High-dose Caffeine Research Articles

Impact of Early- and High-Dose Caffeine on the Cerebellum Development in Newborn Rats

Introduction: Preterm newborns struggle with maintaining an adequate respiratory pattern; early caffeine administration is suggested to stimulate respiration and reduce bronchopulmonary dysplasia, however, its consequences on the immature cerebellum remains unknown. This study aimed to assess the impact of early caffeine administration, at standard and high doses, accompanied by supplemental oxygen on cerebellar development in an experimental model. Methods: Five groups of Wistar pups were formed (n = 8 offspring/group): (a) negative control: no intervention; (b) placebo: pups remaining from birth until the 7th day of life (DOL) exposed to fractional inspired oxygen (FiO2) 45%, resembling preterm infant condition and as a placebo, 0.2 mL oral 5% dextrose, from the first DOL until the 14th DOL; (c) caffeine group: oral caffeine, 1st DOL 20 mg/kg, and from 2nd to 14th DOL, 5 mg/kg (standard dose); (d) caffeine at the standard dose, plus O2: during the first 7 DOLs (FiO2: 45%); (e) caffeine: 40 mg/kg in the first DOL, 10 mg/kg the next 14 DOLs, plus O2 in the first 7 DOLs (FiO2: 45%). Subjects were sacrificed on their 15th DOL; measurements were taken from the cerebellum, specifically the external granular layer (EGL) and molecular layer (ML), with quantification of cell migration. Results: Caffeine administration in pups resulted in a delay in cerebellum development based on persistent transitional EGL cells; this finding was exacerbated in groups exposed to caffeine plus O2, as evident from the thicker EGL. The negative control group showed near-complete cell migration with a thicker ML and a significantly smaller EGL. Conclusions: Early caffeine administration in newborn rats disrupts cerebellar cortex cell processes and connectivity pathways, with exacerbated effects in groups receiving caffeine plus O2.

Potential of high dose caffeine citrate to cause intracranial hemorrhage in a premature rat model

Potential of high dose caffeine citrate to cause intracranial hemorrhage in a premature rat model

A cost-effectiveness analysis for high versus standard (low) dose caffeine for the treatment of apnea in neonatal intensive care unit

A cost-effectiveness analysis for high versus standard (low) dose caffeine for the treatment of apnea in neonatal intensive care unit

Is Early High-Dose Caffeine citrate Improves Outcomes in Preterm Infants?

Is Early High-Dose Caffeine citrate Improves Outcomes in Preterm Infants?

The neuroprotective effect of exogen melatonin upon fetal hippocampus damage caused by high-dose caffeine administration in pregnant rats.

The aim of this study is to evaluate whether exogenous melatonin (MEL) mitigates the deleterious effects of high-dose caffeine (CAF) administration in pregnant rats upon the fetal hippocampus. A total of 32 adult Wistar albino female rats were divided into four groups after conception (n = 8). At 9-20 days of pregnancy, intraperitoneal (i.p.) MEL was administered at a dose of 10mg/kg/day in the MEL group, while i.p. CAF was administered at a dose of 60 mg/kg/day in the CAF group. In the CAF plus MEL group, i.p. CAF and MEL were administered at a dose of 60 and 10mg/kg/day, respectively, at the same period. Following extraction of the brains of the fetuses sacrificed on the 21st day of pregnancy, their hippocampal regions were analyzed by hematoxylin and eosin and Cresyl Echt Violet, anti-GFAP, and antisynaptophysin staining methods. While there was a decrease in fetal and brain weights in the CAF group, it was found that the CAF plus MEL group had a closer weight average to that of the control group. Histologically, it was observed that the pyramidal cell layer consisted of 8-10 layers of cells due to the delay in migration in hippocampal neurons in the CAF group, while the MEL group showed similar characteristics with the control group. It was found that these findings decreased in the CAF plus MEL group. It is concluded that high-dose CAF administration causes a delay in neurogenesis of the fetal hippocampus, and exogenous MEL is able to mitigate its deleterious effects.

The Effects of Prolonged Use of Caffeine on Thyroid and Adrenal Glands: A Retrospective Cohort Study

Abstract Background: Caffeine consumption has skyrocketed in recent decades as we try to match the pace with the machines. Studies have been conducted on animals and a few on humans, mainly on the acute effects of high-dose caffeine intake. Almost none have been conducted on the chronic effects of caffeine consumption. This study involved medical professionals as case subjects, who consumed caffeine daily. Methods: This study, for 3 months, involved 96 volunteers (chosen randomly w.r.t. gender and field in the medical fraternity), including people who drank >500 mg of caffeine a day and people who consumed none. People with any comorbidities at all were excluded straight away. Two sets of blood samples were drawn and assessed. Three groups were created: group 1 (>200 mg caffeine/day), group 2 (15–200 mg caffeine/day) and group 3 (<200 mg caffeine/day). Results: The result of the study found that exposure to caffeine at doses >200 mg/day for more than 6 months leads to a significant difference in circulating free T3 ((-0.96 pmol/L ± 0.07) = (-18.5%), 95% confidence interval (CI), P = .000024) and cortisol ((-123 nmol/L ± 9.8) = (-46.8%), 95% CI, P = .00029) hormones but shows an insignificant effect on circulating thyroid-stimulating hormone (TSH) (0.4 mIU/L, 95% CI, P = .37) and adrenocorticotrophic hormone (ACTH) ((-3.2 pg/ml ± 0.3), 95% CI, P = .53) hormones, which stay within normal physiological ranges, irrespective of the daily dose of consumption. Results also highlight that women are more susceptible to a decrement in fT3 than men (relative risk = 1.58, analysis of variance (ANOVA) F-static = 7.15, P = 0.0105). Conclusions: Caffeine consumption in excess of 200 mg/day, for more than or equal to 6 months, causes significant derangement in basal fT3 and cortisol hormone levels, without affecting the TSH and ACTH (regulatory) hormone levels, indicating disturbance of action at the peripheral and/or cellular levels, possibly via the paraventricular nucleus (PVN)–leptin–CAR–adenosine interactions. Women are more susceptible to a decrement in fT3 levels than men (at the same dose of caffeine).

Diagnostic Ultrasound-Based Investigation of Central vs. Peripheral Arterial Changes Consequent to Low-Dose Caffeine Ingestion.

Caffeine is present in various foods and medicines and is highly accessible through various routes, regardless of age. However, most studies on caffeine have focused on the effects of high-dose caffeine ingestion based on the recommended daily amount for adults. In this study, we examined the physiological changes in the central and peripheral vessels that may occur when ingesting low-dose caffeine due to its high accessibility, with the aim of creating an environment of safe caffeine ingestion. This study included 26 healthy participants in their 20s. Peak systolic velocity (PSV), heart rate (HR), and pulse wave velocity (PWV) for vascular stiffness assessment were measured at 0, 30, and 60 min after caffeine ingestion using diagnostic ultrasound to determine the physiological changes in the blood vessels, common carotid artery (CCA) and radial artery (RA). In addition, percutaneous oxygen saturation (SpO2), blood pressure (BP), and accelerated photoplethysmography (APG) were measured. In comparison with before ingestion, the HR tended to decrease and showed a significant difference at 30 and 60 min (p = 0.014 and p = 0.031, respectively). PSV significantly decreased in both vessels at 30 and 60 min (p < 0.001 and p < 0.001, respectively). APG showed a decreasing trend until 60 min after ingestion, with a significant difference at 30 and 60 min (p = 0.003 and p = 0.012, respectively). No significant difference was observed in SpO2, BP, or PWV; however, they showed a tendency to increase after ingestion. Decreased HR may occur because of the baroreflex caused by an increase in BP. The RA has many branches and a smaller diameter; therefore, the PSV was lower in the RA than that in the CCA. This effect can occur because of the difficulty in the smooth expansion of blood vessels, which leads to a decrease in blood flow. In addition, an increase in intracellular calcium concentration can prevent vasodilation and increase the propagation velocity of pulse waves. The reflected waves can increase systolic blood pressure but reduce PWV and vascular elasticity. These results suggest that even low-dose caffeine can improve blood vessel health by providing temporary stimulation to the blood vessels; however, it can also cause changes in blood flow and blood vessel elasticity, which can lead to serious diseases such as stroke and high blood pressure. Therefore, caution should be exercised when caffeine consumption is indiscriminate.

Determining the impact of caffeine on aggression in Betta splendens

Caffeine is a naturally occurring chemical stimulant found in various products that is becoming more widespread. Around 90% of the world's population consumes caffeine daily, which is absorbed and released into the body in the form of fluids. Consequently, caffeine has appeared in aquatic environments around the world as wastewater contains human fluids that contain caffeine. However, its effects and safety for the health of humans and wildlife remain inconclusive. Thus, in our study, we investigated the impact of varying caffeine concentrations on the aggressive behavior of the Siamese fighting fish Betta splendens territory holders after seeing an intruder. We compared aggression among four experimental groups, including the control group without any caffeine added, low dose caffeine (120 µg/L), medium dose caffeine (200 µg/L), and high dose caffeine (280 µg/L). We predicted that if there was an increase in the caffeine concentration, then the B. splendens would exhibit more aggressive behaviors because of the natural tendency of caffeine to stimulate movement. We found that caffeine exposure did not significantly alter male territory-holding behavior in B. splendens. A better understanding of the relationship between the biological systems of B. splendens responsible for aggressive behavior and caffeine is needed to clarify the urgency of the issue of increasing caffeine concentrations found in bodies of water worldwide.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity.

Combined Exposure to Chronic Sleep Deprivation and Caffeine Potentiates Behavioural Deficits by Altering Neurochemical Profile and Synaptophysin Expression in Long-Evans Rats.

Using the Unpredictable Chronic Sleep Deprivation (UCSD) paradigm we developed, the combined effects of chronic sleep deprivation and high caffeine intake on prefrontal cortical synaptophysin expression, neurochemical profiles, and behavioural outcomes in Long-Evans rats were evaluated. The combination of chronic sleep deprivation and high-dose caffeine treatment produced varying degrees of behavioural impairments, depletion of antioxidants, serotonin, and an upregulation of acetylcholinesterase (AChE) activity in the prefrontal cortex. An immunohistochemical assessment revealed a reduction in synaptophysin protein expression in the prefrontal cortex following exposure to high-dose caffeine and chronic sleep deprivation. Overall, our findings support the advocacy for adequate sleep for optimal mental performance as a high intake of caffeine to attenuate the effects of sleep deprivation that may alter the neurochemical profile and synaptic plasticity in the prefrontal cortex, significantly increasing the risk of neuropsychiatric/degenerative disorders.

Spatial Regulation Control of Oxygen Metabolic Consumption in Mouse Brain.

The mammalian brain relies on significant oxygen metabolic consumption to fulfill energy supply, brain function, and neural activity. In this study, in vivo electrochemistry is combined with physiological and ethological analyses to explore oxygen metabolic consumption in an area of the mouse brain that includes parts of the primary somatosensory cortex, primary motor cortex, hippocampus, and striatum. The oxygen levels at different locations of this boundary section are spatially resolved by measuring the electrical current in vivo using ingeniously designed anti-biofouling carbon fiber microelectrodes. The characteristics of the current signals are further interpreted by simultaneously recording the physiological responses of the mice. Additionally, ethological tests are performed to validate the correlation between oxygen levels and mouse behavior. It is found that high-dose caffeine injection can evoke spatial variability in oxygen metabolic consumption between the four neighboring brain regions. It is proposed that the oxygen metabolic consumption in different brain regions is not independent of each other but is subject to spatial regulation control following the rules of "rank of brain region" and "relative distance." Furthermore, as revealed by in vivo wireless electrochemistry and ethological analysis, mice are at risk of neuronal damage from long-term intake of high-dose caffeine.

Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington's Disease.

There is a controversy about potentially positive or negative effects of caffeine consumption on onset and disease progression of neurodegenerative diseases such as Huntington’s Disease (HD). On the molecular level, the psychoactive drug caffeine targets in particular adenosine receptors (AR) as a nonselective antagonist. The aim of this study was to evaluate clinical effects of caffeine consumption in patients suffering from premanifest and motor-manifest HD. Data of the global observational study ENROLL-HD were used, in order to analyze the course of HD regarding symptoms onset, motor, functional, cognitive and psychiatric parameters, using cross-sectional and longitudinal data of up to three years. We split premanifest and manifest participants into two subgroups: consumers of >3 cups of caffeine (coffee, cola or black tea) per day (>375 mL) vs. subjects without caffeine consumption. Data were analyzed using ANCOVA-analyses for cross-sectional and repeated measures analysis of variance for longitudinal parameters in IBM SPSS Statistics V.28. Within n = 21,045 participants, we identified n = 1901 premanifest and n = 4072 manifest HD patients consuming >3 cups of caffeine/day vs. n = 841 premanifest and n = 2243 manifest subjects without consumption. Manifest HD patients consuming >3 cups exhibited a significantly better performance in a series of neuropsychological tests. They also showed at the median a later onset of symptoms (all p < 0.001), and, during follow-up, less motor, functional and cognitive impairments in the majority of tests (all p < 0.050). In contrast, there were no beneficial caffeine-related effects on neuropsychological performance in premanifest HD mutation carriers. They showed even worse cognitive performances in stroop color naming (SCNT) and stroop color reading (SWRT) tests (all p < 0.050) and revealed more anxiety, depression and irritability subscores in comparison to premanifest participants without caffeine consumption. Similarly, higher self-reported anxiety and irritability were observed in genotype negative/control group high dose caffeine drinkers, associated with a slightly better performance in some cognitive tasks (all p < 0.050). The analysis of the impact of caffeine consumption in the largest real-world cohort of HD mutation carriers revealed beneficial effects on neuropsychological performance as well as manifestation and course of disease in manifest HD patients while premanifest HD mutation carrier showed no neuropsychological improvements, but worse cognitive performances in some tasks and exhibited more severe signs of psychiatric impairment. Our data point to state-related psychomotor-stimulant effects of caffeine in HD that might be related to regulatory effects at cerebral adenosine receptors. Further studies are required to validate findings, exclude potential other unknown biasing factors such as physical activity, pharmacological interventions, gender differences or chronic habitual influences and test for dosage related effects.

Clinical effect of different maintenance doses of caffeine citrate in the treatment of preterm infants requiring assisted ventilation: a pilot multicenter study.

To explore the optimal maintenance dose of caffeine citrate for preterm infants requiring assisted ventilation and caffeine citrate treatment. A retrospective analysis was performed on the medical data of 566 preterm infants (gestational age ≤34 weeks) who were treated and required assisted ventilation and caffeine citrate treatment in the neonatal intensive care unit of 30 tertiary hospitals in Jiangsu Province of China between January 1 and December 31, 2019. The 405 preterm infants receiving high-dose (10 mg/kg per day) caffeine citrate after a loading dose of 20 mg/kg within 24 hours after birth were enrolled as the high-dose group. The 161 preterm infants receiving low-dose (5 mg/kg per day) caffeine citrate were enrolled as the low-dose group. Compared with the low-dose group, the high-dose group had significant reductions in the need for high-concentration oxygen during assisted ventilation (P=0.044), the duration of oxygen inhalation after weaning from noninvasive ventilation (P<0.01), total oxygen inhalation time during hospitalization (P<0.01), the proportion of preterm infants requiring noninvasive ventilation again (P<0.01), the rate of use of pulmonary surfactant and budesonide (P<0.05), and the incidence rates of apnea and bronchopulmonary dysplasia (P<0.01), but the high-dose group had a significantly increased incidence rate of feeding intolerance (P=0.032). There were no significant differences between the two groups in the body weight change, the incidence rates of retinopathy of prematurity, intraventricular hemorrhage or necrotizing enterocolitis, the mortality rate, and the duration of caffeine use (P>0.05). This pilot multicenter study shows that the high maintenance dose (10 mg/kg per day) is generally beneficial to preterm infants in China and does not increase the incidence rate of common adverse reactions. For the risk of feeding intolerance, further research is needed to eliminate the interference of confounding factors as far as possible.

Five-year outcomes of premature infants randomized to high or standard loading dose caffeine.

Objective:To examine five-year outcomes in children enrolled in a pilot randomized controlled trial of a high loading dose of caffeine after preterm birthStudy design:Seventy-four very low birth weight neonates were randomized within the first 24 hours of life to receive a high (80 mg/kg) or standard (20 mg/kg) loading dose of caffeine citrate. At five years of age, we conducted standardized neurodevelopmental tests and collected parent reports of child socioemotional problems.Result:Seventy-four percent of survivors returned for follow up. Children obtained similar scores on neurodevelopmental and socioemotional evaluations. There was no difference in the incidence of any neurodevelopmental delay after controlling for confounding factors.Conclusion:Five year follow up of a pilot trial of high loading dose caffeine citrate documented no profound impacts on childhood neurodevelopment or socioemotional outcome.

Effect of different maintenance doses of caffeine citrate on ventilator weaning in very preterm infants with respiratory distress syndrome: a prospective randomized controlled trial.

To study the effect of different maintenance doses of caffeine citrate on the success rate of ventilator weaning in very preterm infants (gestational age of ≤32 weeks) with respiratory distress syndrome (RDS). A total of 162 preterm infants with RDS who were admitted to the hospital from January 2016 to December 2018 were enrolled in this prospective trial. These infants had a gestational age of ≤32 weeks and required invasive mechanical ventilation. They were randomly divided into a high-dose caffeine group and a low-dose caffeine group, with 81 infants in each group. Within 6 hours after birth, both groups were given caffeine at a dose of 20 mg/kg. After 24 hours, the high- and low-dose caffeine groups were given caffeine at a maintenance dose of 10 mg/kg and 5 mg/kg, respectively. The two groups were compared in terms of re-intubation rate within 48 hours after ventilator weaning, durations of ventilation and oxygen therapy, enteral feeding, weight gain, and the incidence rates of complications and adverse reactions during hospitalization. The high-dose caffeine group had a significantly lower re-intubation rate within 48 hours after ventilator weaning than the low-dose caffeine group (P<0.05), with frequent apnea as the main reason for failed ventilator weaning in both groups. The high-dose caffeine group had significantly shorter durations of mechanical ventilation and oxygen therapy than the low-dose caffeine group (P<0.05). There were no significant differences between the two groups in the time to total enteral feeding, average daily weight gain, body weight at discharge, and the incidence rates of complications (bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and intracranial hemorrhage) and adverse reactions (tachycardia, hypertension, and feeding intolerance) (P>0.05). A high maintenance dose of caffeine can safely and effectively reduce the incidence rate of apnea after ventilator weaning and the failure rate of ventilator weaning in RDS preterm infants with a gestational age of ≤32 weeks, and therefore, it holds promise for clinical application.

Effects of Caffeine Consumption on Autologous Full-Thickness Skin Graft Healing in an Animal Model.

Background There exists contradictory evidence that states both the beneficial and deleterious effects of caffeine on wound healing. The general population might unknowingly consume caffeine that negatively affects wound healing. The main objective of this study is to investigate the effect of daily caffeine consumption on wound healing, specifically full-thickness skin graft (FTSG). Methods Forty Sprague–Dawley rats were randomized into four groups of equal size: control-dose (CD), low-dose (LD), medium-dose (MD), and high-dose (HD) caffeine groups. After autologous FTSG, all subjects in the intervention group were given daily pure caffeine gavage. The FTSG was explanted 7 days posttransplant. The graft viability, secondary contraction, and adherence were evaluated macroscopically, while fibroblast and collagen deposition was analyzed microscopically with hematoxylin eosin stain. Results The least graft viability (72.8 ± 20.7%, clinical wound assessment scale [CWAS] 2.4), highest secondary contraction (11.4 ± 10.5%), and fibroblast count (331.8 ± 88.6 cells/5 high power fields) were observed in the MD group. More collagen synthesis was observed in subjects who consumed caffeine. The level of secondary contraction, fibroblast count as well as graft viability and collagen synthesis were positively correlated. Conclusions Daily consumption of caffeine impairs graft viability when given in medium dose and increases collagen synthesis, irrespective of dosage. This study was in experimental rats; the results are not directly translatable to humans.

Early High-Dose Caffeine Improves Respiratory Outcomes in Preterm Infants

The objective of the study is to determine if early high-dose caffeine (HD) therapy is associated with shorter duration of mechanical ventilation, bronchopulmonary dysplasia (BPD), or decreased need for mechanical ventilation. We conducted a single center, retrospective cohort study of 273 infants less than 32 weeks gestational age (GA). Infants receiving early HD (10 mg/kg/day maintenance) caffeine citrate started within 24 h of life were compared with those receiving LD (6 mg/kg/day) with variable timing of initiation using linear and logistic regression models. The infants in the early HD group had 91.4 (95% confidence interval (CI): −166.6, −16.1; p = 0.018) less hours of mechanical ventilation up to 36 weeks PMA or discharge as compared with the LD group. Moreover, infants in the HD group had 0.37 (95% CI: 0.14, 0.97; p = 0.042) times lower odds of developing moderate/severe BPD compared with the LD group. Infants receiving early HD caffeine had improved respiratory outcomes with no increase in measured comorbidities. Large prospective studies are needed to determine the long-term outcomes of using high-dose caffeine prophylaxis for preterm infants.

Caffeine disrupts ataxia telangiectasia mutated gene-related pathways and exacerbates acetaminophen toxicity in human fetal immortalized hepatocytes

Preterm infants are at greater risk for adverse drug effects due to hepatic immaturity. Multiple interventions during intensive care increases potential for drug interactions. In this setting, high-dose caffeine used for apnea in premature infants may increase acetaminophen toxicity by inhibiting ataxia telangiectasia mutated (ATM) gene activity during DNA damage response. To define caffeine and acetaminophen interaction, we modeled infantile prematurity in late-gestation fetal stage through human immortalized hepatocytes and liver organoids. The acute toxicity studies included assays for cell viability, mitochondrial dysfunction and ATM pathway-related DNA damage. Fetal cells expressed hepatobiliary properties, albeit with lower metabolic, synthetic and antioxidant functions than more mature hepatocytes. Acetaminophen in IC50 amount of 7.5 millimolar caused significant oxidative stress, mitochondrial membrane potential impairments, and DNA breaks requiring ATM-dependent repair. Caffeine markedly exacerbated acetaminophen toxicity by suppressing ATM activity in otherwise nontoxic 2.5 millimolar amount. Similarly, the specific ATM kinase antagonist, KU-60019, reproduced this deleterious interaction in 5 micromolar amount. Replicative stress from combined acetaminophen and caffeine toxicity depleted cells undergoing DNA synthesis in S phase and activated checkpoints for G0/G1 or G2/M restrictions. Synergistic caffeine and acetaminophen toxicity in liver organoids indicated these consequences should apply in vivo. The antioxidant, N-acetylcysteine, decreased oxidative damage, mitochondrial dysfunction and ATM pathway disruption to mitigate caffeine and acetaminophen toxicity. We concluded that hepatic DNA damage, mitochondrial impairment and growth-arrest after combined caffeine and acetaminophen toxicity will be harmful for premature infants. Whether caffeine and acetaminophen toxicity may alter outcomes in subsequently encountered hepatic disease needs consideration.

A short-term effect of caffeinated beverages on blood pressure: A meta-analysis of randomized controlled trails

• Caffeinated beverages intake for less than four weeks elevated blood pressure. • The acute BP increasing effect was greater in the adolescent than in the adult. • Less than 1 week caffeine intake increased BP more markedly than over one week. • High-dose caffeine drinking raised DBP and both high and low-dose increased SBP. Blood pressure alteration after taking caffeinated beverages is controversial. We performed a meta -analysis to synthesize the evidence on the relation between short time caffeinated beverages consumption and blood pressure from randomized controlled trials. PubMed and Web of Science were systematically searched. Ultimately 11 articles and 470 enrolled subjects were included in the present meta -analysis. Fixed-model was used to assess the relationship between caffeine and blood pressure alteration across all included studies. We found an overall blood pressure elevation of 3.04/2.45 mmHg for short-term (within four weeks) caffeinated beverages intake. In adolescent population, BP increased 5.31/2.26 mmHg. In the adult group, the BP increased 2.67/2.55 mmHg. Less than one week of caffeine consumption increased BP by 5.23/2.14 mmHg. More than one week caffeine consumption elevated BP by 2.62/2.66 mmHg. This meta -analysis indicates the possibility of increase in blood pressure in a young population with caffeinated beverages.

Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia.

(1) Background: Caffeine citrate, at standard doses, is effective for reducing the incidence of apnea of prematurity (AOP) and may confer neuroprotection and decrease neonatal morbidities in extremely low gestational age neonates (ELGANs) requiring oxygen therapy. We tested the hypothesis that high-dose caffeine (HiC) has no adverse effects on the neonatal brain. (2) Methods: Newborn rat pups were randomized to room air (RA), hyperoxia (Hx) or neonatal intermittent hypoxia (IH), from birth (P0) to P14 during which they received intraperitoneal injections of LoC (20 mg/kg on P0; 5 mg/kg/day on P1-P14), HiC (80 mg/kg; 20 mg/kg), or equivalent volume saline. Blood gases, histopathology, myelin and neuronal integrity, and adenosine receptor reactivity were assessed. (3) Results: Caffeine treatment in Hx influenced blood gases more than treatment in neonatal IH. Exposure to neonatal IH resulted in hemorrhage and higher brain width, particularly in layer 2 of the cerebral cortex. Both caffeine doses increased brain width in RA, but layer 2 was increased only with HiC. HiC decreased oxidative stress more effectively than LoC, and both doses reduced apoptosis biomarkers. In RA, both caffeine doses improved myelination, but the effect was abolished in Hx and neonatal IH. Similarly, both doses inhibited adenosine 1A receptor in all oxygen environments, but adenosine 2A receptor was inhibited only in RA and Hx. (4) Conclusions: Caffeine, even at high doses, when administered in normoxia, can confer neuroprotection, evidenced by reductions in oxidative stress, hypermyelination, and increased Golgi bodies. However, varying oxygen environments, such as Hx or neonatal IH, may alter and modify pharmacodynamic actions of caffeine and may even override the benefits caffeine.