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Cannabis Research - different effects of different cannabinoids and combinations


Authors
Mazor M, Dvilansky A, Aharon M, Lazarovitz Z, Nathan I
Title
Effect of cannabinoids on the activity of monoamine oxidase in normal human platelets.
Source
Archives Internationales de Physiologie et de Biochimie
Date
1982 Apr
Issue
90(1)
Pages
15-20
Abstract
Platelet MAO activity was affected by preincubation with cannabinoid derivatives in vitro. The psycho-active derivative delta 1-THC inhibited MAO activity in platelets to an extent varying according to its concentration while CBD and (+) delta 6-THC had no inhibitory effect. (-) delta 6-THC, which is minor psychomimetic component, had less inhibitory effect on MAO activity than delta 1-THC. However, (-) DMH delta 6-THC revealed no attenuation effect on MAO inspite of its well-known psychomimetic activity.

Authors
van Ree JM, Niesink RJ, Nir I
Title
delta 1-Tetrahydrocannabinol but not cannabidiol reduces contact and aggressive behavior of rats tested in dyadic encounters.
Source
Psychopharmacology
Date
1984
Issue
84(4)
Pages
561-5
Abstract
A low and a high dose of delta 1-tetrahydrocannabinol (delta 1-THC) and of cannabidiol (CBD) were IP injected in rats that had been isolated for 7 days. Forty-five minutes after injection, the rats were tested for social interactions with non-isolated, untreated test partners in dyadic encounters under standardized conditions. Different aspects of social behavior were analyzed. The high dose of delta 1-THC (10 mg/kg) prevented nearly all social interactions. The low dose of delta 1-THC (1 mg/kg) exerted selective and specific effects on social interactions. Social contact behavior, including crawl over/mounting, and social grooming, and aggressive behavior, including fighting, kicking, and biting, were markedly decreased, whereas social exploratory behavior (exploration of the partner and anogenital investigation) and the behavioral item, approach/follow, were hardly affected by delta 1-THC treatment. Both doses of CBD (2 and 20 mg/kg) failed to change the various aspects of social interaction. It is postulated that the effects of delta 1-THC on close and intimate contact behavior of rats may contribute to the understanding of marihuana taking in humans.

Authors
Turkanis SA, Karler R
Title
Influence of 11-hydroxy-delta-9-tetrahydrocannabinol on spinal motoneurons in cat.
Source
Neuropharmacology
Date
1984 Dec
Issue
23(12A)
Pages
1435-9
Abstract
Intracellular recording techniques were used on spinal motoneurons in the cat in order to define the synaptic pharmacology of 11-hydroxy-delta-9-tetrahydrocannabinol (11-hydroxy-delta-9-THC), the principal metabolite of delta-9-tetrahydrocannabinol (delta-9-THC). The 11-hydroxy derivative increased the amplitude of excitatory postsynaptic potentials; such an excitatory response did not appear to be the result of changes in afferent input. The increase in excitatory postsynaptic potentials, however, may be accounted for by a rise in membrane resistance. The cannabinoid also concomitantly produced synaptic depression, as indicated by a rise in the firing threshold for the motoneuron action potential. The responses to 11-hydroxy derivative suggest synaptic sites and mechanisms of action; for instance, the data indicate that the cannabinoid affected postsynaptic conductance. Finally, the similarity between the synaptic effects of the 11-hydroxy derivative and those of delta-9-THC suggest that the metabolite may contribute to the pharmacological properties of its parent compound.

Authors
ElSohly MA, Harland EC, Benigni DA, Waller CW
Title
Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure of the rabbit.
Source
Current Eye Research
Date
1984 Jun
Issue
3(6)
Pages
841-50
Abstract
Thirty-two different cannabinoids were tested for their ability to reduce intraocular pressure (IOP) in the rabbit. These included many of delta 9- and delta 8-THC derivatives and metabolites along with other natural and synthetic cannabinoids. In addition, some non-cannabinoid constituents of Cannabis were screened using the same model. All compounds were administered intravenously, while only a few were tested topically in mineral oil. Water soluble derivatives of delta 9- and delta 8-THC were prepared and tested topically in aqueous solution. The data revealed that certain derivatives of delta 9-and delta 8-THC were more active in lowering IOP than the parent cannabinoids. In addition, compounds other than delta 9- and delta 8-THC and their derivatives were shown to have activity.

Authors
Schurr A, Rigor BM
Title
Cannabis extract, but not delta 1-tetrahydrocannabinol, inhibits human brain and liver monoamine oxidase.
Source
General Pharmacology
Date
1984
Issue
15(2)
Pages
171-4
Abstract
Mitochondrial monoamine oxidase (MAO) of human brain and liver was inhibited by low concentrations of cannabis extract (CE) and a cannabinoid fraction isolated from it. delta 1-Tetrahydrocannabinol (THC) did not elicit any inhibitory effect on the enzyme. The inhibition of MAO activity by CE and by its active fraction was more pronounced when the monoamine substrates 2-phenylethylamine (PEA) and benzylamine (BA) were used, as compared to the inhibition of the enzyme activity when 5-hydroxytryptamine was the substrate. The active cannabinoid fraction was found to be more potent than CE in inhibiting the activity of MAO with either substrate. The isolated fraction contains at least two cannabinoids with Rf values of 0.67 and 0.71 on silica gel thin layer chromatography (TLC), as determined with toluene/chloroform/methanol (100:10:1, by volume) as the solvent system. The findings of this study emphasize the need for further exploration of the potential of cannabis as a source for therapeutic agents.

Authors
Vincent BJ, McQuiston DJ, Einhorn LH, Nagy CM, Brames MJ
Title
Review of cannabinoids and their antiemetic effectiveness.
Source
Drugs
Date
1983 Feb
Issue
25 Suppl 1
Pages
52-62
Abstract
Marijuana has been used for over 2 centuries. Its major psychoactive constituent, delta-9-tetrahydrocannabinol (THC) was isolated in 1964 and first used to control nausea and vomiting during chemotherapy in the 1970s. THC has cardiovascular, pulmonary and endocrinological effects as well as actions on the central nervous system. Alterations in mood, memory, motor coordination, cognitive ability, sensorium, spatial- and self-perception are commonly experienced. The precise antiemetic mechanism is unknown. THC and nabilone act at a number of sites within the central nervous system. Cannabinoids have also been shown to inhibit prostaglandin synthesis in vitro. In controlled clinical trials, THC is superior to placebo and prochlorperazine in antiemetic effectiveness. Effectiveness of THC correlates to a 'high' experienced by the patient. A variety of chemotherapy regimens respond to THC including high-dose methotrexate and the doxorubicin, cyclophosphamide, fluorouracil combination. Cisplatin is more resistant. Side effects are generally well tolerated but may limit THC use in the elderly or when high doses are administered. Nabilone, a synthetic cannabinoid, is also an effective antiemetic which is more active than prochlorperazine in preventing chemotherapy-induced emesis, including cisplatin-containing regimens. Side effects are similar to THC and may be dose-limiting. Levonantradol, another synthetic cannabinoid, is an effective antiemetic. It may provide more flexibility in the outpatient setting since it can be administered orally or intramuscularly. Most side effects are mild except for dysphoria which may be dose-limiting.

Authors
Sauer MA, Rifka SM, Hawks RL, Cutler GB Jr, Loriaux DL
Title
Marijuana: interaction with the estrogen receptor.
Source
Journal of Pharmacology & Experimental Therapeutics
Date
1983 Feb
Issue
224(2)
Pages
404-7
Abstract
Crude marijuana extract competed with estradiol for binding to the estrogen receptor of rat uterine cytosol. Condensed marijuana smoke also competed with estradiol for its receptor. Pure delta 9-tetrahydrocannabinol, however, did not interact with the estrogen receptor. Ten delta 9-tetrahydrocannabinol metabolites also failed to compete with estradiol for its receptor. Of several other common cannabinoids tested, only cannabidiol showed any estrogen receptor binding. This was evident only at very high concentrations of cannabidiol. Apigenin, the aglycone of a flavinoid phytoestrogen found in cannabis, displayed high affinity for the estrogen receptor. To assess the biological significance of these receptor data, estrogen activity was measured in vivo with the uterine growth bioassay, using immature rats. Cannabis extract in large doses exhibited neither estrogenic nor antiestrogenic effects. Thus, although estrogen receptor binding activity was observed in crude marijuana extract, marijuana smoke condensate and several known components of cannabis, direct estrogenic activity of cannabis extract could not be demonstrated in vivo.

Authors
Karler R, Borys HK, Turkanis SA
Title
Influence of 22-day treatment on the anticonvulsant properties of cannabinoids.
Source
Naunyn-Schmiedebergs Archives of Pharmacology
Date
1982 Aug
Issue
320(2)
Pages
105-9
Abstract
Mice were given delta-9-tetrahydrocannabinol (delta-9-THC) cannabidiol (CBD) or phenytoin (PHT) daily for 22 days. Drug activity was measured weekly in three different anticonvulsant tests: the maximal electroshock threshold, the 60-Hz-electroshock threshold and the 6-Hz-electroshock threshold. In order to correlate potential pharmacodynamic and pharmacokinetic changes resulting from repeated treatment, brain-drug concentrations were determined at each test time. The results from the delta-9-THC study indicate that, although tolerance developed in all three tests, there were no changes in the brain-drug concentration. For CBD the pharmacodynamics were strikingly different: an increase in sensitivity to the drug developed in two of the tests, tolerance in only one test. Here again, there were no changes in brain-drug concentrations. The results of the PHT study differed from both the cannabinoids, for tolerance developed in one test, an increase in sensitivity in one test, and the activity was unchanged in the third test. Again, the brain concentrations remained constant throughout. The results demonstrate that both tolerance and increased sensitivity can develop concomitantly with anticonvulsant effects of the cannabinoids and PHT, and that these modifications in drug activity appear to result from cellular or functional rather than dispositional changes.

Authors
Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG
Title
Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects.
Source
Psychopharmacology
Date
1982
Issue
76(3)
Pages
245-50
Abstract
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by delta 9-THC in normal volunteers, and whether this effect occurs by a general block of the action of delta 9-THC or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg delta 9-THC, 1 mg/kg CBD, a mixture containing 0.5 mg/kg delta 9-THC and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by delta 9-THC, however this effect also extended to marihuana-like effects and to other subjective alterations induced by delta 9-THC. This antagonism does not appear to be caused by a general block of delta 9-THC effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of delta 9-THC. These results suggest that the effects of CBD, as opposed to those of delta 9-THC, might be involved in the antagonism of effects between the two cannabinoids.

Authors
Colasanti BK, Lindamood C 3d, Craig CR
Title
Effects of marihuana cannabinoids on seizure activity in cobalt-epileptic rats.
Source
Pharmacology, Biochemistry & Behavior
Date
1982 Apr
Issue
16(4)
Pages
573-8
Abstract
Rats rendered chronically epileptic by bilateral implantation of cobalt into frontal cortices were simultaneously prepared with permanent electrodes for longitudinal recording of the electroencephalogram (EEG) and electromyogram (EMG). Delta-8-tetrahydrocannabinol (delta-8-THC; 10 mg/kg), delta-9-tetrahydrocannabinol (delta-9-THC; 10 mg/kg), cannabidiol (CBD; 60 mg/kg), or polyvinylpyrrolidone (PVP) vehicle (2 ml/kg) was administered IP twice daily from day 7 through 10 after cobalt implantation, at which time generalized seizure activity in non-treated cobalt-epileptic rats was maximal. Relative to PVP-treated controls, CBD did not alter the frequency of appearance of seizures during the course of repeated administration. In contrast, both delta-8-THC and delta-9-THC markedly reduced the incidence of seizures on the first and second days of administration. Interictal spiking during this period, on the other hand, was actually enhanced. On the third and fourth days, tolerance to the effect on seizures was evident, with a return of seizure frequency of THC-treated rats to values not significantly different from those of controls. Unlike the effect on seizures, no tolerance developed to the marked suppression of rapid eye movement (REM) sleep induces by delta-8-THC and delta-9-THC. REM sleep remained reduced in the treated animals during the first 2 days after termination of THC administration. In contrast, REM sleep time was unaffected by repeated administration of CBD. These results suggest that delta-8-THC and delta-9-THC exert their initial anticonvulsant effect by limiting the spread of epileptogenic activity originating from the cobalt focus.

Authors
Elsohly MA, Harland E, Murphy JC, Wirth P, Waller CW
Title
Cannabinoids in glaucoma: a primary screening procedure.
Source
Journal of Clinical Pharmacology
Date
1981 Aug-Sep
Issue
21(8-9 Suppl)
Pages
472S-478S
Abstract
A procedure was developed for screening of cannabinoids for their ability to reduce intraocular pressure (IOP) using normal rabbits. Eight animals per group were used for statistical significance of data. A negative control group was used for every screen as well as a positive control with 1.5 mg/kg delta 9-THC given intravenously (I.V.). All compounds were tested by I.V. injection and IOP measurements were taken periodically for 5 hours. Data were analyzed by a computer program which takes into account the change in IOP of the control group. Following this procedure we found that delta 8-THC, delta 9-THC, cannabinol, and nabilone were active while cannabidiol was inactive.

Authors
Turkanis SA, Karler R
Title
Electrophysiologic properties of the cannabinoids.
Source
Journal of Clinical Pharmacology
Date
1981 Aug-Sep
Issue
21(8-9 Suppl)
Pages
449S-463S
Abstract
The effects of the psychoactive cannabinoid delta 9-tetrahydrocannabinol (THC) and the nonpsychoactive cannabinoid cannabidiol (CBD) were investigated comparatively on electrically caused transcallosal cortical evoked responses, electrically induced limbic after discharges, photically evoked cortical afterdischarges, spontaneous cortical focal epileptic potentials, and spinal monosynaptic reflexes. In each system, THC produced central excitation; for example, the drug's responses ranged from enhancement of synaptic transmission to precipitation of frank convulsions. In addition to central nervous system stimulation, THC usually elicited depression; the qualitative character of the effect of the drug was dependent upon the dosage and the test system. In contrast to THC, cannabidiol generated no CNS excitation: it was either depressant or inert in these test systems. The results clearly demonstrate the complexity of the CNS properties of THC and the selectivity of the depressant properties of cannabidiol; moreover, the data illustrate the wide range of neuropharmacologic responses that potentially any cannabinoid can effect.

Authors
Fairbairn JW, Pickens JT
Title
Activity of cannabis in relation to its delta'-trans-tetrahydro-cannabinol content.
Source
British Journal of Pharmacology
Date
1981 Mar
Issue
72(3)
Pages
401-9
Abstract
1 Conditions have been worked out for a reliable estimation of the cataleptic activity of delta'-trans-tetrahydrocannabinol (THC) after oral administration to mice, using the ring test over a period of 6 h. 2 By this method, the activity of cannabis herb and 5 crude fractions were measured against THC; at the same time the THC contents were determined chemically. 3 The B/C ratio (biological activity divided by chemical assay) was calculated for each. With cannabis herb the value was 3.3 and with extracts prepared with ethanol or 70% ethanol the values ranged from 3.2 to 7.1, indicating that in all samples the activity was much higher than would be expected from their THC content. 4. The cannabinoids were completely extracted from a sample of herb using petroleum spirit and the marc examined for a possible synergist. Surprisingly, it contained a powerful inhibitor of the action of THC, which could be restored by intraperitoneal prostaglandin E2 (3 microgram/kg). Some crude fractions had inhibitory activities about 10 times that of aspirin. 5 In contrast, the petroleum spirit extract (referred to in 4) had a surprisingly high B/C ratio of 23, indicating that a powerful synergist of THC activity is present. 6 The net effect of the herb and ethanol extracts is probably due to a balance of synergist and inhibitor.

Authors
Hatoum NS, Davis WM, Elsohly MA, Turner CE
Title
Perinatal exposure to cannabichromene and delta 9-tetrahydrocannabinol: separate and combined effects on viability of pups and on male reproductive system at maturity.
Source
Toxicology Letters
Date
1981 May
Issue
8(3)
Pages
141-6
Abstract
The effects of cannabichromene (CBC), delta 9-tetrahydrocannabinol (delta 9-THC) and their combination (all doses 50 mg/kg orally) were determined after being administered to female mice for 7 days beginning on the 20th day of gestation. The THC treatment reduced postnatal viability, impaired male reproductive behavior at maturity and significantly reduced seminal vesicle weights. No changes from control values occurred after CBC or CBC + THC. Thus, CBC alone at this dosage did not act like THC; moreover, it antagonized the effects of THC when the two were given in combination.

Authors
Zuardi AW, Finkelfarb E, Bueno OF, Musty RE, Karniol IG
Title
Characteristics of the stimulus produced by the mixture of cannabidiol with delta 9-tetrahydrocannabinol.
Source
Archives Internationales de Pharmacodynamie et de Therapie
Date
1981 Jan
Issue
249(1)
Pages
137-46
Abstract
Rats, trained to discriminate between delta 9-THC (5 mg/kg) and a control solution, using a T-maze, were submitted to generalization tests wih delta 9-THC (2.5 and 1.25 mg/kg), CBD (40 mg/kg) and the mixtures of delta 9-THC (5 and 1.25 mg/kg) with CBD (40 mg/kg). Doses of delta 9-THC smaller than the training dose, produced a progressive reduction in the number of correct responses together with a decrease in the running time. The choice made by the animals under the effect of CBD (40 mg/kg) did not differ from that of the animals given the control solution but their running time was significantly longer. The mixtures of CBD (40 mg/kg) with delta 9-THC (5 and 1.25 mg/kg) produced approximately 50% response to both sides of the maze, and with run times greater than those observed with delta 9-THC (5 mg/kg). The results suggest that the simultaneous administration of the two cannabinoids might produce a qualitative stimulus different from that produced by delta 9-THC alone.

Authors
Brady KT, Balster RL
Title
The effects of delta 9-tetrahydrocannabinol alone and in combination with cannabidiol on fixed-interval performance in rhesus monkeys.
Source
Psychopharmacology
Date
1980
Issue
72(1)
Pages
21-6
Abstract
It has been reported that cannabidiol (CBD) antagonizes the effects of delta 9-tetrahydrocannabinol (THC) on operant behavior in rats and pigeons. We have replicated this finding with rhesus monkeys. Four rhesus monkeys were trained to lever press on a fixed-interval 5-min schedule of food presentation with a 1-min limited hold and 1-min time out between successive intervals. The effects of 0.3 and 1.0 mg/kg THC alone were determined three times during the experiment; before the CBD-THC interaction, after the CBD-THC interaction and once with the CBD vehicle. A dose of 30 mg/kg CBD, which alone resulted in a 24% reduction in responding, completely antagonized the response rate reduction produced by 0.3 mg/kg THC. The effects of THC revealed a rate-dependent effect that did not conform to the log-linear rate-dependency plots described for most other drugs.

Authors
Colasanti BK, Craig CR, Allara RD
Title
Intraocular pressure, ocular toxicity and neurotoxicity after administration of cannabinol or cannabigerol.
Source
Experimental Eye Research
Date
1984 Sep
Issue
39(3)
Pages
251-9
Abstract
Cannabinol or cannabigerol was administered to cats topically in doses of 250, 500 and 1000 micrograms as a single drop or chronically via osmotic minipumps (20 micrograms hr-1) over a period of 9 days. While cannabinol had a modest effect on intraocular pressure after a single dose, it caused a more significant reduction in ocular tension during chronic administration. Cannabigerol had similar effects, but the magnitude of response to its chronic administration was greater. Cannabinol but not cannabigerol caused conjunctival erythema and hyperemia. After systemic administration of cannabinol (20, 40 or 80 mg kg-1) to rats, 8-13 Hz polyspike discharges appeared in the electrocorticogram during wakefulness and during rapid eye movement sleep episodes. Cannabigerol (10, 30 and 100 mg kg-1) lacked this effect. These results indicate that chronic administration of these cannabinoids lowers ocular tension considerably. Like marihuana and delta-9-tetrahydrocannabinol, cannabinol produced both ocular toxicity and neurotoxicity. As cannabigerol lacked these toxicities, it appears that the ocular hypotensive effect of this cannabinoid is somewhat dissociable from both the adverse central and ocular effects accompanying marihuana intake.

Authors
Gong H Jr, Tashkin DP, Simmons MS, Calvarese B, Shapiro BJ
Title
Acute and subacute bronchial effects of oral cannabinoids.
Source
Clinical Pharmacology & Therapeutics
Date
1984 Jan
Issue
35(1)
Pages
26-32
Abstract
The bronchodilating activity of oral cannabinoids was evaluated in three double-blind experiments that involved the study of dose-response and interactive relationships and the potential development of tolerance. Data indicated that delta 8-tetrahydrocannabinol (delta 8-THC), cannabinol (CBN), and cannabidiol (CBD) in maximal doses of 75 mg, 1200 mg, and 1200 mg, respectively, did not induce significant dose-related physiologic effects in experienced marijuana smokers. delta 8-THC (75 mg) was, however, associated with bronchodilation, tachycardia, and peak highs less than that after delta 9-tetrahydrocannabinol (delta 9-THC). The combinations of CBN and CBD with low-dose delta 9-THC (5 mg) did not induce significant bronchodilation but did exert interactive effects on heart rate and "high." A 20-day study of daily delta 9-THC (20 mg), CBN (600 mg), and CBD (1200 mg) did not indicate tolerance or reverse tolerance to any drug. We conclude that delta 9-THC and, to a lesser extent, delta 8-THC, have acute bronchodilator activity but that CBN, CBD, and their combinations do not provide effective bronchodilation. The daily use of delta 9-THC was not associated with clinical tolerance.

Authors
Stark P, Dews PB
Title
Cannabinoids. I. Behavioral effects.
Source
Journal of Pharmacology & Experimental Therapeutics
Date
1980 Jul
Issue
214(1)
Pages
124-30
Abstract
The effects of two new cannabinoids, nabilone and canbisol, have been compared to delta 9-tetrahydrocannabinol (delta 9-THC) and chlordiazepoxide in behavioral tests in mice, rats, dogs and rhesus monkeys. Activity of mice was measured in a photocell device. Oral doses of 5 and 10 mg/kg of delta 9-THC and 200 mg/kg of chlordiazepoxide caused only a decrease in the initial high activity. Doses of 5 and 10 mg/kg of nabilone and 2.5, 5.0 and 10 mg/kg of canbisol decreased the initial high activity but increased the subsequent low activity. In rats delta 9-THC, nabilone and canbisol, but not chlordiazepoxide, slowed muricide and intracranial self-stimulation. Chlordiazepoxide, nabilone and canbisol, but not delta 9-THC, reduced reactivity of septal-lesioned rats. At the dosages studied only nabilone and canbisol reduced food consumption by rats. Ataxia in dogs was detected following as little as 0.062 mg/kg of delta 9-THC, 0.032 mg/kg of nabilone and 0.004 mg/kg of canbisol when given intravenously; orally, doses of more than 0.25 mg/kg of delta 9-THC, and 0.1 mg/kg of nabilone or canbisol were necessary. Rhesus monkeys working under multiple fixed-ratio fixed-interval schedules showed an increase in rate at some dose of all three cannabinoids but higher doses reduced responding, and responding was abolished following 3.0 mg/kg of delta 9-THC or nabilone or 0.3 mg/kg of canbisol. Chlordiazepoxide increased responding at all doses studied, 3.0 to 30.0 mg/kg. Nabilone and canbisol resemble chlordiazepoxide in som tests and delta 9-THC in other tests.

Authors
Karler R, Turkanis SA
Title
The cannabinoids as potential antiepileptics.
Source
Journal of Clinical Pharmacology
Date
1981 Aug-Sep
Issue
21(8-9 Suppl)
Pages
437S-448S
Abstract
Comparative studies of the anticonvulsant properties of the cannabinoids and prototype antiepileptic drugs in numerous animal seizure models demonstrate that (1) as an anticonvulsant, cannabidiol (CBD), in contrast to delta 9-tetrahydrocannabinol (THC), is relatively selective in terms of both central nervous system (CNS), depressant and excitatory properties; (2) the potency of cannabidiol, unlike that of phenytoin and phenobarbital, varies greatly with the species; (3) the large potency difference between the cannabinoids and the antiepileptics in the mouse appears to be due to dispositional differences, because brain concentrations of all the drugs are very similar; (4) tolerance to the anticonvulsant properties of cannabidiol is not a prominent feature; in three seizure models, tolerance developed in one, but "reverse tolerance" developed in the other two; and (5) the results of a study of the electrophysiologic mechanisms of action indicate that cannabidiol produces some unique effects and that its spectrum of antiepileptic activity may be different from that of the prototype drugs. The anticonvulsant nature of cannabidiol suggests that it has a therapeutic potential in at least three of the four major types of epilepsy: grand mal, cortical focal, and complex partial seizures.

Authors
Deutsch HM, Green K, Zalkow LH
Title
Isolation of ocular hypotensive agents from Cannabis sativa.
Source
Journal of Clinical Pharmacology
Date
1981 Aug-Sep
Issue
21(8-9 Suppl)
Pages
479S-485S
Abstract
Recent work in our laboratories has shown that a hydrophilic fraction from Cannabis sativa (marihuana) has extremely potent intraocular pressure (IOP)-lowering activity as measured in albino rabbits when delivered by intravenous injection. A crude extract reduced IOP by 50-60 per cent (to the episcleral venous pressure) at dosage levels of about 500 micrograms/animal. Fractionation of this material by solvent extraction, high-performance liquid chromatography, and gel filtration chromatography has produced samples with high activity at 50 micrograms/animal. The active material has been shown to be noncannabinoid and of high molecular weight.

Authors
Chesher GB, Jackson DM
Title
Post-swim grooming in mice inhibited by dopamine receptor antagonists and by cannabinoids.
Source
Pharmacology, Biochemistry & Behavior
Date
1980 Sep
Issue
13(3)
Pages
479-81
Abstract
After a period of swimming, mice engaged in vigorous grooming activity. This behaviour was inhibited in a dose dependent manner by dopamine receptor antagonists and by the cannabinoids, delta 9-tetrahydrocannabinol and cannabinol. Cannabidiol was inactive. It is suggested that the post-swin grooming behaviour involves a dopaminergic mechanism. The mechanism of action of the cannabinoids on this behaviour is unknown.

Authors
Poddar MK, Dewey WL
Title
Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes.
Source
Journal of Pharmacology & Experimental Therapeutics
Date
1980 Jul
Issue
214(1)
Pages
63-7
Abstract
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.

Authors
Ganz AJ, Waser PG
Title
[Testing the pharmacological activity of some synthetic cannabinoids in mice (author's transl)].
Language
German
Source
Arzneimittel-Forschung
Date
1980
Issue
30(3)
Pages
471-7
Abstract
A series of synthetic cannabinoids were tested in mice for analgesic, anticonvulsant, sedative and reserpine antagonistic properties as well as for influence on body temperature and on motor coordination and compared with the natural delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC) and cannabidiol (CBD). All cannabinoids were injected s.c. or i.p. in mice as solutions in olive oil. The synthetic cannabinoids, with the exception of the lipophilic ones, were less active than the natural delta 9-THC. 1',1'-dimethyl-delta 8-tetrahydrocannabinol (DM-delta 8-THC) has an analgesic ED 50 of 16 mg/kg s.c. (writhing test) and is three times more active than delta 9-THC, but also eight times less active than morphine. The lipophilic derivatives of delta 8-THC prolonged pentobarbitone narcosis and diminished locomotor activity in mice. Anticonvulsant activities could never be detected; all cannabinoids slightly diminished body temperature and antagonized weakly the hypothermia induced by reserpine. The trained capacity of remaining on the rotating rod was severely shortened for a long time after application of all cannabinoids but mainly by the lipophilic ones. The influence of derivation on the activity of delta 9-THC is discussed.

Authors
Mechoulam R, Devane WA, Breuer A, Zahalka J
Title
A random walk through a cannabis field. [Review]
Source
Pharmacology, Biochemistry & Behavior
Date
1991 Nov
Issue
40(3)
Pages
461-4
Abstract
The present overview covers various aspects of research going on in the Cannabis field in the Department of Natural Products at the Hebrew University. In the first part we discuss, and try to explain, the reason for the absence of the term Cannabis (and possibly also opium) in the Old Testament. In the second part we bring evidence that, contrary to widely held views, stereospecificity of cannabinoid action is extremely high, and in certain cases almost absolute. Previous results seem to have been due to impurities in the samples tested. (+)-Delta-1-THC, (+)-delta-6-THC and (+)-7-hydroxy-delta-6-THC, when purified sufficiently, exhibit activity of about 1% of that of the natural (-) enantiomers. A new labelled cannabinoid ligand has been prepared by catalytic reduction of (-)-7-hydroxy-delta-6-THC dimethylheptyl. The equatorial C-1 epimer obtained binds to the cannabinoid receptor with a KI of 40 pM. This compound is one of the most active cannabinoids tested so far for binding to the canabinoid receptor, and may become an important tool in cannabinoid research.
References
25

Id Code
75213716
Authors
Banerjee SP, Snyder SH, Mechoulam R
Title
Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes.
Source
Journal of Pharmacology & Experimental Therapeutics
Date
1975 Jul
Issue
194(1)
Pages
74-81
Abstract
We have examined the effect of Delta1-tetrahydrocannabinol (delat1-THC) and 12 of its derivatives on the uptake of 3H-labeled norepinephrine (NE), dopamine (DA), serotonin (5-HT) gamma-aminobutyric acid (GABA) into synaptosomes in homogenates of various regions of rat brain. Delta1-THC inhibits the accumulation of NE and 5-HT into hypothalamic preparations and DA into the corpus striatum with Ki values of about 12 to 25 muM while GABA uptake into cerebral cortical preparations is inhibited less (Ki = 140 muM). The affinities of delta6-THC, 7-hydroxy-delta1-THC, 7-hydroxy-delta6-THC and cannabidiol for 5-HT, NE and GABA transports are similar to values for delta1-THC, while cannabigerol, cannabinol and delta6-THC-7-oic acid have substantially less affinity. Thus, hydroxylation of C-7 in delta6-THC does not alter inhibitory potency, but its oxidation to an acid and aromatization of ring A greatly reduce affinity. The hydroxyl at C-3(1) of ring C is critical for inhibition of NE, 5-HT and GABA uptake, since its acetylation or methylation abolishes activity. Inhibition of NE, DA, 5-HT and GABA uptake by all cannabinoids examined is noncompetitive. Only about 1% of delta1-THC and delta6-THC and 5% of cannabidiol are fully soluble under our experimental conditions.

Id Code
76043607
Authors
Wada JA, Osawa T, Corcoran ME
Title
Effects of tetrahydrocannabinols on kindled amygdaloid seizures and photogenic seizures in Senegalese baboons, Papio papio.
Source
Epilepsia
Date
1975 Sep
Issue
16(3)
Pages
439-48
Abstract
Intraperitoneal injections of delta 8-tetrahydrocannabinol (THC) and delta 9-THC failed to affect myoclonic response to photic stimulation in Senegalese baboons (Papio papio). However, both isomers of THC exerted dose-related antiepileptic effects upon established kindled convulsions provoked by electrical stimulation of amygdala in the same species. Delta 9-THC was more potent than delta 8-THC, in terms of both antiepileptic effects and general toxicity. The antiepileptic effects of the THC isomers appear to be due mainly to the suppression of propagation of the induced afterdischarge to distant cerebral structures, although high doses also seem to suppress afterdischarge at the site of stimulation.

Id Code
75218256
Authors
Takahashi RN, Karniol IG
Title
Pharmacologic interaction between cannabinol and delta9-tetrahydrocannabinol.
Source
Psychopharmacologia
Date
1975
Issue
41(3)
Pages
277-84
Abstract
The pharmacological activities of delta9-THC [(minus)-delta9-trans-tetrahydrocannabinol], CBN (Cannabinol) and mixtures of delta9-THC + CBN were studied in rabbits, rats and mice. CBN, although in general less active, mimicked the effects of delta9-THC in several pharmacological tests: corneal arreflexia in rabbits; climbing rope, open-field, irritability and aggressiveness after REM sleep deprivation in rats; catatonia, analgesia and sleeping time in mice. When the mixture delta9-THC + CBN was used, a synergistic effect occurred on most of the depressant effects. On the other hand CBN did not interfere with or slightly inhibited the excitatory effects of delta9-THC. In the one peripheral test used, CBN did not alter the delta9-THC effect.

Id Code
75194497
Authors
Just WW, Erdmann G, Thel S, Werner G, Wiechmann M
Title
Metabolism and autoradiographic distribution of delta-8- and delta-9-tetrahydrocannabinol in some organs of the monkey Callithrix jacchus.
Source
Naunyn-Schmiedebergs Archives of Pharmacology
Date
1975 Mar 25
Issue
287(2)
Pages
219-25
Abstract
Metabolism and autoradiographic distribution of the two isomeric tetrahydrocannabinols, (2,4-14-C)-delta-8-THC and (2,4-14-C)-delta-9-THC, were studied in the marmoset Callithrix jacchus. Of the two cannabinoids, delta-8-THC had a slower initial rate of biotransformation to the psychopharmacologically more potent 11-hydroxylated metabolite. This may explain the minor psychopharmacological activity of the delta-8-isomer. In glandular tissues an accumulation of unchanged delta-9-THC was observed. Autoradiography revealed characteristic label distributions in some organs 30 min after the administration of the drugs. This labelling pattern was found to be changed after a 6-hr incorporation period. The autoradiographic distribution of delta-8 and delta-9-THC appeared to be identical.

Id Code
76054564
Authors
Hine B, Torrelio M, Gershon S
Title
Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats.
Source
Research Communications in Chemical Pathology & Pharmacology
Date
1975 Sep
Issue
12(1)
Pages
185-8
Abstract
The same dose of cannabinol (CBN) or cannabidiol (CBD) further increased the attenuation of precipitated abstinence signs observed in morphine-dependent rats that also received an acute dose of delta 9-THC. By contrast, rotational behavior (turning), which is observed concomitantly in THC-treated rats during morphine abstinence, was not increased by CBN, but was potentiated by CBD. These data illustrate differences between psychoinactive cannabinoids in their interaction with delta 9-THC that might be relevant to possible clinical use of Cannabis in narcotic detoxification.

Id Code
76152559
Authors
Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty RE
Title
Effects of delta9-tetrahydrocannabinol and cannabinol in man.
Source
Pharmacology
Date
1975
Issue
13(6)
Pages
502-12
Abstract
The interaction of delta9-tetrahydrocannabinol (delta9-THC) and cannabinol (CBN) was studied in man. Five male volunteers were given placebo, 50 mg CBN, 25 mg delta9-THC, 12.5 mg delta9-THC + 25 mg CBN, and 25 mg delta9-THC + 50 mg CBN (orally). Administrations were spaced 1 week apart. With physiological measures, delta9-THC produced an increase in heart rate while CBN did not. When combined, no change of the delta9-THC effect occurred. No changes occurred on the electrocardiogram, blood pressure, or body temperature. With psychophysical measures no changes occurred in pain thresholds or skin sensitivity as a function of drug treatment. In time estimates of the passage of 1 minute, delta9-THC alone produced underestimates of the passage of 1 minute and CBN alone had no effect. In combination the two drugs had a tendency to produce significant overestimates and underestimates of the passage of 1 minute. On a 66-item adjective-pair drug reaction scale, the volunteers reported feeling drugged, drunk, dizzy, and drowsy under the delta9-THC condition, but not under the CBN condition. With combined drug treatment, volunteers reported feeling more drugged, drunk, dizzy, and drowsy than under the delta9-THC condition alone. None of the drug treatments produced significant changes on other items which included items on perception, emotion, cognition and sociability. It appears that CBN increases the effect of delta9-THC on some aspects of physiological and psychological processes, but that these effects are small and cannot account for the greater potency which has been reported when plant material is used.

Id Code
76103121
Authors
Martin BR, Dewey WL, Harris LS, Beckner J
Title
Marihuana-like activity of new synthetic tetrahydrocannabinols.
Source
Pharmacology, Biochemistry & Behavior
Date
1975 Sep-Oct
Issue
3(5)
Pages
849-53
Abstract
11-Methy-delta8-, 9-nor-delta8, and 9-nor-delta9-tetrahydrocannabinol (THC), newly synthesized cannabinoids which are not 11-hydroxyated in vivo, were tested for cannabinoid activity. Delta8-, delta9-THC and each synthetic analog produced static ataxia in unanesthetized dogs, hypotension and bradycardia in anesthetized dogs, and decreased spontaneous activity in mice. All synthetic analogs tested produced a greater degree of tolerance to the behavioral effect in dogs than did delta8-THC. 11-Methyl-delta8-THC was more effective than delta8-THC in decreasing spontaneous activity in mice, but was less active in producing the behavioral and cardiovascular effects in dogs. 9-nor-delta9-THC was less active than delta9-TCH, but 9-nor-delta8-THC was as active as delta8-THC in all observations. These results suggest that the 11-hydroxy metabolites of delta8- and delta 9-THC are not solely responsible for the biological activity of tetrahydrocannabinol.

Id Code
75218236
Authors
Ham MT, De Jong Y
Title
Absence of interaction between delta9-tetrahydrocannabinol (delta-THC) and cannabidiol (CBD) in aggression, muscle control and body temperature experiments in mice.
Source
Psychopharmacologia
Date
1975
Issue
41(2)
Pages
169-74
Abstract
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.

Id Code
75197206
Authors
Sofia RD, Vassar HB, Knobloch LC
Title
Comparative analgesic activity of various naturally occurring cannabinoids in mice and rats.
Source
Psychopharmacologia
Date
1975
Issue
40(4)
Pages
285-95
Abstract
The analgesic effectiveness of delta-9-tetrahydrocannabinol (THC), a crude marihuana extract (CME), cannabinol (CBN), cannabidiol (CBD), morphine SO-4 and aspirin following oral administration was directly compared in mice using the acetic-induced writhing and hot plate tests and the Randall-Selitto paw pressure test in rats. THC and morphine were equipotent in all tests except that morphine was significantly more potent in elevating pain threshold in the uninflamed rat hind paw. In terms of THC content, CME was nearly equipotent in the hot plate and Randall-Selitto tests, but was 3 times more potent in the acetic acid writhing test. On the other hand, CBN, like aspirin, was only effective in reducing writhing frequency in mice (3 times more potent than aspirin) and raising pain threshold of the inflamed hind paw of the rat (equipotent with aspirin). CBD did not display a significantly analgesic effect in any of the test systems used. The results of this investigation seem to suggest that both THC and CME possess narcotic-like analgesic activity similar to morphine, while CBN appears to be a non-narcotic type analgesic like aspirin.

Id Code
76003136
Authors
McCallum NK
Title
The effect of cannabinol delta1-tetrahydro-cannabinol clearance from the blood.
Source
Experientia
Date
1975 Aug 15
Issue
31(8)
Pages
957-8
Abstract
The co-administration of cannabinol with delta1-tetrahydrocannabinol accelerates the rate of clearance of delta1-tetrahydrocannabinol from rat blood. This increased rate of clearance appears to follow that of cannabinol. The implications of these findings are discussed.

Id Code
75214189
Authors
Wilson RS, May EL
Title
Analgesic properties of the tetrahydrocannabinols, their metabolites, and analogs.
Source
Journal of Medicinal Chemistry
Date
1975 Jul
Issue
18(7)
Pages
700-3
Abstract
The tetrahydrocannabinols from marihuana were found to have moderate analgesic activity in mice by the hot-plate test (sc administration). Of the several metabolites of these two compounds tested, only the 11-hydroxy derivatives were more potent than the parent compounds. Analogs 1 and 2 (9-demethyl relatives which cannot be metabolized to 11-hydroxy compounds), both of which produce a pharmacological profile generally similar to that of delta8- and delta9-THC, were analgesically inert. This suggests that metabolism to 11-hydroxy congeners may be necessary for the mediation of analgesic activity in the mouse hot-plate test but not for other pharmacologic effects produced by these substances which we have examined.

Id Code
80003560
Authors
Chiu P, Olsen DM, Borys HK, Karler R, Turkanis SA
Title
The influence of cannabidiol and delta 9-tetrahydrocannabinol on cobalt epilepsy in rats.
Source
Epilepsia
Date
1979 Aug
Issue
20(4)
Pages
365-75
Abstract
The mechanisms of the anticonvulsant activity of cannabidiol (CBD) and the central excitation of delta 9-tetrahydrocannabinol (delta 9-THC) were investigated electrophysiologically with conscious, unrestrained cobalt epileptic rats. The well-known antiepileptics, trimethadione (TMO), ethosuximide (ESM), and phenytoin (PHT), were included as reference drugs. Direct measurements were made of spontaneously firing, epileptic potentials from a primary focus on the parietal cortex and convulsions were monitored visually. ESM and TMO decreased the frequency of focal potentials, but PHT and CBD exerted no such effect. Although CBD did not suppress the focal abnormality, it did abolish jaw and limb clonus; in contrast, delta 9-THC markedly increased the frequency of focal potentials, evoked generalized bursts of polyspikes, and produced frank convlusions. 11-OH-delta 9-THC, the major metabolite of delta 9-THC, displayed only one of the excitatory properties of the parent compound: production of bursts of polyspikes. In contrast to delta 9-THC and its 11-OH metabolite, CBD, even in very high doses, did not induce any excitatory effects or convulsions. The present study provides the first evidence that CBD exerts anticonvulsant activity against the motor manifestations of a focal epilepsy, and that the mechanism of the effect may involve a depression of seizure generation or spread in the CNS.

Id Code
77234937
Authors
Turkanis SA, Chiu P, Borys HK, Karler R
Title
Influence of delta9-tetrahydrocannabinol and cannabidiol on photically evoked after-discharge potentials.
Source
Psychopharmacology
Date
1977 Apr 29
Issue
52(2)
Pages
207-12
Abstract
Two cannabinoids, delta9-tetrahydrocannabinol and cannabidiol, and several reference drugs were compared relative to their effects in a recently developed anticonvulsant test system, the after-discharge potentials of the visually evoked response; the potentials were recorded electrophysiologically from electrodes permanently mounted over the visual cortices of conscious rats. In anticonvulsant doses, trimethadione and ethosuximide produced an extensive depression of after-discharge activity, whereas diphenylhydantoin and cannabidiol exerted no such effect. In contrast, anticonvulsant doses of delta9-tetrahydrocannabinol and subconvulsant doses of pentylenetetrazol markedly increased after-discharge activity, which may represent a manifestation of their central nervous system excitatory properties. The data from the present study support our previously published ovservations from several other anticonvulsant tests that indicate the anticonvulsant characteristics of cannabidiol resemble those of diphenylhydantoin rather than those of trimethadione and that the central excitatory properties of delta9-tetrahydrocannabinol distinguish it from cannabidiol. The results consistently suggest that the cannabinoids will be effective against grand mal but not absence seizures.

Id Code
78116101
Authors
Bhargava HN
Title
Time course of the effects of naturally occurring cannabinoids on morphine abstinence syndrome.
Source
Pharmacology, Biochemistry & Behavior
Date
1978 Jan
Issue
8(1)
Pages
7-11
Abstract
The effects of a single intraperitoneal injection (10 mg/kg) of delta9-tetrahydrocannabinol, delta8-tetrahydrocannabinol and 11-hydroxy-delta8-tetrahydrocannabinol on abstinence syndrome were investigated in mice rendered dependent on morphine by pellet implantation. In morphine dependent mice from which the pellets had been removed, delta9-tetrahydrocannabinol inhibited the naloxone-precipitated jumping response as evidenced by an increase in the ED50 of naloxone. This inhibition was evident for 24 hr, the most pronounced effect being produced between two to four hr after delta9-tetrahydrocannabinol administration. Withdrawal defecation was also inhibited for two hours. Similarly, in mice from which pellets were not removed, delta9-tetrahydrocannabinol suppressed the jumping response; however, the intensity of effect was less than when the pellets were removed. delta8-tetrahydrocannabinol and 11-hydroxy-delta8-tetrahydrocannabinol were not effective in suppressing morphine abstinence syndrome two hr following their administration. The suppression of jumping response was specific, since, the vertical jumping behavior induced by coadministration of amphetamine and l-dopa was not affected by cannabinoids. These results demonstrate that single injection of delta9-tetrahydrocannabinol is effective in controlling morphine abstinence syndrome for 24 hr, and that the drugs related to cannabinoids may show promise in narcotic detoxification.

Id Code
79032190
Authors
Revuelta AV, Moroni F, Cheney DL, Costa E
Title
Effect of cannabinoids on the turnover rate of acetylcholine in rat hippocampus, striatum and cortex.
Source
Naunyn-Schmiedebergs Archives of Pharmacology
Date
1978 Sep 12
Issue
304(2)
Pages
107-10
Abstract
The effects of delta9-tetrahydrocannabinol (delta9-THC), the major psychoactive compound of marijuana, and cannabidiol (CBD), a non-psychoactive component, on the acetylcholine (ACh) concentration and the turnover rate of ACh (TRACh) have been studied in various regions of the rat brain. Neither delta9-THC doses from 0.2 to 10 mg/kg nor CBD (10 OR 20 MG/KG) alter the ACh concentration in the brain areas examined 30 min, after the intravenous injection. However, delta9-THC (doses from 0.2 to 10 mg/kg) causes a marked dose-related decrease in the TRACh in hippocampus whereas CBD is without effect in this brain region even when 20 mg/kg is given. Furthermore, high doses of delta9-THC (5 mg/kg) and CBD (20 mg/kg) that produce a significant decrease in the TRACh of striatum fail to change the TRACh in parietal cortex. The low doses of delta9-THC required to reduce hippocampal TRACh suggest that an action on these cholinergic mechanisms may play a role in the psychotomimetic activity of delta9-THC.

Id Code
78039124
Authors
Jarbe TU, Henriksson BG, Ohlin GC
Title
Delta9-THC as a discriminative cue in pigeons: effects of delta8-THC, CBD, and CBN.
Source
Archives Internationales de Pharmacodynamie et de Therapie
Date
1977 Jul
Issue
228(1)
Pages
68-72
Abstract
Pigeons, trained to discriminate the effects of i.m. injections of delta9-tetrahydrocannabinol (delta9-THC, 0.25 mg/kg) from the effects of the vehicle in a drug discrimination paradigm, were tested for generalization with the isomeric delta8-THC, cannabidiol (CBD) and cannabinol (CBN). When given in sufficient doses, delta8-THC and CBN were found to substitute for delta9-THC whereas CBD did not. CBD and CBN did not antagonize the stimulus effect of delta9-THC. The combination of CBN and delta9-THC rather appeared to accentuate the drug response.

Id Code
77126700
Authors
Consroe P, Martin P, Eisenstein D
Title
Anticonvulsant drug antagonism of delta9tetrahydrocannabinol-induced seizures in rabbits.
Source
Research Communications in Chemical Pathology & Pharmacology
Date
1977 Jan
Issue
16(1)
Pages
1-13
Abstract
A population of New Zealand White rabbits exhibit behavioral convulsions when given low doses of psychoactive cannabinoids of marijuana. Carbamazepine, diazepam and phenytoin were most effective in blocking these convulsions caused by delta9tetrahydrocannabinol (delta9THC). Phenobarbital and ethosuximide also blocked convulsions but only at toxic doses. Cannabidiol was effective in blocking convulsions when given concurrently with, but not prior to delta9THC.

Id Code
76164196
Authors
Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB
Title
Influence of cannabidiol on delta-9-tetrahydrocannabinol effects.
Source
Clinical Pharmacology & Therapeutics
Date
1976 Mar
Issue
19(3)
Pages
300-9
Abstract
Experiments investigating the possible interaction of tetrahydrocannabinol (THC) and cannabidiol (CBD), two major components of marihuana, were conducted under controlled laboratory conditions in a double-blind manner. In one study, 15 male volunteers were given placebo or 25 mug/kg of THC together with either placebo or 150 mug/kg of CBD by inhalation of the smoke of a single cigarette. All four treatments were assigned to each subject according to a series of Latin-square designs. CBD significantly attenuated the subjective euphoria of THC. Psychomotor impairment due to THC was not significantly altered by the simultaneous administration of CBD, but a trend indicating a decrease in THC-like effects was observed after the combination. When administered alone CBD was inactive for all the parameters measured. In a second study, 8 male subjects were given CBD (0 or 150 mug/kg) by smoke inhalation 30 min before THC (0 or 25 mug/kg) in a second cigarette. In contrast to the simultaneous administration of both drugs, CBD pretreatment did not alter the effects of THC on the parameters observed.

Id Code
85153165
Authors
Schurr A
Title
Marihuana: much ado about THC. [Review]
Source
Comparative Biochemistry & Physiology - C: Comparative Pharmacology & Toxicology
Date
1985
Issue
80(1)
Pages
1-7
Abstract
The availability of delta 1-THC, the major psychoactive component of marihuana, in pure form offered an opportunity for better understanding of the mechanism of action of this drug. Two decades after the isolation of delta 1-THC its mode of action is still obscure despite the enormous amount of research invested in it. Studying cannabis content as a whole offers a different approach for better understanding of this ancient weed and its effects.
References
75

Id Code
85298612
Authors
Chesher GB, Jackson DM
Title
The quasi-morphine withdrawal syndrome: effect of cannabinol, cannabidiol and tetrahydrocannabinol.
Source
Pharmacology, Biochemistry & Behavior
Date
1985 Jul
Issue
23(1)
Pages
13-5
Abstract
Delta-9-tetrahydrocannabinol (THC), the main psychoactive principle of cannabis, has been shown to attenuate the exhibition of signs of the quasi-morphine withdrawal syndrome in rats. Cannabinol (CBN) showed the same activity but required a dosage of approximately eight times that of THC to produce an equivalent effect. Cannabidiol was without effect at the dosage levels used. The efficacy of these cannabinoids and the potency differences recorded in this study are in accord with their effects on other behaviours, both in experimental animals and in man. The activity of THC and CBN was not affected by the narcotic antagonist, naloxone.

Id Code
91268694
Authors
Colasanti BK
Title
A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol.
Source
Journal of Ocular Pharmacology
Date
1990 Winter
Issue
6(4)
Pages
259-69
Abstract
Both delta 9-tetrahydrocannabinol (delta 9-THC) and cannabigerol, two naturally occurring marihuana cannabinoids, produced only a modest fall in intraocular pressure after acute topical application to the eyes of cats. After chronic administration unilaterally to the cornea via Alzet osmotic minipumps and connecting extraocular cannulas, however, a considerable fall in ocular tension amounting to 4 to 7 mm Hg occurred. After systemic administration of delta 9-THC to rats, polyspike discharges appeared in the cortical electroencephalogram initially during wakefulness and behavioral depression. These polyspikes subsequently became evident within rapid eye movement sleep episodes. Cannabigerol was devoid of this effect. After removal of either sympathetic or parasympathetic input to the eyes of cats, the intraocular pressure lowering effect of delta 9-THC was not changed. Neither delta 9-THC nor cannabigerol altered the rate of formation of aqueous humor. On the other hand, both cannabinoids produced a two-to three-fold increase in aqueous outflow facility. These results suggest that cannabigerol and related cannabinoids may have therapeutic potential for the treatment of glaucoma.

Id Code
90294084
Authors
Onaivi ES, Green MR, Martin BR
Title
Pharmacological characterization of cannabinoids in the elevated plus maze.
Source
Journal of Pharmacology & Experimental Therapeutics
Date
1990 Jun
Issue
253(3)
Pages
1002-9
Abstract
delta 9-Tetrahydrocannabinol (delta 9-THC) induced in both rats and mice an increased aversion to the open arms of the elevated plus maze which was similar to that produced by anxiogenic agents. This effect of delta 9-THC was approximately three times greater in rats than in mice. When the behavioral effects of the cannabinoids were characterized further in the mouse, it was found that delta 9-11-THC, 12 beta-NH2-delta 8-THC, levonantradol and (-)-11-OH-delta 8-THC-DMH produced effects that were similar to those of delta 9-THC. The effect was found to be enantioselective in that (+)-11-OH-delta 8-THC-DMH was inactive even at a dose 200 times greater than an active dose of (-)-11-OH-delta 8-THC-DMH. In contrast to the effects of delta 9-THC, mice treated with cannabidiol and nabilone spent a greater amount of time in the open arm of the maze, an effect similar to that produced by diazepam, the reference anxiolytic agent. In this test situation, 11-nor-delta 8-THC-9-carboxylic acid and abnormal cannabidiol did not alter the behavior of the animals at doses up to 20 and 100 mg/kg, respectively. Pretreatment with either the bidirectional inverse agonist carboline-3-carboxylate or diazepam (at doses that did not modify normal behavior on the elevated plus maze) blocked the effect of delta 9-THC.(ABSTRACT TRUNCATED AT 250 WORDS)

Id Code
88230169
Authors
Formukong EA, Evans AT, Evans FJ
Title
Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L.
Source
Journal of Pharmacy & Pharmacology
Date
1988 Feb
Issue
40(2)
Pages
132-4
Abstract
Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC-induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC-induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.

Id Code
89007037
Authors
Formukong EA, Evans AT, Evans FJ
Title
Analgesic and antiinflammatory activity of constituents of Cannabis sativa L.
Source
Inflammation
Date
1988 Aug
Issue
12(4)
Pages
361-71
Abstract
Two extracts of Cannabis sativa herb, one being cannabinoid-free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ-induced writhing in mouse when given orally and also to antagonize tetradecanoylphorbol acetate (TPA)-induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and delta 1-tetrahydrocannabinol (delta 1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 micrograms/kg. delta 1-THC only became maximally effective in doses of 10 mg/kg. This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CNB demonstrated little activity and even at doses in excess of 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. Cannabinoid (CBD) was the most effective of the cannabinoids at doses of 100 micrograms/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that delta 1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiinflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta 1-THC.

Id Code
88118225
Authors
Watanabe K, Narimatsu S, Yamamoto I, Yoshimura H
Title
Cross-tolerance development to the prolongation of pentobarbitone-induced sleep by delta 8-tetrahydrocannabinol and 11-hydroxy-delta 8-tetrahydrocannabinol in mice.
Source
Journal of Pharmacy & Pharmacology
Date
1987 Nov
Issue
39(11)
Pages
945-7
Abstract
Repeated administration (5 mg kg-1 day-1 i.v.) of delta 8-tetrahydrocannabinol and its active metabolite, 11-hydroxy-delta 8-tetrahydrocannabinol caused tolerance to develop to their prolonging effect on pentobarbitone-induced sleep in mice. Reciprocal cross-tolerance also developed after seven daily doses of these cannabinoids. The magnitude of the tolerance developed by the metabolite was greater than that by delta 8-tetrahydrocannabinol. The results suggest that 11-hydroxy-delta 8-tetrahydrocannabinol plays an important role both in the sleep-prolonging effect of delta 8-tetrahydrocannabinol and its tolerance development.

Id Code
87318405
Authors
Hollister LE, Gillespie HK, Mechoulam R, Srebnik M
Title
Human pharmacology of 1S and 1R enantiomers of delta-3-tetrahydrocannabinol.
Source
Psychopharmacology
Date
1987
Issue
92(4)
Pages
505-7
Abstract
Two enantiomers (1S and 1R) of delta-3-tetrahydrocannabinol were assayed in man for psychoactivity. The 1S enantiomer had definite psychic actions, qualitatively similar to those of delta-1-tetrahydrocannabinol, but quantitatively less potent (1:3 to 1:6). Adding the two enantiomers together did not increase the effect, confirming that activity was solely in the one enantiomer and that there was no interaction between them.

Id Code
87206956
Authors
O'Connell ME, Morrill GA, Fujimoto GI, Kostellow AB
Title
Factors affecting the response of the female rat reproductive system to cannabinoids.
Source
Toxicology & Applied Pharmacology
Date
1987 May
Issue
88(3)
Pages
411-7
Abstract
Chronic oral administration of either crude marihuana extract (CME) or delta 9-tetrahydrocannabinol (THC) to female Fischer rats for 64-72 days, at a dose approximating heavy usage by humans, reduces food intake by about 8%. Pair-feeding studies demonstrate that this decreased food intake accounts for previously described decreases in uterine and ovarian weights, which are much more affected by food restriction than is body weight. THC-treated rats lost weight initially which was not regained. Pair-fed rats gained only about one-half of the weight of the untreated control or vehicle-treated control rats over a 64-day period. Although long-term cannabinoid administration leads to tolerance and the resumption of the estrous cycle, the onset of estrus is often delayed when cannabinoid is administered 5-6 hr before the proestrus luteinizing hormone (LH) surge. Our results indicate that although chronic exposure to cannabinoids can continue to affect the rat estrous cycle, they do not have a direct effect on growth of the reproductive organs. The results reemphasize the need for adequate nutritional controls in marihuana and other toxicological research.

Id Code
87198241
Authors
Beardsley PM, Scimeca JA, Martin BR
Title
Studies on the agonistic activity of delta 9-11-tetrahydrocannabinol in mice, dogs and rhesus monkeys and its interactions with delta 9-tetrahydrocannabinol.
Source
Journal of Pharmacology & Experimental Therapeutics
Date
1987 May
Issue
241(2)
Pages
521-6
Abstract
The present studies examine some of the pharmacological effects of delta-9 (11)-tetrahydrocannabinol (delta 9-11-THC), an analog of delta-9-tetrahydrocannabinol (delta 9-THC). In tests with mice, delta 9-11-THC was similar to but less potent than delta 9-THC in producing hypothermia, analgesia, lethality and in reducing spontaneous activity. In dogs delta 9-THC but not delta 9-11-THC produced classical cannabimimetic signs including static ataxia, hyperreflexia, prancing and tail-tuck. delta 9-11-THC did produce central nervous system depression in 9 of the 15 dogs tested but the effects were not dose-related and appeared earlier and dissipated faster than the depressive effects induced by delta 9-THC. delta 9-THC but not delta 9-11-THC produced signs of ptosis, sedation and ataxia in rhesus monkeys. delta 9-THC also suppressed operant responding completely in four of four monkeys tested whereas in one monkey delta 9-11-THC did not do so up to doses as high as 5.0 mg/kg and was 8 to 100 times less potent in doing so in the other monkeys. When monkeys were pretreated with delta 9-11-THC the doses of delta 9-THC required to produce ptosis, sedation, ataxia and operant suppression were increased. However, when mice and dogs were pretreated with delta 9-11-THC the effects of delta 9-THC were not attenuated and usually were enhanced. The pharmacological profile of delta 9-11-THC is unusual in that it seems to have cannabimimetic activity in mice, noncannabimimetic-like effects in dogs and is perhaps devoid of cannabimimetic effects in rhesus monkeys. In addition, pretreatment with delta 9-11-THC attenuates the cannabimimetic effects of delta 9-THC in rhesus monkeys but not in mice or dogs.

Id Code
88143128
Authors
Mechoulam R, Lander N, Srebnik M, Breuer A, Segal M, Feigenbaum JJ, Jarbe TU, Consroe P
Title
Stereochemical requirements for cannabimimetic activity. [Review]
Source
NIDA Research Monograph
Date
1987
Issue
79
Pages
15-30
Abstract
The SAR of cannabimimetic activity in the cannabinoid series are reviewed with emphasis on the stereochemical requirements. Some new results are presented. The most important are that a, in humans, (-)-(1S)-delta-3-THC is much more active than (+)-(1R)-delta-3-THC; and b, with the 7-OH-delta-6-THC DMH enantiomers (32) and (33), the activity in several animal species resides completely in the (-)-(3R, 4R) enantiomer (32), the difference between the two enantiomers being up to several thousand times. The (3R,4R)-enantiomer (32) is much more active than delta-1- or delta-6-THC in animal tests, the exact level of activity depending on the test employed. The cannabimimetically inactive (+)-(3S,4S) enantiomer (33) was shown to be a potent analgetic in several animal tests. Thus, a complete dissociation between the cannabimimetic and the analgetic effects in a cannabinoid has been achieved, apparently for the first time.
References
30

Id Code
87090567
Authors
Turkanis SA, Karler R
Title
Effects of delta-9-tetrahydrocannabinol, 11-hydroxy-delta-9-tetrahydrocannabinol and cannabidiol on neuromuscular transmission in the frog.
Source
Neuropharmacology
Date
1986 Nov
Issue
25(11)
Pages
1273-8
Abstract
Intracellular recording techniques were used on neuromuscular junctions of the sartorius muscle of the frog, in vitro, to define the synaptic pharmacology of delta-9-tetrahydrocannabinol (THC), 11-hydroxy-THC and cannabidiol (CBD). The frequency of miniature endplate potentials was increased by THC, decreased by CBD and was unaffected by 11-hydroxy-THC, whereas the amplitude of the miniature endplate potentials was depressed by all three cannabinoids. In addition, the mean quantum content of the endplate potential (m) was first increased and then decreased by THC and 11-hydroxy-THC, but CBD produced only depression. Changes in m and the frequency of the miniature endplate potential indicated presynaptic sites of drug action and reduction of the amplitude of the miniature endplate potential suggested a postsynaptic site. The findings suggest possible mechanisms of action for the central excitatory and depressant properties of the cannabinoids.

Id Code
87038613
Authors
Burstein S, Hunter SA, Latham V, Mechoulam R, Melchior DL, Renzulli L, Tefft RE Jr
Title
Prostaglandins and cannabis XV. Comparison of enantiomeric cannabinoids in stimulating prostaglandin synthesis in fibroblasts.
Source
Life Sciences
Date
1986 Nov 10
Issue
39(19)
Pages
1813-23
Abstract
Stereospecificity has been reported for a number of actions of the cannabinoids in a variety of systems. In the present report, we have shown that this effect can also be demonstrated when human lung fibroblasts in monolayer culture are stimulated by cannabinoids to produce prostaglandin E2 (PGE2). Three enantiomeric pairs of cannabinoids, (+) and (-)-delta 1-tetrahydrocannabinol (THC), (+) and (-)-delta 6-THC and (+) and (-)-delta 6-dimethylheptyl (DMH) THC were tested. In each case the (-) isomer was significantly more potent in agreement with the findings of others using different systems. Interestingly, very little stereospecificity was found in fibroblasts when the release of arachidonic acid, the precursor of PGE2, was monitored. This suggests that cannabinoids may act at several sites within the cell some of which show comparatively greater stereoselectivity for these agonists.

Id Code
86295833
Authors
Burstein S, Hunter SA, Latham V, Renzulli L
Title
Prostaglandins and cannabis--XVI. Antagonism of delta 1-tetrahydrocannabinol action by its metabolites.
Source
Biochemical Pharmacology
Date
1986 Aug 1
Issue
35(15)
Pages
2553-8
Abstract
Prior exposure of cells in vitro to delta 1-tetrahydrocannabinol-7-oic acid (delta 1-THC-7-oic acid) reduced the degree of stimulation of prostaglandin synthesis incurred by subsequent treatment with delta 1-THC. The site of action of this inhibitory effect seemed to be on cyclooxygenase and not at the earlier step involving the phospholipase-mediated release of arachidonic acid. delta 1-THC-7-oic acid is a major metabolite of delta 1-THC and has no psychoactivity in humans. Our findings raise the possibility, however, that it may influence the in vivo activities of delta 1-THC by antagonizing its stimulatory action on cellular prostaglandin synthesis.

Id Code
86242290
Authors
Watanabe K, Arai M, Narimatsu S, Yamamoto I, Yoshimura H
Title
Effect of repeated administration of 11-hydroxy-delta 8-tetrahydrocannabinol, an active metabolite of delta 8-tetrahydrocannabinol, on the hepatic microsomal drug-metabolizing enzyme system of mice.
Source
Biochemical Pharmacology
Date
1986 Jun 1
Issue
35(11)
Pages
1861-5
Abstract
The effects of delta 8-tetrahydrocannabinol (delta 8-THC) and its major and active metabolite, 11-hydroxy-delta 8-tetrahydrocannabinol (11-OH-delta 8-THC), on the hepatic microsomal drug-metabolizing enzyme system were studied in mice. The repeated administration of 11-OH-delta 8-THC (5 mg/kg/day, i.v.) for 3 or 7 days increased significantly the activities of aniline hydroxylase and p-nitroanisole O-demethylase. By the same treatment, cytochrome P-450 content (3 days) or NADPH-cytochrome c reductase activity (7 days) was also increased significantly. The treatment with delta 8-THC for 7 days (5 mg/kg/day, i.v.) significantly increased aniline hydroxylase only. 11-OH-delta 8-THC increased the Vmax, but not the Km, values for both drug-metabolizing enzymes, whereas delta 8-THC decreases significantly the Km value (270 microM) for p-nitroanisole O-demethylase as compared with the control (398 microM). Repeated administration of these cannabinoids for 7 days also increased the metabolism of delta 8-THC by hepatic microsomes; this was attributed to an enhanced formation of 11-OH-delta 8-THC. In contrast, microsomal formation of 7 alpha-OH-delta 8-THC was decreased significantly by treatment with delta 8-THC. 11-OH-delta 8-THC, but not delta 8-THC, treatment increased the metabolism of 11-OH-delta 8-THC by hepatic microsomes. These findings indicate that delta 8-THC and 11-OH-delta 8-THC treatment can induce hepatic microsomal drug-metabolizing enzymes and affect differently the catalytic properties of the enzymes.

Id Code
86203947
Authors
Hiltunen AJ, Jarbe TU
Title
Interactions between delta 9-tetrahydrocannabinol and cannabidiol as evaluated by drug discrimination procedures in rats and pigeons.
Source
Neuropharmacology
Date
1986 Feb
Issue
25(2)
Pages
133-42
Abstract
Animals (rats and pigeons) were trained to discriminate between the presence and absence of delta 9-THC; the training doses were, respectively: 0.56 mg/kg (pigeons) and 3.0 mg/kg (rats). Once the drug discrimination was mastered, the pigeons were tested repeatedly after a single intramuscular (i.m.) injection of delta 9-THC (0.56 mg/kg) at the following intervals 0.5, 1.5, 4.5 and 9 hr after the injection. These results were compared with data from a separate procedure, i.e. where the various intervals after injection were examined only once per injection and both procedures yielded essentially the same outcome. Thus, less than 50% appropriate responding to THC was observed at 0.5 and 9 hr after injection, whereas greater than 90% responding to THC occurred at 1.5 and 4.5 hr. The two procedures have previously been compared in rats (Jarbe, Swedberg and Mechoulam, 1981). The repeated tests procedure was then used to evaluate combinations of delta 9-THC and cannabidiol in both species. Cannabidiol prolonged the cue effects of 1 mg/kg of delta 9-THC (intraperitoneal route of administration) in rats but did not change the time-effect curve for delta 9-THC in pigeons (dose range examined: 0.10--0.56 mg/kg); the challenge doses of cannabidiol were, respectively: 30.0 mg/kg (i.p.) and 17.5 mg/kg (i.m.). The rate of responding did not differ in tests with combinations of delta 9-THC and cannabidiol as compared to delta 9-THC given alone in pigeons. Subcutaneously administered 3-PPP, a dopamine pre-synaptic blocker, did not induce responding appropriate for delta 9-THC in rats.

Id Code
87039310
Authors
Hollister LE
Title
Interactions of cannabis with other drugs in man. [Review]
Source
NIDA Research Monograph
Date
1986
Issue
68
Pages
110-6
Abstract
Only THC, of all cannabinoids, has a significant pharmacodynamic interaction with ethanol. Effects in man are additive as expected. THC, but not CBD, showed a similar interaction with barbiturates. Interactions with stimulants were weakly additive, but the former drugs do not reverse impairments from THC. Interactions between cannabinoids are controversial. Some evidence consistently suggests that CBD may block actions of THC, while other evidence could not show a clinically significant interaction. CBD did not alter the kinetics of THC, but it decreased metabolism of hexobarbital. Preliminary studies of interactions between THC and drugs affecting activity of neurotransmitters have not provided good tests of the mechanism of action of the drug, showing, at best, subtle effects of questionable clinical significance. The variable responses of subjects to THC is neither explained by differences in metabolism of drugs nor by differences in the setting in which the drug is taken.
References
22

Id Code
96020211
Authors
Bornheim LM, Kim KY, Li J, Perotti BY, Benet LZ
Title
Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain.
Source
Drug Metabolism & Disposition
Date
1995 Aug
Issue
23(8)
Pages
825-31
Abstract
Tetrahydrocannabinol (THC), a major constituent of marijuana, and several of its metabolites are psychoactive in humans. Cannabidiol (CBD), a nonpsychoactive cannabinoid, inhibits hepatic microsomal THC metabolism and also modulates subjective psychological responses to THC in humans. Treatment of mice with CBD markedly decreased the hepatic microsomal in vitro formation of the major THC metabolites, 6 alpha-OH-THC and 7-OH-THC and increased formation of the minor metabolite 6 beta-OH-THC. THC blood levels were modestly elevated after CBD pretreatment and THC administration, compared with untreated controls, and area under the curve (AUC) of THC increased 50% as a function of decreased clearance. CBD pretreatment modestly increased the Cmax, AUC, or t1/2 of the major THC metabolites in the blood, whereas those kinetic parameters for 6 beta-OH-THC were dramatically increased. Changes in brain concentrations and kinetic parameters of the major THC metabolites did not reflect the relatively modest changes found in blood levels after CBD pretreatment, but exhibited large increases in AUC (7- to 15-fold) and t1/2 (2- to 4-fold), as well as in tmax. Changes in brain concentrations and kinetic parameters for 6 beta-OH-THC reflected the marked changes observed in blood levels after CBD pretreatment. Thus, CBD pretreatment resulted in large increases in AUC and t1/2 of all THC metabolites in brain, with a modest increase in AUC of THC. These changes in THC metabolite brain pharmacokinetics may contribute to the modulation of psychological responses to THC observed after CBD treatment.

Id Code
95384107
Authors
Usami N, Tateoka Y, Watanabe K, Yamamoto I, Yoshimura H
Title
Formation of carbon monoxide during mouse hepatic microsomal oxidative metabolism of cannabidiol; identification and determination.
Source
Biological & Pharmaceutical Bulletin
Date
1995 Apr
Issue
18(4)
Pages
529-35
Abstract
Carbon monoxide (CO) was generated in the process of hepatic microsomal oxidative metabolism of cannabidiol (CBD). After the generated CO was reduced to methane (CH4) with a methanizer, CH4 formed was determined by gas chromatography (GC) with a flame ionization detector. After oxidation with hopcalite, CO was also identified as CO2 by gas chromatography/mass spectrometry (GC/MS). The reaction was NADPH-dependent and required molecular oxygen. It was inhibited by addition of some inhibitors of cytochrome P450-dependent monooxygenase. When CBD (191 microM) was incubated with hepatic microsomes of mice in the presence of an NADPH-generating system and oxygen, concentration of CO determined by GC was 4.7 +/- 0.5 ppm/nmol P450 in the incubation atmosphere. Pretreatment with phenobarbital (100 mg/kg, i.p. for 3d) but not 3-methylcholanthrene (80 mg/kg, i.p.) increased the CO formation 78%, while pretreatment with cobaltous chloride (40 mg/kg, i.p. for 3 d) decreased the formation 56%. When CBD was incubated under oxygen-18 gas, molecular oxygen was not incorporated into the CO molecule. 8,9-Dihydro- and 1,2,8,9-tetrahydro-CBDs also produced CO to some extent, whereas CBD monomethyl- and dimethylethers reduced the ability to produce CO. In addition, cannabidivarin and olivetol produced CO, although none of delta 9-tetrahydrocannabinol, cannabinol and d-limonene did. Thus, the resorcinol moiety of CBD is important for CO formation.

Id Code
95208198
Authors
Nok AJ, Ibrahim S, Arowosafe S, Longdet I, Ambrose A, Onyenekwe PC, Whong CZ
Title
The trypanocidal effect of Cannabis sativa constituents in experimental animal trypanosomiasis.
Source
Veterinary & Human Toxicology
Date
1994 Dec
Issue
36(6)
Pages
522-4
Abstract
The effect of Cannabis sativa on trypanosome-infected rats was examined. An aqueous extract of the seeds administered at a dose of 50 mg/kg/d cured animals infected with Trypanosome brucei brucei of blood stream parasites. Six fractions eluted from the crude extract by column chromatography were assessed for trypanocidal properties. Of these, only 2 fractions retained trypanocidal activity by curing mice infected with T brucei brucei.

Id Code
93221566
Authors
Bornheim LM, Everhart ET, Li J, Correia MA
Title
Characterization of cannabidiol-mediated cytochrome P450 inactivation.
Source
Biochemical Pharmacology
Date
1993 Mar 24
Issue
45(6)
Pages
1323-31
Abstract
Cannibidiol (CBD) has been shown to impair hepatic drug metabolism in several animal species and to markedly inhibit mouse hepatic microsomal delta 1-tetrahydrocannabinol (THC) metabolism by inactivating specific cytochrome P450s (P450) belonging to the 2C and 3A subfamilies. Elucidation of the mechanism of CBD-mediated P450 inhibition would be clinically very important for predicting its effect on metabolism of THC and the many other clinically important drugs known to be metabolized by P450s 2C and 3A. CBD-mediated inactivation of mouse hepatic microsomal P450s did not decrease hepatic microsomal heme content. However, [14C]CBD was found covalently bound to microsomal protein in an approximately equimolar ratio to P450 loss. Immunoprecipitation of microsomal protein with antibodies raised against either P450 2C or 3A revealed that approximately equal amounts of [14C]-CBD were bound to each of these P450s after CBD-mediated inactivation. Furthermore, this specific P450 binding was equivalent to P450 loss and accounted for nearly all of the microsomal [14C]CBD irreversible binding. Although > 80% of the enzyme activities attributed to P450s 2C and 3A were inactivated by CBD at the anticonvulsant dose of 120 mg/kg, P450 2C was approximately 3-fold more sensitive than P450 3A at the lower CBD doses tested. CBD analogs were synthesized in order to elucidate the chemical pathways for CBD-mediated P450 inactivation in vivo. Oxidations at allylic carbon positions or saturation of either the exocyclic double bond or both double bonds of the terpene moiety did not markedly affect the inhibitory properties of the analogs. Methylation of both phenolic groups of the resorcinol moiety completely blocked the P450-inhibitory properties of this analog, revealing the involvement of a free hydroxyl group in the inactivation process. Rotation of the resorcinol moiety in abnormal-CBD did not impair the inhibitory properties of the analog, suggesting that the position of the hydroxyl group relative to the terpene ring is unimportant. Further studies are required to fully understand the chemical basis of CBD-mediated P450 inactivation.

Id Code
93142286
Authors
Talaska G, Schamer M, Bailey JR, Ali SF, Scallet AC, Slikker W Jr, Paule MG
Title
No increase in carcinogen-DNA adducts in the lungs of monkeys exposed chronically to marijuana smoke.
Source
Toxicology Letters
Date
1992 Dec
Issue
63(3)
Pages
321-32
Abstract
Rhesus monkeys exposed to marijuana smoke either 7 or 2 days/weeks (HI and LO groups, respectively), or ethanol-extracted marijuana smoke for 7 days/week (EM) or sham treatment (SH) for 1 year were sacrificed 7 months following the last exposure. Pulmonary levels of carcinogen-DNA adducts were determined. Although mean or median adduct levels were not statistically different, 15 of 22 adduct measures were highest in the EM group and lowest 12 of 22 times in the SH group. The levels of aromatic carcinogen-DNA adducts seem no higher in the lungs of animals exposed to marijuana smoke than in untreated animals. Ethanol-extracted marijuana may have effects greater than marijuana itself.

Authors
- Jaeger W, Benet LZ, Bornheim LM
Title
- Inhibition of cyclosporine and tetrahydrocannabinol metabolism by cannabidiol in mouse and human microsomes.
Language
- Eng
Date
- 1996 Mar
Issue
- 0049-8254
Source
- Xenobiotica
Pages
- 275-84
Country
- ENGLAND
Abstract
- 1. The in vitro and in vivo effects of cannabidiol on mouse and human liver microsomal metabolism of the immunosuppressive drug cyclosporine and the psychoactive compound tetrahydrocannabinol have been examined. 2. Preincubation of mouse or human liver microsomes with cannabidiol decreased the formation of all detectable cyclosporine metabolites by 73-89%. 3. In vivo cannabidiol treatment of mouse similarly decreased the formation of all detectable cyclosporine metabolites by 60-86%. 4. Preincubation of human liver microsomes with cannabidiol selectively decreased the formation of tetrahydrocannabinol metabolites catalyzed by cytochrome P4503A by 60% but had no effect on P4502C9-catalyzed metabolites. 5. Cannabidiol has the potential to clinically affect cyclosporine metabolism which may result in increased cyclosporine blood levels and an increase in its toxic side effects, and likewise may also affect tetrahydrocannabinol and its metabolite levels in man.
Research Institute
- Department of Pharmacy, University of California, San Francisco 94143- 0446, USA.
Source
- Xenobiotica 1996 Mar;26(3):275-84

Authors
- Bornheim LM, Kim KY, Li J, Perotti BY, Benet LZ
Title
- Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain.
Language
- Eng
Date
- 1995 Aug
Issue
- 0090-9556
Source
- Drug Metab Dispos
Pages
- 825-31
Country
- UNITED STATES
Abstract
- Tetrahydrocannabinol (THC), a major constituent of marijuana, and several of its metabolites are psychoactive in humans. Cannabidiol (CBD), a nonpsychoactive cannabinoid, inhibits hepatic microsomal THC metabolism and also modulates subjective psychological responses to THC in humans. Treatment of mice with CBD markedly decreased the hepatic microsomal in vitro formation of the major THC metabolites, 6 alpha-OH- THC and 7-OH-THC and increased formation of the minor metabolite 6 beta- OH-THC. THC blood levels were modestly elevated after CBD pretreatment and THC administration, compared with untreated controls, and area under the curve (AUC) of THC increased 50% as a function of decreased clearance. CBD pretreatment modestly increased the Cmax, AUC, or t1/2 of the major THC metabolites in the blood, whereas those kinetic parameters for 6 beta-OH-THC were dramatically increased. Changes in brain concentrations and kinetic parameters of the major THC metabolites did not reflect the relatively modest changes found in blood levels after CBD pretreatment, but exhibited large increases in AUC (7- to 15-fold) and t1/2 (2- to 4-fold), as well as in tmax. Changes in brain concentrations and kinetic parameters for 6 beta-OH- THC reflected the marked changes observed in blood levels after CBD pretreatment. Thus, CBD pretreatment resulted in large increases in AUC and t1/2 of all THC metabolites in brain, with a modest increase in AUC of THC. These changes in THC metabolite brain pharmacokinetics may contribute to the modulation of psychological responses to THC observed after CBD treatment.
Research Institute
- Department of Pharmacology, University of California-San Francisco 94143-0450, USA.
Source
- Drug Metab Dispos 1995 Aug;23(8):825-31

Authors
- Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC
Title
- Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors.
Language
- Eng
Date
- 1998
Issue
- 0024-3205
Source
- Life Sci
Pages
- PL1-6
Country
- ENGLAND
Abstract
- Delta9-tetrahydrocannabinol (delta9-THC), cannabinol and cannabidiol are three important natural cannabinoids from the Marijuana plant (Cannabis sativa). Using [35S]GTP-gamma-S binding on rat cerebellar homogenate as an index of cannabinoid receptor activation we show that: delta9-THC does not induce the maximal effect obtained by classical cannabinoid receptor agonists such as CP55940. Moreover at high concentration delta9-THC exhibits antagonist properties. Cannabinol is a weak agonist on rat cerebellar cannabinoid receptors and cannabidiol behaves as an antagonist acting in the micromolar range.
Research Institute
- Rhone-Poulenc Rorer S.A., C.R.V.A., Vitry-sur-Seine, France. Francois.PETITET@RP-RORER.FR
Source
- Life Sci 1998;63(1):PL1-6

Authors
- Cabral GA, Dove Pettit DA
Title
- Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease.
Language
- Eng
Date
- 1998 Mar 15
Issue
- 0165-5728
Source
- J Neuroimmunol
Pages
- 116-23
Country
- NETHERLANDS
Abstract
- Marijuana, Cannabis sativa, elicits a variety of effects in experimental animals and humans. Delta-9-tetrahydrocannabinol (THC) is the major psychoactive component in marijuana. This substance has been shown, also, to be immunosuppressive and to decrease host resistance to bacterial, protozoan, and viral infections. Macrophages, T lymphocytes, and natural killer cells appear to be major targets of the immunosuppressive effects of THC. Definitive data which directly link marijuana use to increased susceptibility to infection in humans currently is unavailable. However, cumulative reports indicating that THC alters resistance to infection in vitro and in a variety of experimental animals support the hypothesis that a similar effect occurs in humans.
Research Institute
- Department of Microbiology and Immunology, Medical College of Virginia/Virginia Commonwealth University, Richmond 23298-0678, USA. gacabral@gems.vcu.edu
References
- 57
Source
- J Neuroimmunol 1998 Mar 15;83(1-2):116-23