The use of cannabinoids (substances contained specifically in hemp plants) for therapeutic purposes has received increased attention in recent years. Presently, attention is paid to two main cannabinoids: delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). With respect to the psychotropic effects and dependence potential of THC (though it is very mild), its use is associated with certain restrictions, and thus the therapeutic properties of CBD are frequently emphasized because there are no limitations associated with the risk of dependence. Therefore, this review covers the main pharmacodynamic and pharmacokinetic features of CBD (including characteristics of endocannabinoidome) with respect to its possible beneficial effects on selected diseases in clinical practice. A substantial part of the text deals with the main effects of CBD on aging, including Alzheimer's disease and related underlying mechanisms.

Centre for Pain Management Department of Anesthesiology and Intensive Care St Anne's University Hospital Pekařská 53 602 00 Brno Czech Republic

Department of Pharmacology 3rd Faculty of Medicine Charles University Ruská 87 100 00 Prague Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

International Clinical Research Centre Cannabis Facility St Anne's University Hospital Pekařská 53 602 00 Brno Czech Republic

Zobrazit více v PubMed

Kirkwood T.B.L. Understanding the Odd Science of Aging. Cell. 2005;120:437–447. doi: 10.1016/j.cell.2005.01.027. PubMed DOI

Di Marzo V., Wang J., editors. The Endocannabinoidome: The World of Endocannabinoids and Related Mediators. 1st ed. Academic Press; Cambridge, MA, USA: 2014.

Piomelli D. The molecular logic of endocannabinoid signalling. Nat. Rev. Neurosci. 2003;4:873–884. doi: 10.1038/nrn1247. PubMed DOI

Di Marzo V., Piscitelli F. The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics. 2015;12:692–698. doi: 10.1007/s13311-015-0374-6. PubMed DOI PMC

Pertwee R.G. Handbook of Experimental Pharmacology. Volume 168. Springer; Berlin/Heidelberg, Germany: 2005. Pharmacological actions of cannabinoids; pp. 1–51. PubMed DOI

Paradisi A., Oddi S., Maccarrone M. The Endocannabinoid System in Ageing: A New Target for Drug Development. Curr. Drug Targets. 2006;7:1539–1552. doi: 10.2174/1389450110607011539. PubMed DOI

Micale V., Di Marzo V., Sulcova A., Wotjak C.T., Drago F. Endocannabinoid system and mood disorders: Priming a target for new therapies. Pharmacol. Ther. 2013;138:18–37. PubMed

Beedham W., Sbai M., Allison I., Coary R., Shipway D. Cannabinoids in the Older Person: A Literature Review. Geriatrics. 2020;5:2. doi: 10.3390/geriatrics5010002. PubMed DOI PMC

Bryk M., Starowicz K. Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain: An updated review. Pharmacol. Rep. 2021;73:681–699. doi: 10.1007/s43440-021-00270-y. PubMed DOI PMC

Mangieri R.A., Piomelli D. Enhancement of endocannabinoid signaling and the pharmacotherapy of depression. Pharmacol. Res. 2007;56:360–366. doi: 10.1016/j.phrs.2007.09.003. PubMed DOI PMC

Paredes-Ruiz K.J., Chavira-Ramos K., Orozco-Morales M., Karasu C., Tinkov A.A., Aschner M., Santamaría A., Colín-González A.L. On the Biomedical Properties of Endocannabinoid Degradation and Reuptake Inhibitors: Pre-clinical and Clinical Evidence. Neurotox. Res. 2021;39:2072–2097. doi: 10.1007/s12640-021-00424-z. PubMed DOI

Landa L., Jurica J., Sliva J., Pechackova M., Demlova R. Medical cannabis in the treatment of cancer pain and spastic conditions and options of drug delivery in clinical practice. Biomed. Pap. 2018;162:18–25. doi: 10.5507/bp.2018.007. PubMed DOI

Trojan V., Landa L., Hrib R., Jurica J., Rychlickova J., Zvonicek V., Halamkova L., Halamek J., Demlova R., Belaskova S., et al. Assessment of Delta-9-Tetrahydrocannabinol (THC) in Saliva and Blood After Oral Administration of Medical Cannabis With Respect to its Effect on Driving Abilities. Physiol. Res. 2022;71:703–712. doi: 10.33549/physiolres.934907. PubMed DOI PMC

Fisar Z. Phytocannabinoids and endocannabinoids. Curr. Drug Abus. Rev. 2009;2:51–75. doi: 10.2174/1874473710902010051. PubMed DOI

Zendulka O., Dovrtělová G., Nosková K., Turjap M., Šulcová A., Hanuš L., Juřica J. Cannabinoids and Cytochrome P450 Interactions. Curr. Drug Metab. 2016;17:206–226. doi: 10.2174/1389200217666151210142051. PubMed DOI

Mackie K. Cannabinoid Receptors as Therapeutic Targets. Annu. Rev. Pharmacol. Toxicol. 2006;46:101–122. doi: 10.1146/annurev.pharmtox.46.120604.141254. PubMed DOI

Izzo A.A., Borrelli F., Capasso R., Di Marzo V., Mechoulam R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 2009;30:515–527. doi: 10.1016/j.tips.2009.07.006. Erratum in: Trends Pharmacol. Sci. 2009, 30, 609. PubMed DOI

Battista N., Di Tommaso M., Bari M., Maccarrone M. The endocannabinoid system: An overview. Front. Behav. Neurosci. 2012;6:9. doi: 10.3389/fnbeh.2012.00009. PubMed DOI PMC

Bilkei-Gorzo A. The endocannabinoid system in normal and pathological brain ageing. Philos. Trans. R. Soc. B Biol. Sci. 2012;367:3326–3341. doi: 10.1098/rstb.2011.0388. PubMed DOI PMC

Whiting P.F., Wolff R.F., Deshpande S., Di Nisio M., Duffy S., Hernandez A.V., Keurentjes J.C., Lang S., Misso K., Ryder S., et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015;313:2456–2473. doi: 10.1001/jama.2015.6358. Erratum in: JAMA 2015, 314, 520. Erratum in: JAMA 2015, 314, 837. Erratum in: JAMA 2015, 314, 2308. Erratum in: JAMA 2016, 315, 1522. PubMed DOI

Sulcova A. Pharmacodynamics of cannabinoids. Arch. Pharm. Pharm. Sci. 2019;3:1118. doi: 10.29328/journal.apps.1001013. DOI

Hodges E.L., Ashpole N.M. Aging circadian rhythms and cannabinoids. Neurobiol. Aging. 2019;79:110–118. doi: 10.1016/j.neurobiolaging.2019.03.008. PubMed DOI PMC

Komorowska-Müller J.A., Rana T., Olabiyi B.F., Zimmer A., Schmöle A.-C. Cannabinoid Receptor 2 Alters Social Memory and Microglial Activity in an Age-Dependent Manner. Molecules. 2021;26:5984. doi: 10.3390/molecules26195984. PubMed DOI PMC

Martinelli G., Magnavacca A., Fumagalli M., Dell’agli M., Piazza S., Sangiovanni E. Cannabis sativa and Skin Health: Dissecting the Role of Phytocannabinoids. Planta Medica. 2021;88:492–506. doi: 10.1055/a-1420-5780. PubMed DOI

Ortega-Gutierrez S. Therapeutic perspectives of inhibitors of endocannabinoid degradation. Curr. Drug Target CNS Neurol. Disord. 2005;4:697–707. doi: 10.2174/156800705774933032. PubMed DOI

de Lago E., Fernández-Ruiz J., Ortega-Gutiérrez S., Cabranes A., Pryce G., Baker D., López-Rodríguez M., Ramos J.A. UCM707, an inhibitor of the anandamide uptake, behaves as a symptom control agent in models of Huntington’s disease and multiple sclerosis, but fails to delay/arrest the progression of different motor-related disorders. Eur. Neuropsychopharmacol. 2006;16:7–18. doi: 10.1016/j.euroneuro.2005.06.001. PubMed DOI

de Lago E., Ortega-Gutiérrez S., Ramos J.A., Rodríguez M.L.L., Fernández-Ruiz J. Neurochemical effects of the endocannabinoid uptake inhibitor UCM707 in various rat brain regions. Life Sci. 2007;80:979–988. doi: 10.1016/j.lfs.2006.11.029. PubMed DOI

Piomelli D., Tagne A.M. Endocannabinoid-Based Therapies. Annu. Rev. Pharmacol. Toxicol. 2022;62:483–507. doi: 10.1146/annurev-pharmtox-052220-021800. PubMed DOI

Abrams D.I. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur. J. Intern. Med. 2018;49:7–11. doi: 10.1016/j.ejim.2018.01.003. PubMed DOI

Benito C., Núñez E., Pazos M.R., Tolón R.M., Romero J. The Endocannabinoid System and Alzheimer’s Disease. Mol. Neurobiol. 2007;36:75–81. doi: 10.1007/s12035-007-8006-8. PubMed DOI

Maccarrone M., Gasperi V., Catani M.V., Diep T.A., Dainese E., Hansen H.S., Avigliano L. The Endocannabinoid System and Its Relevance for Nutrition. Annu. Rev. Nutr. 2010;30:423–440. doi: 10.1146/annurev.nutr.012809.104701. PubMed DOI

Dos Reis Rosa Franco G., Smid S., Viegas C. Phytocannabinoids: General Aspects and Pharmacological Potential in Neurodegenerative Diseases. Curr. Neuropharmacol. 2021;19:449–464. doi: 10.2174/1570159X18666200720172624. PubMed DOI PMC

[(accessed on 25 April 2023)]. Available online: https://apps.who.int/iris/bitstream/handle/10665/279948/9789241210225-eng.pdf.

Crippa J.A., Guimarães F.S., Campos A.C., Zuardi A.W. Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Front. Immunol. 2018;9:2009. doi: 10.3389/fimmu.2018.02009. PubMed DOI PMC

Batalla A., Janssen H., Gangadin S.S., Bossong M.G. The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review. J. Clin. Med. 2019;8:1058. doi: 10.3390/jcm8071058. PubMed DOI PMC

Abuhasira R., Schleider L.B.-L., Mechoulam R., Novack V. Epidemiological characteristics, safety and efficacy of medical cannabis in the elderly. Eur. J. Intern. Med. 2018;49:44–50. doi: 10.1016/j.ejim.2018.01.019. PubMed DOI

Abuhasira R., Ron A., Sikorin I., Novack V. Medical Cannabis for Older Patients—Treatment Protocol and Initial Results. J. Clin. Med. 2019;8:1819. doi: 10.3390/jcm8111819. PubMed DOI PMC

Solomon H.V., Greenstein A.P., DeLisi L.E. Cannabis Use in Older Adults: A Perspective. Harv. Rev. Psychiatry. 2021;29:225–233. doi: 10.1097/HRP.0000000000000289. PubMed DOI

Morel A., Lebard P., Dereux A., Azuar J., Questel F., Bellivier F., Marie-Claire C., Fatséas M., Vorspan F., Bloch V. Clinical Trials of Cannabidiol for Substance Use Disorders: Outcome Measures, Surrogate Endpoints, and Biomarkers. Front. Psychiatry. 2021:12565617. doi: 10.3389/fpsyt.2021.565617. PubMed DOI PMC

Sulcova A. Translational research on the effects of treatment with cannabidiol in addictions. Adiktologie. 2021;21:161–165. doi: 10.35198/01-2021-003-0001. DOI

Taylor L., Crockett J., Tayo B., Checketts D., Sommerville K. Abrupt withdrawal of cannabidiol (CBD): A randomized trial. Epilepsy Behav. 2020;104:106938. doi: 10.1016/j.yebeh.2020.106938. PubMed DOI

Wall M.E., Brine D.R., Perez-Reyes M. In: The Pharmacology of Marihuana. Braude M.C., Szara S., editors. Raven Press; New York, NY, USA: 1976. p. 93.

Agurell S., Carlsson S., Lindgren J.E., Ohlsson A., Gillespie H., Hollister L. Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man: Assay of cannabinol and cannabidiol by mass fragmentography. Experientia. 1981;37:1090–1092. doi: 10.1007/BF02085029. PubMed DOI

Huestis M.A. Human Cannabinoid Pharmacokinetics. Chem. Biodivers. 2007;4:1770–1804. doi: 10.1002/cbdv.200790152. PubMed DOI PMC

Lucas C.J., Galettis P., Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br. J. Clin. Pharmacol. 2018;84:2477–2482. doi: 10.1111/bcp.13710. PubMed DOI PMC

Millar S.A., Stone N.L., Yates A.S., O’Sullivan S.E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018;9:1365. doi: 10.3389/fphar.2018.01365. PubMed DOI PMC

Ohlsson A., Lindgren J.-E., Andersson S., Agurell S., Gillespie H., Hollister L.E. Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration. J. Mass Spectrom. 1986;13:77–83. doi: 10.1002/bms.1200130206. PubMed DOI

Gaston T.E., Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017;70:313–318. doi: 10.1016/j.yebeh.2016.11.016. PubMed DOI

Consroe P., Laguna J., Allender J., Snider S., Stern L., Sandyk R., Kennedy K., Schram K. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol. Biochem. Behav. 1991;40:701–708. doi: 10.1016/0091-3057(91)90386-G. PubMed DOI

Mielnik C.A., Lam V.M., Ross R.A. CB1 allosteric modulators and their therapeutic potential in CNS disorders. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2021;106:110163. doi: 10.1016/j.pnpbp.2020.110163. PubMed DOI

Peng J., Fan M., An C., Ni F., Huang W., Luo J. A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD) Basic Clin. Pharmacol. Toxicol. 2022;130:439–456. doi: 10.1111/bcpt.13710. PubMed DOI

Laun A.S., Shrader S.H., Brown K.J., Song Z.H. GPR3. GPR6, and GPR12 as novel molecular targets: Their biological functions and interaction with cannabidiol. Acta Pharmacol. Sin. 2019;40:300–308. doi: 10.1038/s41401-018-0031-9. PubMed DOI PMC

Mlost J., Bryk M., Starowicz K. Cannabidiol for Pain Treatment: Focus on Pharmacology and Mechanism of Action. Int. J. Mol. Sci. 2020;21:8870. doi: 10.3390/ijms21228870. PubMed DOI PMC

Laprairie R.B., Bagher A.M., Kelly M.E., Denovan-Wright E.M. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br. J. Pharmacol. 2015;172:4790–4805. doi: 10.1111/bph.13250. PubMed DOI PMC

Morales P., Hurst D.P., Reggio P.H. Molecular targets of the phytocannabinoids: A complex picture. Prog. Chem. Org. Nat. Prod. 2017;103:103–131. doi: 10.1007/978-3-319-45541-9_4. PubMed DOI PMC

Preedy V.R. Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment. Academic Press; Amsterdam, The Netherlands: 2017. 1143p

Ghovanloo M.R., Shuart N.G., Mezeyova J., Dean R.A., Ruben P.C., Goodchild S.J. Inhibitory effects of cannabidiol on voltage-dependent sodium currents. J. Biol. Chem. 2018;293:16546–16558. doi: 10.1074/jbc.RA118.004929. PubMed DOI PMC

Rodríguez-Muñoz M., Onetti Y., Cortés-Montero E., Garzón J., Sánchez-Blázquez P. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor. Mol. Brain. 2018;11:51. doi: 10.1186/s13041-018-0395-2. PubMed DOI PMC

Ma H., Xu F., Liu C., Seeram N.P. A Network Pharmacology Approach to Identify Potential Molecular Targets for Cannabidiol’s Anti-Inflammatory Activity. Cannabis Cannabinoid Res. 2021;6:288–299. doi: 10.1089/can.2020.0025. PubMed DOI PMC

Iffland K., Grotenhermen F., Reddon H., DeBeck K., Socias M.-E., Lake S., Dong H., Hayashi K., Milloy M.-J., Wright M., et al. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017;2:139–154. doi: 10.1089/can.2016.0034. PubMed DOI PMC

Devinsky O., Cross J.H., Laux L., Marsh E., Miller I., Nabbout R., Scheffer I.E., Thiele E.A., Wright S., Cannabidiol in Dravet Syndrome Study Group Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 2017;376:2011–2020. doi: 10.1056/NEJMoa1611618. PubMed DOI

Maa E., Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55:783–786. doi: 10.1111/epi.12610. PubMed DOI

Raucci U., Pietrafusa N., Paolino M.C., Di Nardo G., Villa M.P., Pavone P., Terrin G., Specchio N., Striano P., Parisi P. Cannabidiol Treatment for Refractory Epilepsies in Pediatrics. Front. Pharmacol. 2020;11:586110. doi: 10.3389/fphar.2020.586110. PubMed DOI PMC

Fong S.L., Kossoff E.H. Cannabinoids as future treatment for epilepsy. Contemp. PEDS J. 2018;35:11–12.

Pietrafusa N., Ferretti A., Trivisano M., de Palma L., Calabrese C., Pavia G.C., Tondo I., Cappelletti S., Vigevano F., Specchio N. Purified Cannabidiol for Treatment of Refractory Epilepsies in Pediatric Patients with Developmental and Epileptic Encephalopathy. Pediatr. Drugs. 2019;21:283–290. doi: 10.1007/s40272-019-00341-x. PubMed DOI

Boyaji S., Merkow J., Elman R.N.M., Kaye A.D., Yong R.J., Urman R.D. The Role of Cannabidiol (CBD) in Chronic Pain Management: An Assessment of Current Evidence. Curr. Pain Headache Rep. 2020;24:4. doi: 10.1007/s11916-020-0835-4. PubMed DOI

Eskander J.P., Spall J., Spall A., Shah R.V., Kaye A.D. Cannabidiol (CBD) as a treatment of acute and chronic back pain: A case series and literature review. J. Opioid Manag. 2020;16:215–218. doi: 10.5055/jom.2020.0570. PubMed DOI

Xu D.H., Cullen B.D., Tang M., Fang Y. The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities. Curr. Pharm. Biotechnol. 2020;21:390–402. doi: 10.2174/1389201020666191202111534. PubMed DOI

Schneider T.M., Zurbriggen L., Dieterle M., Mauermann E.M., Frei P., Mercer-Chalmers-Bender K., Ruppen W.M. Pain response to cannabidiol in induced acute nociceptive pain, allodynia, and hyperalgesia by using a model mimicking acute pain in healthy adults in a randomized trial (CANAB I) Pain. 2022;163:e62–e71. doi: 10.1097/j.pain.0000000000002310. PubMed DOI

Villanueva M.R.B., Joshaghani N., Villa N., Badla O., Goit R., Saddik S.E., Dawood S.N., Rabih A.M., Niaj A., Raman A., et al. Efficacy, Safety, and Regulation of Cannabidiol on Chronic Pain: A Systematic Review. Cureus. 2022;14:e26913. doi: 10.7759/cureus.26913. PubMed DOI PMC

Blake A., Wan B.A., Malek L., DeAngelis C., Diaz P., Lao N., Chow E., O’hearn S. A selective review of medical cannabis in cancer pain management. Ann. Palliat. Med. 2017;6:S215–S222. doi: 10.21037/apm.2017.08.05. PubMed DOI

Corroon J., Phillips J.A. A Cross-Sectional Study of Cannabidiol Users. Cannabis Cannabinoid Res. 2018;3:152–161. doi: 10.1089/can.2018.0006. PubMed DOI PMC

Laczkovics C., Kothgassner O.D., Felnhofer A., Klier C.M. Cannabidiol treatment in an adolescent with multiple substance abuse, social anxiety and depression. Neuropsychiatrie. 2020;35:31–34. doi: 10.1007/s40211-020-00334-0. PubMed DOI PMC

Berger M., Li E., Rice S., Davey C.G., Ratheesh A., Adams S., Jackson H., Hetrick S., Parker A., Spelman T., et al. Cannabidiol for Treatment-Resistant Anxiety Disorders in Young People: An Open-Label Trial. J. Clin. Psychiatry. 2022;83:42111. doi: 10.4088/JCP.21m14130. PubMed DOI

Fliegel D.K., Lichenstein S.D. Systematic literature review of human studies assessing the efficacy of cannabidiol for social anxiety. Psychiatry Res. Commun. 2022;2:100074. doi: 10.1016/j.psycom.2022.100074. PubMed DOI PMC

Zuardi A.W. Cannabidiol: From an inactive cannabinoid to a drug with wide spectrum of action. Rev. Bras. Psiquiatr. 2008;30:271–280. doi: 10.1590/S1516-44462008000300015. PubMed DOI

de Mello Schier A.R., de Oliveira Ribeiro N.P., Coutinho D.S., Machado S., Arias-Carrión O., Crippa J.A., Zuardi A.W., Nardi A.E., Silva A.C. Antidepressant-like and anxiolytic-like effects of cannabidiol: A chemical compound of Cannabis sativa. CNS Neurol. Disord. Drug Targets. 2014;13:953–960. doi: 10.2174/1871527313666140612114838. PubMed DOI

Larsen C., Shahinas J. Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials. J. Clin. Med. Res. 2020;12:129–141. doi: 10.14740/jocmr4090. PubMed DOI PMC

Irving P.M., Iqbal T., Nwokolo C., Subramanian S., Bloom S., Prasad N., Hart A., Murray C., Lindsay J.O., Taylor A., et al. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm. Bowel Dis. 2018;24:714–724. doi: 10.1093/ibd/izy002. PubMed DOI

Bosnjak Kuharic D., Markovic D., Brkovic T., Jeric Kegalj M., Rubic Z., Vuica Vukasovic A., Jeroncic A., Puljak L. Cannabinoids for the Treatment of Dementia. Cochrane Database Syst. Rev. 2021;9:CD012820. PubMed PMC

Sales A.J., Fogaça M.V., Sartim A.G., Pereira V.S., Wegener G., Guimarães F.S., Joca S.R.L. Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Mol. Neurobiol. 2018;56:1070–1081. doi: 10.1007/s12035-018-1143-4. PubMed DOI

Ahmed S., Roth R.M., Stanciu C.N., Brunette M.F. The Impact of THC and CBD in Schizophrenia: A Systematic Review. Front. Psychiatry. 2021;12:694394. doi: 10.3389/fpsyt.2021.694394. PubMed DOI PMC

Poleg S., Golubchik P., Offen D., Weizman A. Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2018;89:90–96. doi: 10.1016/j.pnpbp.2018.08.030. PubMed DOI

Pedrazzi J.F.C., Ferreira F.R., Silva-Amaral D., Lima D.A., Hallak J.E.C., Zuardi A.W., Del-Bel E.A., Guimarães F.S., Costa K.C.M., Campos A.C., et al. Cannabidiol for the treatment of autism spectrum disorder: Hope or hype? Psychopharmacology. 2022;239:2713–2734. doi: 10.1007/s00213-022-06196-4. PubMed DOI

Kirkland A.E., Fadus M.C., Gruber S.A., Gray K.M., Wilens T.E., Squeglia L.M. A scoping review of the use of cannabidiol in psychiatric disorders. Psychiatry Res. 2022;308:114347. doi: 10.1016/j.psychres.2021.114347. PubMed DOI PMC

Khalsa J.H., Bunt G., Blum K., Maggirwar S.B., Galanter M., Potenza M.N. Review: Cannabinoids as Medicinals. Curr. Addict. Rep. 2022;9:630–646. doi: 10.1007/s40429-022-00438-3. PubMed DOI PMC

Ahadi S., Zhou W., Schüssler-Fiorenza Rose S.M., Sailani M.R., Contrepois K., Avina M., Ashland M., Brunet A., Snyder M. Personal aging markers and ageotypes revealed by deep longitudinal profiling. Nat. Med. 2020;26:83–90. doi: 10.1038/s41591-019-0719-5. PubMed DOI PMC

Dash R., Ali C., Jahan I., Munni Y.A., Mitra S., Hannan A., Timalsina B., Oktaviani D.F., Choi H.J., Moon I.S. Emerging potential of cannabidiol in reversing proteinopathies. Ageing Res. Rev. 2020;65:101209. doi: 10.1016/j.arr.2020.101209. PubMed DOI

Farr S.A., Goodland M.N., Niehoff M.L., Banerjee S., Young B.J. Cannabidiol (CBD) improves cognition and decreases anxiety in the SAMP8 mouse model of Alzheimer’s. Alzheimer’s Dement. 2021;17:e054428. doi: 10.1002/alz.054428. DOI

Kreilaus F., Przybyla M., Ittner L., Karl T. Cannabidiol (CBD) treatment improves spatial memory in 14-month-old female TAU58/2 transgenic mice. Behav. Brain Res. 2022;425:113812. doi: 10.1016/j.bbr.2022.113812. PubMed DOI

Trivedi M.K., Mondal S., Gangwar M., Jana S. Effects of Cannabidiol Interactions withCYP2R1, CYP27B1, CYP24A1,and Vitamin D3Receptors on Spatial Memory, Pain, Inflammation, and Aging in Vitamin D3Deficiency Diet-Induced Rats. Cannabis Cannabinoid Res. 2022. ahead of print . PubMed DOI

Jîtcă G., Ősz B.E., Vari C.E., Rusz C.-M., Tero-Vescan A., Pușcaș A. Cannabidiol: Bridge between Antioxidant Effect, Cellular Protection, and Cognitive and Physical Performance. Antioxidants. 2023;12:485. doi: 10.3390/antiox12020485. PubMed DOI PMC

Faria D.d.P., de Souza L.E., Duran F.L.d.S., Buchpiguel C.A., Britto L.R., Crippa J.A.d.S., Filho G.B., Real C.C. Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer’s Disease Rat Model: A Proof-of-Concept Study. Int. J. Mol. Sci. 2022;23:1076. doi: 10.3390/ijms23031076. PubMed DOI PMC

Hassan S., Eldeeb K., Millns P.J., Bennett A.J., Alexander S.P.H., Kendall D.A. Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation. Br. J. Pharmacol. 2014;171:2426–2439. doi: 10.1111/bph.12615. PubMed DOI PMC

Yang S., Du Y., Zhao X., Tang Q., Su W., Hu Y., Yu P. Cannabidiol Enhances Microglial Beta-Amyloid Peptide Phagocytosis and Clearance via Vanilloid Family Type 2 Channel Activation. Int. J. Mol. Sci. 2022;23:5367. doi: 10.3390/ijms23105367. PubMed DOI PMC

Xiong Y., Lim C.-S. Understanding the Modulatory Effects of Cannabidiol on Alzheimer’s Disease. Brain Sci. 2021;11:1211. doi: 10.3390/brainsci11091211. PubMed DOI PMC

Hermush V., Ore L., Stern N., Mizrahi N., Fried M., Krivoshey M., Staghon E., Lederman V.E., Schleider L.B.-L. Effects of rich cannabidiol oil on behavioral disturbances in patients with dementia: A placebo controlled randomized clinical trial. Front. Med. 2022;9:951889. doi: 10.3389/fmed.2022.951889. PubMed DOI PMC

Alexandri F., Papadopoulou L., Tsolaki A., Papantoniou G., Athanasiadis L., Tsolaki M. The Effect of Cannabidiol 3% on Neuropsychiatric Symptoms in Dementia—Six-Month Follow-Up. Clin. Gerontol. 2023 doi: 10.1080/07317115.2023.2209563. PubMed DOI

Bartschi J.G., Greenwood L.-M., Montgomery A., Dortants L., Weston-Green K., Huang X.-F., Pai N., Potter J., Schira M.M., Croft R., et al. Cannabidiol as a Treatment for Neurobiological, Behavioral, and Psychological Symptoms in Early-Stage Dementia: A Double-Blind, Placebo-Controlled Clinical Trial Protocol. Cannabis Cannabinoid Res. 2022;8:348–359. doi: 10.1089/can.2021.0209. PubMed DOI

Hashimoto Y., Ookuma S., Nishida E. Lifespan extension by suppression of autophagy genes in Caenorhabditis elegans. Genes Cells. 2009;14:717–726. doi: 10.1111/j.1365-2443.2009.01306.x. PubMed DOI

Braeckman B.P., Vanfleteren J.R. Genetic control of longevity in C. Elegans. Exp. Gerontol. 2007;42:90–98. doi: 10.1016/j.exger.2006.04.010. PubMed DOI

Vrechi T.A.M., Leão A.H.F.F., Morais I.B.M., Abílio V.C., Zuardi A.W., Hallak J.E.C., Crippa J.A., Bincoletto C., Ureshino R.P., Smaili S.S., et al. Cannabidiol induces autophagy via ERK1/2 activation in neural cells. Sci. Rep. 2021;11:1–13. doi: 10.1038/s41598-021-84879-2. PubMed DOI PMC

Salminen A., Kaarniranta K. SIRT1: Regulation of longevity via autophagy. Cell. Signal. 2009;21:1356–1360. doi: 10.1016/j.cellsig.2009.02.014. PubMed DOI

Wang Z., Zheng P., Chen X., Xie Y., Weston-Green K., Solowij N., Chew Y.L., Huang X.-F. Cannabidiol induces autophagy and improves neuronal health associated with SIRT1 mediated longevity. GeroScience. 2022;44:1505–1524. doi: 10.1007/s11357-022-00559-7. PubMed DOI PMC

Wang Z., Zheng P., Xie Y., Chen X., Solowij N., Green K., Chew Y.L., Huang X.-F. Cannabidiol regulates CB1-pSTAT3 signaling for neurite outgrowth, prolongs lifespan, and improves health span in Caenorhabditis elegans of Aβ pathology models. FASEB J. 2021;35:e21537. doi: 10.1096/fj.202002724R. PubMed DOI

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet] National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda, MD, USA: 2012. [(accessed on 16 March 2023)]. Cannabidiol. Updated 16 February 2023. Available online: https://pubmed.ncbi.nlm.nih.gov/31643176/ PubMed

Leehey M.A., Liu Y., Hart F., Epstein C., Cook M., Sillau S., Klawitter J., Newman H., Sempio C., Forman L., et al. Safety and Tolerability of Cannabidiol in Parkinson Disease: An Open Label, Dose-Escalation Study. Cannabis Cannabinoid Res. 2020;5:326–336. doi: 10.1089/can.2019.0068. PubMed DOI PMC

Lo L.A., Christiansen A., Eadie L., Strickland J.C., Kim D.D., Boivin M., Barr A.M., MacCallum C.A. Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis. J. Intern. Med. 2023;293:724–752. doi: 10.1111/joim.13627. PubMed DOI

Rapin L., Gamaoun R., El Hage C., Arboleda M.F., Prosk E. Cannabidiol use and effectiveness: Real-world evidence from a Canadian medical cannabis clinic. J. Cannabis Res. 2021;3:1–10. doi: 10.1186/s42238-021-00078-w. PubMed DOI PMC