DEA/OD/ODE January 28 , 2014

4 - M ethyl
- N - ethylcathinone (4
- MEC), 4
- M ethyl
- alpha
- pyrrolidinopropiophenone (4
- MePPP), A l pha
- pyrrolidinopentiophenone (α
- PVP), 1 - (1,3
- B enzodioxol
- 5 - yl)
- 2 - (methylamino)butan
- 1 - one ( B utylone) , 2 - ( M ethylamino)
- 1 - phenylpentan
- 1 - one ( P entedrone) , 1 - (1,3
- B enzodioxol
- 5 - yl)
- 2 - (methylamino)pentan
- 1 - one ( P entylone) , 4 - F luoro
- N - methylcathinone (4
- FMC), 3
- F luoro
- N - methylcathinone (3
- FMC), 1 - ( N aphthalen
- 2 - yl)
- 2 - (pyrrolidin
- 1 - yl)pentan
- 1 - one

( N aphyrone), and A lpha
- pyrrolidinobutiophenone (α
- PBP)

Background Information and Evaluation of ‘Three Factor Analysis’ (Factors 4, 5 and 6) for Temporary Scheduling

Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement

Administration, Washington, DC 20537

January 201 4 

### I. Introduction Synthetic cathinones (also commonly referred to as substituted cathinones or cathinone derivatives) are β

- keto

- phenethylamine derivatives. A number of synthetic cathinones produce pharmacological effects that are substantially similar to those of the Schedule I substances cathinone, methcathinone, and 3,4

- methylenedioxymethamphetamine (MDMA) and Schedule II stimulants amphetamine, methamphetamine, and cocaine. P roducts tha t contain s ynthetic cathinones have been falsely marketed as “research chemicals,” “jewelry cleaner,” “stain remover,” “ plant food or fertilizer ,” “insect repellants” or “bath salts.” These products are sold at smoke shops, head shops, convenience stores, adult book stores, and gas stations and can also be purchased on the Internet. The packages of these commercial products usually contain the warning “not for human consumption” most likely in an effort to circumvent statutory restrictions for these subst ances.
The Drug Enforcement Administration (DEA) temporarily place d three synthetic cathinones, namely, 4

- methyl

- N

- methylcathinone ( mephedrone ) , 3,4

- methylenedioxy

- N

methylcathinone ( methylone ) , and 3,4

- methylenedioxypyrovalerone (MDPV) , in Schedule I ofDEA/OD/ODE Page 2 of 35 January 28 , 2014

the Controlled Substances Act (CSA) on October 21, 2011. 76 FR 65371. On July 9, 2012, President Obama signed the Food and Drug Administration Safety and Innovation Act (FDASIA), which made the manufacturing, distribution, dispensing, a nd possession of mephedrone and MDPV illegal 1

. On October 18, 2012, a final order was issued by DEA placing methylone in Schedule I of the CSA. 77 FR 64032.
Around the time that these three synthetic cathinones were scheduled, other synthetic cathinone substances, as evidenced by law enforcement encounters, emerged in the U.S. illicit drug market. These synthetic cathinone substances contain slight alteration s of the chemical structure of known Schedule I or II psychoactive substanc es (phen eth ylamines and β

- keto

phenethylamines). The other synthetic cathinone substances ar e (1) 4

- methyl

- N

ethylcathinone ( “ 4

- MEC ” ) ; (2) 4

- methyl

- alpha

- pyrrolidinopropiophenone ( “ 4

- MePPP ” ) ; (3) al pha

- pyrrolidinopentiophenone ( “ α - PVP ” ) ; (4) 1

- (1,3

- benzodioxol

- 5

- yl)

- 2

- (methylamino)butan

1

- one ( “ butylone ” ) ; (5) 2

- (methylamino)

- 1

- phenylpentan

- 1

- one ( “ pentedrone ” ) ; (6) 1

- (1,3

- benzodioxol

- 5

- yl)

- 2

- (methylamino)pentan

- 1

- one ( “ pentylone ” ) ; (7) 4

- fluoro

- N

- methylcathinone ( “ 4

- FMC ” ) ; (8) 3

- fluoro

- N

- meth ylcathinone ( “ 3

- FMC ” ) ; (9) 1

- (naphthalen

- 2

- yl)

- 2

- (pyrrolidin

- 1

- yl)pentan

- 1

- one ( “ naphyrone ” ) ; and ( 10 ) alpha

- pyrrolidinobutiophenone ( “ α - PBP ” )

. Evidence indicates that 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone , and α - PBP , like the Schedule I cathinone s mephedrone, methylone, and MDPV, are being abused for their psychoactive properties. Many of t hese synthetic cathinone substances share many substantial similarities with Schedule I and Schedule II substances including reported desired and adverse effects

. In general, d esired effects reported by abusers of synthetic cathinone substances include euphoria, sense of well

- being, increased sociabi l ity, energy, empathy, increased alertness, and improved concentrati on and focus. Abusers also report experiencing unwanted effects such as tremor, vomiting, agitation, sweating, fever, chest pain. Other a dverse or toxic e ffects that have been reported with the abuse of synthetic cathinones include tachycardia, hypertension, hyperthermia, mydriasis,

1 Subtitle D of the FDASIA titled the “Synthetic Drug Abuse Prevention Act of 2012,” (SDAPA) amended Schedule I of section 202 of the CSA.DEA/OD/ODE Page 3 of 35 January 28 , 2014

rhabdomyolysis, hyponatremia, seizures , altered mental status (paranoia, hallucinations, delusions), and even death. These 10 synthetic cathinone substances have no known medical use in the United State s but evidence demonstrates that these substances are being used by individuals. There have been documented reports of emergency room admissions and deaths associated with the abuse of synthetic cathinone substances. Th us, th e abuse of synthetic cathinon e substances including these 10 synthetic cathinone substances continues to be a serious public health threat. Evidence from poison centers , emergency departments (EDs) , and law enforcement indicates that synthetic cathinone substances c ontinue to be abused in the United States. According to a press release from the American Association of Poison Control Centers (AAPCC) , 2 there were 30 6 exposure calls related to synthetic cathinones in 20 10 , 6,13 7 calls in 2011 , and 2,6 91 calls in 2012 (AAPCC, 201 3 )

. As of October 31, 2013 , poison centers received 833 calls relating to human exposures to bath salts

. I n addition, according to the Drug Abuse Warning Network (DAWN) report released by t he Substance Abuse and Mental Health Services Administration (SAMHSA) 3 , i n 2011, “bath salts” were involved in 22,904 ED visits.
Both the National Forensic Laboratory Information System (NFLIS), a DEA sponsored program that systematically collects drug identification results and associated information from drug cases analyzed by F ederal , S tate , and local forensic laboratories, and the System T o Retrieve Information from Drug Evidence (STRIDE), a federal database for the drug samples analyzed by DEA forensic laboratories, registered encounters of 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP ( Table 1 , Factor 5 , and the Appendix ). In 2009, NFLIS registered no reports in state and local law enforcement laboratories regard ing these synthetic cathinone substances

. However, in 20 1 0 , there were 13 reports from 5 states related to these substances registered in NFLIS, in 2011 there were 800 reports from 3 2 states , in 2012 there were 5, 485 reports from 41 states , and from January to

2 AAPCC is a non

- profit, national organization that represents the poison control centers of the United States. 3 DAWN is a public health surveillance system that monitors drug

- related ED visits in the United States.DEA/OD/ODE Page 4 of 35 January 28 , 2014

Novem ber 2013 there were 2 , 509 reports from 41 states
. 4 From January 20 10 to Novem ber 201 3 , 1, 732 drug exhibits pertaining to the trafficking, distribution and abuse of 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP were recorded in the STRIDE database (which reports data from DEA laboratories ). 5 Law enforcement have encountered these synthetic cathinones substanc es mainly in powder, crystal , resin, tablet, and capsule forms. With no legitimate medical use and limited pharmacological information, these substances ( 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP ) have emerged on the designer drug market and are being abused for their psychoactive properties. To protect the public health and safety, DEA intends to temporarily place 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP in Schedule I of the CSA. With respect to finding an imminent hazard to the public safety, DEA has considered the factors required under the CSA for the temporary scheduling of 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP

. 21 U.S.C. 811(h)(3) and 811(c)(4)

- (6).

Synthetic Cathinones 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are synthetic cathinones ( β

- keto

- phenethylamines) of the larger phenethylamine structural class (amphetamines, cathinones, 2C compounds, aminoindanes, etc.). They are designer drugs of the phenethylamine class which are structurally and pharmacologically similar to amphetamine, MDMA, cathinone and other related substances. Synthetic cathinones share
a core phenethylamine structure with substitutions at the β

- position , α - position , phenyl ring , or nitrogen atom ( Figure 1 )

. The addition of a beta

- keto (β

- keto) substituent [ i.e., carbonyl (C=O)] to the phenethylamine core structure along with substitutions on the alpha ( α ) carbon (C) atom

4 NFLIS a nalyzed on 12/20/ 2013 for state an d local forensic drug reports. 5 STRIDE data was queried on 12 / 20 /2013 by date submitted to Federal forensic laboratories.DEA/OD/ODE Page 5 of 35 January 28 , 2014

or the nitrogen (N) a tom produce a variety of substances called cathinones or synthetic cathinones.

4 - MEC 4 - MePPP α - PVP B utylone

P entedrone P entylone 4 - FMC N aphyrone

3 - FMC α - PBP Figure 1 : Chemical Structures
Although the abuse potential of 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP has not been systematically studied in humans , the available data indicate that the pharmacological actions of these substances are substantially similar to those of stimulants and hallucinogens such as mephedrone, MDPV, cathinone methcathinone , and MDMA which are Schedule I substances with high potential for abuse. Scientific studies , which include those done by contract researchers for the National Institute on Drug Abuse (NIDA), evaluating the pharmacological activity of these synthetic cathinone substances demonstrate that these substances have pharmacological effects on the central nervous system that are substantially similar to those of the Schedule I and II substances, MDPV, methylone, mephedrone, methamphetamine , MDMA, methcathinone, andDEA/OD/ODE Page 6 of 35 January 28 , 2014

cocaine . Like these Schedule I and II substances, 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP bind to monoamine transporters for dopamine , serotonin, or norepinephrine and promote the release of these monoamines or block their uptake (Han and Gu, 2006; Howell and Kimmel, 2008)

. A ction s at these transporters , especially actions that alter dopaminergic neuro transmission, are believed to be involved in the production of the stimulant effects of the phenethylamine class of drugs (Rothman et al., 2001 ; Mori et al., 2012 ). Data also demonstrate that these synthetic cathinone substances are locomotor stimulants and produce dis criminative stimulus effects (as determined in drug discrimination studies) that are substantially similar to those of the Schedule I and II substances, methamphetamine and cocaine. In the drug discrimination paradigm, if a new drug or substance has discriminative stimulus effects in animals similar to a known drug of abuse, it is highly likely that this new drug will produce pharmacological effects (including subjective effects) in humans similar to the known drug of abuse and would be similarly abus ed by humans (Balster and Bigelow, 2003).
4

- M ethyl

- N

- ethylcathinone (4

- MEC) 4

- MEC , in addition to the β

- keto substituent [a carbonyl (C=O) group which is common amongst synthetic cathinones ] , has a ring substitution of a methyl (

- CH 3 ) group on the phenethylamine core structure and the nitrogen atom is substituted with an ethyl group (

- CH 2 CH 3 ) ( Figure 1 ). Scientific studies evaluating the pharmacological activi ty of 4

- MEC demonstrate that 4

- MEC has pharmacological effects that are substantially similar to those of mephedrone, MDPV, cathinone , methcathinone , and other related substances , which are Schedule I substances with high potential for abuse. In laborator y studies investigating the effects of drugs on monoaminergic systems, 4

- MEC, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in transfected cells (Cozzi et al., 1999; Eshleman et al., 2013; NIDA, 2013 ; Simmler et al., 2013 ). In locomotor activity assays, 4

- MEC, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , is a locomotor stimulant in rodents (Glennon et al., 1995; Baumann etDEA/OD/ODE Page 7 of 35 January 28 , 2014

al., 2012; NIDA, 201 2 ; Gatch et al., 2013 ). In d rug discrimination stud ies, 4

- MEC (ED 50 6 = 18.6 and 11.4 mg/kg ) , like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively, indicating that it is highly likely that this new drug will produce pharmacological effects (including subjective effects) in humans similar to the known drug s of abuse (i.e. methamphetamine or cocaine) and, thus, would be similarly abused by humans ( Balster and Bigelow, 2003 ; NIDA, 201 2 , 2013 ; Gatch et al., 2013 ).
4

- M ethyl

- α - pyrrolidino propiophenone (4

- MePPP) 4

- MePPP , in addition to the β

- keto substituent , has a ring substitution of a methyl (

- CH 3 ) group on the phenethylamine core structure and is substituted on the nitrogen atom to form a pyrrolidine ring ( Figure 1 )

. Scientific studies evaluating the pharmacological activity of 4

- MePPP demonstrate that 4

- MePPP has pharmacological effects that are substantially similar to those of mephedrone, MDPV, cath inone and methcathinone, which are Schedule I substances with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems 4

- MePPP, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in transfected cells (Eshleman et al., 2013; NIDA, 2013; Simmler et al., 2013). In locomotor activity assays, 4

- MePPP, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , increase s locomotor activity in rodents ( Glennon et al., 1995; N IDA, 2012 ; Baumann et al., 2013; Gatch et al., 2013). In d rug discrimination stud ies, 4

- MePPP (ED 50 = 13.35 and 8.91 mg/ kg), like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively ( NIDA, 2012; Gatch et al., 2013 )

.

6 ED 50 for drug discrimination studies is the dose at which the subjects would be expected to make 50% of their responses on the drug

- appropriate leverDEA/OD/ODE Page 8 of 35 January 28 , 2014

A lpha

- pyrrolidinopentiophenone ( α - PVP) In addition to the β

- keto substituent , α - PVP has a substitut ion on the nitrogen atom of the phenethylamine core structure to form a pyrrolidine ring and a chain of three carbon atoms attached to the α

- carbon position ( Figure 1 )

. α - PVP has pharmacological effects on the central nervous system that are substantially similar to those of mephedrone, MDPV, cathinone and methc athinone, which are Schedule I substances with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, α

- PVP, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in rat brain synaptosomes or in cells that have been transfected with the corresponding transporter (Cozzi et al., 1999; Meltzer, 2006; Baumann et al., 2013; Eshleman et al, 2013; NIDA, 2013; Simmler et al., 2013). In locomotor activity assays, α

- PVP, lik e several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , increase s locomotor activity in rodents ( Glennon et al., 1995; Baumann et al., 2013; Gatch et al., 2013; NIDA, 2013 ). In d rug discrimination stud ies , α - PVP (ED 50 = 0.46 and 2.77 mg/kg), like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively ( NIDA, 2012, 2013; Gat ch et al., 2013).
1

- (1,3

- B enzodioxol

- 5

- yl)

- 2

- (methylamino)butan

- 1

- one (butylone) Butylone , in addition to the β

- keto substituent , has an ethyl group (

- CH 2 CH 3 ) at the α position , a methylenedioxy ring attached to the phenyl ring , and a methyl group (

- CH 3 ) attached to the nitrogen atom ( Figure 1 )

. The pharmacological effects of butylone on the central nervous system are substantially similar to those of mephedrone, MDPV, cathinone and methcathinone, which are Schedule I substances w ith high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, butylone, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in transfected cells (Cozzi et al., 1999; Eshleman et al., 2013; Simmler et al., 2013). In locomotor activity assays, butylone, like several other synthetic cathinones ( methcathinone , methylone,DEA/OD/ODE Page 9 of 35 January 28 , 2014

MDPV, and mephedrone) and methamphetamine , has been shown to stimulate locomotor activity in mice ( Glennon et al., 1995; NIDA, 201 2 ; Gatch et al., 2013). In d rug discrimination stud ies, b utylone (ED 50 = 2.52 and 4.78 mg/kg), like several other synthetic c athinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively ( NIDA, 2012; Gatch et al., 2013 ).
2

- ( M ethylamino)

- 1

- phenylpentan

- 1

- one (pentedrone) Pentedrone , in addition to the β

- keto substituent , has a chain of three carbon atoms , a propyl group (

- CH 2 CH 2 CH 3 ) attached to the α

- carbon position , and a methyl group (

- CH 3 ) attached to the nitrogen atom ( Figure 1 ) . Pentedrone has pharmacological effects that are substantially similar to those of mephedrone, MDPV, cathinone and methcathinone, which are Schedule I subs tances with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, pentedrone, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in transfected cells (Cozzi et al., 1999; Eshlemen et al

. , 2013; NIDA, 2013; Simmler et al., 2013). In locomotor activity assays, pentedrone, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , increase s locomotor activity in rodents (Glennon et al., 1995; Baumann et al., 2012; NIDA, 2012). In d rug discrimination stud ies, p entedrone (ED 50 = 2.67 and 2. 5 8 mg/kg ) like several other synthetic c athinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine, respectively (NIDA, 2012 , 2013 ; Gatch et al., 2013)

. 1

- (1,3

- B enzodioxol

- 5

- yl)

- 2

- (methylamino)pentan

- 1

- one (pentylone) In addition to the β

- keto substituent , t he α

- position alkyl group for pentylone is a propyl (

- CH 2 CH 2 CH 3 ) group , the nitrogen atom substitution is a methyl (

- CH 3 ) group , and the phenyl ring substitution is a methylenedioxy group ( Figure 1 )

. Pentylone as pharmacological effects that are substantially similar to those of mephedrone, MDPV, cathinone and me thcathinone,DEA/OD/ODE Page 10 of 35 January 28 , 2014

which are Schedule I substances with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, pentylone, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedro ne) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in transfected cells (Cozzi et al., 1999; Eshlemen et al., 2013; NIDA, 2013). In locomotor activity assays, pentylone, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , is a locomotor stimulant ( Glennon et al., 1995; Baumann et al., 2012; Gatch et al., 2013; NIDA, 2012). In d rug discrimination stud ies, p entylone (ED 50 = 3.86 and 2.33 mg/kg), like severa l other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively (NIDA, 2012; Gatch et al., 2013).
4

- F luoro

- N

- methylcathinone (4

- FMC) 4

- FMC (also known as flephedrone) , in addition to the β

- keto substituent , incorporate s a methyl (

- CH 3 ) group at the α

- carbon and a phenyl ring substitution of a fluorine (F) atom ( Figure 1 ) . Additionally, the nitrogen atom is substituted with a methyl group. 4

- FMC h as pharmacological effects that are substantially similar to those of mephedrone, MDPV, cathinone and methcathinone, which are Schedule I substances with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, 4

- FMC, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in transfected cells (Cozzi et al., 1999; Eshleman et al., 2013; Simmler et al., 2013). In locomotor activity assays, 4

- FMC, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , increase s locomotor activity in rodents (Glennon et al., 1995; Baumann et al., 2012; Marusich et al., 2012; Gatch et al., 2013). In d rug discrimination stud i es, 4

- FMC (ED 50 = 2.69 and 3.24 mg/kg), like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively (NIDA, 2012; Gatch et al., 2013).DEA/OD/ODE Page 11 of 35 January 28 , 2014

3

- F luoro

- N

- methylcathinone (3

- FMC) 3

- FMC , in addition to the β

- keto substituent , incorporates a methyl (

- CH 3 ) group at the
α - carbon and a phenyl ring substitution of a fluorine (F) atom ( Figure 1 ) . Additionally, the nitrogen atom is substituted with a methyl group. 3

- FMC h as pharmacological effects that are substantially similar to those of mephedrone, MDPV, cathinone an d methcathinone, which are Schedule I substances with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, 3

- FMC, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in transfected cells (Cozzi et al., 1999; Eshlemen et al., 2013; NIDA, 2013). In locomotor activity assays, 3

- FMC, like several other sy nthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , increase s locomotor activity in rodents (Glennon et al., 1995; NIDA, 2012; Baumann et al., 2012; Marusich et al., 2012; Gatch et al

. , 2013). In d rug discrimination st ud ies, 3

- FMC (ED 50 =0.84 and 0.82 mg/kg), like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectiv ely ( Gatch et al., 2013; NIDA, 2013 ).
N apthylpyrovalerone (naphyrone) Naphyrone , in addition to the β

- keto substituent , has a p rop yl group (

- CH 2 CH 2 CH 3 ) at the α - position and the nitrogen atom is incorporated into a five membered ring known as a pyrrolidine ring ( Figure 1 ) . The phenyl ring of naphyrone is in the formation of bicyclic ring systems. Naphyrone h as pharmacological effects that are substantially similar to those of mephedrone, MDPV, cathinone and methcathinone, which are Schedule I substances with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, naphyrone, like several other synthetic c athinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in rat brain synaptosomes or cells that have been transfected with the corresponding transporter (Gygi et al., 1997; Meltzer et al., 2006; Kehr et al., 2011; Hadlock et al., 2011; Martinez

- Clemente et al., 2011; Bauman et al., 2012; NIDA, 2012 ; Simmler et al.,DEA/OD/ODE Page 12 of 35 January 28 , 2014

2013; Eshleman et al ., 2013; Iversen et al., 2013 ). In locomotor activity assays, naphyrone , like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine , increase s locomotor activity in mice. In d rug discrimination stud ies,
n aphyrone (ED 50 = 2.96 and 3.20 mg/kg), like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively (NIDA, 2011; NIDA, 2012).
A lpha

- pyrrolidinobutiophenone ( α - PBP)

α - PBP , in addition to the β

- keto substituent , has a chain of two carbon atoms attached to the α

- carbon position and the nitrogen atom is incorporated into a pyrrolidine ring ( Figure 1 )

. α - PBP has pharmacological effects that are substantially similar to those of mephedrone, MDPV, cathinone and methcathinone, which are Schedule I substance s with high potential for abuse. In laboratory studies investigating the effects of drugs on monoaminergic systems, α

PBP, like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) and methamphetamine, inhibits the uptak e of the monoamine neurotransmitter dopamine in cells that have been transfected with the corresponding transporter (Cozzi et al., 1999; Es hleman et al., 2013; NIDA, 2013 ). In locomotor activity assays, α

- PBP, like several other synthetic cathinones ( methcath inone , methylone, MDPV, and mephedrone) and methamphetamine , increase s locomotor activity in rodents (Baumann et al., 2013; Gatch et al., 2013; NIDA, 2013 ). In d rug discrimination stud ies, α - PBP (ED 50 = 2.68 and 3.70 mg/kg), like several other synthetic cathinones ( methcathinone , methylone, MDPV, and mephedrone) , fully substitutes for the discriminative stimulus effects produced by 1 mg/kg methamphetamine and 10 mg/kg cocaine , respectively (Gatch et al., 2013; NIDA, 2013 ).DEA/OD/ODE Page 13 of 35 January 28 , 2014

Factor 4 : Its History and Curre nt Pattern of Abuse The synthetic cathinones 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP have emerged on the United States’ illicit drug market and are being perceived as being ‘legal’ alternative s to mephedrone, methylone, MDPV, cocaine, methamphetamine, and MDMA

. Products containing t hese substances are falsely marketed as “research chemicals,” “jewelry cleaner,” “stain remover,” “ plant food or fertilizer ,” “insect repellants” or “bath salts.” They are sold at smoke shops, head shops, convenience stores, adult book stores, and gas stations and can also be purchased on the Internet. These substances are commonly encountered in the form of powder s , crystal s , resin s , tablet s , and capsule s. The pa ckages of these commercial products usually contain the warning “not for human consumption , ” most likely in an effort to circumvent statutory restrictions for these substances. Some products found to contain 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP include, but are not limited to: “ Doves , ”

“ White Ice , ” “ Oceanic Deeper , ” “ Enchanted , ” “ Platinum , ” and others.
4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, n aphyrone, and α - PBP are likely to be abused in the same manner as other synthetic cathinones such as mephedrone, methylone, and MDPV. I nformation from published scientific studies indicate that t he most common routes of administration for synthetic cathinones like mephedrone, methylone, and MDPV are nasal insufflation by snorting the powder and ingestion by swallowing capsules or tablets (Psychonaut, 20 10 a ; EM C DDA, 2011 ; Kelly, 2011; Prosser and Nelson, 201 2 ; Vardakou et al., 2011 ; Forrester, 2012, 2013; Warrick et al., 2013; Zawilska and Wojcieszak, 2013 ) . The powder can also be injected or swallowed (EM C DDA et al., 2011 ; Zawilska and Wojcieszak, 2013 )

. Ot her methods of intake include rectal administration , ingestion by “ bombing ” (wrapping a dose of powder in a paper wrap and swall ow ing) and intramuscular injection ( ACMD, 20 10 ; Psychonaut, 20 10 a , c ; Miotto et al., 2013; Zawilska and Wojcieszak, 2013 )

. As demonstrated with the Schedule I synthetic cathinones (i.e., MDPV, mephedrone, and methylone) , the main u sers of 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone,DEA/OD/ODE Page 14 of 35 January 28 , 2014

4

- FMC, 3

- FMC, naphyrone, and α - PBP are likely to be youths and young adults ( EMCDDA, 2011; Coppola and Mondola, 2012; Forrester, 2012, 2013; Warrick et al., 2013; Stogner and Miller, 2013; Zawilska and Wojcieszak, 2013 ). Synthetic cathinone exposure s reported to the Texas P oison C enter Network during 20 10 and 2011 involved mostly adolescents (12 to 19

- years - old) and young adults (mean age was 30

- years - old) with the majority of patients being males (Forrester, 2012 , 2013 ). Stogner and Miller (2013) reported that the lifetime use (used at least once) of synthetic cathinones among college students (a t a large Southeas tern U.S. unive rsity ) in the United States is 25 out of 2 , 349 students surveyed

. A survey of college students in 2012 by the Monitoring the Future (MTF) 7 showed that 0.2% of full

- time college students used synthetic cathinone substances (Johnston et al., 201 3 )

. T he use of synthetic cathinone substances among 8 th , 10 th , and 12 th grade students and young adults (non

- college peers aged 19 to 28

- years - old) was 0.8%, 0.6%, 1.3%, and 0.8%, respectively

. 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are likely to have duration of effects like those of Schedule I synthetic cathinones because of their structural and pharmacological similarities

. U sers report (AAPCC, drug surveys, medical literature) that the effects of synthetic cathinones occur a few minutes to 15 minutes after administration, depending on the synthetic cathinone and the route of administration (oral, insufflation, intravenous, etc.) , and the effects can last up to three hours (Karila et al., 20 10 ; Psychonaut, 20 10 b; EMCDDA, 2011 ; German et al., 2013 )

. As found with the Schedule I synthetic cathinones ( mephedrone, methylone, and MDPV ) and sympathomimetic agent s (e.g., cocaine, methamphetamine, amphetamine) , 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are likely to cause stimulant related psychological and somatic effects

. D esired effects reported by abusers of synthetic cathinone substances include euphoria, sense of well

- being, increased sociabi l ity, energy, empathy, increased alertness, and improved concentration and focus. S chedule I s ynthetic cathinones have also been reported to cause s timulant related

7 MTF is a research program conducted at the University of Michigan’s Institute for Social Research under grants from NIDA. MTF tracks drug use trends among American adolescents in the 8 th , 10 th , and 12 th grades and high school graduates into adulthood by conducting national surveys.DEA/OD/ODE Page 15 of 35 January 28 , 2014

psychological and somatic adverse effects such as headache, n ausea, palpitation s , seizures , increased sex drive , paranoia, agitation, t achycardia, hypertension, hyperthermia, mydriasis, rhabdomyolysis, hyponatremia, and excessive sweating ( ACMD, 20 10 ; Frohlich et al., 2011; Karila et al., 2011; Kelly, 2011; Jerry et al., 2012; Prosser and Nelson, 201 2 ; Rojek et al

. , 2012 ; German et al., 2013 ; Zawilska and Wojcieszak, 2013 ). Other a dverse effects reported by synthetic cathinone users include b r uxism (teeth grinding) , tremor , chest pain, sore nasal passages, hot fla shes, fever, sore mouth /throat, nose bleed, suppressed appetite, blurred vision, insomnia, hallucinations, addi c tion/dependence, nausea/vomiting, and nasal burns (EMCDDA, 2011 ; Prosser and Nelson, 201 2 ; Derung et al., 201 1 )

. There is evidence that 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are ingested with other substances . This is likely to either heighten the effects or ameliorate the come

- down effects of the synthetic cathinones ( EMCDDA, 2011; Vardakou et al., 2011 ; Zawilska and Wojcieszak, 2013 )

. Co

- ingestions can be from the ingestion of multiple products separately or a single product that is composed of multiple substances (e.g., one tablet containing both 4

- MEC and M DPV )

. Substances found in combination with 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, or naphyrone are : other synthetic cathinones ( e.g., methylone and MDPV ), common cutting agents ( e.g., lidocaine, caffeine, lignocaine, ephedrine etc.), or other recreational substances ( e.g., 4

- fluoro amphetamine, cocaine, methamphetamine, amphetamine ) (EMCDDA, 2011; Vardakou et al., 2011 ; Coppola and Mondola, 2012; Zuba and Byrska, 2013 ; Caudevilla

- G á lligo et al., 2013 ). Multiple drug use and co

- ingestions are confirmed by f orensic analysis of seized and purchased synthetic cathinone products

. Forensic analysis data also showed that some products contain ed multiple substances

. Summary 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are synthetic cathinone s that emerged on the United States’ illicit drug market around the time of the scheduling of mephedrone, methylone, and MDPV. These synthetic cathinones substances, like the Schedule I synthetic cathinones ( mephedrone, methylone, andDEA/OD/ODE Page 16 of 35 January 28 , 2014

MDPV ) , are promoted as being a ‘legal’ alternative to cocaine, methamphetamine, and MDMA. Products that contain 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are falsely m arketed as “research chemicals,” “jewelry cleaner,” “stain remover,” plant food or fertilizer ,” “insect repellants” or “bath salts ” and are sold at smoke shops, head shops, convenience stores, adult book stores, and gas stations and can also be purchased o n the Internet under a variety of product names ( e.g., “ White Dove ” ,

“ Explosion ” , “ Tranquility ” ). They are commonly encountered in the form of powder s , crystal s , resin s , tablet s , and capsule s. The packages of these commercial products usually contain the warning “not for human consumption

. ” Information from published scientific studies indicate that the most common routes of administration for synthetic cathinone substances is ingestion by swallowing capsules or tablets or nasal insufflation by snorting the powder tablets (Psychonaut, 20 10 a; EMCDDA, 2011; Kelly, 2011; Prosser and Nelson, 201 2 ; Vardakou et al., 2011; Forrester, 2012, 2013; Warrick et al., 2013; Zawilska and Wojcieszak, 2013) . Evidence from poison centers and published reports suggest tha t the main users of methylone are young adults (EMCDDA, 2011; Coppola and Mondola, 2012; Forrester, 2012, 2013; Warrick et al., 2013; Stogner and Miller, 2013; Zawilska and Wojcieszak, 2013) . There is evidence that these synthetic cathinone substances are ingested with other substances including other synthetic cathinones, common cutting agents, or other recreational substances.

Fac tor 5 : The Scope , Duration , and Significance of Abuse Around the time that the legislation made the manufacturing, distribution, dispensing, and possession of mephedrone , MDPV, and methylone illegal 8 , other synthetic cathinone substances, as evidenced by law enforcement encounters, emerged in the U.S. illicit drug market. These substances include but ar e not limited to 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP

.

8 Subtitle D of the FDASIA titled the “Synthetic Drug Abuse Prevention Act o f 2012,” (SDAPA) amended Schedule I of section 202 of the CSA to include MDPV and mephedrone. Methylone was permanently controlled via the administrative process. 77 FR 64032.DEA/OD/ODE Page 17 of 35 January 28 , 2014

The popularity of synthetic cathinone s , including these 10 synthetic cathinone substances, as recreational drugs increased since they first appeared on the U . S. illicit drug market in 2009

. 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are prevalent and they are abused throughout the United States as evidenced by law enforcement seizures

. These substances are readily available from the Internet, retail suppliers (e.g., head shops, tobacco shops , convenience stores, adult book stores, and gas stations) or street dealers. Data, including law enforcement data, indicate that p roducts that contain s ynthetic cathinone s ubstances are generally sold in 50 to 500 milligram packets with prices ranging from $25

- $ 7 0 per 50 mg packet and $60

- $ 70 per gram ( Fass et al., 2012 ; Miotto et al., 2013 )

. These substances can also be bought in bulk quantitie s (e.g., 10 0 g to over 5 kg) . Companies located overseas are primarily responsible for the trafficking of these substances. Studies suggest that synthetic cathinones may be used as an alternative to illicit substances like MDMA and cocaine (ACMD, 20 10 ; EMCDDA, 2011; Ojanperä et al., 2011; Coppola and Mondola, 2012). ACMD reported that “Toot” (most commonly identified as a mixt ure of butylone and methylone) and mephedrone were popular among users of heroin (ACMD, 20 10 ). Information from poison centers and emergency departments indicates that synthetic cathinones continue to be abused by individuals (see Factor 5). AAPCC repor ted in a press release that there were 30 6 exposure calls related to synthetic cathinones in 20 10 , 6,13 7 calls in 2011, and 2,6 91 calls in 2012 (AAPCC, 2013)

. As of October 31, 2013, poison centers received 833 calls relating to human exposures to bath sa lts. According to the Drug Abuse Warning Network (DAWN) report released by SAMHSA , 22,904 ED visits involved “bath salts ” in 2011

. There are convictions of drug traffickers and indictments against alleged drug traffickers in the United States involving most of these substances indicating that these substances are being distributed throughout the United States (see Appendix for a list of some of these cases ). For example, two individuals were convicted of conspiracy to distribute, or to possess with inte nt to distribute a controlled substance analogue ( one of the substances was 4

- MEC) inDEA/OD/ODE Page 18 of 35 January 28 , 2014

violation of 21 USC 846 and conspiracy to import a controlled substance analogue in violation of 21 USC 963 and other violations after a jury trial in the United States D istrict Court Northern District of New York. In another case, the jury returned a guilty verdict in the United States District Court for the Western District of Virginia against an individual for the conspiracy to distribute, or to possess with intent to distribute a controlled substance analogue (one of the substances was 4

- MEC) in violation of 21 USC 846. Several individuals were indicted and subsequently convicted in the United States District Cou rt for the District of Arizona for violation s of the analogue drug provision (substances include d α - PVP, α - PBP, 4

- MePPP, pentedrone, pentylone, butylone, and MDPV).

Table 1 : Synthetic Cathinones
- Number of Reports (State and Local ) Synthetic Cathinone NFLIS (20 10 ) NFLIS

(2011) NFLIS

(2012) NFLIS

(2013*) 4 - MEC 5 175 1,0 52 6 44 4 - MePPP 0 91 18 1 1 6 α - PVP 0 17 2, 730 1, 583 Butylone 3 173 25 8 52 Pentedrone 0 122 9 13 12 5 Pentylone 0 34 16 9 3 2 FMC** 4 168 10 6 13 Naphyrone 1 20 1 9 3 α - PBP 0 0 5 7 41 NFLIS database was queried for drug reports on 12 / 20 /2013 by date submitted to s tate and l ocal f orensic l aboratories

. *2013 Data are January

– Nove mber (data are still being reported for November) ** FMC consists of isomers of FMC including 3

- FMC and 4

- FMC Evidence from law enforcement indicates that 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are being abused in the United States (see Table 1 and Appendix). In 20 10 , NFLIS, a DEA sponsored forensic database , registered 13 reports from 5 states regard ing many of these synthetic cathinone substances that were analyzed by state and local forensic laboratories

. 9 In 2011, there were 800 reports from 33 states related to these substances registered in NFLIS, and in 2012, there were 5, 485 reports from 41 states , and from January to Novem ber 2013 there were 2, 509 reports from 41 states
. From January 20 10 to Novem ber 201 3 , 1, 732 drug exhibits pertaining to the trafficking,

9 NFLIS state and local f orensic drug reports queried on December 20 , 2013.DEA/OD/ODE Page 19 of 35 January 28 , 2014

distribution and abuse of 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP were recorded in the STRIDE database, a federal database for drug items analyzed by DEA forensic laboratories. 10 Among the synthetic cathinone substances, 4

- MEC , butylone, FMC and pentedrone w ere the most prevalent substances encountered by law enforcement as reported in NFLIS in 2011. However, in 2012 and 2013, α - PVP is the most prevalent substances encountered.

Table 2 : Encounters of Synthetic Cathinone Substances by CBP ( 518 Total Shipments) Synthetic Cathinone 20 10 2011 2012 2013 20 10 - 2013 1 4

- MEC 2 29 28 1 9 7 8 42 kg, 4000 packets 2 4

- MePPP 3 4 1 8 3 .6 kg 3 α - PVP 1 18 21 40 70 kg 4 Butylone 2 12 5 2 2 1 8.4 kg 5 Pentedrone 8 9 1 1 8 43 kg 6 Pentylone 6 4 10 21.7 kg, 2000 packets 7, 8 FMC* 3 7 3 1 3 5.4 kg 9 Naphyrone 3 3 4 kg 10 α - PBP 2 8 1 11 7 kg Data analyzed on December 18 , 2013 * FMC consists of isomers of FMC including 3

- FMC and 4

- FMC At selected United States ports of entry, the U.S. Customs and Border Protection (CBP) has encountered several shipments of products from April 20 10 to November 2013 containing these 10 synthetic cathinone substances (see Table 2 ). These encounters of 4

- MEC, 4

- MePPP,
α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP indicate that these substances are popular drugs of abuse. Most of the shipm ents of these synthetic cathinones originated overseas and were destined for delivery throughout the United States to places like Arizona, Arkansas, California, Colorado, Florida, Hawaii, Idaho, Illinois, Michigan, Missouri, Nebraska, Nevada, New Jersey, N ew Mexico, Oklahoma, Oregon, Texas, Virginia, Washington, and Wyoming. Concerns over the abuse of synthetic cathinones have prompted many states to control these substances. Some states have enacted legislation to capture a broad range of synthetic cath inones by utilizing a broad definition to define synthetic cathinones. For example, some

10 STRIDE data was queried on 12 / 20 /2013 by date submitted to Federal forensic laboratories.DEA/OD/ODE Page 20 of 35 January 28 , 2014

states like Arkansas, Idaho, Mississippi, and North Carolina define controlled synthetic cathinones as substances that have certain substitutions (e.g., by substitution in the ring system to any extent with alkyl, alk y lenedioxy, etc; by substitution at the 2

- amino nitrogen atom with alkyl, dialkyl, benzyl, etc.) on a defined structure (i.e., 2

- aminopropan

- 1

- one, 2

- amino

- 1

- phenyl

1

- propanone). In c ontrast, other states, like Arizona, Delaware, Massachusetts, Tennessee, and Washington specifically control one or more of the synthetic cathinones by name. As of June 24 , 2013, more than half of the states in the United States ha ve emergency scheduled o r enacted legislation placing regulatory controls on some or many of the synthetic cathinones that are listed in this document . In addition, the U.S. Armed Forces prohibited the use of synthetic cathinones for intoxication purposes due to its use by service members of the U.S. armed forces (Berry

- Caban et al. , 2012 ; Loeffler et al., 2012 ) . Internationally, several member countries of the European Union have enacted laws placing controls on the possession and/or sale of one or more o f these substances (Winstock et al., 20 10 ; EMCDDA, 2011 ; Morris, 20 1 0 ). Summary 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP , like mephedrone, methylone, and MDPV , are popular recreational drug s . Evidence that these synthetic cathinone substances are being abused is confirmed by law enforcement encounters of these substances. F orensic laboratories have analyzed drug exhibits received from state, local, or federal law enforcement agencies that were f ound to contain 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, or α - PBP

. NFLIS registered over 8 , 0 00 reports from state and local forensic laboratories ident ifying these substances in drug

- related exhibits for a period fr om January 20 1 0 to December 201 3 from 4 2 states. STRIDE registered over 1, 7 00 reports from DEA forensic laboratories from January 20 10 to Nove mber 201 3

. Additionally, large seizures of these substances have occurred by the U.S. Customs and Border Protection (CBP). Concerns over the abuse of these synthetic cathinone substances have prompted many states to regulate them.DEA/OD/ODE Page 21 of 35 January 28 , 2014

F actor 6 : What, If Any , Risk There is to the Public Health Synthetic cathinones , in general, have been reported to cause a number of stimulant

like adverse effects (ACMD, 20 10 ; Karila et al., 20 10 ; Psychonaut, 20 10 a, c; EMCDDA, 2011 ; Prosser and Nelson, 2012 ; Capriola, 2013 )

. Stimulant

- li ke adverse effects include tachycardia, hypertension , hyperthermia, palpitations, hyponatremia, tremor, seizures, vomiting, sweating, headache, rhabdomyolysis, etc. (Frohlich et al

. , 2011; Spiller et al., 2011; Vardakou et al., 2011 ; Derung et al., 2012; Rojek et al., 2012 ; Warrick et al., 2012 ; Zawilska and Wojcieszak, 2013 ). Hyperthermia can be a serious adverse effect and can lead to metabolic acidosis, rhabdomyolysis, renal failure, disseminated intravascular coagulation, coma, and death. The clinica l presentation of intoxication from synthetic cathinones shares some features seen with MDMA and stimulants like cocaine. Clinical case reports indicate that synthetic cathinones also produce other adverse effects such as hallucinations, psychosis, parano ia, delusions, etc. (Frohlich et al

. , 2011; Spiller et al., 2011; Vardakou et al., 2011 ; Derung et al., 201 1 ; Thorton et al., 2012 ). Law enforcement, forensic laboratories , case reports, and public health officials have reported toxic exposure to some of the synthetic cathinone substances that demonstrate the public health risks associated with these substances

. S ubstances that have been specifically identified includ e 4

- MEC , butylone, 4

- FMC, α - PVP, pentylone and naphyrone. According to the DAW N report that was released by SAMHSA , 22,904 visits to the emergency department in 2011 involved “bath salts.” As described below, many individuals have presented at emergency departments following exposure to these synthetic cathi n one substances or products containing these substances. Serious adverse effects including hyperthermia have resulted in documented hospital emergency department (ED) admissions from the ingestion of butylone, 4

- FMC, or naphyrone

. Frohlich et al. (2011) described a case of acute liver failure after the ingestion of synthetic cathinones which included butylone. A 28

- year - old male suffering from bipolar affective disorder (but otherwise healthy) ingested 12 stimulant tablets. Follow ing ingestion he suffered a seizure. He was transported to the emergency department. He also hadDEA/OD/ODE Page 22 of 35 January 28 , 2014

tachycardia, hypertension, hyperpyrexia, and profuse sweating. Rhabdomyolysis, a syndrome caused by injury to skeletal muscle , developed two days after inge stion and likely caused renal failure . The liver failure eventually resolved following treatment and the patient was discharged into psychiatric care. The pills that the patient had ingested were analyzed and found to contain MDPV and butylone. Derungs et al. ( 2012 ) described the case of a 31

- year - old male who suffered sympathomimetic toxicity after ingesting naphyrone. The patient purchased the powder over the internet. He believed that he was purchasing MDMA but instead received naphyrone. The pati ent had no knowledge about naphyrone but chose to ingest the amount that he would have ingested if the substance had been MDMA, so he ingested 10 0 mg of the powder with fruit juice. After administration, he developed blurred visions, increasing restlessne ss, and could not concentrate. He also experienced insomnia for two nights, hallucinations, paranoia and felt
nervous . The patient had a history of heroin use and was on substitution therapy with buprenorphine. He presented to the emergency room exhibiting psychotic symptoms. Upon examination he had mydriasi s and elevated blood pressure indicating that he was suffering from acute sympatomimetic toxidrome. Later in the same day of admission, the patient discharged himself. A toxicological screen of specimens from the patient identified naphyrone. A urine drug screen was positive for benzodiazepines but did not detect other cathinones, cocaine, or amphetamine derivatives.
Thorton et al. ( 2012 ) described the case of a 23

- year - old male who insuffla ted 4

- FMC. After snorting a white powder the patient was agitated, suicidal, and complained of hallucination s . He was taken to the hospital via ambulance. Emergency personnel reported that the patient was hyperthermi c , diaphoretic, and tachycardic with mydriasis. The patient was chemically and physically restrained because he was agitated. Symptoms eventually resolved and the patient was discharged. The patient was diagnosed to suffer from schizoaffective disorder, bipolar disorder, or psychosis secon dary to bath salt (4

- FMC) ingestion. Testing of the bath salt product revealed MDPV and 4

- FMC. A toxicological screen of specimens from the patient identified MDPV and 4

- FMC. A higher concentration of 4

- FMC (346DEA/OD/ODE Page 23 of 35 January 28 , 2014

and 257 ng/mL in serum and urine, respect ively) compared to MDPV (186 and 136 ng/mL in serum and urine, respectively) was detected. Some individuals under the influence of these synthetic substances have acted violently and unpredictably causing harm, or even death, to themselves or others.
Gil et al. (2013) described the case of a 30

- year - old male who died in a road traffic accident after an alleged ingestion of 4

- MEC. 4

- MEC was identified in a zipper bag found on the decedent. 4

- MEC at a concentration of 152 ng/ml (blood) and 122 ng/ml (urin e) was also detected in biological specimens from the decedent. Ethanol ( 0.12 g/dL in blood and 0.19 g/d L in urine) was also present in these s pecimen s. Another case report ed by Gil et al. (2013) described the case of a 27

- year - old ma le who was arrested by the p olice on suspicion of possession of narcotics (white powder) ( Gil et al., 2013). 4

- MEC was identified in the white powder seized from the subject. A toxicological screen identified 4

- MEC in blood samples from this subject.
B utylone has been dire ctly implicated in two fatalities reported in the medical literature

. Warrick et al. (2012) described the death of a 24

- year - old female who ingested two capsules of what was thought to be “Ecstasy” at a concert. After being found unconscious by emergency personnel, the decedent was taken to the emergency department. The co matose patient suffered from hyperthermia, tachycardia, mydriasis, tachypnea and some tremors. Despite efforts to save her life the decedent died. Toxicology tests identified methylone and butylone in specimens from this individual. Laboratory analysis also identified methylone and butylone in the powder obtained from a capsule that was found on the decedent. The cause of death determined by the medical examiner was serotonin syndrome secondary to methylone and butylone ingestion

. Rojek et al. (2012) d escribed the death of a 21

- year - old male who ingested butylone for suicidal intentions. The decedent was admitted to the hospital after ingesting 10 tablets of a substance called “Amph

- i

- bia.” The decedent purchased the substances at a retail shop. On
a dmission, the patient suffered tachycardia, hypertension, mydriasis and was disoriented. HeDEA/OD/ODE Page 24 of 35 January 28 , 2014

subsequently developed seizures and suffered a cardiac and respiratory arrest. Despite efforts to save his life he died. A toxicological screen of specimens from this patient identified butylone. The cause of death was reported as multi

- organ failure resulting from malignant serotonin syndrome.
Other synthetic cathinones , like α - PVP and pentylone , have also been implicated in the deaths of individuals.
Marinetti and Antonides (2013) described several postmortem cases in which synthetic cathinones such as MPDV, α - PVP , pentylone, methylone and methedrone w ere detected in biological , postmortem specimens

. A 44

- year - old female with a history of bipolar disorder and previous suicide and drug abuse died from multiple drug intoxication. She tested positive for pentylone, α - PVP, hydrocodone, promethazine, and other pharmaceutical drugs. A 35

- year - old female with a history o f drug a buse including intravenous drug abuse was found unresponsive in bed. A toxicological screen detected morphine, codeine, citalopram, α - PVP, and 6

- MAM ( 6

- monoacetylmorphine; an active metabolite of heroin) in biological specimen from this individual. A 50

- year - old female with a history of heroin abuse was found unresponsive on a sofa at her home. A toxicological screen detected α - PVP, morphine, codeine, 6

- MAM, and pharmaceutical drugs in biological specimen from this individual. A 51

- year - old male was fat ally shot by police officers after a chase. A toxicological screen detected α - PVP in biological specimen from this individual. A 34

- year - old male was found dead in his basement from hanging. A toxicological screen detected α - PVP and pentylone in biologi cal specimen from this individual. A 32

- year - old female who was morbidly obese was found unresponsive on the floor in her home. A toxicological screen detected MDPV, α - PVP, morphine, methedrone, 6

- MAM, and pharmaceutical drugs in biological specimen from this individual.
The products containing synthetic cathinone substances often do not bear labeling information regarding its ingredients or the health risks and potential hazards associated with these products

. In addition, products may not contain the expected active ingredients (Davies et al., 20 10 ; Spiller et al., 2011; Ayres and Bond, 2012; Zuba and Byrska, 2013)

. Thus, individuals who purchase these products likely have insufficient knowledge of the exact productDEA/OD/ODE Page 25 of 35 January 28 , 2014

contents. This lack of information poses significant risk to users who may not know what they are purchasing or the risk associated with the abuse of those products. I n a study that analyzed products offered for s a l e over a 6 month period , there was significant variation in the active substance (i.e., the products did not contain the active ingredients listed or products marketed to contain a specific legal substance contained a different substance) in one quarter (5 of 20) of the products that were purchased (the same named products such as Head rush, Pure bliss, or Xtacy were purchased repeatedly during a 6 month period) and tested (Davies et al., 20 10 ). In a separate study, the analysis of a specific brand name synthetic cathinone produ ct (e.g., white lightening) , that appeared identical in packaging but o btained at different locations , revealed different synthetic cathinones as the primary ingredient (Spiller et al., 2011). Accordingly , 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP have been identified in varying combinations in packages that have been seized by law enforcement. A study by Brandt et al. (20 10 ) showed that 70% of the products analyzed contained an illicit substance. Another study showed that there wa s poor quality of product information (Schmidt et al., 20 10 ). Of 1 , 308 products evaluated, 40% (524) did not list ingredients, 92% (1,202) failed to list any side effects, and 86% (1,129) f a iled to list any warnings about potential interactions with other substances or medications. Since abusers obtain these drugs through unknown sources, the purity of these drugs is uncertain presenting another level of risk to users (EMCDDA, 2011). Thus, the limited knowledge about product content and its purity and lack of information about its effects pose significant risk s to the
user s . Summary In summary, available evidence on the overall public health risks associated with the use of synthetic cathin ones indicates that 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP can cause acute health problems leading to ED admissions, violent behaviors causing harm to self or others, or death. In addition, products containing these synthetic cathinone substances often do not bear labeling information regarding their ingredients and if they do, it may not contain the expected active ingredients or identify the health risks and potential hazards associated wi th these products

. Acute effects ofDEA/OD/ODE Page 26 of 35 January 28 , 2014

these substance are those typical of a sympathomimetic agent s (e.g. , cocaine , methamphetamine, amphetamine ) and includ e among other effects tachycardia, headache, palpitations, agitation, anxiety, mydriasis, tremor, fev er or sweating, and hypertension (ACMD, 20 10 ; Karila and Reynaud, 20 10 ; EMCDDA, 2011; Prosser and Nelson, 201 2 ; Derung et al., 201 1 ; Rojek et al., 2012; Thorton et al., 2012 ; Capriola, 2013 ). Other effects, with possible public health risk implications, t hat have been reported from the use of synthetic cathinone substances include psychological effects such as psychosis, paranoia, hallucinations, and agitation (Derung et al., 201 1 ; Rojek et al., 2012; Thorton et al., 2012). Finally, the possibility of dea th for individuals abusing 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP also indicates that these substances are a serious public health threat.
Conclusion of 3
- Factor Analysis After a careful review of the scientific literature, Factors 4, 5, and 6, NFLIS, STRIDE, and other law enforcement data and other data and information, it is evident that 4

- MEC, 4

- MePPP,
α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP are trafficked and abused and pose a significant public health risk. These drugs have become popular among drug abusers due to their stimulant

- like effects and pharmacological similarity to mephedrone, MDPV, methylone, cocaine, and methamphetamine

. DEA has considered the three criteria for placing a substance into Schedule I of the CSA (21 U.S.C. 812). The data available and reviewed for 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, and α - PBP indicated that these s ubstances, including their salts, isomers, and salts of isomers, pose an imminent hazard to public safety and health, have no currently accepted medical use in treatment in the United States, and lack accepted safety for use under medical supervision.DEA/OD/ODE Page 27 of 35 January 28 , 2014

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### II. APPENDIX STRIDE, NFLIS, and Examples of Enforcement Activities System To Retrieve Information from Drug Evidence (STRIDE) Reports Data from the forensic laboratory database STRIDE, a federal database for the drug samples analyzed by DEA forensic laboratories, indicate illicit activity involving 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, 4

- FMC, 3

- FMC, naphyrone, or α - PBP. From January 20 10 to Novem ber 2013, Federal law enforcement authorities encountered 1, 732 drug exhibits pertaining to the trafficking, distribution and abuse of these synthetic cathinone substances (Table II. 1).

Table II. 1: Synthetic Cathinones Reports (Federal) Synthetic Cathinone STRIDE (20 10 ) STRIDE

(2011) STRIDE

(2012) STRIDE

(2013*) STRIDE

(20 10 - 2013*) 4 - MEC 4 14 2 162 6 6 3 74 4 - MePPP 0 1 0 10 1 1 1 12 2 α - PVP 0 7 544 10 8 659 Butylone 0 14 56 4 7 4 Pentedrone 0 11 2 6 2 1 5 2 88 Pentylone 0 5 10 7 7 11 9 FMC** 0 10 2 1 6 3 7 Naphyrone 0 5 17 0 22 α - PBP 0 1 32 4 37 TOTAL 4 205 1, 302 221 1, 732 STRIDE data base was queried on 12 /2 0 /2013 by date submitted to federal forensic laboratories. *2013 Data are January

– November (data are still being reported for November)

. **FMC consists of isomers of FMC including 3

- FMC and 4

- FMC

National Forensic Laboratory Information System (NFLIS) Reports In 20 10 , the NFLIS registered 13 reports from 5 states containing 4

- MEC, butylone, FM C, and naphyron e (Table II.2, II.4, and II. 5) analyzed by state and local forensic laboratories. However, in 2011, there were 800 reports from 3 2 states related to these substances (exclude
α - PBP) registered in NFLIS, in 2012 there were 5,485 reports from 41 states, and in the first eleven months of 2013, there were 2, 509 reports from 41 states. These substancesDEA/OD/ODE Page 33 of 35 January 28 , 2014

represented approximately 29 % (8, 80 7 / 30 , 448 ) of all the reports to NFLIS involving synthetic cathinones from January 20 10 to Novem ber 2013 (Table II. 3).

Table II. 2: Synthetic Cathinones
- Number of Reports (State and Local) Synthetic Cathinone NFLIS (20 10 ) NFLIS

(2011) NFLIS

(2012) NFLIS

(2013*) NFLIS

(20 10 - 2013*) 4 - MEC 5 175 1,052 6 44 1,8 76 4 - MePPP 0 91 181 16 288 α - PVP 0 17 2,730 1, 583 4, 330 Butylone 3 173 258 52 486 Pentedrone 0 122 913 12 5 1,1 60 Pentylone 0 34 169 3 2 23 5 FMC** 4 168 10 6 13 291 Naphyrone 1 20 19 3 43 α - PBP 0 0 57 41 98 TOTAL 13 800 5,485 2, 509 8, 807 NFLIS database was queried for drug reports on 12 /2 0 /2013 by date submitted to state and local forensic laboratories *2013 Data are January

– Nove mber (data are still being reported for November) **FMC consists of isomers of FMC including 3

- FMC and 4

- FMC Table II. 3: Number of Reports (State and Local) of All Synthetic Cathinones Substance Category 20 10 2011 2012 2013* 20 10 - 2013* Ten Synthetic Cathinones ‡ 13 800 5,485 2, 509 8, 807 All Synthetic Cathinones 636 6,345 12,959 10 , 508 30 , 448 % Ten Synthetic Cathinones ‡ 2% 13% 42% 2 4 % 29% NFLIS database was queried for drug reports on 12 /2 0 /2013 by date submitted to state and local forensic Laboratories. *2013 Data are January

– Nove mber (data are still being reported for November) ‡ Ten Synthetic Cathinones include 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, FMC, naphyrone, and α - PBP Table II. 4: Number of States where Synthetic Cathinones ‡ was Identified (State and Local) Synthetic Cathinone 20 10 2011 2012 2013 20 10 - 2013* 4 - MEC 3 24 3 7 35 3 8 4 - MePPP 0 13 21 12 2 6 α - PVP 0 6 3 8 33 40 Butylone 1 22 28 1 6 3 4 Pentedrone 0 17 28 17 33 Pentylone 0 8 23 1 6 2 9 FMC** 2 22 26 6 29 Naphyrone 1 9 10 2 16 α - PBP 0 0 1 6 9 1 9 TOTAL STATES 5 3 2 41 41 42 NFLIS database was queried on 12 /2 0 /2013 by date submitted to state and local forensic laboratories. *2013 Data are January

– Nove mber (data are still being reported for November) **FMC consists of isomers of FMC including 3

- FMC and 4

- FMC ‡ Synthetic Cathinones are 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, FMC, naphyrone, and α - PBPDEA/OD/ODE Page 34 of 35 January 28 , 2014

Table II. 5: States where Synthetic Cathinones ‡ were Identified

States with Exhibits from 20 10

- 2013* Synthetic Cathinones Arizona Arkansas California Colorado Connecticut

Florida Georgia Illinois Indiana Iowa Kansas Kentucky Louisiana Maine Maryland Massachusetts Michigan Minnesota Mississippi Missouri Nebraska Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania South Carolina South Dakota Tennessee Texas Utah Virginia Washington West Virginia Wisconsin Wyoming NFLIS database was queried on 12 /2 0 /2013 by date submitted to state and local forensic laboratories. *2013 Data are January

– Nove mber (data are still being reported for November) ‡ Synthetic Cathinones are 4

- MEC, 4

- MePPP, α - PVP, butylone, pentedrone, pentylone, FMC, naphyrone, and α - PBP

Examples of Enforcement Activities 1. On May 14, 2013, two individuals were convicted after a jury trial in the United States District Court Northern District of New York. The individuals were convicted of conspiracy to distribute, or to possess with intent to distrib ute c ontrolled s ubstance
a nalogue s (4

- MEC and mephedrone) in violation of 21 USC 846 and conspiracy to import a controlled substance analogue in violation of 21 USC 963 and /or 19 counts of money l aundering in violation of 18 USC 1956. A third individual who was arrested in this i nvestigation failed to show for trial and is currently a fugitive. Also indicted in this investigation was a foreign individual who allegedly shipped the substances to the convicted individuals

. Eighteen other defendants ple d guilty to conspiracy to dist ribute, or to possess with intent to distribute a c ontrolled s ubstance a nalogue in violation of 21 USC 846.
2. T he jury in the United States District Court for the Western District of Virginia returned a guilty verdict (May 2013) on nine counts against an in dividual for the conspiracy to distribute, or to possess with intent to distribute a controlled substance analogue (4

- MEC , methylone, and MDPV ) in violation of 21 USC 846.
3. Several individuals were indicted ( July 2012) in the United States District Court for the District of Arizona for the alleged violation of the analogue drug provision (substancesDEA/OD/ODE Page 35 of 35 January 28 , 2014

include d α - PVP, α - PBP, 4

- MePPP, pentedrone, pentylone, butylone, and MDPV). Many of the indicted ple d guilty and one indiv idual was found guilty in a jury trial in July 2013.
4. An i ndividual was indicted ( October 2012 ) in the United States District Court for the Western District of Virginia for the alleged violation of the analogue drug provision (substance is α - PVP). Two other individuals were also indicted in this case. One individual ple d guilty and one individual was found guilty in a jury trial in July 2013.
5. Individuals were indicted ( July 2012 ) in the United States District Court for the Southern District of New Yor k for conspiring to distribute and possess with intent to distribute a controlled substance analogue (the synthetic designer drugs was α - PVP) in violation of 21 USC 846

. The defendants plead guilty (April 2013).
6. Four individuals were indicted (April 2012) in the United States District Court for the Northern District of West Virginia for the conspiracy to distribute controlled substance analogue s ( α - PVP was one of the substances) and other related charges in violation of 21 USC 846

. T hree of the individuals pled guilty to some of the charges.