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Caffeine Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.

CAFFEINE

Caffeine blocks the action of adenosine receptors, and in various brain regions, this class of receptors also interacts with dopamine receptors to counteract the effects of dopamine. By reducing the activity of adenosine receptors, caffeine increases dopamine activity, resulting in higher dopamine levels.

Caffeine is well tolerated at the most common doses, although high doses may cause agitation, jitteriness, insomnia, or increases in blood pressure and heart rate.

Scientific Rationale

A1 and A2A adenosine receptors are located in the striatum and are co-localized with D1 and D2 receptors (A1/D1 and A2A/D2).1-3 These adenosine receptors act functionally in an antagonistic fashion, opposing the actions of the dopamine receptors.4 Therefore, antagonism of these adenosine receptors results in the facilitation of dopaminergic post-synaptic transmission.

Caffeine, like other methylxanthines, are nonspecific antagonists at adenosine receptors (A1, A2).5-7 Caffeine has also been shown to modify dopamine release in various brain regions including the striatum.8-9

  1. J Neurochem 1991;57:1062-7.
  2. Mol Brain Res. 1992;14:186-95.
  3. NeuroReport 1994; 6:73-6.
  4. TINS 1997; 20:482-7.
  5. Life Sci 1981;28:2083-97.
  6. Acta Physiol Scan 1982; 115: 283-6.
  7. Pharmacol. Tox. 1995;76;93-101.
  8. J Pharm Pharmacol 1984;36:458-60.
  9. Neurosci Lett 1996;212:53-56.

Animal Model Data

RODENT: Although caffeine is a nonspecific antagonist, its affects on A2A receptors seem to be more important in mediating its anti-PD effects. This belief comes from the fact that rats with unilateral nigrostriatal 6-hydroxydopamine-induced lesions or those undergoing unilateral dopaminergic denervation have their impaired motor symptoms reversed with administration of caffeine.1-4 Symptom relief is comparable to that observed with administration of dopamine agonists alone.3,4 However, selective D2 antagonism will block the beneficial effect. In contrast co-administration of a selective D1 antagonist will have little detrimental effect on the lesioned rats rotational behaviors.3,4 One limitation found with caffeine's effects in PD is tolerance with repeated administration.5-8 For example, caffeine's effects on contralateral rotational behavior in 6-hydroxydopamine denervated rats decreases with repeated administration.5,6 This effect can be relatively rapid (within 1- week). Interestingly, tolerance with caffeine can be reversed with co-administration of the D2 receptor agonist, bromocriptine, however the D1 agonist, SKF38393, cannot does not reverse tolerance.9,10 There is also some evidence to suggest that caffeine may improve memory deficits observed in PD.11 In a rat model of PD-induced amnesia, (rats undergoing intra-nigral MPTP administration), animals pretreated with caffeine had significantly higher avoidance scores. This effect was independent of locomotor ability. However, caffeine's ability to improve memory and learning in this model was limited, in that the caffeine-MPTP treated animals scores never reached those of control animals.

In a murine MPTP model, caffeine pretreatment (5-20 mg/kg, 10 minutes before each MPTP injection) was able to decrease dopamine depletion (surrogate marker of striatal function) to 40% of that observed with controls.12 In addition loss of DAT binding sites (marker of dopaminergic function) was attenuated even after one week following caffeine administration. In this model doses of 5-20 mg/kg were safe and effective in preventing MPTP induced neurotoxicity, however higher doses were toxic and often lethal. Caffeine's protective effects could be mimicked by specific A2A antagonism (KW-6002) and by genetic inactivation (A2A knockout mice) of the A2 receptor. Recently, the role of A2A receptors in PD neuroprotection has been reaffirmed, by the observation that KW-6002, an A2A receptor antagonist, prevents DA neuronal loss in both 6-OHDA and MPTP treated rodents.13 These findings support the fact that caffeine's neuroprotective effects are mediated by its actions on the A2A receptor.

  1. Psychopharmacology 1988;94:38-45.
  2. Neuropharmacology 1989;28:407-409.
  3. J Pharmacology Exp Ther 1995;274;207-14.
  4. Neuroscience. 1992;51;501-12.
  5. J Pharmacol Exp Ther. 1991;256:62-68.
  6. Acta Physiol Scand. 1982;283-286.
  7. J Pharmacol Exp Ther. 1993;266:1563-72.
  8. Eur J Pharmacol. 1982;79:125-8.
  9. European Neuropsychopharmacology. 1999;9:515-521.
  10. Eur J Pharmacol. 2000;396:93-9.
  11. Brain Res Bull. 2001;55:101-6.
  12. J Neurosci. 2001; 21:RC143.
  13. J Neurochem. 2002;262-70.

Pharmacokinetics (including blood brain barrier (BBB) penetration)

In healthy patients clearance = 1.5 ml/kg/min, half life = 4.8 hours elimination slows with hepatic disease. In rat microdialysis studies a 30 mg/dose results in a free brain caffeine concentration of 120 µM.1 This suggests adequate CNS penetration.

  1. Life Sci. 1991;49:1843-52.

Safety/Tolerability in Humans

Well tolerated in common doses, may cause dose-related agitation, jitteriness insomnia or blood pressure, heart rate increases.

Drug Interaction Potential

Caffeine is not highly protein bound, however it is metabolized by CYP1A2 and is prone to hepatic enzyme inducing/inhibiting medications (including fluoxamine, clozapine, theophylline).1

  1. Clin Pharmacokinet. 2000;39:127-53.

Clinical Trial/Epidemiological Evidence in Human PD

Included below are the larger studies evaluating caffeine and the risk of PD. The available studies evaluating caffeine and PD prevention are overall positive, however they are limited, in that they are primarily retrospection/case-control in nature, or they do not assess caffeine intake in a well controlled manner. Typically, caffeine or coffee intake is assessed as a categorical variable (1-2 cups/day of coffee), hence there is also no definite dose or dose-range that has been evaluated.

Benedetti and colleagues reviewed medical records from the Rochester Epidemiology Project from 1976-1995 to identify patients who had developed PD (n=196).1 Incident cases were matched with respect to age and sex to a general control population in an attempt to identify risk factors (smoking/other tobacco use, coffee consumption or alcohol intake) associated for the development or prevention of PD. Of the PD cases 62% were men and 38% were women with median age of PD onset of 71 years (41-97). Coffee consumption was significantly more common in control subjects than in PD cases (OR =0.35, 95% CI= 0.16-0.78). There was also a significant trend of decreasing risk with the number of cups of coffee consumed (1-3 cups OR=0.56, >= 4, OR=0.18). Coffee's effects remained significant even after covariates were considered. Coffee was also associated with a significant delay in the onset of PD (median onset PD no coffee 72 (42-97) years, with coffee consumption 64 (41-80) years, p=0.0002). Among other variables considered, cigarette smoking was less common in PD cases than control subjects however, statistical significance was not reached (OR=0.69, 95% CI=0.45-1.08). Cigarette smoking was not associated with a later onset of PD in those who did and did not smoke. The incidence of pipe and cigar smoking was also comparable in case and control patients. In contrast, tobacco chewing or snuff use was significantly more common in control subjects than in PD cases (OR=0.18, 95% CI=0.04-0.82). In regards to alcohol use, control subjects were also more likely to be diagnosed with alcoholism than PD cases (OR=0.41, 95% CI= 0.19-0.89).

The association of caffeine, particularly coffee intake and PD was also evaluated as of a part of a 30-year follow-up study of 8004 Japanese American men (45-68 years) participating in the Honolulu Heart Program.2 Data were collected through records obtained through hospital records and death certificates (retrospective) and prospectively through office visits occurring after 1991. Caffeine intake was assessed through dietary notes obtained at visits. As part of the study, subjects were asked about their dietary consumption of caffeinated products within the previous 24-hour diary period. This value was extrapolated to the entire week. Information regarding smoking history was also assessed and used as a covariant in the analysis. Median age at enrollment was 53 years (45-68) with a median follow-up of 27 years (0.8-30). Among all the patients 102, (1.3%) developed PD with onset occurring at a median age of 73.6 years (54-89 years). The median time between baseline examination and PD diagnosis was 16.6 years (2-30 years). Those who consumed caffeine had a significantly lower incidence of PD than those who did not (p <0.001). For example, the adjusted incidence of PD decreased from 10.4:10,000 person-years in those who did not consume coffee to 1.9:10,000 person years for those who consumed at least 28 ounces/day. This effect was dose-related with increased caffeine consumption inversely correlated with the risk of developing PD (p<0.01). Caffeine's statistical associations were consistent in smokers and nonsmokers and when data were analyzed for coffee and non-coffee intake caffeine sources.

Ascherio and colleagues evaluated the incidence of PD in 47,351 men and 88,565 women who were involved health care professionals. Subjects were followed prospectively through a series of life style questionnaires containing among other things the quantity of caffeine-containing products consumed and development of PD. Questionnaires were administered at baseline and every 2-4 years and any self-report of PD or PD-like symptoms was evaluated by a physician to confirm the diagnosis of PD. Median follow-up in the study was 10 years in men and 16 years in women. In this time, 157 (0.3%) men and 131 (0.1%) women developed PD. After adjusting for age and smoking, there was a significant inverse relationship in coffee intake and the development of PD (p<0.004). The relative risk (95% CI) compared to coffee nonconsumers was <1 cup/day-0.8 (0.5-1.2), 1-3 cups/day-0.6 (0.4-0.9), 4-5 cups/day 0.5 (0.2-1.2) and 0.6 (0.2-2.6). In women a U-shaped relationship between coffee intake and the development of PD was found. The lowest incidence for the development of PD in women was in the 1-3 cups/day of coffee group. The relative risk (95% CI) compared to coffee nonconsumers in women was <1 cup/day-1.1 (0.6-2.2), 1-3 cups/day-0.6 (0.4-0.9), 4-5 cups/day 1 (0.6-1.7) and 0.6 (0.5-2.2). Among both groups when the total amount of daily caffeine was estimated and results were reanalyzed results remained similar to that observed when only coffee was considered. (Note that association between a decreased risk of PD and decaffeinated coffee was not observed). Interestingly, in this study any association between caffeine and PD risk was less apparent in women.

  1. Neurology 2000;55:1350-7.
  2. JAMA 2000;283:2674-9.
  3. Ann Neurol. 2001;50:56-63.

Last updated February 09, 2005