Park SK et al. A combination of green tea extract and L-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food. 2011 Apr;14(4):334-43. ABSTRACT: A combination of green tea extract and L-theanine (LGNC-07) has been reported to have beneficial effects on cognition in animal studies. In this randomized, double-blind, placebo-controlled study, the effect of LGNC-07 on memory and attention in subjects with mild cognitive impairment (MCI) was investigated. Ninety-one MCI subjects whose Mini Mental State Examination-K (MMSE-K) scores were between 21 and 26 and who were in either stage 2 or 3 on the Global Deterioration Scale were enrolled in this study. The treatment group (13 men, 32 women; 57.58 ± 9.45 years) took 1,680 mg of LGNC-07, and the placebo group (12 men, 34 women; 56.28 ± 9.92 years) received an equivalent amount of maltodextrin and lactose for 16 weeks. Neuropsychological tests (Rey-Kim memory test and Stroop color-word test) and electroencephalography were conducted to evaluate the effect of LGNC-07 on memory and attention. Further analyses were stratified by baseline severity to evaluate treatment response on the degree of impairment (MMSE-K 21-23 and 24-26). LGNC-07 led to improvements in memory by marginally increasing delayed recognition in the Rey-Kim memory test (P .0572). Stratified analyses showed that LGNC-07 improved memory and selective attention by significantly increasing the Rey-Kim memory quotient and word reading in the subjects with MMSE-K scores of 21-23 (LGNC-07, n = 11; placebo, n = 9). Electroencephalograms were recorded in 24 randomly selected subjects hourly for 3 hours in eye-open, eye-closed, and reading states after a single dose of LGNC-07 LGNC-07 (n = 12; placebo, n = 12). Brain theta waves, an indicator of cognitive alertness, were increased significantly in the temporal, frontal, parietal, and occipital areas after 3 hours in the eye-open and reading states. Therefore, this study suggests that LGNC-07 has potential as an intervention for cognitive improvement.
Giesbrecht T et al. The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness. Nutr Neurosci. 2010 Dec;13(6):283-90. ABSTRACT: The non-proteinic amino acid L-theanine and caffeine, a methylxanthine derivative, are naturally occurring ingredients in tea. The present study investigated the effect of a combination of 97 mg L- theanine and 40 mg caffeine as compared to placebo treatment on cognitive performance, alertness, blood pressure, and heart rate in a sample of young adults (n = 44). Cognitive performance, self-reported mood, blood pressure, and heart rate were measured before L-theanine and caffeine administration (i.e. at baseline) and 20 min and 70 min thereafter. The combination of moderate levels of L-theanine and caffeine significantly improved accuracy during task switching and self-reported alertness (both P < 0.01) and reduced self-reported tiredness (P < 0.05). There were no significant effects on other cognitive tasks, such as visual search, choice reaction times, or mental rotation. The present results suggest that 97 mg of L-theanine in combination with 40 mg of caffeine helps to focus attention during a demanding cognitive task.
Einšther SJ et al. L-theanine and caffeine improve task switching but not intersensory attention or subjective alertness. Appetite. 2010 Apr;54(2):406-9. ABSTRACT: Tea ingredients L-theanine and caffeine have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. The current randomized, placebo-controlled, double-blind, cross-over study compared a combination of L-theanine (97 mg) and caffeine (40 mg) to a placebo on two attention tasks and a self-report questionnaire before, and 10 and 60 min after consumption. The combination of L-theanine and caffeine significantly improved attention on a switch task as compared to the placebo, while subjective alertness and intersensory attention were not improved significantly. The results support previous evidence that L-theanine and caffeine in combination can improve attention.
Kim TI et al. L-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways. Free Radic Biol Med. 2009 Dec 1;47(11):1601-10. Epub 2009 Sep 16. ABSTRACT: Amyloid beta (Abeta)-induced neurotoxicity is a major pathological mechanism of Alzheimer disease (AD). In this study, we investigated the inhibitory effect of l-theanine, a component of green tea (Camellia sinensis), on Abeta(1-42)-induced neuronal cell death and memory impairment. Oral treatment of l-theanine (2 and 4 mg/kg) for 5 weeks in the drinking water of mice, followed by injection of Abeta(1-42) (2 microg/mouse, icv), significantly attenuated Abeta(1-42)-induced memory impairment. Furthermore, l-theanine reduced Abeta(1-42) levels and the accompanying Abeta(1-42)-induced neuronal cell death in the cortex and hippocampus of the brain. Moreover, l-theanine inhibited Abeta(1-42)-induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase as well as the activity of nuclear factor kappaB (NF-kappaB). l-Theanine also significantly reduced oxidative protein and lipid damage and the elevation of glutathione levels in the brain. These data suggest that the positive effects of l-theanine on memory may be mediated by suppression of ERK/p38 and NF-kappaB as well as the reduction of macromolecular oxidative damage. Thus, l-theanine may be useful in the prevention and treatment of AD.
Gomez-Ramirez M et al. The effects of L-theanine on alpha-band oscillatory brain activity during a visuo-spatial attention task. Brain Topogr. 2009 Jun;22(1):44-51. ABSTRACT: Background/Objectives Ingestion of the non-proteinic amino acid L-theanine (gamma-glutamylethylamide) has been shown to influence oscillatory brain activity in the alpha band (8-14 Hz) in humans during resting electroencephalographic (EEG) recordings and also during cognitive task performance. We have previously shown that ingestion of a 250-mg dose of L-theanine significantly reduced tonic (background) alpha power during a demanding intersensory (auditory-visual) attentional cueing task. Further, cue-related phasic changes in alpha power, indexing the shorter-term anticipatory biasing of attention between modalities, were stronger on L-theanine compared to placebo. This form of cue-contingent phasic alpha activity is also known to index attentional biasing within visual space. Specifically, when a relevant location is pre-cued, anticipatory alpha power increases contralateral to the location to be ignored. Here we investigate whether the effects of L-theanine on tonic and phasic alpha activity, found previously during intersensory attentional deployment, occur also during a visuospatial task. Subjects/Methods 168-channel EEG data were recorded from thirteen neurologically normal individuals while engaged in a highly demanding visuo-spatial attention task. Participants underwent testing on two separate days, ingesting either a 250-mg colorless and tasteless solution of L-theanine mixed with water, or a water-based solution placebo on each day in counterbalanced order. We compared the alpha-band activity when subjects ingested L-Theanine vs. Placebo. Results We found a significant reduction in tonic alpha for the L-theanine treatment compared to placebo, which was accompanied by a shift in scalp topography, indicative of treatment-related changes in the neural generators of oscillatory alpha activity. However, L-theanine did not measurably affect cue-related anticipatory alpha effects. Conclusions This pattern of results implies that L- theanine plays a more general role in attentional processing, facilitating longer-lasting processes responsible for sustaining attention across the timeframe of a difficult task, rather than affecting specific moment-to-moment phasic deployment processes.
Owen GN et al. The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci. 2008 Aug;11(4):193-8. ABSTRACT: The aim of this study was to compare 50 mg caffeine, with and without 100 mg L-theanine, on cognition and mood in healthy volunteers. The effects of these treatments on word recognition, rapid visual information processing, critical flicker fusion threshold, attention switching and mood were compared to placebo in 27 participants. Performance was measured at baseline and again 60 min and 90 min after each treatment (separated by a 7-day washout). Caffeine improved subjective alertness at 60 min and accuracy on the attention-switching task at 90 min. The L- theanine and caffeine combination improved both speed and accuracy of performance of the attention-switching task at 60 min, and reduced susceptibility to distracting information in the memory task at both 60 min and 90 min. These results replicate previous evidence which suggests that L-theanine and caffeine in combination are beneficial for improving performance on cognitively demanding tasks.
Nobre AC et al. L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr. 2008;17 Suppl 1: 167-8. ABSTRACT: Tea is the most widely consumed beverage in the world after water. Tea is known to be a rich source of flavonoid antioxidants. However tea also contains a unique amino acid, L-theanine that may modulate aspects of brain function in humans. Evidence from human electroencephalograph (EEG) studies show that it has a direct effect on the brain (Juneja et al. Trends in Food Science & Tech 1999;10;199-204). L-theanine significantly increases activity in the alpha frequency band which indicates that it relaxes the mind without inducing drowsiness. However, this effect has only been established at higher doses than that typically found in a cup of black tea (approximately 20mg). The aim of the current research was to establish this effect at more realistic dietary levels. EEG was measured in healthy, young participants at baseline and 45, 60, 75, 90 and 105 minutes after ingestion of 50mg L-theanine (n=16) or placebo (n=19). Participants were resting with their eyes closed during EEG recording. There was a greater increase in alpha activity across time in the L-theanine condition (relative to placebo (p+0.05). A second study replicated this effect in participants engaged in passive activity. These data indicate that L- theanine, at realistic dietary levels, has a significant effect on the general state of mental alertness or arousal. Furthermore, alpha activity is known to play an important role in critical aspects of attention, and further research is therefore focussed on understanding the effect of L-theanine on attentional processes.
Bryan J et al. Psychological effects of dietary components of tea: caffeine and L-theanine. Nutr Rev. 2008 Feb;66(2):82-90. ABSTRACT: This review summarizes the literature on the association between two dietary components of tea, caffeine and L-theanine, and the psychological outcomes of consumption; it also identifies areas for future research. The studies reviewed suggest that caffeinated tea, when ingested at regular intervals, may maintain alertness, focused attention, and accuracy and may modulate the more acute effects of higher doses of caffeine. These findings concur with the neurochemical effects of L-theanine on the brain. L- theanine may interact with caffeine to enhance performance in terms of attention switching and the ability to ignore distraction; this is likely to be reflective of higher-level cognitive activity and may be sensitive to the detrimental effects of overstimulation. Further research should investigate the interactive effects of caffeine, L-theanine, and task complexity, utilize a range of ecologically valid psychological outcomes, and assess the neuroprotective effects of L-theanine using epidemiological or longer-term intervention studies among individuals at risk of neurodegenerative disease.
Haskell CF et al. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol. 2008 Feb;77(2):113-22. ABSTRACT: L-Theanine is an amino acid found naturally in tea. Despite the common consumption of L-theanine, predominantly in combination with caffeine in the form of tea, only one study to date has examined the cognitive effects of this substance alone, and none have examined its effects when combined with caffeine. The present randomised, placebo-controlled, double-blind, balanced crossover study investigated the acute cognitive and mood effects of L-theanine (250 mg), and caffeine (150 mg), in isolation and in combination. Salivary caffeine levels were co-monitored. L-Theanine increased 'headache' ratings and decreased correct serial seven subtractions. Caffeine led to faster digit vigilance reaction time, improved Rapid Visual Information Processing (RVIP) accuracy and attenuated increases in self-reported 'mental fatigue'. In addition to improving RVIP accuracy and 'mental fatigue' ratings, the combination also led to faster simple reaction time, faster numeric working memory reaction time and improved sentence verification accuracy. 'Headache' and 'tired' ratings were reduced and 'alert' ratings increased. There was also a significant positive caffeine x L- theanine interaction on delayed word recognition reaction time. These results suggest that beverages containing L-theanine and caffeine may have a different pharmacological profile to those containing caffeine alone.
Nathan PJ et al. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006;6(2):21-30. ABSTRACT: L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L- theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.
Kimura K et al. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007 Jan;74(1):39-45. ABSTRACT: L-theanine is an amino acid contained in green tea leaves which is known to block the binding of L-glutamic acid to glutamate receptors in the brain. Because the characteristics of L-Theanine suggest that it may influence psychological and physiological states under stress, the present study examined these possible effects in a laboratory setting using a mental arithmetic task as an acute stressor. Twelve participants underwent four separate trials: one in which they took L-Theanine at the start of an experimental procedure, one in which they took L-Theanine midway, and two control trials in which they either took a placebo or nothing. The experimental sessions were performed by double-blind, and the order of them was counterbalanced. The results showed that L-Theanine intake resulted in a reduction in the heart rate (HR) and salivary immunoglobulin A (s-IgA) responses to an acute stress task relative to the placebo control condition. Moreover, analyses of heart rate variability indicated that the reductions in HR and s-IgA were likely attributable to an attenuation of sympathetic nervous activation. Thus, it was suggested that the oral intake of L- Theanine could cause anti-stress effects via the inhibition of cortical neuron excitation.
CDP Choline References
Cavun S et al. CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement. Fundam Clin Pharmacol. 2004 Oct;18(5):513-23. ABSTRACT: In the present study, we investigated the effect of intracerebroventricular (i.c.v.) administration of cytidine-5'-diphosphate (CDP) choline on plasma adrenocorticotropin (ACTH), serum growth hormone (GH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in conscious rats. The involvement of cholinergic mechanisms in these effects was also determined. In basal conditions, CDP-choline (0.5, 1.0 and 2.0 micromol, i.c.v.) increased plasma ACTH levels dose- and time-dependently, but it did not affect the TSH, GH, FSH and LH levels. In stimulated conditions, i.c.v. administration of CDP-choline (1 micromol, i.c.v.) produced an increase in clonidine-stimulated GH, thyrotyropin-releasing hormone (TRH)-stimulated TSH, LH-releasing hormone (LHRH)-stimulated LH, but not FSH levels. Injection of equimolar dose of choline (1 micromol, i.c.v.) produced similar effects on hormone levels, but cytidine (1 micromol, i.c.v.) failed to alter plasma levels of these hormones. Pretreatment with hemicholinium-3, a neuronal high affinity choline uptake inhibitor, (20 microg, i.c.v.) completely blocked the observed hormone responses to CDP-choline. The increase in plasma ACTH levels induced by CDP-choline (1 micromol, i.c.v.) was abolished by pretreatment with mecamylamine, a nicotinic receptor antagonist, (50 microg, i.c.v.) but not atropine, a muscarinic receptor antagonist, (10 microg, i.c.v.). The increase in stimulated levels of serum TSH by CDP-choline (1 micromol, i.c.v.) was blocked by atropine but not by mecamylamine pretreatment. However, CDP-choline induced increases in serum GH and LH levels were greatly attenuated by both atropine and mecamylamine pretreatments. The results show that CDP-choline can increase plasma ACTH and produce additional increases in serum levels of TSH, GH and LH stimulated by TRH, clonidine and LHRH, respectively. The activation of central cholinergic system, mainly through the presynaptic mechanisms, was involved in these effects. Central nicotinic receptors solely mediated the increase in plasma ACTH levels while the activation of central muscarinic receptors was involved in the increase in TSH levels. Both muscarinic and nicotinic receptor activations, separately, mediated the increases in serum GH and LH levels after CDP-choline.
Ceda GP et al. Effects of cytidine 5'-diphosphocholine administration on basal and growth hormone-releasing hormone-induced growth hormone secretion in elderly subjects. Acta Endocrinol (Copenh). 1991 May;124(5):516-20. ABSTRACT: The basal and GH-releasing hormone-stimulated secretion of GH declines in the elderly. We tested the ability of cytidine 5'-diphosphocholine, a drug used in the treatment of stroke and Parkinson's disease, to alter GH secretion in 11 healthy elderly volunteers, aged 69-84. Each subject received an iv infusion of 2 g of cytidine 5'-diphosphocholine or normal saline. GHRH and TRH were also administered during cytidine 5'-diphosphocholine infusions. The infusion of cytidine 5'-diphosphocholine induced a 4-fold (p less than 0.05) increase in serum GH levels over basal values. A small increase in GH was seen after GHRH administration. However, the addition of GHRH to the cytidine 5'-diphosphocholine infusion resulted in a GH response which was significantly greater than that seen after GHRH alone; the integrated concentration of GH was more than 2-fold greater in the cytidine 5'-diphosphocholine treated group (706.85 +/- 185.1 vs 248.9 +/- 61.4 micrograms.l-1.(120 min)-1; p = 0.01). The PRL and TSH responses to TRH were not significantly affected by cytidine 5'-diphosphocholine infusion, indicating that dopaminergic mechanisms are not involved. These studies demonstrate that cytidine 5'-diphosphocholine can enhance basal and GHRH-stimulated GH release in the elderly, but the mechanism of action of the drug remains unclear.
Secades JJ et al. Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol. 2006 Sep;28 Suppl B:1-56. ABSTRACT: Cytidine 5'-diphosphocholine, CDP-choline, or citicoline is an essential intermediate in the biosynthetic pathway of structural phospholipids in cell membranes, particularly phosphatidylcholine. Following administration by both the oral and parenteral routes, citicoline releases its two main components, cytidine and choline. Absorption by the oral route is virtually complete, and bioavailability by the oral route is therefore approximately the same as by the intravenous route. Once absorbed, citicoline is widely distributed throughout the body, crosses the blood-brain barrier and reaches the central nervous system (CNS), where it is incorporated into the membrane and microsomal phospholipid fraction. Citicoline activates biosynthesis of structural phospholipids of neuronal membranes, increases brain metabolism, and acts upon the levels of different neurotransmitters. Thus, citicoline has been experimentally shown to increase norepinephrine and dopamine levels in the CNS. Owing to these pharmacological mechanisms, citicoline has a neuroprotective effect in hypoxic and ischemic conditions, decreasing the volume of ischemic lesion, and also improves learning and memory performance in animal models of brain aging. In addition, citicoline has been shown to restore the activity of mitochondrial ATPase and membrane Na+/K+ATPase, to inhibit activation of certain phospholipases, and to accelerate reabsorption of cerebral edema in various experimental models. Citicoline has also been shown to be able to inhibit mechanisms of apoptosis associated to cerebral ischemia and in certain neurodegeneration models, and to potentiate neuroplasticity mechanisms. Citicoline is a safe drug, as shown by the toxicological tests conducted, that has no significant systemic cholinergic effects and is a well tolerated product. These pharmacological characteristics and the action mechanisms of citicoline suggest that this product may be indicated for treatment of cerebral vascular disease, head trauma (HT) of varying severity, and cognitive disorders of different causes. In studies conducted in the treatment of patients with HT, citicoline was able to accelerate recovery from post-traumatic coma and neurological deficits, achieving an improved final functional outcome, and to shorten hospital stay in these patients. Citicoline also improved the mnesic and cognitive disorders seen after HT of minor severity that constitute the so-called post-concussional syndrome. In the treatment of patients with acute ischemic cerebral vascular disease, citicoline accelerates recovery of consciousness and motor deficit, achieves a better final outcome, and facilitates rehabilitation of these patients. The other major indication of citicoline is for treatment of senile cognitive impairment, either secondary to degenerative diseases (e.g. Alzheimer disease) or to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, citicoline improves scores in cognitive rating scales, while in patients with senile dementia of the Alzheimer type it stops the course of disease, and neuroendocrine, neuroimmunomodulatory, and neurophysiological benefits have been reported. Citicoline has also been shown to be effective in Parkinson disease, drug addictions, and alcoholism, as well as in amblyopia and glaucoma. No serious side effects have occurred in any series of patients treated with citicoline, which attests to the safety of treatment with citicoline.
Serra F et al. Effect of CDP-choline on senile mental deterioration. Multicenter experience on 237 cases. Minerva Med. 1990 Jun;81(6):465-70. ABSTRACT: The efficacy of CDP-choline (1000 mg/die) administered for two 21-day treatment cycles, with a one-week wash-out period between them, was evaluated in out and in-patients suffering from mild to moderate brain aging. The study was performed on 237 fully evaluable patients with the use of the reduced geriatric scale of Plutchik and al., for clinical evaluation of the symptomatology. The clinical data obtained demonstrate that treatment with CDP-choline is able to determine an improvement of symptomatology since the 1st cycle of therapy (p less than 0.001), and a further improvement in the 2nd cycle (p less than 0.001). Particularly, the therapeutic effect of the 1st cycle is persistent in the intermediate wash-out period (suspension of treatment) with a further decrease, of symptomatology regarding some items of Plutchik's scale (p less than 0.01). Finally, treatment with CDP-choline 1000 mg/die for two 21-day cycles in 237 patients suffering from brain aging determined a statistically significant improvement of the cognitive and behavioural parameters taken into consideration: independence/autonomous life; human relations/social life; interest and attentive capacity; individual behaviour. Therefore citicoline is confirmed as a valid therapeutic remedy for the clinical, functional and social recovery of these patients.
Di Trapani G et al. Citicoline in the treatment of cognitive and behavioral disorders in pathologic senile decline. Clin Ter. 1991 Jun 30;137(6):403-13. ABSTRACT: A three months study was performed on 150 aging patients with primary memory deficits in order to verify the effectiveness of CDP-Choline, administered in repeated cycles of four weeks, with an interval of one week between cycles, in improving patients' cognitive and behavioral efficiency and in stabilizing their cognitive decline. Objective measures of memory and attention, and a behavioral rating scale were used to assess treatment effects. CDP-Choline treatment demonstrated both symptomatic efficacy and a long lasting effect on cognition and behavior of these patients. Level of activation and attention responsiveness improved during treatment cycles and no further changes were identified of these variables in the follow-up period. Measures related to specific memory functioning showed, besides improvements during treatment, after-effects still active in the follow-up period, suggesting a long lasting change of the cognitive decline trend characteristic of these patients.
Petkov VD et al. Effect of CDP-choline on learning and memory processes in rodents. Methods Find Exp Clin Pharmacol. 1992 Oct;14(8):593-605. ABSTRACT: The effects of cytidine (5') diphosphocholine (CDP-choline) on learning and memory were studied using conditioned reflex methods for passive avoidance and active avoidance with punishment reinforcement (step-through, step-down, shuttle box and maze), for active avoidance with alimentary reinforcement (staircase maze), and the Morris water maze. The majority of experiments involved comparative studies of the nootropic drugs meclofenoxate and/or piracetam. CDP-choline was administered orally, in some of the experiments also intraperitoneally, at doses of 10-500 mg/kg body weight once or twice daily for 5 or 7 days. In separate cases only single doses were administered. Trainings started one hour after the last dose of the drugs. Retention tests were given 3 h, 24 h, 7 days or 10 days after training. The results obtained with the different methods document CDP-choline's ability to improve learning and memory in rats and mice. No essential differences in the effects of CDP-choline were established upon oral and intraperitoneal administration of the drug. The learning- and memory-facilitating effects of CDP-choline were similar to those of meclofenoxate and piracetam. The results of the present study permit us to define CDP-choline as a substance capable of improving cognitive levels.
Spiers PA et al. Citicoline improves verbal memory in aging. Arch Neurol. 1996 May;53(5):441-8. ABSTRACT: Objective: To test the verbal memory of older volunteers given citicoline. Design: A randomized, double-blind, placebo-controlled, parallel group design was employed in the initial study. After data analysis, a subgroup was identified whose members had relatively inefficient memories. These subjects were recruited for a second study that used a crossover design. The subjects took either placebo or citicoline, 1000 mg/d, for 3 months in the initial study. In the crossover study, subjects took both placebo and citicoline, 2000 mg/d, each for 2 months. SUBJECTS: The subjects were 47 female and 48 male volunteers 50 to 85 years old. They were screened for dementia, memory disorders, and other neurological problems. Of the subjects with relatively inefficient memories, 32 participated in the crossover study. Main Outcome Measure: Verbal memory was tested at each study visit using a logical memory passage. Plasma choline concentrations were measured at baseline; at days 30, 60, and 90 in the initial study; and at day 60 of each treatment condition in the crossover study. Plasma choline concentrations and memory scores were analyzed using repeated-measures analysis of variance and covariance, followed by planned comparisons when appropriate. RESULTS: In the initial study, citicoline therapy improved delayed recall on logical memory only for the subjects with relatively inefficient memories. In the crossover study, the higher dosage of citicoline was clearly associated with improved immediate and delayed logical memory. CONCLUSIONS: Citicoline therapy improved verbal memory functioning in older individuals with relatively inefficient memories. Citicoline may prove effective in treating age-related cognitive decline that may be the precursor of dementia.
Fioravanti M et al. Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly. Cochrane Database Syst Rev. 2004;(2):CD000269. doi: 10.1002/14651858.CD000269.pub2. BACKGROUND: CDP-choline (cytidine 5'-diphosphocholine) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischaemia to free fatty acids and free radicals. Animal studies suggest that CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids. CDP-choline may also attenuate the progression of ischaemic cell damage by suppressing the release of free fatty acids. CDP-choline is the endogenous compound normally produced by the organism. When the same substance is introduced as a drug it can be called citicoline.CDP-choline is mainly used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to whom the treatments were given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review. Due to its effects on the adrenergic and dopaminergic activity of the CNS, CDP-choline has also been used as an adjuvant in the treatment of Parkinson's disease. OBJECTIVES: To assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 22 April 2004 using the terms CDP-choline, CDP, citicoline, cytidine diphosphate choline or diphosphocholine. The Register contains records from all major health-care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% Confidence Interval (CI)) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated. AUTHORS' CONCLUSIONS: There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia.
D'Orlando KJ et al.Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. Neurol Res. 1995 Aug;17(4):281-4. ABSTRACT: Citicoline is approved in Europe and Japan for use in stroke, head trauma and other neurological disorders. It is presently being evaluated in phase II/III stroke trials in the United States. Exogenous administration of CDP-choline provides both choline and cytidine which access the brain and serve as substrates for the synthesis of phosphatidylcholine, a primary neuronal membrane component; the choline also enhances brain acetylcholine synthesis. Membrane repair and regeneration is necessary for recovery from stroke. Furthermore, citicoline may alleviate free fatty acid-induced toxicity which accompanies ischemic insult. Data from many pre-clinical and clinical trials support the hypothesis that citicoline may be a safe and effective treatment for stroke.
Dimpfel W et al. Efficacy of dimethylaminoethanol (DMAE) containing vitamin-mineral drug combination on EEG patterns in the presence of different emotional states. Eur J Med Res. 2003 May 30;8(5):183-91. ABSTRACT: The psychophysiological model of provoking different emotional states by watching film excerpts with various emotional contents was used to characterize drug action in 80 subjects (male/female=50%) with threshold emotional disturbance within a randomized, group-parallel, double-blind, placebo-controlled study. Analyzing the brain's electrical reaction during presentation of 5 videoclips of 7 min duration followed by 3 minutes pause revealed a content specific representation of topographical frequency changes. This procedure was repeated after 6 and 12 weeks of daily intake of a vitamin-mineral drug combination containing dimethylaminoethanol (DMAE) (Vitagerin Geistlich N) or placebo. Subjects taking the active drug for 3 months developed significant less theta and alpha1 power in sensomotoric areas of the cortex. The grade of change and statistical significance was dependend on the content of the excerpt, but the pattern of changes in general remained the same. Since decreases in theta and alpha1 electrical power have been associated with increased vigilance and attention, subjects taking the drug combination obviously were more active and felt better. - Analysis of the emotional change in mood profile as induced by the TV session was achieved by completing two different quenstionaires (POMS and Bf-S). Both scores revealed a better mood for the active drug group thus corroborating the results from EEG analysis. Therefore the vitamine-mineral drug combination containing DMAE can be interpreted to induce a psychophysiological state of better feeling of wellbeing on both levels of analysis mood and electrical pattern of brain activity in subjects suffering from borderline emotional disturbance.
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