Anxiety

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Introduction

cannabinoids play an ambiguous role in anxiety: depending on the circumstances THC can either promote or suppress anxiety but CBD is anxiolytic and thus counteracts potential anxiogenic effects of THC.

Alternative Names

Stress

Group

Wiki Entry

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Phytocannabinoids

Endocannabinoids

Receptors

Enzymes

Terpenes

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Prescription Advice

Clinical evidence primarily suggests CBD to be therapeutic in the treatment of anxiety but THC can also be effective (although THC can also elicit anxiety).

Please follow generic prescription advice.

Please note that, while based on preclinical and/or clinical research, this prescription advice is solely intended as a guideline to help physicians determine the right prescription. We intend to continuously update our prescription advice based on patient and/or expert feedback. If you have information that this prescription advice is inaccurate, incomplete or outdated please contact us here.

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Literature Discussion

CBD:

In rats, CBD injected straight into the dorsal hippocampus (10-30 pmol) impaired consolidation of fear memory when given immediately or one hour after fear conditioning, but not 3 hours after conditioning. The immediate effect of CBD was fully blocked by CB1 and CB2 antagonists, partially blocked by 5-HT1A and A2A antagonists and unchanged by PPARg antagonists. After one hour, the effect was blocked only by PPARg antagonists. FAAH inhibition blocked fear consolidation when applied immediately, but not after one hour (Raymundi et al., 2019). The results suggest than CBD can impair fear memory consolidation up to one hour after conditioning at least partially via AEA, mediated in a time-dependent manner via CB1, CB2 and PPARg, and to some degree via 5-HT1A and A2A receptors. Similar results were obtained with intraperitoneal injection of 3 to 30 mg/kg CBD (Stern et al., 2017).

Similar to CBD, THC (0.3-10 mg/kg intraperitoneal) can also disrupt fear memory consolidation. Moreover, in sub-effective doses, the combination of CBD and THC (10 : 1) could attenuate the maintenance of fear memories suggesting this combination could be used to reduce anxiety without eliciting psychotropic effects (Stern et al., 2015).

In a similar experiment in rats the effect of oral CBD (50 mg/kg), THC (5 or 50 mg/kg) and background material (residual extract after isolation of THC and CBD, 21.5 or 43 mg/kg) on fear memory reconsolidation was tested either alone or in combination. CBD, administered immediately after contextual recall, significantly and persistently (at least 7 days) reduced fear memory reconsolidation. Interestingly, background material had the same effect. THC on the other hand only reduced fear memory consolidation in combination with either CBD or background material (Murkar et al., 2019), suggesting a significant entourage effect on anxiety.

In another stress experiment in rats, intraperitoneal administration of THC (1 mg/kg) was found to be anxiogenic while CBD (5 mg/kg) and CBDA (0.1 to 100 mg/kg) were found to be anxiolytic although they could not alter the anxiogenic response to THC (Rock et al., 2017). Especially the low effective dose of CBDA is surprising.

In streptozotocin-induced diabetic rats, intraperitoneal administration of 30 mg/kg CBD had both anti-depressant and anxiolytic effects. While the anti-depressant effects were blocked by CB1, CB2 and 5-HT1A antagonists, the anxiolytic effects were only blocked by CB1 and 5-HT1A antagonists. CBD also had a positive effect on glycemic control which was CB2-dependent (Chaves et al., 2021).

In another rat experiment intraperitoneal injection of CBD (10 mg/kg) enhanced fear extinction when the conditioning stimulus was strong (6 foot shocks) but impaired fear extinction when the stimulus was relatively weak (2 foot shocks)(Song et al., 2016), suggesting the effect of CBD may be dependent on stress level.

In spontaneously hypertensive rats a low dose of 1 mg/kg intraperitoneal CBD increased social interaction (Almeida et al., 2013), suggesting an anxiolytic effect. Interestingly, the same study found that CBD was not antipsychotic in doses up to 60 mg/kg.

In rats, direct injection of 100 nmol CBD into the ventromedial hypothalamus decreased panic attack-like behavior (induced by local injection of NMDA) and unconditioned fear-induced anti-nociception in a CB1-dependent way (Khan et al., 2020).

In rats, direct injection of 5 mg CBD into the substantia nigra suppressed aversive/anxious behavior induced by GABAergic blockade in the superior colliculus in a CB1-dependent manner (da Silva et al., 2015).

In mice, 10 mg/kg CBD intraperitoneal, administered 24h after fear conditioning, disrupted cued fear memory expression but not generalized anxiety-related behavior. The same dose of CBDA on the other hand disrupted generalized anxiety-related behavior but not cued fear memory expression. Neither CBD nor CBDA affected contextual fear expression (Assareh et al., 2020).

In chronically stressed mice, concomitant chronic administration of 30 mg/kg CBD was anxiolytic by reducing FAAH activity (increasing AEA) and in a CB1 and CB2-dependent manner. In addition, CBD prevented the stress-induced decrease in dendritic remodeling and neurogenesis (Fogaça et al., 2018).

In Xenopus oocytes CBD was found to enhance GABA-A receptor mediated currents up to 4-fold at sub-micromolar concentrations (Bakas et al., 2017) which may also help explain the anti-convulsant and anxiolytic actions of CBD.

In an insightful review it was concluded that CBD can reduce fear expression acutely and by disrupting fear memory consolidation directly via stimulation of the 5-HT1A receptor and indirectly via stimulating AEA action on CB1 and CB2 and possibly Adenosine action on A2A receptors (Lee et al., 2017). While CBD may also act on receptors like TRPV1, TRPA1, TRPV2, TRPM8, GPR55 or PPARg, these effects are not yet substantially supported by experimental data.

Another review concluded that the anxiolytic effects of CBD involve the endocannabinoid system and depend on the used dose (with intermediate doses being more effective than low or high doses), the age, sex, species and strain of laboratory animal and thus that more research is required into the anxiolytic potential of CBD (García-Gutiérrez et al., 2020).

Other:

GPR55 is downregulated in mice after chronic restraint stress and its activation reduced anxiety-like behaviors, involving also PLC-PKC and RhoA-ROCK pathways (Shi et al., 2017)

MAGL inhibitors showed potential therapeutic action to treat cancer, neurodegenerative diseases, ischemic injuries, inflammation, pain, anxiety, nausea and drug-withdrawal symptoms (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013)

DAGLα knockout mice showed a reduction of 80% of 2-AG, reduction of AEA and increased fear and anxiety responses (Jenniches et al., 2016).

In Spontaneously Hypertensive Rats CBD was found to have anxiolytic but not anti-psychotic effects (Almeida et al., 2013)

Literature:

Almeida, V., Levin, R., Peres, F.F., Niigaki, S.T., Calzavara, M.B., Zuardi, A.W., Hallak, J.E., Crippa, J.A., and Abílio, V.C. (2013). Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test. Prog. Neuropsychopharmacol. Biol. Psychiatry 41, 30–35.

Assareh, N., Gururajan, A., Zhou, C., Luo, J.L., Kevin, R.C., and Arnold, J.C. (2020). Cannabidiol disrupts conditioned fear expression and cannabidiolic acid reduces trauma-induced anxiety-related behaviour in mice. Behav Pharmacol.

Bakas, T., van Nieuwenhuijzen, P.S., Devenish, S.O., McGregor, I.S., Arnold, J.C., and Chebib, M. (2017). The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol. Res. 119, 358–370.

Chaves, Y.C., Genaro, K., Crippa, J.A., da Cunha, J.M., and Zanoveli, J.M. (2021). Cannabidiol induces antidepressant and anxiolytic-like effects in experimental type-1 diabetic animals by multiple sites of action. Metab Brain Dis.

Fogaça, M.V., Campos, A.C., Coelho, L.D., Duman, R.S., and Guimarães, F.S. (2018). The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology 135, 22–33.

García-Gutiérrez, M.S., Navarrete, F., Gasparyan, A., Austrich-Olivares, A., Sala, F., and Manzanares, J. (2020). Cannabidiol: A Potential New Alternative for the Treatment of anxiety, depression, and Psychotic Disorders. Biomolecules 10, 1575.

Khan, A.U., Falconi-Sobrinho, L.L., Dos Anjos-Garcia, T., de Fátima Dos Santos Sampaio, M., de Souza Crippa, J.A., Menescal-de-Oliveira, L., and Coimbra, N.C. (2020). Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus. Psychopharmacology (Berl.).

Lee, J.L.C., Bertoglio, L.J., Guimarães, F.S., and Stevenson, C.W. (2017). Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. Br. J. Pharmacol.

Murkar, A., Kent, P., Cayer, C., James, J., Durst, T., and Merali, Z. (2019). Cannabidiol and the Remainder of the Plant Extract Modulate the Effects of Δ9-Tetrahydrocannabinol on Fear Memory Reconsolidation. Front Behav Neurosci 13, 174.

Raymundi, A.M., da Silva, T.R., Zampronio, A.R., Guimarães, F. da S., Bertoglio, L.J., and Stern, C.A.J. (2019). A time-dependent contribution of hippocampal CB1, CB2, and pparγ receptors to cannabidiol-induced disruption of fear memory consolidation. Br. J. Pharmacol.

Rock, E.M., Limebeer, C.L., Petrie, G.N., Williams, L.A., Mechoulam, R., and Parker, L.A. (2017). Effect of prior foot shock stress and Δ9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats. Psychopharmacology (Berl.) 234, 2207–2217.

da Silva, J.A., Biagioni, A.F., Almada, R.C., de Souza Crippa, J.A., Cecílio Hallak, J.E., Zuardi, A.W., and Coimbra, N.C. (2015). Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB1-cannabinoid receptor in the ventral mesencephalon. Eur. J. Pharmacol. 758, 153–163.

Song, C., Stevenson, C.W., Guimaraes, F.S., and Lee, J.L.C. (2016). Bidirectional Effects of Cannabidiol on Contextual Fear Memory Extinction. Front Pharmacol 7, 493.

Stern, C.A.J., Gazarini, L., Vanvossen, A.C., Zuardi, A.W., Galve-Roperh, I., Guimaraes, F.S., Takahashi, R.N., and Bertoglio, L.J. (2015). Δ(9)-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption. Eur Neuropsychopharmacol.

Stern, C.A.J., da Silva, T.R., Raymundi, A.M., de Souza, C.P., Hiroaki-Sato, V.A., Kato, L., Guimarães, F.S., Andreatini, R., Takahashi, R.N., and Bertoglio, L.J. (2017). Cannabidiol disrupts the consolidation of specific and generalized fear memories via dorsal hippocampus CB1 and CB2 receptors. Neuropharmacology.

Almeida, V., Levin, R., Peres, F.F., Niigaki, S.T., Calzavara, M.B., Zuardi, A.W., Hallak, J.E., Crippa, J.A., and Abílio, V.C. (2013). Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test. Prog. Neuropsychopharmacol. Biol. Psychiatry 41, 30–35.

Chen, R., Zhang, J., Wu, Y., Wang, D., Feng, G., Tang, Y.-P., … Chen, C. (2012). Monoacylglycerol lipase is a therapeutic target for Alzheimer’s disease. Cell Reports, 2(5), 1329-1339. https://doi.org/10.1016/j.celrep.2012.09.030

Jenniches, I., Ternes, S., Albayram, O., Otte, D. M., Bach, K., Bindila, L., … Zimmer, A. (2016). anxiety, Stress, and Fear Response in Mice With Reduced endocannabinoid Levels. Biological Psychiatry, 79(10), 858-868. https://doi.org/10.1016/j.biopsych.2015.03.033

Kohnz, R., & Nomura, D. K. (2014). Chemical Approaches to Therapeutically Target the Metabolism and Signaling of the endocannabinoid 2-AG and Eicosanoids. Chemical Society reviews, 43(19), 6859-6869. https://doi.org/10.1039/c4cs00047a

Mulvihill, M. M., & Nomura, D. K. (2013). Therapeutic Potential of Monoacylglycerol Lipase Inhibitors. Life sciences, 92(8-9), 492-497. https://doi.org/10.1016/j.lfs.2012.10.025

Shi, Q.-X., Yang, L.-K., Shi, W.-L., Wang, L., Zhou, S.-M., Guan, S.-Y., … Yang, Q. (2017). The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress. Molecular Brain, 10(1), 38. https://doi.org/10.1186/s13041-017-0318-7

Clinical Trials

In a randomized double-blind placebo-controlled clinical trial among patients with Social anxiety Disorder oral application of 600 mg CBD (in a gelatin capsule), 90 minutes before a Simulated Public Speaking Test (n=12) was compared to placebo (n=12) and healthy controls (n=12). Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort compared to placebo while no significant differences were found with healthy controls (Bergamaschi et al., 2011). In a different experimental setup the same research group also found a dose of 400 mg oral CBD to reduce anxiety.

In a double-blind study with 37 18-19-year-old Japanese teenagers with Social anxiety Disorder administration of cannabis oil containing 300 mg CBD or placebo daily for 4 weeks significantly reduced anxiety (Masataka, 2019).

In 60 healthy volunteers (male and female, aged between 18 and 35 years) 300 mg (but not 100 or 900 mg) oral CBD given ± 150 minutes before a public speaking event significantly reduced anxiety scores compared to placebo measured after the speaking event (Zuardi et al., 2017), suggesting a dose-dependent anxiolytic effect of CBD.

In a double-blind placebo-controlled study with healthy participants the effect of 32 mg CBD on fear extinction was tested. CBD given post-extinction was found to enhance consolidation of extinction learning but not to affect extinction itself (Das et al., 2013).

In a large case series, patients with anxiety (n = 47) or sleep (n = 25) problems were treated with daily capsules containing CBD for at least one month. The vast majority of patients received 25 mg/day, with some patients receiving 50 or 75 mg and one patient receiving 175 mg/day. Patients with anxiety took their capsule after breakfast while patients with sleep problems took their capsule after dinner. At the first monthly assessment after the start of CBD treatment, 79.2% (57/72) and 66.7% (48/72) of all patients experienced an improvement in anxiety and sleep, respectively; 15.3% (11/72) and 25.0% (18/72) experienced worsening symptoms in anxiety and sleep, respectively. Two months after the start of CBD treatment, 78.1% (32/41) and 56.1% (23/41) of patients reported improvement in anxiety and sleep, respectively, compared with the prior monthly visit; again, 19.5% (8/41) and 26.8% (11/41), respectively, reported worsening problems as compared with the prior month (Shannon et al., 2019). The results indicate that CBD is more effective in reducing anxiety than in improving sleep and while effective in the majority of patients, CBD might actually be counter-effective in some patients.

In a functional neuroimaging study with 10 healthy male volunteers given 400 mg oral CBD or placebo, regional cerebral blood flow was measured using SPECT. Compared to placebo, CBD significantly reduced activity in the left amygdala-hippocampal complex extending into the hypothalamus and in the left posterior cingulate gyrus while increasing activity in the left parahippocampal gyrus which may explain why CBD significantly reduced subjective anxiety and increased mental sedation (Crippa et al., 2004)(Crippa et al., 2011).

In a double-blind crossover trial with 8 healthy volunteers, oral CBD (1 mg/kg) was able to block anxiety caused by THC (0.5 mg/kg)(Zuardi et al., 1982). Similar results were obtained in a double-blind trial with 40 healthy men where 15-60 mg of oral CBD was sufficient to block most of the anxiogenic effects of 30 mg THC (Karniol et al., 1974). While this indicates an anxiolytic effect of CBD it cannot be excluded that this is due to direct antagonism of the actions of THC.

In an observational trial among 670 people who inhale cannabis flower to deal with agitation, anxiety and stress the effect of various types of cannabis in 2306 sessions was assessed with the Releaf app. It was found that THC levels positively correlated with symptom relief, specifically for anxiety whereas CBD use was not correlated to changes in symptom intensity (Stith et al., 2020).

In healthy volunteers, THC, but not CBD induces anxiety, dysphoria and psychotic symptoms (Martin-Santos et al., 2012).

THC was shown to enhance fear extinction in humans (Rabinak et al., 2013).

The anxiolytic action of CBD may be mediated by the 5-HT1A receptor (Russo et al., 2005).

Literature:

Bergamaschi, M.M., Queiroz, R.H.C., Chagas, M.H.N., de Oliveira, D.C.G., De Martinis, B.S., Kapczinski, F., Quevedo, J., Roesler, R., Schröder, N., Nardi, A.E., et al. (2011). Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology 36, 1219–1226.

Crippa, J.A. de S., Zuardi, A.W., Garrido, G.E.J., Wichert-Ana, L., Guarnieri, R., Ferrari, L., Azevedo-Marques, P.M., Hallak, J.E.C., McGuire, P.K., and Filho Busatto, G. (2004). Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 29, 417–426.

Crippa, J.A.S., Derenusson, G.N., Ferrari, T.B., Wichert-Ana, L., Duran, F.L., Martin-Santos, R., Simões, M.V., Bhattacharyya, S., Fusar-Poli, P., Atakan, Z., et al. (2011). Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol 25, 121–130.

Das, R.K., Kamboj, S.K., Ramadas, M., Yogan, K., Gupta, V., Redman, E., Curran, H.V., and Morgan, C.J.A. (2013). Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology (Berl.) 226, 781–792.

Karniol, I.G., Shirakawa, I., Kasinski, N., Pfeferman, A., and Carlini, E.A. (1974). Cannabidiol interferes with the effects of Δ9-tetrahydrocannabinol in man. European Journal of Pharmacology 28, 172–177.

Masataka, N. (2019). Anxiolytic Effects of Repeated Cannabidiol Treatment in Teenagers With Social anxiety Disorders. Front Psychol 10, 2466.

Shannon, S., Lewis, N., Lee, H., and Hughes, S. (2019). Cannabidiol in anxiety and Sleep: A Large Case Series. Perm J 23.

Stith, S.S., Li, X., Diviant, J.P., Brockelman, F.C., Keeling, K.S., Hall, B., and Vigil, J.M. (2020). The effectiveness of inhaled Cannabis flower for the treatment of agitation/irritability, anxiety, and common stress. J Cannabis Res 2, 47.

Zuardi, A.W., Shirakawa, I., Finkelfarb, E., and Karniol, I.G. (1982). Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl.) 76, 245–250.

Zuardi, A.W., Rodrigues, N.P., Silva, A.L., Bernardo, S.A., Hallak, J.E.C., Guimarães, F.S., and Crippa, J.A.S. (2017). Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Front Pharmacol 8, 259.

Martin-Santos, R., Crippa, J.A., Batalla, A., Bhattacharyya, S., Atakan, Z., Borgwardt, S., Allen, P., Seal, M., Langohr, K., Farré, M., et al. (2012). Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr. Pharm. Des. 18, 4966–4979.

Rabinak, C.A., Angstadt, M., Sripada, C.S., Abelson, J.L., Liberzon, I., Milad, M.R., and Phan, K.L. (2013). cannabinoid facilitation of fear extinction memory recall in humans. Neuropharmacology 64, 396–402.

Russo, E.B., Burnett, A., Hall, B., and Parker, K.K. (2005). Agonistic properties of cannabidiol at 5-HT1A receptors. Neurochem. Res. 30, 1037–1043.