U.S. Department of Justice Drug Enforcement Administration

Methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate [5F- ADB; 5F-MDMB-PINACA]; methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3- methylbutanoate [5F-AMB]; N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H-indazole-3- carboxamide [5F-APINACA, 5F-AKB48]; N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4- fluorobenzyl)-1H-indazole-3-carboxamide [ADB-FUBINACA]; methyl 2-(1- (cyclohexylmethyl)-1H--3-carboxamido)-3,3-dimethylbutanoate [MDMB-CHMICA, MMB-CHMINACA]; methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3,3- dimethylbutanoate [MDMB-FUBINACA]

Eight Factors Data Review document Pursuant to 21 U.S.C. 812(a) Prepared by Diversion Control Division, Drug and Chemical Evaluation Section Washington, D.C. 20537 March 2019

DEA/DC/DP/DPE Page 1 of 47 March 2019 I. Background

On April 10, 2017, the Acting Administrator of the Drug Enforcement Administration (DEA) published a Final Order in the Federal Register (82 FR 17119) temporarily placing six synthetic (SC) substances in schedule I of the Controlled Substances Act (CSA) upon finding that these substances pose an imminent threat to public safety. The six SCs temporarily controlled under the CSA are methyl 2-(1-(5-fluoropentyl)-1H-indazole-3- carboxamido)-3,3-dimethylbutanoate [5F-ADB; 5F-MDMB-PINACA]; methyl 2-(1-(5- fluoropentyl)-1H-indazole-3-carboxamido)-3-methylbutanoate [5F-AMB]; N-(adamantan-1-yl)- 1-(5-fluoropentyl)-1H-indazole-3-carboxamide [5F-APINACA, 5F-AKB48]; N-(1-amino-3,3- dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide [ADB- FUBINACA]; methyl 2-(1-(cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3- dimethylbutanoate [MDMB-CHMICA, MMB-CHMINACA] and methyl 2-(1-(4-fluorobenzyl)- 1H-indazole-3-carboxamido)-3,3-dimethylbutanoate [MDMB-FUBINACA]. These six SCs have not been investigated for medical use nor are they intended for human use. With no known legitimate use and safety information, manufacturers are surreptitiously adulterating plant material with these SCs and distributors are selling the associated products which pose potentially dangerous consequences to the consumer. The adulterated products, such as “Spice”, “K2” and many others, are marketed under the guise of “herbal incense” or “potpourri” products and as “legal alternatives to marijuana” or “legal high”. Data from law enforcement, health care practitioners, and scientific and medical literature indicate that these products are being abused for their psychoactive properties in the absence of information regarding their safety. There have been reports of admissions to hospital emergency departments (ED) following abuse of these synthetic .

SCs are substances synthesized in laboratories that mimic the biological effects of delta- 9- (THC), the main psychoactive ingredient in marijuana. It is believed SCs were first introduced on the designer drug market in several European countries as “herbal incense” before the initial encounter in the United States by U.S. Customs and Border Protection (CBP) in November 2008. The misuse of SCs began to increase in the United States in 2009, with law enforcement encounters describing SCs applied onto plant material and in other designer drug products intended for human consumption. It has been demonstrated via

DEA/DC/DP/DPE Page 2 of 47 March 2019 medical examiner reports, scientific publications and law enforcement reports that the substances and the associated designer drug products are abused for their psychoactive properties. With many generations of SCs having been encountered since 2009, 5F-ADB, 5F- AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA are some of the latest, and the abuse of these substances is negatively impacting communities.

As observed by the DEA and CBP, SCs originate from foreign sources, such as China. Bulk powder substances are smuggled via common carrier into the United States and find their way to clandestine designer drug product manufacturing operations located in residential neighborhoods, garages, warehouses, and other similar destinations throughout the country. According to online discussion boards and law enforcement encounters, spraying or mixing the SCs with plant material provides a vehicle for the most common route of administration— smoking (using a pipe, a water pipe, or rolling the drug-laced plant material in cigarette papers).

5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA, and MDMB-FUBINACA have no accepted medical use in the United States. Use of these specific SCs has been reported (see factor 6) to result in adverse effects including deaths.

5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA are SCs (figure 1) that have pharmacological effects similar to the schedule I THC (Janowsky et al., 2014; Hasegawa, 2015a,b; correspondence from law enforcement and laboratory data transmitted to the DEA (see factor 6)) and other temporarily and permanently controlled schedule I synthetic cannabinoid substances (e.g., JWH-018). In addition, the misuse of 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB- CHMICA and/or MDMB-FUBINACA has been associated with either overdoses requiring emergency medical intervention or death (see factor 6). With no approved medical use and limited safety or toxicological information, 5F-ADB, 5F-AMB, 5F-APINACA, ADB- FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have emerged on the designer drug market, and the abuse of these substances for their psychoactive properties is concerning. Section 1152 of the Food and Drug Administration Safety and Innovation Act (section 1152) amended the CSA by placing cannabimimetic agents and 26 specific substances (including 15

DEA/DC/DP/DPE Page 3 of 47 March 2019 SCs, 2 synthetic cathinones, and 9 phenethylamines of the -series) in schedule I. 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA were not included among the 15 SCs that are specifically named in section 1152, and do not fall under the legal definition of cannabimimetic agents as provided under this section. On April 22, 2016, the Acting Administrator of the DEA notified the Department of Health and Human Services (HHS) of his intention to publish in the Federal Register a Notice of Intent to temporarily place 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA in schedule I of the CSA. The Assistant Secretary of Health for the U.S. Department of Health and Human Services (HHS) advised DEA on May 2, 2016 that there are no approved new drug applications (NDAs) or investigational new drug applications (INDs) for 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA under section 505 (21 U.S.C. 355) of the Federal Food, Drug, and Cosmetic Act. HHS had no objection regarding the temporary placement of 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA into schedule 1 of the CSA. To protect the public health and safety, the DEA then temporarily placed 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA in schedule I of the CSA on April 10, 2017. 82 FR 17119.

After assessing all the available data, the Food and Drug Administration (FDA) recommended that methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido)-3,3- dimethylbutanoate [5F-ADB; 5F-MDMB-PINACA]; methyl 2-(1-(5-fluoropentyl)-1H-indazole- 3-carboxamido)-3-methylbutanoate [5F-AMB]; N-(adamantan-1-yl)-1-(5-fluoropentyl)-1H- indazole-3-carboxamide [5F-APINACA, 5F-AKB48]; N-(1-amino-3,3-dimethyl-1-oxobutan-2- yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide [ADB-FUBINACA]; methyl 2-(1- (cyclohexylmethyl)-1H-indole-3-carboxamido)-3,3-dimethylbutanoate [MDMB-CHMICA, MMB-CHMINACA] and methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamido)-3,3- dimethylbutanoate [MDMB-FUBINACA] be permanently placed into schedule I of the CSA. The National Institute on Drug Abuse (NIDA) concurred with the FDA recommendation. Schedule I drugs are classified as having a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use of the drug under medical supervision.

DEA/DC/DP/DPE Page 4 of 47 March 2019 II. Eight Factors Determinative of Control

In accordance with the provisions of 21 U.S.C. 811(b) of the Controlled Substances Act (CSA), the DEA has gathered the necessary data, including scientific, public health, and law enforcement information on these six substances, as well as their associated products. The DEA collected data in light of the information to be considered under 21 U.S.C. 811(c). On September 27, 2017, the DEA requested from the Acting Assistant Secretary of Health for HHS a scientific and medical evaluation and scheduling recommendation for 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA pursuant to 21 U.S.C. 811(b). Administrative responsibilities for evaluating a substance for control under the CSA are performed for the HHS by the FDA, with the concurrence of the NIDA ((Memorandum of Understanding, 50 FR 9518–20) (Mar. 8, 1985)). Upon receipt and evaluation of the scientific and medical evaluation and scheduling recommendation from the Assistant Secretary on March 21, 2019, the DEA reviewed these documents and all other relevant data and conducted its own eight-factor analysis on these SCs pursuant to 21 U.S.C. 811(c). The DEA’s eight-factor review as presented below finds that 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA, and their salts, isomers, and salts of isomers warrant control in schedule I of the CSA.

Factor 1: The Actual or Relative Potential for Abuse

The first factor the DEA must consider is the actual or relative potential for abuse of 5F- ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA. In addition to the information the HHS provided in its scientific and medical evaluation document for 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB- CHMICA and MDMB-FUBINACA (HHS, 2019), the DEA considers all other relevant data regarding the actual or relative potential for abuse. The term “abuse” is not defined in the CSA. However, the legislative history of the CSA suggests that the DEA consider the following criteria in determining whether a particular drug or substance has a potential for abuse1:

1 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970); reprinted in 1970 U.S.C.C.A.N. 4566, 4603.

DEA/DC/DP/DPE Page 5 of 47 March 2019 a) There is evidence that individuals are taking the drug or drugs containing such a substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or of the community; or

b) There is significant diversion of the drug or drugs containing such a substance from legitimate drug channels; or

c) Individuals are taking the drug or drugs containing such a substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice; or

d) The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a potential for abuse to make it likely that the drug will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

Of course, evidence of actual abuse of a substance is indicative that a drug has a potential for abuse.

a. There is evidence that individuals are taking the drug or drugs containing such a substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community.

HHS noted that individuals are taking 5F-ADB, 5F-AMB, 5F-APINACA, ADB- FUBINACA, MDMB-CHMICA and/or MDMB-FUBINACA in sufficient amounts to create a health hazard (HHS, 2019). Adverse effects observed following the ingestion of SCs, including 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA, include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitching, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and/or cognitive impairment (Kaneko et al, 2017; EMCDDA, 2017; Barcelo et al., 2017; Langer et al., 2016; Hasegawa 2015a,b; Hess et al., 2015; Shanks and Behonick, 2016; Abouchedid et al., 2016, 2017; Lam et a;, 2017; Shanks et al., 2016; Angerer et al., 2016; Adamowicz, 2016; Bäckberg et al., 2016; Hill et al., 2016; Meyyappan et

DEA/DC/DP/DPE Page 6 of 47 March 2019 al., 2016). SCs like 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA are easily accessible and difficult to detect in standard urine drug screens, which contributes to their popularity and high rates of abuse (Trecki et al., 2015; Tyndall et al., 2015; Adams et al., 2017; Monte et al., 2017).

Poison centers continue to report the abuse of SCs and their associated products. These substances remain a threat to both the short- and long-term public health and safety. Exposures to SCs were first reported to the poison centers in 2011. The American Association of Poison Control Centers2 (AAPCC) reported 1,512 exposure calls in April 2015, representing an almost three-fold increase in exposures to SCs as compared to the previous largest monthly tally (657 exposures in January 2012) since reporting began in 2011. Exposure calls to the AAPCC in 2015 were the highest on record and surpassed the combined totals of 2013 and 2014. In addition, a majority of exposure incidents from 2011 to the present resulted in individuals seeking medical attention at health care facilities. In recent years, poison centers continue to report the abuse of SCs and their associated products, although numbers have been reduced as compared to those reported in 2015.

b. There is significant diversion of the drug or substance from legitimate drug channels

The HHS stated in their letter dated April 22, 2016 that there are no FDA-approved drug products containing 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA in the United States and there appear to be no legitimate sources for these substances as marketed drugs.

2 The American Association of Poison Control Centers collects information logged by the numerous regional Poison Control Centers (PCCs). Records are from self-reported calls; therefore, they reflect only information provided when the public or healthcare professional reports an actual or potential exposure to a substance ( e.g. an ingestion, inhalation, or topical exposure), or requests informational material. It warrants noting that these exposures do not inherently represent an instance of poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance.

DEA/DC/DP/DPE Page 7 of 47 March 2019 c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice

Because 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA are not approved for medical use and are not formulated or available for clinical use, the human use of these substances is assumed to be on an individual’s own initiative, rather than on the basis of medical advice from a practitioner licensed by law to administer drugs. Further, published scientific and medical literature, and reports from AAPCC and law enforcement indicate that individuals are taking these SCs on their own initiative, rather than on the basis of medical advice of a licensed practitioner.

d. The drug or drugs containing such a substance are new drugs so related in their action to a drug or drugs already listed as having a potential for abuse to make it likely that they will have the same potentiality for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

HHS detailed that 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB- CHMICA and MDMB-FUBINACA, similar to schedule I SCs (e.g., JWH-018), bind to and activate CB1 cannabinoid (HHS, 2019; see factor 2). As stated by HHS, 5F-ADB, 5F- AMB, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA produced THC-like discriminative stimulus effects in rats trained to discriminate THC from vehicle control (HHS, 2019). DEA further notes that in drug discrimination studies conducted under the interagency agreement between DEA and FDA, 5F-APINACA also produced THC-like discriminative stimulus effects in rats trained to discriminate THC from vehicle control (see Factor 2). 5F- APINACA also produced typical THC-like effects in cannabinoid tetrad assay (Canazza et al., 2016).

DEA/DC/DP/DPE Page 8 of 47 March 2019 The abuse of 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA, similar to schedule I SCs, has been associated with various adverse health effects (see Factor 6). As stated by the HHS, it is reasonable to assume that these six SCs have substantial capability to be a hazard to the health of the user and to the safety of the community.

Factor 2: Scientific Evidence of Pharmacological Effect, if Known

As noted by HHS, THC is the principle psychoactive substance in marijuana (Schedule 1). HHS reported on in vitro receptor binding and functional assays that were conducted with 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA (HHS, 2019; Table 1). In addition, drug discrimination studies using Sprague Dawley rats investigating the THC-like stimulus effects of these SCs have been completed (Table 2). These results indicate that 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA, similar to other schedule I SCs, bind to CB1 receptors and act as agonists at CB1 receptors and produce THC-like discriminative stimulus effects.

Table 1. Data from in vitro CB1 receptor binding and functional studies for 5F-ADB, 5F- AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA In vitro CB1 Binding Affinity CB1 Functional Activity (Ki, nM) (EC50, nM) 5F-ADB (5F-MDMB- 374e 23.6e, 0.59g PINACA) 5F-AMB 8a 2.17a, 1.9g 5F-APINACA (5F-AKB48) 5.3f, 1.82h 1.36f, 2.57h ADB-FUBINACA 0.85b 0.04b MDMB-CHMICA (MMB- 4.1c 0.57c, 10g CHMINACA) MDMB-FUBINACA 1.35d 0.03d, 3.9g a Janowsky, 2014, b Janowsky, 2015a, c Janowsky, 2015b, d Janowsky, 2015c, e Janowsky, 2015d, f Janowsky, 2015e, g Banister et al., 2016, h Canazza et al., 2016

DEA/DC/DP/DPE Page 9 of 47 March 2019 Table 2. Data from in vivo animal studies (drug discrimination and Tetrad assays) for 5F- ADB, 5F-AMB, ADB-FUBINACA, MDMB-CHMICA, MDMB-FUBINACA and 5F- APINACA In vivo Drug Discrimination (ED50) 5F-ADB (5F-MDMB-PINACA) 0.071 mg/kga (Full Substitution) b 5F-AMB 0.18 mg/kg (Full Substitution) ADB-FUBINACA 0.075 mg/kgd (Full Substitution) MDMB-CHMICA 0.010 mg/kge (Full Substitution) MDMB-FUBINACA 0.015 mg/kgf (Full Substitution) 5F-APINACA (5F-AKB48) 0.276 mg/kgg (Full Substitution) Tetrad 5F-APINACA (5F-AKB48) Induced typical tetrad effect in mice, no ED50 values givenc a NIDA, 2017, b NIDA, 2016, c Canazza et al., 2016, d NIDA 2018a, e NIDA 2018b, f NIDA 2018c, gFDA 2018

The drug discrimination assay is a well-accepted animal model used to predict subjective effects of substances in humans (Schuster and Johanson, 1988; Balster and Bigelow, 2003; Tai and Fantegrossi, 2014). In NIDA-sponsored studies (5F-ADB, 5F-AMB, ADB- FUBINACA, MDMB-CHMICA, and MDMB-FUBINACA) and in drug discrimination studies (5F-APINACA) conducted under the interagency agreement between DEA and FDA, these SCs, similar to other schedule I SCs (e.g., JWH-018; AM2201; ADB-PINACA, AB- FUBINACA etc.), fully substituted for THC in animals trained to discriminate the stimulus effects of THC (3 mg/kg) from its vehicle control (see Table 2). 5F-APINACA also produced typical THC-like effects in cannabinoid tetrad assay (Canazza et al., 2016).

As noted by HHS, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB- CHMICA and MDMB-FUBINACA, similar to THC and schedule I SCs (e.g., JWH-018), produced a time- and dose-dependent depression of locomotor activity (HHS, 2019).

Human Studies

No human studies involving 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have been reported.

DEA/DC/DP/DPE Page 10 of 47 March 2019 Factor 3: The State of Current Scientific Knowledge Regarding 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA

As noted by the HHS, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB- CHMICA and MDMB-FUBINACA are structurally unrelated to THC and are potent cannabinoids (HHS, 2019). Emerging in the early 1980’s, SCs were originally designed to investigate structure activity relationships (SAR) based on the potent substance, 9-nor-9β- hydroxyhexahydrocannabinol (HHC) (Weissman et al., 1982; Melvin et al., 1984). Interest in various structural classes was generated by the mouse vas deferens (MVD) and prostaglandin synthetase activity of and subsequent finding of its affinity to the (Huffman, 2009).

DEA/DC/DP/DPE Page 11 of 47 March 2019 Chemistry and Physical Properties Figure 1. Chemical Structures of 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA

DEA/DC/DP/DPE Page 12 of 47 March 2019 Table 3. The chemical and physical properties of Methyl 2-(1-(5-fluoropentyl)-1H- indazole-3-carboxamido)-3,3-dimethylbutanoate Synonyms 5F-ADB; 5F-MDMB-PINACA Systemic Name (IUPAC, CAS) Methyl 2-(1-(5-fluoropentyl)-1H-indazole-3- carboxamido)-3,3-dimethylbutanoate CAS # 1838134-16-9 Chemical Formula C20H28FN3O3 Molecular Weight 377.5 g mol-1

Table 4. The chemical and physical properties of Methyl 2-(1-(5-fluoropentyl)-1H- indazole-3-carboxamido)-3-methylbutanoate Synonyms 5F-AMB Systemic Name (IUPAC, CAS) Methyl 2-(1-(5-fluoropentyl)-1H-indazole-3- carboxamido)-3-methylbutanoate CAS # 1801552-03-3 Chemical Formula C19H26FN3O3 Molecular Weight 363.4 g mol-1

Table 5. The chemical and physical properties of N-(1-adamantyl)-1-(5-fluoropentyl)-1H- indazole-3-carboxamide Synonyms 5F-APINACA; 5F-AKB48 Systemic Name (IUPAC, CAS) N-(1-adamantyl)-1-(5-fluoropentyl)-1H- indazole-3- carboxamide CAS # 1400742-13-3 Chemical Formula C23H30FN3O Molecular Weight 383.5 g mol-1

Table 6. The chemical and physical properties of N-(1-amino-3,3-dimethyl-1-oxobutan-2- yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide Synonyms ADB-FUBINACA Systemic Name (IUPAC, CAS) N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4- fluorobenzyl)-1H-indazole-3-carboxamide CAS # 1445583-51-6 Chemical Formula C21H23FN4O2 Molecular Weight 382.4 g mol-1

Table 7. The chemical and physical properties of Methyl 2-(1-(cyclohexylmethyl)-1H- indole-3-carboxamido)-3,3-dimethylbutanoate Synonyms MDMB-CHMICA Systemic Name (IUPAC, CAS) Methyl 2-(1-(cyclohexylmethyl)-1H-indole-3- carboxamido)-3,3-dimethylbutanoate CAS # 1971007-95-0 Chemical Formula C23H32N2O3 Molecular Weight 384.5 g mol-1

DEA/DC/DP/DPE Page 13 of 47 March 2019 Table 8. The chemical and physical properties of Methyl 2-(1-(4-fluorobenzyl)-1H- indazole-3-carboxamido)-3,3-dimethylbutanoate Synonyms MDMB-FUBINACA Systemic Name (IUPAC, CAS) Methyl 2-(1-(4-fluorobenzyl)-1H-indazole-3- carboxamido)-3,3-dimethylbutanoate CAS # 1971007-93-8 Chemical Formula C22H24FN3O3 Molecular Weight 397.4 g mol-1

Medical Application As stated by the HHS, if a drug has been approved by FDA under the Federal Food, Drug and Cosmetic Act for medical use in humans or animals, such a drug is considered to have an accepted medical use. In the absence of a FDA approval, if the drug meets the following five elements, such a drug may be considered to have a currently accepted medical use.3

a. The drug’s chemistry is known and reproducible; b. there are adequate safety studies; c. there are adequate and well-controlled studies proving efficacy; d. the drug is accepted by qualified experts; and e. the scientific evidence is widely available.

As mentioned by the HHS, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have not been approved by FDA for medical use in the United States (HHS, 2019). HHS noted that chemically, 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, and MDMB-FUBINACA can be described as 3-carboxamide indazole derivatives while MDMB-CHMICA belongs to the 3-carboxamide indol family. The chemical makeup of all 6 SCs are currently known, reproducible, and available for purchase from legitimate chemical companies within the US for use as laboratory standards or for research purposes. HHS also stated that there are no well-controlled studies of these six 6 SCs showing safety or efficacy. In addition, HHS stated that there is no evidence these six SCs are accepted by qualified experts as having therapeutic uses and there is no widely available scientific evidence on these substances (HHS, 2019). Thus as stated by the HHS, 5F-ADB, 5F- AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have no currently accepted medical use in the United States.

3 [Alliance for Therapeutics v. DEA, 15 F.3d 1131, 1135 (D.C. Cir. 1994)]

DEA/DC/DP/DPE Page 14 of 47 March 2019 Factor 4: Its History and Current Pattern of Abuse

As mentioned in the HHS review, have been developed by researchers over the last 30 years as tools for investigating the (HHS, 2019; Weissman et al., 1982; Huffman et al., 1996; Huffman et al., 1999). The first encounter of a SC within the United States occurred in November 2008 by CBP (Piggee, 2009). Since then, the popularity of SCs in general and their associated products has increased as evidenced by law enforcement seizures, public health information, and media reports. 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA are SCs that have been recently encountered (see factors 5 and 6). The misuse of 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and/or MDMB-FUBINACA has been associated with either overdoses requiring emergency medical intervention or death (see factor 6).

All six SCs were identified internationally prior to their discovery within the US. Initial US encounters are reported in tables 10 and 11. 5F-ADB was first identified in November 2014, in Japan in postmortem samples of an individual who died following use of an herbal product containing this substance (Hasegawa et al., 2015b). 5F-AMB was first identified in herbal smoking mixtures in Japan between November 2013 and May 2014 (Uchiyama et al., 2014). 5F- APINACA was first identified in South Korea beginning in late 2012 (Chung et al., 2014). ADB- FUBINACA was first reported in the scientific literature in a patent by Pfizer in 2009 (compound 1) followed by popularity in Turkey in 2011 prior to its emergence on the US illicit drug market in March, 2014 (Gol and Cok, 2017; WO/2009/106980). According to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA, 2015), the first seizure of MDMB-CHMICA was on September 12, 2014. Germany also reported 9 deaths and 34 non-fatal intoxications involving MDMB-CHMICA from September 2014 through October 2014. According to the United Nations Office on Drugs and Crime (UNODC, 2015), 40 kilograms of MDMB-CHMICA was identified in a seizure by Luxembourg Customs in December 2014. MDMB-FUBINACA was first identified as “MDMB /N/-Bz F” by Russian media outlets following the reported overdoses of 700 people and 25 deaths in October 20144.

4 https://www.rt.com/news/193700-russia-spice-deadly-drug/ (October 7, 2014)

DEA/DC/DP/DPE Page 15 of 47 March 2019 Research and clinical reports have demonstrated that SCs are applied onto plant material so that the material may be smoked as users attempt to obtain a euphoric and psychoactive “high,” believed to be similar to marijuana (McKeever et al., 2015; Bonar et al., 2014). Data gathered from a published study (Bonar et al., 2014), and supplemented by discussions on Internet discussion websites, demonstrate that these products are being abused mainly by smoking for their psychoactive properties. The adulterated products are marketed as “legal” alternatives to marijuana. In recent cases of overdoses or deaths, 5F-ADB, 5F-AMB, 5F-APINACA, ADB- FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have been encountered in form of herbal product (Bäckberg et al., 2016; Hill et al., 2016; Hasegawa et al., 2015b; Holm et al., 2015), similar to the SCs that have been previously encountered (see Factor 6).

The powder form of SCs is typically dissolved in solvents (e.g., acetone) before being applied to plant material or dissolved in a propellant intended for use in electronic cigarette devices. Law enforcement personnel have encountered various application methods including buckets or cement mixers in which plant material and one or more SCs are mixed together, as well as large areas where the plant material is spread out so that a dissolved SC mixture can be applied directly. Once mixed, the SC plant material is then allowed to dry before illicit manufacturers package the product for distribution, ignoring any control mechanisms to prevent contamination or to ensure a consistent, uniform concentration of the substance in each package. Adverse health consequences may also occur from directly ingesting the drug during the manufacturing process.

The designer drug products laced with SCs, including 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA, are often sold under the guise of “herbal incense” or “potpourri,” use various product names, and are routinely labeled “not for human consumption.” Additionally, these products are marketed as a “legal high” or “legal alternative to marijuana” and are readily available over the Internet, in head shops, or sold in convenience stores. There is an incorrect assumption that these products are safe (Fattore and Fratta, 2011; McGuinness and Newell, 2012), that they are a synthetic form of marijuana, and that labeling these products as “not for human consumption” is a legal defense to criminal prosecution under the Controlled Substances Analogue Enforcement Act.

DEA/DC/DP/DPE Page 16 of 47 March 2019 The psychoactive properties are directly linked to the SCs applied onto the plant material sold as retail products (Auwarter et al., 2009; EMCDDA, 2009; Atwood et al., 2010). This was reconfirmed in a publication that analyzed various herbal products that contained SCs (Ogata et al., 2013). A few SC-containing products were found to be applied to psychoactive substances, including Cannabis sativa, and Mitragyna speciosa. The plant material most commonly found as a carrier medium in SC-containing products was devoid of psychoactive effects. Ogata et al (2013) stated that “the plant materials would be used mainly as diluents for the psychoactive synthetic compounds, because no reliable psychoactive effects have been reported for most of the identified plants, with the exception of the psychotropic plants; Cannabis sativa, Salvia divinorum and Mitragyna speciosa”.

A major concern, as reiterated by public health officials and medical professionals, is the targeting and direct marketing of SCs and SC-containing products to adolescents and youth (Auwarter et al., 2009; EMCDDA, 2009; Lindigkeit et al., 2009; Dresen et al., 2010; Hudson et al., 2010; Uchiyama et al., 2010; Uchiyama, 2012a; Uchiyama et al., 2012b; Oluwabusi et al., 2012; Durand et al., 2013; ONDCP, 2015). This is supported by law enforcement encounters and reports from emergency departments (SAMHSA, 2012, 2013, 2014; Fattore and Fratta, 2011; Vandrey et al., 2012); however, all age groups have been reported to abuse SC-related products (Trecki et al., 2015). Individuals, including minors, are purchasing SCs from Internet websites, gas stations, convenience stores, and head shops.

As discussed previously, it is believed most abusers of SCs or SC-related products are smoking the product following application to plant material. Law enforcement has also begun to encounter new variations of SCs in liquid form. It is believed abusers have been applying the liquid to hookahs or “e-cigarettes,” which allows the user to administer a vaporized liquid that can be inhaled.

Factor 5. The scope, duration, and significance of abuse

Following multiple scheduling actions controlling SCs, law enforcement and health care professionals have encountered novel SCs including 5F-ADB, 5F-AMB, 5F-APINACA, ADB-

DEA/DC/DP/DPE Page 17 of 47 March 2019 FUBINACA, MDMB-CHMICA and MDMB-FUBINACA differing only by small structural modifications intended to avoid prosecution while maintaining the pharmacological effects. Law enforcement and health care professionals continue to report the abuse of these substances and their associated products.

As described by NIDA, many substances being encountered in the illicit market, specifically SCs, have been available for years but have reentered the marketplace due to a renewed popularity (NIDA, 2015). The threat of serious injury to the individual following the ingestion of 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA and other SCs persists.

Louisiana issued emergency rulings adding 5F-AMB (July 3, 2014),5 MDMB-CHMICA (January 29, 2015)6 and 5F-ADB (February 26, 2015)7 to the list of schedule I Controlled Dangerous Substances upon the determination that they had a high potential for abuse and should be scheduled as controlled substances to avoid an imminent peril to the public health, safety, and welfare.

Smoking mixtures of these substances are abused for the purpose of achieving intoxication and have resulted in numerous emergency department visits and calls to poison centers, who continue to report the abuse of SCs and their associated products. As reported by the AAPCC, adverse effects including severe agitation, anxiety, racing heartbeat, high blood pressure, nausea, vomiting, seizures, tremors, intense hallucinations, psychotic episodes and suicide, and other harmful thoughts and/or actions can occur following ingestion of SCs. Presentations at emergency departments directly linked to the abuse of 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have resulted in similar symptoms, including nausea, persistent vomiting, agitation, altered mental status, seizures, convulsions, loss of consciousness, cardio toxicity and/or death (see factor 6). Exposures to SCs were first reported to the AAPCC in 2011 (Table 9). The AAPCC reported a

5 State of Louisiana, Department of Health and Hospitals, July 3, 2014. LAC 46:LIII.2704. 6 State of Louisiana, Department of Health and Hospitals, January 29, 2015. LAC 46:LIII.2704. 7 State of Louisiana, Department of Health and Hospitals, February 26, 2015. LAC 46:LIII.2704.

DEA/DC/DP/DPE Page 18 of 47 March 2019 dramatic spike in poison center exposure calls throughout the United States in 2015. The AAPCC reported 1,512 exposure calls in April 2015, representing an almost three-fold increase in exposures to SCs as compared to the previous largest monthly tally (657 exposures in January 2012) since reporting began in 2011. Exposure calls to the AAPCC in 2015 were the highest on record and surpassed the combined totals of 2013 and 2014. In addition, a majority of exposure incidents from 2011 to the present resulted in individuals seeking medical attention at health care facilities.8 SCs remain a threat to both the short- and long-term public health and safety.

Table 9. Exposure cases of synthetic cannabinoids as reported to poison centers* YEAR # OF CASES 2011 6,971 2012 5,225 2013 2,667 2014 3,681 2015 7,795 2016 2,703 2017 1,959 2018 1,954 2019* 194 * AAPCC, March 14, 2019

The following tables (tables 10 and 11) contain data on exhibits/reports obtained through the National Forensic Laboratory Information System (NFLIS) or STRIDE/STARLiMS that correspond to the specific drug listed.

8 The content of this report does not necessarily reflect the opinions or conclusions of the AAPCC. AAPCC (http://www.aapcc.org) maintains the national database of information logged by the United States’ 55 Poison Control Centers (PCCs). Case records in this database are from self-reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a substance (e.g. an ingestion, inhalation, topical exposure, etc.) or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).

DEA/DC/DP/DPE Page 19 of 47 March 2019 Table 10. Reports obtained through the NFLIS9 database§ NFLIS* §

DRUG 2012‡ 2013‡ 2014‡ 2015‡ 2016‡ 2017‡ 2018‡ 2019 STATES ‡ REPORTS 5F-ADB 0 0 43 929 4,481 7,105 7,459 51 Arizona, (5F-MDMB- (Sept) Arkansas, PINACA) California, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maryland, Minnesota, Missouri, Nebraska, New Jersey, New Mexico, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, South Carolina, Tennessee, Texas, Utah, Virginia, Washington, Wisconsin, West Virginia 5F-AMB 0 0 413 2,489 1,366 194 34 0 Alabama, (Jan.) Arizona, Arkansas, California, Colorado, Florida, Georgia, Hawaii, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana,

9 The National Forensic Laboratory Information System (NFLIS) is a national forensic laboratory reporting system that systematically collects results from drug chemistry analyses conducted by State and local forensic laboratories in the United States.

DEA/DC/DP/DPE Page 20 of 47 March 2019 Maryland, Massachusetts, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, New Mexico, New York, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, South Carolina, Tennessee, Texas, Utah, Virginia, Washington, West Virginia, Wisconsin, Wyoming 5F- 160 1,000 355 329 227 63 9 0 Alabama, APINACA (Aug) Arizona, (5F-AKB48) Arkansas, California, Colorado, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maryland, Massachusetts, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, New Jersey, North Dakota, Ohio, Oklahoma, Pennsylvania, Puerto Rico, South Carolina, Tennessee,

DEA/DC/DP/DPE Page 21 of 47 March 2019 Texas, Utah, Virginia, West Virginia, Wisconsin, Wyoming ADB- 0 0 177 392 1,030 1,578 456 1 Arkansas, FUBINACA (Mar) California, Colorado, Connecticut, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maryland, Mississippi, Michigan, Minnesota, Missouri, Nebraska, New Jersey, New Mexico, New York, North Dakota, Ohio, Oklahoma, Pennsylvania, Tennessee, Texas, Utah, Virginia, Wisconsin, Wyoming MDMB- 0 0 0 135 205 99 25 0 Arkansas, CHMICA (Mar) Florida, (MMB- Georgia, Idaho, CHMINACA) Indiana, Kansas, Kentucky, Louisiana, Missouri, Nebraska, Nevada, New Mexico, Ohio, Oklahoma, South Carolina, Texas MDMB- 0 0 0 342 340 23 2 0 Arkansas, FUBINACA (Jul) California, Colorado, Connecticut,

DEA/DC/DP/DPE Page 22 of 47 March 2019 Georgia, Idaho, Indiana, Kansas, Kentucky, Louisiana, Minnesota, Missouri, Nevada, New Jersey, New Mexico, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Tennessee, Texas, Virginia, Wisconsin, West Virginia, Wyoming * Query date: March 5, 2019 ‡ The month in parenthesis (e.g., (March)) corresponds to the month the substance was first encountered. § Laboratories reporting to NFLIS include State, local and other federal laboratories (not including DEA).

Table 11. Reports obtained through the STRIDE10 and STARLiMS11 databases12* § DRUG 2012 2013 2014 2015 2016 2017 2018 2019 STATES/ REPORTS TERRITORIES 5F-ADB (5F- 0 0 0 54 157 248 218 6 Alabama, Alaska, MDMB- Arizona, California, PINACA) Connecticut, District of Columbia, Florida, Georgia, Guam, Idaho, Illinois, Indiana, Kentucky, Maryland, Massachusetts, Mississippi, Missouri, North Carolina, New Hampshire, New Jersey, New Mexico,

10 STRIDE is a database of drug exhibits sent to DEA laboratories for analysis. Exhibits from the database are from the DEA, other federal agencies, and some local law enforcement agencies. 11 STARLiMS is laboratory information management system that systematically collects results from drug chemistry analyses conducted by DEA laboratories. 12 STRIDE data was queried through September 30, 2014, by date submitted to Federal forensic laboratories. On October 1, 2014, STARLiMS replaced STRIDE as the DEA laboratory drug evidence data system of record.

DEA/DC/DP/DPE Page 23 of 47 March 2019 New York, Ohio, Puerto Rico, Texas, Virginia, Washington, Wisconsin, West Virginia 5F-AMB 0 0 12 138 148 8 11 0 Alabama, Arizona, California, Colorado, Connecticut, District of Columbia, Florida, Illinois, Kansas, Kentucky, Louisiana, Maryland, Massachusetts, Mississippi, Missouri, Montana, New Jersey, New Mexico, New York, Tennessee, Texas, Virginia, Washington, West Virginia 5F-APINACA 46 47 22 100 3 4 1 0 Alaska, Alabama, (5F-AKB48) Arizona, California, Connecticut, District of Columbia, Florida, Idaho, Illinois, Maryland, Mississippi, Missouri, New York, North Carolina, Ohio, Oklahoma, South Carolina, Tennessee, Texas, Washington, West Virginia, Wisconsin ADB- 0 0 4 21 135 125 90 0 Alabama, Alaska, FUBINACA California, Connecticut, District of Columbia, Florida, Guam, Illinois, Maryland, Missouri, New

DEA/DC/DP/DPE Page 24 of 47 March 2019 Jersey, New Mexico, New York, Ohio, Pennsylvania, Puerto Rico, Texas, Virginia, Washington, Wisconsin MDMB- 0 0 0 0 1 2 0 0 New Mexico, Texas CHMICA (MMB- CHMINACA) MDMB- 0 0 0 13 60 9 2 0 California, Florida, FUBINACA Guam, Maryland, Missouri, New York * Query date: March 5, 2019 § DEA laboratories only.

Factor 6. What, if any, risk there is to the public health

HHS and DEA documented multiple cases where 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have been identified in overdoses and/or cases involving death attributed to their abuse. Adverse health effects reported from these incidents involving 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and/or MDMB-FUBINACA included nausea, persistent vomiting, agitation, altered mental status, seizures, convulsions, loss of consciousness, cardio toxicity and/or death. Details of these events are summarized below.  In May 2014, a 41 year-old female in Baton Rouge, LA died following the ingestion of a synthetic-cannabinoid containing product. The cause of death as determined by the medical examiner was listed as “stimulant-induced coronary arterial thrombosis, due to synthetic cannabinoid (ADB-FUBINACA) used.”13 Shanks et al. (2016) published a case report regarding the toxicology of this substance.  Bäckberg et al. (2016) documented nine acute intoxications with MDMB-CHMICA between 2014 and 2015. Of the nine patients, eight had a poisoning severity score (PSS)14 of 2 or 3, five were monitored in the intensive care unit, and all survived. Out of the nine cases, only one patient did not have other psychoactive drugs in their blood upon screening; however, MDMB-CHMICA was analytically confirmed in serum samples, and the

13 Correspondence from East Baton Rouge Parish Coroner’s Office to DEA, (March 13, 2015) (on file with DEA). 14 PSS is a standardized measure for classifying the severity of poisoning in adults and children. Severity grades: 0 (None) - No symptoms or signs related to poisoning, 1 (Minor) – Mild, transient and spontaneously resolving symptoms, 2 (Moderate) - Pronounced or prolonged symptoms, 3 (Severe) – Severe or life-threatening symptoms, 4 (Fatal) - Death . Persson et al. (1998)

DEA/DC/DP/DPE Page 25 of 47 March 2019 substance was identified in seven drug materials donated by the patients. Development of seizures and deep unconsciousness were common features as described by the authors.  Hasegawa et al. (2015a) reported the death of a 30 year-old male in Japan following ingestion of a synthetic cannabinoid product. The cause of death as stated by the study authors “was judged as poisoning by multiple drugs, including AB-CHMINACA, 5F-AMB and .” The authors also concluded that the diphenidine appeared to have played the major role in the cause of death, due to the higher concentrations of diphenidine in the specimens tested as compared to the SCs.  Hasegawa et al. (2015b) reported the death of a 34 year-old male in Japan following the inhalation of 5F-ADB smoke. Three opened packages of different brands of herbal blends found under a pillow near the deceased tested positive for 5F-ADB. Official cause of death was not reported, however study authors repeatedly stated that 5F-ADB was thought to have been responsible for approximately 10 deaths since September 2014.  Hess et al. (2015) reported the death of a 25 year-old man in Germany. These authors stated that diabetic ketoacidosis was the primary cause of death, and that the use of synthetic cannabinoids was contributory to the death. Laboratory analysis detected AB-CHMINACA, AB-FUBINACA, AM-2201, 5F-AMB, 5F-APINACA (5F-AKB48), EAM-2201, JWH- 018, JWH-122, MAM-2201, STS135 and THJ-2201 in postmortem blood.  In April 2015, a 48 year-old male in Onondaga County, NY died following the ingestion of a synthetic cannabinoid-containing product. The medical examiner listed the cause of death as “complications of synthetic cannabinoid toxicity (ADB-FUBINACA) with contributory chronic ethanol abuse.”15  In June 2015, a 17 year-old male in Mesquite, TX died following the ingestion of a synthetic cannabinoid-containing product. Laboratory analysis detected 5F-AMB and 5F-APINACA (5F-AKB48) in the herbal product as well as 5F-AMB and AKB48 N-(4-hydroxypentyl) metabolites in biological samples.16,17  Adamowicz (2016) reported a large outbreak of intoxications in Poland in July 2015 following the use of synthetic cannabinoids including a fatal case involving MDMB- CHMICA. A 25 year old man exhibited loss of consciousness and asystole occurred within minutes of ingestion, followed by 4 days of hospitalization. Following the detection of MDMB-CHMICA in blood and internal organ tissues, the medical examiner ruled the cause of death as multi-organ failure.  Hill et al. (2016) described seven cases of men who presented at hospitals in England between July and October, 2015 positive for MDMB-CHMICA. Clinical symptoms included acidosis, reduced consciousness, mydriasis, tachycardia, bradycardia, tonic-clonic convulsions and agitation.  In August 2015, a 33 year-old female in Lorain County, OH died following the ingestion of a synthetic cannabinoid-containing product. The medical examiner listed the cause of death as “cardiopulmonary arrest due to acute intoxication by MDMB-FUBINACA.”

15 Correspondence from Onondaga County Health Department Medical Examiner’s Office to DEA (Dec. 22, 2015) (on file with DEA). 16 Correspondence from Texas Department of Public Safety to DEA (July 9, 2015) (on file with DEA). 17 Correspondence from Dept. of Laboratory Medicine, University of California at San Francisco (UCSF) to DEA (Mar. 9, 2016) (on file with DEA).

DEA/DC/DP/DPE Page 26 of 47 March 2019  From August through September 2015, approximately 80 overdoses due to the ingestion of a synthetic cannabinoid-containing product were reported by local authorities in Anchorage, AK. Thirteen exhibits obtained during that time period tested positive for 5F-AMB, MAB- CHMINACA and AB-CHMINACA.18  In August 2015, a 40 year-old male in Baton Rouge, LA died following the ingestion of a synthetic cannabinoid-containing product. The medical examiner listed the cause of death as “hypoxic-ischemic encephalopathy due to acute synthetic cannabinoid intoxication (MDMB-CHMICA).19  Seywright et al. (2016) described 11 cases of emergency department admissions that were positive for MDMB-CHMICA between September 1 and December 9, 2015. Clinical features reported in these subjects were syncope, recurrent vomiting, hypothermia and sinus tachycardia.  In October 2015, local news media reported 25 overdoses in Tulsa, OK following ingestion of synthetic cannabinoid-containing products. Eight patients received care at emergency facilities and laboratory analysis of biological samples detected metabolites of MDMB- FUBINACA in all eight patients.20  In October 2015, a 20 year-old female in Raleigh County, WV died following the ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a metabolite of 5F-ADB.21  In November 2015, local news media in Hopkinsville, KY reported 13 overdoses following ingestion of synthetic cannabinoid-containing products. Laboratory analysis of evidence (herbal products) retrieved detected MAB-CHMINACA, MDMB-CHMICA, 5F-AMB, MA-CHMINACA and 5F-ADB. Laboratory analysis of biological samples obtained from two patients detected metabolites of MAB-CHMINACA in both individuals.22  In November 2015, local news media reported 12 overdoses in San Diego, CA following ingestion of synthetic cannabinoid-containing products. Laboratory analysis of evidence (herbal products) retrieved detected 5F-AB-PINACA, 5F-AMB, 5F-NNE1 and 5F-ADB. Laboratory analysis of biological samples obtained from five patients detected AB-PINACA as well as metabolites of 5F-ADB and 5F-NNE1 in four out of the five individuals.23  In November 2015, local news media reported a second cluster of 16 overdoses in San Diego, CA following ingestion of synthetic cannabinoid-containing products. Laboratory analysis of evidence (herbal products) retrieved detected AB-FUBINACA, 5F-AMB, 5F- ADB, 5F-NNE1, XLR11, AB-CHMINACA and FUB-PB-22. No biological samples were obtained.24  In December 2015, a 45 year-old female in Raleigh County, WV died following the ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a metabolite of 5F-ADB.25

18 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (Sept. 18, 2015) (on file with DEA). 19 Correspondence from East Baton Rouge Parish Coroner’s Office to DEA (May 24, 2016) (on file with DEA). 20 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (Jan. 19, 2016) (on file with DEA). 21 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (May 27, 2016) (on file with DEA). 22 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (Mar. 9, 2016) (on file with DEA). 23 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (Dec. 21, 2015) (on file with DEA). 24 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (Jan. 14, 2016) (on file with DEA). 25 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (May 27, 2016) (on file with DEA).

DEA/DC/DP/DPE Page 27 of 47 March 2019  In December 2015, a 27 year-old male in Raleigh County, WV died following the ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a metabolite of 5F-ADB.26  In December 2015, a 29 year-old male in Raleigh County, WV died following the ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a metabolite of 5F-ADB.27  In December 2015, a 60 year-old male in Raleigh County, WV died following the ingestion of a synthetic cannabinoid-containing product. The medical examiner listed the cause of death as “the result of synthetic cannabinoid (5F-AMB), diazepam, and mirtazapine intoxication.”28  Meyyappan et al. (2016) reported 3 cases of poisoning due to MDMB-CHMICA. All three patients developed hypercapnia (high amount of carbon dioxide in the blood), two had a reduced level of consciousness, two suffered seizures, one was profoundly bradycardic, while the other two patients were tachycardic and one became agitated on recovery. The authors concluded that use of MDMB-CHMICA can lead to coma, acute respiratory failure, seizures and agitation.  Westin et al. (2016) reported the death of a 22 year-old male in Norway following ingestion of a synthetic cannabinoid product. The authors stated the cause of death as “most probably caused by an overdose of MDMB-CHMICA.” Drug evidence tested positive for MDMB- CHMICA. Postmortem sample analysis detected MDMB-CHMICA, mirtazapine (sub- therapeutic), tetrahydrocannabinol and cetirizine.  In January 2016, a 43 year-old male in Raleigh County, WV died following ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a metabolite of 5F-ADB.29  In January 2016, a 43 year-old male (separate from citation 29 above) in Raleigh County, WV died following ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a metabolite of 5F-ADB.30  In January 2016, a 63 year-old male in Raleigh County, WV died following ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a metabolite of 5F-ADB.31  Shanks and Behonick (2016) reported the death of a 34 year-old male in Opelousas, LA following ingestion of a synthetic cannabinoid product. The authors stated the cause of death as “accidental death due to synthetic cannabinoid toxicity.” Laboratory analysis by the study authors identified the substance as 5F-AMB.  In March 2016, a 17 year-old male in Lacombe, LA died following ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected a shared metabolite of BB-22 and MDMB-CHMICA32.

26 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (May 27, 2016) (on file with DEA). 27 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (May 27, 2016) (on file with DEA). 28 Correspondence from WV OCME to DEA (Feb. 25, 2016) (on file with DEA). 29 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (May 27, 2016) (on file with DEA). 30 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (May 27, 2016) (on file with DEA). 31 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (May 27, 2016) (on file with DEA). 32 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (Apr. 6, 2016) (on file with DEA).

DEA/DC/DP/DPE Page 28 of 47 March 2019  EMCDDA (2016) concluded that through March 2016, 71 serious adverse events associated with MDMB-CHMICA had been reported by 8 Member States (Austria, France, Germany, Hungary, Poland, Spain, Sweden, and the United Kingdom) and Norway. This included 42 serious acute intoxications requiring hospitalization and 29 deaths. As stated by EMCDDA, MDMB-CHMICA appeared to play a role in at least 12 of the 29 deaths.  In April 2016, a 17 year-old male in Raleigh County, WV died following ingestion of a synthetic cannabinoid-containing product. Laboratory analysis of biological samples detected both 5F-AMB and 5F-AMB metabolites.33

In their reviews, HHS and DEA noted multiple sources within the scientific literature that detail adverse effects following the ingestion of SCs. Since 2013, descriptions of overdoses, hospitalizations, severe outbreaks (CDC, 2013a,b,c; Schwartz et al., 2015; Trecki et al., 2015; Tyndall et al., 2015) and deaths (Behonick et al., 2014; Hasegawa et al. 2015a,b; Hess et al., 2015; Trecki et al., 2015; Westin et al., 2016; Shanks and Behonick, 2016, Shanks et al., 2016) involving different SCs have been reported in both scientific publications and in the news media. Clinical effects relating to synthetic cannabinoid ingestion observed in emergency departments requiring medical intervention, and reported by numerous State public health departments, poison control centers, and private organizations include: vomiting, anxiety, agitation, irritability, seizures, hallucinations, tachycardia, elevated blood pressure, loss of consciousness, and non-responsiveness (Griffiths et al., 2010; Vardakou et al., 2010; Forrester et al., 2011; Cohen et al., 2012; Harris and Brown, 2013; Hermanns-Clausen et al., 2013; Zawilska and Wojcieszak, 2013; Schwartz et al., 2015; Tyndall et al., 2015). A 12-month study conducted in 2012 demonstrated that out of 950 self-reported users of SCs, 2.4% reported having a medical emergency requiring treatment resulting from a combination of panic, anxiety, paranoia, and breathing difficulties (Winstock and Barratt, 2013). Data from this study also demonstrated that recent users who reported seeking emergency treatment were significantly younger than those who did not report seeking treatment (Winstock and Barratt, 2013).

Since abusers obtain these drugs through unknown sources, the identity, purity, and quantity of these substances are uncertain and inconsistent, thus posing significant adverse health risks to users. The SCs encountered on the illicit drug market have no accepted medical use within the United States. Regardless, SC products continue to be easily available and

33 Correspondence from Dept. of Laboratory Medicine, UCSF to DEA (Apr. 28, 2016) (on file with DEA).

DEA/DC/DP/DPE Page 29 of 47 March 2019 abused by diverse populations. Unknown factors including detailed product analysis and dosage variations between various packages and batches present a significant danger to an abusing individual (Auwarter et al., 2009; Hudson et al., 2010). Designer drug products have been found to vary in the amount and type of synthetic cannabinoid applied onto the plant material (Vardakou et al., 2010; Vearrier and Osterhoudt, 2010; Schneir et al., 2011; Fattore and Fratta, 2011; Schwartz et al., 2015; Tyndall et al., 2015). Similar to previous SCs, 5F-ADB, 5F- AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have been found applied onto plant material in designer drug products.

By sharing pharmacological similarities with schedule I substances (Δ9-THC, JWH-018 and other temporarily and permanently controlled schedule I SCs), SCs pose a risk to the abuser (Weissman et al., 1982; Compton et al., 1992; Wiley et al., 1998). Likewise, the abuse of 5F- ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and/or MDMB- FUBINACA, SCs with no approved medical use, poses serious risk to the abuser. Tolerance to SCs may develop fairly rapidly with larger doses being required to achieve the desired effect (EMCDDA, 2009). Acute and chronic abuse of SCs in general has been linked to adverse health effects including signs of addiction and withdrawal (Zimmermann et al., 2009; Vardakou et al., 2010; Muller et al., 2010; Nacca et al., 2013; Rominger et al., 2013), numerous reports of emergency department admissions resulting from their abuse (Forrester et al., 2011; Hermanns- Clausen et al., 2013; SAMHSA, 2012, 2013, 2014; Buser et al., 2014; Takematsu et al., 2014; Schwartz et al., 2015; Trecki et al., 2015; Tyndall et al., 2015), overall toxicity (Gunderson et al., 2012; Hermanns-Clausen et al., 2013; Fantegrossi et al., 2014; Konstrand et al., 2013), and death (Patton et al., 2013; Behonick et al., 2014; Shanks et al, 2016; Shanks and Behonick, 2016; Law Enforcement/Toxicology correspondence). Psychiatric case reports have been reported in the scientific literature detailing the harms of SC abuse and psychoses (Oluwabusi et al., 2012; Peglow et al., 2012; Thomas et al., 2012; Castellanos and Thorton, 2012; Papanti et al, 2013; Spaderna et al., 2013; Castaneto et al., 2014). While these adverse effects have been shown by a variety of SCs, similar concerns remain regarding the welfare of the user as it relates to abuse of products laced with 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA. The risk of adverse health effects is further

DEA/DC/DP/DPE Page 30 of 47 March 2019 increased by the fact that similar products vary in the composition and concentration of SCs applied on the plant material.

DEA further notes that The Monitoring the Future (MTF) Report for 2015 reported that in 2012, for the first time, 8th and 10th graders were asked about their use of SCs, colloquially referred to as ‘synthetic marijuana’; annual prevalence rates were 4.4% and 8.8%, respectively. Twelfth graders were first asked about SCs in 2011, with an annual prevalence of 11.4%. Twelfth grade prevalence remained relatively constant in 2012, at 11.3%. Use in the 8th, 10th, and 12th grades dropped in 2013, and the decline was sharp and significant among 12th graders. The declines continued in 2014 and were significant for 10th and 12th graders. In 2014, the annual prevalence’s for 8th, 10th, and 12th graders were 3.3%, 5.4%, and 5.8%, respectively (Johnston et al., 2015). In 2015, the annual prevalence’s for 8th, 10th, and 12th graders were 3.1%, 4.3%, and 5.2%. While these statistics demonstrate a decline in SC use amongst youth, serious adverse effects and deaths following ingestion of SCs, including 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA, by adolescents and teens continue to occur (see Factor 6).

Dresen and colleagues (2010) found that SCs are being abused by individuals in drug treatment centers with a positive rate of 63.3% in forensic psychiatric centers, based on their sampling. According to testimony given by the Deputy Director of the Office of National Drug Control Policy (ONDCP) to the U.S. Senate Caucus on International Narcotics Control Board (September 25, 2013), drug testing misses significant populations of SC users. In an example described in his testimony, a study found that in a sample of men 30 years old or younger within the Washington, D.C., parole and probation system, 39 percent of those who cleanly passed a traditional drug screen tested positive for SCs. The study also showed that between one-quarter and one-third of young men who were tested in the Washington, D.C. criminal justice system had positive test results for SCs, regardless of whether they failed or passed a traditional drug screen. In addition to the characterized psychoses, driving impairment has been encountered with confirmed presence of a SC in the systems of multiple individuals, as confirmed in the scientific literature (Yeakel and Logan, 2013; Musshoff et al., 2014; Tuv et al., 2014; Jaenicke et al., 2014; Lemons, 2014; Louis et al., 2014; Karinen et al., 2015).

DEA/DC/DP/DPE Page 31 of 47 March 2019 Factor 7: Its Psychic or Physiological Dependence Liability

As stated by HHS, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB- CHMICA and MDMB-FUBINACA have pharmacological profiles that are similar to other schedule I SCs (e.g., JWH-018, XLR11 and AKB-48) and therefore it is reasonable to assume that these six SCs possess physiological and psychological dependence liability similar to that of these schedule I SCs (HHS, 2019). As mentioned by HHS, data from case reports showed that products containing SCs produced physical dependence and a withdrawal syndrome. A published case report demonstrated tolerance and withdrawal phenomena attributed to “Spice Gold” (Zimmerman et al., 2009). DEA further notes that according to these authors, this physical withdrawal resembled that of cannabis dependence as per the criteria mentioned in ICD-10 and DSM-IV. HHS also cited another report mentioning psychosis attributed to “Spice” containing JWH-018 and CP 47,497 (Muller et al., 2010). There are no clinical studies evaluating psychic or physiological dependence liabilities specific for 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA.

HHS states that the Diagnostic and Statistical Manual Disorders Fifth Edition (DSM-5) describes the term “Cannabis withdrawal”. The signs and symptoms of cannabis withdrawal, according to HHS, occur approximately within one week. These signs and symptoms include irritability, anger, aggression, nervousness or anxiety, sleep difficulty (e.g., insomnia, disturbing dreams), decreased appetite or weight loss, restlessness, depressed mood, at least one of the following physical symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache (HHS, 2019). 5F-ADB, 5F-AMB, 5F- APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA are likely to be associated with such withdrawal effects.

DEA further notes that in an audit of patients presenting for help in discontinuing their SC abuse from Auckland, New Zealand (Macfarlane and Christie, 2015), common withdrawal symptoms of SCs were agitation, irritability, anxiety and mood swings, requiring management with benzodiazepines and/or an atypical antipsychotic such as quetiapine. Patients with the SC

DEA/DC/DP/DPE Page 32 of 47 March 2019 withdrawal were the third largest group admitted to inpatient detoxification. Many patients required medical management and intensive support.

DEA also notes that Every-Palmer (2010) has reported the recurrence of psychosis in stable individuals with a previous history of psychosis. They reported that the mental status of five individuals deteriorated significantly after ingesting products containing the SCs CP-47,497 and/or JWH-018. Every-Palmer (2011) followed up the initial communication with interviews of 15 patients with severe mental illness in a New Zealand forensic and rehabilitation service. All 15 subjects were aware of a locally available product containing JWH-018, and credited the product’s potent psychoactivity, legality, ready availability, and non-detection in drug tests as reasons for its popularity. Anxiety and psychotic symptoms were common after use, with 69% of users experiencing symptoms of psychotic relapse after smoking JWH-018. Three subjects reported developing a tolerance, but no withdrawal symptoms were reported.

A 2017 case report by Yazici et al. mentioned delirium and high serum creatinine kinase and myoglobin levels related to SC withdrawal.

Factor 8: Whether the Substance is an Immediate Precursor of a Substance Already Controlled

5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA are not immediate precursors of any controlled substance of the CSA as defined by 21 U.S.C 802(23).

III. Findings for Schedule Placement Pursuant to 21 U.S.C. 812(b)

21 U.S.C. 812(b) requires the evaluation of a substance’s abuse potential, accepted medical use, and safety for use under medical supervision for scheduling under the CSA as a controlled substance. After consideration of the above eight factors determinative of control of a substance (21 U.S.C. 811(c)), and a review of the scientific and medical evaluation and scheduling recommendation provided by the HHS, the DEA finds that 5F-ADB, 5F-AMB, 5F-APINACA,

DEA/DC/DP/DPE Page 33 of 47 March 2019 ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA meet the following criteria for placement in schedule I of the CSA pursuant to 21 U.S.C. 812(b)(1).

1) 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA have a high potential for abuse.

5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA are synthetic substances that produce cannabinoid agonist-like pharmacological effects that are similar to those produced by schedule I substances such as THC, JWH-018, XLR11 and AKB-48. 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA, similar to other schedule I SCs, bind to and activate CB1 receptor in vitro and substitutes for THC in drug discrimination tests in animals. In locomotor studies in animals, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA, similar to THC and other schedule I SCs such as JWH-018, produced cannabinoid- like effects including depression of locomotor activity. Additionally 5F-APINACA has THC-like effects in tetrad assay. Thus 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB- CHMICA and MDMB-FUBINACA have pharmacological properties similar to that of THC and other schedule I SCs ( e.g., JWH-018, XLR11 and AKB-48) and thus have high potential for abuse. NFLIS details over 31,512 reports from forensic laboratories identifying 5F-ADB, 5F- AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA for a period from August 2012 through February 2019 (See Table 10). In addition, STRIDE and STARLiMS have 1,685 reports involving 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA from 2012 through February 2019 (See Table 11).

2) 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB- FUBINACA have no currently accepted medical use in treatment in the United States.

According to the HHS, there are no approved NDAs for 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA or MDMB-FUBINACA and there are no clinical studies or petitioners claiming an accepted medical use in the United States for any of these six SCs.

DEA/DC/DP/DPE Page 34 of 47 March 2019 Therefore, 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have no currently accepted medical use in the United States.

3) There is a lack of accepted safety for use of 5F-ADB, 5F-AMB, 5F-APINACA, ADB- FUBINACA, MDMB-CHMICA and MDMB-FUBINACA under medical supervision.

Because 5F-ADB, 5F-AMB, 5F-APINACA, ADB-FUBINACA, MDMB-CHMICA and MDMB-FUBINACA have no approved medical use and have not been thoroughly investigated as new drugs, their safety for use under medical supervision is not determined. Thus, there is a lack of accepted safety for use of these substances under medical supervision.

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