Search

Male Mongolian gerbils were trained to escape electric shocks in a T-shaped maze contingent upon the presence or absence of certain drug effects (state-dependency; StD). The drug discriminative cues used were those of either delta9-tetrahydrocannabinol (THC) or pentobarbital (P-barb.) vis-à-vis the respective vehicles. Several doses of THC (0.5-16.0 mg/kg) were used and compared with P-barb. (20.0 mg/kg), a dose at which the most rapid drug discrimination occurs in the rat. When drug discrimination was established dose-time- and transfer characteristics for the training drugs were studied. Possible potentiation and antagonism was also examined in the pentobarbital trained gerbils. It was found that none of the THC doses were discriminated as rapidly as that of P-barb. Decreasing the amounts of training drug administered or increasing the injection-test intervals resulted in a decline of the number of drug associated choices. There was a maximum of 40% drug choices between THC and P-barb at the transfer tests. Mixtures of the two compounds increased the number of drug choices in an additive or even more than additive manner. Amphetamine (4.0 mg/kg) did not interact with the P-barb. induced choice responding. The analeptic drug, bemegride was found effective in antagonizing the P-barb. cued choice behavior.

Chronic treatment of monkeys with Cannabis reduce the speed of acquisition of learned behavior, yet, learning is nevertheless possible. After acquisition, Cannabis administration disturb the responses in the learning test. In this two experimental procedures, tolerance occurs to the effects of Cannabis.

The authors used several indices to assess the relationship between marijuana and hostility as both inner affect and verbal behavior in a small-group setting. Marijuana subjects reported a small but statistically significant decrease in hostile feelings after the introduction of a frustration stimulus. They also showed significantly less verbal hostility than placebo subjects both before and after introduction of a frustration stimulus. The authors note that research findings on marijuana and hostility are not consistent and suggest a multidetermined relationship based on dose, environment, nature of the frustration stimulus, and intraindividual factors.

In an operant situation pigeons learned to peck one response key 90 min after an injection of 0.25mg/kg delta9-tetrahydrocannabinol (delta9-THC) and another key when trained nondrugged. When tested with doses of delta9-THC lwer than the training dose the birds disciminated 0.20 mg/kg of the drug from the nondrugged state but not 0.15 mg/kg or lower doses. The animals were able to discriminate the drug state from the nondrugged 180 min but not 360 min after the injection At a shorter interval (45 min) both drug and nondrug responding appeared. Cannabinol and cannabidiol (4.0 - 8.0 mg/kg) did not elicit any drug responses, nor did pentobarbital, ditran or amphetamine. Tests with LSD resulted in both drug and nondrug responding. When administering noncannabinoid drugs in combination with delta9-THC 0.15 mg/kg the birds responded at the key associated with the drug state, suggesting interactional effects.

Marihuana or placebo cigarettes were smoked by 12 subjects in two environments, one "favorable" and one "neutral". The object was to determine the contribution of setting to the effects reported from the drug. Two quantifiable self-report measurements, the linear euphoriant scale and the card-sort version of the Addiction Research Center Inventory (marihuana and hallucinogen scales), were the major reporting criteria. Analyses of variance consistently demonstrated strong effects for subjects and drug but not for the environmental conditions. Reports of marihuana effects may be assumed to be highly colored by psychological differences in the mental set of subjects, or biological variations in their responses to the drug. The actual environment in which the drug is taken seems to play little, if any, role.

In this report we give the results of some experiments on the effects of the hashish constituents delta9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on mice. THC produced a dose dependent depression of aggression in isolated mice and a dose dependent depression of body temperature in group caged mice. The drug did not alter motor co-ordination. CBD showed a small, not significant influence on aggressiveness, and no in fluence on body temoerature and muscle control. The dame experiments were carried out with combinations of THC and CBD in several dosages. In these experiments no interaction between both compounds was seen. This means that there can only be an additive action and not potentiation in the pharmacological sense. It also means that the in vitro inhibition by CBD of the drug metabolizing enzymes, responsible for biotransformation of THC. is not strong enough to result in changed effects of THC in the living animal.

Chronic administration of delta9-tetrahydrocannabinol (THC) for 5--8 weeks at 4 dose levels (2, 10, 20, 50mg/kg/day) or of pilocarpine (12.5, 25 mg/kg/day) for 3 weeks induced mouse-killing in 25--70% of previously "non-killer" rats of the Sprague-Dawley strain. The maximum percent of drug-induced mouse-killing depended on the daily dose and housing conditions, 20mg/kg/day THC and 25 mg/kg/day pilocarpine in single-housed rats being the most effective treatments. Drug-induced mouse-killing appeared to be a form of behavioral pathology, differing from the species-specific predatory response, when it first appeared. Concurrent assessment of locomotor and rearing activities showed dose-dependent depressant effects of THC and pilocarpine without evidence for tolerance. Different dose-dependencies and time courses suggest that changes in motor activities are not directly linked to the appearance of the killing behavior.

Tritiated delta-9-tetrahydrocannabinol was administered orally to female rats throughout pregnancy at a dose level of 2 mg/kg/day. Chemical analysis of rat pup tissues indicated an average drug level near 20 ng/gm was attained via placental transfer. Although there was no teratogenicity, the pups showed both transient and relatively permanent behavioral effects. A deficit in acquisition of a passive avoidance response at 21 days of age was observed. This effect was not apparent during retraining and testing at 90 days of age. Rats whose dams had received the drug forced control animals to back out of a push tube in 67% of the tests at 21 days of age and 94% of the tests at 90 days of age.

Marijuana extract, given in daily doses containing 70 to 210 mg delta-9-tetrahydrocannabinol (THC), induced effects on sleep that were virtually identical to those produced by the same doses of relatively pure (96%) THC. Both drugs reduced eye movements density with some tolerance developing to this effect. Stage 4 tendend to increase with drug administration. Abrupt withdrawal led to extremely high densities of eye movement, increased rapid eye movement (REM) durations, and a sharp but transient fall in stage 4 to baseline levels. These effects may be useful in the elucidation of the pharmacology of sleep. The effects on sleep of THC administration (but not withdrawal) closely resemble those induced by lithium. For this reason, we suggest further studies of THC in affective disorders. Evidence available thus far suggests that THC produces dysphoric symptoms in unipolar but not in bipolar depressed patients; these differences in response may prove of diagnostic value. An adequate therapeutic trial of THC in bipolar depressed patients has not yet been carried out.

Fifty-five clinical trials were conducted to determine the cardiovascular combined effects of stressful oral surgery and systemic cannabinols. In a first study, delta9-tetrahydrocannabinol (THC) was given IV as a premedicant and compared with diazepam and with a placebo. A classic dose-related tachycardia followed THC injection. The peak heart rate response of patients premedicated with 0.044 mg/kg THC was 24.1% higher (p less than 0.05) than the peak effect for a nonsurgerized control group, suggesting a synergistic effect between THC and surgical stress. A predisposition to syncopal hypotension followed THC premedication, and antiarrhythmic effects were observed after large doses. The injection of local anesthetic preparations containing epinephrine did not alter THC cardiovascular response. An apparent drug interaction was observed, however, in a second study, in patients given general anesthesia within 72 hours after smoking marijuana. These patients demonstrated sustained abnormal postoperative tachycardia when compared with control nonsmokers, an effect which may have resulted from an interaction between stored cannabinol metabolites and atropine administered as part of the anesthetic technic. It was concluded that THC had no particular advantage over diazepam or placebo as a premedicant. Further, THC altered the patients' adaptivity to stress and interacted undesirably with other anesthetic medications.

Male albino rats were trained to respond differentially on the left or right lever in a 2-lever chamber on the basis of which drug had been given intra-peritoneally (IP) 30 min before experimentation. In 1 group 1.9 mg/kg of delta9-THC and control injections (vehicle) served as the discriminative stimuli associated with each lever and in another group the drug stimuli were 1.0 mg/kg of delta9-THC and 1.0 mg/kg of psilocybin. The results confirmed those of other experiments using different procedures; that delta9-THC can acquire discriminative control over responding. The fact that delta9-THC and psilocybin were also found to differentially control lever choice demonstrates that these 2 drugs probably produce discriminably different states in rats.

Cannabis cigarettes calibrated to deliver 7 mg delta9-THC were administered to experienced cannabis users and to novices in a 2 x 2 state-dependency learning design using psychomotor tasks. Subjects given four training sessions under marihuana performed no better on the fifth (test) session with the drug than those subjects who had trained in the non-drug condition and were tested in the drug condition. Cannabis-induced impairment in the performance of these tasks is such that prior training in the non-drug condition appears to confer no advantage to the subject. There was no evidence of state-dependency effects in psychomotor performance between drug and non-drug conditions.

Cannabis extract caused a marked reduction in the body weight and in the weights of seminal vesicles, ventral prostate, epididymis, preputial gland and perineal complex (Penis and its bulb and levator ani muscle) of castrated adult male mice. Cannabis extract administration in combination with testosterone propionate (TP) inhibited growth stimulation produced by TP alone. Anti-androgenic nature of the compound is suggested.

Several of the cannabinoids found in marihuana have been shown to inhibit tumor growth and increase the life-span of mice bearing the Lewis lung adenocarcinoma. When trypsin-dispersed isolated Lewis lung cells are incubated in vitro, they maintain their capacity to carry out macromolecular synthesis (RNA, DNA, protein). This process can be inhibited by cytosine arabinoside, actinomycin D, or methyl-1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, whereas cyclophosphamide, an agent that must be bioactivated, was inactive. Inhibition of DNA synthesis as measured by [3H]thymidine uptake into acid-insoluble material was used as an index of cannabinoid activity against isolated Lewis lung cells, L1210 leukemia cells, and bone marrow cells incubated in vitro delta9-, delta8-, 1-hydroxy-3-n pentyl-, and 1-delta8-tetrahydrocannabinol, and cannabinol demonstrated a dose-dependent inhibition of DNA synthesis whereas cannabidiol and 1-hydroxy-3-n-pentylcannabidiol were markedly less inhibitory in our in vitro cell systems. Furthermore, our in vitro observations with these cannabinoids are supported by in vivo tumor inhibition studies. Ring modifications as in cannabichromene or cannabicyclol abolish in vitro activity as does dihydroxylation at the 8beta and 11 positions of 1-delta9-trans-tetrahydrocannabinol. Delta9-trans-tetrahydrocannabinol demonstrated the least toxicity of all inhibitory cannabinoids in vivo; this is supported by its lesser effect on bone marrow DNA synthesis in vitro.

A group of experiments is described in which chimpanzees and orangutans are utilized as subjects in research projects designed to evaluate the effects of stimulant and depressant drugs on learning and performance. Efficiency of performance on a task which measures spaced responding was impaired when subjects smoked cigarettes containing delta9-tetrahydrocannabinol prior to testing. In a sequential learning task, these subjects also demonstrated reduced performance when stimulatn drugs were orally administered before testing. Depressant drugs did not produce comparable decrements in sequential learning performance. Physical and behavioral tolerance and dependence on ethanol were investigated in rhesus monkey subjects using a variety of experimental procedures, including forced oral acceptance, intragastric intubation, intravenous infusion, and conditioned voluntary oral acceptance.

The relation between marijuana consumption and the development of tolerance was investigated during a 31-day study. Volunteers with a history of moderate or heavy marijuana use were given access to one-gram (2.1% delta9 tetrahydrocannabinol [THC]) marijuana cigarettes during a 21-day smoking period. Both groups tended to increase consumption during this time. Heavy users averaged 5.7 cigarettes per day and indicated a progressive decline in ratings of intoxication and duration of pulse rate effect. Moderate users averaged 3.2 cigarettes per day but showed no changes in either of these reactions during this time. Results suggested that tolerance does not develop to the two most reliable indexes of marijuana intoxication unless heavy doses of delta9 THC are self-administered repeatedly. Also, the tendency to increase consumption during this time is not necessarily associated with the development of tolerance.

Nabilone is a modified cannabinol derivative with central nervous system activity. Administration of nabilone in single doses of 1 to 5 mg results in dose-related pharmacologic effects in man. One and 2.5 mg doses of nabilone induced relaxant and sedative effects in all subjects. No euphoria, dry mouth, tachycardia, or postural hypotension was seen after 1 mg, minimal effects were seen after 2.5 mg, and marked effects were seen after 5 mg. Effects were evident within 60 to 90 min and persisted for 8 to 12 hr. Nabilone produced no significant tachycardia. There were no changes in supine blood pressure; however, marked postural hypotension occurred after the 5-mg dose. The administration of nabilone at doses of 1 mg or 2 mg two times daily resulted in euphoria and dry mouth during the first two days of drug; thereafter tolerance developed to these effects but there was no apparent decrease in relaxation. Subjects challenged with a single 5-mg dose of nabilone showed a 66% reduction in symptoms and signs after the 7-day drug period compared to that of the same dose after 1 wk of placebo. Comparison of nabilone with other cannabinol derivatives suggests that some of the undesirable pharmacologic effects can be separated within the group.

The effects of delta8- and delta9-tetrahydrocannabinol on the biosynthesis of 3H-acetylcholine (ACh) from 3H-choline in cortical, hypothalamic and striatal rat brain slices were examined. The two cannabinols were found to inhibit the synthesis of 3H-ACh in the three brain regions. Treatment with cannabidiol did not alter ACh synthesis. Delta8-tetrahydrocannabinol was approximately twice as effective as the delta9-isomer. This effect was not associated with alterations in striatal and cortical choline acetyltransferase or with an impaired high-affinity uptake system for choline in the striatum. Treatment with delta8- and delta9-cannabinols, likewise, did not change striatal choline and ACh levels. Antagonism of the ACh biosynthesis inhibition occurred when slices from treated animals were incubated in depolarizing concentration of K+ ion. These results suggest that the inhibition of ACh synthesis observed in tetrahydrocannabinol-treated rats may be related to interference with the propagated action potential or with the depolarization process in cholinergic neurons.

Two experiments were performed with rats trained with either continuous reinforcement (food) or random 50% partial reinforcement for running in a straight alley. Half the rat were trained with daily injections of 0.5 mg/kg delta9-tetrahydrocannabinol (THC) and half with vehicle injections, all animals being extinguished with vehicle injections in Expt. 1 and with THC injections in Expt. 2. The partial reinforcement acquistion effect was abolished by THC during training; the partial reinforcement extinction effect was abolished by THC either during training of during extinction. In these respects THC resembles amylobarbitone and alcohol.

The respiratory effects of smoked marijuana and oral delta-9-tetrahydrocannabinol (delta9THC) have been studied in healthy males by assessing displacement of the respiratory response curve. Both cause slight respiratory depression, in some subjects it stimulates respiration. High doses of pentobarbital depress respiration but low doses apparently do not.

To investigate the hypothesis that delta-9-tetrahydrocannabinol (THC), the major psychoactive ingredient of marihuana, acts by interfering with cholinergic brain mechanisms, 0.75 to 1.25 mg of physostigmine, a centrally active cholinergic drug, was given intravenously to 5 normal volunteers who had ingested 20 to 40 mg of THC 2 hours earlier. Physostigmine decreased the degree of tachycardia and conjunctival injection produced by THC. The major psychologic effects of physostigmine were amplification of the lethargy and somnolence which occur late in the course of THC intoxication. We interpret the lack of physostigmine counteraction of the peak psychologic effects of THC as evidence against the hypothesis that THC acts predominantly by an anticholinergic mechanism.