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Home , Arylcyclohexylamine, Controlled substance, Drug policy of Sweden, Methoxetamine, Methoxyketamine

ISSN 1725-4493 15 RISK ASSESSMENTS

Methoxetamine

EMCDDA Risk Assessments are publications publications Assessments Risk EMCDDA are of risks social and the health examining newindividual psychoactive substances. Report Risk The Assessment an of consists analysis the of scientificenforcement andlaw on the new available information psychoactive the implications and scrutiny under substance of the outcome It is control. it under placing of the of the auspices under convened a meeting Committee. Scientific EMCDDA partprocedure process is of a three-step This involving information exchange/early warning, the in decision-making and assessment risk 2005/387/JHA. Decision Council of framework About this series

psychoactive substances psychoactive framework of the Council Decision on new of the Council Decision on new framework cyclohexanone () in the (methoxetamine) cyclohexanone 2-(3-methoxyphenyl)-2-(ethylamino) Report on the risk assessment of Report on the risk I Contents 3 I EMCDDA actions on monitoring and responding to new

4 I EMCDDA–Europol Joint Report on methoxetamine: a summary

5 I Risk Assessment Report of a new psychoactive substance: methoxetamine

14 I Annex 1: Technical report on methoxetamine

19 I Council Implementing Decision of 25 September 2014 on subjecting 25I-NBOMe, AH-7921, MDPV and methoxetamine to control measures

24 I Participants of the risk assessment meeting

I Acknowledgements

The EMCDDA would like to thank the following for their contribution in producing this publication:

I the members of the extended Scientific Committee of the EMCDDA; the advisers to the Scientific Committee and the invited external experts who took part in the risk assessment meeting; I the Early Warning System (EWS) correspondents of the Reitox national focal points (NFPs) and experts from their national EWS networks; I the services within each Member State that collected the raw data for the risk assessment; I Europol, the European Medicines Agency (EMA) and the European Commission; I Dr Paul Dargan and Dr David Wood for preparing the technical review on the pharmacotoxicological, sociological and criminological evidence and public health risks of methoxetamine; I EMCDDA colleagues: Paul Griffiths, Anabela Almeida, Isabelle Giraudon and Katarzyna Natoniewska, who managed the production of the publication.

EMCDDA project leaders: Michael Evans-Brown, Andrew Cunningham, Ana Gallegos and Roumen Sedefov

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I EMCDDA actions on monitoring and responding to new drugs

The EMCDDA has been assigned a key role in the detection and assessment of new drugs in the under the terms of a Council Decision 2005/387/JHA on the information exchange, risk-assessment and control of new psychoactive substances. It establishes a mechanism for the rapid exchange of information on new psychoactive substances and provides for an assessment of the risks associated with them in order to permit the measures applicable in the Member States for the control of and psychotropic substances to be applied also to new psychoactive substances.

The three-step process involves information exchange/early warning, risk assessment and decision-making (see below). More detailed information can be found in the section ‘Action on new drugs’ of the EMCDDA’s website: www.emcdda.europa.eu/activities/action-on-new-drugs

Council Decision 2005/387/JHA of 10 May 2005 on the information exchange, risk-assessment and control of new psychoactive substances

I. Information exchange EMCDDA–Europol Joint Reports Early-warning system (EWS)

II. Risk assessment EMCDDA Risk Assessments

III. Decision-making Council Decisions on control

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EMCDDA–Europol Joint Report on methoxetamine (2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone) — a I summary EMCDDA–Europol Joint Report on a new psychoactive substance: 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone — in accordance with Article 5 of Council Decision 2005/387/JHA on the information exchange, risk assessment and control of new psychoactive substances

available information on a new psychoactive substance 2-(3-methoxyphenyl)-2- (ethylamino)cyclohexanone, commonly known by the abbreviation ‘methoxetamine’, through a joint assessment based upon the following criteria: (1) the amount of the material seized; (2) evidence of organised crime involvement; (3) evidence of international trafficking; (4) analogy with better-studied compounds; (5) evidence of the potential for further (rapid) spread; and (6) evidence of cases of serious intoxication or fatalities.

The EMCDDA and Europol agreed that the information available on methoxetamine satisfied criteria 1, 3, 4 and 6. The two organisations therefore concluded that sufficient information has been accumulated to merit the production of a Joint Report on methoxetamine as stipulated by Article 5.1 of the Decision. Accordingly, the NFPs, the Europol national units (ENUs), the EMA and the World Health Organization (WHO) were formally asked to provide the relevant information within six weeks from the date of the request, i.e. by 18 November 2013.

The resulting Joint Report on methoxetamine was submitted to the Council, the Commission and the EMA on 16 December 2013. The report concluded that the health and social risks, caused by the use of, the manufacture of, and traffic in methoxetamine, as well as the involvement of organised crime and possible consequences of control measures, could be thoroughly assessed through a risk assessment procedure as foreseen by Article 6 of Council Decision 2005/387/JHA.

The full text of the Joint Report can be found at:

www.emcdda.europa.eu/publications/joint-report/methoxetamine

4 / 26 Risk Assessment Report of a new psychoactive substance: 2-(3-methoxyphenyl)-2-(ethylamino) cyclohexanone (methoxetamine)

I Introduction market. The Council Decision also provides for an assessment of the risks associated with these new psychoactive This Risk Assessment Report presents the summary findings substances so that, if necessary, control measures can be and conclusions of the risk assessment carried out by the applied in the Member States (5). extended Scientific Committee of the European Monitoring Centre for Drugs and (EMCDDA) on the new Methoxetamine was first identified in a sample purchased psychoactive substance 2-(3-methoxyphenyl)-2-(ethylamino) from an Internet retailer in September 2010, and the United cyclohexanone (methoxetamine). The report has been Kingdom formally notified the Early Warning System in prepared and drafted in accordance with the conceptual November 2010. Following an assessment of the available framework and the procedure set out in the Risk assessment information on methoxetamine, and in accordance with Article of new psychoactive substances: operating guidelines (1). It is 5 of the Council Decision, on 16 December 2013 the EMCDDA written as a stand-alone document that presents a summary and Europol submitted a Joint Report on methoxetamine to of the information considered during the detailed analysis of the Council of the European Union, the European Commission the scientific and law enforcement data available at this time. and the European Medicines Agency (EMA) (6). Taking into The conclusion of the report summarises the main issues account the conclusion of the Joint Report and in accordance addressed and reflects the opinions held by the members of with Article 6 of the Council Decision, on 29 January 2014, the the Scientific Committee. A list of the information resources Council formally requested that ‘the risk assessment should considered by the Scientific Committee, including a detailed be carried out by the extended Scientific Committee of the Technical report on methoxetamine, is provided below. EMCDDA and be submitted to the Commission and the Council within 12 weeks from the date of this notification’. The risk assessment has been undertaken in compliance with Article 6 of Council Decision 2005/387/JHA of 10 May 2005 In accordance with Article 6.2, the meeting to assess the risks on the information exchange, risk assessment and control of of methoxetamine was convened under the auspices of the new psychoactive substances (2) (the ‘Council Decision’). The Scientific Committee of the EMCDDA with the participation of Council Decision established a mechanism for the rapid five additional experts designated by the Director of the exchange of information on new psychoactive substances EMCDDA, acting on the advice of the Chairperson of the (hereafter ‘Early Warning System’ (3)) that may pose a threat Scientific Committee, chosen from a panel proposed by to public health and create social problems, including the Member States and approved by the Management Board of involvement of organised crime. The Council Decision the EMCDDA. The additional experts were from scientific therefore allows the institutions of the European Union and fields that were either not represented, or not sufficiently the Member States to act on all new narcotic and psychotropic substances (4) that appear on the European Union drug preparation; ‘new narcotic drug’ means a substance in pure form or in a preparation that has not been scheduled under the 1961 United Nations Single Convention on Narcotic Drugs, and that may pose a threat to public (1) EMCDDA (2010), Risk assessment of new psychoactive substances: health comparable to the substances listed in Schedules I, II or IV; ‘new operating guidelines, Publications Office of the European Union, Luxembourg. psychotropic drug’ means a substance in pure form or in a preparation that (2) OJ L 127, 20.5.2005, p. 32. has not been scheduled under the 1971 United Nations Convention on (3) The information exchange mechanism laid down by the Council Decision is Psychotropic Substances, and that may pose a threat to public health operationalised as the European Union Early Warning System on New comparable to the substances listed in Schedules I, II, III or IV. Psychoactive Substances (‘Early Warning System’). It is operated by the (5) In compliance with the provisions of the 1961 United Nations Single EMCDDA and Europol in partnership with the Reitox national focal points in Convention on Narcotic Drugs and the 1971 United Nations Convention on the Member States, the European Commission and the European Medicines Psychotropic Substances. Agency. (6) EMCDDA and Europol (2014), EMCDDA–Europol Joint Report on a new (4) According to the Council Decision, ‘new psychoactive substance’ is defined psychoactive substance: methoxetamine (2-(3-methoxyphenyl)-2- as ‘a new narcotic drug or a new psychotropic drug in pure form or in a (ethylamino)cyclohexanone), Lisbon.

5 / 26 RISK ASSESSMENTS I Methoxetamine Risk Assessment Report represented, on the Scientific Committee, and whose Physical, chemical and pharmacological contribution was necessary for a balanced and adequate description of methoxetamine and its assessment of the possible risks of methoxetamine, including , including its medical health and social risks. Furthermore, two experts from the value Commission, one expert from Europol and one expert from the EMA participated in the risk assessment. The meeting took I place on 1 and 2 April 2014 at the EMCDDA in Lisbon. The risk Methoxetamine is an substance assessment was carried out on the basis of information (Figure 1). The systematic (International Union of Pure and provided to the Scientific Committee by the Member States, Applied Chemistry, IUPAC) name for methoxetamine is the EMCDDA, Europol and the EMA. A list of the extended (RS)-2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone. Scientific Committee and the other participants attending the Methoxetamine contains one asymmetric carbon atom and risk assessment meeting is included at the end of this thus is a chiral molecule (Figure 1). There are no details publication. available on the enantiomeric form detected (7). It is structurally similar to (8) and the internationally The extended Scientific Committee considered the following control substance (9). There are a number of information resources for the risk assessment: other arylcyclohexylamine substances that have been notified to the Early Warning System, including: 2-, (i) Technical report on 2-(3-methoxyphenyl)-2-(ethylamino) N-ethylnorketamine, 3-MeO-PCE and 4-MeO-PCP (10). cyclohexanone (methoxetamine) (Annex 1); (ii) EMCDDA–Europol Joint Report on a new psychoactive The name ‘methoxetamine’ was reported to have been created substance: methoxetamine (2-(3-methoxyphenyl)-2- as a contraction of methoxy-ketamine. The Chemical Abstract (ethylamino)cyclohexanone; Service (CAS) Registry Numbers for methoxetamine are (iii) scientific articles, official reports and grey literature, and 1239943-76-0 (base) and 1239908-48-5 (hydrochloride salt). Internet drug discussion forums and related websites (hereafter ‘user websites’); (iv) data from EMCDDA monitoring of Internet suppliers FIGURE 1 (which typically appear to be manufacturers and/or The molecular structure, formula and weight of wholesalers) and retailers selling methoxetamine; methoxetamine (the asterisk indicates the asymmetric carbon) (v) Risk assessment of new psychoactive substances: O operating guidelines; and, CH (vi) Council Decision 2005/387/JHA of 10 May 2005 on the 3 information exchange, risk assessment and control of new psychoactive substances. NH CH3 Finally, it is important to note that this Risk Assessment * Report contains a discussion of the available information on non-fatal intoxications and deaths associated with O methoxetamine. Such information is critical to the identification of emerging toxicological problems associated with new psychoactive substances within the European Union. Molecular formula: C15H21NO2 In this context, it is important to recognise that the capacity to Molecular weight: 247.33 g/mol detect, identify and report these events differs both within and between the Member States. Some Member States have 7 introduced programmes in the past few years to strengthen ( ) ‘Detections’ is an all-encompassing term and may include seizures and/or collected and/or biological samples. Seizure means a substance available these capacities. As a result, more information is available; (seized) through law enforcement activities (police, customs, border guards, however, it is likely that serious adverse events remain etc.). Collected samples are those that are actively collected by drug monitoring systems (such as test purchases) for monitoring and research under-detected. purposes. Biological samples are those from human body fluids (urine, blood, etc.) and/or specimens (tissues, hair, etc.). (8) EMCDDA (2002), Report on the risk assessment of ketamine (2-(2-chlorophenyl)-2-(methylaminocyclohexanone) in the framework of the joint action on new synthetic drugs, Lisbon. (9) Phencyclidine is also known as PCP and chemically as 1-(1-phenylcyclohexyl) . (10) 2-methoxyketamine is 2-(2-methoxyphenyl)-2-(methylamino)cyclohexanone; N-ethylnorketamine is 2-(2-chlorophenyl)-2-(ethylamino)cyclohexanone; 3-MeO-PCE is N-Ethyl-1-(3-methoxyphenyl)cyclohexylamine; and 4-MeO-PCP is 1-[1-(4-methoxyphenyl)cyclohexyl]-piperidine.

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The physico-chemical properties of methoxetamine have not Users report that the desired effects last approximately 1–7 been described in the scientific literature. It has been mostly hours depending on the route of administration. encountered in seized or collected samples as a white crystalline powder. There are also reports of it being seized as Only two studies have investigated the of ‘off white’, beige or yellow powder. It appears to be commonly methoxetamine, both of which investigated its metabolism. No sold in powder form, although it is also available in tablets, studies have assessed other pharmacokinetic parameters capsules and liquid form. Common routes of administration such as absorption, distribution or excretion. are nasal insufflation and oral ingestion. Methoxetamine (salt) is soluble in water and the powder can be dissolved for oral The five most abundant phase I and two most abundant phase use or intravenous/intramuscular injection. II metabolites found in the in vitro studies were due to demethylation, reduction, oxidation and glucuronidation. No Methods have been developed for the analysis of data are available on the biological activity of the metabolites. methoxetamine and some of its metabolites, including liquid chromatography coupled with mass spectrometry (LC-MS), Methoxetamine is used in analytical reference materials and gas chromatography coupled with mass spectrometry scientific research investigating its chemistry, pharmacology (GC-MS) and high-performance liquid chromatography and toxicology as a result of its emergence on the drug coupled with ultraviolet detection (HPLC-UV). market. There are currently no known uses of methoxetamine as an industrial, agricultural or cosmetic compound. However, There is one published in vitro study investigating the the name ‘methoxetamine’ has been registered as a trade of methoxetamine, which suggests that it mark in a Member State (December 2010); the significance of has an affinity for the NMDAN ( -methyl-D-aspartate) receptor this trade mark application is unknown. similar to ketamine. However, unlike ketamine, methoxetamine also has affinity for the . According to information provided by EMA, there are no known human or veterinary medical uses of methoxetamine in the No animal studies were identified that investigated the median European Union. There is no marketing authorisation (existing, lethal dose (LD50) of methoxetamine. on-going or suspended) for methoxetamine at the European Union level or in the Member States that responded to the No animal studies were identified that investigated the information request by the EMA that was launched under potential for self-administration of methoxetamine. Article 5 of the Council Decision. There is no information that methoxetamine is used for the manufacture of a medicinal No studies in the scientific literature have assessed the product in the European Union. However, it should be noted psychological and/or behavioural effects of methoxetamine in that there is no European Union database on the synthetic humans. In addition, there are no animal studies on which to routes of all registered medicinal products. There remains a base an extrapolation of potential effects. However, self- theoretical possibility that methoxetamine could in the future reported experiences from user websites suggest that the be developed for use as an due to its actions desired psychological and behavioural effects of at the NMDA receptor; to date there has been no formal methoxetamine are broadly comparable to those reported for evaluation of such a potential application. ketamine, which is a (11) anaesthetic. These include: , empathy, pleasant intensification of sensory Internet suppliers and retailers openly sell methoxetamine in experiences, mild to strong sense of dissociation from the bulk and retail quantities. It is also available from bricks and physical body, derealisation, ‘coziness’, improved social mortar head shops and street-level drug dealers. interaction, distorted sense of reality, vivid hallucinations, introspection and brief antidepressant effects.

According to information from user websites, methoxetamine appears to be used in single doses of between 10–200 mg, Chemical precursors that are used for the although some reports suggest that initial doses should not I manufacture of methoxetamine exceed 50 mg. The onset of desired effects is typically seen within 30–90 minutes of nasal insufflation, 90 minutes after oral ingestion and 5 minutes after intramuscular injection. The method based on the patent on the synthesis of aminoketones from 1966 requires four steps. A Grignard (11) The term ‘dissociative’ has two meanings: first, it refers to an effect on the reagent made from cyclopentyl bromide is reacted with brain, inducing a lack of responsive awareness not only to pain but also to the 3methoxybenzonitrile to form 3-methoxyphenyl cyclopentyl general environment; second, it refers to a feeling of dissociation of the mind from the body (‘out-of-body experience’). ketone, which is then brominated. The resulting α-bromo

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ketone is reacted with ethylamine and the product undergoes to non-fatal intoxications associated with methoxetamine rearrangement to form methoxetamine upon heating. have been reported in the scientific literature; of these, analytical confirmation was reported in 11 cases: (two There is currently no information regarding manufacturing cases), the United Kingdom (seven), (one) and the sites, the chemical precursors or the synthetic routes used for (one). methoxetamine that has been detected on the drug market. Precursors and other chemicals needed for the manufacture Data from these reports, together with information from of methoxetamine are inexpensive and are readily available. self-reported user experiences, suggest that individuals These reactions are feasible in an amateur laboratory setting present with adverse effects similar to ketamine intoxication. and do not require sophisticated equipment. These include: nausea and severe vomiting, diarrhoea, slow and/or irregular heart rates, blackouts/loss of consciousness, There is no information on the purity of methoxetamine that is sweating, distorted vision, buzzing/ringing in ears, difficulty present on the drug market. Analysis of seized products has breathing, headaches, seizures, tremor, disorientation, found methoxetamine on its own, and also in combination post-use depression, mental slowing, anxiety, difficulty with pharmacologically active substances (e.g. lidocaine, speaking or moving limbs, catatonia, confusion, agitation, phenacetin, chlordiazepoxide and ) and/or other aggression, hallucinations, paranoia and . In psychoactive substances (e.g. , ketamine, MDPV, addition, acute methoxetamine intoxications include 4-MEC, AM-2201, 4-HO-MET, 5-MeO-DiPT, and 6-APB). effects (e.g. agitation, tachycardia and hypertension) and cerebellar features (e.g. ataxia and nystagmus) that would not be expected with acute ketamine intoxication.

Methoxetamine may be used on its own or in combination Health risks associated with with other substances. Analysis of various products has I methoxetamine shown that the composition of the products can differ and that the user is unlikely to be aware of the exact dose or compound(s) present. There is the potential therefore that in such cases some or all of the reported symptoms may be due I Individual health risks to other substances or a combination of them, rather than to methoxetamine itself. The assessment of individual health risks includes a consideration of the acute and chronic toxicity of Twenty deaths associated with methoxetamine have been methoxetamine, its dependence potential and its similarities reported to the Early Warning System by six Member States to and differences from other chemically related substances. where the substance has been detected in post mortem biological samples: Austria (one death), Finland (one), France The structural similarities and the available information on the (one), Poland (one), (one) and the United Kingdom in vitro and in vivo properties of methoxetamine would suggest (15). In eight of the cases methoxetamine was the only a pharmacological and toxicological profile similar to ketamine psychoactive substance reported. It should be noted that in and, to a certain extent, PCP, although additional studies are the remaining cases it is possible that other pharmacologically needed to confirm this. active substances (such as controlled drugs and medicines) and/or other medical conditions or trauma may have As noted, information on the acute toxicity associated with contributed to and/or been responsible for death. It is also methoxetamine is not collected uniformly across the notable that four of the 20 deaths mentioned drowning as the European Union. cause of death.

A total of 120 non-fatal intoxications associated with Methoxetamine has been marketed to users as a ‘bladder methoxetamine have been reported by five Member States: friendly’ alternative to ketamine. Since methoxetamine has Belgium (two cases), France (three), Germany (nine), Italy (15) only been reported to be available and used for a relatively and Sweden (91); analytical confirmation of methoxetamine short period of time compared to ketamine, there is currently from biological samples has been reported in 55 of these no human data to support or refute these claims. Using an cases: Belgium (one case), France (three), Italy (13), and established animal model of ketamine toxicity, one published Sweden (38). In addition, 15 clinical case reports (12) relating study showed that three months of intraperitoneal methoxetamine administration in mice was associated with similar bladder and renal tract toxicity that have been seen in (12) The term ‘clinical case reports’ is used to denote both clinical case reports and case series published in the scientific literature. similar animal models of chronic ketamine administration.

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There is currently no data from animal or human studies to be psychoactive substance identified; in other cases it has been able to determine whether chronic methoxetamine use may found in combination with other psychoactive substances, be associated with the other patterns of chronic toxicity seen including ketamine. Similar to other drugs, users may combine with ketamine use. methoxetamine with , and/or including and medicines. However, some There are no data on the potential for interactions between users may have taken methoxetamine unknowingly along with methoxetamine and other drugs, medicinal products, and or instead of other substances, particularly when they may other forms of interaction including inhibitors or inducers of have intended to use ketamine. drug metabolism. In this context, it is worth noting, however, that the use of ketamine with other CNS depressants (e.g. The main routes of administration of methoxetamine appear to alcohol) can potentiate CNS depression and/or increase the be nasal insufflation and oral ingestion. Intramuscular risk of developing respiratory depression. Concurrent use of injection and intravenous injection have also been reported; diazepam or other will increase plasma sharing of injecting equipment carries the additional risks of levels and reduce the clearance rate of ketamine. bacterial infections and transmission of blood-borne viruses.

No published animal or human studies have investigated the There are limited data available on the characteristics and potential for , reproductive toxicity, genotoxicity behaviour of users. Users are likely to overlap with people who and carcinogenic potential of methoxetamine. use ketamine and/or other new psychoactive substances. Information from clinical case reports suggests that No studies have been published on the abuse liability or methoxetamine may be used in a range of settings, including dependence potential of methoxetamine. There has been one the home environment and recreational settings. In the latter self-reported experience of methoxetamine ‘addiction’ on a case this includes informal settings (such as ‘house parties’) user website. and organised events (such as music festivals).

There is no information on the psychosocial consequences of There are currently no coordinated national or European chronic methoxetamine use, such as its effects on population surveys on methoxetamine use. There are data psychological development and the interaction with the social available from non-representative studies in the environment. and the United Kingdom.

One non-representative Internet survey open to respondents I Public health risks across the world found that from 7 700 United Kingdom-based respondents (including ‘clubbers’), both lifetime (4.9 %) and The public health risks associated with methoxetamine may last year (4.2 %) use of methoxetamine was lower than for be categorised in terms of patterns of use (extent, frequency, ketamine (47.5 % and 24.5 % respectively). Data was reported route of administration, etc.); availability and quality of the on four different reasons as to why respondents used drug; information, availability and levels of knowledge methoxetamine: easier to get hold of (73 %); better value for amongst users; and, negative health consequences. money (20 %); curious or it was sold as ketamine (20 %); less damaging to liver/kidneys (18 %). Detections of methoxetamine have been reported to the EMCDDA in 23 Member States, Turkey and Norway since In a survey of 313 individuals attending ‘gay friendly’ November 2010. in south-east London in July 2011, self-reported use of methoxetamine was considerably lower than ketamine Methoxetamine is sold and used as a substance in its own for lifetime (6.1 % vs. 60.3 %), last year (4.8 % vs. 48.7 %) and right; it is also sold as ketamine on the illicit drug market. last month (1.9 % vs. 34.9 %) use. Only 1.6 % reported use or EMCDDA monitoring of Internet suppliers and retailers selling planned use of methoxetamine on the night of the survey, methoxetamine (conducted in the month prior to the risk compared to 41.0 % for and 16.7 % for cocaine. assessment) identified more than ten companies, which may When the survey was repeated in July 2012 there had been a be based within the European Union and China, offering up to significant increase in self-reported use of methoxetamine: multi-kilogram quantities of the substance. This availability lifetime use was 21.0 % in 2012 compared to 6.1 % in 2011; coupled with evidence of its sale as ketamine raises the last year use was 19.2 % compared to 4.8 %; and last month possibility that methoxetamine could be supplied and used as use was 10.1 % compared to 1.9 %. Although there was no a (temporary) replacement for ketamine. In some seizures and significant change in lifetime and last year use of ketamine detections, methoxetamine has been reported to be the only between the two surveys, there was a reduction in last month use of ketamine (24.4 % in 2012, down from 34.9 % in 2011).

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A web survey among frequent visitors to parties, festivals and There are some healthcare costs associated with cases of clubs was undertaken in the Netherlands in 2013. There was acute methoxetamine toxicity presenting to hospitals. Most of limited information on the survey population in this report and these involve short assessments within the emergency no information on the number of individuals surveyed. The department; however, a minority of individuals have had more prevalence rates of methoxetamine use were lower than the prolonged symptoms over a few days or have required rates reported for ketamine at 3.0 % (methoxetamine) and admission to psychiatric facilities due to ongoing symptoms. 19.3 % (ketamine) for lifetime use; 2.3 % and 12.8 % for last year use; and 0.3 % and 5.0 % for last month use. There is no information on the social risks associated with the distribution and trafficking of methoxetamine. As noted, information from a range of sources suggests that methoxetamine is being sold as a ‘legal’ replacement to No systematic studies are available on the characteristics and ketamine and is also sold as ketamine on the illicit drug behaviour of those who use methoxetamine. It is likely that market. It may be relevant to consider the prevalence of they will be similar to those using other dissociative drugs ketamine use in the general population. Data from the such as ketamine and/or experimenting with new 2012/2013 Crime Survey for England and Wales (United psychoactive substances. Kingdom) reported that 0.4 % of adults aged 16–59 and 0.8 % of young adults aged 16–24 reported use of ketamine in the last year. Information on the level of involvement of organised crime, seizures and/or detections by the authorities, and the Social risks associated with manufacture of methoxetamine I methoxetamine I There is no information to suggest the involvement of There is limited information on the social risks associated with organised crime or criminal groups in the manufacture, methoxetamine. distribution (trafficking) and supply of methoxetamine. However, there have been reports of tablets with markings There is no information on whether the use of methoxetamine that would normally be associated with other recreational affects education or career, family or other personal or social drugs (e.g. ‘ecstasy’). relationships, including marginalisation.

Although there are no relevant studies, it may be assumed that the acute behavioural effects of methoxetamine on operating machinery and driving are similar to those caused Information on any assessment of by other dissociative substances. There are currently no methoxetamine in the United Nations reports of methoxetamine detection in either fatal or non-fatal system road traffic accidents. However, two cases were reported by I Germany of driving under the influence of drugs that were associated with methoxetamine; in addition, two cases from The World Health Organization is the specialised agency of the the United Kingdom were reported where methoxetamine was United Nations designated for the evaluation of the medical, detected in biological samples from individuals suspected of scientific and public health aspects of psychoactive driving under the influence of drugs and/or alcohol. The substances under the 1961 United Nations Single Convention available information does not permit comment on the extent on Narcotic Drugs and the 1971 United Nations Convention on to which driving is impaired. Psychotropic Substances.

One Member State (Sweden) reported 17 detections of The World Health Organization informed the EMCDDA that methoxetamine in biological samples related to individuals methoxetamine would be subject to evaluation at the 36th suspected of committing a minor drug offence. Additional meeting of the Expert Committee on Drug Dependence in information on these cases is not available to allow further June 2014. comment.

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Article 7.1 of Council Decision states: legislation). In Poland methoxetamine falls under the definition of a ‘substitution drug’ under the Act amending the Act on ‘No risk assessment shall be carried out in the absence of a Counteracting Drug Addiction and the Act on State Sanitary Europol/EMCDDA Joint Report. Nor shall a risk assessment be Inspection, 2010 and as such its marketing and production is carried out where the new psychoactive substance concerned penalised with a fine (administrative sanctions). In Portugal is at an advanced stage of assessment within the United methoxetamine is listed as controlled under Decree-Law Nations system, namely once the WHO Expert Committee on 54/2013. In Romania the Law 194/2011 subjects to control Drug Dependence has published its critical review together any psychoactive substance that qualifies by conforming to with a written recommendation, except where there is certain criteria (all substances with psychoactive potential are significant new information that is relevant in the framework of subject to control until proven harmless by a special this Decision.’ designated commission). In Slovakia methoxetamine is in the List of Risk Substances published in a Ministry of Health The risk assessment has been carried out on the Regulation No 298/2013 Coll., which came into force on understanding that methoxetamine is not at an advanced 1 October 2013. Spain reported that although there is no stage of assessment within the United Nations system. current specific legislation controlling production, commerce, imports, exports or use/consumption of methoxetamine, given that it may cause harmful effects to users there is general (administrative and criminal) legislation on health protection that, if necessary, is fully applicable. In Norway Description of the control measures that methoxetamine is regulated by the Medicines Act and a are applicable to methoxetamine in the prescription would be required to receive it. I Member States Methoxetamine is not listed for control in the 1961 United Nations Single Convention on Narcotic Drugs or in the 1971 Options for control and the possible United Nations Convention on Psychotropic Substances I consequences of the control measures (together ‘UN drug conventions’).

Nine Member States (Cyprus, Denmark, France, Germany, Under Article 9.1 of the Council Decision the option for control Italy, Lithuania, Slovenia, Sweden and the United Kingdom) that is available is for the Member States to submit the new and Turkey control methoxetamine under legislation by virtue psychoactive substance methoxetamine to control measures of their obligations under the UN drug conventions. and criminal penalties, as provided for under their legislation, by virtue of their obligations under the UN drug conventions. Nineteen Member States (Austria, Belgium, Bulgaria, Croatia, There are no studies on the possible consequences of such the Czech Republic, Estonia, Finland, Greece, Hungary, control measures on methoxetamine. If this option of control is Ireland, Luxembourg, Latvia, Malta, the Netherlands, Poland, pursued, the Committee considers that the following Portugal, Romania, Slovakia and Spain) and Norway do not consequences are possible. Some of these may apply to any control methoxetamine by virtue of their obligations under the new psychoactive substance. UN drug conventions. n This control option could be expected to limit the Of these nineteen Member States, nine (Austria, Finland, availability of methoxetamine and hence the further Hungary, the Netherlands, Poland, Portugal, Romania, Slovakia expansion of the current open trade in this substance. and Spain) and Norway use other legislative measures to However, this may have little impact on the manufacturers control methoxetamine: and suppliers based outside of the European Union. n A positive health consequence that may result from this In Austria methoxetamine is listed as controlled by the New control option is the benefit brought about by the Psychoactive Substances Act. In Finland methoxetamine has presumed reduction in availability and use of been controlled under the Medicines Act (395/87) since methoxetamine. 9 December 2011. In Hungary methoxetamine is listed in n This control option could facilitate the detection, seizure Schedule C of Government Decree 66/2012. In the and monitoring of methoxetamine related to its unlawful Netherlands the sale of methoxetamine in consumer amounts manufacture, trafficking and use. In so doing, it could it is treated as being a medicinal product and must comply facilitate cooperation between the judicial authorities and with medicines legislation (and general product safety law enforcement agencies within the European Union.

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n This control option would imply additional costs for the Methoxetamine has been detected in 23 Member States, criminal justice system, including forensic services, law Turkey and Norway. EMCDDA monitoring of Internet suppliers enforcement and the courts. and retailers selling methoxetamine has identified more than n This control option could lead to replacement with ten companies, which may be based within the European structurally related or other (established or new) Union and China, offering up to multi-kilogram quantities of psychoactive substances that may also have public health the substance. Data on prevalence are limited to non- consequences. representative studies in the United Kingdom and the n It is not possible to gauge to what extent this control is Netherlands. These data suggest that the lifetime, last year likely to impact on current and future research by academic and last month prevalence of the use of methoxetamine is institutes, the pharmaceutical or chemical industries. lower than ketamine. Given that some ketamine users have n This control option could create an illicit market in reported the use of methoxetamine, it is likely that there is an methoxetamine with the increased risk of associated overlap between these groups and/or users of other new criminal activity, including organised crime. psychoactive substances. However, detailed information on n It is a concern that a common technique used by Internet the characteristics of methoxetamine users is not available. retailers within the European Union is to offer price There is no specific information on the social risks that may be discounts or other promotions in order to dispose of related to methoxetamine. remaining stocks of new psychoactive substances when control measures are impending. Therefore, this control The main routes of administration appear to be nasal option could lower the price of any methoxetamine that is insufflation and oral ingestion; intramuscular injection and still available on the market and temporarily increase its intravenous injection have also been reported. The subjective availability. The extent to which this will impact on public effects reported by methoxetamine users are similar to health, criminality or levels of use is difficult to predict. ketamine. There are no published studies assessing the psychological and/or behavioural effects of methoxetamine in In order to examine the consequences of control, the animals or in humans. Committee wishes to note that should this option be pursued it will be important to monitor for the presence of Methoxetamine, either alone or in combination with one or methoxetamine on the market post-control. more substances, has been detected in 120 non-fatal intoxications in five Member States that reported to the Early Aside from the option for control under those stipulated in Warning System; an additional 15 clinical case reports Article 9.1 of the Council Decision, other options for control — Poland (three cases), the United Kingdom (eight), may be available to Member States. These may include Switzerland (one) and the United States (three) — have been medicines legislation or restricting the importation and supply published in the scientific literature. There have been 20 of the substance using other legislative options. deaths associated with methoxetamine in six Member States. It is not possible to determine the significance of the detection of methoxetamine in most of these deaths.

It appears that the effect profile and clinical presentations of I Conclusion acute methoxetamine toxicity share some features seen with ketamine, but that there is the potential for additional effects Methoxetamine is an arylcyclohexylamine substance that is such as stimulant and cerebellar features. The current data chemically similar to ketamine and PCP and, in common with does not allow an accurate assessment to be made on the these, has dissociative properties. Methoxetamine was first extent to which methoxetamine users are likely to experience identified in a collected sample purchased from an Internet health problems. There is currently no data from either animal retailer in September 2010, and the United Kingdom formally studies or human users of methoxetamine to determine its notified to the Early Warning System in November 2010. abuse liability and dependence potential.

Methoxetamine has emerged on the ‘legal highs’ market There is only one animal study that has examined the potential where it is sold as a ‘research chemical’ and advertised as a for chronic health effects of methoxetamine. This study ‘legal’ replacement for ketamine by Internet retailers, brick and suggests that methoxetamine may be associated with similar mortar head shops and street-level drug dealers; it is also sold renal and lower urinary tract effects to ketamine; however, as ketamine. It has been mostly found as a powder, but also as there is no data in humans to substantiate this. No studies tablets and in liquid form. have been published investigating the potential for neurotoxicity, reproductive toxicity, genotoxicity and carcinogenic potential of methoxetamine use.

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Multi-kilogram quantities of methoxetamine in powder form psychoactive substance, could be answered through further have been seized within the European Union but there is no research. Areas where additional information would be information on the involvement of organised crime. Precursors important include: receptor binding and functional activity and other chemicals needed for the manufacture of studies; metabolic pathway studies; behavioural studies; methoxetamine are inexpensive and are readily available. clinical patterns of acute and chronic toxicity in humans; the These reactions are feasible in an amateur laboratory setting potential interaction between methoxetamine and other and do not require sophisticated equipment. substances; prevalence and patterns of use (including targeted studies that examine user groups and risk Methoxetamine is used in analytical reference materials and in behaviours); market studies; chemical profiling studies; scientific research. It has no established or acknowledged studies on the abuse liability and dependence potential; and medical value or use (human or veterinary) in the European studies on the social risks associated with its use. Union. There are no indications that methoxetamine may be used for any other purposes. The Committee notes that a decision to control methoxetamine has potential positive consequences in terms Methoxetamine is not listed for control in the 1961 United of reducing its availability and therefore the adverse health Nations Single Convention on Narcotic Drugs or in the 1971 and social consequences arising from its use. It is important, United Nations Convention on Psychotropic Substances. however, to anticipate and minimise where possible any Methoxetamine is currently undergoing assessment by the potential negative consequences of control. Control measures United Nations system. Nine Member States and Turkey could extend an illegal market in methoxetamine, with the control methoxetamine under legislation by virtue of their associated risk of criminal activity. The implementation of obligations under the UN drug conventions. Nine of the control measures may also lead to the criminalisation of those remaining Member States and Norway use other legislative who continue to use this substance, with the possible measures to control the substance. attendant risks of socio-economic stigmatisation and marginalisation. Finally, control should not inhibit the Many of the questions posed by the lack of evidence on the gathering and dissemination of accurate information on health and social risks of methoxetamine, as for any new methoxetamine to users and to relevant professionals.

13 / 26 ANNEX 1 Technical report on 2-(3-methoxyphenyl)-2-(ethylamino) cyclohexanone (methoxetamine)

This Technical report was prepared under EMCDDA contract The full text of the Technical report on 2-(3-methoxyphenyl)-2- and, while the scientific data presented has been verified to (ethylamino)cyclohexanone (methoxetamine) can be accessed the extent possible, it has not been formally edited by the under the following link: EMCDDA. The Risk Assessment Report of www.emcdda.europa.eu/publications/risk-assessment/ 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone methoxetamine/annex1 (methoxetamine), to which this report is annexed was produced by the Scientific Committee of the EMCDDA and Tables on non-fatal intoxications and deaths, in which shall be regarded as the authoritative document. methoxetamine was analytically confirmed, have been extracted from the Technical report and are presented in the Suggested citation: Technical report on 2-(3-methoxyphenyl)- following pages. 2-(ethylamino)cyclohexanone (methoxetamine), EMCDDA, Lisbon, April 2014.

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TABLE 4 FROM THE TECHNICAL REPORT Non-fatal intoxications reported by the Member States to the Early Warning System in which methoxetamine was analytically confirmed in biological samples

Date of non-fatal Biological Methoxetamine Results for other Country intoxication Notes sample results substances (gender, age) Belgium Oct 2013 Urine + Not detected Powder (confirmed to contain methoxetamine) marketed as ‘Special K’. Most prominent symptoms: euphoria, hallucinations and dissociation. Supportive and symptomatic treatment. France Dec 2011 Blood and 30 µg/L (plasma) Negative Case from Lyon, France. urine 408 µg/L (urine) No further details or clinical information reported. France Jun 2012 Hair + Not reported Case from Toulouse, France. No further details or clinical information reported. France 2012 Blood 136 ng/mL (+) Case from Garches, France. Paracetamol (+) No further details or clinical information reported. Italy Feb 2012 Blood and 0.0002 mg/mL (present in He reported that he had ”snorted half a package” (M, 27) urine (serum) urine) of methoxetamine (2-(3-Methoxyphenyl)-2- 0.167 mg/mL (ethylamino)cyclohexanone) purchased on the (urine) Internet and also ingested an undefined amount of . On admission to the emergency room he was tachycardic (HR 120 bpm), confused, hallucinating and “severely agitated”. He required treatment with intravenous benzodiazepines (diazepam) initially. By the following day he was being treated with 15 mg/day, delorazepam 7 mg/day and valproic acid 400 mg/day; subsequently, the delorazepam dosage was increased up to 20 mg/ day and was added. Although a methoxetamine analytical standard was not available, by use of the product residue, it was estimated that the urine and serum concentrations were 167 microgram/ml and 0.2 microgram/ml respectively. Italy Jun 2012 Blood and 167 ng/mL APB-isomers (164 ng/mL) Admitted from a accompanied by the police (M, 38) urine (blood) (+) with serious agitation and violent behavior. On 7400 ng/mL MDMA (traces) admission he was mydriatic, stuporous, (urine) blood alcohol content sometimes catatonic, hypertensive (150/90 2.3 g/L mmHg) with a normal heart rate (78 bpm) and normothermic (36ºC). The patient was treated with intravenous fluids and left hospital against medical advice after about 8 hours of observation. Italy Jul 2012 Blood and 198 ng/mL (1000 ng/mL) Acute intoxication following attendance at a ‘rave (M, 17) urine (blood) MDMA (500 ng/mL) party’. On admission to the ED, he had severe 9000 ng/ml THC (141 ng/mL) psychomotor agitation associated with (urine) Ketamine/ (+) hallucinations. MDA (+) Italy Oct 2012 Urine + Alcohol (2.7 g/L) Admitted to the ED with severe agitation, stupor, (M, 24) (+) mydriasis, mild hypertension (130/80 mmHg) Cocaine (+) and significant tachycardia (150 bpm); “no Amphetamines (+) hyperthermia”. The patient left the hospital MDMA (+). voluntarily after 8 hours of observation. APB-isomers (+) Levamisole (+) Italy Oct 2012 Urine + THC Intoxication after the consumption of ‘3 red (M, 23) Cocaine (+) cylinders’ and alcohol. The patient was rescued in (+) confused state. At admission to the emergency Levamisole (+) room the patient was slowed, sometimes somnolent, normothermic, normotensive with a normal heart rate. ECG was normal.

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Date of non-fatal Biological Methoxetamine Results for other Country intoxication Notes sample results substances (gender, age) Italy Nov 2012 Urine + Alcohol (2.2 g/L in blood) Reported using ketamine and cannabis at a disco (M, 23) THC (+) and presented to the emergency room in a coma, Ketamine and norketamine with normal vital parameters except for peripheral (+) oxygen saturation (Sat O2 90%). Italy Nov 2012 Urine + THC (+) Reported using ketamine and THC at a disco and (M, 22) Ketamine and norketamine presented to the emergency room with mydriasis, (+) severe psychomotor agitation, hallucinations and in a dissociative state. Italy Nov 2012 Urine + THC (+) Reported to have consumed alcohol and other (F, 16) unspecified substances at a rave party. She presented to the emergency room confused, agitated with some amnesia for the events that happened during the night. Italy Nov 2012 Urine + THC (+) Reported to have consumed alcohol and other (F, 17) Ketamine and norketamine unspecified substances at a rave party. She (+) presented to the emergency room confused, Blood alcohol content disoriented, agitated with some amnesia for the 35 mg/dL events that happened during the night. Italy Jan 2013 Urine + Cocaine and metabolites (+) 22 year old female reported using ketamine, (F, 22) Opiates (+) and alcohol at a New Year’s celebration (+) and presented to the emergency room Levamisole (+) unresponsive with response to painful stimuli only. She was normothermic with a mild hypertension (140/100 mmHg) and mild tachycardia (100 bpm) with no other alterations of the rhythm. It was reported that there was “only slight clinical response to ”; the dose / route of administration were not specified. Italy Jan 2013 Urine + Amphetamine (+) Reported using ketamine at a New Year’s (M, 23) Cocaine and metabolites (+) celebration and presented to the emergency MDMA (+) room unresponsive with response to painful Levamisole (+) stimuli only. On examination he had normal size pupils, vertical nystagmus, was normothermic, with a normal blood pressure and heart rate (98 bpm). There was alcohol halitosis. The patient was treated with naloxone, leading to slight clinical improvement. Blood tests showed slightly elevated CPK (390 IU/L). Italy Feb 2013 Urine + Negative Admitted to the emergency room with chest pain, (F, 22) diffuse pain sensation and tremors having reported that he used both ketamine and LSD. Italy Sep 2013 Urine + Negative Admitted unconscious to the emergency room (M, 24) following use of alcohol and methoxetamine. Sweden Mar 2011 – Blood and + None 11 cases identified from the Swedish Poisons Oct 2012 Urine Information Service. See main text for further discussion of these cases. Sweden Mar 2011 – Blood and + 5-IT (1) (+) 27 cases identified from the Swedish Poisons Oct 2012 Urine Amphetamine (+) Information Service. See main text for further Benzodiazepines (+) discussion of these cases. Buprenorphine (+) Ethanol (+) MDPV (+) (+) 4-OHMET (2) (+) Cannabis/THC (+) (+)

(1) 5-(2-Aminopropyl)indole. (2) 4-Hydroxy-methylethyltryptamine.

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TABLE 6 FROM THE TECHNICAL REPORT Deaths reported by the Member States to the Early Warning System in which methoxetamine was analytical confirmed in post-mortem biological samples

Case Date of death Biological Methoxetamine Country Results for other substances Notes number (gender, age) sample result 1 Austria Aug 2012 Not reported + None reported Cause of death reported as central circulatory failure due to methoxetamine overdose. 2 Finland Aug 2012 Blood 5200 mg/mL Olanzapine (0.24 mg/L) Death by drowning. Medico-legal (0.20 mg/L) status not determined. Clozapine (0.13 mg/L) 3 France Feb 2013 Blood 9.48 µg/mL Benzodiazepines (from hospital Found dead at home. Cause of (M, 38) treatment) death reported as asphyxia. 4 Poland Jul 2012 Blood 0.32 µg/mL Amphetamine (0.06 µg/ml in blood, Cause of death reported as acute (M, 31) Urine 4.36 µg/mL 0.27 µg/ml in urine and poisoning as a result of Hair Negative 0.19 µg/g in hair) methoxetamine and amphetamine. 5 Sweden Feb 2012 Femoral 8.6 µg/g AM-694 (+) The cause of death reported as blood AM-2201 (+) suspected acute intoxication with JWH-018 (+) methoxetamine although the cannabis (+) presence of the three synthetic (+) may have contributed to the death (1). 6 United Aug 2011 Blood + Methadone (645µg/L EDDP in blood, Cause of death was reported as Kingdom (M, 29) also present in urine) and . mirtazepine (69 µg/L in blood, also present in urine) 7 United 2011 (month Blood + Fluoromethcathinone (+) Deceased was found Kingdom not specified) MDMA (+) decomposed at home. (+) MDAI (+) MDPV (+) 5-IAI (+) AMT (+) 8 United Jan 2012 Blood, urine + Alcohol (80 mg/100 ml in blood, 146 Cause of death was reported as Kingdom (M, 25) and vitreous mg/100 mL in urine, 155 mg/100 mL drowning, with methoxetamine humour in vitreous humour) and ingestion noted as a contributory dihydrocodeine (+) factor. 9 United Jan 2012 Blood, urine + Alcohol (80 mg/100 ml in blood, 146 Cause of death was reported as Kingdom (M, 17) and vitreous mg/100 mL in urine, 109 mg/100 mL drowning, with methoxetamine humour in vitreous humour) ingestion noted as a contributory factor. 10 United Jan 2012 Blood 0.89 mg/L (2.8 mg/L in Case of death was reported as Kingdom (M, 43) (unpreserved) unpreserved blood) methoxetamine and 1.1 mg/L methypropamine toxicity [sic]. (preserved) 11 United Mar 2012 Not reported 0.22 mg/L None reported Cause of death was reported as Kingdom (M, 20) drowning. 12 United Sep 2012 Blood + 6-APB (2460 ng/mL) Case of death was reported as Kingdom (F, 27) ingestion of 6-APB (benzofury) and methoxetamine. 13 United Sep 2012 Blood and + Methiopropamine (1.74 mg/L in Cause of death was reported as Kingdom (M, 41) urine (in urine) blood and present in urine), natural causes (ischaemic heart MDA (0.18 mg/L in blood and disease and coronary artery present in urine) and atheroma). Alcohol (7 mg/100 ml in blood and 16 mg/100ml in urine)

(1) Further details of this death have been published in the literature [Wikstrom M JAT 2012] and is discussed in more detail above.

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Case Date of death Biological Methoxetamine Country Results for other substances Notes number (gender, age) sample result 14-19 United 2012 (months Not reported + None reported 6 deaths. Kingdom unspecified) 20 United Jan 2013 Blood, urine, 0.03 mg/L in (0.13 mg/L in blood and Case of death was reported as Kingdom (M, 27) gastric and blood, present present in gastric sample) mixed drug toxicity. nasal swabs in gastric and Cocaine (0.44 mg/L in blood and nasal swab present on nasal swabs) samples Diazepam (4.27 mg/l in blood, 9 mg in gastric sample) and metabolites MDMA (0.20 mg/L in blood, 3 mg in gastric sample and present on nasal swabs) MDA (present in blood)

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I Council Decision

COUNCIL IMPLEMENTING DECISION of 25 September 2014 on subjecting 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) (25I-NBOMe), 3,4-dichloro-N-[[1-(dimethylamino)cyclohexyl]methyl]benzamide (AH-7921), 3,4-methylenedioxy­ (MDPV) and 2-(3-methoxyphenyl)-2- (ethylamino)cyclohexanone (methoxetamine) to control measures (2014/688/EU)

THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty on the Functioning of the European Union,

Having regard to Council Decision 2005/387/JHA of 10 May 2005 on the information exchange, risk-assessment and control of new psychoactive substances (1), and in particular Article 8(3) thereof,

Having regard to the proposal from the European Commission,

Whereas:

(1) Risk assessment reports on the new psychoactive substances 4-iodo-2,5-dimethoxy- N-(2-methoxybenzyl) phenethylamine (25I-NBOMe), 3,4-dichloro-N-[[1-(dimethylamino) cyclohexyl]methyl]benzamide (AH-7921), 3,4-methylenedioxypyrovalerone (MDPV) and 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone (methoxeta­mine) were drawn up in compliance with Decision 2005/387/JHA by a special session of the extended Scientific Committee of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), and were subsequently submitted to the Commission and to the Council on 23 April 2014.

(2) 25I-NBOMe, AH-7921, MDPV and methoxetamine had not been under assessment at the United Nations’ level by the time the risk assessment was requested at Union level, but they were evaluated in June 2014 by the Expert Committee on Drug Dependence of the World Health Organization.

(3) 25I-NBOMe, AH-7921, MDPV and methoxetamine have no established or acknowledged medical use (human or veterinary). Apart from their use in analytical reference materials, and in scientific research investigating their chemistry, pharmacology and toxicology as a result of their emergence on the drug market — and, in the case of 25I-NBOMe, also in the field of neurochemistry — there is no indication that they are being used for other purposes.

(4) 25I-NBOMe is a potent synthetic derivative of 2,5-dimethoxy-4-iodophenethylamine (-I), a classical seroto­nergic , which was subject to risk assessment and to control measures and criminal sanctions at Union level from 2003 by Council Decision 2003/847/JHA (2).

(5) The specific physical effects of 25I-NBOMe are difficult to determine because there are no published studies asses­sing its acute and chronic toxicity, its psychological and behavioural effects, and dependence potential, and because of the limited information and data available.

(1) OJ L 127, 20.5.2005, p. 32. (2) Council Decision 2003/847/JHA of 27 November 2003 concerning control measures and criminal sanctions in respect of the new synthetic drugs 2C-I, 2C-T-2, 2C-T-7 and TMA-2 (OJ L 321, 6.12.2003, p. 64).

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Clinical observations of individuals who have used this substance suggest that it has hallucinogenic effects and has the potential for inducing severe agitation, confusion, intense auditory and visual hallucinations, aggression, violent accidents and self-induced trauma.

(6) There have been four deaths associated with 25I-NBOMe registered in three Member States. Severe toxicity asso­ciated with its use has been reported in four Member States, which notified 32 non-fatal intoxications. If this new psychoactive substance were to become more widely available and used, the implications for individual and public health could be significant. There is no information available on the social risks associated with 25I-NBOMe.

(7) 22 Member States and Norway have reported to the EMCDDA and European Police Office (Europol) that they detected 25I-NBOMe. No prevalence data is available on the use of 25I-NBOMe, but the limited information that exists suggests that it may be consumed in a wide range of settings, such as at home, in bars, nightclubs and at music festivals.

(8) 25I-NBOMe is openly marketed and sold on the internet as a ‘research chemical’ and information from seizures, collected samples, user websites and internet retailers suggests that it is being sold as a drug in its own right and also marketed as a ‘legal’ replacement for LSD. EMCDDA identified more than 15 internet retailers selling this substance, who may be based within the Union and China.

(9) The risk assessment report reveals that there is limited scientific evidence available on 25I-NBOMe and points out that further research would be needed to determine the health and social risks that it poses. However, the avail­able evidence and information provides sufficient ground for subjecting 25I-NBOMe to control measures across the Union. As a result of the health risks that it poses, as documented by its detection in several reported fatal­ities, of the fact that users may unknowingly consume it and of the lack of medical value or use of the substance, 25I-NBOMe should be subjected to control measures across the Union.

(10) Since six Member States control 25I-NBOMe under national legislation complying with the obligations of the 1971 United Nations Convention on Psychotropic Substances, and seven Member States use other legislative measures to control it, subjecting this substance to control measures across the Union would help avoid the emer­gence of obstacles to cross-border law enforcement and judicial cooperation, and would help protect against the risks that its availability and use can pose.

(11) AH-7921 is a structurally atypical synthetic commonly known by internet suppliers, user websites and media as ‘doxylam’. It can be easily confused with ‘’, an antihistaminic medicine with sedative-hypnotic properties, which could lead to unintentional overdoses.

(12) The specific physical effects of AH-7921 are difficult to determine because there are no published studies asses­sing its acute and chronic toxicity, its psychological, behavioural effects, and dependence potential, as well as the limited information and data available. Based on user reports, the effects of AH-7921 appear to resemble those of classical with the feeling of mild euphoria, itchiness and relaxation; nausea appears to be a typical adverse effect. In addition to self-experimentation with AH-7921, as well as ‘recreational use’, some of the users report self-medicating with this new drug to relieve pain, others to alleviate withdrawal symptoms due to cessa­tion of the use of other opioids. This may indicate a potential of AH-7921 to spread among the injecting opioid population.

(13) There is no prevalence data on the use of AH-7921, but the information available suggests that it is not widely used, and that when it is used, that use is in the home environment.

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(14) 15 fatalities were recorded in three Member States between December 2012 and September 2013 where AH-7921, alone or in combination with other substances, was detected in post-mortem samples. While it is not possible to determine with certainty the role of AH-7921 in all of those fatalities, in some cases it has been spe­cifically noted in the cause of death. One Member State reported six non-fatal intoxications associated with AH-7921. If this new psychoactive substance were to become more widely available and used, the implications for individual and public health could be significant. There is no information available on the social risks asso­ciated with AH-7921.

(15) The risk assessment report reveals that there is limited scientific evidence available on AH-7921 and points out that further research would be needed to determine the health and social risks that it poses. However, the avail­able evidence and information provides sufficient ground for subjecting AH-7921 to control measures across the Union. As a result of the health risks that it poses, as documented by its detection in several reported fatalities, of the fact that users may unknowingly consume it, and of the lack of medical value or use of the substance, AH-7921 should be subjected to control measures across the Union.

(16) Since one Member State controls AH-7921 under national legislation complying with the obligations of the 1971 United Nations Convention on Psychotropic Substances and five Member States use other legislative measures to control it, subjecting this substance to control measures across the Union would help avoid the emer­gence of obstacles in cross-border law enforcement and judicial cooperation, and would help protect against the risks that its availability and use can pose.

(17) MDPV is a ring-substituted synthetic derivative of chemically related to pyrovalerone, which are both subject to control under the 1971 United Nations Convention on Psychotropic Substances.

(18) Information on the chronic and acute toxicity associated with MDPV, as well as on psychological and behavioural effects, and on dependence potential, is not collected uniformly across the Union. Information from published studies, confirmed by clinical cases, suggests that the psychopharmacological profile observed for MDPV is similar to that for cocaine and , albeit more potent and longer lasting. Furthermore, MDPV was found to be 10 times more potent in its ability to induce locomotor activation, tachycardia and hyperten­sion.

(19) Users’ websites indicate that its acute toxicity can provoke adverse effects on humans, similar to those associated with other stimulants. These include paranoid psychosis, tachycardia, hypertension, diaphoresis, breathing problems, severe agitation, auditory and visual hallucinations, profound anxiety, hyperthermia, violent outbursts and multiple organ dysfunctions.

(20) 108 fatalities were registered in eight Member States and Norway between September 2009 and August 2013, where MDPV has been detected in post-mortem biological samples or implicated in the cause of death. A total of 525 non-fatal intoxications associated with MDPV have been reported by eight Member States. If this new psychoactive substance were to become more widely available and used, the implications for individual and public health could be significant.

(21) The detection of MDPV has also been reported in biological samples related to fatal and non-fatal road traffic accidents, or driving under the influence of drugs, in four Member States since 2009.

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(22) MDPV has been present in the Union drug market since November 2008 and 27 Member States, Norway and Turkey reported multi-kilogram seizures of the substance. MDPV is being sold as a substance in its own right, but it has also been detected in combination with other substances. It is widely available from internet suppliers and retailers, ‘head shops’ and street-level dealers. There are some indications that suggest a degree of organisation in the tableting and distribution of this substance in the Union.

(23) The risk assessment report reveals that further research would be needed to determine the health and social risks posed by MDPV. However, the available evidence and information provides sufficient ground for subjecting MDPV to control measures across the Union. As a result of the health risks that it poses, as documented by its detection in several reported fatalities, of the fact that users may unknowingly consume it, and of the lack of medical value or use of the substance, MDPV should be subjected to control measures across the Union.

(24) Since 21 Member States control MDPV under national legislation complying with the obligations of the 1971 United Nations Convention on Psychotropic Substances and four Member States use other legislative measures to control it, subjecting this substance to control measures across the Union would help avoid the emergence of obstacles in cross-border law enforcement and judicial cooperation, and would protect against the risks that its availability and use can pose.

(25) Methoxetamine is an arylcyclohexylamine substance which is chemically similar to ketamine and the internation­ally phencyclidine (PCP). Like ketamine and PCP, it has dissociative properties.

(26) There are no studies assessing the chronic and acute toxicity associated with methoxetamine, as well as its psycho­logical and behavioural effects, and dependence potential. Self-reported experiences from user websites suggest adverse effects similar to ketamine intoxication. These include nausea and severe vomiting, difficulty in breathing, seizures, disorientation, anxiety, catatonia, aggression, hallucination, paranoia and psychosis. In addition, acute methoxetamine intoxications may include stimulant effects (agitation, tachycardia and hypertension) and cerebral features, which are not expectable with acute ketamine intoxication.

(27) Twenty deaths associated with methoxetamine were reported by six Member States that detected the substance in post-mortem samples. Used alone or in combination with other substances, methoxetamine was detected in 20 non-fatal intoxications reported by five Member States. If this new psychoactive substance were to become more widely available and used, the implications for individual and public health could be significant.

(28) 23 Member States, Turkey and Norway have reported that they detected methoxetamine, since November 2010. Information suggests that it is sold and used as a substance in its own right, but it is also sold as a ‘legal’ replace­ment for ketamine by internet retailers, ‘head shops’ and street-level drug dealers.

(29) Multi-kilogram quantities in powder form were seized within the Union, but there is no information on the possible involvement of organised crime. The manufacture of methoxetamine does not require sophisticated equipment.

(30) Prevalence data are limited to non-representative studies in two Member States. Those studies suggest that the prevalence of the use of methoxetamine is lower than that

22 / 26 RISK ASSESSMENTS I Methoxetamine Council Decision

of ketamine. The available information suggests that it may be consumed in a wide range of settings, including at home, in bars, nightclubs and at music festivals.

(31) The risk assessment report reveals that further research would be needed to determine the health and social risks posed by methoxetamine. However, the available evidence and information provides sufficient grounds for subjecting methoxetamine to control measures across the Union. As a result of the health risks that it poses, as documented by its detection in several reported fatalities, of the fact that users may unknowingly consume it, and of the lack of medical value or use, methoxetamine should be subjected to control measures across the Union.

(32) Since nine Member States control methoxetamine under national legislation complying with the obligations of the 1971 United Nations Convention on Psychotropic Substances and nine Member States use other legislative measures to control it, subjecting this substance to control measures across the Union would help avoid the emer­gence of obstacles in cross-border law enforcement and judicial cooperation, and would protect against the risks that its availability and use can pose.

(33) Decision 2005/387/JHA reserves to the Council implementing powers with a view to giving a quick and exper­tise-based response at the Union level to the emergence of new psychoactive substances detected and reported by the Member States, by submitting those substances to control measures across the Union. As the conditions and procedure for triggering the exercise of such implementing powers have been met, an implementing decision should be adopted in order to put 25I-NBOMe, AH-7921, MDPV and methoxetamine under control across the Union,

HAS ADOPTED THIS DECISION:

Article 1

The following new psychoactive substances shall be subjected to control measures across the Union:

(a) 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine(25I-NBOMe); (b) 3,4-dichloro-N-[[1-dimethylamino) cyclohexyl]methyl] benzamide (AH-7921); (c) 3,4-methylenedioxypyrovalerone (MDPV); (d) 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone (methoxetamine).

Article 2

By 2 October 2015, Member States shall subject in accordance with their national legislation, the new psychoactive substances referred to in Article 1 to control measures and criminal penalties, as provided for under their legislation complying with their obligations under the 1971 United Nations Convention on Psychotropic Substances.

Article 3

This Decision shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.

Done at Brussels, 25 September 2014. For the Council The President F. Guidi

23 / 26 RISK ASSESSMENTS I Methoxetamine

Participants of the risk assessment meeting, 1 April 2014

Scientific Committee members I Dr Anne-Line Bretteville Jensen, Norwegian Institute for Alcohol and Drug Research, Oslo I Prof. Dr Gerhard Bühringer, Addiction Research Unit, Dep. of Clinical Psychology and Psychotherapy, Technische Universität Dresden, Institut für Therapieforschung (IFT), Munich, Vice-Chair of the Scientific Committee I Dr Catherine Comiskey, Director, Centre for Practice and Healthcare Innovation, Trinity College Dublin, School of Nursing and Midwifery, Dublin I Dr Paul Dargan, Clinical Toxicology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London I Prof. Gabriele Fischer, Medical University Vienna, Center of Public Health, Department of Psychiatry and Psychotherapy, Vienna I Prof. Dr Henk Garretsen, Faculty of Social and Behavioural Sciences, Tilburg University, LE Tilburg I Prof. Dr Matthew Hickman, Social Medicine, Bristol I Prof. Dr Krzysztof Krajewski, Department of Criminology, Jagiellonian University, Kraków I Prof. Letizia Paoli, LINC, Leuven Institute of Criminology, University of Leuven Faculty of Law, Leuven I Dr Fernando Rodriguez de Fonseca, Fundación IMABIS, Hospital Carlos Haya, Málaga I Prof. Dr Brice De Ruyver, Department of Criminal Law and Criminology, Faculty of Law, Universiteit Gent I Prof. Dr Rainer Spanagel, Institute of Psychopharmacology, Central Institute of Mental Health, Mannheim

Advisers to the Scientific Committee I Dr Peter Blanckaert, Belgian Early Warning System on Drugs, DO Public Health and Surveillance, Substance use and related disorders (SURD), Brussels I Dr Simon Brandt, School of and Biomolecular Sciences, Liverpool John Moores University, Liverpool I Prof. Desmond Corrigan, The School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin I Prof. Gaetano Di Chiara, Cagliari University, Biomedical Sciences Department, Cagliari I Dr Dariusz Zuba, Institute of Forensic Research, Kraków

Representatives of the institutions

European Commission I Elsa Maia, Anti-Drugs Policy Unit, European Commission, Brussels I Fabiano Reniero, Joint Research Centre, Institute for Health and Consumer Protection (IHCP), Brussels

24 / 26 RISK ASSESSMENTS I Methoxetamine Participants of the risk assessment meeting

European Medicines Agency (EMA) I Jean-Marc Vidal, Scientific Support and Projects, Non-clinical Safety, Human Medicines Evaluation Division, London

Europol I Daniel Dudek, Project SYNERGY, Europol, The Hague

EMCDDA I Paul Griffiths, Scientific Director, EMCDDA, Lisbon I Roumen Sedefov, Head of unit, Supply reduction and new trends unit, EMCDDA, Lisbon

Invited external experts I Dr Simon Elliott, (ROAR) Forensics Ltd, Worcestershire I Dr István Ujváry, Budapest University of Technology and Economics, Budapest I Dr David Wood, Clinical Toxicology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London

EMCDDA staff present I Ana Gallegos, Head of Sector, Action on new drugs, Supply reduction and new trends unit I Andrew Cunningham, Scientific analyst, Action on new drugs, Supply reduction and new trends unit I Michael Evans-Brown, Scientific analyst, Action on new drugs, Supply reduction and new trends unit I Anabela Almeida, Project assistant, Action on new drugs, Supply reduction and new trends unit I Isabelle Giraudon, Scientific analyst, Health consequences, Prevalence, consequences and data management unit

25 / 26 TD-AK-14-004-EN-N Recommended citation:

European Monitoring Centre for Drugs and Drug Addiction (2014), Report on the risk assessment of 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone (methoxetamine) in the framework of the Council Decision on new psychoactive substances, Risk Assessments, Publications Office of the European Union, Luxembourg.

About the EMCDDA

The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the central source and confirmed authority on drug-related issues in Europe. For over 20 years, it has been collecting, analysing and disseminating scientifically sound information on drugs and drug addiction and their consequences, providing its audiences with an evidence-based picture of the drug phenomenon at European level.

The EMCDDA’s publications are a prime source of information for a wide range of audiences including: policymakers and their advisors; professionals and researchers working in the drugs field; and, more broadly, the media and general public. Based in Lisbon, the EMCDDA is one of the decentralised agencies of the European Union.

Related publications and websites

EMCDDA I Risk assessment of new psychoactive substances — operating guidelines, 2010

EMCDDA and Europol I EMCDDA–Europol Joint Report on a new psychoactive substance: methoxetamine, 2014 I EMCDDA–Europol 2013 Annual Report on the implementation of Council Decision 2005/387/JHA, 2014 I EMCDDA–Europol Early-warning system on new psychoactive substances — operating guidelines, 2007

These and all other EMCDDA publications are available from emcdda.europa.eu/publications

I EMCDDA Action on new drugs website: www.emcdda.europa.eu/drug-situation/new-drugs

Legal notice: The contents of this publication do not necessarily reflect the official opinions of the EMCDDA’s partners, the EU Member States or any institution or agency of the European Union. More information on the European Union is available on the Internet (europa.eu).

Luxembourg: Publications Office of the European Union doi: 10.2810/57161 I ISBN 978-92-9168-747-3

© European Monitoring Centre for Drugs and Drug Addiction, 2014 Reproduction is authorised provided the source is acknowledged.

This publication is only available in electronic format.

EMCDDA, Praça Europa 1, Cais do Sodré, 1249-289 Lisbon, Portugal Tel. (351) 211 21 02 00 I [email protected] emcdda.europa.eu I twitter.com/emcdda I facebook.com/emcdda