New Psychoactive Substances (e.g. kratom, synthetic cannabinoids, synthetic opioids (inc. fentanyl), synthetic cathinones)

"NPS [New Psychoactive Substances] is a category of substances that are fast-evolving, typically volatile and often diversified. The category includes different types of substances in terms of their composition, (il)legitimate use and position in the global drug markets. The great majority of NPS are substances that have no legitimate use, and have no established global large and long-standing markets that compare with the controlled 'traditional' drugs, with few exceptions. One is, for example, khat, a plant-based substance that is not under international control but that has a long-established market in some regions of the world. Another exception is the non medical use of two pharmaceuticals that are not under international control: tramadol and ketamine. Technically, these substances meet the definition of NPS but the underlining challenges posed by these substances are different from the large NPS set of substances. For example, tramadol, which has an established use for pain management, shares similarities with other opioids under international control. In the present report, the discussion of trends in tramadol misuse and seizures is included in the chapter on opioids, while ketamine, which is included in the WHO list of essential medicines and used as a local anaesthetic in many settings, is addressed in the present chapter.

"There are multiple ways to categorize NPS, for example, they can be grouped according to origin – whether plant-based or synthetic, according to psychotropic effects, or according to chemical structure."

"Since around 2008, there has been a dramatic growth in the NPS market as globalisation and new technologies, such as the internet, have allowed them to be produced, sold and supplied on an industrial scale. Between 2009 and 2018, 119 countries and territories reported the emergence of 892 different NPS to UNODC, through the UNODC Early Warning Advisory on NPS (UNODC, 2019b). In Europe, more than 730 NPS have appeared on the drug market since monitoring began in 1997, with around 90 % of these being detected between 2008 and 2018 (EMCDDA, 2019b). The growth in the market has also been reflected in large increases in the number of seizures made by law enforcement agencies, and in reports of severe and fatal overdoses.

"Many NPS are produced and sold openly by chemical and pharmaceutical companies in China. They are imported into Europe, processed into products and sold in shops, on the internet or through the illicit drug markets. To a lesser extent, India is also an important source of some NPS, particularly those sold as medicines (Evans-Brown and Sedefov, 2018). Illicit laboratories in China, India, and Europe also produce some types of NPS."

"Ketamine is closely related to the internationally controlled drug phencyclidine (also known as PCP or ‘angel dust’) which is listed in Schedule II of the 1971 Convention (see section 2.7.2).

"Phencyclidine was investigated as an intravenous anaesthetic in the 1950s but was later withdrawn due to undesired hallucinogenic and delirium effects.³⁴ Following the withdrawal of phencyclidine, ketamine was synthesized as an anaesthetic in 1962, patented in 1963 in Belgium and three years later in the United States. In the early 1970s, ketamine was marketed as a medical alternative to phencyclidine.

"The use of ketamine as a new psychoactive substance dates back to the 1980s and 1990s. At the international level, ketamine was subject to a series of risk assessments. The Expert Committee on Drug Dependence of the WHO pre-reviewed ketamine in 2003 and conducted a critical review in 2006. After reviewing the information contained before it, the Committee concluded that 'this information was not sufficient to warrant scheduling'.³⁵ It also requested an updated version of the critical review to be presented at the next meeting of the Committee which was held in 2012. At that meeting, the Committee decided that 'bringing ketamine under international control is not appropriate.'³⁶ At the level of European Union, in 2000, growing concern over the use of ketamine as a NPS prompted a risk assessment in the framework of the joint action on new synthetic drugs.³⁷ The European Commission concluded that it was not appropriate to introduce control measures and recommended further monitoring of the use of ketamine."

"Ketamine and phencyclidine have similar modes of action, affecting a range of central neurotransmitters. Ketamine is frequently sold as ‘ecstasy’ in illicit ATS [Amphetamine-Type Stimulants] markets. Street names for ketamine include ‘K’, ‘special K’, ‘kit kat’, ‘tac’, ‘tic’, ‘cat valium’, ‘cat tranquilizer’, ‘vitamin K’, ‘ket’, ‘super K’.³⁸
"Pharmaceutical preparations of ketamine are usually found in liquid form, but powder and capsules are also available. The powder prepared by evaporation of the original solution is often nasally insufflated (‘bumping’), smoked or swallowed."

"In the late 1950s, the synthesis of 2-benzylbenzimidazole opioids led to the creation of several compounds now known collectively as nitazenes - although they do not technically meet the current United States Adopted Name (USAN) definition of an “azene.” They were of particular interest because their chemical structures are distinct from the typical morphine-like phenanthrene motif and meperidine analogs like fentanyl. The nitazenes were intended to be developed as analgesics but they were never approved for any therapeutic purpose [1,2] Their potency and street appeal caused them to be compared frequently to fentanyl, although they are structurally unrelated. As the Drug Enforcement Administration (DEA) and the Food and Drug Administration (FDA) have been better able to identify and schedule numerous fentanyl analogs [3], it appears that chemists in clandestine labs have gone back through historical pharmacology research literature for early attempts at developing synthetic opioids [4]. Novel psychoactive substances (NPS), including “novel” synthetic opioid analogs such as the re-emergence of the older nitazene drugs, are considered the driver in the recent upward trends in overdose mortality in the United States [5]. Despite the fact that nitazenes have been identified in the illicit recreational drug supply, few clinicians are aware of them or their implications for emergency medicine."

"During the 1950s, nitazenes were developed by commercial pharmaceutical companies as synthetic opioid candidates and they were described in medical and pharmaceutical literature of the era. Thus, clandestine labs needed only to turn to the historic pharmacological literature to learn about the nitazene family. The European Monitoring Center for Drugs and Drug Addiction was first notified about the presence of isotonitazene in a biological sample obtained in July 2019 [15]. Since that time, isotonitazene has been implicated in over 200 drug-related overdose deaths in Europe and North America [7], but its presence likely is under-detected because many testing facilities are not set up to test for isotonitazene, or any other nitazenes, for that matter [8].

"Metonitazene was first identified in the street drug supply during the COVID-19 pandemic (early 2020) [13]. Metonitazene has been confirmed in 20 authentic forensic autopsies with an average serum concentration level of 6.3 ± 7.5 ng/mL (median 3.8 ng/mL, range 0.5 to 33 ng/mL) and urine concentrations of 15 ± 13 ng/mL (median 11 ng/mL, range 6-46 ng/mL) [13]. In those 20 cases, metonitazene was the sole opioid found in 30% of the decedents, but metonitazene was more often used in combination with other drugs such as fentanyl, benzodiazepines, hallucinogens, and other opioids. Medical examiners listed metonitazene as the drug contributing to the death and the manner of death was determined to be accidental in all cases [13]. A 2021 analysis of unintentional drug overdose deaths that occurred in Knox County, Tennessee, United States, found that 26 of the 218 overdoses (12%) involved metonitazene combined with fentanyl [2].

"Nitazenes are available in powders, counterfeit tablets, or liquids and may be mixed with inert substances and/or combined with other drugs, such as heroin, fentanyl, and benzodiazepines [7]. Their inclusion in other drug products is not detectable by consumers and may not be disclosed to them by sellers. When the new clandestine nitazenes entered the illicit market, they were not scheduled as controlled substances. In December of 2021, the DEA temporarily put numerous nitazenes on its Schedule I [9]. Since there are few validated methods to search for these substances and little is known about the network of clandestine labs and chemists who manufacture these drugs, the geographical distribution of these drugs is not known [7]."

"The most recent data shows that drug producers continue to create new substances to avoid legal controls, although the rate at which new psychoactive substances are now entering the market appears to be slowing. Between 2016 and 2022, typically around 50 new psychoactive substances appeared on the market for the first time each year; this fell to 26 in 2023. In addition, around 400 previously reported new substances are detected on the market each year."

"Novel potent opioids (NPOs) are novel nonfentanyl opioids in the illicit opioid supply. Synthetic opioids are one of the fastest growing classes of opioids being detected in patients in the emergency department (ED) with opioid overdose (OD).1

"A subclass of synthetic opioids referred to as nitazenes contain a 2-benzylbenzimidazole structure that has μ-opioid agonism. Isotonitazene, metonitazene, and N-piperidinyl etonitazene are NPOs with a piperidine benzimidazolone structure. Brorphine is a nonnitazene NPO that is a full μ-opioid receptor agonist with a structure similar to fentanyl. NPOs possess high potency at the μ-opioid receptor and an understudied propensity for adverse health effects. Nitazenes are structurally unrelated to fentanyl, but have been found to be up to 1000-fold more potent than morphine.1

"The exact motivation to produce nitazenes and brorphine are unclear. The increased regulation of fentanyl and fentanyl analogues throughout the last decade may have led to a change in the chemical precursors required for clandestine laboratory production that were not yet regulated.1 This change in chemical precursors may have led to these newer and more potent opioids."

"Historically, there have been a number of US overdose events where a fentanyl was implicated [14▪▪,15▪]. However, the wave of overdose deaths attributed to illicit fentanyls since 2013 is unprecedented. The current rise of fentanyls is considered a positive supply shock, i.e., a supply driven more than demand-driven event [16]. Evidence for this includes: fentanyls are generally sold as ‘heroin’ i.e., fentanyl-adulterated or substituted heroin (FASH) [17,18]; wholesale distribution of FASH [19] and related overdose is regionally distributed with the Northeast and Midwest most affected followed by the South [20–22]; these are illicit products not diverted pharmaceuticals [19]; early on there was mixed desirability for FASH [17,18,23,24]; and there is market incentive in that dose-for-dose fentanyl is cheaper to produce than heroin [3,25]. The reasons why fentanyls were introduced during the current surge is complex; one argument, based on prior episodes, is that they replace heroin during periods of relative shortage [16,26]. In The Future of Fentanyl and other Synthetic Opioids, Pardo et al. highlight a confluence of supply side factors to explain the rise of fentanyls, e.g., more-efficient synthesis methods, internet communication and commerce, and out-paced regulatory environments in source countries e.g. China [27▪▪].

"The fentanyls problem is spreading. Globally, fentanyls have been detected or implicated in deaths in Europe, esp. Estonia, Latvia, and Sweden [27▪▪]. Canada has been particularly hard hit by fentanyl-related overdose [28]. The spread of fentanyls is also happening in the USA. From 2014 to 2017, the fentanyls problem was initially regionally isolated to the US Northeast and Midwest, followed to a lesser degree in the South [20,22]. However, from 2017 to 2018 the region that had the highest relative change in overdose rates due to synthetic opioids was the West [5▪]. Examining CDC data, Shover and colleagues found the share of US synthetic opioid overdose deaths attributable to seven western jurisdictions more than tripled from 2017 to 2019 [29▪▪]. Supply side data also support increasing fentanyls supply, esp. in the form of counterfeit pills, to the West [30]. And the supply is diversifying from China and Mexico to include India as a source country [31▪]."

"Highly potent synthetic opioids have not played such a prominent role in rising deaths among people who use drugs in the UK. Global drug markets are, however, rapidly evolving. Of particular concern is the emergence of nitazenes: a class of synthetic opioids developed by the pharmaceutical industry in the 1950s but never approved as medicines.3 Like other opioids, nitazenes can cause fatal respiratory depression, and some are hundreds of times more potent than heroin (table).3 In the UK, nitazenes have been detected in substances sold as other opioids, benzodiazepines, and cannabis products.4 This means many consumers are using nitazenes inadvertently, unaware of the risks they face."

"Xylazine, also called “tranq” or “tranq dope,” is a non-opioid veterinary tranquilizer. Although not approved by the United States (US) Food and Drug Administration for human use, xylazine is increasingly being identified as an adulterant in illicitly manufactured fentanyl and heroin, and occasionally in other drugs such as cocaine and methamphetamine in the US [1, 2]. Xylazine overdose has no known antidote and can cause central nervous system and respiratory depression, hypotension, and bradycardia in humans [3, 4]. This has led to concern that xylazine could worsen the cardiorespiratory depressive effects and lethality of opioids when the drugs are combined, but its impact on overdose risk and symptoms is still being explored [2, 5–9]. The sedating effects of xylazine, which can last for hours, may also put individuals at greater risk for victimization or injury from assault or exposure to the elements [10]. In addition to its sedating properties, xylazine can also cause severe skin ulcers in humans, regardless of route of use (e.g., injection, smoking, snorting) [2, 11]."

"The number of opioid NPS found on markets worldwide grew from just one substance in 2009 to 14 in 2015, 56 in 2019 and 87 in 2020,²⁰ by which time synthetic opioids had become the third most numerous group of NPS in terms of the number of different substances reported by Member States in 2020 (after NPS stimulants and NPS cannabinoid receptor agonists and slightly ahead of NPS hallucinogens).²¹ Synthetic opioids accounted for the highest number of NPS identified for the first time at global level in 2020, with 22 new substances (29 per cent of those identified), including both fentanyl analogues and other opioids. Although fentanyl has been under international control since 1964 and a number of fentanyl analogue medicaments were scheduled in the 1980s (sufentanil, alfentanil and 3-methylfentanyl) and in the 1990s (thiofentanyl and remifentanil), a far larger number of fentanyl-type NPS (i.e. fentanyl analogues without any recognized medical use) emerged in the 2010s.²²

"The number of NPS categorized as “other substances” has also continued to grow. "Other substances" include synthetic NPS that do not belong to a precise category, in particular NPS with sedative and hypnotic effects, most of which are benzodiazepine-type NPS.²³ Benzodiazepine-type NPS are often sold at very low prices, sometimes in packages mimicking existing medicines, have varying dosages of active ingredients and contain contaminants, including highly potent synthetic opioids.²⁴

"The current trend towards the use of high potent synthetic opioids, especially fentanyl, has caused an extreme increase in the prevalence of non-fatal and fatal overdose events [13, 14]. However, the trend towards higher opioid potency is still ongoing, with several analogues and novel opioids becoming increasingly available. Particularly carfentanil, an analgesic used in veterinary medicine to anesthetise elephants, provides reason for concern. It is estimated to be around 10’000 times more potent than morphine. In 2021, 8% of all illicit drug toxicity deaths in British Columbia (BC) Canada involved this agent [14, 15]. Furthermore, benzimidazole opioids or “nitazenes” emerged in North America and have since gained a foothold in its drug street markets [16, 17]. Nitazenes and their analogues can exceed the potency of fentanyl by a factor of ten and their availability is steadily increasing [18]. For example, isotonitazene was identified in Canadian drug seizures 12 times in 2019, a number that increased to 288 times in 2021 [19]."

"Xylazine is a veterinary tranquilizer, which is not approved for human use in the United States, but is commonly used for sedating large animals (Reyes et al., 2012; Ruiz-Colón et al., 2014). Although human intoxication with xylazine has been reported sporadically over the past several decades in a number of case studies (Ruiz-Colón et al., 2014; Forrester, 2016), it was first described as a more prevalent additive in the unregulated drug supply of Puerto Rico (Reyes et al., 2012; Rodríguez et al., 2008; Torruella, 2011). It was also noted in the literature describing drug overdose deaths in Philadelphia as early as 2006, yet it did not appear in high prevalence at that time (Wong et al., 2008). However, since the mid-2010s, xylazine has been noticed by people who inject drugs (PWID) and public health practitioners as an increasingly commonplace additive in the street opioid supply of Philadelphia (Johnson et al., 2021). Further, recent reports from Connecticut implicated xylazine in a rising fraction of overdose deaths in 2019–2020 (Nunez et al., 2021; Thangada, 2021). A report released in September 2021 leveraged data from 38 states and Washington DC representing the year 2019, and found xylazine to be present in 1.8% of overdose deaths (Kariisa, 2021). However, no time trends were provided, and results were not disaggregated below the level of US Census Region, with limits the usefulness of the results for frontline providers and harm reductionists. Additionally, reports from Philadelphia and Connecticut, as well as media reports from numerous cities, suggest that xylazine-present overdose have increased sharply in 2020–2021."

"The NPS phenomenon remains a considerable challenge due to its evolving nature. The range of compounds currently on the drug market is constantly changing, with new and previously unknown substances entering the market every year. Despite the implementation of regulatory countermeasures and the development of extensive early warning systems and their adaptation to the current situation, NPS including synthetic cathinones are still available and widespread [78, 79]. One of the potential reasons for the continuous phenomenon of NPS is the lack of international consensus on the legal control of these drugs despite the existence of a common basis for UN member countries, namely the three International Drug Control Conventions: the 1961 United Nations Single Convention on Narcotic Drugs, the 1971 United Nations Convention on Psychotropic Substances, and the 1988 United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances. Different legislative approaches in each country affect local drug market appearance and control, and may contribute to different dynamics of developing NPS situations in different regions of the world [80, 81]. Some countries base their drug policy on individual listing, some on generic legislation or analog control, and in many countries there is a hybrid system drawing on solutions from different legislative approaches [81,82,83,84]. In 2013, the UNODC established an Early Warning Advisory (EWA) as a response at the global level to the increasing prevalence of NPS [85]. Since its launch in 2013 until the beginning of 2022, a total of 136 countries had reported a total of over 1100 individual substances [86]. Furthermore, at the European level, EMCDDA had monitored around 830 NPS at the end of 2020, 46 of which had been detected for the first time in Europe in 2020 [87]. In recent years, the number of substances reported in Europe has remained more or less constant at 400 compounds each year. In 2019, synthetic cathinones (156 compounds) were the second most numerous group after synthetic cannabinoids (209 compounds); these categories accounted for almost 60% of the number of seizures in EU Member States [87]."

"The trend towards higher potency is likely most indicative of what to expect from future illicit substance market developments. According to Canadian drug seizure statistics heroin is no longer among the top ten recovered illegal substances [32, 40]. Fentanyl is currently the most-seized opioid but likely in the process of being replaced with even more potent synthetic opioids [10, 11]. This trend is exemplified by the fact that carfentanil is now being found more frequently than heroin during drug seizures [40]. Fentanyl’s evolutions to the drug of choice demonstrates how the market supply itself can define and change drug use patterns [10]. Although there is currently no clear indication of individuals specifically seeking and prioritising nitazenes or fentanyl-analogues over fentanyl, these substances have the potential of becoming the drug of choice in the near future. The transition to ultra-potent synthetic opioids could resemble the one that happened 5 years ago with fentanyl. That is, individuals who use opioids will be gradually exposed to these drugs, as the fentanyl sold will be cut, knowingly or unknowingly to the individuals using it [11, 45]. The exposure to these substances will likely lead to increased tolerance, and fentanyl alone may no longer provide the sought after physical and psychological effect it once did. This allows agents that are initially perceived to be contaminants to become to the drug of choice. Notably, a shift towards less potent and less dangerous substances has to date not been observed either in opioid markets or in other substance classes, making this development seem unidirectional and irreversible."

"At least a decade after Xylazine became a fixture in Puerto Rico, it entered the street opioid supply in Philadelphia as a more prevalent additive in the mid-2010s. The shift was noted by PWID, as well as harm reductionists and city public health officials (Johnson et al., 2021). PWID began to describe xylazine – often referred to as tranq – as a known element of specific ‘stamps’ or brands of opioid products in the illicit retail market. Opioid formulations containing xylazine, (e.g.,“tranq dope”) became largely sought-after, as the addition of xylazine was reported to improve the euphoria and prolong the duration of fentanyl injections, in particular, solving “the problem” of the “short legs” of the otherwise euphoric effects of illicitly manufactured fentanyl."

"Fentanyl test strips (FTS) emerged in this context as a drug checking tool to address the burgeoning fentanyl crisis. FTS was originally developed as a field immunoassay to screen for the presence of fentanyl in urine, but harm reduction organizations discovered that FTS can also detect fentanyl in illicit drug solutions. This realization has led many harm reduction organizations to distribute FTS to people who consume street opioids as an off-label approach to test street drugs for fentanyl (Peiper et al., 2019). Research published during this early period exposed a growing concern of unwitting fentanyl exposure among heroin consumers and a general willingness to use FTS. Studies showed a high percentage of PWID were interested in using FTS to test heroin (Allen et al., 2020; Krieger, Goedel, et al., 2018; Park et al., 2021; Sherman et al., 2019) and syringe services programs were making them increasingly available alongside naloxone in OD prevention kits (Beharie et al., 2023).

"Of particular significance were a handful of studies showing PWID modifying their drug use behavior upon receiving positive FTS results (Goodman-Meza et al., 2022; Krieger, Goedel, et al., 2018; Peiper et al., 2019). Notably, a community-based study in North Carolina found that PWID with positive FTS results had 5 times higher odds of practicing safer drug use compared to PWID with negative results (Peiper et al., 2019). Similar studies arrived at comparable effects and together confirmed that PWID were willing to use FTS and initiate risk reduction behaviors when consuming fentanyl (Park et al., 2020, 2021)."

"This study is the first, to our knowledge, to document the clinical sequelae and naloxone administration for patients who were in the ED following confirmed NPO drug OD. The NPO group was administered a statistically significantly higher number of in-hospital naloxone boluses compared with the fentanyl group, which corresponded to a moderately large effect size. While these findings were based on limited sample sizes, we detected a large effect size for the association between increased naloxone doses and NPO overdose. The majority of patients with ODs that involved NPO received 2 or more doses of naloxone, whereas most of the patients who OD from fentanyl only received 1 dose of naloxone. While this study was statistically underpowered to detect differences in naloxone administration in total cumulative dosage and clinical sequelae between patients with NPO and fentanyl only OD, this study provides important preliminary data on NPOs to inform clinicians and patients of the severity of ODs involving NPOs. Furthermore, this preliminary data underscores the urgent need to study NPOs in a larger, future cohort. These data suggest that NPOs may have higher potency than fentanyl and by extension heroin.

"NPOs, such as nitazenes and brorphine, are relatively new to the illicit opioid supply but may have significant clinical implications based on the findings of the present study. The nitazene drug class is structurally unrelated to fentanyl but has been found to be up to 1000-fold more potent than morphine.1 Isotonitazene and brorphine are 2 of the NPOs that emerged as novel psychoactive substances (NPS) in 2019 and 2020, respectively. Brorphine was initially created in 2018 and first noted on the recreational drug market in 2019.8 Nitazenes and brorphine have consistently demonstrated stronger in vitro μ-opioid receptor activation than fentanyl1 but until now translation of these findings to the clinical setting has been difficult.

"In general, naloxone dosing was high in both groups studied, which may have been influenced by the prehospital administration of 2 mg naloxone intranasally in most regions studied. In the present study, most patients in the NPO group required multiple doses of naloxone. However, the fentanyl only group received almost 50% more naloxone than the NPO groups. Thus, while the present study was underpowered to calculate statistically significant differences in cumulative naloxone administration, true population differences may exist and require further study.

"NPOs have higher μ-opioid receptor activation than morphine and fentanyl, which has previously been demonstrated by an in vitro study which pharmacologically evaluated 10 nitazenes using 2 cell-based β-arrestin2/mini-Gi recruitment assays monitoring μ-opioid receptor activation.1 In addition, there appear to be differences within each drug in the nitazene class. In the present study, metonitazene appears to have the most severe clinical toxicity given that both patients in which metonitazene was detected presented in cardiac arrest, and 1 patient died."

"This study presents an independent, laboratory-based assessment of the potential of the first commercially available NTS for drug checking applications. The NTS displayed limited lot-to-lot variability, with an experimental limit of detection for isotonitazene of 2000 or 3000 ng/mL. Twenty-four of the 33 evaluated nitazene analogues cross-reacted with the NTS at concentrations at or below 9000 ng/mL. The test strips consistently detected the presence of a nitazene analogue in 6 authentic drug samples. Based on our cross-reactivity data, most of the currently circulating nitazene analogues, except for ‘desnitazenes’, are likely detectable with the BTNX NTS, while analogues with a lengthened linker between the aromatic groups may not be detectable. Altogether, taking into account limitations that hold true for test strip-based testing in general, and taking into account the cross-reactivity data presented here, the findings from this study indicate that the BTNX nitazene immunoassay test strips show potential to recognize the presence of nitazene analogues in drug preparations in real-life settings."

"Xylazine is a non-opiate sedative, analgesic, and muscle relaxant that shares its drug class (α2-adrenoreceptor agonists) with medications such as clonidine, lofexidine, tizanidine, and dexmedetomidine [6]. It was initially developed as an antihypertensive agent by Farbenfabriken Bayer AG in 1962; however, subsequent testing revealed severe adverse events related to hypotension and central nervous system (CNS) depression [6, 7]. Consequently, xylazine never gained approval for human use; however, it was approved by the US Food and Drug Administration (FDA) in 1972 exclusively for use in veterinary medicine [6, 7]. At present, xylazine remains unregulated under both the Controlled Substances Act (CSA) in the USA [8] and the Controlled Drugs and Substances Act (CDSA) in Canada [9].

"Fatal xylazine-positive overdoses, often co-occurring with synthetic compounds such as IMF and its analogs, surged dramatically in the past decade in North America. These overdoses have increased approximately 12-fold between 2018 and 2021 in the USA [6]. Importantly, naloxone—an opioid antagonist medication that is safe and effective for reversing opioid-induced respiratory depression during overdose—does not directly address the effects of xylazine as it is not an opioid, thereby introducing new challenges regarding overdose response best practices within clinical- and community-based settings [8, 10]. Altogether, this pressing issue has prompted The White House Office of National Drug Control Policy (ONDCP) to designate fentanyl associated or adulterated with xylazine (FAAX) as an emergent health threat to the USA in April 2023 and issue a comprehensive response plan in July 2023 [11, 12]. Similar cases are also on the rise in Canada and other countries such as the UK, marking the first xylazine-involved overdose outside of North America [9, 13]. Against the backdrop of this global health crisis, it is imperative to renew efforts in delivering evidence-based public health and harm reduction programs to facilitate secondary and tertiary prevention of adverse health outcomes following xylazine exposure."

"Here, we report the first xylazine dose-response locomotor study in male and female mice as well as the first assessment of adrenergic- and opioid-receptor antagonist-precipitated withdrawal symptoms following, xylazine, fentanyl, and xylazine/fentanyl administration in mice. These experiments show that male and female mice are differentially sensitive to xylazine. We find female mice are less sensitive to the motor-suppressing effects of xylazine contrary to the recent findings in rats reported by Khatri et al. (2023), potentially due to their use of repeated dosing of xylazine or species differences [27]. Using a modified version of our 3-day precipitated withdrawal model [40,41,46], we show xylazine is indeed responsive to naloxone, contrary to common assumptions made by both health professionals and in the media [7]. Both sexes exhibited some level of somatic withdrawal behaviors to xylazine and naloxone, though females showed sensitized behavioral responding. Indeed, females appear to be as sensitive, if not more sensitive to xylazine withdrawal than fentanyl withdrawal at tested doses, while males remain much more responsive to fentanyl withdrawal conditions. At the doses tested in our study, the effect of naloxone precipitated withdrawal on xylazine/fentanyl combination was synergistic as compared to each drug in isolation. This was especially apparent when examining increased bouts of paw tremors, which may represent a more passive coping behavior that we have previously observed is sexually dimorphic in opioid withdrawal [41]. In contrast, we did not observe similar findings when withdrawal was precipitated by atipamezole, an α2-AR antagonist used anesthesia reversal in veterinary medicine. These intriguing findings led us to consider the possibility of direct xylazine activity on opioid receptors. Previous studies have shown that xylazine is antinociceptive, results in a cross-tolerance to some mechanisms of opioid induced antinociception, and that these effects are naloxone-sensitive, but surprisingly not sensitive to the κOR selective antagonist nor-BNI [57–60]. Congruent with this data, we did not observe significant expression of withdrawal behavior to nor-BNI precipitated withdrawal, and pretreatment with nor-BNI exacerbated naloxone precipitated withdrawal in female mice. Until now, xylazine was thought to exert these effects through promotion of endogenous opioid release and xylazine has not been directly tested as a potential opioid agonist. We are the first to report definitive evidence that xylazine acts as a full agonist at κOR and is biased towards G-protein signaling pathways."

"Importantly, our results show that evidence of injection was more prevalent among decedents with xylazine and heroin and/or fentanyl detections. Despite limited literature on the health effects of chronic xylazine use, regular injection of xylazine has been associated with skin ulcers, abscesses and lesions in Puerto Rico.^{2 3} Semistructured interviews with people who use xylazine in Puerto Rico revealed that regular use of xylazine leads to skin ulcers.⁴ As skin ulcers are painful, people may continually inject at the site of the ulcer to alleviate the pain as xylazine is a potent α2-adrenergic agonist that mediates via central α2-receptors, which decreases perception of painful stimuli.¹ People may self-treat the wound by draining or lancing it, which can exacerbate negative outcomes.⁸ While Philadelphia has seen a rise in skin and soft tissue infections relating to injection drug use, it is not yet clear whether or not this is due to increased presence of xylazine in the drug supply.⁹"

"Clinical and public health responses to date have focused on acute toxicity from NPS. This attention has grown in previous years with the increased reportings of overdose associated with NPS in several countries. Current examples include rising mortality from benzodiazepine NPS in Scotland (etizolam implicated in 57% of all drugrelated deaths in 2018);¹²³ opioid NPS in North America (fentanyl analogues detected in 20·6% of opioid overdose deaths occurring between July, 2016, and June, 2017, in 10 US states);³³ and from synthetic cannabinoids in New Zealand (reportedly in excess of 40 deaths linked to synthetic cannabinoids in 2017–18).¹²⁴

"In almost all clinical situations of acute toxicity, there is a restricted capacity for rapid confirmation of NPS to inform management: many rapid testing measures are not sensitive to NPS and cannot keep pace with new substances. Current guidance from the Novel Psychoactive Treatment UK Network (NEPTUNE) recommend diagnosis on the basis of clinical assessment and recognition of the clinical toxidrome given that most NPS have similar effects to the more established illicit drugs they are intended to mimic (synthetic cannabinoids being a notable exception).^13,14,125 The NEPTUNE guidelines recommend symptomatic and supportive management, particularly in the absence of research on the management of acute toxicity for the varied NPS.^13,14,125 The exception is opioid NPS overdose, for which the relative higher potency of some opioid NPS might require changes in clinical management. For example, clinical guidance based on reports from fentanyl analogue overdoses suggest some cases might require higher doses of naloxone, rapid escalation of naloxone dosing, and a longer observation period in a hospital setting than other opioids.¹²⁵"

"The phenomenon of new psychoactive substances (NPS) is an ongoing problem in modern forensic toxicology. One of the most important groups among NPS are synthetic cathinones, which are derivatives of cathinone, a natural alkaloid found in the shrub Catha edulis. This substance has been shown to have psychoactive properties, with a widespread centuries-old tradition among the Arabian Peninsula population of chewing the leaves of this plant for recreational purposes [1,2,3]. The last decade has been characterized by a remarkable dynamism of change in the illicit drug market with the constant introduction of new substances synthesized to circumvent regulation. This phenomenon has also applied to synthetic cathinones [4,5,6]. Due to the highly variable nature of the NPS phenomenon, the latest emerging derivatives are largely unknown in terms of their pharmacological properties and toxicity; hence, most of the relevant information is obtained from reported cases of both fatal and non-fatal intoxication [7,8,9]."

"In general, synthetic cathinones are classified as stimulants or amphetamine-type stimulants [109, 110]. However, the pharmacological effects of individual derivatives are strictly dependent on the type of substituents and their location, and the differences in pharmacological profiles between individual cathinone derivatives are considerable. The range of pharmacological profiles of cathinone derivatives varies from those resembling MDMA and cocaine in action, through cathinone derivatives possessing methamphetamine-like psychostimulant effects, to highly dopaminergic pyrovalerone cathinone derivatives [110, 111]. The structure differs depending on the lipophilicity and steric expansion, which affects the pharmacokinetic aspects, but also the key interaction with monoamine transporters (MATs) in the central nervous system [112, 113]. The main systems involved are dopaminergic, serotonergic and noradrenergic, and the main mechanism of their modulation is the interaction with particular transporters, including dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). Synthetic cathinones alter neurotransmitter concentrations by acting as MAT inhibitors or substrates, inducing efflux of endogenous neurotransmitters [110, 111, 114]. Dopaminergic activity is mainly associated with stronger reinforcing effects and abuse liability. In contrast, serotonergic activity is identified with entactogenic effects similar to those of MDMA [111,112,113, 115, 116]. Pyrrolidine cathinone derivatives are particularly potent dopaminergic, while methylone, similar in structure to MDMA, exhibits serotonergic effects; cathinone derivatives substituted at the phenyl ring in the para position also exhibit comparable activity [117]. The strength of action on the noradrenergic system is more or less equal among particular synthetic cathinones; therefore, the main factor distinguishing the action of particular derivatives is selectivity toward DAT and SERT [111]. Depending on the structure of the derivative, the interaction with individual monoaminergic systems is characterized by different strength and selectivity, which translates into desired effects and intoxication symptoms. The main effects of cathinone use include symptoms from the cardiovascular system such as tachycardia and increased blood pressure, and from the nervous system such as euphoria and motor excitation, as well as hyperthermia [7, 118,119,120,121]. In addition to psychostimulant effects, some synthetic cathinones may have hallucinogenic properties similar to MDMA. Synthetic cathinones possessing high selectivity toward the serotonin system may lead to a dangerous serotonergic syndrome resulting from excessive activation of 5-HT2A receptors. Most often, however, the appearance of this type of intoxication results from combined drug intoxication, mainly in combination with selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) [7, 122, 123]."

"Synthetic cannabinoid receptor agonists (hereafter synthetic cannabinoids) are a chemically diverse group of synthesised compounds that often act on similar receptors to those acted on by Δ-9-tetrahydronnabinol in cannabis. Powders are typically dissolved in solvent, sprayed on inert plant material and then smoked, and are often sold as commercial mixtures (eg, Spice, Kronic).¹² Other forms and routes of administration include ingestion of pills or powders, and vaping using solutions containing synthetic cannabinoids. Effects can be similar to those resulting from use of cannabis (eg, euphoria, sedation, and drowsiness), but are typically more severe and sometimes unique from cannabis.¹³"

"Stimulant NPS are drugs with similar effects to amphetamine, cocaine, and 3,4-methylenedioxymethamphetamine (MDMA), which result in increased alertness, energy, confidence, and sociability, and suppression of appetite and fatigue (eg, mephedrone, methylone, α-PVP).¹⁴ They are typically in a powder, capsule, tablet, liquid, or crystal form, and are primarily consumed by swallowing or snorting, as well as by injecting."

"Hallucinogen NPS are a diverse group of substances that alter an individual’s awareness of their surroundings, as well as their thought processes and perception, which can lead to substantial distortions of reality. They can be divided into two main types: dissociatives, which induce euphoria alongside a feeling of weightlessness and detachment from the body; and classic hallucinogens, which produce altered perception,¹⁵ causing cognitive and visual disturbances and an altered state of consciousness. Dissociative NPS (eg, methoxetamine) have similar effects to ketamine; psychedelic NPS (eg, 2C drugs, NBOME drugs) have similar effects to lysergic acid diethylamide (LSD) and natural products like psilocybin, but these effects can vary in duration, intensity, and type of experience. Hallucinogen NPS might be a powder, liquid, tablet, or capsule, or on blotter paper, and depending on the drug, are mostly swallowed, snorted, smoked, or injected."

"Harms of xylazine use in humans are not well documented, but evidence suggests that combined use of xylazine and an opioid such as fentanyl may increase the risk of overdose fatality.¹ Although naloxone, the opioid overdose reversal drug, is not effective against xylazine alone, unintentional fatal overdoses with xylazine detections also had heroin and/or fentanyl detections in Philadelphia, indicating timely administration of naloxone is critical for preventing deaths. Additional treatment for xylazine poisoning may involve supportive care using intubation, ventilation and administration of intravenous fluid.¹

"Of note, as fentanyl has largely replaced the heroin supply in Philadelphia, xylazine has been increasingly found in combination with fentanyl. Some evidence suggests that the combination of xylazine and fentanyl in humans may potentiate the desired effect of sedation and the adverse effects of respiratory depression, bradycardia and hypotension caused by fentanyl alone,¹ comparable to the synergistic effects of combining benzodiazepines with heroin and/or fentanyl.⁷ While benzodiazepines were detected in 97 (58%) of the 168 unintentional overdose deaths with heroin and/or fentanyl detections in Philadelphia in 2010, this decreased to 232 (28%) of the 858 unintentional overdose deaths with heroin and/or fentanyl detections in 2019. This decline may be the result of increasing demand for xylazine among people who use drugs in Philadelphia and/or changes in the illicit drug market as drug seizure data indicate that xylazine is increasing in polydrug samples. Indeed, focus groups with people who use drugs in Philadelphia have suggested that the addition of xylazine to fentanyl “makes you feel like you’re doing dope (heroin) in the old days (before it was replaced by fentanyl)” when the euphoric effects lasted longer."

"Depressant NPS encompass two main types of CNS depressants: opioids, which cause analgesia, euphoria, drowsiness, and sedation (eg, fentanyl analogues); and benzodiazepines, which have sedative, anxiolytic, hypnotic, muscle-relaxant, and anticonvulsant effects (eg, etizolam, phenazepam).¹⁵ These NPS can be sold under their own name, but have also been detected as counterfeit prescription medicines (eg, in tablets or capsules), or adulterated with or sold as more established illicit drugs (eg, in powder form).¹⁶ They are mostly swallowed, snorted, or injected. Some depressant NPS are prescribed medicines in some countries (the benzodiazepine NPS etizolam is a prescription drug in Japan)¹⁷ or have other legitimate uses (the opioid NPS carfentanil is used as a tranquiliser in veterinary contexts and as a selective radiotracer in positron emission tomography).¹⁸"

"In the operating guidelines on the early warning system, EMCDDA [European Monitoring Centre on Drugs and Drug Addiction] made it explicit that 'the term ‘new’ did not refer to newly invented, but rather ‘newly misused’' substances as 'most of the drugs in question were first created many years ago.'²⁰ In fact, investigations into the potential use of piperazines as anthelmintic have been reported in scientific literature since the early 1950s.²¹ Yet they only started to emerge as a health problem in several countries in the decade 2001-2010. Similarly ketamine, which was first developed in the mid-1960s, started to emerge as a health problem in that decade in several countries of East and South-East Asia. Mephedrone was first synthesized in 1929 but was rediscovered only in 2003 and reached the markets towards the end of the decade 2001-2010.²²

"NPS also include plant-based substances that have existed for centuries. In the profiles of 'new drugs', EMCDDA lists plant-based substances such as Salvia divinorum and khat. Khat has been known for hundreds of years in the countries around the Horn of Africa and the southern parts of the Arabian peninsula. However, it is considered to be a new substance in a number of European and American countries, as its use was barely known in those regions until one or two decades ago. The same applies to Salvia divinorum, kratom, and various hallucinogenic mushrooms, which are all considered to be NPS.²³ Using the definition 'newly misused on the market', the overwhelming number of non-controlled psychoactive substances can be regarded as NPS, as there will always be some countries in which they have not been misused before."

"We summarize longitudinal, recent, and geographically specific evidence describing how xylazine is increasingly implicated in overdose deaths in jurisdictions spanning all major US regions and link it to detailed ethnographic observations of its use in Philadelphia open-air narcotics markets. Xylazine presence in overdose deaths grew exponentially during the observed period, rising nearly 20-fold between 2015 and 2020. Whereas the most recent national data from the State Unintentional Drug Overdose Reporting System characterized the level of xylazine-present overdoses in 2019 (Kariisa, 2021), we found that the prevalence increased by nearly 50% from 2019 to 2020 alone, indicating a need for more recent data to guide the public health response. Furthermore, we find that even looking at only 10 jurisdictions a greater number of xylazine-present overdose deaths were seen in 2020 (854), than the previous study looking at 38 states in 2019 (826) (Kariisa, 2021), implying a very fast rate of growth nationally.

"Xylazine prevalence was observed earliest and at the highest magnitude in the Northeast, and may be spreading west, in a pattern similar to the trajectory of illicitly-manufactured fentanyls in recent years (Shover et al., 2020). This similarity may not be incidental, as an analysis of the co-occurrence of fentanyl and xylazine indicates a strong ecological link, with fentanyl nearly universally implicated in xylazine-present overdose deaths. Further, ethnographic data among PWID suggests that the use of xylazine as an illicit drug additive may predominantly serve as a response to the short duration of fentanyl. By ‘giving fentanyl legs’—offering improved duration of effect—the addition of xylazine may confer a competitive market advantage for illicit opioid formulations that contain it, as it remedies one of the most commonly expressed complaints that PWID hold regarding fentanyl-based street opioid formulations."

"A total of 142 unique CEs [Cognitive Enhancers] were identified by NPSfinder®. They were divided into 10 categories, including plants/herbs/products (29%), prescribed drugs (17%), image and performance enhancing drugs (IPEDs) (15%), psychostimulants (15%), miscellaneous (8%), Phenethylamines (6%), GABAergic drugs (5%), cannabimimetic (4%), tryptamines derivatives (0.5%), and piperazine derivatives (0.5%). A total of 105 chemically different substances were uniquely identified by NPSfinder®. Only one CE was uniquely identified by the EMCDDA; no CE was uniquely identified by the UNODC."

"Overall, an average of 2.5% of the students had used NPS at least once in the last 12 months, with the highest prevalence reported in Czechia, Latvia, Estonia, Poland and Monaco (4.0-4.9%) and the lowest prevalence reported in North Macedonia, Finland and Portugal ( 0.4-0.8%; Figure 10a). Generally, differences in NPS use between boys and girls were small; however, significantly more boys than girls reported the use of NPS in Cyprus, Georgia, Greece, Ireland, Montenegro, Norway and Serbia, and significantly more girls than boys reported the use of NPS in Latvia and Slovenia (Figure 10b).

"Among all students who had used NPS in the last 12 months, the majority (54%) reported use of herbal synthetic substances; 27% reported use of NPS in the form of powders or tablets, 13% reported the use of NPS in the form of liquids and 17% reported the use of NPS in other forms. Only a few countries reported higher rates of use of NPS in forms other than herbal smoking mixtures. In particular, powders/tablets were used by the majority of last-year NPS users in Finland (64%) and Norway (54%), liquids were reported by 36% of the users in the Netherlands, and the use of NPS in other forms was reported by half of the users in North Macedonia. Even though on average the differences between boys and girls in the reported appearance of NPS used in the last 12 months were low, in most individual countries noticeable gender differences were found. Focusing only on differences higher than 15 percentage points, with regard to herbal NPS, boys reported higher prevalence rates than girls in Romania, Georgia, Finland, Ireland and the Netherlands, while girls reported higher rates in Bulgaria, Ukraine, Slovakia and Lithuania; for powders/tablets, girls reported higher prevalence rates in many countries (Kosovo, Georgia, Slovakia, Serbia, Spain, Sweden, Ireland and Portugal), while a higher rate was found among boys in Cyprus; and higher prevalence rates were found for liquid forms of NPS among male users than female users in Portugal, Slovakia, Sweden, Lithuania and North Macedonia, with girls reporting higher rates in the Netherlands and Finland (see Additional Table 71a and b)."

"Xylazine, an alpha-2 receptor agonist, is used in veterinary medicine as a sedative and muscle relaxant; it is not approved for use in humans. However, reports of adulteration of illicit opioids with xylazine have been increasing in the United States (1–3). In humans, xylazine can cause respiratory depression, bradycardia, and hypotension (4). Typical doses of naloxone are not expected to reverse the effects of xylazine; therefore, persons who use xylazine-adulterated opioids are at high-risk for fatal overdose. Although some regions of the United States have reported increases in xylazine-involved deaths, xylazine was involved in <2% of overdose deaths nationally in 2019 (2,5). Most xylazine-involved deaths are associated with fentanyls, including fentanyl analogs (1,5)."

"Prior to the widespread availability of xylazine in the Philadelphia drug supply, it was often mentioned in passing by residents of the majority Puerto Rican neighborhood where our fieldwork was based as a powerfully psychoactive additive ‘“back on the Island”.’ Xylazine was occasionally detected in fatal overdoses in Philadelphia as early as 2006 (Wong et al., 2008), but it was not common knowledge among PWID. Significantly, however, many of our long-term informants recently immigrating/returning from Puerto Rico spoke with a mix of intrigue and apprehension about the psychoactive effects and health risks of 'anastesia de caballo [horse tranquilizer]'."

"At least a decade after Xylazine became a fixture in Puerto Rico, it entered the street opioid supply in Philadelphia as a more prevalent additive in the mid-2010s. The shift was noted by PWID, as well as harm reductionists and city public health officials (Johnson et al., 2021). PWID began to describe xylazine – often referred to as tranq – as a known element of specific ‘stamps’ or brands of opioid products in the illicit retail market. Opioid formulations containing xylazine, (e.g.,'tranq dope') became largely sought-after, as the addition of xylazine was reported to improve the euphoria and prolong the duration of fentanyl injections, in particular, solving 'the problem' of the 'short legs' of the otherwise euphoric effects of illicitly manufactured fentanyl."

"In overdose data from 10 jurisdictions – representing all four major US census regions – xylazine was found to be increasingly present in overdose mortality (Fig. 1). The highest prevalence was observed in Philadelphia, (with xylazine present in 25.8% of overdose deaths in 2020), followed by Maryland (19.3% in 2021) and Connecticut (10.2% in 2020). In 2021, xylazine prevalence also grew substantially in Jefferson County, Alabama, reaching 8.4% of overdose fatalities. Across the four census regions, the Northeast had the highest prevalence, and the West had the lowest (Fig. 2), with only six xylazine-present overdose deaths in total detected in Phoenix, Arizona, and 1 in San Diego County, California. Across jurisdictions, a clear increasing trend was noted. Pooling data for 2015, a total xylazine prevalence of 0.36% was observed. By 2020, this had grown to 6.7% of overdose deaths, representing a 20-fold increase. From 2019–2020 – the last year of data available for all jurisdictions – the prevalence increased by 44.8%."

"Cognitive enhancement may be defined as “the amplification or extension of core capacities of the mind through improvement or augmentation of internal or external information processing systems” (1). Both non-pharmacological and pharmacological enhancers are sought by the general public in order to improve performance during studying and at work by increasing concentration, motivation and accuracy, via physical, behavioral and biochemical activities (2).

"Cognitive enhancer drugs (CEs) are also known as “nootropics” (from the Greek ‘nous’ meaning ‘mind’ and ‘trepein’ meaning ‘turning/bending’), a term initially penned by Corneliu Giurgea when piracetam was found to exhibit memory-enhancing properties in clinical trials (3, 4). Cognitive enhancer drugs such as modafinil improve cognition in very specific ways such that it enhances “pattern recognition memory, digit span recall, and mental digit manipulation” (5)."

"The prevalence of homelessness globally is estimated to be roughly 150 million individuals at any given time (Busch-Geertsema et al., 2016). In the UK, recent data from the Shelter organisation estimated that 320,000 people were homeless in 2019/2020 (Bramley & Fitzpatrick, 2018). Problematic drug use among this population has been extensively documented in the scientific literature (O'Flaherty et al., 2018; Paudyal et al., 2017; Van den Bree et al., 2009; Krupski et al., 2015; Linton et al., 2013; Narendorf et al., 2017). Homelessness and drug misuse often coexist, and the recorded prevalence of drug use among homeless individuals in different countries is consistently above the national average (Doran et al., 2018; Johnson & Chamberlain, 2008; Krupski et al., 2015). Although the high prevalence of traditional drugs has been extensively documented within the homeless population, NPS have become an increasing risk to this population, with particular concern regarding the use of synthetic cannabinoid receptor agonists (SCRAs) due to their underdefined toxic effects, difficulty in treating them and lack of confidence from clinicians (Sulaiman and MP, 2019; Thornton, 2018; Williams, 2017)."

"NPSfinder® identified 35 molecules (out of the total of 4,204) that were described by psychonauts as having cognitive enhancing effects, such as improved memory, alertness, attention, and concentration. A further 107 molecules were previously described as CE (7–9), although psychonauts did not explicitly describe them as CE. Since psychonauts experiment with novel substances in order to intentionally experience altered states of consciousness, it is to be expected that their interest also extends to the world of CEs. Among the CEs that they have been discussing online, there are mostly molecules that are known to have nootropic properties, are not illegal, and are likely to be easily available on the market (such as racetam compounds, modafinil and its derivatives, methylphenidate and its derivatives and food supplements). Our results showed that NPSfinder® could be employed as an Early Warning System tool to help clinicians with keeping their knowledge up-to-date with the growing numbers and types of nootropics in the increasingly difficult-to-follow online market."

"Xylazine is currently not a scheduled substance under the United States Controlled Substances Act, though some efforts are underway to change this (Drug Enforcement Administration, 2021; Murphy, n.d.). However, supply side efforts to control xylazine adulteration of fentanyl/heroin are unlikely to work and – similar to trends seen when trying to decrease the availability of alcohol, cannabis, and cocaine – will likely exacerbate adulteration (Cowan, 1986). Xylazine test strips, by contrast, are a demand-driven response to unwanted adulterants and may be able influence the composition of the drug supply if xylazine is linked to specific stamps (i.e., how fentanyl/heroin products are branded in Philadelphia) (Friedman et al., 2022). This new form of drug checking represents a potential tool to further empower PWUD to make informed choices about what and how they consume drugs.

"All participants who spontaneously discussed wanting xylazine test strips, or were asked if they would want them, indicated they would use them to test their fentanyl/heroin before drug consumption, if available. Xylazine test strips are not currently available and, to our knowledge, are not in development. Research is needed from broader monitoring and analysis of the drug supply to determine whether xylazine in fentanyl/heroin is pharmaceutical grade. Additionally, it is important to understand if a xylazine test strip would be capable of detecting any xylazine analogs.

"A xylazine test strip may have the potential to positively impact drug use in a similar manner to fentanyl test strips. Fentanyl test strips have been found to significantly alter drug use behavior and foster safer drug use practices with continued testing. Individuals using fentanyl test strips prior to drug use did so in order to prevent fentanyl overdose and the potential need for emergency interventions (Peiper et al., 2019). Additionally, there have been studies reporting fentanyl test strip use following drug use. Among these individuals, positive results for fentanyl were associated with use of reduced doses on subsequent drug consumption occasions (Karamouzian et al., 2018)."

• "Among young adults (aged 15 to 34), recent national surveys show last year prevalence estimates for both LSD and hallucinogenic mushrooms equal to or less than 1 %. Exceptions for hallucinogenic mushrooms include Czechia (2.7 % in 2021), Finland (2.0 % in 2018), the Netherlands (1.9 % in 2021), Estonia (1.6 % in 2018, 16–34), Denmark (1.5 % in 2021), Spain (1.1 % in 2022) and Germany (1.1 % in 2021). Exceptions for LSD include Ireland (2.4 % in 2019), Finland (2.0 % in 2018), Estonia (1.7 % in 2018, 16–34), Latvia (1.4 % in 2020), Norway (1.3 % in 2021) and the Netherlands (1.2 % in 2021).
• "Among respondents to the European Web Survey on Drugs, 20 % of those who had used drugs within the last 12 months had used LSD, while 13 % had used ketamine.
• "Recent estimates of last year prevalence of ketamine use among young adults (15–34) range from 0.4 % in Denmark (2021, 16–34) to 0.8 % in Romania (2019). The Netherlands reported that ketamine use has increased among young people in nightlife settings.
• "In 2022, generally very low levels of ketamine residues in municipal wastewater were reported by 15 cities, with the highest mass loads being detected in cities in Denmark, Spain, Italy and Portugal (see the figure Ketamine residues in wastewater in selected European cities, 2022, below)."

"In June 2020, the presence of xylazine, a veterinary sedative, was first detected as an active cut in heroin/fentanyl MADDS samples but in very low or trace quantities from 2 sites. By fall 2020, the ratio of xylazine to other active drugs had increased, and by the end of the year, xylazine was identified in 6.3% of MADDS samples (13.4% of fentanyl, 22.2% of heroin) and detected at all sites. At the close of 2020, some samples were found to contain more xylazine than fentanyl (eg, https://DrugsData.org/9661).

"The stimulant supply also exhibited dynamic changes during 2020. In prior work,²¹ FTIR scans of cocaine street samples found few active cuts, the modal cut being levamisole, a deworming agent. However, the 2020 samples exhibited high ratios of phenacetin, an obsolete pain-relieving medication unavailable in the United States. The high ratio of phenacetin found in powder cocaine (eg, https://drugsdata.org/9491) and crack (rock) cocaine samples (eg, https://drugsdata.org/9314) across MADDS sites was of concern because it was unexpected and, if ingested, may have negative health effects for people regularly using cocaine. Phenacetin is a carcinogen and can be harmful to the kidneys,²⁸,²⁹ which is of concern for PWUD. In many drug markets, phenacetin is a common active cut of cocaine. Its presence in 17.1% of cocaine samples and in high ratio (eg, https://drugsdata.org/9588) suggests that cocaine supply chains in Massachusetts were disrupted by SARS-CoV-2. The prevalence of phenacetin might have been to “stretch” the available cocaine supply. Our review of the literature on xylazine and phenacetin prompted an informational bulletin on both substances in early 2021."

"A xylazine-associated death was defined as a positive postmortem xylazine serum toxicology test result in an unintentional, undetermined, or pending intent substance-related death during January 2017–October 2021. Routine postmortem tests were conducted for other substances including fentanyl, fentanyl analogs, cocaine, and naloxone. Xylazine testing is standard in Cook County for suspected drug overdose deaths. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.*

"A total of 236 xylazine-associated deaths were reported during the study period. Xylazine-associated deaths increased throughout the study period; incidence peaked during July 2021 (Figure). The percentage of fentanyl-associated deaths involving xylazine also increased throughout the study period, rising to a peak of 11.4% of fentanyl-related deaths assessed by the Cook County Medical Examiner’s Office during October 2021. Fentanyl or fentanyl analogs were detected on forensic testing in most xylazine-involved deaths (99.2%). Other common co-occurring substances included diphenhydramine (79.7%), cocaine (41.1%), and quinine (37.3%). Naloxone was detected in 32.2% of xylazine-associated deaths."

"The creation of new substances to exploit loopholes in drug control legislation has been a problem since the international drug control system was first established. The proliferation of such substances in recent decades was influenced by the work done by Ann and Alexander Shulgin on phenethylamines⁸ and tryptamines⁹ in the 1960s and the 1970s. The Shulgins reported over 230 psychoactive compounds that they had synthesized and evaluated for their psychedelic and entactogenic potential. More recently, a number of piperazines, synthetic cathinones and synthetic cannabinoids emerged, which were marketed as 'legal' alternatives to controlled substances."

"Reflecting their use as legal replacements for cocaine, amphetamine and other controlled stimulants, there were more than 23 000 seizures of synthetic cathinones reported from across Europe in 2016 (Figure 3). These account for almost one-third of the total number of seizures of new substances over the year, and amounted to almost 1.9 tonnes, making synthetic cathinones the most commonly seized new psychoactive substances by quantity in 2016. The EMCDDA is currently monitoring 130 of these substances, including 14 that were reported for the first time in 2016 and 12 during 2017. Synthetic cathinones are generally found in powder form. The five most commonly seized cathinones in 2016 were alpha-PVP, 4-chloromethcathinone, 3-chloromethcathinone, 4-methyl-N,N-dimethylcathinone and 3-methylmethcathinone. The top five cathinones detected in powders were 4 chloromethcathinone (890 kg), 4-chloroethcathinone (247 kg), N-ethylhexedrone (186 kg), 3-methylmethcathinone (126 kg) and mexedrone (50 kg). In recent years, there have been indications of increasing interest in making synthetic cathinones in Europe, including seizures of precursors, equipment and illicit laboratories used to make mephedrone (which is now under international control), as well as 4-chloromethcathinone and 3-chloromethcathinone."

"Reflecting consumer demand, the market in new benzodiazepines appears to have grown over the past few years. The EMCDDA is currently monitoring 23 of these substances, including six that were reported for the first time in 2016 and three during 2017. While the overall number of seizures reported by law enforcement during 2016 decreased compared with 2015, the quantity reported increased. More than half a million tablets containing new benzodiazepines such as diclazepam, etizolam, flubromazolam, flunitrazolam and fonazepam were reported during 2016 — which was about 70 % more than in 2015. Some of these new benzodiazepines were sold as tablets, capsules or powders under their own names. In other cases, they were used to make fake versions of commonly prescribed benzodiazepine medicines, such as diazepam and alprazolam, and sold directly on the illicit drug market."

"With a total of 38 different opioids reported, the number of synthetic opioids has grown rapidly in Europe since the first substance was reported in 2009. In fact, most of these substances have been reported for the first time during the past two years, with 9 reported in 2016 and 13 during 2017. Although they play a small overall role in Europe’s drug market, many of the new opioids are highly potent substances that pose a risk of life-threatening poisoning because an overdose can cause respiratory depression (slowing down of breathing), which can lead to respiratory arrest (stopping breathing) and death. The public health importance of this risk is reflected in the fact that most deaths involving illicit opioid use are caused by respiratory depression (White and Irvine, 1999). Of particular concern are the new fentanils. These substances currently dominate this group, with a total of 28 reported since they first appeared in 2012.

"Reflecting their small share of the market as well as their high potency, new opioids accounted for only around 2% of the total number of seizures of new substances and about 0.2% of the total quantity reported to the EU Early Warning System during 2016. New opioids are found mainly in powders but also in tablets and, since 2014, liquids. For the most part, seizures are dominated by fentanils. There were around 1,600 seizures of new opioids reported by law enforcement during 2016, of which 70% were related to fentanils. These included 7.7 kg of powders (of which 60% contained fentanils), approximately 23,000 tablets (of which 13% contained fentanils) and 4.5 litres of liquids (of which fentanils accounted for 96% of the total). Some of these liquids are from seizures made by police and customs of nasal sprays, which appear to be growing in popularity as a way of using these substances."

"Alongside their legitimate uses as medicines and in research, the fentanils also have a long history of illicit use as replacements for heroin and other controlled opioids. Between 1979 and 1988, more than 10 fentanils that had been made in illicit laboratories were detected on the drug market in the United States (Henderson, 1991). The first was alpha-methylfentanyl, followed by substances such as 3-methylfentanyl and 4-fluorofentanyl. Typically, they were sold as heroin or ‘synthetic heroin’. Together, these substances were involved in more than 100 deaths, mostly in the state of California. Later, in the mid-2000s, illicitly manufactured fentanyl was sold as heroin or in mixtures with heroin, and was responsible for outbreaks of overdoses that involved hundreds of deaths in the eastern United States (Schumann et al., 2008). It appears that, with the exception of Estonia, where 3-methylfentanyl and fentanyl were responsible for an epidemic of fatal poisonings during this time, these substances caused limited problems elsewhere in Europe (Berens et al., 1996; de Boer et al., 2003; Fritschi and Klein, 1995; Kronstrand et al., 1997; Ojanperä et al., 2008; Poortman-van der Meer and Huizer, 1996).

"Over the past few years, there has been a large increase in the availability of fentanils in the United States, Canada and Europe (Gladden et al., 2016; US CDC, 2015). This has been driven by the opioid epidemics in North America, interest in selling these substances in Europe and broader changes in the illicit drug market."

"Since 2012, a total of 28 new fentanils have been identified on Europe’s drug market. This includes eight substances that were reported for the first time in 2016 and 10 during 2017. During this period, there has also been a large increase in seizures reported by customs at international borders and police at street-level (Figure 4) (see also ‘Reducing the risk of occupational exposure to fentanils’, page 11). While the picture differs widely across Europe, 23 countries have reported detections of one or more of these substances (Figure 5) (2). Reports to the EMCDDA of fatal poisonings have also increased substantially from some countries (EMCDDA, 2016a; EMCDDA, 2017a,b,c,d,e,f,g; EMCDDA, 2018a,b).

"It appears that most shipments of new fentanils coming into Europe originate from companies based in China. Production in illicit laboratories, including in Europe, has also been reported occasionally. Typically, production of fentanyl and other fentanils is relatively straightforward, which adds to the challenges in responding to these substances.

"Like other new substances, one of the reasons behind the increase in these fentanils is that they are not controlled under the United Nations drug control conventions. This means that in many countries they can be manufactured and traded relatively freely and openly — a situation which has been exploited by entrepreneurs and crime groups using companies based in China to make the substances. The fentanils are typically shipped to Europe by express mail services and courier services. From here, they are then sold as ‘legal’ replacements for illicit opioids on the surface web and on the darknet. Unknown to users, they are also sold as heroin or mixed with heroin and other illicit opioids. Occasionally they have also been used to make fake medicines and, less commonly, sold as cocaine (see ‘Fentanils in fake medicines and cocaine’, page 12).

"Fentanils have been found in a variety of physical and dosage forms in Europe. The most common form is powders, but they have also been detected in liquids and tablets. Depending on the circumstances, seizures of powders have ranged from milligram to kilogram quantities. They may be relatively pure, especially when seized coming into the European Union. They may also be mixed with one or more substances. In the latter case, these include commonly used cutting agents (such as mannitol, lactose and paracetamol), as well as heroin and other fentanils/opioids. To a much smaller degree, other drugs, such as cocaine and other stimulants, have also been detected in mixtures with fentanils in Europe. During 2016, more than 4.6 kg of powder containing fentanils was reported, while almost 4.5 litres of liquid and around 2 900 tablets were also reported. Less commonly, fentanils have also been found in blotters and plant material. In these cases, there may be no indication that they contain fentanils, which could pose a risk of poisoning to people who use them."

"Synthetic cannabinoids, also known as synthetic cannabinoid receptor agonists, are a group of drugs that mimic the effects of a substance found in cannabis called tetrahydrocannabinol (THC). THC is responsible for many of the psychoactive effects of cannabis which give that feeling of being ‘stoned’ or ‘high’ (Gaoni and Mechoulam, 1964; Huestis et al., 2001; Pertwee, 2005a; Pertwee, 2014). These effects are caused by activating a receptor in the brain called the cannabinoid receptor type 1 (CB1 receptor) (Huestis et al., 2001; Pertwee, 2014). The receptor is part of a signalling system in the body called the endocannabinoid system, which helps regulate, among other things, behaviour, mood, pain, appetite, sleep and the immune system (Pertwee, 2015).

"Similar to the fentanils, the synthetic cannabinoids were originally developed by scientists to study the body, provide insights into disease and help develop new medicines (Pertwee, 2005b; Reggio, 2009). Around the mid-2000s, they began to appear in Europe in products called ‘Spice’ that were sold as ‘legal’ replacements to cannabis. In these products, powders containing synthetic cannabinoids were mixed with plant material which could then be smoked as cigarettes (‘joints’) (Auwärter et al., 2009; EMCDDA, 2009; Jack, 2009). Since then, 179 cannabinoids have been identified on the drug market in hundreds of different products (Figure 7). The products are commonly referred to as ‘herbal smoking mixtures’, ‘Spice’, ‘K2’, ‘synthetic cannabis’ and ‘synthetic marijuana’. Most of the synthetic cannabinoid powders are made in China, with the final products made in Europe.

"Because synthetic cannabinoids work in a similar way to THC, many of their effects are similar to those of cannabis (Auwärter et al., 2009). Most prominently, they are able to create the feeling of being ‘stoned’. This includes relaxation, euphoria, lethargy, depersonalisation, distorted perception of time, impaired motor performance, hallucinations, paranoia, confusion, fear, anxiety, dry mouth, bloodshot eyes, tachycardia (an abnormally fast heart rate), nausea and vomiting. In some cases, these effects appear to be much more pronounced and severe than those produced by cannabis (Ford et al., 2017; Zaurova et al., 2016)."

"The reasons for the more pronounced psychoactive effects and severe and fatal poisoning seen with synthetic cannabinoids are not particularly well understood, but at least two factors are likely to be important: the high potency of the substances and the unintentionally high doses that users are exposed to.

"Firstly, studies have found that many of the cannabinoids sold on the drug market are much more potent than THC (behaving as so-called ‘full agonists’). This means that even at very small doses they can activate the CB1 receptor much more strongly than THC (Banister et al., 2016; Ford et al., 2017; Longworth et al., 2017a,b; Reggio, 2009; Tai and Fantegrossi, 2017). It is worth noting that little is known about the effects of synthetic cannabinoids on other signalling systems in the body, which may also explain some of the effects of these substances.

"Secondly, the process for mixing the synthetic cannabinoids with the plant material to make smoking mixtures (which are the most common way of using these substances) can lead to dangerous amounts of the substances in the products. This is because producers have to guess the amount of cannabinoids to add, while the mixing process makes it difficult to dilute the cannabinoids sufficiently and distribute them consistently throughout the plant material. This can result both in products that contain toxic amounts of the substances in general, as well as in products where the cannabinoids are clumped together, forming highly concentrated pockets among the plant material (Figure 9) (Ernst et al., 2017; Frinculescu et al., 2017; Langer et al., 2014, 2016; Moosmann et al., 2015; Schäper, 2016). These issues are made worse because the products are smoked (or vaped), allowing the substances to be rapidly absorbed into the bloodstream and to reach the brain, where they cause many of their effects.

"The combination of these two factors makes it difficult for users to control the dose that they are exposed to. This can lead them to unintentionally administer a toxic dose (see ‘Other risks related to synthetic cannabinoids and smoking mixtures’, page 18). Accounts from patients and people who witness poisonings suggest that in some cases a small number of puffs from a joint have been sufficient to cause severe and fatal poisoning."

"To better serve policymaking at the regional and international levels, the term “new psychoactive substances” or NPS was coined. The Commission on Narcotic Drugs introduced this term at the international level in its resolution 55/1 of 16 March 2012.
"The term 'new psychoactive substances' had been legally defined earlier by the European Union as a new narcotic or psychotropic drug, in pure form or in a preparation, that is not scheduled under the Single Convention on Narcotic Drugs of 1961 or the Convention on Psychotropic Substances of 1971, but which may pose a public health threat comparable to that posed by substances listed in those conventions (Council of the European Union decision 2005/387/JHA).
"That legal definition is now widely used and has also been adopted by the EMCDDA.¹⁸"

"The high prevalence of mental health issues among the homeless population has been extensively documented throughout literature, but the consumption of NPS to treat mental health symptoms is of particular concern (Gray et al., 2021; Irving et al., 2015; McLeod et al., 2016; Ralphs et al., 2021). One study demonstrated that the homeless use SCRA to escape from the realities of the streets and provide relief from physical and mental health conditions, similar to the motivations for using cannabis, heroin and crack cocaine within the population (Fountain and Howes 2002; Link, 2014; Peacock et al., 2019)."

"Between 2008 and 2015, a total of 644 NPS had been reported by 102 countries and territories to the UNODC early warning advisory on NPS. The emergence of NPS was reported for the first time in 2015 in Kyrgyzstan and Mauritius. In 2015, the early warning advisory also registered the emergence of NPS in previous years in Belarus, Serbia, South Africa and Tajikistan. The majority of countries and territories that reported the emergence of NPS up to December 2015 were from Europe (41), followed by Asia (30), Africa (16), the Americas (13) and Oceania (2).

"The NPS market continues to be characterized by a large number of new substances being reported. Although data collection for 2015 is still in progress, 75 new substances have been reported to UNODC for the first time, compared with a total of only 66 in 2014. Between 2012 and 2014, most substances reported for the first time belonged to the group of synthetic cannabinoids. The data reported for 2015 so far show a different pattern: first, 20 synthetic cathinones (a group of substances with stimulant effects similar to cocaine or methamphetamine) were reported for the first time — almost as many as synthetic cannabinoids (21); and second, 21 'other substances' (substances not belonging to any of the major groups identified in previous years) were reported for the first time, including synthetic opioids (e.g. fentanyl derivatives) and sedatives (e.g. benzodiazepines).

"A growing number of NPS are reported every year by a large number of countries and territories throughout the world. NPS that have an established presence in the market include ketamine (reported by 62 countries and territories), khat (reported by 56), JWH-018 (reported by 50), mephedrone (reported by 49) and methylone (reported by 47).227 Other NPS are transient in nature and are only reported by a small number of countries and territories for a couple of years."

"Prior to the widespread availability of xylazine in the Philadelphia drug supply, it was often mentioned in passing by residents of the majority Puerto Rican neighborhood where our fieldwork was based as a powerfully psychoactive additive ‘“back on the Island”.’ Xylazine was occasionally detected in fatal overdoses in Philadelphia as early as 2006 (Wong et al., 2008), but it was not common knowledge among PWID. Significantly, however, many of our long-term informants recently immigrating/returning from Puerto Rico spoke with a mix of intrigue and apprehension about the psychoactive effects and health risks of “anastesia de caballo [horse tranquilizer]”."

"Clemson University Professor John Huffman is credited with first synthesizing some of the cannabinoids, such as JWH-018, now used in 'fake pot' substances such as K2. The effects of JWH-018 can be 10 times stronger than those of THC. Dr. Huffman is quoted as saying, 'These things are dangerous—anybody who uses them is playing Russian roulette. They have profound psychological effects. We never intended them for human consumption.'²³ While synthetic cannabinoids may be used with the intention of getting a marijuana-like high, their actual effects are not yet known. Some reported effects of synthetic cannabinoids, such as relaxation and reduced blood pressure, are consistent with effects of marijuana. Other reported effects, such as nausea, increased agitation, elevated blood pressure, and racing heart rates, are not.²⁴ The Centers for Disease Control and Prevention (CDC) has noted epidemiological links between synthetic cannabinoid use and acute kidney injury.²⁵ In at least one case, synthetic cannabinoid use has been blamed for a fatality when an Iowa teen committed suicide reportedly following a K2-induced panic attack.²⁶ In the summer of 2014, the New York City (NYC) Department of Health issued a warning to the public regarding the dangers of synthetic cannabinoid use after 15 people experienced “severe adverse reactions after suspected ingestion of synthetic cannabinoids” over a period of three days.²⁷ In 2015, following a “tenfold increase in medical emergencies from synthetic marijuana” in New York State (NYS) in the summer of 2015 compared to the summer of 2014, Governor Cuomo announced passage of emergency NYS Health Department regulations to combat the sale of these drugs—these emergency regulations included the addition of two classes of chemical compounds to the banned substances list.²⁸"

"According to the Crime Survey for England and Wales,²³⁸ over the period 2014-2015, 279,000 adults (0.9 per cent of the population aged 16-59) reported the use of NPS. Among young adults (ages 16-24), the prevalence of NPS use was much higher (2.8 per cent), the majority of the users being young men. Herbal smoking mixtures were the most commonly used form of NPS, with 61 per cent of the population aged 16-59 reporting their use. According to Public Health England,²³⁹ the number of individuals 'presenting to treatment' for a 'club drug' or NPS more than doubled, from 2,727 to 5,532, between the financial years 2009-2010 and 2014-2015. The largest increase was recorded for mephedrone — from 953 in the period 2010-2011 to 2,024 in the period 2014-2015. Compared with the previous period, the prevalence of past-year use of mephedrone in England and Wales in the financial years 2014-2015 remained stable at 1.9 per cent for young adults and 0.5 per cent for adults, which is similar to the prevalence of past-year use of amphetamines (0.6 per cent) and higher than that of LSD (0.4 per cent) or heroin (0.1 per cent).²⁴⁰"

"In the United States, there are indications of an increase in NPS use among certain user groups between 2009 and 2013; the prevalence of lifetime use of a 'novel psychoactive substance' among the population aged 12-34 was 1.2 per cent in 2013.²³⁵ There are signs of declining use of synthetic cannabinoids among secondary school students in the United States. The prevalence of past-year use of synthetic cannabinoids among twelfth-grade students decreased from 11.4 per cent in 2011 to 5.2 per cent in 2015.²³⁶ This is associated with an increase, over the same period, in the perceived risk of taking synthetic cannabinoids among the same group. The use of NPS with stimulant effects (reported as “bath salts“) among twelfth graders remained stable at 1 per cent in 2015. The prevalence of the use of synthetic cannabinoids among eighth, tenth and twelfth graders has declined to the lowest levels since the collection of such data began. However, the large amount of synthetic cannabinoids seized between 2012 and 2014 (more than 93 tons) and the large number of calls to poison centres for problems related to the use of synthetic cannabinoids (3,682 in 2014 and 7,779 in 2015)²³⁷ indicate the continued presence and use of this NPS group in the United States."

"In the United States, the first report on synthetic cannabinoids from the Drug Abuse Warning Network revealed that an estimated 11,406 visits of the approximately 2,300,000 emergency department visits that involved drug use in 2010 were specifically linked to synthetic cannabinoids. Three quarters of these emergency department visits involved patients aged 12 to 29 (75 percent or 8,557 visits), of which 78 percent were male, and in the majority (59 percent) of these cases, no other substances were involved. The average patient age for synthetic cannabinoids-related visits was 24 years, while it was 30 years for cannabis. Overall, synthetic cannabinoid-related visits were concentrated in the younger age groups: 75 percent of the visits involved patients aged 12 to 29, with 33 percent of the patients aged 12 to 17. In comparison, 58 percent of cannabis-related visits involved patients aged 12 to 29, with 12 percent in the 12 to 17 age group.¹⁷³"

"Synthetic cannabinoids are substances chemically produced to mimic tetrahydrocannabinol (THC), the active ingredient in marijuana. When these substances are sprayed onto dried herbs and then consumed through smoking or oral ingestion, they can produce psychoactive effects similar to those of marijuana.²⁰ Synthetic cannabinoids were first produced for research purposes to study the effects of cannabinoids on brain functioning and their efficacy in treating pain.

"The DEA has indicated that the primary users of these synthetic substances are youth who purchase the substances online or in gas stations, convenience stores, smoke shops, and head shops.²¹ The substances are often sold as herbal incense, and common brand names under which synthetic cannabinoids are marketed are 'Spice' and 'K2.' Other names include 'Blaze,' 'Red X Dawn,' 'Genie,' and 'Zohai,' among others.²²

"Clemson University Professor John Huffman is credited with first synthesizing some of the cannabinoids, such as JWH-018, now used in 'fake pot' substances such as K2. The effects of JWH-018 can be 10 times stronger than those of THC. Dr. Huffman is quoted as saying, 'These things are dangerous—anybody who uses them is playing Russian roulette. They have profound psychological effects. We never intended them for human consumption.'²³ While synthetic cannabinoids may be used with the intention of getting a marijuana-like high, their actual effects are not yet known. Some reported effects of synthetic cannabinoids, such as relaxation and reduced blood pressure, are consistent with effects of marijuana. Other reported effects, such as nausea, increased agitation, elevated blood pressure, and racing heart rates, are not.²⁴ The Centers for Disease Control and Prevention (CDC) has noted epidemiological links between synthetic cannabinoid use and acute kidney injury.²⁵ In at least one case, synthetic cannabinoid use has been blamed for a fatality when an Iowa teen committed suicide reportedly following a K2- induced panic attack.²⁶ In the summer of 2014, the New York City (NYC) Department of Health issued a warning to the public regarding the dangers of synthetic cannabinoid use after 15 people experienced 'severe adverse reactions after suspected ingestion of synthetic cannabinoids' over a period of three days.²⁷ In 2015, following a 'tenfold increase in medical emergencies from synthetic marijuana' in New York State (NYS) in the summer of 2015 compared to the summer of 2014, Governor Cuomo announced passage of emergency NYS Health Department regulations to combat the sale of these drugs—these emergency regulations included the addition of two classes of chemical compounds to the banned substances list.²⁸"

"The khat shrub (Catha edulis) of the celastraceae family is a plant native to the horn of Africa and the Arabian peninsula. Khat chewing is a social custom in the communities living in these areas. The psychoactive effects resulting from the release of cathinone and cathine alkaloids after chewing of khat are well-documented.78 The khat shrub became known to Europeans in the late 18th century and in the 19th century, and the active constituents of the plant were isolated in the 19th and 20th century. A ‘katin’ alkaloid was identified first in 1887, ‘cathine’ in 1930 and ‘cathinone’ in 1975.79
"In Europe and North America, khat was considered to be traditionally used by migrant communities from Ethiopia, Kenya, Somalia and Yemen, but in recent years its use has spread beyond these communities. Respondents to the UNODC questionnaire on NPS from Bahrain, Canada, Finland, Ireland, Italy, New Zealand, Norway, Oman, United States and Hong Kong (China) reported that khat emerged on their markets in 2009, and was the second most popular plant based substance, after salvia divinorum, reported by Member States from 2009 to 2012.
"Catha edulis is not under international drug control, but cathinone and cathine are listed in Schedules I and III, respectively, of the 1971 Convention. Khat is under national control in several countries."

"Street names for khat include ‘qat’, ‘gat’, ‘chat’, ‘miraa’, ‘murungu’ and ‘Arabian or Abyssinian tea’. Due to the degradation of cathinone, khat leaves need to be consumed soon after harvesting and therefore fresh leaves of khat are the preferred form of use, but dried leaves (‘graba’) are also available. Khat is usually consumed by chewing the leaves and shoots of the plant, but infusions are also possible. Recently, alcoholic extracts of khat sold as ‘herbal highs’ have been reported.⁸⁰"

"It has been estimated that a typical chewing session of khat results in the absorption of its active constituents with an activity equivalent to that of approximately 5 mg of amphetamine.⁸¹ The pharmacological effects of khat resemble those of amphetamine use, and includes increased alertness, euphoria, hyperthermia, anorexia, increased respiration rate, heart rate and blood pressure.⁸²
"Fatalities associated with the sole consumption of khat have not yet been reported. However, prolonged use of khat has been linked to adverse effects that range from psychiatric disturbances (from psychosis to depression) to damage of major organs of the body, as well as to similar neurological disorders to those associated with amphetamine and cocaine use.⁸³"

"Mitragyna speciosa Korth (of the Rubiaceae family) is a large tree found in tropical and sub-tropical regions of South-East Asia. In Thailand, the tree known as ‘Kratom’ is found throughout the country but predominantly in the southern region, although the growing and harvesting is prohibited.

"Kratom contains many alkaloids including mitragynine, mitraphylline, and 7-hydroxymitragynine. Traditionally, kratom had been used in Malaysia and Thailand by labourers and farmers to enhance productivity, but also as a substitute to opium and in traditional medicine, allegedly due to its morphine-like pharmacological effects. However, its use as a new psychoactive substance in the global market has been recently reported.

"In the early 2000s, products labelled as ‘kratom acetate’ or ‘mitragynine acetate’ became available in Europe, although it was found that neither of them contained mitragynine. Caffeine and synthetic O-desmethyltramadol (an active metabolite of tramadol) were found in products under the name ‘krypton’.⁸⁴ More recently, products containing kratom have been sold as ‘incense’ for their psychoactive effects, but concentrations of the active components mitragynine and 7-hydroxymitragynine in these products differ depending on the variety of the plant used, the environment and the time of harvesting."

"Evidence suggests that kratom is being used extensively for both medical and nonmedical purposes. Recent studies have shown that kratom contains a variety of active compounds that produce major pharmacologic effects at opioid and other receptors. Kratom and kratom-derived drugs may potentially be used for the management of pain, opioid withdrawal symptoms, and other clinical problems. At the same time, serious questions remain regarding the potential toxic effects and the abuse and addiction potential of kratom. This issue is further confounded by the lack of quality control and standardization in the production and sale of kratom products. The possibilities of kratom products being adulterated or interacting with other drugs are also serious concerns. Until these issues are resolved, it would not be appropriate for physicians to recommend kratom for the treatment of patients. Nevertheless, physicians need to be aware that patients may use kratom or kratom-based products on their own. Further studies to clarify the efficacy, safety, and addiction potential of kratom are needed."

"Street names for kratom include ‘thang’, ‘kakuam’, ‘thom’, ‘ketum’ and ‘biak’. Kratom leaves are usually consumed fresh, although dried leaves in powder form are also available. The fresh leaves are chewed while the powder form is often either swallowed or brewed into tea. Dried leaves are rarely smoked."

"Although the findings of our literature and Internet searches strongly suggest a marked increase in kratom use in the United States and Europe, kratom still appears to be somewhat of an 'underground phenomenon.' During our searches of the literature and the internet, we found no evidence that kratom is currently marketed by any of the large nutritional supplement chain stores in the United States. However, a wide variety of kratom products—including raw leaves, capsules, tablets, and concentrated extracts—are readily available from Internet-based suppliers.^20,21 In addition, these products are often sold in specialty stores commonly known as 'head shops' or 'smoke shops.' In February 2012, our own informal in-person and telephone survey of 5 smoke shops in the metropolitan Chicago area revealed that purported kratom products were available in all of them. Figure 2 and Figure 3 show images of several kratom products (ie, chopped leaves, capsules, and pressed tablets) that were legally purchased at a smoke shop in suburban Chicago.
"From a legal standpoint, kratom is regulated as an herbal product under US law and US Food and Drug Administration and US Drug Enforcement Administration (DEA) policies. As of this writing, Mitragyna speciosa (kratom) is not prohibited by the Controlled Substances Act28 and is considered a legal substance in the United States. However, the DEA's December 2010 version of the Drugs and Chemicals of Concern list states that 'there is no legitimate medical use for kratom in the U.S.'²⁹ Therefore, it cannot legally be advertised as a remedy for any medical condition."

"Data on 27,338 overdose deaths that occurred during July 2016–December 2017 were entered into SUDORS, and 152 (0.56%) of these decedents tested positive for kratom on postmortem toxicology (kratom-positive). Postmortem toxicology testing protocols were not documented and varied among and within states. Kratom was determined to be a cause of death (i.e., kratom-involved) by a medical examiner or coroner for 91 (59.9%) of the 152 kratom-positive decedents, including seven for whom kratom was the only substance to test positive on postmortem toxicology, although the presence of additional substances cannot be ruled out (4).

"In approximately 80% of kratom-positive and kratom-involved deaths in this analysis, the decedents had a history of substance misuse, and approximately 90% had no evidence that they were currently receiving medically supervised treatment for pain. Postmortem toxicology testing detected multiple substances for almost all decedents (Table). Fentanyl and fentanyl analogs were the most frequently identified co-occurring substances; any fentanyl was listed as a cause of death for 65.1% of kratom-positive decedents and 56.0% of kratom-involved decedents. Heroin was the second most frequent substance listed as a cause of death (32.9% of kratom-positive decedents), followed by benzodiazepines (22.4%), prescription opioids (19.7%),** and cocaine (18.4%)."

"In Southeast Asia, kratom has long been used for the management of pain and opium withdrawal.^6,9-11,14 In the West, kratom is increasingly being used by individuals for the self-management of pain or withdrawal from opioid drugs such as heroin and prescription pain relievers.^20,27 It is these aspects of kratom pharmacology that have received the most scientific attention. Although to our knowledge, no well-controlled clinical studies on the effects of kratom on humans have been published, there is evidence^30-38 that kratom, kratom extracts, and molecules isolated from kratom can alleviate various forms of pain in animal models. Studies have used a variety of methods including hot plate,^35,37,39 tail flick,^32,39 writhing,^37,38 and pressure/inflammation^35,38 tests in mice^32,35,38,39 and rats,^35,37 as well as more elaborate tests in dogs and cats.³⁵ In addition, a variety of chemical compounds have been isolated from kratom and shown to exhibit opioid-like activity on smooth muscle systems^31,33,34 and in ligand-binding studies.^39,40 Most notably, many of the central nervous system and peripheral effects of these kratom-derived substances are sensitive to inhibition by opioid antagonists.^31-34,39-41"

"During the past 3 years, there have been an increasing number of case reports^15,17,29 describing unusual adverse reactions in patients who had been using kratom or kratom-based products. The acute adverse effects of kratom experienced by many users appear to be a direct result of kratom's stimulant and opioid activities.6,9,11,30,31 Stimulant effects may manifest themselves in some individuals as anxiety, irritability, and increased aggression. Opioid-like effects include sedation, nausea, constipation, and itching. Again, these effects appear to be dose dependent and to vary markedly from one individual to another. Chronic, high-dose usage has been associated with several unusual effects. Hyperpigmentation of the cheeks, tremor, anorexia, weight loss, and psychosis have been observed in individuals with long-term addiction.⁹ Reports of serious toxic effects are rare and have usually involved the use of relatively high doses of kratom (>15 g).^9,17,45,46 Of particular concern, there have been several recent reports of seizures occurring in individuals who have used high doses of kratom, either alone or in combination with other drugs, such as modafinil.^17,22,45 Kapp et al¹⁵ recently described a case of intrahepatic cholestasis in a chronic user of kratom.
"It is important to note that in each of these case reports, the patients may have had confounding health conditions, may have been using other drugs along with kratom, or both. One of the major problems in evaluating the potential uses and safety of an herbal agent such as kratom is the lack of understanding of how substances in kratom may interact with prescription medications, drugs of abuse, or even other herbal supplements. This issue is compounded by the relative lack of regulations and standardization related to the production and sale of kratom. These potential hazards were highlighted in several case reports of deaths resulting from the use of a kratom-based product known as 'Krypton'.^16,47 This agent, which was touted as a very potent form of kratom, had been marketed in Sweden. During the past 5 years, there have been reports of 9 deaths related to the use of Krypton.¹⁶ In a case series by Kronstad et al,¹⁶ subsequent forensic studies revealed that Krypton contained high amounts of the exogenous pharmaceutical agent O-desmethyltramadol, which has opioid and neuromodulator activity. Evidently, the exogenous O-desmethyltramadol had been added to the plant material. Even though mitragynine was also detected in the products, it was not determined how the 2 substances may have interacted to cause death. Another recent report⁴⁸ described a fatal reaction that appeared to be associated with the use of a combination of propylhexedrine—an ? agonist and an amphetamine-like stimulant—and mitragynine. This latter case highlights the fact that extracts and tinctures containing purified mitragynine, 7-hydroxymitragynine, and 7-acetoxymitragynine have become available for purchase by means of the Internet. These sources can easily be found by conducting an Internet search using the term 'mitragynine purchase.' The possibility that these highly concentrated mitragynine alkaloid extracts could be used in conjunction with other psychoactive drugs (eg, alcohol, sedatives, opioids, stimulants, cannabinoids) raises the potential for serious drug interactions."

"In spite of the increasing use of this substance, scientific literature about the effects and toxicity of kratom alone remains very scarce.
"Kratom is a central nervous system stimulant, from which over 40 alkaloids have been isolated. In low doses it is reported to have stimulant effects (used to combat fatigue during long hours of work), while at high doses, it can have sedative-narcotic effects.⁸⁷ In 1921, the major alkaloid found in this plant, ‘Mitragynine’, was first isolated. Mitragynine has an opioid agonistic activity and its derivative 7-hydroxymitragynine (7-OH-mitragynine) is reported to be more potent than mitragynine or morphine.⁸⁸
"Nine fatal cases of intoxication associated with the use of ‘krypton’, a mixture of mitragynine and O-desmethyltramadol, have been described in scientific literature. However, these fatalities have been attributed to the addition of O-desmethyltramadol to the dried kratom leaves.⁸⁹"

"In the last three to five years an increasing number of reports suggest that people who inject drugs (PWID) in Russia, Ukraine and other countries are no longer using poppies or raw opium as their starting material, but turning to over-the-counter medications that contain codeine (e.g. Solpadeine, Codterpin or Codelac). Codeine is reportedly converted into desomorphine (UNODC, 2012; Gahr et al., 2012a, 2012b, 2012c; Skowronek, Celinski, & Chowaniec, 2012). The drug is called Russian Magic, referring to its potential for short lasting opioid intoxication or, more common, to its street name, krokodil. Krokodil refers both to chlorocodide, a codeine derivate, and to the excessive harms reported, such as the scale-like and discolored (green, black) skin of its users, resulting from large area skin infections and ulcers. At this point, Russia and Ukraine seem to be the countries most affected by the use of krokodil, but Georgia (Piralishvili, Gamkrelidze, Nikolaishvili, & Chavchanidze, 2013) and Kazakhstan (Ibragimov & Latypov, 2012; Yusopov et al., 2012) have reported krokodil use and related injuries as well."

"In considering the drug krokodil, two aspects are of importance, its pharmacology and its chemistry. The short half-life, limited high after the impact effect and, in particular the need for frequent administration may narrow the attention of users on the (circular) process of acquiring, preparing and administering the drug, leaving little time for matters other than avoiding withdrawal and chasing high, as reported in several popular magazines (e.g. Shuster, 2011; Walker, 2011). However, when the layers of bootleg chemistry and attribution are peeled off, what’s left is an opioid analogue (or several ones) that, besides the variations in half-life, behaves pharmacologically not very different than heroin or Hanka (Haemmig, 2011). There are various paths to synthesize desomorphine from codeine, but the chemical process most commonly reported to be used by PWID in Russia and Ukraine is very similar to that of home-produced methamphetamine or Vint (Grund, Zábransky, Irwin, & Heimer, 2009; Zábransky, 2007) – a rudimentary version of a simple chemical reduction. The illicit production of krokodil reportedly involves the processing of codeine into the opiate analogue desomorphine (UNODC, 2012; Gahr et al., 2012a, 2012b, 2012c; Skowronek et al., 2012). Desomorphine (Dihydrodesoxymorphine-D or PermonidTM ) is an opiate analogue first synthesized by Small in 1932 (Small, Yuen, & Eilers, 1933). The analgesic effect of desomorphine is about ten times greater than that of morphine (and thus stronger than heroin), whereas its toxicity exceeds that of morphine by about three times (Weill & Weiss, 1951). The drug’s onset is described as very rapid but its action is of short duration, which may lead to rapid physical dependence and frequent administration."

"In recent years, harm reduction and drug treatment services from Russia, Ukraine, Georgia and Kazakhstan began reporting severe health consequences associated with krokodil injecting. Although serious localized and systemic harms have previously been associated with injecting homemade opiates and stimulants in the region (Grund, 2002; Volik, 2008), the harms associated with krokodil injecting are extreme and unprecedented. The most common complications of krokodil appear to be serious venous damage and skin and soft tissue infections, rapidly followed by necrosis and gangrene (Gahr et al., 2012a, 2012b, 2012c; Skowronek et al., 2012). Our research further identified an impressive, undoubtedly incomplete, list of injuries and symptoms (Table 1), reported in the media (e.g. Shuster, 2011; Walker, 2011) and identified in YouTube clips and photographs on the internet. Importantly, this list includes several parts of the body that are not typically used as sites for injecting drugs. This suggests that the ill effects of krokodil are not limited to localized injuries, but spread throughout the body (Shuster, 2011; UNODC, 2012), with neurological, endocrine and organ damage associated with chemicals and heavy metals common to krokodil production (Lisitsyn, 2010).
"It is important to note that the described harms seem to become manifest relatively shortly after krokodil injecting is initiated. Present accounts of krokodil related harms often concern young people presenting in emergency rooms and surgeries with extreme and advanced complications. According to NGOs that work with people who inject krokodil, these young people have relatively short histories of using the drug. Mortality rates among young krokodil users are reportedly high (Akhmedova, 2012; Shuster, 2011; Walker, 2011), with official reports associating krokodil use with half of all drug-related deaths in at least two Oblasts (Walker, 2011)."

"The estimated number of PWID in Russia was close to 2 million in 2008 (Mathers et al., 2008). 2.3% of the Russian population uses opioids annually and 1.4% heroin, compared to an annual prevalence of 0.4% opioid use in Western and Central Europe (UNODC, 2012). While actual epidemiological data is not available, a number of academic and media reports suggest that 5% or more of Russian drug users (approximately 100,000 PWID) may be injecting krokodil (Walker, 2011), while 'various official estimates' place the numbers of Russian PWID using krokodil as high as one million (Shuster, 2011). Epidemiological data is critical to evaluating claims that the use of krokodil is reaching epidemic proportions in Russia (Walker, 2011), and potentially, the Ukraine. There are an estimated 290,000 to 375,000 PWID in Ukraine (Mathers et al., 2008). A recent national survey found that 7% of PWID have used krokodil in 2011 (Balakireva, 2012), suggesting that around 20,000 PWID in Ukraine may have used krokodil that year. Balakireva and colleagues furthermore found statistically significant differences in krokodil use between the cities in the study, with most krokodil use reported in Uzhhorod (35.6%), Simferopol (26.9%), Kyiv (21.7%), Chernivtsi (15.5%) and Donetsk (12.6%). Estimates from other countries are not available. Outside of the former Soviet region, krokodil has been reported in Germany (Der Spiegel, 2011) and in Tromsø in northern Norway (Lindblad, 2012)."

"In sum, these observations suggest that the relatively limited availability of black market opiates and stimulants and the relative ease of harvesting legal precursors to powerful analogues from the countryside and pharmacies inspired and sustained a Soviet-style homemade drug culture in the Eastern European region that remains radically different from those observed in countries where narco-traffickers dominate the production and distribution of drugs (Booth, Kennedy, Brewster, & Semerik, 2003; Grund et al., 2009; Grund, 2005; Subata & Tsukanov, 1999; Zábransky, 2007).
"The physical and logistical exigencies of home production; its locus in networks of drug injecting friends and the high degree of cooperative action involved (in foraging for, producing and using the drugs); the multiple roles and ambiguous status of injecting paraphernalia; the routine occurrence of well-known risk behaviours (e.g. syringe sharing, frontloading) and those currently less well understood, such as the slapdash nature of the bootleg drug synthesis and its unpredictable outcomes in terms of actual drug product, purity and pollution— indeed all of these factors contribute to and interact within the vastly complex high risk environment of home drug production in the region."

"In Russia and many other post-Soviet countries, the old ideology lingers on in narcological institutes, out of sync with modern public and mental health concepts (Grund et al., 2009). Many narcologists continue to view addiction as criminal or moral deviance and not as a disease. Narcological dispensaries continue to share information with law enforcement (Mendelevich, 2011). The threat of removal of child custody rights may impede women’s access to health care in particular (Shields, 2009). Stigma and discrimination, hostile treatment and lack of confidentiality are persistent in the treatment of PWID and must be viewed as important barriers to timely seeking medical care (Beardsley & Latypov, 2012; Mendelevich, 2011; Wolfe et al., 2010). PWID have therefore strong incentives to avoid narcological facilities and, by association, other state health services. In their personal 'hierarchy of risk,' seeking help for significant health problems is subordinated by the need to stay under the radar of the authorities (Connors, 1992). Several of the YouTube clips on the internet furthermore document not only the gravity of harms among krokodil users, but also poor and inhumane treatment of those hospitalized with krokodil related injuries. In one video a man’s leg is sawn off under the knee with a lint saw in what seems not to be a surgical unit, but perhaps a common hospital ward. The man sits wide-awake in an ordinary wheelchair and holds his leg himself above a bucket, which was lined with a garbage bag just before. These videos and case reports (Asaeva et al., 2011; Daria Ocheret, personal communication, 2012; Sarah Evans, personal communication, 2012) suggest that the care provided to those with krokodil related injuries may be (grossly) substandard, sometimes exacerbated by improper diagnosis and faulty clinical decisions."

"Synthetic cathinones are related to the parent compound cathinone (Figure 1), one of the psychoactive principals in khat (Catha edulis Forsk). Cathinone derivatives are the β-keto (βk) analogues of a corresponding phenethylamine. The group includes several substances that have been used as active pharmaceutical ingredients (API) of medicinal products, e.g. amfepramone (diethylpropion; Figure 2). Since the mid-2000s, unregulated ring-substituted cathinone derivatives have appeared in the European recreational drugs market. The most commonly available cathinones sold on the recreational market in the period up to 2010 appear to be mephedrone (Figure 3) and methylone (Figure 4). These products are usually encountered as highly pure white or brown powders. Ring-substituted cathinone derivatives are claimed to have effects similar to those of cocaine, amphetamine or MDMA (ecstasy), but little is known of their detailed pharmacology. Apart from cathinone (Figure 1), methcathinone (Figure 5) and two API’s amfepramone (Figure 2) and pyrovalerone, cathinone derivatives are not under international control."

"Cathinone and its derivatives are closely related to the phenethylamine family (which includes amphetamine and methamphetamine), but with a lower potency than the latter.¹³ They are characterised by the presence of a ?-keto group on the side chain of the phenethylamines. Cathinone, the principal active ingredient in the leaves of the khat plant (catha edulis), can be considered as the prototype from which a range of synthetic cathinones have been developed.
"Synthetic cathinones appeared in drug markets in the mid 2000s. In 2005, methylone, an analogue of MDMA, was the first synthetic cathinone reported to the European Monitoring Centre on Drugs and Drug Addiction (EMCDDA). In 2007, reports of 4-methyl-methcathinone (mephedrone) use emerged, first in Israel and then in other countries and regions, including Australia, Scandinavia, Ireland and the United Kingdom.¹⁴ Mephedrone was reportedly first synthesized in 1929.¹⁵"

"Synthetic cathinones are frequently found in products sold as ‘research chemicals’, ‘plant food’, ‘bath salts’ or ‘glass cleaner’ and are usually sold in powder, pill or capsule form. Mephedrone (‘m-cat’, ‘meph’, ‘drone’ or ‘miaow’) and methylone (‘explosion’ or ‘top cat’) are usually available as white or brown powders or in the form of pills that are often sold as ‘ecstasy’. Most synthetic derivatives are ingested but may be injected. Mephedrone is commonly nasally insufflated, injected, ingested by swallowing a powder wrapped in paper (‘bombing’), or mixed in a drink."

"Few reports on the toxicity of synthetic cathinones exist to date. Much of the current knowledge on health-related effects comes from user reports and clinical observations. Further research is needed to provide evidence of short and long-term health risks and the addiction potential associated with the use of these substances.
"Whereas cardiac, psychiatric, and neurological signs are some of the adverse effects reported by synthetic cathinone users, agitation, ranging from mild agitation to severe psychosis, is the most common symptom identified from medical observations.²⁵ Studies of patients under the apparent influence of mephedrone have also shown that synthetic cathinones present similar sympathomimetic effects (including tachycardia and hypertension as well as psychoactive effects) to similar amphetamine derivatives.²⁶ In a student survey, more than half of those who had taken mephedrone reported adverse effects associated with the central nervous system, nasal/respiratory system and cardiovascular system.²⁷ The first fatality related to the sole use of mephedrone, confirmed by toxicological analysis, was reported in Sweden in 2008.²⁸ Most fatalities associated with the use of mephedrone involved the use of other substances.²⁹ Deaths associated with the use of other synthetic cathinones include two deaths related to methedrone³⁰ and two other deaths related to butylone.³¹
"The Finnish Poisons Information Centre reported 33 calls regarding exposures to MDPV during the period of January 2008 to October 2009. Post mortem toxicological analysis confirmed 6 deaths related to MDPV between 2009 and 2010, although in most of the cases the presence of other drugs was also detected.³² A report from the United States provided details on the case of 35 patients who visited an Emergency Department over a 3-month-period after ingesting, inhaling or injecting substances sold as ‘bath salts’ and asserted that these products could contain stimulant compounds such as MDPV or mephedrone. One person was dead upon arrival at the emergency department. The toxicological analysis revealed a high level of MDPV, along with cannabis and prescription drugs, but the autopsy results revealed MDPV toxicity to be the primary factor contributing to death.³³"

"Phenethylamines refer to a class of substances with documented psychoactive and stimulant effects and include amphetamine, methamphetamine and MDMA, all of which are controlled under the 1971 Convention.41 The phenethylamines also include ring-substituted substances such as the ‘2C series’, ring-substituted amphetamines such as the ‘D series’ (e.g. DOI, DOC), benzodifurans (e.g. Bromo-Dragonfly, 2C-B-Fly) and others (e.g. p-methoxymethamphetamine (PMMA)).
"Seizures of phenethylamines were first reported from the United States and European countries and since 2009 substances such as 2C-E, 2C-I, 4-FA and PMMA have been commonly reported by several countries in different regions. Other phenethylamines increasingly reported in the UNODC questionnaire on NPS since 2011 include 4-FMA, 5-APB, 6-APB and 2C-C-NBOMe.
"A number of studies have reported the synthesis of some phenethylamines and amphetamine substitutes. In the 1980s and 1990s, Alexander Shulgin, a biochemist and pharmacologist, reported the synthesis of numerous new psychoactive compounds.⁴² This included the ‘D series’ (e.g. DOC, DOI) and the ‘2C series’ (e.g. 2C-T-7, 2C-T-2) of phenethylamines."

"Street names for some phenethylamines include ‘Europa’ for 2C-E; ‘4-FMP’, ‘para-fluoroamphetamine’, ‘RDJ’ for 4-FA; and ‘4-MMA’, ‘Methyl-MA’ for PMMA. Phenethylamines are usually available in form of pills, but FLY compounds are commonly sold in powder form, while oral doses (on a slip of blotter paper) are usually available for ‘D substances’. Ingestion is the most common route of administration of phenethylamines."

"Phenethylamines included in the ‘D series’ are described to be longer lasting, more potent and reportedly more liable to induce vasoconstriction than other members of the phenethylamine family.⁴⁹ Reported adverse effects associated with the use of the ‘D series’ derivatives include agitation, tachycardia, mydriasis, hallucinations, severe limb ischemia, seizures, liver and renal failure.⁵⁰ Bromo-Dragonfly has also been associated with a number of deaths in Scandinavia.⁵¹ A case of acute psychosis after ingestion of 2C-T-4 was reported in Japan.⁵² Three fatal cases associated with the use of 2C-T-7 have been identified, two of which involved poly-drug use.⁵³
"PMA, PMMA and 4-methylthioamfetamine have been more often associated with incidental deaths than other phenethylamines. PMA and PMMA are known to have a particularly high toxicity but there is no data available on fatalities associated with their use. Clinical observations have reported severe hyperthermia following the use of these substances.⁵⁴ Studies in animals have suggested that some metabolites may be exposed to increased toxicity from 4-MTA."

Piperazines

"Piperazines have been described as ‘failed pharmaceuticals’, as some had been evaluated as potential therapeutic agents by pharmaceutical companies but never brought to the market.⁵⁵ While the best known piperazine that has been used as a new psychoactive substance is 1-benzylpiperazine (BZP), during the last decade other compounds such as 1-(3-chlorophenyl) piperazine (mCPP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP) and, to a lesser extent, 1-Benzyl-4-methyl-piperazine (MBZP) and 1-(4-Fluorophenyl)piperazine (pFPP) have been identified on the market.⁵⁶
"BZP was initially developed as a potential antidepressant drug, but was found to have similar properties to amphetamine and therefore liable to abuse. In the 1980s, it was used in Hungary to manufacture piberaline, a substance marketed as an antidepressant, but later withdrawn.57 In the late 1990s, BZP emerged in New Zealand as a ‘legal alternative’ for MDMA and methamphetamine.⁵⁸ In Europe, its use was first reported in Sweden in 1999, but it only became widespread as a NPS from 2004 onwards until controls over the substance were introduced in 2008, in the European Union.⁵⁹
"MCPP, reportedly more widespread than BZP in some regions of the world,⁶⁰ was developed during the late 1970s and is used as an intermediate in the manufacture of several antidepressants, e.g. trazodone and nefazodone.⁶¹ TFMPP is almost always seen in combination with BZP to produce the entactogenic⁶² effects of MDMA.⁶³
"Neither BZP nor any other piperazines are under international control, although several (BZP, TFMPP, mCPP, MDBP) were pre-reviewed by the WHO Expert Committee on Drug Dependence in 2012. Several countries have introduced national control measures over piperazines."

"Piperazines are frequently sold as ‘ecstasy’. Some of the generic names for these substances include, ‘pep pills’, ‘social tonics’ or simply ‘party pills’. The latter term was used to commercialize BZP in New Zealand.⁶⁴ Other street names include Jax, A2, Benny Bear, Flying Angel, Legal E or Legal X, and Pep X, Pep Love or Nemesis.⁶⁵ MCPP is known as 3CPP, 3C1-PP or CPP.
"Piperazines are usually available in the form of pills (regularly pressed with logos similar to ecstasy pills), capsules or loose powders, and are mainly consumed by ingestion. Liquid forms are rarely seen, but injection, smoking and snorting is also possible."

"Information on the toxicological aspects of many piperazines listed in this group remain limited. Further research is required to provide evidence on short and long term health-effects associated with the use of these substances. Current knowledge comes from user reports, studies in animals, limited human studies, and clinical observations.
"Piperazines have been found to act as stimulants as a result of dopaminergic, noradrenergic, and predominantly serotoninergic effects produced in the brain. BZP produces toxic effects similar to amphetamine and other sympathomimetics, although, according to animal studies, its effects are less potent than amphetamine, methamphetamine and MDMA.⁶⁶ TFMPP, used in conjunction with BZP, has been reported to produce some of the effects of MDMA, but with a lower potency,⁶⁷ while mCPP has been indicated to produce similar stimulant and hallucinogenic effects as MDMA.⁶⁸
"In New Zealand, toxic seizures and respiratory acidosis after the use of BZP alone or in conjunction with other drugs were reported from three patients.⁶⁹ Another study of 61 patients reported toxic effects of BZP, with two cases presenting life-threatening toxicity.⁷⁰ Hyperthermia, rhabdomyolysis and renal failure associated with BZP ingestion have also been reported.⁷¹ In the United Kingdom, self-terminating grand mal seizures72 after the use of BZP have also been reported.⁷³
"Between 2004 and 2008, six fatal cases involving piperazines use were reported in Europe. Two of the cases involved the use of BZP in conjunction with TFMPP and none referred to the use of piperazines alone.⁷⁴ BZP and TFMPP were also associated with 19 fatalities between 2007 and 2010.⁷⁵ While reported effects of mCPP include the serotonin syndrome, no fatal poisonings from mCPP have been reported so far.⁷⁶ Similarly, toxic effects from the use of TFMPP alone have not been documented.⁷⁷"

"Salvia divinorum is a perennial herb in the mint family native to certain areas of the Sierra Mazateca region of Oaxaca, Mexico. The plant, which can grow to over three feet in height, has large green leaves, hollow square stems and white flowers with purple calyces, can also be grown successfully outside of this region. Salvia divinorum has been used by the Mazatec Indians for its ritual divination and healing. The active constituent of Salvia divinorum has been identified as salvinorin A. Currently, neither Salvia divinorum nor any of its constituents, including salvinorin A, are controlled under the federal Controlled Substances Act (CSA)."

"The putative primary psychoactive agent in SD [Salvia divinorum] is a structurally novel KOR [kappa opioid receptor] agonist named salvinorin A (Ortega et al., 1982; Valdés et al., 1984). Consistent with KOR agonist activity, users describe SD in lay literature as hallucinogenic: it produces perceptual distortions, pseudo-hallucinations, and a profoundly altered sense of self and environment, including out-of-body experiences (Aardvark, 1998; Erowid, 2008; Siebert, 1994b; Turner, 1996). SD therefore appears to have the potential to elucidate the role of the KOR receptor system in health and disease (Butelman et al., 2004; Chavkin et al., 2004; Roth et al., 2002)."

"Consistent with results from nonhuman animal research (Mowry et al.,2003), the present results suggest a safe physiological profile for salvinorin A at the studied doses, under controlled conditions, and in psychologically and physically healthy hallucinogen-experienced participants. Salvinorin A produced no significant changes in heart rate or blood pressure; no tremor was observed; and no adverse events were reported. Participants tolerated all doses. However, because of the small sample and the healthy, hallucinogen-experienced status of participants, conclusions regarding safety are limited."

"Salvia divinorum is a psychoactive plant that can induce dissociative effects and is a potent producer of visual and other hallucinatory experiences. By mass, salvinorin A, the psychoactive substance in the plant, appears to be the most potent naturally occurring hallucinogen. Its native habitat is the cloud forests in Mexico. It has been consumed for hundreds of years by local Mazatec shamans, who use it to facilitate visionary states of consciousness during spiritual healing sessions.⁵⁷ It is also used in traditional medicine at lower doses as a diuretic to treat ailments including diarrhoea, anaemia, headaches and rheumatism. Effects include various psychedelic experiences, including past memories (e.g. revisiting places from childhood memory), merging with objects and overlapping realities (such as the perception of being in several locations at the same time).⁵⁸ In contrast to other drugs, its use often prompts dysphoria, i.e. feelings of sadness and depression, as well as fear. In addition, it may prompt a decreased heart rate, slurred speech, lack of coordination and possibly loss of consciousness.⁵⁹"

"There was little evidence of dependence in our survey population. At some point, 0.6% (3 people) felt addicted to or dependent upon SD, while 1.2% (6) reported strong cravings for SD. The DSM-IV-R psychiatric diagnostic system in the United States classifies people as drug dependent based on seven criteria. Of the three who reported feelings of addiction or dependence on SD, only one endorsed any DSM-IV criteria (strong cravings and using more SD than planned). When asked about these signs and symptoms individually, 2 additional respondents (0.4%) reported three dependence criteria. None of these individuals reported more than 2 of 13 after-effects characteristic of mu-opioid withdrawal (such as increased sweating, gooseflesh, worsened mood, and diarrhea)."

"A tripwire question asks about use of salvia (or salvia divinorum) in the last 12 months. Salvia is an herb with hallucinogenic properties, common to southern Mexico and Central and South Americas. Although it currently is not a drug regulated by the Controlled Substances Act, several states have passed legislation to regulate its use, as have several countries. The Drug Enforcement Agency lists salvia as a drug of concern and has considered classifying it as a Schedule I drug, like LSD or marijuana. Annual prevalence of this drug has been in a steady decline, and in 2019 levels were less than 1% in all grades at 0.8%, 0.9%, and 0.7% among 8th, 10th, and 12th graders, respectively."

"Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC), the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs."

"MTF first addressed the use of synthetic marijuana in its 2011 survey by asking 12th graders about their use in the prior 12 months (which would have covered a considerable period of time prior to the drugs being scheduled by the DEA). Annual prevalence was found to be 11.4%, making synthetic marijuana the second most widely used class of illicit drug after marijuana itself among 12th graders at that time. Despite the DEA’s intervention, use among 12th graders remained unchanged in 2012 at 11.3%, which suggests either that compliance with the new scheduling had been limited or that producers of these products succeeded in continuing to change their chemical formulae to avoid using the ingredients that had been scheduled, or both. In 2012, for the first time, 8th and 10th graders were asked about their use of synthetic marijuana; their annual prevalence rates also were high at 4.4% and 8.8%, respectively. Use in all three grades dropped in 2013, with a sharp and significant decline among 12th graders, as well as a significant declines for both 10th and 12th graders in 2014. Since those initial measures, annual prevalence has declined appreciably and in 2020 was down to 1.6%, 2.5%, and 2.4% for the three grades."

"Despite its [marijuana's] long history of use and abuse for both medical and recreational purposes, a new generation of synthetic cannabinoids has recently emerged on the market, which are sold on the Internet as herbal mixtures under the brand names of 'Spice,' 'Spice Gold,' 'Spice Diamond,' 'Arctic Spice,' 'Silver,' 'Aroma,' 'K2,' 'Genie,' 'Scene' or 'Dream,' and advertised as incense products, meditation potpourris, bath additives, or air fresheners. These products are often referred to as 'herbal highs' or 'legal highs' because of their legal status and purported natural herbal make-up."

"‘Spice’ and other ‘herbal’ products are often referred to as ‘legal highs’ or ‘herbal highs’, in reference to their legal status and purported natural herbal make-up (McLachlan, 2009; Lindigkeit et al., 2009; Zimmermann et al., 2009). However, albeit not controlled, it appears that most of the ingredients listed on the packaging are actually not present in the ‘Spice’ products and it is seems likely that the psychoactive effects reported are most probably due to added synthetic cannabinoids, which are not shown on the label. There is no evidence that JWH, CP and/or HU [three chemically distinct groups of synthetic cannabinoids] compounds are present in all ‘Spice’ products or even batches of the same product. Different amounts or combinations of these substances seem to have been used in different ‘Spice’ products to produce cannabis-like effects. It is possible that substances from these or other chemical groups with a cannabinoid agonist or other pharmacological activity could be added to any herbal mixture (¹⁷) (Griffiths et al., 2009).

"The emergence of new, smokable herbal products laced with synthetic cannabinoids can also be seen as a significant new development in the field of so-called ‘designer drugs’. With the appearance, for the first time, of new synthetic cannabinoids, it can be anticipated that the concept of ‘designer drugs’ being almost exclusively linked to the large series of compounds with phenethylamine and tryptamine nucleus will change significantly (¹⁸). There are more than 100 known compounds with cannabinoid receptor activity and it can be assumed that further such substances from different chemical groups will appear (with direct or indirect stimulation of CB1 receptors)."

"Much of our understanding of cannabinoid tolerance, dependence, and withdrawal has been based on studies involving ∆⁹-THC, a relatively weak partial agonist at CB1 and CB2 receptors. However, the SCBs [Synthetic Cannabinoids] commonly found in quasi-legal commercial products, such as K2 and Spice, are typically full cannabinoid receptor agonists. Importantly, a drug’s efficacy determines how “powerful” its maximal effects may be in biological systems. A low efficacy cannabinoid like ∆⁹-THC will have a less pronounced maximal effect than a higher efficacy cannabinoid, such as the SCBs present in commercial products, and this difference in maximal effects cannot be overcome simply by increasing the dose of ∆⁹-THC. In other words, no amount of ∆⁹-THC can stimulate cannabinoid receptors to the same degree as the SCBs currently emerging as drugs of abuse. This has left researchers working with these high efficacy SCBs in the unusual position of having to determine whether their effects are related to the unprecedented degree of cannabinoid receptor stimulation elicited by these compounds, or whether they are produced by interactions with other, noncannabinoid receptor systems."

"Synthetic marijuana, so named because it contains synthetic versions of some of the cannabinoids found in marijuana, is a recent and important addition to the smorgasbord of drugs available to young people in the US. These designer chemicals are sprayed onto herbal materials that are then sold in small packets under such brand names as Spice and K-2. They have been readily available as over-the-counter drugs on the Internet and in venues like head shops and gas stations. While many of the most widely used chemicals were scheduled by the Drug Enforcement Administration in March of 2011, making their sale no longer legal, purveyors of these products have skirted the restrictions by making small changes in the chemical composition of the cannabinoids used. Use of these products was first measured in MTF in 2011 in a tripwire question for 12th graders, asking about their frequency of use in the prior 12 months (see Table 2-2). Annual prevalence was found to be 11.4%, making synthetic marijuana the second most widely used class of illicit drug after marijuana that year. In spite of the DEA’s scheduling of the most common ingredients, use among 12th graders remained unchanged in 2012, with 11.3% annual prevalence. Eighth and 10th graders were also asked about use of these drugs in 2012, and their annual prevalence levels were 4.4% and 8.8%, respectively, making synthetic marijuana the second most widely used illicit drug among 10th graders, as well, and the third among 8th graders behind marijuana and inhalants. In 2013 use dropped appreciably in all five populations, including statistically significant drops among 12th graders, college students, and young adults. These declines continued in 2014 with significant drops in prevalence among young adults, college students, 12th and 10th graders (a decline among 8th-grade students was not statistically significant). Efforts by the DEA and various states to make their sale illegal may well have had an impact. In 2015 prevalence continued to decline for 8th, 10th, and 12th grade students, although none of the one-year declines were statistically significant. Among young adults and college students prevalence has leveled, with signs of a possible reversal in course with a slight uptick of .2 points (ns) for young adults and .6 (ns) for college students. There is a relatively low level of perceived risk for trying synthetic marijuana once or twice, despite growing evidence of serious problems resulting from the use of these drugs."

"Because of health concerns and the abuse potential of herbal incense products, many have been banned in several European countries, 18 U.S. states, and the U.S. military.^33,38 In March 2011, the FDA placed 5 synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and cannabicyclohexanol) on Schedule I, making them illegal to possess or sell in the United States.³⁸"

"At this time, forty-six (46) states and the federal government have scheduled one or more synthetic cannabinoids by statute or regulation and twenty-nine (29) states have some form of the generic language. Of the four states that have not scheduled one or more of the synthetic cannabinoids, Louisiana and Nebraska include the generic language. The only two states that have not yet scheduled any of the synthetic cannabinoids or the generic language are Maryland and Rhode Island. Maryland had four bills pending this legislative session, but was unable to get legislation passed before the session adjourned. There is still a regulation pending in Maryland that would schedule certain cannabinoids. The District of Columbia also has legislation pending. Rhode Island, however, does not have anything pending at this time."

"There is shared concern among researchers that adding these substances to Schedule I could hinder medical research. As previously mentioned, Professor Huffman did not intend for K2 to be consumed by humans. He is, however, against adding synthetic cannabinoids to Schedule I, asserting that there is still much to learn about synthetic cannabinoids and that placing them on Schedule I would create too many hurdles for researchers who need to access these drugs.⁵⁸ Professor Huffman has created several synthetic cannabinoids that are seen as showing promise in treating skin cancers, pain, and inflammation."

"While side effects of cannabis are well documented,7 data on human toxicity related to the use of synthetic cannabinoids remains limited. As with other NPS, products sold as synthetic cannabinoids often contain several chemicals in different concentrations, making it very difficult to determine substance-specific effects. Available knowledge on the toxicity of these compounds comes from scientific reports and clinical observations.
"Health-related problems associated with the use of synthetic cannabinoids include cardiovascular problems and psychological disorders,⁸ and it appears that there may be carcinogenic potential with some of the metabolites of the substances contained in these products.⁹
"A study published in 2011 on the severe toxicity following synthetic cannabinoid ingestion suggested that JWH-018 could lead to seizures and tachyarrhythmia (irregular heartbeat).10 In a recent review of clinical reports, addiction and withdrawal symptoms similar to those seen with cannabis abuse were also linked to the use of synthetic cannabinoids.11 An analysis of synthetic
cannabinoids in ‘spice-like’ herbal blends highlighted the increasing number of reports on suicides associated with preceding use of these products.¹²"

"Most of the synthetic cannabinoids added as not-listed ingredients to Spice products are very difficult to detect by commonly used drug screening procedures. Apart from the analogs of THC such as HU-210, the structure of these new synthetic cannabinoids differs from that of THC, so that they probably will not trigger a positive test for cannabinoids in immunoassays of body fluids."

"A dramatic online snapshot of the Spice phenomenon as an emerging trend has been recently given by an important web mapping program, the Psychonaut Web Mapping Project, a European Commission-funded project involving researchers from seven European countries (Belgium, Finland, Germany, Italy, Norway, Spain, and UK), which aims to develop a web scanning system to identify newly marketed psychoactive compounds, and their combinations (e.g., ketamine and Spice, cannabis and Spice), on the basis of the information available on the Internet (Psychonaut Web Mapping Research Group, 2010). As a major result of the Project, a new and updated web-based database is now widely accessible to implement a regular monitoring of the web for novel and recreational drugs."