U.S. Department of Justice Drug Enforcement Administration 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 2 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. 3 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. 4 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. 5 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). 6 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.