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.     

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.     

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.     

Hemodynamic and myocardial effects of (-)-delta9-trans-tetrahydrocannabinol in anesthetized dogs

(?)-Δ⁹-trans-tetrahydrocannabinol (Δ⁹-THC) (39 μg–2.5 mg/kg, i.v.) decreased blood pressure, heart rate, cardiac output and right ventricular contractile force in a dose-related manner in intact dogs under pentobarbital anesthesia. The Δ⁹-THC-induced hypotension appeared to result mainly from a consistent and reproducible attenuation of cardiac output since no marked alteration in total peripheral resistance occured. In these animals the decrease in cardiac output appeared to be related to the bradycardia since there was no change in stroke volume following Δ⁹-THC. However, when the change in heart rate was prevented by atrial pacing or cardiac denervation, a less but significant reduction in cardiac output was induced by Δ⁹-THC. Under these experimental conditions Δ⁹-THC also significantly attenuated stroke volume. In contrast, Δ⁹-THC did not induce any significant changes in cardiac output, blood pressure, and heart rate of dogs pretreated with a ganglionic blocker.Δ⁹-THC appeared to be devoid of any measurable direct effect on the myocardium since the compound neither significantly altered right ventricular contractile force of the denervated or ganglionic blocker-pretreated hearts nor interfered with the positive inotropic responses to i.v. calcium and isoproterenol.In the major vessel occlusion preparation administration of Δ⁹-THC was followed by a reduction in venous tone. Furthermore, measurements of blood and plasma volume excluded an effect of Δ⁹-THC in these parameters.From these findings it is suggested that the reduction in cardiac output induced by Δ⁹-THC is the result of the action of this compound on cardiac rate as well as venous return; no evidence could be documented for a direct effect of this compound on the myocardium.     

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.     

GABAergic mediation in the inhibition of hippocampal acetylcholine turnover rate elicited by delta 9-tetrahydrocannabinol.

Both intravenous Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and intraseptal muscimol reduce the turnover rate of acetylcholine (TR_ACh) in the hippocampus by 50 and 58%, respectively, without affecting the hippocampal content of ACh. The ACh content and the TR_ACh, in other areas of rat brain examined are unchanged. Bicuculline fails to alter the hippocampal TR_ACh when administered intraseptally but prevents the decreased hippocampal TR_ACh induced by Δ⁹-THC or muscimol. The effect is specific to the septal-hippocampal cholinergic pathway since lesioning the fimbria (2 hr) abolishes the effect. Moreover, neither naltrexone nor destruction of septal dopaminergic nerve terminals with 6-hydroxy-dopamine injected into area A₁₀ prevents the decreased TR_ACh after Δ⁹-THC. This suggests that neither endophinergic nor dopaminergic neurons are involved in the reduction of the TR_ACh in the hippocampas following administration of Δ⁹-THC or muscimol. When the metabolism of γ-aminobutyric acid (TR_GABA) is measured, Δ⁹-THC produces a 2-fold increase in the TR_GABA which is specific for the septum. These results suggest that Δ⁹-THC inhibits TR_ACh in the cholinergic septal-hippocampal pathway by increasing the release of GABA from septal GABAergic interneurons.     

Antipyretic, analgesic and anti-inflammatory effects of delta 9-tetrahydrocannabinol in the rat

The effects on body temperature produced by graded doses of Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and phenylbutazone were compared in both normal and pyretic rats. Dose related hypothermic responses were produced by the oral administration of Δ⁹-THC in normal animals. Moreover, Δ⁹-THC significantly reduced elevated temperatures in yeast-induced pyretic rats to near normal levels at doses which exhibited little hypothermic activity in normal rats. The oral antipyretic potency of Δ⁹-THC was approximately 2 times that of phenylbutazone. The comparative oral antinociceptive activity of Δ⁹-THC and selected narcotic and non-narcotic analgesics was determined by the increase in response latency to pressure applied to normal and yeast-inflamed paws. Δ⁹-THC administered orally was essentially inactive at dose levels below those producing pronounced central nervous system depression. The oral anti-inflammatory efficacy of Δ⁹-THC was compared to phenylbutazone and acetylsalicylic acid. Δ⁹-THC was ineffective in inhibiting carrageenin-induced edema of the rat paw following acute or chronic administration.     

Search for an endogenous cannabinoid-mediated effect in the sympathetic nervous system

Activation of CB₁ cannabinoid receptors by exogenous agonists causes presynaptic inhibition of neurotransmitter release from axon terminals. In the central nervous system, presynaptic CB₁ receptors can also be activated by endogenous cannabinoids (endocannabinoids) released from postsynaptic neurons. Except in the vas deferens, there is no indication of endocannabinoid-mediated presynaptic inhibition in the sympathetic nervous system. The aim of the present study was to search for such inhibition in pithed rats. Artificial sympathetic tone was established by continuous electrical stimulation of preganglionic sympathetic axons. The CB₁ cannabinoid receptor antagonist rimonabant (0.5 and 2 mg kg^–1 i.v.) did not change blood pressure, heart rate or plasma noradrenaline concentration. Since activation of G_q/11 protein-coupled receptors enhances endocannabinoid synthesis in the central nervous system, we attempted to stimulate endocannabinoid production by infusion of arginine vasopressin and phenylephrine (both activate G_q/11 protein-coupled receptors). Rimonabant (2 mg kg^–1 i.v.) did not change blood pressure, heart rate or plasma noradrenaline concentration during infusion of phenylephrine or vasopressin. In the final series of experiments we verified that an exogenous cannabinoid agonist produces sympathoinhibition. The synthetic CB₁/CB₂ receptor agonist WIN55212-2 (0.1 and 1 mg kg^–1 i.v.) markedly lowered blood pressure and plasma noradrenaline concentration in pithed rats with electrically stimulated sympathetic outflow. In contrast, in pithed rats with a pressor infusion of noradrenaline, WIN55212-2 did not change blood pressure or heart rate. The results verify that activation of peripheral presynaptic CB₁ receptors inhibits noradrenaline release from sympathetic nerve terminals. The lack of effect of the CB₁ receptor antagonist rimonabant indicates that, even under conditions favouring endocannabinoid synthesis, endocannabinoid-mediated presynaptic inhibition is not operating in the sympathetic nervous system of the pithed rat.     

Rilmenidine (S 3341) and the sympathoadrenal system: adrenoreceptors,plasma and adrenal catecholamines in dogs

1 The effects of rilmenidine, a new alpha₂-adrenoreceptor agonist with antihypertensive properties, were investigated on plasma catecholamines, blood cell adrenoreceptors and adrenal medullary function. 2 In conscious sino-aortic denervated (SAD) dogs, rilmenidine (1 mg kg^?1 orally for 2 weeks) significantly reduced both blood pressure and heart rate when compared with placebo treatment. The drug decreased plasma noradrenaline and adrenaline levels and corrected the decrease in leucocyte beta-adrenoreceptors observed in placebo-treated SAD dogs. There was no change in platelet alpha₂-adrenoreceptors. 3 In anaesthetized normotensive dogs, rilmenidine (0.1 and 0.3 mg kg^?1 i.v.) induced a dose-dependent decrease in both cardiovascular parameters (blood pressure and heart rate) and catecholamine release from the adrenal medulla. 4 The present study shows that rilmenidine decreases sympathetic tone mainly by an action on the adrenal medulla. In addition, its ability to lower blood pressure in SAD dogs, i.e. a model of hypertension in which high sympathetic tone is present, indicates that rilmenidine may also depress other parts of the sympathetic nervous system.     

The effect of Δ-tetrahydrocannabinol on the uptake and release of C-dopamine from crude striatal synaptosomal preparations

Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) and a water soluble ester derivative (compound I) caused a concentration-related decrease in the uptake of ¹⁴C-dopamine into crude synaptosomal preparations derived from mouse striata. Both were less potent than amphetamine in this preparation. In the presence of 10^?7m amphetamine the IC₅₀ of Δ⁹-THC was unaffected. The IC₅₀ is the concentration of drug in the medium which will inhibit the uptake of ¹⁴C-dopamine into the synaptosomes by 50%. However in the presence of 3.0 × 10^?6m Δ⁹-THC, the dose response curve to amphetamine was shifted to the right and the IC₅₀ of amphetamine was increased. Δ⁹-Tetrahydrocannabinol and compound I increased the release of ¹⁴C-dopamine from preparations pre-incubated with ¹⁴C-dopamine. The effect was small but significant. The effects of amphetamine and Δ⁹THC combined were additive on this system. The mode of action of Δ⁹-THC with regard to the dopaminergic system of the striatum is discussed.     

Emergence of the less common cannabinoid Δ8-Tetrahydrocannabinol in a doping sample

Δ⁸-Tetrahydrocannabinol (Δ⁸-THC) as isomer of the well-known Δ⁹-THC has a similar mode of action, and the potency was estimated to be two thirds compared with Δ⁹-THC. Content of Δ⁸-THC in plant material is low, but formulations containing Δ⁸-THC in high concentrations are gaining popularity. Δ⁸-THC is to be regarded as prohibited substance according to the Prohibited List of the World Anti-Doping Agency (WADA). Contradictory results between initial testing procedure and confirmatory quantitation for 11-Nor-9-carboxy-Δ⁹-tetrahydrocannabinol (Δ⁹-THC-COOH) of a doping control sample gave rise for follow-up testing procedures. After alkaline hydrolysis and liquid–liquid extraction, the sample was analyzed by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) using isocratic elution instead of gradient elution, which is used for standard procedure. Isocratic elution resulted in two peaks instead of one using gradient elution. Both peaks showed same fragmentation. Using certified reference materials, one peak could be assigned to Δ⁹-THC-COOH and the other one with higher intensity to the less common 11-Nor-9-carboxy-Δ⁸-Tetrahydrocannabinol (Δ⁸-THC-COOH) in a concentration of approximately 1200 ng/ml. As complementary method, gas chromatography tandem mass spectrometry (GC-MS/MS) can also be used for identification. Here Δ⁸- and Δ⁹-THC-COOH can be distinguished by chromatography and by fragmentation. Additional investigations of doping control samples containing Δ⁹-THC-COOH revealed the simultaneous presence of Δ⁸-THC-COOH in low concentrations (0.22–8.91 ng/ml) presumably due to plant origin. Percentage of Δ⁸-THC-COOH varies from 0.05 to 2.83%. In vitro experiments using human liver microsomes showed that Δ⁸-THC is metabolized in the same way as Δ⁹-THC.     

Chronic ?-tetrahydrocannabinol during adolescence increases sensitivity to subsequent cannabinoid effects in delayed nonmatch-to-position in rats

Early-onset marijuana use has been associated with short- and long-term deficits in cognitive processing. In human users, self-selection bias prevents determination of the extent to which these effects result only from drug use. This study examined the long-term effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the major psychoactive constituent of marijuana, in a delayed nonmatch-to-position task (DNMP). Male Long-Evans rats were injected daily with 10 mg/kg Δ⁹-THC during or after adolescence [postnatal days (PN) 21-50 or PN50-79, respectively] or with vehicle. On PN91, training in DNMP was initiated. Successful acquisition and pharmacological challenge began on approximately PN300. Decreases in accuracy were observed at lower doses of Δ⁹-THC in Δ⁹-THC-treated rats (versus vehicle-treated rats). Administration of chronic Δ⁹-THC at a younger age tended to enhance this effect. While anandamide did not decrease accuracy in any group, rats treated with Δ⁹-THC during adolescence initiated fewer trials at the 30 mg/kg dose of anandamide than did rats in the other two groups. To the extent tested, these differences were pharmacologically selective for cannabinoids, as scopolamine (positive control) decreased accuracy at the same dose in all groups and amphetamine (negative control) did not affect accuracy in any of the groups at doses that did not impair overall responding. These results suggest that repeated administration of a modest dose of Δ⁹-THC during adolescence (PN21-50) or shortly thereafter (PN50-79) produces a long-term increase in latent sensitivity to cannabinoid-induced impairment of performance in a complex operant task.     

THE EFFECT OF δ9-TETRAHYDROCANNABINOL (δ9-THC) ON THE TURNOVER RATE OF BRAIN SEROTONIN OF THE RAT

1. One isotopic and three non-isotopic methods were used to determine the effect of an acute intravenous dose of Δ⁹-tetrahydrocannabinol (Δ⁹-THC, 2 mg/kg) on the rat brain turnover rate of serotonin. 2. In control animals the turnover rate of serotonin was about 2 nmol/g per h. This rate was not altered by Δ⁹-THC when it was calculated from the rise of 5-hydroxyindoleacetic acid following probenecid or from the rise of serotonin following pargyline. 3. Δ⁹-THC did not alter the serotonin turnover rate when it was calculated from the conversion of ³H-tryptophan to ³H-serotonin. 4. The serotonin turnover rate was significantly increased by Δ⁹-THC when the rate was calculated from the decline of 5-hydroxyindoleacetic acid following pargyline. 5. These results suggest that Δ⁹-THC does not alter the turnover of rat brain serotonin. The previously reported Δ⁹-THC-induced changes in body temperature and increased brain levels of 5-hydroxyindoleacetic acid may be mediated by some other mechanism such as interference by Δ⁹-THC of the vesicular binding of serotonin.     

THE EFFECTS OF ADRENALECTOMY ON THE CARDIOVASCULAR RESPONSES TO A'-TETRAHYDROCANNABINOL IN RATS

1. In urethane anaesthetized sham-operated rats, intravenous administration of Δ¹-THC (1 mg/kg) caused an immediate and prolonged fall in blood pressure, with a concomitant reduction in pulse rate. 2. In rats which had been adrenalectomized 24 h previously, Δ¹-THC (1 mg/kg, i.v.) also caused a depressor response, but it was significantly shorter in duration than that observed in sham-operated animals. The durations of the cardiac slowing effect were similar in both groups of rats. 3. Hydrocortisone pretreatment (25 μg/kg> i-v), given 45 min before Δ¹-THC, restored the duration of the depressor response to Δ¹-THC in adrenalectomized rats, but it did not have any effect on the bradycardia induced by Δ-THC. 4. Hydrocortisone did not produce any significant effect on the hypotensive action of Δ¹-THC in sham-operated rats, but the cardiac slowing effect was markedly potentiated. 5. These results suggest a lack of correlation between the hypotensive and cardiac slowing actions of the drug and that a certein level of adrenal steroids is necessary for the maintenance of the depressor response to Δ¹-THC.     

Ovarian hormones and chronic administration during adolescence modify the discriminative stimulus effects of delta-9-tetrahydrocannabinol (Δ⁹-THC) in adult female rats

Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6 mg/kg of Δ⁹-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Δ⁹-THC, OVX/saline, and OVX/Δ⁹-THC). These groups were then trained to discriminate Δ⁹-THC (0.32-3.2 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Δ⁹-THC were substituted for the training dose to obtain dose-effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Δ⁹-THC lower than the training dose, and 3) the OVX/Δ⁹-THC group was significantly less sensitive to the rate-decreasing effects of Δ⁹-THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Δ⁹-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Δ⁹-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal-regulated kinase (ERK) was not significantly affected by either hormone status or chronic Δ⁹-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development.     

Interactions of several cannabinoids with the hepatic drug metabolizing system

Spectral interactions of various cannabinoids with rat liver musomes and their effects on several musomal enzymes were studied. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC), Δ⁸-tetrahydrocannabinol (Δ⁸-THC), cannabinol (CBN), and cannabidiol (CBD) produced type I spectral changes; the spectral dissociation constants K_s were 42, 37, 46 and 11·2 μM, respectively,. Aminopyrine demethylation was competitively inhibited by Δ⁸-THC, Δ⁸-THC, CBN and CBD, by the latter only in concentrations below 10 μM. The inhibitor constants were found to be 58, 60, 68 and 49 μM, respectively. In a similar way morphine demethylation was inhibited. Δ⁸-THC, however, did not inhibit this reaction, and inhibition by CBD was of mixed type at all concentrations. There was no effect of cannabinoids on aniline hydroxylation. The inhibitory potencies of cannabis constituents on drug metabolism in vitro parallel the in vivo results obtained by interaction studies with hexobarbitone. It must be concluded that CBD, which is by far more potent in inhibiting drug metabolism than other cannabinoids, contributes significantly to the effects of crude cannabis preparations at least in rodents.     

Contribution of the metabolite 7-hydroxy-Δ1-tetrahydrocannabinol towards the pharmacological activity of Δ1tetrahydrocannabinol in mice

Tritium-labelled 7-hydroxy-Δ¹-tetrahydrocannabinol (³H-7-hydroxy-Δ¹-THC, specific activity 571 Ci/mmole) was prepared from ³H-Δ¹-THC by oxidation with a rat liver microsome preparation. Brain levels of 7-hydroxy-Δ¹-THC and Δ¹-THC in mice were measured 20 min after intravenous injection of either Δ¹-THC (2.0, 1.0 and 0.5 mg/kg) or 7-hydroxy-Δ¹-THC (1.0, 0.5 and 0.25 mg/kg) and correlated with the inhibition of spontaneous motor activity. A theoretical dose-response relationship for Δ¹-THC in the absence of the metabolite was derived on the assumption of additivity of the behavioural effects due to Δ¹THC and 7-hydroxy-Δ¹-THC present together in the mouse brain. The theoretical dose-response line for Δ¹THC and that obtained experimentally for 7-hydroxy-Δ¹-THC were parallel; on the basis of brain concentrations, 7-hydroxy-Δ¹-THC was found to be more potent than Δ¹-THC in producing behavioural changes and the calculated equipotent molar ratio was 7.1. The ratio of the concentrations of Δ¹THC and 7-hydroxy-Δ¹-THC in the mouse brain 20 min after intravenous injection of Δ¹-THC was 5.3 and the contribution of the metabolite to the overall behavioural effect was calculated as 55–63 per cent. Although metabolites of 7-hydroxyΔ¹-THC accounted for only about 10 per cent of the radioactivity present in the mouse brain 20 min after intravenous injection of ³H-7-hydroxy-Δ¹-THC, about 50 per cent of the radioactivity in the blood was present as a chromatographically more mobile material which has not yet been identified.     

Pharmacological potency of R- and S-3′-hydroxy-Δ9-tetrahydrocannabinol: additional structural requirement for cannabinoid activity

The pharmacological potency of R- and S-3′-hydroxy-Δ⁹-tetrahydrocannabinol (THC) was compared to that of Δ⁹-THC as well as R/S-3′-OH-Δ⁹-THC. The S-isomer was found to be considerably more potent than the R-isomer in producing hypoactivity in mice, static-ataxia in dogs, and in generalization testing in rats trained to discriminate Δ⁹-THC from vehicle. S-3′-OH-Δ⁹-THC was more active than Δ⁹-THC in these tests which means that Δ⁹-THC may be either activated or inactivated in vivo depending upon which metabolite is formed. The difference in potency of these isomers suggests that the conformation of the side chain is critical for behavioral activity. The R and S isomers were found to be equally active in producing hypothermia in mice which is in contrast to the behavioral effects.     

Inhibition of naloxone-induced withdrawal in morphine dependent mice by l-trans-Δ9-tetrahydrocannabinol

The effects of various doses of l-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) on naloxone-induced withdrawal were studied in mice rendered dependent on morphine by the pellet implantation procedure. When administered i.p., 30 min prior to naloxone, Δ⁹-THC, inhibited the naloxone-induced withdrawal jumping response. Two other signs of morphine withdrawal (defecation and rearing behavior) were also suppressed by Δ⁹-THC. It is suggested that Δ⁹-THC or some of its derivatives may have potential use in narcotic detoxification.     

The identification, isolation, and preservation of delta-9-tetrahydrocannabinol (delta-9-THC)

(—)-trans-Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) was isolated from marihuana plant extract, by adsorptive column and glc. The adsorptive column chromatography method consisted of chromatographing marihuana extract on a column packed with a mixture of silica gel (gas chromatography grade (100/120 mesh), silver nitrate and calcium sulphate (CaSO₄·H₂O) (3:1:0·5) with benzene as the eluting solvent. The glc method consisted of chromatographing the extract on a 3 ft silanized glass column (3/8 inch o.d.) packed with 1·5 ft of 2% QF-1 and 1·5 ft of 2% OV-17 on chromosorb W, AW 30–60 mesh, prep grade. A purity of 99% for the isolated Δ⁹-THC was confirmed by infrared spectroscopy, nuclear magnetic resonance, mass spectroscopy. The effects of storage conditions on Δ⁹-THC stability, monitored by glc, indicated the best method for preserving Δ⁹-THC was at 0°, protected from light, stored under nitrogen.