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Antianxiety effect of cannabidiol in the elevated plus-maze



In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.
Psyehopharmaeology (1990) 100: 558-559 Psychopharmacology
©Springer- Verlag 1990
Antianxiety effect of cannabidiol in the elevated plus-maze
F.S. Guimarães 1, T.M. Chiaretti 1, F.G. Graeff 3, and A.W. Zuardi 2
Departments of 1Pharmaeology and of 2Neuropsyehiatry, FMRP, and
3Laboratory ofPsyehobiology, FFCLRP, Campus ofthe University ofSão Paulo, BR 14049, Ribeirão Preto, SP., Brazil
Reeeived Oetober 24,1989/ Final version November 7,1989
Abstract. In order to assess the presence of anxiolytic
properties in cannabidiol (CBD) the drug was tested in
an elevated plus-maze mode! of anxiety, in rats. Doses
of 2.5, 5.0 and 10.0 mg/kg significantly increased the
entry ratio (open/total number of entries), an anxiolytic-
like effect. CBD at a dose of 20.0 mg/kg was no longer
effective. None of the doses of CBD used changed total
number of entries, a measure of total exploratory activi-
ty. Diazepam (2.0 mg/kg) also caused an anxiolytic-like
effect in this model. These results indicate that CBD
causes a selective anxiolytic effect in the elevated plus-
maze, within a limited range of doses.
Key words: Cannabidiol- Anxiety - Elevated plus-maze
Cannabidiol (CBD) is a major component of canabis
saliva, making up to 40% of cannabis extracts (Grlie
1962). Unlike Ll9-tetrahydrocannabinol (Ll9-THC), it is
devoid of psychotomimetic activity. In fact, reported re-
sults show that in addition to its anticonvulsivant prop-
erties (Cunha et aI. 1980), CBD antagonizes the decrease
in body temperature, the increase in heart rate and respi-
ration and the decrease in response rate induced by LI 9_
THC in rats, pigeons and monkeys (Dewey 1986). In
man also, Zuardi et aI. (1982) showed that CBD attenu-
ates the subjective effects induced by high doses of LI 9_
THC, including enhanced anxiety. Therefore, CBD may
have anxiolytic properties. However, the results reported
so far in laboratory animais are contradictory (Silveira
Filho and Tufyk 1981; Zuardi and KarnioI1983).
The recently developed e!evated plus-maze test seems
to be a re!iable animal model of anxiety, since it detec1s
both anxiolytic and anxiogenic-like drug effects, corre-
lating with subjective reports in humans (Pellow et aI.
1985; Pellow and File 1986). Therefore, in the present
study we used the elevated plus-maze to access the anxio-
Iytic action of CBD.
OfJprint requests to: F.S. Guimarães
Material and methods
Animais. Male Wistar rats (200-240 g) were housed in groups of
six to ten with free aeeess to food and water on a 12 h light eycle
(7:00-19:00 hours) at 24± 1° C. Eaeh animal was used only onee.
Apparatus. An elevated plus-maze, as described by Pellow and File
(1986), was used. Briefly, it eonsists of two opposed open arms,
50 x 10 em, and two enclosed arms, 50 x 10 x 40 em, made ofwood,
elevated 50 em above the floor. The central square formed by the
arms was open. Before exposure to the maze the rats were plaeed
in a wooden arena (60 x 60 x 35 em) for 5 mino The experiment
took plaee in a sound isolated room illuminated by a dim light.
The observer sat in the same room.
Drugs. Cannabidiol was supplied by Dr. R. Meehoulam from He-
brew University, Jerusalem. It was dissolved in a solution of 10%
proplyene glyeol - 1% Tween 80 - saline, as proposed by Sofia
et aI. (1971) for L1,9-THC.A suspension of diazepam was prepared
by adding a drop of Tween 80 in saline. Ali solutions, including
vehicles, were injected in a volume of 1 ml/kg.
Procedure. The rats were injeeted IP and plaeed in an individual
eage. CBD was injeeted 60 min, and diazepam 20 min, before the
testo Eaeh animal was then plaeed in the wooden arena for 5 min
and, immediately thereafter, plaeed at the eentre ofthe maze, faeing
a closed armo For the 10-min test period, the number of entries
into eaeh arm was reeorded and the entry ratio (open/total arm
entries) was ealculated.
Statistical analysis. The data of CBD were analyzed by a eomplete-
ly randomized analysis of varianee (ANOV A), followed by the
multiple range test of Dunean. The results of diazepam were ana-
lyzed by a ttesto The signifieanee levei was set at P<0.05.
As shown in Fig. 1, CBD caused a significant increase
in the entry ratio (F4, 45=5.137, P=0.002), as com-
pared to vehicle, at doses of 2.5, 5.0 and 10.0 mg/kg.
However, the dose-effect curve had an inverted U shape,
so that 20.0 mg/kg CBD was no longer effective. No
drug effect occurred on total number of entries (F4,
45= 0.238, NS).
.1 +
The dose of 2.0 mg/kg diazepam used significantly
increased (t= 3.423, df= 18, P<0.005) the entry ratio
(0.52± 0.07) as compared to vehicle (0.26 ± 0.02), with-
out affecting the total number of entries (t = 0.33, df = 18,
NS). References
Acknowledgements. We thank José Carlos de Aguiar for technical
assistance and Dr. R. Mechoulam for the generous supply of can-
nabidiol. This research was supported by a grant from FINEP.
Such a limited range of anxiolytic doses of CBD may
help to explain the contradictory results of the two stu-
dies published so far which have assayed the cannabin-
oid in animal models of anxiety. Thus, in the study by
Zuardi and Karniol (1983) where positive results were
obtained, as indicated by a drug-induced decrease of
suppression of lever-pressing behaviour maintained by
water presentation caused by a conditioned stimulus
warning of an inevitable electric foot shock, a dose of
CBD was used (10 mg/kg) which also produced an an-
xiolytic effect in the present experimento In contrast, Sil-
veira Filho and Tufik (1981) reported that doses above
100 mg/kg CBD were ineffective in re1easing punished
responding in a Geller-Seifter type of conflict test as
well as in increasing eating suppressed by neophobia.
Accordingly, in the present results a dose of only 20 mg/
kg CBD was no longer anxiolytic.
In conclusion, the present as well as previously re-
ported results with animal models of anxiety indicate
that CBD causes anxiolytic effects of modera te intensity
and within a limited range of doses.
v5.0 10.0
eBO (11I9/119)
Fig.1. Effect of cannabidiol (CBD) and vehiele (V) on entry ratio
(open/total number of entries) and total entries. Points in figure
representmeans ±SE of ten animais. The asterisks indicate a signif-
icant differencefrom vehiele (Duncan test, P<0.05)
li: .3
l&l .z
!E zo +
l&l ••••
...J 15 ~
~ I
The increases in the ratio of open arm entries per total
entries in the elevated plus-maze caused by the three
lower doses of CBD used (2.5, 5 and 10 mg/kg) indicate
that this drug has anxiolytic properties. Moreover, this
anxiolytic effect of CBD does not seem to be associated
with sedation or impaired locomotion, since the number
af entries in either closed or open arms of the maze
was not significantly decreased.
However, the dose-effect curve obtained shows that
the range of anxiolytic doses of CBD is narrow. Thus,
the maximum effect was caused by 5 mg/kg, and 20 mg/
kg no longer increased the entry ratio. The last dose
also did not significantly decrease the total number of
entries. Therefore, the inverted U shape of the dose-
effect curve of CBD, shown by the present results, is
unlikely to be due to the interference of sedative effects
that might be caused by the highest doses. Also, the
maximum effect of CBD (entry ratio=0.39±0.04) was
smaller than that of 2 mg/kg of the prototype anxiolytic
diazepam (entry ratio=0.52±0.07).
Cunha JM, Carlini EA, Pereira AE, Ramos OL, Pimentel C, Gag-
liardi R, Sannito WL, Lander N, Mechoulam R (1980)Chronic
administration of cannabidiol to hea1thy volunteers and epilep-
tic patients. Pharmacology 21: 175-185
Dewey WL (1986) Cannabidiol pharmacology. Pharmacol Rev
Grlie L (1976) A comparative study on some chemical and biologi-
cal characteristics of various samples of cannabis resin. Buli
Narc 14:37-46
Pellow S, File SE (1986) Anxiolytic and anxiogenic drug effects
on exploratory activity in an elevated plus-maze. A novel test
of anxiety in the ratoPharmacol Biochem Behav 24: 525-529
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:
elosed arm entries in an elevated plus-maze as a measure of
anxiety in the rato J Neurosci Methods 14: 149-167
Silveira Filho NG, Tufik S (1981) Comparative effects between
cannabidiol and diazepam on neophobia, food intake and con-
flict behavior. Res Commun Psychol Psychiatr Behav 6:25-66
Sofia RD, Kubena RK, Barry H (1971) Comparison of four vehi-
elesfor intraperitoneal administration of 1-tetrahydrocannabin-
01.J Pharm Pharmacol 23: 889-891
Zuardi AW, Karniol IG (1983) Changes in the conditioned emo-
tional response of rats induced by 9-THC, CBD and mixture
ofthe two cannabinoids. Arq Biol TecnoI26:391-397
Zuardi AW, Shirakawa I, Finke1farb E, Karniol IG (1982) Action
of cannabidiol on the anxiety and other effects produced by
9-THC in normal subjects. Psychopharmacology 76:245-250
... Studies published over the past forty years suggest that cannabidiol (CBD) can modulate the expression of both aversive memories and anxiety-related responses in rodents and humans (Zuardi and Karniol, 1983;Guimarães et al., 1990;Onaivi et al., 1990;Zuardi and Karniol, 1983;Resstel et al., 2006; for a review, see Lee et al., 2017;Bitencourt and Takahashi, 2018;O'Sullivan et al., 2021;Petrie et al., 2021). However, the experimental subjects have predominantly been males or, occasionally, a combination of males and females (e.g., Bolsoni et al., 2022). ...
... Adult male rodents tested in the elevated plus-maze following acute treatment with CBD (2.5-30 mg/kg, i.p.) usually present less avoidance of the open arms (Guimarães et al., 1990;Onaivi et al., 1990;Guimarães et al., 1994;Schiavon et al., 2016;Gonzalez-Cuevas et al., 2018;Zieba et al., 2019;Austrich-Olivares et al., 2022; but see Kasten et al., 2019). Female studies using this anxiety test are scarcer and yield mixed findings. ...
... Both 3.0 and 10 mg/kg of CBD reduced open arms avoidance in female rats tested in the elevated plus-maze, suggesting an anxiolytic-like effect. This result agrees with that reported in males upon acute systemic treatment with 2.5-30 mg/kg (Guimarães et al., 1990(Guimarães et al., , 1994; Gonzalez-Cuevas et al., 2018) and females administered with 3.0 mg/kg The CBD 1 and VEH groups behaved similarly. These results suggest that CBD only reduced anxiety-related behaviors at the two higher doses tested. ...
Growing evidence from male rodent and human studies suggests that cannabidiol (CBD) modulates the expression of aversive memories and anxiety-related responses. The limited data on whether and how CBD influences these aspects in females could have therapeutic implications given the increased susceptibility of women to anxiety- and stress-related disorders relative to men. Female studies are also essential to examine inherent aspects that potentially contribute to differences in responsiveness to CBD. Here we addressed these questions in adult female rats. Contextually fear-conditioned animals acutely treated with CBD (1.0–10 mg/kg) were tested 45 min later. In subsequent experiments, we investigated the estrous cycle effects and the contribution of dorsal hippocampus (DH) serotonin 1A (5-HT1A) and cannabinoid types 1 (CB1) and 2 (CB2) receptors to CBD-induced effects on memory retrieval/expression. The effects of pre-retrieval systemic or intra-DH CBD administration on subsequent fear extinction were also assessed. Lastly, we evaluated the open arms avoidance and stretched-attend postures in females exposed to the elevated plus-maze after systemic CBD treatment. CBD 3.0 and 10 mg/kg administered before conditioned context exposure reduced females' freezing. This action remained unchanged across the estrous cycle and involved DH 5-HT1A receptors activation. Pre-retrieval CBD impaired memory reconsolidation and lowered fear during early extinction. CBD applied directly to the DH was sufficient to reproduce the effects of systemic CBD treatment. CBD 3.0 and 10 mg/kg reduced anxiety-related responses scored in the elevated plus-maze. Our findings demonstrate that CBD attenuates the behavioral manifestation of learned fear and anxiety in female rats.
... Each rat was carefully placed in the center of the EPM with his head facing the open arm. Rat activity during the five-minute experiment was measured in two ways: (a) how often the rat went into the open arms and (b) how long it remained in the arms [28,29]. ...
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The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH 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 ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH 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 ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH 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 ?9-TCH.
A novel test for the selective identification of anxiolytic and anxiogenic drug effects in the rat is described, using an elevated + -maze consisting of two open arms and two enclosed arms. The use of this test for detecting such drug effects was validated behaviourally, physiologically, and pharmacologically. Rats made significantly fewer entries into the open arms than into the closed arms, and spent significantly less time in open arms. Confinement to the open arms was associated with the observation of significantly more anxiety-related behaviours, and of significantly greater plasma corticosterone concentrations, than confinement to the closed arms. Neither novelty nor illumination was a significant contributor to the behaviour of the rats on the + -maze. A significant increase in the percentage of time spent on the open arms and the number of entries into the open arms was observed only within clinically effective anxiolytics (chlordiazepoxide, diazepam and, less effectively, phenobarbitone). Compounds that cause anxiety in man significantly reduced the percentage of entries into, and time spent on, the open arms (yohimbine, pentylenetetrazole, caffeine, amphetamine). Neither antidepressants nor major tranquilisers had a specific effect. Exposure to a holeboard immediately before placement on the + -maze showed that behaviour on the maze was not clearly correlated either with exploratory head-dipping or spontaneous locomotor activity.
The current studies further investigated the effects, in animal models of anxiety, of novel putative anxiolytic and anxiogenic compounds believed to induce their effects by actions at the GABA-benzodiazepine receptor complex. It was expected that the results would also provide further validation for a novel test of anxiety based on the ratio of open to closed arm entries in an elevated plus maze in the rat. The novel putative anxiolytics CL 218,872 (10-20 mg/kg) and tracazolate (5 mg/kg) significantly elevated the percentage of time spent on the open arms of an elevated plus-maze, consistent with their anxiolytic activity in several other animal tests. Also consistent with results from other animal tests, no anxiolytic activity was observed for the phenylquinoline PK 8165 (10-25 mg/kg), the 3,4-benzodiazepine tofisopam (25-50 mg/kg), or buspirone (0.5-20 mg/kg). The benzodiazepine receptor inverse agonists FG 7142 (1-5 mg/kg) and CGS 8216 (3-10 mg/kg) had anxiogenic activity in this test, as did the atypical benzodiazepine Ro 5-4864 (1-5 mg/kg). Interestingly, however, the benzodiazepine receptor antagonists Ro 15-1788 (10-20 mg/kg) and ZK 93426 (5-10 mg/kg) had no anxiogenic activity in this test.
The pharmacology of the cannabinoids is characterized by at least two very provocative phenomena. First, the multiplicity of effects. As I have mentioned throughout this review, most of these effects are due to actions on the central nervous system. The major problem in the search for a therapeutic agent in this series has been due to the inability to find a cannabinoid with the therapeutic action at doses below those that produce side effects. The high lipid solubility of the cannabinoids allows them to be distributed throughout the brain at reasonable doses. The second aspect of their pharmacology worthy of special mention is their low toxicity. Throughout this review, I have indicated that the minimal effective dose of delta 9-THC for a particular pharmacological effect in animals was higher than that usually consumed by man. Yet, in almost all cases, it was much lower than the dose which produced toxic effects in the same species. These two characteristics of the animal pharmacology of cannabinoids carry over to humans. For instance, each of the cannabinoids tested in man causes many side effects at active doses and lethal effects of overdose by humans are nonexistent or rare. Toxicity following chronic use may be a different issue. A great deal of work has been carried out in an attempt to characterize the pharmacological effects of cannabinoids. It is clear from the material reviewed in this article that most if not all of the predominant effects of cannabinoids in whole animals are due to the direct effects of these compounds on the central nervous system. Our state of knowledge is too limited to rule out the possibility that they also produce effects on certain peripheral organs. It is expected that the majority of these effects will be shown to be due to the interaction of the cannabinoids with the neuronal innervation of the organ rather than directly with the organ tissue itself. Very high doses of cannabinoids just like all active drugs have an effect on many organ systems. These are toxicologic not pharmacologic and are nonspecific. The effects of cannabinoids at the molecular level have been reviewed by Martin (182a) in this series. This type of research is expected to elucidate the mechanism of action of cannabinoids at the cellular level. It is clear that the cannabinoids produce a unique behavioral syndrome in laboratory animals and in man.(ABSTRACT TRUNCATED AT 400 WORDS)