Illegal drug use-related hazards and problems, which evolve and differ with drug types from time to time, have been a worldwide concern. The drug use epidemics, extending from heavy consumption of opium smoking in China in the late 19th century to extensive misuse of synthetic drugs, such as amphetamine(s), LSD, and sedatives in the early 20th century, sequentially result in the enactment of three United Nations Drug Conventions in 1961, 1971, and 1988, respectively [1,2]. These three United Nations Drug Conventions shape the present system of worldwide drug control. In recent years, however, the emergence of new psychoactive substances (NPS) that are not controlled in the 1961 or 1971 United Nations Drug Conventions has become a new global challenge. According to the 2019 World Drug Report, as of December 2018, the United Nations Office on Drugs and Crime (UNODC) identified a total of 892 NPS; the number was more than triple than the 273 substances controlled under the 1961 and 1971 conventions . These NPS, classified by the UNODC into nine categories, including synthetic cannabinoids, synthetic cathinones, ketamine and PCP-type substances, phenethylamines, piperazines, tryptamines, aminoindanes, plant-based substances, and others , are predominantly derivatives or analogs of existing controlled substances [5,6]. Because of their elusiveness from the United Nations Drug Conventions and uncertain toxicological profiles, the NPS may pose a potential threat to public health and social security [7,8]. Therefore, to further understand the potential problems and current status of NPS use, the 2019 International Conference on NPS, co-sponsored by Taiwan Food and Drug Administration and Kaohsiung Medical University, was held in Taipei on 10–11 July 2019. This study is primarily based on the presentation at the conference.
BRIEF HISTORY OF ILLEGAL DRUG USE AND RECENT SITUATION OF NPS ABUSE IN TAIWAN
In Taiwan, there have been three major waves of drug epidemics in the recorded history. Each wave involved different types of drugs that were tackled with different policy and measures: first wave – opium smoking and gradual prohibition policy during the Japanese colonial period (1895–1945); second wave – methamphetamine use along with heroin use and drug law reform in the 1990s; third wave – HIV spread among heroin intravenous drug users (IDUs) and the rise of NPS since the early 2000s [1,2].
The major drugs of the first two waves were traditional controlled substances, including opium, heroin, and methamphetamine. These two waves of drug epidemics were brought into manageable situations by differential legislation and policies. In the third wave, the issue of HIV spread by needle-syringe/dilution solution sharing among heroin IDUs was effectively contained with harm reduction policy, which mainly included a methadone maintenance treatment program and a needle/syringe exchange program, along with mandatory HIV testing and education on drug users . The experiences learned from these three waves indicate that up-to-date legislations and policies are crucial to effectively curb the drug use-related problems [2,10].
Since early 2000s, use of club drugs, including methamphetamine, MDMA, ketamine, and flunitrazepam (also known as FM2 in Taiwan), has become popular in local rave parties and dance clubs. Some club drugs such as ketamine are now more familiar to the public as NPS . In 2002, a study with urine tests on 931 specimens collected from illegal drug use arrestees in Taiwan identified a drug positive rate of 74% and 39 drugs. The positive rate of ketamine use was 4.7% (44/931). These club drug (including ketamine) users, with a smaller sex gap (male/female ratio 3.5), were younger (mostly under 27 years old), urbanized, and better educated . Another study, conducted with focus groups on Taiwanese club drug users, showed a specific sequence of use called ‘Trinity’ (MDMA, ketamine, and marijuana) were illegally practiced in the ‘Head-shaked bars’ and ‘KTVs.’ This early study indicated the trend of polydrug use pattern among NPS users . The ’trinity’ can be regarded as a primitive form of ’instant coffee sachet.’
In 2005, the first National Household Survey on Health and Substance Abuse was carried out on the population aged between 12 and 64 years old in Taiwan . The prevalence for people ever used illegal drugs was 1.2%. In this survey, of the illegal drugs consumed, ketamine ranked third (22.0%), only behind amphetamines (49%) and MDMA (35.1%). Meanwhile, the trend of ketamine seizures was also increasing: from 0.0 kg (no seizure) in 2000 and 2001, 63.2 kg in 2002, 600.5 kg in 2003, 613.4 kg in 2004, 441.2 kg in 2005, to 827.9 kg in 2006. Apart from its psychedelic and dependence effects, ketamine-associated bladder dysfunction has also been reported in Taiwan . As a result, ketamine has been listed as a schedule III drug in Taiwan since 2002 . Ketamine is also widely abused in ethnic Chinese communities in Asia .
The subsequent lifetime prevalences of illegal drug use from the National Household Surveys on Substance Abuse were 1.4% in 2009 and 1.29% in 2014, respectively [17,18]. In the 2014 survey, lifetime prevalence of club drugs (0.78%, including marijuana, ecstasy, GHB, bath salts, Magic mushroom, ketamine, FM2, para-methoxymethamphetamine (PMMA), 2C-B, K2, mephedrone, and N2O) was slightly higher than hard drugs (0.71%, including heroin, methadone, and methamphetamine) . Although the lifetime prevalence of drug use in total in 2014 was similar in comparison with that in 2005, the shift of drug use from hard drugs (traditional drugs) to club drugs (mainly NPS) was obvious. Concurrent use of alcohol was extremely strong correlates of club drugs. In addition, users of club drugs only were more likely to be female, be younger, have a higher educational level, and be more likely to be divorced or widowed than users of hard drugs only .
Ketamine remained the most predominant item of NPS in Taiwan from early 2000s till 2016 as shown in an overview of the top five detected substances among all NPS seizures for the period of 2014 to October 2019 (Table 1) . From 2017 on, synthetic cathinones (mephedrone and MEAPP) replaced ketamine as the most predominant NPS. These ranked NPS items belong to four categories of NPS, that is, ketamine, synthetic cathinones [mephedrone, methylone (bk-MDMA), chloromethcathinone, ethylone, 4-chloroethcathinone, N-pentylone, chloromethcathinone (CMC), N-ethylpentylone, 4-CEC, MEAPP, and methyl-α-ethylaminopentiophenone], tryptamines (5-MeO-MIPT), and others (phenazepam). Some other NPS categories, such as synthetic cannabinoids (e.g. JWH-250, JWH-018), phenethylamines, and plant-based substances [Kratom (Mitragyna speciosa) and Salvia (Salvia divinorum)] have also been reported [1,5,8,11,13,18,20]. Apparently, abused NPS have been diversified in both categories and items. Synthetic cathinones deserve further attention in Taiwan for their abuse liability in recent years.
TOXICOLOGICAL PROFILES OF NPS USE IN TAIWAN
A recent clinical study reported six patients with ‘coffee sachets’ use were all identified with a variety of synthetic cathinones in their urines [21▪]. These cathinone users were relatively young (14–26 years old). Although it was difficult to attribute their clinical manifestations to cathinone only, the results highlighted the multiple drug use patterns of NPS users, and most of them showed highly suicidal or aggressive behaviors.
Due to their uncertain toxicity, abuse of NPS is expected to cause adverse health effects, even death. According to the report of Institute of Forensic Medicine, Ministry of Justice, the drug use-related deaths in Taiwan from 2001 to 2016 are shown in Table 2. Heroin and methamphetamine have been the major causes of drug use-related deaths over the past two decades. Ketamine-related deaths began to appear in 2002 with a ranking of fifth, then gradually moved up to the second place in 2011.
Another report of the Institute of Forensic Medicine on 250 cases of drug use-related death collected from 1361 medico-legal autopsy cases in 2018 shows that ketamine ranked fifth (n = 32, 12.8%) on the drug use-related death list. The other top four death-related drugs were: methamphetamine (n = 82, 32.8%), heroin (n = 65, 26.0%), flunitrazepam (FM2) (n = 35, 14.0%), and estazolam (n = 33,13.2%) . Apart from ketamine, other death-related NPS included: mephedrone (n = 12, 4.8%), ethylone (n = 8, 3.2%), methylone (n = 7, 2.8%), butylone (bk-MDBD) (n = 5, 2.0%), N-ethylpentylone (n = 5, 2.0%), pentylone (bk-MBDP) (n = 5, 2.0%), dibutylone (bk-DMBDB) (n = 4, 1.6%), methyl-α-ethylaminopentiophenone (4-MEAPP) (n = 2, 0.8%), 4-chloroamphetamine (n = 2, 0.8%), N-ethylhexedrone (NEH) (n = 2, 0.8%), 4-chloro-alpha-pyrrolidinopentiophenone (4-Cl-α-PVP) (n = 1, 0.4%), 4-CMC (n = 1, 0.4%), and eutylone (n = 1, 0.4%). These NPS-related decedents, mostly users of ketamine and synthetic cathinones, died relatively young (28.2 ± 0.6 years old) if compared with the average age of drug use-related deaths (40.9 ± 03 years old). Furthermore, an average of 5.6 drugs per case were found in the NPS use-related decedents, demonstrating multiple drug interaction may be an important factor contributing to the harm and fatality of NPS use . From October to December in 2019, PMMA – an analog of MDMA – has claimed 34 fatalities, again implying the unpredictability of NPS toxicity .
Hence, the evidence-based research on NPS-related adverse health effects, now still limited, is desperately needed to learn the harm and danger of NPS.
COMPARISON OF NPS USE PATTERN BETWEEN TAIWAN AND SOUTH KOREA
Methamphetamine – a prototype of NPS in the phenethylamine family – was initially a pharmaceutical that was legally manufactured but widely misused in Japan after World War II. Illegal use of methamphetamine then spread to Korea and Taiwan in the 1970s and early 1990s, respectively [2,10]. In Taiwan, to tackle the methamphetamine epidemic in the early 1990s, the obsolete ‘Act for Eradication of Illicit Narcotics’ (for illegal narcotic control) and ‘Narcotics Control Act’ (for medical narcotics control), which only observed the 1961 Single Convention of Narcotic Drugs, was revised into ‘Act for Prevention and Control of Illicit Drug Hazard’ and ‘the Controlled Drugs Act’ and promulgated in 1998 and 1999, respectively [1,2]. Thus, drug law reform in Taiwan to conform to the three UN Drug Conventions mainly because of the methamphetamine epidemic. Although methamphetamine remained as a predominant drug in both Taiwan and South Korea for decades, the illegal drug use situation in Taiwan was at a higher stake than that in South Korea as compared from 2006 to 2014. For NPS use, ketamine has been a major drug in Taiwan, whereas it was seldom found in Korea . Furthermore, although the quantity of total NPS seizures was much larger in Taiwan than in South Korea, the controlled NPS items in Taiwan (23) were far less than those in South Korea (93), which may be due to the implementation of temporary designation systems (emergency scheduling) and analogue controls on NPS in South Korea since 2011.
COMPARISON OF NPS USE PATTERN BETWEEN TAIWAN AND JAPAN
From 2007 to 2015, a total of 940 NPS was reported in four Northeast Asian countries, including South Korea, Japan, China, and Taiwan . Among the 940 NPS, 882 NPS (94%) were legally controlled in at least one country. For the NPS regulation, Japan tops with 41% of the total number of controlled NPS, followed by South Korea (28%), China (21%), and Taiwan (10%). The swift increase in newly controlled NPS in Japan was because the precautionary principle was adopted by promulgating the designated drug regulation in 2007 and the Dangerous Drug Regulation, including the analog control for synthetic cannabinoids in 2013 and analog controls for synthetic cathinones in 2013 and 2015.
The legislation for NPS control in Japan has had an effect on both supply and demand reductions of NPS [26,27▪▪]. Ketamine use, like in South Korea, has not been an issue in Japan so far.
CHALLENGES AND STRATEGIES FOR NPS CONTROL IN TAIWAN
In Taiwan, the trend of drug use is gradually shifting from traditional drugs to NPS. Facing the emergence of NPS, several challenges should be tackled with practical and evidence-based strategies:
- (1) With their easy modification on the chemical structures to avoid control and unknown toxicological profiles to cause the morbidity and mortality, most NPS are not internationally, but only nationally, controlled [3,27▪▪,28]. Therefore, identification and scheduling of an NPS into a controlled drug in a country is essential to tackle the NPS-related problems. However, Taiwan controlled fewer NPS than Japan and South Korea because of its current rigid criteria – addictive potential, abuse liability, and social harm liability – to schedule specific drugs as controlled substances. Hence, a dilemma of chicken-and-egg conundrum for effective NPS control would occur because it is usually difficult to prove whether a new NPS is addictive in due time and, in turn, difficult for authorities to collect data on the liability of use and social harm of uncontrolled substances [27▪▪]. In this regard, a flexible legislative mechanism would be the first step toward effective NPS control.
- (2) NPS use may cause severe adverse health effects, but studies on their toxicological effects are scant. In addition, the toxicological profiles of NPS, especially their addiction/dependence potentials, are quite different from those of traditional drugs. The in-vitro or in-silico studies that provide preliminary toxicological results may be an alternative to estimate the potential toxicity of NPS.
- (3) Although harm-reduction policies have been implemented in the first and third waves, they have not been systematically contemplated for the NPS-related problems. In the future, it may be necessary to adopt suitable harm reduction measures, such as provision of medical facilities in settings where NPS use is common; introduction of ’pill testing’ to determine the exact constituents of NPS sold in the illicit market to prevent people from intoxication; and assessing the value of the presence of police and other law enforcement officers at such venues so that their presence does not aggravate the harm that comes from NPS.
- (4) The NPS users tend to be younger and with higher education attainment. It is crucial to reach out to the susceptible populations with suitable campaigns for the potential danger of NPS use.
The proliferation of NPS has been a global phenomenon. In Taiwan, use of NPS, especially ketamine and synthetic cathinones, has also been an issue. However, so far, current international drug conventions and domestic drug laws were enacted primarily to control traditional addictive drugs. The flexibility of new legislation and corresponding drug policy, as exemplified by the temporary designation system and analog control system in South Korea, and the revision of the Pharmaceutical Affairs Law to enact the Designated Drug Regulation (and the subsequent Dangerous Drug Regulation) in Japan, has proved to be essential for the efficacious and timely control of NPS.
Apart from timely and flexible legislative mechanism(s) for early identification, surveillance, and comprehensive evaluation, it is also suggested that researches on NPS epidemiology and toxicology are needed to firm up evidence-based strategies for effective prevention, treatment, and harm-reduction measures.
We would like to express our gratitude to Professor Kaiping Shaw for his kind help in providing the data of drug use-related deaths from the Institute of Forensic Medicine.
Financial support and sponsorship
This presentation was supported in part by grants from the Ministry of Science and Technology, Taiwan (MOST103-2923-B-037-001-MY2; 104-3011-F-037-001) and Taiwan Food and Drug Administration (MOHW107-FDA-D-114-000633; MOHW108-FDA-D-114-000634).
Conflicts of interest
There are no conflicts of interest.
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