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Rationale. LAAM (α-l-acetylmethadol) is a derivative of the synthetic mu-opiate agonist methadone and is one of the four isomers of acetylmethadol. Methadone and LAAM have similar pharmacological properties and both are approved medications for the treatment of heroin dependency disorders. Few studies have reported on the pharmacology of acetylmethadol's other isomers and most of these have focused on their potential analgesic activity. Objectives. The purpose of the present investigation was to examine the discriminative stimulus effects of LAAM, the other isomers of acetylmethadol, and methadone in rats trained to discriminate heroin from water, and to compare the duration of the discriminative stimulus effects of heroin, methadone, and LAAM. Methods. Long-Evans rats were trained to discriminate 0.3 mg/kg heroin from water under a fixed ratio 10 (FR10) schedule of food reinforcement. Dose-response functions for heroin, methadone, LAAM, three other isomers of acetylmethadol: α-d-acetylmethadol, β-d-acetylmethadol, β-l-acetylmethadol, and its precursor, β-l-methadol were examined. Additionally, the time course effects for heroin, methadone, and LAAM were examined. Results. LAAM and methadone dose-dependently occasioned heroin-like discriminative stimulus effects. Two of acetylmethadol's isomers, α-d-acetylmethadol and β-d-acetylmethadol, were more potent than LAAM in producing heroin-like effects. The β-l-methadol precursor and β-l-acetylmethadol did not fully substitute for heroin's discriminative stimulus. LAAM elicited heroin-like discriminative stimulus effects for at least 6 h and generated partial generalization up to 36 h following administration. Conclusions. Methadone, LAAM, β-d-acetylmethadol and α-d-acetylmethadol, but not β-l-acetylmethadol and β-l-methadol evoke heroin-like discriminative stimulus effects.

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.

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.

The effects of long-acting narcotic agonist preparations on the severe withdrawal syndrome following abrupt cessation of daily injections of codeine phosphate were studied in rats. Twelve hours after the last codeine injections, one injection of either a high or low dose of the zinc tannate salt of heroin, levo-alpha-acetylmethadol (LAAM) or hydromorphone in slow-release vehicle (SRV) was administered. Body weight, core temperature and hyperirritability scores (Teiger, 1974) were recorded every 6 h for the next 3 days. With the exception of the group that received the lower dose of heroin zinc tannate, all drug-treated groups lost significantly less weight than the SRV controls. All rats injected with either LAAM or hydromorphone zinc tannate exhibited prolonged marked hyperthermia, but the low, the high dose heroin groups and the SRV groups showed no significant differences in diurnal temperature patterns. Rats treated with the narcotic agonists were generally less irritable, as indicated by lower Teiger scores. These results indicate that a single injection of heroin, LAAM or hydromorphone zinc tannate can ameliorate the characteristic and intense signs of abstinence following withdrawal from codeine.

1-Alpha-acetylmethadol (LAAM) maintenance treatment has been proposed as a favorable alternative to methadone maintenance. With an unobtrusive actometer we recorded two successive 24-h cycles of spontaneous motor activity from 12 patients receiving LAAM every other day, and from five receiving methadone every day. LAAM patients were about 50% more active on days of drug administration than on no-dose days (P less than 0.001). There were no significant day-to-day differences in motility of methadone patients. LAAM administered every other day may significantly modify the human circadian rhythm of spontaneous motility; further research is thus needed before this treatment is widely adopted.

Adult female Sprague-Dawley rats were prepared with chronic cortical and muscle electrodes and i.v. cannulas, made tolerant to and physically dependent on morphine, and trained to lever press for i.v. morphine self-injections to maintain dependence. Methadone or l-alpha-acetylmethadol (LAAM) was then substituted for morphine in some of these rats. During self-maintained dependence on either morphine or methadone, head shakes appeared and increased in frequency before lever pressing for selfinjections. In contrast, there were fewer head shakes during LAAM dependence, which were evenly distributed over the entire duration of the interinjection interval. These findings suggest a relationship between head-shake distributions, drug-seeking behavior, and the pharmacodynamics of these three narcotics.

Monkeys receiving acetylmethadol thrice weekly were more active on dosing days, and less active on between-dose days, than while drug-free. Aggressive social behaviours increased significantly on drug-dosing days, while quiescent resting behaviors were much more common on between-dose days. Tolerance to these effects was modest, and the effects were not blocked by naltrexone. These subtle but potentially disruptive behavioral effects appear to parallel many of the actions of acetylmethadol in man.