Research Index | Medline Index
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