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Chai R, Wang N, Nie J, Xu Z, Zhang S, Deng S, Wang R, Li M, Gao X, Geng R, Li H, Li L, Wu H, Li Z, Cheng TL, Xu XH, Shu Y, Hong H, Huang X, Wang W. Endocannabinoids disinhibit the ventral tegmental nucleus of Gudden to dorsal premammillary nucleus pathway to enhance escape behavior following learned threat experience. Nat Commun 2025; 16:4885. [PMID: 40419467 PMCID: PMC12106801 DOI: 10.1038/s41467-025-60080-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 05/13/2025] [Indexed: 05/28/2025] Open
Abstract
Innate escape behaviors, while not requiring prior learning, are shaped by an animal's learned experiences, such as previous exposure. Here, we found that learned threat experience in mice enhances flight behaviors, which is linked to increased activation of cholecystokinin-expressing neurons in the dorsal premammillary nucleus (PMdCCK neurons), a population that controls circa-strike escape responses. This heightened activity coincides with reduced inhibition from parvalbumin-expressing GABAergic neurons in the ventral tegmental nucleus of Gudden (VTgPV), which typically suppress PMdCCK activity and escape behaviors. Furthermore, threat memory prompts a prefrontal projection to stimulate the release of endocannabinoids, inhibiting the axon terminals of VTgPV neurons. The necessity of this endocannabinoid-mediated disinhibition for the observed enhancement in flight behaviors is confirmed through genetic deletion or pharmacological blockade of endocannabinoid receptors on VTgPV neurons. Thus, our study uncovers a neural mechanism by which experience amplifies innate escape behaviors, highlighting the crucial role of endocannabinoids.
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Affiliation(s)
- Ruikai Chai
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Nawen Wang
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Jinlu Nie
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Zongyi Xu
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Shuqian Zhang
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Suixin Deng
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Rongxin Wang
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Mu Li
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Xinyi Gao
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Ruijie Geng
- Department of Psychological Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Haibin Li
- Department of Psychological Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Lei Li
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Hebi Wu
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Zhiming Li
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China
| | - Tian-Lin Cheng
- Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Xiao-Hong Xu
- Institute for Brain Science, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China
| | - Yousheng Shu
- Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China.
| | - Huilin Hong
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China.
| | - Xiao Huang
- Department of Psychological Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Weisheng Wang
- Department of Neurology, Jinshan Hospital, Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 201508, China.
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Roberts L, Sorial E, Budgeon CA, Lee K, Preen DB, Cumming C. Medicinal cannabis in the management of anxiety disorders: A systematic review. Psychiatry Res 2025; 350:116552. [PMID: 40413923 DOI: 10.1016/j.psychres.2025.116552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 05/16/2025] [Accepted: 05/16/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND With rising anxiety disorder diagnoses, many individuals are seeking alternatives to standard pharmacotherapies, like medicinal cannabis. This systematic review focuses exclusively on anxiety-related disorders and examines a wide range of cannabis-based preparations and interventions. METHOD We searched MEDLINE, EMBASE, CINAHL, and PsycInfo (October-December 2023) for peer-reviewed empirical studies, excluding case series, case studies, and review papers. Inclusion criteria were studies on adults (18+ years) diagnosed with anxiety-related disorders, examining the efficacy or effectiveness of medicinal cannabis. Studies on recreational cannabis or cannabis-use-disorder were excluded. The MASTER and QualSyst tools were used to assess bias. RESULTS Fifty-seven studies met the inclusion criteria: 40 % cohort (n = 23), 30 % randomised controlled trials (n = 17), 18 % cross-sectional (n = 10), 12 % qualitative or other designs (n = 7). The MASTER scale revealed a high risk of bias, with a mean score of 62.9 (out of 100) due to inadequate reporting. Among the 13 highest-quality studies, 70 % (n = 9) reported a positive improvement for disorders including generalised anxiety disorder (GAD), social anxiety disorder (SAD), and post-traumatic stress disorder (PTSD). 30 % (n = 4) reported a negative result for conditions like obsessive-compulsive disorder, trichotillomania, test anxiety and SAD. Over 90 % of all studies, including lower quality studies, reported positive outcomes for CBD and THC-based cannabis. However, 53 % (n = 30) either omitted, or included self-reported data on either form and/or dosage. CONCLUSION Medicinal cannabis demonstrates potential in reducing anxiety symptoms, but the long-term benefits and overall impact on quality of life remain unclear. Further high-quality, longitudinal research with standardised dosing is needed.
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Affiliation(s)
- Leah Roberts
- School of Population and Global Health, 35 Stirling Hwy, Crawley WA 6009, Australia; NHMRC Centre of Research Excellence in Medicines Intelligence, University of South Australia, University of New South Wales, University of Sydney, University of Western Australia, Australia.
| | - Elizabeth Sorial
- School of Population and Global Health, 35 Stirling Hwy, Crawley WA 6009, Australia.
| | - Charley A Budgeon
- School of Population and Global Health, Cardiovascular Epidemiology Research Centre, University of Western Australia, 35 Stirling Hwy, Crawley WA 6009, Australia.
| | - Kenneth Lee
- Department of Pharmacy, School of Allied Health, 35 Stirling Hwy, Crawley WA 6009, Australia.
| | - David B Preen
- School of Population and Global Health, 35 Stirling Hwy, Crawley WA 6009, Australia; NHMRC Centre of Research Excellence in Medicines Intelligence, University of South Australia, University of New South Wales, University of Sydney, University of Western Australia, Australia.
| | - Craig Cumming
- School of Population and Global Health, 35 Stirling Hwy, Crawley WA 6009, Australia; NHMRC Centre of Research Excellence in Medicines Intelligence, University of South Australia, University of New South Wales, University of Sydney, University of Western Australia, Australia.
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Liu S, Ma Z. The role of cannabinoid-mediated signaling pathways and mechanisms in brain disorders. Cell Signal 2025; 128:111653. [PMID: 39952540 DOI: 10.1016/j.cellsig.2025.111653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/17/2025] [Accepted: 02/07/2025] [Indexed: 02/17/2025]
Abstract
Cannabinoids play significant roles in the central nervous system (CNS), but cannabinoid-mediated physiopathological functions are not elaborated. Cannabinoid receptors (CBRs) mediate functions that include the regulation of neuroinflammation, oxidative stress, apoptosis, autophagy, and neurogenesis. Microglia are the primary immune cells responsible for mediating neuroinflammation in the CNS. Therefore, this article primarily focuses on microglia to summarize the inflammatory pathways mediated by cannabinoids in the CNS, including nuclear factor-κB (NF-κB), NOD-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinase (MAPK), protein kinase B (Akt), and cAMP-dependent protein kinase (PKA) signaling pathways. Additionally, we provide a table summarizing the role of cannabinoids in various brain diseases. Medical use of cannabinoids has protective effects in preventing and treating brain diseases; however, excessive and repeated use can be detrimental to the CNS. We propose that cannabinoids hold significant potential for preventing and treating brain diseases, including ferroptosis, lactate metabolism, and mitophagy, providing new insights for further research on cannabinoids.
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Affiliation(s)
- Shunfeng Liu
- School of Basic Medicine, Qingdao University, Qingdao 266071, China; Institute of Brain Science and Disorders, Qingdao University, Qingdao 266071, China
| | - Zegang Ma
- School of Basic Medicine, Qingdao University, Qingdao 266071, China; Institute of Brain Science and Disorders, Qingdao University, Qingdao 266071, China.
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Walsh CA, Euler E, Do LA, Zheng A, Eckel SP, Harlow BL, Leventhal AM, Barrington-Trimis JL, Harlow AF. Cannabis use and sleep problems among young adults by mental health status: A prospective cohort study. Addiction 2025; 120:688-696. [PMID: 39476498 PMCID: PMC11908928 DOI: 10.1111/add.16705] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 10/01/2024] [Indexed: 03/15/2025]
Abstract
BACKGROUND AND AIMS Young adult cannabis use is common; while cannabis is often marketed as a product that can improve sleep, evidence supporting these claims is limited, and effects may differ for individuals with underlying mental health issues. This study measured the association between cannabis use and sleep problems among young adults and determined whether associations differ by mental health status. DESIGN, SETTING AND PARTICIPANTS Using two waves of a young adult cohort study (baseline: March-September 2020; follow-up: January-June 2021), we measured the association of cannabis use frequency with subsequent sleep problems overall and stratified by baseline sleep quality and mental health status in separate moderation analyses. This study was conducted in Southern California, USA, and included 1926 participants aged 20-23 years (mean age = 21; 61% female, 46% Hispanic). MEASUREMENTS Exposure was baseline cannabis use frequency (never use, prior use, 1-5 days/month, 6-19 days/month, ≥ 20 days/month). The outcome was sleep problems at follow-up (range = 4-24, higher score indicating worse sleep). Models were adjusted for socio-demographic factors, baseline sleep problems, mental health symptoms (depression and/or anxiety versus neither) and past 30-day nicotine or alcohol use. In moderation analyses, models were additionally stratified by mental health symptoms and baseline sleep quality (excellent versus imperfect sleep). FINDINGS Among the young adult sample, 11% used cannabis ≥ 20 days/month at baseline. For participants without baseline anxiety or depression symptoms, using cannabis ≥ 20 days/month (versus never use) was associated with greater sleep problems at follow-up [mean difference (MD) = 1.66, 95% confidence interval (CI) = 0.59-2.74]. Among participants with anxiety and/or depression and pre-existing sleep problems at baseline, using cannabis ≥ 20 days/month (versus never use) was associated with fewer sleep problems at follow-up (MD = -1.42, 95% CI = -2.81 to -0.02). CONCLUSIONS The effects of cannabis use on sleep appear to differ by underlying mental health symptoms. Frequent cannabis use may improve sleep for young adults with depression and/or anxiety who have pre-existing sleep problems, but worsen sleep for young adults without depression and/or anxiety.
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Affiliation(s)
- Claire A. Walsh
- Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
- Institute for Addiction Science, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
| | - Erin Euler
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
| | - Lauren A. Do
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
| | - Amy Zheng
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
| | - Sandrah P. Eckel
- Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
| | - Bernard L. Harlow
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
| | - Adam M. Leventhal
- Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
- Institute for Addiction Science, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
| | - Jessica L. Barrington-Trimis
- Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
- Institute for Addiction Science, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
| | - Alyssa F. Harlow
- Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
- Institute for Addiction Science, University of Southern California Keck School of Medicine, CA, Los Angeles, USA
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Sainz-Cort A, Martín-Islas M, Oña G, Jimenez-Garrido D, López-Navarro M, Muñoz-Marron E, Viejo-Sobera R, Bouso JC. Spanish versions and validation of a series of rating scales and visual analogue scales to assess the subjective effects of cannabis. Int Clin Psychopharmacol 2025; 40:91-99. [PMID: 37982285 DOI: 10.1097/yic.0000000000000498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
Cannabis is being legalized for medical and recreational purposes all around the world. However, the understanding of the psychological effects of cannabis is still limited, and it has been previously linked to mental disorders such as schizophrenia. Lately, new scales have been created and adapted to measure its psychological effects. The aim of this study is to create Spanish versions of some of these scales and test their psychometric characteristics. One hundred sixteen participants were recruited from Cannabis Social Clubs (CSC) in Barcelona, Spain. Participants under the effects of their own cannabis completed the Cannabis Experience Questionnaire-modified version (CEQ-mv), Addiction Research Centre Inventory-18 (ARCI-18), Psychotomimetic States Inventory (PSI) and Visual Analogue Scales (VAS). Questionnaires were completed in the CSC, providing a naturalistic setting for the study. Exploratory factor analysis and internal consistency were analyzed. PSI was reduced from a 6-factor to a 4-factor model with adequate to low reliability, ARCI-18 was reduced from a 3-factor to a 2-factor model with good reliability, and VAS were reduced from a 4-factor to a 3-factor model, also with good reliability. These questionnaires showed adequate reliability and can be used in future studies to test the subjective effects of cannabis in clinical and naturalistic settings.
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Affiliation(s)
- Alberto Sainz-Cort
- Faculty of Health Sciences. Universitat Oberta de Catalunya (UOC)
- International Center for Ethnobotanical Education, Research and Service (ICEERS), Barcelona
| | - Marta Martín-Islas
- International Center for Ethnobotanical Education, Research and Service (ICEERS), Barcelona
| | - Genís Oña
- International Center for Ethnobotanical Education, Research and Service (ICEERS), Barcelona
- Universitat Rovira i Virgili, Medical Anthropology Research Center (MARC), Tarragona, Spain
| | - Daniel Jimenez-Garrido
- International Center for Ethnobotanical Education, Research and Service (ICEERS), Barcelona
| | - Miriam López-Navarro
- Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | | | - Jose Carlos Bouso
- International Center for Ethnobotanical Education, Research and Service (ICEERS), Barcelona
- Universitat Rovira i Virgili, Medical Anthropology Research Center (MARC), Tarragona, Spain
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Fu X, Yu Z, Fang F, Zhou W, Bai Y, Jiang Z, Yang B, Sun Y, Tian X, Liu G. Cannabidiol attenuates lipid metabolism and induces CB1 receptor-mediated ER stress associated apoptosis in ovarian cancer cells. Sci Rep 2025; 15:4307. [PMID: 39910152 PMCID: PMC11799381 DOI: 10.1038/s41598-025-88917-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/31/2025] [Indexed: 02/07/2025] Open
Abstract
Ovarian cancer (OC) is the most deadly gynecological tumor. OC cells utilize cellular metabolic reprogramming to gain a survival advantage, particularly through aberrant lipid metabolic process. As the primary ingredient in exogenous cannabinoids, cannabidiol (CBD) has been confirmed to exhibit antitumor activity in preclinical studies. However, it is still unclear whether CBD can disrupt fatty acid metabolism and induce apoptosis in OC cells. In this study, we have demonstrated that CBD significantly inhibits the proliferation of OCs through a cannabinoid receptor type 1 (CB1R)-mediated manner. Fatty acid metabolic profiling and flow cytometry analysis revealed that CBD has the ability to decrease fatty acid levels and significantly suppress the transcription of genes involved in fatty acid uptake and synthesis in ES-2 cells. In addition, the analysis from RNA-seq and real-time RT-PCR revealed that CBD activated the endoplasmic reticulum (ER) stress pathway. Conversely, by supplementation with unsaturated fatty acid or blocking CB1R, ER stress or reactive oxygen species (ROS) signals with specific inhibitors could significantly relieve CBD induced, dose-dependent, ER stress associated apoptosis, G0-G1 phase arrest, and mitochondrial dysfunction. Taken collectively, these data indicate that CBD may disrupt lipid metabolism, and lead to ER stress-related apoptosis in OCs. Our findings may provide a theoretical mechanism for anti-ovarian cancer using CBD.
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Affiliation(s)
- Xuanhe Fu
- Department of Immunology, Shenyang Medical College, No. 146 Huanghe North Stree, Shenyang, 110034, PR China
- Key Lab of Environmental Pollution and Microecology of Liaoning Province, Shenyang, China
| | - Zhixiong Yu
- Department of Pathogen Biology, Shenyang Medical College, Shenyang, China
| | - Fang Fang
- Department of Pathogen Biology, Shenyang Medical College, Shenyang, China
| | - Weiping Zhou
- Department of Pathogen Biology, Shenyang Medical College, Shenyang, China
| | - Yuxin Bai
- Department of Pathogen Biology, Shenyang Medical College, Shenyang, China
| | - Zhongjia Jiang
- Department of Biochemistry and Molecular Biology, Shenyang Medical College, Shenyang, China
| | - Biao Yang
- Department of Pathogen Biology, Shenyang Medical College, Shenyang, China
| | - Ye Sun
- Department of Pathogen Biology, Shenyang Medical College, Shenyang, China
| | - Xing Tian
- Department of Physiology, Shenyang Medical College, Shenyang, China
| | - Guangyan Liu
- Key Lab of Environmental Pollution and Microecology of Liaoning Province, Shenyang, China.
- Department of Pathogen Biology, Shenyang Medical College, Shenyang, China.
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Wang S, Yu L, Guo H, Zuo W, Guo Y, Liu H, Wang J, Wang J, Li X, Hou W, Wang M. Gastrodin Ameliorates Post-Stroke Depressive-Like Behaviors Through Cannabinoid-1 Receptor-Dependent PKA/RhoA Signaling Pathway. Mol Neurobiol 2025; 62:366-385. [PMID: 38856794 DOI: 10.1007/s12035-024-04267-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 05/26/2024] [Indexed: 06/11/2024]
Abstract
Post-stroke depression (PSD) is a significant complication in stroke patients, increases long-term mortality, and exaggerates ischemia-induced brain injury. However, the underlying molecular mechanisms and effective therapeutic targets related to PSD have remained elusive. Here, we employed an animal behavioral model of PSD by combining the use of middle cerebral artery occlusion (MCAO) followed by spatial restraint stress to study the molecular underpinnings and potential therapies of PSD. Interestingly, we found that sub-chronic application of gastrodin (Gas), a traditional Chinese medicinal herb Gastrodia elata extraction, relieved depression-related behavioral deficits, increased the impaired expression of synaptic transmission-associated proteins, and restored the altered spine density in hippocampal CA1 of PSD animals. Furthermore, our results indicated that the anti-PSD effect of Gas was dependent on membrane cannabinoid-1 receptor (CB1R) expression. The contents of phosphorated protein kinase A (p-PKA) and phosphorated Ras homolog gene family member A (p(ser188)-RhoA) were decreased in the hippocampus of PSD-mice, which was reversed by Gas treatment, and CB1R depletion caused a diminished efficacy of Gas on p-PKA and p-RhoA expression. In addition, the anti-PSD effect of Gas was partially blocked by PKA inhibition or RhoA activation, indicating that the anti-PSD effect of Gas is associated with the CB1R-mediated PKA/RhoA signaling pathway. Together, our findings revealed that Gas treatment possesses protective effects against the post-stroke depressive-like state; the CB1R-involved PKA/RhoA signaling pathway is critical in mediating Gas's anti-PSD potency, suggesting that Gas application may be beneficial in the prevention and adjunctive treatment of PSD.
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Affiliation(s)
- Shiquan Wang
- College of Life Sciences, Northwest University, Xi'an, 710127, Shaanxi, China
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Liang Yu
- Department of Information, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Haiyun Guo
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Wenqiang Zuo
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Yaru Guo
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Huiqing Liu
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jiajia Wang
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Jin Wang
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Xia Li
- Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Wugang Hou
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Minghui Wang
- Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi, China.
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8
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Bhandari B, Naeini SE, Rezaee S, Rogers HM, Khodadadi H, Bosomtwi A, Seyyedi M, MacKinnon NJ, Dhandapani KM, Salles ÉL, Hess DC, Yu JC, Moore-Hill D, Vale FL, Wang LP, Baban B. Optimization of seizure prevention by cannabidiol (CBD). Transl Neurosci 2025; 16:20220362. [PMID: 40177581 PMCID: PMC11964187 DOI: 10.1515/tnsci-2022-0362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 04/05/2025] Open
Abstract
Objective Cannabidiol (CBD) is one of the most prominent non-psychotropic cannabinoids with known therapeutic potentials. Based on its anti-seizure efficacy, the first cannabis derived pharmaceutical grade CBD-based medication was approved in the USA in 2018 for the treatment of seizures in patients 2 years and older. Despite the effectiveness in reducing seizures, there remain several major questions on the optimization of CBD therapy for epilepsy such as the optimal dosage, composition, and route of delivery, which are the main objective of this current study. Methods We evaluated the antiseizure effects of CBD through different compositions, routes of delivery, and dosages in a pre-clinical model. We used a kainic acid-induced epilepsy model in C57BL/6 mice, treated them with placebo and/or CBD through inhalation, oral, and injection (intraperitoneal) routes. We used CBD broad spectrum (inhaled and intraperitoneal) vs CBD isolate formulations. We employed the Racine scaling system to evaluate the severity of the seizures, flow cytometry for measuring immune biomarkers and neurotrophic factors, and histologic analysis to examine and compare the groups. Results Our findings showed that all forms of CBD reduced seizures severity. Among the combination of CBD tested, CBD broad spectrum via inhalation was the most effective in the treatment of epileptic seizures (p < 0.05) compared to other forms of CBD treatments. Conclusion Our data suggest that route and CBD formulations affect its efficacy in the prevention of epileptic seizures. Inhaled broad spectrum CBD showed a potential superior effect compared to other delivery routes and CBD formulations in the prevention of epileptic seizures, which warrants further research.
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Affiliation(s)
- Bidhan Bhandari
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States of America
- Center for Excellence in Research, Scholarship and Innovation (CERSI), Dental College of Georgia, Augusta, Augusta University, Augusta, GA, United States of America
- The Graduate School, Augusta University, Augusta, GA, United States of America
| | - Sahar Emami Naeini
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States of America
- Center for Excellence in Research, Scholarship and Innovation (CERSI), Dental College of Georgia, Augusta, Augusta University, Augusta, GA, United States of America
| | - Sholeh Rezaee
- Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Hannah M. Rogers
- College of Education, Augusta University, Augusta, GA, United States of America
| | - Hesam Khodadadi
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Asamoah Bosomtwi
- Georgia Cancer Center and Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Mohammad Seyyedi
- Piedmont Ear, Nose, Throat and Related Allergy, Atlanta, GA, United States of America
| | - Neil J. MacKinnon
- School of Public Health, Augusta University, Augusta, GA, United States of America
| | - Krishnan M. Dhandapani
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Évila Lopes Salles
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States of America
- Center for Excellence in Research, Scholarship and Innovation (CERSI), Dental College of Georgia, Augusta, Augusta University, Augusta, GA, United States of America
| | - David C. Hess
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Jack C. Yu
- Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Debra Moore-Hill
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Fernando L. Vale
- Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
| | - Lei P. Wang
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States of America
- Center for Excellence in Research, Scholarship and Innovation (CERSI), Dental College of Georgia, Augusta, Augusta University, Augusta, GA, United States of America
- School of Public Health, Augusta University, Augusta, GA, United States of America
| | - Babak Baban
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States of America
- Center for Excellence in Research, Scholarship and Innovation (CERSI), Dental College of Georgia, Augusta, Augusta University, Augusta, GA, United States of America
- Department of Neurology, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
- Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, United States of America
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9
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Dammann I, Rohleder C, Leweke FM. Cannabidiol and its Potential Evidence-Based Psychiatric Benefits - A Critical Review. PHARMACOPSYCHIATRY 2024; 57:115-132. [PMID: 38267003 DOI: 10.1055/a-2228-6118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2024]
Abstract
The endocannabinoid system shows promise as a novel target for treating psychiatric conditions. Cannabidiol (CBD), a naturally occurring cannabinoid, has been investigated in several psychiatric conditions, with diverse effects and an excellent safety profile compared to standard treatments. Even though the body of evidence from randomised clinical trials is growing, it remains relatively limited in most indications. This review comprises a comprehensive literature search to identify clinical studies on the effects of CBD in psychiatric conditions. The literature search included case studies, case reports, observational studies, and RCTs published in English before July 27, 2023, excluding studies involving nabiximols or cannabis extracts containing CBD and ∆9-tetrahydrocannabinol. Completed studies were considered, and all authors independently assessed relevant publications.Of the 150 articles identified, 54 publications were included, covering the effects of CBD on healthy subjects and various psychiatric conditions, such as schizophrenia, substance use disorders (SUDs), anxiety, post-traumatic stress disorder (PTSD), and autism spectrum disorders. No clinical studies have been published for other potential indications, such as alcohol use disorder, borderline personality disorder, depression, dementia, and attention-deficit/hyperactivity disorder. This critical review highlights that CBD can potentially ameliorate certain psychiatric conditions, including schizophrenia, SUDs, and PTSD. However, more controlled studies and clinical trials, particularly investigating the mid- to long-term use of CBD, are required to conclusively establish its efficacy and safety in treating these conditions. The complex effects of CBD on neural activity patterns, likely by impacting the endocannabinoid system, warrant further research to reveal its therapeutic potential in psychiatry.
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Affiliation(s)
- Inga Dammann
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Endosane Pharmaceuticals GmbH, Berlin, Germany
| | - Cathrin Rohleder
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Endosane Pharmaceuticals GmbH, Berlin, Germany
- Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - F Markus Leweke
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
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Carlson E, Teboul E, Canale C, Coleman H, Angeliu C, Garbarini K, Markowski VP. Perinatal Tetrahydrocannabinol Compromises Maternal Care and Increases Litter Attrition in the Long-Evans Rat. TOXICS 2024; 12:311. [PMID: 38787090 PMCID: PMC11126083 DOI: 10.3390/toxics12050311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 05/25/2024]
Abstract
The marijuana legalization trend in the U.S. will likely lead to increased use by younger adults during gestation and postpartum. The current study examined the hypothesis that delta-9-tetrahydrocannabinol (THC) would disrupt voluntary maternal care behaviors and negatively impact offspring development. Rat dams were gavaged with 0, 2, 5, or 10 mg/kg THC from the 1st day of gestation through the 21st postnatal day. Somatic growth and developmental milestones were measured in the offspring, and maternal pup retrieval tests were conducted on postnatal days 1, 3, and 5. THC did not affect body growth but produced transient delays in the righting reflex and eye opening in offspring. However, there was significant pup mortality due to impaired maternal care. Dams in all THC groups took significantly longer to retrieve their pups to the nest and often failed to retrieve any pups. Serum levels of THC and metabolites measured at this time were comparable to those in breastfeeding women who are chronic users. Benchmark doses associated with a 10% reduction of pup retrieval or increased pup mortality were 0.383 (BMDL 0.228) and 0.794 (BMDL 0.442) mg/kg THC, respectively. The current findings indicate that maternal care is an important and heretofore overlooked index of THC behavioral toxicity and should be included in future assessments of THC's health risks.
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Affiliation(s)
- Emma Carlson
- Department of Psychology, State University of New York at Geneseo, One College Circle, Geneseo, NY 14454, USA; (E.C.); (C.C.); (H.C.); (C.A.); (K.G.)
| | - Eric Teboul
- Departments of Neurosurgery and Neuroscience, Brown University & Rhode Island Hospital, Providence, RI 02912, USA;
| | - Charlene Canale
- Department of Psychology, State University of New York at Geneseo, One College Circle, Geneseo, NY 14454, USA; (E.C.); (C.C.); (H.C.); (C.A.); (K.G.)
| | - Harper Coleman
- Department of Psychology, State University of New York at Geneseo, One College Circle, Geneseo, NY 14454, USA; (E.C.); (C.C.); (H.C.); (C.A.); (K.G.)
| | - Christina Angeliu
- Department of Psychology, State University of New York at Geneseo, One College Circle, Geneseo, NY 14454, USA; (E.C.); (C.C.); (H.C.); (C.A.); (K.G.)
| | - Karissa Garbarini
- Department of Psychology, State University of New York at Geneseo, One College Circle, Geneseo, NY 14454, USA; (E.C.); (C.C.); (H.C.); (C.A.); (K.G.)
| | - Vincent P. Markowski
- Department of Psychology, State University of New York at Geneseo, One College Circle, Geneseo, NY 14454, USA; (E.C.); (C.C.); (H.C.); (C.A.); (K.G.)
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11
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Sorkhou M, Dent EL, George TP. Cannabis use and mood disorders: a systematic review. Front Public Health 2024; 12:1346207. [PMID: 38655516 PMCID: PMC11035759 DOI: 10.3389/fpubh.2024.1346207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
Background Problematic cannabis use is highly prevalent among people with mood disorders. This underscores the need to understand the effects of cannabis and cannabinoids in this population, especially considering legalization of recreational cannabis use. Objectives We aimed to (1) systematically evaluate cross-sectional and longitudinal studies investigating the interplay between cannabis use, cannabis use disorder (CUD), and the occurrence of mood disorders and symptoms, with a focus on major depressive disorder (MDD) and bipolar disorder (BD) and; (2) examine the effects of cannabis on the prognosis and treatment outcomes of MDD and BD. Methods Following PRISMA guidelines, we conducted an extensive search for English-language studies investigating the potential impact of cannabis on the development and prognosis of mood disorders published from inception through November 2023, using EMBASE, PsycINFO, PubMed, and MEDLINE databases. Results Our literature search identified 3,262 studies, with 78 meeting inclusion criteria. We found that cannabis use is associated with increased depressive and manic symptoms in the general population in addition to an elevated likelihood of developing MDD and BD. Furthermore, we observed that cannabis use is linked to an unfavorable prognosis in both MDD or BD. Discussion Our findings suggest that cannabis use may negatively influence the development, course, and prognosis of MDD and BD. Future well-designed studies, considering type, amount, and frequency of cannabis use while addressing confounding factors, are imperative for a comprehensive understanding of this relationship. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023481634.
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Affiliation(s)
- Maryam Sorkhou
- Institute for Mental Health Policy and Research at CAMH, Toronto, ON, Canada
- Department of Psychiatry, Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Eliza L. Dent
- Department of Psychology, McGill University, Montreal, QC, Canada
| | - Tony P. George
- Institute for Mental Health Policy and Research at CAMH, Toronto, ON, Canada
- Department of Psychiatry, Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
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12
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Yang W, Gong X, Sun H, Wu C, Suo J, Ji J, Jiang X, Shen J, He Y, Aisa HA. Discovery of a CB 2 and 5-HT 1A receptor dual agonist for the treatment of depression and anxiety. Eur J Med Chem 2024; 265:116048. [PMID: 38150961 DOI: 10.1016/j.ejmech.2023.116048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/29/2023] [Accepted: 12/11/2023] [Indexed: 12/29/2023]
Abstract
Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3' site and the cycloalkyl group at the C-4' site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.
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Affiliation(s)
- Wenjiao Yang
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xudong Gong
- Vigonvita Shanghai Co., Ltd, Shanghai, 201210, China
| | - Haiguo Sun
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Chunhui Wu
- Vigonvita Shanghai Co., Ltd, Shanghai, 201210, China
| | - Jin Suo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jing Ji
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiangrui Jiang
- University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jingshan Shen
- University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Yang He
- University of Chinese Academy of Sciences, Beijing, 100049, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Haji Akber Aisa
- State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, and Key Laboratory of Plant Resources and Chemistry of Arid Zone, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
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13
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Sainz-Cort A, Jimenez-Garrido D, Muñoz-Marron E, Viejo-Sobera R, Heeroma J, Bouso JC. The Effects of Cannabidiol and δ-9-Tetrahydrocannabinol in Social Cognition: A Naturalistic Controlled Study. Cannabis Cannabinoid Res 2024; 9:230-240. [PMID: 35881851 DOI: 10.1089/can.2022.0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Social cognition abilities such as empathy and the Theory of Mind (ToM) have been shown to be impaired in neuropsychiatric conditions such as psychotic, autistic, and bipolar disorders. The endocannabinoid system (ECS) seems to play a role in social behavior and emotional processing while it also seems to play a role in those neuropsychiatric conditions showing social cognition impairments. Main plant cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) modulate the ECS and, due to their opposite effects, have been proposed as both cause and treatment for neuropsychiatric-related disorders such as schizophrenia, anxiety, or post-traumatic stress disorder (PTSD). The aim of this study was to test the effects of THC and CBD on social cognition abilities in chronic cannabis users. Method: Eighteen members from a cannabis social club were tested for social cognition effects under the effects of different full spectrum cannabis extracts containing either THC, CBD, THC+CBD, or placebo in a naturalistic randomized double-blind crossover placebo-controlled study. Results: Results showed that participants under the effects of THC showed lower cognitive empathy when compared with the effects of CBD but not when those were compared with THC+CBD or placebo. Also, participants showed higher cognitive ToM under the effects of CBD when compared with the effects of placebo, but not when those were compared with THC or THC+CBD. However, we did not find differences on the emotional scales for empathy or ToM. Conclusions: This study provides evidence for the interaction between the effects of THC and CBD and social cognition abilities in a naturalistic environment, which can be of special interest for the clinical practice of medical cannabis on neuropsychiatric disorders. We show for the first time that CBD can improve ToM abilities in chronic cannabis users. Our results might help to understand the role of the ECS in social cognition, and their association with psychiatric and neurodevelopmental disorders such as schizophrenia or autism. Finally, we demonstrate how reliable methodologies can be implemented in naturalistic environments to collect valid ecological evidence outside classic laboratory settings.
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Affiliation(s)
- Alberto Sainz-Cort
- Faculty of Health Sciences, Universitat Oberta de Catalunya (UOC), Barcelona, Spain
- International Center of Ethnobotanic Education, Research and Service (ICEERS), Barcelona, Spain
- GH Medical, Amsterdam, The Netherlands
| | - Daniel Jimenez-Garrido
- International Center of Ethnobotanic Education, Research and Service (ICEERS), Barcelona, Spain
| | - Elena Muñoz-Marron
- Faculty of Health Sciences, Universitat Oberta de Catalunya (UOC), Barcelona, Spain
| | - Raquel Viejo-Sobera
- Faculty of Health Sciences, Universitat Oberta de Catalunya (UOC), Barcelona, Spain
| | | | - Jose Carlos Bouso
- International Center of Ethnobotanic Education, Research and Service (ICEERS), Barcelona, Spain
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14
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Fleszar-Pavlović SE, Alegria KE, Vasquez JJ, Epperson AE. Past Cannabis Use, Health-Related Worry, and Beliefs About Perceived Benefits of Cannabis Among American Indians/Alaska Natives. J Racial Ethn Health Disparities 2023; 10:2844-2850. [PMID: 36454395 DOI: 10.1007/s40615-022-01461-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND Most adults report beliefs that cannabis has at least one benefit (e.g., stress relief, chronic pain management); however, the benefits are not well established. Beliefs about cannabis benefits are associated with the initiation of use, whereas beliefs about the risks of cannabis are protective factors against its use. Little is known about how health-related beliefs impact cannabis use among American Indians/Alaska Natives (AIAN). PURPOSE This exploratory study examined beliefs about perceived benefits (i.e., stress relief, pain management) of cannabis, how beliefs vary as a function of use, and associations between health worry and benefits of cannabis among AIAN adults. METHODS Participants (n = 182) were on average 41.4 (SD = 16.3) years old, 63.9% female, and identified as AIAN. Participants were asked questions about general demographics, health-related worry and perceptions, and cannabis use. Linear regressions were conducted to examine associations. RESULTS Those who used cannabis in the past year were more likely to agree that cannabis relieves stress and less likely to believe that those who use cannabis should be very worried about their health. Participants who agreed that those who use cannabis should be worried about their health were less likely to report beliefs that cannabis relieves stress or helps with chronic pain. CONCLUSIONS Our study confirms the role of health-related perceptions and worry about cannabis products with cannabis use among this population that may be at risk for higher cannabis use. Findings may have implications for cannabis policy at the tribal, state, and federal levels and the need for the development of targeted communications about the true health risks of cannabis.
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Affiliation(s)
- Sara E Fleszar-Pavlović
- Department of Psychological Sciences, School of Social Sciences, Humanities, and Arts, University of California, Merced, 5200 North Lake Road, Merced, CA, 95343, USA
- Nicotine and Cannabis Policy Center, Health Sciences Research Institute, University of California, Merced, CA, USA
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Katie E Alegria
- Department of Psychological Sciences, School of Social Sciences, Humanities, and Arts, University of California, Merced, 5200 North Lake Road, Merced, CA, 95343, USA
- Nicotine and Cannabis Policy Center, Health Sciences Research Institute, University of California, Merced, CA, USA
- Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA
| | - Jan J Vasquez
- Nicotine and Cannabis Policy Center, Health Sciences Research Institute, University of California, Merced, CA, USA
| | - Anna E Epperson
- Department of Psychological Sciences, School of Social Sciences, Humanities, and Arts, University of California, Merced, 5200 North Lake Road, Merced, CA, 95343, USA.
- Nicotine and Cannabis Policy Center, Health Sciences Research Institute, University of California, Merced, CA, USA.
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15
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Sirotiak Z, Gallagher BT, Smith-Hernandez CA, Showman LJ, Hillard CJ, Brellenthin AG. Endocannabinoid and psychological responses to acute resistance exercise in trained and untrained adults. PLoS One 2023; 18:e0291845. [PMID: 38039265 PMCID: PMC10691681 DOI: 10.1371/journal.pone.0291845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/20/2023] [Indexed: 12/03/2023] Open
Abstract
INTRODUCTION This study examined the effects of acute resistance exercise on circulating endocannabinoid (eCB) and mood responses in trained and untrained healthy adults. METHODS Thirty-two healthy adults (22.1 ± 2.9 years) were recruited from trained (reporting resistance exercise at least twice per week for ≥ previous three months) and untrained (performing no resistance exercise for ≥ previous three months) groups. Participants (13 male, 19 female) completed three sets of resistance exercise (16 repetitions at 50% 1-repetition max, 12 repetitions at 70% 1-repetition max, 8 repetitions at 80% 1-repetition max). Resistance machines targeted the legs, chest, back, and abdominal muscles. Mood states, affect, and circulating eCB concentrations were evaluated before and after resistance exercise. RESULTS There were significant decreases in AEA, PEA, and OEA levels following acute resistance exercise (p <0.05; ds = -0.39, -0.48, -0.65, respectively), with no significant group differences or group by time interactions. 2-AG did not change significantly. Positive affect increased significantly following resistance exercise (p = 0.009), while negative affect decreased (p <0.001). Depressive symptoms, anger, confusion, and total mood disturbance decreased significantly (p <0.05), while vigor increased significantly following resistance exercise (p = 0.005). There were no significant group differences or group by time interactions for any psychological outcomes. CONCLUSION These results indicate that acute resistance exercise may reduce eCB and related lipid concentrations, which is opposite to the increase in lipids typically observed with acute aerobic exercise. Furthermore, psychological improvements occur after resistance exercise regardless of decreases in eCBs, supporting the notion that psychological changes with exercise likely occur through a wide variety of biological and environmental mechanisms.
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Affiliation(s)
- Zoe Sirotiak
- Department of Kinesiology, Iowa State University, Ames, Iowa, United States of America
| | - Brandon T. Gallagher
- Department of Kinesiology, Iowa State University, Ames, Iowa, United States of America
| | | | - Lucas J. Showman
- W.M. Keck Metabolomics Research Laboratory, Iowa State University, Ames, Iowa, United States of America
| | - Cecilia J. Hillard
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
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Stachowicz K. Deciphering the mechanisms of reciprocal regulation or interdependence at the cannabinoid CB1 receptors and cyclooxygenase-2 level: Effects on mood, cognitive implications, and synaptic signaling. Neurosci Biobehav Rev 2023; 155:105439. [PMID: 37898448 DOI: 10.1016/j.neubiorev.2023.105439] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/24/2023] [Accepted: 10/24/2023] [Indexed: 10/30/2023]
Abstract
The lipid endocannabinoid system refers to endogenous cannabinoids (eCBs), the enzymes involved in their synthesis and metabolism, and the G protein-coupled cannabinoid receptors (GPCRs), CB1, and CB2. CB1 receptors (CB1Rs) are distributed in the brain at presynaptic terminals. Their activation induces inhibition of neurotransmitter release, which are gamma-aminobutyric acid (GABA), glutamate (Glu), dopamine, norepinephrine, serotonin, and acetylcholine. Postsynaptically localized CB1Rs regulate the activity of selected ion channels and N-methyl-D-aspartate receptors (NMDARs). CB2Rs are mainly peripheral and will not be considered here. Anandamide metabolism, mediated by cyclooxygenase-2 (COX-2), generates anandamide-derived prostanoids. In addition, COX-2 regulates the formation of CB1 ligands, which reduce excitatory transmission in the hippocampus (HC). The role of CB1Rs and COX-2 has been described in anxiety, depression, and cognition, among other central nervous system (CNS) disorders, affecting neurotransmission and behavior of the synapses. This review will analyze common pathways, mechanisms, and behavioral effects of manipulation at the CB1Rs/COX-2 level.
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Affiliation(s)
- Katarzyna Stachowicz
- Department of Neurobiology, Maj Institute of Pharmacoslogy, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
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17
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Shen CL, Newman JW, Elmassry MM, Borkowski K, Chyu MC, Kahathuduwa C, Neugebauer V, Watkins BA. Tai Chi exercise reduces circulating levels of inflammatory oxylipins in postmenopausal women with knee osteoarthritis: results from a pilot study. Front Med (Lausanne) 2023; 10:1210170. [PMID: 37654656 PMCID: PMC10466388 DOI: 10.3389/fmed.2023.1210170] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 07/25/2023] [Indexed: 09/02/2023] Open
Abstract
Background Tai Chi (TC) controls pain through mind-body exercise and appears to alter inflammatory mediators. TC actions on lipid biomarkers associated with inflammation and brain neural networks in women with knee osteoarthritic pain were investigated. Methods A single-center, pre- and post-TC group (baseline and 8 wk) exercise pilot study in postmenopausal women with knee osteoarthritic pain was performed. 12 eligible women participated in TC group exercise. The primary outcome was liquid chromatography tandem mass spectrometry determination of circulating endocannabinoids (eCB) and oxylipins (OxL). Secondary outcomes were correlations between eCB and OxL levels and clinical pain/limitation assessments, and brain resting-state function magnetic resonance imaging (rs-fMRI). Results Differences in circulating quantitative levels (nM) of pro-inflammatory OxL after TC were found in women. TC exercise resulted in lower OxL PGE1 and PGE2 and higher 12-HETE, LTB4, and 12-HEPE compared to baseline. Pain assessment and eCB and OxL levels suggest crucial relationships between TC exercise, inflammatory markers, and pain. Higher plasma levels of eCB AEA, and 1, 2-AG were found in subjects with increased pain. Several eCB and OxL levels were positively correlated with left and right brain amygdala-medial prefrontal cortex functional connectivity. Conclusion TC exercise lowers pro-inflammatory OxL in women with knee osteoarthritic pain. Correlations between subject pain, functional limitations, and brain connectivity with levels of OxL and eCB showed significance. Findings indicate potential mechanisms for OxL and eCB and their biosynthetic endogenous PUFA precursors that alter brain connectivity, neuroinflammation, and pain. Clinical Trial Registration ClinicalTrials.gov, identifier: NCT04046003.
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Affiliation(s)
- Chwan-Li Shen
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - John W. Newman
- United States Department of Agriculture, Agricultural Research Service, Western Human Nutrition Research Center, Davis, CA, United States
- Department of Nutrition, University of California, Davis, Davis, CA, United States
- West Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, CA, United States
| | - Moamen M. Elmassry
- Department of Molecular Biology, Princeton University, Princeton, NJ, United States
| | - Kamil Borkowski
- West Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, CA, United States
| | - Ming-Chien Chyu
- Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Medical Engineering, Texas Tech University, Lubbock, TX, United States
| | - Chanaka Kahathuduwa
- Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Psychiatry, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Volker Neugebauer
- Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, United States
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Bruce A. Watkins
- Department of Nutrition, University of California, Davis, Davis, CA, United States
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Kogan NM, Begmatova D, Vinnikova L, Malitsky S, Itkin M, Sharon E, Klinov A, Gorelick J, Koman I, Vogel Z, Mechoulam R, Pinhasov A. Endocannabinoid basis of personality-Insights from animal model of social behavior. Front Pharmacol 2023; 14:1234332. [PMID: 37663250 PMCID: PMC10468576 DOI: 10.3389/fphar.2023.1234332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
Rationale: The endocannabinoid system is known to be involved in learning, memory, emotional processing and regulation of personality patterns. Here we assessed the endocannabinoid profile in the brains of mice with strong characteristics of social dominance and submissiveness. Methods: A lipidomics approach was employed to assess the endocannabinoidome in the brains of Dominant (Dom) and Submissive (Sub) mice. The endocannabinoid showing the greatest difference in concentration in the brain between the groups, docosatetraenoyl ethanolamine (DEA), was synthesized, and its effects on the physiological and behavioral responses of Dom and Sub mice were evaluated. mRNA expression of the endocannabinoid receptors and enzymes involved in PUFA biosynthesis was assessed using qRT-PCR. Results: Targeted LC/MS analysis revealed that long-chain polyunsaturated ethanolamides including arachidonoyl ethanolamide (AEA), DEA, docosatrienoyl ethanolamide (DTEA), eicosatrienoyl ethanolamide (ETEA), eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) were higher in the Sub compared with the Dom mice. Untargeted LC/MS analysis showed that the parent fatty acids, docosatetraenoic (DA) and eicosapentaenoic (EPA), were higher in Sub vs. Dom. Gene expression analysis revealed increased mRNA expression of genes encoding the desaturase FADS2 and the elongase ELOVL5 in Sub mice compared with Dom mice. Acute DEA administration at the dose of 15 mg/kg produced antinociceptive and locomotion-inducing effects in Sub mice, but not in Dom mice. Subchronic treatment with DEA at the dose of 5 mg/kg augmented dominant behavior in wild-type ICR and Dom mice but not in Sub mice. Conclusion: This study suggests that the endocannabinoid system may play a role in the regulation of dominance and submissiveness, functional elements of social behavior and personality. While currently we have only scratched the surface, understanding the role of the endocannabinoid system in personality may help in revealing the mechanisms underlying the etiopathology of psychiatric disorders.
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Affiliation(s)
- Natalya M. Kogan
- Department of Molecular Biology, Ariel University, Ariel, Israel
- The Institute of Personalized and Translational Medicine, Ariel University, Ariel, Israel
- Institute of Drug Research, Hebrew University, Jerusalem, Israel
| | | | | | - Sergey Malitsky
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Maxim Itkin
- Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Eyal Sharon
- The Institute of Personalized and Translational Medicine, Ariel University, Ariel, Israel
| | - Artem Klinov
- Department of Molecular Biology, Ariel University, Ariel, Israel
| | | | - Igor Koman
- Department of Molecular Biology, Ariel University, Ariel, Israel
- The Institute of Personalized and Translational Medicine, Ariel University, Ariel, Israel
| | - Zvi Vogel
- Department of Neurbiology, Weizmann Institute of Science, Rehovot, Israel
| | | | - Albert Pinhasov
- Department of Molecular Biology, Ariel University, Ariel, Israel
- Adelson School of Medicine, Ariel University, Ariel, Israel
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19
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Bourdy R, Befort K. The Role of the Endocannabinoid System in Binge Eating Disorder. Int J Mol Sci 2023; 24:ijms24119574. [PMID: 37298525 DOI: 10.3390/ijms24119574] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Eating disorders are multifactorial disorders that involve maladaptive feeding behaviors. Binge eating disorder (BED), the most prevalent of these in both men and women, is characterized by recurrent episodes of eating large amounts of food in a short period of time, with a subjective loss of control over eating behavior. BED modulates the brain reward circuit in humans and animal models, which involves the dynamic regulation of the dopamine circuitry. The endocannabinoid system plays a major role in the regulation of food intake, both centrally and in the periphery. Pharmacological approaches together with research using genetically modified animals have strongly highlighted a predominant role of the endocannabinoid system in feeding behaviors, with the specific modulation of addictive-like eating behaviors. The purpose of the present review is to summarize our current knowledge on the neurobiology of BED in humans and animal models and to highlight the specific role of the endocannabinoid system in the development and maintenance of BED. A proposed model for a better understanding of the underlying mechanisms involving the endocannabinoid system is discussed. Future research will be necessary to develop more specific treatment strategies to reduce BED symptoms.
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Affiliation(s)
- Romain Bourdy
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Université de Strasbourg, UMR7364, CNRS, 12 Rue Goethe, 67000 Strasbourg, France
| | - Katia Befort
- Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Université de Strasbourg, UMR7364, CNRS, 12 Rue Goethe, 67000 Strasbourg, France
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20
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Applied Clinical Tandem Mass Spectrometry-Based Quantification Methods for Lipid-Derived Biomarkers, Steroids and Cannabinoids: Fit-for-Purpose Validation Methods. Biomolecules 2023; 13:biom13020383. [PMID: 36830753 PMCID: PMC9953102 DOI: 10.3390/biom13020383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/09/2023] [Accepted: 02/11/2023] [Indexed: 02/22/2023] Open
Abstract
The emergence of metabolomics and quantification approaches is revealing new biomarkers applied to drug discovery. In this context, tandem mass spectrometry is the method of choice, requiring a specific validation process for preclinical and clinical applications. Research on the two classes of lipid mediators, steroids and cannabinoids, has revealed a potential interaction in cannabis addiction and metabolism-related disorders. Here we present the development of GC-MS/MS and LC-MS/MS methods for routine quantification of targeted steroids and cannabinoids, respectively. The methods were developed using an isotopic approach, including validation for linearity, selectivity, LLOQ determination, matrix effect, carryover, between- and within-run accuracy and precision, and stability tests to measure 11 steroids and seven cannabinoids in human plasma. These methods were satisfactory for most validity conditions, although not all met the acceptance criteria for all analytes. A comparison of calibration curves in biological and surrogate matrices and in methanol showed that the latter condition was more applicable for our quantification of endogenous compounds. In conclusion, the validation of our methods met the criteria for GLP-qualified rather than GLP-validated methods, which can be used for routine analytical studies for dedicated preclinical and clinical purposes, by combining appropriate system suitability testing, including quality controls in the biological matrix.
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21
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Hasbi A, Madras BK, George SR. Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review. Brain Sci 2023; 13:brainsci13020325. [PMID: 36831868 PMCID: PMC9953886 DOI: 10.3390/brainsci13020325] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/10/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components-tetrahydrocannabinol (THC) and cannabidiol (CBD)-or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.
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Affiliation(s)
- Ahmed Hasbi
- Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Correspondence: (A.H.); (S.R.G.)
| | - Bertha K. Madras
- McLean Hospital, Belmont, MA 02478, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA
| | - Susan R. George
- Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Correspondence: (A.H.); (S.R.G.)
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22
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Royse SK, Lopresti BJ, Mathis CA, Tollefson S, Narendran R. Beyond monoamines: II. Novel applications for PET imaging in psychiatric disorders. J Neurochem 2023; 164:401-443. [PMID: 35716057 DOI: 10.1111/jnc.15657] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/07/2022] [Accepted: 06/08/2022] [Indexed: 11/27/2022]
Abstract
Early applications of positron emission tomography (PET) in psychiatry sought to identify derangements of cerebral blood flow and metabolism. The need for more specific neurochemical imaging probes was soon evident, and these probes initially targeted the sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. For nearly 30 years, the centrality of monoamine dysfunction in psychiatric disorders drove the development of an armamentarium of monoaminergic PET radiopharmaceuticals and imaging methodologies. However, continued investments in monoamine-enhancing drug development realized only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely parallelled drug development priorities, resulting in the development of new PET imaging agents for non-monoamine targets. In part two of this review, we survey clinical research studies using the novel targets and radiotracers described in part one across major psychiatric application areas such as substance use disorders, anxiety disorders, eating disorders, personality disorders, mood disorders, and schizophrenia. Important limitations of the studies described are discussed, as well as key methodologic issues, challenges to the field, and the status of clinical trials seeking to exploit these targets for novel therapeutics.
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Affiliation(s)
- Sarah K Royse
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Brian J Lopresti
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Chester A Mathis
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Savannah Tollefson
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Rajesh Narendran
- Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.,Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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23
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FAAH Inhibition Restores Early Life Stress-Induced Alterations in PFC microRNAs Associated with Depressive-Like Behavior in Male and Female Rats. Int J Mol Sci 2022; 23:ijms232416101. [PMID: 36555739 PMCID: PMC9782513 DOI: 10.3390/ijms232416101] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Early life stress (ELS) increases predisposition to depression. We compared the effects of treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597, and the selective serotonin reuptake inhibitor paroxetine, on ELS-induced depressive-like behavior and the expression of microRNAs (miRs) associated with depression in the medial prefrontal cortex (mPFC), hippocampal CA1 area, lateral habenula and dorsal raphe in rats. We also examined the mRNA expression of serotonergic (htr1a and slc6a4) and endocannabinoid (cnr1, cnr2 and faah) targets in the mPFC following ELS and pharmacological treatment. Adult males and females exposed to the 'Limited Bedding and Nesting' ELS paradigm demonstrated a depressive-like phenotype and late-adolescence URB597 treatment, but not paroxetine, reversed this phenotype. In the mPFC, ELS downregulated miR-16 in males and miR-135a in females and URB597 treatment restored this effect. In ELS females, the increase in cnr2 and decrease in faah mRNAs in the mPFC were reversed by URB597 treatment. We show for the first time that URB597 reversed ELS-induced mPFC downregulation in specific miRs and stress-related behaviors, suggesting a novel mechanism for the beneficial effects of FAAH inhibition. The differential effects of ELS and URB597 on males and females highlight the importance of developing sex-specific treatment approaches.
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24
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Zada W, VanRyzin JW, Perez-Pouchoulen M, Baglot SL, Hill MN, Abbas G, Clark SM, Rashid U, McCarthy MM, Mannan A. Fatty acid amide hydrolase inhibition and N-arachidonoylethanolamine modulation by isoflavonoids: A novel target for upcoming antidepressants. Pharmacol Res Perspect 2022; 10:e00999. [PMID: 36029006 PMCID: PMC9418665 DOI: 10.1002/prp2.999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 12/01/2022] Open
Abstract
Modulation of the endocannabinoid system (ECS) is a novel putative target for therapeutic intervention in depressive disorders. Altering concentrations of one of the principal endocannabinoids, N‐arachidonoylethanolamine, also known as anandamide (AEA) can affect depressive‐like behaviors through several mechanisms including anti‐inflammatory, hormonal, and neural circuit alterations. Recently, isoflavonoids, a class of plant‐derived compounds, have been of therapeutic interest given their ability to modulate the metabolism of the endogenous ligands of the ECS. To determine the therapeutic potential of isoflavonoids, we screened several candidate compounds (Genistein, Biochanin‐A, and 7‐hydroxyflavone) in silico to determine their binding properties with fatty acid amide hydrolase (FAAH), the primary degrative enzyme for AEA. We further validated the ability of these compounds to inhibit FAAH and determined their effects on depressive‐like and locomotor behaviors in the forced swim test (FST) and open field test in male and female mice. We found that while genistein was the most potent FAAH inhibitor, 7‐hydroxyflavone was most effective at reducing immobility time in the forced swim test. Finally, we measured blood corticosterone and prefrontal cortex AEA concentrations following the forced swim test and found that all tested compounds decreased corticosterone and increased AEA, demonstrating that isoflavonoids are promising therapeutic targets as FAAH inhibitors.
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Affiliation(s)
- Wahid Zada
- Department of Pharmacy, COMSATS University Islamabad, Khyber Pakhtunkhwa, Pakistan.,Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Jonathan W VanRyzin
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Miguel Perez-Pouchoulen
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Samantha L Baglot
- Hotchkiss Brain Institute and Mathison Center for Mental Health Research and Education, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Matthew N Hill
- Hotchkiss Brain Institute and Mathison Center for Mental Health Research and Education, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Cell Biology and Anatomy & Psychiatry, University of Calgary, Calgary, Alberta, Canada
| | - Ghulam Abbas
- Department of Pharmacology, Faculty of Pharmacy, Ziauddin University, Karachi, Pakistan
| | - Sarah M Clark
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Umer Rashid
- Department of Chemistry, COMSATS University Islamabad, Khyber Pakhtunkhwa, Pakistan
| | - Margaret M McCarthy
- Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Abdul Mannan
- Department of Pharmacy, COMSATS University Islamabad, Khyber Pakhtunkhwa, Pakistan
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25
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Almada RC, Falconi-Sobrinho LL, da Silva JA, Wotjak CT, Coimbra NC. Augmented anandamide signalling in the substantia nigra pars reticulata mediates panicolytic-like effects in mice confronted by Crotalus durissus terrificus pit vipers. Psychopharmacology (Berl) 2022; 239:2753-2769. [PMID: 35650304 DOI: 10.1007/s00213-022-06127-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 03/26/2022] [Indexed: 12/30/2022]
Abstract
RATIONALE The endocannabinoid modulation of fear and anxiety due to the on-demand synthesis and degradation is supported by a large body of research. Although it has been proposed that anandamide (AEA) in the substantia nigra pars reticulata (SNpr) seems to be important for the organisation of innate fear-related behaviours, a role for endogenous AEA has yet to be clarified. METHODS Mice were treated with the fatty acid amide hydrolase (FAAH) selective inhibitor URB597 at different concentrations (0.01, 0.1, 1 nmol/0.1 µL) in the SNpr and confronted by rattlesnakes (Crotalus durissus terrificus). The most effective dose of URB597 (1 nmol) was also preceded by microinjections of the CB1 receptor antagonist AM251 (0.1 nmol) into the SNpr, and mice were then confronted by the venomous snake. RESULTS URB597 (0.1 and 1 nmol) in the SNpr decreased the expression of defensive behaviours such as defensive attention, escape, and time spent inside the burrow of mice confronted by rattlesnakes. Moreover, pretreatment of SNpr with AM251 suppressed these antiaversive effects of URB597 in this midbrain structure. CONCLUSION Overall, these data clearly indicate that the panicolytic consequences of endogenous AEA enhancement in the SNpr are mediated by CB1 receptor signalling.
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Affiliation(s)
- Rafael C Almada
- Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.,Department of Biological Sciences, School of Science, Humanities and Languages, São Paulo State University (UNESP), Assis, São Paulo, Brazil
| | - Luiz Luciano Falconi-Sobrinho
- Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.,Behavioural Neurosciences Institute (INeC), São Paulo, Ribeirão Preto, Brazil.,Ophidiarium LNN-FMRP-USP/INeC, Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil.,NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Juliana A da Silva
- Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.,Behavioural Neurosciences Institute (INeC), São Paulo, Ribeirão Preto, Brazil
| | - Carsten T Wotjak
- Laboratory of Neuronal Plasticity, Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.,Central Nervous System Diseases Research, Boehringer Ingelheim Pharmaceuticals Gesellschaft Mit Beschränkter Haftung & Compagnie Kommanditgesellschaft, Biberach an der Riß, Germany
| | - Norberto C Coimbra
- Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. .,Behavioural Neurosciences Institute (INeC), São Paulo, Ribeirão Preto, Brazil. .,Ophidiarium LNN-FMRP-USP/INeC, Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil. .,NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
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26
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Wei D, Tsheringla S, McPartland JC, Allsop AZASA. Combinatorial approaches for treating neuropsychiatric social impairment. Philos Trans R Soc Lond B Biol Sci 2022; 377:20210051. [PMID: 35858103 PMCID: PMC9274330 DOI: 10.1098/rstb.2021.0051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 05/13/2022] [Indexed: 01/30/2023] Open
Abstract
Social behaviour is an essential component of human life and deficits in social function are seen across multiple psychiatric conditions with high morbidity. However, there are currently no FDA-approved treatments for social dysfunction. Since social cognition and behaviour rely on multiple signalling processes acting in concert across various neural networks, treatments aimed at social function may inherently require a combinatorial approach. Here, we describe the social neurobiology of the oxytocin and endocannabinoid signalling systems as well as translational evidence for their use in treating symptoms in the social domain. We leverage this systems neurobiology to propose a network-based framework that involves pharmacology, psychotherapy, non-invasive brain stimulation and social skills training to combinatorially target trans-diagnostic social impairment. Lastly, we discuss the combined use of oxytocin and endocannabinoids within our proposed framework as an illustrative strategy to treat specific aspects of social function. Using this framework provides a roadmap for actionable treatment strategies for neuropsychiatric social impairment. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.
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Affiliation(s)
- Don Wei
- Department of Psychiatry, UCLA, Los Angeles, CA, USA
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27
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Cannabidiol Prevents Spontaneous Fear Recovery after Extinction and Ameliorates Stress-Induced Extinction Resistance. Int J Mol Sci 2022; 23:ijms23169333. [PMID: 36012600 PMCID: PMC9409311 DOI: 10.3390/ijms23169333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/14/2022] [Accepted: 08/17/2022] [Indexed: 12/15/2022] Open
Abstract
Cannabidiol, the main non-psychotropic constituent of cannabis, has potential as a treatment for anxiety-related disorders since it reduces learned fear expression and enhances fear extinction. The return of fear over time after successful extinction and stress-induced extinction resistance are potential barriers to the treatment of these disorders with extinction-based psychological therapy. In two experiments using rats subjected to auditory fear conditioning, we determined the effects of systemic cannabidiol treatment on (1) delayed extinction and later spontaneous fear recovery, and (2) extinction resistance caused by immediate extinction (the immediate extinction deficit (IED)). In Experiment 1, cannabidiol was given before delayed extinction occurring 24 h after conditioning, with extinction recall and spontaneous fear recovery tested drug-free 1 and 21 days after extinction, respectively. We found that cannabidiol had no effect on extinction recall but it prevented spontaneous fear recovery. In Experiment 2, the IED procedure was first validated, with immediate extinction occurring 30 min after conditioning. We confirmed that immediate extinction impaired extinction recall, compared to delayed extinction. Next, cannabidiol was given before immediate or no extinction, with extinction recall tested drug-free the next day. We found that cannabidiol rescued the IED, which did not involve effects on fear memory consolidation. In summary, cannabidiol prevented spontaneous fear recovery after delayed extinction and ameliorated extinction resistance caused by immediate extinction. Although the pharmacological mechanisms underlying these effects remain to be determined, our results add to evidence indicating that cannabidiol might prove useful as an adjunct for potentiating the psychological treatment of anxiety-related disorders.
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28
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The intersection of astrocytes and the endocannabinoid system in the lateral habenula: on the fast-track to novel rapid-acting antidepressants. Mol Psychiatry 2022; 27:3138-3149. [PMID: 35585261 DOI: 10.1038/s41380-022-01598-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 02/04/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022]
Abstract
Despite attaining significant advances toward better management of depressive disorders, we are still facing several setbacks. Developing rapid-acting antidepressants with sustained effects is an aspiration that requires thinking anew to explore possible novel targets. Recently, the lateral habenula (LHb), the brain's "anti-reward system", has been shown to go awry in depression in terms of various molecular and electrophysiological signatures. Some of the presumed contributors to such observed aberrations are astrocytes. These star-shaped cells of the brain can alter the firing pattern of the LHb, which keeps the activity of the midbrain's aminergic centers under tight control. Astrocytes are also integral parts of the tripartite synapses, and can therefore modulate synaptic plasticity and leave long-lasting changes in the brain. On the other hand, it was discovered that astrocytes express cannabinoid type 1 receptors (CB1R), which can also take part in long-term plasticity. Herein, we recount how the LHb of a depressed brain deviates from the "normal" one from a molecular perspective. We then try to touch upon the alterations of the endocannabinoid system in the LHb, and cast the idea that modulation of astroglial CB1R may help regulate habenular neuronal activity and synaptogenesis, thereby acting as a new pharmacological tool for regulation of mood and amelioration of depressive symptoms.
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29
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Fu J, Zhang K, Lu L, Li M, Han M, Guo Y, Wang X. Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD). Pharmaceutics 2022; 14:pharmaceutics14081533. [PMID: 35893789 PMCID: PMC9332327 DOI: 10.3390/pharmaceutics14081533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/13/2022] [Accepted: 07/20/2022] [Indexed: 02/01/2023] Open
Abstract
Cannabidiol (CBD), a nonpsychoactive major component derived from Cannabis sativa, widely used in neurodegenerative diseases, has now been proven to have growth inhibitory effects on many tumor cell lines, including breast tumors. Meanwhile CBD can effectively alleviate cancer-associated pain, anxiety, and depression, especially tumor cachexia, thus it is very promising as an anti-tumor drug with unique advantages. 20(S)-Protopanaxadiol (PPD) derived from the best-known tonic Chinese herbal medicine Ginseng was designed to be co-loaded with CBD into liposomes to examine their synergistic tumor-inhibitory effect. The CBD-PPD co-loading liposomes (CP-liposomes) presented a mean particle size of 138.8 nm. Further glycosyl-modified CP-liposomes (GMCP-liposomes) were prepared by the incorporation of n-Dodecyl β-D-maltoside (Mal) into the liposomal bilayer with glucose residue anchored on the surface to act as a ligand targeting the GLUT1 receptor highly expressed on tumor cells. In vivo studies on murine breast tumor (4T1 cells)-bearing BALB/c mice demonstrated good dose dependent anti-tumor efficacy of CP-liposomes. A high tumor inhibition rate (TIR) of 82.2% was achieved with good tolerance. However, glycosylation modification failed to significantly enhance TIR of CP-liposomes. In summary, combined therapy with PPD proved to be a promising strategy for CBD to be developed into a novel antitumor drug, with characteristics of effectiveness, good tolerance, and the potential to overcome tumor cachexia.
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Affiliation(s)
- Jingxin Fu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, No.151, Malianwa North Road, Haidian District, Beijing 100193, China; (J.F.); (L.L.); (M.L.); (M.H.); (Y.G.)
| | - Kunfeng Zhang
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China;
| | - Likang Lu
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, No.151, Malianwa North Road, Haidian District, Beijing 100193, China; (J.F.); (L.L.); (M.L.); (M.H.); (Y.G.)
| | - Manzhen Li
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, No.151, Malianwa North Road, Haidian District, Beijing 100193, China; (J.F.); (L.L.); (M.L.); (M.H.); (Y.G.)
| | - Meihua Han
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, No.151, Malianwa North Road, Haidian District, Beijing 100193, China; (J.F.); (L.L.); (M.L.); (M.H.); (Y.G.)
| | - Yifei Guo
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, No.151, Malianwa North Road, Haidian District, Beijing 100193, China; (J.F.); (L.L.); (M.L.); (M.H.); (Y.G.)
| | - Xiangtao Wang
- Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, No.151, Malianwa North Road, Haidian District, Beijing 100193, China; (J.F.); (L.L.); (M.L.); (M.H.); (Y.G.)
- Correspondence:
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30
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Clary KL, Kang H, Quintero Silva L, Bobitt J. Weeding Out the Stigma: Older Veterans in Illinois Share Their Experiences Using Medical Cannabis. J Psychoactive Drugs 2022:1-8. [PMID: 35640046 DOI: 10.1080/02791072.2022.2082901] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Many U.S. Veterans are using cannabis for medical purposes. Modern research findings continue to point to medical cannabis as a potentially effective alternative to prescription medications for treating a range of medical conditions. While research exists on the use levels of cannabis, limited research can be found on the perceived stigma of using cannabis, especially among older Veterans. We surveyed 121 older U.S. Veterans who were enrolled in the Illinois Medical Cannabis Patient Program during Fall 2020. We then used maximum variation sampling to select a subset of 32 Veterans to partake in a phone interview. Two researchers conducted and qualitatively coded 30-minute audiotaped semi-structured interviews. Interview topics included (1) the use of cannabis, opioids, and benzodiazepines; (2) interactions with medical providers; (3) stigma regarding cannabis use; and (4) educational materials. We share findings from stigma. We identified three themes: (1) stereotypes regarding people who use cannabis, (2) media portrayal of cannabis users, and (3) hesitation in disclosing cannabis use. Stigma creates situations in which older Veterans may be hesitant to disclose their use of cannabis with physicians and friends/family, which can be dangerous and socially isolating. Additional research is needed to expand upon our findings with more generalizable methods.
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Affiliation(s)
- Kelly Lynn Clary
- School of Social Work, Texas State University, San Marcos, TX, USA
| | - Hyojung Kang
- Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Laura Quintero Silva
- Community Health, University of Illinois at Urbana-Champaign, Champaign, IL, USA
| | - Julie Bobitt
- Center for Dissemination and Implementation Science, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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31
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Bright U, Akirav I. Modulation of Endocannabinoid System Components in Depression: Pre-Clinical and Clinical Evidence. Int J Mol Sci 2022; 23:5526. [PMID: 35628337 PMCID: PMC9146799 DOI: 10.3390/ijms23105526] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/09/2022] [Accepted: 05/09/2022] [Indexed: 02/05/2023] Open
Abstract
Depression is characterized by continuous low mood and loss of interest or pleasure in enjoyable activities. First-line medications for mood disorders mostly target the monoaminergic system; however, many patients do not find relief with these medications, and those who do suffer from negative side effects and a discouragingly low rate of remission. Studies suggest that the endocannabinoid system (ECS) may be involved in the etiology of depression and that targeting the ECS has the potential to alleviate depression. ECS components (such as receptors, endocannabinoid ligands, and degrading enzymes) are key neuromodulators in motivation and cognition as well as in the regulation of stress and emotions. Studies in depressed patients and in animal models for depression have reported deficits in ECS components, which is motivating researchers to identify potential diagnostic and therapeutic biomarkers within the ECS. By understanding the effects of cannabinoids on ECS components in depression, we enhance our understanding of which brain targets they hit, what biological processes they alter, and eventually how to use this information to design better therapeutic options. In this article, we discuss the literature on the effects of cannabinoids on ECS components of specific depression-like behaviors and phenotypes in rodents and then describe the findings in depressed patients. A better understanding of the effects of cannabinoids on ECS components in depression may direct future research efforts to enhance diagnosis and treatment.
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Affiliation(s)
- Uri Bright
- Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa 3498838, Israel;
- The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel
| | - Irit Akirav
- Department of Psychology, School of Psychological Sciences, University of Haifa, Haifa 3498838, Israel;
- The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa 3498838, Israel
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32
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Cannabinoid CB1 Receptor Involvement in the Actions of CBD on Anxiety and Coping Behaviors in Mice. Pharmaceuticals (Basel) 2022; 15:ph15040473. [PMID: 35455470 PMCID: PMC9027088 DOI: 10.3390/ph15040473] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/07/2022] [Accepted: 04/11/2022] [Indexed: 12/16/2022] Open
Abstract
The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD.
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Cameron LD, Fleszar-Pavlović SE, Yepez M, Manzo RD, Brown PM. Beliefs about marijuana use during pregnancy and breastfeeding held by residents of a Latino-majority, rural region of California. J Behav Med 2022; 45:544-557. [PMID: 35378643 PMCID: PMC9304043 DOI: 10.1007/s10865-022-00299-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 02/14/2022] [Indexed: 11/25/2022]
Abstract
Marijuana use among pregnant and breastfeeding women is on the rise and carries risks for infant health and well-being. Decisions to use marijuana while pregnant and breastfeeding are motivated by beliefs that use poses minimal risk to infants and offers benefits to maternal users. Misperceptions and usage trend higher among disadvantaged populations. This study surveyed 401 community residents on beliefs about risks and benefits of marijuana use by pregnant and breastfeeding women. The study utilized techniques to enhance recruitment of Latino and disadvantaged residents of rural communities in California, a state where recreational marijuana use is legal. Analyses revealed substantial endorsement of beliefs about benefits and low risks of marijuana use while pregnant and breastfeeding, many of which run counter to current evidence. Misperceptions were particularly prevalent for cannabis users and male respondents. Trends in valid beliefs, while modest, were higher for Latinos and parents.
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Affiliation(s)
- Linda D Cameron
- Department of Psychological Sciences, University of California Merced, 5200 North Lake Road, Merced, CA, 95343, USA.
- Health Sciences Research Institute, University of California, Merced, CA, USA.
| | - Sara E Fleszar-Pavlović
- Department of Psychological Sciences, University of California Merced, 5200 North Lake Road, Merced, CA, 95343, USA
- Health Sciences Research Institute, University of California, Merced, CA, USA
| | - Marisela Yepez
- Department of Psychological Sciences, University of California Merced, 5200 North Lake Road, Merced, CA, 95343, USA
- Health Sciences Research Institute, University of California, Merced, CA, USA
| | - Rosa D Manzo
- Health Sciences Research Institute, University of California, Merced, CA, USA
| | - Paul M Brown
- Health Sciences Research Institute, University of California, Merced, CA, USA
- Department of Public Health, University of California, Merced, CA, USA
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34
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Epps SA. Commonalities for comorbidity: Overlapping features of the endocannabinoid system in depression and epilepsy. Front Psychiatry 2022; 13:1041460. [PMID: 36339877 PMCID: PMC9626804 DOI: 10.3389/fpsyt.2022.1041460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 09/29/2022] [Indexed: 11/13/2022] Open
Abstract
A wealth of clinical and pre-clinical data supports a bidirectional comorbidity between depression and epilepsy. This suggests commonalities in underlying mechanisms that may serve as targets for more effective treatment strategies. Unfortunately, many patients with this comorbidity are highly refractory to current treatment strategies, while others experience a worsening of one arm of the comorbidity when treating the other arm. This highlights the need for novel pharmaceutical targets that may provide safe and effective relief for both depression and epilepsy symptoms. The endocannabinoid system (ECS) of the brain has become an area of intense interest for possible roles in depression and epilepsy. Several existing literature reviews have provided in-depth analysis of the involvement of various aspects of the ECS in depression or epilepsy separately, while others have addressed the effectiveness of different treatment strategies targeting the ECS in either condition individually. However, there is not currently a review that considers the ECS when both conditions are comorbid. This mini-review will address areas of common overlap between the ECS in depression and in epilepsy, such as commonalities in endocannabinoids themselves, their receptors, and degradative enzymes. These areas of overlap will be discussed alongside their implications for treatment of this challenging comorbidity.
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Affiliation(s)
- S Alisha Epps
- Department of Psychology, Whitworth University, Spokane, WA, United States
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35
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Preuss UW, Schaefer M, Born C, Grunze H. Bipolar Disorder and Comorbid Use of Illicit Substances. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:1256. [PMID: 34833474 PMCID: PMC8623998 DOI: 10.3390/medicina57111256] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/09/2021] [Accepted: 11/12/2021] [Indexed: 02/05/2023]
Abstract
Substance use disorders (SUD) are highly prevalent in bipolar disorder (BD) and significantly affect clinical outcomes. Incidence and management of illicit drug use differ from alcohol use disorders, nicotine use of behavioral addictions. It is not yet clear why people with bipolar disorder are at higher risk of addictive disorders, but recent data suggest common neurobiological and genetic underpinnings and epigenetic alterations. In the absence of specific diagnostic instruments, the clinical interview is conducive for the diagnosis. Treating SUD in bipolar disorder requires a comprehensive and multidisciplinary approach. Most treatment trials focus on single drugs, such as cannabis alone or in combination with alcohol, cocaine, or amphetamines. Synopsis of data provides limited evidence that lithium and valproate are effective for the treatment of mood symptoms in cannabis users and may reduce substance use. Furthermore, the neuroprotective agent citicoline may reduce cocaine consumption in BD subjects. However, many of the available studies had an open-label design and were of modest to small sample size. The very few available psychotherapeutic trials indicate no significant differences in outcomes between BD with or without SUD. Although SUD is one of the most important comorbidities in BD with a significant influence on clinical outcome, there is still a lack both of basic research and clinical trials, allowing for evidence-based and specific best practices.
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Affiliation(s)
- Ulrich W. Preuss
- Klinik für Psychiatrie, Psychotherapie und Psychosomatische Medizin, Klinikum Ludwigsburg, Posilipostrasse 4, 71640 Ludwigsburg, Germany
- Klinik für Psychiatrie, Psychotherapie und Psychosomatik, Martin-Luther-Universität, Halle-Wittenberg, Julius-Kühn-Str. 7, 06112 Halle/Saale, Germany
| | - Martin Schaefer
- Klinik für Psychiatrie, Psychotherapie, Psychosomatik und Suchtmedizin, Evang. Kliniken Essen-Mitte, Henricistr. 92, 45136 Essen, Germany;
- Klinik für Psychiatrie und Psychotherapie (CCM), Charité Universitätsmedizin, 10117 Berlin, Germany
| | - Christoph Born
- Psychiatrie Schwäbisch Hall, 74523 Schwäbisch Hall, Germany; (C.B.); (H.G.)
- Campus Nuremberg-Nord, Paracelsus Medical University, 90419 Nuremberg, Germany
| | - Heinz Grunze
- Psychiatrie Schwäbisch Hall, 74523 Schwäbisch Hall, Germany; (C.B.); (H.G.)
- Campus Nuremberg-Nord, Paracelsus Medical University, 90419 Nuremberg, Germany
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36
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Bersani G, Pacitti F, Iannitelli A, Caroti E, Quartini A, Xenos D, Marconi M, Cuoco V, Bigio B, Bowles NP, Weisz F, Fanelli F, Di Lallo VD, Belluomo I, Nicoletti F, Nasca C. Inverse correlation between plasma 2-arachidonoylglycerol levels and subjective severity of depression. Hum Psychopharmacol 2021; 36:e2779. [PMID: 33559925 DOI: 10.1002/hup.2779] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Endocannabinoids have been implicated in the pathophysiology of Major Depressive Disorder (MDD) and might represent potential targets for therapeutic intervention. Objectives of the study were: (1) to measure plasma levels of endocannabinoids in a group of antidepressant-free depressed outpatients; (2) to explore their relationship with the severity of depressive symptoms as subjectively perceived by the patients; and (3) to investigate the effect of the selective serotonin reuptake inhibitor escitalopram on endocannabinoid levels. METHODS We measured plasma levels of the two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anadamide), in 12 drug-free outpatients diagnosed with MDD and in 12 matched healthy controls. In the patient group, endocannabinoids plasma levels were assessed at baseline and after 2 months of treatment with escitalopram. RESULTS Baseline plasma levels of the two endocannabinoids did not differ between depressed patients and healthy controls. However, there was a significant inverse correlation between 2-arachidonoylglycerol levels and the severity of subjectively perceived depressive symptoms. Treatment with escitalopram did not change endocannabinoid levels in depressed patients, although it caused the expected improvement of depressive symptoms. CONCLUSIONS Our results suggest that 2-arachidonylglycerol, the most abundant endocannabinoid in the central nervous system, might act to mitigate depressive symptoms, and raise the interesting possibility that 2-arachidonylglycerol and anandamide are differentially regulated in patients affected by MDD. Also, our data suggest but do not prove that the endocannabinoid system is not regulated by serotonergic transmission, at least in depressed patients.
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Affiliation(s)
- Giuseppe Bersani
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Francesca Pacitti
- Department of Clinical Sciences and Applied Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Angela Iannitelli
- Department of Clinical Sciences and Applied Biotechnology, University of L'Aquila, L'Aquila, Italy
| | - Eleonora Caroti
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Adele Quartini
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Dionysios Xenos
- Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Michela Marconi
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Valentina Cuoco
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Benedetta Bigio
- The Rockefeller University, Center for Clinical & Translational Science, New York, New York, USA
| | - Nicole P Bowles
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York, USA
| | - Filippo Weisz
- Department of Physiology and Pharmacology "V. Erspamer", University of Rome "Sapienza", Rome, Italy
| | - Flaminia Fanelli
- University of Bologna, Centre for Applied Biomedical Research, Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Valentina D Di Lallo
- University of Bologna, Centre for Applied Biomedical Research, Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Ilaria Belluomo
- University of Bologna, Centre for Applied Biomedical Research, Policlinico S.Orsola-Malpighi, Bologna, Italy
| | - Ferdinando Nicoletti
- Department of Physiology and Pharmacology "V. Erspamer", University of Rome "Sapienza", Rome, Italy
- IRCCS Neuromed, Pozzilli, Italy
| | - Carla Nasca
- Laboratory of Neuroendocrinology, The Rockefeller University, New York, New York, USA
- Department of Physiology and Pharmacology "V. Erspamer", University of Rome "Sapienza", Rome, Italy
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Wang F, Multhoff G. Repurposing Cannabidiol as a Potential Drug Candidate for Anti-Tumor Therapies. Biomolecules 2021; 11:biom11040582. [PMID: 33921049 PMCID: PMC8071421 DOI: 10.3390/biom11040582] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/07/2021] [Accepted: 04/12/2021] [Indexed: 01/09/2023] Open
Abstract
In recent years, evidence has accumulated that cannabinoids-especially the non-psychoactive compound, cannabidiol (CBD)-possess promising medical and pharmacological activities that might qualify them as potential anti-tumor drugs. This review is based on multiple studies summarizing different mechanisms for how CBD can target tumor cells including cannabinoid receptors or other constituents of the endocannabinoid system, and their complex activation of biological systems that results in the inhibition of tumor growth. CBD also participates in anti-inflammatory activities which are related to tumor progression, as demonstrated in preclinical models. Although the numbers of clinical trials and tested tumor entities are limited, there is clear evidence that CBD has anti-tumor efficacy and is well tolerated in human cancer patients. In summary, it appears that CBD has potential as a neoadjuvant and/or adjuvant drug in therapy for cancer.
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Affiliation(s)
- Fei Wang
- Radiation-Immuno Oncology Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, TU München, Einsteinstr. 25, 81675 Munich, Germany;
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
- Correspondence: ; Tel.: +49-89-4140-4514; Fax: +49-89-4140-4299
| | - Gabriele Multhoff
- Radiation-Immuno Oncology Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, TU München, Einsteinstr. 25, 81675 Munich, Germany;
- Department of Radiation Oncology, Klinikum rechts der Isar, TU München, 81675 Munich, Germany
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38
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Chaves YC, Genaro K, Crippa JA, da Cunha JM, Zanoveli JM. Cannabidiol induces antidepressant and anxiolytic-like effects in experimental type-1 diabetic animals by multiple sites of action. Metab Brain Dis 2021; 36:639-652. [PMID: 33464458 DOI: 10.1007/s11011-020-00667-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022]
Abstract
Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists - 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.
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MESH Headings
- Animals
- Anti-Anxiety Agents/pharmacology
- Anti-Anxiety Agents/therapeutic use
- Antidepressive Agents/pharmacology
- Antidepressive Agents/therapeutic use
- Cannabidiol/pharmacology
- Cannabidiol/therapeutic use
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/psychology
- Diabetes Mellitus, Type 1/chemically induced
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/psychology
- Male
- Maze Learning/drug effects
- Maze Learning/physiology
- Rats
- Rats, Wistar
- Receptor, Cannabinoid, CB1/agonists
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Serotonin, 5-HT1A/metabolism
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Affiliation(s)
- Yane Costa Chaves
- Department of Pharmacology, Biological Science Sector, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Karina Genaro
- Institute of Neurosciences and Behavior (INeC), University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
- Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA
| | - José Alexandre Crippa
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
- National Institute of Science and Technology for Translational Medicine (INCT-TM- CNPq), Ribeirão Preto, São Paulo, Brazil
| | - Joice Maria da Cunha
- Department of Pharmacology, Biological Science Sector, Federal University of Paraná, Curitiba, Paraná, Brazil
- Institute of Neurosciences and Behavior (INeC), University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil
| | - Janaína Menezes Zanoveli
- Department of Pharmacology, Biological Science Sector, Federal University of Paraná, Curitiba, Paraná, Brazil.
- Institute of Neurosciences and Behavior (INeC), University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil.
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39
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Luan D, Zhao MG, Shi YC, Li L, Cao YJ, Feng HX, Zhang ZJ. Mechanisms of repetitive transcranial magnetic stimulation for anti-depression: Evidence from preclinical studies. World J Psychiatry 2020; 10:223-233. [PMID: 33134113 PMCID: PMC7582130 DOI: 10.5498/wjp.v10.i10.223] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/11/2020] [Accepted: 09/02/2020] [Indexed: 02/05/2023] Open
Abstract
This review summarizes the anti-depressant mechanisms of repetitive transcranial magnetic stimulation in preclinical studies, including anti-inflammatory effects mediated by activation of nuclear factor-E2-related factor 2 signaling pathway, anti-oxidative stress effects, enhancement of synaptic plasticity and neurogenesis via activation of the endocannabinoid system and brain derived neurotrophic factor signaling pathway, increasing the content of monoamine neurotransmitters via inhibition of Sirtuin 1/monoamine oxidase A signaling pathway, and reducing the activity of the hypothalamic-pituitary-adrenocortical axis. We also discuss the shortcomings of transcranial magnetic stimulation in preclinical studies such as inaccurate positioning, shallow depth of stimulation, and difficulty in elucidating the neural circuit mechanism up- and down-stream of the stimulation target brain region.
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Affiliation(s)
- Di Luan
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ming-Ge Zhao
- Department of Nursing, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ya-Chen Shi
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ling Li
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yu-Jia Cao
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Hai-Xia Feng
- Department of Nursing, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Zhi-Jun Zhang
- Department of Neurology, Affiliated Zhongda Hospital, Research Institution of Neuropsychiatry, School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
- Department of Psychology, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
- Mental Health Center, Zhejiang University School of Medicine, Hangzhou 310013, Zhejiang province, China
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40
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Pereira SR, Tello Velasquez J, Duggan S, Ivanisevic B, McKenna JP, McCreary C, Downer EJ. Recent advances in the understanding of the aetiology and therapeutic strategies in burning mouth syndrome: Focus on the actions of cannabinoids. Eur J Neurosci 2020; 55:1032-1050. [DOI: 10.1111/ejn.14712] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 02/06/2020] [Accepted: 02/20/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Sónia R. Pereira
- Discipline of Physiology School of Medicine Trinity Biomedical Sciences Institute Trinity College Dublin Dublin 2 Ireland
| | - Johana Tello Velasquez
- Discipline of Physiology School of Medicine Trinity Biomedical Sciences Institute Trinity College Dublin Dublin 2 Ireland
| | - Sarah Duggan
- Discipline of Physiology School of Medicine Trinity Biomedical Sciences Institute Trinity College Dublin Dublin 2 Ireland
| | - Bojana Ivanisevic
- Cork University Dental School and Hospital University College Cork Cork Ireland
| | - Joseph P. McKenna
- Cork University Dental School and Hospital University College Cork Cork Ireland
| | - Christine McCreary
- Cork University Dental School and Hospital University College Cork Cork Ireland
| | - Eric J. Downer
- Discipline of Physiology School of Medicine Trinity Biomedical Sciences Institute Trinity College Dublin Dublin 2 Ireland
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Woelfl T, Rohleder C, Mueller JK, Lange B, Reuter A, Schmidt AM, Koethe D, Hellmich M, Leweke FM. Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Emotion, Cognition, and Attention: A Double-Blind, Placebo-Controlled, Randomized Experimental Trial in Healthy Volunteers. Front Psychiatry 2020; 11:576877. [PMID: 33304282 PMCID: PMC7693539 DOI: 10.3389/fpsyt.2020.576877] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 10/15/2020] [Indexed: 01/31/2023] Open
Abstract
The two main phytocannabinoids-delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)-have been extensively studied, and it has been shown that THC can induce transient psychosis. At the same time, CBD appears to have no psychotomimetic potential. On the contrary, emerging evidence for CBD's antipsychotic properties suggests that it may attenuate effects induced by THC. Thus, we investigated and compared the effects of THC and CBD administration on emotion, cognition, and attention as well as the impact of CBD pre-treatment on THC effects in healthy volunteers. We performed a placebo-controlled, double-blind, experimental trial (GEI-TCP II; ClinicalTrials.gov identifier: NCT02487381) with 60 healthy volunteers randomly allocated to four parallel intervention groups, receiving either placebo, 800 mg CBD, 20 mg THC, or both cannabinoids. Subjects underwent neuropsychological tests assessing working memory (Letter Number Sequencing test), cognitive processing speed (Digit Symbol Coding task), attention (d2 Test of Attention), and emotional state (adjective mood rating scale [EWL]). Administration of CBD alone did not influence the emotional state, cognitive performance, and attention. At the same time, THC affected two of six emotional categories-more precisely, the performance-related activity and extraversion-, reduced the cognitive processing speed and impaired the performance on the d2 Test of Attention. Interestingly, pre-treatment with CBD did not attenuate the effects induced by THC. These findings show that the acute intake of CBD itself has no effect per se in healthy volunteers and that a single dose of CBD prior to THC administration was insufficient to mitigate the detrimental impact of THC in the given setting. This is in support of a complex interaction between CBD and THC whose effects are not counterbalanced by CBD under all circumstances.
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Affiliation(s)
- Timo Woelfl
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Cathrin Rohleder
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Youth Mental Health Team, Brain and Mind Centre, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Juliane K Mueller
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe University Frankfurt, Frankfurt, Germany
| | - Bettina Lange
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anne Reuter
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Anna Maria Schmidt
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Dagmar Koethe
- Youth Mental Health Team, Brain and Mind Centre, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.,Department of Psychosomatics Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Martin Hellmich
- Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - F Markus Leweke
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,Youth Mental Health Team, Brain and Mind Centre, Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
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Wheater M, Baghaie F, Chamseddine S, Awad S. General knowledge of marijuana and kratom in an urban dental patient population: A cross-sectional study. J Int Oral Health 2020. [DOI: 10.4103/jioh.jioh_9_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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