Habitual caffeine consumption moderates the antidepressant effect of dorsomedial intermittent theta-burst transcranial magnetic stimulation.

BACKGROUND: Potentiating current antidepressant treatment is much needed. Based on animal studies, caffeine may augment the effects of currently available antidepressants. OBJECTIVE: Here, we tested whether habitual caffeine consumption moderates the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS) using intermittent theta-burst stimulation (iTBS). METHODS: Forty patients with current depressive episodes were randomized to active iTBS (n = 19) or sham treatment (n = 21; shielded side of the coil and weak transcutaneous electrical stimulation) delivered two times per day for 10-15 weekdays. Neuronavigated stimulation was applied to the dorsomedial prefrontal cortex. Symptom improvement was measured using change in self-reported Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Pretreatment habitual caffeine consumption was quantified using self-reports of number of cups of coffee and energy drinks consumed the 2 days before the treatment starts. RESULTS: Habitual caffeine consumption was associated with symptom improvement following active iTBS (r = 0.51, 95% confidence interval (CI): 0.08-0.78, p = 0.025) but not following sham treatment (r = -0.02, 95% CI: -0.45 to 0.42, p = 0.938). A multiple regression analysis corroborated the findings by showing a significant caffeine consumption × treatment group interaction (ß = 0.62, p = 0.043), but no main effects of treatment group (ß = 0.22, p = 0.140) or caffeine consumption (ß = -0.01, p = 0.948). No group differences in pretreatment symptom scores or caffeine consumption were detected (p values > 0.86). CONCLUSION: Habitual caffeine consumption moderated the antidepressant effect of dorsomedial iTBS, consistent with caffeine improving antidepressant pharmacological treatments in animals. Caffeine is an antagonist of adenosine receptors and may enhance antidepressant effects through downstream dopaminergic targets.

Habitual Caffeine Consumption Does Not Interfere With the Acute Caffeine Supplementation Effects on Strength Endurance and Jumping Performance in Trained Individuals.

The long-standing caffeine habituation paradigm was never investigated in strength endurance and jumping exercise performance through a straightforward methodology. The authors examined if habitual caffeine consumption would influence the caffeine ergogenic effects on strength endurance and jumping performance as well as perceptual responses. Thirty-six strength-trained individuals were mathematically allocated into tertiles according to their habitual caffeine consumption: low (20 ± 11 mg/day), moderate (88 ± 33 mg/day), and high consumers (281 ± 167 mg/day). Then, in a double-blind, crossover, counterbalanced fashion, they performed a countermovement vertical jump test and a strength endurance test either after caffeine (6 mg/kg) and placebo supplementation or after no supplementation (control). Perceptual responses such as ratings of perceived exertion and pain were measured at the termination of the exercises. Acute caffeine supplementation improved countermovement vertical jump performance (p = .001) and total repetitions (p = .004), regardless of caffeine habituation. Accordingly, analysis of absolute change from the control session showed that caffeine promoted a significantly greater improvement in both countermovement vertical jump performance (p = .004) and total repetitions (p = .0001) compared with placebo. Caffeine did not affect the rating of perceived exertion and pain in any exercise tests, irrespective of tertiles (for all comparisons, p > .05 for both measures). Caffeine side effects were similar in low, moderate, and high caffeine consumers. These results show that habitual caffeine consumption does not influence the potential of caffeine as an ergogenic aid in strength endurance and jumping exercise performance, thus challenging recommendations to withdraw from the habitual caffeine consumption before supplementing with caffeine.

Coffee effectively attenuates impaired attention in ADORA2A C/C-allele carriers during chronic sleep restriction.

Many people consume coffee to attenuate increased sleepiness and impaired vigilance and attention due to insufficient sleep. We investigated in genetically caffeine sensitive men and women whether 'real world' coffee consumption during a simulated busy work week counteracts disabling consequences of chronically restricted sleep. We subjected homozygous C-allele carriers of ADORA2A (gene encoding adenosine A2A receptors) to five nights of only 5 h time-in-bed. We administered regular coffee (n = 12; 200 mg caffeine at breakfast and 100 mg caffeine after lunch) and decaffeinated coffee (n = 14) in double-blind fashion on all days following sleep restriction. At regular intervals four times each day, participants rated their sleepiness and performed the psychomotor vigilance test, the visual search task, and the visuo-spatial and letter n-back tasks. At bedtime, we quantified caffeine and the major caffeine metabolites paraxanthine, theobromine and theophylline in saliva. The two groups did not differ in age, body-mass-index, sex-ratio, chronotype and mood states. Subjective sleepiness increased in both groups across consecutive sleep restriction days and did not differ. By contrast, regular coffee counteracted the impact of repeated sleep loss on sustained and selective attention, as well as executive control when compared to decaffeinated coffee. The coffee also induced initial or transient benefits on different aspects of baseline performance during insufficient sleep. All differences between the groups disappeared after the recovery night and the cessation of coffee administration. The data suggest that 'real world' coffee consumption can efficiently attenuate sleep restriction-induced impairments in vigilance and attention in genetically caffeine sensitive individuals. German Clinical Trial Registry: # DRSK00014379.

Defining a Time Window for Neuroprotection and Glia Modulation by Caffeine After Neonatal Hypoxia-Ischaemia.

Hypoxic-ischemic (HI) brain injury remains an important cause of brain damage in neonates with potential life-long consequences. Caffeine, which is a competitive inhibitor of adenosine receptors, is commonly used as treatment for preterm apnoea in clinical settings. In the current study, we investigated the effects of caffeine given at 0 h, 6 h, 12 h or 24 h after HI in P10 mouse pups. Open field and rotarod behavioural tests were performed 2 weeks after injury, and brain morphology was then evaluated. Gene expression and immunohistological analyses were assessed in mice 1- and 5-day post-HI. A single dose of caffeine directly after HI resulted in a reduction of the lesion in the grey and white matter, judged by immunostaining of MAP2 and MBP, respectively, compared to PBS-treated controls. In addition, the number of amoeboid microglia and apoptotic cells, the area covered by astrogliosis, and the expression of pro-inflammatory cytokines were significantly decreased. Behavioural assessment after 2 weeks showed increased open-field activity after HI, and this was normalised if caffeine was administered immediately after the injury. Later administrations of caffeine did not change the outcomes when compared to the vehicle group. In conclusion, caffeine only yielded neuroprotection and immunomodulation in a neonatal model of brain hypoxia ischaemia if administered immediately after injury.

Coffee time: Low caffeine dose promotes attention and focus in zebrafish.

In this study we investigated the ability of zebrafish to discriminate visual signs and associate them with a reward in an associative-learning protocol including distractors. Moreover, we studied the effects of caffeine on animal performance in the task. After being trained to associate a specific image pattern with a reward (food) in the presence of other, distractor images, the fish were challenged to locate the exact cue associated with the reward. The distractors were same-colored pattern images similar to the target. Both the target and distractors were continually moved around the tank. Fish were exposed to three caffeine concentrations for 14 days: 0 mg/L (control, n = 12), 10 mg/L (n = 14), and 50 mg/L (n = 14). Zebrafish spent most of the time close to the target (where the reward was offered) under the effects of 0 and 10 mg/L caffeine, and the shortest latency to reach the target was observed for the 10-mg/L caffeine group. Both caffeine treatments (10 and 50 mg/L) increased the average speed and distance traveled when compared to the control group. This study confirms previous results showing that zebrafish demonstrate conditioned learning ability; however, low-dose caffeine exposure seems to favor visual cue discrimination and to increase zebrafish performance in a multicue discrimination task, in which primarily focus and attention are required in order to obtain the reward.

Disagreement between splenic switch-off and myocardial T1-mapping after caffeine intake.

Caffeine is an adenosine receptor antagonist and a possible cause of inadequate stress perfusion. Splenic switch-off (SSO) and splenic rest-stress T1-mapping have been proposed as indicators of stress adequacy during perfusion cardiac magnetic resonance (CMR). We compared myocardial rest-stress T1-mapping with SSO and splenic rest-stress T1-mapping in patients with and without recent coffee intake. We analyzed 344 consecutive patients suspected of myocardial ischemia with adenosine perfusion CMR. All 146 normal CMR studies with a normal T1-rest of the myocardium, used as standard of reference, were included and divided in two groups. 22 patients accidentally ingested coffee < 4 h before CMR, compared to control group of 124 patients without self-reported coffee intake. Two independent readers graded SSO visually. T1-reactivity (ΔT1) was defined as percentual difference in T1-rest and T1-stress. Follow-up data were extracted from electronic patients records. In patients with recent coffee intake SSO was identified in 96%, which showed no significant difference with SSO in controls (94%, p = 0.835), however event rates were significantly different (13.6 and 0.8%, respectively (p < 0.001), median FU 17 months). Myocardial ΔT1 in the coffee group (- 5.2%) was significantly lower compared to control (+ 4.0%, p < 0.001), in contrast to the splenic ΔT1 (- 3.7 and - 4.0%, p = 0.789). The splenic T1-mapping results failed to predict false negative results. SSO and splenic rest-stress T1-mapping are not reliable indicators of stress adequacy in patients with recent coffee intake. Therefore, the dark spleen sign does not indicate adequate myocardial stress in patients with recent caffeine intake. Myocardial rest-stress T1-mapping is an excellent indicator of stress adequacy during adenosine perfusion CMR.

Effects of caffeine intake prior to stress cardiac magnetic resonance perfusion imaging on regadenoson- versus adenosine-induced hyperemia as measured by T1 mapping.

The antagonistic effects of caffeine on adenosine receptors are a possible cause of false-negative stress perfusion imaging. The purpose of this study was to determine the effects of coffee intake <4 h prior to stress perfusion cardiac magnetic resonance imaging (CMR) in regadenoson- versus adenosine-induced hyperemia as measured with T1-mapping. 98 consecutive patients with suspected coronary artery disease referred for either adenosine or regadenoson perfusion CMR were included in this analysis. Twenty-four patients reported coffee consumption <4 h before CMR (15 patients with adenosine, and 9 patients with regadenoson); 74 patients reported no coffee intake (50 patients with adenosine, and 24 patients with regadenoson). T1 mapping was performed using a modified look-locker inversion recovery sequence. T1 reactivity was determined by subtracting T1rest from T1stress. T1rest, T1stress, and T1 reactivity in patients referred for regadenoson perfusion CMR were not significantly different when comparing patients with <4 h coffee intake and patients who reported no coffee intake (976 ± 4 ms, 1019 ± 48 ms, and 4.4 ± 3.2% vs 971 ± 33 ms, 1023 ± 43 ms, and 5.4 ± 2.4%) (p = 0.70, 0.79, and 0.40), and similar to values in patients without coffee intake undergoing adenosine CMR. In patients with <4 h coffee intake, T1stress, and T1 reactivity were significantly lower for adenosine (898 ± 51 ms, and -7.8 ± 5.0%) compared to regadenoson perfusion CMR (p < 0.001). Coffee intake <4 h prior to regadenoson perfusion CMR has no effect on stress-induced hyperemia as measured with T1 mapping.

Caffeine intake increases plasma ketones: an acute metabolic study in humans.

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

A Multicenter Clinical Study on Treating Post-Dural Puncture Headache with an Intravenous Injection of Aminophylline.

BACKGROUND: Post-dural puncture headache (PDPH) is the most common complication of lumbar puncture. Aminophylline has been reported to be effective in the prevention of PDPH in some clinical studies, but its efficacy for the treatment of PDPH has been unproven. OBJECTIVE: To evaluate the efficacy and safety of an intravenous (IV) injection of aminophylline on PDPH. STUDY DESIGN: The study was a multicenter, open-label study to assess the effectiveness and safety of aminophylline on PDPH. SETTING: The First Affiliated Hospital of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, and Henan Province Hospital of Traditional Chinese Medicine. METHODS: Thirty-two PDPH patients received an IV injection of aminophylline. The primary and secondary endpoints were the degree of headache and the patient's overall response to the treatment, respectively. Treatment safety was evaluated based on the occurrence of adverse reactions. RESULTS: Thirty-one patients completed the study. Before the initial aminophylline administration, the visual analog scale (VAS) score was 7.72 ± 1.65. The VAS scores at 30 minutes, one hour, 8 hours, one day, and 2 days post-treatment were 4.84 ± 2.53, 3.53 ± 2.06, 2.38 ± 1.96, 1.44 ± 1.87, and 0.81 ± 1.79, respectively, and were statistically significantly different (P < 0.05) compared with those before treatment. More than 50% (17/32) of the patients reported that they were "very much improved" or "much improved" 30 minutes after the initial treatment, increasing to 93.8% (30/32) at 2 days post-treatment. One patient experienced mild allergic reaction after treatment. LIMITATIONS: Although this study had the largest sample size among current studies on treating PDPH with theophylline drugs, the sample size was still relatively small and the method employed was not compared with a placebo or other current clinical treatments for PDPH. CONCLUSION: An IV injection of aminophylline may be an effective and safe early-stage treatment for PDPH.

Prenatal and developmental toxicity study of meclizine and caffeine combination in female albino Wistar rats.

Meclizine and caffeine combination is used for the treatment of morning sickness. Both compounds are teratogenic and caffeine is known to possess anti-fertility activity also. The present study was undertaken to evaluate the reproductive toxic effect of meclizine and caffeine combination. Three doses were taken for the study; low dose (LD; meclizine 3.7 mg/kg and caffeine 3 mg/kg) was selected from commercially available formulation, middle dose (MD; meclizine 37 mg/kg and caffeine 30 mg/kg) and high dose (HD; meclizine 370 mg/kg and caffeine 300 mg/kg). The mixture was administered 1-7 days and 8-14 days for fertility and embryotoxic studies respectively. Laparotomy was done on 10t day of gestation period. Number of implants and corpora lutea were counted, pre and post-implantation losses were determined. In embryo toxicity study fetuses were evaluated for external, skeletal and visceral examination. High dose was removed from both fertility and embryotoxicity studies due to its severe toxicity to the dam. Significant anti-fertility activity was observed at middle dose. Embryotoxicity study showed significant reduction in fetal body weight, body length and body mass index, dam body weight gain on gestation day 14. Absolute kidney weight in MD and absolute and relative spleen weight in both LD and MD were significantly reduced. There was no increase in external or internal congenital anomalies at both LD and MD. The, results suggest that prescription of meclizine and caffeine for morning sickness in early pregnancy should be reviewed carefully.