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PubMedDate not supplied

Mechanism for inhibitory effect of cannabidiol on microsomal testosterone oxidation in male rat liver.

Effects of four cannabinoids [cannabidiol (CBD), delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol, and cannabinol] on hepatic microsomal oxidation of testosterone (17 beta-hydroxy-androst-4-ene-3-one) were examined in adult male rats. Only CBD (30 microM) competitively inhibited 2 alpha-hydroxy-testosterone (2 alpha-OH-T) and 16 alpha-OH-T formation by hepatic microsomes but did not affect androstenedione (androst-4-ene-3,17-dione) and 7 alpha-OH-T formation. Kinetic analyses demonstrated that the inhibitory profile of CBD for testosterone oxidation was different from those of SKF 525-A, which caused competitive inhibition for 2 alpha- and 16 alpha-hydroxylations and noncompetitive inhibition for 6 alpha-hydroxylation, and of metyrapone, which inhibited only 6 beta-hydroxylation competitively. CBD also suppressed formation of 2 alpha-OH-T, 16 alpha-OH-T, and androstenedione from testosterone, catalyzed by a reconstituted system containing hepatic cytochrome P-450 purified from phenobarbital-treated rats. Pretreatment of the rat with CBD (10 mg/kg, ip, once a day for 3 days) decreased testosterone oxidation at the 2 alpha-, 16 alpha-, and 17-positions and increased 7 alpha-OH-T formation, while total cytochrome P-450 content was decreased. These results suggest that CBD suppresses hepatic testosterone oxidation at the 2 alpha-, 16 alpha-, and 17-positions through selective inhibition of the male-specific cytochrome P-450 in the adult male rat.

Animals↗
PubMed1986

Acute effects of marihuana smoking on maximal exercise performance.

To evaluate the effects of marihuana smoking on exercise performance, 12 healthy young subjects did progressive exercise testing on an ergocycle to exhaustion under two conditions: non-smoking (control) and 10 min after smoking a marihuana cigarette (containing 1.7% of delta-9-tetra-hydro-cannabinol) of 7 mg X kg-1 body weight. Heart rate, arterial blood pressure, minute ventilation (VE), breathing rate (fb), oxygen uptake (VO2), and carbon dioxide output (VCO2) were measured before, during, and for 4 min after the exercise. Tidal volume was calculated from VE X fb-1. The exercise duration was also measured. Forced expiratory volume (FEV1) was measured: before smoking (rest); before exercise (10 min after smoking); and after exercise. Carboxyhemoglobin levels were measured before and 10 min after smoking in four subjects. Marihuana smoking reduced exercise duration (16.1 +/- 4.0 to 15.1 +/- 3.3 min, P less than 0.05). At peak exercise performance, there were no differences in VO2, VCO2, heart rate, and VE between the two experimental conditions. Marihuana induced tachycardia at preexercise (94.3 +/- 13.3 beats X min-1 to 119.0 +/- 18.0, P less than 0.01) that was sustained up to 80% of maximum effort and during the recovery period. After marihuana, VE, VO2 and VCO2 were increased above control from 50% of maximum effort to the end of the test. Marihuana induced a bronchodilation (FEV1 from 4.28 +/- 1.00 to 4.43 +/- 1.031, P less than 0.0) that was still present after exercise. Exercise induced a bronchodilation in the control condition but not in the marihuana smoking condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Effects of cannabinoids on levels of acetylcholine and choline and on turnover rate of acetylcholine in various regions of the mouse brain.

The psychoactive cannabinoids, delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-delta 9-THC) and 9-nor-9 beta-hydroxyhexahydrocannabinol (beta-HHC), as well as the nonpsychoactive cannabinoids, cannabinol (CBN), cannabidiol (CBD), abnormal CBD, delta 8-THC methyl ether (1-OCH3-delta 8-THC) and 9-nor-9 alpha-hydroxyhexahydrocannabinol (alpha-HHC), were used to assess the role of cholinergic mechanisms in the different behavioral actions of these cannabinoids. Their effects on mouse brain choline and acetylcholine (ACh) levels and on ACh turnover were determined in cortex, hippocampus, striatum, midbrain and medulla-pons. delta 9-THC (30 mg/kg) caused a significant elevation of ACh in all five brain areas. 11-OH-delta 9-THC (30 mg/kg) increased ACh in hippocampus, striatum and midbrain. delta 8-THC (30 mg/kg) increased ACh in cortex and hippocampus. delta 9-THC and 11-OH-delta 9-THC increased choline in midbrain and cortex, whereas beta-HHC increased choline in all areas, except hippocampus, at a dose of 30 mg/kg. Also at this dose, delta 9-THC, 11-OH-delta 9-THC, delta 8-THC and beta-HHC decreased ACh turnover in the hippocampus, as did CBN (10-30 mg/kg), 1-OCH3-delta 8-THC (100 mg/kg) and alpha-HHC (100 mg/kg). ACh turnover was also decreased in midbrain by 1-OCH3-delta 8-THC and in the striatum by alpha-HHC. Thus, the most consistent effects of cannabinoids, both psychotomimetic and nonpsychotomimetic, were to increase ACh and decrease ACh turnover in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1973

Cardiovascular and respiratory effects of cannabis in cat and rat.

1. In anaesthetized rats, intravenous administration of cannabis extract (10 mg/kg), Delta(1)-tetrahydrocannabinol (THC) (0.5 mg/kg) and Delta(6)-THC (0.5 mg/kg) caused a reduction in systemic blood pressure, pulse rate and respiratory rate.2. Neither cannabinol (1 mg/kg, i.v.) nor cannabidiol (1 mg/kg, i.v.) had any observed effects on the cardiovascular and respiratory systems of the rat.3. Pretreatment of rats with atropine (1 mg/kg, i.v.) reduced the hypotension and bradycardia caused by Delta(1)-THC or the extract.4. In anaesthetized cats with autoperfused hindquarters, cannabis extract (10 mg/kg, i.v.) and Delta(1)-THC (0.2 mg/kg, i.v.) caused hypotension, bradycardia, depression of respiratory rate and reduction of hindlimb perfusion pressure.5. Both cannabis extract and Delta(1)-THC potentiated reflex vasodilation and direct vasoconstriction in the hindlimb induced by intravenous noradrenaline in the cat; they reduced reflex hindlimb vasoconstriction elicited by histamine, acetylcholine or bilateral carotid occlusion.6. Tolerance to these cardiovascular and respiratory effects of cannabis extract developed in rats which had been treated i.p. with the extract at (50 mg/kg) per day for 14 days.

Animals↗
PubMed1984

Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes.

Adenylate cyclase in plasma membranes was inhibited by micromolar concentrations of delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol and by levonantradol and desacetyllevonantradol. This inhibition was noncompetitive for stimulation of the enzyme at the prostanoid receptor by prostaglandin E1 or prostacyclin, or at the peptide receptor by secretin or vasoactive intestinal peptide. Forskolin-activated adenylate cyclase was also inhibited by cannabimimetic agents. Inhibition by cannabinoid compounds was neither synergistic nor additive with muscarinic or alpha-adrenergic agents when each was present at maximally inhibitory concentrations. Cannabinoid inhibition was not blocked by atropine, yohimbine, or naloxone, suggesting that muscarinic, alpha 2-adrenergic and certain opiate receptors may not be required for the response. The inhibition of adenylate cyclase was specific for psychoactive cannabinoids, since cannabinol and cannabidiol produced minimal or no response. Inhibition was also stereoselective, since dextronantradol did not produce the response. A biphasic log dose-response curve was observed for each of the cannabinoid drugs, such that reversal of the inhibition occurred at 3-10 microM. Possible mechanisms for the effects of cannabinoid drugs on adenylate cyclase activity are discussed.

Adenylyl Cyclase Inhibitors↗
PubMedDate not supplied

A decreased influence of cannabinoids on macromolecular biosynthesis and cell proliferation in human cells which metabolize polycyclic hydrocarbon carcinogens.

The influence of psychoactive and nonpsychoactive cannabinoids on macromolecular biosynthesis and cell proliferation was compared in normal and transformed human cells which differ with respect to their abilities to metabolize polycyclic hydrocarbon-containing carcinogens. delta 9-THC, delta 8-THC, 11-OH-delta 9-THC, cannabinol and cannabidiol cause a dose-dependent inhibition of [3H]thymidine, [3H]uridine and [3H]leucine incorporation and a dose-dependent inhibition of cell growth in both normal and transformed human cells. The effectiveness of cannabinoids in modifying nucleic acid biosynthesis, protein biosynthesis, and cell growth does not appear to be related to expression of the transformed phenotype; however, cells with enhanced drug metabolizing capacities, including abilities to metabolize polycyclic hydrocarbon-containing carcinogens, are significantly less sensitive to cannabinoid-induced effects on macromolecular biosynthesis and cell growth.

Cannabinoids↗
PubMed1980

Cannabis sativa: effects on brain function and ultrastructure in rhesus monkeys.

Two studies, designed to control for as many variables as possible, were conducted in 21 rhesus monkeys, some with brain electrodes and some unoperated, to determine the effects of marijuana on brain function and ultrastructure. Some monkeys were exposed to smoke of active marijuana (using different dose schedules), some were administered delta-9-THC (0.69 mg/kg iv), and others were exposed to smoke of inactive marijuana (from which all cannabinols had been removed). To deliver smoke to the monkeys, two different apparatuses were used. Dose schedules comparable to those of human marijuana smokers were established, as determined by plasma levels of delta-9-THC. After 2- to 3-months' exposure, the monkeys that were heavy- and moderate-smokers of active marijuana, and those administered delta-9-THC iv, developed chronic recording changes at deep brain sites, most marked in the septal region, hippocampus, and amygdala. These changes persisted throughout the exposure period (6 or 8 months) and during the postexposure observation period (1 to 8 months). Brains of these electrode-implanted monkeys, as well as those without electrodes that were exposed to delta-9-THC, showed ultrastructural alterations characterized by changes at the synapse, destruction of rough endoplasmic reticulum, and development of nuclear inclusion bodies. In contrast, brains of monkeys exposed to smoke of inactive marijuana and of unexposed controls showed no ultrastructural changes. The findings indicate that exposure to delta-9-THC, the psychoactive ingredient of marijuana, at doses commensurate with those used by human marijuana smokers can produce permanent alterations in brain function and structure of monkeys.

Animals↗
PubMed1980

Antiemetics for patients treated with antitumor chemotherapy.

The clinical efficacy of antiemetic drugs was tested in cancer patients who were given a placebo and two antiemetic drugs alone and in combination according to random sequences. The method of investigation allowed assessment of the antiemetic effect and side effects of each drug or combination of drugs using a minimum number of patients. The trial design takes into account carry-over effects and biased selection and is potentially useful in the study of drug side effects. Fifteen patients received cyclizine, metoclopramide, cyclizine and metoclopramide, or placebo in a random sequence without evidence that the drugs tested were better than the placebo. A combination of Nabilone and metoclopramide was used in an unrandomized pilot study (prior to the withdrawal of Nabilone from clinical use); these patients recorded better scores for nausea and vomiting and patient acceptability than those in the randomized study. Present antiemetics remain inadequate and although cannabinol derivatives show an improved antiemetic effect, they cause moderate side effects themselves.

Adolescent↗
PubMed1982

Combined high-performance liquid chromatography and radioimmunoassay method for the analysis of delta 9- tetrahydrocannabinol and its metabolites in plasma and urine.

A high-performance liquid chromatography-radioimmunoassay method for the measurement of cannabinoids in plasma and urine is described. The experimental procedure consists of chromatographing a plasma extract or hydrolysed urine sample by high-performance liquid chromatography and quantifying the eluting cross-reacting cannabinoids with radioimmunoassay. The concentrations of delta 9- tetrahydrocannabinol (THC), cannabinol, mono-hydroxylated metabolites, di-hydroxylated metabolites, delta 9-THC-11-oic acid, and delta 9-THC-11-oic acid ester glucuronide may be measured by this technique.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

[Monoaminergic component in the effect of D-9-tetrahydrocannabinol on conditioned reflex activity].

The involvement of monoaminergic system in the realization of the effect of D-9-hydrocannabinol on different parameters of the conditioned reflex was examined on cats. It appeared that the effect of D-9-cannabinol on the differentiation of long-term and short-term stimuli depends but to a different degree on the activity of both the serotoninergic and catecholaminergic systems. The effect of D-9-tetrahydrocannabinol on the rate of the performance of the conditioned reflex depends on the activity of the dopaminergic system.

Animals↗
PubMed1983

Chromophoric labeling of cannabinoids with 4-dimethylaminoazobenzene-4'-sulfonyl chloride.

A simple and sensitive assay for the cannabinoids is presented using a dabsylation procedure. Dabsyl derivatives of delta 9-tetrahydrocannabinol (delta 9-THC) and cannabinol (CBN) were prepared by reacting with 4-dimethylaminoazobenzene-4'-sulfonyl chloride (dabsyl chloride) in acetone in the presence of sodium carbonate-sodium bicarbonate buffer (pH 10). Crystalline dabsylcannabinoids gave intense absorption in the visible region. With these derivatives, analysis by thin-layer chromatography (TLC) and high performance liquid chromatography (HPLC) were tested. These techniques gave good separation and nanogram detection of dabsyl-THC and -CBN by using n-hexane-ethyl acetate-diethylamine (20:5:1) for TLC and MeOH--H2O (95:5) at 450 nm for HPLC.

Cannabinoids↗
PubMedDate not supplied

Two dimensional thin-layer chromatography of ganja (Cannabis sativa L.).

An efficient and reliable two-dimensional thin-layer chromatographic technique for separation and identification of cannabinoids present in cannabis resin (Cannabis sativa L.) is described. A total of 47 different cannabinoids were successfully separated and 5 of these, cannabinol, cannabidiol, cannabichromene, trans-delta-8-tetrahydrocannabinol and delta-9-tetrahydrocannabinol, were identified. A 0.1 per cent solution of Fast blue salt B in 45 per cent ethanol was employed as chromogenic reagent.

Cannabinoids↗
PubMed1983

Prostaglandins and cannabis. XII. The effect of cannabinoid structure on the synthesis of prostaglandins by human lung fibroblasts.

Earlier findings indicated that several other cannabinoids in addition to delta 1-tetrahydro-cannabinol (THC) were able to stimulate the synthesis of prostaglandins in cell culture systems. The present study was initiated to delineate the structural requirements for this effect within the cannabinoid series. Among the primary cannabinoids, we found that the trend was for more planar structures to show greater activity. In the case of THC metabolites, the order of activity was delta 1-THC greater than 7-oxo-delta 1, 6-THC greater than 7-OH-delta 1-THC greater than 3"-OH-delta 1-THC = 6 beta-OH-delta 1-THC = 6 alpha-OH-delta 1-THC greater than delta 1, 6-THC-7-oic acid. The latter sequence compares favorably with the available data on the behavioral assay in the rhesus monkey and the subjective "high" in humans. We also observed a good correlation between the release of arachidonic acid and the production of prostaglandin E, over a series of eight cannabinoids. This gives further support that the site of action in this effect is the elevation of activity of the phospholipase(s) responsible for supplying precursor arachidonic acid for prostaglandin synthesis.

Arachidonic Acids↗
PubMed1980

Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes.

In vitro effects of delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), cannabinol (CBN) and cannabidiol (CBD) have been studied on the uptake and release of 3H-labeled dopamine (DA) and norepinephrine (NE) in the synaptosomal preparation of rat brain corpus striatum and hypothalamus. The uptake of both DA and NE in these two regions was stimulated at low concentrations of delta 9-THC (1 x 10(-7) and 2 x 10(-7) M) and delta 8-THC (5 x 10(-9) and 1 x 10(-8) M), whereas at higher concentrations (1 x 10(-5) and 1 x 10(-4) M) both delta 9-THC and its delta 8-isomer inhibited the uptake of DA and NE. Similarly, the release of DA and NE from the preloaded synaptosomes of these two brain regions were inhibited at low concentrations of delta 9-THC (1 x 10(-7) M) and delta 8-THC (1 x 10(-8) M) and stimulated at high concentrations of both isomers (1 x 10(-5) and 1 x 10(-4) M). High concentrations of both CBN and CBD were needed to produce only an inhibitory effect on the uptake and the stimulation on the release of DA and NE in synaptosomes of the two brain regions. No significant effect was found at lower concentrations of CBN and CBD. These results demonstrate that 1) delta 9- and delta 8-THC, but not CBN and CBD, produce a biphasic effect on the uptake and release of DA and NE in the corpus striatum and hypothalamic regions of brain and 2) delta 8-THC is more potent than delta 9-THC on both uptake and release of DA and NE in these two brain regions.

Animals↗
PubMed1977

Chemotaxis and movement of Physarum polycephalum and its responses to some neurotransmitters and psychomimetic compounds.

A method was developed for studying the effect of some neurotransmitters and drugs on the rate of movement and the chemotactic value of the plasmodium of Physarum polycephalum. Epinephrine (adrenaline) at a concentration of 1 mg/ml, reduced the rate of movement and shortened the length of the cycles of shuttle streaming, but did not affect the chemotactic response. The drugs DL-amphetamine, cannabinol and heroin diminished the rate of movement, whereas Na-barbitol misled the chemotactic response.

Amphetamine↗
PubMed1978

[Toxic effects of essential oil of Cannabis sativa L. and main constituents on planarian (Dugesia tigrina) (author's transl)].

Regenerating pieces of planarian worms are able to absorbe insoluble substances deposited on the base of the vessels in which they are cultivated. This biological test was used to study the toxic effects of the essential oil of Cannabis sativa L. The hydrocarbons such as pinene (alpha and beta), caryophyllene and so on were not toxic. On the contrary caryophyllene oxide was highly toxic. It was not possible to detect any protection by 5-hydroxytryptamine as it was the case against delta 1-tétrahydro-cannabinol and cannabidiol.

Animals↗
PubMed1995

Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors.

The recently cloned CB2 cannabinoid receptor subtype was stably transfected into AtT-20 and Chinese hamster ovary cells to compare the binding and signal transduction properties of this receptor with those of the CB1 receptor subtype. The binding of [3H]CP 55,940 to both CB1 and CB2 was of similar high affinity (2.6 and 3.7 nM, respectively) and saturable. In competitive binding experiments, (-)-delta 9-tetrahydrocannabinol and CP 55,940 were equipotent at the CB1 and CB2 receptors, but WIN 55212-2 and cannabinol bound with higher affinity to the CB2 than the CB1 receptor. HU 210 had a higher affinity for the CB1 receptor. Anandamide, a recently identified endogenous cannabinoid agonist, was essentially equipotent at both receptor subtypes. The structurally related fatty acid ethanolamides dihomo-gamma-linolenylethanolamide and mead ethanolamide also bound with relatively equal affinity to both receptors, but adrenylethanolamide had a higher affinity for the CB1 receptor. The rank order of potency and efficacy for binding of the selected agonists to the CB1 and CB2 receptors was mimicked in functional inhibition of cAMP accumulation experiments for all compounds tested. Both CB1 and CB2 receptors couple to the inhibition of cAMP accumulation that was pertussis toxin sensitive. SR141716A, a CB1 receptor antagonist, was a poor antagonist at the CB2 receptor in both binding and functional inhibition of cAMP accumulation experiments. When expressed in AtT-20 cells, the CB1 receptor mediated an inhibition of Q-type calcium channels and an activation of inward rectifying potassium channels. In contrast, the CB2 receptor did not modulate the activity of either channel under identical assay conditions. Similar to results obtained for CB1 receptor, the CB2 receptor did not couple to the activation of phospholipases A2, C, or D or to the mobilization of intracellular Ca2+. Except for its inability to couple to the modulation of Q-type calcium channels or inwardly rectifying potassium channels, the CB1 and CB2 receptors display similar pharmacological and biochemical properties.

Adenylyl Cyclase Inhibitors↗