AB-PINACA. Critical Review Report

AB-PINACA (N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indazole-3-carboxamide), originally developed by Pfizer Inc. as a synthetic cannabinoid receptor agonist (SCRA), has been encountered outside medical settings as a synthetic constituent and found in herbal smoking mixtures that are sold under a variety of brand names. It is common for retailers to purchase bulk quantities of the synthetic substance and add the synthetic material to plant matter that is then distributed onto the market. However, AB-PINACA is also available in powdered form as a “research chemical”. The identification of AB-PINACA was reported first in 2012 by Japan and more forensic detections began to emerge in other countries in 2013. Data from law enforcement suggest that AB-PINACA was one of the most prevalent substances in the United States of America in 2014, which dropped again in the following years. A small number of in vitro and in vivo studies are currently available but the data indicate that AB-PINACA binds to and activates human CB1 and CB2 receptors at low nanomolar concentrations, and that it induces a number of biological responses also triggered by the naturally occurring phytocannabinoid Δ9-THC. In tetrad assays (locomotor suppression, antinociception, hypothermia, and catalepsy), for example, AB- PINACA was shown to be 2- to 14-fold more potent than Δ9-THC and the effects were rimonabant-reversible. In some in vitro assays, AB-PINACA acted as a full agonist with slight selectivity for the hCB2 receptor. AB-PINACA also fully substituted for Δ9-THC in the drug discrimination paradigm and was 1.5-fold more potent than the training drug, which suggests that AB-PINACA may have abuse liability similar to Δ9-THC and/or other internationally controlled synthetic cannabinoid receptor agonists. Reports indicate an increasing trend for SCRAs being implicated in mini epidemics that have been associated with severe adverse drug effects including deaths. Reported adverse drug reactions associated with a range of SCRAs frequently include gastrointestinal (e.g. nausea/hyperemesis), neurological (e.g. hallucination, agitation, anxiety, paranoia, confusion, delusions, catatonia, lethargy, psychosis (including susceptible individuals)), cardiovascular (e.g. tachycardia, hypertension) and renal (e.g. acute kidney failure) features. The total number of cases reported in the scientific literature that make a causal link with AB-PINACA is very small. Intoxications and deaths associated with AB-PINACA have been reported but very few details are available. ‘Driving Under the Influence’ cases linked to AB-PINACA intoxication and ‘Drug Recognition Expert’ exams revealed significant impairment. Although not specific to just AB-PINACA, there are indications that socially vulnerable and stigmatized drug users for example found in homeless and prison populations, are increasingly associated with problematic use of SCRA products. Heavy use of SCRAs has been associated with problematic withdrawal symptoms even though further research is needed to investigate the underlying mechanisms. Epidemiological data, such as prevalence of use, abuse and dependence information specifically related to AB-PINACA could not be identified

4-Fluoroamphetamine (4-FA). Critical Review Report.

1-(4-Fluorophenyl)propan-2-amine (4-fluoroamphetamine, 4-FA) is a psychomotor stimulant that was first synthesized in the early 1940s. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) received the first formal notification of the detection of 4-FA in Europe in December 2008 although its presence has been noted since at least 2007. In Europe, it has been found in tablets sold as ‘ecstasy’/MDMA, paste or powder sold as amphetamine. In addition, it can be obtained from Internet retailers as a ‘research chemical’ and it has also been detected as an adulterant present in other illicit controlled substances. 4-FA appears to be most commonly administered orally or by nasal insufflation (snorting). The EMCDDA has been notified of seizures from various locations in Europe since 2008. Data indicate that 4-FA may be able to inhibit monoamine oxidase and that it functions as a substrate-type releasing agent of dopamine, norepinephrine and serotonin. It has been shown to display amphetamine-like features in vivo and in vitro and further research is warranted to investigate the extent to which 4-FA displays a potential for abuse and dependence in both animals in humans that is comparable to substances such as amphetamine, cocaine or related psychostimulants. Case report data in the scientific literature that unambiguously confirm a causal relationship between adverse effects of 4-FA and its presence in biofluids are limited to only a relatively small number of cases. In cases where this information is available, reported clinical features were associated with those of a sympathomimetic toxidrome. The EMCDDA has received reports from positive identifications in biofluids samples from 2009 onward. It has been reported that 4-FA might have established itself as a drug of choice in a surveyed convenience sample of 249 life-time users of 4-FA in one European country. Surveys that systematically assess the prevalence of use 4-FA within the general population are not available

1-Phenyl-2-(pyrrolidin-1-yl)pentan-1- one (α-PVP). Critical Review Report.

1-Phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PVP) is a psychomotor stimulant that has originally been explored in the 1960s. It is the desmethyl analogue of pyrovalerone, which is listed in Schedule IV of the 1971 United Nations Convention on Psychotropic Substances. A closely related derivative of α-PVP gives rise to 1-(1,3-benzodioxol-5-yl)-2-(pyrrolidin-1-yl)pentan-1-one (3,4-methylenedioxypyrovalerone, MDPV) that has recently been placed in Schedule II of the UN Convention on Psychotropic Substances (1971). The first official notification of α-PVP detection in the European Union was received in February 2011. α-PVP is a synthetic cathinone derivative and commonly referred to as a new psychoactive substance (NPS), ‘research chemical’, ‘bath salt’ or ‘designer drug’. α-PVP appears to act as a potent blocker at the dopamine and norepinephrine transporter and pre-clinical research into areas of abuse liability, psychomotor activity and drug discrimination suggests that the properties of α- PVP are reminiscent of MDPV, methamphetamine and cocaine. Data indicate that α-PVP is most commonly encountered in powdered and tablet form. In addition to being available from Internet vendors in both wholesale and consumer amounts, α-PVP has also been encountered in products destined for the traditional illicit drugs market, for example, in form of ‘ecstasy’ tablets. More than 130 deaths have been associated with α-PVP and among the non-fatal acute intoxications reported, hospitalizations were required. In cases where α-PVP use was established unambiguously, neurological and cardiovascular effects consistent with an extensive psychostimulant toxidrome have been observed and included cardiotoxicity, violent behavior and display of psychotic behavior. In addition to use by traditional recreational drug users it appears that α-PVP is also used by high-risk drug users including those who inject

Critical Review Report: p-Fluoro-butyrylfentanyl

Substance identification p-Fluoro-butyrylfentanyl (IUPAC name: N-(4-fluorophenyl)-N-[1-(2-phenylethyl)piperidin-4- yl]butanamide) is a synthetic analog of the opioid analgesic fentanyl. In Europe, it was first reported in 2014 followed by the Untied States of America in 2015. Samples obtained from seizures and collections suggest that p-fluoro-butyrylfentanyl appears in powder, tablet, nasal spray and e-liquid form. Examples exist where it might be found in samples mixed with heroin. WHO Review History p-Fluoro-butyrylfentanyl has not been previously pre-reviewed or critically reviewed. Chemistry There is no specific information available about the routes of synthesis employed for the p-fluoro- butyrylfentanyl products circulating on the drug market but straightforward methods for its preparation exist without requiring access to precursors that are controlled internationally. Routes of synthesis also exist that might require the use of a controlled precursor. Ease of convertibility into controlled substances p-Fluoro-butyrylfentanyl could be converted to its isomer p-fluoro-isobutyrylfentanyl (IUPAC name: N-(4-fluorophenyl)-2-methyl-N-[1-(2-phenylethyl)piperidin-4-yl]propanamide), which is listed in Schedule I of the Single Convention on Narcotic Drugs of 1961, as amended by the 1972 Protocol. Similarity to known substances / Effects on the central nervous system Data from human studies are not available but the information available so far suggests that the effects induced by p-fluoro-butyrylfentanyl are also shared by other synthetic opioids such as fentanyl and heroin. General pharmacology Pharmacological studies have shown that p-fluoro-butyrylfentanyl is qualitatively similar to fentanyl and heroin. p-Fluoro-butyrylfentanyl binds to μ-opioid receptors (MOR) with high selectivity over the κ- and δ-opioid receptors and has been shown to act as a partial agonist at MOR in a [35S]GTPγS binding assay. Similar to both fentanyl and morphine, p-fluoro- butyrylfentanyl was also shown to induce locomotor activity and antinociceptive effects in mice. Antinociceptive effects were attenuated by pre-treatment with naltrexone. Toxicology Data on the toxicology of p-fluoro-butyrylfentanyl could not be identified. Adverse reactions in humans p-Fluoro-butyrylfentanyl has been detected in biological samples obtained from fatal intoxication cases although unambiguous differentiation from the p-fluoro-isobutyrylfentanyl isomer was not always possible. A report detailing an acute intoxication revealed that clinical features included disorientation, slurred speech and hypotension. Dependence potential No studies available. Experience with fentanyl and other synthetic opioids suggest that the dependence potential might extend to p-fluoro-butyrylfentanyl but further studies are warranted to explore this. Abuse potential Whilst no formal studies exist, the limited available information indicates that p-fluoro- butyrylfentanyl is used by experimental users (psychonauts) and people who also use synthetic opioids and opiates. It is likely that p-fluoro-butyrylfentanyl will be associated with abuse liability. Therapeutic applications / usefulness p-Fluoro-butyrylfentanyl is not known to have any therapeutic uses. Listing on WHO Model List of Essential Medicines p-Fluoro-butyrylfentanyl is not listed. Marketing authorizations p-Fluoro-butyrylfentanyl is not known to have any marketing authorizations. Industrial use p-Fluoro-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Non-medical use The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). Similar to other fentanils, p-fluoro-butyrylfentanyl may be administered as a solution (e.g. using nasal sprays), orally as a powder (including in capsules or tablets), or by insufflation of a powder; it can also be administered sublingually or intranasally via a spray; administered by injection (intramuscular or intravenous) or inhaled by vaporizing. Nature and magnitude of public health problems Use of p-fluoro-butyrylfentanyl appears to be limited to recreational substance users rather than the general population. Marginalized and vulnerable opioid users including those who inject such substances also use fentanyl analogs. However, users may not be aware of using them and the high potency associated with fentanyl analogs might result in increased risks of life-threatening overdoses. At the same time, fentanyl and its analogs pose a serious risk of accidental exposure to such products with the potential for subsequent poisoning of the public, law enforcement and emergency personnel, as well as medical/laboratory personnel. Licit production, consumption, and international trade p-Fluoro-butyrylfentanyl is not known to have any agricultural, industrial or cosmetic uses even though it is available for purchase as a ‘research chemical’. Illicit manufacture and traffic So far the total number of reports describing the identification of p-fluoro-butyrylfentanyl seems comparatively low but it an increase in detections has been reported in the US. p-Fluoro- butyrylfentanyl can be purchased from Internet retailers. Current international controls and their impact p-Fluoro-butyrylfentanyl is not controlled under the 1961, 1971 or 1988 United Nations Conventions. Current and past national controls p-Fluoro-butyrylfentanyl is controlled in some UN Member States

4-Methylethcathinone (4-MEC). Critical Review Report. Agenda Item 4.3.

Expert Committee on Drug Dependence. World Health Organisation. Thirty-eighth Meeting. Geneva, Switzerland, 14-18 November 2016

Technical report on 1-phenyl-2- (pyrrolidin-1-yl)pentan-1-one (α-pyrrolidinovalerophenone, α-PVP)

This publication presents the data and findings of the risk assessment on α-PVP (1-phenyl- 2-(1-pyrrolidinyl)-1-pentanone), carried out by the extended Scientific Committee of the EMCDDA on 18 November 2015. α-PVP is the eleventh new psychoactive substance to be risk assessed under the terms of Council Decision 2005/387/JHA. On the basis of the Risk Assessment Report — and on the initiative of the European Commission — on 27 June 2016, the Council decided that α-PVP should be subject to control measures across the Member States

Critical Review Report: 5F-MDMB-PICA.

Substance identification: The identification of 5F-MDMB-PICA (5F-MDMB-2201) (IUPAC name: methyl (2S)-2-{[1-(5-fluoropentyl)-1H-indole-3-carbonyl]amino}-3,3-dimethylbutanoate) has been described first in 2016. Information obtained from seizures and collections suggests that it has been encountered in powdered form and as a synthetic constituent in herbal plant mixtures most commonly distributed for the purpose of smoking and/or vaping. It is the indole analogue of 5F-ADB (5F-MDMB-PINACA) that is listed in Schedule II of the Convention on Psychotropic Substances of 1971. WHO Review History: 5F-MDMB-PICA has not been previously pre-reviewed or critically reviewed. Chemistry: There is no specific information available about the routes of synthesis employed for seized 5FMDMB-PICA products circulating on the drug market but straightforward methods for its preparation exist without requiring access to precursors that are controlled internationally. The presence of an asymmetric carbon atom gives rise to the (R)- and (S)-enantiomer and it seems likely for 5F-MDMB-PICA to be most commonly available as the (S)-enantiomer. Ease of convertibility into controlled substances: There is no specific information available but it appears unlikely that 5F-MDMB-PICA is converted into a substance currently listed in any of the international drug conventions. Similarity to known substances / Effects on the central nervous system: The information currently available suggests that 5F-MDMB-PICA functions as a synthetic cannabinoid receptor agonist (SCRA). Information about effects induced in vivo is currently not available but the existing data suggest that 5F-MDMB-PICA will likely exhibit a profile shared by other SCRAs controlled internationally (potent full agonists at cannabinoid receptors) such as 5F-ADB. General pharmacology: 5F-MDMB-PICA, in its pure form but mostly as a synthetic constituent added to a plant matrix, is primarily smoked (or vaped) although reliable data about dosage are unavailable. A small number of in vitro studies are currently available and the data indicate that 5F-MDMB-PICA binds to and activates human CB1 and CB2 receptors at low nanomolar concentrations. 5F-MDMB-PICA acted as a full agonist at both receptor subtypes with significantly higher potency than Δ9-THC which has also been observed with other SCRAs that are listed in the Convention on Psychotropic Substances of 1971. Data collected from in vitro metabolism studies and detections in biological specimens revealed that the biotransformation observed included mono-hydroxylation, oxidative defluorination, dehydrogenation, amide, and ester hydrolysis, as well as combinations thereof. Glucuronidation products have also been detected. Toxicology: Information could not be identified. Adverse reactions in humans: Detailed information about the clinical features associated with the consumption of 5F-MDMBPICA specifically is not available. However, “mass-overdose” cases were described in Connecticut (United States of America (USA)) that have been associated with the detection of 5F-MDMB-PICA and other SCRAs and fentanyl. Clinical features reported included decreased mental status, agitated delirium, and seizures. Within a 6-day period in September 2018, 244 overdose cases (details not reported) have been identified in Washington, DC, (USA) that also included the detection of 5F-ADB and other SCRAs. Data collected from intoxication cases with other SCRAs suggest that clinical features might include a range of adverse effects on gastrointestinal, neurological, and cardiovascular systems. Dependence potential: No studies carried out in humans or animals could be identified. Abuse potential: Studies specifically linked to 5F-MDMB-PICA could not be identified. Therapeutic applications / usefulness: 5F-MDMB-PICA is not known to have any therapeutic uses. Listing on WHO Model List of Essential Medicines: 5F-MDMB-PICA is not listed. Marketing authorizations: 5F-MDMB-PICA is not known to have any marketing authorisations. Industrial use: 5F-MDMB-PICA is not known to have any agricultural, industrial or cosmetic uses. Non-medical use: The mode of use may involve the combinational use (intentionally or unintentionally) of other drugs and users may be unaware of the exact dose or compound being ingested (by whatever route). Household or subpopulation surveys that specifically probe for prevalence of 5F-MDMBPICA could not be identified. People who use SCRAs in general include recreational users, high-risk substance users but also individuals who are subject to drug testing such as people in drug treatment, prisoners, abstinence control programs and drivers. Nature and magnitude of public health problems: Products sold as herbal smoking mixtures frequently change in drug composition and quantity, often without indications on product labels, which results in challenges to unambiguously correlate harms to public health with a specific drug such as 5F-MDMB-PICA. People who use these drugs are most likely not aware of the identity of the constituent and the quantity. The consumption of these products might be attractive to a variety of users, such as regular users of cannabis and those who believe that SCRA use might help with avoiding a positive finding in drug testing procedures. There are indications that socially vulnerable and stigmatised substance users, for example found in homeless and prison populations, are increasingly associated with problematic use of SCRA products. Heavy use of SCRAs has been associated with problematic withdrawal symptoms and further research is needed to evaluate the underlying mechanisms. Licit production, consumption, and international trade: 5F-MDMB-PICA is available as standard reference material and produced for scientific research by a number of commercial suppliers. Other uses could not be identified. Illicit manufacture and traffic: 5F-MDMB-PICA began to emerge at the end 2016 both in Europe and the USA. In general, SCRAs are often imported in their pure form and converted into herbal forms on the domestic level. In recent years it has emerged that SCRAs have been smuggled into prisons in the form of impregnated papers (e.g. letters) and textiles and this extended to the detection of 5F-MDMBPICA. Current international controls and their impact: 5F-MDMB-PICA is not controlled under the 1961, 1971 or 1988 United Nations Conventions. Current and past national controls: 5F-MDMB-PICA is controlled in some UN Member States