/375-million-tramadol-tablets-seized-10402425 (Accessed: 9 October 2017).

Nichols, W. and Kravitz, M. (2015) ‘Soldiers of Abu Hilalain ’:, (May), pp. 1–65.

Nickel, B., Niebch, G., Peter, G., von Schlichtegroll, A. and Tibes, U. (1986) ‘Fenetylline: new results on pharmacology, metabolism and kinetics.’, Drug and alcohol dependence. Ireland, 17(2–3), pp. 235–257.

O’Loughlin, T. (2008) Besieged and stressed Gazans fall victim to black market painkiller | World news | The Guardian. Available at: https://www.theguardian.com/world/2008/dec/15/young-gazan-men-addicted- tramadol (Accessed: 9 October 2017).

Ohler, N. (2016) Blitzed: Drugs in Nazi Germany. Penguin Books. Available at: https://books.google.it/books?id=t7HkCwAAQBAJ&printsec=frontcover&dq=nazi+drug s+blitzed&hl=it&sa=X&ved=0ahUKEwjNwfqL4rXVAhVDORoKHbbGDOcQ6AEIJzAA#v=on

epage&q=nazi drugs blitzed&f=false (Accessed: 1 August 2017).

Orsolini, L., Papanti, D., Corkery, J. and Schifano, F. (2017) ‘An insight into the deep web; why it matters for addiction psychiatry?’, Human Psychopharmacology: Clinical and Experimental, 32(3), p. e2573. doi: 10.1002/hup.2573.

Otis, J. (2014) ‘The FARC and Colombia’s ’. Available at: https://www.wilsoncenter.org/sites/default/files/Otis_FARCDrugTrade2014.pdf (Accessed: 3 August 2017).

Paris attackers not on drugs, toxicology report finds - France 24 (2016). Available at: http://www.france24.com/en/20160105-paris-attackers-not-drugs-toxicology-report- finds-captagon-terrorism-france (Accessed: 30 September 2017).

Peters, G. (2009) ‘How Opium Profits the Taliban United StateS inStitUte of Peace Library of Congress Cataloging-in-Publication Data’. Available at: www.usip.org (Accessed: 3 August 2017).

Première saisie en France de Captagon, la « drogue du conflit syrien » (2017). Available at: http://www.lemonde.fr/police-justice/article/2017/05/30/premiere-saisie-en- france-de-captagon_5135807_1653578.html (Accessed: 3 October 2017).

Question - - Captagon Use , Captagon , Fenethylinne | Drugs-Forum (no date). Available at: https://drugs-forum.com/threads/captagon-use-captagon- fenethylinne.300765/ (Accessed: 6 October 2017).

Raffa, R. B., Buschmann, H., Christoph, T., Eichenbaum, G., Englberger, W., Flores, C. M., Hertrampf, T., Kögel, B., Schiene, K., Straßburger, W., Terlinden, R. and Tzschentke, T. M. (2012) ‘Mechanistic and functional differentiation of tapentadol and tramadol’, Expert Opinion on Pharmacotherapy, 13(10), pp. 1437–1449. doi: 10.1517/14656566.2012.696097.

Sansone, R. A. and Sansone, L. A. (2009) ‘Tramadol: seizures, serotonin syndrome, and coadministered antidepressants.’, Psychiatry (Edgmont (Pa. : Township)). Matrix Medical Communications, 6(4), pp. 17–21. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19724727 (Accessed: 22 September 2017).

Santacroce, R., Bosio, E., Scioneri, V. and Mignone, M. (no date) ‘The new drugs and the sea: the phenomenon of narco-terrorism’, International Journal of Drug Policy. Available at: Accepted for publication on Oct. 12th, 2017.

Sarkar, S., Nebhinani, N., Singh, S. M., Mattoo, S. K. and Basu, D. (2012) ‘Tramadol dependence: a case series from India.’, Indian journal of psychological medicine. Medknow Publications and Media Pvt. Ltd., 34(3), pp. 283–5. doi: 10.4103/0253- 7176.106038.

Scott, J. C., Woods, S. P., Matt, G. E., Meyer, R. A., Heaton, R. K., Atkinson, J. H. and Grant, I. (2007) ‘Neurocognitive effects of methamphetamine: A critical review and meta-analysis’, Neuropsychology Review, 17(3), pp. 275–297. doi: 10.1007/s11065- 007-9031-0.

Scott, L. J. and Perry, C. M. (2000) ‘Tramadol: a review of its use in perioperative pain.’, Drugs, 60(1), pp. 139–76. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10929933 (Accessed: 20 September 2017).

Sekine, Y., Ouchi, Y., Takei, N., Yoshikawa, E., Nakamura, K., Futatsubashi, M., Okada, H., Minabe, Y., Suzuki, K., Iwata, Y., Tsuchiya, K. J., Tsukada, H., Iyo, M. and Mori, N. (2006) ‘Brain and Aggression in Abstinent Methamphetamine Abusers’, Archives of General Psychiatry. American Medical Association, 63(1), p. 90. doi: 10.1001/archpsyc.63.1.90.

Shufman, E. and Dickman, M. (1999) ‘Fenethyllin psychosis: description of two cases.’, The Israel journal of psychiatry and related sciences, 36(2), pp. 129–31. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10472747 (Accessed: 22 September 2017).

Shulgin, A. T. (1975) ‘Drugs of Abuse in the Future’, Clinical Toxicology, 8(4), pp. 405– 456. doi: 10.3109/15563657508990076.

Sweileh, W. M., Zyoud, ed H., Al-Jabi, S. W. and Sawalha, A. F. (2014) ‘Substance use disorders in Arab countries: research activity and bibliometric analysis’, 9, pp. 1–9. doi: 10.1186/1747-597X-9-33.

Tramadol? : Drugs (no date). Available at:

https://www.reddit.com/r/Drugs/comments/2esswt/tramadol/ (Accessed: 10 October 2017).

Tramadol | Drugs-Forum (no date). Available at: https://drugs- forum.com/forums/tramadol.399/ (Accessed: 10 October 2017).

Tramadol Uses, Side Effects, Dosage & Warnings - Drugs.com (2017). Available at: https://www.drugs.com/tramadol.html (Accessed: 21 September 2017).

Trying Captagon for studying? : DarkNetMarkets (no date). Available at: https://www.reddit.com/r/DarkNetMarkets/comments/4dhpc9/trying_captagon_for_ studying/ (Accessed: 6 October 2017).

Twark, C. and Suzuki, J. (2016) ‘Fenethylline-Induced Psychosis, Fenethylline-Themed Paranoid Delusions, or Both?’, Psychosomatics. Elsevier. doi: 10.1016/j.psym.2017.03.014.

Ulucay, A., Arpacik, C. and Aksoy, M. F. (2012) ‘Acute myocardial infarction associated with Captagon use’, Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology, 12(2), pp. 182–185. doi: 10.5152/akd.2012.046.

United Nations Office on Drugs and Crime (2017) MARKET ANALYSIS OF SYNTHETIC DRUGS. Amphetamine-type stimulants, new psychoactive substances. Available at: http://www.unodc.org/documents/scientific/Booklet_4_Market_Analysis_of_Syntheti c_Drugs_ATS_NPS.pdf.

UNODC (2014) Global Synthetic Drugs Assessment. Available at: https://www.unodc.org/documents/scientific/2014_Global_Synthetic_Drugs_Assessm ent_web.pdf.

World Customs Organisation (2014) Illicit Trade Report. Available at: https://illicittrade.com/reports/downloads/WCO Illicit Trade Report 2014.pdf (Accessed: 9 October 2017).

World Health Organization (2014) Tramadol. Available at: http://www.who.int/medicines/areas/quality_safety/6_1_Update.pdf.

Yoshimura, H., Yoshimitsu, T., Yamada, H., Koga, N. and Oguri, K. (1988) ‘Metabolic fate of fenetylline in rat and man’, Xenobiotica, 18(8), pp. 929–940. doi: 10.3109/00498258809167516.

Zacny, J. P. (2005) ‘Profiling the subjective, psychomotor, and physiological effects of tramadol in recreational drug users’, Drug and Alcohol Dependence, 80(2), pp. 273– 278. doi: 10.1016/j.drugalcdep.2005.05.007.

Zalkind, S. (2016) Pills laced with deadly opioid infiltrating drug market, DEA says | US news | The Guardian. Available at: https://www.theguardian.com/us- news/2016/jul/24/counterfeit-prescription-pills-laced-deadly-opioid-fentanyl (Accessed: 10 October 2017).