DEA/OD/ODE page 1 of 39 December 2014

N - (1 - amino - 3 - methyl - 1 - oxobutan - 2 - yl) - 1 - (cyclohexylmethyl) - 1 H - indazole - 3 - carboxamide (AB - CHMINACA), N - (1 - amino - 3 - methyl - 1 - oxobutan - 2 - yl) - 1 - pentyl - 1 H indazole - 3 - carboxamide (AB - PINACA ) and [ 1 - (5 - fluoropentyl) - 1 H - indazol - 3 -

yl] (naphth alen - 1 - yl)methanone (THJ - 2201) Background Information and Evaluation of ‘ Three Factor Analysis ’ (Factor s 4, 5 , and 6) for T emporary S cheduling Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement

Administration, Washington , DC 20537

December 2014 Introduction Recently , several synthetic cannabinoids (SCs) namely N
- (1

- amino
- 3
- methyl

- 1
- oxobutan

- 2
- yl)

- 1
- (cyclohexylmethyl)

- 1 H
- indazole

- 3
- carboxamide (AB

- CHMINACA), N
- (1

- amino
- 3
- methyl

- 1
- oxobutan

- 2
- yl)

- 1
- pentyl

- 1 H
- indazole

- 3
- carboxamide (AB

- PINACA ) and [ 1
- ( 5
- fluoropentyl)

- 1 H
- indazol

- 3
- yl] (napht halen

- 1
- yl)methanone (THJ

- 2201) emerged in the illicit drug market. In light of this, the Drug Enforcement Administration (DEA) reviewed the available scientific, medical, law enforcement and other data on these substances. The data presented in this document support the determination by the DEA to control these substances under the temporary s cheduling provision of the Controlled S ubstances Act (CSA). 21 U.S.C. 811(h)(1). SCs are substances synthesized in laboratories that mimic the biological effects of THC, the main psycho active ingredient in marijuana. These chemicals, such as CP
47,497 and cannabicyclohexanol (designed in the 198 0s and currently controlled), were initially used as research tools to investigate the biological mechanisms in the cannabinoid system and to develop novel therapies for various clinical conditions . Other SCs in cluding JWH
- 018, JWH
- 073, and JWH

- 200 (all permanently controlled pursuant to the Food and Drug Administration Safety and Innovation Act. (FDASIA), Pub. L. 112

- 144 ) were synthesized in the mid

- 1990s and studied to further advance the understanding of drug

- receptor interactions regarding the cannabinoid system. SCs were first marketed in several European countries as herbal incense before the initial encounter in the United States by Customs and Border Protection (CBP) in November 2008. In 2009, their use began increasing in the U nited S tates with lawDEA/OD/ODE page 2 of 39 December 2014

enforcement encounters describing SCs laced on plant material and being abused for their psychoactive properties. In addition, forensic analyses by the DEA and other Federal , State , and local laboratories have identified multiple variations in both the type and the amount of SC applied to the plant material. As observed by the DEA and CBP, SCs originate from foreign sources, including China and other countries in Southeast Asia. Bulk powder substances are smuggled via common carrier into the U nited S tates and find their way to clandestine designer drug product manufacturing operations located in residential neighborhoods, garages, warehouses , and other similar destinations throughout the country. T he powder form of SCs are typically dissolved in solvents ( e.g., acetone) before being applied to a green plant material or dissolved in a propellant intended for use in e

- cigarette d e vices. Law enforcement personnel have encountered various application metho ds including , buckets or cement mixers in which green plant material and one or more SCs are mixed together , as well as large areas where the green plant material is spread out so that a dissolved SC mixture can be applied directly. According to o nline dis cussion boards and law enforcement encounters, spraying or mixing the SCs on plant material provides a vehicle for the most common route of administration
— s moking (using a pipe, a water pipe, or rolling the drug

- spiked plant material in cigarette papers). Once mixed, the SC/green 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. A dverse health consequences may also occur from directly ingesting the drug during the manufacturing process. SCs are marketed under hundreds of different brand names, including “ Spice,” “K2,” “Blaze,” “Red X Dawn,” “Paradise,” “Demon,” “Black Magic,” “Spike,” “Mr. Nice Guy,” “Ninja,” “Zohai,” “Yucatan,” “Fire, ” “Crazy Clown, ” “Mojo , ” “Black Mamba , ” “Black Voodoo , ” “Scooby Snax,” “Bizzaro,” and many others. In addition, various “new generations” of SCs reflect the same or similar product labels while yielding a higher intensity and longer lasting highs, but with the user still being deprived of knowledge as to exactly what is contained inside the packagin g. The designer drug products laced with SCs are often sold under the guise of
“ herbal i ncense, ” “ potpourri, ” etc . , 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 Interne t, in head shops, or sold in convenience stores. There is an incorrect assumptionDEA/OD/ODE page 3 of 39 December 2014

that these products are safe (Fattore and Fratta, 2011; McGuinness and Newell, 2012) and further, that mislabeling these products as “ not for human consumption ” is a legal de fense to criminal prosecution. These substances have no accepted medical use in the U nited S tates and have been reported to produce adverse health effects in humans while having a negative effect on communities. Acute and chronic abuse of SCs in general have been linked to adverse health effects including signs of addiction and withdrawal (Zimmermann et al., 2009; Muller et al., 2010 ; Nacca et al., 2013 ; Rominger et al., 2013 ), numerous reports of emergency room admissions resulting from their abuse (Forrester et al., 2011; Hermanns
- Clausen et al., 2013 ; SAMHSA, 2012 ; Buser et al., 2014; Takematsu et al., 2014 ) , overall toxicity ( Gunderson et al., 2012; Hermanns

- Clausen et al., 2013; Fantegrossi et al., 2014 ; Konstrand et al., 2013 ) , and death ( Behonick et al., 2014; Patton et al., 2013; 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 ; Th omas et al., 2012 ; Castellanos and Thorton, 2012; Papanti et al, 2013 ; Spaderna et al., 2013; Castaneto et al., 2014 ). T he risk of adverse health effects is further increased by the fact that similar products vary in the composition and concentration of SC s applied on the plant material. In March 2011, May 2013 , and February 2014 , the DEA emergency
- scheduled multiple SCs to protect the public health and safety . They included JWH
- 018, JWH
- 073, JWH
- 200, CP
- 47,497, and CP

- 47,497 C8 ( temporarily scheduled on March 1, 2011 , at 76 FR 11075 , and later placed in s chedule I by s ection 1152 of FDASIA on July 9, 2012 ) ; UR
144, XLR 11 and AKB48 ( temporarily scheduled on May 16, 2013 , at 78 FR 28735 ) ; and PB
- 22, 5F
- PB
- 22, AB
- FUBINACA and ADB

- PINACA (temporarily scheduled on February 10 , 2014 , at 79 FR 7577 )
. Section 1152 of the FDASIA amended the Controlled Substances Act ( CSA ) by placing cannabimimetic agents and 26 specific substances (including 15 SCs , 2 synthetic cathinones, and 9 phenethylamines of the 2C

- se ries) in s chedule I. Although s eizures of JWH

- 018, JWH
- 073, JWH
- 200 , CP
- 47,497, and CP

- 47,497 C8 homolog ue showed a decline shortly after the se drugs were scheduled, new SCs began to emerge on the designer drug market. A new generation of SCs , including UR
144, XLR11 , and AKB48 quickly became the new drugs of choice in the synthetic marketplace
. Following the temporary scheduling of UR

- 144, XLR11 and AKB48, the next generation of SCs quickly began emerging, which included PB
- 22, 5F
- PB
- 22, AB
FUBINACA , and ADB

- PINACA. M ore recently , law enforcement has been encountering yet another generation of SCs including N
- (1

- amino
- 3
- methyl

- 1
- oxobutan

- 2
- yl)

- 1
- (cyclohexylmethyl)

- 1 H
- indazole

- 3
- carboxamide (AB

- CHMINACA), N
- (1

- amino
- 3
- methyl

-DEA/OD/ODE page 4 of 39 December 2014

1
- oxobutan

- 2
- yl)

- 1
- pentyl

- 1 H
- indazole

- 3
- carboxamide (AB

- PINACA ) and [ 1
- (5

- fluoropentyl)

- 1 H
- indazol

- 3
- yl] (naphth alen

- 1
- yl)methanone (THJ

- 2201 )
. AB
- CHMINACA is a synthetic cannabinoid ( figure 1) that has pharmacological effects similar to the schedule I hallucinogen delta

- 9
- tetrahydrocannabinol (Δ9

- THC) (RTI, 2014) and other temporarily and permanently controlled schedule I substances
. AB
- CHMINACA was not reported in the scientific literature prior to its appearance on the illicit drug market. According to the System to Retrieve Informa tion from Drug Evidence (STRIDE 1 ) data, there are 21 records for AB

- CHMINACA from January 1 , 2010 , through September 30 , 2014 (Query date: October 1 , 2014). T he National Forensic Labor atory Information System (NFLIS 2 ) registered 586 reports containing AB
CHMINACA in 19 states from J anuary 1, 2010 , through November 25 , 2014 (Query date: November 25 , 2014 ). In addition, at least four deaths and multiple overdoses requiring emergency medical intervention have been reported involving the use of AB
- CHMINACA (see F actor 6). AB
- PINACA is a synthetic cannabinoid ( f igure 1 ) that has pharmacological effects similar to the s chedule I hallucinogen delta

- 9
- tetrahydrocannabinol (Δ9

- THC) (RTI, 2014) and other temporarily and permanently controlled schedule I substances
. A B
- PINACA first appeared in the scientific literature as a designer drug found in illegal products (Uchiyama et al., 2012). T here are 245 records involving AB

- PINACA in STRIDE from J anuary 1, 2010 , through September 30 , 2014 (Query date: October 1, 2014 ) . There are 3, 783 reports in NFLIS from J anuary 1, 2010 , through November 25 , 2014 (Query date: November 25 , 2014 ) in 39 states . At least three deaths and multiple overdoses requiring emergency medical intervention have been reported involving the use of AB

- PINACA (see F actor 6). THJ
- 2201 is a synthetic cannabinoid ( f igure 1) that has pharmacological effects similar to the schedule I hallucinogen delta

- 9
- tetrahydrocannabinol (Δ9

- THC) ( Janowsky, 2014 ) and other temporarily and permanently controlled schedule I substances
. THJ
2201 was not reported in the scientific literature prior to its appearance on the illicit drug market. Accord ing to STRIDE data, there are 65 records for THJ

- 2201 from J anuary 1, 2010 , through September 30 , 2014 (Query date: October 1, 2014 ). T he National Forensic Laboratory Information System (NFLIS) registered 220 reports containing THJ
-
1 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 law enforcement agencies. 2 NFLIS is a national forensic laboratory reporting system that systematical ly collects results from drug chemistry analyses conducted by state and local forensic laboratories in the United States
.DEA/OD/ODE page 5 of 39 December 2014

2201 in 13 states from J anuary 1, 2010 , through September 30 , 2014 (Query date: October 1, 2014 ). With no approved medical use and with limited or no safety or toxicological information , these substances ( AB
- CHMINACA, AB
- PINACA and THJ
- 2201 ) have emerged on the designer drug market and are being abused for their psychoactive properties. AB
CHMINACA, AB
- PINACA and THJ
- 2201 were not included among the 15 SCs that are specifically named under FDASIA , and d o not fall under the legal definition of cannabimimetic agents as provided under FDASIA
. To protect the public health and safety, the DEA intends to temporar il y place AB
- CHMINACA, AB
- PINACA and THJ
- 2201 in s chedule I of the CSA
. With respect to finding an imminent hazard to the public safety , the DEA has considered the factors required under the CSA for the temporary scheduling of A B
- CHMINACA, AB
- PINACA and THJ
- 2201
. 21 U.S.C. 811(h)(3) and 811(c)(4)

- (6).

Figure 1 . Chemical Structures AB
- CHMINACA, AB
- PINACA , and THJ

- 2201 are classified as pentyl indazoles and share structural features with the schedule I substances AKB48 and AB

- FUBINACA
. AB
CHMINACA was not reported in the scientific literature prior to its emergence on the illicit drug market. AB
- PINACA was f irst reported in the scientific literature following an extraction from “Fragrance Powder” purchased via the Internet in July 2012 ( Uchiyama et al., 2013). Additionally, THJ
- 2201 ’s emergence on the illicit drug market preceded any report in the scientific literature.DEA/OD/ODE page 6 of 39 December 2014

Synthetic Cannabinoids N - (1 - amino - 3 - methyl - 1 - oxobutan - 2 - yl) - 1 - (cyclohexylmethyl) - 1 H - indazole - 3 - carboxamide (AB - CHMINACA) AB
- CHMINACA shares structural features with schedule I substances such as AB
- FUBINACA and AKB48. AB
- CHMINACA, AB
- FUBINACA , and AKB48 have the same core structure where the 1

- and 3

- positions of the indazole ring system are substituted. All three substances are substituted at the 3

- position with a carbonyl linker and an additional nitrogen atom collectively known as an amide. AB

- CHMINACA and AB

FUBINACA are further substituted at the amide nitrogen atom with the 1

- amino
- 3
- methyl

- 1
- oxobutan

- 2
- yl group. The 1

- position of the core indazole ring system is substituted in both AB

- CHMINACA and AB

- FUBINA CA. In AB
- CHMINACA, the 1

- position is substituted with a cyclohexylmethyl group, and in AB

- FUBINACA, the 1

- position of the indazole ring is substituted with a 4

- fluorobenzyl group. A study conducted by contract researchers at RTI International indicated that AB

- CHMINACA binds to the CB1 receptor (RTI, 2014)
. 3
N - (1 - amino - 3 - methyl - 1 - oxobutan - 2 - yl) - 1 - pentyl - 1 H - indazole - 3 - carboxamide (AB PINACA) AB
- PINACA is also based on the same indazole core structure as AB

- CHMINACA, AB
- FUBINACA , and AKB48, where the 1

- and 3

- positions of the indazole ring system are substituted. All four of these substances are substituted at the 3

- position with an amide. Like AB

- CHMINACA and AB

- FUBINACA, AB
- PINACA is substituted at the amide nitrogen atom with t he same 1

- amino
- 3
- methyl

- 1
- oxobutan

- 2
- yl group. AB

- PINACA, like AKB48, contains a pentyl group on the indazole 1

- position. Research has demonstrated that AB

PINACA binds to the CB1 receptor (RTI, 2014 4 ; Prather, 2014 ) and is an agonist at the CB1 receptor
. [ 1 - (5 - fluoropentyl) - 1 H - indazol - 3 - yl ] (naphthalen - 1 - yl)methanone (THJ - 2201) THJ
- 2201 is also based on the same indazole core structure as AB

- PINACA, AB
CHMINACA, AB
- FUBINACA , and AKB48 where the 1

- and 3

- positions of the indazole ring syste m are substituted. These substitutions for THJ

- 2201 are the same substitutions as are found in AM

- 2201, where the core is indole. This single atom substitution from indole to indazole is the only difference between AM

- 2201 and THJ

- 2201. AM
- 2201 and

3 Personal communication from RTI International to DEA, 09/08/2014
. 4 Personal communication from RTI International to ODEC, DEA, 09/08/2014
.DEA/OD/ODE page 7 of 39 December 2014

THJ
- 220 1 are both substituted at the 3

- position with a carbonyl group known as a ketone. The ketone groups of both substances are further substituted with a naphthyl group. The 1

- position of core structures of THJ

- 2201 and AM

- 2201 are substituted with a fluorinat ed alkyl group, known as a 5

- fluoropentyl group (Huffman et al., 1994; Wiley et al., 1998; Aung et al., 2000; Manera et al., 2008; Huffman, 2009). In v itro CB1 Binding Affinity (K i ) CB1 Functional Activity (EC 50 ) AB - CHMINACA 0.74 nM a TBD AB - PINACA 2.64 nM a ; 0.93 nM c 14.3 nM c THJ - 2201 10.3 nM b 1.05 nM b

a Correspondence from RTI International to DEA, 9/08/2014 b Janowsky, 2014 c Prather, 2014 TBD – to be determined Table 1. In v itro data for AB - CHMINACA, AB - PINACA and THJ - 2201 Factor 4. H istory and current pattern of abuse SCs have been developed over the last 30 years as tools for investigating the cannabinoid system (Weissman et al., 1982; Huffman et al., 1996; Huffman et al., 1999). Synthetic cannabinoids intended for illicit use were first reported in the United States in a November 2008 encounter, where a shipment of "Spice" was seized and analyzed by CBP in Dayton, Ohio. Additionally at approximately the same time, in December 2008, JWH

- 018 and cannabicyclohexanol (CP

- 47,497 C8 homo logue) were identified by German forensic laboratories. Since the initial identification of JWH

- 018 (November 2008), many other SCs have been found applied on plant material and encountered as designer drug products ( Auwarter et al., 2009 ; DEA, 2009; DEA, 2012; DEA, 2013; DEA, 2014 ) . The popularity of these cannabinoids and their associated products appears to have increased since January 2010 in the U nited S tates based on seizure evidence and public health and media reports. Numerous SCs have been identified as pr oduct adulterants , and law enforcement has seized bulk pow d er of these substances. The first SCs identified as being abused included JWH

- 018, JWH
- 073, JWH
- 200, CP
- 47,497, and CP

- 47,497 C8 homologue, followed shortly thereafter by new generations of SCs including drugs such as UR

- 144, XLR11, AKB48, PB
- 22, 5F
- PB
- 22, AB
- FUBINACA, ADB
- PINACA and numerous other SCs varying only by slight modifications to their chemical structure. JWH
- 018, JWH
- 073, JWH
- 200, CP
47,497, and CP

- 47,497 C8 homologue were temporaril y scheduled on March 1, 2011 (76 FR 11075), and later permanently placed in schedule I by s ection 1152 of FDASIA on July 9,DEA/OD/ODE page 8 of 39 December 2014

2012. Section 1152 of FDASIA amended the CSA by placing cannabimimetic agents and 26 specific substances (including 15 synthetic can nabinoids, 2 synthetic cathinones, and 9 synthetic phenethylamines of the 2C

- series) into schedule I. UR

- 144, XLR11, and AKB48 were temporarily scheduled on May 16, 2013 (78 FR 28735). PB

- 22, 5F
- PB
- 22, AB
FUBINACA, and ADB

- PINACA were temporarily schedule d on February 10, 2014 (79 FR 7577). A nother generation of SCs including AB
- CHMINACA, AB
- PINACA and THJ
- 2201 has recently been encountered. These substances and laced pr oducts are commonly marketed as “ legal highs ” with a disclaimer of “ not for human consumption. ” As detailed in reports, law enforcement and public health officials are encountering the abuse of these substances (CDC, 2013a, 2013b, 2013c; NFLIS, 2014; STRIDE, 2014 ). Numerous herbal incense products have been found to contain one or mo re SC(s) laced on plant material (Appendix 2). 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, ” similar to marijuana ( McKeever et al., 2014; Bonar et al., 2014). Data gathered from published studies, supplemented by discussions on Internet discussion websites and personal communications demonstrate that these products are being abused mainly by smoking for their psychoact ive properties. The adult erated products are marketed as “ legal ” alternatives to marijuana. To lace the plant material, the SCs are generally dissolved in a solvent and sprayed on the plant material or the plant material is soaked in a solution of the d issolved substance (Vardakou et al., 2010 ; Wells and Ott, 2011). The majority of the substances encountered on the illicit market have not been tested beyond preliminary pre

- clinical laboratory screens before clandestine operators applied them on plant mat erial (Lewin et al., 2014 ). The psychoactive properties are directly linked to the SCs laced on the plant material sold as retail products (Auwarter et al., 2009 ; EMCDDA, 2009 ; Atwood et al., 2010). This was reconfirmed in a recent publication analyzing various herbal products reporting that the green plant material found in SC products was devoid of psychoactive effects (Ogata et al., 2013) demonstrating that the effects observed following ingestion of a SC product originates from the actual SC, and not the plant material. A major concern as reiterated by public health officials and medical professionals , remains 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 ; Oluwabasi et al., 2012; Durand et al., 2013 ; ONDCP, 2014 )
. This is supported by law enforcement encounters and reports fro m emergency rooms (SAMHSA,DEA/OD/ODE page 9 of 39 December 2014

2012 ; Fattore and Fratta, 2011; Vandrey et al., 2012); however, all age groups have been reported by media as abusing these substances and re lated products. In 2010, an estimated 11,406 emergency department (ED) visits involved a synthetic cannabinoid product (SAMHSA, 2012). Three

- fourths of these visits (75%) involved patien ts between the ages of 12

- 29 . In addition, the majority (59%) of these emergency department visits of patients aged 12 to 29 did not involve any other substance. Of the remaining 41% of individuals, the most frequently abused substance in combination with SCs was marijuana (17%), pharmaceuticals (17%) and alcohol (13%) (SAMH SA, 2012) . Individuals, including minors, are purchasing SCs from Internet websites, gas stations, convenience stores, and head shops. Reports from clinicians and law enforcement personnel have documented overdoses in juveniles as low as 13 and 14 years ol d (see Factor 6). In addition, an infant with confirmed exposure to SC was admitted to the intensive care unit following ingestion of a SC

- containing product (see Factor 6). Two research articles propose that the packaging is professional and inconspicuou s (unlabeled), targeting young people, possibly eager to use cannabis, but who are afraid of the judicial consequences and/or association with illicit drugs (Lindigkeit et al., 2009 ; Schifano, 2009). In addition, a recent survey directed at patients seekin g substance abuse disorder treatment reported multiple motives for use with the most commonly endorsed including curiosity (91%), feeling good/getting high (89%), relaxation (71%), and getting high without having a positive drug test (71%). Demographicall y, those with lifetime SC use were significantly younger than respondents who abused drugs other than SCs (Bonar et al., 2014). This data coincides with U.S. Drug Courts 5 that have communicated concerns related to the abuse of SCs and a response rate of greater than 30% by juveniles subject to routine drug screens from a sampling (information communicated to the DEA). The Monitoring the Future (MTF) 6 Report for 2012 detailed that while synthetic cannabinoid use , compared to 2011, has remained level in 12 th graders at 11.3%, “the fact that its prevalence rate has remained high despite federal and state efforts to reduce its use is troublesome” (Johnston et al., 2013). S ynthetic cannabinoid use in 8 th and 10 th graders was measured for the first time in 2012 , with annual prevalence rates of 4.4% and

5 Drug courts were developed to achieve a reduction in recidivism and substance abuse among nonviolent, substance abusing offenders by increasing their likelihood for successful rehabilitation through early, continuous, and intense judici ally supervised treatment, mandatory periodic drug testing, and the use of appropriate sanctions and other rehabilitation services. Drug courts analyze specimens from participants for new and existing drugs of abuse. 6 MTF is a national survey conducted by the Institute for Social Research at the University of Michigan under a grant from the NIDA that tracks drug use trends among American adolescents in the 8 th , 10 th , and 12 th grades.DEA/OD/ODE page 10 of 39 December 2014

8.8% , respectively. The MTF Report for 2013 detailed that there was a significant decline in the use of SCs among 12 th graders , decre asing from 11.3% in 2012 to 7.9% in 2013
. Synthetic marijuana use decreased in the past year from 8.8% in 2012 to 7.4% in 2013 among 10 th graders and from 4.4% to 4.0% among 8 th graders (Johnston et al., 2014). Dresen and colleagues ( Dresen et al., 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 recent testimony given by the Deputy Director of the Office of National Drug Control Policy (ONDCP) to the U.S. Senate Caucus on Internat ional Narcotics Control Board (September 25, 2013), current drug testing misses significant populations of synthetic cannabinoid users. In an example described in his testimony, a study found that in a sample of men 30 years old or younger within the Distr ict of Columbia parole and probation system, 39 percent of those who cleanly passed a traditional drug screen tested positive for SCs
. 7 The study continued 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 had failed or passed a traditional drug screen
. 8 In addition to the characterized psychoses, drivers with driving impairment have been encountered with confirmed presence of a synthetic cannabinoid in their systems (Yeakel and Logan, 2013). In October 2013, a 40 year old male was killed following an automobile accident in Tulsa, O klahoma . Toxicology results of the opposing driver detected AB

- FUBINACA and AB

PINACA in biological samples (see Factor 6). Several SCs have been shown to display higher potency in vitro and in vivo when compared to Δ9

- THC (Compton et al., 1992; Wiley et al., 1998; Weibelhaus et al., 2012). Smoking mixtures of these substances abused for the purpose of achieving intoxication have resulted in numerous emergency room visits and calls to poison control centers. Abuse of SCs and their products has been characterized with both acute and long term public health and safety issues. Distinct pharmacological prop erties and metabolism of SCs have been suggested to contribute to the observed toxicity associated with the abuse of SCs (Fantegrossi et al., 2014 ). As discussed previously, most users of SCs or SC
- related products abuse these substances by smoking the product following application to plant material. Recently, law

7 Office of National Drug Control Policy. Community Drug Early Warning Sy stem: The CDEWS Pilot Project, 13. September 13, 2013. 8 Id . p. vi.DEA/OD/ODE page 11 of 39 December 2014

enforcement has also been encountering new variations of SCs in liquid form. The liquids contain one or more SC ( s ) , including examples such as AB

- FUBINACA, AB
- CHMINACA, AB
PINACA , and XLR11. Us ers have been identified applying the liquid to hookahs (an instrument for vaporizing and smoking a given material whereby the smoke or vapor passes through a water basin prior to inhalation), vaporizers (also known as “ vaping ” or an “ e - cigarette, ” which allows the user to administer a liquid to be aerosolized and then inhaled) , and hookah pens (a type of vaporizer, often much smaller and intended for increased discretion while smoking). As reported by users, specifically adolescents, this method of ing esting a SC is viewed as being safer than traditional smoking (blunt, pipe, cigarette , etc.). In the study conducted by Bo nar et al. (2014), while 91% of SC users reported ingesting the product via a cigarette or blunt, 27% of the respondents also reported using methods that included vaporization, water pipe, bong , or hookah as a delivery method. Similar to conventional illicit manufacturing of SC products, liquid preparations of these substances do not adhere to any manufacturing standards with regard to d osage, the substance(s) included, purity , or contamination. It is important to note that following manufacturing principles or standards would not eliminate the adverse effects observed with SC products and SCs would still be considered a threat to public safety. The American Association of Poison Control Centers (AAPCC) reported a 219% increase from 2012 to 2013 in e

- cigarette and liquid nicotine exposures (AAPCC, October 2014). Through October 31, 2014, the AAPCC has received 3,353 e - cigarette device and liquid nicotine exposures ( t able 2). As per the AAPCC, t he term “exposure” means someone has had contact with the substance in some way; for example, ingested, inhaled, absorbed by the skin or eyes, etc. Not all exposures are poisonings or overdoses. YEAR # of Exposures 2011 271 2012 460 2013 1,5 42 2014* 3,353 Table 2. E - cigarette Device and Liquid Nicotine Reported Exposures to Poison Control Centers‡ ‡ AAPCC, 2014 * Through October 31, 2014 SummaryDEA/OD/ODE page 12 of 39 December 2014 Recently, law enforcement has been encountering AB
- CHMINACA, AB
- PINACA and THJ
- 2201 in increasing numbers. SCs and their associated products are available over the Internet or found to be sold in gas stations, convenience stores, and tobacco and head shops
. AB
- CHMINACA, AB
- PINACA and THJ
- 2201 , similar to the previously scheduled SCs (DEA, 2012; DEA, 2013 ; DEA, 2014 ), have been seized alone and/or spiked on products that are marketed as herbal incense and promoted as “ legal ” alternatives to marijuana. Factor 5. The scope, duration, and significance of abuse Following multiple scheduling actions in an attempt to safeguard the public from the adverse effects and safety issues associated with SCs , continued encounters by law enforcement and health care pro fessionals are directly related to the increasing abuse of these substances and their associated products. With the passing of each Federal action, drug manufacturers and suppliers are adapting at an alarmingly quick pace to switch the ingredients to new , non - controlled variations of SCs . Emergency control of UR

- 144, XLR11 , and AKB48 on May 16, 2013 , resulted in an increase in the availability, trafficking and abuse of PB

- 22, 5F
- PB
- 22, AB
- FUBINACA, and ADB

- PINACA . Emergency control of PB
- 22, 5F
- PB
- 22, AB
- FU BINACA, and ADB

- PINACA on February 10, 2014 , resulted in a similar pattern, with the emergence of AB
- CHMINACA, AB
- PINACA and THJ
- 2201
. Exposure incidents involving SCs continue to be documented by poison control centers in the U nited S tates as the abuse of these substances remain s a threat to both the short

- and long

- term public health and safety
. E xposures to SCs were first reported to t he AAPCC in 2011 ( table 3 )
. Recently , AAPCC exposure reports are beginning to increase . T he number of exposures reported demonstrates the dangerous health effects observed involving these chemicals. Exposures for August 2014 ( 442 ) were the highest received in a monthly period by the AAPCC since July 2012 ( 459 ) (AAPCC, October 2014). In addition, a majority of expos ure incidents from 2012 to the present resulted in individuals seeking medical attention at health care facilities. 9

9 The content of this report does not necessarily reflect the opinions or conclusions of the American Association of Poison Control Centers (AAPCC)
. AAPCC ( http://www.aapcc.org ) maintains the national database of information logged by the country’s 57 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/OD/ODE page 13 of 39 December 2014

YEAR # OF CASES 2011 6,968 2012 5,230 2013 2,6 6 6 2014 (through October 31 , 2014 ) 2, 996 Table 3 . Exposure cases of synthetic cannabinoids as reported to poison centers* * AAPCC, October 31, 2014 Chronic abuse of SCs has been linked to signs of addiction and withdrawal similar to that experienced with cannabis abuse ( Zimmermann et al., 2009 ; Muller et al., 2010 ; Vardakou et al., 2010 )
. T olerance to these drugs may develop fairly rapidly with larger doses being require d to achieve the desired effect ( EMCDDA, 2009 ) . In 2010, the Substance Abuse and Mental Health Services Administration (SAMHSA) reported an estimated 11,406 emergency department visits involving a synthetic cannabinoid product. In 2011, SAMHSA reported the number of emergenc y department visits involving a synthetic cannabinoid product had increased significantly to an estimated 28,531 (SAM HSA, 2013) ( figure 2 ).

Figure 2. Emergency department visits involving synthetic cannabinoids (SAMHSA, 2013). Synthetic cannabinoid data were not reported prior to 2010. *Estimates of ED visits are based on a representative sample of non

- Federal, general, short

- stay hospitals wi th 24

- hour EDs in the U nited S tates . 11,406 28,531

0 5,000 10,000 15,000 20,000 25,000 30,000

2010 2011 Number of ED visits 

## Emergency Department Visits Involving

Synthetic Cannabinoids*DEA/OD/ODE page 14 of 39 December 2014 The following tables ( table 4; table 5) represent exhibits /reports obtained through both STRID E and NFLIS that correspond to the specific drug listed
. Additional information can be located in Appendix 1. System to Retrieve Information from Drug Evidence (STRIDE) * DRUG EXHIBITS ‡ DATES QUERIED AB
- CHMINACA 21 (March 2014) 01/01/201 0 – 09/30 /2014 AB
- PINACA 245 (June 2013) 01/01/201 0 – 09/ 30 /2014 THJ
- 2201 65 (September 2013) 01/01/201 0 – 09/ 30 /2014 Table 4 . Reports obtained through the STRIDE database * Query date: October 1 , 2014 ‡ The month in parenthesis (e.g., (March)) corresponds to the month the substance was first encountered NFLIS * § DRUG 2013 REPORTS ‡ 2014 REPORTS ‡ STATES AB
- CHMINACA 0 586 (February) Arkansas, Arizona, California,

Colorado, Georgia, Iowa, Indiana, Kansas, Kentucky, Louisiana, Missouri, North Dakota, New Jersey, Ohio, Oklahoma, Pennsylvania, Tennessee, Texas, Wisconsin AB
- PINACA 963

(March) 2, 820 Alabama, Arkansas, Arizona, California, Colorado, Connecticut, Florida, Georgia, Iowa, Idaho, Illinois, Indiana, Kansa s , Kentucky, Louisiana, Massachusetts , Michigan, Minnesota, Missouri, Mississippi , North Dakota, Nebraska, New Hampshire, New Jersey, Neva da, New York, Ohio, Oklahoma, Oregon, Pennsylvania, South Carolina,DEA/OD/ODE page 15 of 39 December 2014 Tennessee, Texas, Utah, Virginia, Washington, Wisconsin, West Virginia, Wyoming THJ
- 2201 0 220 (January) Arkansas, Arizona, Connecticut,

Georgia, Iowa, Illinois, Indiana, Kansas, Kentucky, Minnesota, Missouri, North Dakota, Nebraska, New Hampshire, New Jersey, Ohio, Pennsylvania, Tennessee , Wisconsin Table 5 . Reports obtained through the NFLIS database § * Query date: November 25 , 2014 ‡ The month in parenthesis (e .g., (Ma rch )) corresponds to the month the substance was first encountered § Laboratories reporting to NFLIS include state, local and other federal laboratories (not including DEA) Summary The abuse of SCs is characterized in the scientific literature and by law enforcement encounters with reported adverse health effects. Numerous calls have been received by poison control centers regarding the abuse of products potentially laced with SCs that have resulted in visits to emergency departments. Follow ing legislative control of JWH

- 018, JWH
- 200, JWH
- 073, CP
- 47,497, and cannabicyclohexanol , by FDASIA in July of 2012 and temporary control of UR
- 144, XLR11 , and AKB48 in May 2013 and PB

- 22, 5F
- PB
- 22, AB
- FUBINACA , and ADB

- PINACA in February 2014, law enforcement has once again begun encountering novel SCs including AB
- CHMINACA, AB
- PINACA and THJ
- 2201
. Factor 6. What, if any, risk there is to the public health THJ
- 2201 was first observed in September 2013 while AB

- CHMINACA was first observed in February of 2014. AB
- PINACA has been for sale on the illicit drug market as early as March 2013. From December 2013 through September 2014 , CBP reported select encounters of these substances with most shipments originating in China and intended for destinations within the U nited S tates : AB
- CHMINACA – 17 seizures involving 15.825 kg; AB
PINACA – 4 seizures involving 6 kg; THJ
- 2201 – 6 seizures involving 5 .5 kg (Appendix 2)
. 10 The

10 Correspondence from CBP to DEA, (December 2013

– September 2014)
.DEA/OD/ODE page 16 of 39 December 2014

DEA has reported multiple encounters of large quantities of A B
- CHMINACA, AB
- PINACA and THJ
- 2201 that have been confirmed by forensic laboratories (STRIDE and/or NFLIS ). Since abusers obtain these drugs through unknown sources, purity of these drugs is uncertain, thus posing significant adverse health risk to these users ( EMCDDA, 2009 , Dresen et al., 2010 ) . From October 2013 through the present, multiple deaths and severe overdoses have occurred involving AB

- CHMINACA and AB
- PINACA. Details of the se events are summarized below.

 In October 2013, a 40 year old male was killed in Tulsa, Oklahoma, following a head on motor vehicle collision. Toxicology results of the opposing driver detected AB

PINACA and AB

- FUBINACA in biological samples
. 11
 In early 2014, two deaths were reported (19 year old male , Angola , I ndiana ; 37 year old male , Omaha, N ebraska ) involving AB

- PINACA. Cause of death in both cases were deemed synthetic cannabinoid

- related
. 12
 In April 2014, a 21 year old f emale in Lafayette, Louisiana, died with the cause of death determined to be drowning with contribution of poly

- drug toxicity. Laboratory results detected AB

- CHMINACA in both drug evidence and biological samples
. 13
 In April 2014, a male presented at a local emergency department in Mobile, A labama with excited delirium following ingestion of a synthetic cannabinoid
. Laboratory results on drug evidence detected AB

- CHMINACA
. 14
 In April 2014, a 38 y ear o ld male in Bay Minette, A labama, died following ingestion of a synthetic cannabinoid product. Laboratory results detected AB

- CHMINACA in biological samples
. 15
 In April 2014, a 52 year old male in Lafayette, L ouisiana, suffered severe injuries after jumping through a window due to excited delirium following ingestion of a synthetic cannabinoid product “Mojo. ” Laboratory results on drug evidence detected AB

- CHMINACA
. 16
 In May 2014, an 18 year old male in Seattle, W ashington, suffered adverse effects following ingestion of a synthetic cannabinoid product “Black Voodoo
. ” Laboratory results on drug evidence and biological samples detected AB

- CHMINACA
. 17

11 Correspondence from US Postal Inspection Service to DEA, 3/28/2014
. 12 Correspondence from AIT Laboratories to DEA, 06/03/2014
. 13 Correspondence from Lafayette, Parish Coroner’s Office to DEA, 05/29/2014
. 14 STRIDE, DEA
. 15 Correspondence from A IT Laboratories to DEA, 08/07 /2014
. 16 Correspondence from LA State Crime Lab to DEA, 05/01/2014
. 17 Correspondence from Dept. of La boratory Medicine (UCSF) to DEA, 07/24/2014
.DEA/OD/ODE page 17 of 39 December 2014

 In May 2014, a 32 year old male in Corvallis, O regon, died following ingestion of a synthetic cannabinoid product “Scooby Snax
. ” Laboratory results on drug evidence and biol ogical samples detected AB

- CHMINACA. The cause of death as determined by the medical examiner was toxic effects of synthetic cannabinoids: AB

CHMINACA
. 18
 In May /June 2014, over 29 individuals in Gainesville, Florida, presented at local emergency departments while experiencing seizures and comas following ingest ion of a synthetic cannabinoid . Laboratory analysis conducted on biological samples from 13 of the patients identified AB

- CHMINACA as the drug responsible for the effects listed previously
. 19
 In June 20 14, a 14 year old male in New Orleans, Louisiana, experienced convulsions and sever e shaking after ingesting a synthetic cannabinoid product “Mojo
. ” Laboratory results on drug evidence and biological samples detected AB

CHMINACA
. 20 21
 In June 2014, a 13 year old female in Irving, Texas, experienced convulsions after ingesting a synthetic cannabinoid product. Laboratory results on biological samples detected AB

- CHMINACA
. 22
 In June 2014, a 16 year old male and 17 year old female in Atlantic City, New Jersey, both experienced delirium after ingesting a liquid synthetic cannabinoid ingested through a hookah pen. Laboratory results on drug evidence detected AB

- PINACA
. 23
 In June 2014, a 39 year old male in Baton Rouge, Louisiana, was transported by EMS to a local e mergency department after experiencing severe agitation following ingesti on of a synthetic cannabinoid product. Laboratory results on biological samples detected AB
- CHMINACA
. 24
 In July 2014, a 19 year old male in Newport Beach, California, died following in gestion of a synthetic cannabinoid product. Laboratory analysis of drug evidence and biological samples detected AB

- CHMINACA
. 25 The cause of death as determined by the medical examiner was toxic ef fects of synthetic cannabinoid AB
- CHMINACA
. 26
 In July 20 1 4, a 10 month old infant in Shreveport, Louisiana , was admitted to the prenatal intensive care unit (PICU) following ingesting of a synthetic cannabinoid

18 Report from the Office of the State Med ical Examiner (OR) to DEA, 08/07/2014
. 19 Correspondence from Dept. of Laboratory Medicine (UCSF) to DEA, 07/24/2014
. 20 Correspondence from Dept. of Laboratory Medicine (UCSF) to DEA, 07/24/2014
. 21 Correspondence from Jefferson Parish Sheriff’s Office to DEA, 07/10/2014
. 22 Correspondence from Dept. of Laboratory Medicine (UCSF) to DEA, 07/24/2014
. 23 Correspondence from Atlantic City PD to DEA, 07/02/2014
. 24 Correspondence from Dept. of La boratory Me dicine (UCSF) to DEA, 07/24/2014
. 25 Correspondence from Orange County Crime Laboratory to DEA, 08/07/2014
. 26 Correspondence from Orange County Sheriff’s Office to ODEC, DEA, 11/21/2014
.DEA/OD/ODE page 18 of 39 December 2014 product. Laboratory analysis of drug evidence and biological samples detected AB

CHMINACA
. 27
 In August 2014, three juvenile females (14, 15 and 17 years old) in St. Louis, M issouri, suffered a loss of consciousness and seizures following ingestion of a synthetic cannabinoid product. Laboratory results of evidence detected AB
- PINACA and AB
- CHMINACA
. 28
 In August 2014, over 44 individuals in Manchester, New Hampshire, presented at local emergency departments suffering seizures and serious medical reactions following the ingestion of synthetic cannabinoid products. Laboratory analysis of evidence collected detected multiple SCs including AB
- CHMINACA
. 29
 In September 2014, four juveniles were taken to local emergency departments following ingestion of a synthetic cannabinoid e

- liquid identified as “ Cloud 9. ” Laboratory results of the product detected AB

- PINACA
. 30 Throughout 2013 and 2014, descriptions of overdoses , hos pitalizations , severe outbreaks (CDC , 2013a,b ,c ) and deaths (Behonek et al., 2014) involving different SCs have been reported in both scientific publications and in the news media
. Human studies intended to investigate the health implications resulting from exposure to these substances are not safe due to the severe adverse effects associated with ingestion of illicit SCs. However, clinical effects following ingestion of SCs have bee n reported by physicians and emergency medical personnel (Griffiths et al., 2010; Vardakou et al., 2010). Common clinical effects observed in emergency rooms requiring medical intervention and reported by numerous state public health departments, poison co ntrol centers , and private organizations include: vomiting, anxiety, agitation, irritability, seizures, hallucinations, tachycardia, elevated blood pressure, loss of consciousness , and non - responsiveness (Forrester et al., 2011; Cohen et al., 2012; Harris and Brown, 2013; Hermanns
- Clausen et al., 2013; Zawilska and Wojcieszak, 2013) (see reports from state health departments and poison centers including AAPCC, Appendix 1). Specifically, clinical symptoms as reported from overdoses with AB

- CHMINACA and AB

- PI NACA in particular have included excited delirium, seizure, coma, agitation, myocardial infarction, convulsions, difficulty breathing , and an altered state of consciousness (correspondence from law enforcement/laboratory/clinical personnel, see Factor 6 li st of OD/Death reports). A 12
- month study conducted in 2012 demonstrated that out of 950 self

- reported users, 2.4% reported having a medical emergency requiring treatment

27 Correspondence from Shreveport, Louisiana PD to DEA, 10/07/2014
. 28 C orrespondence from Franklin County Missouri Sheriff’s Office to DEA, 08/26 /2014
. 29 Correspondence from Dept. of Laboratory Medicine (UCSF) to DEA, 08/26/2014
. 30 Correspondence from Michigan State Police to DEA, 09/16/2014
.DEA/OD/ODE page 19 of 39 December 2014

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). These data correspond t o figures reported by SAMSHA, which demonstrates that youth, specifically those aged 12 to 17 years old , comprise a large percentage of users requiring emergency medical a ttention ( figure 3 ) (SAMSHA, 2012). Since abusers obtain these drugs through unknown sources, the identity, purity, and quantity of these substances is uncertain and inconsistent, thus posing significant adverse health risks t o users. The SCs encountered on the illicit drug market have no accepted medical use within the U nited S tates . Reg ardless, SC products continue to be easily available and 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 (Au warter et al., 2009; Hudson et al., 2010). Similar products have been found to vary in the amount and type of synthetic cannabinoid laced on the plant material, which could be one explanation for the numerous emergency department admissions that have been connected to these substances (Vardakou et al., 2010; Vearrier and Osterhoudt, 2010; Schneir et al., 2011; Fattore and Fratta, 2011). By sharing pharmacological similarities with schedule I substances (Δ9

- THC , JWH
018 and other temporarily and permanently controlled schedule I substances ), SCs pose a risk to the abuser (Weissman et al., 1982 ; Compton et al., 1992; Wiley et al., 1998), and the chronic abuse of products laced with SCs has been linked to addiction and wit hdrawal (Vardakou et al., 2010).DEA/OD/ODE page 20 of 39 December 2014

Figure 3. Age - related emergency department visits involving synthetic cannabinoids and marijuana (SAMHSA, 2014 ). The CSA (21 U.S.C. 811(h)(4) ) requires the Attorney General to notify the Secretary of the Department of Health and Human Services (HHS) of his intention to temporarily place a substance into s chedule I of the CSA. 31 The Deputy Administrator transmitted notice of his intent to place AB
- CHMINACA, AB
- PINACA and THJ
- 2201 in schedule I on a temporary basis to the Assistant Secretary by letter dated September 17 , 2014
. The Assistant Secretary responded to this notice by letter dated September 30 , 2014 , and advised that based on review by the Food and Drug Administ ration (FDA), there are currently no approved new

31 The Secretary of HHS has delegated to the Assistant Secretary for HHS the authority to make domestic drug scheduling recommendations. As set forth in a memorandum of understanding entered into by the HHS, the FDA, and NIDA, the FDA acts as the lead agency within the HHS in carrying out the Secretary’s scheduling responsibilities under the CSA, with the concurrence of NIDA. 50 FR 9518. 0 5 10 15 20 25 30 35

Aged 12-17 Aged 18-20 Aged 21-24 Aged 25-29 Percent of ED Visits



### Age Group



## Chart Title

Synthetic Cannabinoids Marrijuana 

## Age Related Synthetic Cannabinoid and Marijuana - Related Emergency Department (ED)

Visits - 2011DEA/OD/ODE page 21 of 39 December 2014

drug applications or investigational new drug applications for AB
- CHMINACA, AB
- PINACA , or THJ
- 2201 . The Assistant Secretary also stated that HHS has no objection to the temporary placement of AB
- CHMINACA, AB
- PINACA , and THJ
- 2201 into schedule I of the CSA. The DEA has taken into consideration the Assistant Secretary’s comments. In accordance with 21 USC 811(h)(1), AB
- CHMINACA, AB
- PINACA , and THJ
- 2201 are not currently listed in any schedule under the CSA, a nd no exemptions or approvals are in effect for these substances under s ection 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355)
. T he DEA finds that the scheduling of AB

- CHMINACA, AB
- PINACA and THJ

- 2201 in schedule I on a temporary basis is n ecessary to avoid an imminent hazard to public safety and therefore intends to issue a temporary scheduling order . Any additional comments submitted by the Assistant Secretary in response to this notification shall also be taken into consideration before a final order is published. 21 U.S.C. 811(h)(4). Conclusion of 3 - Factor Analysis After a careful review of the scientific literature, Factors 4, 5, and 6, NFLIS, STRIDE, and other law enforcement data and sources of information, it is evident that AB
CHMINACA, AB
- PINACA , and THJ
- 2201 are trafficked and abused and pose an imminent hazard to public safety
. The DEA has considered the three criteria for placing a substance into s chedule I of the CSA (21 U.S.C. 812). The data available and reviewed for AB
- CHMINACA, AB
- PINACA , and THJ
- 2201 indicated that these substances , including their salts, isomers, and salts of isomers, pose an imminent hazard to public safety and health, have high potential for abuse, have no currently accepted medical use in treatment in the U nited S tates , and lack accepted safety for use under medical supervision.DEA/OD/ODE page 22 of 39 December 2014

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- Butyl

- 3
- (1

- naphthoyl)indole (JWH

- 073), 1

- pentyl

- 3
- (1

- naphtoyl)indole (JWH

- 018), 1

- [2

- (4

- morpholinyl)ethyl]

- 3
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- 200), 5

- (1,1

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- 2
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- hydroxycyclohexyl)

- phenol (CP

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- (1,1

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- 3
- (2,2,3,3

- tetramethylcyclopropoyl)indole (5

- fluoro

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- (1

- adamantyl)

- 1
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- 8
- yl 1

- pentyl

- 1H
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- 3
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- 22; QUPIC), quinolin

- 8
- yl 1

- (5

- fluoropentyl)

- 1H
- indole

- 3
- carboxylate (5

- fluoro

- PB
- 22; 5F
- PB
22), N
- (1

- amino
- 3
- methyl

- 1
- oxobutan

- 2
- yl)

- 1
- (4

- fluorobenzyl)

- 1H
- indazole

- 3
- carboxamide (AB

- FUBINACA) and N

- (1

- amino
- 3,3
- dimethyl

- 1
- oxobutan

- 2
- yl)

- 1
- pentyl

- 1H
- indazole

- 3
- carboxamide (ADB

- PINACA) : Background Information and Evaluation of ‘Three Factor Analysis’ ( Factors 4, 5 and 6) for Temporary Scheduling. 79 FR 7577.DEA/OD/ODE page 24 of 39 December 2014

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- (aminocarbonyl)

- 2
- methylpropyl]

- 1
- (cyclohexylmethyl)

- 1H
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- 3
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- CHMINACA), N
- (1

- amino
- 3
- methyl

- 1
- oxobutan

- 2
- yl)

- 1
- pentyl

- 1H
- indazole

- 3
- carboxamide (AB

- PINACA), (1

- (5

- fluoropentyl)

- 1H
- benzoimidazol

- 2
- yl)(naphthalen

- 1
- yl)methanone (FUBIMINA) and naphthalen

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Appendix 1 Public Health 1. The Substance Abuse and Mental Health Services Administration (SA MHSA) reported that in 2010, an estimated 11,406 emergency department visits involved a synthetic cannabinoid product. 2. SAMHSA reported that in 2011, an estimated 28,531 emergency department visits involved a s ynthetic cannabinoid product, a significant increase over the 2010 estimated visits. 3. Monitoring the Future study results for 2012 (released 12/19/2012) state that for the second year of reporting, u se of synthetic marijuana amongst 12 th graders held level at 11.3%. Study authors stated that while a leveling was encouraging, the high prevalence rate despite F ederal and S tate efforts to reduce its use was troublesome. 4. Monitoring the Future study results for 2013 (released 12/18/2013) state that use of synthetic marijuana amongst 12th graders fell from 11.3% in 2012 to 7.9% in 2013
. 5. Health effects from the drug can be life

- threatening and can include: a. Severe agitation and anxiety. b. Fast, racing hear tbeat and higher blood pressure. c. Nausea and vomiting. d. Muscle spasms, seizures, and tremors. e. Intense hallucinations and psychotic episodes. f. Suicidal and other harmful thoughts and/or actions. g. http://www.aapcc.org/alerts/synthetic

- marijuana/ 6. ...these substances are among the worst they have ever seen. People high on these drugs can get very agitated and violent, exhibit psychosis and severe behavior changes, and have harmed themselves and others. Some have been admitted to psychiatric hospitals and have experience continued neurological and psychologic al effects (News Release
– American Association of Poison Control Centers: AAPCC Issues Statement on the Synthetic Drug Abuse Prevention Act, July 11, 2012)
. 7. Synthetic cannabinoids, commonly known as “synthetic marijuana,” “K2,” or “Spice , ” are often sold in legal retail outlets as “herbal incense” or “potpourri” . They are labeled “not for human consumption” to mask their intended purpose and avoid Food and Drug Administration (FDA) regulatory oversight of the manufacturing process. (Office of National Drug Control Policy) 8. At least 43 states have taken action to control one or more synthetic cannabinoids. (Office of National Drug Control Policy , 2014 ) 9. Spice users report experiences similar to those produced by marijuana
— elevated mood, relaxat ion, and altered perception
— and in some cases the effects are even stronger than those of marijuana. Some users reportDEA/OD/ODE page 31 of 39 December 2014 psychotic effects like extreme anxiety, paranoia, and hallucinations. (National Institute on Drug Abuse , 2014 ) 10. Spice abusers who have bee n taken to Poison Control Centers report symptoms that include rapid heart rate, vomiting, agitation, confusion, and hallucinations. Spice can also raise blood pressure and cause reduced blood supply to the heart (myocardial ischemia), and in a few cases i t has been associated with heart attacks. Regular users may experience withdrawal and addiction symptoms. (National Institute on Drug Abuse , 2014 ) 11. In order to protect public health and well

- being, Governor Maggie Hassan today declared a State of Emergency in the State of New Hampshire as a result of recent overdoses in Manchester and Concord as a result of the use or misuse of the synthetic cannabinoid identified as "Sma cked ! ”
. (Press Release: Governor Hassan Declares State of Emergency as a Result of Overd oses from Synthetic Cannabinoid
– August 14, 2014) 12. CESAR FAX, a publication from the Center for Substance Abuse Research at the University of Maryland (College Park), reported the results from Bonar et al. (2014) describing the results of the study of pati ents in a Midwestern residential treatment program. Results demonstrated that 71% of those reporting synthetic cannabinoid abuse used an SC

- containing product to avoid a positive drug test. The two most common reasons for SC use was “curiosity” (91%) and “ to feel good or get high” (89%). (September, 2014) Poison Control Centers 1. March 24 , 2010, AAPCC Press Release. As of March 24, 2010, 112 exposure calls had been received since 2009 regarding synthetic cannabinoids and associated products, including 59 exposure calls since March 1, 2010, according to the National Poison Data System ( NPDS )
. 2. July 23, 2010 , AAPCC Press Release. As of July 23, 2010, 761 exposure calls had been received regarding synthetic cannabinoids and associated products according to NP DS. 3. August 20, 2010 , AAPCC Press Release. As of August 20, 2010, 1,057 exposure calls had been received regarding synthetic cannabinoids and associated products according to NPDS. 4. September 27, 2010, AAPCC Press Release. As of September 27, 2010, 1,503 e xposure calls had been received regarding synthetic cannabinoids and associated products according to NPDS. 5. November 3, 2010 , AAPCC Press Release. As of November 3, 2010, 1,966 exposure calls have been received by poison centers regarding products purported to contain synthetic cannabinoids according to NPDS. Calls have been received in 48 states and the District of Columbia.DEA/OD/ODE page 32 of 39 December 2014 6. November 22, 2010 , AAPCC Press Release . As of November 22, 2010, poison centers have reported 2,304 exposure calls regardin g products purported to contain synthetic cannabinoids according to NPDS. Poison centers have received exposure calls in 49 states and the District of Columbia. 7. December 21, 2010 , AAPCC Press Release. As of December 21, 2010, U.S. poison centers have rep orted receiving more than 2,500 exposure calls this year alone. As of December 21, 2010, poison centers have reported 2,752 exposure calls about the products according to NPDS. 8. January 18, 2011 , AAPCC Press Release. As of January 18, 2011, U.S. poison ce nters have received more than 3,000 exposure calls regarding products purported to contain synthetic cannabinoids. In 2010, poison centers reported 2,867 exposure calls. As of January 18, 2011, U.S. poison centers have reported 217 exposure calls for 201 1. 9. February 3, 2011, AAPCC Press Release. As of February 3, 2011, U.S. poison centers have reported 385 exposure calls for 2011. 10. February 10, 2011, AAPCC Press Release. Synthetic marijuana products have spurred more than 3,000 exposure calls to U.S. pois on centers since 2010. 11. February 24, 2011, AAPCC Press Release. As of February 24, 2011, U.S. poison centers have reported 706 exposure calls for 2011. The total number of calls since 2010 is more than 3,500 exposure calls. 12. April 20, 2011, AAPCC Press R elease. Synthetic marijuana products have spurred more than 4,500 exposure calls to U.S. poison control centers since 2010. 13. July 11, 2012, AAPCC Press Release. In 2010, poison centers nationwide responded to about 3,200 exposure calls related to synthetic marijuana and bath salts. In 2011, the number jumped to more than 13,000. Sixty percent of these cases involved patients 25 and younger. 14. November 28, 2011, AAPCC Press Release. Poison center data provides vital information lea ding to the DEA ban of synthetic drugs. 15. February 16, 2012, AAPCC Press Release. American Association of Poison Control Centers joins the Office of National Drug Control Policy Working Group in address ing the dangers o f synthetic drugs. 16. May 31, 2012, AAPCC Press Release. The AAPCC commends the U.S. Senate for passing a ban of synthetic drugs in SB 3187 and call on the U.S. House of Representatives to include the language in the final version of the bill. 17. July 11, 2012, AAPCC Press Release. AAPCC comment t he nation’s policy makers on passage into the law the Synthetic Drug Abuse Prevention Act of 2012.DEA/OD/ODE page 33 of 39 December 2014 18. From January 1, 2012 through December 31 , 2012 , poison center s nationwide have received 5,230 exposure calls regarding exposure to synthetic cannabinoids. 19. Fr o m January 1, 2013 through December , 2013 , poison center s nationwide have received 2,66 6 exposure calls regarding exposure to synthetic cannabinoids. 20. From January 1, 2014 through October , 2014 , poison cen ters nationwide have received 2, 996 exposure calls regarding exposure to synthetic cannabinoids.DEA/OD/ODE page 34 of 39 December 2014

Table 3. NFLIS – State and Local and other Federal Laboratory (not DEA) Forensic Laboratory Reports (Quer y date: November 25 , 2014 ) 2010 2011 2012 2013 2014 Total

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 ‡ JWH - 018; JWH 073; JWH - 200; CP 47,497 CP - 47,497 C8 homologue 138 413 670 1,198 1,515 997 661 542 427 356 233 15 0 1 10 98 8 3 4 6 66 24 9 7, 736

UR - 144; XLR11; AKB48 1* 0 0 0 0 0 0 50 571 3, 376 6, 361 5, 279 6, 695 6, 664 3, 945 2, 844 3, 607 2, 852 1,644 43,889
PB - 22; 5F - PB - 22; AB - FUBINACA; ADB - PINACA 0 0 0 0 0 0 0 0 0 0 1 0 356 1, 017 2, 066 2, 361 3, 262 2,408 1,055 12,526

AB - CHMINACA 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 34 205 347 586

AB - PINACA 0 0 0 0 0 0 0 0 0 0 0 0 0 39 413 511 1,038 1,162 620 3, 783

THJ - 2201 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 17 94 109 220 *Enco unter confirmed in March 2012; ‡ = data are incomplete for third quarter 201 4 , still being reported
. C orresponds to the date substances were placed under temporary controlDEA/OD/ODE page 35 of 39 December 2014

Table 4. ST RIDE Records (January 1, 2010 through September 30, 2014) (Quer y date: October 1 , 2014 ): NUMBER OF RECORDS AB - CHMINACA 21 AB - PINACA 245 THJ - 2201 65DEA/OD/ODE page 36 of 39 December 2014

Appendix 2 T able 5 . Selected Reports from Customs and Border Prote ction Laboratory ( December 2013 – September 2014 ) Date of Detention Identified

Substance(s) Detained at Originated from Destination TOTAL WEIGHT 12/27/2013 THJ
- 2201 San Francisco Intl Mail China West Valley City, UT 500 g m 0 1/ 0 3/2014 THJ
- 2201 San Francisco Intl Mail China El Paso, TX 1 kg 0 2/28/2014 AB
- CHMINACA San Francisco Intl Mail China Houston, TX 1 kg 0 3/10/2014 AB
- CHMINACA San Francisco Intl Mail China Texarkana, AR 1 kg 0 3/22/2014 THJ
- 2201 FedEx Anchorage, AK China Las Vegas, NV 1 kg 04/29/2014 AB
- PINACA FedEx Anchorage, AK China Dothan, AL 1kg 0 5/ 0 9/2014 THJ
- 2201 San Francisco Intl Mail China Las Vegas, NV 500 gm 05/21/2014 THJ
- 2201 San Francisco Intl Mail China Las Vegas, NV 500 gm 05/21/2014 AB
- PINACA San Francisco Intl Mail China Spokane, WA 1 kg 0 5/28/2014 THJ
- 2201 San Francisco Intl Mail China Brooklyn, NY 2 kg 06/26/2014 AB
- PINACA San Francisco Intl Mail China Canoga Park, CA 3 kg 07/03/2014 AB
- CHMINACA San Francisco Intl Mail China Metairie, LA 100 gm 07/15/2014 AB
- CHMINACA San Francisco Intl Mail China Baton Rouge, LA 25 gm 0 7/16/2014 AB
- PINACA San Francisco Intl Mail China Baytown, TX 1 kg 0 7/31/2014 AB
- CHMINACA San Francisco Intl Mail China Baton Rouge, LA 1 kg 0 7/31/2014 AB
- CHMINACA San Francisco Intl Mail China Houston, TX 2 kgDEA/OD/ODE page 37 of 39 December 2014

0 7/31/2014 AB
- CHMINACA San Francisco Intl Mail China Machesney Park, IL 100

grams 0 7/31/2014 AB
- CHMINACA San Francisco Intl Mail China Machesney Park, IL 100

grams 0 8/6/2014 AB
- CHMINACA San Francisco Intl Mail China Houston, TX 1 kg 0 8/6/2014 AB
- CHMINACA San Francisco Intl Mail China Hatillo, PR 1.3 kg 0 8/13/2014 AB
- CHMINACA San Francisco Intl Mail China Las Cruces, NM 1.2 kg 0 8/13/2014 AB
- CHMINACA San Francisco Intl Mail China Las Vegas, NV 1 kg 0 8/19/2014 AB
- CHMINACA San Francisco Intl Mail China Las Vegas, NV 2 kg 0 9/2/2014 AB
- CHMINACA San Francisco Intl Mail China Baytown, TX 1 kg 0 9/9/2014 AB
- CHMINACA San Francisco Intl Mail China Cypress, TX 1 kg 0 9/16/2014 AB
- CHMINACA San Francisco Intl Mail China Fort Worth, TX 1 kg 0 9/30/2014 AB
- CHMINACA San Francisco Intl Mail China Baytown, TX 1 kg

Table 6 . STRIDE S ample Laboratory Results Date Label Flavor/ Characteristic Confirmed Substance 6/26/2013 Diablo AB
- PINACA 6/26/2013 Dead Man Walking AB
- PINACA 6/26/2013 Joker AB
- PINACA 6/26/2013 Bizzaro AB
- PINACA 6/26/2013 Bling Monkey AB
- PINACA 7/15/2013 Funky Green Stuff AB
- PINACA 7/15/2013 LOL AB
- PINACA 7/15/2013 Out World AB
- PINACA 7/22/2013 3 AB
- PINACA 7/22/2013 4
- D AB
- PINACA 8/21/2013 Diablo AB
- PINACA 8/21/2013 Platinum AB
- PINACA 8/29/2013 Buddha Exotic Aroma AB
- PINACA 9/13/2013 Scooby Snax AB
- PINACA 10/25/2013 Bizzarro AB
- PINACADEA/OD/ODE page 38 of 39 December 2014

10/25/2013 Ripped AB
- PINACA 11/7/2013 Scuby Snax AB
- PINACA 11/14/2013 The Hedgehog Blueberry AB
- PINACA 11/15/2013 El Diablo AB
- PINACA 11/15/2013 Diesel AB
- PINACA 11/15/2013 Blackout AB
- PINACA 11/19/2013 Cloud XXX Car Freshener* Coconut AB
- PINACA 11/21/2013 Mega Buzz AB
- PINACA 12/7/2013 Buddha Exotic Aroma AB
- PINACA 12/7/2013 Buddha Exotic Aroma Coconut Twist AB
- PINACA 12/7/2013 Super Nova AB
- PINACA 12/10/2013 Super Nova AB
- PINACA 12/11/2013 Blackout AB
- PINACA 12/11/2013 El Diablo AB
- PINACA 12/11/2013 Red Bull AB
- PINACA 12/11/2013 Hawaiian Bliss AB
- PINACA 12/11/2013 Fist Pump AB
- PINACA 12/11/2013 Deadman AB
- PINACA 12/11/2013 Buddha Exotic Aroma Sexy Strawberry AB
- PINACA 12/11/2013 Buddha Exotic Aroma Coconut Twist AB
- PINACA 12/11/2013 Buddha Exotic Aroma AB
- PINACA 12/13/2013 Scooby Snax Sour Apple AB
- PINACA 12/13/2013 XXX Booty Licious Blue Barry AB
- PINACA 12/13/2013 Scooby Snax XXX

Potpourri Blueberry AB
- PINACA 12/13/2013 Scooby Snax Herbal Kush

Potpourri Pomegranate AB
- PINACA 12/13/2013 Scooby Snax Herbal Kush

Potpourri Strawberry AB
- PINACA 12/13/2013 Scooby Snax Herbal Kush

Potpourri Yum Yum AB
- PINACA 12/13/2013 XXX Rated Pussy Cat Pomegranate AB
- PINACA 12/13/2013 XXX Rated Sexy Strawberry AB
- PINACA 12/19/2013 Spice Gold AB
- PINACA 12/19/2013 Bizarro Original AB
- PINACA 12/19/2013 Black Mamba Blueberry AB
- PINACA 1/9/2014 Histeria Black AB
- PINACA 1/9/2014 Game Over Potpourri AB
- PINACA 1/9/2014 Dr. Feelgood AB
- PINACA 1/14/2014 The Hedgehog Blueberry AB
- PINACA 1/15/2014 Primo AB
- PINACADEA/OD/ODE page 39 of 39 December 2014

1/15/2014 Platinum XXX AB
- PINACA 1/22/2014 Ocean Mist Scented Oil* AB
- PINACA 1/22/2014 Gypsy Moon* AB
- PINACA 1/31/2014 Original Potpourri Knockout AB
- PINACA 1/31/2014 Scooby Snax Kush AB
- PINACA 2/6/2014 Scooby Snax Cherry AB
- PINACA 2/6/2014 Scooby Snax AB
- PINACA 2/6/2014 Knockout AB
- PINACA 2/12/2014 Scooby Snax AB
- PINACA 2/12/2014 Platinum XXX AB
- PINACA 2/12/2014 Black Diamond AB
- PINACA 2/12/2014 Black Diamond AB
- PINACA 2/12/2014 Get Real AB
- PINACA 2/12/2014 XXX Platinum AB
- PINACA 2/19/2014 Good Times* AB
- PINACA 2/19/2014 Tropical Rush* AB
- PINACA 3/6/2014 WTF Watermelon AB
- PINACA 3/6/2014 Mad Hatter Blueberry AB
- PINACA 3/7/2014 Autumn Air THJ
- 2201 3/18/2014 Purefire AB
- PINACA 3/18/2014 King Kong AB
- PINACA 3/18/2014 California Dreams THJ
- 2201 3/20/2014 Hulk’d Out Kitty AB
- CHMINACA 3/27/2014 Fragile:

Feeling Easily Hurt AB
- PINACA 4/3/2014 Hookah Blast THJ
- 2201 4/3/2014 Super Nova THJ
- 2201 4/24/2014 Diablo AB
- CHMINACA 4/26/2014 Caution AB
- PINACA 4/29/2014 AK
- 47 24 Karat Gold AB
- PINACA 4/29/2014 Green Giant AB
- PINACA 4/29/2014 Smacked Pineapple AB
- PINACA 4/29/2014 Smacked Lemon Lime AB
- PINACA 4/30/2014 AK
- 47 24 Karat Gold AB
- PINACA 5/7/2014 Bomb! Marley Blueberry AB
- CHMINACA 5/7/2014 OMG THJ
- 2201 5/7/2014 AK
- 47 24 Karat Gold THJ
- 2201 5/12/2014 7H AB
- PINACA 5/20/2014 Black Voodoo AB
- CHMINACA 5/27/2014 Scooby Snax Strawberry AB
- CHMINACA * Substance was identified in a liquid rather than being identified in a powder or applied to plant material
.