Istradefylline: The Adenosine Blocker for Parkinson's Disease

Table of Contents

1. What "Off" Episodes Are
2. Adenosine A2A Receptors and the Movement Circuit
3. The Coffee Connection
4. The Trials That Showed Less "Off" Time
5. The Trials That Did Not Show a Benefit
6. What the Pooled Numbers Add Up To
7. The 2008 Non-Approval, Japan and the 2019 Approval
8. Side Effects Listed on the Label
9. Hallucinations and Impulse Control
10. Smoking and Drug Interactions
11. Liver Disease, Pregnancy and the Animal Findings
12. Smaller Studies Beyond "Off" Time
13. What Is Not Known
14. Key Research Papers
15. Connections
16. Featured Videos

What "Off" Episodes Are

Parkinson's disease involves the loss of brain cells that make dopamine, and levodopa is the medicine the brain converts into dopamine. Early in treatment a dose can seem to last all day. Over the years, many people notice the benefit fading before the next dose is due. Doctors call this wearing-off, and the stretches of stiffness, slowness or shaking that return are called "off" time. "On" time is when the medicine is working.

A second problem can appear during "on" time. Dyskinesia means involuntary movements, often writhing or jerking, that are a side effect of dopamine treatment. Trials separate dyskinesia that is troublesome from dyskinesia that does not interfere with daily life, which is why the phrase "on time without troublesome dyskinesia" recurs in this research.

These problems are common:

• In a study of 301 people with early Parkinson's disease followed for 48 to 58 months, 62.8% developed motor fluctuations, dyskinesia or both. Higher cumulative levodopa doses were associated with earlier onset (Hauser 2006).
• In an Italian study of 617 people treated for an average of 6.6 years, neurologists identified wearing-off in 56.9%, while a self-rated questionnaire identified it in 67.3%. The most frequent symptoms were slowness of movement (55.8%) and reduced dexterity (48.8%) (Stocchi 2014).

Patients in the main istradefylline trials had the disease for 9 years on average and were spending about 6 hours a day "off" before the study began, according to the label. They recorded their state in 24-hour diaries, and those diaries produced the main result of nearly every trial below.

Adenosine A2A Receptors and the Movement Circuit

Deep in the brain, a group of structures called the basal ganglia helps start and smooth movement. It is often described as having two routes: a direct pathway that favors movement and an indirect pathway that holds movement back. Dopamine normally keeps the two in balance. When dopamine runs low, the holding-back route becomes too active.

Adenosine A2A receptors are concentrated in this circuit, on the motor pathways leaving the part of the basal ganglia called the striatum (LeWitt 2020; Dungo 2013). In the indirect pathway they sit alongside dopamine D2 receptors, and the two work against each other. Switching on the adenosine receptor makes the neighboring D2 receptor respond less to dopamine-like drugs (Berger 2020). The reasoning behind the drug follows from that: blocking the adenosine receptor could quiet the overactive pathway without adding more dopamine.

Three points keep that explanation in proportion:

• The United States label states that the precise way istradefylline works in Parkinson's disease is unknown. Its blocking action on the adenosine A2A receptor was shown in laboratory and animal studies.
• A brain-scan study using positron emission tomography in 10 patients found that the drug binds these receptors in people, more so at the higher dose. The modeled maximum occupancy was 93.5% in the ventral striatum, 69.5% in the caudate and 66.8% in the putamen. Receptor availability did not differ significantly between the patients and 6 healthy people of similar age (Ishibashi 2018).
• The label covers the drug only as an addition to levodopa with carbidopa, not as a treatment on its own.

A 2020 review describes it as the first non-dopamine drug approved by the United States Food and Drug Administration (FDA) for Parkinson's disease in two decades (Chen 2020).

The Coffee Connection

Caffeine also blocks adenosine receptors, but it is not selective, meaning it acts on more than one type (Postuma 2012). The label describes istradefylline as having a xanthine structure, the chemical family caffeine belongs to. The site's caffeine and adenosine animation shows the basic idea.

Population studies link caffeine and coffee to a lower risk of developing the disease:

• In 8,004 Japanese-American men followed for 30 years, 102 developed Parkinson's disease. Age-adjusted incidence fell from 10.4 per 10,000 person-years in men who drank no coffee to 1.9 in men who drank at least 28 ounces a day (Ross 2000).
• In a European cohort of 184,024 people, the highest coffee drinkers had a hazard ratio of 0.63 compared with non-drinkers, a roughly 37% lower rate. Higher blood caffeine years before diagnosis also went with lower risk among 351 cases and 351 matched controls (Zhao 2024).

These studies show an association. They cannot prove that coffee is the cause, and they concern developing the disease, not treating it. When caffeine was tested as a treatment in people who already had Parkinson's disease, the results were different:

• A 6-week trial in 61 patients gave caffeine up to 200 mg twice daily. The main measure, daytime sleepiness, did not change significantly, while total and motor rating scores improved by 4.69 and 3.15 points (Postuma 2012).
• A larger trial gave 121 patients caffeine 200 mg twice daily or placebo for 6 to 18 months. Motor scores did not improve, with a difference of 0.48 points (95% confidence interval -3.21 to 2.25). Dyskinesia was slightly higher and cognitive test scores averaged 0.66 points worse on caffeine (Postuma 2017).

The authors of the larger trial concluded that the link between caffeine and lower risk does not appear to be explained by effects on symptoms. The site's page on coffee and Parkinson's disease covers the food side in more depth. The istradefylline label makes no statement about coffee or caffeine.

The Trials That Showed Less "Off" Time

All of these were 12-week, placebo-controlled trials in people already taking levodopa. The last four listed below are the ones whose results appear on the United States label, as identified in a 2022 review (Isaacson 2022).

• 2003, exploratory (83 patients). The trial gave up to 20 or up to 40 mg a day, with 19 outcomes and no main outcome chosen in advance. The share of waking time spent "off" fell by 7.1% on the drug and rose by 2.2% on placebo. "Off" time fell by 1.2 hours against a rise of 0.5 hours. Time "on" with dyskinesia increased, and overall rating scores showed no difference (Hauser 2003).
• 2008, 6002-US-006 (395 patients). The trial gave 20 or 60 mg a day. The share of "off" time fell by 4.35% and 4.49% more than placebo, which was significant. In hours, the differences were 0.64 and 0.77, with an overall treatment effect that missed significance (p = 0.065) (Stacy 2008).
• 2008, North America, 6002-US-005 (196 patients). The trial gave 40 mg a day. Daily "off" time fell by 1.8 hours against 0.6 hours on placebo (p = 0.005) (LeWitt 2008).
• 2008, United States, 6002-US-013 (231 patients). The trial gave 20 mg a day. "Off" time fell by 0.7 hours more than placebo (p = 0.03), and 5.2% on the drug against 6.1% on placebo withdrew because of side effects (Hauser 2008).
• 2010, Japan (363 patients). The trial gave 20 or 40 mg a day. "Off" time fell by 1.31 and 1.58 hours against 0.66 hours on placebo (Mizuno 2010).
• 2013, Japan (373 patients). The trial gave 20 or 40 mg a day. "Off" time fell by 0.99 and 0.96 hours against 0.23 hours on placebo (Mizuno 2013).

The placebo groups improved too, by more than half an hour in some trials, so the figure to read is the gap between drug and placebo. In the five later trials that gap ranged from about 38 minutes to about 72 minutes a day.

Two longer follow-ups had no placebo group, so they cannot separate the drug's effect from other influences:

• A 52-week open-label extension in 308 Japanese patients reported that the reduction in "off" time held up. Nasopharyngitis (24.4%) and dyskinesia (21.4%) were the most frequent reported events (Kondo 2015).
• An interim post-marketing report on 476 patients in Japan recorded reduced "off" time in 38.2% and a physician rating of effective in 61.3%. Dyskinesia and hallucination were the most common adverse reactions (Takahashi 2018).

The Trials That Did Not Show a Benefit

Not every trial found a difference, and the negative results matter as much as the positive ones:

• 6002-US-018 (610 patients randomized, 584 analyzed). The trial gave 10, 20 or 40 mg a day for 12 weeks. At the end, the amount and percentage of "off" time did not differ from placebo. Motor scores did improve significantly at 40 mg, by 2.9 points against 0.8 (Pourcher 2012).
• 6002-US-051, the drug alone in early disease (176 patients). The trial gave 40 mg a day to patients not on dopamine medicines. The motor score reached significance at week 2 but not at the main endpoint, with a difference of 1.11 points. The authors reported that efficacy in early disease was not statistically demonstrated (Fernandez 2010).
• Two trials, 6002-EU-007 and 6002-014, stayed unpublished until they were included in a 2021 pooled analysis, which reports that they did not show statistically significant differences in endpoints (Hauser 2021).

Two other drugs of the same type did not reach patients. Preladenant did not significantly reduce "off" time in two phase 3 trials of 778 and 476 patients. Rasagiline, an established comparison drug in the first trial, also failed to separate from placebo, and the authors suggested that the design or conduct of the trials may have played a part (Hauser 2015). Tozadenant's phase 3 work was stopped after reports of blood toxicity (LeWitt 2020).

What the Pooled Numbers Add Up To

The fullest picture comes from a 2021 analysis of all eight phase 2b and 3 trials of the drug added to levodopa. It covered 2,719 patients on placebo or the two approved doses.

• All eight trials: "off" time fell by 0.38 hours a day more than placebo at 20 mg (95% confidence interval -0.61 to -0.15) and by 0.45 hours at 40 mg (-0.68 to -0.22). That is about 23 and 27 minutes.
• The four trials behind the United States approval: 0.75 hours at 20 mg and 0.82 hours at 40 mg, or about 45 and 49 minutes.
• Dyskinesia as a reported side effect: 9.6% on placebo, 16.1% at 20 mg and 17.7% at 40 mg.

So the estimate for all the evidence is about half the estimate for the four trials chosen for the label (Hauser 2021). An earlier meta-analysis of 6 studies found that 40 mg a day reduced "off" time and improved motor symptoms, while the result for 20 mg varied more between studies. It added that dyskinesia might be worsened, but that publication bias prevented this from being clear (Sako 2017).

Researchers have also looked for groups who respond better. In two pooled Japanese trials, reduction in "off" time was more favorable in patients aged 65 or older and in those with at least 8 hours of "off" time a day at the start (Hattori 2020). These are after-the-fact comparisons and were not separately tested in new trials in the papers read for this page.

The evidence base comes mainly from the manufacturer's own development program, and the 2025 pooled analysis lists authors employed by the manufacturer (Hattori 2025).

The 2008 Non-Approval, Japan and the 2019 Approval

• February 2008: the Food and Drug Administration issued a non-approvable letter for the first application (Dungo 2013). A 2022 review attributes this to the relatively modest clinical benefit in trials of the whole Parkinson's population, and says the later application was limited to patients with "off" episodes (Cummins 2022).
• 2013: Japan approved the drug as an add-on treatment, the first approval anywhere (Dungo 2013; Isaacson 2022).
• August 27, 2019: the Food and Drug Administration approved it as an add-on to levodopa with carbidopa in adults with "off" episodes. A review describes this as following studies in more than 4,000 patients (Chen 2020).
• Europe: a 2022 review states that the European Medicines Agency had not given approval, primarily because of negative findings in the European setting (Isaacson 2022).

The same 2022 review says the Food and Drug Administration examined all eight trials and placed the results of four in the prescribing information. A 2021 review calls the drug's clinical development relatively complicated and describes it as the only adenosine A2A blocker then in clinical use (Jenner 2021). Another review describes the price as relatively expensive, with implications for insurance coverage (Cummins 2022).

The label also shows who was studied. In the four trials it uses for safety, 734 patients took the drug, of whom 67% were Asian and 32% were White.

Side Effects Listed on the Label

The figures below come from the four 12-week trials pooled in the United States label on DailyMed, in this order: 20 mg (356 patients), 40 mg (378 patients) and placebo (426 patients).

• Dyskinesia: 15%, 17%, 8%
• Dizziness: 3%, 6%, 4%
• Constipation: 5%, 6%, 3%
• Nausea: 4%, 6%, 5%
• Hallucination: 2%, 6%, 3%
• Insomnia: 1%, 6%, 4%
• Decreased appetite: 1%, 3%, 1%

Stopping treatment because of any side effect was about equal: 5%, 6% and 5%. Dyskinesia was the most frequent reason. The label states that the drug given with levodopa may cause dyskinesia or worsen existing dyskinesia, and 1% stopped for this reason on either dose against 0% on placebo.

A 2025 analysis of the pooled trials found dyskinesia in 17% of patients on the drug. Rates were higher in women (21%), in patients with a body mass index below 18.5 (22%), in those also taking a catechol-O-methyltransferase inhibitor and a dopamine agonist (22%), and in those also taking a monoamine oxidase B inhibitor (25%). The reduction in "off" time did not depend on whether dyskinesia was already present (Hattori 2025).

The label reports that a heart-rhythm study at up to four times the maximum dose found no clinically significant lengthening of the QT interval, an electrical measure of the heartbeat. It reports one overdose in the trials, a patient who took 120 mg with alcohol and developed hallucinations, agitation and worse dyskinesia. No specific antidote is known. The drug's half-life is about 83 hours, so it stays in the body for days after the last dose, and a steady level is reached within 2 weeks.

Hallucinations and Impulse Control

The label carries warnings on two psychiatric effects.

Hallucinations and psychotic behavior. Hallucinations were reported in 2% at 20 mg, 6% at 40 mg and 3% on placebo, and 1% at 40 mg stopped treatment for this reason. "Abnormal thinking and behavior", which includes paranoid ideas, delusions, confusion and agitation, was reported in 1%, 2% and 1%. Because of the possible risk of worsening psychosis, the label states that people with a major psychotic disorder are not to be treated with the drug, and it describes lowering the dose or stopping if hallucinations or psychotic behavior develop.

Impulse control. The label describes intense urges to gamble or spend money, binge eating, increased sexual urges and an inability to control these urges in patients taking the drug and one or more other Parkinson's medicines. Only one patient in the controlled trials was reported with this problem, at 40 mg. Post-marketing reports add cases, some of which stopped when the dose was lowered or the drug discontinued. The label notes that patients may not recognize these behaviors as abnormal and tells prescribers to ask patients or their caregivers directly. Increased libido is also listed from post-approval use outside the United States.

Two later analyses of safety data add to this:

• A meta-analysis of 8 randomized trials found an odds ratio of 1.77 for dyskinesia (95% confidence interval 1.32 to 2.36) and 2.08 for hallucinations (1.11 to 3.90) compared with placebo. The same study identified 2,597 patients with adverse events in the Food and Drug Administration's reporting database (Yoosuf 2026).
• An analysis of 3,633 reports in that database flagged signals the authors described as new, including Parkinsonism hyperpyrexia syndrome (3 reports), compulsions (5) and freezing (60). The authors called for further validation (Jiang 2024).

Reports in this database are voluntary. They raise questions about a possible link, but they cannot show how often an effect occurs or prove that the drug caused it, and freezing is also a feature of Parkinson's disease itself. By contrast, the 2021 pooled analysis reported little or no increase in hallucinations and impulse control disorders in its data (Hauser 2021).

Smoking and Drug Interactions

The body clears this drug entirely by breaking it down, mainly through the enzymes cytochrome P450 1A1 and cytochrome P450 3A4 (CYP3A4). Anything that speeds or slows those enzymes changes how much drug is in the blood. These are the label's figures:

• Heavy smoking. Blood levels of the drug at steady state are 38% to 54% lower in people who smoke 20 or more cigarettes a day, which the label says may reduce its effect. For these people, the label lists 40 mg once daily as the recommended dose. A review attributes this to tobacco speeding up cytochrome P450 1A1 (Cummins 2022). The site's page on nicotine and Parkinson's disease covers a separate line of research.
• Drugs that strongly block cytochrome P450 3A4. Ketoconazole increased total exposure 2.5-fold. With drugs of this type, such as itraconazole, ketoconazole and clarithromycin, the label sets a maximum of 20 mg once daily.
• Drugs that strongly speed up cytochrome P450 3A4. Rifampin cut peak levels by 45% and total exposure by 81%. The label advises against use with drugs of this type, naming carbamazepine, rifampin, phenytoin and St. John's wort.
• Effects on other medicines. At 40 mg, the drug raised peak level and total exposure of atorvastatin 1.5-fold. It raised digoxin peak level by 33% and total exposure by 21%. The label describes monitoring for increased side effects of such drugs.
• Levodopa and carbidopa. Their blood levels were not changed by the drug. A 2021 analysis describes the drug as not altering dopamine metabolism (Hauser 2021).

The label says the drug can be taken with or without food. A high-fat meal raised total exposure 1.25-fold, which the label does not expect to be clinically significant.

Liver Disease, Pregnancy and the Animal Findings

• Liver disease. In moderate liver impairment, exposure is predicted to be 3.3 times higher, and the label sets a maximum of 20 mg once daily with close monitoring. It has not been studied in severe liver impairment, and the label advises against use in that group.
• Kidney disease. The label lists no dose change for mild, moderate or severe kidney impairment. It has not been studied in end-stage kidney disease.
• Pregnancy. There are no adequate human data. In rats and rabbits, the drug caused birth defects, fetal death and poor growth at exposures relevant to human doses, and in rabbits the effects were substantially greater with levodopa and carbidopa. The label states that use in pregnancy is not recommended and that contraception is advised during treatment for women who could become pregnant.
• Breastfeeding. There are no human data. In lactating rats, milk levels reached up to 10 times the level in the mother's blood.
• Older adults. The label reports no overall differences in effectiveness in those aged 65 and older, who were 53% of trial patients.
• Children. Safety and effectiveness have not been established.
• Brain mineral deposits in rats. In a two-year study in rats, the drug increased calcium and phosphorus deposits in brain blood vessels at all doses, and at higher doses these partly or fully blocked some vessels. There was no sign of nerve cell damage or inflammation. The deposits were not found in mice over two years or in dogs over 52 weeks. The label does not describe this finding in people.

Smaller Studies Beyond "Off" Time

Japanese researchers have tested the drug against other Parkinson's problems. Except for the first study below, these had no comparison group, so they cannot separate a drug effect from placebo response, and the authors of the mood study called for confirmation in a blinded placebo-controlled trial.

• Levodopa dose. In an open-label randomized study of 114 patients, the drug group needed less added levodopa over 37 weeks (p < 0.0001). Adverse drug reactions occurred in 28.8% against 13.2%, with none serious. Because patients and doctors knew who took the drug and the levodopa dose was raised according to clinical severity, this design carries more room for bias than a blinded trial (Hatano 2024).
• Mood. In 30 patients, pleasure, apathy and depression scores improved over 12 weeks (Nagayama 2019).
• Daytime sleepiness. In 22 patients, the sleepiness score fell by 3.3 points at 3 months, and total nighttime sleep scores did not change (Suzuki 2017).
• Walking and freezing. In 31 patients, gait and freezing scores improved over 12 weeks, and adverse events occurred in 7 (Iijima 2019).
• Posture. In a 24-week study, 24 of 31 patients completed treatment, and the dystonia rating score improved by 4.84 points (Takahashi 2022).

A 2021 review suggests that using the drug to spare levodopa in earlier disease would be worth exploring, partly because animal models show a stronger effect at low levodopa doses (Jenner 2021). That remains a research question.

What Is Not Known

• How it works in people. The label states that the precise mechanism in Parkinson's disease is unknown.
• Why the trials disagree. Some showed a clear gap from placebo and others none. Trial design or conduct was raised for the related drug preladenant (Hauser 2015), and a review points to negative findings in the European setting (Isaacson 2022), but the papers read for this page do not settle the matter.
• Whether the drug slows the disease. The trials here measured symptoms over months. A 2020 review lists neuroprotection as a future opportunity for this drug class, not an established effect (Chen 2020).
• Long-term controlled effects. The placebo-controlled trials lasted 12 or 16 weeks. The longer data come from studies without a placebo group.
• How it compares with other add-on medicines. One of the eight trials included entacapone as another treatment arm (Hauser 2021), but the papers read for this page report no trial designed to rank istradefylline against other add-on medicines.
• Whether coffee changes the drug's effect. The label makes no statement on caffeine, and no study read for this page tested it.
• What the rat brain deposits mean for people, and how often the rare psychiatric effects occur in everyday use.

Decisions about starting, monitoring or stopping a prescription medicine belong with the clinician who prescribes it.

Key Research Papers

1. Berger AA, Winnick A, Welschmeyer A, Kaneb A, Berardino K, Cornett EM, Kaye AD, Viswanath O, Urits I. Istradefylline to Treat Patients with Parkinson's Disease Experiencing "Off" Episodes: A Comprehensive Review. Neurol Int. 2020;12(3):109-129. PubMed PMID: 33302331
2. Chen JF, Cunha RA. The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson's disease. Purinergic Signal. 2020;16(2):167-174. PubMed PMID: 32236790
3. Cummins L, Cates ME. Istradefylline: A novel agent in the treatment of "off" episodes associated with levodopa/carbidopa use in Parkinson disease. Ment Health Clin. 2022;12(1):32-36. PubMed PMID: 35116210
4. Dungo R, Deeks ED. Istradefylline: first global approval. Drugs. 2013;73(8):875-82. PubMed PMID: 23700273
5. Fernandez HH, Greeley DR, Zweig RM, Wojcieszek J, Mori A, Sussman NM, 6002-US-051 Study Group. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16(1):16-20. PubMed PMID: 19616987
6. Hatano T, Sengoku R, Nagayama H, Yanagisawa N, Yoritaka A, Suzuki K, Nishikawa N, Mukai Y, Nomura K, Yoshida N, Seki M, Matsukawa MK, Terashi H, Kimura K, Tashiro J, Hirano S, Murakami H, Joki H, Uchiyama T, Shimura H, Ogaki K, Fukae J, Tsuboi Y, Takahashi K, Yamamoto T, Kaida K, Ihara R, Kanemaru K, Kano O. Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study. Neurol Ther. 2024;13(2):323-338. PubMed PMID: 38227133
7. Hattori N, Elmer L, Isaacson SH, Pahwa R, Rascol O, Sethi K, Stocchi F, Nakajima Y, Cummings H, Kostiuk L. Safety and Efficacy of Istradefylline in Parkinson's Disease Patients With and Without Preexisting Dyskinesia: Pooled Analysis of 8 Randomized Controlled Trials. J Mov Disord. 2025;18(3):262-267. PubMed PMID: 40276907
8. Hattori N, Kitabayashi H, Kanda T, Nomura T, Toyama K, Mori A. A Pooled Analysis From Phase 2b and 3 Studies in Japan of Istradefylline in Parkinson's Disease. Mov Disord. 2020;35(8):1481-1487. PubMed PMID: 32501582
9. Hauser RA, Hattori N, Fernandez H, Isaacson SH, Mochizuki H, Rascol O, Stocchi F, Li J, Mori A, Nakajima Y, Ristuccia R, LeWitt P. Efficacy of Istradefylline, an Adenosine A2A Receptor Antagonist, as Adjunctive Therapy to Levodopa in Parkinson's Disease: A Pooled Analysis of 8 Phase 2b/3 Trials. J Parkinsons Dis. 2021;11(4):1663-1675. PubMed PMID: 34486986
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PubMed Topic Searches

1. Istradefylline and Parkinson's disease
2. Istradefylline randomized trials
3. Adenosine A2A blockers in Parkinson's disease
4. Caffeine and Parkinson's disease trials

Label

1. Istradefylline tablets, United States prescribing information, version published May 23, 2025. DailyMed, U.S. National Library of Medicine

Connections

• Drugs — the section this page belongs to
• Parkinson's Disease — the illness this drug treats
• Parkinson's Disease: History and Discovery — how levodopa came to be used
• Coffee and Parkinson's Disease — the population research on coffee and caffeine
• Caffeine, Adenosine and Why Coffee Stops Working — an animation of the receptor involved
• Mucuna Pruriens: Parkinson's Research — a plant source of levodopa
• Nicotine and Parkinson's Disease — another drug studied in this illness
• Cabergoline — a dopamine-acting drug with a history in Parkinson's disease
• St. John's Wort — an herb named in the label's interaction section

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