시티콜린

Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

1. J Nutr. 2021 Aug 7;151(8):2153-2160. doi: 10.1093/jn/nxab119. Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Nakazaki E(1), Mah E(2), Sanoshy K(2), Citrolo D(3), Watanabe F(1). Author information: (1)Research & Innovation

Citicoline (CDP-choline) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke.

2. J Neurochem. 2013 Sep;126(6):819-26. doi: 10.1111/jnc.12269. Epub 2013 May 13. Citicoline (CDP-choline) increases Sirtuin1 expression concomitant to neuroprotection in experimental stroke. Hurtado O(1), Hernández-Jiménez M, Zarruk JG, Cuartero MI, Ballesteros I, Camarero G, Moraga A, Pradillo

Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

3. Cochrane Database Syst Rev. 2005 Apr 18;2005(2):CD000269. doi: 10.1002/14651858.CD000269.pub3. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Fioravanti M(1), Yanagi M. Author information: (1)Depart

Lifestyle-based interventions targeting neurocognition in bipolar disorders - a systematic review of randomized controlled trials.

1. Psychiatry Res. 2025 Sep;351:116618. doi: 10.1016/j.psychres.2025.116618. Epub 2025 Jun 30. Lifestyle-based interventions targeting neurocognition in bipolar disorders - a systematic review of randomized controlled trials. Balanzá-Martínez V(1), Galdámez-Huertas A(2), Sánchez-Ortí JV(3), Kapczinski F(4), De Boni RB(5), Pomarol-Clotet E(6), Van Rheenen TE(7). Author information: (1)Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, University of Valencia, Avda Blasco Ibáñez, 15, 46010 Valencia, Spain; VALSME (Valencia Estigma i Salut Mental), University of Valencia, Avda Blasco Ibáñez, 15, 46010 Valencia, Spain; Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. Pabellón 11. 28029 Madrid, Spain; INCLIVA Health Research Institute, Menéndez y Pelayo, 4, 46010 Valencia, Spain. Electronic address: vicente.balanza@uv.es. (2)Medical School, University of Valencia, Avda Blasco Ibáñez, 15, 46010 Valencia, Spain. (3)Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. Pabellón 11. 28029 Madrid, Spain; INCLIVA Health Research Institute, Menéndez y Pelayo, 4, 46010 Valencia, Spain. (4)Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil. Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos 2350, Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Psiquiatria e Ciências do Comportamento, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos 2400, Porto Alegre, RS, Brazil; Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1280 Main St. West, Hamilton, ON, L8S 4L8, Canada. (5)Institute of Scientific and Technological Communication and Information in Health (ICICT), Oswaldo Cruz Foundation (FIOCRUZ), 4365 Manguinhos, Rio de Janeiro, Brazil. (6)Centro de Investigación Biomédica en red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5. Pabellón 11. 28029 Madrid, Spain; FIDMAG Hermanas Hospitalarias Research Foundation, Dr Pujadas 38, 08830 Sant Boi de Llobregat, Barcelona, Spain. (7)Department of Psychiatry, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Level 3, Alan Gilbert Building, 161 Barry St, Carlton Vic 3053, Melbourne, Australia; Centre for Mental Health and Brain Sciences, Swinburne University of Technology, Melbourne Australia. INTRODUCTION: A substantial proportion of individuals with bipolar disorder (BD) show some degree of cognitive impairment. Emerging evidence suggests that lifestyle-based interventions (LBIs) can improve clinical outcomes in BD, although few studies have assessed their efficacy on cognition. AIM: To evaluate the methodological quality and efficacy of randomized controlled trials (RCTs) comprising LBIs for improving cognition in people with BD. METHODS: A systematic search following PRISMA guidelines. PubMed, Embase, Scopus, Web of Science, PsycINFO and ClinicalTrials.gov were searched from inception until February 1st, 2024. RCTs examining the effects of LBIs on cognition, assessed by validated neuropsychological tests, in individuals with BD (of any age, mood or comorbidity) were eligible. Risk of bias and methodological quality were assessed with the Cochrane RoB 2 tool and the PEDro scale, respectively. Results were narratively synthesized. RESULTS: Seven RCTs ( = 275) were included, each targeting one lifestyle domain. Six assessed nutraceuticals (e.g., vitamins B1/B6, DHA, NAC, citicoline, creatine) and one evaluated a mind-body intervention (Tai Chi/Qigong). Two RCTs reported pro-cognitive effects of nutraceuticals: citicoline was associated with improvements in declarative memory and verbal learning, and creatine with improved verbal fluency. Mean intervention duration was 12 weeks. Cognition was a primary outcome in three RCTs. Overall, methodological quality was high, and risk of bias was low. CONCLUSION: Specific nutraceuticals may offer pro-cognitive effects for BD. However, the evidence is limited by the small number of included studies and substantial heterogeneity in populations, interventions, and cognitive assessments. Future studies should examine whole-diet, physical activity/exercise and multimodal LBIs. Copyright © 2025. Published by Elsevier B.V. DOI: 10.1016/j.psychres.2025.116618 PMID: 40639301 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors have nothing to declare.

Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis "Nutra NMA SCZ".

2. Mol Psychiatry. 2025 Jan;30(1):168-187. doi: 10.1038/s41380-024-02645-y. Epub 2024 Jul 18. Nutraceuticals and phytoceuticals in the treatment of schizophrenia: a systematic review and network meta-analysis "Nutra NMA SCZ". Fornaro M(#)(1), Caiazza C(#)(2), Billeci M(2), Berk M(3)(4)(5)(6)(7), Marx W(8), Balanzá-Martinez V(9), De Prisco M(10), Pezone R(2), De Simone G(2), Solini N(2), Iasevoli F(2)(11), Berna F(12), Fond G(13)(14), Boyer L(13)(14), Carvalho AF(15), Dragioti E(16), Fiedorowicz JG(17)(18)(19), de Bartolomeis A(2)(11), Correll CU(20)(21)(22)(23), Solmi M(17)(18)(19)(23). Author information: (1)Department of Neuroscience, Reproductive Sciences, and Dentistry, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy. dott.fornaro@gmail.com. (2)Department of Neuroscience, Reproductive Sciences, and Dentistry, Section of Psychiatry, University School of Medicine Federico II, Naples, Italy. (3)Deakin University, IMPACT, the Institute for Mental and Physical Health and Clinical Translation Strategic Research Centre, School of Medicine, Geelong, VIC, Australia. (4)Mental Health Drug and Alcohol Services, Barwon Health, Geelong, VIC, Australia. (5)Orygen, The National Centre of Excellence in Youth Mental Health, Melbourne, VIC, Australia. (6)Centre for Youth Mental Health, Florey Institute for Neuroscience and Mental Health, Melbourne, VIC, Australia. (7)Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia. (8)Food & Mood Centre, Deakin University, IMPACT (the Institute for Mental and Physical Health and Clinical Translation), Geelong, VIC, Australia. (9)Teaching Unit of Psychiatry and Psychological Medicine, Department of Medicine, Centro de Investigación Biomédica En Red de Salud Mental (CIBERSAM), University of Valencia, Valencia, Spain. (10)Bipolar and Depressive Disorders Unit, Institute of Neuroscience, Hospital Clinic, CIBERSAM, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain. (11)Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Odontostomatology, University Medical School of Naples "Federico II", Naples, Italy. (12)Department of Psychiatry, Strasbourg University Hospital, University of Strasbourg, Strasbourg, France. (13)CEReSS-Health Service Research and Quality of Life Center, UR3279, Assistance Publique des Hôpitaux de Marseille, Aix-Marseille University, Marseille, France. (14)Fondation FondaMental Fondation de Coopération Scientifique en Santé Mentale, Université Paris Est, Créteil, France. (15)Innovation in Mental and Physical Health and Clinical Treatment (IMPACT) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia. (16)Pain and Rehabilitation Center, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden. (17)Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada. (18)Department of Mental Health, The Ottawa Hospital, Ottawa, ON, Canada. (19)Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada. (20)Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA. (21)Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. (22)Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA. (23)Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany. (#)Contributed equally Update of Res Sq. 2024 Jan 12:rs.3.rs-3787917. doi: 10.21203/rs.3.rs-3787917/v1. Sub-optimal response in schizophrenia is frequent, warranting augmentation strategies over treatment-as-usual (TAU). We assessed nutraceuticals/phytoceutical augmentation strategies via network meta-analysis. Randomized controlled trials in schizophrenia/schizoaffective disorder were identified via the following databases: PubMed, MEDLINE, EMBASE, Scopus, PsycINFO, CENTRAL, and ClinicalTrials.gov. Change (Standardized Mean Difference = SMD) in total symptomatology and acceptability (Risk Ratio = RR) were co-primary outcomes. Secondary outcomes were positive, negative, cognitive, and depressive symptom changes, general psychopathology, tolerability, and response rates. We conducted subset analyses by disease phase and sensitivity analyses by risk of bias and assessed global/local inconsistency, publication bias, risk of bias, and confidence in the evidence. The systematic review included 49 records documenting 50 studies (n = 2384) documenting 22 interventions. Citicoline (SMD =-1.05,95%CI = -1.85; -0.24), L-lysine (SMD = -1.04,95%CI = -1.84; -0.25), N-acetylcysteine (SMD = -0.87, 95%CI = -1.27; -0.47) and sarcosine (SMD = -0.5,95%CI = -0.87-0.13) outperformed placebo for total symptomatology. High heterogeneity (tau2 = 0.10, I2 = 55.9%) and global inconsistency (Q = 40.79, df = 18, p = 0.002) emerged without publication bias (Egger's test, p = 0.42). Sarcosine improved negative symptoms (SMD = -0.65, 95%CI = -1.10; -0.19). N-acetylcysteine improved negative symptoms (SMD = -0.90, 95%CI = -1.42; -0.39)/general psychopathology (SMD = -0.76, 95%CI = -1.39; -0.13). No compound improved total symptomatology within acute phase studies (k = 7, n = 422). Sarcosine (SMD = -1.26,95%CI = -1.91; -0.60), citicoline (SMD = -1.05,95%CI = -1.65;-0.44), and N-acetylcysteine (SMD = -0.55,95%CI = -0.92,-0.19) outperformed placebo augmentation in clinically stable participants. Sensitivity analyses removing high-risk-of-bias studies confirmed overall findings in all phases and clinically stable samples. In contrast, the acute phase analysis restricted to low risk-of-bias studies showed a superior effect vs. placebo for N-acetylcysteine (SMD = -1.10, 95%CI = -1.75,-0.45), L-lysine (SMD = -1.05,95%CI = -1.55, -0.19), omega-3 fatty acids (SMD = -0.83,95%CI = -1.31, -0.34) and withania somnifera (SMD = -0.71,95%CI = -1.21,-0.22). Citicoline (SMD = -1.05,95%CI = -1.86,-0.23), L-lysine (SMD = -1.04,95%CI = -1.84,-0.24), N-acetylcysteine (SMD = -0.89,95%CI = -1.35,-0.43) and sarcosine (SMD = -0.61,95%CI = -1.02,-0.21) outperformed placebo augmentation of TAU ("any phase"). Drop-out due to any cause or adverse events did not differ between nutraceutical/phytoceutical vs. placebo+TAU. Sarcosine, citicoline, and N-acetylcysteine are promising augmentation interventions in stable patients with schizophrenia, yet the quality of evidence is low to very low. Further high-quality trials in acute phases/specific outcomes/difficult-to-treat schizophrenia are warranted. © 2024. The Author(s), under exclusive licence to Springer Nature Limited. DOI: 10.1038/s41380-024-02645-y PMID: 39026098 [Indexed for MEDLINE] Conflict of interest statement: Competing interests: MF received honoraria for his speaker activity from the American Society of Clinical Psychopharmacology (ASCP) and served as a consultant for Angelini, Otsuka, Lundbeck, Sanofi-Aventis, and Boehringer Ingelheim. WM has previously received university grants/fellowships from La Trobe University, Deakin University, University of Queensland, and Bond University. WM has received funding and/or has attended events funded by Cobram Estate Pty. Ltd and Bega Dairy and Drinks Pty Ltd. WM has received travel funding from the Nutrition Society of Australia. WM has received consultancy funding from Nutrition Research Australia and ParachuteBH. MS has received honoraria/has been a consultant for AbbVie, Angelini, Lundbeck, and Otsuka. VBM received honoraria from Angelini, unrelated to the present work. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Car dio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. All other authors declare no conflicts of interest relevant to this work.

The acute dose and baseline amplitude-dependent effects of CDP-choline on deviance detection (MMN) in chronic schizophrenia: A pilot study.

3. Exp Clin Psychopharmacol. 2022 Apr;30(2):235-248. doi: 10.1037/pha0000418. Epub 2021 Feb 25. The acute dose and baseline amplitude-dependent effects of CDP-choline on deviance detection (MMN) in chronic schizophrenia: A pilot study. Aidelbaum R(1), Labelle A(2), Choueiry J(3), Knott V(3). Author information: (1)Clinical Neuroscience of Schizophrenia Laboratory. (2)Schizophrenia Program. (3)Clinical Neuroelectrophysiology & Cognitive Research Laboratory. The detection of deviant auditory features is empirically supported as impaired in schizophrenia and has been shown to associate with functional outcome. Modulated by glutamate neurotransmission, this sensory process has also been shown to relate to the α7 nicotinic acetylcholine receptor (nAChR) system, a prioritized molecular target for the development of novel cognition targeted pharmacological treatments. This pilot study assessed the acute effects of CDP-Choline, a choline supplement with α7 nAChR agonist properties, on the mismatch negativity (MMN), an event-related potential index of the detection of an acoustic change, in a sample of individuals diagnosed with chronic schizophrenia. Utilizing a randomized, placebo-controlled, double-blind design, the dose-dependent (500 mg, 1,000 mg, 2,000 mg), baseline amplitude-dependent (low vs. high), and deviant feature-dependent effects of CDP-Choline on the MMN were examined. CDP-choline's effects interacted with dosage, deviance feature, and baseline amplitude with low baseline amplitude patients demonstrating enhanced MMNs, and high baseline amplitude patients demonstrating suppressed MMNs in response to CDP-Choline. These findings offer tentative support for the involvement of the α7 nAChR system in auditory MMN abnormalities in schizophrenia and supports further research assessing the effects of long-term treatment with CDP-Choline in the personalized treatment of auditory deviance processing impairments. (PsycInfo Database Record (c) 2022 APA, all rights reserved). DOI: 10.1037/pha0000418 PMID: 33630646 [Indexed for MEDLINE]

[Clinical observation on post-stroke oculomotor nerve palsy treated with the interaction of twelve meridian muscle regions and contralateral needling therapy].

4. Zhongguo Zhen Jiu. 2020 Aug 12;40(8):805-9. doi: 10.13703/j.0255-2930.20190514-k0006. [Clinical observation on post-stroke oculomotor nerve palsy treated with the interaction of twelve meridian muscle regions and contralateral needling therapy]. [Article in Chinese] Liu XX(1), Wu JY(2), Zhao Y(1). Author information: (1)Clinic Department of Acupuncture-Moxibustion, First Teaching Hospital of Tianjin University of TCM/National Clinical Medical Research Center of Acupuncture-Moxibustion in TCM, Tianjin 300000, China. (2)Department of TCM, Tianjin Huanhu Hospital. OBJECTIVE: To observe the clinical effect on post-stroke oculomotor nerve palsy treated with the interaction of twelve meridian muscle regions and contralateral needling therapy. METHODS: A total of 46 patients with post-stroke oculomotor nerve palsy were randomized into an observation group and a control group, 23 cases in each one. In the control group, the intramusclar injection of mecobalamine at the buttock region was given, 1 mL each time, once every two days, 3 times weekly. Besides, citicoline sodium capsules were prescribed for oral administration, 0.2 g each time, 3 times daily. In the observation group, on the base of the treatment as the control group, the interaction of twelve meridian muscle regions and contralateral needling therapy was supplemented. Acupoints on the health sides included Juliao (ST 3) and Hanyan (GB 4), acupoints on the affected side included Jingming (BL 1), Sibai (ST 2), Yangbai (GB 14), Cuanzhu (BL 2), Shangming (Extra), Sizhukong (TE 23), Tongziliao (GB 1) and bilateral Fengchi (GB 20), Quchi (LI 11), Pianli (LI 6), Waiguan (TE 5), Hegu (LI 4) were selected. The needles were retained for 30 min in each acupuncture treatment, once a day, 5 times weekly. The treatment for 4 weeks was required in the two groups. Before and after treatment, the score of cervical range of motion (CROM), pupil size, eye fissure width and eyeball mobility were observed in the patients of the two groups. The clinical effect was evaluated in the two groups. RESULTS: After treatment, CROM scores and pupil size were reduced in the patients of the two groups (P<0.05), and the values in the observation group were lower than the control group (P<0.05). The eye fissure width and eyeball mobility were increased in the two groups (P<0.05), the eye fissure width and the mobility of the muscles of rectus internus, inferior rectus and inferior oblique in the observation group were larger than the control group (P<0.05). The effective rate was 82.6% (19/23) in the observation group, higher than 65.2% (15/23) in the control group (P<0.05). CONCLUSION: The interaction of twelve meridian muscle regions and contrallateral needling therapy effectively relieves diplopia, pupil dilation, narrow eye fissure and limited eyeball mobility in the patients with post-stroke oculomotor nerve palsy. DOI: 10.13703/j.0255-2930.20190514-k0006 PMID: 32869586 [Indexed for MEDLINE]

Consumption of plant extract supplement reduces platelet activating factor-induced platelet aggregation and increases platelet activating factor catabolism: a randomised, double-blind and placebo-controlled trial.

5. Br J Nutr. 2019 May;121(9):982-991. doi: 10.1017/S0007114519000308. Epub 2019 Apr 3. Consumption of plant extract supplement reduces platelet activating factor-induced platelet aggregation and increases platelet activating factor catabolism: a randomised, double-blind and placebo-controlled trial. Gavriil L(1), Detopoulou M(1), Petsini F(1), Antonopoulou S(1), Fragopoulou E(1). Author information: (1)Department of Nutrition and Dietetics,Harokopio University,70 Eleftheriou Venizelou Avenue Kallithea,17671Athens,Greece. Platelet-activating factor (PAF) is a potent mediator of inflammation that plays a crucial role in atherosclerosis. The purpose of this study was to evaluate the effect of a dietary supplement containing mainly plant extracts on PAF actions and metabolism in healthy volunteers. A double-blind, placebo-controlled, 8 weeks' duration study was performed. Healthy volunteers were randomly allocated into the supplement or the placebo group and fifty-eight of them completed the study. The supplement contained plant extracts (Aloe gel, grape juice, Polygonum cuspidatum) and vitamins. The activities of PAF metabolic enzymes: the two isoforms of acetyl-CoA:lyso-PAF acetyltransferase, cytidine 5'-diphospho-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-cholinephosphotransferase) and platelet-activating factor-acetylhydrolase (PAF-AH) in leucocytes and lipoprotein associated phospholipase-A2 in plasma were measured along with several markers of endothelial function. Platelet aggregation against PAF, ADP and thrombin receptor activating peptide was measured in human platelet-rich plasma by light transmission aggregometry. No difference was observed on soluble vascular cell adhesion molecule-1, sP-selectin and IL-6 levels at the beginning or during the study period between the two groups. Concerning PAF metabolism enzymes' activity, no difference was observed at baseline between the groups. PAF-AH activity was only increased in the supplement group at 4 and 8 weeks compared with baseline levels. In addition, supplement consumption led to lower platelet sensitivity against PAF and ADP compared with baseline levels. However, a trial effect was only observed when platelets were stimulated by PAF. In conclusion, supplementation with plant extracts and vitamins ameliorates platelet aggregation primarily against PAF and secondarily against ADP and affects PAF catabolism by enhancing PAF-acetylhydrolase activity in healthy subjects. DOI: 10.1017/S0007114519000308 PMID: 30940217 [Indexed for MEDLINE]

A Randomized, Double-Blind, Placebo-Controlled Trial of Citicoline in Patients with Alcohol Use Disorder.

6. Alcohol Clin Exp Res. 2019 Feb;43(2):317-323. doi: 10.1111/acer.13928. Epub 2018 Dec 24. A Randomized, Double-Blind, Placebo-Controlled Trial of Citicoline in Patients with Alcohol Use Disorder. Brown ES(1), Van Enkevort E(1), Kulikova A(1), Escalante C(1), Nakamura A(1), Ivleva EI(1), Holmes T(1). Author information: (1)Department of Psychiatry(ESB, EVE, AK, CE, AN, EII, TH), The University of Texas Southwestern Medical Center, Dallas, Texas. BACKGROUND: Alcohol use disorder is a major societal and individual burden that exacerbates health outcomes, decreases quality of life, and negatively affects U.S. healthcare spending. Although pharmacological treatments are available for alcohol use disorder, many of them are limited by small effect sizes and used infrequently. Citicoline is a widely available over-the-counter supplement with a favorable side effect profile. It acts through cholinergic pathways and phospholipid metabolism. The current report examines the effect of oral citicoline on alcohol use, craving, depressive symptoms, and cognitive outcomes in individuals with alcohol use disorder. METHODS: A 12-week, randomized, double-blind, parallel-group, placebo-controlled, pilot study of citicoline (titrated to 2,000 mg/d) in 62 adults (age 18 to 75) with alcohol use disorder was conducted. Alcohol use, such as number of drinking days, amount used, and number of heavy drinking days, was assessed using the Timeline Followback method and liver enzymes, while alcohol craving was measured using the Penn Alcohol Craving Scale. A neurocognitive battery (e.g., Rey Auditory Verbal Learning Test) and depressive symptoms scale (e.g., Inventory of Depressive Symptomatology Self-Report) scores were also collected. Data were analyzed using a random regression analysis. RESULTS: The primary outcome analysis was conducted in the intent-to-treat sample and consisted of 55 participants (78.2% men and 21.8% women, mean age of 46.47 ± 9.15 years). In the assessment period, the drinking days, on average, represented 77% of the assessed days. Significant between-group differences were not observed on alcohol use, craving, and cognitive or depressive symptom measures. Citicoline was well tolerated. CONCLUSIONS: This proof-of-concept study observed that citicoline was well tolerated, but was not associated with a reduction in alcohol use or other outcomes, as compared to placebo. The favorable effects reported with citicoline for cocaine use, cognitive disorders, and other conditions do not appear to extend to alcohol use disorder. © 2018 by the Research Society on Alcoholism. DOI: 10.1111/acer.13928 PMCID: PMC6370505 PMID: 30457668 [Indexed for MEDLINE] Conflict of interest statement: Conflict of Interest: Dr. Brown has recent research grants from NIH, The Stanley Medical Research Institute and Otsuka. Dr. Ivleva has research grants from NIH. All other authors have no conflicts of interest to declare.

Assessing the acute effects of CDP-choline on sensory gating in schizophrenia: A pilot study.

7. J Psychopharmacol. 2018 May;32(5):541-551. doi: 10.1177/0269881117746903. Epub 2018 Jan 17. Assessing the acute effects of CDP-choline on sensory gating in schizophrenia: A pilot study. Aidelbaum R(1)(2), Labelle A(3), Baddeley A(1), Knott V(1). Author information: (1)1 Clinical Neuroelectrophysiology and Cognitive Research Laboratory, University of Ottawa Institute of Mental Health Research, ON, Canada. (2)2 Department of Psychology, Carleton University, ON, Canada. (3)3 Schizophrenia Program, Royal Ottawa Mental Health Centre, ON, Canada. Deficient sensory gating (SG) in schizophrenia is associated with functional outcome and offers a therapeutic target as it is linked to the altered function/expression of the α7 nicotinic acetylcholine receptors (nAChRs). This study analyzed the effects of citicoline (CDP-choline), a supplement with α7 nAChRs agonist properties, on SG in a sample of schizophrenia (SZ) patients. Using a randomized, placebo-controlled, double-blind design the dose-dependent (500 mg, 1000 mg, 2000 mg) and baseline-dependent (deficient versus normal suppressors) effects of CDP-choline on SG were examined using the P50 event-related potential (ERP) index of SG. Overall analysis failed to demonstrate treatment effects but CDP-choline improved SG (500 mg) in the deficient SZ subgroup by increasing suppression of the S2 P50 amplitude. These findings tentatively support α7 nAChR dysfunction in the expression of SG deficits and suggest further trials to assess the effects of sustained α7 nAChR activation on SG with low doses of CDP-choline. DOI: 10.1177/0269881117746903 PMID: 29338621 [Indexed for MEDLINE]

The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males.

8. J Atten Disord. 2019 Jan;23(2):121-134. doi: 10.1177/1087054715593633. Epub 2015 Jul 15. The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males. McGlade E(1), Agoston AM(1), DiMuzio J(1), Kizaki M(2), Nakazaki E(2), Kamiya T(3), Yurgelun-Todd D(1). Author information: (1)1 University of Utah, Salt Lake City, UT, USA. (2)2 KYOWA HAKKO BIO CO., LTD, Tsukuba, Ibaraki, Japan. (3)3 KYOWA HAKKO U.S.A., INC., New York, NY, USA. OBJECTIVE: This study assessed the effects of citicoline, a nutraceutical, on attention, psychomotor function, and impulsivity in healthy adolescent males. METHOD: Seventy-five healthy adolescent males were randomly assigned to either the citicoline group ( n = 51 with 250 or 500 mg citicoline) or placebo ( n = 24). Participants completed the Ruff 2&7 Selective Attention Test, Finger Tap Test, and the Computerized Performance Test, Second Edition (CPT-II) at baseline and after 28 days of supplementation. RESULTS: Individuals receiving citicoline exhibited improved attention ( p = 0.02) and increased psychomotor speed ( p = 0.03) compared with those receiving placebo. Higher weight-adjusted dose significantly predicted increased accuracy on an attention task ( p = 0.01), improved signal detectability on a computerized attention task ( p = 0.03), and decreased impulsivity ( p = 0.01). DISCUSSION: Adolescent males receiving 28 days of Cognizin® citicoline showed improved attention and psychomotor speed and reduced impulsivity compared to adolescent males who received placebo. DOI: 10.1177/1087054715593633 PMID: 26179181 [Indexed for MEDLINE]

CDP-choline: effects of the procholine supplement on sensory gating and executive function in healthy volunteers stratified for low, medium and high P50 suppression.

9. J Psychopharmacol. 2014 Dec;28(12):1095-108. doi: 10.1177/0269881114553254. Epub 2014 Oct 14. CDP-choline: effects of the procholine supplement on sensory gating and executive function in healthy volunteers stratified for low, medium and high P50 suppression. Knott V(1), Smith D(2), de la Salle S(3), Impey D(3), Choueiry J(2), Beaudry E(3), Smith M(3), Saghir S(3), Ilivitsky V(4), Labelle A(4). Author information: (1)Institute of Mental Health Research, University of Ottawa, Ottawa, ON, Canada Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada School of Psychology, University of Ottawa, Ottawa, ON, Canada Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada Verner.Knott@theroyal.ca. (2)Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada. (3)School of Psychology, University of Ottawa, Ottawa, ON, Canada. (4)Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada. Diminished auditory sensory gating and associated neurocognitive deficits in schizophrenia have been linked to altered expression and function of the alpha-7 nicotinic acetycholinergic receptor (α7 nAChR), the targeting of which may have treatment potential. Choline is a selective α7 nAChR agonist and the aim of this study was to determine whether cytidine 5'-diphosphocholine (CDP-choline), or citicoline, a dietary source of choline, increases sensory gating and cognition in healthy volunteers stratified for gating level. In a randomized, placebo-controlled, double-blind design involving acute administration of low, moderate doses (500 mg, 1000 mg) of CDP-choline, 24 healthy volunteers were assessed for auditory gating as indexed by suppression of the P50 event-related potential (ERP) in a paired-stimulus (S1, S2) paradigm, and for executive function as measured by the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery. CDP-choline improved gating (1000 mg) and suppression of the S2 P50 response (500 mg, 1000 mg), with the effects being selective for individuals with low gating (suppression) levels. Tentative support was also shown for increased GMLT performance (500 mg) in low suppressors. These preliminary findings with CDP-choline in a healthy, schizophrenia-like surrogate sample are consistent with a α7 nAChR mechanism and support further trials with choline as a pro-cognitive strategy. © The Author(s) 2014. DOI: 10.1177/0269881114553254 PMID: 25315828 [Indexed for MEDLINE]

Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women.

10. Am J Clin Nutr. 2013 Dec;98(6):1459-67. doi: 10.3945/ajcn.113.066092. Epub 2013 Oct 16. Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women. Yan J(1), Jiang X, West AA, Perry CA, Malysheva OV, Brenna JT, Stabler SP, Allen RH, Gregory JF 3rd, Caudill MA. Author information: (1)Division of Nutritional Sciences, Cornell University, Ithaca, NY (JY, XJ, AAW, OVM, JTB, and MAC); the Family & Consumer Sciences-Nutrition, Shepherd University, Shepherdstown, WV (CAP); the Department of Medicine and Division of Hematology, University of Colorado School of Medicine, Aurora, CO (SPS and RHA); and the Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL (JFG). BACKGROUND: Although biomarkers of choline metabolism are altered by pregnancy, little is known about the influence of human pregnancy on the dynamics of choline-related metabolic processes. OBJECTIVE: This study used stable isotope methodology to examine the effects of pregnancy on choline partitioning and the metabolic activity of choline-related pathways. DESIGN: Healthy third-trimester pregnant (n = 26; initially week 27 of gestation) and nonpregnant (n = 21) women consumed 22% of their total choline intake (480 or 930 mg/d) as methyl-d9-choline for the final 6 wk of a 12-wk feeding study. RESULTS: Plasma d9-betaine:d9-phosphatidylcholine (PC) was lower (P ≤ 0.04) in pregnant than in nonpregnant women, suggesting greater partitioning of choline into the cytidine diphosphate-choline (CDP-choline) PC biosynthetic pathway relative to betaine synthesis during pregnancy. Pregnant women also used more choline-derived methyl groups for PC synthesis via phosphatidylethanolamine N-methyltransferase (PEMT) as indicated by comparable increases in PEMT-PC enrichment in pregnant and nonpregnant women despite unequal (pregnant > nonpregnant; P < 0.001) PC pool sizes. Pregnancy enhanced the hydrolysis of PEMT-PC to free choline as shown by greater (P < 0.001) plasma d3-choline:d3-PC. Notably, d3-PC enrichment increased (P ≤ 0.011) incrementally from maternal to placental to fetal compartments, signifying the selective transfer of PEMT-PC to the fetus. CONCLUSIONS: The enhanced use of choline for PC production via both the CDP-choline and PEMT pathways shows the substantial demand for choline during late pregnancy. Selective partitioning of PEMT-PC to the fetal compartment may imply a unique requirement of PEMT-PC by the developing fetus. DOI: 10.3945/ajcn.113.066092 PMCID: PMC6410899 PMID: 24132975 [Indexed for MEDLINE]

A randomized, double-blind, placebo-controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence.

11. J Affect Disord. 2012 Dec 20;143(1-3):257-60. doi: 10.1016/j.jad.2012.05.006. Epub 2012 Sep 11. A randomized, double-blind, placebo-controlled trial of citicoline for bipolar and unipolar depression and methamphetamine dependence. Brown ES(1), Gabrielson B. Author information: (1)Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8849, USA. Sherwood.Brown@UTSouthwestern.edu BACKGROUND: Methamphetamine use disorders are common and severe problems. Persons with mood disorders, particularly bipolar disorder, have high rates of substance use disorders. We previously reported promising findings on drug use, memory and study retention in patients with a history of mania and cocaine dependence given the nutritional supplement citicoline. In the current proof-of-concept study, we examined citicoline in bipolar or unipolar depression and methamphetamine dependence. METHODS: Sixty adults with bipolar depression or major depressive disorder and methamphetamine dependence were randomized to citicoline (2000mg/day) or placebo for 12 weeks. Mood was assessed using Inventory of Depressive Symptomatology-Clinician Version (IDS-C), and cognition with the Hopkins Auditory Verbal Learning Test (HVLT). Drug use was assessed by urine drug screens. RESULTS: An ANCOVA of the intent-to-treat sample showed that those receiving citicoline (n=28) had a statistically significantly greater improvement in IDS-C scores than those receiving placebo (n=20). Survival in the study was significantly longer and completion rates significantly greater with citicoline than placebo. No significant differences were observed in memory or methamphetamine use. Citicoline was well tolerated. LIMITATIONS: Sample heterogeneity and small sample size were limitations. CONCLUSIONS: To our knowledge this is the first placebo-controlled trial in a dual diagnosis sample with methamphetamine use disorders. Findings suggest that citicoline may have antidepressant properties in this population. Greater treatment retention with citicoline is also noteworthy in a patient population with substance dependence. Larger trials targeting depressive symptoms and treatment retention seem warranted. Copyright © 2012 Elsevier B.V. All rights reserved. DOI: 10.1016/j.jad.2012.05.006 PMID: 22974472 [Indexed for MEDLINE]

Improvements in quantitative EEG following consumption of a natural citicoline-enhanced beverage.

12. Int J Food Sci Nutr. 2012 Jun;63(4):421-5. doi: 10.3109/09637486.2011.632623. Epub 2011 Nov 7. Improvements in quantitative EEG following consumption of a natural citicoline-enhanced beverage. Bruce SE(1). Author information: (1)Department of Psychology, University of Missouri-St. Louis, MO 63121-4499, USA. brucese@umsl.edu The present study examined the impact of a taurine-free drink enhanced with citicoline and other natural ingredients on electrophysiological markers of mental alertness. Ten healthy adult participants enrolled in a double-blind, placebo-controlled crossover study and were randomized to receive either placebo or the citicoline supplement on the first visit. Measures of electrical brain activity using electroencephalogram (EEG) were collected 30 min after consuming the beverage. Seven days after the initial assessment participants completed the alternative condition (placebo or citicoline beverage). Compared to placebo, significant improvements were found in frontal alpha EEG and N100 event related potentials (ERP) associated with the citicoline-enhanced supplement. These preliminary findings suggest that a novel brain drink containing compounds known to increase choline in the brain significantly improved attention as measured by ERP and EEG. These findings suggest that a viable and alternative brain supplement without potential compounds such as taurine may augment attentional mechanisms in healthy individuals. DOI: 10.3109/09637486.2011.632623 PMID: 22578105 [Indexed for MEDLINE]

Efficacy of citicoline as an acute stroke treatment.

13. Expert Opin Pharmacother. 2009 Apr;10(5):839-46. doi: 10.1517/17460440902835475. Efficacy of citicoline as an acute stroke treatment. Clark WM(1). Author information: (1)Department of Neurology CR131, Oregon Health Sciences University, Oregon Stroke Center, Portland, OR97201, USA. Clarkw@ohsu.edu Citicoline (cytidine-5'-diphosphocholine or CDP-choline) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischemia to free fatty acids and free radicals. Animal studies suggest that citicoline may protect cell membranes by accelerating resynthesis of phospholipids and suppressing the release of free fatty acids, stabilizing cell membranes, and reducing free radical generation. Numerous experimental stroke studies with citicoline have shown improved outcome and reduced infarct size in both ischemic and hemorrhagic stroke models. Citicoline has been studied worldwide in both ischemic and hemorrhagic clinical stroke with excellent safety and possibly efficacy found in several trials. A meta-analysis of four randomized US clinical citicoline trials concluded that treatment with oral citicoline within the first 24 h after a moderate to severe stroke is safe and increases the probability of complete recovery at 3 months. Citicoline clinical efficacy trials are now continuing outside of the US in both ischemic and hemorrhagic stroke. A citicoline supplement is now available from several sources on the internet. DOI: 10.1517/17460440902835475 PMID: 19351232 [Indexed for MEDLINE]

Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair.

14. Rev Neurol Dis. 2008 Fall;5(4):167-77. Citicoline: update on a promising and widely available agent for neuroprotection and neurorepair. Saver JL(1). Author information: (1)UCLA Stroke Center and Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Choline precursors promote repair and growth of cell membranes and hold promise in a variety of neurologic diseases, including ischemic and hemorrhagic stroke. Citicoline, the most well-studied choline agent precursor, is widely prescribed throughout the world and recently became available in the United States as a dietary supplement. In experimental stroke models, citicoline conferred acute neuroprotection and enhanced neuroplasticity and neurorepair in the subacute period. Although individual human stroke trials have been inconclusive, meta-analysis of 10 trials enrolling 2279 patients suggests patients receiving citicoline had substantially reduced frequencies of death and disability. Reinvestigation of citicoline with modern neuroimaging and clinical trial methods are underway and will provide more definitive information regarding the mechanistic and clinical effects of this promising neurotherapeutic agent. PMID: 19122569 [Indexed for MEDLINE]