Mechanism and clinical research progress of cannabidiol for mental disorders_West China Medical Journal

Authors：

XU Huifang ^1,2 , KUANG Weihong ¹ ,  LI Jin ¹

1. Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Acute Psychiatry, Chengdu Fourth People’s Hospital, Chengdu, Sichuan 610036, P. R. China;

Corresponding author：

LI Jin, Email: jin000424@163.com

Keywords：

Cannabidiol; mental disorders; treatment; mechanisms of action

DOI：

10.7507/1002-0179.202302206

Video：

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Abstract Full text Figures/Tables Video References Cited by

Mental disorders are a type of behavioral, emotional, cognitive, or thinking disorder that cause pain and social dysfunction, and are one of the top ten global disease burdens. Cannabidiol (CBD) is one of the main components of cannabis, with high safety and tolerability, and is a hot topic in drug research. CBD has a wide range of therapeutic effects, and research has found that CBD has neuropsychiatric effects such as anti-addiction, anti-depression, anti-anxiety, and anti-stress, making it one of the candidate drugs for mental disorders. This article summarizes the mechanism and research progress of CBD for major mental disorders, in order to provide useful references for CBD-related compounds in the treatment of mental disorders.

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2.	GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry, 2022, 9(2): 137-150.
3.	Freeman AM, Petrilli K, Lees R, et al. How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review. Neurosci Biobehav Rev, 2019, 107: 696-712.
4.	Cerino P, Buonerba C, Cannazza G, et al. A review of hemp as food and nutritional supplement. Cannabis Cannabinoid Res, 2021, 6(1): 19-27.
5.	刘凯, 张静, 何媛, 等. 大麻二酚临床疗效及递送系统研究进展沈阳药科大学学报, 2021, 38(12): 1361-1372.
6.	Nguyen LC, Yang D, Nicolaescu V, et al. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv, 2022, 8(8): eabi6110.
7.	Martinenghi LD, Jønsson R, Lund T, et al. Isolation, purification, and antimicrobial characterization of cannabidiolic acid and cannabidiol from cannabis sativa L. Biomolecules, 2020, 10(6): 900.
8.	Viegas FPD, Gontijo VS, de Freitas Silva M, et al. Curcumin, resveratrol and cannabidiol as natural key prototypes in drug design for neuroprotective agents. Curr Neuropharmacol, 2022, 20(7): 1297-1328.
9.	Kirkland AE, Fadus MC, Gruber SA, et al. A scoping review of the use of cannabidiol in psychiatric disorders. Psychiatry Res, 2022, 308: 114347.
10.	Navarrete F, García-Gutiérrez MS, Gasparyan A, et al. Role of cannabidiol in the therapeutic intervention for substance use disorders. Front Pharmacol, 2021, 12: 626010.
11.	Peng J, Fan M, An C, et al. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD). Basic Clin Pharmacol Toxicol, 2022, 130(4): 439-456.
12.	Rana T, Behl T, Sehgal A, et al. Integrating endocannabinoid signalling in depression. J Mol Neurosci, 2021, 71(10): 2022-2034.
13.	Kibret BG, Ishiguro H, Horiuchi Y, et al. New insights and potential therapeutic targeting of CB2 cannabinoid receptors in CNS disorders. Int J Mol Sci, 2022, 23(2): 975.
14.	Vitale RM, Iannotti FA, Amodeo P. The (poly)pharmacology of cannabidiol in neurological and neuropsychiatric disorders: molecular mechanisms and targets. Int J Mol Sci, 2021, 22(9): 4876.
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16.	Silva-Cardoso GK, Lazarini-Lopes W, Hallak JE, et al. Cannabidiol effectively reverses mechanical and thermal allodynia, hyperalgesia, and anxious behaviors in a neuropathic pain model: possible role of CB1 and TRPV1 receptors. Neuropharmacology, 2021, 197: 108712.
17.	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(8): 1517-1521.
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24.	Tito PAL, Bernardino TCS, Bellozi PMQ, et al. Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain. Pharmacol Rep, 2021, 73(6): 1680-1693.
25.	Florensa-Zanuy E, Garro-Martínez E, Adell A, et al. Cannabidiol antidepressant-like effect in the lipopolysaccharide model in mice: modulation of inflammatory pathways. Biochem Pharmacol, 2021, 185: 114433.
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27.	Galaj E, Bi GH, Yang HJ, et al. Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT_1A and TRPV1 receptor mechanisms. Neuropharmacology, 2020, 167: 107740.
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45.	Marçal AP, Soares N, Asth L, et al. Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice. Metab Brain Dis, 2022, 37(8): 2711-2718.
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47.	Kwee CM, Baas JM, van der Flier FE, et al. Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: a randomised controlled trial. Eur Neuropsychopharmacol, 2022, 59: 58-67.
48.	Gasparyan A, Navarrete F, Manzanares J. Cannabidiol and sertraline regulate behavioral and brain gene expression alterations in an animal model of PTSD. Front Pharmacol, 2021, 12: 694510.
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50.	Bayer H, Stern CAJ, Troyner F, et al. Medial prefrontal cortex mechanisms of cannabidiol-induced aversive memory reconsolidation impairments. Neuropharmacology, 2022, 205: 108913.
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52.	Sadaka AH, Ozuna AG, Ortiz RJ, et al. Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice. J Transl Med, 2021, 19(1): 220.
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1. Huang Y, Wang Y, Wang H, et al. Prevalence of mental disorders in China: a cross-sectional epidemiological study. Lancet Psychiatry, 2019, 6(3): 211-224.
2. GBD 2019 Mental Disorders Collaborators. Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry, 2022, 9(2): 137-150.
3. Freeman AM, Petrilli K, Lees R, et al. How does cannabidiol (CBD) influence the acute effects of delta-9-tetrahydrocannabinol (THC) in humans? A systematic review. Neurosci Biobehav Rev, 2019, 107: 696-712.
4. Cerino P, Buonerba C, Cannazza G, et al. A review of hemp as food and nutritional supplement. Cannabis Cannabinoid Res, 2021, 6(1): 19-27.
5. 刘凯, 张静, 何媛, 等. 大麻二酚临床疗效及递送系统研究进展沈阳药科大学学报, 2021, 38(12): 1361-1372.
6. Nguyen LC, Yang D, Nicolaescu V, et al. Cannabidiol inhibits SARS-CoV-2 replication through induction of the host ER stress and innate immune responses. Sci Adv, 2022, 8(8): eabi6110.
7. Martinenghi LD, Jønsson R, Lund T, et al. Isolation, purification, and antimicrobial characterization of cannabidiolic acid and cannabidiol from cannabis sativa L. Biomolecules, 2020, 10(6): 900.
8. Viegas FPD, Gontijo VS, de Freitas Silva M, et al. Curcumin, resveratrol and cannabidiol as natural key prototypes in drug design for neuroprotective agents. Curr Neuropharmacol, 2022, 20(7): 1297-1328.
9. Kirkland AE, Fadus MC, Gruber SA, et al. A scoping review of the use of cannabidiol in psychiatric disorders. Psychiatry Res, 2022, 308: 114347.
10. Navarrete F, García-Gutiérrez MS, Gasparyan A, et al. Role of cannabidiol in the therapeutic intervention for substance use disorders. Front Pharmacol, 2021, 12: 626010.
11. Peng J, Fan M, An C, et al. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD). Basic Clin Pharmacol Toxicol, 2022, 130(4): 439-456.
12. Rana T, Behl T, Sehgal A, et al. Integrating endocannabinoid signalling in depression. J Mol Neurosci, 2021, 71(10): 2022-2034.
13. Kibret BG, Ishiguro H, Horiuchi Y, et al. New insights and potential therapeutic targeting of CB2 cannabinoid receptors in CNS disorders. Int J Mol Sci, 2022, 23(2): 975.
14. Vitale RM, Iannotti FA, Amodeo P. The (poly)pharmacology of cannabidiol in neurological and neuropsychiatric disorders: molecular mechanisms and targets. Int J Mol Sci, 2021, 22(9): 4876.
15. Tham M, Yilmaz O, Alaverdashvili M, et al. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol, 2019, 176(10): 1455-1469.
16. Silva-Cardoso GK, Lazarini-Lopes W, Hallak JE, et al. Cannabidiol effectively reverses mechanical and thermal allodynia, hyperalgesia, and anxious behaviors in a neuropathic pain model: possible role of CB1 and TRPV1 receptors. Neuropharmacology, 2021, 197: 108712.
17. 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(8): 1517-1521.
18. Khalsa JH, Bunt G, Maggirwar SB, et al. COVID-19 and cannabidiol (CBD). J Addict Med, 2021, 15(5): 355-356.
19. Corpetti C, Del Re A, Seguella L, et al. Cannabidiol inhibits SARS-Cov-2 spike (S) protein-induced cytotoxicity and inflammation through a PPARγ-dependent TLR4/NLRP3/caspase-1 signaling suppression in caco-2 cell line. Phytother Res, 2021, 35(12): 6893-6903.
20. Kaplan JS, Stella N, Catterall WA, et al. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A, 2017, 114(42): 11229-11234.
21. Karimi-Haghighi S, Razavi Y, Iezzi D, et al. Cannabidiol and substance use disorder: dream or reality. Neuropharmacology, 2022, 207: 108948.
22. Bakas T, van Nieuwenhuijzen PS, Devenish SO, et al. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res, 2017, 119: 358-370.
23. Sharifi A, Karimi-Haghighi S, Shabani R, et al. Cannabidiol impairs the rewarding effects of methamphetamine: involvement of dopaminergic receptors in the nucleus accumbens. Prog Neuropsychopharmacol Biol Psychiatry, 2022, 113: 110458.
24. Tito PAL, Bernardino TCS, Bellozi PMQ, et al. Cannabidiol prevents lipopolysaccharide-induced sickness behavior and alters cytokine and neurotrophic factor levels in the brain. Pharmacol Rep, 2021, 73(6): 1680-1693.
25. Florensa-Zanuy E, Garro-Martínez E, Adell A, et al. Cannabidiol antidepressant-like effect in the lipopolysaccharide model in mice: modulation of inflammatory pathways. Biochem Pharmacol, 2021, 185: 114433.
26. Metz VG, da Rosa JLO, Rossato DR, et al. Cannabidiol prevents amphetamine relapse and modulates D1- and D2-receptor levels in mesocorticolimbic brain areas of rats. Eur Neuropsychopharmacol, 2021, 50: 23-33.
27. Galaj E, Bi GH, Yang HJ, et al. Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT_1A and TRPV1 receptor mechanisms. Neuropharmacology, 2020, 167: 107740.
28. Norris C, Loureiro M, Kramar C, et al. Cannabidiol modulates fear memory formation through interactions with serotonergic transmission in the mesolimbic system. Neuropsychopharmacology, 2016, 41(12): 2839-2850.
29. Galaj E, Xi ZX. Possible receptor mechanisms underlying cannabidiol effects on addictive-like behaviors in experimental animals. Int J Mol Sci, 2020, 22(1): 134.
30. Manzanares J, Cabañero D, Puente N, et al. Role of the endocannabinoid system in drug addiction. Biochem Pharmacol, 2018, 157: 108-121.
31. Freeman TP, Hindocha C, Baio G, et al. Cannabidiol for the treatment of cannabis use disorder: a phase 2a, double-blind, placebo-controlled, randomised, adaptive Bayesian trial. Lancet Psychiatry, 2020, 7(10): 865-874.
32. Hurd YL, Spriggs S, Alishayev J, et al. Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: a double-blind randomized placebo-controlled trial. Am J Psychiatry, 2019, 176(11): 911-922.
33. Meneses-Gaya C, Crippa JA, Hallak JE, et al. Cannabidiol for the treatment of crack-cocaine craving: an exploratory double-blind study. Braz J Psychiatry, 2021, 43(5): 467-476.
34. Mongeau-Pérusse V, Brissette S, Bruneau J, et al. Cannabidiol as a treatment for craving and relapse in individuals with cocaine use disorder: a randomized placebo-controlled trial. Addiction, 2021, 116(9): 2431-2442.
35. Dalhuisen I, Smit F, Spijker J, et al. rTMS combined with CBT as a next step in antidepressant non-responders: a study protocol for a randomized comparison with current antidepressant treatment approaches. BMC Psychiatry, 2022, 22(1): 88.
36. McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry, 2021, 178(5): 383-399.
37. Campos AC, Ortega Z, Palazuelos J, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol, 2013, 16(6): 1407-1419.
38. Melas PA, Scherma M, Fratta W, et al. Cannabidiol as a potential treatment for anxiety and mood disorders: molecular targets and epigenetic insights from preclinical research. Int J Mol Sci, 2021, 22(4): 1863.
39. Réus GZ, Stringari RB, Ribeiro KF, et al. 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 Neuropsychiatr, 2011, 23(5): 241-248.
40. Linge R, Jiménez-Sánchez L, Campa L, et al. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT_1A receptors. Neuropharmacology, 2016, 103: 16-26.
41. Wieckiewicz G, Stokłosa I, Stokłosa M, et al. Cannabidiol (CBD) in the self-treatment of depression-exploratory study and a new phenomenon of concern for psychiatrists. Front Psychiatry, 2022, 13: 837946.
42. Bartoli F, Bachi B, Calabrese A, et al. Cannabidiol for mood disorders: a call for more research. Can J Psychiatry, 2021, 66(2): 182-183.
43. Berger M, Li E, Rice S, et al. Cannabidiol for treatment-resistant anxiety disorders in young people: an open-label trial. J Clin Psychiatry, 2022, 83(5): 21m14130.
44. Fogaça MV, Reis FM, Campos AC, et al. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT_1A receptors and previous stressful experience. Eur Neuropsychopharmacol, 2014, 24(3): 410-419.
45. Marçal AP, Soares N, Asth L, et al. Cannabidiol ameliorates the anxiogenic and compulsive-like behaviors induced by chronic consumption of a high-carbohydrate diet in male mice. Metab Brain Dis, 2022, 37(8): 2711-2718.
46. Franzen JM, Werle I, Vanz F, et al. Cannabidiol attenuates fear memory expression in female rats via hippocampal 5-HT_1A but not CB1 or CB2 receptors. Neuropharmacology, 2023, 223: 109316.
47. Kwee CM, Baas JM, van der Flier FE, et al. Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: a randomised controlled trial. Eur Neuropsychopharmacol, 2022, 59: 58-67.
48. Gasparyan A, Navarrete F, Manzanares J. Cannabidiol and sertraline regulate behavioral and brain gene expression alterations in an animal model of PTSD. Front Pharmacol, 2021, 12: 694510.
49. Steardo L Jr, Carbone EA, Menculini G, et al. Endocannabinoid system as therapeutic target of PTSD: a systematic review. Life (Basel), 2021, 11(3): 214.
50. Bayer H, Stern CAJ, Troyner F, et al. Medial prefrontal cortex mechanisms of cannabidiol-induced aversive memory reconsolidation impairments. Neuropharmacology, 2022, 205: 108913.
51. Pang L, Zhu S, Ma J, et al. Intranasal temperature-sensitive hydrogels of cannabidiol inclusion complex for the treatment of post-traumatic stress disorder. Acta Pharm Sin B, 2021, 11(7): 2031-2047.
52. Sadaka AH, Ozuna AG, Ortiz RJ, et al. Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice. J Transl Med, 2021, 19(1): 220.
53. Han X, Song X, Song D, et al. Comparison between cannabidiol and sertraline for the modulation of post-traumatic stress disorder-like behaviors and fear memory in mice. Psychopharmacology (Berl), 2022, 239(5): 1605-1620.
54. Elms L, Shannon S, Hughes S, et al. Cannabidiol in the treatment of post-traumatic stress disorder: a case series. J Altern Complement Med, 2019, 25(4): 392-397.
55. Bolsoni LM, Crippa JAS, Hallak JEC, et al. The anxiolytic effect of cannabidiol depends on the nature of the trauma when patients with post-traumatic stress disorder recall their trigger event. Braz J Psychiatry, 2022, 44(3): 298-307.
56. Bonn-Miller MO, Sisley S, Riggs P, et al. The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: a randomized cross-over clinical trial. PLoS One, 2021, 16(3): e0246990.
57. Pedrazzi JFC, Ferreira FR, Silva-Amaral D, et al. Cannabidiol for the treatment of autism spectrum disorder: hope or hype?. Psychopharmacology (Berl), 2022, 239(9): 2713-2734.
58. Folkes OM, Báldi R, Kondev V, et al. An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability. J Clin Invest, 2020, 130(4): 1728-1742.
59. Poleg S, Kourieh E, Ruban A, et al. Behavioral aspects and neurobiological properties underlying medical cannabis treatment in Shank3 mouse model of autism spectrum disorder. Transl Psychiatry, 2021, 11(1): 524.
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