Table 3.

Summary of the human epidemiological studies and the in vitro and in vivo animal studies investigating the effect of caffeine on Parkinson's disease (PD)

Parkinson's disease (PD)—human epidemiological studies
Reference	Participants	Duration	Main results	Conclusion
Postuma et al., 2012	61 PD patients Placebo: n=31 (19 M, 12 F) Caffeine: n=30 (25 M, 5 F) 65‐68 y	6 wk 1st three wk: 100 mg caffeine, 2×/d 2nd three wk: 200 mg caffeine, 2×/d	Improved the total UPDRS (unified Parkinson's disease rating scale) by 4.7 points Improved the motor manifestation by 3.2 points	Caffeine treatment in PD patients has potential motor benefits
Ross et al., 2000	8004 American Japanese men 53 y	27 y	Caffeine >421 mg of caffeine: 5× ↓ risk of developing PD vs nondrinkers, 2.6× ↓ risk vs 124‐208 mg/d, 3.8× ↓ risk vs 209‐287 mg/d, and 2× ↓ risk vs 288‐420 mg/d.	Caffeine has an inverse association with the risk of developing PD.
Liu et al., 2012	318 260 participants 187 499 women 130 761 men 61 y	9‐11 y	Coffee at >5 cups/d: ↓ risk of PD in men (OR=0.70, CI=0.47‐1.04) and women (OR=0.74, CI=0.42‐1.29) vs nonusers Women on hormone therapy: ↓ risk of PD development upon caffeine consumption 129‐511 mg/d OR=0.66 (CI=0.42‐1.05) vs intakes <17.4 mg/d 511‐590 mg/d OR=0.64 (CI=0.39‐1.04) vs intakes <17.4 mg/d >590 mg/d OR=0.53 (CI=0.28‐0.98) vs intakes <17.4 mg/d	Caffeine has an inverse association with the risk of developing PD.
Qi et al., 2014	492 722 participants for caffeine Women and men 901 764 participants for coffee Women and men	For every 200 mg/d increment of caffeine, risk of PD ↓ by 17% Coffee at ~ three cups/d (volume not identified): ↓ risk of PD (RR=0.72, CI=0.65‐0.81) Coffee at two cups/d: 26% ↓ risk of PD vs nonusers Coffee consumption (3 cups/d) ↓ PD risk in men (RR=0.68, CI=0.59‐0.78) and women (RR=0.76, CI=0.63‐0.93) vs nonusers	Coffee and caffeine consumption have inverse associations with the risk of developing PD.
Palacios et al., 2012	63 590 women 69 y 48 532 men 71 y	8 y	Men—caffeine at 120 mg/d: ↓ risk of PD by 38% (RR=0.62, CI=0.40‐0.95) vs 9.2 mg/d Men—caffeine at ≥274 mg/d (≥2 cups coffee/d) ↓ risk of PD by ~50% (RR=0.54, CI=0.37‐0.80) vs 9.2 mg/d Men—caffeine at 478 mg/d ↓ risk of PD (RR=0.43, CI=0.26‐0.71) vs 9.2 mg/d Women—caffeine at 435 mg/d (3.2 cups coffee/d) ↓ risk of PD by 40% (RR=0.61, CI=0.34‐1.09) vs 5.6 mg/d.	Caffeine has a protective effect against the risk of developing PD.
Hu et al., 2007	15 042 women 64.0 y 14 293 men 62.2 y	12.9 y	In men, 0, 1‐4 cups, and >5 cups of coffee (100 mL/cup) had a hazard ratio of 1.00, 0.55 (CI=0.26‐1.15) and 0.41 (CI=0.19‐0.88), respectively, of PD In women, 0, 1‐4 cups and >5 cups of coffee (100 mL/cup) had a hazard ratio of 1.00, 0.50 (CI=0.22‐1.12) and 0.39 (CI=0.17‐0.89), respectively, for PD.	Coffee drinking is associated with lower risk of developing PD
Ascherio et al., 2003	77 713 women 30‐55 y	18 y	Postmenopausal hormone users + ~1/2 a cup of coffee/d (68 mg/d of caffeine): ↓ 34% risk of PD Postmenopausal hormone users + five cups of coffee/d (688 mg/d of caffeine): ↑ 55% risk among	Use of postmenopausal hormone therapy was associated with a lower risk of PD in women with low caffeine intake, but it was associated with higher risk of PD in women with high caffeine intake.

Parkinson's disease—in vitro and in vivo animal studies
Reference	Subjects	Treatment	Main results	Conclusion
Bagga et al., 2015	PD mice n=10 control n=7 caffeine n=10 MPTP n=8 MPTP and caffeine Males 4 mo	0.9 mg of caffeine 8 d of caffeine administration 30 min prior to MPTP treatment	Caffeine: ↓ neuron damage in the striatum Caffeine: ↑ motor function (60.6% improvement in grip strength)	Pretreatment with caffeine provides partial neuroprotection against severe striatal degeneration in PD.
Sonsalla et al., 2012	Sprague Dawley rats n=5 per group Males Age not identified	Oral caffeine (1 g/L in drinking water—equivalent to 60‐80 mg/kg/d in humans and plasma concentrations at ~22 μmol/L)	Caffeine: ↓ loss of nigral dopamine cell bodies Caffeine at 1 wk or 3 wk: ↓ the loss of nigral cells by 94% and 69%, respectively Caffeine: ↓ microglia activation in the substantia nigra	Caffeine protects against the loss of nigral dopamine neurons in a chronic progressive rat model of PD.
Chen et al., 2001	C57BL6 mice n=13 MPTP n=5 saline Male 9 mo	Caffeine administered 10 min before MPTP administration (5, 10, 20, and 30 mg/kg)	Caffeine (10 mg/kg): residual dopamine was 40% of control vs 15% of control Caffeine (20 mg/kg): reversed MPTP‐induced dopamine depletion Caffeine at higher dosage caused excessive systemic toxicity.	There is a potential neural basis for the neuroprotection effects of caffeine in PD.
Xu et al., 2006	C57BL6 mice n=3‐7 saline treatment n=4‐15 MPTP Females and males Young: 10 wk Old: 6‐9 mo	10, 20, 40 mg/kg of caffeine treatment Caffeine administration 10 min before MPTP administration	Caffeine: ↓ MPTP‐induced dopamine loss (38% of the control dopamine levels) in a dose‐dependent manner in young male mice, with maximal effects achieved at 10 mg/kg (78% of the control dopamine levels with caffeine). In old male mice, MPTP‐induced dopamine loss (3% of control without caffeine) ↓ by caffeine pretreatment in a dose‐dependent manner, with 10 mg/kg of caffeine offering the most neuroprotective effect (~30% of control with caffeine). In female mice, caffeine ↓ toxicity only at 40 mg/kg. In ovariectomized mice treated with placebo (striatal dopamine 27% of control), caffeine at 5, 10, 20 mg/kg was neuroprotective. In ovariectomized mice treated with estrogen (striatal dopamine 39% of control), caffeine was neuroprotective only at higher doses (40 mg/kg). In males treated with estrogen, estrogen was neuroprotective, but caffeine in these mice did not attenuate their striatal dopamine loss.	Estrogen can prevent the neuroprotective effects of caffeine in a model of PD mice.
Nakaso et al., 2008	Human dopaminergic neuroblastoma cell lines	Caffeine concentrations (10 and 100 μmol/L)	Caffeine ↓cell death and ↓the number of apoptotic nuclei from 13.1% to 9.7% under MPP+‐exposed conditions Caffeine (10 and 100 μmol/L) ↓ caspase 3 in a dose‐dependent manner (21% and 23%, respectively), ↑ Akt phosphorylation (1.96‐fold and 2.96‐fold, respectively). Inhibiting PI3K/Akt pathway abolished caffeine's effects.	The neuroprotective effects of caffeine involve the PI3K/AKT pathway