As a leading cause of disability, depression affects 322 million people worldwide. The disorder is characterized by a depressed mood and inability to experience pleasure, accompanied by sleep, eating, and mood disorders, and in more severe cases, suicidal thoughts [1]. Almost all available antidepressants act by increasing serotonin levels in the brain to increase the neuroplasticity, which is an essential and fundamental mechanism of neuronal adaptation that is disrupted in depression. These current antidepressants face challenges in terms of slow onset, single-modal mechanism, and partial or non-responses in nearly half of depression patients [1]. More effective medications with new mechanisms of action are needed to overcome the limitations of the current available antidepressants. CBD has the potential for being a new treatment option for depression with its complex pharmacology and the ability to interact with multiple neurotransmitter systems involved in depression.
Increasing evidence suggested that CBD promotes both a rapid and a sustained antidepressant effect in animal models [1]. In 2010, a group of scientists from Brazil first demonstrated that CBD is an antidepressant in animal models, a finding confirmed by multiple animal studies afterwards [2–14]. The potential mechanisms underlying CBD's antidepressant effects involve multiple neurotransmitter systems, including serotonergic, glutamatergic, and endocannabinoid systems, which play important roles when dealing with stress and depression. CBD promotes stress-coping behavior and resilience to chronic stress by modulating several pharmacological targets involved in the neurobiology of depression, regulating neurotransmission, and increasing functional neuroplasticity and cognitive flexibility [1]. Another study showed that chronic stress reduced the production of endocannabinoids, which are brain-produced cannabinoids that are involved in establishing and maintaining human health, resulting in depression-like behavior in animal models. Cannabinoids may restore normal endocannabinoid function and potentially help stabilize moods and alleviate symptoms of depression [15].
THC has also been reported to have antidepressant effects in animal models [3, 16] and in sub-euphoric doses in humans [17]. However, there are no randomized clinical trials published studying the effects of CBD or THC in depression in humans. Clinical studies are needed to investigate the potential antidepressant effect of cannabis, THC, and CBD as new medications, or in combination with available anti-depressants, for the treatment of depression.
Reference
Silote GP, Sartim A, Sales A, Eskelund A, Guimarães FS, Wegener G, Joca S (2019) Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms. Journal of Chemical Neuroanatomy 98:104–116
Zanelati TV, Biojone C, Moreira FA, Guimarães FS, Joca SRL (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. British Journal of Pharmacology 159:122–128
El-Alfy AT, Ivey K, Robinson K, Ahmed S, Radwan M, Slade D, Khan I, ElSohly M, Ross S (2010) Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacology Biochemistry and Behavior 95:434–442
Réus GZ, Stringari RB, Ribeiro KF, et al (2011) Administration of cannabidiol and imipramine induces antidepressant-like effects in the forced swimming test and increases brain-derived neurotrophic factor levels in the rat amygdala. Acta Neuropsychiatrica 23:241–248
Campos AC, Ortega Z, Palazuelos J, et al (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. International Journal of Neuropsychopharmacology 16:1407–1419
Schiavon AP, Bonato JM, Milani H, Guimarães FS, Weffort de Oliveira RM (2016) Influence of single and repeated cannabidiol administration on emotional behavior and markers of cell proliferation and neurogenesis in non-stressed mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 64:27–34
Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, Pazos A, Adell A, Díaz Á (2016) Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology 103:16–26
Shoval G, Shbiro L, Hershkovitz L, Hazut N, Zalsman G, Mechoulam R, Weller A (2016) Prohedonic Effect of Cannabidiol in a Rat Model of Depression. NPS 73:123–129
Sartim AG, Guimarães FS, Joca SRL (2016) Antidepressant-like effect of cannabidiol injection into the ventral medial prefrontal cortex—Possible involvement of 5-HT1A and CB1 receptors. Behavioural Brain Research 303:218–227
Fogaça MV, Campos AC, Coelho LD, Duman RS, Guimarães FS (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
Sartim AG, Sales AJ, Guimarães FS, Joca SR (2018) Hippocampal mammalian target of rapamycin is implicated in stress-coping behavior induced by cannabidiol in the forced swim test. J Psychopharmacol 32:922–931
Sales AJ, Crestani CC, Guimarães FS, Joca SRL (2018) Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels. Progress in Neuro-Psychopharmacology and Biological Psychiatry 86:255–261
Sales AJ, Fogaça MV, Sartim AG, Pereira VS, Wegener G, Guimarães FS, Joca SRL (2019) Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Mol Neurobiol 56:1070–1081
García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J (2020) Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders. Biomolecules (2218-273X) 10:1575–1575
Haj-Dahmane S, Shen R-Y (2014) Chronic Stress Impairs α1-Adrenoceptor-Induced Endocannabinoid-Dependent Synaptic Plasticity in the Dorsal Raphe Nucleus. J Neurosci 34:14560–14570
Häring M, Grieb M, Monory K, Lutz B, Moreira FA (2013) Cannabinoid CB1 receptor in the modulation of stress coping behavior in mice: The role of serotonin and different forebrain neuronal subpopulations. Neuropharmacology 65:83–89
Ashton CH, Moore PB, Gallagher P, Young AH (2005) Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential. J Psychopharmacol 19:293–300
