Comments on Kratom and Mitragynine National Drugs and Poisons Schedule Committee (Australia) Meeting 39, Oct 2003 13.4 MITRAGYNINE PURPOSE The Committee considered the foreshadowed inclusion of mitragynine and Mitragyna speciosa in Schedule 9 of the SUSDP. Mitragynine (also known as Kratom) is one of the alkaloids found in the leaves of the South-East Asian tree Mitragyna speciosa, which is used extensively in Thailand to increase work output and tolerance of direct sunlight. Mitragynine has psychoactive properties and has been associated with being used as an opium substitute. Kratom leaves are usually chewed, smoked or drunk as tea to achieve the desired affect. Mitragyna speciosa is regulated in the same way as cocaine and heroin in Thailand and carries the same restrictions and penalties as cocaine. There have also been reports of use of mitragynine in Malaysia. Poisindex indicates that in adults, a dose of 50 mg of pure mitragynine has produced motor excitement, rombergism, giddiness and tremors of the face, extremities and tongue. In 1975, a study of 30 Thai Kratom users considered chronic (more than 5 years use) noted that the leaves were chewed three times to 10 times a day, with stimulant effects occurring after five minutes to 10 minutes. The February 2003 Meeting considered preliminary information in relation to mitragynine and Mitragyna speciosa. This consideration was initiated by an inquiry to the TGA from an Australian resident wishing to import mitragynine and concern regarding its potential for abuse. Members discussed the pharmacology and toxicology of mitragynine, its potential for abuse, and the potential impact of its inclusion in the SUSDP. The Committee agreed that there were grounds for inclusion of mitragynine and Mitragyna speciosa in the SUSDP, based on mitragynine.s mode of action. To allow appropriate public consultation, the Committee agreed to foreshadow the inclusion of mitragynine and Mitragyna speciosa in Schedule 9 of the SUSDP, for consideration at the June 2003 meeting. The June 2003 Meeting noted the studies which showed that mitragynine exerted agonistic effects on opioid receptors in in-vitro studies as well as an antinociceptive action, which suggested that mitragynine has a morphine-like action on gastric acid secretion. A member pointed out that tramadol is a mu-opioid receptor agonist included in S4 and that it has a low potential for producing dependence. Members noted that the information from Poisindex (Micromedex Healthcare) indicated that addiction and withdrawal symptoms had occurred with chronic use of Mitragyna speciosa. The Committee subsequently agreed to defer further consideration of the foreshadowed decision on the view that additional information was required to better characterise the physiological effects and mechanisms of action of mitragynine. The Committee noted the advice received from XXXXXXXXXX stating that it had not seen conclusive evidence relating to abuse or misuse of Mitragyna speciosa or mitragynine. XXXXXXXXXX submitted that evidence on addiction and other harms seen with Mitragyna speciosa or mitragynine had been largely anecdotal, and in some instances contradictory. XXXXXXXXXX was of the view that given the range of psychoactive substances being advertised on internet web sites, the limited user base and the nature of use, it was unlikely that abuse of Mitragyna speciosa would become widespread in Australia. The Committee noted the literature review of pharmacological and toxicological data on mitragynine prepared by the Secretariat. Animal experiments with mitragynine had shown that it possessed pain threshold-elevating and antitussive properties. A series of pharmacological studies in animal models, in vivo and in vitro, indicated that similar to morphine, mitragynine and its derivatives produced central antinociception, inhibition of intrinsic activity or electrically elicited guinea pig ileum contraction and drug-induced gastric acid secretion, and inhibition of cAMP content. It was demonstrated in receptor binding studies that these effects were mediated by opioid receptors and that further studies also indicated that the pharmacological actions of mitragynine were selectively blocked by antagonists for some sub-types of opioid receptors, predominantly mu- and delta-receptor subtypes. (Matsumoto et al, Eur J Pharmacol 1996; Thongpradichote et al, Life Sciences 1998; Tohda et al, Biological & Pharmaceutical Bulletin 1997; Tsuchiya et al, Eur J Pharmacol 2002; Takayama et al, J Med Chem 2002; Yamanoto et al, General Pharmacol 1999). Based on available data, members noted that habitual users of mitragynine could develop marked withdrawal syndromes, including hostility, aggression, rhinitis, inability to work, excess tears, muscle and bone aches and jerky limb movement. Members concurred with the view that there was a strong possibility of addiction if mitragynine was used in doses high enough for mu-receptor crossover (1974-2003 Thomson Micromedex. Micromedex(R) Healthcare Series Vol. 115) and agreed to restrict the use of the substance. Members discussed whether similar restrictions should be imposed on the plant species, Mitragyna speciosa, in the light of reports that the leaves of the plant were being used for smoking and chewing, and the leaf extracts drank as tea, to achieve the .desired. effects. A member also raised the issue that there was a possibility that the plant was being used for ornamental purposes and that the Committee should defer confirmation of the foreshadowed decision to the next meeting to allow further information to be sought on this matter. DECISION 2003/39 – 23 The Committee agreed to take a pro-active approach and included mitragynine in Schedule 9 of the SUSDP based on its potential for abuse. The Committee recognised that whilst there were no widespread reports of abuse of mitragynine in Australia at this time, the information relating to the use of mitragynine for psychoactive effects, particularly in Asian countries, was well documented and easily found on the internet. Schedule 9 – New Entry MITRAGYNINE. The Committee agreed to consider the foreshadowed inclusion of the plant species, Mitragyna speciosa, in S9 of the SUSDP at the February 2004 to seek additional information on the plant's uses. Foreshadow for consideration at the February 2004 meeting Schedule 9 – New Entry MITRAGYNA SPECIOSA.