DEPARTMENTOF HEALTH & HUMAN SERVICES

The HonorableThomas M

. Harrigan Deputy Administrator DrugEnforcement Administration U.S. Department ofJustice 8701 Morrissette Drive Springfield, VA 22152 DearMr. Harrigan: Office of the Secretary

Office ofthe Assistant Secretaryfor Health Washington, D.C. 20201



## MAY 11 2015

Pursuant to the Controlled Substances Act [CSA, 21 U.S.C. § 811 (b), (c), and 

### (f)], the Department ofHealth and Human Services is recommendingthatthe substances (1-pentyl-1Hindol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone [street name: UR-144), [l-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone [street names: 5-fluoro-UR144 andXLR11], and N-(1-adamantyl)-1-pentyl-lH-indazole-3-carboxamide (street names: APINACA and AKB48] and their sa lts be added to Schedule I ofthe CSA. UR-144, XLRll, and AKB48 are synthetic cannabinoids that have recently become popular as recreational marijuana alterna tives. UR-144, XLRll, and AKB48, as well as other synthetic cannabinoids are used as ingredients or additives in "herbal products" that aremarketed globally via theInternet and over-the-counter as incense. The synthetic cannabinoid products are often referred to as synthetic marijuana, herbal blends, and herbal high products, and are sold under a variety ofnames, suchas "Scooby Snaz," "Mr. Nice Guy," and "Relaxinol." 

### In vitro and 

### In vivo preclinical studies indi<.:ate that the pharmacological effects ofUR-144, XLR11, and AKB48 are similarto delta-9 

### (1::,9)- tetrahydrocannabinol (THC, Schedule I) and 1-pentyl-3-(1-naphthoyl)indole (JWH-018, Schedule I). These studies, combined with casereports and anecdotal observations in humans, suggestthe subjective effects ofUR -144, XLR11, and AKB48 are cannabis-like and similarto those elicited by marijuana. UR-144, XLR11 , and AKB48 have no known accepted medical use. These substances are not the subjects ofany approved newdrug applications (NDAs) or investigational newdrug applications (INDs), and they are not currently mar keted as approved drug products.
The Food and Drug Administration (FDA) and the National Institute on Drug Abuse have also considered the abuse potential ofUR-144, XLR11 , and AKB48. Afterreviewingthe available information, the agencies conclude thatUR-144, XLR11, and AKB48, andtheir salts should be controlled in Schedule I ofthe CSA. Enclosed are the documents prepared by FDA's Controlled Substance Staffthat are the bases for the recommendations.

U

.S

. Public Health Service

### Page 2

- The Honora ble Thomas M. Harrigan Should you have any questions regarding these recommendations, please contact Corinne P

. Moody, Science Policy Analyst, Controlled Substance Staff, Center for Drug Evaluation and Research, at (30 1) 796-3152.

Enclosures aren B. DeSalvo, MD, MPH, MSc Acting Assistant Secretary for Health

# Enclosure 1

### BASIS FORTHE RECOMMENDATION TO PLACE 1-(5-FLUORO-PENTYL)-lHINDOL-3-YL 2,2,3,3-TETRAMETHYLCYCLOPROPYL METHANONE (XLRll)AND ITS SALTS IN SCHEDULE I OFTHE CONTROLLED SUBSTANCES ACT I. 

### SUMMARY The Food and DmgAdministration (FDA) recommends that 1-(5-t1uoro-pentyl)-1H-indol-3-yl 2,2,3,3-tetramethylcyclopropyl methanone, also known as XLR 11, and its salts beplaced into Schedule I ofthe Controlled Substances Act (CSA). XLRll is a synthetic cannabinoid thathas recently becomepopular as arecreational marijuana altemative. XLRll, as well as other synthetic cannabinoids, is used as an ingredient or additive in "herbal products"that are sold as incense and for other uses (National Forensic Laboratory Infonnation System (NFLIS), 2012). The synthetic cannabinoid products are often refened to as syntheticmarijuana, herbal blends, and herbal high products, and a!'e sold under a variety ofnames. As discussed in further detail below, XLRll is not present in every marketed synthetic cannabinoidproduct. For clarity, this document will explicitly refer to XLRII when discussing synthetic cannabinoids in which XLRII was confitmed as an ingredient, or when discussing case reports where the repmt specificallyindicates the presence ofXLRll. 

### In 

### vitro and 

### in 1>ivo preclinical studies suggest that the pharmacological effects ofXLR11 are similar to delta-9 (i\.9)- tetrahydrocannabinol (THC, Schedule I) and JWH-018 (Schedule I). These studies, combined with case reports and anecdotal observations in humans, suggest that the subjective effects ofXLR!l are cannabis-like and similar to those ofmarijuana. The Drug Enforcement Administration (DBA) notified the DepartmentofHealth and Human Services (HHS) in writing ofits intentto temporarilyplace XLRll into Schedule I ofthe CSA on Februa!'y 14,2013. On March 14,2013, in response to the notification by the DEA, HHS stated that there are no exemptions or approvals in effect for XLR11 under Section 505 ofthe Federal Food, Dmg, and Cosmetic Act. On May 16,2013,the final ordertemporatilyplacing XLR11 into Schedule 

### Iofthe CSA waspublished in the

### FedmtlRegister 

### (78 FR 28735).


### In this document, FDA recommends that XLRll bepem1anentlyplaced into Schedule 

### I ofthe CSA. 

### II. BACKGROUND Synthetic cannabinoids are relatively new substances ofabuse. Overthe past several years, recreational use ofsynthetic cannabinoid substances has increased in the United States (Cohen et al., 2012). Synthetic cannabinoids aremarketed under aplethora ofnames. These compounds commonly are sold at gas stations, convenience stores, and on the Intemet. Analyses byDBA have detected XLRll in product samples marketed under the following names: Bizarro; Zensence; Orgazmo; Scooby Snax; Green Giant; Kush 1 OX; WTF; Diablo; Smokin Dragon Potpouni; Mad Hatter; Puff; Smokin Dragon, G-20; Mr. Happy; Everest; Darkness; Mystic; Down2Earth; AK-47; Syn Swag; Syn Smooth; The Original Cloud 9; Kaptain Kush; Ultra Zombie Matter Halo; Legal Devil; Potpouni; Hi 5; Handy; HiS Potpouni Hi 5; Fly'n High; Joker; Sin City; M G, Sky Bomb; SkyPilot; Blue Kush; Black Venom; Mary & Jane; Miami 1Spice; Screamin Demon; Shockwave; Hammer Head; Platinum; Caution; You Only Live Once; Demon; Dank; Aloha

...get Lei'd; NOLA Diamond Potpouni; Relaxinol; SonicZero; Avalanche; Neutronium; Lava Extra Sh·ength; Pure Sin; Clown Loyal; Mad Monkey; 7H; Zombie Life; Purple Diesel; Sour Diesel; Wanted; Sonic Boom; Supemova; Zombie Matter Halo; Tiger ShaTk; New King Kong; Atomic; 9mm XXX; BloodyMary Halo; White Widow; Hayze Hawaiian; Super Stank; Knockout; Kosmic Kush; New King Kong; Botanical Potpouni; Hysteria Black; Black Sabbath; Mind Trip; Express Barely Legal; Barely In; Mad Hatter/Cloud 9; Mr. Nice Guy; Vesuvius; Haze Hawaiian Ultra; and Green Cobra. On July9, 2012, 15 synthetic cannabinoids (including CP-47,497, CP-47,497 C8-homolog, JWH-018, JWH-073, and JWH-200) were placedinto Schedule I ofthe CSA by Section 1152 ofthe Food and Drug Administration Safety and Innovation Act (FDASIA) under TITLE XI-OTHER PROVISIONS, SubtitleD-Synthetic Drugs. 1 However, XLR11 was not among those controlled substances. It is theorized that following the placement of the aforementioned cannabinoids into ScheduleI ofthe CSA via FDASIA, additional substances (e.g., XLRII) with cannabinoid receptor agonist activity appeared, likely in an attempt to evade CSA control. XLR11 is a synthetic cannahinoid classified as a cyclopropylindole. XLRII is structurally related to the substance UR-144, another indole-derived cannabinoid explored under patent by Abbott Labs (Wiley eta!., 2013). Based on data fi·om the System to Retrieve Infonnation on Dmg Evidence2 (STRIDE), a DEA database that collects data on samples tested by DEA's labs, and the NFLIS,3 a DEA database that collects infonnation on samples tested by state and local jurisdictions, XLRII was found in samples statiing in 2011. In fact, there were I,798 STRIDE reports from January 2011 through Febmary 2014, and 24,257 NFLIS repmis fi·om January 2011 through December 2013, involving XLRll.

1WhenFDASIA was enacted, a total ofeight substances were already covered byDEA temporary scheduling orders: five synthetic cannabinoids (.TWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue) and three synthetic cathinones (mephedrone, MDPV, !Uld methylone). DEA had also issued aNotice ofProposed Rulemaking on March I, 2012, to place the five synthetic cannabinoids (JWH-018, JWH-073, JWII-200, CP-47,497, and CP-47,497 C8 homologue) pennanentlyin Schedule I (77 FR 12508). With the exception ofmethylone, these compounds were specifically placed in Schedule Iby FDASIA on July 9, 2012. Theretbre, it was no longer necessary to finalize the NPRM regarding the five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue), or to take additional action with respect to two ofthe three syntl1etic cathinones (mephedrone and MDPV). However, DEA has posted acopy ofthe HHS Scientific and Medical Evaluation and Scheduling Recommendations regarding the five synthetic cannabinoids on www.regulations.gov. These HHS documents canbe found on www.regulations.gov under Docket No. DEA-2012-0001.

2 DEA's STRJDE reflects the results ofdrug evidence analyzed atDEA laboratories nationwide. See the NFLIS 2012 annual report at http://www.deadiversion.usdoj.gov/nflis/201 2annual_!]Jt.pdf "DEA's NFLIS systematically collects results from drug chemistry analyses conducted by state and local forensic laboratories across !he country. As a national drug forensic laboratory reporting system, NFLJS provides timely m1d detailed analytical results ofdrugs seized byJaw enforcement. See http://www.deadiversion.usdoj.gov/nflisl 2XLR 11 has no known accepted medical use. It is not the subject ofan approved new drug application (NDA) or an investigational new drug application (IND), and itis not currently marketed as an approved drug product. In addition, law enforcement and health care practitioners continue encountering individuals who have abused synthetic cannabinoids and need hospital emergency depmtment (ED) admission. Since the composition ofmanyproducts changes overtime as a reaction to prohibition and prosecution ofresellers, neither the reseller nor the consumer ofthese mixtures knows the actual content and amount ofsynthetic cannabinoids in products under the labeling guise of"incense" (Dresen et al., 201 0). The American Association ofPoison Control Centers (AAPCC)4repmied 2,639 human exposures to synthetic marijuana (THC homologs) in 2013 (AAPCC, 2013). In response, numerous states and other countries have already placed measures ofcontrol on products containing synthetic cannabinoids. Pursuant to 21 U.S.C.§ 811, the Secretary is required to consider, in the scientific and medical evaluation, eight factors with respect to control, rescheduling, orremoval ofa substance from the schedules ofthe CSA. The eight factors are: l. The drug's actual or relative potential for abuse; 2. Scientific evidence ofthe drug's phannacological effects; 3. The state ofcurrent scientificknowledge regarding the drug or other substance; 4. Its history and cunentpattem ofabuse; 5. The scope, duration, and significance ofabuse; 6. What, ifany, risk there is to the publichealth; 7. Its psychic orphysiologic dependence liability; and 8. Whether the substance is an immediateprecursor ofa substance already controlled. Following consideration ofthe eight factors, the Secretary must make three findings and a recommendation regarding scheduling a drug or substance. The three required findings relate to the substance's abuse potential, legitimate medical use, and safety ordependence potential (21 

# u.s.c. § 812(b)). Administrativeresponsibilities for evaluating a substance for control under the CSA are performed for HHS byFDA, with the concunence ofthe National Institute on Drug Abuse (NJDA) ((Memorandum ofUnderstanding, 50 FR 9518, 9518-20) (March 8, 1985)).

4 AAPCC collects information Jogged by the country's Poison Control Centers (PCs). Records are fi·om selfreported calls; therefore, they reflect only infomtation provided when tlre public orhealth care professional reports an actual or potential exposure to asubstance (e.g. an ingestion, inhalation) or topical exposure), or

**request~** informational material. It warrants noting that these exposures do not inherently represent an instance ofpoisoning or overdose. The AAPCC is not able to completely verify the accuracy ofevery report made to member centers. Additional exposures may go unreported to PCs and data referenced from the AAPCC should not be construed to represent the complete incidence ofnational exposures to any substance. The AAPCC indicated that a significantproportion ofthe reports were generated from hospital emergency department!> or en-route to amedical treatment facility.

3This evaluation discusses the scientific and medical infonnation relative to each ofthe eight factors, presents findings in the three required areas, and makes a recommendation regarding the placement of l-(5-fluoro-pentyl)-1H-indol-3-y12,2,3,3-tetramethylcyclopropylmethanone (XLR!l) into Schedule I under the CSA. III. EVALUATING XLRll UNDER THE EIGHT FACTORS This section presents an evaluation ofthe current scientific and medical knowledge about XLRI I under the eight factors thatmust be considered pursuantto 21 U.S.C. 

### § 811 (c). FACTOR 1; Its Actual or Relative Potential for Abuse The first factor the Secretarymust consider is the actual orrelativepotential for abuse ofXLR11. The term "abuse"is not defined in the CSA. However, the legislative history of the CSA suggests the following points in detem1ining whether a particular drug or substance has a potential for abuse5 :

a. Individuals are taking the substance in amounts sufficient to create a hazard to their health orto the safety ofotherindividuals or to the community. b. There is significant diversion ofthe drug or substance from legitimate drug channels. c. Individuals are taking the substance on their own initiative rather than on thebasis of medical advice from apractitionerlicensed by law to administer such substance. d. The substance is so related in its action to a substance already listed as having a potential for abuse to make itlikely thatit will have the samepotential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to orwithout medical advice, or that ithas a substantial capability ofcreating hazards to tl1e health ofthe user or to the safety ofthe community. There is no single test or assessment procedure that, by itself, provides a full and complete characterization ofa substance's abuse potential, as this is a complex deteimination that is multidimensional. When assessing the abusepotential ofa substance, the Secretary considers multiple factors, data sources, and analyses. These factors include the prevalence, frequency, and manner ofuse in the general public and specific subpopulations; the amount ofmaterial that is available for illicit use; and evidencerelevant to populations that maybe atparticularrisk. Animal, human, and epidemiological data are all used in determining a substance's abuse potential. Specifically, a comprehensive evaluation ofthe relative abuse potential ofa substance includes consideration ofthe drug's receptor binding affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus etiects, dependence-producingpotential, pharmacokinetics and routes ofadministration, toxicities, assessment ofthe clinical efficacy safety databaserelative to actual abuse, clinical abuse-potential studies, and the publichealth
'Comprehensive Dmg Abuse Prevention and Control Act of1970, H.R. Rep. No. 91·1444, 91" Congressional, Sess. I (1970) reprinted in U.S.C.C.A.N. 4566,4603. 4risks following marketing ofthe substance. Epidemiological data can also be an important indicator ofactual abuse. Finally, evidence ofclandestine production and illicit trafficking ofa substance are also impmiant factors. Belowis a discussion ofthe four indicators ofabuse as they relate to XLRJI. A). Individuals are taking the substance bt amountsSl(fficient to create a hazard to their health o1· the safety of other individuals or to the community. The epidemiological and case repmi data discussed in this section suggest that individuals are taking XLRII in amounts sufficient to create a hazard to theirhealth or to the safety ofother individuals or to the community. Case reports ofXLRll intake resulting in side effects such as nausea; vomiting; and abdominal, flank, and back pain are present in the literature. The Wyoming Depmiment ofHealth and with the Centers for Disease Control (CDC) recently published a notice outlining an apparent association between XLRll and acute kidney injury (AKI) (CDC, 2013). See FACTOR 6 for more detailed infom1ation. According to a 2012 survey, synthetic cannabinoids m·e the second-most commonly used illegal drug among young adults, with only cannabis use occtming at a higher rate (Johnston et al., 2012). Use ofsynthetic cannabinoids produces psychoactive effects similar to those ofcannabis; moreover, synthetic cannabinoids are easily accessible and difficult to detect in standard urine drug screens (Auwarter et al., 2009), which contribute to their high rate ofuse. For example, in relation to XLRll specifically, the Medical Examiner's ot11ce in San Francisco, California, reported an analysis ofXLR11 abuse on March 7, 2013. A 22-year-old malehit a lawfully stopped vehicle in traffic. Law enforcement officers noted that the man had ablank stare, mellow speech, and abarely audible. voice. Medical personnel described the man's symptoms as follows: hypothermia, rigid muscle tone, lack ofhorizontal gaze nystagmus, lack ofvertical gaze nystagmus, non-convergence ofeyes, a11d dilated pupil size. The driver stated that he had previously nsed "bluebenyspice"but could not state when. Toxicologyresults revealed that XLR 11, at a concentration of 1.34ng/ml,was the only identified substance in the driver's blood (San Frm1cisco Office ofChiefMedical Examiner, 2013). From January 2010 through March 2013, DEArep01ied thatNFLIS and STRIDE data for the three synthetic cannabinoids UR-144, XLRll, and AKB48 reached a total of16,014 cases. The detection ofthese substances in seized drugs is consistent with DEA findings on the dmg exhibits collected during law enforcement seizures with other Schedule I synthetic cannabinoids, designated as JWH and CP. The number and type ofsynthetic cannabinoids, reported as an aggregate, increased since 2008, as evidenced by the number ofreports submitted to NFLIS. According to the NFLIS, there were 29,467 synthetic cannabinoid drug repotis in 2012, an increase of 1,402 percent since 2009 (DEA, 2013 National DrugThreat Assessment Summary). NFLIS laboratories identified 62,540 hallucinogens in 2012, representing 4 percent ofall dmgreports. Almost 13 percent (8,097) of thesehallucinogens were identified as XLR11 (2012 NFLIS annual report).

5The AAPCC reported approximately 5,200 calls about exposures to synthetic marijuana (THC homologs) in 2012. This number is lower than the nmpber ofcalls reported in 2011 (6,968), but is still significantly greater than those reported in 2010 (2,906) (DEA, 2013 National Drug Threat Assessment Summary), Additionally, AAPCC recently released a report of2,639 human exposures to synthetic marijuana (THC homologs) in 2013. 

### B). There is significantdiversion of the drug orsubstanceji·omlegitimate drug

**channel~~** Since XLRII is not an FDA-approved drug product for treatment in the United States and there appear to be no legitimate sources for XLRII as a marketed drug, this characteristic ofabuse potential is not applicable. C). 

### Individuals are taktitg the substance 011 their own i11itiative rather than 011 

### the bas1:1· of medicaladvicefi'om apractitionerlicensedby law to administersuch substances.
BecauseXLR!l is not approved for medical use and is not fom1Ulated or available tor clinical use, all human

**selt~administration** is assumed to be on an individual's own initiative, rather than on tl1e basis ofmedical advice fl'om a practitioner licensed by Jaw to administer drugs. AAPCC reports, literature case reports, law enforcement seizures, and anecdotal Internet user experience posts (e.g., http://www.dmgs-fomm.com) indicate that individuals are taking XLRIJ on their own initiative, rather than on the medical advice ofa licensed practitioner. D). 

### The substance is so related in its action to asub51ance already listedas havinga potential for abuse to make it likely that it will have the samepotential for abuse as such substance, thusmakingIt reasonable to assume thatthere may be sign(ficant diversions from legitimate chanitels, sign(ficaJtt use contrary to or Withoutmedical advice, or that ithasasubstantial capability of creatinghazards to the health of the user orto the safety of the community. In vitro and 

### in vivo pham1acology data for XLR11 is similar to other Schedule I cannabinoids. Research studies show that psychoactive cannabinoids ofvarious structural classes, including tetrahydrocannabinols (such as .6.9-THC), bicyclic cannabinoid analog (e.g., CP55,940), aminoalkylindoles (e.g., WIN55, 212-2), and otherindole- and pyrol-derived cannabinoids (e.g., JWH-018 Schedule 1), share a common phannacologicalprofile ofeffects. The psychoactive cannabinoids bind to and activate cannabinoid-J(CBJ) receptors in 

### vitro (Devane eta!., 1988; Griffin eta!., 1998). For example, JWH-018 (which, as noted above, is controlled in Schedule I) is a full cannabinoid agonist with high affinity for both CB 1 and cannabinoid-2 (CB2) receptor subtypes. In a study examining the relative affinity ofJWH-018 for CB 1 and CB2 receptors, JWH-018 displayed slightly greater relative affinity for CB2 receptors (Ki

**~** 2.94 nM) relative to CB 1receptors (Ki

**~** 9.0 nM) (Aung et al., 2000). This resulted in a CB 11CB2bindingratio that is slightly increased for JWH-018 relative to THC (3.06 versus J.l2), though the significance ofthe CB 11CB2binding ratio is unknown. Similarly, XLRll has a high affinity for both CB 1and 

### CBz receptor subtypes. In a study exalnining the 6relative affinities, results demonstrated that XLRll binds with K; values of24.2 nM at CB 1 and 2.13 nM at CB 2 (RTl, 2013). Secondly, psychoactive cannabinoids are repmied to substitute for 1',9-THC in a dmg discrimination procedure in rodents (Wiley et al., 1995; Vann eta!., 2009). This procedure is used 

### as an animal model ofmarijuana intoxication and, when utilized as such, is also a highly predictive procedure in identifying compounds that humans label "marijuana-like" (Balster and Prescott, 1992). In drug discrimination studies in rodents trained to discriminate t, 9

-THC, .TWH018 (Schedule I) produced complete substitution for stimulus effects of69

-THC with an ED506 of 0.39 mglkg 

### (NJDA study report, 2011). Similarresults were obtained byJarbe and colleagues, who found that JWH-018 fully substituted for the stimulus effects of1',9

-THC in rodents trained to discriminate 1',9

-THC; fmiher, JWH-018 was found to be eight times morepotentthan t,9

- THC (.Tarbe eta!., 2011 ). Similarly, as with other psychoactive cannabinoids (e.g., JWH-018; Jarbe eta!., 2011), XLRll was shown to fully substitute the discriminative stimulus effects of 1',9-THC with an ED50 of3.3 Jllllo!lkg (RTI, 2013). Thirdly, psychoactive cannabinoids produce characteristic effects in a tetrad ofin vivo tests in mice, including suppression oflocomotor activity, antinociception, hypothennia, and catalepsy (Mmiin eta!., 1991 ). XLR11 was found to bemorepotent than 1',9

-THC acro·ss the tetrad measures (RTJ, 2013). FACTOR

### 2: Scientific Evidence oftheDrug's Pharmacological Effects The second factor the Secretarymust consideris the phannacological effects ofXLR11. Elsken eta!. (2013) and RTI (2013) performed receptor binding, dmg discrimination, and.locomotor studies with XLRI 1. In mice, XLR11 dose-dependentlyproduced a profile ofphamJacological effects characteristic ofCB 1 agonists including suppression oflocomotor activity, antinociception, hypothermia, m1d catalepsy. Consistent withits greater affinity at the CB 1 receptor, XLR11 was more potentthan 1',9-THC in each test Furthennore, as previous.ly mentioned, XLR11 fully and dose-dependently substituted for 1',9-THC in m1ce trained to discriminate L\9-THC fi·om a saline vehicle (RTI, 2013). Together, these results suggestthat XLR11 is a psychoactive CB 1receptor agonist (RTI, 2013) which is similar to 1',9

-THC.
As for locomotor activity, treatment with XLRI I resulted in time- and dose-dependent depression oflocomotor activity, following 10 and 30 mglkgdoses in non-habituated SwissWebstermice. Depressant effects of 10 and 30 mglkgoccurred within 10 minutes following injection and lasted 40-60 minutes. The 

### ID5

### o(doseproducing 

### Yz maximal depressant activity, wheremaximal depression = 0 counts/30 min) was estimated to be I0.3 mg/kg (Elksen et a!., 2013).

6 ED5 0 (effective do8e) is a dose ofaphamJacologic agent which will have atherapeutic effect 7In vitro CB 1 receptor binding assays for XLRII were perfonned with membranepreparations isolated from a HEK-393 expression system. 7 These transfected cell membrane preparations demonstrated a nM affinity at the CB; receptor binding site, with XLRll having an apparent K1 of24.2 ;± 4.6 nM (RTl, 2013). XLRII also showed nM affinity for the CB 2receptor, with XLRII having an apparent K; of2.13 ;± 0.62 nM (RTI, 2013). XLR11 was researched by functional assayusing guanosine triphosphate (GTP-y)5S). XLRll stimulated GTP-y-35S turnoverthrough both the CB1 receptor and the CB2receptor at nM concentrations, which is indicative ofcompounds that can act as agonists atthese G-protein coupled receptor sites (RTI, 2013). Both CB 1and CB2 receptors are members ofthe 7 transmembrane G-protein coupled receptor (GPCR) superfamily (Begg et al., 2005). The drug discrimination assay is an in vivo preclinical procedure to identify drugs with similar subjective effects to a well-characterized training drug. Thus, when studying emerging synthetic cannabinoid drugs ofabuse, a dose ofL\9-THC is typically used as the standard training stimulus (Tai et al., 2014). XLRll was shown to dose-dependently substitute for L\9-THC in singly housed male C57/BI6J inbred mice (RTI, 2013). Before the sta1t ofthe investigation, mice were trained to discriminate 5.6 mglkg Ll.9

-THC from a vehicle and a L\9

-THC dose effect curve was established. L\9-THC (positive control) dose-dependently substituted for the training dose, with an ED 508 of5.4 !J.1110l!kg (4.5-6.4 JJ.!llol/kg). XLR1 I was shown to fully and dose-dependently substitute for L\9-THC. XLRI 1was 1.6-fold more potent than L\9-THC, with an ED5 0 of3.3 !J.lllO!Ikg (2.4-4.5 fllllOl/kg) (RTI, 2013). XLR11 tetrad studies were perfonned in male ICR mice. Mice were used for assessment in a battery offour "tetrad" tests in which canllabinoid agonists produced a characteristicprofile ofin vivo effects (Martinet al., 1991). These tests examined locomotor suppression, antinociception, hypothennia, and catalepsy. With L\9

-THC as apositive control, researchers showed that XLR11 exhibited the profile ofcannabinoid effects inthe tetrad tests in mice. XLR11 demonstrated dose-dependent suppression ofspontaneous activity, antinociception, hypothennia, and catalepsy (RTI, 2013). Across the four tests, potencies ranged from 3 to 15 1-1mol/kg for 1:!.9

-THC and from 0.6 to 3.3 J.lmo1/kg for XLRI 1 (RTI, 2013). Thus, as previously stated, XLRll was 4- to 17-tbld times more potentthan L\9

-THC in all tetrad measures. Furthennore, these effects are believed to be CB 1-receptor mediated since other researchers showed pretreatment with CB;-receptor antagonists can blockthese effects (Tai et al., 20 14). Phannaco1ogically, XLRI I is a full cannabinoid agonistwith no antagonist activity. XLR1 I is more potent than L\9-THC, theprincipal psychoactive chemical in marijuana (Schedule I) and similar in activity to JWH-01 8 (Schedule I) (RTI, 2013).

7Human embryonic kidney (HEK)-393 expresssion system is a cell line widely used to study avariety ofcellbiological interactions in neurobiology.

8 EC50 Halfmaximal effective concentration (EC50) refers to tl1e concentration ofa drug, antibody or toxicant which induces aresponse halfway between the baseline and maximum after aspecified exposure time. 8FACTOR 3: The State ofCurrent Scientific Knowledge Regarding the Drug or Other Substance Thethird factor the Secretary must consideris the state ofcuiTent scientific knowledge regarding XLRll. XLRll is a potent cannabinoid that is repo1ied to be smoked for recreational purposes. XLR11 is pharmacologically similar to 69

-THC, the principal psychoactive chemical in marijuana (Schedule 1). The chemical name ofXLRll is H5-fluoro-pentyl)-1H-indo!-3-yl 2,2,3,3-tetramethylcyclopropyl methanone. Altemative abbreviated names for this substance include 5-tluro-UR-144 and FUR-144, as it is a fluorinated derivative ofUR-144 (Shanks et al., 2013). The molecular formula is C21H28FNO and its molecular weight is 329.5 gran1s. The Chemical Abstract Service Number (CAS#) ofXLR11 is 1364933-54-9. The tetramethylcyclopropylindole compounds are a subset ofsynthetic cannabinoids that contain an indole moiety and an alkyl chain, but differ in the naphthoyl region ofthe compound. The aromatic naphthoylmoiety is completelyreplaced by an aliphatic tetramethylcyclopropyl moiety. Members ofthis subclass ofsynthetic cannabinoids have binding affinities at the CB 1 and CB2 receptor, though many ofthe miginal substances were synthesized specifically for their selectively at the CB2 receptor (Shanks et al., 2013). Researchers demonstrated, in pooled human hepatocytes, that XLR11 undergoes phase I and II metabolism, producing over 25 metabolites resulting from hydroxylation, carboxylation, hemiketal and hemiacetal fonnation, internal dehydration, and further gl11curonidation ofsome oxidative metabolites. XLR11 was also detluorinated and forms UR-144 metabolites. Mass spectroscopy analyses determined the major metabolites are 2'-carboxy-XLRll, UR-144 pentanoic acid, 5-hydroxy-UR-144, hydroxy-XLR!l glucuronides, and 2'-carboxy-UR-144 pentanoic acid. Minor metabolites include combinations ofthebiotransfonnations previously desc1ibed, many ofwhich are glucuronidated (Wohlfarth et al., 2013). FACTOR 4: History and Current Pattern ofAbuse The fourth factor the Secretary must consider is thehistory and cunentpattern ofab11se of XLRll. Many synthetic cannabinoids were developed overthe last 30 years for use as vehicles for investigating the cannabinoid system for research purposes (Weissman et al., 1982; Huffman et al., 1996). Recently, these substances were found in retail products available worldwide (Auwa1ier et al., 2009; European Monitoring Centre for Drugs and Drug Addiction, 2009; Lindigkeit et al., 2009; Dresen et al., 2010; Hudson et al., 2010; Uchiyama et al., 2010). The first synthetic cannabinoid was found in plant material for retail sale in the year 2008. A commercial laboratory in Frankfu11, Gennany, announced that it had identified JWH-018, one of several cannabinoid agonists originally developed at Clemson University, in samples ofherbal incense from Europe. Researchers hypothesize that the producers buy cannabinoids from laboratories in China orother countries that offer cheap organic syntheses, dissolve the compounds in a solvent, spray the solution on the plant matedal, and evaporate the solvent before packaging the herbal mixtures (Piggee, 2009). Finding effective measures to cu1iail synthetic cannabinoid availabilityhas been particularly challenging given the constantly changing composition ofcommercial synthetic cannabinoid 9products (Seely et al., 2013). Commercial preparations ofsy11thetic cannabinoids often contain multiple combinations and varying concentrations ofsynthetic cannabinoids, even within

· products marketed with the same name and packaging, leading to marked dose/drug

inconsistencies from batch to batch (Lindigkeit et al., 2009; Piggee, 2009). Although commercial synthetic cannabinoid products are typically sold as mixtures ofplant materials (that is, as ''herbal incense'' or "potpourri"), they have also been documented to exist as tablets, capsules, and powders (Seely et al., 2013). The first emergence ofsynthetic cannabinoids in the United States was discussed in a U.S. Customs and Border Protection (CBP) .announcement from mid-January 2009, which reported a seizure ofherbal incense shown to contain the synthetic cannabinoid HU-210 in Dayton, Ohio (Piggee, 2009). When CBP officers at the Dayton, Ohio, facility ofan international express couder saw the dried plant material inside a shipment, they perfonned a field test for the presence ofTHC, but it was negative. However, fmiher analysis at the CBP labomtory in Chicago confirmed thepresence ofthe synthetic cannabinoid HU-21 0. Over a 3-month period, CBP seized over I00 lbs ofHU-2 I0-laced herbal mixtures in five separate shipments (Piggee, 2009). Law enforcement and publichealth officials continue to encounter abuse ofthese substances (Substance Abuse and Mental Health Services Administration (SAMHSA), TheDAWNReport, 2012, NFLJS, 2013; STRIDE, 2013). In the U.S., XLR11 was identified as another novel synthetic cannabinoid adulterant in late 2011. As aforementioned, based on data from STRIDE and NFLIS, widespread use ofXLRl 1 was found in the United States. Specifically, from January 1, 201 l, through February 24, 2014, there were I ,798 STRIDErep01is involving XLR 11. From January 2011 through December 2013, there were 24,257 NFLIS reports of XLRll. Youth appear to be the primary abusers ofsynthetic cannabinoids and synthetic cannabinoid containingproducts, as demonstrated by law enforcement encounters and reports from hospital EDs. TheDAWNReport stated that, ofapproximately2,300,000 ED visits that involved dmg misuse or abuse in 20l0, synthetic cannabinoids were specificallylinked to an estimated 11,406 visits (SAMHSA, 2012). According to the report, 75 percent ofthe 11,406 ED visits in 2010 involved synthetic cannabinoid use among patients aged 12 to 

### 29. Forpatients aged 12 to 29, males complised more than three quarters (78 percent) ofED visits involving synthetic cannabinoids in 2010. As aforementioned, the AAPCC also reported 2,639 human exposures to synthetic marijuana (THC homologs) in 2013. Synthetic cannabinoid popularity is attributed to intense psychoactive effects, lack ofdelectability in routine urine dmg tests, and, until they were added to Schedule I ofthe CSA in 2012, lack ofCSA control (Gunderson eta!., 2012; Vandrey et al., 2012; Winstock and Ban·ett, 2013). 

### FACTOR5: The Scope, Duration, and Significance ofAbuse The fifth factor the Secretary must consideris the scope, duration, and significance ofabuse of XLRJI. Based on its phannacological prope1iies, it is reasonable to assume that, ifuncontrolled, the scope, duration, and significance ofXLRIJ abuse could be similar to 1:,9

-THC or marijuana (which contains /:,9

-THC as the plincipal psychoactive chemical). 10Because XLR11 is often packaged as an "herbal blend" with multipleingredients, including other synthetic cannabinoid agonists, the scope, duration, and significance ofabuse is difiicult to disaggregate. However, the available data, includingreceptorbinding, in vitro, and preclinical studies strongly suggest that XLRII has apharmacological mechanism ofaction that will produce phannacological and subjective effects similar to .0.9-THC (Schedule l) and JWH-OJ 8 (Schedule 1). As aforementioned, NFLIS laboratOJies identified 62,540 hallucinogens in2012, representing 4 percent ofall drug reports. Almost 13 percent (8,097) ofthese hallucinogens were identified as XLR 11 (NFLIS annual report, 20 12). The use ofXLRII recreationally is repmied anecdotally by users posting on Intemet drug sites (e.g., http://www.drugs-fonnn.com). For example, at http://www.drugsforum.com/fornm/showthread.php?t=181961, one user-repolied experience with XLRll reads as follows:"heyI tried ur-144

**~!Uw·-144** and ab-001 andI can say1love ur144 more then any previous rc noids hut

**-~furl44** is clos in its similarity topotbut its way more stoning" Another userposted: "Two nights ago I received a 10grampackage

**~f ~fur-144.**  Iplaced3mg in aglass vaporizerandhititone time, not heavily either, within 5 minutes I was sweatlng uncontrollab(v.felt crazy high, like 1hadan instantLSD type trip. Bqfore the nextfive minutespassedI 1yas scared, pulse out

**~{time,** stuttering even, I couldn't even nwnage to c1y outso sudden was this. Ifdl on my bed, then to the.floor. It was over 45 minutes

**b~fore** I couldget up. " FACTOR 6: What, IfAny, Risk There Is to the Public Health The sixth factor the Secretary must consider is the risk XLRII poses to the public health. Based solely on XLRII'sphannacological similarityto .0.9

-THC and its potency, the subjective risks to the public health are similar to those ofother cannabinoid agents, i.e., similarto marijuana and t.9-THC, which are controlled in Schedule I ofthe CSA. Detailed product analyses describe variations in the amount ofsynthetic cannabinoid inco11lorated into the plant material even within samplings ofthe sameproduct (Hudson et al., 20I0). These unknowns pose a substantial 1isk ofham1 to individuals who abuse synthetic cannabinoids (Auwarter eta!., 2009; Hudson et ' al., 2010). Patients presenting to EDs as a result ofsynthetic cannabinoids routinely exhibit the following symptoms: vomiting, anxiety, agitation, in·itability, seizures, hallucinations, tachycardia, elevated blood pressure, and loss ofconsciousness (Hal1'is and Brown, 2013; Hennanns-Cla.usen eta!., 2013; Fonestcr ct al., 2011; Cohen eta!., 2012). Additionally, consumption ofsynthetic cannabinoids can lead to impainnent similar to typical perfonnance deficits caused by cannabis. These deficits, which are not compatible with safe driving, include sedating effects and impainnent offine motor skills necessary for safely driving a vehicle.
IIThe use ofXLR 11 in relation to safety and mortality risks were recently described bythe Centers for Disease Control (CDC, 2013). In March 2012, the Wyoming Depa1tment ofHealth was notified about three patientshospitalized for unexplained AKI, all ofwhom repmied recent use ofsynthetic cannabinoids, sometimes refened to as "syntheticmarijuana" (CDC, 201 3). After the Wyoming Department ofHealth launched an investigation, a total of 16 cases ofacutekidney injury (AKI) after synthetic cannabinoid use were reported in six states. Toxicological analysis ofproduct samples and clinical specimens identified XLRII in four offlve available product samples and four ofsix available patients' clinical specimens (CDC, 201 3). Ali 16 patients initially visited EDs and subsequently were hospitalized, and all but one experienced nausea and vomiting. Twelve patients repmted abdominal, flank, and back pain. Nonereported preexisting renal dysfunction oruse ofmedication that might have caused renal problems. Although XLRll was not proven as the causative agent, either the parent compound was detected in the implicated product ortoxicological results strongly suggested XLR11 (detection ofparent compound in serum or UR-144 pentanoic acid in urine). The CDChas recommended that public health practitioners, poison center staffmembers, and clinicians be aware ofthe potential for renal or other unusual toxicities in users ofthese products, and that they should ask about t11eir use in cases ofunexplained AKI (CDC, 2013). Management ofsuspected toxicity due to synthetic cannabinoids is symptomatic and requires suppor1ive treatment, as no antidote exists. Although related to

**-THC,** the active ingredient in marijuana, syntl1etic cannabinoids are two to three times more likely to be associated with sympathomimetic effects (e.g., tachycardia and hypertension), and approximately flve times more likely to be associated with hallucinations (Forrester et al., 20 12). Researchers expressed concern regarding a possible serotonin syndromerelated to synthetic cannabinoids ofthe indole stmctural class due to the similarity to serotonin (Wells and Ott, 2011 ). Symptoms ofserotonin syndrome include shivering, diarrhea, muscle rigidity, fever, and seizures. Serotonin syndrome is a potential1ylife-threatening dmgreaction that may occur following therapeutic drug use, inadvertent drug interactions, drug overdose, orrecreational dmg use. FACTOR 7: The Drug's Psychic OI' Physiologic DependenceLiability The seventh factor the Secretary must consider is the psychic orphysiologic dependence liability ofXLR!l. The pharmacologicprofile ofXLRll strongly suggests that it possesses a physiological and psychological dependence liability that is similar to that of

**-THC** (Schedule I) and JWH-018 (Schedule 1). Case reports demonstrate that herbal products containing synthetic cannabinoids produced physical dependence and a withdrawal syndrome. There is onepublished case report of tolerance and withdrawal phenomena in the literature (Zimmem1ann et al., 2009) and another of drug-induced psychosis (Miiiier et al., 201 0). Both cases wel'e attributed to "Spice," which at tl1e time contained the Schedule I synthetic cannabimimetics JWH-018 and CP 47,497. While XLRII is phannacologicallyrelated to JWH-08, there are still no speciflc studies involving the psychic or dependence liability currently identified for XLR11. !2Drug dependence is not directly observable in 1•ivo. Rather, it is assumed to bepresent when either the discontinuation ofdrug administration (spontaneous withdrawal) orthe administration ofan antagonist (precipitated withdrawal) elicits a withdTawal syndrome. Thetenninology "cannabis withdrawal" has gained medical acceptance as described bythe Diagnostic and Statistical Manual ofMental Disorders Fifth Edition (DSM-5). The following signs and symptoms develop within approximately I week ofwithdrawal: initability, anger, aggression, nervousness or anxiety, sleep difficulty (e.g., insomnia, disturbing dreams), decreased appetite or weight Joss, restlessness, and depressed mood. Further, at least one ofthe following physical symptoms causes significant discomfmt: abdominal pain, shakiness/tremors, sweating, fever, chills, orheadache (DSM-5, AmericanPsychiatric Association, 2013; Gorelick et a!., 2012).
In multiple species, cannabinoid administration maylead to rapid tolerance to antinociceptive effects, anticonvulsant activity, cataleptic effects, suppression oflocomotor activity hypothem1ia, hypotension, release ofcorticosteroids, and other effects (Adams et al., 1996)

.

. FACTOR 

### 8: Whether the Substance Is an Immediate Precursor 

### ofa SubstanceThat

### Is Already Controlled XLR1l is not an immediate precursor ofany controlled substance. RECOMMENDATION After consideration ofthe eight factors determinative ofa substance (21 U.S.C 811 (c)), FDA recommends that l-(5-fluoro-pentyl)-1H-indol-3-yl 2,2,3,3-tetramethylcyclopropyl methanone, also known as XLR1l, be placed in Schedule I ofthe CSA (21 U.S.C 812(b)(l)). XLR11 produces effects similar to those ofJWH-018, which is controlled in Schedule I ofthe CSA. NIDA concurs with the recommendation. The necessary criteria for placing a substance into Schedule I ofthe CSA are set ftHih in 21 U.S.C 812 (b)(1), as follows: 

### A) The drug or other substance hasa highpotentialforabuse.
XLR 11 is a synthetic substance that produces cannabinoid-like effects, and is similarto L\9

-THC, JWH-018, and other synthetic cannabinoids. The phannacological similarity ofXLR11 to A 9

- THC makes it reasonable to assume that iis potential for abuse is high and would be similar to that ofJWH-018, which is controlled in Schedule I ofthe CSA. 

### B) The drug or other substance hasno currentlyacceptedmedical use in treatmem in the UnitedStates. There are no approved NDAs for XLR11 in the United States. There is no known therapeutic application for XLR11. Therefore, XLR11 has no currently accepted medical use in the United States.

13C) There is a lack of acceptedsafe()>for use o.ftlte drug orothersubstance under medical superPision. Since XLR 11 has no approved medical use and has notbeen thoroughly investigated as a new dmg, its safety for use under medical supervisionis undetermined. In addition, adverse consequences thought to be related to abuse ofXLR11 are documented in case reports. Thus, there is a Jack ofaccepted safety for use ofthis substance under medical supervision.
FDA therefore recommends that XLR11 and its salts be controlled in Schedule I ofthe CSA.

14References: Adams l.B. and Mariin B.R. (1996) Cannabis: Phannacology and toxicology in animals and humans. Addiction. 91(11):1585-614. American Association ofPoison Control Centers. Synthetic Marijuana Data; December 31, 2013. Available at https:/ /aapcc.s3.amazonaws.com/files!Iibrary/Synthetic

__MarijuanaWebDatathrough _12.2013

**.pdf~** Last accessed on February 5, 2014. American Psychiatric Association: Diagnostic and Statistical Manual ofMental Disorders, 5th Edition.American PsychiatricAssociation, Arlington, VA, 2013. Aung M.M., Griffin G., Huffman J.W., Wu M., Keel C. et al. (2000) Influence ofthe N-1 alkyl chain length ofcannabimimetic indoles upon CB(l) and CB(2) receptor binding. DrugAlcohol 

### Depend. 60:133-140. Auwa1ier V., Dresen S., Weinmann W., Muller M., Putz M., et al. (2009) "Spice" and other herbal blends: Ham1lcss incense or cannabinoid designer drugs? 

### Journal ofMass Spectrometry. 44:832-837. BalsterR.L. and Prescott W.R. (1992) t.9-Tetrahydrocannabinol discrimination.in rats as a model for cannabis intoxication.

### New·osci Biobehav

### Rev. 16:55-62. Begg M., Pacher P., Batkai S., Osei-Hyiaman D., Offertaler L., etal. (2005) Evidence for novel cannabinoid receptors. 

### Pharmacol Ther. I06(2):133-45. Centers for Disease Control and Prevention (CDC). (Febmary 15, 2013) Acute Kidney Injury Associated with Synthetic Cannabinoid Use-Multiple States, 2012. Morbidity and M01iality Weekly Report (MMWR) 62(6). Cohen J., Moni.son S., Greenberg J., Saidinejad M. (2012) Clinical presentation ofintoxication due to synthetic cannabinoids. Pediatrics. 4:129 DevaneW.A., Dysarz F.A., Johnson M.R., Melvin L.S., and Howlett A.C. (1988) Detennination and characterization ofa cannabinoid receptor in rat brain. 

### Mol Pharmacal. 34:605-613.
Dresen S., Ferreiros N., Putz M., Westphal F., Zimme1mann R., eta!. (2010) Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. 

### Journal o.fMass Spectrome/Jy. 4S:1186-1194. DEA. Schedules ofcontrolled substances: Temporaryplacement ofthree synthetic cannabinoids into Schedule 

### I. Final order. Fed

### Regist. (2013). 78(95): 28735-9.

15DEA National DrugTiu·eat Assessment Summary. (November 2013) Documentprepared prepared by the DEA's Office ofIntelligence Warning, Plans and Programs. Available at http://www.justice.gov/dca/resource-center/D!R-0 17-13%20NDT A%20Summary%20final.pdt: Last accessed on February 24,2014. Drug User Forum. 5F-UR-144 (XLRll) Drug Info. Available at http://www.drugsforum.com/forum/showthread.php?t=181961. Last access.ed on April4, 2014. Elsken C.S., Flores E., and Forster M.J. (2013) Time course (8-h) mouse locomotor activity test vs delta(9)-THC time course: UR-144. NIDA Contract NOIDA-7-8872. European Monitoring Centre for Drugs and Drug Addiction (2009) Understanding the "Spice" Phenomenon. The European Monitoring Centre for Drugs and Drug Addiction. Lisbon, Portugal. Fergusson D.M., Poulton R., Smith P.F., and Boden J.M. (2006) Cannabis and psychosis. BMJ. 332:172-175. Fon·ester M.B., Kleinschmidt K., Schwarz E., and Young A. (2011) Synthetic cannabinoid exposures repmied to Texas poison centers. JAddictDis. 30(4):351-8. Forrester M.B., Kleinschmidt K., Schwarz E., and YoungA. (2012) Synthetic cannabinoids and marijuana exposures reported to poison center. Hum Exp Toxicol. 31:I006-11. Gorelick D.A., Levin K.H., Copersino M.L., Heishman S.J., Liu F. eta!. (2012) Diagnostic

**crite1~a** for crumabis withdrawal syndrome. DrugandAlcoholDependence. 123:141- 147. Griffin G., Atkinson P.J., ShowalterV.M., Mmiin B.R., and Abood M.E. (1998) Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5'-0-(3-[35S]thio)- tliphosphatebinding assay in rat cerebellarmembranes. 

### JPharmacal 

### &p 1'lwr. 285:553-560. Gunderson E., Haughey H., Ait-Daoud N., Joshi A., Hart C. (2012) "Spice" and "K2" herbal highs: A case selies and systematicreview ofthe clinical effects and biopsychosocial implications ofsynthetic cannabinoid use in humans.Am. J Addict. 21:320-326. Harris C.R. and Brown A. (2013) Synthetic cannabinoid intoxication: A case selies and review. EmergMed. 44(2):360-6. HCimanns-Ciausen M., Kneisel S., Szabo B., and Auwarter V. (2013) Acute toxicity due to the confirmed consumption ofsynthetic cannabinoids: Clinical and laboratory findings. Addiction. 108(3):534-44. Hoyte C.O., Jacob J., Monte A.A., Al-Jumaan M., Bronstein

### A.C., eta!. (2012) A characterization ofsynthetic cannabinoids exposures reported to the National Poison Data System in 2010.AnnEmergMed. 60:435-8. 16Hudson S., Ramsey J., King L., Timbers S., Maynard S., eta!. (2010) Use ofhigh-resolution accurate mass spectrometry to detect reported and previously unrepmied cannabinomimetics in "herbal high" products.

**Journal~![** Analytical Toxicology. 34:252-260. I-luffrnan J.W., Yu S., ShowalterV., Abood M.E., Wiley .T.L., et al. (1996) Synthesis and pharmacology ofa very potent cannabinoid lacking a phenolic hydroxyl with high affinity for the CB2 receptor
. .!Med Cherm. 39(20):3875-7. Jarbe T.U., Deng H., Vadivel S.K., and Makriyannis A. (2011) Cannabinergic aminoalkylindoles, including AM678=JWHOJ8 found in "Spice," examined using drug (Delta9- tetrahydrocannabinol) discrimination for rats. BehavPharmacal. 22:498-507. Johnston L.D., O'Malley P.M., Bachman J.O., and Schulenberg J.E. The rise in teen marijuana use stalls, synthetic marijuana use levels, and use of"bath salts" is very low. University of Michigan News Service: Ann Arbor, MI. Available at http://www.moniioringthefuture.org/pressreleases/12drugpr_ complete.pdf, 2012. Last accessed on April 2, 2014. Lindigkeit R., BoehmeA., Eiserloh 

### 1., Luebbecke M., and Wiggem1ann M., eta!. (2009). Spice: A never ending story? Forensic Science Imernational. 191 :58-63. Mmtin B.R., Compton D.R., Thomas B.F., Prescott W.R., Little B.J., et 

### al. (1991) Behavioral, bio.chemical, and molecular modeling evaluations or cannabinoid analogs. Pharmacology BiochemistJy andBehavior. 40:471-4

### 78. Moore T.H., Zammit S., Lingtbrd-Hughes A., Barnes T.R., Jones P.B., et al. (2007) Cannabis use and risk ofpsychotic or affective mental health outcomes: A systematic review. Lancet. 370:319-328. Morgan C.J. and Cmnn H.V. (2008) Effects ofcannabidiol on schizophrenia-like symptoms in people who use cannabis. Br

. 

### .!. Psychiat1y. 192:306-307. Muller H., Sperling W., Kohnnann K., Huttner H.B., Kornhuber J., et al. (2010) The synthetic cannabinoid Spice as 

### atrigger for an acute exacerbation ofcannabis-inducedrecurrent psychotic episodes. Schizophrenia Research. 118:309-310. Muller-Yah! K.R. and Emrich H.M. (2008) Cmmabis and schizophrenia: Towards 

### a cannabinoid hypoihesis ofschizophrenia. ExpertRevNeurother. 8:1037-1048. MusshoffF., Madea B., Kernbach-Wighton 

### 0., Bicker W., Kneisel S., et al. (2014) Driving under the influence ofsynthetic cannabinoids ("Spice"): 

### A case series. 

### lnt JLegMed. 128:59- 64. National Forensic Laboratory Infonmtion System (2012) Annual Rep01t. Available at http://www.deadiversion.usdoj.gov/nflis/2012annual_rpt.pdf. Last accessed on Mm·ch 5, 2014.
17Piggee C. (2009) Investigating a not-so-natural high.Anal Chem. 81 (9):3205-7.
RTI lntemational (2013). In Vitro and In Vivo Abuse Liability Testing of(l-(5-fluoropentyi)- 1 H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone and (1-pentyi-1H-indol-3-yl)- (2,2,3,3-tetramethylcyclopropyl)methanone, RTI Technical Report. RTl Project No. 0213753. Sponsored byDEA. San Francisco Office ofChiefMedical Examiner (2013) Available at www.softtox.org/files/Designer_Drugs/XLR_ll_March_2013.pdf. Last accessed on April2, 2014. Seely K.A., Patton A.L., Moran C.L., Womack M.L., Prather P.L., et al. (2013) Forensic investigation of

### K2, Spice, and "bath salt" commercial preparations: A three-year study ofnew designer drug products containing synthetic cannabinoid, stimulant, and hallucinogenic compounds. Forensic SciInt. 233(1-3):416-22. Shanks K.G., Behonick G.S., Dahn T., and Tmell 

### A. (2013) Identification ofnovel thirdgeneration synthetic cannabinoids in products byultra-perfom1ance liquid chromatography and time-of-flight mass spectrometry. Journal<!( Analytical Toxicology. 37:517-525. Tai S. and Fantegrossi W. (2014) Synthetic cannabinoids: Pharmacology, behavioral effects, and abuse potential. CurrAddictRep. I:129-136. Uchiyama 

### N., Kikura-Hanajiri R., Ogata 

### .J., and Gada, 

### Y. (2010) Chemical analysis ofsynthetic cannabinoids as designer drugs in herbal products. Forensic Sci Int. 198:31-38. Vandrey R., Dunn K., Fry J., Girling E. (2012) A survey studyto characterize use ofspice products (synthetic cannabinoids). DrugAlcoholDependence. 120:238-241. Vann R.E., WamerJ.A., Bushell K., Buffinan J.W., Martin B.R., et al. (2009) Discriminative stimulus prope1iies ofdelta-9-tetrahydrocannabinol (THC) in

### C57Bl/6J mice. EurJPharmacal. 615:102-107. Weissman A., Milne G.M., and Melvin, Jr., L.S. (1982) Cannabimimetic activityfrom CP4

### 7 ,497, a derivative of3-phenylcyclohexanol. The Journal q( Pharmacology andExperimental Therapeutics. 223:516-523. Wells D.L. and Ott C.A. (2011) The "new" marijuana. The Annals rifPharmacotherapy. 45:414- 417. Wiley J.L., Huffman J.W., BalsterR.L., and Martin B.R. (1995) Pharmacological specificity of the discriminative stimulus effects ofdelta-9-tetrahydrocannabinol in rhesus monkeys. Drug AlcoholDepend. 40: 81-86. WileyJ., Marusich J., Lefever T., Grabenauer M., Moore K., et al. (2013) Cannabinoids in disguise: 

### 1:19-Tetrahydrocannabinol-like effects oftetramethylcyclpropyl ketone indoles. Neuropharmacology. 75: 145-154. 18Winstock A. and BmTett M. (2013) Synthetic cannabis: A comparison ofpattems ofuse and effect profile with natural cannabis in a large global sample. DrugAlcoholDepend. 131:106- 111. Wohlfarth A., PangS., Zhu M., Gandhi A., Scheidweiler A., eta!. (2013) First metabolic profile ofXLR11, a novel synthetic cannabinoid, obtained by usinghuman hepatocytes and highresolution mass spectrometry. Clinical Chemist1y. 59(11): 1638-1648. Zimme1111ann U.S., Winkelmann P.R., Pilhatsch M., Nees J.A., Spanagel R., eta!. (2009) Withdrawal phenomena and dependence syndrome after the consumption of"spice gold."

. DeutschesArzteblattInternational. 106:464-467.

19

# Enclosure 2

### BASIS FOR THERECOMMENDATION TO PLACE N-(1-ADAMANTYL)-1-PENTYLlH-INDAZOLE-3-CARBOXAMIDE (AKB48) AND ITS SALTS IN SCHEDULE I OF THE CONTROLLED SUBSTANCES ACT I. 

### SUMMARY The Food and Drug Administration (FDA) recommends that (N-(1-adamantyl)-1-pentyl-JHindazole-3-carboxamide), also known as AKB48 or APJNACA, and its salts beplaced in Schedule I ofthe Controlled Substances Act (CSA). AKB48 was first identified in 2011 as 

### a "designer drug" 1present in "herbal products" (Uchiyama eta!., 2012;NFLIS, 2011). AKB48 is
a synthetic cannabinoid or cannabimimeticthat has recently becomepopular as a recreational marijuana alternative. AKB48 was detected in herbal products marketed globally via the Internet under a variety ofnames and in specialized shops (WHO, 20 14). The amount ofAKB48 among the different marketed packages varies. As discussed in further detail below, AKB48 is not presentin eve1y marketed synthetic cannabinoid product. For clarity, this document will explicitlyrefer to AKB48 when discussing case reports where AKB48 has been specifically identified in products. In vitro and in vivo preclinical studies indicate that the pharmacological effects ofAKB48 are similar to delta-9 (69) -tetrahydrocannabinol (THC, Schedule I) and 1-pentyl-3-( 1-naphthoyl) indole (JWJ-:1-018, Schedule 1). These studies, combined with case reports and anecdotal observations in humans, suggest the subjective effects ofAKB48 are cannabis-like and similar to those ofmarijuana. The Drug Enforcement Administration (DEA) notified the Department ofHealth and Human Services (J-:IHS) in writing ofits intent to temporarilyplaceAKB48 into Schedule I ofthe CSA on February 14, 2013. On March 14, 2013, in response to the notification bythe DEA, HHS stated that there are no investigational new drug (IND) applications or approved new drug applications (NDA) for AKB48. On May 16, 2013, the final order temporarily placing AKB48 into Schedule I ofthe CSA was published in the Federal Register (78 FR 28735).
In this document, FDA recommends that AKB48 be petmanentlyplaced into Schedule I ofthe CSA. 

### II. BACKGROUND Synthetic cannabinoids are relatively new substances ofabuse. Over the past several years, recreational use ofsynthetic cannabinoid compounds has increased in the United States (Cohen eta!., 20 12). These compounds are commonly sold at gas stations, convenience stores, and on the Internet. In general, synthetic cannabinoids are marketed under aplethora ofnames. Analyses byDEAhave detected AKB48 in product samples marketed under the name

1The te1m "designer dmgs" relaJes to psychotropic substances that are either synthetically changed natural compounds, modified molecularstmctures ofexisting drugs, or-less conunonly-wmpletely

**differen~** designed chemicals (Wohlfarth & Wolfgang, 2010)."Relaxinol." Uchiyama et al. (2012) identified AKB48 in product samples marketed in Japan under the name "Fragrance Powder." On July 9, 2012, 15 synthetic cannabinoids (including CP-47,497, CP-47,497 C8-homolog, JWH-018, JWH-073, and .TWH-200) were placed into Schedule I ofthe CSA by Section 1152 of the Food and Dmg Administration Safety and Innovation Act (FDASIA) under TITLE XIOTHER PROVISIONS, Subtitle D-SyntheticDmgs.Z As a newly recognized synthetic cannabinoid at that time, AKB48 was not listed among those controlled substances. Following placement ofthe aforementioned cannabinoids into Schedule I ofthe CSA, new compounds (e.g., AKB48) with cannabinoid receptor activity appeared, likely in an attempt to evade CSA control. AKB48 is a pentyl indazole with structural similruity to JWH-018 (Schedule I). AKB48's structure resembles a group ofpatented compounds that include an indole-like structure with one or more heteroatoms (Patent W02003035005). Data from the System to Retrieve lnfonnation on Drug Evidence (STRIDE), a DEA database that collects data on samples tested by DEA's Jabs, and the National Forensic Laboratory Infonnation System (NFLIS), a DEA database tl1at collects inforn1ation on samples tested by state and local laboratories, indicate that AKB48 was found in samples starting in 2011. Specifically, there were 87 STRIDE reports from January 2011 through February 24,2014, ru1d 791 NFL!S reports from .Trumm·y 2010 through December 2013, involving AKB48. AKB48 has no known accepted medical use. Itis not the subject ofan NDAor an 1ND, and it is not currentlymarketed as an approved drug product.
In addition, law enforcement and health cru·e practitioners continue to encounter individuals who have abused synthetic cannabinoids and need hospital emergency department (ED) admission. Since the composition ofthese products change overtime as a reaction to prohibition and prosecution ofsellers, neither the rescUer nor the consumer ofthese mixtures knows the actual content and amotmt ofsynthetic cannabinoid in products under the labeling guise of"incense" (Dresen et al. 2010). The American Association ofPoison Control Centers (AAPCC)3 reported

2When FDASJA was enacted, atotal ofeight substances were already coveredby DEA temporary scheduling orders: five synthetic cannabinoids (JWH-018: 1-penty1-3-(l-naphthoy1)indo1e, JWH-073: naphthalen-1-yl-(1-buty!indol-3-yl)methanone, JWH-200: ( 1 -(2-morpholin-4-ylethyl)indol-3-yl)-naphtlmlenJ-ylmethanone, CP-47,497: 2-[(1R,3S)-3-hydroxycyclohexyl]- 5·(2-methyloctan-2-yl)phenol, and CP-47.497 C8 homologue) and three synthetic cathinones (mephedrone, MDPV, and methylene). DEA issued aNotice ofProposed Rulemaking on March I, 2012, to place tl1e five synthetic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue) permanently in Schedule I (77 FR 12508). With the exception ofmethylone, these compounds were placed in Schedule Iby FDASIA on July 9, 2012. With final enactment ofFDASJA, final scheduling ofthe five syntl1etic cannabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue), mephedrone, and MDPV was accomplished. DEA posted the HHS Seientitic and Medical Evaluation and Scheduling Recmmnendations regarding the five synthetic cannabinoids on www.regulations.gov. These HHS documents can be found on www.regulations.gov under Docket No. DEA-2012-0001. ' AAPCC collects infonnation Jogged by the country's Poison Control Centers (PCs). Records are from selfrepmied calls; therefore, they reflect otlly infonnation provided when the public or ahealth care professional reports an actual orpotential exposure to asubstance (e.g., an ingestion, inhalation, or topical exposure), or requests infom1ationalmateriaL It warrants noting that these exposures do not inherent.ly represerit an instance ofpoisoning or overdose. The AAPCC is not able to completely verify the accuracy ofevery report 22,639 human exposures to synthetic marijuana (THC homologs) in 2013 (AAPCC, 2013). According to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), AKB48 has been reported in Romania, Italy, the United Kingdom, the Czech Republic, Latvia, Croatia, Denmark, Spain, Belgium, Hungary, Germany, Sweden, and Bulgaria. Numerous U.S. states and other countries (e.g., Japan and NewZealand) have implemented control measures on AKB48 (FindTheBest.com, 20 14). Pursuant to 21 U.S. 

### C.§ 811, the Secretary is required to consider, in the scientific and medical evaluation, eight factors with respect to control, rescheduling, or removal ofa substance from the schedules ofthe CSA. The eight factors are: I. The drug's actual orrelative potential for abuse; 2. Scientific evidence ofthe drug's pharmacological effects; 3. The state ofcurrent scientific knowledge regarding the drug or other substance; 4. Its history and cuJTent pattern ofabuse; 5. The scope, duration, and significance ofabuse; 6. What, ifany, risk there is to the public health; 7. Its psychic orphysiologic dependence liability; and 8. Whether the substance is an immediateprecursor ofa substance already controlled. Following consideration ofthe eight factors, the Secretary must make three findings and a recommendation regarding scheduling a dmg or substance. The three required findings relate to the substance's abuse potential, legitimate medical use, and safety or dependence potential (21 

## u.s.c. § 812(b)). Administrativeresponsibilities for evaluating a substance for control under the CSA are perfonned for HHS by FDA, with the concuJTence ofthe National Institute on Drug Abuse (NIDA) ((Memorandum oflJnderstanding, 50 FR 9518, 9518-20) (March 8, 1985)). This evaluation discusses the scientific and medical infonnationrelative to each ofthe eight factors, presents findings in the three required areas, and makes a recommendation regarding the placement ofN-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB48) into Schedule I under the CSA. 

### III. EVALUATING AKB48 UNDER THE EIGHT FACTORS This section presents an evaluation ofthe cuJTent scientific and medical knowledge about AKB48 under the eight factors thatmustbe considered pursuantto 21 U.S.C 

### § 81l(c).

made to membercenters. Additional exposures may go unrepmied to PCs and data referenced fi·om the AAPCC should not be construed to represent the complete incidence ofnational exposures to any substance. AAPCC indicated that a significant proportion ofthe reports were generated from hospital emergency departments or en-route to amedical treatment facility. 3

### FACTOR 1: Its Actual orRelative Potential for Abuse The first factor the Secretary must consider is the actual orrelative potential for abuse of AKB48. Thetenn "abuse" is not defined in the CSA. However, the legislative history ofthe CSA suggests the following points in determining whether a particular dmg or substancehas a potential for abuse 4:

a. Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety ofother individuals or to the community. b. There is significant diversion ofthe dmgor substan.ce from legitimate drug channels. c. individuals are taking the substance on their own initiativerather than. on thebasis of medical advice from a practitioner licensed by law to administer such substance. d. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions fi·om legitimate channels, significant use contrary to or without medical advice, orthat it has a substantial capability ofcreating hazards to the health ofthe user or to the safety ofthe community. There is no single test or assessment procedure that, by itself, provides a full and complete characterization ofa substance's abuse potential, as this is a complex determination that is multidimensional. When assessing the abuse potential ofa substance, the Secretary considers multiple factors, data sources, and analyses. These factors include theprevalence, frequency, and manner ofuse in the general public and specific subpopulations; the amount ofmaterial that is available for illicit use; and evidence relevant to populations that maybe atparticularrisk. Animal, human, and epidemiological data are all used in determining a substance's abuse potential. Specifically, a comprehensive evaluation ofthe relative abuse potential ofa substance includes consideration ofthe drug's receptor binding affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus eil:ects, dependence-producing potential, pharmacokinetics, routes ofadministration, toxicities, assessment ofthe clinical efficacy safety database relative to actual abuse, clinical abuse-potential studies, and pub.lic health risks following marketing ofthe substance. Epidemiological data can also be an impottant indicator ofactual abuse. Finally, evidence ofclandestineproduction and illicit trafficking ofa substance are also important factors. Below is a discussion ofthe four indicators ofabuse as theyrelate to AKB48. 

### A). Individuals are taking the substancein amounts sufficientto create a hazard to their health or the safety of other individuals or to the community. The epidemiological and caserepmt data discussed in this section suggest that individuals are taking AKB48 in amounts sufficient to create ahazard to theirhealth orto the safety ofother

**individ~1als** or to the community. Common symptoms associated with intoxication byother

4 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 9!st Cong., Sess. I (1970) reprinted in U.S.C.C.A.N. 4566,4603. 4synthetic cannabinoids which are similar to AKB48 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 cognitive impairment (Castaneto eta!., 2014). Long-term orresidual effects are cun·ently unknown. Acute symptoms usually subside within a few hours and most symptoms are similar to high doses ofcannabis, except for agitation and seizures (which are not seen after taking high doses ofcannabis) (1-lemanns-Clausen eta!., 2013). According to a 2012 survey, synthetic cannabinoids are the second-most commonlyused illegal drug among young adults, with only cannabis use occun·ing at ahigherrate (Johnston eta!., 20 12). Use ofsynthetic cannabinoids produces psychoactive effects similar to those ofcannabis; moreover, synthetic cannabinoids are easily accessible and difficult to detect in standard urine drug screens (Auwarter et a!., 2009), which contribute to their high rate ofuse. From January 2010 through March 2013, DEA reported that NFLIS 5 and STRIDE6 data for the three synthetic cannabinoids UR-144, XLR-11, and AKB48 totaled 16,014 reported cases. The detection ofthese substances in drug seizures is consistent with DEA findings on the drug exhibits collected during law enforcement seizures with other Schedule I synthetic cannabinoids designated as JWH and CP. These substances, according to the DEA, are intended for human use as recreational drugs. Thenumber and thetype ofsynthetic cannabinoids, as an aggregate, have increased since 2008, as evidenced by the number ofrepmis submitted to NFLIS. Accordingto NFLIS, there were 29,467 synthetic cannabinoid drug repmis in 2012, an increase of 1,402 percent since 2009 (DEA National Drug Threat Assessment Summary, 2013). Specifically, in its 2013 midyear report, NFLIS repotied AKB48 specificallyto be 1.65 percent (285 I 17,242) ofall synthetic cannabinoids tested. This datarepresents results ofdrug cases submitted to state and local laboratories from January 2013 through June 2013 and analyzed by September 30, 2013. The AAPCC repotied approximately 5,200 calls about exposures to synthetic marijuana (THC homologs) in 2012. This number is lower than the number ofcalls repmted in 201 1 (6,968), but showed a greater than!OO percent increase over those reported in 2010 (2,906) (DEA, 2013 National DrugThreat Assessment Summary). Additionally, AAPCCjustrecentlyreleased a repmt of2,639 human exposures to synthetic marijuana in2013 (AAPCC, 2013). Although the AAPCC does not identify specific cannabinoid substances, the data does indicate the magnitude ofadverse exposure to synthetic cannabinoids.

'DEA's NFLIS systematically collects results from drug chemistry analyses conducted by state and local forensic laboratories across the country. As a national drug forensic laboratory reporting system, NFL!S provides timely and detailed analytical results ofdrugs seized by Jaw enforcement. See http://www.deadiversion.usdoj.gov/nflis/.

6 DEA's STRIDE reflects the results ofdrug evidence analyzed at DEA laboratories nationwide. See the 2012 NFLIS a1mual repm1 at http://www.deadiversion.usdoj.gov/nflis/2012rumual_rpt.pdf. 5

### B). The1·e issignificantdiversion of the drug orsubstance.fi·om legitimtlte drug channels. Since AKB48 is not an FDA-approved drug product for treatment inthe United States and there appear to be no legitimate sources for AKB48 as a marketed drug, this characteristic ofabuse potential is not applicable. C). 

### Individuals are taking the substance on their own initiative rather than on the basis of medical advice.fi·mn apractitionerlicensedby law to administersuch substance.
BecauseAKB48 is not approved for medical use and is not formulated or available for clinical use, all human self-administration is assumed to be on an individual's own initiative, ratherthan on the basis ofmedical advice from a practitionerlicensed by Jaw to administer drugs.
Law enforcement seizures and anecdotallnternet user experienceposts (e.g., http://www.drugsforum.com) indicate that individuals are taking AKB48 on their own initiative, ratherthan on the medical advice ofa licensed practitioner. 

### D). The substance is so related in its action to asubstance already listedas having a potentia/forabuse to make it likely that lt

### wiUhave the samepotentia/forabuse as such substance, thus making it reasonable to assume that there maybe significant diversionsfrom legitimate channels, sign(ficant use contrary to orwithoutmedical advice, orthatit

### has asubstantialcapability of creating ha.zards to the health o.fthe user orto the .mfety o.fthe community. AKB48 

### in vitro and 

### in vivo pharmacologically data is similar to other Schedule I cannabinoids (DEA, 2013). Research studies show thatpsychoactive cannabinoids ofvarious structural classes, including tetrahydrocannabinols (such as 1'19•THC),bicyclic cannabinoid analog (e.g., CP55,940), aminoalkylindoles (e.g., WIN55, 212-2) and other indole- and pyrol-derived cannabinoids (e.g., JWJ-1-0 18; Schedule I), share a common pham1acological profile ofeffects. Consideringthe close pharmacological resemblance ofAKB48 to 1'19

-THC (Schedule I), abuse of AKB48 is likely to occur (WHO, 2014). Psychoactive cannabinoids are shown to bind and activate cannabinoid-1 (CBI) receptors in 

### vitro (Devane et al., 1988; Griffin et al., 1998). For example, JWH-018 (Schedule I) is a fully synthetic cannabinoid or cannabimimetic agonist with high affinity for CB 1receptors. In 

### a study examining the relative affinity ofJWH-0 18 for CB 1 receptors, JWH-018 displayed a K; of9.0 nM (Aung et al., 2000). Similarly, in a study examiningrelative affinities, results demonstrated that AKB48 binds with 

### a 

### K; value of304.50 nM at CB 1• Secondly, psychoactive cannabinoids are reported to substitute for 1'19-TJ-IC in a drug discrimination procedure in rodents (Wiley et al., 1995; Vann et al., 2009). This procedure is used as an animal model ofmarijuar1a intoxication and, when utilized as such, is also a highly predictiveprocedure in identifying compounds that humans label "marijuana-like" (Balster and Prescott, 1992). In drug discrimination studies in rodents trained to discriminate ,1;9-THC, JWH6018 (Schedule I) produced complete substitution for stimulus effects oft:.9

-THC with an ED507 of 0.39 mglkg (NIDA contract N01 DA-13-8908). Similarresults were obtained by Jarbe and colleagues, who found that JWH-018 fully substituted for the stimulus effects of69-THC in rodents trained to discriminate THC and was eight times more potent than THC (Jarbe et al, 20!1). As with other psychoactive cannabinoids (e.g., JWH-018; Jarbe et al., 2011), AKB48 was shown to fully substitute the discriminative stimulus effects of69-THC with an EDso of0.23 mg/kg (NIDA NOJDA-13-8908). FACTOR 2: Scientific Evidence ofthe Drug's Pharmacological Effects The second factor the Secretary must consider is the phannacological effects ofAKB48. AKB48 produces pharmacological effects similar to those ofCB 1 agonists including marijuana, 69-THC, and JWH-018, all ofwhich are listed in Schedule I ofthe CSA. Receptor binding (K;), CB 1 functional assay, drug discrimination, and locomotor studies with AKB48 wereperfonned (NIDA 12:9177, NIDA NOlDA-13-8908, and NIDA NOlDA-7-8872). In rodents, AKB48 dose-dependently produced a profile ofphannacological effects characteristic ofCB 1receptor agonists, which includes suppression oflocomotor activity and full substitution for 69-THC from a saline vehicle. Together, these results suggest tJmt AKB48 is a psychoactive CB 1receptor agonist which is similar to 6 9-THC. Regarding locomotor activity, AKB48 was assessed by time course (8 hour) tests versus /).9-THC in groups ofeight non-habituated male Swiss-Webster mice. In all studies, horizontal activity counts, as a function ofdose, via inten'Uption ofphotocellbeams, weremeasured for 8 hours within 10-minuteperiods (NIDA NO! DA-7-8872). Each group ofmice was either injected with a saline vehicle, AKB48, or69-THC. AKB48 concentrations from 3 mg to 30 mglkg demonstrated time and dose-dependent depression oflocomotor activity (NIDA N01DA-7- 8872). Depressant effects ofAKB48 at 3 mg/kg occurred within 20 minutes following injection and lasted 70 minutes. The IDso (dose producing Y, maximal depressant activity, where the maximal depression = 0 counts/30 min) was estimated to be 2.2 mglkg. Similarly, treatment with 6 9-THC resulted in time- and dose-dependent depression oflocomotor activity following 10 and 30 mg/kg. Depressant effects of69-THC at 10 and 30 mg/kg oCCUlTed withinl0-40 minutes following injection and persisted for 90-120 minutes (NIDA NOlDA-7-8872). The binding affinity ofAKB48 for cannabinoid CB 1 and CB2receptors was investigated. Itwas shown that ABK48 has an approximately two-fold higher affinity at the human recombinant CB2 receptor compared to CB 1 (ICso value of430 nM and 824 nM, respectively) (Uchiyama, 2013). Theresults also showed that AKB48 had affinity for the CB1 and CB2 receptors. AKB48 for the CB 1receptor was approximately five times lower than that ofJWH-018 (Schedule I). The affinity ofAKB48 for tl1e CB 1receptor was 25.8-fold lower than that of(R)-(+)-WJN-55, 212-2,

7 ED50 (effective dose) is a dose ofaphannacologic agent which will have a therapeulic effect. In the context of rodents, ED5 0 refers to the effective dose for obJaining the pharmacological response. In this study it is the effective dose for drug discrimination.

7positive control (Uchiyama, 2013). As compared to THC, these values associate a 12- to 30-fold lower binding affinity to CB 1receptors and a 12- to 17-fold lowerbinding affinity to CB 2 receptors. In another NJDA-contracted study, duplicate dose-response curves for IC50 and K; studies wereperfmmed. Concentrations of 10, 100, 200, 500, I000, 2,000, 5,000, and I0,000 nM were tested in triplicate. The K; value ofAKB48 at CB 1receptors was reported at 304.50 nM (NlDA Task Order: 12-9177). AKB48 was researched byCB 1 (h) functional assay using G-protein coupled receptor sites (NIDA Task Order: 12-9177). Concentrations of 10, 30, 100, 300, I,000, 3,000, 10,000, and 30,000 nM were tested in triplicate. AKB48 demonstrated agonism at these G-protein coupled receptor sites producing maximal responses, for at least one log unit, ofgreaterthan 80 percent ofa full known agonist tested under the same conditions. The average ECso value was 585 nM (NIDA Task Order: 12-9177). Drug discrimination experiments also serve as behavioral studies that assess the interoceptive cues produced by drugs. Animal responses to a drug are shown by changes in the animal's behavior. For example, in drug discrimination studies, the ability ofthe animal to identify ifthe test dmg elicits a similar response to the positive control drug is measured (Marona-Lewicka and Nichols, 1998). AKB48 standard drug discrimination experiments were perfonned on rats, which were already trained to discriminate ll9

-THC fi·om a vehicle (NIDA NO! DA-13-8908). In onepatiicular study, six male Sprague-Dawley rats were trained to discliminate ll9-THC (3 mglkg)

**fi~om** a vehicle using two-lever methodology. Either intraperitoneal injections (lmg/kg) or a vehicle was stmied 30 minutes priorto the stati ofthe session and a dose range of0.025 to 2.5 mglkg was examined. This range included doses that were inactive to those thathad biological activity as evidenced by full substitution. AKB48 demonstrated the ability to fully substitute (ED50 

## = 0.23mg/kg) for the discriminative stimulus effects produced by 3 mg/kg of,t,9-THC (N!DA Final Study Repmt NO!DA-13-8908). Researchers repmted unexpected effects being observed following any dose ofAKB48. FACTOR3: The State ofCurrent Scientific Knowledge Regarding the Drug or Other Substance The third factor the Secretary must consider is the state ofcun·ent scientific knowledge regm·ding AKB48. AKB48 is a potent cannabinoid that is repo1ted to be smoked for recreational purposes. AKB48 is phannacologically similar to C\9-THC, the principal psychoactive chemical in malijuana (Schedule I). The chemical name ofAKB48 is N-1-adamantyl-I-pentyl-JH-indazo1e3-carboxamide. Altemative abbreviations for this substance include APJNACA and 1-pentyl-Ntri.cyclo (3,3,1,13,7)dec-J-yl-JH-indazole-3-carboxamide. In pure fom1, AKB48 is a white powder which is soluble in methanol and ethanol. Its molecularformula is C23H.11N3o and its molecular weight is 365.2. The melting point ofAKB48 is at 63.6 degrees Celsius (WHO, 2014). AKB48 has been found to be insoluble in 0.9 percent saline, deionized water, and 0.16 percent tartaric acid (NIDA contract N01DA-7-8872). AKB48 is identified under Chemical Abstract Service (CAS) Number 1345973-53-6. 8The chemical structure ofAKB48 is unrelated to THC. Although many ofthe synthetic cannabinoids detected in illegal products, such as JWH-018 (Schedule 1), have a 3-carbonyl indole moiety, AKB48 is a new type ofsynthetic cannabinoid with an amide structure and an adamantane group. AKB48 also has an indazole group in place ofan indole group (Uchiyama et a!., 2012). It does not appear to be an analogue to any Schedule I substance. While the exact metabolic pathway for AKB48 is unknown in humans, aNIDA-supported study with human hepatocytes was recently performed by Gandhi eta!. (2013). Reseru·chers showed that the major metabolic pathways arehydroxylation on the aliphatic adamantane moiety followed by glucuronidation. Oxidation ofthe N-pentyl side chain fanning a ketone appears to be a minor metabolicpathway. Based upon other studies, AKB48 shares common metabolic pathways, e.g., mono- or dihydroxylation ofthe N-pentyl side chain or the indole moiety similar to JWH-018 (Schedule I) orhydroxylation ofthe aliphatic adamantane ring, followed by glucuronidation. Eleven majormetabolites were monohydroxylated, dihydroxylated, trihydmxylated, and mono- ru1d dihydroxylated with ketone fonnation at the N-pentyl side chain. No glutathione or sulfate conjugates were f01:md. Sinceparent synthetic cannabinoids are rarely present in the urine, metabolite identification is imperative for proving intake ofsynthetic cannabinoids (Gandhi et al., 2013). Additionally, based on the lack ofhuman toxicological infmmation for AKB48, it is difficult to predict all thehealth risks associated with its use (Uchiyama et al., 2012). Factor 4: History and Current Pattern ofAbuse The fomth factor the Secretarymust consider is the history and cunent pattern ofabuse of AKB48. Many synthetic cannabinoids were developed overthe last 30 years for use as vehicles for investigating the cannabinoid system for research purposes (Weissman eta!., 1982; Huffman et al., 1996). Most ofthe data available on the synthetic cannabinoidsrepresents data on the drug class, as opposed to data on individual substances. Becauseofthe similarityin phannacology and apparent abuse as evidencedby seizure repmts, the history and pattem of abuse ofAKB48 is likely to be similar to that ofother synthetic cannabinoids that have been placed into Schedule 

### I. Recently, substances like AKB48 were found in retail products available worldwide (Uchiyama et al., 2012; Uchiyama et al., 2013; WHO, 2014; NFLJS, 2013). The first synthetic cannabinoid was found in plantmaterial for retail sale in 2008. A commercial laboratory in Frankfu11, Gennany, announced that ithad identified JWH-0 18, one ofseveral synthetic cannabinoid agonists originally developed at Clemson University, in samples ofherbal incense from Europe. Producers buy cannabinoids from laboratories in China or other countries where they are synthesized. The substances arc dissolved in solvents sprayed on plant matetial and evaporated to dryness before beingpackaged and sold as herbal mixtures (Piggee, 2009). Clandestine manufacturers continue to develop new unscheduled synthetic cannabinoids with numerous structural alterations, but without loss ofthe psychoactivepotential. Often times, different types of"designer drugs" such as cathinones (stimulants) or tryptamines (hallucinogens) are mixed together with synthetic crumabinoids and sold. The combination presents potential additional serious health risks associated with use. 

### Itis postulated that the
9continual development ofthese new synthetic cannabinoids, such as AKB48, is primarily based on attempts to evade regulatory control ofsynthetic cannabinoids. The first emergence ofsynthetic cannabinoids in the United States can be traced back to a U.S. Customs and Border Protection (CBP) announcement from mid-January 2009, which repOJted a seizure ofherbal incense shown to contain the synthetic cannabinoid HU-21 0 in Dayton, Ohio (Piggee, 2009). When CBP officers at the Dayton, Ohio, facility ofan international express courier saw the dried plantmaterial inside a shipment, theyperfonned a field test for the presence ofTHC, but it was negative

.. However, fmther analysis at the CBP laboratory in Chicago confinned the presence ofthe synthetic cannabinoid HU-21 0. Over a 3-monthperiod, CBP seized over 100 1bs ofHU-210-laced herbal mixtures in five sepamte shipments (Piggee, 2009). Law enforcement and public health officials continue to encounter abuse ofthese substances (Substance Abuse and Mental Health Services Administration (SAMHSA), The DAWNRepol't, 2012; NFLIS, 2013). As aforementioned, there were 87 STRIDE repotis fi·om January2011 through February24, 2014, and 791 NFLIS repOJts from January 2010 through December 2013, involving AKB48. Specifically, prior to the last quarter of2011, NFLJS reported no cases involving AKB48. Youth appear to bethe primary abusers ofsynthetic cannabinoids and synthetic cannabinoidcontainingproducts, as demonstrated by law enforcement encounters and repotis ti·om hospital EDs. TheDAWNReport stated that, ofapproximately 2,300,000 ED visits that involved drug misuse or abuse in 2010, synthetic cannabinoids were specifically linked·to an estimated 11,406 visits (SAMHSA, 2012). According to the report, 75 percent ofthe 11,406 ED visits in 2010 involved synthetic cannabinoid use among patients aged 12 to 29. For this age group, males comprised more than three qumters (78 percent) ofED visits involving synthetic cannabinoids in 2010. As aforementioned, the AAPCC also reported 2,639 human exposures to synthetic marijuana in 2013. Synthetic cannabinoid popularity is attributed to intense psychoactive effects, lack ofdelectability in routine urine drug tests, and, until recently, the lack ofCSA control (Gunderson et al., 2012; Vandrey et al., 2012; Winstock and Ban·ett, 2013). 

### Facto1· 5: 

### The Scope, Duration, and Significance ofAbuse The fifth factor the Secretary must consideris the scope, duration, and significance ofabuse of AKB48. Based on its pharmacological properties, itis reasonable to assume that, if uncontrolled, the scope, duration, and si?nificance ofAKB48 abuse would be similar to either t:,.9

-THC or malijuana (which contains /::,

-THC as the principal psychoactive chemical substance). Because AKB48 is often packaged as an "herbal blend" with multiple ingredients, including other synthetic cannabinoid agonists, the scope, duration, and significance ofabuse is difficult to disaggregate. However, the available data, includingreceptor binding, 

### in vitro, and preclinical studies strongly suggest that AKB48 has a pharmacological mechanism ofaction and that it will produce phannacological and subjective effects similar to /::,9-THC (Schedule I) and JWH-018
10(Schedule!). As aforementioned, in its 2013 midyear report, NFLIS identified AKB48 specifically to occur in 1.65 percent (285 I 17,242) ofall synthetic cannabinoids tested. The use ofAKB48 recreationally is reported anecdotally byusers posting on Internet drug sites (e.g., http://drugs-forum.com). From the aforementioned link, it is documented that users repmted experiences with AKB48 as being very clean, gradual, ve1y pleasant, similar to marijuana, extremelypleasurable, enjoyable, a favoritecannabinoid with low anxiety and little to no negative effects. FACTOR 6: What, IfAny, Risk There Is to the Public Health The sixth factor the Secretary must consideris the risk AKB48 poses to the public health. The phannacology ofAKB48 as described in FACTOR 2 (above) demonstrates that the risks to the publichealth are largelyrelated to thepotential serious adverse effects that the substance will have on individual users. Based on the results ofin vitro (cannabinoid receptor binding/functional assay) and in vivo preclinical (discrimination/locomotor) studies, and considering that AKB48 possesses iTt vivo pharmacological similarity to /1.9-THC along with ahigh potency at nanomolar concentrations, the subjectiverisks to the public health ofAKB48 are likely to be similarto those ofother cannabinoid agents, specifically marijuana and 

### L\9-THC, which are controlled in Schedule I of the CSA. As previously described in FACTOR 1, common symptoms associated with intoxication by other synthetic cannabinoids which are similarto AKB48 include nausea and vomiting, sh01tness of breath ordepressed breathing, hypertension, tachycardia, chest pain, muscle twitching, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impainnent (Castaneto eta!., 2014). Long-term or residual effects are currently unknown. Acute symptoms usually subside within a few hours and most symptoms are similarto high doses ofcannabis (except for agitation and seizures, which are not seen after taking high doses ofcannabis) (Hemanns-Clausen et al., 2013). Detailed product analyses desclibe variations in the amount ofsynthetic cannabinoid on plant material even within samples from the sameproduct (Hudson et al., 2010). The heterogeneity of products poses an additional substantial risk ofham1 to synthetic cannabinoid-abusing individuals (Auwatter et al., 2009; Hudson et al., 2010). Consumption ofsynthetic cannabinoids can lead to impainnent similar to typical performance deficits caused by cannabis use. These deficits, which are not compatible with safe dliving, include sedating effects and impainnent of fine motor skills necessary for safely driving a vehicle. FACTOR 7: The Drug's Psychic or Physiologic Dependence Liability The seventh factor the Secretarymust consider is the psychic orphysiologic dependence liability ofAKB48. The phannacologicprofile ofAKB48 strongly suggests that it maypossess a physiological and psychological dependence liability that is similarto that of/1.9

-THC (Schedule 

### I) and JWH-018 (Schedule !). 11Case reports demonstrate that herbal products containing synthetic cannabinoids produce physical dependence and a withdrawal syndrome. There is onepublished case repmt of tolerance and withdrawal phenomena in the literature (Zimmermann eta!., 2009) and another of drug-induced psychosis (Muller eta!., 2010). Both cases were attributed to "Spice,"which at the time contained the Schedule I synthetic cannabimimetics JWH-018 and CP47,497. While there are no specific studies involving the psychic or dependence liability cmTently identified for AKB48 specifically, because ofthe similarityin phannacology and recognized abuse ofthe class ofsubstances byhumans, AKB48 is likely to exhibit the same dependence liability as JWH-018 and CP47,497. Drug dependence is not directly observable 

### in vivo. Rather, it 

### is assumed to bepresent when either the discontinuation ofdrug administration (spontaneous withdrawal) orthe administration ofan antagonist (precipitated withdrawal) elicits a withdrawal syndrome. Thetem1inology "cannabis withdrawal" has gained medical acceptance as described by the Diagnostic and Statistical Manual ofMental Disorders Fifth Edition (DSM-5). The following si!,>nS and symptoms develop within approximately 1week ofwithdrawal: initability, anger, aggression, nervousness or anxiety, sleep difficulty (e.g., insomnia, disturbing dreams), decreased appetite or weight loss, restlessness, and depressed mood. Further, at least one ofthe following physical symptoms causes significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, orheadache (DSM-5, American Psychiatric Association, 2013; Gorelick et al., 2012).
In multiple species,. cannabinoid administration may lead to rapid tolerance to antinociceptive effects, anticonvulsant activity, cataleptic effects, suppression oflocomotor activity hypothetmia, hypotension, release ofcorticosteroids, and other effects (Adams eta!., 1996). FACTOR 

### 8: Whether 

### the Substance Is an Immediate Precursor of

### a SubstanceThat Is Already Controlled AKB48 is not an immediate precursor ofany controlled substance. RECOMMENDATION After consideration ofthe eight factors detenninative ofa substance (21 U.S.C. 

### § 811 (c)), FDA recommends that AKB48 (N-1-adamantyl-1-pentyl-1H-indazole-3-carboxamide) and its salts he placed in Schedule Iofthe CSA (21 U.S.C.§ 812(h)(l)). AKB48 produces effects similar to those ofJWH-018, which is controlled in Schedule I ofthe CSA. NIDA concurs with the FDA scheduling recommendation. The necessary critetia for placing a substance into Schedule I ofthe CSA are set forth in 21 U.S.C.§ 812(b)(l), as follows: 

### A) The drug or othersubstauce has a highpotential for abuse. AKB48 is a synthetic substance that produces cannabinoid-like effects. The pharmacological similmity ofAKB48 to 1'19-THC makes 

### it reasonable to assume that its potential for abuse is high 12and would be similar to that ofJWH-018, a synthetic cannabimimetic which is controlled in Schedule I ofthe CSA 

### B) The drug orothersubstance has no currently acceptedmedical use in treatment in the UnitedStates. There are no approved NDAs for AKB48 in the United States. There is no known therapeutic application for AKB48. Therefore, AKB48 has no cun·ently accepted medical use in treatment in the United States. 

### C) There is alack of acceptedsafety for use of the drug or othersubstance undermedical supervision. SinceAKB48 has no approved medical use and has not been thoroughly investigated as a new drug, its safetyfor use undermedical supervision is undetennined, Thus, there is a lack of accepted safety for use ofthis substance under medical supervision, FDA therefore recommends that AKB48 and its salts be controlled in Schedule I ofthe CSA.

13References: Adams I.B. and Mmtin B.R. (1996) Cannabis: Phannacology and toxicology in animals and humans. Addiction. 91(11):1585·614. AKB48 (APINACA) Drug Info. Drugs-Forum (an Internet dmg user forum). Available at https://www.dnlgs-forum.com/forum/showthread.php?t=l 87522. Last accessed on October 6, 2014. American Association ofPoison Control Centers. Synthetic Marijuana Data, December 31, 2013. Available at https://aapcc.s3.amazonaws.com/files/library/Synthetic

_Mmijuana _Web_ Data_through_l2.20 pdf. Last accessed on February 5, 2014. Aung M., Griffin G., Huffman J., Wn M., Keel C., eta!. (2000) Influence ofthe N-1 alkyl chain length ofcannabimimetic indoles upon CB (1) and CB(2) receptorbinding. DrugAlcohol Depend, 60:133-140. Auwarter V., Dresen S., Weinmann W., Muller M., Putz M., eta!. (2009) "Spice" and other herbal blends: Harmless incense or cannabinoid designer drugs? Journal of Mass Spectromel!y, 44:832-837. Balster R.L. and Prescott W.R. (1992) L\9-Tetrahydrocannabinol disCiimination in rats as a model for cannabis intoxication. New·osci BiobehavRev, 16:55-62. Castaneto M., Gorelick D., Desrosiers N., Hartman R., Pirard S., and Huestis M. (2014) Synthetic cannabinoids: Epidemiology, phannacodynamics, and clinical implications. Drugand AlcoholDependence, 144:12-41. Cohen 

### J., Monison S., Greenberg

### J ., and Saidinejad M. (20 12) Clinical presentation of intoxication dne to synthetic cannabinoids. Pediatrics, 4:129. Drug Enforcement Administration, National Drug Threat Assessment Summary (November 2013). Document prepared by the DEA's Office ofIntelligence Warning, Plans and Programs. Available at http://www.justice.gov/dea/resource-center/DIR-O17 13%20NDTA%20Summary%20final.pdf. Last accessed on February 24, 2014. Drug Enforcement Administration. (2013) Background infonnation and evaluation of"three factor analysis" (factors 4, 5 and 6) for temporary scheduling. Available at http://www.deadiversion.usdoj.gov/fed_regs/rules/2013/fi·0516.htm. Last accessed on October 28, 2014. DevaneW.A., Dysarz F.A., Johnson M.R., Melvin L.S., and Howlett A.C. (1988) Detennination and characterization ofa cannabinoid receptor in ratbrain. MolPharmacal, 34:605-613.

14Dresen S., Feneiros N., Putz M., Westphal F., Zimmermann Z., et al. (2010) Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. Journal of Mass Spectromet1y, 4S: 1186-1 I94. Gandhi A., Zhu M., PangS., Woh1fatih A., Scheidweiler K., Liu H., and Huestis M. (2013) First characterization ofAKB48 metabolism, a novel synthetic cannabinoid, using humanhepatocytes and high-resolution mass spectrometry.AmericanAssociation of PharmaceuticalScientists, 15(4):1091-1098. Gorelick D.A., Levin K.H., Copersino M.L., Heishman S.J., Liu F. et al. (2012) Diagnostic criteria for cannabis withdrawal syndrome. Drug andAlcoholDependence, 123:141-147. Griffin G., Atkinson P.J., ShowalterV.M., Mmiin B.R., and Abood M.E. (1998) Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5'-0-(3-[35S]thio)- triphosphatebinding assay in rat cerebellarmembratJes. J Pharmaco/Exp Ther, 285:553-560. European Monitoring Centre tor Drugs and Drug Addiction (2009) Understanding the "Spice" Phenomenon. In: The European Monitoring Centre for Drugs and Drug Addiction. Lisbon, Portugal. FindTheBest.com (2014). FAQ for APINACA and AKB48 N-(1-Adamantyl)-1-pentyllHindazole-3-carboxamide. Available at http://controlledsubstances.findthebest.com/l/53/ APINACA-and-AKB48-N-1-Adamantyl-1-pentyl-lHindazole3-carboxamide. Last accessed on October 31, 2014. Gunderson E., Haughey H., Ait-Daoud N., Joshi A., and Hart C. (2012) "Spice" and "K2" herbal highs: A case series atld systematic review ofthe clinical effects and biopsychosocial implications ofsynthetic cannabinoid use in humans. Am. J. Addiction, 21:320-326. Hennanns-Ciausen M., Kneisel S., Szabo B., and Auwarter V. (20 !3) Acutetoxicity due to the confirmed consumption ofsynthetic catmabinoids: Clinical and laboratory findings. Addiction, I08(3):534-44. Jarbe T.U., Deng H., Vadivel S.K., and Makriyannis A. (2011) Cannabinergic aminoalkylindoles, including AM678=JWHOI8 found in "Spice," examined using drug (Delta9- tetrahydrocannabinol) discrimination for rats. BehavPharmacal, 22:498-507. Johnston L.D., O'Malley P.M., Bachman J.G., and Schulenberg J.E. Therise in teen marijuana use stalls, syntheticmarijuana use levels, and use of"bath salts" is very low. University of Michigan News Service: Ann Arbor, MI. Available at http://www.monitoringthefuture.org/pressreleases/12drugpr _complete.pelt; 2012. Last accessed on April 2, 2014. Hudson S., RamseyJ., King L., Timbers S., and Maynard S. (2010) Use ofhigh-reso1ution accurate mass spectrometry to detect reported and previouslyunreported cannabinomimetics in "herbal high" products. Journal of Analytical Toxicology, 34:252-260. 15Huffinan J.W., Yu S., Showalter V., Abood M.E., WileyJ.L., eta!. (1996) Synthesis and phannacology ofa verypotent cannabinoid lacking a phenolichydroxyl with high affinity for the CB2 receptor. J

### Med Cherm, 39(20):3875-7. Marona-Lewicka D. and Nichols D. (July 1998) Drug discrimination studies ofthe interoceptive
cues producedby selective serotonin uptake inhibitors and selective serotonin releasing agents. 

### P.IJ'Chopharmacology, 138(l):67-75. Muller H., Sperling W., Kohnnann K., Huttner H.B., KomhuberJ., et a!. (20I0) The synthetic cannabinoid Spice as a trigger for an acute exacerbation ofcannabis-inducedrecurrent psychotic episodes. 

### Schizophrenia Research, 118:309-310. NIDA Final Study Report NOIDA-13-8908 (HHSN 271201300001). Compound: AKB48. Study: Testofsubstitution for the discriminative stimulus effects ofDelta(9)-THC. Conducted under contract by University ofNo1ih Texas Health Science Center at Fort Worth and NIDA. Report date: June II, 2013. NIDA Final StudyReportNOIDA-7-8872 (HHSN 271200700014C). Compound: AKB48. Study: Time course (8-h) mouse locomotor activity test vs Delta(9)-THC. Conducted under contractbyUniversity ofNorth Texas Health Science Center at Fmi Wmih and NIDA. Report date: June 25, 2013. NIDA Task Order: 12-9177 TDP#AKB48 Cannabinoid, CBI (h) Testing Profile and IC50/Ki Determination. Report date: January 14,2013. NIDA Task Order: 12-9177 TDP#AKB48 Cannabinoid, CBI (h) Agonist Cellular Functional Assay. Report date: January 14, 2013. National Forensic Laboratory Jnfonnation System (NFLJS). (2013) MidyearRepmi. Available at http://www.deadiversion.usdoj.gov/n11is/2013midyear.pdf. Last accessed on October 31, 2014.
Patent (W02003035005) HETEROINDANES: A NEW CLASS OF POTENT CANNABIMIMETIC LIGANDS. Available at http://patentscope.wipo.intlsearch/en/detail.jsf?docld=W02003035005. Last accessed on October 31, 2014. SAMHSA (2012). TheDAWN repmi: Drug-related emergency depat1ment visits involving syntheticcannabinoids (December4, 20!2), Rockville, MD. Available at http://www.samhsa.gov/data/2kl2/DA WNI05/SRl05-synthetic-marijuana.pdf. Last accessed on March 5, 2014. Uchiyama N., Kawamura M., Kikura-Hanajiri R., Goda Y. (2012) Identification oftwo new-type synthetic cannabinoids, N-(1-adamantyl)-1- pentyl-1H-indole-3-carboxamide (APICA) at1d N- (1-adamantyl)-1-pentyl-1 H-indazole- 3-carboxamide (APINACA), and detection offive
16synthetic cannabinoids, AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and AM-1248, as designer dmgs in illegal products. Forensic Toxicology, 30(2): I 14-125. Uchiyama N., Kawamura M., Kikura-Hanajiri R., Goda Y. (2013) URB-754: A new class of designer dmg and 12 synthetic cannabinoids detected in illegal products. Forensic Sci International, 227(1-3): 21-32. Vandrey R., Dunn K., Fry J., Girling E. (2012) A survey studyto characterize use ofspice products (synthetic cannabinoids). DrugA/cholDependence, 120:238-241. Vann R.E., Wamer J.A., Bushell K., Huffinan J.W., Matiin B.R., et al. (2009) Discriminative stimulus propetiies ofdelta-9-tetrahydrocannabinol (THC) in C57BI/6J mice. EurJ Pharmacal, 615: 102-107. Weissman A., Milne G.M., and Melvin Jr., L.S. (I 982) Cannabimimetic activity fi·om CP47,497, a derivative of3-phenylcyclohexanol. The Journal of Pharmacology andExperimental 77terapeutics, 223:516-523. Winstock A. and Barrett M. (2013) Synthetic cannabis: A comparison ofpatterns ofuse and effect profile with natural cannabis in a large global sample. DrugAlcohol Depend, 131:106-111. WHO Expe11 Committee on Drug Dependence 36th Meeting Geneva, 16-20 .Tune 2014. AP1NACA Critical Review Rep01i Agenda item 4.9. Available at http://www.who.int/medicines/areas/quality_safety/4_9 _review.pdf. Last accessed on October 31,2014. Wiley J.L., Huffinan J.W., Balster R.L., and Mm1in, B.R. (1995) Pharmacological specificity of the discriminative stimulus effects ofdelta-9-tetrahydrocannabinol in rhesus monkeys. Drug AlcoholDepend, 40:81-86. Wohlfarth A. and Wolfgang W. (2010) Bioanalysis ofnew designer drugs. Bioana(vsis, 2(5):965-979 Zimmermann U.S., Winkelmann P.R., Pilhatsch M., Nees J.A., Spanagel E., eta!. (2009) Withdrawal phenomena and dependence syndrome after the consumption of"spice gold." DeutschesArzteblattInternational, 106:464-467.

17

# Enclosure 3BASIS FOR THE RECOMMENDATION TO PLACE 1-PENTYL-lH-INDOL-3-YL 2,2,3,3-TETRAMETHYLCYCLOPROPYL METHANONE (UR-144) AND ITS SALTS IN SCHEDULE I OF THE CONTROLLED SUBSTANCES ACT (CSA) I. SUMMARY The Food and Drug Administration (FDA) recommends that (1 -pentyl-lH-indol-3-yl)-(2,2,3,3- tetramethylcyclopropyl)methanone, also known as UR-144, and its salts he placed in Schedule 

### J ofthe Controlled Substances Act (CSA). UR-144 is a synthetic cannabinoid that has recently becomepopular as a recreational mm·ijuana alternative. UR-144, as well as other synthetic cannabinoids, is used as an ingredient or additive in "herbal products" that are marketed overthe-counter as incense as well as mm1y otherproducts (EMCDDA, 2009; NFLIS, 2012). The synthetic cannabinoid products are oftenreferred to as synthetic marijuana, herbal blends, and herbal high products, and are sold under a variety ofnmnes. As discussed in further detail below, UR-144 is not present in every marketed synthetic cannabinoidproduct. Fm' clmity, this document will explicitly refer to UR-144 when discussing synthetic cannabinoids in which UR144 was confirmed as an ingredient, or when discussing case repmis where thereport specificallyindicates thepresence ofUR-144. 

### in vitro and preclinical studies suggest that the phannacological effects ofUR-144 are similar to delta-9 (i\9) -tetrahydrocannabinol (THC, Schedule I) and JWH-0 18 (Schedule 1). These studies, combined with case reports and anecdotal observations in humans, suggest that the subjective effects ofUR-144 are cannabis-like and similar to those ofmarijuana. The Drug Enforcement Administration (DEA) notified the Deparbnent ofHealth and Human Services (HHS) in w1iting ofits intent to temporarilyplace UR-144 into Schedule I ofthe CSA on February 14, 2013. On March 14, 2013, in response to the notification bytl1e DEA, HHS stated that there are no exemptions or approvals in effect for UR-144 under Section 505 ofthe Federal Food, Drug, and Cosmetic Act. On May 16, 2013, the final order tempormilyplacing UR-144 into Schedule 

### I ofthe CSA was published in the 

### Federal Register 

### (78 FR 28735).
In this document, FDA recommends that UR-144 be permanentlyplaced into Schedule I ofthe CSA. II. BACKGROUND Synthetic cannabinoids are new substances ofabuse. Over the past several years, recreational use ofsynthetic cmmabinoid compounds has increased in the United States (Cohen et al., 2012). These compounds are commonly sold at gas stations, convenience stores, and on the Intemet. Synthetic cannabinoids are marketed under a plethora ofnames. Analyses by DEA have detected UR-144 in product samples which are marketed underthe following names: Scooby Snaz; Smokil1 Dragon Potpourri; Puff; Diablo; Liberty Herbal Incense; Darkness; Down2Earth; Kaptain Kush; Luscious Aroma; Madd Hatter; Mary & Jane, Miami Spice; Screamin Demon; Shockwave; AK-47; Caution; You Only Live Once; Demon; Dank; Aloha

...get Lei'd; Zensense; Lava Extra Strength; Pure Sin; K4 Max; Mad Monkey; Zombie Life; Purple Diesel; Sour Diesel; Wanted; Sonic Boom; Tiger Shark; Atomic; INew King Kong; 7H; 7-g Smoking Rasta; Mad Monkey; White Widow; Sonic Boom; Hysteria Black; Black Sabbath; Hayze Hawaiian Ultra; Joker; Mind Trip; Out World; Barely Legal High Octane; Mad Hatter/Cloud 9; Kick Ass; Mr. Nice Guy; Dead Man Walking; Fire Extreme; Black Mamba; Mr. Spice Green; Magic Man; and MaryJanes. On July 9, 2012, 15 synthetic cannabinoids (including CP-47,497, CP-47, 497 C8-homolog, JWH-01 8, JWH-073, and JWH-200) were placed into Schedule I ofthe CSA by Section 1152 of the Food and Drug Adminish·ation Safety and Innovation Act (FDASIA) under TITLE XIOTHER PROVISIONS, SubtitleD-SyntheticDrugs. 1 However, UR-144 was not among those controlled substances. At that time, UR-144 was relatively novel in the synthetic cannabinoid illicit market. It is theorized that following the placement ofthe aforementioned compounds into Schedule I ofthe CSA, further compounds (e.g.UR-144) with cannabinoid receptor activity began to appear in an attempt to evade CSA control. Abbott laboratories first developed UR-144 as a research compound in2006 (Pace, eta!. 2006). UR-144 is a synthetic cannabinoid, classified as a cyclopropylindole. Data from the System to Retrieve Infotmation on Drug Evidence (STRIDE), a DEA database that collects data on samples tested byDEA's Jabs, and the National Forensic Laboratory lnfotmation System (NFLIS), a DEA database that collects infonnation on samples tested bystate and localjurisdictions, indicate that UR-144 was found in samples starting in 2010. Specifically, there were 2,035 STRIDE repmts from January I, 2010, through February 24, 2014, and 7,582 NFLIS repotis fi·om Janumy 2010 through December 2013 involving UR-144. Cunently, UR-144 has no known accepted medical use. 

### It is not the subject ofan approved new drug application (NDA) or an investigational new drug application (IND), and it is not cunently marketed as an approved drug product. In addition, law enforcement and health care practitioners continue to encounter individnals that have abused synthetic cannabinoids, many requiring hospital emergency department (ED) admission. Since the composition ofmanyproducts changes repeatedly over time as areactiott to prohibition and prosecution ofresellers, neither the resellernorthe conswner ofthese

1When FDASIA was enacted, a total ofeight substances were already covered by DEA tempormy scheduling order<: five synthetic ca1U1abinoids (JWH-0 18, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue) and 3 synthetic cathinones (mephedrone, MDPV, and methylene). DEA had also issued a Notice ofProposed Rulemaking (NPRM) on March I, 2012, to place the five synthetic cannabinoids (JWH018, JWH-073, JWH-200, CP-47,497, and CP-47,497 C8 homologue) permanently in Schedule I. [77 FR 12508] With the exception ofmethylone, these compounds were placed in Schedule I by FDAS!A on July 9, 2012. Therefore, it was no longer necessary to finalize the NPRM regarding the five synthetic ca1mabinoids (JWH-018, JWH-073, JWH-200, CP-47,497, and CP-47,497 CS homologue), or to take additional action with respect to 2 ofthe 3 synthetic cathinones (mepbedrone and MDPV). However, DEAhas posted a copy ofthe HHS Scientific and Medical Evaluation and Scheduling Recommendations regarding the five synthetic cannabinoids on www.regulations.gov. These HHS documents canbe found on www.regulations.gov under Docket No.DEA-2012-000I.

2mixtures knows the actual content and amount ofsynthetic cannabinoid inproducts under the labeling guise of"incense" (Dresen et al. 201 0). Case reports, which include UR-144, have demonstrated that herbal products containing synthetic cannabinoids produce signs and symptoms ofphysical dependence and withdrawal. The American Association ofPoison Control Ce:nters2 (AAPCC) repmted 2,639 human exposures to synthetic marijuana (THC homologs) in 2013 (AAPCC, 2013).3 In response, numerous states and other countries have already placed measures ofcontrol on products containing synthetic cannabinoids. Pursuant to 21 U.S.C. 

### § 811, the Secretary is required to considerin the scientific and medical evaluation eight factors with respect to the substance's abuse potential, legitimate medical use, and safety or dependence potential (21 U.S.C. 

### § 812(b)). Administrative responsibilities for evaluating a substance for control under the CSA are perfon:ned for HHS by FDA, with the concuiTence ofthe National Institute on Drug Abuse (NIDAl ((Memorandum ofUnderstanding, 50 FR 9518, 9518-20) (March 8, 1985)). This evaluation discusses the scientific and medical information relative to each ofthe eight factors, presents findings in the three required areas, and makes a recommendation regarding scheduling UR-144 under the CSA. In this document, FDA recommends that UR-144 be controlled in Schedule l under the CSA.
III. EVALUATING UR-144 UNDER THE EIGHT FACTORS This sectionpresents an evaluation ofthe current scientific and medical information about UR144under the eight factors that must be considered pursuant to 21 U.S.C. 

### § 8ll(c). FACTOR 1: Its Actual or Relative Potential for Abuse The first factor the Secretarymust consider is the actual orrelative potential for abuse ofUR144. The term "abuse" is notdefined in the CSA. However, the legislative history ofthe CSA

1 AAPCC collects information Jogged by the country's Poison Control Centers (PCs). Records are fmm selfrepOited calls; therefore, they reflect only infom1ation provided when the public or health care professional reports an actual orpotential exposure to asubstance (e.g. an ingestion, inhalation, or topical exposure), or requests informational materiaL It warrants noting that these

**exposure~** do not inherently represent an instance ofpoisoning or overdose. The AAPCC is not able to completely verify the accuracy ofeveryreport made to member centers. Additional exposures may go unreported to PCs and data referenced from the AAPCC should not be constmed to represent the complete incidence ofnational exposures to any substance. AAPCC indicated that a significant proportion ofthe reports were generated ti·mn hospital emergency departments or enMroute to amedical treatment facility.

3suggests the following points in determining whether a particular drug or substance has a potential for abuse4• Individuals are taking the substancein amounts sufficient to create a hazard to their health orto the safety ofother individuals orto the community. There is significant diversion ofthe drug or substance from legitimate d!'llg channels. Individuals are taking the substance on their own initiativerather than on the basis ofmedical advice from apractitionerlicensed by Jaw to administer such substance. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions fi:om legitimate channels, significant use contrary to orwithout medical advice, or that it has a substantial capability of creating hazards to thehealth ofthe user orto the safety ofthe community. There is no single test or assessment procedure that, byitself, provides a full and complete characterization ofa substance's abuse potential, as this is a complex determination that is multidimensional. When assessing the abuse potential ofa substance, the Secretary considers multiple factors, data sources, and analyses. These factors include the prevalence, fi·equency and manner ofuse in the general public and specific subpopulations; the amount ofmaterial that is available for illicit use; and evidence relevant to populations that may be ofparticularrisk. Animal, human, and epidemiological data are all used in determining a substance's abuse potential. Specifically, a comprehensive evaluation ofthe relative abuse potential ofa substance includes consideration ofthe dn1g's receptor binding af1inity, preclinical pharmacology, reinforcing effects, discdminative stimulus effects, dependence-producingpotential, phannacokinetics and routes ofadministration, toxicities, assessment ofthe clinical efficacy safety database relative to actual abuse, clinical abuse-potential studies, and the publichealth risks following marketing ofthe substance. Epidemiological data can also be an important indicator ofactual abuse. Finally, evidence ofclandestine production and illicit trafficking ofa substance are also important f\wtors. Bdow is a discussion ofthe four indicators ofabuse as they relate to UR-144. 

### A), Individuals are taking the substance in amountssufficientto create a hazardto their health orthe safe(v of other individuals or to the community. The epidemiological and case report data discussed in this section suggest that individuals are taking UR-144 in amounts sufficient to create a hazard to their health or to the safety ofother individuals or to the community. UR-144 can be taken orally or vaporized and inhaled. The effects persist I to 2 hours (high doses 4 hours) after smoking. Common negative effects are anxiety, paranoia, attention disturbance, depression, and hallucinations which maypersist for several days. High doses are described as psychedelic. Overdoses can cause symptoms like tachycardia, nausea, disodentation, dysphoria, blurry vision, inability to communicate, extreme

4 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91 st Cong., Sess. 1 (1970) reprinted in U.S.C.C.A.N. 4566, 4603. 4hallucinations, and loss ofconsciousness (Adamowicz et al., 20 13). From 

### Janumy 2010 through March 2013, DEA repmted that NFLIS 5 and STRIDE6 data for the three synthetic cannabinoids UR-144, XLR11, and AKB48 totaled 16,014 repmted cases. The detection ofthese substances in drug seizures is consistent with DEA findings on the dmg exhibits collected during law enforcement seizures with the Schedule I synthetic cannabinoids JWH and CP. The number and the type ofsynthetic cannabinoids, as an aggregate, have increased exponentially since 2008, as evidenced by the number ofrepmts submitted to the NFLIS. According to the NFLIS, there were 29,467 synthetic cannabinoid dmgreports in 2012, an increase of 1,402 percent from2009 (DEA National Drug Threat Assessment Summary, 2013). NFLIS also reported that 9percent, which is about 5,631 of56,540, ofidentified hallucinogens in 2012 were UR-144 (NFLIS annual repo1t, 2012). The AAPCC repmted approximately 5,200 calls about exposures to synthetic marijuana (THC homologs) in 2012. This number is lower than the number ofcaBs repotted in 2011 (6,968),but it was still significantlyhigher than those reported in 2010 (2,906) (DEA, 2013 National Drug Threat Assessment Summary). Additiona11y, AAPCCjustrecentlyreleased a reported 2,639 human exposures to synthetic marijuana (THC homologs) in 2013 (AAPCC, 2013). 

### B). There is significantdiversion of the drug orsubstance.fi·om legitimate drug channels. Since UR-144 is not an FDA-approved dmg product for treatment in the United States and there appear to be no legitimate sources for UR-144 as a marketed drug, this characteristic ofabuse potential is not applicable. 

### C). Individuals are taking the substance on their own initiative rather than on the basis of medicaladvice.fi·om apractitioner licensed by 

### law to administer such substance. Because UR-144 is not approved for medical use and is not fommlated or available for clinical use, all human self-administration is assumed to be on an individual's own initiative, ratherthan on thebasis ofmedical advice fi·om a practitioner licensed bylaw to administer dmgs. AAPCC reports, literature case reports, law enforcement seizures, and anecdotal internet user experienceposts (e.g., bluelight.org) indicatethat individuals are takingUR-144 on their own initiative, rather than on the medical advice ofa licensed practitioner.

'DEA's NFLIS systet.natically collects results fi·om dntg chemistry analyses conducted by state and local forensic laboratories across the country. As a national <hug forensic laboratory reporting system, NFLIS provides timely and detailed analytical results ofdmgs seized by law enforcement. See http://www.deadiversion.usdoj.gov/nflisl.
'' DEA's STRIDE reflects the results ofdrug evidence analyzed at DEA laboratories nationwide. See the 2012 NFLIS annual report at http://www.deadiversion.usdoj.govlnflis/20 12annual_rpt.pdf. 5D). The substance isso related i11 itsaction to a substance already listed as having a potentia/forabuse to make it likely that itwill haJ'e the samepotentia/forabuse as such substance, thusmakingIt reasonable to assume that there maybe significant diversions.fi·om legitimate channels, significant use contrary to or withoutmedical advice, or that 

### ithasa substantial capabili(Vof creating hazards to the health of the user or to the safety of the community. UR-144 has pharmacological prope1iies similar to other Schedule I cannabinoids, including delta-9-tetrahydrocannabinol (6.9

- THC) and JWH-018 (Weissman et al., 1982; Compton et al., 1992; Wiley et al., 1998; Wiley et al., 2012). Earlier research showed that psychoactive cannabinoids ofvarious structural classes, including tetrahydrocannabinols, bicyclic (e.g., CP-55,940), aminoalkylindoles (e.g., WIN-55,212-2) and other indole- and pyrol-derived cannabinoids (e.g., JWH-018), share a profile of

### in. vitro and in Fivo pharmacological effects. Psychoactive cannabinoids are shown to bind and activate CB1 receptors in vitro {Devane et al., 1988; Griffin et al., 1998). For example, JWH-018 (which, as noted above, is controlled in Schedule I) is a full cannabinoid agonist withhigh affinity for both CB 1and 

### CBz receptor subtypes. In a study examining the relative affinity ofJWH-018 for CB 1and CBzreceptors, JWH-018 displayed slightly greater relative affinity for 

### CBz receptors (Ki = 2.94nM), relative to CB 1receptors (Ki 

## =9.0 nM) (Aung et al., 2000). This resulted in a 

### CBtrCBz bindingratio that is slightly increased for JWH-018 relative to THC (3.06 versus 1.12), though the significance ofthe CB 11CB 2binding ratio cul1'ently is still unknown. Similarly, UR-144 has ahigh affinity for both cannabinoid-1 (CB 1) and cannabinoid-2 (CB2) receptor subtypes. In a study examining the relative affinities, results demonstrated that UR-144 binds with Ki values of28.9nM at CBt and 4.5lnM at 

### CBz (RTI, 2013). Secondly, psychoactive cannabinoids are reported to substitutefor 6.9-tetrahydrocannabinol (6.9

- THC) in a drug discrimination

**procedur~** in rodents (Wiley et al., 1995; Vann et al., 2009). This procedure is used as an animal model ofmarijuana intoxication and when utilized as such is also a highly predictive procedurein identifying compounds that humans label "marijuana-like" (Balster and Prescott, 1992). In drug discrimination studies in rodents trained to discriminate 6.9

- THC, JWH-018 (Schedule 1) produced complete substitution for stimulus effects of6.9-THC with an ED 507 of0.39 mg/kg (N!DA study report, 2011 ). Similarresults were obtained byJarbe and colleagues, who found that JWH-018 fully substituted for the stimulus effects of119-THC in rodents trained to discriminate THC and was eight times more potent than THC (Jm·be eta!, 2011).

7 ED50 (effective dose) is a dose ofa pharmacologic agent which will have a therapeutic effect. ED5 0 in the context ofrodents refers to the effective dose for obtaining the phannacological response. In this study it is the effective dose for dmg discrimination.

6As with other psychoactive cannabinoids (e.g. JWH-01 8, source Jarbe et al., 2011 ), UR-144 was shown to fully substitute the discriminative stimulus effects ofb.9

-THC with an ED5 0 of7.1 J,tmol/kg (RTI, 2013). FACTOR 2: Scientific Evidence ofthe Drug's Pharmacological Effects The second factor the Secretarymust consider is the pharmacological effects ofUR-144. Receptor binding, dmg discrimination, and .locomotor studies with UR-144 havebeen performed (Elksen et al., 2013, RTI, 2013). In mice, UR-144 dose-dependently produced a profile of pharmacological effects characteristic ofCB 1receptor agonists including: suppression of locomotor activity, antinociception, hypothennia, and catalepsy. Consistent with its greater affinity at the CB 1receptor, UR-144 was several-fold more potent than i\9-THC in each test. Furihennore, as previously mentioned, UR-144 fully and dose-dependently substituted for i\9

- THC in mice trained to discriminate i\ 9-THC from 

### a saline vehicle (RTI, 2003). Together, these results suggest that UR-144 is 

### a psychoactive CB 1receptor agonist (RTI, 2013) which is similar to i\9-THC. As for locomotor activity, UR-144 caused time- and dose-dependent depression oflocomotor activity following I0 and 30 mg/kg doses in non-habituated male Swiss-Webster mice. Depressant effects of

### I0 and 30 mg/kg doses occurred within 

### 10 minutes following injection and lasted 60-90 minutes. The 

### JD50 (dose producing l/2 maximal depressant activity, where maximal depression= 0 counts/30 min) was estimated to be 

### 7.8 mg/kg (Elksen et al., 2013). Dmg discrimination expeliments also serve as behavioral studies that assess the interoceptive cues produced by drugs. Animals' subjective responses to a drug are shown bythe way that the animal will behave. 

### In drug discrimination studies, this ability ofthe animals is useful for identifying ifthe test drug is similar to the positive control drug (Lewicki and Nichols, 1998). UR-144 

### CB 1receptor binding assays were perfonned with membranepreparations isolated from a HEK-293 expression system. These transfected cell membrane preparations demonstrated that UR-144 binds to the CB 1receptor with a Ki affinity of28.9 nM and to the CB 2 receptor with a Ki affinity of4.51 nM (RTI, 2013). UR-144 was researched by functional assay, using guanosine triphosphate GTP-y.3 5S). UR-144 stimulated GTP-y-35S turnover through both the hCB1 receptor and the hCB 2 receptor at nM concentrations, which indicates agonism at these G-protein coupled receptor sites. UR-144 was an agonist at both the CB 1receptor (EC5 

### oof98.1nM) and 

### CBz receptor (EC508 of334 nM) (RTI, 2013). UR-144 dmg discrimination experiments were performed on singly housed male C57/BI6J inbred mice, which were aJready trained to discriminate i\ 9-THC from vehicle. Mice were

8 EC50 (halfmaximal effective concentration) refers to the concentration ofad1ug1 antibody, or toxicant which induces a response halfway between the baseline and maximum after aspecified exposure time. 7trained to discriminate 5.6 mg/kg 6 9-THC from vehicle and a 6 9-THC dose-etTect curve was detennined. The 69-THC (positive control) dose-dependently substituted for the training dose, with an ED 50 of5.4 °mol/kg (95% CI: 4.5-6.4 °mollkg). Subsequently, UR-144 fully and dosedependently substituted for 6 9-THC, with an EC5

### oof7.1 °mol/kg (95% Cl: 5.8-8.6 °mol/kg). Full substitution occurred at a dose of5.6 mg/kg, which did not decrease response rates (RT!, 2013). UR-144 tetrad studies were performed in male ICR mice. Each mouse was tested in a battery of four tests, in which cannabinoid agonists produce a characteristicprot1le ofin vivo effects (Ma1iin et 

### a]., 1991): suppression oflocomotor activity, antinociception in tl1e warm water tail withdrawal assay, decreased rectal temperature, and ring immobility. With .6.9

-THC as a positive control, researchers showed that UR-144 exhibited the profile ofcannabinoid effects in the tetrad tests in mice. UR-144 produced dose-dependent suppression ofspontaneous activity, antinociception, hypothermia, and ring immobility. Across the four tests, potencies ranged from 3 to 15 °mol/kg for 69-THC and fi"Om 0.6 to 2.6 °11101/kg for UR-144. UR-144 was 3- and 15-fold more potent than .6.9

-THC. Consistent with their similar CB 1receptorbinding affinities, the two test compounds were relatively equipotent with each other across all tourmeasures. With the exception ofthe effect ofUR-144 on spontaneous activity, one ormore doses ofeach compound significantly affected each measure (p< 0.05, compared to vehicle, the negative control). Although UR-144 showed a trend towards decreased activity, theeffect did not reach statistical significance (RTI, 2013). UR-144 binds to CB1 receptors, with the magnitude ofaffinity dependent upon radioligand. Consistent with the results ofprevious studies with CP-55,940, WIN-55,212-2, and 6 9

-THC (Thomas eta!., 1998), UR-144 exhibited better displacement ofthe CB1 agonist [3H] CP55, 940 than ofthe CB 1receptor antagonist [3H]SR141617A. With [3H]CP55,940 as theradioligand, the affinity ofboth compounds was better than that of.6.9-THC (Ki = 28.9 for UR-144 and Ki = 41nM tor 6 9-THC, as repotied byWileyet a!., 1998). UR-144 also had excellent affinity for the CB 2 receptor, as has been rep01ied for a number ofindole-derived synthetic cannabinoids (Huffinan and Padgett, 2005). Fmihem1ore, UR-144 stimulated GTP-y-35S tumover in CB 1and CB2receptorpreparations, suggesting that they are agonists at each type ofcannabinoidreceptor (RTI, 2003). Phannacologically, UR-144 is a full cannabinoid agonist with no antagonist activity that is described as being more potent than marijuana (Scheduly I) and similar to JWH-018 (Schedule I) (RTJ, 2013). FACTOR 3: The State ofCurrent Scientific Knowledge Regarding the Drug or Other Substance The third factor the Secretary must consider is the state ofCUITent scientific knowledge regarding UR-144. UR-144 is a potent cannabinoid that is reported to be smoked for recreational purposes. UR-144 is phannacologically similar to .6.9-THC, the principal psychoactive chemical in marijuana (Schedule I). The chemical name ofUR-144 is (1-pentyl-IH-indol-3-yl)-(2,2,3,3- tetramethylcyclopropyl)methanone. Altemative abbreviations for this substance include TMCP018, KM-XI, MN- 00I and YX-17 (Adamowicz eta!., 20 13). The molecular fonnula is 8C21H29NO and its molecular weight is 311.5 grams. The Chemical Abstract Services number (CAS#) ofUR-144 is 1199943-44-6. The chemical structure ofUR-144 is unrelated to THC. UR-144 shares structural similarities with JWH-018, the first synthetic cannabinoid detected in 'herbal high' preparations. They both contain a n-pentyl side chain attached to the nitrogen atom ofthe indole moiety, which is connected by the bridging carbonyl group with the second ring. JWH-018 contains a naphthyl ring at this position, while UR-144 has a tetramethylcyclopropyl group (Adamowicz et a!., 2013). Pyrolysis studies showed UR-144 to berelatively unstable. The thennal isomerization ofUR144 in the absence ofair (i.e. GC injector port column) orin the presence ofair (i.e. burning of UR-144 containing products) leads to opening ofthe cyclopropanering and fonnation ofa trimethylbutene product. Hydration ofthe cyclopropyl ring in UR-144 or its trimethylbutene moiety

**res~1lts** in the fonnation ofa group ofunmodifiable compounds. However, the pham1acological and toxicological propetties ofthese compounds are unknown (Kavanagh eta!., 2013). FACTOR 4: History and Current Pattern ofAbuse The fomih factor the Secretary must consider is the history and current pattem ofabuse ofUR144. Many synthetic cannabinoids were developed overthe last 30 years for use as vehicles for investigating the cannabinoid system for research pUJ1JOses (Weissman et al., 1982; Huffman et al., 1996; Huffman et a!., 1999). Recently, these substances were found in retail products available worldwide (Auwatier et al., 2009; EMCDDA, 2009; Lindigkeit eta!., 2009; Dresen et al., 20 10; Hudson eta!., 2010; Uchiyama eta!., 2010;). The first synthetic cannabinoid was found laced on plant material for retail sale in 2008. A commercial laboratory in Franknnt, Gennany, announced that ithad identified JWH-018, one ofseveral cannabinoid agonists originally developed at Clemson University, in samples ofherbal incense from Europe. Researchers hypothesize that the producers buy cannabinoids from laboratories.in China or other counhies that offer inexpensive organic syntheses, dissolve the compounds in a solvent, spray the solution on theplant material, and evaporate the solvent before packaging the herbal mixtures (Piggee, 2009). The first documented appearance ofsynthetic cannabinoids in the United States was discussed in a U.S. Customs and BorderProtection (CBP) announcement in January 2009, which reported a seizure ofherbal incense containing the synthetic cannabinoid HU-210. When CBP officers at the Dayton, Ohio, facility ofan international express courier saw the dried plant material inside a shipment, they performed a field test for thepresence ofTHC, butitwas negative. However, fmiher analysis at the CBP laboratotyin Chicago confirmed the presence ofthe synthetic cannabinoid HU-210. Over a 3-month period, CBP seized over 100 lbs ofHU-210-laced herbal mixtures in five separate shipments (Piggee, 2009). Law enforcement and publichealth officials continue to encounter abuse ofthese substances (Substance Abuse and Mental Health Services Administration (SAMHSA); 

### The Dawn Report, 2012; NFLIS, 2013; STRIDE, 2013). UR-144 was identified as another novel synthetic 9cannabinoid adulterant in the United States in early 2010. As mentioned above, based on data fi·om STRIDE and NFLIS, widespread use ofUR-144 was found in the United States. Specifically, there were 2,035 STRIDE reports fi·om January 1, 2010, through February 24, 2014, and 7,582 NFLIS reports from January 2010 through December 2013 involving UR-144. UR-144 NFLIS Query date 02/25/2014 

### 2010-2013 Total 

### NFLIS Reports= 

### 7582 *Quarters refer to calendar year versus federal government fiscal calendar YEAR TotalReports 2010 I 2011 2 2012 5999 2013 1580

- UR-144 STRIDE Query date 02/25/2014 

### Numba of Reports.fi·om 

### 111/2011-2/24/2014 DATE RANGE [}!I/201

**]~2/24/201** 4 12035 Total Reports

Youth appear to be the primary abusers ofsynthetic cannabinoids and synthetic cannabinoidcontaining products, as demonstrated by Jaw enforcement encounters and reports fi·om hospital emergency departments (ED). 

### TheDAWNReport, which noted that there were approximately 2,300,000 ED visits that involved drug misuse or abuse in 20I0, stated that synthetic cannabinoids were !;pecifically linked to an estimated 11,406 visits (SAMHSA, 

### The 

### Dawn Report, 2012). Seventy-fivepercent ofthe ]I,406 ED visits in 2010 involved synthetic cannabinoid use among patients aged 12 to 29 (SAMHSA, 

### The Dawn Report, 2012). For patients aged 12 to 29, males comprised more than three quarters (78 percent) ofED visits involving synthetic cannabinoids 

### in 2010 (SAMHSA, 

### The 

### Dawn Report, 20!2). As mentioned above, the AAPCC also reported 2,639 human exposures to synthetic marijuana (THC homologs) in2013. Synthetic cannabinoid popularity is attributed to intense psychoactive effects, Jack ofdelectability in routine urine drug tests, and, until they were added to Schedule I ofthe CSA in 2012, lack ofCSA control (Gunderson eta!., 2012; Vandrey eta!., 2012; Winstock and Barrett, 2013). FACTOR 5: The Scope, Duration, and Significance ofAbuse The fifth factor the Secretary must consider is the scope, duration, and significance ofabuse of UR-144. Based on its pharn1acological propetties, it is reasonable to assume that, if uncontrolled, the scope, duration, and significance ofUR-144 abuse could be similar to marijuana. Because UR-144 is often packaged as an "herbal blend" with multiple ingredients, including other synthetic cannabinoid agonists, the scope, duration, and significance ofabuse is difficult to disaggregate. However, the available data strongly suggests that UR-144 has a pharmacological 10mechanism ofaction and that it will produce pharmacological and subjective effects similar to delta-9 (I\9) --tetrahydrocannabinol (Schedule I) and JWH-018 (Schedule I). NFLIS laboratories identified 62,540 hallucinogens in 2012, representing 4percent ofall drug reports. Ninepercent ofthese hallucinogen reports were attributed to UR-144 (2012 NFLIS annual report). The use ofUR-144 recreational!yis repotied anecdotally byusers posting on intemet drug sites such as bluelight.org (http://www.hluelight.org/vh/threads/6194 21-MEGA-SyntheticCannahinoid-Discussion-Take-4/page2?highlight=ur-144). This website documents auserreported experience with UR-144 as "when] used UR-144 like 5grams a week I wouldgo into horrible withdrawal, projectile vomiting, etc." FACTOR 6: What, IfAny, Risk There Is to the Public Health The sixth factor the Secretarymust consider is the risk UR-144 poses to the public health. Based solely on its phannaco!ogical similarityto THC and its potency, the subjective risks to the public health ofUR-144 are similar to that ofother cannabinoids, i.e., similarto that ofmarijuana and THC, which are controlled in Schedule I ofthe CSA. Detailed product analyses describe variations in the amount ofsynthetic cannabinoid laced on the plant material even within samplings ofthe same product (Hudson et al., 2010). These unknowns pose a substantial risk of ha:nn to

**S)~1thetic** cannabinoid-abusing individuals (Auwarter et al., 2009; Hudson et al., 2010). Patients presenting to EDs as a result ofsynthetic cannabinoid use routinely exhibit the.following symptoms: vomiting, anxiety, agitation, initability, seizures, hallucinations, tachycardia, elevated blood pressure, and loss ofconsciousness (Harris and Brown, 2013; Hennami.s-Ciausen et al., 2013; Forrester et al., 2011; Cohen et al., 2012). Additionally, consumption ofsynthetic cannabinoids can lead to impai1ment similar to typical performance deficits caused bycannabis use, which are not compatible with safe driving. These deficits include sedating effects and impairment offine motor skills necessary for safely driving a vehicle. UR-144 was detected in product combinations containing other synthtJtic canuabinoids. Several repo1is ofclinical symptoms and intoxication signs were published during the last few years. Unfortunately, a majority ofthese reports lacked any analytical data for synthetic cannabinoids in bodily fluids. The following paragraph presents a case rep01t ofdriving under the influence of synthetic cannabinoids, including UR-144: "A 22-year-old male on a motorbike was about to bechecked at a general road traffic control. Firstly, he escaped by car overrunning several red traffic lights, later he skedaddled by foot.". Duringhis anest, the police noted: 'retarded movement sequence, apathetic, nervous, inert, and delayed reaction ofpupils to light.' Onehour and 35 min later, while taking ablood sample, the physician recorded no abnonnalities. Toxicological results: AM-2201 <0.1 ng/ml JWH-0 18 1.9 ng/ml JWH-122 28 ng/ml JWH-21 0 2.5 ng/ml 11JWH-307 <0.1 ng/ml MAM-2201 <0.1 ng/ml UR-144 <0, 1nghnl" (Musshoffet al., 2013.) The use ofUR-144 in relation to safety and mortality risks was recently described by the Centers for Disease Control (CDC, 2013). In March 2012, theWyoming Depmtment ofHealth was notified about three patients hospitalized for unexplained acute kidney injury (AKJ), all ofwhom repmied recent use ofsynthetic cannabinoids, sometimes referred to as "synthetic marijuana (CDC, 2013)." After the Wyoming Department ofHealth launched an investigation, a total of 16 cases ofacnte AKI after synthetic cannabinoid use were repo1ied in six states. Toxicological analysis ofproduct samples and clinical specimens identified UR-144 in one offive available product samples m1d one ofsix available patients' clinical specimens (CDC, 2013). In case 11, ti'Om Kansas, analysis ofthe implicated product "Mr. Happy" and serum specimen revealed the presence ofXLRII and UR-144; a urine specimen contained the N-pentanoic acid metabolite of XLR11, The case 11 patient's chiefsymptoms at presentation were nausea and vomiting, abdominal pain, and back pain. Renal ultrasound results showed increased cmtical echogenicity. CDC has recommended that publichealth practitioners, poison center staffmembers, and clinicians be aware ofthe potential for renal or other unusual toxicities in users ofthese products and should ask about their use in cases ofunexplained AKI (CDC, 2013). Management of suspected toxicity due to synthetic cannabinoids is syn1ptomatic and supportive treatment as no antidote exists. Resem·chers also expressed concem regarding a possible serotonin syndrome related to synthetic cannabinoids ofthe indole structural class, due to tl1e similarity to serotonin (Wells and Ott, 2011). Symptoms ofserotonin syndrome include shivering, dial1'hea, muscle rigidity, fever, and seizures. Serotonin syndrome is a potentially life-threatening drug reaction that may occur following therapeutic drug use, inadvertent drug interactions, drug overdose, orrecreational drug use. FACTOR 7: The Drug's Psychic or Physiologic Dependence Liability The seventh factor the Secretarymust consideris UR-144'spsychic orphysiologic dependence liability. The pharmacologic profile ofUR-144 strongly suggests that it possesses a physiological and psychological dependence liability that is similarto that ofdelta-9 (1:!.9)

- tetrahydrocannabinol (Schedule I) and JWH-018 (Schedule I). Caserepmis demonstrate that herbal products containing synthetic cannabinoids produce physical dependence and a withdrawal syndrome. There is onepublished casereport of tolerance and withdrawal phenomenain the literature (Zimmennann et al., 2009) and another of 'hug-induced psychosis (Muller et al., 2010). Both these cases were attributed to "Spice," which at the time contained the Schedule 1synthetic cmmabimimetics JWH-018 aJJd CP 47,497. Also, as previously mentioned in FACTOR 5, a drug user forum description of"horrible withdrawal, projectile vomi!ing, etc." was described in a post attributing dependence symptoms to UR-144.
12FACTOR 8: Whether the Substance Is an Immediate Precursor ofa SubstanceThatIs Already Controlled UR-144 is not an immediateprecursor ofany controlled substance. RECOMMENDATION After consideration ofthe eight factors determinative ofa substance (21 U.S.C. 

### § 811 (c)), FDA recommends that UR,l44 be placed in Schedule I ofthe CSA (21 U.S.C. 

### § 812(b)(l)). NIDA concurs with this recommendation. UR-144 produces effects similar to those ofJWH-0 18, which is controlled in Schedule I ofthe CSA. The necessary criteria for placing a substance into Schedule I ofthe CSA are set forth in 21 U.S.C. 

### § 812(b)(1), as follows: 

### A) The drug or othersubstance has ahighpotential for abuse. UR-144 is a synthetic substance that produces cannabinoid-like effects. Thephannacological similarity ofUR-144 to tY-THC makes it reasonable to assume that its potential for abuse is high and would be similar to that ofJWH-018, which is controlled in Schedule I ofthe CSA. 

### B) The drug or othersubstance has 110 

### currently acceptedmedical use in treatment in the UnitedStates. There are no approved NDAs for UR-144 in the United States. There is no known therapeutic application for UR-144. Therefore, UR-144 has no currently accepted medical use in the United States. 

### C) There is a lack of accepted

**safe~v.for** 

### use of the drug or othersubstance undermedical supervision. Since UR-144 has no approved medical use and has not been thoroughly investigated as a new dmg, its safety for use under medical supervision is undetennined. In addition, adverse consequences thought to berelated to abuse ofUR-144 are documented in casereports. Thus, there is a lack ofaccepted safety for use ofthis substance under medical supervision.
FDA therefore recommends that UR-144 and its salts be controlled in Schedule I ofthe CSA.

13References: Adamowicz, P., Zuba, D., and Sekula, K. (2013) Analysis ofUR-144 and its pyrolysis product in blood and their metabolites in urine. Forensic Science Internationa/.233:320-327. Aung, M.M., Griffin, G., Huffinan, J.W., Wu, M., Keel, C. eta!. (2000) Influence ofthe N-1 alkyl chain length ofcannabimimetic indoles upon CB(J) and CB(2) receptorbinding. Drug AlcoholDepend. 60:133-140. Auwarter, V., Dresen, S., Weinmann, W., Muller,.M., Putz, M. et al.(2009) 'Spice' and other herbal blends: Hannless incense or cannabinoid designer drugs? Journal of Mass Spec:tromell:Ji. 44:832-837. Balster, R.L. and Prescott, W.R. (1992) 1:;.9-Tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication.

### Neurosci BiobehavRev. 16:55-62. Bluelight. [MEGA] Synthetic Cannabinoid Discussion- Take 4. Available at http://www.bluelight.org/vb/threads/61942J-MEGA-Synthetic-Cannabinoid-Discussion-Take**4/page2?highlight~ur-144.** Accessed 2/26/2014. American Association ofPoison Control Centers. Synthetic Marijuana Data, December 31, 2013. Available at https://aapcc.s3.amazonaws.com/files/library/Synthetic Marijuana Web Data through 12.2013 .pdf. Last accessed on Febmary 5, 2014. Centers for Disease Control and Prevention (CDC). Acute Kidney Injury Associated with Synthetic Cannabinoid Use- Multiple States, 2012. Morbidity and MmialityWeekly Repmt (MMWR). February 15, 2013; 62(6). Cohen, J., Morrison,S., Greenberg,J., Saidinejad,M.(2012) Clinical presentationof intoxication due to synthetic cannabinoids. Pediatrics.4:129. Compton, D.R., Johnson, M.R.,Melvin, L.S., and Martin,B.R. (1992) Pharmacological profile of a series ofbicyclic cannabinoid analogs:classification as cannabimimetic agents. Journal c!f'Pharmacology and Experimental111erapeutics, 260(1):201-209. Dmg Enforcement Administration, National Drug ThreatAssessment Summary. (November 2013) Documentprepared prepared by the DEA's Office oflntelligence Waming, Plans and Programs. Available at http://www.justice.gov/dea/resource-center/DIR-017- 13%20NDTA%20Summary%20final.pdf. Last accessed February24,2014. Devane, W.A., Dysarz, F.A., Johnson, M.R., Melvin, L.S., and Howlett, A.C. (1988) Detennination and characterization ofa cannabinoid receptor in rat brain. Mol 

### Pharmacol. 34:605-613. 14Dresen, S., Fen·eiros, N., Putz, M., Westphal, F., Zimmen11ann, R. eta!. (2010) Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. Journal of Mass SpectromellJ'. 4S:ll86-1194. Elsken, C.S.,Flores, E.,and Forster, M.J.(2013) Time course (8-h) mouse locomotoractivity test vs delta(9)-THC time course: UR-144.NIDA Contract NOI DA-7-8872. European Monitoring Centre for Drugs and Dmg Addiction (EMCDDA). Understanding the 'Spice' Phenomenon. In: The European MonitoringCentre for Drugs and Drug Addiction Lisbon, Portugal, 2009. Food and DrugAdministration Safety and Innovation Act, Public Law No. 112-144, 126 Stat. 993 (July 9, 2012). Available athttp://www.gpo.gov/fdsys/pkg/BILLS112s3187enr/pdf/BILLS-112s3187enr.pdf. Last accessed on March 5, 2014. Fergusson, D.M., Poulton, R., Smith, P.F., and Boden, J.M.(2006) Cannabis and psychosis. BMJ. 332: 172-175. Fon·ester, M.B., Kleinschmidt, K., Schwarz, E., and Young, A.(2011) Synthetic cannabinoid exposures reported to Texaspoison centers. JAddict Dis., 30(4):351-8. Griffin, G., Atkinson, P.J., Showalter, V.M., Mmtin, B.R., and Abood, M.E. (1998) Evaluation ofcannabinoid receptor agonists and antagonists using the guanosine-5'-0-(3-[35S)thio)- triphosphate binding assay.i11 rat cerebellar membranes. J Pharmacal bxp Ther. 285:553-560. Griffiths,P., Sedefov, R., Gallegos, A.,and Lopez, 0.(2010) How globalization and market innovation challenge how we think about and respond to drug use: 'Spice' a case study. Addiction. I05:951-953. Gunderson E., Haughey H., Ait-Daoud N., Joshi A., Hart C.(2012). "Spice" and "K2''herbal highs: a case series and systematic review ofthe clinical effects and biopsychosocial implications ofsynthetic cannabinoid usein humans. Am. J. Addict. 21:320-326. Harris C.R. and Brown, A.(20 13) Synthetic cannabinoid intoxication: a case series and review EmergMed. 44(2):360-6. Hermanns-Ciausen, M., Kneisel, S., Szabo, B.,Auwarter, V. (2013) Acute toxicity due to the confirmed consumption ofsynthetic cannabinoids: clinical and laboratory findings.Addiction.l 08(3):534-44. Hudson, S., Ramsey, J., King, L., Timbers, S.,andMaynard, S.(2010) Use ofhigh-resolution accurate mass spectrometry to detect repo1ied and previously umeported cannabinomimetics in "herbalhigh" products. Journal ofanalytical toxicology.34:252-260. Huffinan, J.W. and Padgett, L.W.(2005) Recent developments in the medicinal chemistry of cannabimimeticindoles, pynoles and indenes. Curr Med Chem. 12: 1395-1411. 15

### Huffinan, J.W.,Yu, S., Showalter,V.,Abood, M.E.,Wiley, 

### J.L., ttal.,(1996) Synthesis and pharmacology of a very potent cannabinoid lacking 

### aphenolic hydroxyl with high affinity for the 

### CB2 receptor. 

### JMed Chcrm. 39(20):3875-7. Huffman, 

### J.W., Liddle, 

### J., Yu, S.,Aung, M.M, Abood, M.E., eta

### 1. (1999) 3-(l',1 '- Dimethylbutyl)-1- deoxy-delta8-THC and related compounds: synthesis of selective ligands for the 

### CB2 receptor. Bioorg Med Cherm. 

### 7(12):2905-14. Jarbe, T.U., Deng, 

### H., Vadivel, S.K., and Makriyannis, A. 

### (2011) Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (Delta9-tetrahydrocannabinol) discrimination for rats. Behav Pharmacal. 

### 22:498-507. Lindigkeit, R., Boehme, A., Eiserloh, I.,Luebbecke, M., and Wiggem1ann, M., et al. (2009) Spice: 

### a never ending story? Forensic sciel!ce international. 

### 1.91:58-63. Marona-Lewicki, D., and Nichols, D.E. (1998) Dmg discrimination studies ofthe interoceptive cues produced by selective serotonin uptake inhibitors and selective serotonin releasing agents. Psychopharmacology.l38:67-75. 

### Moore, T.H., Zammit, S., Lingford-Hughes, A., Bames, T.R., Jones, P.B., et al. (2007) Cannabis use and risk ofpsychotic oraffective mental health outcomes: a systematic review. Lancet. 

### 370:319-328. Morgan, C.J. and CmTan, H.V. (2008) Effects ofcannabidiol on schizophrenia-like symptoms in people who use cannabis. 

### Br. J. P.1ychiat1y. 

### 192:306-307. Muller, H., Sperling,W., Kohnnann, K., Huttner, H.B., Kornhuber, J.etaL(2010) The synthetic cannabinoid Spice as a trigger for an acute exacerbation ofcannabis-induced recurrent psychotic episodes. Schizophrenia research. 

### 118:309-310. Muller-Vahl, 

### J<.R. and Emrich, H.M. (2008) Cannabis and schizophrenia: towards a cannabinoid hypothesis ofschizophrenia. Expert

### Rev Neurother. 

### 8:1037-1048. Musshoff: F.,Madea, B.,Kernbach-Wighton, 

### G.,Bicker, W.,Kneisel,Hutter, S., eta!. (2013) Driving under the influence ofsynthetic cannabinoids ("Spice"): acase series. lnt JLegal 

### Med.Epub: May 1,2013. National Institute ofDrugAbuse (NIDA). (2011) 1-pentyl-3-(1-naphthoyl)indo1e (JWH-0 18) Test ofSubstitution for the Discriminative Stimulus Effects ofDelta(9)- THC. National Forensic Laboratory lnfmmation System (NFLJS) (2012) Annual Report. Available at http://www.deadiversion.usdoj.gov/nflis/2012annual_rpt.pdf. Last accessed on March 5, 2014.

16Pace, J.M., Tietje, K., Da1i, M.J., Meyer, M.D. (June 29, 2006) "3-Cycloalkylcarbonyl indoles as cannabinoid receptor ligands",.

### AbbottLaboratories (Europeanpatient office. Available at http://worldwide.espacenet.com/publicationDetaiIs/biblio'ICC=WO&NR=2006069196&KC=&F T=E&locale=en_EP. Accessed 3/5/2014. Piggee,

### C. (2009) Investigating a not-so-natural high. 

### Anal Chem. 81 (9):3205-7. 

### RT! Intei11ational (2013). In Vitro and In Vivo Abuse Liability Testing of (1-(5- tluoropentyi)-1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone and (I-pentyi1H-indol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone. RTI Technical Report. RTI Project No. 0213753. Sponsored by 

### United States Drug Enforcement Administration. SAMHSA(2012). TheDA WN Report: Dmg-related emergency depa1imentvisits involving synthetic cannabinoids (December 4, 2012), Rockville,MD. Available at http://www.samhsa.gov/data/2k12/DAWN1 05/SR 1 05-synthetic-marijuana.pdf" Last accessed on March 5, 2014. Thomas, B.F., Gilliam, A.F., Burch, D.F., Roche, M.J., and Seltzman, H.H. (1998) Comparative receptorbinding analyses ofcannabinoid agonists and antagonists. 

### JPharmacolExp Ther. 285: 285-292. Uchiyama,N., Kikura-Hanajiri, R., Ogata, J.,and Goda, Y. (2010) Chemical analysis ofsynthetic cannabinoids as designer drugs in herbal products. 

### Forensic science international. 198:31- 38. Vandrey,R., Dunn, K., Fry, J., Girling, E. (2012) A survey study to characterize use ofspice prodncts (synthetic cannabinoids). 

### DrugAlcholDependence. 120:238-241. Vann, R.E., Wamer, J.A., Bushell, K., Huffman, J.W., Martin, B.R., eta!. (2009) Discriminative stimulus propeliies ofdelta-9-tetrahydrocannabinol (THC) in C57Bl/6J mice. 

### EurJPharmacal. 615: 102-107. Vardakou, 

### !., Pistos, 

### C., and Spiliopoulou, C. (2010) Spice drugs as anew trend: mode of action, identification and legislation. 

### Toxicology letters. 197:157-162. Weissman, A., Milne, G.M., and Melvin,Jr.,L.S. (1982) Cannabimimetic activity fi·om CP47,497,a derivative of

### 3- phenylcyclohexanol. 

### The Journal (!(pharmacology and experimental therapeutics. 223:516-523. Wells, D.L. and Ott, C.A. (2011) The "new" marijuana.771e

### Annals ofpharmacotherapy. 45:414-417. Wiley, J.L., Huffman, J.W., Balster, R.L., and Martin, B.R. (1995) Pharmacological specificity ofthe discriminative stimulus effects ofdelta-9-tetrahydrocannabinol 

### in rhesus monkeys. 

### Drug Alcohol Depend. 40: 81-86. 17

### Wiley,J.L., Compton, D.R., Dai, D., Lainton, J.A., Phillips, M., eta!. (1998) Structure-activity relationships ofindole- and pyrrole-derived cannabinoids. The Journal of pharmacology 

### and experimental therapeutics. 285:995-!004. Wiley, J.L.,Marusich, J.A., Martin, B.R.,and Huftlnan, J.W. (2012), 1-Pentyl-3- phenylacetylindoles and JWH-018 share in vivo cannabinoid profiles in mice. DrugAlcohol Depend. 123:148-153. Winstock, A., BmTett, M. (2013). Synthetic cannabis: a comparison ofpattems ofuse and effect profile with natural cannabis in a large global sample. DrugAlcoholDepend. 131:106-111 Zimmermann, U.S., Winkelmann, P.R., Pilhatsch, M., Nees, J.A., Spanagel, R., et al. (2009) Withdrawalphenomena m1d dependence syndrome after the consumption of "spice gold". Deutsche.\'Arzteblatt international. 106:464-467.

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