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18

GLOBAL September S MART PDATE

U VOLUME

Non-medical use of : a growing threat to public health? ENES

Research 2017 GLOBAL SMART UPDATE About the SMART Update

Synthetic constitute one of the most significant The Global SMART Update (GSU) series is published problems worldwide. After , amphet- twice a year in English, Spanish and Russian and pro- amine-type (ATS) are the second most vides information on emerging patterns and trends of widely used drugs across the globe, with use levels the global synthetic drug situation in a concise format. often exceeding those of and/or . Along Each issue of the Global SMART Update contains a with ATS, the continued growth of the new psychoactive special segment and short segments on the topic of substances (NPS) market over the last years has become interest.* This issue is fully dedicated to the topic of a policy challenge and a major international concern. A the concomitant use of benzodiazepines and , growing interplay between these new drugs and tradi- and does not contain country-specific segments. Past tional illicit drug markets is being observed. By August issues have covered topics such as the fentanyl group 2017, the emergence of NPS had been reported from of synthetic opioids, UNGASS 2016 recommendations, 110 countries and territories. Trends on the synthetic injecting use of synthetic drugs, legal responses to NPS, drug market evolve quickly each year. and key facts about synthetic . Electronic The UNODC Global Synthetics Monitoring: Analyses, copies of the Global SMART Updates and other pub- Reporting and Trends (SMART) Programme enhances lications are available at: www.unodc.org/unodc/en/ the capacity of Member States in priority regions to scientists/publications-smart.html. generate, manage, analyse, report and use synthetic drug information to design effective policy and -pro gramme interventions. Launched in September 2008, the Global SMART Programme provides capacity building to laboratory personnel, law enforcement and research officers in the Pacific, East and South-East Asia, South Asia, the Near and Middle East, Africa and Latin America; and regularly reviews the global -type stimulants and new psychoactive substances situation. Its main products include online drug data collection, situation reports, regional assessments and the UNODC Early Warning Advisory (EWA) on new psychoactive substances. The EWA is a webportal that offers regu- lar updates on new psychoactive substances, including trend data on emergence and persistence, chemical data, supporting documentation on laboratory analysis and national legislative responses (available at: www. unodc.org/NPS).

* The information and data contained within this report are from official Government reports, press releases, scientific journals or incidents confirmed by UNODC Field Offices. This report has not been formally edited. The contents of this publication do not necessarily reflect the views or policies of UNODC or contributory organizations and neither do they imply any endorsement. Suggested citation: UNODC, Global SMART Update Volume 18, September 2017.

2 Volume 18 Non-medical use of benzodiazepines: a growing threat to public health?

ABSTRACT non-medical use of opioids however Non-medical use of prescription benzodiazepines, has been a long- presents serious risks including the potential for abuse, dependence, established problem that has been associated with a large number overdose and fatalities. Benzodi- of overdose worldwide. Most recently, the concomitant azepines are a class of medicines use of benzodiazepines and opioids has been linked to a number widely used to treat conditions such of deaths that occurred in the recent crisis, featuring in a as , and . In rising number of fatalities and adverse events in North America terms of non-medical use, benzodi- and in Europe. In recent years, several new psychoactive substanc- azepines have been used to produce es (NPS) belonging to the class have also emerged effects such as relief of mental on the market and are being sold under street names such as “le- and anxiety, improved coping with gal benzodiazepines”, “designer benzodiazepines”, and “research situational pressures or psychologi- cal problems, or relief of side-effects chemicals”. The use of such NPS belonging to the benzodiazepine associated with over-stimulation or class and the non-medical use of pharmaceutical benzodiazepines withdrawal of other drugs. Chronic pose a great threat to public health. use of benzodiazepines may result in the development of tolerance Introduction and dependence. Both opioids and The previous Global SMART Update benzodiazepines have been placed benzodiazepines are central nervous Volume 17 provided an overview of under international control to pre- system and concomitant the rapidly unfolding public health vent their abuse whilst ensuring the use may lead to pronounced drowsi- threat posed by extremely potent availability of some of these benzo- ness, respiratory depression, synthetic opioids, fentanyl and its diazepines as essential medicines.1 or . analogues in light of the sharp rise In recent years, the documented Non-medical use of benzodiazepines in opioid-related deaths (mainly risks entailed in the concomitant in combination with prescription in North America and, to a lesser non-medical use of opioids and opioids has been implicated in a extent, in Europe). Recently, increas- / have been number of overdose deaths. In the ing evidence has emerged that further exacerbated by the ready United States, the use of prescrip- polydrug use particularly involving availability of counterfeited ben- tion benzodiazepines and opioids sedatives/hypnotics such as benzo- zodiazepines and the increasing coupled with the use of additional diazepines, might be linked to some emergence of “designer benzodi- drugs, such as heroin, have culmi- of these fatalities. azepines”, a common street name nated in several fatalities. From The current Global SMART Update for new psychoactive substances 1999 to 2013, data from the United focusses on the concomitant use of (NPS) belonging to the benzodiaz- States has shown that drug-related benzodiazepines and opioids in the epine class. Many NPS belonging to deaths involving opioid context of the recent opioid crisis the benzodiazepine class are sub- have accounted for around 175,000 in certain parts of the world. Non- stances that have not been approved fatalities.2 Over this period, the rate medical use of benzodiazepines as medicines in the pharmaceuti- of deaths involving benzodiazepines in combination with the misuse cal industry on the basis of safety increased by 514 per cent and the of prescription opioids has been and/or efficacy. Such substances rate of deaths encompassing both implicated in a growing number of are potentially more harmful than prescription benzodiazepines and deaths in the United States. Benzodi- pharmaceutical benzodiazepines opioids rose by 819 per cent.3 Over azepines are also the most common with unknown pharmacological/toxi- a five-year period, between 2010 prescription medicines associated cological profiles and have added to and 2014, and with acute intoxication cases in the complexity and dangers of the were among the 10 drugs most fre- Europe. Whereas benzodiazepines illicit market for benzodiazepines. quently involved in are a class of medicines widely used The threat of benzodiaz- deaths. Among the deaths involving to treat various medical conditions, alprazolam and diazepam, more than both opioids and benzodiazepines epines: deaths and intoxica- 95 per cent also involved more than are depres- tions associated with opioid two other additional drugs. Based sants in which concomitant use and polydrug use on 47,055 drug overdose deaths may lead to pronounced drowsi- ness, respiratory depression, coma Opioids represent a class of power- ful substances used in medicine for 2 Office of National Drug Control Policy or death. The non-medical use of (2015) National Drug Control Strategy 2015. the treatment of severe pain. The benzodiazepines with opioids has 3 Centers for Disease Control and Prevention been, and continues to be, a factor (CDC); National Center for Health Statistics. 1 World Health Organization (WHO) 20th “Underlying Cause of Death on CDC Wide- of concern for control and preven- WHO Model List of Essential Medicines: 20th ranging Online data for Epidemiology for tive measures. Since 1984, certain List. March 2017. Research.” 2015.

3 GLOBAL SMART UPDATE Table 1: Most frequent concomitantly used drugs in cases of drug overdose deaths involving alprazolam and diazepam – United States, 2014

BENZODIAZEPINES Most frequent concomitantly used drug in cases of drug overdose deaths First Second Third Fourth Fifth Alprazolam Heroin Diazepam Oxycodone Hydrocodone Alprazolam Heroin Morphine Source: Warner, M. et al. (December 2016) “Drugs most frequently involved in drug overdose deaths: United States, 2010-2014.” National Vital Statistics Reports 65 (10): 1-5.

examined in the report, the most frequent drug used concomitantly with alprazolam and diazepam was the opioid, oxycodone.4 Moreover, according to the European Drug Emergencies Network (Euro- DEN), the most common substances associated with acute intoxica- tion cases related to prescription medicines in Europe included ben- Source: UNODC zodiazepines and opioids.5 National Statistics of Scotland also reported : Benzodiazepines associated with more than that of the 706 drug-related deaths half of non-fatal overdoses of PWID in 2015, the use of benzodiazepines (e.g. diazepam) was implicated in, QUEENSLAND, Australia – February 2017. A drug use study conducted or potentially contributed to, 27 per during September and October 2013, among 50 people who inject drugs cent of drug-related deaths in Scot- (PWID) and who reported to have had a non-fatal overdose in the past 12 land. Also, among the total number months, found that the non-medical use of benzodiazepines were associ- of drug-related deaths in 2015 in ated with 52 per cent of the overdoses. In this regard, these substances have Scotland, 57 deaths involved the use been associated with more than half of non-fatal overdoses of people who of benzodiazepine NPS (such as eti- inject drugs. In these cases of non-fatal overdose, benzodiazepines (mostly zolam, or ).6 under the brand name of either “Xanax®” or “Valium”) had been used by participants within 24 hours before the overdose occurred. Polydrug use was Although benzodiazepines are rarely also commonly reported among participants. After benzodiazepines, 44 per identified in post-mortem toxicology cent of participants reported to have used heroin, followed by 42 per cent as the only drug involved in a case of reporting the use of other prescription drugs, and 36 per cent reporting the death, evidence suggests that ben- use of fentanyl and its analogues. In the presence of other drugs is it difficult zodiazepines are present in a large to establish a direct link between the benzodiazepines either on their own proportion of cases or in synergy with other substances as a cause of the non-fatal intoxication. recorded in recent years in North 7 Najman, J. M., et al. (March 2017) “When Knowledge and Experience Do Not Help: America and Europe. A Study of Nonfatal Drug Overdoses.” Journal of Medicine: 1-6. Abstract available at: www.ncbi.nlm.nih.gov/pubmed/28368905

4 Warner, M. et. al. (December 2016) “Drugs most frequently involved in drug overdose Pharmaceutical benzodiazepines hospital emergency departments deaths: United States, 2010-2014.” National have also often been misused by in 10 European countries (constitut- Vital Statistics Reports 65 (10): 1-5. polydrug users in concomitance ing the European Drug Emergencies 5 European Monitoring Centre for Drugs with other drugs, such as opioids Network, Euro-DEN) showed that, and Drug Addiction (EMCDDA) “Addic- tion Hospital emergency presentations and and cannabis. For high-risk opioid after at 59.4 per cent, ben- acute drug in Europe: update from users in Europe, the most commonly zodiazepines at 22.8 per cent were the Euro-DEN Plus research group and the reported pharmaceutical benzodi- most commonly used in combination EMCDDA.” Lisbon, August 2016. azepines associated in drug-related with cannabis among the 320 hos- 6 National Records of Scotland. Drug-related 9 deaths in Scotland in 2015, August 2016. deaths are alprazolam, , pital cases involving cannabis use. 7 Sun, E.C. et. al. (March 2017) “Associa- diazepam, and oxaz- 8 tion between concurrent use of prescription epam. Between October 2013 to opioids and benzodiazepines and overdose: March 2014, data collected from retrospective analysis.” The BMJ: 356; Abra- hamsson, T. et. al. (May 2017) “Benzodiaz- 9 Dines, A. M. et. al. and Euro-DEN Research epine, z-drug and prescriptions 8 European Monitoring Centre for Drugs and Group (December 2015) “Presentations to and mortality among patients in opioid Drug Addiction (EMCDDA) “Perspectives the emergency department following can- maintenance treatment—A nation-wide on Drugs: The misuse of benzodiazepines nabis use—a multi-centre case series from register-based open cohort study.” Drug and among high-risk opioid users in Europe.” ten European countries.” Journal of Medical 174: 58-64. Lisbon, June 2015. Toxicology 11(4): 415-421.

4 Volume 18

Table 2: International control of benzodiazepines under the United Nations Convention on Psychotropic Substances of 1971

YEAR OF SCHEDULING SCHEDULE SUBSTANCE NAME DECISION 1984 IV Alprazolam Clonazepam Diazepam 1990 IV 1995 III Flunitrazepam IV 2016 IV Phenazepam Source: UNODC Early Warning Advisory (EWA) on NPS. “April 2017 – UNODC: Several countries place benzodiazepine derivatives under national control.” April 2017. Available at: www.unodc.org/LSS/Announcement/Details/065118d5-b238-48d8-9d7f-b95fb5d11411

Various forms of polydrug use involv- Benzodiazepines – thus considered effective and safe ing benzodiazepines have been Ensuring access for treat- medicines that should be accessible associated with a number of health in healthcare systems. consequences, which has been of ment while countering abuse Over time, some pharmaceuti- public concern for some years (see cal benzodiazepine products have Box for case of benzodiazepines Benzodiazepines are extensively been discontinued. For instance, associated with non-fatal overdoses used in the treatment of conditions nimetazepam (frequently sold of people who inject drugs and fre- including anxiety, insomnia and sei- under the brand name “Erimin”) is quent polydrug users). Generally, the zures. However, their non-medical/ a pharmaceutical benzodiazepine combined use of benzodiazepines recreational use has been a long- for which licensed production was and other CNS drugs is established problem that has been discontinued in 2015.11 Despite this associated with an overall greater associated with abuse, dependence measure, unlicensed preparations risk of overdose and HIV transmis- and a large number of overdose of nimetazepam are available and, sion that can impede treatment for deaths worldwide. More recently, in recent years, it has become avail- opioid addiction and exacerbate in North America and in Europe, the able online and is reportedly used respiratory depression, leading to non-medical use of benzodiazepines 10 in a club-drug context in the United potential fatalities. has featured in a rising number of Kingdom.12 Nimetazepam also con- fatalities and adverse events. tinues to be illicitly sold in some Since 1984, a total of 36 benzodi- regions. azepines have been placed under Some benzodiazepines not under 10 Horsfall, J.T. and Sprague, J.E. (February international control under the international control, were approved 2017) “The Pharmacology and Toxicology United Nations Convention on of the ‘Holy Trinity’.” Basic and Clinical Pharmacology and Toxicology 120 (2): 115-9; Psychotropic Substances of 1971, Jones, J.D., Mogali, S., and Comer, S.D. designed to ensure access to these 11 Lim, W. J. L. et al. (February 2017) “Detec- (September 2012) “Polydrug abuse: a review useful medicines whilst countering tion of phenazepam in illicitly manufactured of opioid and benzodiazepine combination Erimin 5 tablets.” Drug Testing and Analysis 9 use.” Drug and Alcohol Dependence 125 (1-2): their liability for abuse and depen- (2): 293-305. 8-18; Ickowicz, S. et. al. (October 2015) dence. Benzodiazepines, diazepam, 12 NEPTUNE (Novel Psychoactive Treatment “Benzodiazepine use as an independent risk lorazepam and midazolam, are cur- UK Network) “Guidance on the Clinical factor for HIV infection in a Canadian set- th Management of Acute and Chronic Harms ting.” Drug and Alcohol Dependence 155: rently listed in the 20 WHO Model of Club Drugs and Novel Psychoactive Sub- 190-4. List of Essential Medicines and are stances.” London, 2015.

5 GLOBAL SMART UPDATE Table 3: List of effects of benzodiazepines

DESIRED EFFECTS UNDESIRED ACUTE EFFECTS EFFECTS OF CHRONIC USE • Relief of tension, mental stress • Reduced mental activity and • Development of tolerance, and anxiety alertness, drowsiness, lethargy psychological and physical • Positive feelings of calmness, and impairment of clarity of dependence relaxation and well-being in thought and judgement may • , , , anxious individuals occur memory impairment, depres- • Improved coping with • Potential impairment of muscle sion, insomnia and situational pressures or coordination, , low • Abrupt cessation may lead to psychological problems blood pressure, or fainting withdrawal syndrome which • Relief of side effects associ- • Diminished emotional responses can include insomnia, anxiety, ated with over-stimulation or to external stimuli, e.g. pain perceptual hypersensitivity, withdrawal of other drugs (i.e. , irritability, and as part of a pattern of multiple , mental confusion and drug use) life-threatening Source: United Nations (2016) Terminology and Information on Drugs.

as pharmaceuticals only in a placed under international control and the Province restricted number of countries and in 2016.16 of China, have reported non-medical 21 remained largely unknown in most , a pharmaceutical product use of benzodiazepines. In Malay- countries. For example, phenaz- licensed in , and India, sia, nimetazepam is a commonly epam, a benzodiazepine developed was first reported in 2011 in the abused and is used as a in the former in the on the internet.17 substitute of heroin. It is also increas- 1970s, was only licensed in the Particularly, the recreational use of ingly used by Russian Federation and some parts users to facilitate a come-down after etizolam has been widespread in 22 of the Commonwealth of Indepen- Scotland and has been associated excessive use. dent States (CIS) as a pharmaceutical with drug-related deaths in various In recent years, several new psycho- product prescribed to treat anxiety 18 active substances (NPS) belonging 13 parts of the United Kingdom. How- and withdrawal symptoms. ever, there is limited information on to the benzodiazepine class have Over time, there have been increas- the dependence potential or the also emerged on the market and ing reports of non-medical use number of fatalities associated with are being sold under street names of phenazepam, which has been etizolam.19 For this reason, etizolam such as “legal benzodiazepines”, associated with a rising number of is currently under surveillance by the “designer benzodiazepines”, and fatalities, particularly in Europe.14 In World Health Organization (WHO).20 “research chemicals”. The use of some cases, phenazepam has been Several countries in East and such NPS belonging to the benzodi- found to remain in the human body South-East Asia, including azepine class pose a great threat to for a long period of time after inges- Darussalam, (China), public health, particularly in view of tion, with some reports of severe , , the , the absence of information on their adverse effects lasting up to five days pharmacological and toxicological or to three weeks following inges- 16 Phenazepam is currently under international profiles. 15 tion. As a result, phenazepam was control under Schedule IV of the United Nations Convention on Psychotropic Sub- The complex nature of the stances of 1971. illicit market for benzodiaz- 13 World Health Organization (WHO) Expert 17 O’Connor, L.C., Torrance, H.J., and McK- epines Committee on Drug Dependence. “Phen- eown, D.A. (March 2016) “ELISA detec- azepam: Pre-Review Report. Agenda item tion of phenazepam, etizolam, , Benzodiazepines encountered on 5.8.” Thirty-seventh Meeting, Geneva, 16-20 , diclazepam and delorazepam the illicit drug market are primarily November 2015; Drug Enforcement Admin- in blood using Immunalysis® Benzodiazepine istration (DEA) “Phenazepam.” April 2014. Kit.” Journal of Analytical Toxicology 40 (2): diverted from the legitimate trade of 159-161. 14 Corkery, J.M., Schifano F., and Ghodse, A.H. medicines rather than synthesized in (May 2012) “Phenazepam abuse in the UK: 18 Advisory Council on the Misuse of Drugs clandestine laboratories.23 The risk an emerging problem causing serious adverse (ACMD) “Advice on U-47,700, etizolam health problems, including death.” Human and other designer benzodiazepines.” United 27 (3): 254-61; Kriikku Kingdom, 2 December 2016. P., et. al. (July 2012) “Phenazepam abuse in 19 World Health Organization (WHO) Expert 21 UNODC, Annual Report Questionnaire; Finland: findings from apprehended drivers, Committee on Drug Dependence. “Etizolam Drug Abuse Information Network for Asia post-mortem cases and police confiscations.” (INN): Pre-Review Report. Agenda item and the Pacific (DAINAP). Forensic science international 220 (1-3): 5.7.” Thirty-seventh Meeting, Geneva, 16-20 22 Abdullah, A. F. L. et. al. (January 2012) 111-7. November 2015. “Forensic drug profiling of Erimin-5 using 15 World Health Organization (WHO) Expert 20 World Health Organization (WHO) “Sub- TLC and GC-MS.” Malaysian Journal of Committee on Drug Dependence. “Phen- stances under Surveillance.” Available at: Forensic Sciences 3(1): 11-15. azepam: Pre-Review Report. Agenda item www.who.int/medicines/access/controlled- 23 United Nations Office on Drugs and Crime 5.8.” Thirty-seventh Meeting, Geneva, 16-20 substances/substancesundersurveillance. (UNODC) Terminology and Information on November 2015. pdf?ua=1 Drugs. 3rd edition. March 2016.

6 Volume 18 of diversion of medicines from their intended use in medical treatment to non-medical use and sale on illicit drug markets can occur at all points of the pharmaceutical trade. Diver- sion can occur at pharmaceutical manufacturing sites, at wholesale distribution of medicines, at the phy- Source: UNODC sician’s office, at retail pharmacies, or when patients receive treat- United States: Leader of an online pharmacy that ment.24 Methods of diversion are also wide-ranging and can include: illegally distributed prescription drugs was sentenced the illegal sale and repeated use to prison of prescriptions by physicians and SEATTLE, United States – 27 January 2017. In early 2017, a man pleaded pharmacists; patients obtaining pre- guilty at the United States District Court for the Western District of Virginia in scriptions from several doctors (also Harrisonburg for purchasing tablets containing between June known as the “doctor shopping” 2015 and September 2015 and distributing these with the false claim that phenomenon); theft of medicines; they contained alprazolam (often sold under the brand name of “Xanax®”).27 and forgery and/or alteration of pre- According to the defendant, the tablets he distributed did not contain any scriptions by patients.25 labeling to inform users of their flubromazolam content. Under the names Over the years, benzodiazepines of “Discount Pharmacy” and “A-1 Pharmacy”, this internet operation had have been diverted from legitimate shipped hundreds of thousands of alprazolam (“Xanax®”), as well as hydro- trade on a large scale in various codone, phentermine, and (sold under various brand names such as regions worldwide for onward sale “Tylenol 4”) tablets to thousands of people across the country who did not at illegal drug markets. For instance, have valid prescriptions for these substances. The investigation of this case revealed that the defendant employed this approach to misbrand 100-300 in the United States, the leader of an tablets purchased from the “dark web”. online pharmacy that illegally dis- tributed benzodiazepines including United States Attorney’s Office Western District of Virginia. “Cross Junction Man other prescription drugs and illegal Pleads Guilty to Misbranding Charge.” 3 February 2017. Available at: www.justice. tablets was sentenced to prison in gov/usao-wdva/pr/cross-junction-man-pleads-guilty-misbranding-charge January 2017.26 Under the names of “Discount Pharmacy” and “A-1 almost 40,000 alprazolam reports In the course of the investigation, Pharmacy”, this internet operation from federal, state and local foren- authorities discovered an extensive had shipped hundreds of thousands sic laboratories in 2011 and another network engaging in the diversion of of tablets, including the opioid 18,068 reports between January and prescription medicines that involved hydrocodone and the benzodiaz- June 2012.28 wholesale dealers and other busi- epine alprazolam (under the brand nesses as well as some registered Large scale diversion of benzodi- name “Xanax®”), across the United pharmacies in the United Kingdom. States to thousands of people who azepines has also been reported did not have valid prescriptions for in the United Kingdom, where the The diversion of benzodiazepines these substances. Over a three-year Medicines and Healthcare products and other medicines from licit trade period, the operation generated a Regulatory Agency (MHRA) con- is a problem in a number of regions. revenue of more than USD 9 million. ducted a large scale investigation into However, quantifying the magnitude the diversion of prescription medi- of such diversion remains difficult In the United States, alprazolam is given that there is a lack of data and considered to be among the top cines to the illegal drug market in 29 information on this subject and few three prescription medicines that December 2016. Two pharmacists based in the Yorkshire region of the available systematic monitoring and are diverted from the licit market. data collection mechanisms. According to the Drug Enforcement country were arrested after having Administration (DEA), there were purchased more than 200,000 packs Counterfeiting and substitu- of benzodiazepines and other drugs. tion of pharmaceuticals 24 European Monitoring Centre for Drugs and 27 United States Attorney’s Office Western Dis- involving benzodiazepines Drug Addiction (EMCDDA) “Perspectives trict of Virginia. “Cross Junction Man Pleads on Drugs: Strategies to prevent diversion of Guilty to Misbranding Charge.” 3 February Over the years, benzodiazepines opioid substitution treatment medications.” 2017. Available at: www.justice.gov/usao- have also been employed in the May 2016. wdva/pr/cross-junction-man-pleads-guilty- large scale manufacture of coun- 25 European Monitoring Centre for Drugs and misbranding-charge terfeit medicines, also referred Drug Addiction (EMCDDA) “Perspectives 28 Drug Enforcement Administration (DEA) on Drugs: Strategies to prevent diversion of “Benzodiazepines.” January 2013. to as “fraudulent medicines” or 30 opioid substitution treatment medications.” 29 Medicines and Healthcare products Regu- “falsified medicines”. Such coun- May 2016. latory Agency (MHRA) “Press Release: terfeit medicines are usually made to 26 United States Drug Enforcement Adminis- Regulator investigating the diversion of tration. “Leader of Illegal Online Pharmacy prescription only medicines.” 16 December Sentenced to 8 Years in Prison.” 27 January 2016. Available at: www.gov.uk/government/ 30 United Nations “Countering fraudulent 2017. Available at: www.dea.gov/divisions/ news/regulator-investigating-the-diversion-of- medicines, in particular their trafficking.” sea/2017/sea012717.shtml1 prescription-only-medicines Resolution 20/6.

7 GLOBAL SMART UPDATE resemble pharmaceutical products that instead contain different sub- India: Authorities stances that may be harmful. Thus, dismantle a clandestine the content of counterfeit medicines laboratory manufacturing can vary significantly, ranging from products that contain the wrong alprazolam ingredients, or that are without ANDHRA PRADESH, India – Octo- active ingredients, or that have an The Democratic Republic ber 2016. On 5th October 2016, insufficient or excessive quantity of Congo: 400 patients officers of the Vishakhapatnam of the active ingredients.31 Cases of suffer acute intoxication Directorate of Revenue Intelligence counterfeit medicine use involving after use of counterfeit dismantled a clandestine labora- benzodiazepines discussed in this tory in Jawaharlal Nehru Pharma report are a global phenomenon that diazepam City in the Andhra Pradesh State of can potentially result in unexpected NONO, Democratic Republic of India. In addition, a total of 101 kg adverse effects and/or a deteriora- Congo – July 2015. On 2nd July 2015, of alprazolam were seized at the tion of medical conditions. the WHO issued an alert when over site and authorities also arrested 400 patients in the area of Nono to 5 people in connection with this Given that the counterfeiting of case. A day earlier, on 4th October medicines is difficult to detect and the north-east of the Democratic Republic of Congo suffered acute 2016, the Central Bureau of Narcot- quantify, the extent of the prob- intoxications after having used diaz- ics seized 700 grams of alprazolam lem and the size of the market for epam for their health treatment. in Indore in Madhya Pradesh State counterfeit medicines involving ben- Laboratory analysis of the tablets and arrested 3 people in connec- zodiazepines is unknown. However, labeled as diazepam showed that tion with the case. reports show that benzodiazepines the tablets did not contain any diaz- feature in cases concerning counter- Control Bureau. Drug Situa- epam but instead had a content of tion Report/Significant Events Report feit products worldwide. 10-20 milligrams of haloperidol for India for the Month of October In Europe, there have been various per . Although most acute 2016. October 2016. reports in recent years of counterfeit intoxications occurred in the area medicines that had been intercepted of Nono, large quantities of such and found to contain benzodiazepine tablets were also reported to have tablets seized in both countries usu- NPS. For instance, in 2016, Police been observed in other parts of the ally solely contained nimetazepam or Scotland reported that seized tablets Democratic Republic of Congo such nimetazepam together with a rela- sold as diazepam on the illicit drug as the Ituri Health District. tively small quantity of nitrazepam. market have instead been found to World Health Organization (WHO), In North America, cases of counterfeit contain various other benzodiaze- “Medical Product Alert No. 4/2015: medicines involving benzodiazepines pines such as etizolam, diclazepam, Adverse reactions caused by Falsified have featured in the United States Diazepam in Central Africa”, Geneva, for a number of years.36 Recently, in flubromazepam and the synthetic 2 July 2015. opioid U-47700.32 Moreover, accord- January 2017, the leader of an online ing to the European Monitoring pharmacy that illegally distributed Centre for Drugs and Drug Addiction reported to have seized 26 batches tablets containing flubromazolam (EMCDDA), tablets sold in Europe as of phenazepam of which some con- with the false claim that they con- alprazolam were found to contain sisted of a mixture of phenazepam tained alprazolam, in addition to flubromazolam in 2015 whereas tab- and other drugs.34 illegally distributing various other lets sold as diazepam tablets in that prescription drugs and same year were discovered to have In South-East Asia, there have also tablets, was sentenced to 8 years in contained phenazepam.33 In Finland, been reports of nimetazepam being prison (see Box for more informa- between 1st July 2010 and 30th substituted with phenazepam in tion on this online pharmacy in the June 2011, the Finish police also the content of “Erimin 5” tablets in United States). recent years. According to the Illicit Drugs Laboratory of the Health In some regions there have also been 31 World Health Organization (WHO) “Sub- Sciences Authority in Singapore, reports of products sold as benzo- standard, spurious, falsely labelled, falsified phenazepam has been discovered diazepine medicines, that were and counterfeit (SSFFC) medical products.” found to contain other substances. January 2016. Available at: http://www.who. in the content of “Erimin 5” tablet int/mediacentre/factsheets/fs275/en/; World seizures in Singapore and in Malaysia For instance, in July 2015, the Health Organization (WHO) “Counterfeit since 2012.35 Previously, “Erimin 5” World Health Organization (WHO) Drugs.” WHO/IFPMA Workshop, Geneva, issued an alert concerning tablets 1-3 April 1992. labeled as diazepam that were 32 Police Scotland, “The illicit benzodiazepine market in Scotland.” Drug Trend Bulletin – 34 Kriikku P., et. al. (July 2012) “Phenazepam Issue 13, September 2016; Police Scotland, abuse in Finland: findings from apprehended 36 For more information, see: Drug Enforce- “The illicit benzodiazepine market in Scot- drivers, post-mortem cases and police con- ment Administration (DEA) “Micro- land”, Drug Trend Bulletin – Issue 8, April fiscations.” Forensic science international 220 gram Bulletin.” August 2009; United 2016. (1-3): 111-7. States Food and Drug Administration, 33 European Monitoring Centre for Drugs and 35 Lim, W. J. L. et al. (February 2017) “Detec- “Counterfeit Drugs – An FDA Perspec- Drug Addiction (EMCDDA) European Drug tion of phenazepam in illicitly manufactured tive.” Available at: http://indy.afdo.org/ Report 2016: Trends and Developments. Lux- Erimin 5 tablets.” Drug Testing and Analysis 9 uploads/1/5/9/4/15948626/ddc-1035-flurer- embourg, 2016. (2): 293-305. pharma-counterfeiting.pdf

8 Volume 18

Source: UNODC Source: UNODC

Malaysia: 2.5 million nimetazepam tablets seized in a : Two cases of container from Taiwan Province of China “Xanax®” tablet seizures PORT KLANG, Malaysia – March 2017. At Port Klang in the state of Selan- in Kildare and Limerick gor, the Special Tactical Intelligence Narcotics Group (STING) and the Royal City Malaysian Customs seized 2.5 million nimetazepam tablets, at a value of KILDARE AND LIMERICK CITY, around 50 million Malaysian Ringgit, concealed in a container from Taiwan Ireland – February 2017. On 13th Province of China in March 2017. According to the Malaysian Narcotics February 2017, the Irish National Criminal Investigation Department, these tablets were intended to be sold Police Service, the Gardaí, seized a on drug markets in Malaysia, as well as in Indonesia, Singapore, and . large quantity of “Xanax®” tablets Malaysian police arrested 10 men in connection with the case. (presumed to contain alprazolam) Free Malaysia Today. “Cops seize Ermin 5 pills worth RM50 million.” 11 March 2017. with an estimated value of EUR Available at: www.freemalaysiatoday.com/category/nation/2017/03/11/cops-seize- 19,000 and 6.5 kg of “ecstasy” (pre- erimin-5-pills-worth-rm50-million/ sumed to contain MDMA). These substances were seized when the Gardaí from Naas Traffic Corps found to contain haloperidol in the by countries in North America stopped and searched a car at a north-eastern parts of the Demo- and South Asia. In North America, checkpoint in Kildare Town after cratic Republic of Congo (for more Canada reported to have disman- which a man and a woman were information see box on the acute tled 2 medium-sized packaging arrested in connection with the intoxication cases in the Democratic operations illicitly manufacturing case. Previously, on 24th June 2016, Republic of Congo).37 Previously, in alprazolam in 2014, while in South the Gardaí seized “Xanax®” tablets 2011, the United States Food and Asia, the Narcotics Control Bureau in with a street value of EUR 9,000 Drug Administration (FDA) issued a India reported to have dismantled a together with a quantity of canna- warning on placing orders for alpra- clandestine laboratory in 2016 (see bis herb during a search operation zolam (often sold under various Box for more information on the at a house in Limerick City. 39 brand names such as “Xanax®”) and illicit laboratory in India). An Garda Síochána – Ireland’s National certain other pharmaceutical prod- In East and South-East Asia, Malay- Police Service. “Press Release: Drug ucts over the internet.38 According and arrests in Kildare on the sia also reported to have dismantled 13/2/17.” 14 February 2017. Avail- to the FDA, there had been several an illicit laboratory manufacturing cases in which such tablets that had able at: www.garda.ie/Controller. nimetazepam in 2011 and another aspx?Page=19911&Lang=1 been ordered over the internet were such laboratory in 2015.40 found to contain haloperidol. An Garda Síochána – Ireland’s National Seizures and trafficking of Police Service. “Press Release: Drug Clandestine manufacture benzodiazepines seizure and arrest in Limerick on of benzodiazepines the 24/6/16.” 25 June 2016. Avail- In recent years, countries worldwide able at: www.garda.ie/Controller. In addition to the diversion of ben- have reported seizures of various aspx?Page=18494&Lang=1 zodiazepines from medical sources, benzodiazepines to UNODC. there is also some evidence of illicit Nimetazepam 41 manufacture. In recent years, coun- kg). In early 2017, it was confirmed tries in various regions have reported Between 2011 and 2015, nimetaz- that another 2.5 million tablets of the dismantling of laboratories illic- epam seizures were reported in nimetazepam were seized in a single itly manufacturing alprazolam and South-East Asian countries that seizure in the Taiwan Province of nimetazepam. included Brunei Darussalam (totaling China (for more information, see Box on nimetazepam seizure reported With respect to alprazolam, illicit less than 1 kg) and the Taiwan Prov- ince of China (at a total of around 12 in Malaysia that had been trafficked manufacture has been reported from Taiwan Province of China).

37 World Health Organization (WHO), “Medi- Alprazolam cal Product Alert No. 4/2015: Adverse reac- tions caused by Falsified Diazepam in Central 39 UNODC, Annual Report Questionnaire for Over the years, most alprazolam sei- Africa.” Geneva, 2 July 2015. Canada, 2014; Narcotics Control Bureau. zures were reported in the United 38 United States Food and Drug Administration “Drug Situation Report/Significant Events States where almost 5 tons were (FDA), “The Possible Dangers of Buying Report for India for the Month of October Medicines over the Internet.” 26 January 2016.” October 2016. 2011. Available at: www.fda.gov/ForConsum- 40 UNODC, Annual Report Questionnaire for 41 UNODC, Annual Report Questionnaire, ers/ConsumerUpdates/ucm048396.htm Malaysia, 2011 and 2015. 2011-2015.

9 GLOBAL SMART UPDATE Table 4: List of benzodiazepine NPS that have been reported by Member States to the UNODC Early Warning Advisory (EWA) and benzodiazepine NPS that were observed based on other sources of information

BENZODIAZEPINE NPS 3-hydroxyphenazepam Flubromazepam 4-chlorodiazepam Flubromazolam Alprazolam triazolobenzophenone derivative Cloniprazepam Norfludiazepam Phenazepam43 Diclazepam Pyrazolam Etizolam42 Source: UNODC Early Warning Advisory (EWA) on NPS, 2017.

reported to have been seized in 2014 Other benzodiazepines belonging to the benzodiazepine and another 0.01 tons were reported Other seizures of benzodiazepines class have pharmacological profiles in 2015. 44 In addition, seizures of similar to controlled pharmaceutical (such as clonazepam, flunitrazepam, 48 this substance, annually totaling lorazepam, midazolam, nitrazepam, benzodiazepines, profiles of most 1-5 kg or less per country, have also phenazepam, and temazepam) have of the emerging substances are not been reported between 2011 and also been reported in recent years well-described. 2015 in various regions worldwide, from various countries worldwide The risk of polydrug use involving in countries that include Bahrain, that mostly consisted of annual sei- benzodiazepines and opioids are Chile, Gambia, India, Italy, Pakistan, zures totaling around 1 kg or less. further intensified by NPS belong- the Russian Federation, the Taiwan Larger quantities were reported ing to the benzodiazepine class. Province of China and Yemen. Most in the Russian Federation in 2014, Given the limited information on the recently in early 2017, two seizure where more than 28 kg of clonaz- pharmacology and toxicity of these cases of “Xanax®” tablets (presumed epam were reported to have been substances, variations in the dosage, to contain alprazolam) were also seized. onset of effects, combination of reported in Ireland. The emergence of NPS belong- substances, potency, and general Diazepam patient or individual variability, the ing to the benzodiazepine class concomitant use of these substances Since 2010, annual seizures of with other drugs entails a number diazepam mostly consisting of less As a relatively new phenomenon, of risks. than 1 kg per country (sold under NPS belonging to the benzodi- various brand names that include azepine class have emerged on So far, 18 NPS belonging to the “Relanium” and “Valium”) have been the market and are being sold benzodiazepine class have been reported in a number of regions such under street names such as “legal reported by Member States to the as Europe, Central Asia and Transcau- benzodiazepines”, “designer benzo- UNODC Early Warning Advisory casian countries, South and Central diazepines” or “research chemicals”. (EWA) and the emergence of an America, South Asia, East and South- This group of substances includes additional 4 NPS belonging to the East Asia, Africa, and the Near and substances that were tested but benzodiazepine class were observed Middle East. Between 2010 and not approved as medicines in the based on other sources of informa- 2015, larger quantities of diazepam or that tion (for more information see Box were reported to have been seized have been manufactured by modi- on the list of benzodiazepine NPS). fying the core structure of existing In 2011, , and in India (totaling 24 kg), Myanmar 46 (totaling 7 kg), and the Russian Fed- pharmaceutical benzodiazepines. the United Kingdom were the first eration (again totaling 7 kg).45 Some of the first NPS belonging to the benzodiazepine class that were liminary data on its and pharma- available online included substances 42 Etizolam is currently in the ‘Substances under cokinetics.” Drug Testing and Analysis 6 (7-8): Surveillance’ list of the World Health Organi- such as diclazepam, flubromazepam 757-763. zation. and pyrazolam.47 While certain NPS 48 World Health Organization (WHO) Expert 43 Phenazepam is currently in Schedule II of the Committee on Drug Dependence. “Phen- azepam: Pre-Review Report. Agenda item Convention on Psychotropic Substances of 46 Moosmann, B., King, L. A., and Auwärter, 1971. 5.8.” Thirty-seventh Meeting, Geneva, 16-20 V. (June 2015) “Designer benzodiazepines: a November 2015; World Health Organiza- 44 UNODC, Annual Report Questionnaire, new challenge.” World Psychiatry 14 (2): 248. tion (WHO) Expert Committee on Drug 2014-2015. 47 Moosmann, B., Bisel, P., and Auwärter, V. Dependence. “Etizolam (INN): Pre-Review 45 UNODC, Annual Report Questionnaire, (January 2014) “Characterization of the Report. Agenda item 5.7.” Thirty-seventh 2010-2015. designer benzodiazepine diclazepam and pre- Meeting, Geneva, 16-20 November 2015.

10 Volume 18

Figure 1: Number of countries reporting NPS belonging to the benzodiazepine class to UNODC EWA, 2011-2015 2

20

1

10

0 2011 2012 201 201 201

Source: UNODC Early Warning Advisory (EWA) on NPS, 2017. countries to report the emergence Ongoing challenges of NPS belonging to the benzodiaz- The market for benzodiazepines is epine class, which included etizolam highly complex and presents a variety and phenazepam. of challenges. In the context of the Over the years, there was an increase opioid crisis, the concomitant use of in the number of NPS belonging to opioids and benzodiazepines poses the benzodiazepine class reported by a significant risk to public health countries to UNODC EWA. Between and their use has been involved in 2011 and 2016, there were a total of a rising number of fatalities in North 209 reports of such substances and America and in Europe. Moreover, etizolam, phenazepam, diclazepam, there are a large variety of benzo- flubromazepam and pyrazolam, were diazepines available on the market, among the most commonly reported ranging from counterfeit products substances of this group. More than to NPS belonging to the benzodiaz- 72 per cent of these reports were epine class, which vary significantly received from European countries. in terms of their duration of action, Overall, the number of countries pharmacology and toxicology. reporting the emergence of NPS In particular, there continues to belonging to the benzodiazepine be a lack of data and information class has annually increased from 3 on counterfeit benzodiazepines countries in 2011 to 21 countries in and NPS belonging to the benzo- 2015 (see Figure 1). diazepine class. The chemical and As an increasing number of benzo- pharmacological profile of many NPS diazepine derivatives have appeared belonging to the benzodiazepine on NPS markets, several countries class is unknown and the content of worldwide have placed some of counterfeit medicines can also differ. these substances under national Thus, there is a need for further control. For example, in Europe, research to understand the content NPS belonging to the benzodiaz- and nature of these products on market so as to develop effective epine class are reported to have policy responses. It is also essen- been placed under national control tial to raise awareness of potential in countries such as the Denmark, severe adverse effects surrounding Finland, Sweden, , Turkey polydrug use in combination with and the United Kingdom. In East and benzodiazepines and the dangers South-East Asia, the Republic of in acquiring counterfeit medicines. Korea is also reported to have placed diclazepam under national control and in the Middle East, the United Arab Emirates have placed diclaze- pam, etizolam, flubromazepam and pyrazolam under national control.

11 Recent Global SMART Publications

Afghanistan Synthetic Drugs Situation Assessment

UNODC Global SMART Programme

January 2017

Global SMART Global SMART Global SMART Afghanistan Synthetic Drugs Update Volume 17 Update Volume 16 Update Volume 15 and 14 Situation Assessment (English and Spanish) (English, Russian and Spanish) (now in Russian) 2017

To celebrate 20 years since its inception, the World Drug MARKET ANAL Report 2017 is presented in a new five-booklet format designed to improve reader friendliness while maintaining the SYNTHETIC DRUGS wealth of information contained within. YSIS OF Booklet 1 summarizes the content of the four subsequent Amphetamine-type stimulants, substantive booklets and presents policy implications drawn from their findings. Booklet 2 deals with the supply, use and new psychoactive substances health consequences of drugs. Booklet 3 focuses on the cultivation, production and consumption of the three plant-based drugs (cocaine, and cannabis) and on the impact of new cannabis policies. Booklet 4 provides an extended analysis of the global synthetic drugs market and contains the bulk of the analysis for the triennial global synthetic drugs assessment. Finally, Booklet 5 contains a discussion on the nexus between the drug problem, organized crime, illicit financial flows, corruption and terrorism.

Enhanced by this new format, the World Drug Report 2017 is, as ever, aimed at improving the understanding of the world drug problem and contributing towards fostering greater international cooperation for countering its impact on health and security. Y The statistical annex is published on the UNODC website: www.unodc.org/wdr/2017 EXECUTIVE SUMMAR CONCLUSIONS ANDTIONS POLICY IMPLICA

ISBN 978-92-1-148296-6 To celebrate 20 years since its inception, the World Drug Report 2017 is presented in a new five-booklet format designed to improve reader friendliness while maintaining the WORLD wealth of information contained within. Booklet 1 summarizes the content of the four subsequent substantive booklets and presents policy implications drawn 9 789211 DRUG from their findings. Booklet 2 deals with the supply, use and 482966 health consequences of drugs. Booklet 3 focuses on the cultivation, production and consumption of the three REPORT plant-based drugs (cocaine, opiates and cannabis) and on the impact of new cannabis policies. Booklet 4 provides an extended analysis of the global synthetic drugs market and 2017 contains the bulk of the analysis for the triennial global synthetic drugs assessment. Finally, Booklet 5 contains a discussion on the nexus between the drug problem, organized crime, illicit financial flows, corruption and terrorism.

Enhanced by this new format, the World Drug Report 2017 is, 4 as ever, aimed at improving the understanding of the world drug problem and contributing towards fostering greater international cooperation for countering its impact on health and security.

The statistical annex is published on the UNODC website: www.unodc.org/wdr/2017 WORLD

ISBN 978-92-1-148292-8 1 DRUG 2017 REPORT 482928 9 789211 The Challenge of Synthetic Drugs World Drug Report Early Warning Advisory Updated New Psychoactive in East and South-East Asia - 2017 Newsletter Volume Substance leaflet and poster Trends and Patterns of 11 and 12 (now in Russian) Amphetamine-type Stimulants and NPS 2017

Global SMART UNODC Early Warning Publications Advisory on NPS

Contact details Global SMART Programme Vienna International Centre www.unodc.org/unodc/en/scientists/smart-new.html P.O. Box 500 www.unodc.org/nps A-1400, Vienna www.apaic.org [email protected]

UNODC would like to thank the following Governments for their financial contributions to the Global SMART Programme.

Australia Canada China Japan New Zealand Republic of Korea

Russian Federation Thailand United Arab Emirates United Kingdom United States