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Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test

Abstract

Objective:

Cannabidiol (CBD), one of the non-psychotomimetic compounds of Cannabis sativa, causes anxiolytic-like effects in animals, with typical bell-shaped dose-response curves. No study, however, has investigated whether increasing doses of this drug would also cause similar curves in humans. The objective of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers performing a simulated public speaking test (SPST), a well-tested anxiety-inducing method.

Method:

A total of 57 healthy male subjects were allocated to receive oral CBD at doses of 150 mg (n=15), 300 mg (n=15), 600 mg (n=12) or placebo (n=15) in a double-blind procedure. During the SPST, subjective ratings on the Visual Analogue Mood Scale (VAMS) and physiological measures (systolic and diastolic blood pressure, heart rate) were obtained at six different time points.

Results:

Compared to placebo, pretreatment with 300 mg of CBD significantly reduced anxiety during the speech. No significant differences in VAMS scores were observed between groups receiving CBD 150 mg, 600 mg and placebo.

Conclusion:

Our findings confirm the anxiolytic-like properties of CBD and are consonant with results of animal studies describing bell-shaped dose-response curves. Optimal therapeutic doses of CBD should be rigorously determined so that research findings can be adequately translated into clinical practice.

Anxiety; cannabis; cannabidiol; CBD; simulated public speaking


Introduction

Historically, Cannabis sativa has been used by many cultures for medical purposes. The plant contains more than 80 cannabinoids, of which two have been the most studied: tetrahydrocannabinol (THC), responsible for the main psychoactive effects of cannabis, and cannabidiol (CBD), which may account for up to 40% of the plant.11. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 2006;28:153-7.,22. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr. 2008;30:271-80.

CBD has been shown to be a safe compound with a favorable adverse effects profile.33. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6:237-49. A number of studies have shown that this cannabinoid has a broad range of therapeutic properties, including antipsychotic,44. Campos AC, Fogaça MV, Sonego AB, Guimarães FS. Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res. 2016;112:119-27. sleep-regulating,55. Chagas MH, Crippa JA, Zuardi AW, Hallak JE, Machado-de-Sousa JP, Hirotsu C, et al. Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats. J Psychopharmacol. 2013;27:312-6. antidepressant and mood-stabilizing,66. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159:122-8. antiepileptic,77. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270-8. anti-inflammatory88. Esposito G, Filippis DD, Cirillo C, Iuvone T, Capoccia E, Scuderi C, et al. Cannabidiol in inflammatory bowel diseases: a brief overview. Phytother Res. 2013;27:633-6. and analgesic99. Boychuk DG, Goddard G, Mauro G, Orellana MF. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache. 2015;29:7-14. effects, in addition to improving Parkinson symptoms.1010. Chagas MH, Eckeli AL, Zuardi AW, Pena-Pereira MA, Sobreira-Neto MA, Sobreira ET, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J Clin Pharm Ther. 2014;39:564-6. Reduced anxiety has also been one of the compound’s most consistently observed effects in both animal models and human studies.1111. Crippa JA, Zuardi AW, Hallak JE. [Therapeutical use of the cannabinoids in psychiatry]. Rev Bras Psiquiatr. 2010;32:S56-66. 12. Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl). 1990;100:558-9.-1313. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7:82-8.

Regarding the former, anxiolytic-like effects have been observed in different experimental models, including the Vogel conflict test,1414. Moreira FA, Aguiar DC, Guimarães FS. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1466-71. contextual fear conditioning,1515. Lemos JI, Resstel LB, Guimarães FS. Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res. 2010;207:105-11. and the elevated plus maze (EPM).1616. Onaivi ES, Green MR, Martin BR. Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther. 1990;253:1002-9. Using the EPM, Guimarães et al. observed that CBD increases open arm exploration (an anxiolytic-like effect) at doses of 2.5 to 10 mg/kg).1212. Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl). 1990;100:558-9. Higher, doses, however, were ineffective. Inverted U-shaped dose-response curves in the EPM have also been described in mice1717. Campos AC, Guimarães FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl). 2008;199:223-30. and in rats after direct injection of CBD into periaqueductal gray matter.1818. Nazario LR, Antonioli RJ, Capiotti KM, Hallak JE, Zuardi AW, Crippa JA, et al. Reprint of "Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio)". Pharmacol Biochem Behav. 2015;139:134-40. This dose-response curve pattern, which was also observed in other animal models such as an anxiety test in adult zebrafish1919. Silveira Filho NG, Tufik S. Comparative effects between cannabidiol and diazepam on neophobia, food intake and conflict behaviour. Res Commun Psychol Psychiatr Behav. 1981;6:251-66. and forced swimming tests,66. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159:122-8. is similar to the known clinical effect of CBD. Despite these data, there are also contradictory results, Silveira Filho & Tufik1919. Silveira Filho NG, Tufik S. Comparative effects between cannabidiol and diazepam on neophobia, food intake and conflict behaviour. Res Commun Psychol Psychiatr Behav. 1981;6:251-66. found no significant effects of high doses of CBD (100 mg/kg) in rats submitted to the Geller-Seifter conflict test. Another study registered anxiogenic-like effects from chronic CBD administration in rats (10 mg/kg) subjected to two behavioral tests: locomotor activity and conditioned emotional response.2020. ElBatsh MM, Assareh N, Marsden CA, Kendall DA. Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology (Berl). 2012;221:239-47.

The presence of anxiolytic properties has been supported by some human studies. The pioneer study was conducted in 1982 and concluded that oral administration of CBD (1 mg/kg) to healthy volunteers attenuates the anxiogenic effect of THC (0.5 mg/kg).2121. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl). 1982;76:245-50. In the 1990s, another trial compared the effects of ipsapirone (5 mg) and CBD (300 mg) to those of diazepam (10 mg) and placebo in healthy volunteers during a simulated public speaking test (SPST), an anxiety-inducing task. The results indicated that CBD attenuates speech-induced anxiety compared to placebo.1313. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7:82-8. However, for 600 mg CBD, Bhattycharyya et al.2222. Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35:764-74. found only trend-level effects on anxiety as measured by the State-Trait Anxiety Inventory and no effect on a fearful faces task.

In a recent trial involving a SPST, our group found that pretreatment with CBD (600 mg) significantly reduced anxiety, cognitive impairment, and distress during speeches by patients with generalized social anxiety disorder, and significantly decreased alertness in the anticipatory period before the speech.2323. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219-26. Corroborating these findings, studies using functional neuroimaging techniques showed that the anxiolytic properties of CBD are associated with the modulation of different limbic and paralimbic areas in both healthy volunteers2424. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66:95-105. and social anxiety disorder patients.2525. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran F, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25:121-30.

Taken together, the results obtained after single-dose administration of CBD indicate that this cannabinoid could be anxiolytic in humans, although no study has yet investigated whether increasing doses of this drug would also cause bell-shaped dose-response curves in humans. This lack of data is of particular importance for determining the effective therapeutic windows of CBD for treating anxiety and other clinical conditions. Therefore, the present study aimed to compare the acute effects of three different doses CBD vs. placebo in healthy volunteers during a SPST.

Methods

Subjects

A total of 57 healthy male subjects were allocated to receive different doses of CBD (150 mg; 300 mg; 600 mg) or placebo in a double-blind, randomized design. Only men were included in the present investigation to decrease possible gender-related variations. The groups were matched according to age, years of education, and socioeconomic status. None of the participants suffered from psychiatric disorders according to the Portuguese version2626. Del-Ben CM, Vilela JAA, Crippa Jade S, Hallak JEC, Labate CM, Zuardi AW. Confiabilidade da "Entrevista clínica estruturada para o DSM-IV - versão clínica" traduzida para o português. Rev Bras Psiquiatr. 2001;23:156-9. of the Structured Clinical Interview for the DSM-IV, clinical version (SCID-CV).2727. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV Axis I disorders -- clinician version (SCID-CV). Washington: American Psychiatric; 1997. Individuals with a history of head trauma, neurological illness, or major medical illnesses (assessed with a semi-standardized medical questionnaire and physical examination) were not included. All participants were non-smokers and had not taken any medications for at least three months prior to study. None of the subjects had used marijuana more than five times in their lives (no use in the past year) and none had ever used any other illegal drugs. All subjects gave written consent to participate after being fully informed about the research procedures, which had been approved by the local ethics committee (process no. 0290/2012).

Experimental anxiety procedure

The SPST was performed according to the procedures described by McNair et al.,2828. McNair DM, Frankenthaler LM, Czerlinsky T, White TW, Sasson S, Fisher S. Simulated public speaking as a model of clinical anxiety. Psychopharmacology (Berl). 1982;77:7-10. with minor modifications introduced by Guimarães et al.2929. Guimarães FS, Zuardi AW, Graeff FG. Effect of chlorimipramine and maprolitine on experimental anxiety in humans. J Psychopharmacol. 1987;1:184-92. and Bergamaschi et al.2323. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219-26. (Table 1). In brief, after arriving at the Laboratory of Psychopharmacology at the Faculdade de Medicina de Ribeirão Preto university hospital, the first part of the consent form was carefully read and, after a 15-minute adaptation period, baseline measurements (B) were taken, followed by a single dose of oral CBD (150 mg, n=15; 300 mg, n=15; 600 mg, n=12) or placebo (n=15) in a double-blind procedure. CBD or placebo was administered one hour and thirty minutes before the test.

Table 1
Phases and procedures of the experimental session

Pretest measurements (P) were made 90 minutes after taking the drug or placebo. Immediately afterwards, the participants received the pre-recorded video instructions for the test. The participants were told they had two minutes to prepare a four-minute speech about “the public transportation system of your city.” They were also informed that the speech would be recorded on video and later analyzed by trained psychologists. Measurements of anticipatory anxiety (A) were taken just prior to the speech. Each participant then began speaking in front of the camera while viewing his image on TV (LED 3D 49’ LG® 49LF6450 Full HD). The speech was interrupted in the middle and VAMS and BP measurements (S) were taken again. The remaining two minutes of speech were then recorded, with post-test measurements taken immediately after the end of the speech and 30 minutes later (F1 and F2, respectively).

CBD

CBD (150 mg, 300 mg, or 600 mg) in powder form (99.9% purity, kindly supplied by STI-Pharm, Brentwood, UK), was dissolved in corn oil.33. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6:237-49.,55. Chagas MH, Crippa JA, Zuardi AW, Hallak JE, Machado-de-Sousa JP, Hirotsu C, et al. Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats. J Psychopharmacol. 2013;27:312-6. The same amount of corn oil was used as placebo, and both the drug and placebo were packed inside identical gelatin capsules. These doses were chosen based on previous evidence that acute anxiolytic effects have been observed in healthy subjects given doses ranging from 300 to 600 mg of CBD.2424. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66:95-105. The interval between the administration of the capsules and the measurements was chosen based on previous evidence that the plasma peak of an oral dose of CBD usually occurs 1-2 h after ingestion.1111. Crippa JA, Zuardi AW, Hallak JE. [Therapeutical use of the cannabinoids in psychiatry]. Rev Bras Psiquiatr. 2010;32:S56-66.,2424. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66:95-105.,2525. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran F, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25:121-30.,3030. Agurell S, Carlsson S, Lindgren JE, Ohlsson A, Gillespie H, Hollister L. Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man. Assay of cannabinol and cannabidiol by mass fragmentography. Experientia. 1981;37:1090-2.,3131. Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA, Seal ML, et al. Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol Psychiatry. 2008;64:966-73.

Psychological measurements

The Portuguese version3232. Zuardi AW, Karniol IG. Estudo transcultural de uma escala de auto-avaliação para estados subjetivos. J Bras Psiquiatr. 1981;30:403-6. of the Visual Analogue Mood Scale (VAMS),3333. Norris H. The action of sedatives on brain stem oculomotor systems in man. Neuropharmacology. 1971;10:181-91. was used to evaluate the state anxiety level and other subjective states during the test. It is a self-administered instrument in which subjects are asked to mark a point that identifies his/her current subjective state on a 100-mm straight line between two words that describe opposite mood states (e.g., calm-excited). The VAMS contains 16 items that can be grouped into the following four factors for factorial analysis: 1) anxiety (items calm-excited, relaxed-tense, and tranquil-troubled); 2) sedation (items alert-drowsy and attentive-dreamy); 3) cognitive impairment (items quick witted-mentally slow, proficient-incompetent, energetic-lethargic, clear headed-muzzy, gregarious-withdrawn, well-coordinated-clumsy, and strong-feeble); and 4) distress (items interested-bored, happy-sad, contented-discontented, and amicable-antagonistic).2323. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219-26.,3434. Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JE, Guimarães FS, et al. Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol. 2017;8:259.

Physiological measurements

Systolic and diastolic blood pressure were measured with a mercury sphygmomanometer (Becton Dickinson, Brazil).

Data analysis

Clinical and demographic data were analyzed with Student’s t-test for continuous data.

VAMS scores and systolic and diastolic measurements were transformed by calculating the difference between the score in each phase of the procedure and the pre-test measures for each participant (delta scores). Delta scores were then analyzed using repeated-measures analysis of variance (ANOVA) with group, phase, and group-phase interaction as factors. When sphericity was not attained, the degrees of freedom of repeated factors were corrected using Huynh-Feldt epsilon. Whenever a significant phase by group interaction occurred, comparisons among the groups were made at each phase using one-factor ANOVA followed by multiple comparisons with Bonferroni’s test.

All analyses were performed in SPSS version 20.0 and with statistical significance set at p < 0.05.

Results

The demographic characteristics of the study participants are shown in Table 2. No significant differences were observed between the four groups.

Table 2
Demographic characteristics of the groups

Visual Analogue Mood Scale (VAMS): anxiety

Figure 1 presents variations in the VAMS anxiety factor for groups receiving placebo and different doses of CBD during the SPST. The repeated-measures ANOVA showed phase (F2.48; 131.6 = 13.36; p < 0.001) and group effects (F3;53 = 2.714; p = 0.05), but no significant interaction between group and phase (F7.45;131.6 = 1.72; p = 0.1). Comparisons between groups for each phase with post hoc tests showed lower anxiety levels in the group treated with CBD 300 mg in phase S than placebo (p = 0.042).

Figure 1
Visual Analogue Mood Scale (VAMS) anxiety factor scores in each phase of the simulated public speaking test (SPST) for groups treated with cannabidiol (CBD) 150, 300, and 600 mg or placebo (points in the curve refer to mean scores and vertical lines refer to mean standard errors).* Lower anxiety levels in the group treated with CBD 300 mg relative to the placebo phase (p = 0.042). PT = pre-test; A = anticipatory anxiety; S = speech; F1= post-test 1; F2 = post-test 2.

No significant phase, group, or group-phase interaction effects were found for the VAMS factors sedation, cognitive impairment, or distress. Neither the task nor the drug affected any other VAMS dimensions.

Physiological measures: BP

Regarding systolic BP, we found a significant phase (F3.9; 211.314; 212 = 6.7; p < 0.05) but not group (F3; 53 = 0.7; p > 0.05) or group-phase interaction effect (F12; 211 = 0.99; p > 0.05). Repeated-measures ANOVA showed significant phase (F4; 212 = 2.8; p = 0,027), but not group (F3; 53 = 0.67; p > 0.05) or group-phase interaction effects (F12; 212 = 0.46; p > 0.05) for diastolic BP.

Discussion

Confirming several preclinical and clinical studies, our results indicate that acute doses of CBD can decrease anxiety. This effect has also been previously demonstrated in studies using a SPST to induce anxiety in healthy subjects1313. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol. 1993;7:82-8. and patients with social anxiety.2323. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219-26. In the latter study, CBD (600 mg) treatment was associated with significant reductions in anxiety, cognitive impairment, and distress during the speech, as well as with reduced arousal during the anticipatory phase.2323. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011;36:1219-26.

Previous clinical investigations of the anxiolytic properties of CBD, however, have been based on single doses. In the present study, we tested increasing doses of this drug in a SPST. The VAMS results showed that CDB at 150, 300 and 600 mg produced an inverted U-shaped dose-response curve. In other words, the lowest or highest doses of CBD had little or no effect on SPST- induced anxiety and a significant response was only achieved with an intermediate dose. This dose-response pattern is consistent with evidence from CBD animal studies1212. Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl). 1990;100:558-9.,1616. Onaivi ES, Green MR, Martin BR. Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther. 1990;253:1002-9.,1818. Nazario LR, Antonioli RJ, Capiotti KM, Hallak JE, Zuardi AW, Crippa JA, et al. Reprint of "Caffeine protects against memory loss induced by high and non-anxiolytic dose of cannabidiol in adult zebrafish (Danio rerio)". Pharmacol Biochem Behav. 2015;139:134-40. and with our recent findings in a group of subjects who underwent a real-life public speaking test.3434. Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JE, Guimarães FS, et al. Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol. 2017;8:259.

The molecular and neural mechanisms involved in the anxiolytic effects of CBD are incompletely understood. One complicated topic is the bell-shaped dose-response curve produced by CBD in distinct biological systems. CBD has several pharmacological targets (for a review, see Campos et al.3636. Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012;367:3364-78.), among which is its activation of TRPV1 receptors at higher doses. These receptors increase glutamate release, which could oppose 5HT1A- or CB1-mediated anxiolytic/antidepressant effects.3636. Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012;367:3364-78.,3737. Campos AC, Guimarães FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1517-21. Campos et al.3737. Campos AC, Guimarães FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1517-21. showed that pretreatment with the TRPV1 receptor antagonist capsazepine turned the higher, ineffective dose of CBD into an anxiolytic one. This result suggests that activation of TRPV1 receptors at high CBD concentrations could be one mechanism involved in its anxiolytic bell-shaped dose response curves.

It is worth mentioning, however, that CBD bell-shaped dose response curves are not exclusively associated with the drug’s anxiolytic effect. They have been described, for example, in depression using the forced swimming test66. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159:122-8. and the tail suspension test,3838. Schiavon AP, Bonato JM, Milani H, Guimarães FS, Weffort de Oliveira RM. Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice. Prog Neuropsychopharmacol Biol Psychiatry. 2016;64:27-34. in compulsive behavior measured with the marble-burying test,3939. Casarotto PC, Gomes FV, Resstel LB, Guimarães FS. Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav Pharmacol. 2010;21:353-8. in schizophrenia using prepulse inhibition4040. Levin R, Peres FF, Almeida V, Calzavara MB, Zuardi AW, Hallak JE, et al. Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain. Front Pharmacol. 2014;5:10. and pain,4141. Genaro K, Fabris D, Arantes AL, Zuardi AW, Crippa JA, Prado WA. Cannabidiol is a potential therapeutic for the affective-motivational dimension of incision pain in rats. Front Pharmacol. 2017;8:391. and in models of type 1 diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis.88. Esposito G, Filippis DD, Cirillo C, Iuvone T, Capoccia E, Scuderi C, et al. Cannabidiol in inflammatory bowel diseases: a brief overview. Phytother Res. 2013;27:633-6. It is probable that different mechanisms are responsible for these effects.3737. Campos AC, Guimarães FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1517-21. In addition, these results indicate that the optimal dose of CBD could depend on the condition, which highlights the need to test different doses when planning human and animal studies.

Neuroimaging investigations in humans indicate that the action of CBD occurs in limbic and paralimbic brain areas, which are known to be associated with anxiety. Previous studies using single-photon emission computed tomography and functional magnetic resonance imaging have shown that the anxiolytic effects of CBD are associated with activity modulation in the amygdala, hippocampus, parahippocampal gyrus and cingulate cortex.2424. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry. 2009;66:95-105.,2525. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran F, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25:121-30.,2727. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV Axis I disorders -- clinician version (SCID-CV). Washington: American Psychiatric; 1997. In addition, studies using animal models of anxiety suggest that facilitation of serotonin 5HT1A receptor-mediated neurotransmission in defense-related areas66. Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SR. Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol. 2010;159:122-8.,1717. Campos AC, Guimarães FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl). 2008;199:223-30.,3737. Campos AC, Guimarães FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1517-21.,4242. Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimarães FS. 5-HT receptors are involved in the cannabidiol- induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009;156:181-8. could be a major mechanism responsible for the acute anxiolytic effects of CBD. However, the decrease in the metabolism/uptake of anandamide by CB1-receptor antagonists3939. Casarotto PC, Gomes FV, Resstel LB, Guimarães FS. Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav Pharmacol. 2010;21:353-8. or facilitation of CB1-mediated pro-neurogenic responses4343. Syed YY, McKeage K, Scott LJ. Delta-9-tetrahydrocannabinol/cannabidiol (Sativex®): a review of its use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs. 2014;74:563-78. could also be involved.

Despite the results, certain limitations should be mentioned. This paper only reports the effects of CBD on subjective reports of anxiety, and not physiological effects, such as salivary cortisol levels or autonomic nervous system measures. Determining the effects of CBD on physiological responses to stress would have been a valuable addition to our findings. Since previous studies have shown that women present a greater arousing effect in SPST tests,4444. Monteiro-dos-Santos PC, Graeff FG, dos-Santos JE, Ribeiro RP, Guimarães FS, Zuardi AW. Effects of tryptophan depletion on anxiety induced by simulated public speaking. Braz J Med Biol Res. 2000;33:581-7. we decided to include only men in the present study and, thus, our findings cannot be generalized to women. Another relevant point is the relative similarity of CBD’s effects at all doses, which suggests that a larger sample is needed to enhance the statistical data.

In conclusion, we observed again that single acute doses of CBD cause an inverted U-shaped dose-response pattern in human subjects submitted to an experimental model of anxiety. The narrow therapeutic window of CBD makes it difficult to use the drug in clinical settings before rigorous chronic dose-response clinical trials have established optimal doses. Therefore, determining adequate treatment ranges for clinical anxiety (and any other medical condition for which CBD can be considered a treatment option) remains a challenge. However, recent well-designed clinical trials with large samples involving the chronic administration of CBD have shown that it is possible to establish the therapeutic windows of this compound for different conditions.77. Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15:270-8. Likewise, different preparations (e.g., inhaled, patches or i.v.) and combinations of cannabinoids can be produced in an attempt to optimize the therapeutic effects of CBD. Finally, further research is necessary to establish CBD’s precise mechanisms of action in different disorders and to evaluate whether therapeutic drug monitoring would be helpful in optimizing CBD outcomes and safety.

Acknowledgements

AWZ, FSG, and JAC are recipients of fellowship awards from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil – 1A). The present study was supported by grants from CNPq and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (CNPq/MS/SCTIE/DECIT 26/2014 – Pesquisas sobre Distúrbios Neuropsiquiátricos; 466805/2014-4). IML is recipient of a CNPq fellowship. We kindly thank Dr. Mateus Bergamaschi and Mrs. Sandra Bernardo for the assistance in data collection.

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Publication Dates

  • Publication in this collection
    11 Oct 2018
  • Date of issue
    Jan-Feb 2019

History

  • Received
    12 Feb 2017
  • Accepted
    10 Jan 2018
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