Play all audios:
![You have full access to this article via your institution. Download PDF Cannabidiol (CBD) is one of the major cannabinoid constituents of the C_annabis_ plant. Recently, CBD has sparked the interest of medical researchers because of its more than 65 identified molecular targets. Of those, mostly studied in brain disorders are cannabinoid, 5HT1A receptors, G-protein receptor protein 55 (GPR55), transient receptor potential (TRP) channels, and cytochrome P450s [1]. Here we discuss possible mechanisms of actions of CBD in several brain disorders. The evidence suggests that the antiepileptic potential of CBD may be via its modulation of TRP (vanilloid 1 and TRPA), potassium channels, NMDA receptors, and more recently by the interaction with GPR55 to reduce neuronal excitability [1, 2]. Although in the US, CBD is currently prescribed as an adjuvant treatment for seizures in Lennox-Gastaut and Dravet syndromes, as well as tuberous sclerosis complex, it is still unknown if CBD’s antiepileptic properties are due to its direct interaction with the molecular targets, or possibly through potentiating effects of antiepileptic treatments by modulation of cytochrome P450s [1, 3]. CBD exhibited anxiolytic properties by acting on the 5HT1A receptors in animal models [1]. Most recently, an in vitro study showed that CBD might also elicit anxiolytic effects by allosterically modulating GABAA receptors [4]. Human studies using CBD were limited to assessing the short-term effects of CBD on social anxiety disorder (SAD) [1]. By the mechanism of action on the CB1 receptor, CBD attenuated behavioral responses to different forms of aversive memories in rodent PTSD models [5]. Although in human studies, CBD was associated with reduced PTSD symptomatology, the evidence is only limited to case studies, while possibly being confounded by the co-administration of other psychiatric treatments [6]. The antidepressant properties of CBD by activation of 5HT1A receptors were revealed in animal models of depression [1]. However, to date, CBD’s effects on clinical depression have not been studied. CBD has been proposed to have anti-psychotic effects by modulating dopamine D2, cannabinoid receptors, and TRPV1 channels; however, these mechanisms are somewhat speculative, given the lack of reproducibility of findings. In human studies, CBD produced conflicting evidence to either augment or improve the symptoms of schizophrenia [1]. The anti-addictive potential of CBD was demonstrated in animal models of cannabis, opioid, alcohol, methamphetamine, and cocaine use disorders. Although CBD’s molecular pathways are still poorly understood, they may include neuronal excitability, 5HT1A receptors and possibly cannabinoid and opioid systems. In small-scale clinical trials, CBD reduced cigarette consumption and heroin cue-induced craving. The anecdotal evidence also shows the positive effects of CBD on reducing symptoms of cannabis and alcohol use disorders, yet these effects need further investigation in larger trials [1]. In summary, the complexity of CBD pharmacology is due to CBD’s ability to interact with several molecular targets, making it a good candidate for further therapeutic investigation. Currently, in the US, CBD is only prescribed for treatment of childhood epilepsies, while other indications are still under exploration. To fully elucidate its true therapeutic potential in other brain disorders, CBD needs to be tested in larger-scale randomized, placebo-controlled trials. FUNDING AND DISCLOSURE BLF has received in-kind donation of cannabis products from Canopy Innovations Inc. and Aurora Cannabis and medication donation from Pfizer and Bioprojet. He was provided a coil for the TMS study from Brainsway. BLF will conduct research with funding obtained from Canopy Innovations Inc. and Aphria (through research grants handled by CAMH and University of Toronto), Bioprojet, ACS and Alkermes. BLF has received in kind donations of nabiximols from GW Pharma for studies funded by CIHR and NIH. The authors declare no competing interests. REFERENCES * Elsaid S, Kloiber S, Le Foll B. Effects of cannabidiol (CBD) in neuropsychiatric disorders: a review of pre-clinical and clinical findings. Prog Mol Biol Transitional Sci 2019 (accepted for publication). * Kaplan JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci USA. 2017;114:11229–11234. Article CAS Google Scholar * Devinsky O, Patel AD, Cross HJ, Vicente V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. New Engl J Med 2018;378:1888–1897. Article CAS Google Scholar * Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, Chebib M. Pharmacol Res 2017;119:358–370. Article CAS Google Scholar * Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 2015;12:825–836. Article CAS Google Scholar * Elms L, Shannon S, Hughes S, Lewis N. Cannabidiol in the treatment of post-traumatic stress disorder: a case series. J Altern Complement Med 2019;25:392–397. Article Google Scholar Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Translational Addiction Research Laboratory, Centre for Addiction and Mental Health (CAMH), 33 Russell Street, T-700, Toronto, ON, M5S 2S1, Canada Sonja Elsaid & Bernard Le Foll * The Institute of Medical Science, Faculty of Medicine, University of Toronto, 27 King’s College Circle, Toronto, ON, M5S 1A1, Canada Sonja Elsaid & Bernard Le Foll * Departments of Pharmacology & Toxicology, Family and Community Medicine and Psychiatry, University of Toronto, 27 King’s College Circle, Toronto, ON, M5S3H7, Canada Bernard Le Foll Authors * Sonja Elsaid View author publications You can also search for this author inPubMed Google Scholar * Bernard Le Foll View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Bernard Le Foll. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Elsaid, S., Le Foll, B. The complexity of pharmacology of cannabidiol (CBD) and its implications in the treatment of brain disorders. _Neuropsychopharmacol._ 45, 229–230 (2020). https://doi.org/10.1038/s41386-019-0518-1 Download citation * Published: 11 September 2019 * Issue Date: January 2020 * DOI: https://doi.org/10.1038/s41386-019-0518-1 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative](data:image/svg+xml;base64,<svg height="81" width="57" xmlns="http://www.w3.org/2000/svg"><g fill="none" fill-rule="evenodd"><path d="m17.35 35.45 21.3-14.2v-17.03h-21.3" fill="#989898"/><path d="m38.65 35.45-21.3-14.2v-17.03h21.3" fill="#747474"/><path d="m28 .5c-12.98 0-23.5 10.52-23.5 23.5s10.52 23.5 23.5 23.5 23.5-10.52 23.5-23.5c0-6.23-2.48-12.21-6.88-16.62-4.41-4.4-10.39-6.88-16.62-6.88zm0 41.25c-9.8 0-17.75-7.95-17.75-17.75s7.95-17.75 17.75-17.75 17.75 7.95 17.75 17.75c0 4.71-1.87 9.22-5.2 12.55s-7.84 5.2-12.55 5.2z" fill="#535353"/><path d="m41 36c-5.81 6.23-15.23 7.45-22.43 2.9-7.21-4.55-10.16-13.57-7.03-21.5l-4.92-3.11c-4.95 10.7-1.19 23.42 8.78 29.71 9.97 6.3 23.07 4.22 30.6-4.86z" fill="#9c9c9c"/><path d="m.2 58.45c0-.75.11-1.42.33-2.01s.52-1.09.91-1.5c.38-.41.83-.73 1.34-.94.51-.22 1.06-.32 1.65-.32.56 0 1.06.11 1.51.35.44.23.81.5 1.1.81l-.91 1.01c-.24-.24-.49-.42-.75-.56-.27-.13-.58-.2-.93-.2-.39 0-.73.08-1.05.23-.31.16-.58.37-.81.66-.23.28-.41.63-.53 1.04-.13.41-.19.88-.19 1.39 0 1.04.23 1.86.68 2.46.45.59 1.06.88 1.84.88.41 0 .77-.07 1.07-.23s.59-.39.85-.68l.91 1c-.38.43-.8.76-1.28.99-.47.22-1 .34-1.58.34-.59 0-1.13-.1-1.64-.31-.5-.2-.94-.51-1.31-.91-.38-.4-.67-.9-.88-1.48-.22-.59-.33-1.26-.33-2.02zm8.4-5.33h1.61v2.54l-.05 1.33c.29-.27.61-.51.96-.72s.76-.31 1.24-.31c.73 0 1.27.23 1.61.71.33.47.5 1.14.5 2.02v4.31h-1.61v-4.1c0-.57-.08-.97-.25-1.21-.17-.23-.45-.35-.83-.35-.3 0-.56.08-.79.22-.23.15-.49.36-.78.64v4.8h-1.61zm7.37 6.45c0-.56.09-1.06.26-1.51.18-.45.42-.83.71-1.14.29-.3.63-.54 1.01-.71.39-.17.78-.25 1.18-.25.47 0 .88.08 1.23.24.36.16.65.38.89.67s.42.63.54 1.03c.12.41.18.84.18 1.32 0 .32-.02.57-.07.76h-4.36c.07.62.29 1.1.65 1.44.36.33.82.5 1.38.5.29 0 .57-.04.83-.13s.51-.21.76-.37l.55 1.01c-.33.21-.69.39-1.09.53-.41.14-.83.21-1.26.21-.48 0-.92-.08-1.34-.25-.41-.16-.76-.4-1.07-.7-.31-.31-.55-.69-.72-1.13-.18-.44-.26-.95-.26-1.52zm4.6-.62c0-.55-.11-.98-.34-1.28-.23-.31-.58-.47-1.06-.47-.41 0-.77.15-1.07.45-.31.29-.5.73-.58 1.3zm2.5.62c0-.57.09-1.08.28-1.53.18-.44.43-.82.75-1.13s.69-.54 1.1-.71c.42-.16.85-.24 1.31-.24.45 0 .84.08 1.17.23s.61.34.85.57l-.77 1.02c-.19-.16-.38-.28-.56-.37-.19-.09-.39-.14-.61-.14-.56 0-1.01.21-1.35.63-.35.41-.52.97-.52 1.67 0 .69.17 1.24.51 1.66.34.41.78.62 1.32.62.28 0 .54-.06.78-.17.24-.12.45-.26.64-.42l.67 1.03c-.33.29-.69.51-1.08.65-.39.15-.78.23-1.18.23-.46 0-.9-.08-1.31-.24-.4-.16-.75-.39-1.05-.7s-.53-.69-.7-1.13c-.17-.45-.25-.96-.25-1.53zm6.91-6.45h1.58v6.17h.05l2.54-3.16h1.77l-2.35 2.8 2.59 4.07h-1.75l-1.77-2.98-1.08 1.23v1.75h-1.58zm13.69 1.27c-.25-.11-.5-.17-.75-.17-.58 0-.87.39-.87 1.16v.75h1.34v1.27h-1.34v5.6h-1.61v-5.6h-.92v-1.2l.92-.07v-.72c0-.35.04-.68.13-.98.08-.31.21-.57.4-.79s.42-.39.71-.51c.28-.12.63-.18 1.04-.18.24 0 .48.02.69.07.22.05.41.1.57.17zm.48 5.18c0-.57.09-1.08.27-1.53.17-.44.41-.82.72-1.13.3-.31.65-.54 1.04-.71.39-.16.8-.24 1.23-.24s.84.08 1.24.24c.4.17.74.4 1.04.71s.54.69.72 1.13c.19.45.28.96.28 1.53s-.09 1.08-.28 1.53c-.18.44-.42.82-.72 1.13s-.64.54-1.04.7-.81.24-1.24.24-.84-.08-1.23-.24-.74-.39-1.04-.7c-.31-.31-.55-.69-.72-1.13-.18-.45-.27-.96-.27-1.53zm1.65 0c0 .69.14 1.24.43 1.66.28.41.68.62 1.18.62.51 0 .9-.21 1.19-.62.29-.42.44-.97.44-1.66 0-.7-.15-1.26-.44-1.67-.29-.42-.68-.63-1.19-.63-.5 0-.9.21-1.18.63-.29.41-.43.97-.43 1.67zm6.48-3.44h1.33l.12 1.21h.05c.24-.44.54-.79.88-1.02.35-.24.7-.36 1.07-.36.32 0 .59.05.78.14l-.28 1.4-.33-.09c-.11-.01-.23-.02-.38-.02-.27 0-.56.1-.86.31s-.55.58-.77 1.1v4.2h-1.61zm-47.87 15h1.61v4.1c0 .57.08.97.25 1.2.17.24.44.35.81.35.3 0 .57-.07.8-.22.22-.15.47-.39.73-.73v-4.7h1.61v6.87h-1.32l-.12-1.01h-.04c-.3.36-.63.64-.98.86-.35.21-.76.32-1.24.32-.73 0-1.27-.24-1.61-.71-.33-.47-.5-1.14-.5-2.02zm9.46 7.43v2.16h-1.61v-9.59h1.33l.12.72h.05c.29-.24.61-.45.97-.63.35-.17.72-.26 1.1-.26.43 0 .81.08 1.15.24.33.17.61.4.84.71.24.31.41.68.53 1.11.13.42.19.91.19 1.44 0 .59-.09 1.11-.25 1.57-.16.47-.38.85-.65 1.16-.27.32-.58.56-.94.73-.35.16-.72.25-1.1.25-.3 0-.6-.07-.9-.2s-.59-.31-.87-.56zm0-2.3c.26.22.5.37.73.45.24.09.46.13.66.13.46 0 .84-.2 1.15-.6.31-.39.46-.98.46-1.77 0-.69-.12-1.22-.35-1.61-.23-.38-.61-.57-1.13-.57-.49 0-.99.26-1.52.77zm5.87-1.69c0-.56.08-1.06.25-1.51.16-.45.37-.83.65-1.14.27-.3.58-.54.93-.71s.71-.25 1.08-.25c.39 0 .73.07 1 .2.27.14.54.32.81.55l-.06-1.1v-2.49h1.61v9.88h-1.33l-.11-.74h-.06c-.25.25-.54.46-.88.64-.33.18-.69.27-1.06.27-.87 0-1.56-.32-2.07-.95s-.76-1.51-.76-2.65zm1.67-.01c0 .74.13 1.31.4 1.7.26.38.65.58 1.15.58.51 0 .99-.26 1.44-.77v-3.21c-.24-.21-.48-.36-.7-.45-.23-.08-.46-.12-.7-.12-.45 0-.82.19-1.13.59-.31.39-.46.95-.46 1.68zm6.35 1.59c0-.73.32-1.3.97-1.71.64-.4 1.67-.68 3.08-.84 0-.17-.02-.34-.07-.51-.05-.16-.12-.3-.22-.43s-.22-.22-.38-.3c-.15-.06-.34-.1-.58-.1-.34 0-.68.07-1 .2s-.63.29-.93.47l-.59-1.08c.39-.24.81-.45 1.28-.63.47-.17.99-.26 1.54-.26.86 0 1.51.25 1.93.76s.63 1.25.63 2.21v4.07h-1.32l-.12-.76h-.05c-.3.27-.63.48-.98.66s-.73.27-1.14.27c-.61 0-1.1-.19-1.48-.56-.38-.36-.57-.85-.57-1.46zm1.57-.12c0 .3.09.53.27.67.19.14.42.21.71.21.28 0 .54-.07.77-.2s.48-.31.73-.56v-1.54c-.47.06-.86.13-1.18.23-.31.09-.57.19-.76.31s-.33.25-.41.4c-.09.15-.13.31-.13.48zm6.29-3.63h-.98v-1.2l1.06-.07.2-1.88h1.34v1.88h1.75v1.27h-1.75v3.28c0 .8.32 1.2.97 1.2.12 0 .24-.01.37-.04.12-.03.24-.07.34-.11l.28 1.19c-.19.06-.4.12-.64.17-.23.05-.49.08-.76.08-.4 0-.74-.06-1.02-.18-.27-.13-.49-.3-.67-.52-.17-.21-.3-.48-.37-.78-.08-.3-.12-.64-.12-1.01zm4.36 2.17c0-.56.09-1.06.27-1.51s.41-.83.71-1.14c.29-.3.63-.54 1.01-.71.39-.17.78-.25 1.18-.25.47 0 .88.08 1.23.24.36.16.65.38.89.67s.42.63.54 1.03c.12.41.18.84.18 1.32 0 .32-.02.57-.07.76h-4.37c.08.62.29 1.1.65 1.44.36.33.82.5 1.38.5.3 0 .58-.04.84-.13.25-.09.51-.21.76-.37l.54 1.01c-.32.21-.69.39-1.09.53s-.82.21-1.26.21c-.47 0-.92-.08-1.33-.25-.41-.16-.77-.4-1.08-.7-.3-.31-.54-.69-.72-1.13-.17-.44-.26-.95-.26-1.52zm4.61-.62c0-.55-.11-.98-.34-1.28-.23-.31-.58-.47-1.06-.47-.41 0-.77.15-1.08.45-.31.29-.5.73-.57 1.3zm3.01 2.23c.31.24.61.43.92.57.3.13.63.2.98.2.38 0 .65-.08.83-.23s.27-.35.27-.6c0-.14-.05-.26-.13-.37-.08-.1-.2-.2-.34-.28-.14-.09-.29-.16-.47-.23l-.53-.22c-.23-.09-.46-.18-.69-.3-.23-.11-.44-.24-.62-.4s-.33-.35-.45-.55c-.12-.21-.18-.46-.18-.75 0-.61.23-1.1.68-1.49.44-.38 1.06-.57 1.83-.57.48 0 .91.08 1.29.25s.71.36.99.57l-.74.98c-.24-.17-.49-.32-.73-.42-.25-.11-.51-.16-.78-.16-.35 0-.6.07-.76.21-.17.15-.25.33-.25.54 0 .14.04.26.12.36s.18.18.31.26c.14.07.29.14.46.21l.54.19c.23.09.47.18.7.29s.44.24.64.4c.19.16.34.35.46.58.11.23.17.5.17.82 0 .3-.06.58-.17.83-.12.26-.29.48-.51.68-.23.19-.51.34-.84.45-.34.11-.72.17-1.15.17-.48 0-.95-.09-1.41-.27-.46-.19-.86-.41-1.2-.68z" fill="#535353"/></g></svg>)
You have full access to this article via your institution. Download PDF Cannabidiol (CBD) is one of the major cannabinoid constituents of the C_annabis_ plant. Recently, CBD has sparked the
interest of medical researchers because of its more than 65 identified molecular targets. Of those, mostly studied in brain disorders are cannabinoid, 5HT1A receptors, G-protein receptor
protein 55 (GPR55), transient receptor potential (TRP) channels, and cytochrome P450s [1]. Here we discuss possible mechanisms of actions of CBD in several brain disorders. The evidence
suggests that the antiepileptic potential of CBD may be via its modulation of TRP (vanilloid 1 and TRPA), potassium channels, NMDA receptors, and more recently by the interaction with GPR55
to reduce neuronal excitability [1, 2]. Although in the US, CBD is currently prescribed as an adjuvant treatment for seizures in Lennox-Gastaut and Dravet syndromes, as well as tuberous
sclerosis complex, it is still unknown if CBD’s antiepileptic properties are due to its direct interaction with the molecular targets, or possibly through potentiating effects of
antiepileptic treatments by modulation of cytochrome P450s [1, 3]. CBD exhibited anxiolytic properties by acting on the 5HT1A receptors in animal models [1]. Most recently, an in vitro study
showed that CBD might also elicit anxiolytic effects by allosterically modulating GABAA receptors [4]. Human studies using CBD were limited to assessing the short-term effects of CBD on
social anxiety disorder (SAD) [1]. By the mechanism of action on the CB1 receptor, CBD attenuated behavioral responses to different forms of aversive memories in rodent PTSD models [5].
Although in human studies, CBD was associated with reduced PTSD symptomatology, the evidence is only limited to case studies, while possibly being confounded by the co-administration of
other psychiatric treatments [6]. The antidepressant properties of CBD by activation of 5HT1A receptors were revealed in animal models of depression [1]. However, to date, CBD’s effects on
clinical depression have not been studied. CBD has been proposed to have anti-psychotic effects by modulating dopamine D2, cannabinoid receptors, and TRPV1 channels; however, these
mechanisms are somewhat speculative, given the lack of reproducibility of findings. In human studies, CBD produced conflicting evidence to either augment or improve the symptoms of
schizophrenia [1]. The anti-addictive potential of CBD was demonstrated in animal models of cannabis, opioid, alcohol, methamphetamine, and cocaine use disorders. Although CBD’s molecular
pathways are still poorly understood, they may include neuronal excitability, 5HT1A receptors and possibly cannabinoid and opioid systems. In small-scale clinical trials, CBD reduced
cigarette consumption and heroin cue-induced craving. The anecdotal evidence also shows the positive effects of CBD on reducing symptoms of cannabis and alcohol use disorders, yet these
effects need further investigation in larger trials [1]. In summary, the complexity of CBD pharmacology is due to CBD’s ability to interact with several molecular targets, making it a good
candidate for further therapeutic investigation. Currently, in the US, CBD is only prescribed for treatment of childhood epilepsies, while other indications are still under exploration. To
fully elucidate its true therapeutic potential in other brain disorders, CBD needs to be tested in larger-scale randomized, placebo-controlled trials. FUNDING AND DISCLOSURE BLF has received
in-kind donation of cannabis products from Canopy Innovations Inc. and Aurora Cannabis and medication donation from Pfizer and Bioprojet. He was provided a coil for the TMS study from
Brainsway. BLF will conduct research with funding obtained from Canopy Innovations Inc. and Aphria (through research grants handled by CAMH and University of Toronto), Bioprojet, ACS and
Alkermes. BLF has received in kind donations of nabiximols from GW Pharma for studies funded by CIHR and NIH. The authors declare no competing interests. REFERENCES * Elsaid S, Kloiber S, Le
Foll B. Effects of cannabidiol (CBD) in neuropsychiatric disorders: a review of pre-clinical and clinical findings. Prog Mol Biol Transitional Sci 2019 (accepted for publication). * Kaplan
JS, Stella N, Catterall WA, Westenbroek RE. Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci USA. 2017;114:11229–11234. Article
CAS Google Scholar * Devinsky O, Patel AD, Cross HJ, Vicente V, Wirrell EC, Privitera M, et al. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. New Engl J Med
2018;378:1888–1897. Article CAS Google Scholar * Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, Chebib M. Pharmacol Res 2017;119:358–370. Article CAS Google
Scholar * Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 2015;12:825–836. Article CAS Google Scholar *
Elms L, Shannon S, Hughes S, Lewis N. Cannabidiol in the treatment of post-traumatic stress disorder: a case series. J Altern Complement Med 2019;25:392–397. Article Google Scholar
Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Translational Addiction Research Laboratory, Centre for Addiction and Mental Health (CAMH), 33 Russell Street, T-700,
Toronto, ON, M5S 2S1, Canada Sonja Elsaid & Bernard Le Foll * The Institute of Medical Science, Faculty of Medicine, University of Toronto, 27 King’s College Circle, Toronto, ON, M5S
1A1, Canada Sonja Elsaid & Bernard Le Foll * Departments of Pharmacology & Toxicology, Family and Community Medicine and Psychiatry, University of Toronto, 27 King’s College Circle,
Toronto, ON, M5S3H7, Canada Bernard Le Foll Authors * Sonja Elsaid View author publications You can also search for this author inPubMed Google Scholar * Bernard Le Foll View author
publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Bernard Le Foll. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature
remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE
Elsaid, S., Le Foll, B. The complexity of pharmacology of cannabidiol (CBD) and its implications in the treatment of brain disorders. _Neuropsychopharmacol._ 45, 229–230 (2020).
https://doi.org/10.1038/s41386-019-0518-1 Download citation * Published: 11 September 2019 * Issue Date: January 2020 * DOI: https://doi.org/10.1038/s41386-019-0518-1 SHARE THIS ARTICLE
Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided
by the Springer Nature SharedIt content-sharing initiative