DEPARTMENT OF HEALTH & HUMAN SERVICES 

The Honorable Thomas M. Harrigan 

Deputy Administrator 

Drug Enforcement Administration 

U.S. Department of Justice 

8701 Morrissette Drive 

Springfield, VA 22152 

Dear Mr. Harrigan: 

Office of the Secretary 

Office of the Assistant Secretary for 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 of Health and Human Services is recommending that the 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 and XLR11], and N-(1-adamantyl)-1-pentyl-lH-indazole-3-carboxamide (street names: 

APINACA and AKB48] and their salts be added to Schedule I of the CSA. UR-144, XLRll, 

and AKB48 are synthetic cannabinoids that have recently become popular as recreational 

marijuana alternatives. 

UR-144, XLRll, and AKB48, as well as other synthetic cannabinoids are used as ingredients or 

additives in "herbal products" that are marketed globally via the Internet 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 of names, such as "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 similar to delta-9 (1::,9

)-

tetrahydrocannabinol (THC, Schedule I) and 1-pentyl-3-(1-naphthoyl)indole (JWH-018, 

Schedule I). These studies, combined with case reports and anecdotal observations in humans, 

suggest the subjective effects of UR -144, XLR 11, and AKB48 are cannabis-like and similar to 

those elicited by marijuana. 

UR-144, XLR11 , and AKB48 have no known accepted medical use. These substances are not 

the subjects of any approved new drug applications (NDAs) or investigational new drug 

applications (INDs), and they are not currently marketed 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. After reviewing the available 

information, the agencies conclude that UR-144, XLR11, and AKB48, and their salts should be 

controlled in Schedule I of the CSA. Enclosed are the documents prepared by FDA's Controlled 

Substance Staff that are the bases for the recommendations. 

U.S. Public Health Service 
Page 2 - The Honorable 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 FOR THE RECOMMENDATION TO PLACE 1-(5-FLUORO-PENTYL)-lHINDOL-3-YL 2,2,3,3-TETRAMETHYLCYCLOPROPYL ME THAN ONE (XLRll) AND 

ITS SALTS IN SCHEDULE I OF THE CONTROLLED SUBSTANCES ACT 

I. SUMMARY 

The Food and Dmg Administration (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 be placed into 

Schedule I of the Controlled Substances Act (CSA). XLRll is a synthetic cannabinoid that has 

recently become popular as a recreational 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 synthetic marijuana, herbal blends, 

and herbal high products, and a!'e sold under a variety of names. As discussed in further detail 

below, XLRll is not present in every marketed synthetic cannabinoid product. 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 

specifically indicates 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 of marijuana. 

The Drug Enforcement Administration (DBA) notified the Department of Health and Human 

Services (HHS) in writing of its intent to temporarily place XLRll into Schedule I of the 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 XLR 11 under Section 505 of the 

Federal Food, Dmg, and Cosmetic Act. On May 16,2013, the final ordertemporatilyplacing 

XLR11 into Schedule I ofthe CSA was published in the Fedmtl Register (78 FR 28735). 

In this document, FDA recommends that XLRll be pem1anently placed into Schedule I of the 

CSA. 

II. BACKGROUND 

Synthetic cannabinoids are relatively new substances of abuse. Over the past several years, 

recreational use of synthetic cannabinoid substances has increased in the United States (Cohen et 

al., 2012). Synthetic cannabinoids are marketed under a plethora of names. These compounds 

commonly are sold at gas stations, convenience stores, and on the Intemet. Analyses by DBA 

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; Sky Pilot; Blue Kush; Black Venom; Mary & Jane; Miami 

1 
Spice; Screamin Demon; Shockwave; Hammer Head; Platinum; Caution; You Only Live Once; 

Demon; Dank; Aloha ... get Lei'd; NOLA Diamond Potpouni; Relaxinol; Sonic Zero; 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; Bloody Mary 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 placed into Schedule I of the CSA by Section 

1152 of the Food and Drug Administration Safety and Innovation Act (FDASIA) under 

TITLE XI-OTHER PROVISIONS, SubtitleD-Synthetic Drugs. 1 However, XLR 11 

was not among those controlled substances. It is theorized that following the placement of 

the aforementioned cannabinoids into Schedule I of the CSA via FDASIA, additional 

substances (e.g., XLR II) with cannabinoid receptor agonist activity appeared, likely in an 

attempt to evade CSA control. 

XLR 11 is a synthetic cannahinoid classified as a cyclopropylindole. XLR II 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. 

1 When FDASIA was enacted, a total of eight substances were already covered by DEA 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 

a Notice of Proposed 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) pennanently in Schedule I (77 FR 12508). 

With the exception ofmethylone, these compounds were specifically placed in Schedule I by 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 of the three syntl1etic cathinones (mephedrone and MDPV). However, 

DEA has posted a copy of the HHS Scientific and Medical Evaluation and Scheduling Recommendations 

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. 

2 DEA 's STRJDE reflects the results of drug evidence analyzed at DEA 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 of drugs seized by Jaw enforcement. See http://www.deadiversion.usdoj.gov/nflisl 

2 
XLR 11 has no known accepted medical use. It is not the subject of an approved new drug 

application (NDA) or an investigational new drug application (IND), and it is 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 of many products changes over time as a reaction to prohibition and 

prosecution ofresellers, neither the reseller nor the consumer of these mixtures knows the actual 

content and amount of synthetic cannabinoids in products under the labeling guise of "incense" 

(Dresen et al., 201 0). The American Association of Poison Control Centers (AAPCC)4 repmied 

2,639 human exposures to synthetic marijuana (THC homologs) in 2013 (AAPCC, 2013). In 

response, numerous states and other countries have already placed measures of control 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, or removal of a substance from the 

schedules of the CSA. The eight factors are: 

l. The drug's actual or relative potential for abuse; 

2. Scientific evidence of the drug's phannacological effects; 

3. The state of current scientific knowledge regarding the drug or other substance; 

4. Its history and cunent pattem of abuse; 

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

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

7. Its psychic or physiologic dependence liability; and 

8. Whether the substance is an immediate precursor of a substance already controlled. 

Following consideration of the 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 or dependence potential (21 

u.s.c. § 812(b)). 

Administrative responsibilities for evaluating a substance for control under the CSA are 

performed for HHS by FDA, with the concunence of the 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 or health care professional 

reports an actual or potential exposure to a substance (e.g. an ingestion, inhalation) or topical exposure), or 

request~ informational material. It warrants noting that these exposures do not inherently represent an 

instance of poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report 

made to member centers. Additional exposures may go unreported to PCs and data referenced from the 

AAPCC should not be construed to represent the complete incidence of national exposures to any substance. 

The AAPCC indicated that a significant proportion of the reports were generated from hospital emergency 

department!> or en-route to a medical treatment facility. 

3 
This evaluation discusses the scientific and medical infonnation relative to each of the 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 of the current scientific and medical knowledge about 

XLRI I under the eight factors that must be considered pursuant to 21 U.S.C. § 811 (c). 

FACTOR 1; Its Actual or Relative Potential for Abuse 

The first factor the Secretary must consider is the actual or relative potential for abuse ofXLR 11. 

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 or to the safety of other individuals or to the community. 

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

c. Individuals are taking the substance on their own initiative rather than on the basis of 

medical advice from a practitioner licensed by law to administer such 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 from legitimate channels, significant use contrary to or without medical 

advice, or that it has a substantial capability of creating hazards to tl1e health of the 

user or to the safety of the community. 

There is no single test or assessment procedure that, by itself, provides a full and complete 

characterization of a substance's abuse potential, as this is a complex deteimination that is multidimensional. When assessing the abuse potential of a substance, the Secretary considers 

multiple factors, data sources, and analyses. These factors include the prevalence, frequency, 

and manner of use in the general public and specific subpopulations; the amount of material that 

is available for illicit use; and evidence relevant to populations that may be at particular risk. 

Animal, human, and epidemiological data are all used in determining a substance's abuse 

potential. Specifically, a comprehensive evaluation of the relative abuse potential of a substance 

includes consideration of the drug's receptor binding affinity, preclinical pharmacology, 

reinforcing effects, discriminative stimulus etiects, dependence-producing potential, 

pharmacokinetics and routes of administration, toxicities, assessment of the clinical efficacy 

safety database relative to actual abuse, clinical abuse-potential studies, and the public health 

'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. 

4 
risks following marketing of the substance. Epidemiological data can also be an important 

indicator of actual abuse. Finally, evidence of clandestine production and illicit trafficking of a 

substance are also impmiant factors. Below is a discussion of the four indicators of abuse as 

they relate to XLRJI. 

A). Individuals are taking the substance bt amounts Sl(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 their health or to the safety of other 

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 of Health 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 of synthetic cannabinoids produces psychoactive effects similar to those of cannabis; 

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 of use. 

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 male hit a 

lawfully stopped vehicle in traffic. Law enforcement officers noted that the man had a blank 

stare, mellow speech, and a barely audible. voice. Medical personnel described the man's 

symptoms as follows: hypothermia, rigid muscle tone, lack of horizontal gaze nystagmus, lack 

of vertical gaze nystagmus, non-convergence of eyes, a11d dilated pupil size. The driver stated 

that he had previously nsed "bluebeny spice" but could not state when. Toxicology results 

revealed that XLR 11, at a concentration of 1.34ng/ml, was the only identified substance in the 

driver's blood (San Frm1cisco Office of Chief Medical Examiner, 2013). 

From January 2010 through March 2013, DEA rep01ied thatNFLIS and STRIDE data for the 

three synthetic cannabinoids UR-144, XLRll, and AKB48 reached a total of16,014 cases. The 

detection of these 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 of synthetic cannabinoids, reported as an aggregate, increased since 2008, 

as evidenced by the number of reports 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 Drug Threat Assessment Summary). NFLIS laboratories identified 62,540 

hallucinogens in 2012, representing 4 percent of all dmg reports. Almost 13 percent (8,097) of 

these hallucinogens were identified as XLR11 (2012 NFLIS annual report). 

5 
The AAPCC reported approximately 5,200 calls about exposures to synthetic marijuana (THC 

homologs) in 2012. This number is lower than the nmpber of calls 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 significant diversion of the drug or substance ji·omlegitimate drug 

channel~~ 

Since XLR I I is not an FDA-approved drug product for treatment in the United States and there 

appear to be no legitimate sources for XLR II as a marketed drug, this characteristic of abuse 

potential is not applicable. 

C). Individuals are taktitg the substance 011 their own i11itiative rather than 011 the bas1:1· 

of medical advice fi'om a practitioner licensed by law to administer such substances. 

Because XLR!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 of medical 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 of a licensed practitioner. 

D). The substance is so related in its action to a sub51ance 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 thatthere may be sign(ficant 

diversions from legitimate chanitels, sign(ficaJtt use contrary to or Without medical 

advice, or that it has a substantial capability of creating hazards to the health of the 

user or to the safety of the community. 

In vitro and in vivo pham1acology data for XLR 11 is similar to other Schedule I cannabinoids. 

Research studies show that psychoactive cannabinoids of various structural classes, including 

tetrahydrocannabinols (such as .6.9

-THC), bicyclic cannabinoid analog (e.g., CP55,940), 

aminoalkylindoles (e.g., WIN 55, 212-2), and other indole- and pyrol-derived cannabinoids (e.g., 

JWH-018 Schedule 1), share a common phannacological profile of effects. 

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 of JWH-018 

for CB1 and CB2 receptors, JWH-018 displayed slightly greater relative affinity for CB2 

receptors (Ki ~ 2.94 nM) relative to CB1 receptors (Ki ~ 9.0 nM) (Aung et al., 2000). This 

resulted in a CB11CB2 binding ratio that is slightly increased for JWH-018 relative to THC (3.06 

versus J.l2), though the significance of the CB11CB2 binding ratio is unknown. Similarly, 

XLRll has a high affinity for both CB1 and CBz receptor subtypes. In a study exalnining the 

6 
relative affinities, results demonstrated that XLRll binds with K; values of24.2 nM at CB1 and 

2.13 nM at CB2 (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 of marijuana 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, .TWH0 18 (Schedule I) produced complete substitution for stimulus effects of 6 9

-THC with an ED50

6 of 

0.39 mglkg (NJDA study report, 2011). Similar results were obtained by Jarbe and colleagues, 

who found that JWH-018 fully substituted for the stimulus effects of 1',9

-THC in rodents trained 

to discriminate 1',9 -THC; fmiher, JWH-0 18 was found to be eight times more potent than t,9 -

THC (.T arbe eta!., 2011 ). Similarly, as with other psychoactive cannabinoids (e.g., JWH-0 18; 

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 of in vivo tests in 

mice, including suppression oflocomotor activity, antinociception, hypothennia, and catalepsy 

(Mmiin eta!., 1991 ). XLR 11 was found to be more potent than 1',9

-THC acro·ss the tetrad 

measures (RTJ, 2013). 

FACTOR 2: Scientific Evidence of the Drug's Pharmacological Effects 

The second factor the Secretary must consider is the phannacological effects ofXLR 11. Elsken 

eta!. (2013) and RTI (2013) performed receptor binding, dmg discrimination, and. locomotor 

studies with XLRI 1. In mice, XLR11 dose-dependently produced a profile ofphamJacological 

effects characteristic ofCB1 agonists including suppression of locomotor activity, 

antinociception, hypothermia, m1d catalepsy. Consistent with its greater affinity at the CB 1 

receptor, XLR11 was more potent than 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 suggest that 

XLR11 is a psychoactive CB 1 receptor 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 of locomotor activity, following 10 and 30 mglkg doses in non-habituated SwissWebster mice. Depressant effects of 10 and 30 mglkg occurred within 10 minutes following 

injection and lasted 40-60 minutes. The ID5o (dose producing Yz maximal depressant activity, 

where maximal depression = 0 counts/30 min) was estimated to be I 0.3 mg/kg (Elksen et a!., 

2013). 

6 ED 50 (effective do8e) is a dose of a phamJacologic agent which will have a therapeutic effect 

7 
In vitro CB1 receptor binding assays for XLRII were perfonned with membrane preparations 

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 

of 24.2 ;± 4.6 nM (R Tl, 2013). XLR II also showed nM affinity for the CB2 receptor, with 

XLRII having an apparent K; of2.13 ;± 0.62 nM (RTI, 2013). 

XLR 1 1 was researched by functional assay using guanosine triphosphate (GTP-y)5

S). XLRll 

stimulated GTP-y-35S turnover through both the CB1 receptor and the CB2 receptor at nM 

concentrations, which is indicative of compounds that can act as agonists at these G-protein 

coupled receptor sites (RTI, 2013). Both CB1 and CB2 receptors are members of the 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 of abuse, a dose of L\ 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/B I 6J inbred mice (RTI, 2013 ). Before the sta1t of the 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 ED50

8 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 1 was 1.6-fold more potent than L\9

-THC, with an ED 50 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 of four "tetrad" tests in which canllabinoid agonists produced a characteristic profile of in 

vivo effects (Martinet al., 1991). These tests examined locomotor suppression, antinociception, 

hypothennia, and catalepsy. With L\9

-THC as a positive control, researchers showed that XLR11 

exhibited the profile ofcannabinoid effects in the tetrad tests in mice. XLR11 demonstrated 

dose-dependent suppression of spontaneous 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 potent than L\ 9

-THC in all tetrad measures. Furthennore, these effects are believed to 

be CB1-receptor mediated since other researchers showed pretreatment with CB;-receptor 

antagonists can block these effects (Tai et al., 20 14). 

Phannaco1ogically, XLRI I is a full cannabinoid agonist with no antagonist activity. XLR1 I is 

more potent than L\9

-THC, the principal psychoactive chemical in marijuana (Schedule I) and 

similar in activity to JWH-01 8 (Schedule I) (RTI, 2013). 

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

8 EC50 Half maximal effective concentration (EC50) refers to tl1e concentration of a drug, antibody or toxicant which 

induces a response halfway between the baseline and maximum after a specified exposure time. 

8 
FACTOR 3: The State of Current Scientific Knowledge Regarding the Drug or Other 

Substance 

The third factor the Secretary must consider is the state of cuiTent scientific knowledge regarding 

XLRll. XLRll is a potent cannabinoid that is repo1ied to be smoked for recreational purposes. 

XLR11 is pharmacologically similar to 6 9

-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 of UR-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 of synthetic cannabinoids that contain 

an indole moiety and an alkyl chain, but differ in the naphthoyl region of the compound. The 

aromatic naphthoylmoiety is completely replaced by an aliphatic tetramethylcyclopropyl 

moiety. Members of this subclass of synthetic cannabinoids have binding affinities at the CB 1 

and CB2 receptor, though many of the miginal substances were synthesized specifically for their 

selectively at the CB2 receptor (Shanks et al., 2013 ). 

Researchers demonstrated, in pooled human hepatocytes, that XLR 11 undergoes phase I and II 

metabolism, producing over 25 metabolites resulting from hydroxylation, carboxylation, 

hemiketal and hemiacetal fonnation, internal dehydration, and further gl11curonidation of some 

oxidative metabolites. XLR 11 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 ofthe biotransfonnations previously 

desc1ibed, many of which are glucuronidated (Wohlfarth et al., 2013). 

FACTOR 4: History and Current Pattern of Abuse 

The fourth factor the Secretary must consider is the history and cunent pattern of ab11se of 

XLRll. Many synthetic cannabinoids were developed over the 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 of herbal 

incense from Europe. Researchers hypothesize that the producers buy cannabinoids from 

laboratories in China or other 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 availability has been particularly 

challenging given the constantly changing composition of commercial synthetic cannabinoid 

9 
products (Seely et al., 2013). Commercial preparations ofsy11thetic cannabinoids often contain 

multiple combinations and varying concentrations of synthetic 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 of plant 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 of synthetic 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 of herbal incense shown to contain the synthetic cannabinoid HU-210 in Dayton, Ohio 

(Piggee, 2009). When CBP officers at the Dayton, Ohio, facility of an 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 the presence of the synthetic cannabinoid HU-21 0. Over a 3-month period, 

CBP seized over I 00 lbs of HU-2 I 0-laced herbal mixtures in five separate shipments (Piggee, 

2009). 

Law enforcement and public health officials continue to encounter abuse of these substances 

(Substance Abuse and Mental Health Services Administration (SAMHSA), TheDA WN Report, 

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 STRIDE rep01is involving 

XLR 11. From January 2011 through December 2013, there were 24,257 NFLIS reports of 

XLRll. 

Youth appear to be the primary abusers of synthetic cannabinoids and synthetic cannabinoid 

containing products, as demonstrated by law enforcement encounters and reports from hospital 

EDs. TheDA WN Report stated that, of approximately 2,300,000 ED visits that involved dmg 

misuse or abuse in 20 l 0, synthetic cannabinoids were specifically linked to an estimated 1 1,406 

visits (SAMHSA, 2012). According to the report, 75 percent of the 11,406 ED visits in 2010 

involved synthetic cannabinoid use among patients aged 12 to 29. For patients aged 12 to 29, 

males complised more than three quarters (78 percent) of ED 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 of delectability in routine urine dmg tests, and, until they were 

added to Schedule I of the CSA in 2012, lack ofCSA control (Gunderson eta!., 2012; Vandrey 

et al., 2012; Winstock and Ban·ett, 2013). 

FACTOR 5: The Scope, Duration, and Significance of Abuse 

The fifth factor the Secretary must consider is the scope, duration, and significance of abuse of 

XLRJI. Based on its phannacological prope1iies, it is reasonable to assume that, if uncontrolled, 

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). 

10 
Because XLR 11 is often packaged as an "herbal blend" with multiple ingredients, including 

other synthetic cannabinoid agonists, the scope, duration, and significance of abuse is difiicult to 

disaggregate. However, the available data, including receptor binding, in vitro, and preclinical 

studies strongly suggest that XLRII has a pharmacological mechanism of action 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 of all drug reports. Almost 13 percent (8,097) of these 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: 

"hey I tried ur-144 ~!Uw·-144 and ab-001 and I can say 1 love ur144 more then any 

previous rc no ids hut -~furl44 is clos in its similarity to pot but its way more stoning" 

Another user posted: 

"Two nights ago I received a 10 gram package ~f ~fur-144. I placed 3mg in a glass 

vaporizer and hit it one time, not heavily either, within 5 minutes I was sweatlng 

uncontrollab(v. felt crazy high, like 1 had an instant LSD type trip. Bqfore the nextfive 

minutes passed I 1yas scared, pulse out ~{time, stuttering even, I couldn't even nwnage to 

c1y out so sudden was this. Ifdl on my bed, then to the.floor. It was over 45 minutes 

b~fore I could get up. " 

FACTOR 6: What, If Any, Risk There Is to the Public Health 

The sixth factor the Secretary must consider is the risk XLR I I poses to the public health. Based 

solely on XLR II 's phannacological similarity to .0.9

-THC and its potency, the subjective risks to 

the public health are similar to those of other cannabinoid agents, i.e., similar to marijuana and 

t.9

-THC, which are controlled in Schedule I of the CSA. Detailed product analyses describe 

variations in the amount of synthetic cannabinoid inco11lorated into the plant material even 

within samplings of the same product (Hudson et al., 20 I 0). 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 of synthetic cannabinoids routinely exhibit the following 

symptoms: vomiting, anxiety, agitation, in·itability, seizures, hallucinations, tachycardia, 

elevated blood pressure, and loss of consciousness (Hal1'is and Brown, 2013; Hennanns-Cla.usen 

eta!., 2013; Fonestcr ct al., 2011; Cohen eta!., 2012). Additionally, consumption of synthetic 

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 of fine motor skills necessary for safely driving a vehicle. 

II 
The use of XLR 11 in relation to safety and mortality risks were recently described by the Centers 

for Disease Control (CDC, 2013). In March 2012, the Wyoming Depa1tment of Health was 

notified about three patients hospitalized for unexplained AKI, all of whom repmied recent use 

of synthetic cannabinoids, sometimes refened to as "synthetic marijuana" (CDC, 201 3). After 

the Wyoming Department of Health launched an investigation, a total of 16 cases of acute kidney 

injury (AKI) after synthetic cannabinoid use were reported in six states. Toxicological analysis 

of product samples and clinical specimens identified XLRII in four offlve available product 

samples and four of six 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. None reported preexisting 

renal dysfunction or use of medication 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 or toxicological results strongly suggested XLR 11 (detection of parent compound in 

serum or UR-144 pentanoic acid in urine). The CDC has recommended that public health 

practitioners, poison center staff members, and clinicians be aware of the potential for renal or 

other unusual toxicities in users of these products, and that they should ask about t11eir use in 

cases of unexplained AKI (CDC, 2013). Management of suspected 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 syndrome related to synthetic 

cannabinoids of the indole stmctural class due to the similarity to serotonin (Wells and Ott, 

2011 ). Symptoms of serotonin syndrome include shivering, diarrhea, muscle rigidity, fever, and 

seizures. Serotonin syndrome is a potential1y life-threatening dmg reaction that may occur 

following therapeutic drug use, inadvertent drug interactions, drug overdose, or recreational dmg 

use. 

FACTOR 7: The Drug's Psychic OI' Physiologic DependenceLiability 

The seventh factor the Secretary must consider is the psychic or physiologic dependence liability 

of XLR!l. The pharmacologic profile 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 one published 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 phannacologically related to JWH-08, there are still no speciflc studies involving the 

psychic or dependence liability currently identified for XLR11. 

!2 
Drug dependence is not directly observable in 1•ivo. Rather, it is assumed to be present when 

either the discontinuation of drug administration (spontaneous withdrawal) or the administration 

of an antagonist (precipitated withdrawal) elicits a withdTawal syndrome. The tenninology 

"cannabis withdrawal" has gained medical acceptance as described by the Diagnostic and 

Statistical Manual of Mental Disorders Fifth Edition (DSM-5). The following signs and 

symptoms develop within approximately I week of withdrawal: 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 of the following physical 

symptoms causes significant discomfmt: abdominal pain, shakiness/tremors, sweating, fever, 

chills, or headache (DSM-5, American Psychiatric Association, 2013; Gorelick et a!., 2012). 

In multiple species, cannabinoid administration may lead to rapid tolerance to antinociceptive 

effects, anticonvulsant activity, cataleptic effects, suppression oflocomotor activity hypothem1ia, 

hypotension, release of corticosteroids, and other effects (Adams et al., 1996) . 

. FACTOR 8: Whether the Substance Is an Immediate Precursor of a Substance That Is 

Already Controlled 

XLR1l is not an immediate precursor ofany controlled substance. 

RECOMMENDATION 

After consideration of the eight factors determinative of a substance (21 U.S.C 811 (c)), FDA 

recommends that l-(5-fluoro-pentyl)-1 H-indol-3-yl 2,2,3 ,3-tetramethylcyclopropyl methanone, 

also known as XLR1l, be placed in Schedule I of the CSA (21 U.S.C 812(b)(l)). XLR11 

produces effects similar to those of JWH-018, which is controlled in Schedule I of the CSA. 

N IDA concurs with the recommendation. 

The necessary criteria for placing a substance into Schedule I of the CSA are set ftHih in 21 

U.S.C 812 (b)(1), as follows: 

A) The drug or other substance has a high potentialfor abuse. 

XLR 11 is a synthetic substance that produces cannabinoid-like effects, and is similar to L\9

-THC, 

JWH-018, and other synthetic cannabinoids. The phannacological similarity ofXLR11 to A9

-

THC makes it reasonable to assume that iis potential for abuse is high and would be similar to 

that of JWH-018, which is controlled in Schedule I of the CSA. 

B) The drug or other substance has no currently accepted medical use in treatmem in the 

United States. 

There are no approved NDAs for XLR 11 in the United States. There is no known therapeutic 

application for XLR11. Therefore, XLR11 has no currently accepted medical use in the United 

States. 

13 
C) There is a lack of accepted safe()> for use o.ftlte drug or other substance under medical 

superPision. 

Since XLR 11 has no approved medical use and has not been thoroughly investigated as a new 

dmg, its safety for use under medical supervision is undetermined. In addition, adverse 

consequences thought to be related to abuse of XLR 11 are documented in case reports. Thus, 

there is a Jack of accepted safety for use of this substance under medical supervision. 

FDA therefore recommends that XLR 11 and its salts be controlled in Schedule I of the CSA. 

14 
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19 
Enclosure 2 
BASIS FOR THE RECOMMENDATION 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 be placed in 

Schedule I of the Controlled Substances Act (CSA). AKB48 was first identified in 2011 as a 

"designer drug" 1 present in "herbal products" (Uchiyama eta!., 2012; NFLIS, 2011). AKB48 is 

a synthetic cannabinoid or cannabimimetic that has recently become popular as a recreational 

marijuana alternative. AKB48 was detected in herbal products marketed globally via the Internet 

under a variety of names and in specialized shops (WHO, 20 14). The amount of AKB48 among 

the different marketed packages varies. As discussed in further detail below, AKB48 is not 

present in eve1y marketed synthetic cannabinoid product. For clarity, this document will 

explicitly refer 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 of AKB48 are 

similar to delta-9 (6 9

) -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 of AKB48 are cannabis-like and similar to 

those of marijuana. 

The Drug Enforcement Administration (DEA) notified the Department of Health and Human 

Services (J-:IHS) in writing of its intent to temporarily place AKB48 into Schedule I of the CSA 

on February 14, 2013. On March 14, 2013, in response to the notification by the DEA, HHS 

stated that there are no investigational new drug (IN D) applications or approved new drug 

applications (NDA) for AKB48. On May 16, 2013, the final order temporarily placing AKB48 

into Schedule I of the CSA was published in the Federal Register (78 FR 28735). 

In this document, FDA recommends that AKB48 be petmanently placed into Schedule I of the 

CSA. 

II. BACKGROUND 

Synthetic cannabinoids are relatively new substances of abuse. Over the past several years, 

recreational use of synthetic 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 a plethora of names. 

Analyses by DEA have detected AKB48 in product samples marketed under the name 

1 The te1m "designer dmgs" relaJes to psychotropic substances that are either synthetically changed natural 

compounds, modified molecular stmctures of existing drugs, or-less conunonly-wmp letely 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 of the CSA by Section 1152 of 

the Food and Dmg Administration Safety and Innovation Act (FDASIA) under TITLE XIOTHER PROVISIONS, Subtitle D-Synthetic Dmgs.Z As a newly recognized synthetic 

cannabinoid at that time, AKB48 was not listed among those controlled substances. Following 

placement of the aforementioned cannabinoids into Schedule I of the 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 of patented 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. It is not the subject of an 

NDA or an 1ND, and it is not currently marketed 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 of these products change over time as a reaction to prohibition and 

prosecution of sellers, neither the rescUer nor the consumer of these mixtures knows the actual 

content and amotmt of synthetic cannabinoid in products under the labeling guise of "incense" 

(Dresen et al. 201 0). The American Association of Poison Control Centers (AAPCC)3 reported 

2 When FDASJA was enacted, a total of eight substances were already covered by 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-morphol in-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 a Notice 

of Proposed 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 I by FDASIA on July 9, 2012. With final 

enactment ofFDASJA, final scheduling of the 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 a health care professional 

reports an actual or potential exposure to a substance (e.g., an ingestion, inhalation, or topical exposure), or 

requests infom1ationalmateriaL It warrants noting that these exposures do not inherent.ly represerit an 

instance of poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report 

2 
2,639 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 New Zealand) 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 of a substance from the 

schedules of the CSA. The eight factors are: 

I. The drug's actual or relative potential for abuse; 

2. Scientific evidence of the drug's pharmacological effects; 

3. The state of current scientific knowledge regarding the drug or other substance; 

4. Its history and cuJTent pattern of abuse; 

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

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

7. Its psychic or physiologic dependence liability; and 

8. Whether the substance is an immediate precursor of a substance already controlled. 

Following consideration of the 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)). 

Administrative responsibilities for evaluating a substance for control under the CSA are 

perfonned for HHS by FDA, with the concuJTence of the National Institute on Drug Abuse 

(NIDA) ((Memorandum oflJnderstanding, 50 FR 9518, 9518-20) (March 8, 1985)). 

This evaluation discusses the scientific and medical infonnation relative to each of the eight 

factors, presents findings in the three required areas, and makes a recommendation regarding the 

placement ofN-(1-adamantyl)-1-pentyl-1 H-indazole-3-carboxamide (AKB48) into Schedule I 

under the CSA. 

III. EVALUATING AKB48 UNDER THE EIGHT FACTORS 

This section presents an evaluation of the cuJTent scientific and medical knowledge about 

AKB48 under the eight factors that must be considered pursuant to 21 U.S.C § 81l(c). 

made to member centers. Additional exposures may go unrepmied to PCs and data referenced fi·om the 

AAPCC should not be construed to represent the complete incidence of national exposures to any substance. 

AAPCC indicated that a significant proportion of the reports were generated from hospital emergency 

departments or en-route to a medical treatment facility. 

3 
FACTOR 1: Its Actual or Relative Potential for Abuse 

The first factor the Secretary must consider is the actual or relative potential for abuse of 

AKB48. The tenn "abuse" is not defined in the CSA. However, the legislative history of the 

CSA suggests the following points in determining whether a particular dmg or substance has 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 of other individuals or to the community. 

b. There is significant diversion of the dmg or substan.ce from legitimate drug channels. 

c. individuals are taking the substance on their own initiative rather than. on the basis of 

medical advice from a practitioner licensed by law to administer such 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, or that it has a substantial capability of creating hazards to the health of the 

user or to the safety of the community. 

There is no single test or assessment procedure that, by itself, provides a full and complete 

characterization of a substance's abuse potential, as this is a complex determination that is multidimensional. When assessing the abuse potential of a substance, the Secretary considers 

multiple factors, data sources, and analyses. These factors include the prevalence, frequency, 

and manner of use in the general public and specific subpopulations; the amount of material that 

is available for illicit use; and evidence relevant to populations that may be at particular risk. 

Animal, human, and epidemiological data are all used in determining a substance's abuse 

potential. Specifically, a comprehensive evaluation of the relative abuse potential of a substance 

includes consideration of the drug's receptor binding affinity, preclinical pharmacology, 

reinforcing effects, discriminative stimulus eil:ects, dependence-producing potential, 

pharmacokinetics, routes of administration, toxicities, assessment of the clinical efficacy safety 

database relative to actual abuse, clinical abuse-potential studies, and pub.lic health risks 

following marketing of the substance. Epidemiological data can also be an impottant indicator 

of actual abuse. Finally, evidence of clandestine production and illicit trafficking of a substance 

are also important factors. Below is a discussion of the four indicators of abuse as they relate to 

AKB48. 

A). Individuals are taking the substance in amounts sufficient to create a hazard to 

their health or the safety of other individuals or to the community. 

The epidemiological and case repmt data discussed in this section suggest that individuals are 

taking AKB48 in amounts sufficient to create a hazard to their health or to the safety of other 

individ~1als or to the community. Common symptoms associated with intoxication by other 

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. 

4 
synthetic 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 or residual effects are cun·ently unknown. Acute symptoms 

usually subside within a few hours and most symptoms are similar to high doses of cannabis, 

except for agitation and seizures (which are not seen after taking high doses of cannabis) 

(1-lemanns-Clausen eta!., 2013). According to a 2012 survey, synthetic cannabinoids are the 

second-most commonly used illegal drug among young adults, with only cannabis use occun·ing 

at a higher rate (Johnston eta!., 20 12). Use of synthetic cannabinoids produces psychoactive 

effects similar to those of cannabis; 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 of use. 

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 of these 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 D EA, are intended for human 

use as recreational drugs. 

The number and the type ofsynthetic cannabinoids, as an aggregate, have increased since 2008, 

as evidenced by the number ofrepmis submitted to NFLIS. According to 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 specifically to be 1.65 percent (285 I 17,242) of all synthetic 

cannabinoids tested. This data represents results of drug 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 

homo logs) in 2012. This number is lower than the number of calls repmted in 201 1 (6,968), but 

showed a greater than!OO percent increase over those reported in 2010 (2,906) (DEA, 2013 

National Drug Threat Assessment Summary). Additionally, AAPCC just recently released 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 

of adverse 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 of drugs seized by Jaw enforcement. See http://www.deadiversion.usdoj.gov/nflis/. 

6 DEA 's STRIDE reflects the results of drug 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 is significant diversion of the drug or substance.fi·om legitimtlte drug 

channels. 

Since AKB48 is not an FDA-approved drug product for treatment in the United States and there 

appear to be no legitimate sources for AKB48 as a marketed drug, this characteristic of abuse 

potential is not applicable. 

C). Individuals are taking the substance on their own initiative rather than on the basis 

of medical advice.fi·mn a practitioner licensed by law to administer such substance. 

Because AKB48 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, rather than 

on the basis of medical advice from a practitioner licensed by Jaw to administer drugs. 

Law enforcement seizures and anecdotallnternet user experience posts (e.g., http://www.drugsforum.com) indicate that individuals are taking AKB48 on their own initiative, rather than on the 

medical advice of a licensed practitioner. 

D). The substance is so related in its action to a substance already listed as having a 

potentia/for abuse to make it likely that lt wiU have the same potentia/for abuse as 

such substance, thus making it reasonable to assume that there may be significant 

diversions from legitimate channels, sign(ficant use contrary to or without medical 

advice, or that it has a substantial capability of creating ha.zards to the health o.fthe 

user or to 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 that psychoactive cannabinoids of various structural 

classes, including tetrahydrocannabinols (such as 1'19 

• THC), bicyclic cannabinoid analog (e.g., 

CP55,940), aminoalkylindoles (e.g., WIN 55, 212-2) and other indole- and pyrol-derived 

cannabinoids (e.g., JWJ-1-0 18; Schedule I), share a common pham1acological profile of effects. 

Considering the close pharmacological resemblance of AKB48 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 1 receptors. In a study examining the relative affinity of JWH-0 18 for CB1 

receptors, JWH-018 displayed a K; of9.0 nM (Aung et al., 2000). Similarly, in a study 

examining relative affinities, results demonstrated that AKB48 binds with a K; value of 304.50 

nM at CB1• 

Secondly, psychoactive cannabinoids are reported to substitute for 1'19

-TJ-IC in a drug 

discrimination procedure in rodents (Wiley et al., 1995; V ann et al., 2009). This procedure is 

used as an animal model ofmarijuar1a 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 ,1;9

-THC, JWH6 
018 (Schedule I) produced complete substitution for stimulus effects oft:. 9

-THC with an ED 50 

7 of 

0.39 mglkg (NIDA contract N01 DA-13-8908). Similar results were obtained by Jarbe and 

colleagues, who found that JWH-018 fully substituted for the stimulus effects of 69

-THC in 

rodents trained to discriminate THC and was eight times more potent than THC (J arbe 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 of 69

-THC with an EDso of0.23 

mg/kg (NIDA NOJDA-13-8908). 

FACTOR 2: Scientific Evidence of the Drug's Pharmacological Effects 

The second factor the Secretary must consider is the phannacological effects of AKB48. 

AKB48 produces pharmacological effects similar to those of CB1 agonists including marijuana, 

69

-THC, and JWH-018, all of which are listed in Schedule I of the CSA. 

Receptor binding (K;), CB1 functional assay, drug discrimination, and locomotor studies with 

AKB48 were perfonned (NIDA 12:9177, NIDA NOlDA-13-8908, and NIDA NOlDA-7-8872). 

In rodents, AKB48 dose-dependently produced a profile ofphannacological effects 

characteristic of CB1 receptor 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 CB1 receptor 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 of eight non-habituated male Swiss-Webster mice. In all studies, horizontal activity 

counts, as a function of dose, via inten'Uption of photocell beams, were measured for 8 hours 

within 10-minute periods (NIDA NO! DA-7-8872). Each group of mice was either injected with 

a saline vehicle, AKB48, or 6 9

-THC. AKB48 concentrations from 3 mg to 30 mglkg 

demonstrated time and dose-dependent depression oflocomotor activity (NIDA N01DA-7-

8872). Depressant effects of AKB48 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 of AKB48 for cannabinoid CB 1 and CB2receptors was investigated. It was 

shown that ABK48 has an approximately two-fold higher affinity at the human recombinant CB2 

receptor compared to CB1 (ICso value of 430 nM and 824 nM, respectively) (Uchiyama, 2013). 

The results also showed that AKB48 had affinity for the CB1 and CB2 receptors. AKB48 for the 

CB1 receptor was approximately five times lower than that of JWH-018 (Schedule I). The 

affinity of AKB48 for tl1e CB1 receptor was 25.8-fold lower than that of (R)-(+)-WJN-55, 212-2, 

7 ED50 (effective dose) is a dose of a phannacologic agent which will have a therapeulic effect. In the context of 

rodents, ED 50 refers to the effective dose for obJaining the pharmacological response. In this study it is the effective 

dose for drug discrimination. 

7 
positive control (Uchiyama, 2013). As compared to THC, these values associate a 12- to 30-fold 

lower binding affinity to CB1 receptors and a 12- to 17-fold lower binding affinity to CB2 

receptors. In another NJDA-contracted study, duplicate dose-response curves for IC50 and K; 

studies were perfmmed. Concentrations of 10, 100, 200, 500, I 000, 2,000, 5,000, and I 0,000 

nM were tested in triplicate. The K; value of AKB48 at CB 1 receptors was reported at 304.50 

nM (NlDA Task Order: 12-9177). 

AKB48 was researched by CB1 (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, of greater than 80 percent 

of a 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 of the animal to identify if the 

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 one patiicular 

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 prior to the stati of the session and a dose range of 0.025 to 2.5 mglkg 

was examined. This range included doses that were inactive to those that had 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 of AKB48. 

FACTOR 3: The State of Current Scientific Knowledge Regarding the Drug or Other 

Substance 

The third factor the Secretary must consider is the state of cun·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 of AKB48 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 molecular formula is C23H.11N3o and its 

molecular weight is 365.2. The melting point of AKB48 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 N01 DA-7-8872). AKB48 is identified under Chemical 

Abstract Service (CAS) Number 1345973-53-6. 

8 
The chemical structure of AKB48 is unrelated to THC. Although many of the synthetic 

cannabinoids detected in illegal products, such as JWH-018 (Schedule 1), have a 3-carbonyl 

indole moiety, AKB48 is a new type of synthetic cannabinoid with an amide structure and an 

adamantane group. AKB48 also has an indazole group in place of an 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, a NIDA-supported study 

with human hepatocytes was recently performed by Gandhi eta!. (2013). Reseru·chers showed 

that the major metabolic pathways are hydroxylation on the aliphatic adamantane moiety 

followed by glucuronidation. Oxidation of the N-pentyl side chain fanning a ketone appears to 

be a minor metabolic pathway. Based upon other studies, AKB48 shares common metabolic 

pathways, e.g., mono- or dihydroxylation of the N-pentyl side chain or the indole moiety similar 

to JWH-018 (Schedule I) or hydroxylation of the aliphatic adamantane ring, followed by 

glucuronidation. Eleven major metabolites 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. Since parent synthetic cannabinoids are rarely 

present in the urine, metabolite identification is imperative for proving intake of synthetic 

cannabinoids (Gandhi et al., 2013). Additionally, based on the lack of human toxicological 

infmmation for AKB48, it is difficult to predict all the health risks associated with its use 

(Uchiyama et al., 2012). 

Factor 4: History and Current Pattern of Abuse 

The fomth factor the Secretary must consider is the history and cunent pattern of abuse of 

AKB48. Many synthetic cannabinoids were developed over the last 30 years for use as vehicles 

for investigating the cannabinoid system for research purposes (Weissman eta!., 1982; Huffman 

et al., 1996). Most of the data available on the synthetic cannabinoids represents data on the 

drug class, as opposed to data on individual substances. Because of the similarity in 

phannacology and apparent abuse as evidenced by seizure repmts, the history and pattem of 

abuse of AKB48 is likely to be similar to that of other 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 plant material for retail sale in 2008. A commercial 

laboratory in Frankfu11, Gennany, announced that it had identified JWH-0 18, one of several 

synthetic cannabinoid agonists originally developed at Clemson University, in samples of herbal 

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 being packaged and sold as herbal mixtures (Piggee, 2009). 

Clandestine manufacturers continue to develop new unscheduled synthetic cannabinoids with 

numerous structural alterations, but without loss of the psychoactive potential. 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. It is postulated that the 

9 
continual development of these new synthetic cannabinoids, such as AKB48, is primarily based 

on attempts to evade regulatory control of synthetic cannabinoids. 

The first emergence of synthetic 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 of herbal incense shown to contain the synthetic cannabinoid HU-21 0 in Dayton, Ohio 

(Piggee, 2009). When CBP officers at the Dayton, Ohio, facility of an international express 

courier saw the dried plant material inside a shipment, they perfonned a field test for the 

presence of THC, but it was negative .. However, fmther analysis at the CBP laboratory in 

Chicago confinned the presence of the synthetic cannabinoid HU-21 0. Over a 3-month period, 

CBP seized over 100 1bs of HU-21 0-laced herbal mixtures in five sepamte shipments (Piggee, 

2009). 

Law enforcement and public health officials continue to encounter abuse of these substances 

(Substance Abuse and Mental Health Services Administration (SAMHSA), The DAWN Repol't, 

2012; NFLIS, 2013). As aforementioned, there were 87 STRIDE repotis fi·om January 2011 

through February 24, 2014, and 791 NFLIS repOJts from January 2010 through December 2013, 

involving AKB48. Specifically, prior to the last quarter of 2011, NFLJS reported no cases 

involving AKB48. 

Youth appear to be the primary abusers of synthetic cannabinoids and synthetic cannabinoidcontaining products, as demonstrated by law enforcement encounters and repotis ti·om hospital 

EDs. TheDA WN Report stated that, of approximately 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 of the 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) of ED 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 of delectability 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 of Abuse 

The fifth factor the Secretary must consider is the scope, duration, and significance of abuse of 

AKB48. Based on its pharmacological properties, it is reasonable to assume that, if 

uncontrolled, the scope, duration, and si?nificance of AKB48 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 of abuse is difficult to 

disaggregate. However, the available data, including receptor binding, in vitro, and preclinical 

studies strongly suggest that AKB48 has a pharmacological mechanism of action 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) of all synthetic cannabinoids tested. 

The use of AKB48 recreationally is reported anecdotally by users 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, extremely pleasurable, enjoyable, a favoritecannabinoid with low anxiety and little to 

no negative effects. 

FACTOR 6: What, If Any, Risk There Is to the Public Health 

The sixth factor the Secretary must consider is the risk AKB48 poses to the public health. The 

phannacology of AKB48 as described in FACTOR 2 (above) demonstrates that the risks to the 

public health are largely related to the potential serious adverse effects that the substance will 

have on individual users. 

Based on the results of in 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 a high potency at nanomolar concentrations, 

the subjective risks to the public health of AKB48 are likely to be similar to those of other 

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 similar to AKB48 include nausea and vomiting, sh01tness of 

breath or depressed 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 similar to high doses of cannabis 

(except for agitation and seizures, which are not seen after taking high doses of cannabis) 

(Hemanns-Clausen et al., 2013). 

Detailed product analyses desclibe variations in the amount of synthetic cannabinoid on plant 

material even within samples from the same product (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 of synthetic 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 Secretary must consider is the psychic or physiologic dependence liability 

of AKB48. The phannacologic profile of AKB48 strongly suggests that it may possess a 

physiological and psychological dependence liability that is similar to that of /1.9

-THC (Schedule 

I) and JWH -018 (Schedule !). 

11 
Case reports demonstrate that herbal products containing synthetic cannabinoids produce 

physical dependence and a withdrawal syndrome. There is one published case repmt of 

tolerance and withdrawal phenomena in the literature (Zimmermann eta!., 2009) and another of 

drug-induced psychosis (Muller eta!., 201 0). 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 of the similarity in phannacology and recognized abuse of the class 

of substances by humans, 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 be present when 

either the discontinuation of drug administration (spontaneous withdrawal) or the administration 

of an antagonist (precipitated withdrawal) elicits a withdrawal syndrome. The tem1inology 

"cannabis withdrawal" has gained medical acceptance as described by the Diagnostic and 

Statistical Manual of Mental Disorders Fifth Edition (DSM-5). The following si!,>nS and 

symptoms develop within approximately 1 week of withdrawal: 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 of the following physical 

symptoms causes significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, 

chills, or headache (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 of corticosteroids, and other effects (Adams eta!., 1996). 

FACTOR 8: Whether the Substance Is an Immediate Precursor of a Substance That Is 

Already Controlled 

AKB48 is not an immediate precursor of any controlled substance. 

RECOMMENDATION 

After consideration of the eight factors detenninative of a substance (21 U.S.C. § 811 (c)), FDA 

recommends that AKB48 (N-1-adamantyl-1-pentyl-1 H-indazole-3-carboxamide) and its salts he 

placed in Schedule I of the CSA (21 U.S. C.§ 812(h)(l)). AKB48 produces effects similar to 

those of JWH-018, which is controlled in Schedule I of the CSA. NIDA concurs with the FDA 

scheduling recommendation. 

The necessary critetia for placing a substance into Schedule I of the CSA are set forth in 21 

U.S. C.§ 812(b)(l), as follows: 

A) The drug or other substauce has a high potential for abuse. 

AKB48 is a synthetic substance that produces cannabinoid-like effects. The pharmacological 

similmity of AKB48 to 1'19

-THC makes it reasonable to assume that its potential for abuse is high 

12 
and would be similar to that ofJWH-018, a synthetic cannabimimetic which is controlled in 

Schedule I of the CSA 

B) The drug or other substance has no currently accepted medical use in treatment in the 

United States. 

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 accepted safety for use of the drug or other substance under medical 

supervision. 

Since AKB48 has no approved medical use and has not been thoroughly investigated as a new 

drug, its safety for use under medical supervision is undetennined, Thus, there is a lack of 

accepted safety for use of this substance under medical supervision, 

FDA therefore recommends that AKB48 and its salts be controlled in Schedule I of the CSA. 

13 
References: 

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humans. Addiction. 91(11):1585·614. 

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https://www.dnlgs-forum.com/forum/showthread.php?t=l 87522. Last accessed on October 6, 

2014. 

American Association of Poison Control Centers. Synthetic Marijuana Data, December 31, 

2013. Available at 

https://aapcc.s3 .amazonaws.com/files/library/Synthetic _ Mmijuana _Web_ Data_ through_l2.20 

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Aung M., Griffin G., Huffman J., Wn M., Keel C., eta!. (2000) Influence of the N-1 alkyl chain 

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44:832-837. 

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28, 2014. 

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and characterization of a cannabinoid receptor in rat brain. Mol Pharmacal, 34:605-613. 

14 
Dresen S., Feneiros N., Putz M., Westphal F., Zimmermann Z., et al. (2010) Monitoring of 

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characterization of AKB48 metabolism, a novel synthetic cannabinoid, using human hepatocytes 

and high-resolution mass spectrometry. American Association of Pharmaceutical Scientists, 

15(4):1091-1098. 

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cannabinoid receptor agonists and antagonists using the guanosine-5'-0-(3-[35S]thio)-

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Portugal. 

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Gunderson E., Haughey H., Ait-Daoud N., Joshi A., and Hart C. (2012) "Spice" and "K2" herbal 

highs: A case series atld systematic review of the clinical effects and biopsychosocial 

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I 08(3 ):534-44. 

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aminoalkylindoles, including AM678=JWHOI8 found in "Spice," examined using drug (Delta9-

tetrahydrocannabinol) discrimination for rats. Behav Pharmacal, 22:498-507. 

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15 
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cannabinoid Spice as a trigger for an acute exacerbation of cannabis-induced recurrent psychotic 

episodes. Schizophrenia Research, 118:309-310. 

NIDA Final Study Report NOIDA-13-8908 (HHSN 271201300001). Compound: AKB48. 

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under contract by University ofNo1ih Texas Health Science Center at Fort Worth and NIDA. 

Report date: June II, 2013. 

NIDA Final Study Report NOIDA-7-8872 (HHSN 271200700014C). Compound: AKB48. 

Study: Time course (8-h) mouse locomotor activity test vs Delta(9)-THC. Conducted under 

contract by University of North 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, CB I (h) Agonist Cellular Functional 

Assay. Report date: January 14, 2013. 

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CANNABIMIMETIC LIGANDS. Available at 

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http://www.samhsa.gov/data/2kl2/DA WNI 05/SRl 05-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-1 H-indole-3-carboxamide (APICA) at1d N-

(1-adamantyl)-1-pentyl-1 H-indazole- 3-carboxamide (APINACA), and detection of five 

16 
synthetic 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 study to characterize use of spice 

products (synthetic cannabinoids). Drug A/chol Dependence, 120:238-241. 

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stimulus propetiies of delta-9-tetrahydrocannabinol (THC) in C57BI/6J mice. Eur J 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 and Experimental 

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17 
Enclosure 3 
BASIS 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 

of the Controlled Substances Act (CSA). UR-144 is a synthetic cannabinoid that has recently 

become popular 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 other products (EMCDDA, 2009; NFLIS, 2012). The 

synthetic cannabinoid products are often referred 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 cannabinoid product. 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 the report 

specifically indicates the presence 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 of marijuana. 

The Drug Enforcement Administration (DEA) notified the Deparbnent of Health and Human 

Services (HHS) in w1iting of its intent to temporarily place UR-144 into Schedule I of the CSA 

on February 14, 2013. On March 14, 2013, in response to the notification by tl1e DEA, HHS 

stated that there are no exemptions or approvals in effect for UR-144 under Section 505 of the 

Federal Food, Drug, and Cosmetic Act. On May 16, 2013, the final order tempormily placing 

UR-144 into Schedule I of the CSA was published in the Federal Register (78 FR 28735). 

In this document, FDA recommends that UR-144 be permanently placed into Schedule I of the 

CSA. 

II. BACKGROUND 

Synthetic cannabinoids are new substances of abuse. Over the past several years, recreational 

use of synthetic 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 of names. Analyses by DEA have 

detected UR-144 in product samples which are marketed under the 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; 

I 
New 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 Mary Janes. 

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 of the CSA by Section 1152 of 

the Food and Drug Adminish·ation Safety and Innovation Act (FDASIA) under TITLE XIOTHER PROVISIONS, SubtitleD-Synthetic Drugs. 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 of the aforementioned compounds into 

Schedule I of the 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 by DEA's Jabs, and the National Forensic Laboratory lnfotmation System (NFLIS), a 

DEA database that collects infonnation on samples tested by state and local jurisdictions, 

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 of an 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 of many products changes repeatedly over time as a reactiott 

to prohibition and prosecution of resellers, neither the reseller nor the conswner of these 

1 When FDASIA was enacted, a total of eight substances were already covered by DEA tempormy 

scheduling order<: five synthetic ca1U1abinoids (JWH-0 18, JWH-073, JWH-200, CP-47,497, and CP-4 7,497 

C8 homologue) and 3 synthetic cathinones (mephedrone, MDPV, and methylene). DEA had also issued a 

Notice of Proposed 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 of the 3 synthetic cathinones (mepbedrone and MDPV). However, DEA has posted a copy 

of the HHS Scientific and Medical Evaluation and Scheduling Recommendations regarding the five synthetic 

cannabinoids on www.regulations.gov. These HHS documents can be found on www.regulations.gov under 

Docket No.DEA-2012-000 I. 

2 
mixtures knows the actual content and amount of synthetic cannabinoid in products 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 of physical dependence and withdrawal. 

The American Association of Poison 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 of control 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 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 of the National Institute on Drug Abuse 

(NIDAl ((Memorandum of Understanding, 50 FR 9518, 9518-20) (March 8, 1985)). 

This evaluation discusses the scientific and medical information relative to each of the 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 section presents an evaluation of the current scientific and medical information about UR144 under 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 Secretary must consider is the actual or relative potential for abuse of UR144. The term "abuse" is not defined in the CSA. However, the legislative history of the 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 or potential exposure to a substance (e.g. an ingestion, inhalation, or topical exposure), or 

requests informational materiaL It warrants noting that these exposure~ do not inherently represent an 

instance of poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report 

made to member centers. Additional exposures may go unreported to PCs and data referenced from the 

AAPCC should not be constmed to represent the complete incidence of national exposures to any substance. 

AAPCC indicated that a significant proportion of the reports were generated ti·mn hospital emergency 

departments or enMroute to a medical treatment facility. 

3 
suggests the following points in determining whether a particular drug or substance has a 

potential for abuse4

• 

Individuals are taking the substance in amounts sufficient to create a hazard to their health or to 

the safety of other individuals or to the community. 

There is significant diversion of the drug or substance from legitimate d!'llg channels. 

Individuals are taking the substance on their own initiative rather than on the basis of medical 

advice from a practitioner licensed 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 or without medical advice, or that it has a substantial capability of 

creating hazards to the health of the user or to the safety of the community. 

There is no single test or assessment procedure that, by itself, provides a full and complete 

characterization of a substance's abuse potential, as this is a complex determination that is multidimensional. When assessing the abuse potential of a substance, the Secretary considers 

multiple factors, data sources, and analyses. These factors include the prevalence, fi·equency and 

manner of use in the general public and specific subpopulations; the amount of material that is 

available for illicit use; and evidence relevant to populations that may be of particular risk. 

Animal, human, and epidemiological data are all used in determining a substance's abuse 

potential. Specifically, a comprehensive evaluation of the relative abuse potential of a substance 

includes consideration of the dn1g's receptor binding af1inity, preclinical pharmacology, 

reinforcing effects, discdminative stimulus effects, dependence-producing potential, 

phannacokinetics and routes of administration, toxicities, assessment of the clinical efficacy 

safety database relative to actual abuse, clinical abuse-potential studies, and the public health 

risks following marketing of the substance. Epidemiological data can also be an important 

indicator of actual abuse. Finally, evidence of clandestine production and illicit trafficking of a 

substance are also important f\wtors. Bdow is a discussion of the four indicators of abuse as 

they relate to UR-144. 

A), Individuals are taking the substance in amounts sufficient to create a hazard to 

their health or the 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 of other 

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 may persist 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. 

4 
hallucinations, and loss of consciousness (Adamowicz et al., 20 13). From J anumy 2010 through 

March 2013, DEA repmted that NFLIS5 and STRIDE6 data for the three synthetic cannabinoids 

UR-144, XLR11, and AKB48 totaled 16,014 repmted cases. The detection of these 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 of synthetic 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 dmg reports in 2012, an 

increase of 1,402 percent from2009 (DEA National Drug Threat Assessment Summary, 2013). 

NFLIS also reported that 9 percent, which is about 5,631 of 56,540, of identified hallucinogens 

in 2012 were UR-144 (NFLIS annual repo1t, 2012). 

The AAPCC repmted approximately 5,200 calls about exposures to synthetic marijuana (THC 

homo logs) in 2012. This number is lower than the number of caBs repotted in 2011 (6,968),but 

it was still significantly higher than those reported in 2010 (2,906) (DEA, 2013 National Drug 

Threat Assessment Summary). Additiona11y, AAPCC just recently released a reported 2,639 

human exposures to synthetic marijuana (THC homologs) in 2013 (AAPCC, 2013). 

B). There is significant diversion of the drug or substance.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 of abuse 

potential is not applicable. 

C). Individuals are taking the substance on their own initiative rather than on the basis 

of medical advice.fi·om a practitioner 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, rather than 

on the basis of medical advice fi·om a practitioner licensed by law to administer dmgs. 

AAPCC reports, literature case reports, law enforcement seizures, and anecdotal internet user 

experience posts (e.g., bluelight.org) indicate that individuals are taking UR-144 on their own 

initiative, rather than on the medical advice of a 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 of dmgs seized by law enforcement. See http://www.deadiversion.usdoj.gov/nflisl. 

'' DEA's STRIDE reflects the results of drug evidence analyzed at DEA laboratories nationwide. See the 2012 

NFLIS annual report at http://www.deadiversion.usdoj .govlnflis/20 12annual_rpt.pdf. 

5 
D). The substance is so related i11 its action to a substance already listed as having a 

potentia/for abuse to make it likely that it will haJ'e the same potentia/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, or that it has a substantial capabili(V of 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 of various 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 with high affinity for both CB 1 and CBz receptor 

subtypes. In a study examining the relative affinity of JWH-018 for CB1 and CBzreceptors, 

JWH-018 displayed slightly greater relative affinity for CBz receptors (Ki = 2.94nM), relative to 

CB1 receptors (Ki = 9.0 nM) (Aung et al., 2000). This resulted in a CBtrCBz binding ratio that is 

slightly increased for JWH-018 relative to THC (3.06 versus 1.12), though the significance of the 

CB 11CB2 binding ratio cul1'ently is still unknown. Similarly, UR-144 has a high affinity for both 

cannabinoid-1 (CB1) 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 substitute for 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 of marijuana 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 6.9

-

THC, JWH-018 (Schedule 1) produced complete substitution for stimulus effects of 6.9

-THC with 

an ED50

7 of0.39 mg/kg (N!DA study report, 2011 ). Similar results were obtained by Jarbe and 

colleagues, who found that JWH-018 fully substituted for the stimulus effects of 119

-THC in 

rodents trained to discriminate THC and was eight times more potent than THC (Jm·be eta!, 

2011). 

7 ED 50 (effective dose) is a dose of a pharmacologic agent which will have a therapeutic effect. ED 50 in the context 

of rodents refers to the effective dose for obtaining the phannacological response. In this study it is the effective 

dose for dmg discrimination. 

6 
As 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 of b. 9

-THC with an ED 50 of 7.1 

J,tmol/kg (RTI, 2013). 

FACTOR 2: Scientific Evidence of the Drug's Pharmacological Effects 

The second factor the Secretary must consider is the pharmacological effects ofUR-144. 

Receptor binding, dmg discrimination, and .locomotor studies with UR-144 have been performed 

(Elks en et al., 2013, RTI, 2013 ). In mice, UR-144 dose-dependently produced a profile of 

pharmacological effects characteristic ofCB1 receptor agonists including: suppression of 

locomotor activity, antinociception, hypothennia, and catalepsy. Consistent with its greater 

affinity at the CB 1 receptor, 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 CB1 receptor agonist (RTI, 2013) which is similar 

to i\9

-THC. 

As for locomotor activity, UR-144 caused time- and dose-dependent depression of locomotor 

activity following I 0 and 30 mg/kg doses in non-habituated male Swiss-Webster mice. 

Depressant effects of I 0 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 by the way that the 

animal will behave. In drug discrimination studies, this ability of the animals is useful for 

identifying if the test drug is similar to the positive control drug (Lewicki and Nichols, 1998). 

UR-144 CB 1 receptor binding assays were perfonned with membrane preparations isolated from 

a HEK-293 expression system. These transfected cell membrane preparations demonstrated that 

UR-144 binds to the CB 1 receptor with a Ki affinity of 28.9 nM and to the CB2 receptor with a Ki 

affinity of 4.51 nM (RTI, 2013). 

UR-144 was researched by functional assay, using guanosine triphosphate GTP-y.35

S). UR-144 

stimulated GTP-y-35S turnover through both the hCB1 receptor and the hCB2 receptor at nM 

concentrations, which indicates agonism at these G-protein coupled receptor sites. UR-144 was 

an agonist at both the CB1 receptor (EC5o of98.1nM) and CBz receptor (EC50

8 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 (half maximal effective concentration) refers to the concentration of a d1ug1 antibody, or toxicant which 

induces a response halfway between the baseline and maximum after a specified exposure time. 

7 
trained to discriminate 5.6 mg/kg 69

-THC from vehicle and a 69

-THC dose-etTect curve was 

detennined. The 69

-THC (positive control) dose-dependently substituted for the training dose, 

with an ED 50 of 5.4 °mol/kg (95% CI: 4.5-6.4 °mollkg). Subsequently, UR-144 fully and dosedependently substituted for 6 9

-THC, with an EC5o of7.1 °mol/kg (95% Cl: 5.8-8.6 °mol/kg). 

Full substitution occurred at a dose of 5.6 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 characteristic prot1le of in vivo effects 

(Ma1iin et a]., 1991 ): suppression of locomotor 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 of cannabinoid effects in the tetrad 

tests in mice. UR-144 produced dose-dependent suppression of spontaneous 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 1 receptor binding affinities, the two 

test compounds were relatively equipotent with each other across all tour measures. With the 

exception of the effect ofUR-144 on spontaneous activity, one or more doses of each compound 

significantly affected each measure (p< 0.05, compared to vehicle, the negative control). 

Although UR-144 showed a trend towards decreased activity, the effect did not reach statistical 

significance (RTI, 2013). 

UR-144 binds to CB1 receptors, with the magnitude of affinity dependent upon radioligand. 

Consistent with the results of previous studies with CP-55,940, WIN-55,212-2, and 6 9

-THC 

(Thomas eta!., 1998), UR-144 exhibited better displacement of the CB1 agonist [3H] CP55, 940 

than of the CB1 receptor antagonist [3H]SR141617A. With [3H]CP55,940 as the radioligand, 

the affinity of both compounds was better than that of .6.9

-THC (Ki = 28.9 for UR-144 and Ki = 

41nM tor 69

-THC, as repotied byWileyet a!., 1998). UR-144 also had excellent affinity for the 

CB2 receptor, as has been rep01ied for a number of indole-derived synthetic cannabinoids 

(Huffinan and Padgett, 2005). Fmihem1ore, UR-144 stimulated GTP-y-35S tumover in CB1 and 

CB2 receptor preparations, suggesting that they are agonists at each type of cannabinoid receptor 

(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 of Current Scientific Knowledge Regarding the Drug or Other 

Substance 

The third factor the Secretary must consider is the state of CUITent 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 TMCP0 18, KM-XI, MN- 00 I and YX-17 (Adamowicz eta!., 20 13). The molecular fonnula is 

8 
C21 H29NO and its molecular weight is 311.5 grams. The Chemical Abstract Services number 

(CAS#) of UR-144 is 1199943-44-6. 

The chemical structure of UR-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 of the 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 be relatively unstable. The thennal isomerization ofUR144 in the absence of air (i.e. GC injector port column) or in the presence of air (i.e. burning of 

UR-144 containing products) leads to opening of the cyclopropane ring and fonnation of a 

trimethylbutene product. Hydration of the cyclopropyl ring in UR-144 or its trimethylbutene 

moiety res~1lts in the fonnation of a group ofunmodifiable compounds. However, the 

pham1acological and toxicological propetties of these compounds are unknown (Kavanagh eta!., 

2013). 

FACTOR 4: History and Current Pattern of Abuse 

The fomih factor the Secretary must consider is the history and current pattem of abuse of UR144. Many synthetic cannabinoids were developed over the 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!., 201 0; Uchiyama eta!., 201 0;). The first synthetic cannabinoid was 

found laced on plant material for retail sale in 2008. A commercial laboratory in Franknnt, 

Gennany, announced that it had identified JWH-018, one of several cannabinoid agonists 

originally developed at Clemson University, in samples of herbal 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 the plant material, and evaporate the solvent before packaging the herbal 

mixtures (Piggee, 2009). 

The first documented appearance of synthetic cannabinoids in the United States was discussed in 

a U.S. Customs and Border Protection (CBP) announcement in January 2009, which reported a 

seizure of herbal incense containing the synthetic cannabinoid HU-21 0. When CBP officers at 

the Dayton, Ohio, facility of an international express courier saw the dried plant material inside a 

shipment, they performed a field test for the presence of THC, but it was negative. However, 

fmiher analysis at the CBP laboratoty in Chicago confirmed the presence of the 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 public health officials continue to encounter abuse of these 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 

9 
cannabinoid 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 

YEA R Tot a lR eports 

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 of synthetic cannabinoids and synthetic cannabinoidcontaining products, as demonstrated by Jaw enforcement encounters and reports fi·om hospital 

emergency departments (ED). TheDA WN Report, which noted that there were approximately 

2,300,000 ED visits that involved drug misuse or abuse in 20 I 0, stated that synthetic 

cannabinoids were !;pecifically linked to an estimated 11,406 visits (SAMHSA, The Dawn 

Report, 2012). Seventy-five percent of the ]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) of ED 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 

homo logs) in2013. Synthetic cannabinoid popularity is attributed to intense psychoactive 

effects, Jack of delectability in routine urine drug tests, and, until they were added to Schedule I 

of the CSA in 2012, lack ofCSA control (Gunderson eta!., 2012; Vandrey eta!., 2012; Winstock 

and Barrett, 2013). 

FACTOR 5: The Scope, Duration, and Significance of Abuse 

The fifth factor the Secretary must consider is the scope, duration, and significance of abuse 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 of abuse is difficult to 

disaggregate. However, the available data strongly suggests that UR-144 has a pharmacological 

10 
mechanism of action and that it will produce pharmacological and subjective effects similar to 

delta-9 (I\ 9

) --tetrahydrocannabinol (Schedule I) and JWH-0 18 (Schedule I). NFLIS laboratories 

identified 62,540 hallucinogens in 2012, representing 4 percent of all drug reports. Nine percent 

of these hallucinogen reports were attributed to UR-144 (2012 NFLIS annual report). 

The use of UR -144 recreational! y is repotied anecdotally by users 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 a userreported experience with UR-144 as "when] used UR-144 like 5 grams a week I would go into 

horrible withdrawal, projectile vomiting, etc." 

FACTOR 6: What, If Any, Risk There Is to the Public Health 

The sixth factor the Secretary must consider is the risk UR-144 poses to the public health. Based 

solely on its phannaco!ogical similarity to THC and its potency, the subjective risks to the public 

health ofUR-144 are similar to that of other cannabinoids, i.e., similar to that of marijuana and 

THC, which are controlled in Schedule I of the CSA. Detailed product analyses describe 

variations in the amount of synthetic cannabinoid laced on the plant material even within 

samplings of the same product (Hudson et al., 201 0). 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 of synthetic cannabinoid use routinely exhibit the.following 

symptoms: vomiting, anxiety, agitation, initability, seizures, hallucinations, tachycardia, 

elevated blood pressure, and loss of consciousness (Harris and Brown, 20 13; Hennami.s-Ciausen 

et al., 2013; Forrester et al., 2011; Cohen et al., 2012). Additionally, consumption of synthetic 

cannabinoids can lead to impai1ment similar to typical performance deficits caused by cannabis 

use, which are not compatible with safe driving. These deficits include sedating effects and 

impairment of fine motor skills necessary for safely driving a vehicle. 

UR-144 was detected in product combinations containing other synthtJtic canuabinoids. Several 

repo1is of clinical symptoms and intoxication signs were published during the last few years. 

Unfortunately, a majority of these reports lacked any analytical data for synthetic cannabinoids 

in bodily fluids. The following paragraph presents a case rep01t of driving under the influence of 

synthetic cannabinoids, including UR-144: 

"A 22-year-old male on a motorbike was about to be checked at a general road traffic control. 

Firstly, he escaped by car overrunning several red traffic lights, later he skedaddled by foot.". 

During his anest, the police noted: 'retarded movement sequence, apathetic, nervous, inert, and 

delayed reaction of pupils to light.' One hour and 35 min later, while taking a blood 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 

11 
JWH-307 <0.1 ng/ml 

MAM-2201 <0.1 ng/ml 

UR-144 <0, 1 nghnl" 

(Musshoffet al., 2013.) 

The use of UR-144 in relation to safety and mortality risks was recently described by the Centers 

for Disease Control (CDC, 2013). In March 2012, the Wyoming Depmtment of Health was 

notified about three patients hospitalized for unexplained acute kidney injury (AKJ), all of whom 

repmied recent use of synthetic cannabinoids, sometimes referred to as "synthetic marijuana 

(CDC, 2013)." After the Wyoming Department of Health launched an investigation, a total of 16 

cases of acnte AKI after synthetic cannabinoid use were repo1ied in six states. Toxicological 

analysis of product samples and clinical specimens identified UR-144 in one of five available 

product samples m1d one of six available patients' clinical specimens (CDC, 2013). In case 11, 

ti'Om Kansas, analysis of the implicated product "Mr. Happy" and serum specimen revealed the 

presence of XLR II and UR-144; a urine specimen contained the N-pentanoic acid metabolite of 

XLR 11, The case 11 patient's chief symptoms at presentation were nausea and vomiting, 

abdominal pain, and back pain. Renal ultrasound results showed increased cmtical echogenicity. 

CDC has recommended that public health practitioners, poison center staff members, and 

clinicians be aware of the potential for renal or other unusual toxicities in users of these products 

and should ask about their use in cases of unexplained 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 of the indole structural class, due to tl1e similarity to serotonin (Wells and Ott, 

2011). Symptoms of serotonin 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, or recreational drug 

use. 

FACTOR 7: The Drug's Psychic or Physiologic Dependence Liability 

The seventh factor the Secretary must consider is UR-144 's psychic or physiologic dependence 

liability. The pharmacologic profile ofUR-144 strongly suggests that it possesses a 

physiological and psychological dependence liability that is similar to that of delta-9 (1:!.9

) -

tetrahydrocannabinol (Schedule I) and JWH-018 (Schedule I). 

Case repmis demonstrate that herbal products containing synthetic cannabinoids produce 

physical dependence and a withdrawal syndrome. There is one published case report of 

tolerance and withdrawal phenomena in 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 1 synthetic 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. 

12 
FACTOR 8: Whether the Substance Is an Immediate Precursor of a Substance That Is 

Already Controlled 

UR-144 is not an immediate precursor of any controlled substance. 

RECOMMENDATION 

After consideration of the eight factors determinative of a substance (21 U.S.C. § 811 (c)), FDA 

recommends that UR,l44 be placed in Schedule I of the CSA (21 U.S.C. § 812(b)(l)). NIDA 

concurs with this recommendation. UR-144 produces effects similar to those of JWH-0 18, 

which is controlled in Schedule I of the CSA. 

The necessary criteria for placing a substance into Schedule I of the CSA are set forth in 21 

U.S.C. § 812(b)(1), as follows: 

A) The drug or other substance has a high potential 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 of JWH-018, which is controlled in Schedule I of the CSA. 

B) The drug or other substance has 110 currently accepted medical use in treatment in the 

United States. 

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 other substance under medical 

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 be related to abuse of UR-144 are documented in case reports. Thus, 

there is a lack of accepted safety for use of this substance under medical supervision. 

FDA therefore recommends that UR-144 and its salts be controlled in Schedule I of the CSA. 

13 
References: 

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 of the N-1 

alkyl chain length of cannabim imetic indoles upon CB(J) and CB(2) receptor binding. Drug 

Alcohol Depend. 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 Biobehav Rev. 16:55-62. 

Bluelight. [MEGA] Synthetic Cannabinoid Discussion- Take 4. Available at 

http://www.bluelight.org/vb/threads/61942 J -MEG A-Synthetic-Cannabinoid-Discussion-Take4/page2?highlight~ur-144. Accessed 2/26/2014. 

American Association of Poison 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 Mmiality Weekly Repmt 

(MMWR). February 15, 2013; 62(6). 

Cohen, J., Morrison,S., Greenberg,J., Saidinejad,M.(2012) Clinical presentation of 

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 of bicyclic cannabinoid analogs: classification as cannabimimetic agents. Journal 

c!f'Pharmacology and Experimental111erapeutics, 260(1 ):20 1-209. 

Dmg Enforcement Administration, National Drug Threat Assessment Summary. (November 

2013) Document prepared 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 February 24,2014. 

Devane, W.A., Dysarz, F.A., Johnson, M.R., Melvin, L.S., and Howlett, A.C. (1988) 

Detennination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 

34:605-613. 

14 
Dresen, 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 locomotor activity 

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