DEA/OD/ODE page 1 of 14 October 1 6 , 2013

2 - (4 - iodo - 2,5 - dimethoxyphenyl) - N - (2 - methoxybenzyl)ethanamine (25I - NBOMe ; 2C - I - NBOMe; 25I; Cimbi - 5 ), 2 - (4 - chloro - 2,5 - dimethoxyphenyl) - N - (2 - methoxybenzyl)ethanamine (25C - NBOMe ; 2C - C - NBOMe; 25C; Cimbi - 82 ) and 2 - (4 - bromo - 2,5 - dimethoxyphenyl) - N - (2 - methoxybenzyl)ethanamine (25B - NBOMe ; 2C - B - NBOMe; 25B; Cimbi - 36 ) Background Information and Evaluation of ‘ Three Factor Analysis ’ (Factor s 4, 5 and 6) for T emporary S cheduling Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement

Administration, 8701 Morrissette Drive, Springfield, VA 22152

October 2013 Introduction Since 2011 , there has been a marked increase in th e law enforcement encounters of new synthetic substances as substitutes for Schedule I hallucinogens in the United States . Both law enforcement and public health reports suggest the sustained popularity of these substances i n the designer drug market, most commonly purported or mistaken for more well
- known hallucinogens, like lysergic acid diethylamide (LSD) and extracts of psilocybin mushrooms . The se synthetic substances are readily available over the I nternet and are sold through illicit channels . Th ese substances have no accepted medical use in the United States and have been reported to produce adverse effects in humans. Dr ug induced toxicity and violent, erratic behavior due to the abuse of these synthetic substances has led to numerous repo rts of emergency department admissions and deaths (Kelly et al. , 2012; Rose et al. , 2012; Rose et al . , 2013; Hill et al ., 2013; Stellpflug et al ., 2013) . 2 - (4
- I odo
- 2,5 - dimethoxyphenyl)
- N - (2
- methoxybenzyl)ethanamine (25I
- NBOMe; 2C - I - NBOMe; 25I; Cimbi
- 5), 2 - (4
- chloro
- 2,5 - dimethoxyphenyl)
- N - (2
- methoxybenzyl)ethanamine (25C
- NBOMe; 2C - C - NBOMe; 25C; Cimbi
- 82) and 2
- (4
- bromo
- 2,5 - dimethoxyphenyl)
- N - (2
- methoxybenzyl)ethanamine (25B
- NBOMe; 2C - B NBOMe; 25B; Cimbi
- 36) (Figure 1) are pharmacologically similar to Sched ule I hallucinogens like LSD, psilocin, 5 - methoxy
- N , N - dimethyltryptamine ( 5 - MeO - DMT ) , 2,5 - dimethoxy
- 4 - bromoamphetamine (DOB), 2C
- I, 2C - B (Braden et al ., 2006; Ettrup et al ., 2011; Nichols, 2012) . 25I - NBOMe and 25B
- NBOMe w ere first reported in 2003 by RalfDEA/OD/ODE page 2 of 14 October 1 6 , 2013

Heim at the Free University of Berlin (Heim, 2003) , and were subsequently investigated as r esearch tool s by a group at Purdue University beginning in 20 06 (Braden et al ., 2006; Nichols et al ., 2008; Juncosa Jr et al ., 2012; Nichols, 2012) . 25C - NBOMe was first reported in the scie ntific literature in early 2011 (Ettrup et al., 2011) . These substances began showing up in forensic laboratory reports on drug seizures later in that same year. F rom November 20 11 through June 2013 according to the DEA’s System to Retrieve Information on Drug Evidence (STRIDE 1 ) data, there are 54 exhibits involving 27 cases for 25I - NBOMe , 27 exhibits involving 12 cases for 25C - NBOMe and 4 exhibits involving 4 cases for 25B - NBOMe . From June 201 1 through June 2013 , the National Forensic Laboratory Information System (NFLIS 2 ) registered hundreds of reports containing these synthe tic substances ( 25I - NBOMe – 795 reports; 25C - NBOMe – 144 reports; 25B - NBOMe – 20 reports) from all reporting local, state and other federal forensic laboratories in the U.S . 25I - NBOMe, 25C - NBOMe, and 25B
- NBOMe were not reported to NFLIS prior to June of 201 1 , and the number of reports for these substances increased in every quarter of 2012, and in the first quarter of 2013 . With no legitimate medical use and limited pharmacological information , these substances ( 25I - NBOMe, 25C - NBOMe and 25B - NBOMe ) have emerged on the designer drug market and ar e being abused for their psychoactive properties. To protect the public health and safety, the Drug Enforcement Administration (DEA) is temporar il y placing 25I - NBOMe, 25C - NBOMe and 25B - NBOMe in S chedule I of the Controlled Substances Act (CSA) . With respect to finding an imminent hazard to the public safety , DEA has considered the three factors required under the CSA for the temporary scheduling of 25I - NBOMe, 25C - NBOMe and 25B - NBOMe . 21 U.S.C. 811(h)(3) and 811(c)(4)
- (6).

Figure 1 . Chemical Structures

1 STRIDE, a DEA database which compiles information on exhibits analyzed in DEA laboratories. 2 NFLIS, a DEA database which compiles information on exhibits analyzed in state, local, and federal laboratories. 25I - NBOMe 25C - NBOMe 25B - NBOMeDEA/OD/ODE page 3 of 14 October 1 6 , 2013 25I - NBOMe, 25C - NBOMe and 25B - NB OMe are classified as 2C compounds, a structural class with a p henethylamine core substituted with methoxy groups on the 2 and 5 positions of the phenyl ring. Th e name “ 2C ” indicat es the presence of a t wo carbon ethylene group (
- CH 2 CH 2 - ) between the phenyl ring and the amino group. Historically, a number of substances from this class of compounds have been abused for their psychoactive properties. I n 199 4 , 4 - bromo
- 2,5 - dimethoxyphenethylamine ( 2C - B ) was temporarily added to Schedule I of the CSA , an action that was made permanent the following year . 2,5 - Dimethoxy
- 4 - n - propylthiophenethylamine ( 2C - T - 7 ) was emergency scheduled in 2002, and permanently ad ded to Schedule I in 2004. In 2012, Congress passed the Synthetic Drug Abuse Prevention Act placing n i ne additional 2C compounds ( 2 - (2,5
- dimethoxy
- 4 - ethylphenyl)ethanamine, 2C - E ; 2 - (2,5
- d imethoxy
- 4 - methylphenyl)ethanamine , 2C - D ; 2 - (4
- c hloro
- 2,5 - dimethoxyphenyl)ethanamine , 2C - C ; 2 - (4
- i odo
- 2,5 - dimethoxyphenyl)ethanamine , 2C - I ; 2 - (4
- e thylthio
- 2,5 - dimethoxyphenyl)ethanamine , 2C - T - 2 ; 2 - (4
- i sopropylthio
- 2,5 - dimethoxyphenyl ) ethanamine , 2C - T - 4 ; 2 - (2,5
- d imethoxyphenyl)ethanamine , 2C - H ; 2 - (2,5
- d imethoxy
- 4 - nitrophenyl)ethanamine , 2C - N ; and 2 - (2,5
- d imethoxy
- 4 - n propylphenyl) ethanamine, 2C - P) in Schedule I of the C SA . 25I - NBOMe, 25C - NBOMe and 25B - NB OMe are structurally similar to these 2C compounds, with the addition of the 2 - methoxybenzyl group to the nitrogen atom (NBOMe) of 2C
- I, 2C - C, and 2C
- B, respectively. This addition has been shown to substantial ly enhance the pharmacolog ical potency of these drugs (Braden et al ., 2006 , Juncosa Jr et al ., 2012 ) . General Information 2 - (4 - iodo - 2,5 - dimethoxyphenyl) - N - (2 - methoxybenzyl)ethanamine (25I - NBOMe; 2C - I NBOMe; 25I; Cimbi - 5) 25I - NBOM e has been shown to bind to rat and human 5 - HT 2A (serotonin) receptor s with nanomolar affinity and is described as a “superpotent” 5
- HT 2A agonist in those research models (Braden et al ., 2006; Ettrup et al ., 2011) . The 5
- HT 2A receptor is a critical site of action for hallucinogens like LSD, psilocin, and 5
- MeO - DMT (Braden et al ., 2006) . Researchers have explored using radioactively labeled 25I
- NBOMe as a research tool to map 5 - HT 2A receptors in the brain (Ettrup et al., 2010; Ettrup et al., 2011) . 25I - NBOMe is structurally similar to 2C
- I, a Schedule I hallucinogen that can be used as a synthetic precursor for 25I
- NBOMe. The addition of the N - 2 - methoxybenzyl ( N BOMe) group significantly increases the 5
- HT 2A affinity of 2C
- I (Braden et al ., 2006) . 25I - NBOMe has been shown to produce hallucinogen
- like behavioral effects in mice, and it was 14 - fold more potent than 2C
- I in this model (Halberstadt and Geyer, 2013). 25I - NBOMe was first encountered by law enforcement in the United States in the second quarter of 2011DEA/OD/ODE page 4 of 14 October 1 6 , 2013

(Appendix 1) . It has been encountered in bulk pow d er forms and on blotter paper. The first reported fatality attributed to 25I - NBOMe, confirmed by postmortem blood toxicology , occurred in March of 2012. 2 - (4 - chloro - 2,5 - dimethoxyphenyl) - N - (2 - methoxybenzyl)ethanamine (25C - NBOMe; 2C C - NBOMe; 25C; Cimbi - 82) 25 C - NBOMe has been shown to bind to the 5 - HT 2A receptor with nano molar affinity and acts as a 5 - HT 2A agonist in a rat model (Ettrup et al., 2011) . The 5
- HT 2A receptor is a critical site of action for hallucinogens like LSD, psilocin, and 5
- MeO - DMT (Braden et al ., 2006) . Researchers have explored using radioactively labeled 25 C - NBOMe as a research tool to map 5 - HT 2A receptors in the brain (Ettrup et al., 2011) . 25 C - NBOMe is structurally similar to 2C - C , a Schedule I hallucinogen that can be used as a synthe tic precursor for 25 C NBOMe. Blotter papers containing 25C
- NBOMe first appeared on the designer drug market in 2011 and a number of law enforcement encounters were reported in the first half of 2012 (Zuba et al ., 2013; NFLIS) . The first reported fatality a ttributed to 25C
- NBOMe , confirmed by postmortem blood toxicology, occurred in June of 2012. 2 - (4 - bromo - 2,5 - dimethoxyphenyl) - N - (2 - methoxybenzyl)ethanamine (25B - NBOMe; 2C B - NBOMe; 25B; Cimbi - 36) 25 B - NBOMe has been shown to bind to rat and human 5
- HT 2A receptors with nanomolar affinity and is a 5 - HT 2A agonist in the rat model (Ettrup et al., 2011; Juncosa Jr et al., 2012) . The 5
- HT 2A receptor is a critical site of action for hallucinogens like LSD, psilocin, and 5
- MeO - DMT (Braden et al ., 2006) . Researchers have explored using radioactively labeled 25B
- NBOMe as a research tool to map 5
- HT 2A receptors in the brain (Ettrup et al., 2011; Ettrup et al., 2013) . 25 B - NBOMe is structurally similar to 2C
- B , a Schedule I hallucinogen that can be used as a s ynthetic precursor for 25 B - NBOMe. There is a roughly 30 - fold increase in affinity at the human 5
- HT 2A receptor when the N - 2 - methoxybenzyl ( N BOMe) group is added to 2C
- B (Juncosa Jr et al., 2012) . 25B - NBOMe was first encountered by law enforcement in the United States in the fourth quarter of 2012 (NFLIS) . It has been encountered in bulk forms and on blotter paper. The first reported fatality attributed to 25B
- NBOMe , confirmed by postmortem blood toxicology, occurred in February of 2013.DEA/OD/ODE page 5 of 14 October 1 6 , 2013

Table 1 . Summary of Available Pharmacology Data for 25I - NBOMe, 25C - NBOMe and 25B - NBOMe

Binding (K i ) at Rat 5 - HT 2A a Rat 5 - HT 2A

Activation (ED 50 ) b Intrinsic

Activity c Binding (K i ) at

Human 5 - HT 2A Human 5 - HT 2A

Activation (EC 50 ) Intrinsic

Activity h 25I - NBOMe 1.49±0.35 nM 1.02±0.08 nM 91 % 0.044±0.006 nM d 0.44±0.07 nM g 81 % 25C - NBOMe 2.89±1.05 nM 2.31±0.11 nM 88 % 0.9 nM e

– – 25B - NBOMe 1.01±0.17 nM 0.51±0.19 nM 87 % 0.19±0.01 nM f

– – All values are reported in nM ( ± SEM ) . Fields marked with – indicate unavailability of data. a M easured against [ 3 H]MDL100907 at GF
- 62 cells (a NIH - 3T3 cell line) overexpressing rat 5 - HT 2A receptors (Ettrup et al., 2011) b R at 5 - HT 2A activation (PI hydrolysis) at GF - 62 cells (Ettrup et al., 2011) c Mean maximal activation compared to 10 μM 5 - HT (Ettrup et al., 2011) d M easured against ( ± )[ 125 I]DOI at human embryonic kidney (HEK) 293 cells expressing wild
- type human 5 - HT 2A receptors (Braden et al ., 2006) e Measured against [ 3 H]LSD (Ettrup et al., 2011) f M easured against [ 3 H]ketanserin at HEK 293 cells expressing wild
- type human 5 - HT 2A receptors (Juncosa Jr et al., 2012) g H uman 5 - HT 2A activation (PI hydrolysis) at HEK 293 cells (Braden et al ., 2006) h Mean maximal activation (Braden et al ., 2006) Factor 4. Its history and current pattern of abuse The 2 - methoxybenzyl series of 2C substances has been developed over the last 10 years to be used as tools for mapping and investigating the 5
- HT 2A receptors in the brain (Ettrup et al., 2010; Ettrup et al., 2011; Ettrup et al., 2013) . The first reported seizure of 25I NBOMe in the United States was by the Milwaukee Police Department in June of 2011. Law enforcement reports since that time have document ed encounters with bulk quantities of powdered substances or blotter papers identified as containing one or more of 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe . F rom November 20 11 through June 2013 according to STRIDE data, there are 54 exhibits involving 27 cases for 25I - NBOMe , 27 exhibits involving 12 cases for 25C - NBOMe and 4 exhibits involving 4 cases for 25B - NBOMe . From June 2011 through June 2013, NFLIS registered hundreds of reports containing these synthetic substances (25I
- NBOMe – 795 reports; 25C - NBOMe – 144 reports; 25B - NBOMe – 20 reports) across all reporting local, state and other federal agencies (Appendix 1) . Information and d ata from published studies, law enforcement reports , discussions on Internet forum websites, and personal communications document numerous routes of administration for these substances. 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe are administered as powders by nasal insufflation, as liquids by intravenous injection or applied to the nasal membrane, or the substance s are dissolved in solutions and soaked onto blotter paper and delivered by sublingual or buccal administration (Zuba & Sekuła, 2012; HillDEA/OD/ODE page 6 of 14 October 1 6 , 2013

et al ., 2013; Stellpflug et al ., 2013) . In a number of cases , food items were laced with the drugs. Severe adverse reactions have been report ed for each o f these routes of administration . Deaths have been reported for most routes of administration, including nasal insufflation, liquid solutions applied to nasal membrane, sublingual or buccal a dministration of blotter paper, and consumption of adulterated food items. Law enforcement reports, discussions on Internet forum websites, and personal communications confirm that these substances are commonly purported to be othe r Schedule I hallucinogens like LSD, psilocin , and 2C
- B. Users and sellers have reported they believed they were abusing and traffick ing LSD, although subsequent laboratory analysis revealed the blotter papers, liquid s , or powder s contain some combination of 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe instead. Bulk quantities of powdered 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe have been seized from shipments originating overseas, particularly from Asia (Customs and Border P rotection Data) . Given the relatively small quantity of these substances predicted to produce a hallucinogenic effect in humans (Ettrup et al., 2013) , some of these international shipments of bulk powder are sufficient to produce more than 300,000 dosage units when applied to blotter papers . Based on the suggest ed human dosages from online drug user reports , a single bulk seizure of 25I
- NBOMe in 2012 contained enough powdered material to produce over 3.5 million individual dosage units. Single s eizures of nearly 40,000 individual dosage units of 25B
- NBOMe prepared on blotter papers have been reported. Abuse of 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe has been characterized with acute public health and safety issues both domestically and abroad (Advisory Council on the Misuse of Drugs, 2013) . I n response, a number of states, including Arkansas, Florida, Louisiana, Nebraska, Ohio, Utah and Virginia have controlled one or more of these substances. Abuse of these substances abroad has prompted the United Kingdom, Israel, and Russia to control these substances as well. Youth appear to be the primary abusers o f these synthetic substances , as supported by the available emergency department reports and reports of death . Case reports detailing 25I - NBOMe toxicity in emergency departments often describe groups of teens and young adults presented simultaneously, or within a short period of time. In 2012, four males , age 17 to 18 years were presented simultaneously to emergency dep artments in Michigan after 25I - NBOMe exposure (Kelly et al ., 2012) . In the first quarter of 2012, ten teens and young adults (average age 17 years, range 14 to 20 years) were presented to emergency departments in Virginia after 25I
- NBOMe exposure (Rose et al ., 2012) . Two publications inDEA/OD/ODE page 7 of 14 October 1 6 , 2013

2013 detail 25I
- NBOMe exposure in a male and female (age 18 years) patient who presented to emergency departments in Virginia and Minnesota, respectively (Rose et al ., 2013; Stellpflug et al ., 2013) . A case series of sev en males, age 19 to 29 years (average age 22 years) , detailed emergency department treatment of 25I - NBOMe toxicity in Northeast England over a one week period in January 2013 (Hill et al., 2013) . In 2013, a male, age 19 years presented to an emergency department in Virginia after exposure to 25B
- NBOMe (Poklis et al., 2013). The average age of decedents where 25I
- NBOMe, 25C - NBOMe or 25B NBOMe was confirmed to be a contributing factor in the death i s 20 years (n=1 7 ) . Individuals , including minors , are purchasing synthetic substances through traditional illicit channels and f rom Internet websites . There is at least one law enforcement encounter with 25I
- NBOMe in the United States that described prepared dosage units on blotter paper with a printed disclaimer of ‘not for human consumption ’ . Most seizure reports suggest that 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe prepared on blotter paper are claimed to be LSD and the actual chemical composition or quantity of the adulterant is not specified. Summary Recently , law enforcement has been encountering 25I - NBOMe, 25C - NBOMe and 25B - NBOMe with increasing frequency . Synthetic substances are available over the Internet and sold through illicit channels, often purported to be Schedule I hallucinogens , like LSD . 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe have been seized as powders, solutions, on blotter paper, and laced on food items. Reports of 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe abuse leading to emergency department intervention or death describe primarily teens and young adults. Factor 5. The scope, duration, and significance of abuse NFLIS, a national database capturing data from forensic laboratories, has a total of 959 drug reports ( June 2011 through June 2013 ) in which 25I - NBOMe, 25C - NBOMe or 25B - NBOMe were identified from a number of s tates including, Alabama, Arkansas, Arizona, California, Colorado, Connecticut, Florida, Georgia, Iowa, Indiana, Illinois, Kansas, Kentucky, Louisiana, Maryland, Maine, Michigan, Minnesota, Missouri , New Hampshire, New Jersey, New Mexico, North Dakota, Nebraska, Nevada, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Utah, Virginia, Wisconsin and Wyoming as of June 2013. (query date: October 9 , 2013 ) . STRIDE has 54, 27, and 4 exhibits for 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe , respectively, from November 2011 through June 2013 (query date: October 9 , 2013 ) .DEA/OD/ODE page 8 of 14 October 1 6 , 2013 A variety of 2 - methoxybenzyl analogues of 2C compounds have been available over the Internet since 2010 (Zuba & Sekuła, 2012; Zuba et al ., 2013) , and t he first identified domestic law enforcement encounter with 25I - NBOMe occurred in June of 2011 in Milwaukee, Wisconsin . Since that time , the number of encounters involving 25I NBOMe, 25C - NBOMe and 25B - NBOMe has steadily increased, reflecting the increased abuse of these substances. Throughout 2012 and 2013, in the United States, there has been a significant increase in availability, trafficking and abuse of 25I - NBOMe, 25C NBOMe and 25B - NBOMe , evident from the increasing number of encounters reported by forensic laboratories and continued reports toxicity and death reported by emergency departments and medical examiners . E vidence of abuse of 25I - NBOMe initially appeared in 2011, and evidence of abuse of 25C - NBOMe and 25B
- NBOMe appeared in 2012. In r esponse to this increased abuse and threat to public health, a number of states and foreign governments have controlled one or more of these substances. Florida, Louisiana, Ohio and Virginia have controlled 25I
- NBOMe . 25 C - NBOMe is controlled in Arkansas . Nebraska and Utah have controlled all three substances discus sed here . Internationally, several countries have controlled one or more of these substances, including t he United Kingdom, Israel, and Ru ssia. Summary The abuse of this new generation of synthetic substances including 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe is characterized in the public health reports, scientific literature and by law enforcement encounters with reports of bizarre behavior, acute toxicity, and death. These adverse effect reports, and the number of law enforcement encounters with these substa nces ha ve steadily increased since 2011. In response to these increased encounters and adverse health effects, a number of states and foreign governments have controlled one or more of these synthetic substance s . Factor 6. What, if any, risk there is to the public health The scientific literature and reports received by DEA suggest that there is a significant risk of acute toxicity from the abuse of 25I - NBOMe, 25C - NBOMe and 25B
NBOMe. Law enforcement and public health officials have reported exposure incidents that demonstrate the dangers associated with abuse of these substances to both the individual abusers and those around them . Warnings regarding the dangers associated with abuse of these synthetic substances have been issued by numerous public health departments , lawDEA/OD/ODE page 9 of 14 October 1 6 , 2013

enforcement organizations, and the families impacted by the death of someone abusing 25I - NBOMe, 25C - NBOMe, or 25B - NBOMe . At the 2012 North American Congress of Clinical Toxicology C onference , Dr. Adam Kelly and coworkers detailed a case series of four males , age 17 to 18 years , simultaneously presented to emergency departments in Mic higan after 25I
- NBOMe exposure (Kelly et al ., 2012) . Laboratory analysis confirmed 25I
- NBO Me exposure in three of the four cases. The clinical features observed for the suspected and confirmed 25I - NBOMe toxicity include tachycardia ( n= 4), psychomotor agitation (4), prolonged seizures (3) , rhabdomyolysis (1), and renal failure (1). The three patients with prolonged seizures “ necessitated aggressive pharmacologic therapy ” and supportive measures that included intubation and mechanical ventilation . At the same conference , Dr. S. Rutherfoord Rose and coworkers reported a case series of ten teens and young adults (average age 17 years, range 14 to 20 years) who presented to emergency departments in Virginia after 25I
- NBOMe exposure (Rose et al ., 2012) . All cases occurred in the first quarter of 2012. Although each patient self
- reported 25I - NBOMe use , confirmatory laboratory test results are not available. The clinical features observed for the suspected 25I
- NBOMe toxicity include tachycardia ( n= 9 ), hypertension ( 7 ), agitation ( 6 ) and hallucinations (5 ). One patient was found unresponsive, and two were in a state of persistent seizure. For one of the seizing patients, Dr. Rose and coworkers observed multiple, discrete intraparenchymal hemorrhages and acute kidney injury. Dr. S. Rutherfoord Rose and cow orkers later published a nother case report of 25I
NBOMe toxicity where they describe a male , age 18 years, who presented to an emergency department in Virginia after jumping from a moving vehicle (Rose et al ., 2013) . Laboratory analysis confirmed 25I
- NBOMe exposure . Clinical features were consistent with previous cases, namely tachycardia , hypertension , hallucinations, and severe agitation , which required continuous sedation for approximately three days. Later in 2013, Dr. Simon Hill and coworkers published a case series of seven males , age 19 to 29 years , who presented to emergency departments in Northeast England over a one week period in January 2013 (Hill et al., 2013) . Laboratory testing confirmed 25I
NBOMe ex posure in each case . The clinical features were consistent with previous reports, namely tachycardia ( n= 7), hypertension (4), agitation (6), hallucinations (6), seizures (3), hyperpyrexia (3), clonus (2), elevated white cell count (2), elevated creatine kinase (7), metabolic acidosis (3), and acute kidney injury (1). One of the most striking cases of recorded survival after 25I - NBOMe toxicity described a male , age 29 years, who injected aDEA/OD/ODE page 10 of 14 October 1 6 , 2013

solution of 25I
- NBOMe and required a total of 43 days in the hospi tal, 38 of which were in the intensive care unit . Dr. Samuel Stellpflug reported a similar case in 2013, with laboratory confirmation of a self
- reported sublingual dose of 25I
- NBOMe (Stellpflug et al ., 2013) . The female, age 18 years, was admitted to an emergency department in Minnesota after a reported grand mal seizure . The clinical features reported include tachycardia, hypertension, agitation, and confusion . A clinical case study of 25B
- NBOMe exposure co nfirmed by laboratory analysis of biological samples was published by Justin Poklis and coworkers in 2013 (Poklis et al., 2013) . The male, age 19 years , was admitted to an emergency department in Virginia after he was found unresponsive and with seizure ac tivity. The seizure activity continued for nearly three days and required continuous administration of sedatives. In addition to clinical features consistent with 25I
- NBOMe exposures, the patient had elevated creatine kinase levels that indicated rhabdomyolysis. In addition to the risk of acute toxicity , abusers of these substances put themselves and others in danger due to unpredictable, violent behavior. 25I
- NBOMe, 25C - NBOMe, and 25B - NBOMe , similar to other Schedule I hallucinogens (e.g., DOM) b ind to and activate 5 - HT 2A receptor s . As of October , 2013, DEA has obtained medical examiner and postmortem toxicology reports implicating some combination of 25I - NBOMe, 25C - NBOMe and 25B
NBOMe in the death of 1 7 individuals . The average age of these individuals is 20 years (range 15 to 2 9 years). The circumstances surrounding the deaths include acute toxicity (1 4 ), or unpredictable, violent behavior due to 25I
- NBOMe toxicity ultimately leading to death (3). Reports describe de aths in a number of states, including Alabama, Arizona, California, Florida, Louisiana, North Carolina, North Dakota, Ohio, Tennessee , Texas , and West Virginia . In three of the postmortem toxicology report s , fluoxetine , an FDA approved selective serotonin reuptake inhibitor (SSRI), and its metabolite, norfluoxetine , were detected. In one of the published emergency department admission s , flu oxetine was also reported (Hill et al. , 2013) . The authors noted greater toxicity in this case, relative to other admissions, and questioned whether 25I - NBOMe combined with this SSRI may have led to enhanced effects of the substance.DEA/OD/ODE page 11 of 14 October 1 6 , 2013 Since abusers obtain these substance s through unknown sources, the identity, purity, and quan tity of these substance s are uncertain and inconsistent , thus posing significant adverse health risk to these users (Hill et al., 2013) . As detail ed above, there are reported instances of emergency department admissions and deaths associated with the abus e of these synthetic substances . There is no accepted medical use of these substances in the United States. Summary The clinical features of severe toxicity following 25I
- NBOMe exposure have been documented in the scientific literature by a number of independent emergency room physicians and toxicologists (Kelly et al ., 2012; Rose et al ., 2012; Rose et al ., 2013; Hill et al ., 2013; Stellpflug et al ., 2013) . In addition to the risk of acute toxicity, the beha vioral effects of these substance s pose risks to the abuser and the general public. Since they first appeared in 2011, 25I - NBOMe, 25C - NBOMe and 25B
- NBOMe have been implicated in the death of 1 7 indivi duals in the United States, primarily teenagers. The possibility of deadly drug interactions with FDA approved medications has been noted. Conclusion of 3 - Factor Analysis After a careful review of the scientific literature, Factors 4, 5, and 6, NFLIS, STRIDE, and other law enforcement data and other source s of information, it is evident that 25I NBOMe, 25C - NBOMe and 25B
- NBOMe are trafficked and abused , and that they pose a n imminent hazard to public safety . These drugs have become popular among young due to their purported pharmacological similarity to Schedule I hallucinogens . DEA has considered the three criteria for placing a substance into Schedule I of the CSA (21 U.S.C. 812). The data available and reviewed for 25I - NBOMe, 25C - NBOMe, and 25B - NBOMe indicated that these substances , including their o ptical, positional, and geometric isomers, salts, and salts of isomers, pose an imminent hazard to public safety and health, have no currently accepted medical use in treatment in the United States, and lack accepted safety for use under medical supervisio n. References Advisory Council on the Misuse of Drugs. (2013). 'NBOMe' compounds: A review of the evidence of use and harm. London: Advisory Council on the Misuse of Drugs. Braden, M., Parrish, J., Naylor, J., & Nichols, D. (2006). Molecular interaction of serotonin 5 - HT 2A receptor residues Phe339 (6.51) and Phe340 (6.52) with superpotent N - benzyl phenethylamine agonists. Molecular Pharmacology, 70 (6), 1956
- 1964.DEA/OD/ODE page 12 of 14 October 1 6 , 2013

Ettrup, A., Hansen, M., Santini, M., Paine, J., Gillings, N., Palner, M., Lehel, S., Herth, M., Madsen, J., Kristensen, J., Begtrup, M., & Knudsen, G. (2011). Radiosynthesis and in vivo evaluation of a series of substituted 11 C - phenethylamines as 5
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- HT 2A Receptor Agonist PET Radioligand [ 11 C]Cimbi
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Appendix 1 NFLIS Reports (as of October 9 , 2013 ) * :

Q2 2011 Q3 2011 Q4 2011 Q1 2012 Q2 2012 Q3 2012 Q4 2012 Q1 2013 Q2 2013 ‡ TOTAL 25I - NBOMe 3 6 1 24 91 144 148 200 178 795 25C - NBOMe 1 1 13 31 54 44 144 25B - NBOMe 1 13 6 20 * No reports identified in NFLIS regarding 25I - NBOMe, 25C - NBOMe, or 25B - NBOMe prior to June , 201 1 . ‡ D ata collection ongoing for 2013 . STRIDE Records ( November , 20 11 through June, 2013 , retrieved October 9 , 2013 ) * :

Cases Exhibits 25I - NBOMe 2 7 54 25C - NBOMe 1 2 2 7 25B - NBOMe 4 4 * No reports identified in STRIDE regarding 25I - NBOMe, 25C - NBOMe, or 25B - NBOMe prior to November , 20 11