July 15, 2020

July 15, 2020 Basis for the Recommendation to Control N-ethylpentylone and Its Optical, Geometric, and Positional Isomers, Salts, and Salts of Isomers in Schedule I of the Controlled Substances Act

I. SUMMARY

On September 25, 2019, the Drug Enforcement Administration (DEA) requested that the Department of Health and Human Services (HHS) conduct a medical and scientific evaluation of N-ethylpentylone (“2019 DEA request to HHS”) to determine whether it should be recommended for control under the Controlled Substances Act (CSA). N- ethylpentylone (also known as ephylone and N-ethylnorpentylone; 1-(1,3-benzodioxol-5- yl)-2-( ethylamino)pentan-1-one) is a synthetic cathinone that functions as a central nervous system (CNS) stimulant (lkeji, 2017). The medical and scientific evaluation of whether a substance should be recommended for control under the CSA is performed for HHS by the Food and Drug Administration (FDA), with the concurrence of the National Institute on Drug Abuse (NIDA) (see the Memorandum of Understanding, 50 FR 9518, 9518-20, Mar. 8, 1985).

N-ethylpentylone has no known medical use in the United States, does not have an approved new drug application, and is not currently marketed anywhere in the world as an approved drug product.

On August 31, 2018, the DEA published a temporary scheduling order in the Federal Register (83 FR 44474) temporarily placing N-ethylpentylone, as well as its optical, geometric, and positional isomers, salts, and salts of isomers in Schedule I of the CSA upon finding that this action was necessary to avoid an imminent hazard to the public safety.

Between 2014 and 2019, U.S. law enforcement agencies encountered N-ethylpentylone in 44 states as well as in the District of Columbia and Puerto Rico, indicating that this drug was available for abuse purposes.

Chemically, N-ethylpentylone is structurally related to the Schedule I cathinone stimulants, methylenedioxypyrovalerone (MDPV), methylone, mephedrone, 4-methyl-N- ethylcathinone (4-MEC), 4-methyl-pyrrolidinopropiophenone (4-MePPP), alpha- pyrrolidinopentiophenone (α-PVP), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)butan-1- one (butylone), 2-(methylamino)-1-phenylpentan-1-one (pentedrone), 1-(1,3- benzodioxol-5-yl)-2-(methylamino)pentan-1-one (pentylone), 4-fluoro-N- methylcathinone (4-FMC; flephedrone), 3-fluoro-N methylcathinone (3-FMC), 1- (naphthalen-2-yl)-2-(pyrrolidin-1-yl)pentan-1-one (naphyrone), and alpha- pyrrolidinobutiophenone (α-PBP). N-ethylpentylone also elicits pharmacological effects similar to these Schedule I cathinones.

N-ethylpentylone CSA Schedule I Recommendation

Pursuant to 21 U.S.C. 811(b), the Secretary of HHS is required to consider in a scientific and medical evaluation, eight factors determinative of control under the CSA. These eight factors are the following:

1. Its actual or relative potential for abuse; 2. Scientific evidence of its pharmacological effect, if known; 3. The state of current scientific knowledge regarding the drug or other substance; 4. Its history and current pattern of abuse; 5. The scope, duration, and significance of abuse; 6. What, if any, risk there is to the public health; 7. Its psychic or physiological dependence liability; and 8. Whether the substance is an immediate precursor of a substance already controlled under the CSA.

Following consideration of these eight factors, the Secretary must make three findings and a recommendation for scheduling a drug or substance in the CSA. The three findings relate to a substance's abuse potential, legitimate medical use, and safety or dependence potential (see 21 U.S.C. 812(b)).

After assessing all the available data, FDA recommends that N-ethylpentylone and its optical, geometric, and positional isomers, salts, and salts of isomers be controlled in Schedule I of the CSA. Schedule I drugs are classified as having a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use of the drug under medical supervision. NIDA concurs with this recommendation.

II. EVALUATING N-ETHYLPENTYLONE UNDER THE EIGHT FACTORS

This section evaluates the scientific and medical information about N-ethylpentylone under the eight factors that must be considered pursuant to 21 U.S.C. 811(c). Available information that was evaluated included information provided in the 2019 DEA request to HHS, papers published in scientific and medical literature, law enforcement data from seizures and surveillance, and anecdotal reports on the human use of N-ethylpentylone.

FACTOR 1. ITS ACTUAL OR RELATIVE POTENTIAL FOR ABUSE

The term “abuse” is not defined in the CSA. However, the legislative history of the CSA1 describes the potential for abuse of a particular substance as follows:

a. Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community.

1 Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1 (1970), reprinted in U.S.C.C.A.N. 4566, 4603.

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

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

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

There is no single test or assessment procedure that, by itself, provides a full and complete characterization of a substance’s abuse potential because this is a complex determination that is multi-dimensional. When assessing the abuse potential of a substance, the Secretary considers multiple factors, data sources, and analyses. These factors include the prevalence, frequency, and manner of use in the general public and specific subpopulations, the amount of material that is available for illicit use, and evidence relevant to populations that may be at particular risk.

Animal, human, and epidemiological data are all used in determining a substance’s abuse potential. Specifically, a comprehensive evaluation of the relative abuse potential of a substance includes consideration of available data regarding the drug’s receptor binding affinity, preclinical pharmacology, reinforcing effects, discriminative stimulus effects, dependence-producing potential, pharmacokinetics, routes of administration, and toxicities, as well as an assessment of the clinical efficacy safety database relative to actual abuse, clinical abuse potential studies, and the public health risks following marketing of the substance. Epidemiological data can also be an important indicator of actual abuse. Finally, evidence of clandestine production and illicit trafficking of a substance are also important factors.

Below is a discussion of the four indicators of abuse as they relate to N-ethylpentylone. a. Individuals are taking the substance in amounts sufficient to create a hazard to their health or to the safety of other individuals or to the community.

Evidence that individuals are taking N-ethylpentylone in amounts sufficient to create a health hazard is found in DEA databases and published medical reports (see Factor 2). N-ethylpentylone has also been seized by law enforcement in the United States (see Factor 5), demonstrating the availability of the substance as a drug of abuse. Thus, N- ethylpentylone presents safety hazards to the health of individuals who consume it.

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

Given that N-ethylpentylone is not an approved drug product in the United States and there are no known legitimate drug channels from which this substance can be diverted, this characteristic of abuse potential is not applicable. c. Individuals are taking the substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substances.

N-ethylpentylone is not an approved drug product in the United States, so a practitioner may not legally prescribe the drug and it cannot be dispensed to an individual. Therefore, individuals who use N-ethylpentylone are doing so without medical advice.

N-ethylpentylone is an illicit substance that has been seized by law enforcement. According to the 2019 DEA request to HHS and anecdotal reports (see Factor 2), N- ethylpentylone had pharmacological effects similar to the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, as well as to the Schedule II stimulants, cocaine and methamphetamine. Thus, individuals who use N-ethylpentylone are doing so on their own initiative. d. The substance is so related in its action to a substance already listed as having a potential for abuse to make it likely that it will have the same potential for abuse as such substance, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that it has a substantial capability of creating hazards to the health of the user or to the safety of the community.

N-ethylpentylone has a chemical structure that is similar to the Schedule I cathinones, MDPV, methylone, and mephedrone. The pharmacological actions of N-ethylpentylone have similarity to that of the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, which have a high abuse potential but do not have an accepted medical use. N-ethylpentylone also has pharmacological actions that have similarity to the Schedule II stimulants, cocaine and methamphetamine (see Factor 2).

As noted in the 2019 DEA request to HHS, N-ethylpentylone had been sold as “Molly,” the name of a street drug with stimulant properties, often thought by the user to be 3,4- methylendioxymethamphetamine (MDMA) (see Factor 5). Data from animal drug discrimination studies demonstrated that N-ethylpentylone produced full generalization to the Schedule II stimulants methamphetamine and cocaine (see Factor 2). Full generalization to methamphetamine and cocaine was also produced by the Schedule I cathinones, pentylone and MDPV.

The risks associated with N-ethylpentylone, as with other Schedule I and II stimulants, are primarily related to stimulant-like responses in humans, which can include euphoria, hallucinations, psychosis, tachycardia, hypertension, and hyperthermia at higher doses

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(Baumann et al., 2018). Because of the psychological and cognitive disturbances associated with these responses, it is reasonable to assume that N-ethylpentylone has a substantial capability to be a hazard to the health of the user and to the safety of the community.

FACTOR 2. SCIENTIFIC EVIDENCE OF ITS PHARMACOLOGICAL EFFECTS, IF KNOWN

The scientific evidence of the pharmacological effects of N-ethylpentylone includes its neurochemical effects and its CNS effects in animals and humans.

Neurochemical Effects

The neurochemical effects of N-ethylpentylone occur primarily through the dopamine, norepinephrine, and serotonin sites in the brain. Specifically, N-ethylpentylone binds to the transporters for these three monoamines (see Table 1) and functions as a reuptake inhibitor at these sites without acting as a releaser of these neurotransmitters (see Tables 2 and 3). N-ethylpentylone also functions to increase levels of dopamine and serotonin (Lin et al., 2019a). The pharmacological mechanisms of action produced by N- ethylpentylone have similarities to those of the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, and of the Schedule II stimulants, cocaine and methamphetamine.

Receptor Binding

As shown in Table 1, N-ethylpentylone has binding affinities (Ki values) at the monoamine transporter sites (dopamine, norepinephrine, and serotonin) similar to those produced by the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, and by the Schedule II stimulants, cocaine and methamphetamine (Eshleman et al., 2013 and 2019; Janowsky, 2016).

Table 1: Ki Values of Schedule I and II Stimulants and N-ethylpentylone for the Dopamine, Norepinephrine, and Serotonin Transporter Sites in the Brain

Drug Dopamine Norepinephrine Serotonin Transporter Transporter Transporter (Ki) (Ki) (Ki)

Cocaine 495-591 nM 1,410-1,950 nM 495-651 nM (positive control) Methamphetamine 2,580-4,410 nM 2,510-4,000 nM 150,000- (positive control) 172,000 nM Pentylone 394 nM 8,190 nM 3,380 nM (positive control) Mephedrone 4,800 nM 11,800 nM 21,000 nM (positive control)

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Methylone 5,020 nM 16,500 nM 95,500 nM (positive control) MDPV 19 nM 107 nM 1,250 nM (positive control)

N-ethylpentylone 102 nM 2,380 nM 893 nM

Ki is the inhibitory constant (Eshleman et al., 2013 and 2019; Janowsky, 2016).

Reuptake Inhibition

As shown below in Table 2, N-ethylpentylone demonstrated significant activity as a monoamine reuptake inhibitor (Eshleman et al., 2013 and 2019; Costa et al., 2019). Reuptake inhibition (IC50) by N-ethylpentylone was prominent at the dopamine transporter, a pharmacological action that is associated with abuse potential. The inhibition of the monoamine transporters produced by N-ethylpentylone was similar to that produced by the Schedule II stimulants cocaine and methamphetamine and by the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV.

Table 2: IC50 Induced by Schedule I and II Stimulants and N-ethylpentylone at the Dopamine, Norepinephrine, and Serotonin Transporter Sites in the Brain

Drug Dopamine Norepinephrine Serotonin Transporter Transporter Transporter (IC50) (IC 50) (IC 50)

Cocaine 425 nM 382 nM 364 nM (positive control) Methamphetamine 97 nM 26 nM 9,300 nM (positive control) Pentylone 154-167 nM 401-650 nM 810-1198 nM (positive control) Mephedrone 98 nM 54 nM 510 nM (positive control) Methylone 343-1,389 nM 234-712 nM 1,149-1,920 nM (positive control) MDPV 13 nM 19 nM 1,380 nM (positive control)

N-ethylpentylone 37-55 nM 105-114 nM 383-460 nM

The IC50 value is the drug concentration giving half-maximal inhibition (Eshleman et al., 2013 and 2019; Costa et al., 2019).

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Monoamine Release

As shown below in Table 3, N-ethylpentylone did not have significant activity as a releaser at any of the three monoamine transporter sites (Eshleman et al., 2013 and 2019; Janowsky, 2016; Costa et al., 2019). This was similar to the lack of activity in releasing monoamines that was observed with the Schedule I synthetic cathinones, pentylone and MDPV.

Table 3: Release of Neurotransmitters (EC50 and Maximal Stimulation (%)) Induced by Schedule I and II Stimulants and N-ethylpentylone at the Dopamine, Norepinephrine, and Serotonin Transporter Sites in the Brain

Drug Dopamine Norepinephrine Serotonin Transporter Transporter Transporter EC50 EC50 EC50) (% maximal (% maximal (% maximal release) releas e) releas e) Methamphetamine 1200 nM 255 nM 14,500 nM (positive control) (107%) (147%) (102%) Pentylone >10 μM >10 μM 476 nM to >10 μM (positive control) (minimal) (minimal) (minimal) Mephedrone 1,190 nM 410 nM 11,900 nM (positive control) (68%) (152%) (53%) Methylone 178-11,800 nM 81-426 nM 342-6,700 nM (positive control) (41%) (122%) (78%) MDPV >10 μM >10 μM >10 μM (positive control) (5%) (18%) (7%)

N-ethylpentylone >10 μM 6.7 μM >10-100 μM (<1%) (16%) (7%) The EC50 value is the drug concentration giving half-maximal acceleration/stimulation (Eshleman et al., 2013 and 2019; Janowsky, 2016; Costa et al., 2019).

Increase in Monoamine Levels

Based on the ability of N-ethylpentylone to induce reuptake inhibition at monoamine transporters, it would be expected that this pharmacological activity may lead to an increase in levels of the monoamines. Lin et al. (2020) administered N-ethylpentylone to conscious rats and conducted an in vivo microdialysis evaluation of the extracellular concentrations of dopamine, serotonin, and their respective metabolites 3,4‐dihydroxyphenylacetic acid (DOPAC) and 5‐hydroxyindole‐3‐acetic acid (5-HIAA). N-ethylpentylone dose-dependently increased dopamine and serotonin concentrations in the nucleus accumbens, an area of the brain associated with reward. Dopamine was increased to a degree greater than serotonin, suggesting a meaningful abuse potential. N-ethylpentylone reduced the rate at which DOPAC and 5-HIAA were formed, indicating a prolonged action by dopamine and serotonin.

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CNS Effects

The CNS effects of N-ethylpentylone were demonstrated through animal studies and through reported effects in humans. As described below, studies in animals suggested that the pharmacological effects of N-ethylpentylone had similarities to the Schedule I synthetic cathinones, pentylone and MDPV, and to the Schedule II stimulants, methamphetamine and cocaine.

Animal Studies

Animal studies conducted with N-ethylpentylone included those evaluating locomotor activity and drug discrimination.

Locomotor Activity2

In a variety of locomotor activity studies (Li et al., 2019; Gatch et al., 2013, 2015, and 2019; Sumien et al., 2017), rodents received the following positive control drugs: Schedule I cathinones, pentylone and MDPV, and the Schedule II stimulants, cocaine and methamphetamine. The rodents received these drugs to establish baseline locomotor responses to known stimulants. Animals were then administered N-ethylpentylone prior to placement in the activity monitoring cage. As shown below in Table 4, N- ethylpentylone produced levels of locomotor activity that were 90% of the activity produced by methamphetamine and 93% of the activity produced by cocaine. Similarly, pentylone produced 95% and MDVP produced 109% of the locomotor activity produced by methamphetamine and 104% and 103%, respectively, of the activity of cocaine.

Table 4: Locomotor Activity Produced in Rodents by N-ethylpentylone in Comparison to the Schedule II Stimulants Cocaine and Methamphetamine and the Schedule I Cathinones Pentylone and MDPV

Drug ED50 Duration of Action Percentage of Percentage of Methamphetamine Cocaine Response Response Cocaine 7.2-9.4 mg/kg 120-170 min -- -- (positive control) Methamphetamine 0.3-0.5 mg/kg 140-270 min -- -- (positive control) Pentylone 11.5 mg/kg 120-170 min 95% 104% (positive control) MDPV 1.3 mg/kg 190 min 109% 103% (positive control)

2 Evaluation of locomotor activity is a behavioral method of determining whether a test drug has stimulant properties. In this method, animals receive a drug and are placed into an activity monitoring cage. This cage is equipped with infrared beams in grids across each wall of the cage. When an animal moves about the cage, these beams are broken, which allows for measurement of the amount of activity generated by the animal.

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N-ethylpentylone 0.73 mg/kg 30-130 min 90% 93%

ED50 is the median effective dose that produces 50% maximum locomotor activity (Li et al., 2019; Gatch et al., 2013, 2015, and 2019; Sumien et al., 2017).

These behavioral data showed that N-ethylpentylone produced increases in locomotion that were similar to those produced by the Schedule I cathinones, pentylone and MDPV, and to the Schedule II stimulants, cocaine and methamphetamine.

Drug Discrimination3

A number of drug discrimination studies were conducted in animals to evaluate whether N-ethylpentylone and the Schedule I cathinones, pentylone and MDPV, had stimulus properties that were similar to the Schedule II stimulants, methamphetamine and cocaine. In these studies, rats were trained to discriminate the effects of the Schedule II stimulants, methamphetamine or cocaine, from the effects of saline. As shown below in Table 5, when the rats were challenged with pentylone, MDPV, and N-ethylpentylone, each of these drugs produced full generalization to the methamphetamine and cocaine cues (Gatch et al., 2013, 2015, and 2019; Forster et al., 2017). N-ethylpentylone had an ED50 for generalization to methamphetamine and cocaine that was between that of pentylone and MDPV, suggesting that N-ethylpentylone was a less potent stimulant than MDPV but a more potent stimulant than pentylone.

Table 5: Drug Discrimination Studies: Generalization and ED50 Produced in Rats by N-Ethylpentylone to the Schedule II Stimulants Methamphetamine and Cocaine

Drug Methamphetamine Cocaine (ED 50) (ED50) Cocaine Full Full (positive control) (4.89 mg/kg) (2.73 mg/kg) Methamphetamine Full Full (positive control) (0.34 mg/kg) (0.62 mg/kg) Pentylone Full Full (positive control) (3.86 mg/kg) (2.33 mg/kg) MDPV Full Full (positive control) (0.67 mg/kg) (0.68 mg/kg)

3 Drug discrimination is an experimental method used to determine whether an animal experiences the physiological or behavioral effects of a particular drug as similar to the physiological or behavioral effects of another drug (or class of drugs) to which the animal was previously exposed. In this test method, animals are trained to press one bar in the test cage following administration of a specific known drug of abuse and to press another bar following administration of placebo. A challenge session with the novel drug determines which of the two bars the animal presses more often as an indicator of whether the test drug is more like the known drug of abuse or more like placebo. The novel drug is said to have “full generalization” to the known drug of abuse when the novel drug produces bar pressing >75% on the bar associated with the known drug of abuse (Doat et al., 2003; Sannerud and Ator, 1995).

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N-ethylpentylone Full Full (1.65 mg/kg) (1.98 mg/kg) ED50 is the dose at which the subjects would be expected to make 50% of their responses on the drug-appropriate lever (Gatch et al., 2013, 2015, and 2019; Forster et al., 2017).

Thus, the drug discrimination data demonstrated that N-ethylpentylone produced stimulus effects that were similar to those of the Schedule II stimulants methamphetamine and cocaine.

Effects in Humans

The effects of N-ethylpentylone in humans have not been well characterized to date. According to the World Health Organization (WHO) (2018), Boehringer Ingelheim (BI) pharmaceutical company patented N-ethylpentylone and several of its analogs in 1967. Although compound specific data were not provided, the patent suggested dosage units in humans of up to 150 mg for oral administration and up to 25 mg for parenteral administration. It is unclear if these data were generated by BI in clinical studies, but to date, there have been no published studies in humans with N-ethylpentylone for drug development purposes or for investigational purposes to understand the drug’s behavioral pharmacology.

Schedule I synthetic cathinones (e.g., pentylone, mephedrone, methylone, and MDPV) produce classic stimulant effects in humans, including elevated mood, euphoria, hallucinations, psychosis, tachycardia, hypertension, and hyperthermia at higher doses (Baumann et al., 2018), similar to other stimulants in Schedule I (e.g., MDMA) and Schedule II (e.g., cocaine, amphetamine, and methamphetamine). Given that the mechanisms of action and behavioral effects in animals produced by N-ethylpentylone have similarities to the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, as well as to the Schedule II stimulants, cocaine and methamphetamine, it is likely that N-ethylpentylone will produce stimulant-like effects in humans.

The website Erowid, where recreational drug users report on their experiences with various substances, has numerous reports stating that N-ethylpentylone produces stimulant-like effects. Drug users who believed they had taken N-ethylpentylone did so via oral and sublingual administrations, as well as via nasal insufflations and intravenous injections. Given the illicit nature of N-ethylpentylone, it is not possible to accurately determine the doses taken by these recreational users.

Published papers reporting on adverse events following N-ethylpentylone ingestion have been consistent with known stimulant effects, including diaphoresis, insomnia, mydriasis, hyperthermia, vomiting, agitation, disorientation, paranoia, abdominal pain, cardiac arrest, respiratory failure, coma, and death (Atherton et al., 2018; Thirakul et al., 2017; Costa et al., 2018; Krotulski et al., 2018a, b; 2019 DEA request to HHS).

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FACTOR 3. THE STATE OF CURRENT SCIENTIFIC KNOWLEDGE REGARDING THE DRUG OR OTHER SUBSTANCE

The current scientific knowledge of N-ethylpentylone includes information about its chemistry and pharmacokinetics.

Chemistry

Based on information in the 2019 DEA request to HHS and on information from the WHO (2018), N-ethylpentylone [also known as ephylone, N-ethylnorpentylone; 1-(1,3- benzodioxol-5-yl)-2-( ethylamino)pentan-1-one] has the CAS number 727641-67-0 (base). The base of N-ethylpentylone has a molecular weight of 249.3 and a molecular formula of C14H19NO3. The hydrochloride salt of N-ethylpentylone has the CAS number 17763-02-9, a melting point of 238–241°C, and is a crystalline, solid, off-white powder. The solubility of the hydrochloride salt of N-ethylpentylone in phosphate buffered saline (pH 7.2) is 1 mg/ml. The hydrochloride salt of N-ethylpentylone is also soluble in dimethyl sulfoxide, methanol, and water and partially soluble in dichloromethane.

Pharmacokinetics

In a pharmacokinetic evaluation in rats (Lin et al., 2020), N-ethylpentylone rapidly crossed the blood-brain barrier following intraperitoneal administration, leading to a maximum concentration (Cmax) 40 minutes after drug administration. In this pharmacokinetic distribution study, more than 90% of plasma N-ethylpentylone was located in the brain, with 4% in the nucleus accumbens, an area of the brain associated with reward.

A pharmacokinetic evaluation of N-ethylpentylone has not been conducted in humans. However, Krotulski et al. (2018b) conducted an in vitro analysis of N-ethylpentylone metabolism in human liver microsomes from blood and oral fluid samples that had tested positive for N-ethylpentylone. In blood samples taken from individuals driving under the influence of the drug (n = 5), the concentration of N-ethylpentylone ranged from 21 to 87 ng/ml, with a mean of 41 ng/ml and a median of 34 ng/ml. In the oral fluid samples (n = 5) from drug users who had attended a music festival, the average concentration of N- ethylpentylone was 318 ng/mL, the median was 36 ng/mL and the range was 13 to 1,377 ng/ml. In blood samples from death investigations (n = 17), the concentration of N- ethylpentylone ranged from 12 to 790 ng/ml, with a mean of 305 ng/ml and median of 185 ng/ml.

The Krotulski et al. (2018b) pharmacokinetic analysis also found that N-ethylpentylone produced four metabolites through sequential hydrogenation (M1), deethylation (M2), demethylation (M3), and hydroxylation (M4). Of these metabolites, M1 and M3 are unique metabolites of N-ethylpentylone, with M1 being the major metabolite.

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FACTOR 4. ITS HISTORY AND CURRENT PATTERN OF ABUSE

The history and current pattern of abuse of N-ethylpentylone are shown through law enforcement data from DEA and the U.S. Customs and Border Protection (CBP) regarding drug seizures, indicating that N-ethylpentylone has been available for abuse purposes.

Table 6 shows data from the DEA’s System to Retrieve Information from Drug Evidence (STRIDE)/STARLiMS4 database, from the DEA’s National Forensic Laboratory Information System (NFLIS)5 database, and from the CBP database.

Table 6: N-Ethylpentylone Forensic Laboratory Reports (2013 to 2019) (2019 DEA Request to HHS)

2013 2014 2015 2016 2017 2018* 2019* TOTAL

Local/Municipal 0 1 6 2191 6134 8547 291 17,170 and State: (NFLIS) (0%) (0%) (0%) (25%) (61%) (79%) (33%) (and % of Total Synthetic Cathinones) Federal: 0 0 1 124 279 256 8 668 STRIDE/ STARLiMS Federal: CBP 0 0 0 15 103 182 0 300 * The 2018 and 2019 data are still pending in full

Starting in 2014, law enforcement began to encounter Nethylpentylone as a street drug. The number of drug exhibits for Nethylpentylone remained low until 2016, when NFLIS reported 2191 exhibits (representing 25% of all synthetic cathinone drug exhibits) and STARLiMS reported 124 exhibits.

By 2017, NFLIS and STARLiMS reported approximately two- to three-fold increases in drug exhibits for Nethylpentylone compared to 2016. In 2017, 6134 exhibits for

4 STRIDE is a database of drug exhibits sent to DEA’s laboratories for analysis. Exhibits in the database are from the DEA, other federal agencies, and local law enforcement agencies. STRIDE is not a representative sample of drugs available in the United States but reflects all evidence submitted to DEA laboratories for analysis, from both domestic and foreign sources, including drug seizures. STARLiMS is a web-based, commercial laboratory information management system that replaced STRIDE in 2014. See http://www.dea.gov/resource-center/stride-data.shtml.

5 The DEA’s NFLIS systematically collects results from drug chemistry analyses conducted by state and local forensic laboratories across the country. As a national drug forensic laboratory reporting system, NFLIS provides timely and detailed analytical results of drugs seized by law enforcement. It is a unique source of information for monitoring and understanding drug abuse and trafficking in the United States, including the diversion of legally manufactured drugs into illegal markets. See http://www.deadiversion.usdoj.gov/nflis/.

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Nethylpentylone were reported by NFLIS, representing 61% of all synthetic cathinone drug exhibits, while STARLiMS reported 279 exhibits. This upward trend further increased in 2018 (a year for which reporting is still incomplete), when NFLIS reported 8547 drug exhibits for Nethylpentylone, representing 79% of all synthetic cathinone drug exhibits. The increase in 2018 is especially concerning given that 2018’s reporting is still incomplete. During 2018, there was a parallel increase in CBP seizures of Nethylpentylone, with 103 drug exhibits in 2017 and 182 exhibits in 2018 (a year for which reporting is still incomplete). These NFLIS and STARLiMS data strongly suggest that Nethylpentylone was a popular synthetic cathinone available for illicit stimulant use.

By 2017, NFLIS and STARLiMS reported that Nethylpentylone had been encountered in the District of Columbia and Puerto Rico, as well as in all but the following six states in the United States: Hawaii, Montana, New Mexico, Rhode Island, South Dakota, and Vermont. CBP began to encounter N-ethylpentylone in 2016, with encounters by 2018 occurring in the border states of Alabama, California, Florida, Georgia, Illinois, New Jersey, and New York.

These law enforcement data from three federally-maintained databases showed that N- ethylpentylone has been available for purchase and illicit use in the United States since at least 2014.

FACTOR 5. THE SCOPE, DURATION, AND SIGNIFICANCE OF ABUSE

Evidence of the scope, duration, and significance of abuse of N-ethylpentylone is provided by its use as an unscheduled stimulant and as a substitute for MDMA.

Based on the pharmacological properties of N-ethylpentylone, it is reasonable to assume that, if uncontrolled, the scope, duration, and significance of abuse of N-ethylpentylone would be similar to stimulants that are scheduled under the CSA, including the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, as well as the Schedule II stimulants, cocaine and methamphetamine. Notably, as detailed in Factor 4, law enforcement seizure data showed that N-ethylpentylone has been available for illicit purchase in at least 44 states in the United States as an unscheduled stimulant since 2014. Based on data in case reports and state mortality records (Karila et al., 2015; Meyers et al., 2015), the use of N-ethylpentylone appeared to be primarily by young adults.

There are two published reports detailing stimulant-like adverse events resulting from N- ethylpentylone use that subsequently worsened until the individual died. Thirakul et al. (2017) reported on a 29-year-old man who was reported to be agitated, disoriented, and belligerent after consuming N-ethylpentylone, with an elevated temperature and

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tachycardia prior to his death. Similarly, Ikeji et al. (2018) reported on a 21-year-old man who consumed N-ethylpentylone and exhibited combative and confused behavior, in addition to heavy sweating, prior to his death.

The 2019 DEA request to HHS notes the following:

newly identified synthetic cathinones may produce pharmacological effects including recreational effects that are substantially similar to those of the schedule I controlled substances such as cathinone, methcathinone, MDPV, and pentylone, 3,4- methylenedioxymethamphetamine (MDMA) and schedule II stimulants methamphetamine and cocaine. Synthetic cathinones and their products in the illicit drug market have been falsely marketed as ‘research chemicals,’ ‘jewelry cleaner,’ ‘stain remover,’ ‘plant food or fertilizer,’ ‘insect repellants,’ or ‘bath salts’ and are abused for their psychoactive properties. They are sold at smoke shops, head shops, convenience stores, adult book stores, 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.

The 2019 DEA request to HHS also states the following:

N-Ethylpentylone has been encountered as a replacement for MDMA, a schedule I controlled substance. N-Ethylpentylone has been identified in law enforcement seizures that were initially suspected to be MDMA and marketed as ‘Molly.’ In addition, information from law enforcement reports indicate the N-ethylpentylone was detected in biological samples from individuals who thought they were using ‘Molly.’

Krotulski et al. (2018a) confirmed this assertion in a paper that reported on surveys conducted with participants at four electronic dance parties (“raves”) between 2014 to 2017 where individuals had an oral fluid sample taken for drug analysis following recent use of recreational drugs. Out of the four samples that were positive for N- ethylpentylone, each of the individuals identified the drug they had consumed as “Molly,” a name applied to street drugs that may contain MDMA, 3,4-methylenedioxy- amphetamine (MDA), or other novel stimulants. In each of these samples that was positive for N-ethylpentylone, MDA was present with or without MDMA.

Krotulski et al. (2018b) subsequently reported toxicological analyses that confirmed the presence of N-ethylpentylone in 26 blood samples collected as part of a larger sample from death investigations and toxicology casework involving intoxicated drivers. The demographics of the 26 individuals included the following: 24 males and two females with an average age of 35 years (range of 23 to 53 years old). N-ethylpentylone was also confirmed in five oral fluid samples obtained from five volunteer subjects as part of a larger sample from attendees at a music festival. Each of these five subjects (two male and three female, with an average age of 26 years (range of 20 to 34 years) stated that they had ingested what they understood to be “Molly”.

14 N-ethylpentylone CSA Schedule I Recommendation

Thus, the use of N-ethylpentylone for its stimulant properties showed that the drug had a scope, duration, and significance of abuse that supports scheduling under the CSA.

FACTOR 6. WHAT, IF ANY, RISK THERE IS TO THE PUBLIC HEALTH

Public health risks resulting from abuse of N-ethylpentylone relate primarily to its ability to induce stimulant-like responses similar to other synthetic cathinones, which may lead to adverse events that include cognitive impairment and even death.

Use of cathinones can produce typical stimulant effects such as increased energy, elevated mood, and euphoria at lower doses, but can produce hallucinations, psychosis, tachycardia, hypertension, hyperthermia, and aggression at higher doses (Baumann et al., 2018). Given that N-ethylpentylone has a mechanism of action and behavioral effects in animals that are similar to the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, and to the Schedule II stimulants, cocaine and methamphetamine, it is likely that N-ethylpentylone will produce stimulant-like effects in humans.

Most critically, 151 deaths that occurred from 2016 to 2018 in Maryland and Pennsylvania were reported to DEA. Twenty-five of these deaths were reported in 2016 and 2017 by the Maryland Office of the Chief Medical Examiner and were confirmed to be associated with N-ethylpentylone (according to the 2019 DEA request to HHS). An additional 125 deaths that occurred between 2016 and 2018 were reported by NMS Labs, a toxicology laboratory in Horsham, PA, in a March 1, 2018, correspondence with DEA. Each of these deaths was associated with a confirmation of N-ethylpentylone in blood or urine samples obtained from the deceased individuals.

Finally, the following four papers published in the medical literature report on deaths associated with the recreational use of N-ethylpentylone:

• Thirakul et al. (2017) reported on the death of a 29-year-old man in Florida in which a sample of N-ethylpentylone was found in the decedent’s car and a postmortem blood analysis was positive for N-ethylpentylone but not for any other drug of abuse. Prior to his death, the man was agitated, disoriented, and belligerent after consuming N-ethylpentylone, with an elevated temperature and tachycardia prior to his death.

• Ikeji et al. (2018) reported on a 21-year-old man who consumed N-ethylpentylone and exhibited combative, paranoid, and confused behavior in addition to heavy sweating prior to his death. Biological samples were found to be positive for N- ethylpentylone, benzodiazepine, and alcohol.

• Costa et al. (2018) reported on the following six individuals who ingested N- ethylpentylone and received medical attention, one of whom died:

15 N-ethylpentylone CSA Schedule I Recommendation

o A 32‐year‐old man exhibited agitation and aggressiveness, then fainted and died en route to the hospital. The patient’s postmortem whole blood was positive for N‐ethylpentylone (170 ng/ml).

o An 18‐year‐old man exhibited agitation alternating with depression, tachycardia, and mydriasis. His urine and blood were positive for N‐ethylpentylone. The patient recovered and was discharged.

o A 26‐year‐old woman was found unconscious but subsequently became conscious while exhibiting confused, sleepy behavior with disconnected speech and visual hallucinations. Her urine was positive for MDMA and N‐ethylpentylone. The patient was discharged the following day.

o A 19‐year‐old man attended a rave party and subsequently presented himself to the hospital agitated with palpitations and tachycardia. His urine was positive for MDMA, caffeine, and cotinine, as well as N‐ethylpentylone (19 ng/ml). The patient was treated symptomatically.

o A 35‐year‐old man who had been consuming alcohol and other drugs of abuse was found unconscious in his home. His serum level of N‐ethylpentylone was 149 ng/ml. The patient was later diagnosed with vertebral artery dissection and hemorrhage of the brainstem, which left him in a vegetative state. o A 26‐year‐old man presented with symptoms of psychosis, paranoia, sleeplessness, and inconsistent speech. His serum level of N‐ethylpentylone was 61 ng/ml. The patient was subsequently discharged with psychiatric oversight.

• Atherton et al. (2018) reported on the following two deaths in Alabama in 2017 that were attributed to N-ethylpentylone toxicity:

o A 34-year-old man had been acting erratic and paranoid after consuming “Molly.” He was found dead the next day, and his blood was positive for N-ethylpentylone.

o A second 34-year-old man had a cardiac arrest in an emergency department and subsequently died. The cause of death was listed as methamphetamine, cocaine, fentanyl, and N-ethylpentylone toxicity.

These case reports demonstrate that drug users who seek out N-ethylpentylone, likely for its stimulant effects, have suffered adverse events that include death. This represents a risk to the individual drug abuser and to the public health.

FACTOR 7. ITS PSYCHIC OR PHYSIOLOGIC DEPENDENCE LIABILITY

In the 2019 DEA request to HHS, DEA states that it “is not aware of any clinical studies that have evaluated the dependence potential of N-ethylpentylone.” However, the psychic or physiological dependence liability of N-ethylpentylone is demonstrated by

16 N-ethylpentylone CSA Schedule I Recommendation

animal abuse-related studies and positive subjective effects from N-ethylpentylone in humans.

In a drug discrimination study, N-ethylpentylone fully generalized to the discriminative stimulus effects produced by the Schedule II stimulants cocaine and methamphetamine (see Factor 2). In locomotion studies, N-ethylpentylone produced behavioral stimulation similar to the Schedule II stimulants cocaine and methamphetamine (see Factor 2). The results with N-ethylpentylone were similar to the results produced in these two studies by the Schedule I cathinones, pentylone and MDPV.

Use of cathinones can produce typical stimulant effects such as increased energy, elevated mood, and euphoria at lower doses or hallucinations, psychosis, tachycardia, hypertension, hyperthermia, and aggression at higher doses (Baumann et al., 2018). Krotulski et al. (2018a) reported that stimulant abusers ingested N-ethylpentylone for its stimulant properties.

These data strongly suggested that N-ethylpentylone produced behavioral effects in animals and humans that are similar to those of Schedule I and II stimulants. Thus, it is reasonable to conclude that the stimulant properties of N-ethylpentylone produces a psychic dependence liability.

FACTOR 8. WHETHER THE SUBSTANCE IS AN IMMEDIATE PRECURSOR OF A SUBSTANCE ALREADY CONTROLLED UNDER THE CSA

N-ethylpentylone is not known to be an immediate precursor of any substance already controlled under the CSA.

III. RECOMMENDATION

After consideration of the eight factors determinative of control of a substance (21 U.S.C. 811(c)), FDA recommends that N-ethylpentylone as well as its optical, geometric, and positional isomers, salts, and salts of isomers be controlled in Schedule I. NIDA concurs with this recommendation. N-ethylpentylone produces effects similar to other drugs with a high risk of abuse, including MDPV, methylone, and mephedrone, all of which are controlled in Schedule I of the CSA, as well as cocaine and methamphetamine, which are controlled in Schedule II of the CSA. The necessary criteria for placing a substance into Schedule I of the CSA are set forth in 21 U.S.C. 812(b)(1), as follows:

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

N-ethylpentylone is a synthetic cathinone stimulant with a high potential for abuse that produces neurochemical effects that are similar to the Schedule I cathinones, pentylone, mephedrone, methylone, and MDPV, as well as to the Schedule II stimulants, cocaine and methamphetamine. In locomotion studies, N-ethylpentylone produced behavioral

17 N-ethylpentylone CSA Schedule I Recommendation

stimulation similar to the Schedule I synthetic cathinones, methylone and MDPV, and the Schedule II stimulants, cocaine and methamphetamine. In drug discrimination studies, N-ethylpentylone fully generalized to the discriminative stimulus effects produced by the Schedule II stimulants, cocaine and methamphetamine. The Schedule I synthetic cathinones, methylone and MDPV, similarly produced full generalization to cocaine and methamphetamine. Thus, N-ethylpentylone elicits pharmacological effects qualitatively similar to the Schedule I cathinones, methylone and MDPV, as well as to the Schedule II stimulants, cocaine and methamphetamine.

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

FDA has not approved a marketing application for a drug product containing N-ethylpentylone for any therapeutic indication. Moreover, there are no clinical studies or petitioners that claim an accepted medical use in the United States. Therefore, FDA concludes without further consideration that N-ethylpentylone has no currently accepted medical use in the United States.

Since N-ethylpentylone has no approved medical use and has not been thoroughly investigated as a new drug, its safety under medical supervision is not determined. Thus, there is a lack of accepted safety for use of N-ethylpentylone under medical supervision.

FDA therefore recommends that N-ethylpentylone as well as its optical, geometric, and positional isomers, salts, and salts of isomers be controlled in Schedule I of the CSA.

IV. REFERENCES

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Baumann MH, Walters HM, Niello M, Sitte HH. Neuropharmacology of Synthetic Cathinones. Handb Exp Pharmacol. 2018;252:113-142.

Costa JL, Cunha KF, Lanaro R, Cunha RL, Walthers D, Baumann MH. 2019. Analytical quantification, intoxication case series, and pharmacological mechanism of action for N‐ethylnorpentylone (N-ethylpentylone or ephylone). Drug Test Anal 11(3):461-471.

Doat MM, Rabin RA, Winter JC. 2003. Characterization of the discriminative stimulus properties of centrally administered (-)-DOM and LSD. Pharmacol Biochem Behav. 74(3):713-21.

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Drug Enforcement Administration/Department of Justice. Data Review Document: Eight Factor Analysis for N-ethypentylone. Submitted to Dr. Brett P. Giroir, Assistant Secretary for Health, Department of Health and Human Services on September 25, 2019.

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Krotulski AJ, Papsun DM, De Martinis BS, Mohr ALA, Logan BK. 2018b. N-Ethyl Pentylone (Ephylone) Intoxications: Quantitative Confirmation and Metabolite Identification in Authentic Human Biological Specimens. Journal of Analytical Toxicology, 42:467-475.

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Lin Z, Chen Y, Li J, Xu Z, Wang H, Lin J, Ye X, Zhao Z, Shen Y, Zhang Y, Zheng S, Rao Y. 2019a. Pharmacokinetics of N-ethylpentylone and its effect on increasing levels of dopamine and serotonin in the nucleus accumbens of conscious rats. Addiction Biology. 2019 Apr 15:e12755. doi: 10.1111/adb.12755. [Epub ahead of print]

Meyers K, Kaynak 0, Bresani E, Curtis B, McNamara A, Brownfield K, Kirby KC. 2015. The availability and depiction of synthetic cathinones (bath salts) on the Internet: Do online suppliers employ features to maximize purchases? International Journal of Drug Policy, 26:670- 674.

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