cannabinoids play an ambiguous role in Anxiety: THC typically promotes Anxiety but CBD is anxiolytic and thus counteracts the anxiogenic effects of THC.

Literature Discussion: 

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)


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 Reports2(5), 1329-1339.

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.

Kohnz, R., & Nomura, D. K. (2014). Chemical Approaches to Therapeutically Target the Metabolism and Signaling of the endocannabinoid 2-AG and Eicosanoids. Chemical Society reviews43(19), 6859-6869.

Mulvihill, M. M., & Nomura, D. K. (2013). Therapeutic Potential of Monoacylglycerol Lipase Inhibitors. Life sciences92(8-9), 492-497.

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.

Clinical Trials: 

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

In one trial, 600 mg of oral CBD significantly reduced Anxiety, cognitive impairment and discomfort in a simulated public speaking test (Bergamaschi et al., 2011).

Apart from reducing Anxiety, CBD also enhances the extinction of fear memories (Das et al., 2013). Similarly, THC was shown to enhance fear extinction in humans (Rabinak et al., 2013).

Funtional Magnetic Resonance Imaging revealed that the anxiolytic properties of CBD are associated with increased activity in the limbic regions of the brain which are involved in emotional processing (Crippa et al., 2004).

The anxiolytic action of CBD may be mediated by the 5-HT1a receptor (Russo et al., 2005).


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. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 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. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 29, 417–426.

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.

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.

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