### U.S. Department of Justice

Drug Enforcement Administration

Schedule of Controlled Substance: Placement of 3,4

- Methylenedioxy

- N

methylcathinone ( Methylone ) into Schedule I Background, Data, and Analysis: Eight F actors Determinative of Control and Findings Pursuant to 21 U.S.C. 812(b)

Prepared by : Office of Diversion Control, Drug and Chemical Evaluation Section 8701 Morrissette Drive, Springfield, V irginia 22152

October 201 2Page 2 of 36

I. Background

Methylone is a synthetic cathinone (also commonly referred to as substituted cathinones or cathinone derivatives) that share s many similarities with the Schedule I substances cathinone

, methcathinone

, and 3,4

- methylenedioxymet hamphetamine (MDMA) and Schedule II stimulants amphetamine, methamphetamine, and cocaine. Evidence indicates that methylone and other synthetic cathinones , like amphetamine, methamphetamine and cocaine, are being abused for their psychoactive properties. These synthetic cathinone substances are falsely marketed as “research chemicals,” “plant food,” or “bath salts.” They have been 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 substances

. Methylone has no known medical use in the United States but evidence demonstrates that methylone is being abused by individuals and has become a serious public health threat

. Consequently, t her e have been documented reports of emergency room admissions and deaths associated with the abuse of methylone ( Boulanger

- Gobeil et al., 201 2 ; Pearson et al., 2012 ; Warrick et al., 201 2 )

. Methylone has been reported to cause a number of adverse effects tha t are characteristic of sympathomimetic agent such as amphetamine , methamphetamine, and cocaine ( ACMD, 2010; Karila and Reynaud , 2010 ; Boulanger

- Gobeil et al., 201 2 ; Pearson et al., 2012 ; Warrick et al., 2012 )

. Adverse effects associated with the consumption of methylone include palpitations, hyperthermia, seizures, hyponatremia, bruxism, sweating, hypert ension, tachycardia, headache, palpitations, thirst, mydriasis, tremor, fever

, sweating, and hypertension (A CMD, 2010; Karila and Reynaud , 2010 ; Boulanger

- Gobeil et al., 201 2 ; Pearson et al., 2012 ; Warrick et al., 201 2 )

. Other effects that have been reported from the use of methylone include psychological effects such as confusion, psychosis, paranoia, hallucin ations, combativeness, and agitation. T he possibility of death for ind ividuals abusing methylone also indicates that methylone is a serious public health threat ( Boulanger

- Gobeil et al., 201 2 ; Pearson et al., 2012 ; Warrick et al., 201 2 )

.

Evidence from poison centers and law enforcement indicates that the abuse of synthetic cathinones like methylone is widespread. According to a press release from the American Association of Poison Control Centers (AAPCC), 1 there were 304 exposure calls re lated to synthetic cathinones in 2010 and 6,138 calls in 2011 (AAPCC, 2012)

. A s of September 10, 2012, poison centers received 2,251 calls relating to human exposures to bath salts. These calls were received in poison centers representing at least 47 sta tes and the District of Columbia. Both the National Forensic Laboratory Information System (NFLIS), a D rug Enforcement Administration (DEA) sponsored program that systematically collects drug ide ntification results

1 AAPCC is a non

- profit, national organization that represents the poison control centers of the United States.Page 3 of 36

and associated information from drug cas es analyzed by state, local, and federal forensic laboratories, and the System To Retrieve Information from Drug Evidence (STRIDE), a federal database for the drug samples analyzed by DEA forensic laboratories, registered encounters of methylone (see Facto r 1 and Factor 5 ). In 2009, NFLIS registered 4 reports in state and local law enforcement laboratories from 3 states containing methylone

. 2 However, in 2010, there were 71 reports from 18 states related to methylone , in 2011 there were 1,655 reports from 41 states , and in 2012 there were 1,067 reports from 36 states . From January 2009 to June 2012

, 220 drug exhibits pertaining to the trafficking, distribution and abuse of methylone were recorded in the STRIDE database (which reports data from 6 DEA laboratories).

S tate public health and poison centers have warned of the dangers associated with the use of synthetic cathinones and their associated products being found on the designer drug market. In response to the abuse of methylone and other synthe tic cathinones , a s of Sept ember 2012, at least 42 states have emergency scheduled or enacted legislation placing regulatory controls on some or many of the synthetic cathinones including mephedrone, methylone, MDPV and/or a defined general class of cathino nes. At least 27 states specifically control methylone. Numerous local jurisdictions have also placed controls on methylone and other synthetic cathinones

. All five branches of the U.S. military prohibit military personnel from possessing or using synth etic cathinones including methylone.

On October 21, 2011 , the Administrator of the Drug Enforcement Administration (DEA) published a Final Order in the Federal Register temporarily placing methylone, along with two other synthetic cathinones (4

- methyl

- N

- meth yl cathinone (mephedrone) and 3,4

- methylenedioxypyrovalerone (MDPV)) in to Schedule I of the Controlled Substances Act (CSA) upon finding that th ese substance s pose an imminent threat to public safety. 76 FR 65371.

Pursuant to 21 U.S.C. 811(b) and after gathering the necessary data, in a letter dated March, 30 , 2012, DEA requested from the Department of Health and Human Services ( HHS ) a scientific and medical evaluation and a scheduling recommendation for methylone and two other synthetic cathin ones (mephedrone and MDPV)

. On July 9, 2012, President Obama signed the Food and Drug Administration Safety and Innovation Act (Pub. L. 112

- 144) (FDASIA), which amended several provisions of the CSA. In particular, the FDASIA amended Schedule I of sectio n 202(c) of the CS A to include mephedrone and MDPV , but not methylone

. O n August 1 4 , 2012, pursuant to 21 U.S.C. 811 (b) and (c), HHS provided DEA with the following scientific and medical evaluation and scheduling recommendation : “Basis for the Recommend ation to P lace 3,4

- Methylenedioxymethcathinone (Methylone) and its Salts in Schedule I of the Controlled Substances Act (CSA)

. ” Th is evaluation recommended that methylone be added to Schedule I of the CSA.

2 Analyzed on September 12 , 2012

, s tate and local forensic drug reports. The 201 2 drug reports are likely to be incomplete as of September 12 , 2012

, due to laboratory reporting lag timePage 4 of 36

The CSA requires the Administrator of the DEA

, as delegated by the Attorney General, 3 to determine whether HHS ’ s scientific and medical evaluation and all other relevant data constitute substantial evidence of potential for abuse such that the substance should be scheduled. 21 U.S.C. 811(b)

.

3 28 CFR 0.100(b)

.Page 5 of 36

II. Eight Factors Determinative of Control

Pursuant to 21 U.S.C. 811(c), DEA must consider eight factors in making any finding of substantial evidence of potential for abuse, including the necessary data and law enforcement information relevant theret o.

Factor 1 : Its Actual or Relative Potential for Abuse

Methylone is a synthetic cathinone ( 

- keto

- phenethylamine) of the larger phenethylamine structural c lass (e.g., amphetamines, cathinones, 2C compounds, aminoindanes, etc.)

. Other

s ynthetic cathinones include but are not limited to mephedrone (Schedule I), MDPV (Schedule I), butylone, 4

- fluoromethcathinone (4

- FMC), 3

- fluoromethcathinone (3

- FMC), 4

- methoxymethcathinone (methedrone), 4

- methyl

- N

- ethylcathinone (4

- MEC), ethylone, buphedrone, dime thylcathinone, diethylcathinone, and 3,4

- methylenedioxy

- 

- pyrrolidinopentiophenone (MDPBP). Although the abuse potential of methylone in humans ha s not been tested

, t he available data indicate that the p harmacological actions of methylone is similar to th ose of Schedule I and II substances such as cathinone (Schedule I), methcathinon e (Schedule I), MDMA (Schedule I)

, amphetamine (Schedule II), methamphetamine (Schedule II), and cocaine (Schedule II) which have a high potential for abuse (see information be low and in Factor 2).

a. Legislative History and Determination of A buse P otential

The legislative history of the CSA provides four factors to consider in determining whether a particular drug or substance has potential for abuse: 4

i. There is evidence that individuals are taking the drug or other substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community; or ii. There is significant diversion of the drug or substance from legitimate drug channels; or iii. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs; or iv. The drug is a new drug so related in its action to a drug or other substance alread y listed as having a potential for abuse to make it likely that the drug or other substance will have the same potential for abuse as such drugs, thus making it reasonable to assume that there may be significant diversion from legitimate channels, signific ant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

4 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91

- 1444, 91st Con g., Sess. 1 (1970); 1970 U.S.C.C.A.N. 4566, 4601.Page 6 of 36

i. Individuals are taking methylone in amounts sufficient to create a hazard to their healt h or to the safety of other individuals or to the community

.

A ccording to HHS, a number of case reports and case series have shown that individuals take methylone and products containing methylone in amount s sufficient to induce adverse health effects similar to those induced Schedule I and II substances such as by amphetamine, methamphetamine, coc a ine, and MDMA (HHS, 2012)

. These effects includ ed elevated body temperature, increase d heart rate

, respiratory exchange, and blood pressure, seizures , extreme anxiety leading to panic attacks

, and the precipitation or exacerbation of psychotic episodes ( Shimizu et al., 2007; Boulanger

- Gobeil et al., 201 2 ; Pearson et al., 2012 ). Further HHS states that several reports from emergency room and me dical examiners cases indicate that methylone use is associated with deaths ( Warrick et al., 2011; Pearson et al., 2012 ). Further, law enforcement encounters suggest the occurrence of a fatal automotive accident caused by a driver under the influence of a product containing methylone and there is a reported incident of a homicide perpetrated by an individual under the influence of methylone (Marinetti et al., 2011 ; Cawrse et al., 2012 )

.

ii. Significant diversion of methylone from legitimate channels and/or ea se with which drug can be obtained

.

Since October 21 , 2011, methylone has been temporarily controlled in Schedule I and ha s thus not been legally available unless for research purposes. However, i ndividuals have been purchasing methylone from i nternet vendors, gas stations, convenience stores, and head shops

, while other reports indicate U.S. military personnel have likewise been purchasing and abusing synthetic cathinones . These products are commonly marketed as “legal highs” under a variety of produc t names (e.g., White Dove, Euphoria, Dynamite, Tranquility, Explosion and others) and with a disclaimer “ not for human consumption. ”

Additionally, large seizures of methylone containing products have occurred by law enforcement and the U.S. Customs and Border Protection (CBP) (see Factor 5) . The National Forensic Laboratory Information System (NFLIS) details over 2,500 reports from state and local forensic laboratories identifying methylone in drug related exhibits for a period from J une 200 8
to June 20 1 2 from 42 states.

iii. Individuals are taking methylone on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substance.

According to HHS, t here is currently no accepted medical use for met hylone and no medical practitioner is currently licensed by law to administer methylone (HHS, 2012) . Indeed, the U. S. Food and Drug Administration ( FDA ) has not evaluated or approved a new drug application (NDA) for m ethylone for any therapeutic indication, and no investigational new drug (IND) application is currently active.Page 7 of 36

iv. Methylon e is so related in their action to a substance already listed as having a potential for abuse to make it likely that they will have the same pot ential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that they have a substantial capability of creating hazards to the health of the user or to the safety of the community.

According to HHS, in preclinical studies methylone pr oduces pharmacological effects similar to those produced by the Schedule I substance, MDMA and Schedule II stimulants such as amphetamine, m ethamphetamine

, and cocaine (HHS, 2012) . Likewise, t he pharmacological profile (as inferred from its toxicological profile observed in emergency room and medical examiner cases) of methylone in humans is similar to that from preclinical studie s

. For exam ple, HHS also states that methylone blocks the reuptake of dopamine, seroto n in, and norepinephrine into nerve terminals and stimulates the release of the same neurotransmitters from nerve terminals leading to increase in e xtracellular levels of the same in nucleus accumbens. Similarly, the s erotonergic profile of methylone is similar to that of MDMA. In locomotor and drug discrimination studies, methylone shares substantial similarities to the Schedule I and II stimulants methamphetamine, MDMA, amphetamin e, and cocaine.

According to HHS , published studies also report that methylone has pharmacological effects similar to amphetamine, methamphetamine, MDMA, and cocaine. In these studies, m ethylone has been demonstrated to increase serotonin release and to inhibit serotonin and dopamine reuptake in rat brain synaptosomes and in cells expressing the dopamine transporter (DAT), norepinephrine transporter (NET), and the serotonin transporter (SERT) (Cozzi et al., 1999; Nagai et al., 2007; Sogawa et al., 2011 ; N ational Institute on Drug Abuse (NIDA) , 2012 ; HHS, 2012 ). Like methamphetamine and MDMA, methylone elicited the release of dopamine, norepinephrine and serotonin from cells expressing the DAT, NET, and SERT (Sogawa et al., 2011 ; Nagai et al., 2007 ). Methylone, similar to MDMA, also increased extracellular serotonin and dopamine in rat brain (Bauman n et al., 2011). Increased monoamine concentration s in the central nervous system (CNS) is thought to be involved in stimulant and hallucinogenic effects

o f the phenethylamine class of drugs (Dal Cason et al., 1997). In drug discrimination assays, methylone substituted for MDMA and amphetamine, which suggests that methylone will likely produce subjective effects in humans similar to these substances and hav e a similar pattern of abuse (Dal Cason et al., 1997; Balster and Bigelow, 2003). Studies also showed methylone to be a weak locomotor st imulant ( Bauman n et al., 2011 ; Lopez

- Arnau et al., 2012; Miyazawa et al., 2012; NIDA, 2012 ). The data from studies co nducted by the National Institute on Drug Abuse (NIDA) contract researchers are consistent with this ( see Table 6 and Factor 2 ).

In light of the above mentioned similarities between methylone and other Schedule I and II substances of abuse, it is reasonable to assum e that there will be significant diversion of methylone; significant use of methylone contrary to or without medical advice; and that methylone has a substantial capability of creating hazards to the user or the safety of t he community. In fact

, the available evidence as presented above and elsewhere in this document (see Factors 4, 5 and 6) supports the above statements

.Page 8 of 36

b. Actual or Relative Abuse Potential

i. Animal Studies

Drug Discrimination Studies

The drug discrimination paradigm is used as an animal model of human subjective effects. This procedure provides a direct measure of stimulus specificity of a test drug in comparison with a known standard drug, or a neutral stimulus (e.g. injection of saline water). In the dru g 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 simi lar to the known drug of abuse and would be similarly abused by humans (Bal ster and Bigelow, 2003; Panlilio and Goldberg , 2007).

At the time of temporary scheduling of methylone , DEA requested that the National Institute on Drug Abuse (NIDA) conduct pharmacological studies including drug discrimination studies

on methylone ( NIDA, 2011 ). The data from these studies as well as the data published in the scientific literature demonstrate that the discriminative stimulus effects of methylone ar e similar
t o those of the Schedule I and I I substance s amphetamine, methamphetamine, cocaine, and MDMA (Dal Cason, 2007; NIDA, 2011; HHS, 2012)

. In contrast, methylone does not substitute for 2,5

- dimethoxy

- 4

- methylphenethylamine (DOM), a Schedule I hallucinogen (Dal Cason et al., 1997). The results of these studies are summarized below in Table 1 and can also be found in Factor 2.

Table 1 . Summary of D rug Discrimination Studies Involving Methylone
Training Drug (Dose) Methamphetamine (1 mg/kg) Cocaine (10 mg/kg) MDMA (1.5 mg/kg) DOM (1 mg/kg) Methylone Full substitution Full substitution Full substitution No substitution

ii. Clinical S tudies and Case R eports

According to HHS, m ethylone has not been evaluated in human abuse liability studies (HHS, 2012) . Furthermore, no studies have been undertaken to evaluate the toxicology and safety of methylone in humans.

c. Actual Abuse

Available information demons trates that methylone, like Schedule I and II substances, is being abused for its psychoactive effects.

Forensic Laboratory Data

The National Forensic Laboratory Information System (NFLIS) is a program sponsored by DEA's Office of Diversion Control. NF LIS compiles information on exhibits analyzed in statePage 9 of 36

and local law enforcement laboratories. The System to Retrieve Information from Drug Evidence (STRIDE) is a DEA database which compiles information on exhibits analyzed in DEA laboratories. NFLIS and STRIDE together capture data for all substances reported by forensic laboratory analyses. More than 1,700 unique substances are reported to these two databases.

Methylone has been encountered by law enforcement as reported in NFLIS. 5 NFLIS details 2,79 7 reports from state and local forensic laboratories identif ying methylone in drug related exhibits for a period from January 2009 to June 2012 from 42 States ( Table 2 and Table 3 ). In 2009, the NFLIS registered 4 reports from 3 states containing methylone. However, in 2010, there were 71 reports from 18 states related to methylone registered in NFLIS, in 2011 there

were 1,655 reports from 41 states, and in 201 2 there were 1,067 reports from 36 states

. Methylone represents approximately 2 6 % ( 2,797 / 10

, 798 ) of all the reports involving synthetic cathinones that have been reported to NFLIS from 2009 to 2012

.

Table 2

. Synthetic Cathinones

– Number of Exhibits (State and Local)

2009 2010 2011 2012* TOTALS Methylone 4 71 1,655 1,067 2,797 Mephedrone 9 231 305 25 570 MDPV 2 304 3,143 1,327 4,776 Other Synthetic Cathinones ‡ 12 34 972 1,637 2,655 TOTAL Synthetic Cathinones 27 640 6,075 4,056 10,798 *January

– June 2012 NFLIS database was queried on 9/ 1 2/ 201 2 for s tate and l ocal f orensic l aboratory drug reports

. ‡ Other synthetic cathinones include 3,4

- d imethylmethcathinone (3,4

- dmmc), 3,4

- methylenedioxyethylcathinone (ethylone), 4'

- methoxy

- alpha

- pyrrolidinopropiophenone (moppp), 4'

- methyl

- alpha

- pyrrolidinopropiophenone (4

- meppp)

, 4

- methyl

- n

- ethylcathinone (4

- mec)

, alpha

- pyrrolidinobutiophenone (alpha

- pbp)

, alpha

pyrrolidinopentiophenone ( 

- pvp)

, butylone (ß

- keto

- n

- methylbenzo

- dioxylpropylamine)

, dibutylone

, dimethylone

, ethylcathinone

, fluoromethcathinone

, mdpbp

, mdppp

, ethcathinone

, ethedr one (4

- methoxymethcathinone)

, naphthylpyrovalerone (naphyrone)

, pentedrone (2

- (methylamino)

- 1

- phenylpentan

- 1

- one)

, pentylone (ß

- keto

methylbenzodioxolylpentanamine)

, pyrovalerone

, substituted cathinone (not specifically identified)

Table 3

. Number of States where Methylone was Identified (State and Local)

2009 2010 2011 2012* TOTAL STATES Methylone 3 18 41 36 42 *January

– June 2012 NFLIS database was queried on 9/ 1 2/ 201 2; State and l ocal f orensic l aboratory drug reports

STRIDE also details reports from federal forensic laboratories identif ying methylone in drug related exhibits for a period from January 2009 to June 2012 ( Table 4 ). Data from the forensic laboratory database STRIDE, a federal database for the drug samples analyzed by DEA forensic

5 State and l ocal f

orensic drug reports from January 2009 to June 2012 , a nalyzed on September 12, 2012

. The 201 2 drug reports are likely to be incomplete as of September 12, 2012 , due to laboratory reporti ng lag time.Page 10 of 36

laboratories, indicate illicit activity involving methylone. From 2009 to 201 2 , Federal law enforcement authorities encountered 220 drug exhibits pertaining to the trafficking, distr ibution and abuse of methylone.

Table 4

. Methylone Exhibits (Federal)

2009 2010 2011 2012* TOTALS Methylone 1 7 107 105 220 *January

– June 2012 STRIDE database was queried on 9/ 1 2/ 201 2 by date submitted t o f ederal forensic laboratories

Concerns over the abuse of methylone and other synthetic cathinones have prompted many states to control these substances. As of September 2012, at least 42 states have emergency scheduled or enacted legislation placing regulatory controls on some or many of the synthetic cathinones including mephedrone, methylone

, MDPV and/or a defined general class of cathinones. At least 27 states specifically control methylone. These states include Alabama, Arizona, Arkansas, Delaware, Florida, Georgia, Rhode Island, Illinois, Indiana, Kansas, Kentucky, Louisiana, Maine, Maryland, M innesota, Mississippi, Nebraska, New Jersey, New Mexico, Ohio, Oklahoma, Pennsylvania, Tennessee, Texas, Utah, Virginia, and Wyoming. In addition, the U.S. Armed Forces prohibited the use of synthetic cathinones including mephedrone, methylone or MDPV. I nternationally, several member countries of the European Union have enacted laws placing controls on the possession and/or sale of one or more of these substances (Winstock et al., 2010; European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) , 201 1 ).

Table 5

. List of States where Methylone was Identified

States with Exhibits from 2009

- 201 2* Methylone Alabama Arizona Arkansas California Colorado

Connecticut Florida Georgia Hawaii 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 Pennsylvania South Carolina Tennessee Texas Utah Virginia Washington West Virginia Wisconsin Wyoming *January

– June 2012 NFLIS database was queried on 9/12 /2012 by submission

, s tate and l ocal f orensic laboratory drug r eports.

U.S. Customs and Border Protection (CBP)

At selected United States ports of entry, the U.S. Customs and Border Protection (CBP) has encountered shipments of products containing methylone. Of all the shipments of synthetic cathinones reported to DEA, the most commonly encountered synthetic cathin one was methylone. As of July 2012, methylone was identified in 127 of 330 shipments encountered by CBP from June 2008 to July 2012

. These shipments of methylone were in powdered form ranging from 1 gram to multi

- kilogram quantities. Other synthetic cat hinones encountered by CBP were MDPV, mephedrone, 4

- MEC, butylone, fluoromethcathinone , and dimethylcathinone.Page 11 of 36

Most of the shipments of these synthetic cathinones that contained methylone originated in China and were destined for delivery throughout the United States to places like Alaska, Arizona, Arkansas, California

, Colorado, Florida, Hawaii, Illinois, Kansas, Louisiana, Oklahoma, Oregon, Missouri, Nevada, New Mexico, Tenness ee, Texas, Washington, and West Virginia.

Other Encounters of Methylone

Methylone has also been identified during the toxicological screening of individual human urine samples. Redwood Toxicology Laboratory screened over 2000 urine samples for the fol lowing 14 designer stimulants: amphetamines [3,4

- methylenedioxyamphetamine (MDA), MDMA, 3,4

- methylenedioxymethamphetamine (MDEA), methylbenzyldioxolylbutanamine ( MBDB) ] , cathinones [ ( m ethylone, e thylone, b utylone, c athinone, m ethcathinone, MDPV,

m ephedron e) ] and designer piperazines [N,N

- benzylpiperazine ( BZP )

, 1

- (3

- trifluoromethylphenyl)

- piperazine ( TFMPP ) and 1

- (3

- chlorophenyl)piperazine ( mCPP )] (Rana et al., 2011) . Six of these 14 designer stimulants were detected in 159 urine specimens of which 21% (33/159) were methylone either alone or in combination with other substances . The other substances detected were MDPV, mephedrone, butylone, TFMPP, and BZP. A similar study that screened urine samples (209) from attendees of a methadone maintenance progr am in the Republic of Ireland found that 13.9% (29) of samples were positive for mephedrone and 3.3% (7) were positive for methylone (McNamara et al., 2010; EMCDDA, 2011).

U.S. Drug Courts have communicated concerns related to the abuse of synthetic cathinones because d rug courts have detected methylone in human urine samples during mandatory periodic drug screens. Drug courts were developed to achieve a reduction in recidivism and substance abuse among nonviolent, substance abusing offenders by incr easing their likelihood for successful rehabilitation through early, continuous, and intense judicially supervised treatment, mandatory periodic drug testing, and the use of appropriate sanctions and other rehabilitation services. Drug courts analyze spec imens from participants for new and existing drugs of abuse. Drug courts submitted to DEA 18 reports from the analysis of biological specimens that contained synthetic cathinones. Me thylone was mentioned in 5 of these reports

. 6 Other substances detected included mephedrone, MDPV, butylone, lidocaine, benzocaine, and MDMA. It is possible that drug court participants ab use synthetic cathinones because they believe that these substances are legal and, thus, they can avoid being charged with violating their parole by using synthetic cathinones.

Information from poison center s indicates that the use of synthetic cathinones which likely include methylone is widespread (see Factor 4 )

. AAPCC reported in a press release that poison centers took 30 4 calls in 2010 regarding synthetic cathinones exposures and 6,138 calls in 2011 (AAPCC, 201 2 ). A s of September 12, 2012

, poison centers received 2,251 calls relating to these

6 Some specimens contain more than one cathinone.Page 12 of 36

products as of this year. These calls were received in poison centers representing at least 47 states and the District of Columbia. Although methylone may not be specifically identified during exposure calls or identified by toxicology testing by AAPCC, it is likely that some of these retail products described by the caller s contained meth ylone

, based on the identification of methylone in approximately 2 6 % of all synthetic cathinones related exhibits reported to NFLIS from January 2009 to June 2012 ( Table 2 ).

Summary

In summary, evidence indicate s that methylone has a high potential for abuse. According to HHS’s scientific and medical evaluation and scheduling recommendation, methylone is a CNS stimulant that share s many similarities with the Schedule I stimulants cathinone and methcathinone and Schedule II substances, MDMA, amphetamine, methamphetamine, and cocaine (HHS, 2012)

. Methylone has no known medical use in the United States but evidence demonstrates that m ethylone i s being abused by individuals for its psychoactive effects. Methylone has been encountered by law enforcement throughout the United States as reported in NFLIS and in STRIDE databases suggesting that individuals are abusing methylone

. Evidence of the abuse of methylone is confirmed by drug courts. Drug court reports have identified methylone in specimens from drug court participant s. Methylone has also been identified during the toxicological screening of individual human urine samples which a lso demonstrates that individuals are abusing this substance. In addition, information from poison centers indicates that the use of synthetic cathinones which likely include methylone is widespread

. In conclusion , t hese encounters of methylone through l aw enforcement

, drug screenings

, and poison
center data indicate that methylone is a popular drug of abuse and has a high abuse potential

.

Factor 2 : S cientific E vidence of its P harmacological E ffects , if Known

HHS states in their recommendation to place methylone in Schedule I of the CSA that based on the results of preclinical studies and the toxicological profile observed in emergency room cases and medical examiner cases it is probable that methylone produces pharmacological effects in humans that are similar to those produced by the Schedule I and II substances, amphetamine, methamphetamine, cocaine, and MDMA (HHS, 2012)

. These studies are described below.

In addition to data from published studies, contract researchers for the National Institute on Drug Abuse ( NIDA ) also provided data on the pharmacological effects of methylone. Studies conducted by NIDA included drug discrimination, locomotor activity assays, and in vitro receptor binding and functional assays.

Preclinical In Vivo Studies

– Behavioral Effects

The available published scientific studies and studies by NIDA evaluating the behavioral effects of synthetic cathinones i n animals suggest that methylone produces pharmacological effects in animals that are similar to those produced by methamphetamine, cocaine, and MDMA

. Behavior studies included drug discrimination, conditioned place preference , and locomotor activity studies.Page 13 of 36

The d rug discrimination paradigm is an accepted animal model used to predict subjective effects of substances in humans (Balster and Bigelow

, 2003 ). In NIDA

- sponsored drug discrimination studies

, methylone fully substitute d with ED 50 values of 1.47 mg/kg and 2.66 mg/kg for the Schedule II stimulant s, cocaine (ED 50 = 2.73 mg/kg) and methamphetamine (ED 50 = 0.34 mg/kg), respectively ( Table 6 )

. This data is consistent with a published report on discriminative stimulus effects of methylone (Dal Cason et al., 1997)

. Methylone (ED 50 = 2.36 mg/kg) fully substituted for amphetamine (ED 50 = 0.33 mg/kg) or MDMA (ED 50 = 1.60 mg/kg) in rats trained to discriminate amphetamine (training dose = 1 mg/kg) or MDMA (training dose = 1.5 mg/kg), respectively, from saline. In con trast, methylone d id not substitute for the DOM ( training dose = 1 mg/kg) , a Schedule I hallucinogen (Dal Cason et al., 1997).

The c onditioned place preference (CPP) paradigm is a preclinical behavioral model used to study the reinforcing effects (rewarding or aversive) of drugs ( Stolerman, 1992; Prus et al., 2009 ). CPP tests are able to detect addictive substances. Psychostimulants, such as amphetamine and cocaine, often produce a robust CPP. In the conditioned place preference test, mice trea ted with of methylone ( intraperitoneal doses of 2.5 and 5.0 mg/kg) developed CPP confirming that methylone , like methamphetamine, has a rewarding effect (Miyazawa et al. 2011)

.

Stimulant effects can be quantified using locomotor activity studies. Stim ulants like amphetamine and methamphetamine enhance physical performance. Several studies show that

m ethylone, like methamphetamine and cocaine

, is a CNS stimulant (Baumann et al., 2011; Lopez

- Arnau et al., 2012; Miyazawa et al., 2012; NIDA, 2012)

. In N IDA

- sponsored locomotor activity studies, t reatment with the compound methylone resulted in time

- and dose

- dependent stimulation of locomotor activity in doses from 3 to 30 mg/kg ( Table 6 )

. Stimulant effects of 3 and 10 mg/kg occurred within 10 minutes following injection and lasted 60 to 120 minutes. Based on the 30

- minute time period in which maximal stimulant effects occurred (0 to 30 minutes following injection), an ED 50 of 1.5 mg/kg was calculated. The maximal stimulant effect of methylone was 87% of the maximal stimulant effect of methamphetamine and 82% that of cocaine. In comparison, treatment with methamphetamine resulted in time

- and dose

- dependent stimulati on of locomotor activity following 0.5 to 4 mg/kg with stimulant effects occurring within 10 minutes following injection and lasting 130 to 310 minutes. The ED 50 of methamphetamine was estimated at 0.48 mg/kg. Treatment with cocaine resulted in time

- and dose dependent stimulation of locomotor activity following 10 to 40 mg/kg with stimulant effects of 10 and 20 mg/kg occurring within 10 minutes following injection and lasting 120 to 170 minutes. The ED 50 of cocaine was estimated at 7.2 mg/kg.Page 14 of 36

Table 6

. Summary of In Vivo NIDA Studies Regarding Methylone in Rodents
In Vivo Study Locomotor Activity 8

- hr test Effect & E D 50 Duration of Action ( DOA ) % stim ulation Drug Discrimination Cocaine ( TD = 10 mg/kg) Effect & E D 50 Drug Discrimination

Methamphetamine ( TD = 1 mg/kg) Effect & E D 50 Methylone Stimulant ED 50 =1.5 mg/kg DOA = 120 min 87% methamphetamine stimulation 82% cocaine stimulation Full substitution ED 50 = 1.47 mg/kg Full substitution

ED 50 = 2.66 mg/kg

Methamphetamine Stimulant ED 50 = 0.48 mg/kg DOA = 310 min Full substitution ED 50 = 0.34 mg/kg

Cocaine Stimulant ED 50 = 7.2 mg/kg DOA = 170 min Full substitution ED 50 = 2.73 mg/kg

ED 50 for locomotor activity studies is the median effective dose that produces 50% maximum locomotor activity 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 lever TD is the trai ning dose used for the drug discrimination study

Results from several published studies are consistent with those from the NIDA

- sponsored study regarding stimulant activity . In mice that have been given methylone by oral administration, m ethylone (5

- 10 0 mg/kg) , like MDMA and methamphetamine, significantly increase d locomotor activity (Miyazawa et al., 2012). The maximum increase in locomotor activity for methylone occurred at 50 mg/kg

. In comparing the effects of these three substances administered to mice at a equivalent dose of 0.205 mmol/kg (which is equivalent to 50 mg/kg methylone) on locomotor activity , methylone increased locomotor activity more than methamphetamine or MDMA.

Intravenous (IV) administration of methylone, like MDMA and methamphetamine, is a psychomotor stimulant (Baumann et al., 2011). The effects of methylone in stimulating locomotor activity is similar to that of MDMA but weaker (i.e., less potent) than that o f methamphetamine. IV administration (IV) of methylone (1.0 mg/kg) also produced an increase in locomotor activity that was 5

- fold above baseline. Similarly, MDMA (IV, 1.0 mg/kg) increased in locomotor motor activity 5

- fold above baseline. In contrast , methamphetamine (IV, 1.0 mg/kg) increased locomotor motor activity 30

- fold above baseline. In addition, methylone at 100 mg/kg increased body temperature and respiratory rate and produced salivation and piloerections.

DEA notes that i n a similar study investi gati ng the effects of methylone and other synthetic cathinones on locomotor activity, subcutaneous administration of methylone (5

– 25 mg/kg), like MDMA (5 mg/kg), dose

- dependently increased locomotor activity in mice (Lopez

- Arnau et al., 2012).Page 15 of 36

Preclinical In Vitro Studies

- Receptor Binding Profile

C ontract researchers for NIDA investigated the affinity and functional effects of methylone
at serotonin and dopamine receptors using radioligand binding and functional assays ( Table 7 ).

DEA notes that i n radioligand binding and functional assays done by NIDA

, methylone has very low affinity for the serotonin ( 5HT ) 1A , 5HT 2A and 5HT 2C receptors. Methylone has very low affinity (63,280 nM) for the 5HT 1A receptor and is a partial agonist with very low potency (143,000 nM). Methylone has very low affinity (48,500 nM) for the 5HT 2A receptor and is an antagonist with very low potency (159,000 nM). Methylone ha s very low affinity (11,770 nM) for the 5HT 2C receptor and is a weak antagonist with very low potency (>1 mM). Methylone has very low to no measurable affinity (>10,000 nM) for the dopamine D 1 , D 2 , D 3 and D 4.4 receptors.

Table 7

. Affinity of Methylone to Serotonin and Dopamine Receptors and Function in Transfected Clonal Cells

Methylone 5HT 1A 5HT 2A 5HT 2C D 1 D 2 D 3 D 4.4 K i 63,280 nM 48,500 nM 11,770 nM >10  M >10  M >10  M >10  M EC 50 Maximal Stimulation 143,000 nM 47% >1 mM

<3% >1 mM

<1% IC 50 Maximal Inhibition 159,000 nM 84.7% >1 mM

28% Radioligand s w ere [ 3 H]8

- OH

- DPAT for serotonin ( 5HT ) 1A , [ 125 I] DOI for 5HT 2A and 5HT 2C , [ 3 H]SCH23390 for dopamine ( D ) 1 , [ 3 H]YM

- 09151

- 2 for D 2 , D 3 , and D 4.4 EC 50 is the drug concentration giving half

- maximal acceleration/ stimulation of [ 35 S]GTP  S binding for 5HT 1A receptors and i no sitol

- 1

- p hosphate (IP) production for 5HT 2A and 5HT 2C receptors in HEK cells IC 50 is the drug concentration giving half

- maximal inhibition on IP formation in HEK cells

Preclinical In Vitro Studies

– Binding and Functional Activity at Biogenic Amine Transporters

The available published scientific studies and studies by NIDA evaluating the pharmacological activity of synthetic cathinones on animals suggest that methylone , like Schedule I and II substances , affect s monoamine neurotransmission. Studies conducted by N IDA contract researchers show that m ethylone has low affinity for the dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters , however, it is a substrate for these sites based on inhibition of uptake and release studies ( Table 8 )

.

DEA notes that i n functional assays with transporter cell lines ( human embryonic kidney ( HEK ) cells expressing the cDNA for the human dopamine, serotonin, or norepinephrine transporter)

, m ethylone is an uptake blocker with low potency at the DAT and NET. Methylone is an uptake blocker with very low potency at the SERT and no measurable effect at the vesicular monoamine transporter 2 ( VMAT2 )

. The rank order of potency for inhibition of uptake for

m ethylone was NET=DAT>SERT whereas the rank order for cocaine is NET= SERT= DAT.

DEA also notes that i n functional assays with transporter cell lines (HEK cells expressing the cDNA for the human dopamine, serotonin, or norepinephrine transporter)

, methyl one causes release of neurotransmitters via the transporters. Methylone has partial efficacy and very low potency at releasing neurotransmitter via the DAT. Methylone has substantial efficacy and very low potency at releasing neurotransmitter via the SER T. Methylone has very high efficacy andPage 16 of 36

low potency at releasing neurotransmitter via the NET. Methylone has low efficacy at releasing neurotransmitter via the VMAT2. The rank order for release by methylone was NET>SERT=DAT. The rank order for release b y methamphetamine is NET=SERT>DAT.

Table 8

. Effect of Methylone on Human Monoamine Transporters in Transfected HEK cells

Transporter Binding

- K i Uptake Inhibition

- IC 50 Release

- EC 50 , Maximal Stimulation Methylone Serotonin 95,500 nM 1,920 nM 6,700 nM, 78%

Dopamine 5,020 nM 343 nM 11,800 nM, 41% Norephinephrine 16,500 nM 234 nM 444 nM, 152% Vesicular >10  M >100  M (5HT) >100  M, 22% (NE) Cocaine Serotonin 234 nM 257 nM

Dopamine 552 nM 370 nM Norephinephrine 1,380 nM 218 nM Methamphetamine Serotonin 22,450 nM, 97.6%

Dopamine 400 nM, 101.9% Norephinephrine 128 nM, 92.7% Vesicular 867,000 nM 4,720 nM (5HT) 147,000 nM, 96% (NE) K i value s are binding affinity values; Radioligand was [ 125 I]RTI

- 55 IC 50 value is the drug concentration giving half

- maximal inhibition EC 50 value is the drug concentration giving half

- maximal acceleration / stimulation 5HT is serotonin; NE is norepinephrine

The above

- mentioned data from the studies performed by the NIDA contract researchers are consistent with the several published reports on the effe cts of methylone of inhibition of uptake and release of neurotransmitters

. These studies are described below.

DEA notes that i n rat brain synaptosomes, methylone inhibited the uptake of dopamine (IC 50 = 0.56  M), serotonin (IC 50 = 0.23  M), and norepinep hrine (IC 50 = 0.53  M) ( Lopez

- Arnau et al., 2012 ).

In rat b rain synaptosome s , methylone inhibited the uptake of dopamine (IC 50 = 2.9  M), serotonin (IC 50 = 2.3  M)

, and norepinephrine (IC 50 = 0.74  M) (Nagai et al., 2007)

. In comparison, MDMA, cocaine, and methamphetamine also inhibit ed the uptakes of these neurotransmitters i n rat brain synaptosomes

. The IC 50 values for these Schedule I and II substances for the inhibition of dopamine, serotonin, and norepinephrine were 1.4  M, .072  M, and 0.66  M fo r MDMA, 0 .85  M, 2.1  M, and 0.34  M for cocaine, and 0.37  M, 4.0  M, and 0.20  M for methamphetamine, respectively.

Methylone , like methamphetamine , methcathinone and MDMA

, potently inhibits monoamine trans porters (Cozzi et al., 2008, 2009). I n human platelet cells that naturally express the SERT , methylone (IC 50 = 5.75 mM) was half as potent as methamphetamine ( I C 50 = 11.6
 M)

, six

- fold more potent than methcathinone (IC 50 = 34.6  M), and 2.7

- fold less potent than MDMA (IC 50 = 2.14  M) in inhibiting platelet serotonin accumulation

. Methylone also inhibited the uptake of do pamine (IC 50 = 0.819  M) and noradrenaline (i.e., norepinephreine) (IC 50 = 1. 22  M) in C6 glial cells that express the rat DAT or the human NET, respectively.

Methylone, like met hamphetamine, dose

- dependently inhibited the uptake of dopamine (IC 50 = 2.84  M), serotonin (IC 50 = 8.42  M), and norepinephrine (IC 50 = 0.48  M) in Chinese hamster ovary ( CHO ) cells expressing the rat DAT, SERT, or NET . Like methamphetamine,Page 17 of 36

methylone wa s more potent at inhibiting the uptake of dopamine than serotonin (Sogawa et al., 2011)

. In addition to inhibiting the uptake of neurotransmitters, m ethylone, like methamphetamine and MDMA, has monoamine releasing activity (Nagai et al., 2007 ; Baumann et al., 2011; Sogawa et al., 2011 ).

Methylone stimulated the release of dopamine (EC 50 = 0 .38  M), serotonin (EC 50 = 0 .22
 M), and norepinephrine (EC 50 = 93 nM) in rat brain synaptosomes (Nagai et al., 2007)

. MDMA and methamphetamine were pot ent releasers of these neurotransmitters. The EC 50 values for the release of dopamine, serotonin, and norepinephrine were 0.20  M, 58 nM, and 86 nM for MDMA and 28 nM, 0.79  M, and 11 nM for methamphetamine, respectively. In contrast, cocaine did not sti mulate the release of these neurotransmitters. MDMA was more potent in rel easing serotonin than dopamine, and methamphetamine was more potent in releasing dopamine than serotonin. However, m ethylone was nearly equipotent at releasing the se two neurotrans mitters ( i.e., dopamine and serotonin )

.

DEA notes that m ethylone, like MDMA and methamphetamine, stimulate d the release of radiolabeled substrates by the dopamine transporter (E C 50 = 133 n M), serotonin transporter ( E C 50 = 242 n M), and norepiniephrine transporter ( E C 50 = 152 n M) in rat brain synaptosomes in an equipotent manner (Baumann et al., 201 1 ). The profile of neurotransmitter release by methylone resembled that of MDMA ( dopamine transporter , EC 50 = 51 nM; serotonin transporter , EC 50 = 50 nM; an d norepinephrine transporter , EC 50 = 50 nM) than that of methamphetamine ( norepinephrine transporter , EC 50 = 8.5 nM; serotonin transporter , EC 50 = 1291 nM; and NET, EC 50 = 14 nM) which was mo st potent at stimulating release at the norepinephrine and dopami ne transporter.

DEA notes that m ethylone, like methamphetamine, induce d the release of dopamine, serotonin, and norepinephrine from CHO cells expressing the rat DAT, SERT, or NET (Sogawa et al., 2011)

.

Preclinical In Vivo Studies

– Functional Activity at Biogenic Amine Transporters

In laboratory studies using microdialysis technique, intravenous administration of methylone (0.3 and 1.0 mg/kg), like MDMA and methamphetamine, increased extracellular concentrations

o f dopamine and serotonin in rat brain (nucleus accumbens) (Baumann et al., 2011). In these studies, the effects of methylone resembled those of MDMA such that methylone, although less potent than MDMA (0.3 and 1.0 mg/kg), had a greater effect on extracell ular serotonin concentration than dopamine concentration. In contrast, methamphetamine (0.3 and 1.0 mg/kg) preferentially increased extracellular dopamine rather than serotonin.

Preclinical In Vitro Studies

– Cytotoxi ci ty

S tudies show that methylone , lik e MDMA, can be cytotoxic to liver cells ( Nakagawa et al., 2009 ; Sogawa et al., 2011 ) . Incubation of hepatocy t es (liver cells) with methylone or MDMA caused cell death (Nakagawa et al., 2009). In addition, high concentrations of methylonePage 18 of 36

induced the rele ase of lactate dehydrogenase (LDH), an indication of decreased cell viability

, in cells that stably expressed the SERT (Sogawa et al., 2011). However, m ethylone in combination with methamphetamine had a synergistic cytotoxic effect on CHO cells that expre ssed the DAT, NET, or SERT . These data suggest that using methylone alone and in combination with other psychoactive substances may cause damage to liver cells.

Summary

The above mentioned data indicate that methylone produces pharmacological effects that are similar to those produced by Schedule I and II substances methamphetamine, cocaine, and MDMA

. Methylone, like methamphetamine , amphetamine, and cocaine is a CNS stimulant and produces locomotor stimulant effects in mice. (Baumann et al., 2011; Lopez

- Arnau et al., 2012; Miyazawa et al., 2012; NIDA, 2012). Methylone substitute s for MDMA , cocaine, or amphetamine in rats trained to discriminate MDMA , cocaine, or amphetamine from saline

, respectively (Dal Cas on et al., 1997; NIDA, 2011)

. Methylone

, like methamphetamine, produced rewarding effect as studied in CPP tests (Miyazawa et al. 2011)

. Methylone is an inhibitor of dopamine, serotonin and norepinephrine uptake and also causes the release of these

neuro transmitters in the CNS (Nagai et al., 2007; Cozzi et al., 2009; Sogawa et al., 2011; Baumann et al., 2011; Lopez

- Arnau et al., 2012)

. Furthermore, s tudies show that methylone

, like MDMA, can be cytotoxic to liver cells (Sogawa et al., 2011)

. B ased on the results of preclinical studies , HHS postulates that in humans, methylone is likely to produce pharmacological effects similar to those produced by amphetamine, methamphetamine, cocaine, and MDMA

.

Factor 3 : The State of Current Scientific Knowledge Rega rding the Drug or Other Substance

HHS also considered the state of current scientific knowledge regarding methylone (HHS, 2012) . A summary of HHS’s findings is provided below.

Chemical Structure

Methylone ( 3,4

- methylenedioxy

- N

- methylcathinone ) is a synt hetic cathinone ( 

- keto

phenethylamines) of the larger phenethylamine structural c lass ( e.g., amphetamines, cathinones, 2C compounds , aminoindanes ). M ethylone share s the core phenethylamine structure with substitution s at the 

- position

, 

- position on the phenyl ring

, and nitrogen atom (Figure 1)

. The addition of a beta

- keto (β

- keto ne ) substituent to the phenethylamine core structure produces a group of substances with a 

- keto

- phenethylamine core structure. Methylone incorporate s a keto functional group [carbonyl

, (C=O)] at the 

- position on the ethylamine side chain and the nitrogen atom is substituted with an alkyl group , methyl . The 

- position is also substituted with an alkyl group (methyl) giving two stereoisomeric forms for methylone (racemic mixt ures). The phenyl ring is substituted with a methylenedioxy moiety.Page 19 of 36

Figure 1

. Chemical Structures for G eneral P henethylamine s , 

- K eto phenethylamine, and Methylone

Chemistry and Physical Properties

Table 9

. The Chemical and Physical Properties for Methylone

Substance Methylone CAS # 186028

- 79

- 5; 191916

- 41

- 3 (+); 186028

- 80

- 8 (hydrochloride) Systematic name: IUPAC, CAS, etc. 1

- (benzo[d][1,3]dioxol

- 5

- yl)

- 2

- (methylamino)propan

- 1

- one

Common Name bk

- MDMA ; 3,4

- methylenedioxy

- N

- methylcathinone Molecular Formula C 11 H 13 NO 3 Exact Mass 207.09 Melting point 226

- 228 o C (free base ?; Dal Cason, 1997); 244 + 3 o C (hydrochloride salt; Lipomed); 213

- 216 o C (TRC CoA) Appearance Off

- white solid, c rystalline solid (hydrochloride)

Synthesis

Methylone may be prepared by general procedures as detailed in the scientific and patent literature (Collins , 2011). The scientific literature suggests that m ethylone was first synthesized in 1994. This substance can be prepared from its corresponding ketone by a two

- step synthesis. To date, clandestine synthetic operations have not been encountered pertaining to this substance

, but the procedures for the clandestine synthesis of methylone could be easily adapted from established procedu res

.

Metabolism and Pharmacokinetics

Metabolism studies have been conducted for methylone ( Kamata et al., 2006; Katagi et al., 2010; Meyer and Maurer, 2010 ; Meyer et al., 2010 ). In general, humans metabolize synthetic cathinones to their corresponding am phetamine s followed by reduction of the beta

- keto group to the corresponding alco hol (Meyer and Maurer, 2010). Speci fically, methylone is demethyl ated and subsequently O

- methylated as well as N

- dealkylated to produce the metabolites 3,4

- methylenedioxycath inone (MDC), 4

- hydroxy

- 3

- methoxymethcathinone (HMMC) and 3

- hydroxy

- 4

- methoxymethcathinone (3

- OH

- 4

- MeO

- MeO

- MC) (Meyer and Maurer, 2010; Kamata et al., 2006; Katagi et al., 2010 ). These metabolites, MDC, HMMC, and 3

- OH

- 4

- MeO

- MC have been found in the urine sample of humans who consumed methylone and rats administered methylone via intraperitoneal injection ( Kamata et al., 2006; Katagi et al., 2010 )

. A nalyticalPage 20 of 36

methods for the better detection of these substances in biological specimens continue to be devel oped by laboratories ( Katagi et al., 2010; Meyer et al., 2010 )

. Medical Application

Research in anti

- depressant and anti

- parkinson agents resulted in the synthesis and patenting of m ethylone in 1996 (Jacob and Shulgin, 1996). However, t here is no evidence that methylone has a legitimate non

- research use and according to HHS there are no approved human drug products, NDAs

, or INDs that contain methylone (HHS, 2012)

. DEA is not aware of any currently accepted medical use for methylone. I n addition, HHS states that there are no studies published in the scientific and medical literature indicating clinical use of methylone. In a letter dated June 15, 2011, t he Administrator of the DEA notified the Assistant Secretary for Health, Department for Health and Human Services about the agency’s intent ion to temporarily place three synthetic cathinones, mephedrone, methylone, and MDPV

, in S chedule I and solicited comments, including whether there is an exemption or approval in effect for the substa nces in question under the Federal Food, Drug and Cosmetic Act. In a letter dated July 25, 2011, t he Assistant Secretary for Health responded to this request and informed DEA that there were no
current INDs or approved NDAs for these synthetic cathinone s.

A drug has a “currently accepted medical use” if all of the following five elements have been satisfied: the drug’s chemistry is known and reproducible; and there are adequate safety studies; and there are adequate and well

- controlled studies proving efficacy; and the drug is accepted by qualified experts; and the scientific evidence is widely available. 57 FR 10499. According to HHS, methylone has not been evaluated in human abuse liability studies (HHS, 2012)

. Furthermore, no studies have been undertaken to evaluate the toxicology and safety of methylone in humans. DEA notes that although the chemistry o f methylone is known and has been reproduced, there are no controlled studies proving efficacy or safety studies. Thus, methylone has no currently accepted medical use and there is a lack of accepted safety for use of methylone under medical supervision

. Summary

Methylone is a β

- keto phenethyl amines (i.e., synthetic cathinone) that is structurally and pharmacologically similar to amphetamine, MDMA, cathinone and other related substances

. Research in anti

- depressant and anti

- parkinson agents resulted in t he synthesis and patenting of methylone. However, according to HHS, there are no known therapeut ic applications for methylone, t here are no approved drug products containing methylone in the United States, and
t here are no current INDs or approved NDAs fo r methylone. Thus , t here is a lack of accepted safety for use of this substance under medical supervision.

Factor 4 : Its H istory and C urrent P attern of A buse

Methylone is a synthetic cathinone that emerged on the United States’ illicit drug market in 2009 and prior to its temporary control was promoted as being a ‘legal’ alternative to cocaine, methamphetamine, and MDMA

. Methylone and other synthetic cathinones are falsely marketed as “research chemicals,” “plant food,” or “bath salts.” Products c ontaining methylone have beenPage 21 of 36

sold at smoke shops, head shops, convenience stores, adult book stores, and gas stations and can also be purchased on the Internet. It is commonly encountered in the form of powders, capsules, and tablets. The packages of these retai l products usually contain the warning “not for human consumption

, ” most likely in an effort to circumvent statutory restrictions for methylone and other synthetic cathinones . Some products found to contain methylone include, b ut are not limited to: Explosion, Tranquility, Pure, White Dove

, Euphoria, Dynamite, and others.

A n independent analysis (queried March 2012) of AAPCC data that was procured by DEA revealed the following information regarding synthetic cathinones which l ikely includes methylone

. Methylone may not be specifically identified during exposure calls as the caller may be unaware of the actual ingredients in the retail product. In addition, AAPCC does not verify the identification of the product or its ingredi ents that have been indicated by the caller to have been consumed

. However, despite these uncertainties it is likely that some of these retail products contain methylone based on the identification of methylone in products obtained from seizures by law enforcement.

Figure 2

.

Source: The A merican Association of Poison Control Centers (AAPCC) National Poison Data System.

The following AAPCC data is nominally different than what was reported in the AAPCC’s Bath Salts Data press release (see Factor 5) because DEA receives quarterly updates from AAPCC and cases may change as they are closed or additional information is received. According to these data, in 2010 (July

– December), the poison centers received 304 exposure calls regarding synthetic cathinones and in 2011 (January

– December) they received 6,137

3 14 20 20 64 183 301 489 639 601 719 745 680 600 511
401

231 220

0 100 200 300 400 500 600 700 800

Jul '10 Aug '10 Sep '10 Oct '10 Nov '10 Dec '10 Jan '11 Feb '11 Mar '11 Apr '11 May '11 Jun '11 Jul '11 Aug '11 Sep '11 Oct '11 Nov '11 Dec '11 Number of Exposure Calls



### Month/Year Number of Synthetic Cathinone ("Bath Salts") Exposure Calls to U.S. Poison Centers July 2010

- December 2011Page 22 of 36

synthetic cathinone exposure calls ( Figure 2 ) . Exposure calls refer to actual or potential human exposure to a synthetic cathinone (e.g., inhalation, ingestion, topical exposure). The calls represented exposed individuals from all 50 states, the District of Columbia, an d a category identified as “overseas/US military/diplomatic.”

Most of the synthetic cathinones reported by the poison centers were identified as “bath salts

. ” A large majority (91.9%) of the exposures were by intentional abuse

, misuse , or suspected suicide . The most common known forms of the synthetic cathinones were identified

as powder/granules and tablets/capsules/caplets. Most of the exposures (70. 7 %) were described
as acute

. 7 Exposures described as acute

- on

- chronic 8 or chronic 9 accounted for 8.4 % and 10 .6 % of the cases, respectively. Another 1 0.3 % of the exposures were of unknown chronicity. Males accounted for 70% of all exposures from July 2010 to December 2011. In every age group, more males than females were exposed to synthetic cathino nes. Most of the exposed individuals were aged 18

- 25 years (34.1%) and 26

- 35 years (28.3%). A few of the callers (1.2%) identified the exposed individuals as being in their 20s. Also, 18.7% of the persons were 36

- 50 years of age. AAPCC data also identi fied the most common route of administration for the synthetic cathinones as inhalation/nasal

.

I nformation from published scientific studies indicate that t he most common routes of administration for methylone is ingestion by swallowing capsules or tablet s or nasal insufflation by snorting the powder ( ACMD, 2010; Boulanger

- Gobeil et al., 2012; Prosser and Nelson, 2012 )

. Ot her methods of intake for synthetic cathinones include d rectal administration

, ingestion by “ bombing ” (wrapping a dose of powder in a paper wrap and swall ow ing) and intramuscular injection ( Karila and Reynaud, 2010; Kelly, 2011)

. In agreement with the findings of AAPCC data, information from the scientific literature and law enforcement suggest that the main users of methylone (or syn thetic cathinones) are young adults ( Shimizu et al., 2007; Boulanger

- Gobeil et al., 201 2 ; Cawrse et al., 2012; Kovac s et al., 2012; Pearson et al., 2012 ). These substances are popular with youths with males appearing to abuse methylone more than females. Data also suggest that these substances are used by other population groups such as mid

- to

- late adolescents and older adults ( Marinetti et al., 2011; Cawrse et al., 2012 ).

7 The AAPCC describes an acute chronicity as a single, repeated or continuous exposure occurring over a period of eight hours or less.

8 Acute

- on

- chronic is a single exposure that was preceded by a continuous, repeated, or intermittent exposure occurring over a period exceeding eight hours.

9 Chronic is a continuous, repeated, or intermittent exposure to the same substance lasting longer than eight hours.Page 23 of 36

U sers report 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, and the effects can last up to three hours ( ACMD, 2010; Karila and Reynaud , 2010; Kelly, 2011; )

. P oison center data also indicate that th e clinical effects of synthetic cathinones most commonly last 8 to 24 hours ( 23.0 %) followed by a duration of 2 to 8 hours (15.7%) and 24 hours to 3 days ( 15.5 %).

Like Schedule I stimulants

, methylone ha s been reported to cause s timulant related psychological and somatic effects such as headache, nausea, palpitation, increased sex drive

, and excessive sweating , hypertension, hyperthermia, and tachycardia ( Shimizu et al., 2007; Boulanger

- Gobeil et al., 201 2 ; Kovac s et al., 2012; Pe arson et al., 2012 ). Other a dverse effects reported by users include b r uxism (teeth grinding) , paranoi a , suppressed appetite

, insomnia, hallucinations, addi c tion/dependence, nausea/vomiting, agitation, and confusion

. The reported average amount of use of methylone ranged widely (from approximately 100 to 250 milligrams) depending on the substance, duration of intake, and route of administration ( Shimizu et al., 2007; Karil a and Reynaud, 2010; Kelly , 2011) . The typical oral dose reported for methylone ranged from 100 to 250 mg (Kelly, 2010).

There is evidence that methylone may be co

- ingested with other substance. Substances reported to have been used in combination with methylone is : other synthetic cathinones ( e.g., mephedrone, ethcathinone, butylone and MDPV .), pharmaceutical agents ( e.g., lidocaine, caffeine, oxymorphone

, clonazepam, and dextromethorphan ), or other recreational substances ( e.g., amphetamine, methamphetamine, cocaine, barbiturates, phencyclidine, cannabinoids, 5

- MeO

- MIPT, 4

- OH

- DIPT ) ( Shimizu et al., 2007; ACMD, 2010; Katagi et al., 2010; DEA

, 2011a,b ; Marinetti et al., 2011; Boulanger

- Gobeil et al., 2012; Cawrse et al., 2012; Kovac et al., 2012; Pearson et al., 2012 ; Warrick et al., 2012 ). Multiple drug use is confirmed by investigative toxicology reports from drugs screens of drug abuse rs

. Additionally, f orensic analysis of seized and purchased synthetic cathinone products revealed that some products contain ed multiple substances

. This finding also confirms that co

- ingestions are likely

. Summary

Methylone is a synthetic cathinone that emerged on the United States’ illicit drug market in 2009 and prior to its temporary control was promoted as being a ‘legal’ al ternative to cocaine, methamphetamine, and MDMA. Methylone is falsely marketed as “research chemicals,” “plant food,” or “bath salts ” and has been sold at smoke shops, head shops, convenience stores, adult book stores, and gas stations and can also be purchased on the Internet under a variety of product names (White Dove, Explosion, Tranquility etc.). It is commonly encountered in the form of powde rs, capsules, and tablets. The packages of these commercial products usually contain the warning “not for human consumption”. AAPCC reported a large number of toxic exposu res to these products. A large majority of these exposures were by intentional abu se, misuse, or suspected suicide. Most of these exposures were described as acute. AAPCC data also identified the most common route of administration for the synthetic cathinones as inhalation/nasal. Information from published scientific studies indica te that the most common routes of administration for methylone is ingestion by swallowing capsules or tablets or nasalPage 24 of 36

insufflation by snorting the powder. Evidence from poison centers, published case reports, and law enforcement encounters suggest that t he main users of methylone are young adults (Shimizu et al., 2007; Boulanger

- Gobeil et al., 2011; Cawrse et al., 2012; Kovac et al., 2012; Pearson et al., 2012). These substances are popular among youths and young adults with males appearing to abuse meth ylone more than females. There is evidence that methylone may be co

- ingested with other substances including other synthetic cathinones, pharmaceutical agent s , or other recreational substances.

Fac tor 5 : The S cope , Duration , and S ignificance of A buse

Th e popularity of methylone and other synthetic cathinones as recreational drugs has increased since they first appeared on the United States’ illicit drug market in 2009

. These substances are increasingly prevalent and abused throughout the United States. Possible r easons for the increased abuse (besides eliciting MDMA and amphetamine

- like effects) of methylone and other synthetic cathinones may be attributed to their ease of availability

, price , and legal
status

. Based on findings in the European design er drug market, a n additional explanation that has been provided is that some cathinones are being sold as ecsta s y/ MDMA ( Griffiths et al., 2010 ). Griffiths and colleagues (2010) further stated that cathinones are growing in importance as ‘legal’ alternatives and end

- users are seeking out specific substances due to a growing

awareness. Methylone is readily available from the Internet, retail suppliers (e.g., head shops, tobacco shops

, convenience stores, adult book stores, and gas stations) or street dealers

. These substances can also be bought in bulk quantities (e.g., 100 g to over 5 kg) as indicated by seizure s of these substances by law enforcement

. Companies located in China are primarily responsible for the trafficking of these substances from overseas

. T he perceived noncontrolled
status of synthetic cathinones, in general, may give synthetic cathinones an added appeal (Measham et al., 2010).

Evidence of the abuse of methylone is confirmed by d rug c ourts

. Drug c ourt reports have identified methylone and other synthetic cathinones ( e.g., mephedrone, MDPV, and butylone ) in urine specimens submitted for testing by drug court participants confirming the abuse of these substances by supposedly former rec overing drug abuse rs. Drug courts analyze specimens from participants for new and existing drugs of abuse. Drug courts submitted to DEA 18 reports from the analysis of biological specimens that contained synthetic cathinones. Methylone was mentioned in 5 of these reports.

Studie s suggest that methylone or other synthetic cathinones may be used as an alternative to illicit substances with stimulant effects ( ACMD, 20 10 ). ACMD reported that mephedrone and “Toot” (most commonly identified as a mixture of butylone and methylone) were popular among users of heroin (ACMD, 20 10 ).

Evidence from law enforcement indicates that the abuse of methylone is widespread

. In 2009, t he National Forensic Laboratory Information System (NFLIS), a DEA sponsored databasePage 25 of 36

f or exhibits analyzed by state and local forensic laboratories, registered 4 reports from 3 states containing of methylone ( Table 2 and Table 3 in Factor 1)

. 10 However, in 2010, there were 71 reports from 18 states related to methylone registered in NFLIS, and in 201 1 there were 1,655 reports from 41 states . F rom January to June 201 2 there were 1,067 reports from 36 states related to methylone

. A ccording to the System to Retrieve Information from Drug Evidence (STRIDE) (which reports data from 6 DEA laboratories), a federal database for drug items analyzed by DEA forensic labora tories, law enforcement authorities encountered a number of drug exhibits and filed a number of cases pertaining to the trafficking, distribution and abuse of methylone ( Table 4 in Factor 1)

. The f orms of exhibits encountered were mainly as powders, crystals, resins, tablets, or capsules. In 2009, STRIDE registered 1 exhibit pertaining to methylone. In 2010, there were 7 exhibits pertaining to the trafficking, distribution and abuse of methylone

. In 2011, 107 drug exhibits pertaining to the trafficking, distr ibution and abuse of methylone were recorded in the STRIDE database and in 2012 there were 105

.

In additio n to report s involving methylone that have been recorded in NFLIS and STRIDE, DEA received reports from police departments regarding the ir seizure s of methylone.

The New Hampshire Forensic Laboratory reported to DEA seizures of confiscated substances that were confirmed by forensic analysis to contain methylon e. These substances were received from law enforcement departments located t hroughout the state of New Hampshire. Substances submitted were of various forms and amounts. The following are
examp les of some of these substance s that contained methylone: 0.10g white powder, capsules with off

- white powder, capsules with white powder, 0.54 g of white powder and 2.64 g of tan powder, and various colored powders in capsules that also contained butylone and pentylone

.

The Forensic Science Center in Illinois submitted a report to DEA detailing substances that were analyzed and confirmed to contain methylone. Substances analyzed consisted of capsules containing white powder, plastic bag containing white powder consistent with methylone, plastic bag containing w hite powder consistent with methylone, MDPV and other synthetic cathinones.

DEA forensic laboratories have analyzed drug exhibits received from state, local, or federal law enforcement agencies that were found to contain methylone.

The Las Vegas Metropolitan Police Department submitted 44 illicitly manufactured tablets (10 peach and round and imprinted with a trefoil radiation symbol, 34 red and round and imprinted with the Motorola logo) to th e Harris County Institute of Forensic Sciences Drug Chemistry Section for analysis. Laboratory analysis of the 10 peach tablets identified methamphetamine, methylone, and caffeine. The red tablets were identified to be methylone and caffeine (DEA, 2011 a )

.

10 Analyzed on September 12 , 2012, s tate and l ocal f orensic drug reports. The 201 2 drug reports are likely to be incomplete as of September 12 , 2012, due to laboratory reporting lag time.Page 26 of 36

The Harris County Institute of Forensic Sciences Drug Chemistry Section (Texas) received submissions of tablets confirmed to contain MDPV, TFMPP, and caffeine. A syringe containing MDPV, oxymorphone, methylone, and lidocaine was also seized (DEA, 2011 b )

. The Harris County Institute of Forensic Sciences Drug Chemistry Section (Texas) also received submissions of four clear capsules from law enforcement in Houston, Texas. The capsules were confirmed to contain mephedrone and methylone (DEA, 2011 c ).

Th e DEA South Central Laboratory received submissions of a blue

- black sealed packet labeled “White Dove Bath Salt” that contained a white powder and a small ziplock bag labeled “Night Cap Bath Bomb 500 mg” that contained a tan powder. Analysis of the substa nces identified methylone in both samples (DEA, 2011 d ).

The DEA Mid

- At lantic Laboratory received eight packets labeled “HappeeGRO” from Alcohol, Tobacco, Firearms, and Explosives agents (Virginia). Analysis of the off

- white powder in the packet identifie d methylone (DEA, 2011 e)

At selected United States ports of entry, the U.S. Customs and Border Protection (CBP) has encountered shipments of products containing methylone. The most commonly identified synthetic cathinone was methylone. Methylone was first encountered in 2009. A s of July 2012

, o f 330 synthetic cathinones shipments encountered from June 2008 to July 2012 , 127 of these shipments contained methylone. Most of the shipments of these synthetic cathinones that contained methylone originated in China and were destined for delivery throughout the United States to places like Alaska, Arizona, Arkansas, California, Colorado, Florida, Hawaii, Illinois, Kansas, Louisiana, Oklahoma, Oregon, Missouri, Nevada, New Mexico, Tennessee, Texas, Washington , and West Virginia.

Evidence from poison center s indicates that the abuse of synthetic cathinones like methylone is widespread. AAPCC reported in a press release that as of September 10 , 2012

, poison centers took 30 4 calls regarding synthetic cathinones exposure s in 2010 and 6,138 calls in 2011 (AAPCC, 201 2 )

. As of September 10, 201 2

, poison centers have received 2,251 calls relating to exposures of these products for this year. These calls were received in poison centers representing at least 47 states a nd the District of Columbia.

Concerns over the abuse of methylone and other synthetic cathinones have prompted many states to control these substances. As of September 2012, at least 42 states have emergency scheduled or enacted legislation placi ng regulatory controls on some or many of the synthetic cathinones including mephedrone, methylone, MDPV and/or a defined general class of cathinones. At least 27 states specifically control methylone. These states include Alabama, Arizona, Arkansas, Del aware, Florida, Georgia, Rhode Island, Illinois, Indiana, Kansas, Kentucky, Louisiana, Maine, Maryland, Minnesota, Mississippi, Nebraska, New Jersey, New Mexico, Ohio, Oklahoma, Pennsylvania, Tennessee, Texas, Utah, Virginia, and Wyoming. In addition, the U.S. Armed Forces prohibited the use of synthetic cathinones including mephedrone, methylone or MDPV. Internationally, several member countries of the European Union have enacted laws placing controls on the possession and/or sale of one or more of these substances (Winstock et al., 2010; EMCDDA, 2011).Page 27 of 36

Summary

M ethylone is a popular recreational drug that first appeared on the United States’ illicit drug market in 2009

. Evidence that methylone is being abused is confirmed by drug courts , calls to poiso n centers, and encounters by law enforcement

. Methylone has been identified in specimens from individuals submitted for testing by drug court participants

. Evidence from poison centers also indicates that the abuse of synthetic cathinones like methylone is widespread. Evidence of the increased abuse of methylone is supported by law enforcement encounter s of methylone. DEA forensic laboratories have analyzed drug exhibits received from state, local, or federal law enforcement agencies tha t were found to contain methylone. The National Forensic Laboratory Information System (NFLIS) details over 2, 5 00 reports from state and local forensic laboratories identifying methylone in drug related exhibits for a period from January 2009 to June 201 2 from 42 states. Additionally, large seizures of methylone have occurred by law enforcement and the U.S. Customs and Border Protection (CBP)

. Concerns over the abuse of methylone have prompted at least 27 states to control methylone.

F actor 6 : What, I f A ny , R isk T here is to the P ublic H ealth

HHS reported that public health risks resulting from the abuse of methylone relate primarily to the ability of this drug to induce adverse events that are characteristic of CNS stimulants (HHS, 2012) . HHS cited sev eral published case reports in the medical literature that involved individuals who sought emergency care for the abuse use of methylone. Deaths from the abuse of methylone were also cited by HHS. These reports are described below.

These reports also co me from l aw enforcement, forensic laboratories , and public health officials that have reported toxic exposure to methylone and other synthetic cathinones demonstrating the public health risks associated with these substances.

Adverse Effects of Methylo ne

M ethylone ha s been reported to cause a number of stimulant

- like adverse effects ( Shimizu et al., 2007; ACMD, 2010; Karila and Reynaud , 2010 ; Boulanger

- Gobeil et al., 201 2 ; Pearson et al., 2012 )

. The clinical presentation of intoxication from methylone share s some features seen with MDMA and stimulants like cocaine. Clinical case reports indicate that these methylone produce s a number of stimulant

- like adverse effects such as palpitation s , seizure s , vomiting, sweating, headache, hyperthermia, mydriasis

, hypertension, tachycardia and hyper

- reflexia ( Shimizu et al., 2007; ACMD, 2010; Karila and Reynaud , 2010; Boulanger

- Gobeil et al., 201 2 ; Pearson et al., 2012 ; Warrick et al., 2012 ). Other a dverse effects associated with the consumption of methylone as reported by users include nausea, bruxism (teeth grinding)

, paranoia, muscular tension, agitation, anxiety, tremor, fever

, and sweating ( ACMD, 2010; Karila and Reynaud , 2010 ). Hyperthermia can be a serious adverse effect and can lead to metabolic acido sis, rha b domyolysis, renal failure, disseminated intravascular coagulation, coma

, and death. S erious adverse effects including hyperthermia have resulted in documented hospital emergency department (ED) admissions from the ingestion of methylone

.Page 28 of 36

DEA not es that s tudies show that methylone , like MDMA, can be cytotoxic to liver cells

. Incubation of hepatocy t es (liver cells) with methylone or MDMA caused cell death (Nakagawa et al., 2009). In addition, high concentrations of methylone induced the release of lactate dehydrogenase (LDH), an indication of decreased cell viability

, in cells that stably expressed the SERT (Sogawa et al., 2011). However, m ethylone in combination with methamphetamine had a synergistic cytotoxic effect on cells that expressed the DAT, NET, or SERT . This finding is particularly important because there have been report s of ab use of synthetic cathinones in combination with other drugs of abuse. These data suggest that using methylone alone and in combination with other psychoactive substances may cause damage to liver cells. Indeed a case of liver toxicity w as reported in the scientific literature. Boulanger

- Gobeil et al. (201 2 ) described a 22

- year

- old female who developed rhabdomyolysis ( liver injury occurs in 25% of patients wit h rhabdomyolysis (Huerta

- Alardin et al., 2004) ) after ingesting a product called “legal ecstasy” which was analyzed to be a mixture of methylone and ethcathinone.

Case Reports Involving Methylone

As describe d below , n umerous individuals have presented at emergency departments following
exposure to methylone or products containing methylone

. Boulanger

- Gobeil et al. (201 2 ) described a case of a 22

- year

- old female developed rhabdomyolysis after ingesting “legal ecstasy” which was analyzed to be a mixture of methylone and ethcathinone . She also suffered from recurrent seizures, severe hyponatremia (abnormally low concentration of sodium in the blood), nystagmus (involuntary rapid eye movem ent), hyperreflexia, and bruxism. All her symptoms resolved after treatment that required hospitalization.

DEA notes that Katagi et al. (201 0 ) reported two cases of acute toxicity from the confirmed ingestion of methylone. A 19

- year

- old male was taken to the emergency department suffering from dementia after ingesting an unknown amount of methylone powder. In the second case, a 29

- year

- old male was taken to the emergency department suffering from acute toxicity after taking an unknown amount of a mix ture of methylone and a hallucinogen.

Some of these i ndividual s under the influence of methylone have acted violent ly and unpredictably causing harm, or even death, to themselves or other s

. Shimizu et al. (2007) reported a case of acute drug intoxication from the ingestion of a mixture of methylone and 5

- methoxy

- N

- methyl

- N

- isopropyltryptamine (5

- MeO

- MIPT) powder. A 27

- year

- old Japanese male presented to the emergency room after taking approx imately 200 milligrams of powder that was analyzed to be a mixture of methylone and 5

- MeO

- MIPT powder by oral ingestion that he purchased over the Internet. According to the report, the subject was transported to the hospital after reportedly acting stran gely. At the hospital, the subject had an elevated heart rate and blood pressure, while exhibiting dilated pupils and sweating. The patient’s symptoms resolved after five hours of treatment.

DEA notes that Cawrse et al. (2012) described the death of a 3 8

- year

- old male by suicide and a 35

- year

- old female by homicide. The 35

- year

- old male was found dead in bed with a gunshotPage 29 of 36

wound to the head which was determin ed to be the cause of death. The 38

- year

- old female who was the girlfriend of the 38

- year

- old m ale was found unresponsive in bed with a wound on her neck and a gunshot wound to the head. She died at the scene and her cause of death was cutting wound of neck and gunshot wound to the head

. Toxicology tests identified methylone in specimens from thes e individuals.

Individuals suspected of driving under the influence of intoxicating substances have been found to have positive test results for methylone

. Some of these incidents involving m ethylone intoxications have resulted in the deaths of individual s suspected of driving while under the influence of these drugs

.
Marinetti et al. ( 2011 ) reported the death of a 37

- year

- old male who was involved in a motor vehicle accident in which the decedent was at fault. The Miami Valley Regional Crime Laboratory identified methylone, MDPV, THC, and a THC product in blood specimen from this individual

. DEA note s that i n another case reported by Marinetti et al. (2011) , a 30

- year

- old male was found passed out in a vehicle. The individual was charged with having weapons while under disability. Toxicology testing identified methylone, MDPV, clonazepam, and other substances in blood specimens from this individual.

Fatalities Involving Methylone

There are a t least three reporte d deaths in which methylone was ruled as the cause of death by the medical examiner or after an autopsy

.

A 19

- year

- old female who took a pill known as “Molly” collapsed and recovered then complained of not feeling well (Pearson et al., 2012)

. Thereafter, she was observed to have seizures. Emergency personnel were called and the decedent was transported to the hospital. At the hospital she suffered cardiac complication s and despite efforts to save her life she died. Toxicology tests identifie d methylone in specimens from the decedent. No other recreational substances were detected. The medical examiner concluded that the cause of death was methylone intoxication.

Pearson et al. (2012) also described the death of a 23

- year

- old male. The dec edent was witnessed to take what was thought to be LSD at a club. The decedent was acting erratically and irrationally and so the decedent was removed from the club and placed in the back of a van by securing the decedent to a chair using saran wrap. Som etime later, the decedent was found having seizures. Emergency personnel was called and the decedent was transported to the hospital. The decedent was suffering from various ailments such as hyperthermia. Despite efforts to save his life the decedent die d 45 minutes after his arrival at the hospital. The medical examiner listed the cause of death as intoxication by methylone.

In another incident reported by Pearson et al. (201 2 ), the death of a 23

- year

- old male suspected of using methylone was described. The decedent was walking in and out of traffic and acting belligerently. The decedent was detained by law enforcement and transported to the hospital. The decedent had a high te mperature and subsequently went into respiratory failure. After several attempts by medical personnel to stabilize the decedent, he died. ToxicologyPage 30 of 36

testing identified methylone in specimens from this individual. The medical examiner listed the cause of death as intoxication by methylone.

M ethylone ha s also been implicated (i.e., the primary cause of death is not methylone toxicity ) in drug induced overdose deaths

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

- year

- old female who ingested two caps ules 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 comatose patient suffered from hyperthermia, tachycardia, mydriasis, tachypnea and some t remors. 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 f ound on the decedent. The cause of death by the medical examiner was serotonin syndrome secondary to methylone and butylone

.

DEA notes additional publications that involve a death involving methylone. Cawrse et al. ( 2012 ) described the death of a 19

- year

- old male . The deceden t died while performing a physical fitness assessment. Toxicology tests identified methylone in specimens from this individual. The cause of death was cardiac arrest associated with methylone. A death of a 39

- year

- old ma le

wa s reported by Wyman et al. (2011). Family members indicated that the male, who had a history of schizophrenia, depression, and drug abuse, had been snorting “bath salts.” The subject was found dead in his bed. Empty jars of “bath salts” (TranQuility and Infinity) and synthetic

cann a binoids (Demon and Flame) were found in the trash. A toxicological screen detected MDPV distributed among multiple tissues, urine and blood samples from the decedent. Other substances detected were nicotine, cotinin e, pseudo ephedrine, m

- chlorophenylpiperazine and methylone . The cause of death was acute MDPV intoxication.

Kovac s et al. ( 2012 ) described the case of a 16

- year

- old male that lost consciousness at a party. The decedent died of sudden cardiac death at the hospita l after attempts to save his life were unsuccessful. The decedent suffered from cardiac malformation and bronchial asthma. Toxicology test identified methylone in the specimens from this individual. The authors concluded that the predisposing factors al ong with methylone may have resulted in the sudden cardiac death of this individual.

Identification of Products Containing Methylone or Other Synthetic Cathinones

The products containing methylone and other synthetic cathinones often do not bear labeling information regarding their ingredients or the health risks and potential hazards associated with these products

. In addition, products may not contain the expected active ingredients. Thus, individuals who purchase these products l ikely have insufficient knowledge of the exact product
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 expected active ingredients 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, orPage 31 of 36

Xtacy were purchased repeatedly during a 6 month period) and tested (Davies et al., 2010). In a separate study, the analysis of a specific brand name synthetic cathinone product (e.g., white lightening)

, that appeared identical in packaging but o btained at different locations

, revealed different synthetic cathinones as the primary ingredient (Sp iller et al., 2011). In this study, methylone was identified in 6 of the 15 bath salt products purchased for the analyses. A study by Brandt et al. (2010) 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., 2010). 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 w ith 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 puri ty and lack of information about its effects pose significant risk s to the user s

. Summary

In summary, a vailable evidence on the overall public health risks associated with the use of methylone indicate that th is substance can cause acute health problems leading to ED admissions, violent behaviors causing harm to self or others, and motor vehicle accidents if driving while intoxicated or can cause death

. Additionally, products containing methylone and other synthetic cathinones 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 with these products

. A dverse effects include those typical of a sympathomimetic agent including tachycardia, headache, palpitations, agitation, anxiety, mydriasis, tremor, fever or sweating

, and hypertension ( Shimizu et al., 2007; ACMD, 2010; Karila and Reynaud , 2010 ; Boulanger

- Gobeil et al., 201 2 ). Other effects , with possible public hea lth risk implications, that have been reported from the use of these substances include psycho logical effect s such as psychosis, paranoia, hallucinations, and agitation ( Shimizu et al., 2007; ACMD, 2010; Karila and Reynaud, 2010 ; Pearson et al., 2012 ). Finally, t he reports of death for individuals abusing methylone indicates that it is are a serious public health threat

.

Factor 7 : I ts P sychic or P hysiological D ependence L iability

According to HHS, there are no studies or case reports that document the psychic or physiological dependence potential of methylone (HHS, 2012) . However, HHS states that because methylone shares pharmacological properties with those of the Schedule I and II substances amphetamine, methamphetamine, cocaine, and MDMA, it is probabl e that methylone has a dependence profile similar to that of th e se substances which are known to cause substance dependence.

Factor 8 : W hether the S ubstance is an I mmediate P recursor of a S ubstance A lready C ontrolled U nder this S ubchapter

M ethylone is not considered to be an immediate precursor of any controlled substance of the CSA as defined by Title 21, U.S.C § 802(23).Page 32 of 36

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 a buse potential, accepted medical use, and safety for use under medical supervision for placement in the CSA as a controlled substance. After consideration 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 HHS, DEA finds that methylone meets the three criteria for placement in Schedule I of the CSA pursuant to 21 U.S.C. 812(b)(5).

1) Methylone has a high potential for abuse.

According to HHS, data from animal, human, and epidemiological studies described in the scientific literature demonstrate that methylone has a high potential for abuse. The profile of pharmacological effects of methylone is similar to that of the Schedul e I and Schedule II substances amphetamine, methamphetamine, cocaine, and MDMA. In addition, law enforcement data suggests that t he abuse of methylone is widespread in the United States as indicated by the increased encounters of methylone by law enforcement in various regions of the United States

. Based on these findings by HHS and DEA, DEA concludes that methylone has a high potential for abuse.

2) Methylone has no currently accepted medical use in treatment in the United States.

According to H HS

, methylone has no approved medical use in the United States, does not have an approved NDA, and is not currently marketed in the United States in an FDA

- approved drug product

. A drug has a “currently accepted medical use” if all of the following five e lements have been satisfied: the drug’s chemistry is known and reproducible; and there are adequate safety studies; and there are adequate and well

- controlled studies proving efficacy; and the drug is accepted by qualified experts; and the scientific evid ence is widely available. According to HHS, there are no published clinical studies involving methylone. DEA has also not found any references to clinical studies involving methylone in the scientific and medical literature. A lthough the chemistry of me thylone i s known and has been reproduced

, as mentioned above there are no clinical studies involving methylone. Thus, methylone has no currently accepted medical use in treatment in the United States.

3) There is a lack of accepted safety for use of methy lone under medical supervision.

According to HHS

, methylone has no approved medical use, has not been investigated as a new drug, and its safety for use under medical supervision has not been determined. In addition, methylone has not been evaluated in human abuse liability studies and no studies have been undertaken to evaluate the toxicology and safety of methylone in humans. Thus, HHS concluded that t here is a lack of accepted safety for use of methylone as a medication

. Therefore, DEA concludes that t here is a lack of accepted safety for use of methylone under medical supervision.Page 33 of 36

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