The effect of (minus)-delta 9-trans-tetrahydrocannibinol on myocardial contractility and venous return in anesthetized dogs

Administration of (?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC, 2.5 mg/kg i.v.) to pentobarbital-anesthetized dogs in which heart rate was maintained constant by electrical pacing, decreased aortic blood pressure, cardiac output, left ventricular peak pressure and left ventricular end diastolic pressure and dP/dt. However, the contractility index (max. dP/dt)/I.P. was not altered by the compound. Furthermore, it was shown that the decrease in cardiac output due to Δ⁹-THC could be restored to original levels by an infusion of saline-dextran in quantities sufficient to elevate the left ventricular end diastolic pressure to pre-Δ⁹-THC level.In dogs in which cardiac output was maintained constant by a right heart bypass procedure Δ⁹-THC decreased blood pressure and total peripheral resistance and augmented intravascular blood volume. This increase in intravascular blood volume was significantly less (74%) in animals in which the splanchnic (superior, inferior and celiac) arteries were ligated prior to the administration of Δ⁹-THC. On the other hand, in spinal dogs Δ⁹-THC was devoid of any measurable cardiovascular effects.These observations clearly support the hypothesis that the diminution of cardiac output induced by Δ⁹-THC in animals with constant cardiac rate is primarily due to diminished venous return to the heart and not to an impaired ability of the myocardium.     

Role of the central autonomic nervous system in the hypotension and bradycardia induced by (-)-delta 9-trans-tetrahydrocannabinol

(-)-Δ⁹-trans-Tetrahydrocannabinol (Δ⁹-THC), when given intravenously (2 mg kg^?1) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (C₁-C₂) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of Δ⁹-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after Δ⁹-THC administration. These observations support the hypothesis that Δ⁹-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that Δ⁹-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that Δ⁹-THC did not interact with α- or β- adrenoceptors. The possible action of Δ⁹-THC on central sympathetic structures was investigated by perfusion of Δ⁹-THC into the lateral cerebral ventricle. Δ⁹-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or ¹⁴C-Δ⁹-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that Δ⁹-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone.     

Interactions of Δ9-tetrahydrocannabinol with phenobarbital,ethanol and chlordiazepoxide

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.     

Hypothermic effects of intraventricular and intravenous administration of cannabinoids in intact and brainstem transected cats

Δ⁹-Tetrahydrocannabinol (Δ⁹-THC, 500 μg in 40 μl), and the synthetic cannabinoid Dimethylheptylpuran (DMHP, 75 μg in 6.0 μl) were injected into ventricles III or IV of chronically implanted unanesthetized cats to determine the effect on body temperature. The hypothermia induced by administration of Δ⁹-THC into ventricle IV was faster in onset and reached a greater maximum than that induced by ventricle HI administration. Five hundred μg (i.v.) of Δ⁹-THC produced significantly less hypothermia than interventricular microinjection.Administration of Δ⁹-THC (2 mg/kg i.v.) to animals with a midcollicular transection produced significant decreases in blood pressure, heart rate, and body temperature when compared to animals receiving vehicle alone. Cats transected at C-1 were utilized to determine the rate at which body temperature was lost in animals unable to temperature regulate. Δ⁹-Tetrahydrocannabinol had no effect in these preparations indicating that direct peripheral mechanisms have little or no role in Δ⁹-THC induced hypothermia. It was further noted that Δ⁹-THC had little effect on blood pressure or heart rate in C-1 transected animals. These findings suggest a caudal brain stem site of action for the hypothermie effect of the cannabinoids.     

Studies on the bradycardia induced by (-)- -trans-tetrahydrocannabinol in anesthetized dogs

(?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC) (39 μg-5 mg/kg, i.v.) decreased heart rate in a dose related manner in dogs under pentobarbital anesthesia. This cardiac effect of Δ⁹-THC was neither due to an impairment of transmission across the sympathetic ganglia nor to a specific stimulation of parasympathetic ganglia. Selective blockade of either parasympathetic (atropine, bilateral vagotomy) or sympathetic (propranolol, spinal section at C₂C₄ neurogenic activity to the heart partially prevented the negative chronotropic effect of Δ⁹-THC. However the bradycardic effect of Δ⁹-THC was completely abolished in animals in which the autonomic pathways to the heart were pharmacologically or surgically inactivated.Administration of Δ⁹-THC into the vascularly isolated, neurally intact cross-perfused head of dogs significantly slowed the heart rate in intact as well as debuffered recipients. This bradycardia was reduced in recipients in which the trunk was atropinized prior to cerebral administration of Δ⁹-THC into the femoral vein of the recipient in the dog cross circulation preparation also caused a significant decrease in heart rate which was essentially abolished either by bilateral vagotomy or by atropinization of the recipients.These results are compatible with the hypothesis that the negative chronotropic effects of Δ⁹-THC in dogs under pentobarbital anesthesia is of central origin and involves both a direct and reflexogenic alteration of central autonomic outflow regulating the heart rate.     

Influence of acute pretreatment with delta 9-tetrahydrocannabinol on the LD50 of various substances that alter neurohumoral transmission

Δ⁹-THC significantly influenced the acute lethal effects (24 hr after a single dose) in mice of several drugs which alter cholinergic, adrenergic and serotoninergic neurotransmission. The LD50 values of carbachol chloride, arecoline HCl, physostigmine salicylate and neostigmine methylsalicylate were all significantly potentiated after pretreatment with 20.0 mg/kg of Δ⁹-THC. Paradoxically, lethality produced by methacholine and exogenously administered acetylcholine were attenuated. Evidence for an α-adrenergic receptor blocking effect of Δ⁹-THC was noted by the significantly larger LD50 values for 1-norepinephrine bitartrate and phenylephrine HCl when each was given in combination with Δ⁹-THC. Moreover, bretylium tosylate and dl-α-methyl-p-tyrosine toxicities were also attenuated by pretreatment with Δ⁹-THC. Finally, the combination of Δ⁹-THC and cyproheptadine HCl was more toxic than the latter compound alone, suggesting an additive antiserotonin effect.     

Cannabidiol interferes with the effects of delta 9 - tetrahydrocannabinol in man

Based on previous observations that cannabidiol (CBD) blocks some effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) in laboratory animals, the present work was carried out to study possible interaction between CBD and Δ⁹-THC in human beings. In a double blind procedure, 40 healthy male volunteers were assigned to 1 of 8 experimental groups, receiving per oral route, placebe, 30 mg Δ⁹-THC, 15 30 or 60 mg of CBD, and mixtures of 30 mg of Δ⁹-THC plus either 15, 30 or 60 mg of CBD respectively. Pulse rate, time production tasks and psychological logical reactions were measured at several time intervals after drug ingestion. 30 mg Δ⁹-THC alone increased pulse rate, disturbed time tasks and induced strong psychological reactions in the subjects. 15–60 mg of CBD alone provoked no effects. On the other hand, CBD was efficient in blocking most of the effects of Δ⁹-THC when both drugs were given together. CBD also decreased the anxiety component of Δ⁹-THC effects, in such a way that the subjects reported more pleasurable effects.     

Central excitatory properties of Δ9-tetrahydrocannabinol and its metabolites in iron-induced epileptic rats

The effects of δ⁹-tetrahydrocannabinol (Δ⁹-THC), two of its metabolites, 8β-hydroxy-Δ⁹-THC and 11-hydroxy-Δ⁹-THC, and cannabidiol were comparatively studied by means of an iron-induced cortical focal epilepsy in conscious rats with chronically implanted electrodes. Δ⁹-Tetrahydrocannabinol produced depression of the spontaneously firing epileptic focus, excitatory behavior, generalized after-discharge-like bursts of epileptiform polyspikes and frank convulsions. The pharmacological profiles of the two metabolites differed from that of the parent compound: 11-Hydroxy-Δ⁹-THC did not precipitate convulsions, but it did elicit all the other effects of Δ⁹-THC; the 8β-hydroxy derivative, on the other hand, exerted only two Δ⁹-THC-like effects; that is, it evoked polyspike bursts and convulsions. In contrast, cannabidiol, even in large doses (100 mg/kg) was devoid of all the effects of Δ⁹-THC. Furthermore, pretreatment with cannabidiol markedly altered the responses to Δ⁹-THC in the following ways: focal depression was partially blocked, polyspike activity was enhanced and convulsions abolished. Phenytoin pretreatment elicited similar effects, but it failed to block the Δ⁹-THC-induced convulsions. In general, the cannabinoids exhibit a wide spectrum of CNS effects ranging from focal depression to convulsions; specifically, however, the pharmacological profile of each agent can differ markedly; for example, the convulsant properties of Δ⁹-THC are not a universal characteristic of this class of drugs.     

Tolerance to the hypothermic and aggression-attenuating effect of delta 8 - and delta 9 - tetrahydrocannabinol in mice

The effects of repeated administration of Δ⁸-andΔ⁹-tetrahydrocannabinol (Δ⁹-and Δ⁹-THC) on both temperature aggression of isolated aggressive mice were investigated. In the first experiment, Δ⁹-THC, mg/kg, caused significant hypothermia and diminished aggression. Acute tolerance to the hypothermic effect developed, which significant hypothermia and diminished aggression. Acute tolerance to the hypothermic effect developed, which could be overcome by doubling the dose. In the same mice no tolerance to the aggression inhibiting effect was seen. In the second experiment Δ⁸- and Δ⁸-THC were compared. Both compounds caused a dose-dependent decrease of body temperature. The effect of Δ⁹-THC on body temperature was about 1.5 times as strong as that Δ⁸-THC. Tolerance to the hypothermic effect appeared in one day for the 10 mg/kg dose, and in about 3 days in the 25 mg/kg group; no tolerance was seen to the aggression-attenuating effect.     

Tolerance to the effects of Δ9-THC on shuttle-box performance and body temperature

Two groups of rats were trained in a shuttle-box and received Δ⁹-tetrahydrocannabinol (Δ⁹-THC), either before of after being tested. The drug-before group showed tolerance — within 3–6 sessions — to the response-inhibiting effect of THC. The drug-after animals appeared also to be tolerant when they received Δ⁹-THC before being tested. It is concluded that the tolerance to this effect probably is not learned, but has a physiological base. This is corroborated by the finding that during the same study all the animals developed tolerance to the hypothermic effect of Δ⁹-THC.     

Influence of several anesthetic agents on the effects of Δ9-tetrahydrocannabinol on the heart rate and blood pressure of the mongrel dog

Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) 1 mg/kg, i.v. produced a slight but significant reduction in the heart rate of conscious mongrel dogs, and these effects were greatly potentiated by pentobarbital and/or urethane anesthesia. However, significant increase in the heart rate was noted following Δ⁹-THC administration in the dogs anesthetized with a combination of morphine plus chloralose; further, neither morphine nor chloralose alone could reverse the bradycardic effects of Δ⁹-THC. Tachycardia induced by Δ⁹-THC in these dogs could be reversed by bilateral vagotomy or by pretreatment of the animals with methylatropine, or propranolol and/or practolol. The data indicated a complex interaction between Δ⁹-THC and morphine-chloralose combination and the tachycardia induced by Δ⁹-THC under this anesthesia may be due to release of epinephrine by a reflexogenic mechanism involving afferent vagi. Further, while the bradycardic effects of Δ⁹-THC were essentially identical under pentobarbital or urethane anesthesia, the hypotensive effects were similar in urethane or chloralose anesthetized dogs. The study emphasizes that anesthetic interaction should be taken into consideration while investigating mechanisms of actions of pharmacological agents.     

Effects of delta1-tetrahydrocannabinol on schedule-induced aggression in pigeons

The effects of Δ¹-tetrahydrocannabinol (Δ¹-THC) on key-pecking maintained by a response-initiated fixed interval (FI) schedule of food presentation and schedule-induced aggression in the pigeon were studied. The rate of attack responses was suppressed more than the rate of key-pecking, relative to their vehicle control rates, following the administration of Δ¹-THC (Experiment 1). In order to determine if the relatively selective effect of Δ¹-THC on attack rate was the result of a rate-dependent drug effect, the rates of key-pecking and attack responding were equated prior to drug administration in Experiment 2. Again a selective decrease in the rate of attack responses by Δ¹-THC, compared to its effects on key-pecking, was observed when the rate of the two behaviors was comparable. The suppressing effect of Δ¹-THC on attack responses cannot be attributed to a generalized motor impairment, since doses of Δ¹-THC (0.125 and 0.25 mg/kg) which had little or no effect on the rate of key-pecking resulted in substantial decreases in the rate of attack responses.     

Factors inflencing tolerance to the effects of Δ9-THC on a conditioned avoidance response

Male, Fischer strain rats were resistant to the impairing effects of Δ⁹-THC (15–60 mg/kg, IG) on performance of a conditioned pole-climb avoidance response (CAR) after daily subacute pretreatment for 4 or 6 days. A single administration of 20 mg/kg Δ⁹-THC independent of the performance test did not attenuate the subsequent impairment caused by Δ⁹-THC when tested 1–6 days later; however, administration 2 hr before each test attenuated the effect on subsequent tests given at intervals of 1–5 weeks. Similarly, subacute treatment with 20 mg/kg Δ⁹-THC for 4 days independent of the performance test attenuated the impairment caused by Δ⁹-THC during tests given to separate groups of rats 1 or 6, but not 14 days later. However, when the tests for tolerance were conducted repeatedly in the same rats, the attenuation appeared to persist for intervals up to 5 weeks. The results are discussed in terms of metabolic, functional and compensatory (behavioral) tolerance.     

The effect of cannabinoids (Δ9-THC and Δ8-THC) on hepatic microsomal metabolism of testosterone in vitro

The effects of Δ⁹-THC and Δ⁸-THC on testosterone metabolism by rat liver microsomal enzymes were studied in vitro. Δ⁹-THC (25 μM) inhibit the 5α-reduction of testosterone while Δ⁸-THC has no effect at double the concentration. Both Δ⁹-THC and Δ⁸-THC inhibit the hydroxylation of testosterone. This inhibition is dose dependent over the dose range (25–100 μM) tested. At the same molar concentration, Δ⁸-THC inhibits testosterone hydroxylation to a greater extent than Δ⁹-THC. The kinetic data suggest that the observed inhibition on 5α-reduction and total hydroxylation by the tetrahydrocannabinoids is of the competitive type.     

Interaction of cannabinoids with pentobarbital in rats

The effect of cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), Δ⁸-tetrahydrocannabinol (Δ⁸-THC), and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) on the in vivo metabolism of [¹⁴C]pentobarbital (¹⁴C-P) was investigated in rats. The cannabinoids were administered ip (20 mg/kg) 30 min prior to either oral or iv treatment with ¹⁴C-P. When ¹⁴C-P was given po, the ¹⁴C blood concentrations were initially depressed and later elevated by CBG and CBD, increased by Δ⁸-THC and Δ⁹-THC and unaffected by CBN. When ¹⁴C-P was injected iv, the blood ¹⁴C values were elevated by CBD and unchanged by CBG, Δ⁸-THC or Δ⁹-THC. Urinary excretion of total ¹⁴C and the metabolites of P was decreased by CBD, CBG and Δ⁸-THC during the first 6 hr following treatment. The effect of CBD on the blood concentration and urinary excretion of ¹⁴C was dose-related. In rats treated with CBD + P, the liver and serum concentrations of P metabolites were significantly lower and the liver, serum and brain concentrations of unmetabolized P were significantly higher than in P-treated rats. Pentobarbital induction and sleeping times were potentiated by CBD and Δ⁹-THC and antagonized by CBG. It was concluded that CBD delayed P metabolism, CBG decreased the rate of P absorption and excretion. Δ⁸-THC and Δ⁹-THC decreased elimination of P and CBN had little effect on P absorption, metabolism or excretion. The effect of CBD + P on sleeping time was correlated with brain P concentrations.     

Oral delta9-tetrahydrocannabinol toxicity in rats treated for periods up to six months.

The chronic toxicity of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) given orally 28, 90, and 180 days to Fischer rats at doses of 2, 10, and 50 mg/kg was investigated. Some 180-day treated animals were monitored after a 30-day recovery interval. The lower doses used corresponded to the Δ⁹-THC content of marihuana or hashish. In the first 10 days CNS-depression, incoordination, ataxia and passivity, poikilothermia, and hypopnea occurred to which tolerance developed. During days 10–20, irritability, hypersensitivity, hyperactivity, and aggression predominated. Fighting occurred between days 20–100. Tremors and clonic convulsions appeared after day 70 in 50% of the animals at 50 mg/kg and 12% at 10 mg/kg. Tolerance developed to CNS-stimulation, fighting and neurotoxicity and lethal cumulative toxicity was seen although the cause of death was not established. Growth rate of both sexes was inhibited despite an elevation in food consumption after a transient anorexia No morphological changes could be ascribed to Δ⁹-THC. Except for a rise of 28–45% in SGOT and 46–69% in SGPT in males at higher doses and a belated hyperglycemia in both sexes, clinical chemistry, hematological, and urinalysis parameters were within normal ranges. The greatest changes were seen in ratios of organ/FBW at 50 mg/kg: 10–20% increase in brain, lungs, kidneys, heart, and liver; 45% increase in adrenals; 96% increase in male pancreas and 13–25% increase in testis and prostate. The present investigation implicated reasonable doses of Δ⁹-THC in undesirable behavioral changes highlighted by fighting aggression, convulsive activity, and lethal cumulative toxicity. The absence of morphological changes despite changes in growth rate and organ weights indicated a functional impairment that was not an immediate threat to the life of the organism because of initiation of as yet unknown protective mechanisms.     

Comparison in mice of pharmacological effects of delta 8-tetrahydrocannabinol and its metabolites oxidized at 11-position

Pharmacological effects of Δ⁸-tetrahydrocannabinol (Δ⁸-THC) and its metabolites, 11-hydroxy-Δ⁸-THC, 11-oxo-Δ⁸-THC and Δ⁸-THC-11-oic acid were compared using mice. The cataleptogenic effect of the 11-hydroxy and 11-oxo metabolites was 5 and 1.5 times greater respectively, than that of the parent compound. The hypothermic effect of Δ⁸-THC, 11-hydroxy-Δ⁸-THC and 11-oxo-Δ⁸-THC was almost equivalent in both potency and duration at a dose of 10 mg/kg i.v., but the metabolites exhibited a somewhat higher potency and longer duration that the parent compound at a dose of 5 mg/kg i.v. In addition, 11-hydroxy- and 11-oxo-Δ⁸-THC were more active to prolong pentobarbital-induced sleeping time than Δ⁸-THC. In spite of the loss of cataleptogenic and hypothermic effects, Δ⁸THC-11-oic acid slightly prolonged pentobarbital-induced sleeping time at a dose of 10 mg/kg i.v. The LD₅₀s (i.v.) with their 95% confidence limits of Δ⁸-THC, 11-hydroxy-Δ⁸-THC and 11-oxo-Δ⁸-THC were estimated to be 27.5 (23.1–32.7), 110.0 (79.1–152.9) and 63.0 (54.5–72.8) mg/kg (P < 0.05), respectively. No animals were killed with the 150 mg/kg dose of Δ⁸-THC-11-oic acid.These results indicate that both 11-hydroxy- and 11-oxo-Δ⁸-THC can be categorized as active metabolites of Δ⁸-THC. Further studies are necessary, however, to clarify whether or not these metabolites contribute, at least in part, to the effect of Δ⁸-THC on biological systems in vivo.     

A study of teratological effects of intravenous, subcutaneous, and intragastric administration of delta9-tetrahydrocannabinol in mice.

Delta-9-tetrahydrocannabinol (Δ⁹-THC) has been recognized to be the principal psychoactive component of cannabis. Pregnant Swiss Webster mice were given single treatments of Δ⁹-THC at doses ranging from 3.0 to 400 mg/kg by the iv, sc, and po routes on gestational Days 7 to 11. Untreated and vehicle-injected controls were used for each series. All fetuses were examined on Day 18 of gestation. Significant fetal growth retardation was induced by several dose levels. No malformations were found after single iv doses of 10 and 20 mg/kg of Δ⁹-THC. Subcutaneous injections of 6.25 mg/kg of Δ⁹-THC produced few abnormal fetuses (3.9%). However, a high po dose of 400 mg/kg given on Day 9 was teratogenic; 12.1% of the live fetuses were malformed. Fetuses from DBA mice given single po doses of Δ⁹-THC on Days 8, 9, or 10 of pregnancy also had a significantly increased incidence of gross external abnormalities as compared to corresponding controls; 23% of the fetuses from dams given 200 mg/kg of Δ⁹-THC on gestational Day 10 were abnormal. Skeletal anomalies were also induced in fetuses from dams treated with 200 mg/kg of Δ⁹-THC on Day 10 by gastric intubation. These results are considered in relation to previous reports of a complete lack of teratogenic activity of multiple exposure to Δ⁹-THC and a highly significant teratogenicity of crude extracts of cannabis in experimental animals.     

Involvement of brain histamine in Δ9-tetrahydrocannabinol tolerance and withdrawal

The involvement of brain histamine (HA) in Δ⁹-tetrahydrocannabinol (Δ⁹-THC) tolerance and dependence was studied in rats. Rats treated for 5 days with Δ⁹-THC (2–6 mg/kg, IV) developed tolerance to the hypothermic effects of the drug. Tolerance also developed over the 5 day period to the decrease in brain regional HA concentrations observed after an acute injection of Δ⁹-THC. Administration of the tricyclic antidepressant drug clomipramine hydrochloride to tolerant rats induced a withdrawal-like behavioural syndrome. Accompanying this behaviour was a fall in HA concentrations of the midbrain, cortex, medulla oblongata/pons and the cerebellum. Administration of Δ⁹-THC, but not of the Δ⁹-THC vehicle, prior to clomipramine challenge attenuated both the intensity of the withdrawal-like syndrome and the reductions in brain regional HA concentration.