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PubMed2005

Treatment for methaqualone dependence in adults.

BACKGROUND: Methaqualone is a potent quinazoline, a class of sedative-hypnotics, that has a high potential for abuse. While the oral use of methaqualone (Quaalude, Mandrax) has waned in western countries since the mid-late 1980's, the practice of smoking methaqualone is a serious public health problem in South Africa, other parts of Africa and India. In the context of diminishing resources devoted to substance abuse treatment in regions affected by methaqualone abuse, it would be desirable to base treatment on the best evidence available. This review aimed to provide health care workers, policy-makers and consumers with the necessary information to make decisions regarding effective treatment of this highly dependence-producing drug. OBJECTIVES: To compare the effectiveness of any type of pharmacological or behavioural treatment administered in either an in-patient or out-patient setting compared with either a placebo or no treatment or a waiting list, or with another form of treatment administered in either an in- or out-patient setting. SEARCH STRATEGY: The authors searched the following databases: Cochrane Drugs and Alcohol Group'Register of Trials (February 2004); Cochrane Central Register of Controlled Trials (CENTRAL-The Cochrane Library, Issue 2, 2004); MEDLINE (OVID - January 1966 to february 2004), PsycInfo (OVID - January 1967 to february 2004). Relevant conference proceedings and reference lists of relevant articles were hand-searched. Broad internet searches were conducted and contact made with experts in the field. SELECTION CRITERIA: All randomised controlled trials and quasi-randomised trials of the effectiveness of treatment programmes (in- or out-patient) for methaqualone dependence and abuse were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: The authors independently assessed study eligibility and quality. MAIN RESULTS: No studies were found that met the inclusion criteria. AUTHORS' CONCLUSIONS: To date, no randomized controlled trials appear to have been conducted. Consequently, the effectiveness of inpatient versus outpatient treatment, psychosocial treatment versus no treatment, and pharmacological treatments versus placebo for methaqualone abuse or dependence has yet to be established.

Adult↗
PubMed1989

Serotonin as a facilitatory neurotransmitter in the anticonvulsant activity of methaqualone.

The neuromodulatory role of serotonin in the anticonvulsant activity of methaqualone was investigated. A dose-dependent increase in the ability of methaqualone to provide protection against pentylenetetrazol (90 mg/kg SC)-induced convulsions in mice was observed. The ED50 value for the anticonvulsant activity of methaqualone was calculated and found to be 60 mg/kg, IP. Pretreatment of mice with 5-hydroxytryptophan (100 mg/kg, IP, 2 hr) and p-chlorophenylalanine (300 mg/kg, IP, 2 hr), causing an increase in brain serotonin levels, resulted in a 60% and 80% increase, respectively, in the anticonvulsant activity of methaqualone. Similar pretreatment with p-chlorophenylalanine (300 mg/kg, IP, 48 hr), causing a lowering of brain serotonin, and methysergide (10 mg/kg, IP, 0.5 hr), causing blockade of brain serotonin receptors, resulted in a 40% and 20% decrease, respectively, in the ability of methaqualone to provide protection against pentylenetetrazol-induced convulsions. These results suggest a facilitatory role of serotonin in the anticonvulsant activity of methaqualone.

5-Hydroxytryptophan↗
PubMed1983

Selective induction of xenobiotic metabolizing esterases/amidases of liver by methaqualone consumption.

The present investigation reports the influence of po and ip methaqualone administration on the hydrolytic metabolism of acetylsalicylic acid, procaine, p-nitrophenylacetate, acetanilid, and butyrylcholine in the liver, kidney, and brain of male rats. Oral administration of methaqualone (60 mg/kg/day) to rats for 20 days caused 41.0, 46.5, and 55.0% stimulation of acetylsalicyclic acid esterase I, acetylsalicyclic acid esterase II, and acetanilid N-deacetylase, respectively, in the liver. Under such conditions, the activities of other esterases remained unaffected. The responses of tissue esterases to ip methaqualone treatment (40 mg/kg/day for 6 days) were similar to those observed after po methaqualone administration. Since a single po dose of methaqualone failed to produce any alteration in the rate of metabolism of acetylsalicylic acid, procaine, p-nitrophenylacetate, acetanilid, and butyrylcholine within 20 hr, it may be interpreted that the stimulation of acetylsalicylic acid and acetanilid metabolism is possibly due to selective enhanced de novo synthesis of the enzymes/isozymes necessary for the hydrolysis of the two drugs. The ability of the kidney and brain to metabolize the esters/amides was not modified by po or ip methaqualone pretreatment suggesting the possibility of noninducible forms of renal and neuronal esterases/amidases.

Amidohydrolases↗
PubMed1981

Effects of methaqualone on social-sexual behavior in monkeys (M. mulatta) II. Simultaneously dosed subjects.

In a previous publication, we reported on the effects of 10 mg/kg i.m. injections of methaqualone on behavioral changes in treated animals and untreated members of a well-established colony of 10 rhesus monkeys (Macaca mulatta). The drug showed a biphasic effect, causing more passive behaviors in the first 80-100 min postinjection, followed by either aggression or increased sexual activity. After approximately 2 h, the social status and behavior of all animals returned to predrug levels. In general, affiliative activities increased under the influence of the drug, phenomena somewhat parallel tho those described among humans taking methaqualone in group settings. We also speculated that the drug may have an aphrodisiac potency. In the present experiments, 3 animals were caged together and injected simultaneously with the dose used earlier: an adult but naive male, who had been caged alone for infancy; an adult and subadult female, the 2 latter having had extensive social experience. After establishing baseline behaviors, five experiments with methaqualone were conducted, each lasting 2 h; and after the 2nd and 4th experiments, saline controls were carried out. There was a continuous increase from experiment to experiment in the affiliative behaviors of the animals; but during the saline trials, their behaviors returned nearly to those exhibited during baseline studies. Under the influence of methaqualone, the naive male attempted to copulate, which he achieved by the 4th drug trial; and at the same time he established his dominance. The conclusion was reached that methaqualone, indeed, has aphrodisiac potency, best measured by the time the male spent with erection under the influence of the drug, as compared with no erection during the baseline studies or the saline trials. The biphasic effect of methaqualone on behavior reported in the previous review [1] was also observed during the present experiments.

Agonistic Behavior↗
PubMed1980

Differential stimulation of diphenhydramine, pethidine, morphine and aniline metabolism by chronic methaqualone treatment.

In the present study, the effect of chronic oral methaqualone treatment (60 mg/kg/24 h for 25 days) was examined on the metabolism of diphenhydramine, pethidine, morphine and aniline in rat liver microsomes. Such chronic methaqualone treatment caused an enhancement of microsomal drug metabolizing enzymes catalyzed N-demethylations of diphenhydramine, pethidine, morphine and aromatic hydroxylation of aniline. A single oral dose of methaqualone (60 mg/kg) did not result in any significant change in the activities of drug metabolizing enzymes. Methaqualone inhibited drug metabolizing enzymes when used at final concentrations of 1 and 3 mmol/l in vitro. These observations led to suggest that the stimulation of drug metabolism noted in this study is possibly due to the induction of microsomal drug metabolizing enzymes. It was interesting to note that the induction of N-demethylases by repeated methaqualone intake was differential in nature since diphenhydramine and morphine N-demethylases were induced about twofold whereas pethidine N-demethylase was enhanced about fourfold. These results should be of extreme importance in understanding the biochemical mechanism of the specific and differential drug tolerance by continued methaqualone abuse and its possible interaction with other drugs.

Aniline Compounds↗
PubMedDate not supplied

Metabolism of methaqualone by the epoxide-diol pathway in man and the rat.

The metabolism of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone) has been studied in man and the rat using gas phase analytical methods. Seven new metabolites formed by the epoxide-diol pathway were detected in human urine after methaqualone administration. Five of these compounds were characterized as dihydrodiols and two as hydroxydihydrodiols. The seven dihydrodiol metabolites were present in the nonhydrolyzed fraction isolated from urine. After intraperitoneal administration of methaqualone to the rat (40 mg/kg) the major monohydroxyl metabolites of the drug in hydrolyzed urine were identified as 2-methyl-3-(2'-hydroxymethylphenyl)-4(3H)-quinazolinone (I) and 2-hydroxymethyl-3-o-tolyl-4(3H)-quinazolinone (II). Two dihydroxyl metabolites were also present, but only trace amounts of a dihydrodiol were detected. The major monohydroxyl metabolites of methaqualone detected in human urine after enzymic hydrolysis were I, II, 2-methyl-3-(3'-hydroxy-2'-methylphenyl)-4(3H)-quinazolinone (III), and 2-methyl-3-(4'-hydroxy-2'-methylphenyl)-4(3H)-quinazolinone (IV). Hydroxylation of the tolyl moiety of methaqualone probably occurs by way of an epoxide intermediate. The phenols, III and IV, may be formed from an epoxide or from the dihydrodiol(s) by enzymic or nonenzymic reactions. The results obtained suggest that epoxidation of methaqualone represents a major pathway of metabolism in the human.

Animals↗
PubMed1983

Changing patterns of methaqualone abuse. A survey of 246 fatalities.

Of 246 methaqualone-related deaths identified during an 11-year period (1971 through 1981), 76% have occurred since 1977 and 72% have involved fatal trauma. One third of the victims died in vehicular crashes. Sharp increases in methaqualone-related traumatic suicides, nonvehicular accidents, and homicides have occurred since 1978. This report discusses demographic and toxicological findings, particularly in regard to counterfeit methaqualone. The pattern of fatal methaqualone abuse has changed from an overdose phenomenon in the early 1970s to one of traumatic death. Victims frequently have exhibited poor judgment, impulsive behavior, and somnolence while attempting to function in their environment. The socioeconomic impact of recreational methaqualone abuse should be curtailed by appropraite governmental action and restraint in the prescribing of methaqualone.

Accidents↗
PubMed1975

Effects of dixyrazine and methaqualone on the sleep pattern in normal man.

Whole night EEG and polygraphic recordings were made in ten young, healthy, male volunteers after dixyrazine (12.5 mg, 25 mg, 50 mg), methaqualone (250 mg) and Isonox (methaqualone 250 mg + etodroxizine 50 mg). A total of 156 recording nights (36 adaptation nights were not included in the analyses) were scored for different sleep stages according to accepted criteria. The smallest dose of dixyrazine (12.5 mg) had no significant effect upon sleep pattern: the larger doses (25 mg and 50 mg) caused significant decreases in REM-sleep during the first nights of administration. The decrease disappeared during the following two nights of treatment. No withdrawal effects were seen. Methaqualone also caused moderate depression of REM-sleep during the first night of treatment, and this effect, too, disappeared during prolonged administration. Isonox (methaqualone + etodroxizine) had a somewhat stronger surpressive effect upon REM-sleep than methaqualone alone.

Adult↗
PubMedDate not supplied

Methaqualone ingestion: evaluation of present status.

Sixty cases of methaqualone ingestion have been reviewed from 1977 through 1980. Serum methaqualone concentrations, clinical information, and demographic data were studied in order to define the present status of abuse of this drug. The average user was a 27 year-old man who ingested Quaalude plus at least one additional drug (usually a narcotic analgesic, ethanol, a benzodiazepine, or a barbiturate, in that order). He was admitted to the emergency room with a depressed level of consciousness and a serum methaqualone concentration of 5 +/- 3 mg/L (mean +/- SD). Following a brief period of observation and supportive care, he was discharged from the hospital. Serum methaqualone concentrations showed no significant correlation with the physical findings, except that levels greater than or equal to 9 mg/L were always associated with a depressed level of consciousness, whether or not other drugs were present. Despite strict federal controls, methaqualone abuse appears to be a continuing problem, and analysis for this drug should be part of the toxicology screen.

Adolescent↗
PubMed1988

Methaqualone.

Methaqualone is considered a sedative hypnotic drug with a pattern of pharmacological effects similar to those of barbiturates such as pentobarbital. It does have chemical similarities to the barbiturates but was, in fact, synthesized as part of an Indian program looking for antimalarial drugs (Brown and Goenechea, 1973). Methaqualone was selected for the focus of this study five years ago, because of its popularity as a euphoriant among casual recreational drug users in the Boston area. Methaqualone, instead of a barbiturate hypnotic, was therefore used to test our proposed methodology for the assessment of the abuse liability of sedative drugs. As one reviews the history of the clinical use and illicit abuse of methaqualone, it appears particularly unfortunate that a study of this sort was neither completed nor available to our Food and Drug Administration (FDA) and Drug Enforcement Agency (DEA) in 1965. It was at this time that the drug was approved for prescription use and placed in Schedule V, a schedule which essentially places no restrictions on the clinical use of a prescription drug (Falco, 1976). This paper will both review the development of methaqualone and present an experimental methodology for assessing its abuse liability under seminaturalistic conditions.

Adult↗
PubMed1982

The influence of the menstrual cycle on the metabolism and clearance of methaqualone.

1 The rate of methaqualone metabolism in women was shown to be significantly increased at the time of ovulation. 2 The apparent first order rate constants for the formation of five C-monohydroxy metabolites of methaqualone on day 15 of the menstrual cycle were approximately double that on day 1. 3 The N-oxidation of methaqualone showed considerable inter-individual variation in its sensitivity to the menstrual cycle, and in a group of ten women the difference in N-oxide excretion between days 1 and 15 was not statistically significant. 4 The serum clearance of methaqualone on day 15 was higher (mean value 94.6 ml min-1 on day 1, 176.0 ml min-1 on day 15), serum half-life shorter (mean t1/2 beta 16.3 h on day 1, 11.6 h on day 15) and the AUC alpha smaller (mean value 44.0 micrograms ml-1 h on day 1, 24.4 micrograms ml-1 h on day 15) than on day 1. 5 The relative importance of the five hydroxy metabolites was unchanged during the menstrual cycle but the C/N oxidation ratio was greater on day 15 than on day 1. 6 The data for methaqualone metabolism in a control group of men was similar to than in women on day 1 of a menstrual cycle.

Adult↗
PubMed1979

Dose-response studies on tolerance to multiple doses of secobarbital and methaqualone in a polydrug abuse population.

Patients from a polydrug abuse treatment program were titrated with either secobarbital or methaqualone, their primary drug of abuse, to a state of mild intoxication, consisting of lateral and vertical nystagmus, ataxia, slurred speech, and drownsiness. The mean dose required to produce each sign was compared to that determined in a similarly treated control group. Tolerance to secobarbital was more easily demonstrated than tolerance to methaqualone, and nystagmus was the least sensitive indicator of patient tolerance. The individual signs were also cumulated into a graded rating scale of central nervous system depression which would be related to the dose administered. Tolerence was easily demonstrated at the higher stages of toxicity for secobarbital in the overall patient population, but tolerance to methaqualone was only unequivocal in the subjects indicating a relatively high frequency of abuse. Tolerance to methaqualone occurred at the lower stages of toxicity, suggesting that there is a difference between tolerance to secobarbital and tolerance to methaqualone. There was no indication that patients who also abuse alcohol are more tolerant than their patient counterparts. The patients who also had a history of amphetamine abuse, however, were less tolerant than the nonusers of these drugs.

Adolescent↗
PubMedDate not supplied

Urinary excretion pattern of methaqualone metabolites in man.

A method based on selected ion monitoring for determination of five monohydroxy metabolites of methaqualone in urine has been worked out. By means of this method the time course of metabolite excretion was studied in three healthy volunteers receiving an oral therapeutic dose of methaqualone. In all subjects the main monohydroxy metabolite was conjugated 4'-hydroxymethaqualone, but the relative importance of the five metabolites showed intersubject variation. Metabolite excretion was still going on, when urine sampling was discontinued after 70 hr. Only small amounts (less than 1% of the dose during 70 hr) of unmetabolized methaqualone were excreted. On the other hand, it was confirmed that methaqualone-N1-oxide is an important metabolite. The presence of a hydroxy methoxy metabolite of methaqualone, very probably 4'-hydroxy-5'-methoxymethaqualone, as a minor metabolite was established by comparison with authentic, synthetic material. 8-Hydroxymethaqualone and 2-nitrobenz-o-toluidide, reported by other groups, could not be detected.

Adult↗
PubMed1978

Radioimmunoassay of methaqualone in human urine compared with chromatographic methods.

The 125I-radioimmunoassay for methaqualone in human urine was evaluated by a comparison with newly modified gas-liquid chromatographic and thin-layer chromatographic methods. The statistically significant sensitivity value for the radioimmunoassay was at 2 microgram of methaqualone per liter of urine. The coefficient of variation was 2.88 +/- 0.39% interassay and 2.71 +/- 0.16% intraassay. There was cross-reactivity only with metabolites of methaqualone, 4'-hydroxymethaqualone being twice as sensitively measured as methaqualone. There was complete agreement between results by radioimmunoassay and by gas-liquid chromatography in 96.7% of the samples analyzed. Only 1.2% of the radioimmunoassay values were false positives, and 2.1% false negatives (phi = 0.8917, P less than 0.001). Comparisons between the thin-layer chromatographic data and the gas-liquid chromatographic or radioimmunoassay data showed less agreement because of the 50- to 200-fold higher sensitivity of the latter two techniques. Gas-liquid chromatography therefore appears to represent the best reference method for the evaluation of the radioimmunoassay, which appears to be a very sensitive and reliable technique for detecting methaqualone and its metabolites in human urine.

Chromatography, Gas↗
PubMed1994

Determination of methaqualone and its metabolites in urine and blood by UV, GC/FID and GC/MS.

A systematic procedure for the determination of methaqualone and its metabolites in blood and urine by UV spectrophotometry, GC and GC/MS was developed. Urine and blood samples were from a suicidal patient who ingested 18 tablets of methaqualone. Both solid phase and liquid-liquid extractions were used in the extraction and clean-up of the samples. The total amount of methaqualone and its metabolites was measured by UV spectrophotometry. The amount of parent methaqualone was quantitated by GC/FID. Methaqualone and its 10 metabolites including two acetyl metabolites were found in urine and blood. This procedure is useful for monitoring drugs in emergency treatment.

Chromatography, Gas↗
PubMed1976

Blood levels in methaqualone in man following chronic therapeutic doses.

Human serum was analyzed for methaqualone (MTQ) and hydroxylated metabolites by gas liquid chromatographic (GLC), ultraviolet spectrophotometric (UV) and spectrofluorimetric (SF) procedures. Intact methaqualone was found to be the major circulating drug component after administration of multiple 300 mg daily doses over a 28-day period. Hydroxylated methaqualone metabolites, if present, were estimated to be in extremely low concentrations. After acute ingestion of large quantities of methaqualone (2.4-3.0 g), at least one methaqualone metabolite, [2-methyl-3-(2' hydroxymethylphenyl)-4(3H)-quinazolinone] was present in serum obtained from subjects with a history of chronic drug abuse.

Adult↗
PubMed1978

Effect of diphenhydramine on methaqualone metabolism: an in vitro study.

A GLC assay to quantitate the methaqualone metabolite 2-methyl-3-(2-hydroxymethylphenyl)-4(3H)-quinazolinone was developed. Standard curves were linear, and recovery of the metabolite from tissue homogenates averaged 89%. In vitro metabolism of methaqualone by the 10,000Xg supernatant fraction of rat liver homogenate was measured by monitoring metabolite formation with the GLC assay. Diphenhydramine inhibited the in vitro metabolism of methaqualone. The percentage inhibition increased with increasing diphenhydramine concentration. The significance of this inhibition in relation to use and abuse of methaqualone--diphenhydramine combinations is discussed.

Animals↗
PubMed1977

The effects of methaqualone on the seizure susceptibility of mice.

Methaqualone produces dose- and time-dependent decreases in susceptibility to electrically, chemically, and sound-induced seizures. The antagonism of methaqualone to electroconvulsive shock can be dissociated from its effects on temperature regulation and plasma corticosterone. Studies with SKF525A, a drug known to block enzymes in the liver that metabolize drugs, suggest that methaqualone, rather than a metabolite produced in the liver, is responsible for its anticonvulsant effects. Tolerance to the anticonvulsant effects of methaqualone is also demonstrated.

Acoustic Stimulation↗