U.S. Department of Justice Drug Enforcement Administration

Home , Mitragyna speciosa, Mitragynine

Mitragynine and 7-Hydroxymitragynine

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

Prepared by

Office of Diversion Control, Drug and Chemical Evaluation Section Washington, D.C. 20537 August 2016

Introduction

Mitragyna speciosa Korth (commonly known as kratom) is a psychoactive plant that

is known to produce opioid-like effects. The plant’s history of abuse was once limited to

Southeast Asia and has recently been encountered in the United States. The abuse of the

plant is increasing as evident by the quantities of known importations and the increasing

number of actions taken by the United States Food and Drug Administration in response

to kratom. The well-documented misuse and abuse of opioids and their impact on

communities is a public health and safety epidemic in the United States. Increasing

encounters of kratom in the recent years is extremely concerning to public and law

enforcement, especially within this context. The active constituents in the plant are

documented to be a substitute for opioids. As documented, kratom, which contains the

main active alkaloids mitragynine and 7-hydroxymitragynine, has emerged on the recreational drug market. Over 40 different constituents have been isolated from kratom

(EMCDDA, 2012, Gogineni et al., 2014), but it is the only known species of Mitragyna to contain mitragynine and 7-hydroxymitragynine (Chan, 2005, EMCDDA, 2012, Cinosi et al., 2015). Mitragynine and 7-hydroxymitragynine are the main active constituents of kratom and responsible for its psychoactive effects (Warner et al., 2016).

Kratom products, which contain the main active alkaloids mitragynine and 7- hydroxymitragynine, are often marketed as “legal highs” and labeled ‘not for human consumption’ (Gibbons, 2012). These products are readily available over the Internet or in head/smoke shops in the form of powders, tablets, capsules, resin, extracts, or crushed leaves. As reported by law enforcement and public health officials, the availability and abuse of kratom has dramatically increased in the United States. Between February 2014

and February 2016, over 55, 000 kilograms (kg) of dried kratom leaves and powder have

been encountered at several ports of entry within the United States.1 Law enforcement

has encountered these products being falsely identified at ports of entry. These false

importations include mislabeling as cosmetics, fertilizer, soaps, or dietary supplements.2

This is similar to other attempts to import controlled substances or substances intended to

mimic controlled substances. The large influx of kratom into the United States highlights

the growing demand for and widespread availability of this product and opioids on the

recreational drug market.

Kratom, which contains the main active alkaloids mitragynine and 7-

hydroxymitragynine, is documented to produce adverse health effects in humans to

include hepatotoxicity, seizure, coma, psychosis, agitation or irritability, dizziness,

insomnia, tachycardia, vomiting, poor concentration, and hallucinations (Grewal, 1932b,

Suwanlert, 1975, Nelsen et al., 2010, Forrester et al., 2013, Kapp et al., 2011, Galbis-

Reig et al., 2016, Singh et al., 2015, Anwar et al., 2016). Similar to the chronic abuse of

opioids, addiction or dependence and withdrawal have been documented with long-term,

regular use of kratom (Thuan, 1957, Suwanlert, 1975, Assanangkornchai et al., 2007a,

Boyer et al., 2008, McWhirter and Morris, 2010, Vicknasingam et al., 2010, Sheleg and

Collins, 2011, Ahmad and Aziz, 2012, Saingam et al., 2012, Saingam et al., 2014, Singh

et al., 2014, Singh et al., 2015, Galbis-Reig, 2016). Also, there are documented reports of

hospitalizations/emergency room visits and deaths involving the use of kratom (see factor

1 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR 20.85) dated August 4, 2016. Represents Customs and Border Patrol (CBP) seizures from February 2014 through July 2016. 2 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR 20.85) dated August 4, 2016.

6) (Nelsen et al., 2010, Holler et al., 2011, Kapp et al., 2011, Kronstrand et al., 2011,

CSAT, 2013, Neerman et al., 2013, Karinen et al., 2014, McIntyre et al., 2014,

Autopsy/Toxicology reports3).

With no approved medical use and limited safety or toxicological information,

kratom, which contains the main active alkaloids mitragynine and 7-hydroxymitragynine, has emerged on the recreational drug market and is being abused for its opioid-like properties. In a letter dated May 18, 2016, the Department of Health and Human

Services (HHS), stated that there are currently no approved new drug applications or investigational new drug applications for mitragynine and 7-hydroxymitragynine.

Therefore, to avoid an imminent hazard to the public safety, the DEA is initiating an expedited action to temporarily place mitragynine and 7-hydroxymitragynine in schedule

I of the Controlled Substances Act (CSA). With respect to finding an imminent hazard to

the public safety, the DEA has considered the three factors required under the CSA for

the temporary scheduling of mitragynine and 7-hydroxymitragynine. 21 U.S.C.

811(h)(3) and 811(c) (4)–(6): the substance’s history and current pattern of abuse; the scope, duration and significance of abuse; and what, if any, risk there is to the public health. 21 U.S.C. 811(h)(3). Consideration of these factors includes actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution. 21 U.S.C. 811(h)(3).

General Information about mitragynine and 7-hydroxymitragynine

Mitragynine (Figure 1) was first reported in the scientific literature in 1921 (Field, 1921)

when it was identified as an alkaloid of kratom, and its chemical structure was fully

3 Autopsy/Medical Examiner (ME) reports on file with DEA.

elucidated by Joshi et al. (1963) and Zacharias et al. (1965). 7-Hydroxymitragynine

(Figure 1) was first identified in the scientific literature by Ponglux et al. (Ponglux et al.,

1994) as a minor alkaloid constituent of kratom.

O O OH

N N N N H H H CH3 CH3

O O O O

O O

Mitragynine 7-Hydroxymitragynine

Figure 1. Chemical Structures of Mitragynine and 7-Hydroxymitragynine

Mitragynine is an indole alkaloid with a methoxy group substitution at the 8-

position. The indole moiety is fused to a substituted quinolizine ring. The quinolizine

ring is substituted with an ethyl group at the 3-position and a methyl β-methoxyacrylyl

group at the 2-position (Zacharias et al., 1965, Benchikh et al., 2014). The chemical structure of 7-hydroxymitragynine is the same as mitragynine, with the addition of a

hydroxyl group at the 7α-position (Ponglux et al., 1994). The chemical structures of

these substances are unlike those of other known opioid ligands; however, a protonatable

nitrogen is conserved amongst these substances and classic opioids (Adkins et al., 2011).

Similar to other opioids, such as morphine, mitragynine and 7-

hydroxymitragynine have been shown to bind to the opioid receptors, with the highest

affinity at the µ-opioid receptor (Takayama et al., 2002, Matsumoto et al., 2004, DEA-

VA, 2015). Some of these results are presented in Table 1.

Table 1. Opioid Receptor Binding of Mitragynine and 7-Hydroxymitragynine

Compound Mu Delta Kappa Name [3H]DAMGO (nM) [3H]DPDPE (nM) [3H]U69,593 (nM) 7.24a 60.2a 1096a Mitragynine 39.4b 2270b 560b

13.4a 154.9a 123.0a 7-Hydroxymitragynine 9.77c 144.5c 194.8c

aTakayama et al., 2002. Binding affinities were originally reported as the pKi. However, for purposes of this document, pKi values were converted to Ki values for ease of comprehension and consistency among all data reported. bDEA-VA, 2015. Binding affinities reported as the Ki. c Matsumoto et al., 2004. Binding affinities were originally reported as the pKi. However, for purposes of this document, pKi values were converted to Ki values for ease of comprehension and consistency among all data reported.

The analgesic effects of mitragynine have been evaluated in hot plate and tail-

pinch tests, which are common pharmacological tests of analgesia (Macko et al., 1972,

Matsumoto et al., 1996a, Matsumoto et al., 1996b, Thongpradichote et al., 1998,

Shamima et al., 2012, Carpenter et al., 2016). One study reported that intraperitoneal

administration of mitragynine (35 mg/kg) increased the pain threshold in hot plate test,

and its effects were inhibited by naloxone (1 mg/kg), which is an opioid receptor

antagonist (Shamima et al., 2012). These results suggest that the opioid receptors are

involved in the analgesic effects of mitragynine. Studies have also evaluated

mitragynine’s effects on the noradrenergic and serotonergic systems and calcium

channels (Matsumoto et al., 1996a, Tohda et al., 1997, Matsumoto et al., 2005b).

7-Hydroxymitragynine has also been reported to produce analgesia when evaluated

in in vivo pharmacological studies. These effects are reported to be caused by its actions on opioid receptors (Matsumoto et al., 2004, Takayama et al., 2004, Matsumoto et al.,

2005a, Matsumoto et al., 2006). For example, Matsumoto et al. (2006) reported that when 7-hydroxymitragynine was administered subcutaneously (s.c.) in mice, there was an increase in the pain threshold for both the tail-flick (ED50 = 0.80 mg/kg) and hot plate

(ED50 = 0.93 mg/kg) tests, and its effects were inhibited by naloxone (Matsumoto et al.,

2006, Matsumoto and Horie, 2014). Comparatively, the ED50 of morphine (s.c.) in tail-

flick and hot-plate tests are 4.57 mg/kg and 4.08 mg/kg, respectively (Matsumoto et al.,

2006; Matsumoto and Horie, 2014).

Several studies have investigated the abuse potential and rewarding effects of 7-

hydroxymitragynine, kratom (extract and fraction), or mitragynine using conditioned place preference and drug discrimination studies. Studies reported that administration of

7-hydroxymitragynine (2 mg/kg) (Matsumoto et al., 2008) and mitragynine (5, 10, and 30 mg/kg) (Sufka et al., 2014, Yusoff et al., 2014) to rats induced place preference.

Additionally, one study showed that mitragynine (15 mg/kg) and 7-hydroxymitragynine

(3.0 mg/kg) fully substituted for morphine in a drug discrimination study in rats (Harun et al., 2015). Pretreatment with naloxone (0.3 mg/kg) resulted in full reversal of morphine substitution for 7-hydroxymitragynine and partial reversal for mitragynine. These studies suggest that mitragynine and 7-hydroxymitragynine have abuse potential and produce rewarding effects similar to other opioids, including morphine.

Factor 4. History and Current Pattern of Abuse

Kratom, which contains the main active alkaloids mitragynine and 7- hydroxymitragynine, has a long history of use in Southeast Asia as an opium substitute

(Wray, 1907, Burkhill, 1930). Kratom is also known in Southeast Asia as thang, thom, krathom, kakuam, ketum, and biak (Aziz, 2014, Cinosi et al., 2015). In recent years, the presence of the psychoactive plant kratom has increased dramatically on the recreational drug market due to its opioid-like effects (Takayama et al., 2004, Babu et al., 2008,

Hassan et al., 2013; Prozialeck et al., 2012; Cinosi et al., 2015; Dorman et al., 2015).

Numerous vendors selling kratom have appeared in the past few years, markedly increasing its availability. Additionally, in the United States, there have also been large encounters of kratom powder and dried leaves by law enforcement, substantiating the high demand for this product.

Kratom preparations, which contain the main active alkaloids mitragynine and 7- hydroxymitragynine, are easily obtained from smoke shops, and the Internet (Hillebrand et al., 2010, Schmidt et al., 2011, Gibbons, 2012, Van Hout, 2014, Dorman et al., 2015).

The Internet is the most utilized source for the purchase of kratom products, making kratom just “a click” away for users (Cinosi et al., 2015, Warner et al., 2016). These products are sold as crushed or powdered leaves, resins, capsules, tinctures, and extracts

(Scott et al., 2014, Cinosi et al., 2015). In Europe kratom is one of the most popular new psychoactive substances sold via the Internet (EMCDDA, 2012, Oliveira et al., 2016), and it is one of the most seized plant-based substances reported by several countries internationally (UNODC, 2013a). In the United States, law enforcement has identified

kratom and/or mitragynine products in the following forms: powder/plant, powder, plant

or vegetable material, capsules, tablets, liquids, gum/resin, and drug patch.

Since abusers obtain kratom, which contains the main active alkaloids mitragynine

and 7-hydroxymitragyine, through unknown sources, the identity, purity, and quantity of

these substances are uncertain and inconsistent, thus posing significant adverse health

risks to users (Oliveira et al., 2016). Several studies have analyzed the concentrations of

mitragynine4 and/or 7-hydroxymitragyine5 in different kratom products (Kikura-Hanajiri

et al., 2009, Scott et al., 2014, Oliveira et al., 2016). The studies showed that there were

inconsistencies in the levels of the opioid mitragynine present in similar kratom products,

and some products contained other psychoactive substances (Scott et al., 2014, Oliveira

et al., 2016). For example, the analyses of a set of kratom products consisting of

shredded and powdered leaves showed a mitragynine content (0.640 to 3.04 mg/g) that

was much lower than the mitragynine content (0.8 to 21.4 mg/g) of a similarly marketed

group of products (Kikura-Hanajiri et al., 2009, Oliveira et al., 2016). Also, the analyses

of several kratom “powered” extract products showed that the potency (“power”)

described on the packaging (15x and 25x) did not match the concentration of mitragynine

(15x product: 4.30 mg/g; 15x product: 2.66 mg/g; 25x product: 2.70 mg/g) in the

products (Oliveira et al., 2016). Based on the variability of the mitragynine concentration

4 Mitragynine is the most abundant alkaloid in kratom and constitutes about 66 percent of the total alkaloid content of the plant according to Ponglux et al (1994). The alkaloid content of mitragynine was 45 percent of all alkaloids detected in analyses performed by Oliveira et al (2014). Such large relative differences in proportions of plant alkaloids (66%:45%) are common among plant species and will lead to variations in potency and the risk of overdose. 5 7-Hydroxymitragynine is a more potent opioid agonist than mitragynine although it only comprises about 1.6 percent of the total alkaloid content of the plant (Ponglux et al., 1994, Matsumoto et al., 2006). The alkaloid content of 7-hydroxymitragynine was 4 percent of all alkaloids detected in analyses performed by Oliveira et al (2014). Such large relative differences in proportions of plant alkaloids (4.0%:1.6%) are common among plant species and will lead to variations in potency and the risk of overdose.

9 in each product, users may experience differing effects when consuming similar amounts of different products (Scott et al., 2014).

Evidence suggests that kratom, which contains the main active alkaloids mitragynine and 7-hydroxymitragynine, is abused individually, and with other psychoactive substances ( Arndt et al., 2011, Kronstrand et al., 2011, Tanguay, 2011, Van Hout, 2014,

Anwar et al., 2016). In a 2016 publication, the Centers for Disease Control (CDC) characterized kratom exposures reported to poison centers and uploaded to the National

Poison Data System (NPDS)6 from January 2010 through December 2015 (Anwar et al.,

2016). During the stated timeframe, U.S. poison centers received 660 calls related to kratom exposure. Of the calls reported, 487 (73.8%) reported intentional exposure to kratom, and 595 (90.2%) reported ingestion of the drug. In addition to reports of isolated exposures to kratom (428 (64.8%)), reports of kratom being used with other substances

(ethanol, benzodiazepines, narcotics, acetaminophen, and other botanicals) were also recorded. Additionally, forensic laboratory analyses of drug evidence have identified kratom/mitragynine, along with synthetic cannabinoids and synthetic opioids during the analyses of products seized on the illicit market (Forensic laboratory data, CDC/NIOSH,

2016). The consumption of kratom individually, or in conjunction with alcohol or other drugs is of serious concern as it can lead to severe adverse effects and death (McIntyre et al., 2014, Anwar et al., 2016).

Information from the published literature, poison control center data, and medical examiner data, suggests that kratom, which contains the main active alkaloids

6 The National Poison Data System (NPDS) is a national database of information logged by the country's regional poison centers serving all 50 United States, Puerto Rico and the District of Columbia. The NPDS is maintained by the American Association of Poison Control Centers. NPDS case records are the result of call reports made by users (i.e., self-reports), friends and family members, and health care providers.

mitragynine and 7-hydroxymitragynine, is abused by a diverse population to include

recreational opioid users, young adults, and adults (Boyer et al., 2008, Forrester, 2013,

Saingam et al., 2012, Saingam et al., 2014, Singh et al., 2014, Anwar et al., 2016,

Autopsy/Medical Examiner Reports). Kratom exposures reported to the Texas Poison

Center Network and the NPDS from 2009 to 2015 involved mostly young adults (aged in

their 20’s, or reported as a mean age of 28 years old) and the majority of patients were

males (Forrester, 2013; Anwar et al., 2016).

Kratom does not have an approved medical use in the United States and has not been

studied as a treatment agent in the United States. Kratom has a history of being used as

an opium substitute in Southeast Asia, and in folk medicine to treat common medical

problems, as noted in the scientific literature (Wray, 1907, Burkhill, 1930, Suwanlert,

1975). Recent literature notes, kratom has also been used to self-treat chronic pain and withdrawal symptoms from opioid misuse and dependence (Boyer et al., 2007, Boyer et al., 2008, Vicknasingam et al., 2010, Ahmad and Aziz, 2012, Hassan et al., 2013, Singh et al., 2014, 2015). Especially concerning, reports note users have turned to kratom as a replacement for other opioids, such as heroin (Vicknasingam et al., 2010, Neerman et al.,

2013, Singh et al., 2014).

In the United States, the misuse and abuse of kratom has mimicked some of the uses reported in the scientific literature. Kratom is misused to self-treat chronic pain and to self-treat opioid withdrawal symptoms, with users reporting its effects to be comparable to prescription opioids (Cinosi et al., 2015, Erowid and Erowid, 2014). Users7 have also

7 Drug user information from the Internet has not been proven scientifically, and the purported substances used have not been substantiated. This information is only presented to demonstrate the purported use of these substances.

reported dose-dependent psychoactive effects to include euphoria, simultaneous

stimulation and relaxation, analgesia, vivid dreams, and sedation (at higher doses)

(Erowid and Erowid, 2014, Swogger et al., 2015). As noted in the actions by the United

States Food and Drug Administration,8 kratom products have been encountered with false

claims, an extremely concerning issue for public health and safety. These products are

marketed to be safe for self-medication (Cinosi et al., 2015), but have not been approved

by the United States Food and Drug Administration for any medical uses.

The most commonly described route of administration of kratom, which contains the main active alkaloids mitragynine and 7-hydroxymitragynine, is oral. The leaves are typically brewed and ingested as a tea; however, smoking, chewing the raw leaves (done traditionally), and ingestion of kratom capsules or resin extracts have also been described

(Marcan, 1929, Grewal, 1932b, Macmillan, 1991, Ahmad and Aziz, 2012, Erowid and

Erowid, 2014, Singh et al., 2014, Rech et al., 2015).

Factor 5. Scope, Duration and Significance of Abuse

The abuse of kratom, containing the main active alkaloids mitragynine and 7- hydroxymitragynine, is increasing in the United States and remains extremely concerning for law enforcement and public health (Anwar et al., 2016, FDA 2016a,c). There is growing concern over the abuse of the drug, its effects and safety of its use. As the abuse of the plant increases, as demonstrated by the increasing availability per border

8 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR 20.85) dated August 4, 2016.

encounters,9 it has been noted that physicians should be aware of kratom’s adverse health

effects, toxicity, dependence, and withdrawal (Galbis-Reig, 2016). Reports from law enforcement indicate that kratom is being imported for widespread distribution to the public within the United States.10 Between February 2014 and July 2016, over 55,000 kilograms (kg) of kratom material were encountered at various ports of entry within the

United States (that have been detected by law enforcement).11 Since the plant is often

smuggled and falsely manifested for importation, the amount that is being imported is

presumed to be greater. The quantities of kratom seized by CBP are as follows: 13,349

kg in 2014; 5,054 kg in 2015; and 36,841 kg in 2016.12 Additionally, over 57,000 kg of

kratom material offered for import at numerous ports of entry, between 2014 and 2016,

are awaiting an FDA admissibility decision.13 The amount of kratom currently seized or

awaiting an admissibility decision, by law enforcement, from 2014 to 2016, is enough to

produce over 12 million doses of kratom.14 Such alarming quantities create an imminent

public health and safety threat.

The FDA has reported an increase in the number of shipments of dietary supplements

and bulk dietary ingredients that are, or contain kratom. In 2014 and 2016, the FDA

requested the seizure, by US Marshals, of more than 25,000 pounds of raw kratom

9 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR20.85) dated August 4, 2016. 10 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR20.85) dated August 4, 2016. Represents Customs and Border Patrol (CBP) seizures from February 2014 through July 2016. 11 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR 20.85) dated August 4, 2016. 12 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR20.85) dated August 4, 2016. Represents Customs and Border Patrol (CBP) seizures from February 2014 through July 2016. 13 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR 20.85) dated August 4, 2016. 14 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR 20.85) dated August 4, 2016. Assuming a high dose of 9 g of kratom.

material and nearly 90,000 bottles of dietary supplements labeled as containing kratom ,

respectively (FDA 2014a, 2016a). The FDA stated that kratom products “pose a risk to

the public health and have the potential for abuse” and the seizure of certain kratom products was necessary “to safeguard the public from a dangerous product” (FDA,

2014a). Most recently, in August 2016, the FDA reported the seizure, by U.S. Marshals,

of more than 100 cases of products labeled as kratom (FDA, 2016c). The FDA has

warned the public not to use any products labeled as containing kratom due to serious

concerns about toxicity and potential health impacts (FDA, 2016c). To further protect

the public health and safety from the large influx of kratom materials, the FDA issued

and updated two import alerts (FDA, 2014b, 2016b) related to numerous kratom and kratom-containing products. These import alerts allow for detention without physical examination of dietary supplements and bulk ingredients that are or contain kratom, and detention without physical examination of unapproved new drugs promoted in the United

States that make false health claims, which includes kratom products. Since 2014, 121 firms have been added to these import alerts for importing kratom products.15

Drug reports pertaining to the trafficking, distribution, and abuse of

kratom/mitragynine were analyzed by Federal, State, and local forensic laboratories.16

Prior to October 1, 2014, the System to Retrieve Information from Drug Evidence

(STRIDE) collected the results of drug evidence analyzed at DEA laboratories, which were submitted by the DEA, other Federal law enforcement agencies, and some local law enforcement agencies. STRIDE data were queried through September 30, 2014, by date

15 2015-CDER-DEA Memorandum of Understanding for sharing information (Provided under 21 CFR 20.85) dated August 4, 2016. 16 While law enforcement data is not direct evidence of abuse, it can lead to an inference that a drug has been diverted and abused.

submitted to DEA forensic laboratories. Since October 1, 2014, STARLiMS (a web-

based, commercial laboratory information management system) has replaced STRIDE as the DEA laboratory drug evidence data system of record. DEA laboratory data submitted after September 30, 2014, are reposited in STARLiMS. Data from STRIDE and

STARLiMS were queried on April 24, 2016. The National Forensic Laboratory

Information System (NFLIS) is a program of the DEA that collects drug identification results from drug cases analyzed by other Federal, State, and local forensic laboratories.

NFLIS reports from other Federal, State, and local forensic laboratories were queried on

July 26, 2016.17

According to data from STRIDE and STARLiMS, between January 2006 and March

2016, there were 293 records for kratom and/or mitragynine.18 From January 2010

through May 2016, NFLIS registered 720 reports containing mitragynine. Specifically,

in 2006 there was one report from one state related to these substances in the NFLIS and

STRIDE/STARLiMS databases;19 in 2009,20 there were four reports from one state; in

2010, there were two reports from two states; in 2011 there were 62 reports from 12

states; in 2012 there were 279 reports from 35 states; in 2013, there were 315 reports

from 24 states; in 2014, there were 135 reports from 27 states; in 2015, there were 174

reports from 29 states; and in 2016, there were 41 reports from 14 states. NFLIS and

STRIDE/STARLiMS reports for kratom and/or mitragynine21 were reported across 43

17 Data are still being reported for March –May 2016, due to normal lag time for laboratories to report to NFLIS. 18 Mitragynine is used to confirmatively identify plant material as kratom. 19 Report for 2006 represents reports found in STRIDE only. There are no reports for kratom/mitragynine in NFLIS prior to 2010. 20 There were no reports of kratom/mitragynine in NFLIS or STRIDE from 2007 through 2008. 21 STRIDE, STARLiMS, and NFLIS data reflect data reported by the forensic laboratory systems. Encounters reported in these systems, and the overall number of seizures, may be low because

states (see Appendix 1). The identification of these substances during drug evidence

analyses indicates the availability and abuse of these substances on the recreational drug market.

The growing concern over kratom’s use is reflected in the increased requests for analyses of mitragynine and 7-hydroxymitragynine in human toxicology panels

(blood/urine samples)22 to private analytical laboratories.23 These analyses have been

requested by addiction treatment facilities/pain management doctors, drug courts,

medical examiner/coroner offices, drug testing facilities, state laboratory systems, state

police department, and private entities.24 One laboratory25 reported 31 positive results

from August 2012 to July 2013 for mitragynine and/or 7-hydroxymitragynine. The

second laboratory26 reported 274 positive results for mitragynine between July 2013 and

May 2014. Lastly, the third laboratory reported 555 positive results for mitragynine between December 2014 and March 2016.27 The increasing trend in the number of

positive results from these analyses demonstrates the growing abuse and popularity of

these substances and the concern related to the abuse of this plant material and its

psychoactive constituents.

kratom/mitragynine is not federally controlled under the CSA. Typically, after control, these numbers will increase. 22 The quantitative values for mitragynine and 7-hydroxy mitragynine were not available for all positive results shown. 23 Substances are tested as part of a toxicology panel that includes illicit or commonly abused substances routinely analyzed. 24 Email correspondences with analytical laboratories in Willow Grove, PA, Clearwater, FL, and Santa Rosa, CA. 25 Located in Willow Grove, PA, analyzed blood/urine samples from Canada and thirteen U.S. states. Correspondences on file with DEA. 26 Located in Clearwater, FL, analyzed urine samples from multiple states across the U.S. Correspondences on file with DEA. 27 Located in Santa Rosa, CA, analyzed urine samples from multiple states across the United States. Correspondences on file with DEA.

Evidence from poison control centers in the United States also shows that there is an increase in the number of individuals abusing kratom, which contains the main active

alkaloids mitragynine and 7-hydroxymitragynine. There has been a steady increase in the

reporting of kratom exposures by poison control centers. Early reporting by the

American Association of Poison Control Centers identified two exposures to kratom

between 2000 and 2005 (Babu et al., 2008). Additionally, the Texas Poison Center

Network (TPCN), which is comprised of six poison centers that service the State of

Texas, reported 14 exposures to kratom between January 2009 and September 2013

(Forrester, 2013). Between January 2010 and December 2015, U.S. poison centers

received 660 calls related to kratom exposure (Anwar et al. 2016). The number of

reported exposures significantly increased during this time, from 26 in 2010 to 263 in

2015. This represents a ten-fold increase in the number of calls received and indicates

the increased abuse and popularity of this substance.

The abuse and addictive properties of kratom, which contains the main active

alkaloids mitragynine and 7-hydroxymitragynine, have caused at least 15 countries to

pass laws and regulations on these substances (EMCDDA, 2012, Aziz, 2014, Ireland

Misuse of Drugs Act28). In the United States, 6 states and the District of Columbia have

banned kratom, mitragynine and/or 7-hydroxymitragynine and two states have placed

regulatory controls on kratom, mitragynine, and/or 7-hydroxymitragynine.29 Six other

28 Misuse of Drugs Act 1977 Order 2011 (S.I. No. 551/2011) (Ir.); Misuse of Drugs (Amendment Regulations 2011 (S.I. No. 552/2011) (Ir.). 29 Alabama—ALA. CODE § 20-2-23; Arkansas—ARK. ADMIN. CODE 007.07.2; District of Columbia—22-B DC ADC § 1201; Illinois—IL ST CH 720 § 642/5; Indiana—IC 35-31.5-2-321; Louisiana—LA R.S. 40:989.3; Tennessee—T.C.A. § 39-17-452; Vermont—VT. ADMIN. CODE 12-5-23:4.0; Wisconsin—W.S.A. 961.14.

States within the United States have proposed to ban or place regulatory controls on these

substances.30

Internationally, the increased presence and abuse of kratom, containing the main

active alkaloids mitragynine and 7-hydroxymitragynine, has garnered the attention of the

International Narcotics Control Board (INCB)31 (INCB, 2011). In a 2010 report, the

INCB noted the increased interest in the recreational use of kratom,32 and highlighted the

use of the Internet to educate potential users about kratom. The report also notes that any

impairing effects from the use of kratom might have serious consequences for the well- being of other persons, similar to driving under the influence of a psychoactive substance.

The INCB recommended that governments experiencing problems with persons trafficking or using kratom recreationally, which had not already controlled kratom and kratom preparations, should consider doing so at the national level where necessary.

Factor 6. What, if Any, Risk There Is to the Public Health

The use of kratom and associated products, which contain the main active alkaloids

mitragynine and 7-hydroxymitragine, pose an imminent hazard to public safety. These

substances produce opioid-like effects making their abuse a serious public health

concern. Information from published literature, public health officials, and poison

control center data demonstrate that the use of kratom, which contains the main active

30 New Hampshire—2015 NH S.B. 540 and 2015 NH S.B. 540; New Jersey—2016 NJ A.B. 3281; New York—2015 NY A.B. 9121, 2015 NY A.B. 9068, 2015 NY A.B. 8670, and 2015 NY S.B. 6345; North Carolina—2015 NC H.B. 747 (NS) and 2015 NC S.B. 830 (NS); Florida—2016 FL S.B. 1182 and 2016 FL H.B. 73; and Kentucky—2016 KY S.B. 136. 31 The INCB is an independent monitoring body that is responsible for evaluating the implementation of the United Nations international drug controls conventions. 32 Kratom was listed as a plant material containing psychoactive substances in the 2010 INCB report for which recommendations were made for specified plant materials.

18 alkaloids mitragynine and 7-hydroxymitragynine, has caused numerous adverse effects on users.

In a 2016 publication, the CDC characterized kratom exposures reported to poison centers and uploaded to the NPDS from January 2010 through December 2015 (Anwar et al., 2016). During the stated timeframe, U.S. poison centers received 660 calls related to kratom exposure.33 The medical outcomes associated with these exposures were characterized as minor, moderate, or major. These outcomes are shown in Table 2.

Table 2. Medical outcomes associated with kratom exposure reported to Poison Control Centers in the United States between January 2010 and December 2015.a Type of Outcome Number of Exposures Percentage of calls Minorb 162 24.5 Moderatec 275 41.7 Majord 49 7.4 Deathe 1 --- No effects or no 173 26.2 follow upf a Anwar et al., 2016. b Minor is defined as having minimal signs or symptoms that resolved rapidly with no residual disability. c Moderate is defined as having non-life threatening and no residual disability, but requiring some form of treatment. d Major is defined as having life-threatening signs or symptoms with some residual disability. e Death involved exposure to kratom as well as paroxetine and lamotrigine. f No effects were reported, or poison center staff were unable to follow up again regarding effects.

The study also reported several adverse effects related to kratom exposure, which include agitation or irritability (n= 157, 23.8%), tachychardia (165, 25.0%), nausea (97,

14.7%), drowsiness (128, 19.4%), and hypertension (77, 11.7%). Additionally, statistical analysis of the number of calls and reported outcomes showed a significant association between severe outcomes (moderate effects, major effects, and death) and exposure to kratom plus other substances, compared with non-severe outcomes (no effect and minor

33 Calls from healthcare providers comprised a large portion of calls received, representing 496 (75.2 %) of calls reported.

19 effect) (p<0.001). The severity of the reported outcomes, health effects, and increased use of kratom suggests an emerging public health threat (Anwar et al., 2016).

Information from the scientific literature also demonstrates the health risks associated with kratom use. Reports of hepatotoxicity, psychosis, seizure, weight loss, insomnia, tachycardia, vomiting, poor concentration, hallucinations, and death associated with kratom use have been documented (Suwanlert, 1975, Boyer et al., 2008, Roche et al.,

2008, Nelsen et al., 2010, Kapp et al., 2011, Ahmad and Aziz, 2012, Forrester, 2013,

Trakulsrichai et al., 2013, Singh et al., 2015, Dorman et al., 2015, McIntyre et al., 2014).

Additionally, published case reports describe events where individuals sought medical care for the purported use of kratom (Roche et al., 2008, Nelsen et al., 2010, Kapp et al.,

2011, CSAT, 2013, Dorman et al., 2015). Some examples of the reported adverse events involving kratom are described below.

• A case report by Nelson et al. (2010), reported a case of a 64 year-old male who

presented to the emergency department (ED) after ingesting a tea made with

kratom and Datura stramonium.. The patient suffered a seizure at home after

drinking the tea and was unresponsive upon arrival at the ED. The patient

suffered a second seizure while in the ED and was intubated to protect his airway.

Approximately 30 hours after initial admittance, he was extubated. Laboratory

analyses confirmed mitragynine in urine samples. History of the patient revealed

that he self-treated pain and depression with amitriptyline, oxycodone, and

kratom.

• A case report by Kapp et al. (2011), reported a 25 year-old male admitted to the

hospital in Germany with jaundice and pruritus 10 days after ceasing to consume

kratom powder (“Thai Pimp” and “Malaysian Green”) daily (he took increasingly

larger doses for two weeks). Further analyses of the liver (2 days after

admittance) led to a diagnosis of canalicular cholestasis. Laboratory results

confirmed the presence of mitragynine in blood and urine samples approximately

12-14 days after supposed cessation of use of kratom.

• A case report by Dorman et al. (2015), reported a 58 year-old man admitted to the

hospital for jaundice and liver injury suspected to be resulting from kratom use.

One year prior, the patient developed jaundice after taking kratom (“pure maeng

da kratom leaf”) daily for 3 months. The patient had restarted taking kratom daily

one month prior to his most recent admittance. Laboratory confirmation was not

available, though patient had history of jaundice presentation while taking kratom.

Numerous deaths associated with kratom, which contains the main active constituents mitragynine and 7-hydroxymitragynine, have been reported indicating that this substance is a serious public health threat. In 2016, DEA received correspondences from public/state officials indicating that there have been a significant number of overdoses and traffic fatalities directly, or indirectly, involving kratom.34 Deaths related to kratom exposure have been reported in the scientific literature beginning in 2009-2010, with a cluster of nine deaths in Sweden from use the kratom product “Krypton’ (Kronstrand et al, 2011). Since then, five more deaths related to kratom exposure were reported in the scientific literature (Holler et al., 2011, Neerman et al., 2013, Karinen et al., 2014,

McIntyre, 2014, Anwar et al., 2016), and at least 16 additional deaths connected to kratom exposure, have been confirmed by autopsy/medical examiner reports

34 Correspondence on file with DEA (dated April 19, 2016).

(mitragynine and/or 7-hydroxymitragynine were identified in biological samples).35 Of these deaths, 15 occurred between 2014 and 2016. This information further demonstrates the severe risks associated with kratom misuse and highlights the increasing occurrence of fatal outcomes related to kratom exposure. Details of some of these events are summarized below.

• A paper by Kronstrand et al. (2011), reported nine deaths (7 males, 2 females;

ages 22 to 33 year-old) in Sweden occurring late 2009 to early 2010 after

suspected ingestion of the kratom product ‘Krypton’. Laboratory analyses

identified mitragynine and O-desmethyltramadol (known substances in Krypton

blend) and other substances in blood samples. The cause of death was deemed

accidental drug intoxication in all cases.

• A case report by Neerman et al. (2013), reported the death of a 17-year-old male.

The decedent was found unresponsive in bed with no obvious signs of trauma.

He was pronounced dead at the scene. The decedent had reportedly taken a liquid

kratom product the night before. A ziplock bag of the decedent’s medications and

a box of “Bali Kratom” were found at the scene. The decedent had a history of

self-medicating with kratom. Laboratory analyses identified mitragynine and

therapeutic levels of dextromethorphan, temazepam, 7-amino-clonazepam, and a

slightly elevated level of diphenhydramine in blood samples. The cause of death

was determined by the Medical Examiner as “possible Kratom toxicity”.

• A case report by Karinen et al. (2014), reported the death of a middle-aged man in

Norway. The decedent was found dead in his bed. He had been using kratom to

35 Autopsy/Medical Examiner (ME) reports on file with DEA.

avoid “positive” results on drug tests. Family described him as “unwell” and

“clearly intoxicated” the afternoon prior to his death. Laboratory identified

mitragynine and 7-hydroxymitragynine, zipiclone, citalopram, and lamotrigine in

blood samples. The cause of death was deemed to be intoxication with “Kratom”,

possibly in combination with other substances detected.

• A case report by McIntyre et al. (2014), reported the death of a 24 year-old man.

The decedent was found unresponsive in bed. Resuscitation efforts were

unsuccessful and he was pronounced dead. He was described as being “out of it”,

tired and depressed the night before his death, and took a “sleeping pill” before

bed. Prescription bottles of mirtazapine, omeprazole, and a single capsule of

loperamide were found with his possessions. Laboratory analyses identified

mitragynine, along with therapeutic levels of venlafaxine, diphenhydramine,

mirtazapine, and ethanol. The cause of death, as determined by the Medical

Examiner’s Office, was mixed drug intoxication—primarily mitragynine.

• In 2013, a 36 year-old man in Denver, CO, was transported to the hospital after he

apparently suffered a seizure. He was pronounced brain dead 3 days later at the

hospital. Analysis of the suspected mitragynine drug product (“da pimp bomb”)

only identified mitragynine. Laboratory analyses of blood samples identified

mitragynine and 7-hydroxymitragynine. The cause of death, as determined by the

Medical Examiner, was severe hypoxic encephalopathy complicating apparent

mitragynine toxicity.

• In 2014, a 29-year old male in Palm Beach FL, was found unresponsive on the

floor of his closet. He was reported to take a Kratom extract. Laboratory

analyses of blood samples identified mitragynine along with venlafaxine,

fentanyl, amphetamine, and caffeine. The cause of death, as determined by the

Medical Examiner, was multiple drug toxicity.

• In 2015, a 27-year old male in Dekalb County, GA, was found lifeless on his

kitchen floor. He was pronounced dead at the scene. A clear plastic baggie

containing a green leafy substance (consistent with Marijuana) and a prescription

bottle labeled as Indomethacin were found at the scene. The decedent had a

history of opioid abuse and was recently hospitalized for an overdose. Laboratory

analyses of blood samples identified the presence of mitragynine, along with

fentanyl, benzodiazepines, and cannabinoids. The cause of death, as determined

by the Medical Examiner, was intoxication with fentanyl and mitragynine.

• In 2015, a 22-year old male in San Diego, CA, was found unresponsive and not

breathing in bed. Life-saving efforts were unsuccessful and he was pronounced

dead at the scene. A plastic bag filled with packaged syringes, two empty plastic

containers marked “Royal Kratom” and “Maeng Da”, empty packets of “Prop

100” and “Tren 100”, an empty vial of injectable testosterone, marijuana wrapped

in cellophane, and half of a Xanax tablet were found at the scene. An unlabeled

bottle with pink liquid was found in his car. Laboratory analyses of blood

samples identified the presence of mitragynine, along with methadone and

alprazolam. The cause of death, as determined by the Medical Examiner, was

mixed mitragynine, methadone, and alprazolam intoxication.

• In 2015, a 45-year old male in San Diego, CA, was found unresponsive on his

bathroom floor, with obvious signs of decomposition. Medications, capsules

filled with a green substance, and a plastic bag filled with a green-colored,

powdery substance were found at the home. Laboratory analyses of blood

samples identified mitragynine and ethanol (may be due to decomposition). The

cause of death, as determined by the Medical Examiner, was acute mitragynine

(Kratom) intoxication. The amount of mitragynine found in the liver was 200

times more than reported by McIntyre, et al. (2014), where mitragynine

intoxication was determined to be the primary cause of death.

• In 2015, a 31-year old male from San Diego, CA, was found not breathing on his

couch. Advanced cardiac life support was initiated, but was unsuccessful. He

was pronounced dead. He drank alcohol and took Xanax the night before his

death. He was described as lethargic and having slurred speech. Laboratory

analyses of blood samples identified the presence of mitragynine, fentanyl,

alprazolam, and an active clonazepam metabolite. The cause of death, as

determined by the Medical Examiner, was acute mitragynine, clonazepam,

alprazolam, and fentanyl intoxication.

• In 2015, a 23-year old male in San Diego, CA, was found dead on the floor and

was pronounced dead by first responders. He drank alcohol, smoked heroin, and

ingested Xanax and Narco the night before his death. He was described as being

intoxicated and stumbled when he walked. Laboratory analyses of blood samples

identified the presence of mitragynine, along with alcohol, benzodiazepines, and

opiates. The cause of death, as determined by the Medical Examiner, was

mitragynine, benzodiazepines, heroin, and alcohol intoxications.

• In 2016, a 56-year old man was found with a self-inflicted gunshot wound to the

head. He was pronounced dead at the scene. A suicide note was found at the

scene. The decedent had a history of alcohol and drug abuse. Laboratory

analyses identified mitragynine and caffeine in blood samples. The cause of

death, as determined by the Medical Examiner, was gunshot wound of head.

• In 2016, a 25-year-old male in Golden, CO was found unresponsive in bed and

declared dead at the scene. Syringes, spoons and plastic bags containing kratom

products (“Green Malaysian”, “Yellow Vein Maeng Da”, and “Red Borneo”), and

vials labeled U-47700 were found at the scene. Laboratory analyses of blood

samples identified the presence of mitragynine and the opioid antagonist

naloxone. The cause of death, as determined by the Medical Examiner, was

probable polypharmacy overdose.

Since abusers obtain kratom, which contains the main active alkaloids mitragynine and 7-hydroxymitragyine, through unknown sources, the identity, purity, and quantity of these substances are uncertain and inconsistent, thus posing significant adverse health risks to users (Oliveira et al., 2016). According to the FDA, in a letter dated May 18,

2016, there are no approved new drug applications, or investigational new drug applications for mitragynine or 7-hydroxymitragynine. As such, kratom products have no accepted medical use within the United States. Despite the FDA warnings, kratom products continue to be easily available and abused by diverse populations. Distributors of kratom are knowingly putting the public at risk. Unknown factors including detailed product analysis and dosage variations between various packages present a significant danger to an abusing individual (Scott et al., 2014, Oliveira et al., 2016). With no

26 approved medical use, the abuse of kratom, which contains the main active alkaloids mitragynine and 7-hydroxymitragynine, poses an imminent hazard to the public safety

(Nelsen et al., 2010, Neerman et al., 2013).

Conclusion of 3-Factor Analysis

In accordance with 21 U.S.C. 811(h)(3), after a careful review of Factors 4, 5, and 6 of

21 U.S.C. 811(c), including the scientific literature, STRIDE, STARLiMS, NFLIS, and other law enforcement data and other sources of information, it is evident that kratom is trafficked and abused for its opioid-like effects. As such, mitragynine and 7- hydroxymitragynine, which are responsible for the plant’s opioid-like effects, pose an imminent hazard to the public safety.

The 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 mitragynine and 7- hydroxymitragynine indicate that mitragynine and 7-hydroxymitragynine, including their isomers, esters, ethers, salts, and salts of isomers, esters, and ethers, pose an imminent hazard to the public safety and health, have a high potential for abuse, have no currently accepted medical use in treatment in the United States, and lack accepted safety for use under medical supervision.

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Appendix 1

States Where Encounters of Kratom and/or Mitragynine Occurred1

Alabama Illinois Mississippi Oregon Alaska Iowa North Carolina Pennsylvania Arizona Indiana North Dakota South Carolina Arkansas Kansas Nebraska Tennessee California Kentucky New Hampshire Texas Colorado Louisiana New Mexico Utah Connecticut Massachusetts New Jersey Virginia Florida Maryland New York Washington Georgia Maine Nevada Wisconsin Hawaii Minnesota Ohio West Virginia Idaho Missouri Oklahoma 1Substances encountered were analyzed by other Federal, State, and local forensic laboratories. Data sources: NFLIS (queried on 07-26-2016 by submission date for Jan 2010–May 2016.), STRIDE, and STARLiMS (queried on 07-26-2016 by submission date for Jan 2006–May 2016).