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Synthetic delta 9-tetrahydrocannabinol (THC) was dissolved in undiluted propylene glycol and administered in daily subcutaneous doses of 15.0, 30.0 or 60.0 mg/kg to pregnant New Zealand white rabbits on days 7--19 of gestation. Maternal food consumption and weight gain were markedly reduced at all dose levels. Embryotoxicity and embryocidal effects were observed in the form of reduced litter weight and number of viable fetuses, respectively, in offspring from pregnant mothers treated with THC. However, on the basis of extensive external, visceral and skeletal examination of all fetuses it may be concluded that THC is not teratogenic in the New Zealand white strain rabbit following subcutaneous administration of doses as high as 60.0 mg/kg/day during the critical period of organogenesis (days 7--19 of gestation). On the other hand, an oral dose of thalidomide (200.0 mg/kg/day), the positive control used in this study, was both embryocidal and teratogenic.

delta9-Tetrahydrocannabinol (THC) inhibited ulcer formation in the pylorus-ligated rat (Shay rat test). However, this antiulcer activity of THC was substantially less than for the anticholinergic substance tridihexethyl chloride both in terms of degree of activity and potency. In addition, the results of the present study suggested different mechanism(s) of action for the antiulcer effects of these substances.

Delta-9-Tetrahydrocannabinol (THC) was dissolved in propylene glycol and 25, 50, or 100 mg/kg administereed dialy sc to pregnant Charles River Sprague-Dawley rats on days 6-15 of gestation (presence of sperm considered day 1). Maternal weight gain was depressed, but a significant decrease in fetal weight occurred only in the 50 mg/kg group. No malformations were noted, only some abnormalities consisting of several instances of rudimentary 14th rib and soft or spongy spinal cords.

Delta9- Tetrahydrocannabinol (THC) was administered subcutaneously to female New Zealand white strain rabbits for 13 days. The animals were randomly divided into six groups of five animals each of which consisted of untreated controls, vehicle (undiluted propylene glycol)-treated, and THC treatment at dose levels of 100, 30, 10, and 3 mg/kg/day. All animals survived for the duration of the study. The THC-treated rabbits did not gain significant body weight which seems to be due to a decreased food consumption. There were some variations in various hematologic values, but they all were within the normal range for our laboratory. Blood chemistry evaluations showed decreased serum levels of potassium, glucose, blood urea nitrogen, alkaline phosphatase, and albumin/globulin (A/G) ratio and an increase in cholesterol levels of all treated animals. A significant increase in billirubin values was noted in the animsls of the 3- and 10-mg/kg groups. The injection site in the skin of the THC-treated rabbits showed signs of local irritation (erythema and subcutaneous abscesses). There was a reduction in absolute and percent of body weight of the liver and absolute weight of the lungs of the treated animals. However, no histopathologic alterations were observed. It may be concluded that THC treatment subcutaneously for 13 days in rabbits up to a dose level of 100 mg/kg/day did not produce any significant toxicity, except anorexia and some local dermal irritation.

Tetrabenazine evoked a biphasic response in rectal temperature of the rat following intraperitoneal administration of 4.4--70.0 mg/kg. The initial hyperthermia was inversely related to the dose while the subsequent hypothermia was dose-dependent. This biphasic effect on temperature was similar to that seen with THC at 0.5 mg/kg, thus adding further evidence of a similarity in the mode of action of the two drugs. In contrast, only hypothermia was evident following chlorpromazine administration.

The level of serotonin (5-HT) was increased in the whole rat brain as well as in the hypothalamus plus midbrain region at 0.5 hr after the fifth or sixth daily dose of delta9-tetrahydrocannabinol (THC), 20.0 mg/kg, i.p., respectively. A decreased rate of 5-HT synthesis was also observed. A slight development of tolerance was indicated by the fact that elevation of 5-HT was smaller than that seen after a single dose (1).

delta9-Tetrahydrocannabinol (THC) was compared with diphenylhydantoin (DPH), phenobarbital (PB) and chlordiazepoxide (CDP) using two electroshock procedures to determine anticonvulsant activity in mice, i.e., electroshock seizure threshold (EST) and the reduced EST caused by hyponatremia (injection of isotonic glucose). Using doses of each drug which were ineffective against MES, only CDP (10.0 mg/kg) was able to raise the EST by 20%. The lowered EST due to hyponatremia was reveresed by al four drugs. In these tests latency to convulsions and lethality associated with electroshock were more sensitive to THC.

delta 9-Tetrahydrocannabinol (THC) markedly potentiated barbital Na sleeping time in mice and rats. The magnitude and duration of this effect were markedly enhanced when the animals were pretreated with SKF 525-A, a nonspecific inhibitor of liver microsomal enzymes responsible for drug metabolism. Moreover, depending on the method and species of animal used, THC was found to be one half (mouse hot plate), one third (mouse tail flick), and one eighth (rat tail flick) as potent an analgesic as morphine SO4. However, pretreatment with SKF 525-A significantly potentiated the analgesic activity in mice. These data suggest that intact THC and not necessarily a metabolite(s) is principally responsible for the CNS depressant and analgesic effects observed.

Delta9-tetrahydrocannabinol (THC) was compared with diphenylhydantoin (DPH), phenobarbital (PB) and chlordiazepoxide (CDP) using several standard laboratory procedures to determine anticonvulsant activity in mice, i.e., the maximal electroshock test (MES), and seizures induced by pentylenetetrazol, strychnine and nicotine. In the MES test, THC was the least potent and DPH the most potent blocker of hind limb tonic extensor convulsions whereas THC was the most potent and DPH the least potent in increasing the latency to this response and in preventing mortality. Seizures and mortality induced by pentylenetetrazol or by strychnine were enhanced by THC and DPH and were blocked by PB and CDP. In the test with nicotine, none of the four anticonvulsant agents prevented seizures; DPH was the only one which failed to increase latency; THC and DPH were less potent than PB and CDP in preventing mortality. THC most closely resembled DPH in the tests with chemical convulsant agents, but a sedative action of THC, resembling that of PB and CDP, was indicated by low ED5 0 for increased latency and for prevention of mortality in the MES test.

THC was neither ulcerogenic in 'semi-fasted' of 18-hour fasted rats following an oral dose of 100.0 mg/kg nor did it promote fecal blood loss (51Cr-labelled erythrocyte test) in the fasted rat after a dose of 200.0 mg/kg. On the contrary, 200.0 mg/kg of acetylsalicylic acid was ulcerogenic and caused fecal blood loss in the fasted rat. Neither substance caused mortalities at the doses tested.