Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vivo and in vitro assays. The second report in this series describes the results for one of these compounds, Methadone. A previous report described the results for Naltrexone. Methadone is a synthetic narcotic analgesic used as a substitute for Heroin in drug detoxification programs. Methadone demonstrated weak activity in the E. coli DNa repair system and in the Neurospora crassa and the mouse lymphoma forward-mutation assays under the conditions of this evaluation. Additional analysis of the ad-3 mutants induced by a related compound, LAAM, in Neurospora indicated that they were the result of a parasexual phenomena rather than forward mutation. Therefore, the methadone-induced ad-3 mutants also may be due to a parasexual phenomena.

Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vivo and in vitro assays. This third report in the series describes the results for one of these compounds, LAAM (L-alpha-acetyl methadol). Previous reports described results from a three phase testing program for Naltrexone and Methadone. LAAM is related chemically to the narcotic analgesic oxymorphine, and is related chemically to a narcotic antagonist, naloxone. LAAM exhibited genetic activity in the ad-3 forward-mutation test in Neurospora crassa and also was weakly mutagenic in the mouse lymphoma forward-mutation assay. Further analysis of the ad-3 mutants from N. crassa indicated that they were the result of a parasexual phenomenon rather than forward mutation. There was one confirmed translocation carrier in the heritable translocation study, which by conservative interpretation might imply some germ-cell risk associated with exposure to LAAM.

Mescaline (MES) and d-amphetamine (AMP) served as reference agents in a study of acute toxic and behavioral effects of four methoxy derivatives of AMP: dl-4-methoxyamphetamine (PMA), dl-2,5-dimethoxyamphetamine (DMA), dl-2,5-dimethoxy-4-bromoamphetamine (DOB), and dl-2,5-dimethoxy-4-methylamphetamine (DOM). Acute (24-hr) LD50 values were determined in mice (iv and oral), rats (ip), and dogs (iv). Estimation of the iv lethal dose range for each agent was conducted in a small number of rhesus monkeys. In terms of millimoles per kilogram of the base, MES was consistently the least toxic, whereas DOB or DOM was the most toxic for all species except the mouse. AMP was the most toxic for the mouse and was third in toxicity for all other species. At lethal and sublethal doses of these agents, observations were made for their effects on automatic, motor, and CNS functions and on behaviors possibly correlating with human hallucinogenic effects. According to the resulting profiles, DMA, DOM, and DOB had effects most similar to those of MES, whereas PMA had more in common with AMP. Howeve, PMA, like the other three derivatives and mescaline, caused visual tracking in monkeys and dogs, a sign which may reflect a hallucinatory action.

Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vitro assays. initial report describes the results for one of these compounds, Naltrexone. Nal trexone is a relatively nontoxic drug antagonist related to Naloxone which appears to be effective in diminishing the euphoria and dependence upon heroin in clinical studies. With the exception of weak nonspecific DNA damage observed in an g. coli DNA repair test and possibly with WI-38 cells as well, Naltrexone did not demonstrate significant potential for the i nduction of gene mutations or chromosomal aberrations under the conditions of this evaluation.

Several compounds used clinically in drug abuse therapy were evaluated for genetic activity in a series of in vitro assays. This initial report describes the results for one of these compounds, Naltrexone. Nalrexone is a relatively nontoxic drug antagonist related to Naloxone which appears to be effective in diminishing the euphoria and dependence upon heroin in clinical studies. With the exception of weak nonspecific DNA damage observed in an E. coli DNA repair test and possibly with WI-38 cells as well, Naltrexone did not demonstrate significant potential for the induction of gene mutations or chromosomal aberrations under the conditions of this evaluation.

The acute, reciprocal dose-response interactions between Δ9-tetrahydrocannabinol (Δ9 - THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three stimulants - d-amphetamine (dA; 1, 2 and 4 mg/kg; IP), cocaine (COC; 10, 20 and 30 mg/kg; IP), and nicotine (NIC; 0.25, 0.5 and 1.0 mg/kg; IP) were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. Δ9 - THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three stimulants influenced CAR performance, but dA and COC increased the number of intertrial responses, and this latter effect was partially antagonized by Δ9 - THC. dA and COC, but not NIC, stimulated photocell activity. Δ9-THC completely blocked this effect of dA, whereas there was mutual antagonism between Δ9 - THC and COC on this measure and NIC markedly potentiated the depression caused by Δ9 - THC. dA and COC tended to offset the impairment of rotarod performance caused by Δ9 - THC, whereas NIC augmented it. The bradycardia and hypothermia caused by Δ9 - THC tended to be augmented by these stimulants, especially NIC. The interactions were also studied after subacute treatment for six days with Δ9 - THC and/or each of the three stimulants. There was evidence for tolerance to the effects of Δ9-THC on all measures and this tolerance generally resulted in less interactive effects between Δ9 - THC and the stimulants. Little or no tolerance was seen for the effects of the three stimulants of their interaction with Δ9 - THC. The time course of radioactivity derived from 14C-Δ9-THC and each of the radiolabelled stimulants was determined in plasma and brain. Only minor interactive effects were found and, in general, they could not account for the functional interactions.

When rats in a standardized deprivation-induced fluid consumption test system were given single doses of a variety of narcotic antagonists, dose-dependent reductions in fluid intake were obtained, once a threshold level was reached. Sub-threshold doses of the antagonists were without effect. In contrast, a variety of narcotic agonists, produced biphasic responses, with an initial dipsogenic effect followed by a subsequent dose-dependent decrease in fluid consumption as doses were increased.

delta9-Tetrahydrocannabinol (THC; 2.5, 5.0, 10.0 mg/kg, PO) impaired avoidance and rotarod performance, and caused bradycardia and hypothermia. Phencyclidine (PCP; 1.25, 2.5, 5.0 mg/kg, IP) impaired avoidance and rotarod performance and caused a marked increase in photocell activity. When combined, the depressant properties of each drug were enhanced and the stimulation of photocell activity cg/kg THC and its interactions with PCP followed subacute treatment for six days, whereas many of the effects of PCP were enhanced after subacute treatment with a dose of 2.5 mg/kg. Open-field behavior was affected by each drug alone and in combination in a similar way as photocell activity, but the depression caused by their interaction was greater; both drugs caused an increase in urination. Response rates on an FR-10 schedule of food reinforcement were decreased by 2.5 mg/kg PCP, but not by 5.0 mg/kg THC; the combination caused greater response suppression than either drug alone. The functional interactions between THC and PCP were not related to changes in the concentrations of 14C or 3H in plasma or brain derived from 14C-delta9-THC and 3H-PCP, respectively.

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.

The acute, reciprocal dose-response interactions between Δ9-tetrahydrocannabinol (Δ9-THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three depressants — phenobarbital (PB; 10, 20 and 40 mg/kg; IP), ethanol (ETOH; 0.5, 1.0 and 2.0 g/kg; IP), and chlordiazepoxide (CDP; 2.5, 5.0 and 10.0 mg/kg; IP) — were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. Δ9-THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three depressants significantly influenced CAR performance but they all decreased photocell activity and impaired rotarod performance at one or more doses. PB and ETOH also decreased heart rate and body temperature at the highest doses. When combined with Δ9-THC each of the three drugs at some dose combinations caused greater depressant effects on most measures than caused by either drug alone. Only CDP did not augment the impairment of CAR performance caused by Δ9-THC. The highest dose combinations of Δ9-THC and each of the three drugs almost completely eliminated photocell activity and rotarod performance. The interactions were also studied after subacute treatment for six days with Δ9-THC and/or each of the three depressants. There was clear evidence for tolerance to the effects of Δ9-THC and each of the depressants. There was also evidence for tolerance to the effects of PB and ETOH on some measuresbut not CDP. The reduction of effects alone or combined with Δ9-THC could be accounted for by assuming a partial loss of potency after subacute treatment that decreased the pharmacologically effective doses of either or both interacting drugs.

Chronic treatment for 12 weeks in rhesus monkeys with α-ℓ-acetylmethadol (LAAM) or methadone failed to cause clinically significant changes in various parameters of blood biochemistry, hemotology, or liver function. However, one of four monkeys showed recurrent episodes of LAAM-induced depression during the 12-week period of chronic treatment.