Many face an initial stress response from coffee, flee from it, and lose its numerous health benefits. Coffee’s side effects subside in within two weeks of continuous consumption, and even moderate consumption has health benefits.
Complete tolerance to caffeine’s effects on the central nervous system develops after 18 days of chronic consumption:
“Subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days…after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group. This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.”
Caffeine continues to raise blood pressure even after tolerance develops:
“BP responses to caffeine above those found on placebo-placebo (P-P) week were found for both tolerance groups when caffeine was consumed after a week of receiving a placebo.”
Even low doses (<75 mg) of caffeine improve exercise performance, but tolerance develops to this effect, so athletes should consume more:
“…performance benefit was no longer apparent after 4 weeks of caffeine supplementation, but was retained in the placebo group…chronic ingestion of a low dose of caffeine develops tolerance in low-caffeine consumers…individuals with low-habitual intakes should refrain from chronic caffeine supplementation to maximize performance benefits from acute caffeine ingestion.”
In rats, after about 2 weeks, the anxiogenic effects of caffeine diminishes completely as tolerance develops:
“Adenosine receptors to fully upregulate to caffeine’s antagonism. It seems that a gradual increase in caffeine dosage, and maybe co-administration with a benzodiazepine during the 14-day period will completely eliminate any side effects from caffeine.”
Tolerance to caffeine develops after 14 to 21 days of chronic consumption:
“Subchronic administration of caffeine for 21 days, in different groups of animals, induced a significant degree of tolerance…statistically significant after 14 and 21 days.”
Caffeine anxiety appears around 48 hours after the last time of consumption:
“When caffeine was withdrawn after 21 days administration, to a separate group of rats, significant withdrawal anxiety was observed 48 h later as noted in the elevated plus-maze test. The investigations support clinical evidence of caffeine-induced anxiety, tolerance to anxiety on continued use, and withdrawal anxiety in chronic caffeine-containing beverage users.”
Caffeine shows promising effects in Parkinson’s disease at around the 3-week mark:
“Patients with PD with daytime somnolence were given caffeine 100 mg twice daily ×3 weeks, then 200 mg twice daily ×3 weeks, or matching placebo. Caffeine reduced the total Unified Parkinson’s Disease Rating Scale score (−4.69 points; −7.7, −1.6) and the objective motor component (−3.15 points; −5.50, −0.83).”
“In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.”
Signs of caffeine withdrawal include headache, fatigue, anxiety, cognitive impairment, nausea, vomiting, and caffeine craving:
“…headache and fatigue are the most frequent withdrawal symptoms, with a wide variety of other signs and symptoms occurring at lower frequency (e.g. anxiety, impaired psychomotor performance, nausea/vomiting and craving).”\
Caffeine withdrawals begins the same day of cessation, worsens the following day, and lasts for about a week:
“The withdrawal syndrome has an onset at 12-24 h, peak at 20-48 h, and duration of about 1 week.”
The vast majority of caffeine users experience caffeine withdrawal:
“The proportion of heavy caffeine users who will experience withdrawal symptoms has been estimated from experimental studies to range from 25% to 100%.”
Partial tolerance develops to caffeine’s effects of slowing reducing cerebral blood flow and mood, but it continues to raise blood pressure and improve cognitive performance:
“Twelve healthy volunteers were randomized using a double-blind, cross-over design to take either 200 mg caffeine or placebo twice daily for 1 week. Following baseline measurements being made, the responses to 200 mg caffeine (blood-pressure, middle cerebral artery velocity, mood and cognitive performance) were examined over the subsequent 120 min. Blood glucose was not allowed to fall. …middle cerebral artery blood velocity decreased in both conditions but was greater in the placebo group. Systolic blood pressure rise was not significantly different. Mood was adversely affected by regular caffeine consumption with tense aspect of mood significantly higher at baseline in the caffeine group. Cognitive performance was not affected by previous caffeine exposure. Tolerance is incomplete with respect to both peripheral or central effects of caffeine.”
Further evidence of the initiation of physical dependency points to a period of adenosine adaptation of one to two weeks:
“Withdrawal symptoms have been documented after relatively short-term exposure to high doses of caffeine (i.e. 6-15 days of greater than or equal to 600 mg/day).”
Substances that lower cortisol can help caffeine adaptation and include adequate carbohydrate as sugar, aspirin, niacinamide, pregnenolone, progesterone, l-theanine, taurine, glycine and anti-serotonin drugs that also lower adrenaline including cyproheptadine and mirtazapine.
References
Evans, S. M., & Griffiths, R. R. (1992). Caffeine tolerance and choice in humans. Psychopharmacology, 108(1–2), 51–59.
Thirty-two healthy subjects with histories of moderate caffeine consumption abstained from dietary caffeine throughout the study. Subjects were stratified into two groups based on several factors including caffeine preference, which was assessed using a caffeine versus placebo choice procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days, and thereafter were exposed again to a caffeine versus placebo choice procedure. The study documented tolerance development to the subjective effects of caffeine: after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group. The study also provided indirect evidence for tolerance development: during chronic dosing, the chronic caffeine and placebo groups did not differ meaningfully on ratings of mood and subjective effect. When subjects were categorized into caffeine choosers or nonchoosers, caffeine choosers tended to report positive subjective effects of caffeine and negative subjective effects of placebo. Nonchoosers, in contrast, tended to report negative subjective effects of caffeine. Chronic caffeine did not alter the reinforcing effects of caffeine as assessed by caffeine versus placebo choice, possibly because the relatively short duration of caffeine abstinence in the placebo condition was not sufficient to result in maximal withdrawal effects after termination of the relatively high caffeine dose. This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.
Ammon, H. P. (1991). Biochemical mechanism of caffeine tolerance. Archiv Der Pharmazie, 324(5), 261–267.
Most of the biological actions of caffeine are possibly mediated through its antagonistic effects to adenosine. Adenosine activates an inhibitory GTP-binding protein (Gi). One of the physiological actions of Gi is the inhibition of cAMP formation. Caffeine overcomes this action thus leading to elevation of cAMP. Firing of neurons and the release of neurotransmitters is also inhibited by adenosine. Caffeine overcomes this effect, thus producing increased CNS-activity. During long term administration of caffeine many functions of the organism develop tolerance including cardiovascular and central nervous systems. Present evidence suggests that caffeine tolerance following continuous severe coffee ingestion is the response of the body against caffeine through the upregulation of adenosine receptors.
Farag, N. H., Vincent, A. S., Sung, B. H., Whitsett, T. L., Wilson, M. F., & Lovallo, W. R. (2005). Caffeine Tolerance is Incomplete: Persistent Blood Pressure Responses in the Ambulatory Setting. American Journal of Hypertension, 18(5 Pt 1), 714–719. https://doi.org/10.1016/j.amjhyper.2005.03.738
Background Caffeine in dietary doses is a well-established pressor agent. Tolerance to this pressor effect occurs in only about half of regular consumers in acute laboratory tests. The clinical significance of this incomplete tolerance depends on whether the pressor effect is maintained throughout the day with repeated intake. Therefore, we examined the ability of a standard dose of caffeine (250 mg × 3) to maintain a blood pressure (BP) elevation during 18 hours of ambulatory BP monitoring (ABPM) after 5 days of regular daily intake of varying background doses. Methods Eighty-five men and women completed a four-week double blind, crossover trial. During each week, subjects consumed capsules totaling 0, 300, or 600 mg/day of caffeine in 3 divided doses. On day 6, they consumed capsules with either 0 or 250 mg at 9:00 am and 1:00 pm, in the laboratory, and again at 6:00 pm during ABPM. Tolerance was defined as a reduction in the diastolic BP response to two challenge doses given in the lab in response to increasing daily intake. Data were analyzed using multivariate repeated measures analysis of variance. Results BP responses to caffeine above those found on placebo-placebo (P-P) week were found for both tolerance groups when caffeine was consumed after a week of receiving a placebo. However, only the low tolerance group showed increases, above those found on P-P week, after 300 mg/day in systolic/diastolic BP during the waking hours (mean ± standard error of the mean = 2.8 ± 1.1, P = .01/2.2 ± 0.9, P = .02) and in systolic BP during sleep (2.3 ± 1, P = .03). Conclusions Persistent elevations in BP occurring on a daily basis in some habitual caffeine consumers may hold clinical significance.
Beaumont, R., Cordery, P., Funnell, M., Mears, S., James, L., & Watson, P. (2017). Chronic ingestion of a low dose of caffeine induces tolerance to the performance benefits of caffeine. Journal of Sports Sciences, 35(19), 1920–1927. https://doi.org/10.1080/02640414.2016.1241421
This study examined effects of 4 weeks of caffeine supplementation on endurance performance. Eighteen low-habitual caffeine consumers (<75 mg · day(-1)) were randomly assigned to ingest caffeine (1.5-3.0 mg · kg(-1)day(-1); titrated) or placebo for 28 days. Groups were matched for age, body mass, V̇O2peak and Wmax (P > 0.05). Before supplementation, all participants completed one V̇O2peak test, one practice trial and 2 experimental trials (acute 3 mg · kg(-1) caffeine [precaf] and placebo [testpla]). During the supplementation period a second V̇O2peak test was completed on day 21 before a final, acute 3 mg · kg(-1) caffeine trial (postcaf) on day 29. Trials consisted of 60 min cycle exercise at 60% V̇O2peak followed by a 30 min performance task. All participants produced more external work during the precaf trial than testpla, with increases in the caffeine (383.3 ± 75 kJ vs. 344.9 ± 80.3 kJ; Cohen’s d effect size [ES] = 0.49; P = 0.001) and placebo (354.5 ± 55.2 kJ vs. 333.1 ± 56.4 kJ; ES = 0.38; P = 0.004) supplementation group, respectively. This performance benefit was no longer apparent after 4 weeks of caffeine supplementation (precaf: 383.3 ± 75.0 kJ vs. postcaf: 358.0 ± 89.8 kJ; ES = 0.31; P = 0.025), but was retained in the placebo group (precaf: 354.5 ± 55.2 kJ vs. postcaf: 351.8 ± 49.4 kJ; ES = 0.05; P > 0.05). Circulating caffeine, hormonal concentrations and substrate oxidation did not differ between groups (all P > 0.05). Chronic ingestion of a low dose of caffeine develops tolerance in low-caffeine consumers. Therefore, individuals with low-habitual intakes should refrain from chronic caffeine supplementation to maximise performance benefits from acute caffeine ingestion.
Bhattacharya, S. K., Satyan, K. S., & Chakrabarti, A. (1997). Anxiogenic action of caffeine: an experimental study in rats. Journal of Psychopharmacology (Oxford, England), 11(3), 219–224. https://doi.org/10.1177/026988119701100304
The anxiogenic action of caffeine (10, 25 and 50 mg/kg, i.p.) was investigated in rats and compared with that of yohimbine (2 mg/kg, i.p.). The experimental methods used were the open-field, elevated plus-maze, social interaction and novelty-suppressed feeding latency tests. Caffeine produced a dose-related profile of behavioural changes, which were qualitatively similar to those induced by yohimbine and which indicate an anxiogenic activity in rodents. Thus, both the drugs reduced ambulation and rears, and increased immobility and defaecation in the open-field test. They decreased the number of entries and time spent on the open arms of the elevated-plus maze, reduced social interaction in paired rats and increased the feeding latency in an unfamiliar environment in 48-h food-deprived rats. Lorazepam, a well known benzodiazepine anxiolytic agent, attenuated the anxiogenic effects of caffeine and yohimbine. Subchronic administration of caffeine (50 mg/kg, i.p.) for 21 days, in different groups of animals, induced a significant degree of tolerance in the elevated plus-maze test, which was statistically significant after 14 and 21 days’ treatment. Yohimbine, however, did not induce similar tolerance. When caffeine (50 mg/kg, i.p.) was withdrawn after 21 days’ administration, to a separate group of rats, significant withdrawal anxiety was observed 48 h later as noted in the elevated plus-maze test. The investigations support clinical evidence of caffeine-induced anxiety, tolerance to anxiety on continued use, and withdrawal anxiety in chronic caffeine-containing beverage users.
Postuma, R. B., Lang, A. E., Munhoz, R. P., Charland, K., Pelletier, A., Moscovich, M., … Shah, B. (2012). Caffeine for treatment of Parkinson disease. Neurology, 79(7), 651–658. https://doi.org/10.1212/WNL.0b013e318263570d
Objective: Epidemiologic studies consistently link caffeine, a nonselective adenosine antagonist, to lower risk of Parkinson disease (PD). However, the symptomatic effects of caffeine in PD have not been adequately evaluated. Methods: We conducted a 6-week randomized controlled trial of caffeine in PD to assess effects upon daytime somnolence, motor severity, and other nonmotor features. Patients with PD with daytime somnolence (Epworth >10) were given caffeine 100 mg twice daily ×3 weeks, then 200 mg twice daily ×3 weeks, or matching placebo. The primary outcome was the Epworth Sleepiness Scale score. Secondary outcomes included motor severity, sleep markers, fatigue, depression, and quality of life. Effects of caffeine were analyzed with Bayesian hierarchical models, adjusting for study site, baseline scores, age, and sex. Results: Of 61 patients, 31 were randomized to placebo and 30 to caffeine. On the primary intention-to-treat analysis, caffeine resulted in a nonsignificant reduction in Epworth Sleepiness Scale score (−1.71 points; 95% confidence interval [CI] −3.57, 0.13). However, somnolence improved on the Clinical Global Impression of Change (+0.64; 0.16, 1.13, intention-to-treat), with significant reduction in Epworth Sleepiness Scale score on per-protocol analysis (−1.97; −3.87, −0.05). Caffeine reduced the total Unified Parkinson’s Disease Rating Scale score (−4.69 points; −7.7, −1.6) and the objective motor component (−3.15 points; −5.50, −0.83). Other than modest improvement in global health measures, there were no changes in quality of life, depression, or sleep quality. Adverse events were comparable in caffeine and placebo groups. Conclusions: Caffeine provided only equivocal borderline improvement in excessive somnolence in PD, but improved objective motor measures. These potential motor benefits suggest that a larger long-term trial of caffeine is warranted. Classification of evidence: This study provides Class I evidence that caffeine, up to 200 mg BID for 6 weeks, had no significant benefit on excessive daytime sleepiness in patients with PD.
Rogers, P. J., Hohoff, C., Heatherley, S. V., Mullings, E. L., Maxfield, P. J., Evershed, R. P., … Nutt, D. J. (2010). Association of the Anxiogenic and Alerting Effects of Caffeine with ADORA2A and ADORA1 Polymorphisms and Habitual Level of Caffeine Consumption. Neuropsychopharmacology, 35(9), 1973–1983. https://doi.org/10.1038/npp.2010.71
Caffeine, a widely consumed adenosine A1 and A2A receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine. Participants were 162 non-/low (NL) and 217 medium/high (MH) caffeine consumers. In a randomized, double-blind, parallel groups design they rated anxiety, alertness, and headache before and after 100 mg caffeine and again after another 150 mg caffeine given 90 min later, or after placebo on both occasions. Caffeine intake was prohibited for 16 h before the first dose of caffeine/placebo. Results showed greater susceptibility to caffeine-induced anxiety, but not lower habitual caffeine intake (indeed coffee intake was higher), in the rs5751876 TT genotype group, and a reduced anxiety response in MH vs NL participants irrespective of genotype. Apart from the almost completely linked ADORA2A SNP rs3761422, no other of eight ADORA2A and seven ADORA1 SNPs studied were found to be clearly associated with effects of caffeine on anxiety, alertness, or headache. Placebo administration in MH participants decreased alertness and increased headache. Caffeine did not increase alertness in NL participants. With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.
Griffiths, R. R., & Woodson, P. P. (1988). Caffeine physical dependence: a review of human and laboratory animal studies. Psychopharmacology, 94(4), 437–451.
Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been poorly characterized in laboratory animals and only moderately well characterized in humans. In humans, a review of 37 clinical reports and experimental studies dating back to 1833 shows that headache and fatigue are the most frequent withdrawal symptoms, with a wide variety of other signs and symptoms occurring at lower frequency (e.g. anxiety, impaired psychomotor performance, nausea/vomiting and craving). When caffeine withdrawal occurs, severity can vary from mild to extreme (i.e. incapacitating). The withdrawal syndrome has an onset at 12-24 h, peak at 20-48 h, and duration of about 1 week. The pharmacological specificity of caffeine withdrawal has been established. The proportion of heavy caffeine users who will experience withdrawal symptoms has been estimated from experimental studies to range from 25% to 100%. Withdrawal symptoms have been documented after relatively short-term exposure to high doses of caffeine (i.e. 6-15 days of greater than or equal to 600 mg/day). Although animal and human studies suggest that physical dependence may potentiate the reinforcing effects of caffeine, human studies also demonstrate that a history of substantial caffeine intake is not a necessary condition for caffeine to function as a reinforcer. The similarities and differences between caffeine and classic drugs of abuse are discussed.
Watson, J., Deary, I., & Kerr, D. (2002). Central and peripheral effects of sustained caffeine use: tolerance is incomplete. British Journal of Clinical Pharmacology, 54(4), 400–406. https://doi.org/10.1046/j.1365-2125.2002.01681.x
Aims It is widely held that tolerance develops to the effects of sustained caffeine consumption. This study was designed to investigate the effects of chronic, staggered caffeine ingestion on the responses of an acute caffeine challenge, during euglycaemia. Methods Twelve healthy volunteers were randomized using a double-blind, cross-over design to take either 200 mg caffeine (C-replete) or placebo (C-naïve) twice daily for 1 week. Following baseline measurements being made, the responses to 200 mg caffeine (blood-pressure, middle cerebral artery velocity, mood and cognitive performance) were examined over the subsequent 120 min. Blood glucose was not allowed to fall below 4.0 mmol l−1. Results After the caffeine challenge, middle cerebral artery blood velocity decreased in both conditions but was greater in the C-naïve condition (−8.0 [-10.0, −6.1] cm s−1 vs −4.9 [-6.8, −2.9] cm s−1 C-replete, P < 0.02). Systolic blood pressure rise was not significantly different in C-naïve, although this rise was more sustained over time (P < 0.04). Mood was adversely affected by regular caffeine consumption with tense aspect of mood significantly higher at baseline in C-replete 11.6 ± 0.6 C-naïve vs 16.3 ± 1.6 C-replete, P < 0.01). Cognitive performance was not affected by previous caffeine exposure. Conclusions Overall these results suggest that tolerance is incomplete with respect to both peripheral or central effects of caffeine.
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