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Caffeine and the central nervous system: Mechanisms of action, biochemical, metabolic and psychostimulant effects
Abstract
Caffeine is the most widely consumed centralnervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
... Caffeine is a type of methylxanthine (i.e., alkaloids present in coffee and tea), which is absorbed rapidly upon ingestion and acts as a central nervous system stimulant (Nehlig et al. 1992). Caffeine is most consumed in caffeinated beverages such as coffee, energy drinks, and soft drinks (see Table 1). ...
... At least three neurotransmitter systems are influenced by caffeine intake. The most widely accepted primary mechanism of action for caffeine is the blockade of adenosine receptors (Nehlig et al. 1992). Adenosine receptors control the presence and actions of the inhibitory neurotransmitter adenosine, which influences the release of neurotransmitters in the central nervous system. ...
... In mice, chronic caffeine consumption increases the density of adenosine A 1 receptors and serotonin 5-HT 1 and 5-HT 2 receptors, but not striatal dopamine receptors (Shi et al. 1993). Caffeine does increase brain dopamine levels, but has varied effects on dopamine release, uptake, and turnover (Nehlig et al. 1992). Dopamine is thought by Adapted from Zucconi et al. (2013) some researchers to be necessary for aggressive behavior (Nelson and Trainor 2007) and is associated with increased reward-seeking and aggression (Chester et al. 2016;Seo et al. 2008). ...
... Its main mechanism of action is the antagonism of adenosine receptors, which, consequently, increases dopaminergic actions in the cortex [62]. In addition to these dopaminergic effects, caffeine produces secondary effects on acetylcholine and noradrenaline [63]. ...
(1) Background: Attention-deficit/hyperactivity disorder (ADHD) is typically treated with stimulant medications, which may lead to several adverse effects. Recent animal studies have shown that caffeine can improve the symptoms of ADHD. This systematic review and meta-analysis sought to evaluate the effect of caffeine on ADHD symptoms in children. (2) Methods: PubMed, Embase, and Cochrane databases were searched for randomized controlled trials comparing caffeine with placebo in children, comparing overall symptoms of ADHD, inattention, hyperactivity, and impulsivity. (3) Results: We included seven RCTs in the systematic review for qualitative assessment, with 104 patients aged 5 to 15 years. Four of these studies (n = 76) were included in the meta-analysis. After qualitative analysis, four studies indicated no improvement in any of the ADHD symptoms compared with placebo. One study showed improvement in ADHD symptoms based on 1 of 5 scales applied. One study indicated significant improvement in general symptoms, inattention, and hyperactivity. One study indicated improvement in sustained attention but a worsening of impulsivity. In contrast, when using a quantitative analysis of the general symptoms of ADHD, the data showed no significant difference when comparing placebo with caffeine (standardized mean difference −0.12; 95% CI −0.44 to 0.20; p = 0.45; I2 = 0%). (4) Conclusion: overall, the totality of the evidence suggests no significant benefit of caffeine over placebo in the treatment of children with ADHD.
... Caffeine, known as a psychoactive component, has been found to have a significant stimulatory effect on the central nervous system (Nehlig et al., 1992). This substance is known to elicit anxiety-like responses in animals, including diving behavior, increased thigmotaxis, decreased exploration, and increased erratic behavior during swimming (Ladu et al., 2015). ...
Caffeine is an emerging contaminant in aquatic environments. The study utilized a validated method to investigate the presence and distribution of caffeine in the surface water of the Yellow and Bohai Seas, urban rivers, and the Yantai estuary area. The analytical method conforms to EPA guidelines and exhibits a limit of quanti-fication that is 200 times lower than that of prior investigations. The study revealed that the highest concentration of 1436.4 ng/L was found in convergence of ocean currents in the Yellow and Bohai Seas. The presence of larger populations and the process of urban industrialization have been observed to result in elevated levels of caffeine in offshore regions, confirming that caffeine can serve as a potential indicator of anthropogenic contamination. Fish larvae exhibited hypoactivity in response to caffeine exposure at environmentally relevant concentrations. The study revealed that caffeine pollution can have adverse effects on marine and offshore ecosystems. This emphasizes the importance of decreasing neurotoxic pollution in the aquatic environment.
... The present study revealed that consuming coffee reduces the serum level of melatonin, which is in concordance with previous studies [23][24][25] , according to several studies conducted to investigate the mechanisms by which sleep is interrupted after coffee consumption had shown that Caffeine consumption by day causes a reduction in 6sulfatoxymelatonin (the primary metabolite of melatonin) on a next night [23,[26][27][28] . ...
Caffeine intake reduces sleep quality and melatonin secretion, the hormone responsible for regulating sleep. Chewing gum increases alertness and improves concentration. This study aims to investigate the impact of coffee consumption and gum chewing on serum melatonin levels in a study population of 40 Jordanian subjects (mean age, 21.15±3.21 years), including 23 males and 17 females. A total of 40 participants volunteered and met the inclusion criteria and were divided into four groups; a control group did not consume espresso coffee and chewed gum during the study period, a second group consumed two cups of espresso coffee (240 ml), and the third group chewed Gum constantly throughout the procedure; finally, the fourth group consumed two cups of espresso coffee and chewed Gum constantly throughout the process. Melatonin serum levels were measured one hour before and one hour after the completion of the study; the duration was five hours. The findings revealed that the coffee plus chewing gum participants had the lowest serum levels of melatonin (13.1± 2.0). Among the intervention groups, the coffee group and the last group regarding melatonin levels were the chewing gum group, 15.3± 1.2 and 19.2± 2.2, respectively. In conclusion, Significant differences existed between the interventions and control groups (P < 0.05). Furthermore, there were significant differences between coffee plus chewing gum and the coffee group and the chewing gum group (P < 0.002, P < 0.02, P < 0.004, respectively).
... In Xanthine based compounds are well known for their drug-like properties. Many xanthine based plant alkaloids have been used as psycho-stimulant and anti-asthmatic drugs (Baraldi et al., 2007;Burbiel et al., 2006;Nehlig et al., 1992). They show activity towards PDEs due to their structural resemblance with substrates (cAMP or cGMP) of PDEs. ...
Xanthine is a versatile nitrogenous alkaloid. The pharmaceutical active nature of xanthine derivatives is widely known for treating various diseases. Therefore, xanthine can act as structurally rigid scaffold which provides enormous possibility for molecular diversity in drug development process. Xanthine based compounds are reported for their non-specific phosphodiesterase inhibition, however, xanthine based inhibitors have not been reported for PDE9A inhibition. With introduction of “xanthine” as a scaffold, the present study was an attempt to bring molecular diversification in PDE9A research. The current study was emphasized on two approaches – one was virtual screening to find out the possibilities of existing xanthine based derivatives to regulate the catalytic action of PDE9A and the second approach was to use the xanthine as scaffold for designing new xanthine derivatives and again the same xanthine was used as ‘starting material’ for synthesizing selected xanthine derivatives. Two schemes were developed based on getting clear understanding over the molecular structure of xanthine. The biological studies were carried out to understand the biological affinity of the selected virtual screened compounds and chemically synthesized new compounds by using spectrophotometric inhibition studies for structural activity relationship (SAR) analysis and thermal shift assay for stability studies of protein-ligand complex. The biological studies showed chemically synthesized xanthine derivatives as better inhibitors than virtual screened compounds.
... As a known antioxidant, coffee can effectively prevent several chronic illnesses, including cancer, diabetes, and heart disease [6]. Moreover, caffeine is a central nervous system stimulant that can increase alertness, decrease weariness, improve performance, and enhance mental function [7,8]. However, higher doses of caffeine (>500 mg per day) pose harmful effects as the quality and duration of sleep are the most frequently noted problems. ...
... Organic molecular methylxanthine in caffeine causes an increase in energy metabolism and influences cognitive function. These positive impacts are widely discussed in several studies on humans and animals [50][51][52][53][54][55][56][57] . McLellan et al. performed a comprehensive review of multiple studies verifying the effects of caffeine in enhancing alertness, attention, and reaction time 58 . ...
Inspired by advances in wearable technologies, we design and perform human-subject experiments. We aim to investigate the effects of applying safe actuation (i.e., auditory, gustatory, and olfactory) for the purpose of regulating cognitive arousal and enhancing the performance states. In two proposed experiments, subjects are asked to perform a working memory experiment called n-back tasks. Next, we incorporate listening to different types of music, drinking coffee, and smelling perfume as safe actuators. We employ signal processing methods to seamlessly infer participants’ brain cognitive states. The results demonstrate the effectiveness of the proposed safe actuation in regulating the arousal state and enhancing performance levels. Employing only wearable devices for human monitoring and using safe actuation intervention are the key components of the proposed experiments. Our dataset fills the existing gap of the lack of publicly available datasets for the self-management of internal brain states using wearable devices and safe everyday actuators. This dataset enables further machine learning and system identification investigations to facilitate future smart work environments. This would lead us to the ultimate idea of developing practical automated personalized closed-loop architectures for managing internal brain states and enhancing the quality of life.
... Caffeine promotes relative brain hypoperfusion by increasing energy metabolism while simultaneously diminishing cerebral blood flow. Caffeine stimulates noradrenaline neurons, and [4] appears to affect release of dopamine locally. Caffeine is quickly and nearly entirely (up to 99%) [5] absorbed into the bloodstream after consumption. ...
Considering the growing public health significance of some forms of caffeine use, such as the consumption of energy drinks with high caffeine content that are currently largely unregulated or combinations of caffeine and methamphetamine, the International Classification of Diseases 11 (ICD 11) separates caffeine from other stimulants. A stimulant and diuretic, caffeine is a bitter alkaloid that is mostly found in coffee, tea, cacao, and kola nuts. As a stimulant of the Central Nervous System(CNS) it boosts the body's flow of hormone like cortisol. Caffeine promotes relative brain hypoperfusion by increasing energy metabolism while simultaneously diminishing cerebral blood flow. Caffeine stimulates noradrenaline neurons, and appears to affect releaseof dopamine locally.Caffeine is quickly and nearly entirely (up to 99%) absorbed into the bloodstream after consumption.
Anthropogenic sources of environmental pollution are ever‐increasing as urban areas expand and more chemical compounds are used in daily life. The stimulant caffeine is one of the most consumed chemical compounds worldwide, and as a result, has been detected as an environmental contaminant in all types of major water sources on all continents. Exposure of wildlife to environmental pollutants can disrupt the energy balance of these organisms, as restoration of homeostasis is prioritised. In turn, energy allocated to other key biological processes such as growth or reproduction may be affected, consequently reducing the overall fitness of an individual. Therefore, we aimed to investigate if long‐term exposure to environmentally relevant concentrations of caffeine had any energetic consequences on wildlife. Specifically, we exposed wild eastern mosquitofish ( Gambusia holbrooki ) to one of three nominal concentrations of caffeine (0, 100 and 10,000 ng/L) and assayed individuals for metabolic rate, general activity, antipredator and foraging behaviour and body size as measures of energy expenditure or energy intake. We found no differences in any measured traits between any of the given exposure treatments, indicating that exposure to caffeine at current environmental levels may not adversely affect the energy balance and fitness of vulnerable freshwater fish.
Depression, anxiety, cognitive impairment, and pain are the most common mental symptoms exhibited in a wide range of diseases. Recent progress in neuroscience has led to better understanding of those dreadful symptoms; currently, state-of-the-art brain research attempts to untangle this complex phenomenon through preclinical, clinical, and computational approaches. This E-Book complies the most recent studies published in the Special Issue “Crosstalk between Depression, Anxiety, Dementia, and Chronic Pain: Comorbidity in Behavioral Neurology and Neuropsychiatry 2.0”, discussing the most recent cutting-edge research and its integrative potential of interdisciplinary arena for new study design and methodology in behavioral neurology and neuropsychiatry.
Deoxycoformycin (DCF) is an inhibitor of adenosine deaminase (ADA). Twenty-one courses of DCF were administered to 13 patients ranging in age from 15 to 78 yr. Eight patients had T-cell disorders, and five patients had non-T-cell malignancies. The i.v. bolus dose was escalated from 5 to 30 mg/sq m/day, and the duration of the courses ranged from 1 to 5 days. The DCF plasma half-life ranged from 4.9 to 6.2 hr and was independent of dose. The dose-limiting toxicities involved the central nervous system (CNS) and the kidneys. Other toxicities included bronchitis, decreases in hematocrit, arthralgias, and myalgias. Mortality was encountered in three patients. These toxic effects may have been secondary to the accumulation of the metabolites adenosine and deoxyadenosine. Deoxyadenosine and adenosine were both detectable in plasma (10(-6) M) and in urine (10(-3) M). Two partial remissions were observed: one in a patient with T-cell ALL and another in a patient with mycosis fungoides. Minimal responses characterized by either declines in peripheral blast counts or partial resolution of adenopathy were observed in five other patients. No responses were observed in six patients. These observations suggest that DCF is effective in the treatment of T-cell lymphoid malignancies.
Caffeine and theophylline are effective in the treatment of apnea in the newborn infant. Controlled studies of efficacy and comparative efficacy and studies of toxicity are visibly lacking. Both drugs exert their anti-apneic activity by stimulation of the respiratory center. Both drugs are eliminated from the baby slowly (caffeine even slower than theophylline) and doses should be adjusted accordingly. Neonates excrete caffeine largely unchanged and they methylate theophylline to caffeine significantly. Caffeine seems preferable to theophylline because of its wider therapeutic index, ease of administration (i.e., given once per day), lesser fluctuation in plasma concentration owing to longer half-life, potent central respirogenic effect, and fewer peripheral side effects. Areas of concern and feasible research have been discussed.
The purpose of this investigation was to determine if amphetamine (dexedrine) or caffeine affects the performance of a subject exposed to heat and exercise stress. Stress was provided by an ambient temperature of 110 deg. F and treadmill walking at four miles per hour, zero grade. Fifteen subjects each reported for three-hour experiments. Psychomotor and physiological measurements were taken each day under conditions held constant except for double-blind administration of drugs. Results indicate that, except for an increase in heart rate, neither amphetamine (dexedrine) nor caffeine produced facilitating or deleterious effects on any of the psychomotor or physiological measurements in this investigation.
Eighteen normal-sleeping young (mean age 25.6 years) volunteers received either ethanol (0.75 g/kg producing blood ethanol concentrations of 71.1 ± 24.3 mg/100 ml on average) or caffeine (4.0 mg/kg dissolved in 300 ml of 97% caffeine-free instant coffee) at 0920-0950 h after spending 5, 8, or 11 h time in bed (TIB) the previous night. Latency to sleep onset was tested at 1000, 1200, 1400, and 1600 h. Mean sleep latency differed significantly between drugs on each day of testing, with subjects being sleepier after ethanol than caffeine. On day 2 the TIB manipulation produced significant differences in latency, with the 11-h condition differing from both the 8- and 5-h conditions. The significant interaction revealed that in fully rested subjects (l1-h TIB), ethanol did not produce sleepiness to the degree it did after 5 or 8 h in bed. In this condition latencies were similar to those of the caffeine and 5- or 8-h TIBs.
