Studies on Colour Tests for Field Detection of Narcotic Drugs and Psychotropic Substances Under International Control (No
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UNITED NATIONS INTERNATIONAL DRUG CONTROL PROGRAMME SCIENTIFIC AND TECHNICAL NOTES SCITEC/13 December 1996 Studies on Colour Tests for Field Detection of Narcotic Drugs and Psychotropic Substances under International Control (No. II) Screening Colour Test and Specific Colour Test for the Detection of Non-barbiturate Sedatives and Hypnotics Methaqualone and Mecloqualone Keizo Watanabe prepared by LABORATORY SECTION TECHNICAL SERVICES BRANCH - 1 - Table of Contents Purpose of this note......................................................................................................... 2 Manufacture and international control 2 Medical use 3 Chemical identification 6 Synthesis 7 Colour test 9 Experimental 10 Results and discussion ................................................................................................... 14 References...........................................................................................................................23 - 2 - Purpose of this note 1. In view of the increasing interest expressed by Member States in the possibility of identifying methaqualone and mecloqualone by means of a simple colour reaction, a study was carried out to explore such a possibility at the UNDCP laboratory. This note summarizes the results of that study. Manufacture and international control (1,2) 2. In 1972, methaqualone emerged as a major drug of non-medical use in the United States and subject of widespread publicity and public concern. It also had a similar history in other countries, particularly in Great Britain, Germany and Japan. Methaqualone was first synthesized in 1951 and introduced in Europe in 1956. In 1959, it was introduced in Great Britain and marketed as Melsedin in 150 mg tablets by the Boots Pure Drug Company. This preparation was never widely prescribed. 3. Methaqualone was introduced to the former West Germany in 1960, marketed by Merck as Revonal in 200 and 300 mg tablets. Two years later, the drug became available in the former East Germany, marketed under the trade name Dormutil. In both East and West Germany, methaqualone was sold over the counter, unlike barbiturates which required a prescription, and quickly became widely used and abused, particularly by young people. In the decade following methaqualone's introduction into the world market, it became a drug of non-medical use in France, Italy, Sweden, Argentina, Norway, Ireland and Australia. Overdose from methaqualone was considered to be a serious problem. 4. Methaqualone was introduced to Japan in October 1960 by the Eisai Company and marketed under the trade name Hyminal. Freely available without prescription, methaqualone was widely used for non-medical purposes. 5. In 1965, Roussel introduced a combination tablet, Mandrax, which contained 250 mg of methaqualone base and 25 mg of diphenhydramine hydrochloride. Mandrax rapidly achieved a considerable popularity and a survey in 1968 showed that it was the most commonly used hypnotic, accounting for 30 of all hypnotic prescriptions. Other preparations were marketed, but none reached equal popularity. It is surprising that Mandrax, a methaqualone preparation marketed six years after the first methaqualone containing product, became so much more widely used. It is claimed that this is because methaqualone together with diphenhydramine is a more efficient hypnotic. The apparent effect of diphenhydramine in promoting the absorption and increasing the peak plasma methaqualone concentration can be seen in comparative studies on Melsedin versus Mandrax. 6. The major episodes of methaqualone misuse and the most fully documented, occurred in Great Britain, Germany and Japan. Until 1973, however, federal officials in the United States did not give much weight to the foreign reports on methaqualone misuse and dependence liability. The warning statement to doctors accompanying methaqualone products, approved by the FDA in 1967 and unchanged until the imposition of Schedule II control in 1973, stated only that "psychological dependence has been rarely reported; physical dependence has not clearly been demonstrated". Despite the British, German and Japanese reports available at that time, in 1967, the FDA approved the marketing of a new 300 mg methaqualone preparation, Quaalude. 7. A review of the foreign experience with methaqualone misuse reveals certain pattern which were - 3 - later repeated in the United States. First, methaqualone was widely marketed as a new, safe sedative hypnotic superior to the barbiturates and other traditional sleeping medications. Secondly, it was readily accepted both by physicians and by the drug-using public because of its particular pharmacological properties, its free availability and its reputation for producing a pleasant, allegedly safe euphoria. As a result, methaqualone rapidly developed a following among recreational drug users. Thirdly, as methaqualone emerged as a high frequency drug of misuse, reports regarding its toxicity, its tolerance potential, and its dependence liability became more numerous. 8. In its 1964 report, the World Health Organization Expert Committee on Addiction Producing Drugs noted the "epidemic-like outbreak of abuse of hypnotic drugs in a particular region. Methaqualone is reported to constitute about 4/5 of the total amount of hypnotic drugs abuse in the group studied."(5) In 1979, the Commission on Narcotic Drugs decided to place methaqualone under international control, initially in Schedule IV and later transferred it to Schedule II of the 1971 Convention on Psychotropic Substances. 9. No diversion of substances included in Schedule II of the 1971 Convention from the licit manufacture and trade into the illicit channels has been identified since l990. However, although diversion of methaqualone last occurred in 1988, attempts at diversion of this substance has continued, mainly through the use of falsified import authorizations. Indeed, in summer 1991, a Swiss trading company approached a company in India in order to obtain 10 million tablets containing 400 mg of methaqualone and 40 mg of diphenhydramine hydrochloride each. When requested by the Indian company for the export permit, the Indian authorities informed the United Nations International Narcotics Control Board. Inquiry with the Swiss authorities revealed that the Swiss company interested in the purchase of methaqualone was not licensed to deal in pharmaceuticals and had never applied for the import permit. Investigations of the case continue in Switzerland.(6) 10. Only a few countries in Europe, namely Belgium, Spain and Switzerland, continue to use methaqualone in significant quantities for medical purposes. In recent years, the medical needs for methaqualone in those countries have been satisfied by using stocks in Switzerland or, occasionally, through manufacturing the substance in the Czech Republic (214 kg in 1994).(8) Mecloqualone has not been manufactured since 1980. Portugal, the only country that had reported having small stocks of the substance, exhausted those stocks in 1993. 11. Two international meetings took place recently on the subject of illicit traffic in methaqualone: 1) International Conference on the Illicit Traffic in Methaqualone between the Indian Sub-Continent and the East/Southern Region of Africa, organized by ICPO/Interpol, New Delhi, India, from 9 to 11 December 1992, and 2) Regional Seminar on Methaqualone, organized by UNDCP, Nairobi, Kenya, from 18 to 20 January 1993.(7) Medical use (I) Methaqualone 12. Methaqualone is a non-barbiturate sedative-hypnotic agent of the quinazoline group, used to produce sleep and daytime sedation in doses ranging from 150mg to 400mg.(9)(10)(11) Methaqualone is a central nervous system depressant, effective for sedation at dosage ranges of 75 mg four times daily. Onset of sedative-hypnotic action occurs within 30 min. of ingestion and lasts between 6 to 8 hours. (1) - 4 - 13. Virtually insoluble in water, methaqualone is unsuitable for intravenous injection and is administered orally. Adverse physiological reactions to methaqualone include headache, hangover, menstrual disturbance, dryness of the mouth, nosebleed, dizziness, numbness, diarrhea and anorexia,(12) neurotoxic effects have been discussed (15). Absorption and plasma levels of methaqualone after oral administration to man have been studied.(13) 14. Studies on methaqualone's metabolism in man were reported in 1960, and in animals in 1963.(12)(13) Methaqualone was introduced pharmaceutically in 1959 for use as a non-addictive, non- barbiturate sleeping pill. Metabolite detection for forensic science purposes was reported in 1976. 14. Pharmacokinetic studies on methaqualone have shown a wide subject variation in the rate of absorption and a faster absorption rate for the hydrochloride salt than for the free base.(14) It is known that methaqualone is concentrated in body fat and brain and that it is metabolised at a rate which ensures 80 elimination in 24 hours. Methaqualone is readily absorbed from the gastrointestinal tract and metabolized almost entirely in the liver.(15) It is very rapidly and extensively metabolized in man via hydroxylation, so that very little unchanged drug, usually less than 5, is excreted in urine. 16. Metabolic pathways involving formation of dihydroxy- and hydroxy-methoxy-derivatives exist. However, the major pathway is monohydroxylation at any one of ten possible sites (14). and the five most common monohydroxy metabolites in human urine are shown in Figure 1. 17. Methaqualone is particularly attractive