Time to Recover From Daily Caffeine Intake

Abstract

Caffeine elicits widespread effects in the central nervous system and is the most frequently consumed psychostimulant worldwide. First evidence indicates that, during daily intake, the elimination of caffeine may slow down, and the primary metabolite, paraxanthine, may accumulate. The neural impact of such adaptions is virtually unexplored. In this report, we leveraged the data of a laboratory study with N = 20 participants and three within-subject conditions: caffeine (150 mg caffeine × 3/day × 10 days), placebo (150 mg mannitol × 3/day × 10 days), and acute caffeine deprivation (caffeine × 9 days, afterward placebo × 1 day). On day 10, we determined the course of salivary caffeine and paraxanthine using liquid chromatography-mass spectrometry coupled with tandem mass spectrometry. We assessed gray matter (GM) intensity and cerebral blood flow (CBF) after acute caffeine deprivation as compared to changes in the caffeine condition from our previous report. The results indicated that levels of paraxanthine and caffeine remained high and were carried overnight during daily intake, and that the levels of paraxanthine remained elevated after 24 h of caffeine deprivation compared to placebo. After 36 h of caffeine deprivation, the previously reported caffeine-induced GM reduction was partially mitigated, while CBF was elevated compared to placebo. Our findings unveil that conventional daily caffeine intake does not provide sufficient time to clear up psychoactive compounds and restore cerebral responses, even after 36 h of abstinence. They also suggest investigating the consequences of a paraxanthine accumulation during daily caffeine intake.

Keywords: brain; caffeine; metabolism; paraxanthine; withdrawal.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Lin, Weibel, Landolt, Santini, Garbazza, Kistler, Rehm, Rentsch, Borgwardt, Cajochen and Reichert.

Figures

Figure 1

An overview of the study design. Each condition consisted of 9 ambulatory days (grey shading) and a subsequent 21-h laboratory measurement starting in the evening of day 9 (blue shading). The timing of caffeine or placebo intake is indicated by capsules (blue: caffeine, transparent: placebo), the timing of saliva collection to measure caffeine and paraxanthine levels is indicated by drops. Top: Caffeine condition. Caffeine capsules (150 mg caffeine) × 3 times/ day (at 45 min, 4 h, and 8 h after waking up) were administered throughout the 10 days. Saliva was collected repeatedly during the laboratory stay from right before the first capsule until 12 h after the latest caffeine intake. The MRI scan (grey bar) took place at 5.5 h after the latest caffeine intake. Middle: Acute caffeine deprivation. Caffeine capsules (150 mg caffeine) × 3 times/ day was administered for 8 days, followed by a switch to placebo capsules on day 9. Saliva was collected between 24 and 43 h after the latest caffeine intake. The MRI scan was scheduled at 36.5 h after the latest caffeine intake, a time window when strong withdrawal symptoms are often expressed (25). Bottom: Placebo condition. Placebo capsules (150 mg mannitol) × 3 times/ day were administered throughout the ambulatory and laboratory days. Saliva was collected at baseline through the entire laboratory phase at the corresponding time points as in the other two conditions. The MRI scan was scheduled at the same time of day as in the other two conditions.

Figure 2

The paraxanthine and caffeine concentrations at the respective time points and the dynamics of cerebral responses on the laboratory day (day 10) in daily caffeine and caffeine deprivation conditions, respectively. (A) juxtaposes the profiles of caffeine (squares) and paraxanthine (triangle) in caffeine condition (blue shading, left panel) and after the caffeine deprivation (red shading, right panel) against the duration after the latest dose of caffeine on the x-axis. Echoing Figure 1, the gradient red arrow parallel to the x-axis schematically indicates the duration of the caffeine deprivation. The times of treatments are denoted by blue capsules. Detailed statistics are addressed in the Result section. In brief, the main effects of conditions indicated that paraxanthine levels remained elevated throughout the caffeine and the caffeine deprivation conditions compared to placebo, while caffeine levels were elevated in caffeine conditions but did not significantly differ from placebo in the deprivation. Asterisks (*) indicated the time points exhibiting significantly elevated levels compared to placebo by a post-hoc analysis on the significant Condition x Sample interaction. (B) illustrates the magnitudes of the changes in hippocampal GM intensity (straight line) and the precuneus + subcortical CBF quantity (dashed line) during daily caffeine intake and after caffeine deprivation, relative to placebo (dotted horizontal line). The asterisks indicated significant differences compared to placebo. Detailed statistics are addressed in the Results section.

Figure 3

Associations of habitual daily intake and half-lives of caffeine and paraxanthine. (A,B) The negative association between habitual self-reported caffeine intake (mg/kg/day) and the half-life of caffeine and paraxanthine in the caffeine condition, respectively. (C) The association between habitual caffeine intake (mg/kg/day) and the ratio of AUC of paraxanthine (AUC-PX) to AUC of CA (AUC-CA). In (C) a high ratio of AUC-PX to AUC-CA indicates a larger disproportional accumulation between paraxanthine and caffeine.