Novel Psychoactive Substances

1. New Psychoactive Substances (NPS)

"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."

UNODC, World Drug Report 2013 (United Nations publication, Sales No. E.13.XI.6), p. 60.
https://www.unodc.org/unodc/se...

2. New Psychoactive Substances (NPS) Defined

"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"

UNODC, World Drug Report 2013 (United Nations publication, Sales No. E.13.XI.6), p. 60.
https://www.unodc.org/unodc/se...

3. New Psychoactive Substances Defined

"In the operating guidelines on the early warning system, EMCDDA 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."

UNODC, World Drug Report 2013 (United Nations publication, Sales No. E.13.XI.6), pp. 62-63.
https://www.unodc.org/unodc/se...

4. Worldwide Growth in Novel Psychoactive Substances

"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."

United Nations Office on Drugs and Crime, World Drug Report 2016 (United Nations publication, Sales No. E.16.XI.7), p. 56.
http://www.unodc.org/wdr2016/
http://www.unodc.org/doc/wdr20...

5. Prevalence of NPS Use Among Young People in England and Wales

"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"

United Nations Office on Drugs and Crime, World Drug Report 2016 (United Nations publication, Sales No. E.16.XI.7), p. 60.
http://www.unodc.org/wdr2016/
http://www.unodc.org/doc/wdr20...

6. Prevalence of New Psychoactive Substances (NPS) Among US Youth

"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."

United Nations Office on Drugs and Crime, World Drug Report 2016 (United Nations publication, Sales No. E.16.XI.7), p. 60.
http://www.unodc.org/wdr2016/
http://www.unodc.org/doc/wdr20...

7. Emergency Room Visits Related to NPS Use

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 38.
http://www.unodc.org/documents...

8. History of Ketamine and Control Efforts

Ketamine

"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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 8.
http://www.unodc.org/documents...

9. Description 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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 8.
http://www.unodc.org/documents...

10. Background on Khat

Khat

"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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 13.
http://www.unodc.org/documents...

11. Description of Khat

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 13.
http://www.unodc.org/documents...

12. Reported Adverse Effects of Khat

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), pp. 13-14.
http://www.unodc.org/documents...

13. Background on Kratom

Kratom

"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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 14.
http://www.unodc.org/documents...

14. Current Use of Kratom in the US

"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."

Prozialeck, WC, Jivan, JK, and Andurkar, SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. Journal of the American Osteopathic Association. December 2012;112(12):792-9.
https://www.ncbi.nlm.nih.gov/p...
http://jaoa.org/article.aspx?a...

15. Description of Kratom

"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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 14.
http://www.unodc.org/documents...

16. Current Legal Status of Kratom in the US

"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."

Prozialeck, WC, Jivan, JK, and Andurkar, SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. Journal of the American Osteopathic Association. December 2012;112(12):792-9.
https://www.ncbi.nlm.nih.gov/p...
http://jaoa.org/article.aspx?a...

17. Analgesic and opioid-like effects of Kratom

"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 evidence30-38 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/inflammation35,38 tests in mice32,35,38,39 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 systems31,33,34 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"

Prozialeck, WC, Jivan, JK, and Andurkar, SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. Journal of the American Osteopathic Association. December 2012;112(12):792-9.
https://www.ncbi.nlm.nih.gov/p...
http://jaoa.org/article.aspx?a...

18. Toxic Effects of Kratom

"During the past 3 years, there have been an increasing number of case reports15,17,29 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."

Prozialeck, WC, Jivan, JK, and Andurkar, SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. Journal of the American Osteopathic Association. December 2012;112(12):792-9.
https://www.ncbi.nlm.nih.gov/p...
http://jaoa.org/article.aspx?a...

19. Reported Adverse Effects of Kratom

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), pp. 14-15.
http://www.unodc.org/documents...

20. The Emergence of 'Krokodil'

Krokodil

"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."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

21. Krokodil Production

"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."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

22. Harms Associated with Krokodil Use

"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)."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

23. Prevalence of Krokodile Use

"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)."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

24. Krokodil - Reasons and Risks

"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."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

25. Stigmatization and Inhumane Treatment of Krokodil Users

"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."

Grund, J. -P. C., et al. "Breaking worse: The emergence of krokodil and excessive injuries among people who inject drugs in Eurasia." International Journal of Drug Policy (2013), http://dx.doi.org/10.1016/j.dr...
http://www.ijdp.org/article/S0...

26. Mephedrone and Synthetic Cathinones

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 5.
http://www.unodc.org/documents...

27. Description of Synthetic Cathinones

"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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 7.
http://www.unodc.org/documents...

28. Reported Adverse Effects and Toxicity of Synthetic Cathinones

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 7.
http://www.unodc.org/documents...

29. Background on Phenethylamines

Phenethylamines

"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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 9.
http://www.unodc.org/documents...

30. Description 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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 10.
http://www.unodc.org/documents...

31. Reported Adverse Effects 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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), pp. 10-11.
http://www.unodc.org/documents...

32. Background on Piperazines

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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), pp. 11-12.
http://www.unodc.org/documents...

33. Description of 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."

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 12.
http://www.unodc.org/documents...

34. Reported Adverse Effects of Piperazines

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), pp. 12-13.
http://www.unodc.org/documents...

35. Description of Salvia Divinorum

"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)."

Drug Enforcement Administration, Office of Diversion Control, "Salvia Divinorum and Salvinorin A," (Washington, DC: U.S. Department of Justice, October 2013).
https://www.deadiversion.usdoj...

36. Effects of Salvia Divinorum

"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."

Johnson, Matthew W.; MacLean, Katherine A.; Reissig, Chad R.; Prisinzano, Thomas E.; Griffiths, Roland R., "Human sychopharmacology and dose-effects of salvinorin A, a kappa opioid," Drug and Alcohol Dependence (Philadelphia, PA: The College on Problems of Drug Dependence, December 3, 2010), p. 4-5.
http://www.washingtonpost.com/...

37. Description of Salvia and Its Effects

"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"

UNODC, World Drug Report 2013 (United Nations publication, Sales No. E.13.XI.6), p. 66.
https://www.unodc.org/unodc/se...

38. Effects of Salvia Divinorum

"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)."

Baggott, Matthew J.; Earth Erowid; Fire Erowid; Galloway, Gantt P.; Mendelson, John, "Use patterns and self-reported effects of Salvia divinorum: An internet-based survey," Drug and Alcohol Dependence (Philadelphia, PA: College on Problems of Drug Dependence, October 2010), p. 2.
http://www.maps.org/w3pb/new/2...
http://www.ncbi.nlm.nih.gov/pu...

39. Potential for Abuse or Dependence of Salvia Divinorum

"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)."

Baggott, Matthew J.; Earth Erowid; Fire Erowid; Galloway, Gantt P.; Mendelson, John, "Use patterns and self-reported effects of Salvia divinorum: An internet-based survey," Drug and Alcohol Dependence (Philadelphia, PA: College on Problems of Drug Dependence, October 2010), p. 4.
http://www.maps.org/w3pb/new/2...

40. Prevalence of Use of Salvia Divinorum Among Young People in the US

"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 2015 levels were only 0.7%, 1.2%, and 1.9% among 8th, 10th, and 12th graders, respectively."

Miech, R. A., Johnston, L. D., O’Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (2016). Monitoring the Future national survey results on drug use, 1975–2015: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan, p. 93. Available at http://monitoringthefuture.org...
http://monitoringthefuture.org...

41. Synthetic Cannabinoids

"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."

Sacco, Lisa N. and Finklea, Kristin M., "Synthetic Drugs: Overview and Issues for Congress," Congressional Research Service (Washington, DC: Library of Congress, October 28, 2011), p. 5.
http://www.fas.org...

42. Synthetic Cannabinoids

"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."

Fattore, Liana and Fratta, Walter "Beyond THC: the new generation of cannabinoid designer drugs," Frontiers in Behaviorial Neuroscience (Lausanne, Switzerland: September 2011) Volume 5, Article 60, p. 1.
http://www.ncbi.nlm.nih.gov...

43. Spice Use Among Youth In The US

"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). Annual prevalence was found to be 11.4%, making synthetic marijuana the second most widely used class of illicit drug after marijuana among 12th graders. 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 has been limited or that producers of these products have succeeded in continuing to change their chemical formulas to avoid using the ingredients that have been scheduled. In 2012 for the first time 8th and 10th graders were asked about their use of synthetic marijuana; annual prevalence rates were 4.4% and 8.8%, respectively. Use in all 3 grades dropped in 2013, but the decline was significant only among 12th graders. The 2013 rates were 4.0%, 7.4%, and 7.9% for 8th, 10th, and 12th graders, respectively. Among 8th graders, this was the third highest category of illicit drug being used after marijuana and inhalants."

Johnston, L. D., O’Malley, P. M., Miech, R. A., Bachman, J. G., & Schulenberg, J. E. (2014). Monitoring the Future national results on drug use: 1975-2013: Overview, Key Findings on Adolescent Drug Use. Ann Arbor: Institute for Social Research, The University of Michigan, p. 13.
http://www.monitoringthefuture...

44. "Spice" and Synthetic Cannabinoids

"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."

Fattore, Liana and Fratta, Walter "Beyond THC: the new generation of cannabinoid designer drugs," Frontiers in Behaviorial Neuroscience (Lausanne, Switzerland: September 2011) Volume 5, Article 60, p. 1.
http://www.ncbi.nlm.nih.gov...

45. Limited Understanding of Synthetic Cannabinoids

"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."

Sherrica Tai and William E. Fantegrossi, "Synthetic Cannabinoids: Pharmacology, Behavioral Effects, and Abuse Potential," Current Addiction Reports, March 15, 2014, DOI 10.1007/s40429-014-0014-y.
http://link.springer.com/artic...

46. "Spice" and Other Herbal Highs

"‘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)."

"Understanding the 'Spice' phenomenon," European Monitoring Centre for Drugs and Drug Addiction (Luxembourg: Office for Official Publications of the European Communities, 2009), p. 21.
http://www.emcdda.europa.eu...

47. Synthetic Cannabinoids K2 and "Spice"

"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.'"

Sacco, Lisa N. and Finklea, Kristin M., "Synthetic Drugs: Overview and Issues for Congress, Congressional Research Service (Washington, DC: Library of Congress, October 28, 2011), p. 5.
http://www.fas.org...

48. Prevalence of Synthetic Cannabinoid Use Among Young People in the US

"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."

Miech, R. A., Johnston, L. D., O’Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (2016). Monitoring the Future national survey results on drug use, 1975–2015: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan, pp. 15-16. Available at http://monitoringthefuture.org...
http://monitoringthefuture.org...

49. "Spice" Prohibition

"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"

Pierre, Joseph M., "Cannabis, synthetic cannabinoids, and psychosis risk: What the evidence says," Current Psychiatry (Parsippany, NJ: September 2011) Vol. 10, No. 9, p. 56.
www.mdedge.com...

50. Scheduling of "Spice"

"On March 1, 2011, the DEA used its temporary scheduling authority and issued a final rule to place five synthetic cannabinoids on the list of controlled substances under Schedule I of the CSA.26 The five substances are
"• 1-pentyl-3-(1-naphthoyl)indole (JWH-018);
"• 1-butyl-3-(1-naphthoyl)indole (JWH-073);
"• 1-[2-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200);
"• 5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (CP-47,497); and
"• 5-(1,1-dimethyloctyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (cannabicyclohexanol; CP-47,497 C8 homologue).
"Pursuant to the temporary scheduling authority, these substances will remain on the list of Schedule I controlled substances for one year, and then may be given one six-month temporary extension. To remain on Schedule I thereafter, the substances would need to be permanently scheduled within the CSA."

Sacco, Lisa N. and Finklea, Kristin M., "Synthetic Drugs: Overview and Issues for Congress, Congressional Research Service (Washington, DC: Library of Congress, October 28, 2011), p. 6.
http://www.fas.org...

51. State Bans on Synthetic Cannabinoids

"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."

Gray, Heather, "An Introduction to Synthetic Drugs," National Alliiance for Model State Drug Laws (Santa Fe, NM: June 2012), p. 11.
http://www.namsdl.org...

52. Schedule One and Limits on Research

"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."

Sacco, Lisa N. and Finklea, Kristin M., "Synthetic Drugs: Overview and Issues for Congress, Congressional Research Service (Washington, DC: Library of Congress, October 28, 2011), p. 13.
http://www.fas.org...

53. Reported Adverse Effects of Synthetic Cannabinoids

"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"

UN Office on Drugs and Crime, "The Challenge of New Psychoactive Substances: A Report from the Global SMART Programme" (Vienna, Austria: UNODC Laboratory and Scientific Section, March 2013), p. 5.
http://www.unodc.org/documents...

54. Testing for Use of Synthetic Cannabinoids

"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."

Fattore, Liana and Fratta, Walter "Beyond THC: the new generation of cannabinoid designer drugs," Frontiers in Behaviorial Neuroscience (Lausanne, Switzerland: September 2011) Volume 5, Article 60, p. 4.
http://www.ncbi.nlm.nih.gov...

55. Monitoring of Spice and New Psychoactive Substances

"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."

Fattore, Liana and Fratta, Walter "Beyond THC: the new generation of cannabinoid designer drugs," Frontiers in Behaviorial Neuroscience (Lausanne, Switzerland: September 2011) Volume 5, Article 60, p. 3.
http://www.ncbi.nlm.nih.gov...