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2018;63:17-25. neuroprotective,7878. Peres FF, Lima AC, Hallak JE, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a promising strategy to treat and prevent movement disorders? Front Pharmacol. 2018;9:482.,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage.

2019;146:1-11. cardiovascular,8080. Mc, Queen DS, Bond SM, Smith PJ, Balali-Mood K, Smart D. Cannabidiol lacks the vanilloid VR1-mediated vasorespiratory effects of capsaicin and anandamide in anaesthetised rats. Eur J Pharmacol. 2004;491:181-9.,8181. Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors.

1999;96:14136-41. and anti-inflammatory. 7878. Peres FF, Lima AC, Hallak JE, Crippa JA, Silva RH, Abilio VC. Cannabidiol as a promising strategy to treat and prevent movement disorders? Front Pharmacol. 2018;9:482.,8282. Rajesh M, Mukhopadhyay P, Batkai S, Patel V, Saito K, Matsumoto S, et al. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

2010;56:2115-25. These actions do not seem to be dependent on cannabinoid receptors. 6161. Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. Moreover, it is not completely understood whether these effects are related to CBD or to other organic compounds present in Cannabis extracts, such as myrcene and other terpenoids.

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Russo EB. Cannabidiol claims and misconceptions. Trends Pharmacol Sci. 2017;38:198-201. Therefore, more studies using pure CBD are needed to confirm the effects of CBD in animals and humans. CBD binds to cannabinoid receptors only at micromolar concentrations (≥ 10 µM),6161. Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG.

Br J Pharmacol. 2015;172:737-53. acting as a low-potency agonist, inverse agonist, antagonist, or even as an allosteric modulator of the cannabinoid CB1 receptor. 6161. Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol.

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Howlett AC, Fleming RM. Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol. 1984;26:532-8.,8585. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172:4790-805. Some CBD effects are antagonized by CB1 receptor inverse agonists,6161.

Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53. suggesting this drug may exert “indirect agonism” at CB1 receptors. Studies show that CBD can increase AEA concentration by blocking the AEA membrane transporter (AMT) or the FAAH enzyme, which catalyzes AEA hydrolysis.

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Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis PLOS Medicine

Mc, Partland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737-53.,8686. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide.

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2001;134:845-52.,8787. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215. CBD also enhances membrane fluidity,8888. Howlett AC, Scott DK, Wilken GH. Regulation of adenylate cyclase by cannabinoid drugs. Insights based on thermodynamic studies. Biochem Pharmacol. 1989;38:3297-304. increases 2-AG levels,8989.

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Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol. 2011;162:584-96. and upregulates CB1 receptor expression. 9090. Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernandez-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease. J Neurosci Res.

Several studies have demonstrated the neuroprotective properties of the CBD in different conditions, such as newborn hypoxic-ischemic encephalopathy,7979. Barata L, Arruza L, Rodriguez MJ, Aleo E, Vierge E, Criado E, et al. Neuroprotection by cannabidiol and hypothermia in a piglet model of newborn hypoxic-ischemic brain damage. Neuropharmacology. 2019;146:1-11. chronic cerebral hypoperfusion,9191.

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Effects of cannabidiol on diabetes outcomes and chronic cerebral hypoperfusion comorbidities in middle-aged rats. Neurotox Res. 2019;35:463-74. neonatal iron overload,9292. da Silva VK, de Freitas BS, Garcia RC, Monteiro RT, Hallak JE, Zuardi AW, et al. Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload.