1 

### U.S. Department of Justice Drug Enforcement Administration

Schedules of Controlled Substances: Placement of (1

- pentyl

- 1 H

- indol

- 3

- yl)(2,2,3,3

- tetramethylcyclopropyl)methanone (UR

- 144), [1

- (5

- fluoro

- pentyl)

- 1 H

- indol

- 3

- yl](2,2,3,3

- tetramethylcyclopropyl)methanone (5

- fluoro

- UR

- 144, XLR11) , and N

- (1

- adamantyl)

- 1

- pentyl

- 1 H

indazole

- 3

- carboxamide (APINACA, AKB48) into Schedule I

Background, Data, and Analysis: Eight Factors Determina tive of Control and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by

Office of Diversion Control, Drug and Chemical Evaluation Section

Washington, D.C. 20537 May 20152

I. Background
On April 12, 2013, the Deputy Administrator of the Drug Enforcement Administration ( DEA ) published a Notice of Intent to temporarily place (1

- pentyl

- 1 H

- indol

- 3

- yl)(2,2,3,3

- tetramethylcyclopropyl)methanone (UR

- 144), [1

- (5

- fluoro

- pentyl)

- 1 H

- indol

- 3

- yl](2,2,3,3

- tetramethylcyclopropyl)methanone (5

- fluoro

- UR

- 144, XL R11) , and N

- (1

- adamantyl)

- 1

- pentyl

1 H

- indazole

- 3

- carboxamide (APINACA, AKB48) into s chedule I pursuant to the temporary scheduling provisions of the CSA (7 8 FR 21858 ). On May 16, 2013, the Deputy Administrator published a Final Order in the Federal Register (78 FR 28735) amending 21 CFR 1308.11(h) to temporarily place these three synthetic cannabinoids into s chedule I of the CSA pursuant to the temporary scheduling p rovisions of 21 U.S.C. 811(h). This Final Order, which became effective on the date of publication, was based on findings by the Deputy Administrator of the DEA that the temporary scheduling of these three synthetic cannabinoids was necessary to avoid an imminent hazard to the public safety pursuant to 21 U.S.C. 811(h)(1). As described in the May 16, 2013 Final Order, UR

- 144, XLR11 and AKB48 are synthetic cannabinoids that are pharmacologically similar to delta 9

- tetrahydrocannabinol (Δ9

- THC) and
JWH

- 018

. A review of the scientific literature finds that UR

- 144, XLR11 , and AKB48 ha ve no currently accepted medical uses and the substances are being misused and abused for their psychoactive properties . The Assistant Secretary of Health for the U.S. Departme nt of Health and Human Services (HHS) has advised that there are no exemptions or approvals in effect for
UR

- 144, XLR11 , and AKB48 under section 505 (21 U.S.C. 355) of the Federal Food, Drug , and Cosmetic Act. As stated by the HHS, UR

- 144, XLR11 and AKB48 h ave no known accepted medical use. They are not the subject of any approved new drug applications (NDA) or investigational new drug applications (IND), and are not currently marketed as approved drug products. With no known industrial or medical use an d no safety information, manufacturers

are surreptitiously adulterating plant material with these synthetic cannabinoids or dissolving in liquids for distribut ion to the consumer with potentially dangerous consequences. The adulterated products, such as “Spice , ” “ K2 , ” and many others, are marketed under the guise of herbal incense products and as legal alternatives to marijuana. It has been established that these products are being abused for their psychoactive properties in the absence of information

re garding their use and safety

.3

Since 2009, there has been a marked increase in law enforcement encounters of various synthetic cannabinoids in the United States. Both law enforcement and public health reports suggest the sustained popularity of these subs tances in the designer drug market, which are most commonly abused as plant material adulterants. These associated products are often being sold as incense and labeled “ not for human consumption. ” Additionally, these products are marketed as a “ l egal high” or “legal alternative to marijuana” and are readily available over the internet, in head shops, or sold in convenience stores. The three substances have no currently accepted medical use in treatment in the United States and have been reported to p roduce adverse effects in humans. Chronic abuse of synthetic cannabinoids has been linked to adverse health effects including signs of addiction and withdrawal (Zimmermann et al., 2009; Muller et al., 2010), as well as numerous reports of
emergency room a dmissions resulting from their abuse (Forrester et al., 2011; Hermanns

Clausen et al., 2013 ; SAMHSA, 2012). The American Association of Poison Control Centers (AAPCC) has reported that many of the synthetic cannabinoid calls are from either emergency depa rtments or placed while en route to a medical facility.
UR

- 144, XLR11 and AKB48 are synthetic cannabinoids (Figure 1) and are pharmacologically similar to the s chedule I hallucinogen delta

- 9

- tetrahydrocannabinol (Δ9

- THC). UR

- 144 and XLR11 are classified as cycloprop o ylindoles , while AKB48 is classified as

a n indazole

- 3

- carboximide

. UR

- 144 was first developed as a research tool by Abbott
L aboratories (Frost et al., 2010). XLR11 and AKB48 were not designed as research tools ; however , these two substances were reported by law enforcement in drug seizures dating back

to 2011. A ccording to data from the System to Retrieve Information on Drug Evidence (STRIDE) and STARLiMS , 1 from January 1, 2010 through December 31, 2014, there were 2,049 reports involving 245 cases for UR

- 144 ; 4,041 reports involving 487 cases for XLR11 ; and 201 reports involving 63 cases for AKB48. From January 2010 to December 2014, the National Forensic Laboratory Information System (NFLIS ) 2 registered 46,3 24 reports

1 STRIDE collected the results of drug evidence analyzed at DEA laboratories and reflects evidence submitted by the DEA, other Federal law enforcement agencies, and some local law enforcement agencies. On October 1, 2014, STARLiMS replaced STRIDE as the DEA laboratory drug evidence data system of record. 2 The National Forensic Laboratory Information System (NFLIS) is a comprehensive information system that includes data from forensic laboratories that handle approximately 90% of an estimated 1.0 million distinct annual State and local drug analysis cases. NFLIS includ es drug chemistry results from completed analyses only. While NFLIS data is not direct evidence of abuse, it can lead to an inference that a drug has been diverted and abused. See 76 FR 77330, 77332, Dec. 12, 2011.4

containing these synthetic cannabinoids

— including 8,548 reports of UR

- 144 ; 36,837 reports of
XLR11 ; and 939 reports of AKB48

— across at least 43 states. No reports regarding UR

- 144,
XLR11 , or AKB48 were reported in NFLIS prior to March 2010.
Fo r the period from January 2010 through December 2014, NFLIS reports for the three synthetic cannabinoids UR

- 144, XLR11, and AKB48 (46,324 total reports) exceeded the number of reports for the five synthetic cannabinoids JWH

- 018, JWH

- 073, JWH

- 200, CP

47,497 , and CP

- 47,497 C87,743 total reports). JWH

- 018, JWH

- 200, JWH

- 073, CP

- 47,497 and
CP

- 47,497 C8 homologue were temporarily scheduled on March 1, 2011, and were controlled

as s chedule I substances by Section 1152 of the Food and Drug Administration Safety an d Innovation Act (FDASIA), Pub. L. 112

- 144, on July 9, 2012. Section 1152 of FDASIA amended the CSA by controlling cannabimimetic agents and 26 specific substances (including 15 synthetic cannabinoids, 2 synthetic cathinones, and 9 phenethylamines of the 2C

- series) as

s chedule I substances . UR

- 144, XLR11, and AKB48 were not included among the 15 specific named synthetic cannabinoids, and do not fall under the definition of cannabimimetic agents under FDASIA.
UR

- 144, XLR11 , and AKB48 appeared on the designer drug market with limited to no pharmacological information and were being abused for their psychoactive properties. Due to the number of health and safety issues associated with the trafficking and abuse of these substa nces, studies were initiated. These studies further demonstrate the dangers of introducing

a non

- approved drug substance to consumers. Numerous state public health departments and poison control centers have warned of the dangers associated with the mis us e and abuse of synthetic cannabinoids and their associated products being encountered on the designer drug market

. In response to the use and abuse of these substances , numerous states and local jurisdictions have controlled these designer drugs. The American Association of Poison Control Centers (AAPCC) began report ing exposure calls corresponding to products purportedly laced with synthetic cannabinoids since 2011, although the data provided do not generally include biological sample testing that would confirm the specific type of cannabinoid. AAPCC reported 6,968 exposure calls in 2011 and 5,230 calls in
2012. While exposure calls decreased in 2013 to 2,668, calls involving exposure to a synthetic cannabinoid rebounded in 2014 , reaching 3,680. In addition, 623 calls have been reported from January 1 through February 28, 2015. A majority of these exposure incidents resulted in5

medical attention being sought at health care facilities. Products containing at least one or more of the afore mentioned three synthetic cannabinoids have been connected to these exposure incidents

. Prior to the publication of the DEA Final Order on May 1 6 , 201 3 , the aforementioned substances and their associated products were obtainable on Internet websites and in local retail shops (e.g., head shops, convenient stores, and tobacco shops) , and with no regard for human health or safety, these substance were introduced with human consumption inten ded

. While mixed with green plant material, it is the laced synthetic cannabi noid that is considered to be the pharmacologically active component in these products (Zuba et al. , 2011 ; Wells and Ott, 2011 )

. Even with no currently accepted industrial or medical use for these substances, law enforcement, including Customs and Border Protection, has had numerous encou nters of bulk quantities (often exceeding 1 k g ) of synthetic cannabinoids, including UR

- 144, XLR11 and
AKB48

. Additionally, law enforcement officials ha ve uncovered clandestine product manufacturing labs of varying sizes. Furthermore, l aw enforcement has encountered individuals abusing herbal incense products, driving under the influence of herbal incense products, manufacturing said products, and responding to exposure incident s that warrant admission of the user s of these products to emergency departments. Accidental overdosing with complications is a public health concern . This is further exa cerbated by products that are marketed under one retail name despite having different amount s and t ypes of synthetic cannabinoid adulterated on to the plant material ( A u w ä rter et al., 2009; Dresen et al., 2010 ; Zuba et al. , 2011 )

. Finally, the lack of information regarding product i ngredients and composition
poses a dditional health and safety concerns for the unsuspecting user

.

I I. Eight Factors Determinative of Control
In accordance with the provisions of 21 U.S.C. § 811(b) of the Controlled Substances Act (CSA), the DEA has gathered the necessary data, including scientific, public health, and law enforcement information on these three substances , as well as the ir associated products. The DEA collected data in light of the information to be considered under 21 U.S.C. § 811(c). On August 31, 2013, the DEA request ed a scientific and medical evaluation and scheduling recommendation from the Assistant Secretary of Health for HHS for UR

- 144, XLR11 and AKB48 pursuant to 21 U.S.C. 811(b). Upon receipt and evaluation of the scientific and medical6

evaluation and scheduli ng recommendation from the Assistant Secretary, the DEA concluded its analysis of all other relevant data and implemented its proposal to place UR

- 144, XLR11 and AKB48 into s chedule I of the CSA.

Factor 1 : The A ctual or R elative P otential for A buse

Potential for Abuse The abuse potential of s chedule I hallucinogens, such as lysergic acid diethylamide (LSD), psilocybin, mescaline , and JWH

- 018 , is well documented. The abuse of these hallucinogens is associated with their ability to evoke hallucinogeni c effects. UR

- 144, XLR11 and AKB48 share pharmacological properties with s chedule I substance s , including delta

- 9

- tetrahydrocannabinol ( Δ 9

- THC ) and JWH

- 018 ( Weissman et al., 1982; Compton et al. , 1992; Wiley et al., 1998 ; Wiley et al., 2012 ). Behavioral evaluations in animal models, especially drug discrimination studies , demonstrate that cycloprop o ylindoles and indazole

- 3

- carboximides produce Δ 9

- THC

- like discriminative stimulus effects ( Wiley et al. , 2013; Perkin Elmer, 2013a; Perkin Elmer, 2013b; Frost et al., 2010; Aung et al., 2000; Wiley et al., 2012 ). The d rug discrimination study in animals is a pharmacologically selective behavioral animal model of

“ perceived” effects of psychoactive agents and highly predictive of psyc h oactivity in humans (Compto n et al., 1993; Solinas et al

. , 2006). Additionally, Compton and colleagues (1993) stated that their study provided evidence that in vitro cannabinoid binding affinity is predictive of in vivo potency in the rat drug discrimination model. In addition to these studies, t here are also numerous anecdotal self

- reports substantiating that these substances and the associated products are abused by humans for their hallucinogenic effects, as well as published reports indicating an increase in the abuse of the se substances (Lindigkeit et al., 2009; Every

- Palmer, 2011 ; AAPCC Press Releases)

. In evaluating symptoms upon smoking herbal incense products, Hermanns

- Clausen and colleagues (2009) reported similarities between cases resembling severe cannabis

- intoxicat ion in an abstract to the International Congress of the European Association of Poison Centres and Clinical Toxicologists . Furthermore, the observed health effects are not anticipated based on the declared herbs ( Auw ä rter et al., 2009; Lindigkeit et al., 2009; Zuba et al., 2011 ; Ernst et al. , 2011 )

.7

CB1 receptor binding studies conducted using UR

- 144, XLR11 and AKB48 resulted in binding affinity ( K i ) values of 28.9, 24.2 , and 304.5 nM , respectively . These dat a demonstrat e that UR

- 144, XLR11 , and AKB48 bind to the CB1 receptor with high affinity (Wiley et al. , 2013; Perkin Elmer, 2013a) . CB1 receptor functional assays for UR

- 144, XLR11 , and AKB48 resulted in EC 50 values of 98.1, 159 , and 585 nM , respectively . These data further demonstrate

t hat these compounds act as a gonists of the CB1 receptor (Wiley et al. , 2013; Perkin Elmer, 2013b). In addition, UR

- 144 , XLR11 , and AKB fully substituted for the discriminative effects of Δ 9

- THC in t he drug discrimination test (Wiley et al. , 2013 ; NIDA study reports ).

Abuse Liability Studies in Humans
UR

- 144, XLR11 , and AKB48 ha ve not been evaluated in human abuse liability studies. Furthermore, no studies have been undertaken to evaluate the toxicology and safety of these substances in humans. Due to the adverse health and safety concerns associated with the abuse of synthetic cannabinoids, research groups have investigated and published on the detection of synthetic cannabinoid s in specimens. A number of recent paper s reported on the detecti on of the urinary metabolites for UR

- 144, XLR11, and AKB48 ( Amaratunga et al, 2014; Mohr et al., 2014; Scheidweiler and Huestis, 2014; Scheidweiler et al., 2015)

.

Actual Abuse State public health departments and poison control center s have issue d warnings in response

to adverse health effects associated with herbal incense products containing synthetic cannabinoids to include tachycardia, elevated blood pressure, unconsciousness, tremors, seizures, vomiting, hallucinations, agitation, anxiety, pall or, numbness and tingling. N umerous public health and poison control centers have issued warnings regarding the abuse of synthetic cannabinoids and the ir associated products (Appendix 1 )

. Law enforcement has encountered incidents of exposure , primarily in response to the smoking of products purported to be laced with these substances ( Appendix 1 ). Synthetic cannabinoids have been reported in association with driving under the influence of drugs. Two articles publish ed results relating to UR

- 144 and one of the articles also included data on XLR11 (Louis et al., 2014; Karinen et al, 2015). Further, a scientific article described the effects produced by UR

- 144 and the associated impairment unsafe for driving (Adamowicz and Lechowicz, 2015). Bans o n the us e of these8

synthetic cannabinoids by m ilitary personnel have been issued in response to the abuse of synthetic cannabinoids and the ir related products (Bebarta et al. , 2010 ). Dresen and colleagues (2011) analyzed 101 serum samples from 80 subjects provided by different hospitals, detoxification and therapy centers, forensic psychiatry centers, and Institutes of Forensic Medicine. The prevalence of positive samples for synthetic cannabinoids was highest amongst those originating from forensic psychiatric centers, with 63.3% positive samples. Additionally, U.S. Drug Courts 3 have communicated concerns related to the abuse of synthetic cannabinoids. In addition, The Monitoring the Future study reported that 1 in 9 high school students have reported using synthetic cannabinoids (Johnston et al., 2013)

.

Factor 2 : Scientific E vidence of P harmacological E ffect, if K nown UR

- 144 and XLR11 are classified as cycloprop o ylindoles, a class of compounds that have previously been investigated due to their possible cytotoxic, anti

- cancer , or anti

- HIV potentials (Wang et al., 1996, Milbank et al., 1999, Sharma et al., 2001, Choi and Ma, 2010, Hassam, 2012) , as well as their affinity for cannabinoid receptors (Frost et al., 2010). Cu rrently available data for UR

- 144 include binding (Frost et al., 2010 ; Perkin Elm er, 2013a; Wiley et al , 2013) , locomotor ( NIDA 2013 e ) , and drug discrimination (Wiley et al. , 2013 ; NIDA 2013j ) data (Table 1). Similarly, currently available data for XLR11 include binding , functional , and drug discrimination data (Wiley et al. , 2013) , as well as locomotor data ( NIDA 2013 f ; Table 1). AKB48 is classified as a n indazole

- 3

- carboxamide and has been reported in the literature as a

cann abinoid agonist (Uchiyama et al. , 2013 ; Uchiyama et al., 2012 ). To date, AKB48 has been evaluated in in vitro binding and functional assays (Perkin Elmer, 2013a; Perkin Elmer 2013b) and in in vivo , locomotor (2013g; see Table 1) , and drug discrimination (NIDA 2013l; see Table 1) assays

.

Receptor Binding Profile s UR

- 144 : The CB1 receptor binding assay for UR

- 144 involved membrane preparations isolated from a HEK

- 293 expression system. UR

- 144 binds to CB1 receptor with a reported

3 Drug courts were developed to achieve a reduction in recidivism and substance abuse among nonviolent, substance abusing offenders by increasing their likelihood for successful rehabilitation through early, continuous, and intense judicially supervised tre atment, mandatory periodic drug testing, and the use of appropriate sanctions and other rehabilitation services. Drug courts analyze specimens from participants for new and existing drugs of abuse.9

binding affinity (K i ) of 150 nM and to the CB2 receptor with a reported binding affinity (K i ) of
1.8 nM (Frost et al., 2010). Another study shows that UR

- 144 binds to the CB1 receptor with an apparent K i value of 28.9 nM and to the CB2 receptor with an apparent K i value of 4.51 nM (Wiley et al. , 2013)

. XLR11 : The CB1 receptor binding assay for XLR11 involved membrane preparations isolated from a HEK

- 293 expression system. XLR11 was shown to bind to the CB1 receptor with an apparent K i value of 24.2 nM and to the CB2 receptor with an apparent K i value of 2.13
nM (Wiley et al. , 2013).
AKB48 : AKB48 has been evaluated in a human CB1 receptor binding study. AKB48 was shown to bind to the CB1 receptor with an apparen t K i value of 304.5 nM ( NIDA 2013c ).

Receptor Activation
UR

- 144 : UR

- 144 has been investigated via a functional assay , guanosine triphosphate (GTP γ [ 35 S]) binding assay

. UR

- 144 stimulated GTPγ[35S] turnover through the human CB1 receptor at nanomolar concentrations, which is indicative of compounds that can act as agonists

at G protein

- coupled receptor sites. UR

- 144 is an agonist at the CB1 receptor with a reported
EC 50 of 98.1 nM and an agonist at the CB2 receptor with a reported EC 50 of 334 nM (Wiley et al. , 2013).
XLR11 : XLR11 has been investigated via a functional assay , GTP γ [ 35 S] binding assay

. XLR11 stimulated GTP

- γ

35 S turnover through the human CB1 receptor at nanomolar concentrations, which is indicative of compounds that can act as agonists at G protein

- coupled receptor sites. XLR11 is an agonist at the CB1 recept or with a reported EC 50 of 159 nM and an agonist at the CB2 receptor with a reported EC 50 of 145 nM (Wiley et al. , 2013). AKB48 : AKB48 has been investigated via a functional assay. A functional CB1 (human) assay was performed using CHO cells that expressed the human CB1 receptor. AKB48 is an agonist at the CB1 receptor with a reported EC 50 of 585 nM ( NIDA 2013c ).

Animal Studies

– Drug Discrimination
A c an nabinoid drug discrimination stud y is an accepted animal model for predicting subjective effects in humans (Balster and Prescott, 1992).10

UR

- 144 : UR

- 144 substituted fully ( median effective dose, ED 50 = 7.1 μmol /kg, 30 minutes before testing) for the discriminative stimulus effects of THC in mice trained to discriminate 5.6 mg/kg of THC from vehicle control. Full substitution occurred at a dose (5.6 mg/kg) that did not alter response rate (Wiley et al. , 2013).
XLR11 : XLR11 substituted fully (ED 50 = 3.3 μmol/kg, 30 minutes before testing) for the discriminative stimulus effects of THC in mice trained to discriminate 5.6 mg/kg of THC from vehicle control. Full substitution occurred at a dose (3 mg/kg) that did no t alter re sponse rate (Wiley et al. , 2013).
AKB48 : XLR11 substituted fully (ED 50 = 0.23 mg/kg, 30 minutes before testing) for the discriminative stimulus effects of THC in mice trained to discriminate 3.0 mg/kg of THC from vehicle control. (NIDA, 2013l ).

Animal Studies

– Locomotor Effects
UR

- 144 : Treatment with UR

- 144 resulted in time

- and dose

- dependent depression of locomotor activity following 10 and 30 mg/kg ( NIDA 2013 e ) . Depressant effects of 10 and 30 mg/kg occurred within 10 minutes following inje ction and lasted 60 to 90 minutes. An ID 50 of 7.8 mg/kg was estimated based on a 30

- minute time period in which maximal depressant effects occurred (10 to 40 minutes following injection).
XLR11 : Treatment with XLR11 resulted in time

- and dose

- dependent depression of locomotor activity following 10 and 30 mg/kg ( NIDA 2013 f ) . Depressant effects of 10 and 30 mg/kg occurred within 10 minutes following injection and lasted 40 to 60 minutes. An ID 50 of 10.3 mg/kg was estimated based on a 30

- minute time period in which maximal depressant effects occurred (10 to 40 minutes following injection).
AKB48 : Treatment with AKB48 resulted in time

- and dose

- dependent depression of locomotor activity following 3 to 30 mg/kg ( NIDA 2013 g ) . Depressant effects of 3 mg/kg

occu rred within 20 minutes following injection and lasted 70 minutes. An ID 50 of 2.2 mg/kg was estimated based on a 30

- minute time period in which maximal depressant effects occurred (10 to 40 minutes following injection). Animal Studies

– Tetrad Test The mouse tetrad is a well

- established paradigm for evaluating substances for cannabimimetic properties (Martin et al., 1991). Each mouse i s tested in a battery of four tests,11

in which cannabinoid agonists have been previously shown to produce a character istic profile of in vivo effects including: 1) suppression of locomotor activity, 2) antinociception in the warm water tail withdrawal assay, 3) decreased rectal temperature and 4) ring immobility. UR

- 144 and XLR11 ha ve been evaluated in all four parameter s of the mouse tetrad ( Wiley et al. , 2013 ). Δ 9

- THC (positive control), and they exhibited the complete profile of cannabinoid effects in the tetrad tests in mice, with each compound producing dose

- dependent suppression of spontaneous activity, antinociception, hypothermia and ring immobility. ED 50 values are listed in Table 1. With the exception of the effect of UR

- 144 on spontaneous activity, one or more doses of each compound significantly affected each meas ure (p<0.05, compared to vehicle/ne gative control).
UR

- 144 showed a trend towards decreased activity; however the effect did not reach statistical significance. AKB48 was not evaluated using the mouse tetrad test.

Table 1. Potencies of compounds in the tetrad test for Δ 9

- THC, UR

- 144 and XLR11 A

Compound Spontaneous

Activity Hot Water Tail

Immersion Test Rectal

Temperature Ring Immobility

Δ 9

- THC 15 12 4 3
UR

- 144 1 2.6 0.6 1
XLR11 0.9 3.3 0.6 0.6

A Values represent ED 50 in μmol/kg . ( Wiley et al. , 2013 )12

Table 2

. Summary of Available Pharmacology Data for UR

- 144, XLR11 , and AKB48

In vitr o In vivo Binding at CB1 Function at CB1 Locomotor Activity (8

- hr session) THC Drug

Discrimination

UR

- 144 K i = 28.9 nM H

K i = 150 nM M K i = 29 nM N Agonist

EC 50 = 98 nM N Agonist EC 50 = 1295 nM A Depressed

ID 50 =7.8 mg/kg E Full Substitution ED 50 = 7.1 μmol/kg N Full Substitution ED 50 = 0.44 mg/kg J XLR11 K i = 24.2 nM I

K i = 24 nM N Agonist

EC 50 = 159 nM N Agonist EC 50 = 98.1 nM B Depressed

ID 50 =10.3 mg/kg F Full Substitution ED 50 = 3.3 μmol/kg N Full Substitution ED 50 = 0.16 mg/kg K AKB48 K i = 304.5

nM C Agonist

EC 50 = 585 nM D Depressed

ID 50 =2.2 mg/kg G Full Substitution

ED 50 = 0.23 mg/kg L

A NIDA , 2013a
B NIDA , 2013b C NIDA, 2013c
D NIDA, 2013d
E NIDA, 2013e
F NIDA, 2013f
G NIDA, 2013g
H NIDA, 2013h
I NIDA, 2013i
J NIDA, 2013j
K NIDA, 2013k
L NIDA, 2013l
M ( Frost et al., 2010 )
N ( Wiley et al., 2013 )

Human Studies No human clinical studies involving UR

- 144, XLR11 , or AKB48 have been reported.

Factor 3 : The S tate of C urrent S cientific K nowledge R egarding UR

- 144, XLR11 , and AKB48 Synthetic cannabinoids emerged in the early 1980s

. They were o riginally designed to investigate structure activity relationships ( SAR ) based on the potent substance, 9

- nor

- 9β

hydroxyhexahydrocannabinol (HHC) (Weissman et al., 1982; Melvin et al. , 1984). I nterest in13

various s tructural class es was generated by the mouse vas deferens (MVD) and prostaglandin synthetase activity of pravadol ine and subsequent finding of affinity to the cannabinoid receptor (Huffman, 2009)

. The emergen ce of synthetic cannabinoids in the designer drug marke t can be traced to the initial forensic laboratory confirmation i n mid

- December 2008 . A commercial laboratory in Frankfurt , Germany announced the identification of JWH

- 018 in samples of herbal incense , and others were identified shortly after this initial determination (Piggee, 2009). UR

- 144 and XLR11 are classified as cycloprop o ylindoles , whereas AKB48 is classified as a n indazole

- 3

-

c arboximide . While UR

- 144 was first developed as a rese arch tool by Abbott L aboratories (Frost et al., 2010) , XLR11 and AKB48 were not designed for use in the laboratory and began showing up in seizures in 2011.14

Chemistry and Physical Properties

Figure 1. Chemical Structures of UR

- 144, XLR11 , and AKB48

Table 3

. The chemical and physical properties of 1

- pentyl

- 3

- (2,2,3,3

- tetramethylcyclopropoyl)indole
1

- pentyl

- 3

- (2,2,3,3

- tetramethylcyclopropoyl)indole CAS # 1199943

- 44

- 6 Chemical Formula C 21 H 29 NO Molecular Weight 311.5 Synonyms UR

- 144 Systemic Name (IUPAC, CAS) (1

- pentyl

- 1 H

- indol

- 3

- yl)(2,2,3,3

- tetramethylcyclopropyl)methanone

Table 4

. The chemical and ph ysical properties of 1

- (5

- fluoro

- pentyl)

- 3

- (2,2,3,3

- tetramethylcyclopropoyl)indole 1

- (5

- fluoro

- pentyl)

- 3

- (2,2,3,3

- tetramethylcyclopropoyl)indole CAS # 1364933

- 54

- 9 Chemical Formula C 21 H 28 FNO Molecular Weight 329.5 Synonyms XLR11 , XLR

- 11 , 5

- fluoro

- UR

- 144, 5

- F

UR

- 144 Systemic Name (IUPAC, CAS) [1

- (5

- fluoro

- pentyl)

- 1 H

- indol

- 3

- yl](2,2,3,3

- tetramethylcyclopropyl)methanone15

Table 5

. The chemical and physical properties of N

- (1

- adamantyl)

- 1

- pentyl

- 1 H

- indazole

- 3

- carboxamide

N

- (1

- adamantyl)

- 1

- pentyl

- 1H

- indazole

3

- carboxamide CAS # 1345973

- 53

- 6 Chemical Formula C 23 H 31 N 3 O Molecular Weight 365.5 Synonyms AKB48 , APINACA Systemic Name (IUPAC, CAS) N

- (1

- adamantyl)

- 1

- pentyl

- 1 H

- indazole

- 3

- carboxamide

Laboratory analyses of numerous herbal incense products have been conducted and results have been published in the scientific literature detail ing the identification of these synthetic cannabinoids in products and the variations in the amount of the substance spiked on the plant material in products sold through retail channels (A u w ä rter et al., 2009; EMCDDA, 2009 ; Dresen et al., 2010; Uchiyama et al., 2010; Hudson et al., 2010 ; Zuba et al. , 2011 ; Uchiyama et al., 2013; Langer et al., 2013; Kavanagh et al., 2013 ).

Metabolism and Pharmacokinetics Sobolesvsky et al. (2012) analyzed the metabolites of UR

- 144 both in vitro and from human urine samples. Results demonstrated a high level of correlation between the in vitro and in vivo results with, with three out of the five metabolites detected in urine samples. It was noted that
UR

- 144 almost completely metabolizes i n vivo , and it was suggested that both the mono

- and dihydroxy metabolites of UR

- 144 should be detectable at least one week following administration (Sobolevsky et al., 2012). Grigoryev et al. (2013) described the detection of 16 metabolites of UR

- 144 and 21 metabolites of the major UR

- 144 pyrolysis products obtained from urine samples as shown via LC

- MS (liquid chromatography

– mas spectroscopy) and GC

MS (gas chromatography

- mass spectroscopy). Compounds containing hydroxyl groups on the aliphatic moieti es were identified as the most abundant metabolites (Grigoryev et al., 2013). Wohlfarth et al. (2013) reported that XLR

- 11 underwent phase I and II metabolism, producing more than 25 metabolites resulting from hydroxylation, carboxylation, hemiketal , and hemiacetal formation, internal dehydration, and further glucuronidation of some oxidative metabolites. XLR11 was shown to be deflourinated, thus producing UR

- 144 metabolites as well. Based on results from mass spectrometry, Wohlfarth et al. (2013) report ed major16

metabolites of XLR11 that included 2

- carboxy

- XLR

- 11, UR

- 144 pentanoic acid, 5

- hydroxy

UR

- 144, hydroxy

- XLR

- 11 glucuronides, and 2

- carboxy

- UR

- 144 pentanoic acid.

Medical Application The DEA is not aware of any currently accepted medical use or New Drug Applications (NDA) for UR

- 144, XLR11 , or AKB48

. A letter dated February 14, 2013 was sent from DEA Deputy Administrator to Assistant Secretary for Health, Departme nt for Health and Human Services as notification of intent to tempor arily place these three substances in s chedule I and solicited comments, including whether there is an exemption or approval was in effect for the substances in question under the Federal Food, Drug and Cosmetic Act. The Assistant Secretary of Health responde d that there were no current INDs or NDAs for these synthetic cannabinoids in a letter to the DEA Assistant Administrator dated March 14, 2013

. In their scheduling recommendation, the HHS reiterated that UR

- 144, XLR11 , and AKB48 have no known accepted medical use, are not the subject of any approved new drug applications (NDA) or investigational new drug applications (IND), and are not currently marketed as any approved drug products.

Factor 4: H istory and C urrent P attern of A buse Synthetic cannabinoids were first reported in the United States in a December 2008 encounter, where a shipment of “Spice” was seized and analyzed by U.S. Customs and Border Patrol in Dayton, Ohio. Additionally around the same time, in December 2008, JWH

- 018 and cannabicyclohexanol were identified by German forensic laboratories (EMCDDA, 2009). Though these substances were not identified until 2008, these substances likely existed and were abused some time prior to their identificat ion (Psychonaut Web Mapping Research Group, 2009). Since the initial identification of JWH

- 018 (December 2008), many additional synthetic cannabinoids have been found laced on related products (Auwarter et al., 2009 ; DEA, 2009). The popularity of these ca nnabimimetic substances and their associated products appears to have increased since January 2010 in the United States based on seizure exhibits and media reports. This trend appears to mirror those experienced in Europe since 2008 (EMCDDA, 2009). Synth etic cannabinoids are being encountered in most regions of the U.S. with the17

substances found as adulterants on plant material or being abused alone as self

- reported on internet discussion boards (Atwood et al., 2010). Data gathered from published studie s, supplemented by discussions on Internet discussion websites and personal communications demonstrate that these products are being abused mainly by smoking for their psychoactive properties. The adulte rated products are marketed as “ legal ” alternatives to marijuana. It is believed t his characterization and their reputation as potent herbal intoxicants has contributed to their increased their popularity (Lindigkeit et al., 2009). These substances alone or laced on plant material have the potential to be extremely harmful to the user due to their method of manufacture and the potency of the substances. Several synthetic cannabinoids have been shown to display higher potency in vitro and in vivo when compared to Δ 9

- THC (Compton et al., 1992a ; Wiley et al., 1998). Smoking mixtures of these substances abused for the purpose of achieving intoxication have resulted in numerous emergency room visits and calls to poison control centers. Numerous states, local jurisdictions, and the international community h ave also controlled these substances. Synthetic cannabinoids have been developed over the last 30 years to be used as tools for investigating the cannabinoid system (Weissman et al., 1982; Huffman et al., 1996; Huffman et al., 1999). Subsequently, these s ubstances have been identified as adulterants in numerous retail products (Auwa rter et al., 2009; EMCDDA, 2009; Lindigkeit et al., 2009 ; Dresen et al.,
2010 ; Hudson et al., 2010 ; Uchiyama et al., 2010 ; Uchiyama, 2012 ; Uchiyama et al., 2013; Kavanagh et al. , 2013 ). JWH

- 018 was the first synthetic cannabinoid to be identified as a product adulterant in Germany in 2008. This substance was initially synthesized as a research tool to investigate the cannabinoid system (Huffman et al. , 1994 ; Wiley et al., 1998) . Since then, numerous other synthetic cannabinoids including UR

- 144, XLR11 and AKB48 have been identified as product adulterants and bulk seizures have occurred by law enforcement. NFLIS details over 48,324 reports from forensic laboratories identifying UR

- 144, XLR11 and AKB48 in drug related reports for a period from January 2010 to December 2014. In addition, STRIDE and STARLiMS have 6,271 reports involving UR

- 144, XLR11 and AKB48 from January 1, 2010 through December 31, 2014. Youth appear to be the primary abusers of synthetic cannabinoids and synthetic cannabinoid

- containing products, as supported by law enforcement encounters and reports from18

emergency rooms (SAMHSA, 2012) 4 ; however, all age groups have been discussed in media reports as abusing these substances and related products. In 2010, an estimated 11,406 emergency department (ED) visits involved a synthetic cannabinoid product. For patients between the ages of 12

- 29 , 75% of emergency department visits in 2010 involved synthetic cannabinoids. In 2011, the estimated ED visits involving a synthetic cannabiniod increased significantly to an estimated 28,531 visits (SAMHSA, 2014). Synthetic cannabinoids were involved in 79% of ED patients between the ages of 12 and 29 in 2011. In addition, the majority (65%) of emergency department visits of patients aged 20 and younger, which involved SCs, did not involve any other substance. Of the remaining 35% of these individuals, the most frequently abused substances in combination with SCs were marijuana (17%), pharmaceuticals (16%) and alcohol (15%) (SAMHSA, 2014) . Individuals , including minors , are purchasing synthetic cannabinoids from Internet websites, gas stations, conveni ence stores, and head shops. These substances and pro ducts laced with synthetic cannabinoids are commonly marketed as “legal highs” with a disclaimer of “ not for human consumption

. ” As detailed in reports, law enforcement and public health officials are encountering the abuse of these substances and their associated products (CDC, 2013 ; NFLIS, 2013 ; STRIDE, 2013 , STARLiMS, 2014 ).
Numerous “ herbal incense ” products have been found to contain one or more synthetic cannabinoid(s) ( ex. UR

- 144, XLR11 and/or AKB48) laced on plant material (Appendix 1). There is no known explanation for the addition of these synthetic cannabinoids to plant material being marketed as herbal incense, other than for their psychoactive properties (Lindigkeit et al., 2009). The ps ychoactive properties are directly linked to the synthetic cannabinoids laced on the plant material sold as retail products (Auwarter et al., 2009 ; EMCDDA, 2009, Atwood et al., 2010). To lace the plant material, the synthetic cannabinoids are generally di ssolved in a solvent and sprayed on the plant material or the plant material is soaked in a solution of the dissolved substance (Vardakou et al., 2010 ; Wells and Ott, 2011). Two research articles propose that the packaging is professional and inconspicuou s (unlabeled), targeting young people who are eager to use cannabis but are afraid of the judicial consequences and its association with illicit drugs (Lindigkeit et al., 2009 : Schifano, 2009).

4 SAMHSA is a branch of the U.S. Department of Health and Human Services. It is charged with improving the quality and availability of prevention, treatment, and rehabilitative services in order to reduce illness, death, disability, and cost to society resulting from substance abuse and mental illnesses.19

Dresen and colleagues (2010) found that synthetic cannabinoid s are being abused by individuals in drug treatment centers with a positive rate of 63.3% in forensic psychiatric centers based on their sampling. U.S. Drug Courts have communicated concerns related to the abuse of synthetic cannabinoids and a response ra te of greater than 30% by juveniles subject to routin e drug screens from a sampling

. As part of the Monitoring the Future (MTF) 5 Report for 2012, some of the most important findings were presented in a press release on December 19, 2012. In this press re lease, the MTF study detailed that while synthetic cannabinoid use has remained level in 12th graders at 11.3%, “the fact that its prevalence rate has remained high despite federal and state efforts to reduce its
use is tro ublesome” (Johnston et al., 2013 ) . For the first time, synthetic cannabinoid use in 8th and 10th graders was measured, with annual prevalence rates being 4.4% and 8.8% respectively. In the most recent report from MTF (2014), annual prevalence for synthetic cannabinoid use was 3.3% for 8t h graders, 5.4% for 10 th graders , and 5.8% for 12 th graders (Johnston et al., 2014).

Summary Recently, law enforcement has encountered UR

- 144, XLR11 , and AKB48 and their products in increasing numbers. Synthetic cannabinoids and their associated products are available over the Internet , in gas stations, convenience stores, and tobacco and head shops.
UR

- 144, XLR11 and AKB48, similar to the previously scheduled synthetic cannabinoids (DEA, 2012), have been seized alone and spiked on products that are marketed as herbal incense and promoted as legal alternatives to marijuana. The misuse and abuse of these substances and their associated products is a s ignificant problem for public health and safety.

Factor 5 : The S cope, D uration, and S ignificance of A buse As stated by the HHS, based on their pharmacological properties, it is reasonable to assume that, if uncontrolled, the scope, duration, and significance of UR

- 144, XLR11 , and AKB48 abuse could be similar to marijuana. NFLIS, a national database capturing data from forensic laboratories, has reported 46,324 reports (January 2010 to December 2014) related to UR

- 144,

5 MTF i s a national survey conducted by the Institute for Social Research at the University of Michigan under a grant from the National Institute on Drug Abuse (NIDA) that tracks drug use trends among American adolescents in the 8th, 10th, and 12th grades.20

XLR11 and AKB48 from 44 states (Table 10) (query date: April 30, 2015). STRIDE and STARLiMS have 6,271 reports involving UR

- 144, XLR11 and/or AKB48 from January 1, 2010 through December 31, 2014. Recently, increased exposure incidents have been documented by poison control centers in the United States as the abuse of synthetic cannabinoids has b een associated with both acute and long

- term public health and safety concerns. The American Association of Poison Control Centers (AAPCC) has reported exposure calls corresponding to products purportedly laced with synthetic cannabinoids since 2011, alth ough the data provided does not generally include biological sample testing that would confirm the specific cannabinoid. AAPCC reported 6,968 exposure calls in 2011 and 5,230 calls in 2012. While exposure calls decreased in 2013 to 2,668, calls involving exposure to a synthetic cannabinoid rebounded in 2014 reaching 3,680. In addition, 623 calls have been reported from January 1 through February 28, 2015. 6 A majority of exposure incidents resulted in seeking medical attention at health care facilities. C hronic abuse of synthetic cannabinoids has been linked to signs of addiction and withdrawal similar to that experienced with cannabis abuse (Zimmermann et al., 2009, Muller et al., 2010, Vardakou et al., 2010). Additionally, tolerance to these drugs may d evelop fairly rapidly with larger doses being required to achieve the desired effect (EMCDDA, 2009). In 2010, the Substance Abuse and Mental Health Services Administration (SAMHSA) reported 11,406 emergency department visits involv ing a synthetic cannabino id product. In 2011, SAMHSA reported the number of emergency department visits involving a synthetic cannabinoid product had increased 2.5 times to 28,531 (SAMHSA, 2013) (Figure 2). Synthetic cannabinoids and the ir associated products are sold over the Int ernet and found to be abused by diverse populations. Since synthetic cannabinoids were never intended for human consumption, minimal information exists as to the short and long term health implications resulting from exposure to these substances (Griffith s et al., 2010 ; Vardakou et al., 2010). The

6 The content of this report does not necessarily reflect the opinions or conclusions of the American Association of Poison Control Centers. The American Association of Poison Control centers (AAPCC; http://www.aapcc.org) maintains the national database of infor mation logged by the country’s 57 Poison Control Centers (PCCs). Case records in this database are from self

- reported calls: they reflect only information provided when the public or healthcare professionals report an actual or potential exposure to a sub stance (e.g. an ingestion, inhalation, or topical exposure, etc.), or request information/educational materials. Exposures do not necessarily represent a poisoning or overdose. The AAPCC is not able to completely verify the accuracy of every report made to member centers. Additional exposures may go unreported to PCCs and data referenced from the AAPCC should not be construed to represent the complete incidence of national exposures to any substance(s).21

scientific literature and reports re viewed by the DEA suggest that tolerance and dependence to synthetic cannabinoids may develop (Zimmermann et al., 2009). The increased abuse of these synthetic cannabinoids in the United States is supported by an increasing number of encounters by law enforcement. Over the past year, in the United States, there has been a significant increase in availability, trafficking and abuse of UR

- 144, XLR11 , and AKB48, evident from th e increasing number of encounters reported by forensic laboratories (NFLIS data). The initial indication of the evidence of abuse of AKB48 appeared in 2011 upon identification in products, with evidence of abuse of UR

- 144 and XLR11 appearing in 2012. A
p revious temporary scheduling action of five synthetic cannabinoids (JWH

- 018, JWH

- 200,
JWH

- 073, CP

- 47,497 and CP

- 47,497 C8 homologue [cannabicyclohexanol], March 1, 2011), followed by the FDAISA (Food and Drug Administration Safety and Innovation Act) (July 9, 2012) permanently placed these initial five substances into s chedule I

. M anufacturers and users of synthetic cannabinoids then turned to new synthetic cannabinoids, namely UR

- 144, XLR11 and AKB48.

Figure 2. Emergency department visits involving synthetic cannabinoids (SAMHSA, 2013). Data were not collected prior to 2010.

*Estimates of ED visits are based on a representative sample of non

- Federal, general, short

- stay hospitals with 24

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

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

2010 2011 Number of ED Visits 

## Emergency Department Visits Involving

Synthetic Cannabinoids*22

Product analyses have yielded important information regarding these synthetic substances (Seely et al., 2013) . Smoking mixtures sold in Russia have been analyzed and found to contain
UR

- 144 along with other compounds, including JWH

- 018 (Sobolevsky et al ., 2012). AKB48,
UR

- 144 and XLR11 have also been identified in designer drugs currently bein g sold in Japan (Uchiyama et al. , 2013 ; Uchiyama et al., 2012 ). The chronic abuse of products laced with synthetic cannabinoids has been linked to addiction and withdrawal (Vardakou et al., 2010). Summary The abuse of synthetic cannabinoids is characterized in the scientific literature and by law enforcement encounters with reported adverse health effects. Numerous calls have been received by poison control cente rs regarding the abuse of products potentially laced with synthetic cannabinoids that have resulted in visits to emergency departments. Following the passage of FDAISA in July of 2012, new generations of synthetic cannabinoids including UR

144, XLR11 and AKB48 increasingly replaced those cannabinoids that were placed into

s chedule I of the CSA.

Factor 6 : What, I f A ny, R isk T here is to the P ublic H ealth Law enforcement, military, and public health officials have reported exposure incidents that demonstrate the dangers associated with the misuse and abuse of synthetic cannabinoids to both the individual abusers and other affected individuals since these substances were never intended for human use. Warnings regarding the dangers associated with a buse of synthetic cannabinoids and their products have been issued by numerous state public health departments , poison control centers , and private organizations. Detailed product analyses describe variations in the amount and specific synthetic cannab inoid laced on the plant material even within samplings of the same product (Hudson et al., 2010). These unknowns present a significant risk

o f danger to the abusing individuals (Auwarter et al., 2009, Hudson et al., 2010). Wells and Ott (2011) expressed concern regarding the possibility of serotonin syndrome related to synthetic cannabinoids of the indole structural class due to the similarity to serotonin. Some of the common clinical effects reported in emergency rooms in response to the abuse of synth etic cannabinoids include vomiting, anxiety, agitation, irritability, seizures, hallucinations, tachycardia, elevated blood pressure, and loss of consciousness (Harris and Brown, 2013;
Hermanns

- Clausen et al., 2013 ; Forrester et al., 2011; Cohen et al., 20 12) (see reports from state23

health departments and poison control centers including AAPCC, Appendix 1). In addition, Mushoff et al. (2013) detailed various driving under the influence case reports where users operated a motor vehicle while intoxicated with synthetic cannabinoids, including UR

- 144. By sharing pharmacological similarities with certain s chedule I substances (Δ 9

- T HC and
JWH

- 018), synthetic cannabinoids pose a risk to the abuser (Weissman et al., 1982, Compton et al., 1992a, Wiley et al., 1998), and the chronic abuse of products laced with synthetic cannabinoids has been linked to addiction and withdrawal (Vardakou et al., 2010). Submissions to DEA laboratories from January 2012 through April 03, 2013 have documented over 150 distinct packaging examples containing mixtures of UR

- 144, XLR11 , and/or AKB48. Similar products have been found to vary in the amount and ty pe of synthetic cannabinoid laced on the plant material, which could b e one explanation for the numerous emergency department admissions that have been connected to synthetic cannabinoids in general (Vearrier and Osterhoudt, 2010 ; Schneir et al., 2011). I n 2010, 11,406 emergency department visits involved a synthetic cannabinoid product (SAMHSA, 2012). In 2011, SAMHSA reported the number of emergency department visits involving a synthetic cannabinoid product had increased 2.5 times those reported in 2010 to 28,531 (SAMHSA, 2013). Health warnings have been issued by numerous state public health departments and poison control centers describing adverse health effects associated with smoking (inhaling) these products , including agitation, vomiting, tachycar dia, elevated blood pressure, seizures, hallucinations and non

- responsiveness (Appendix 1). Due to increasing trends in this newer generation of synthetic cannabinoids, UR

- 144 and XLR11 have been added to the toxicological panel (i.e. a list of synthetic cannabinoids commonly tested for) from two major laboratories. NMS Laboratories (Willow Grove, PA) re

analyzed 46 blood samples collected in July 2012. These samples initially tested positive for a synthetic drug compound, but they were not specifically tested for UR

- 144 or XLR11 at that time . Upon re

- analysis, 27/46 (58%) were positive for UR

- 144 and 14/4 6 (30%) were positive
for XLR11

. 7 An additional 28 samples that were collected in December 2012 were analyzed using NMS Laboratories new scope which includes UR

- 144 and XLR11 testing. Results from these 28 samples demonstrated 8/28 (28%) positivity for UR

- 144 and 1 2/28 (44%) positivity for

7 Correspondence from NMS Laboratories to DEA 12/3 1/201224

XLR11

. 8 Redwood Laboratories (Santa Rosa, CA) has also recently added UR

- 144 and XLR11 to their toxicological pan el. From January through June 2012, Redwood Laboratories reported between 6.5

– 9.7% positivity for synthetic cannabinoids , not including UR

- 144 or XLR11

. 9 These levels diminished in the subsequent 6 months between July and December 2012, falling from 8.0 % in July 2012 to a low of 2.8% positivity in December 2012. Using a new panel, Redwood Laboratories re

- analyzed 300 randomly chosen samples from December 2012, and found the positivity results climb to 16% (39/300 for UR

- 144 and/or XLR11 alone) for all synthetic cannabinoids tested when including UR

- 144 and XLR11 in the panel where tests without UR

- 144 and XLR11 showed only 2. 8 % positivity (Table 5 )

. 10 These data suggest

newer non

- controlled synthetic cannabinoids are being abused, specifically UR

- 144 a nd XLR11. A third company, Premier Integrity Solutions (Russell Springs, KY), supplies the toxicological services for the state of Kentucky’s drug court program. Data provided by the court coordinator for the state of Kentucky demonstrated that there wer e 310 drug tests for synthetic cannabinoids dating from July 1, 2012 , through December 20, 2012. Of these 310 drug tests, 24 were positive for synthetic cannabinoids, with 19/24 showing positivity for UR

144 or one of its metabolite s

. 11 , 12 No testing for XL R11 or AKB48 was reported.

Table 6

. Synthetic Cannabinoid Testing by Redwood Laboratories
Percent Positivity Synthetic Cannabinoids a (Excluding UR

- 144/XLR11) Synthetic Cannabinoids b (Including UR

- 144/XLR11) December 2012 2.8 % 16 %

a 238/8118 total blood samples tested by Redwood Laboratories in December 2012 b 39/300 randomly selected blood samples by Redwood Laboratories from December 2012

Since abusers obtain these drugs through unknown sources, purity of these drugs is uncertain, thus posing significant adverse health risk to these users (EMCDDA, 2009 ; Dresen et al., 2010). As mentioned above, there are reported instances of emergency department admissions in association with the abuse of these THC

- like substances. There is no cu rrently accepted medical use of these substances in the United States.

8 Correspondence from NMS Laboratories to the DEA on 12/20/2012

. 9 Correspondence from Redwood Laboratories to the DEA on 01/07/2013

. 10 Correspondence from Redwood Laboratories to the DEA on 01/07/2013

. 11 Correspondence from Kentucky Court System to the DEA on 12/20/2012

. 12 Correspondence from Kentucky Court System to the DEA on 12/21/2012

.25

At least one death has been reported in Minnesota following ingestion of UR

- 144 and
XLR11

. 13 One death has been reported following the ingestion of AKB48

. 14 In 2013 in California, a 27

- year

- old female developed hypertension, tachycardia and rhabdomyolisis prior to being intubated and admitted to the ICU for protection of the airway following ingestion of a synthetic cannabinoid product containing XLR11

. 15 A 33

- year

- old man developed acut e cerebral ischemia and infarction shortly following the use of XLR11 (Takematsu et al., 2014)

. In addition, reports have detailed various driving under the influence cases where users operated a motor vehicle while intoxicated with synthetic cannabinoids, including UR

- 144, XLR11 , and/or AKB48 (Louis et al., 2014; Karinen et al., 2015)

. In a recent publication describing various adverse effects from synthetic cannabinoids, numerous cases are presented involving UR

- 144 and/or XLR11 (Gurney et al., 2014)

. Adverse effects reported included nausea, vomiting, flank and abdominal pain, mild agitation, panic attacks, involuntary muscle twitching, confusion, somnolence, dilated pupils, increased heart rate, low potassium in blood, mild increase in blood glucose a nd acute kidney injury (Gurney et al., 2014). In February 2013, the Centers for Disease Control (CDC) reported on an association between XLR11 exposure and acute kidney injury (CDC, 2013) . The CDC examined 16 patients with acute kidney injury who reported recent smoking of synthetic cannabinoids. Seven of the 16 patients smoked substances that were positive for XLR11 or its metabolite. In addition, one of these seven cases also tested positive for UR

- 144 (Thornton et al., 2013) . A case series describing nine patients with acute kidney injury following ingesting of XLR11 was reported from the Oregon and southwestern Washington state area from May

- October, 2012 (Buser et al., 2014). Additional case reports reported adverse health effects including nausea, v omiting, agitation, panic attacks, involuntary muscle twitching and confusion following ingestion of UR

144 and/or XLR11. According to a letter from Assistant Secretary of Health , Department of Health and Human Services (dated March 14, 2013, see attached ), the Food and Drug Administration has reported there are currently no approved drug applications and no investigational new drug applications for UR

- 144, XLR11 or AKB48.

13 Correspondence from Midwest Medical Examiner’s Office, Ramsey, MN to DEA 03/19/2015 14 Correspondence from Armed Forces Medical Examiner, Department of Defense to DEA 05/01/2015 15 Correspondence from FDA to DEA 05/12/201426

Factor 7 : P sychic or P hysiological D ependence L iability Chronic abuse of synthetic cannabinoids has been linked to signs of addiction and

w ithdrawal. According to the HHS , the pharmacologic profile s of UR

- 144, XLR11 , and AKB48 strongly suggest that they possess a physiological and psychological dependence liability that is sim ilar to that of delta

- 9 (∆9)

– tetrahydrocannabi nol ( s chedule I) and JWH

- 018 ( s chedule I). Additionally, tolerance to these drugs may develop fairly rapidly with larger doses being required to achieve the desired effect. While UR

- 144 and XLR11 are struct urally and pharmacologically related to JWH

- 018 , there are no studies or case reports that document the psychic or physiological dependence potential of UR

- 144, XLR11, or AKB48. Every

- Palmer (2010) has reported of the recurrence of psychosis in stable i ndividuals with a previous history. Every

- Palmer ( 2011 ) followed

- up the initial communication with interviews of 15 patients with severe mental illness in a New Zealand forensic and rehabilitation service. In a case report, dependence syndrome corresponding to the ICD

- 10 and DSM

- IV criteria and the physical withdrawal resembled cannabis dependence (Zimmermann et al., 2010) after the consumption of “Spice Gold.” Spice Gold has been found to contain the substance JWH

- 018

.

Factor 8 : Whether U R

- 144, XLR11 , and AKB48 are I mmediate P recursor s of a S ubstance A lready C ontro l led
UR

- 144, XLR11 , and AKB48 are not considered an immediate precursor of any controlled substance of the CSA as defined by Title 21, U.S.C § 802(23).

III. Findings for Schedule Placement Pursuant to 21 U.S.C. 812(b) 21 U.S.C. 812(b) requires the evaluation of a substance’s abuse potential, accepted medical use, and safety for use under medical supervision for scheduling under the CSA as a controlled substance. After con sideration of the above eight factors determinative of control of a substance (21 U.S.C. 811(c)), and a review of the scientific and medical evaluation and scheduling recommendation provided by the HHS, the DEA finds that UR

- 144, XLR11 , and AKB48 meet the following criteria for placement in Schedule I of the CSA pursuant to 21 U.S.C. 812 (b)( 1 ).27

1) UR

- 144, XLR11 , and AKB48 have a high potential for abuse.
UR

- 144 , XLR11 and AKB48 are synthetic substance s that produce cannabinoid

- like effects. The pharmacological similarity of UR

- 144 , XLR11 , and AKB48 to ∆9

- THC makes it reasonable to assume that their potential for abuse is high and would be similar to that of JWH

018, which is controlled in s chedule I of the CSA. NFLIS details over 48,324 reports from forensic laboratories identifying UR

- 144, XLR11 , and AKB48 for a period from January 2010 to December 2014. In addition, STRIDE and STARLiMS have 6,271 reports involving UR

144, XLR11 and AKB48 from Januar y 1, 2010 through December 31, 2014.

2) UR

- 144, XLR11 and ABK48 have no currently accepted medical use in treatment in the United States. According to the HHS, t here are no approved NDAs for UR

- 144, XLR11 , or AKB48 in the United States. There is no known therapeutic application for UR

- 144, XLR11 , or AKB48

. Therefore, UR

- 144, XLR11 , and AKB48 have no currently accepted medical use in the United
States.

3) There is a lack of accepted safety for use of UR

- 144, XLR11 and AKB48 under medical supervision. Since UR

- 144, XLR11 , and AKB48 have no approved medical use and have not be en thoroughly investigated as new drug s, their safety for use under medical supervision is not determined. In addition, adverse consequences t hought to be related to abuse of UR

- 144, XLR11 and /or AKB48 are documented in case reports. Se rious adverse effects including tachycardia, agitation, seizures and/or death have been reported following the ingestion of UR

144, XLR11 and/or AKB48. Thus, there is a lack of accepted sa fety for use of these substance s under medical supervision.28 References Adamowicz P, Lechowicz (2015). The influence of synthetic cannabinoid UR

- 144 on human psychomotor performance

– a case report demonstrating road traffic risks. Traffic Injury Prevention [epub ahead of print]
Amaratunga P, Thomas C, Lemberg BL, Lemberg D (2014). Quantitative measurement of XLR11 and UR

- 144 in oral fluid by LC

- MS

- MS. Jou rnal of Analytical Toxicology 38(6):315

- 321.
Atwood BK, Huffman J, Straiker A, Mackie K (2010)

. JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB receptor agonist. British Journal of P harmacology 160:585

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Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (2000) Influence of the N

- 1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding. Drug and Alcohol Dependence 60:133

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Auwarter V, Dresen S, Weinmann W, Muller M, Putz M, Ferreiros N (2009) 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? Journal of Mass S pectrometry 44:832

- 837. Balster RL and Prescott WR (1992). Δ9

- Tetrahydrocannabinol discrimination in rats as a model for cannabis intoxication. Neuroscience and Biobehavioral Reviews 16:55

- 62. Bebarta VS, Varney S, Sessions D, Barry D, and Borys D (2009). Spice: A New “Legal” Herbal Mixture Abused by Young Active Duty Military Personn el. NACCT 2010 Abstracts [abstract]. Clinical Toxicology 48(6):604

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Buser GL, Gerona RR, Horowitz BZ, Vian KP Troxell ML, Hendrickson RG, Houghton DC, Rozansky D, Su SW, Leman RF (2014). Acute kidney injury associated with smoking synthetic cannabino id. Clinical Toxicology 52:664

- 673.
Centers for Disease Control and Prevention (CDC). (2013) Acute kidney injury associated with synthetic cannabinoid use

-- multiple states, 2012. MMWR Morb ity Mortal ity W ee kly Rep ort 62(6):93

- 8.
Choi T, Ma E (2010)

. Structural necessity of indole C5

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- substitution of seco

- duocarmycin analogs for their cytotoxic activity. Molecules 15:7971

- 7984.
Cohen J, Morrison S, Greenberg J, Saidinejad M. (2012)

. Clinical presentation of intoxication due to synthetic cannabinoids. Pediatrics 129(4 ):e1064

- 1067.
Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR (1992a) Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9

- tetrahydrocannabinol. The Journal of Pharmacology and E xperimental T herapeutics 263:1118

- 1126.29

Compton DR, Johnson MR, Melvin LS, Martin BR (1992b). Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cann abimimetic agents. Journal of Pharmacology and Experimental Therapeutics 260(1):201

- 209.
Compton DR, Rice KC, De Costa BR, Razdan RK, Melvin LS, Johnson MR, Martin BR (1993). Cannabinoid structure

- activity relationships: correlation of receptor binding and in vivo activities. Journal of Pharmacology and Experimental Therapeutics 265:218

- 226.
D'Ambra TE, Estep KG, Bell MR, Eissenstat MA, Josef KA, Ward SJ, Haycock DA, Baizman ER, Casiano FM, Beglin NC, et al. (1992)

. Conformationally restrained analogue s of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor. Journal of Medicinal C hemistry 35:124

- 135.
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- 126.37 Appendix 1 Public Health 1. The Substance Abuse and Mental Health Services Administration (SAMHSA) reported that in 2010, an estimated 11,406 emergency department visits involved a synthetic cannabinoid product. 2. SAMHSA reported that in 2011, an estimated 28,531 emergency department visits involved a synthetic cannabinoid product, a significant increase over the 2010 estimated visits. 3. Monitoring the Future study results for 2012 (released 12/19/2012) state that for the second year of reporting, use of synthetic [cannabinoids] marijuana amongst 12 th graders held level at 11.3%. Study authors stated that while a leveling was encouraging, the high prevalence rate despite Federal and State efforts to reduce its use was trou blesome. 4. Monitoring the Future study results for 2013 (released 12/18/2013) state that use of synthetic marijuana amongst 12th graders fell from 11.3% in 2012 to 7.9% in 2013. 5. Health effects (as described by the AAPCC) from synthetic cannabinoids can be li fe

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

- marijuana/ 6. ...these substances are among the worst they have ever seen. People high on these drugs can get very agitated and violent, exhi bit psychosis and severe behavior changes, and have harmed themselves and others. Some have been admitted to psychiatric hospitals and have experience continued neurological and psychological effects (News Release

– American Association of Poison Control Ce nters: AAPCC Issues Statement on the Synthetic Drug Abuse Prevention Act, July 11, 2012). 7. Synthetic cannabinoids, commonly known as “synthetic marijuana,” “K2,” or “Spice,” are often sold in legal retail outlets as “herbal incense” or “potpourri”. They
are labeled “not for human consumption” to mask their intended purpose and avoid Food and Drug Administration (FDA) regulatory oversight of the manufacturing process. (Office of National Drug Control Policy) 8. At least 43 states have taken action to control one or more synthetic cannabinoids. (Office of National Drug Control Policy, 2014) 9. Spice users report experiences similar to those produced by marijuana

— elevated mood, relaxation, and altered perception

— and in some cases the effects are even stronger than tho se of marijuana. Some users report psychotic effects like extreme anxiety, paranoia, and hallucinations. (National Institute on Drug Abuse, 2014) 10. Spice abusers who have been taken to Poison Control Centers report symptoms that include rapid heart rate, vom iting, agitation, confusion, and hallucinations. Spice can also raise blood pressure and cause reduced blood supply to the heart (myocardial ischemia), and in a few cases it has been associated with heart attacks. Regular users38 may experience withdrawal an d addiction symptoms. (National Institute on Drug Abuse, 2014) 11. In order to protect public health and well

- being, Governor Maggie Hassan today declared a State of Emergency in the State of New Hampshire as a result of recent overdoses in Manchester and Conc ord as a result of the use or misuse of the synthetic cannabinoid identified as "Smacked!”. (Press Release: Governor Hassan Declares State of Emergency as a Result of Overdoses from Synthetic Cannabinoid

– August 14, 2014) 12. CESAR FAX, a publication from the Center for Substance Abuse Research at the University of Maryland (College Park), reported the results from Bonar et al. (2014) describing the results of the study of patients in a Midwestern residential treatment program. Results demonstrated that 71% of those reporting synthetic cannabinoid abuse used an SC

- containing product to avoid a positive drug test. The two most common reasons for SC use was “curiosity” (91%) and “to feel good or get high” (89%). (September, 2014)

Poison Control Centers

1. From January 1, 2011 through December 31, 2011 , poison centers nationwide have received 6,968 exposure calls regarding exposure to synthetic cannabinoids. 2. From January 1, 2012 through December 31, 2012 , poison centers nationwide have received 5,230 exposure calls regarding exposure to synthetic cannabinoids. 3. From January 1, 2013 through December 31, 2013 , poison centers nationwide have received 2,668 exposure calls regarding exposure to synthetic cannabinoids. 4. From January 1, 2014 through December 31, 2014 , p oison center s nationwide have received 3,680 exposure calls regarding exposure to synthetic cannabinoids. 5. From January 1, 2015 through February 28, 2015 , poison center s nationwide have received 623 exposure calls regarding exposure to synthetic cannabinoid s.39 Appendix 2 STRIDE and NFLIS Encounters

Table 8a. NFLIS

– State, Local, and other Federal National Forensic Laboratory Information System (NFLIS) Reports for 2010 (Queried on April 30, 2015)

2010 Total Q1 Q2 Q3 Q4 JWH

- 018 JWH

- 073 JWH

- 200 CP

- 47,497 CP

- 47,497 C8 homologue 138 413 670 1197 2418

UR

- 144 XLR11 AKB48 1* 0 0 0 1

*Encounter confirmed in Mar 2012; # = data is incomplete for 2013 Q1, still being reported

Table 8b. NFLIS

– State, Local, and Other FederalNational Forensic Laboratory Information System (NFLIS) Reports for 2011 (Queried on May 6, 2013)

2011 Total Q1 Q2 Q3 Q4 JWH

- 018 JWH

- 073 JWH

- 200 CP

- 47,497 CP

- 47,497 C8 homologue 1,515 994** 659 536 3,704

UR

- 144 XLR11 AKB48 0 0 0 50 50

** JWH

- 018, JWH

- 073, JWH

- 200, CP

- 47,497 and CP

- 47,497 C8 homologue were placed under emergency
s chedule I of the CSA on March 1, 2011.40

Table 8c. NFLIS

– State, Local, and other Federal National Forensic Laboratory Information System (NFLIS) Reports for 2012(Queried on April 30, 2015)

2012 Total Q1 Q2 Q3 Q4 JWH

018; JWH

- 073; JWH

200; CP

- 47,497 CP

47,497 C8 homologue 426 341 233 150 1,146

UR

- 144; XLR11; AKB48 548 3,368 6,306 5,257 15,479

Table 8d. NFLIS

– State, Local, and other Federal National Forensic Laboratory Information System (NFLIS) Reports for 2010 (Queried on April 30, 2015)

2013 Total Q1 Q2 Q3 Q4 JWH

- 018 JWH

- 073 JWH

- 200 CP

- 47,497 CP

- 47,497 C8 homologue 110 97 83 57 347

UR

- 144 XLR11 AKB48 6,733 6,616 3,954 2,838 20,14141

Table 8e. NFLIS

– State, Local, and other Federal National Forensic Laboratory Information System (NFLIS) Reports for 2010 (Queried on April 30, 2015)

2014 Total Q1 Q2 Q3 Q4 JWH

- 018 JWH

- 073 JWH

- 200 CP

- 47,497 CP

- 47,497 C8 homologue 68 29 16 11 124

UR

- 144 XLR11 AKB48 3,672 3,092 2,482 1,407 10,653

Table 8f. NFLIS

– State and Local National Forensic Laboratory Information System (NFLIS) Reports 2010

- 2014 Total (Queried on April 30, 2015)

2010 2011 2012 2013 2014 Total JWH

018; JWH

- 073; JWH

200; CP

- 47,497 CP

47,497 C8 homologue 2,418 3,704 1,150 347 124 7,743

UR

- 144; XLR11; AKB48 1 50 15,479 20,141 10,653 46,324

Table 9. STRIDE and STARLiMS Records (January 1, 2010 through December 31, 2014 *# ):

CASES RECORDS AKB48 63 201 UR

- 144 245 2,049 XLR11 487 4,041

* No reports identified in STRIDE regarding UR

- 144, XLR11 or AKB48 prior to January 2010 # Multiple records in STRIDE contained a combination of AKB48, UR

- 144 or XLR11 STRIDE collected the results of drug evidence analyzed at DEA laboratories and reflects evidence submitted by the DEA, other Federal law enforcement agencies, and some local law enforcement agencies. STRIDE data were queried through 09/30/2014 by date submitted to Federal forensic laboratories. On October 1, 2014, STARLiMS replaced STRIDE as the DEA laboratory drug evidence data system of record.42

Table 10. States reporting enco unters to NFLIS, state, local, and other Federal data 16

Alabama Alaska Arizona Arkansas California Colorado Connecticut Florida Georgia Hawaii Idaho Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Minnesota Missouri Mississippi Nebraska Nevada New Hampshire New Mexico North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania South Carolina Tennessee Texas Utah Virginia Wisconsin Wyoming New Jersey New York Washington West Virginia

Table 11. Selected Reports from Customs and Border Protection Laboratory ( August 2012

– December 2014)

Date of Detention Identified

Substance(s) Detained at Originated

from Destination TOTAL WEIGHT 8/22/2012 UR

- 144, URB602,

URB754 (mixture) Honolulu Intl Mail unknown Sun City, AZ unknown

9/12/2012 XLR11 Domestic seizure China Rancho Cordova, CA 2 kg

9/12/2012 AKB48 San Francisco Intl Mail China Las Cruces, NM 2 kg

10/5/2012 XLR11 San Francisco Intl Mail China Tustin, CA 3 kg

10/11/2012 XLR11 San Francisco Intl Mail China Sugarland, CA 6 kg

10/11/2012 XLR11 San Francisco Intl Mail China Houston, TX 6 kg

10/11/2012 XLR11 San Francisco Intl Mail China Stafford, TX 6 kg

10/11/2012 XLR11 San Francisco Intl Mail China Houston, TX 6 kg

10/18/2012 UR

- 144 San Francisco China Las Cruces, NM 1 kg

16 NFLIS data queried April 30, 2015 for the period between January 2010 and December 2014

.43 Intl Mail

10/18/2012 AKB48 San Francisco Intl Mail China Las Vegas, NV 1.5 kg

10/18/2012 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

10/18/2012 XLR11 San Francisco Intl Mail China Montebello, CA 3 kg

10/26/2012 AKB48 San Francisco Intl Mail China Hammond, LA 4 kg

10/26/2012 XLR11 San Francisco Intl Mail China El Monte, CA 4 kg

11/2/2012 UR

- 144 San Francisco Intl Mail China Las Cruces, NM 1 kg

11/8/2012 UR

- 144 San Francisco Intl Mail China Las Cruces, NM 1 kg

11/8/2012 UR

- 144 San Francisco Intl Mail China Las Cruces, NM 1.5 kg

11/8/2012 UR

- 144 San Francisco Intl Mail China Rowlett, TX 2 kg

11/29/2012 UR

- 144 San Francisco Intl Mail China Spokane, WA 500 grams

11/29/2012 XLR11 San Francisco Intl Mail China Ogden, UT 500 grams

12/6/2012 UR

- 144 San Francisco Intl Mail China Las Cruces, NM 1 kg

12/6/2012 XLR11 San Francisco Intl Mail China Sanford, FL 3 kg

12/20/2012 XLR11 FedEx Anchorage, AK China Bellrose, NY 2 kg

12/28/2011 UR

- 144 UPS Ontario unknown Las Vegas, NV unknown44 (LA Transfer) 12/31/2012 XLR11 San Francisco Intl Mail China Los Angeles, CA 1 kg

12/31/2012 AKB48 San Francisco Intl Mail China Los Angeles, CA 1 kg

12/31/2012 XLR11 San Francisco Intl Mail China Houston, TX 1 kg

12/31/2012 XLR11 San Francisco Intl Mail China Houston, TX 1 kg

12/31/2012 AKB48 San Francisco Intl Mail China Denham Springs, LA 1 kg

1/7/2013 UR

- 144 San Francisco Intl Mail China Las Cruces, NM 1 kg

1/7/2013 XLR11 San Francisco Intl Mail China Los Angeles, CA 2 kg

1/7/2013 AKB48 San Francisco Intl Mail China Los Angeles, CA 1 kg

1/18/2013 UR

- 144 San Francisco Intl Mail China Los Angeles, CA 2 kg

1/18/2013 XLR11 San Francisco Intl Mail China Houston, TX 1 kg

1/18/2013 XLR11 San Francisco Intl Mail China Richmond, TX 2 kg

1/18/2013 AKB48 San Francisco Intl Mail China Springfield, MO 1 kg

1/18/2013 UR

- 144 San Francisco Intl Mail China Los Angeles, CA 2 kg

1/24/2013 XLR11 San Francisco Intl Mail China Fullerton, CA 1 kg

1/24/2013 XLR11 San Francisco China Perris, CA 2 kg45 Intl Mail

1/24/2013 XLR11 San Francisco Intl Mail China Pleasanton, TX 2 kg

1/24/2013 XLR11 San Francisco Intl Mail China Lubbock, TX 1 kg

1/24/2013 XLR11 San Francisco Intl Mail China Lubbock, TX 1 kg

1/24/2013 XLR11 San Francisco Intl Mail China Tulsa, OK 2 kg

1/24/2013 XLR11 San Francisco Intl Mail China Perris, CA 2 kg

1/24/2013 XLR11 San Francisco Intl Mail China Perris, CA 2 kg

1/24/2013 XLR11 San Francisco Intl Mail China Fullerton, CA 2 kg

1/24/2013 XLR11 San Francisco Intl Mail China Fullerton, CA 2 kg

1/24/2013 XLR11 San Francisco Intl Mail China Perris, CA 2 kg

2/7/2013 XLR11 San Francisco Intl Mail China Lawndale, CA 1 kg

2/13/2013 UR

- 144 San Francisco Intl Mail China Freeland, WA 1 kg

2/13/2013 XLR11 San Francisco Intl Mail China Albuquerque, NM 600 grams

2/20/2013 XLR11 San Francisco Intl Mail China Park City, UT 1.3 kg

2/20/2013 UR

- 144 San Francisco Intl Mail China Salt Lake City, UT 600 grams

2/28/2013 XLR11 San Francisco China Bellingham, WA 1.2 kg46 Intl Mail

2/28/2013 XLR11 San Francisco Intl Mail China Houston, TX 1.6 kg

2/28/2013 UR

- 144 San Francisco Intl Mail China Las Cruces, NM 1.5 kg

2/28/2013 AKB48 San Francisco Intl Mail China Bainbridge Island, WA 1.3 kg

2/28/2013 AKB48 San Francisco Intl Mail China Newman Lake, WA 300 grams

3/6/2013 UR

- 144 San Francisco Intl Mail China Houston, TX 1.2 kg

3/13/2013 UR

- 144 Domestic seizure unknown Anchorage, AK 50 grams

3/21/2013 XLR11 FedEx Anchorage, AK China Santa Rosa, CA 7.8 kg

3/27/2013 XLR11 San Francisco Intl Mail China Las Vegas, NV 1.2 kg

3/29/2013 UR

- 144 San Francisco Intl Mail China Pineville, LA 500 grams

3/29/2013 UR

- 144 San Francisco Intl Mail China Boise, ID 500 grams

3/29/2013 XLR11 San Francisco Intl Mail China Pflugerville, TX 1 kg

3/29/2013 AKB48 San Francisco Intl Mail China Pflugerville, TX 1 kg

4/10/2013 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

4/10/2013 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

4/10/2013 XLR11 San Francisco China Houston, TX 3 kg47 Intl Mail

4/10/2013 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

4/17/2013 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

4/17/2013 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

4/17/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

4/17/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

4/17/2013 XLR11 Memphis TN Fed Ex China Salt Lake City, UT 3.5 kg

4/25/2013 XLR11 San Francisco Intl Mail China New Mexico 500 grams48

4/25/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

4/25/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

4/29/2013 XLR11 San Francisco Intl Mail China St. George, UT 4 kg

4/29/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

4/29/2013 XLR11 San Francisco Intl Mail China Chapparal, NM 1 kg

4/29/2013 XLR11 San Francisco Intl Mail China Clearfield, UT 500 grams

5/6/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

5/6/2013 XLR11 San Francisco Intl Mail China Stockton, CA 2 kg

5/6/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

5/6/2013 XLR11 San Francisco Intl Mail China Millbrae, CA 2 kg

5/6/2013 XLR11 San Francisco Intl Mail China Clearfield, UT 500 grams

5/10/2013 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

5/10/2013 XLR11 San Francisco Intl Mail China Danville, IL 500 grams

5/10/2013 UR

- 144 San Francisco Intl Mail China Metairie, LA 10 grams

5/16/2013 UR

- 144 San Francisco Intl Mail China Houston, TX 200 grams49

5/16/2013 UR

- 144 San Francisco Intl Mail China Houston, TX 5 kg

6/3/2013 UR

- 144 San Francisco Intl Mail China El Paso, TX 400 grams

6/3/2013 UR

- 144 San Francisco Intl Mail China Cypress, TX 100 grams

6/3/2013 XLR11 San Francisco Intl Mail China Kansas City, KS 1 kg

6/13/2013 XLR11 San Francisco Intl Mail China Delano, CA 1 kg

6/13/2013 XLR11 San Francisco Intl Mail China Belano, CA 1 kg

6/13/2013 XLR11 San Francisco Intl Mail China Seymour, TX 500 grams

7/1/2013 XLR11 FedEx Anchorage, AK China Sanford, FL 3 kg

7/2/2013 XLR11 FedEx Anchorage, AK China Sanford, FL 3.3 kg

7/10/2013 XLR11 San Francisco Intl Mail China Kansas City, KS 1 kg

8/22/2013 XLR11 San Francisco Intl Mail China New Laney, TX 200 grams

8/22/2013 XLR11 San Francisco Intl Mail China Casper, WY 1 kg

9/12/2013 XLR11 San Francisco Intl Mail China Raton, NM 1 kg

10/3/2013 XLR11 San Francisco Intl Mail unknown unknown 3.3 kg

10/3/2013 XLR11 San Francisco Intl Mail unknown unknown 1 kg50

10/17/2013 XLR11 San Francisco Intl Mail China Salt Lake City, UT 2 kg

10/17/2013 XLR11 San Francisco Intl Mail China Englewood, CO 1 kg

11/19/2013 XLR11 San Francisco Intl Mail China Canyon Country, CA 2 kg

11/19/2013 XLR11 San Francisco Intl Mail China Canyon Country, CA 3 kg

11/19/2013 XLR11 San Francisco Intl Mail China Canyon Country, CA 2 kg

11/19/2013 AKB48 San Francisco Intl Mail China Albuquerque, NM 3 kg

11/19/2013 AKB48 San Francisco Intl Mail China Albuquerque, NM 3 kg

12/5/2013 UR

- 144 San Francisco Intl Mail China Hidalgo, TX 200 grams

1/2/2014 XLR11 San Francisco Intl Mail China Los Angeles, CA 1 kg

3/20/2014 XLR11 San Francisco Intl Mail China Caguas, PR 4 kg

3/27/2014 XLR11 San Francisco Intl Mail China Salt Lake City, UT 1 kg

3/27/2014 XLR11 San Francisco Intl Mail China Houston, TX 1 kg

4/10/2014 UR

- 144 San Francisco Intl Mail China Los Angeles, CA 1 kg

4/17/2014 XLR11 San Francisco Intl Mail China Colorado Springs, CO 1 kg

4/29/2014 XLR11 San Francisco Intl Mail China Houston, TX 1 kg51

5/8/2014 XLR11 San Francisco Intl Mail China Marmaduke, AR 20 grams

5/15/2014 XLR11 San Francisco Intl Mail China Sand Springs, OK 6 grams

5/15/2014 XLR11 San Francisco Intl Mail China Los Angeles, CA 1 kg

6/10/2014 XLR11 San Francisco Intl Mail China Buena Park, CA 4 kg

6/6/2014 XLR11 San Francisco Intl Mail China Sand Springs, OK 6 grams

7/3/2014 XLR11 San Francisco Intl Mail China Albuquerque, NM 200 grams

7/22/2014 XLR11 FedEx Anchorage, AK China Recifel Pina, Brazil 20 grams

7/24/2014 XLR11 San Francisco Intl Mail China Albuquerque, NM 1 kg

7/31/2014 XLR11 San Francisco Intl Mail Hong

Kong Trumbull, CT 2 kg

7/31/2014 UR

- 144 San Francisco Intl Mail Hong

Kong Trumbull, CT 1 kg

7/31/2014 XLR11 San Francisco Intl Mail China Fountain Valley, CA 1 kg

8/19/2014 XLR11 San Francisco Intl Mail China Houston, TX 3 kg

8/26/2014 XLR11 San Francisco Intl Mail China Thomasville, GA 200 grams

9/2/2014 XLR11 San Francisco Intl Mail China Fountain Valley, CA 1 kg

9/16/2014 XLR11 FedEx Anchorage, AK China Louisville, KY 1 kg52

9/16/2014 XLR11 San Francisco Intl Mail China Dallas, TX 10 grams

9/26/2014 XLR11 Oakland FedEx China Astoria, NY 1 kg

10/15/2014 XLR11 San Francisco Intl Mail China Albany, CA 10 grams

10/21/2014 XLR11 San Francisco Intl Mail China Hartingen, TX 1 kg

10/21/2014 XLR11 San Francisco Intl Mail China Buena Park, CA 2 kg

10/21/2014 XLR11 San Francisco Intl Mail China Anaheim, CA 1 kg

10/21/2014 XLR11 San Francisco Intl Mail China Oakland, CA 150 grams

10/30/2014 XLR11 San Francisco Intl Mail China Jefferson, LA 1 kg

11/4/2014 XLR11 San Francisco Intl Mail China Los Angeles, CA 1 kg

12/16/2014 XLR11 San Francisco Intl Mail China Bakersfield, CA 1 kg

12/23/2014 XLR11 San Francisco Intl Mail China Donna, TX 400 grams

12/23/2014 XLR11 San Francisco Intl Mail China Donna, TX 500 grams