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(1975). 1-α -Acetylmethadol (LAAM) Pharmacokinetics and Metabolism: Current Status. The American Journal of Drug and Alcohol Abuse: Vol. 2, No. 3-4, pp. 301-305.

Therapeutic counseling has been widely adovacted with methadone maintenance, but its effectiveness has not been demonstrated. A review of the literature revealed a dearth of scientific investigations comparing treatment outcomes with and without counseling services. The few studies which have been reported seem to suggest that counseling does not significantly change treatment outcomes as measured by the usual indicators of illicit drug use, arrests, employment, and retention in the program. These studies suffered from a number of methodological flaws, however, including failure to adhere to research design, small sample size, poorly matched control groups, inadequate outcome criteria, and absence of post-treatment follow-up. Previous investigators have been nearly unanimous in calling for further studies of this issue. Since the cost of counseling services represents a major portion of treatment program budgets, there is an urgent need to document the effectiveness of these services with definitive studies.

Rats maintained dependence by the self-administration of LAAM or morphine. Following the substitution of saline for LAAM, REM sleep was not disrupted, and the frequency of lever pressing for saline self-injections peaked at about 24 hr. In contrast, following the substitution of saline for morphine, REM sleep was suppressed for 24 hr while the frequency of lever pressing for saline self-injections peaked within 8 hr. When abstinence was induced by hourly iv naloxone injections, REM sleep occurrences were suppressed to a similar degree and for similar durations during naloxone-induced abstinence from both morphine and LAAM. These results suggest that the level of physical dependence maintained during self-administration of LAAM and morphine was similar. The relatively mild abstinence syndrome that was seen during saline substitution in LAAM-dependent rats was most likely related to the long plasma half-lives of the pharmacologically active N-demethylated metabolites of LAAM.

A gas chromatographic method is reported for simultaneously determining acetylmethadol, noracetylmethadol, and dinoracetylmethadol in plasma. Minimum detectable concentrations are 10 ng ml-1 for acetylmethadol using a flame ionization detector, and 5 and 25 ng ml-1 for noracetylmethadol and dinoracetylmethadol respectively using electron capture detection. Extraction efficiency is quantitative for acetylmethadol but lower for the metabolites. The method is useful for monitoring drug levels following therapeutic doses of acetylmethadol.

Adult female Sprague-Dawley rats were prepared with chronic intravenous cannulas and cortical and muscle electrodes for recording electroencephalograms and electromyograms, respectively. They were made physically dependent on morphine by automatic intravenous injections and then trained to lever press in order to self-administer morphine on a FR-20 schedule of reinforcement. Upon stabilization of morphine self-administration, one group continued to self-administer morphine, while two other groups were switched to methadone or 1-alpha-acetylmethadol (LAAM) self-administration for an additional five to ten days. Continuous EEG and EMG recordings were collected. Initially, automatic injections of morphine suppressed rapid eye movement (REM) sleep time, then tolerance developed to this effect. REM sleep time in rats self-administering LAAM, methadone or morphine was within the lower limit of the normal range. Following withdrawal, REM sleep was severely suppressed during the first 24 h with morphine and methadone, but only moderately suppressed with LAAM. Increases in lever pressing during withdrawal from morphine and methadone occurred earlier and were more intense and prolonged than for LAAM. The incidence of head shakes peaked earlier and was higher for morphine and methadone during withdrawal than for LAAM. Irritability scores increased for morphine and methadone during the first day of withdrawal, but did not show any increase until the third day for LAAM. These findings suggest that in dependent rats withdrawal from LAAM is less severe than withdrawal from morphine or methadone.

Conflicting reports exist regarding the “selective” induction of rat hepatic microsomal epoxide hydratase (EH) by trans stilbene oxide ( t -SO). We reasoned that rats of differing age and sex used in previous studies could be the source of the apparent discrepancy. To clarify the effect of t -SO on the microsomal enzymes, immature male, adult male and adult female rats were used. The rats were treated with t -SO, phenobarbital, or l - α -acetylmethadol (LAAM), all inducers of EH, and the effects of age and sex on the responses of selected microsomal enzymes were determined. t -SO was found to increase benzo[ a ]pyrene hydroxylase (AHH) activity in the adult females and immature males. However, it did not increase AHH activity in the adult male. t -SO increased aminopyrene N -demethylase activity in adult males and adult females, and it elevated EH activity in all rats studied. The effects of t -SO were similar to those of phenobarbital. LAAM was found to increase EH in adult male and adult female rats; it increased AHH in the females, but not in the males. In castrated male rats, t -SO and phenobarbital affected AHH in a fashion equivalent to that observed in normal adult males. In adult males, each of the agents studied raised EH activity without a simultaneous increase in AHH activity. This “selectivity”, however, did not hold for other cytochrome P-450-dependent monooxygenases.

Selected behavioral and physiological effects of maintenance on (−)-α-acetylmethadol (LAAM) were examined for 67 men beginning LAAM maintenance. Thirty-four began LAAM maintenance after 1 month or more on methadone; 33 others were using street heroin immediately before beginning LAAM. Subjects were followed for 20 weeks on LAAM; assessment focused on changes in alcohol and diazepam use, sexual behavior and testicular function, and cardiovascular function. There was a trend toward increased alcoholism-related behaviors, but not consumption of alcohol, when on LAAM. Use of diazepam remained low. Subjects reported slightly enhanced sexual activity: reported number of ejaculations tended to increase, although interest in sexual activity remained constant. Semen volume values remained in the low normal range. In contrast to an earlier published report of reduced sperm motility in methadone and heroin users, normal motility was noted in this sample. The incidence of abnormal sperm morphology decreased from baseline to the end of the study. Cardiovascular function, as assessed by response to standard exercise, was unchanged during LAAM maintenance. Electrocardiograms revealed minor abnormalities prior to beginning LAAM maintenance ; but these abnormalities did not consistently change during treatment. There is little evidence that the effects of LAAM maintenance differ from the effects of methadone maintenance on these behavioral and physiological functions.

Prenatal exposure of rats to 0.2 mg LAAM/kg/day but not to 0.05 mg LAAM/kg/day resulted in faster hot-plate escape latencies in 6 mo old offspring. No differences in tail-flick latencies were observed at 7 mo of age in offspring exposed to either dose of LAAM prenatally. Subsequent testing of littermates at 16 mo of age revealed that the greater sensitivity to the hot-plate observed in rats prenatally exposed to LAAM is apparently a result of neonatal withdrawal rather than a primary consequence of the drug. The data are discussed in relation to possible effects of drug or withdrawal on central nervous system development.

Rats bearing cerebrocortical electrodes for recording the electroencephalogram (EEG) were rendered tolerant to and physically dependent on morphine and subsequently trained to self-administer morphine (10 mg/kg injection) through a chronic intravenous cannula. Morphine was available for self-administration 24 h/day. Once morphine intake had stabilized (10-12 injections/day), levo-alpha-acetylmethadol (LAAM) was administered noncontingently via a chronic intragastric (IG) cannula as a single daily dose of either 1 or 4 mg/kg. These morphine self-administering rats were maintained on daily LAAM treatment for 12 consecutive days. Analysis of the patterns of lever pressing, morphine self-injections, and sleep-awake behavior revealed that daily IG administration of LAAM effectively suppressed morphine self-administration. The 1 mg/kg dose of LAAM reduced morphine intake by 30%-50%, while 4 mg/kg produced an 80%-90% decrease. The reduction in morphine self-administration occurred in the absence of overt signs of narcotic withdrawal, behavioral toxicity, or disruption of sleep-awake behavior in these rats. Termination of LAAM maintenance resulted in a gradual return of level pressing and morphine intake to pre-LAAM levels.

Dependence is viewed as a dynamic state which may be altered with time respecting pattern, magnitude and quality of physical dependence, due in part to the interaction of the parent opioid with its normetabolites. The principal metabolites of acetylmethadol are noracetylmethadol and dinor-acetylmethadol; they are active morphine-like agonists, and their long half-life and accumulation in the plasma apparently account for the delayed onset of abstinence (72 h) after the acetylmethadol is withdrawn. The normetabolites of propoxyphene, norpropoxyphene and dinorpropoxyphene, are very weak morphine-like agonists. Because they accumulate in the plasma in a high ratio compared with the parent compound, they may well account, at least in part, for the relatively mild abstinence that follows propoxyphene withdrawal. Normeperidine is inactive as a morphine-like agonist and appears to have a different action in that it primarily is a convulsant. Although the formation and accumulation of normeperidine may account in part for the characteristics of its abstinence syndrome, undoubtedly a dominant factor is the disappearance of meperidine from the blood plasma (70% per hour in the dog and 17% per hour in man). In the case of normorphine, norcodeine and norlevorphanol, there is difficulty in direct addiction tests in man in elevating the dosage as compared to the parent compound, primarily because of excessive sedation and respiratory depression. Examination of the source of abstinence scores for subcutaneous normorphine, oral norcodeine, oral codeine, oral morphine, subcutaneous morphine, and oral methadone suggests that these compounds may be divided into two categories. Normorphine and norcodeine are in one category and methadone is in the other, probably because of methadone's incapacity to form active normetabolites. The relevance of the observations to comparative studies of abuse of opioids is illustrated.

Plasma testosterone levels were measured in a group of 13 men maintained on acetylmethadol for treatment of opiate dependence. Prior to acetylmethadol administration, plasma testosterone levels were within normal adult ranges. Four hours following ingestion of acetylmethadol, plasma testosterone levels were significantly depressed and continued to fall 7-9 hr after drug administration. Plasma testosterone levels remained low 24-25 hr after the drug was taken, but, 48 hr following drug, plasma testosterone levels rose to values approximating those prior to drug. Depression of plasma testosterone levels following acetylmethadol ingestion was not only statistically but also biologically significant, since in many patients the levels were below the normal range for adult males.

1. 1. 1-α-Acetylmethadol (LAAM) and its major metabolites, 1-α-acetylnormethadol (N-LAAM) and 1-α-acetyldinormethadol (DN-LAAM) produced negative chronotropic responses in isolated right atrial preparations of three species. All species were not equally sensitive to this effect. The order of decreasing species sensitivity is: guinea-pig > rabbit > rat. 2. 2. LAAM and congeners exhibited negative inotropic properties in isolated tissue preparations. Cat and rabbit were most sensitive, followed by guinea-pig and rat. Species sensitivity to the Ca2+-antagonist effect of LAAM showed the same pattern.

Six reagents-trichloroacetyl chloride, trichloroacetic anhydride, pentafluorobenzoyl chloride, heptafluorobutyryl chloride, heptafluorobutyric anhydride, and trifluoroacetic anhydride- were evaluated as potential derivatizing reagents for quantitating the metabolites of l-alpha-acetylmethadol (LAAM) -noracetylmethadol, dinoracetylmethadol, methadol, and normethadol-by electron capture gas-liquid chromatography. All of the reagents studied reacted quantitatively with all of the metabolites except methadol; however, trichloroacetyl chloride was found to be the most satisfactory general reagent for analyzing these metabolites in biological fluids. A gas-liquid chromatographic method is presented which combines both flame ionization and electron capture detection for quantitating plasma and urine levels of methadone, l-alpha-acetylmethadol and its metabolites.

With the expansion of methadone maintenance there has been an increase in accidental ingestion and related deaths. This is at least partially due to programs involving take-home methadone. The use of 1-alpha-acetylmethadol (LAAM), a congener of methadone that suppresses withdrawal for up to 72 hours, may reduce diversion and accidental overdose.

1. 1. 1-α-Acetylmethadol (LAAM) and its major metabolites, 1-α-acetylnormethadol (N-LAAM) and 1-α-acetyldinormethadol (DN-LAAM), were shown to exert significant anticholinesterase activity in preparations of guinea pig heart homogenate, guinea pig plasma, purified acetylcholinesterase (EC 3.1.1.7) and purified butyrylcholinesterase (EC 3.1.1.8), P 2. 2. LAAM and congeners did not decrease heart homogenate cholinesterase activity at low concentrations (5 × 10−6M) which produce bradycardia in vitro that can be blocked completely with atropine. 3. 3. The data suggest that cholinesterase inhibition does not contribute to the bradycardia effected by lower concentrations of LAAM. However, cholinesterase inhibition may contribute to LAAM-induced bradycardia at higher concentrations.

This study was performed as an initial step in systematically defining the hepatic interactions between ethanol and opioids using a controlled in vitro system. The acute effects of ethanol on the initial uptake and distribution of long- and short-acting narcotics were studied using isolated rabbit liver perfused with rabbit blood without or with ethanol. A pulse injection of 1.5 mg of 14C-labeled narcotic [methadone, 1-alpha-acetylmethadol (LAAM), morphine, or meperidine] was made into the portal vein cannula followed by perfusion for 2 min. Radioactivity was determined in liver homogenates and subcellular fractions; methadone and its metabolites were measured by thin-layer chromatography with zonal scanning in each fraction. Ethanol preperfusion and concomitant ethanol perfusion did not effect hepatic uptake of methadone, LAAM, morphine, or meperidine. Although subcellular localization of morphine and meperidine differed from that of methadone and LAAM, perfusion with ethanol did not alter the acute hepatic uptake and distribution of any of the narcotics. These findings suggest that acute exposure to ethanol does not alter the acute hepatic disposition of narcotics.

The authors studied the responses of 28 adult male volunteers who were openly changed from methadone to l-alpha-acetylmethadol (LAAM) maintenance. They found that patients who had been receiving middle-range doses (50-70 mg) of methadone required a significantly lower mean increase in LAAM than patients who had been receiving either high or low methadone doses and that the patients who accepted LAAM differed significantly from those who did not in MMPI 2-point-code ratings and mean social adjustment scale scores. These findings may provide prognostic indicators for response to LAAM, a possible alternative to methadone.

The levels of acetylmethadol and its active biotransformation products were quantitated in the plasma and urine of subjects on acetylmethadol maintenance by the use of solvent extraction and gas-liquid chromatography. The time-course of plasma acetylmethadol, noracetylmethadol, and dinoracetylmethadol over 48 hr was determined concurrently with the time-action of pupillary constriction in 8 subjects receiving an average oral maintenance dose of 50 mg. The plasma level of acetylmethadol reached a peak at 4 hr and had nearly disappeared by 24 hr. The mean apparent half-life was 7 hr. The plasma level of noracetylmethadol peaked at 4 to 8 hr and slowly declined over the next 40 hr. The mean apparent half-life of noracetylmethadol was 48 hr. Dinoracetylmethadol plasma levels remained relatively constant throughout the dosing interval. The miotic effect reached a peak at 8 hr and decayed at a rate slower than that of plasma elimination of acetylmethadol but more rapidly than that of noracetylmethadol and dinoracetylmethadol. Substantial variation in the plasma levels of the compounds was observed in subjects after the same doses. The study indicated that the relatively long duration of opiate effects of acetylmethadol results from biotransformation to active and persistent metabolites.

(1975). On the Role off Chemotherapy in the Treatment of Heroin Addiction. The American Journal of Drug and Alcohol Abuse: Vol. 2, No. 3-4, pp. 279-288.

The distribution in vitro of (-)1-α-acetylmethadol (LAAM) in human blood constituents was studied. In concentrations close to those found in humans who are maintained on LAAM (0.35 nmole/ml serum), the drug was distributed almost evenly between plasma proteins and red blood cells. At similar concentrations of the drug in plasma alone, over 80 per cent was bound to protein. The strength of binding to proteins was very weak, as demonstrated by our inability to obtain a protein-LAAM complex by conventional Sephadex G-200 column chromatography. However, equilibration and elution of the column with buffer containing 0.35 nM drug, using [3H]LAAM as tracer, allowed the identification of a LAAM-protein complex. The fraction responsible for the bulk of LAAM binding in serum was identified as an α-globulin with a molecular weight of about 400,000. Equilibrium dialysis experiments showed that the role played by albumin in the binding of LAAM was insignificant. The binding of LAAM to serum proteins was highly reversible, as attested by the displacement of [3H]LAAM from its binding sites by unlabeled drug. The major metabolites of LAAM, noracetylmethadol and dinor-acetylmethadol, were also weakly and reversibly bound by serum proteins and competed with LAAM for protein binding sites. A Scatchard plot, after equilibrium dialysis of various concentrations of LAAM against human serum, indicates that the maximum specific binding of drug was 8.2 nmoles/ml serum. These data suggest that, assuming at least one binding site per protein molecule, the binding occurs to a protein of very low concentration (about 1 mg/ml) in plasma. This is consistent with the data that suggest an insignificant role of human serum albumin in the binding of LAAM and the identification of a very high molecular weight protein as the possible binding entity. The data suggest that LAAM, its metabolites, and methadone compete for the same protein binding sites and that the binding capacities of plasma for both LAAM and methadone are of the same order of magnitude. The results failed to show any cooperativity on the plasma protein binding of LAAM, its metabolites or methadone.

The effects of levo-alpha-acetylmethadol (LAAM) on locomotor activity and operant behavior were examined in rats. LAAM increased locomotor activity when given intraperitoneally (IP) at doses of 1 mg/kg and 3 mg/kg, but 10 mg/kg produced a slight decrease in motor activity over the 10-hour period. The largest increases and decreases in locomotor activity occurred 6–8 hours after administration of the drug. Other rats were trained to lever press for food pellets under a fixed-interval 90-second, fixed-ratio 10-response multiple schedule. LAAM only decreased rates of responding under the multiple schedule. Marked decreases in rates of responding under both components of the schedule occurred when LAAM was administered IP either 3 or 6 hours before the session at doses of 3 mg/kg and 10 mg/kg. The rate-decreasing effects of LAAM became greater the longer the interval between administration of the drug and initiation of the session.

The discriminative stimulus properties of l -α-acetylmethadol (LAAM), its metabolites l -α-acetyl-N-normethadol (NorLAAM) and l -α-acetyl-N,N-dinormethadol (DiNorLAAM), and methadone were evaluated in rats trained to discriminate between saline and morphine in a two-choice discrete-trial avoidance paradigm. All four compounds produced dose-related increases in the number of trials completed on the morphine-appropriate choice lever after either SC or oral administration indcating that the discriminative stimulus properties of the four compounds and morphine are qualitatively similar. LAAM and DiNorLAAM had a slow onset and long duration of action, and an oral: parenteral potency ratio of 1:3. NorLAAM had a more rapid onset and shorter duration of action and was more potent following SC administration than either LAAM or DiNorLAAM; its oral: parenteral potency ratio was 1:10. These results are consistent with evidence from other studies that the pharmacologic activity of LAAM is dependent upon the conversion of LAAM to an active metabolite, probably NorLAAM. The similarities between DiNorLAAM and LAAM suggest that the discriminative stimulus effects of the former compound are also attributable to a metabolite.

A 2.0 mg per kg oral dose of l-alpha-acetylmethadol (LAAM) administered daily to female rats prior to mating and throughout pregnancy increased ethylmorphine N-demethylase activity in liver microsomes of the dams measured 24 h after parturition. This dose of LAAM decreased maternal weight gain during gestation and increased postnatal mortality. However, 0.05 mg LAAM per kg was sufficient to produce dependence in the dams without affecting hepatic drug metabolism, gestational weight gain or neonatal mortality. The data indicate that it is not necessary to use doses of LAAM which can affect drug metabolizing enzymes in dams and increase pup mortality to maintain opioid-type physical dependence.

Adult female Sprague-Dawley rats were prepared with chronic intravenous cannulae and cortical and muscle electrodes for recording electro-encephalograms (EEG) and electromyograms (EMG), respectively. They were made physically dependent on morphine by automatic intravenous injections and then trained to lever press in order to self-administer morphine on a FR-20 schedule of reinforcement. Upon stabilization of morphine self-administration, methadone, l-alpha-acetylmethadol (LAAM), or nor-LAAM (NLAAM) was substituted for morphine. After a week in those rats self-administering methadone, LAAM or NLAAM was substituted for methadone. Continuous EEG and EMG recordings were collected. It was found that self-maintained dependence on morphine or methadone was characterized by regularly spaced single or double injections. Each morphine or methadone self-injection suppressed occurrences of rapid eye movement (REM) sleep for 30 min or more. The substitution of methadone for morphine resulted in the gradual establishment of shorter interinjection intervals within 12 h. The substitution of LAAM for morphine or methadone disrupted self-injection patterns for a day or more, and suppressed occurrences of REM sleep for several hours. LAAM self-injection patterns eventually stabilized within two to three days, and the diurnal variation in occurrences of REM sleep became relatively normal. Upon substitution of NLAAM for morphine or methadone, regularly spaced interinjection intervals were established immediately. Each NLAAM self-injection suppressed occurrences of REM sleep for about 1 h. The findings suggest that stabilization of LAAM self-administration may require accumulation of LAAM metabolites.

We have used the developing chicken to determine if ornithine decarboxylase (ODC) activity is altered in fetuses chronically exposed to the opiate N-desmethyl-l-α-acethylmethadol (NLAAM) or rendered abstinent by acute injection of naloxone (Nx). Exposure to NLAAM from day 3 of embryogenesis did not significantly change brain ODC activity in 15, 17 or 19-day-old fetuses. Acute treatment of 17-day-old fetuses with a motility suppressant dose of NLAAM did not differentially affect ODC activity in NLAAM-dependent fetuses, but an additional treatment with Nx, which precipitated withdrawal, resulted in a significant increase in ODC activity in this group. We conclude that withdrawal can alter fetal ODC activity which otherwise appears normal, even though fetuses have been chronically exposed to and dependent upon an opiate.

As time increased between drug administration and the start of experimental sessions, effects of drugs on food-maintained responding the rhesus monkeys increased to a maximum and then decreased. d-Amphetamine, ethanol, and α-l-acetylmethadol (LAAM) generally decreased high response rates in one component of a chain schedule, while very low response rates in another component were increased reliably only by ethanol. The time of peak LAAM and ethanol concentrations in blood or plasma corresponded with or overlapped the time of maximal behavioral effect, while the time of maximal behavioral effect with d-amphetamine occurred somewhat prior to the time of peak plasma-amphetamine concentration. With d-amphetamine and perhaps with ethanol, effects on operant responding were greater after 30-min pretreatment intervals than after six-hr pretreatment intervals despite higher plasma or blood concentrations at six hours than at 30 min.

A method employing solvent extraction and gas-liquid chromatography has been developed for the quantitative determination of acetylmethadol simultaneously with its two major biotransformation products, noracetylmethadol and dinoracetyl-methadol. Noracetylmethanol and dinoracetylmethanol are analyzed following their conversion to the corresponding amides. The amide structure is confirmed by the use of chemical ionization mass spectrometry and infrared spectroscopy. The method can be used to determine the concentration of acetylmethadol and these compounds in plasma samples from acetylmethadol maintenance subjects. Methanol and normethadol do not attain measurable plasma levels. Urine contains predominantly noracetylmethadol and dinoracetylmethadol. Evidence was also obtained for the urinary excretion of acetylmethadol, methadol and normethadol. A mean quantity equal to 28% of the administered dose was extreted in the urine of a 48-h dosing interval as acetylmethadol and metabolites.

1-alpha-acetylmethadol (LAAM) is a new drug under development for the treatment of heroin dependence. A new analytical method applicable to the accurate biodispositional study of the drug and its metabolities is described and critically discussed in this report. The procedure involves sample preparation and direct organic solvent extraction using eta-butyl chloride, amide derivatization by molecular rearrangement, and gas chromatography-chemical ionization mass spectrometry-selected ion monitoring, with methane as the carrier and ammonia as reagent gases. Deuterated (d3 stable isotopes of LAAM and its metabolites are used as internal standards. The method is free from qualitative interferences and has quantitative sensitivity to 5 ng/ml for 2.0 ml samples with 10-15% accuracy and precision in the range 5-100 ng/ml; and 2-5% at concentrations up to 750 ng/ml. Specimens of plasma, whole blood, urine, bile, brain, liver, and other visceral samples have been successfully analyzed, as well as in vitro preparations such as hepatic microsomes. By appropriate data processing, the method lends itself to routine analysis and high volume work; even manually the method is capable of at least 50 samples per week. A simplified procedure for the analysis of LAAM and its metabolites in urine only is also presented and discuet up and use the methods.

Outpatients receiving daily methadone-maintenance treatment were crossed over to alternating-day doses of 1-alpha-acetylmethadol, receiving placebo on between-dose days. Spontaneous motility was dramatically higher on acetylmethadol dose days than on placebo days; activity on methadone days was intermediate between these extremes. Patients reported less vigor, more fatigue, and fewer ejaculations on placebo days than on acetylmethadol days, and patients' mood while on this drug was slightly euphoric in comparison to methadone. These effects are subtle, but such drug-induced variations in day-to-day behavior might adversely affect social interactions.

Fifty of sixty original study subjects were assessed via two questionnaires and urinalysis tests between six months and one year following completion of the experimental program. Results indicate a high rate of retention in methadone/methadyl acetate treatment, and point to the need for positive social context, satisfactory interpersonal relationships, and good role functioning as concomitants to achieving drug-free status.

The disposition of 1-alpha-acetylmethadol (LAAM) in plasma and urine was monitored by GC/CIMS following oral administration of 10 doses (0.73-1.5 mg/kg) over 42 days, to twelve human subjects. Plasma concentration-time course profiles fitted a two-compartment, first order kinetic model. Mean plasma t1/2 alpha for LAAM was 2.4 hours; t1/2 beta was 37.5 hours for the first dose and 46.8 hours for the last dose. The mean terminal half-life for nor-LAAM was 38.2 hours for first and 64.6 for last dose; for dinor-LAAM t1/2 beta was 168 hours, last dose. Drug accumulation occurred in some subjects, but within the study range, dosage was not related to maximum plasma levels nor to accumulation. In urine, the sum of LAAM, nor-LAAM, and dinor-LAAM represented 25% of the dose, and unconjugated methadol metabolites, 1.6-1.7%.

Sixty subjects participated in a double-blind study comparing methadyl acetate (80 mg) with two dosages of methadone (50 mg and 100 mg) in the maintenance of opiate addicts. The safety of all three regimens was supported and methadyl acetate was as effective as methadone in the retention of subjects.

A quantitative GLC-mass spectrometric assay was developed for the determination of methadyl acetate in urine. The assay utilizes selective ion focusing to monitor, in a GLC effluent, the M – 15 ion generated by electron-impact ionization of methadyl acetate. Methadyl acetate- d 4 was used as an internal standard. The assay can measure 10 ng of drug/ml with about 6% precision. The curve relating the amounts of drug added to control urine versus the amounts experimentally found over a large concentration range is a straight line with a slope of 0.98 ± 0.02 and a nearly zero intercept. Assay specificity was confirmed by complete identity of the mass spectrum of methadyl acetate in the biological extract with that of the authentic material. The method was used for the urinary analysis of methadyl acetate in a rabbit given a single intravenous dose. The animal excreted less than 1% of the intact drug with a half-life of approximately 15 hr. Consequently, the long-acting characteristic of methadyl acetate must be attributed to its metabolism into active metabolites.

Nine male heroin addicts maintained on L-alpha-acetylmethadol (LAAM) for about 5 mo had normal plasma levels of testosterone and luteinizing hormone 72 hr after a dose of LAAM and also during 2 wk after abrupt LAAM withdrawal.

The behavioral effects of acute IP administration of 1-alpha-acetylmethadol, its metabolites, 1-alpha-noracetylmethadol and 1-alpha-dinoracetylmethadol, and morphine were studied in the rat using behavior controlled by a fixed-interval schedule of food reinforcement. Administraiton of all compounds produced a dose-related decrease in response rate. The metabolites were approximately three to four times the potency of the parent compound which was approximately five times the potency of morphine. Data obtained from cumulative response records suggested that the onset of effects for the metabolites was more rapid than for the parent compound.

Narcotics like morphine and methadone produce effects on striatal dopaminergic mechanisms as evidenced by changes in a stereotyped behavior induced by apomorphine and binding or radioactive ligands to dopamine (DA) receptors. LAAM may replace methadone in the treatment of narcotic addiction. We investigated the effect of LAAM on apomorphine induced stereotypy and the binding of 3H-spiroperidol to dopamine receptors isolated from mouse and guinea pig striata. Chronic LAAM treatment produced a behavioral supersensitivity to apomorphine. The biochemical expression of the behavioral effect was a significant increase in the number of dopamine receptor binding sits in mouse and guinea pig striata. These effects can be due to either a direct chronic blockade or postsynaptic dopamine receptors or stimulation of a presynaptic receptor which acts to reduce the amount of dopamine released during nerve activity. Work is in progress to determine the mechanism of this effect.

Inotropic effects of 1-alpha-acetylmethadol, 1-alpha-acetylnormethadol and 1-alpha-acetyldinormethadol were studied uilizing isolated left atria of guinea pigs. All three agents produced a biphasic response. Lower concentrations produced a slight, but significant increase in contractile force (p less than 0.05) and higher concentrations decreased contractile force (p less than 0.05). Significant drug interactions also were observe. The parent compound, 1-alpha-acetylmethadol, decrease the maximum positive inotropic response obtained with ouabain as well as that obtained with norepinephrine.

Heroin, α- l -acetylmethadol (LAAM), morphine, and methadone each maintained self-administration in rhesus monkeys. The order of relative potency was heroin ≥ LAAM > morphine ≥ methadone. Total daily drug intake increased as dose per injection increased; maximum daily intake was inversely related to relative potency. At high doses, self-injection of methadone and LAAM caused stupor and/or respiratory failure in some monkeys. These toxic effects were partly or completely reversible by naloxone.