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Enrich your students’ educational experience with case-based teaching

The NCCSTS Case Collection, created and curated by the National Center for Case Study Teaching in Science, on behalf of the University at Buffalo, contains over a thousand peer-reviewed case studies on a variety of topics in all areas of science.

Cases (only) are freely accessible; subscription is required for access to teaching notes and answer keys.

Subscribe Today

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Development of the NCCSTS Case Collection was originally funded by major grants to the University at Buffalo from the National Science Foundation , The Pew Charitable Trusts , and the U.S. Department of Education .

  • UB Directory

News Center

Nanoshells in nine different boxes.

The catalysts can be used for dry reforming, an industrial process that turns greenhouse gases into useful chemicals.

Student walking in front of Alfiero Center.

CEO Magazine has ranked the UB School of Management’s new Online MBA program No. 64 in its annual Global MBA ranking, while the school’s Full-Time MBA program was ranked as “Tier One.”  

Digitally restored black-and-white daguerrotype of Emily Dickinson, c. early 1847.

First such collection published in 60 years reveals “what an extraordinary friend Emily Dickinson was to so many people.”

Two people seated on a lawn, one in a wheelchair, looking up and wearing eclipse glasses.

UB ophthalmologists and medical residents in ophthalmology will hold a post-eclipse eye clinic from 4-9 p.m. on April 8. 

How much caffeine you should actually have—and when

Published January 10, 2024

The Wall Street Journal quoted Jennifer Temple , in a story on how much caffeine is appropriate for adults. Government and health groups recommend that healthy adults consume no more than 400 milligrams of caffeine daily, which, Temple said, comes out to about four 8-ounce cups of coffee.

Media Contact Information

Media Relations (University Communications) 330 Crofts Hall (North Campus) Buffalo, NY 14260-7015 Tel: 716-645-6969 [email protected]

UB Faculty Experts

Head shot of Heidi Julien.

Heidi Julien

Professor of Information Science

Expertise: digital literacy, information literacy, information behavior, information practice

Phone: 716-645-1474

Email: [email protected]

John Violanti at night in front of a blurred police car with lights on.

John M. Violanti

Research Professor of Epidemiology and Environmental Health

Expertise: police stress, health and suicide; PTSD

Phone:  716-829-5481

Email: [email protected]

Portrait of James Gardner, UB election law and constitutional law expert, in a suit and tie.

James A. Gardner

Bridget and Thomas Black SUNY Distinguished Professor of Law

Expertise: election law, constitutional law, federalism, voting rights, redistricting, democracy, state constitutional law

Phone: 716-645-3607

Email: [email protected]

Head shot of Antoine Yoshinaka, University at Buffalo political science expert.

Antoine Yoshinaka

Associate Professor of Political Science

Expertise: American politics, U.S. political parties, polarization, party switching, legislatures, political lobbying, redistricting

Phone:  716-645-8435

Email: [email protected]

Head shot of Jeffrey M. Lackner, University at Buffalo IBS and chronic pain expert.

Jeffrey M. Lackner, PsyD

Chief of the Division of Behavioral Medicine

Expertise: irritable bowel syndrome (IBS), psychosocial aspects of chronic pain disorders, behavioral medicine, brain-gut interactions, impact of chronic disease on quality of life, chronic care management

Phone:  716-898-5671

Email: [email protected]

Head shot of Timothy Cook in a laboratory.

Timothy Cook

Professor of Chemistry

Expertise: molecular self-assembly, photochemistry, fluorescence, phosphorescence, batteries, alternative energy

Phone:  716-645-4327

Email: [email protected]

Head shot of Kenneth W. Regan.

Kenneth W. Regan

Professor of Computer Science and Engineering

Expertise: cheating in chess

Phone:  716-645-4738

Email: [email protected]

Portrait of Y. Chris Li, University at Buffalo electrochemistry and waste conversion expert.

Y. Chris Li

Assistant Professor of Chemistry

Expertise:  electrochemistry, waste conversion, transforming greenhouse gases into useful products, chemistry of CO2, plastics

Phone:  716-645-4285

Email:  [email protected]

Head shot of Julie Gorlewski, University at Buffalo education access and teacher preparation expert.

Julie Gorlewski

Senior Associate Dean for Academic Affairs and Teacher Education

Expertise: access and equity in education; literacy; teacher preparation

Phone:  716-645-2455

Email: [email protected]

Portrait of Brian Tsuji, University at Buffalo superbugs and antibiotic resistance expert.

Brian Tsuji

Professor of Pharmacy Practice

Expertise:  superbugs, antibiotic-resistant bacteria, antibiotics

Phone:  716-881-7543

Email:  [email protected]

Head shot of Phillips Stevens Jr. in front of a world map.

Phillips Stevens Jr.

Associate Professor of Anthropology

Expertise:  cultural anthropology, religion, spiritualism, cults, superstition, witchcraft, zombies, vampires, curses, rites of passage, populism, nativism, xenophobia

Phone:  716-645-0416

Email: [email protected]

Head shot of Kim Griswold, University at Buffalo expert on health care for refugees, immigrants and survivors of torture.

Kim Griswold, MD

Professor Emerita of Family Medicine and Psychiatry

Expertise:  health care for refugees and immigrants; trauma; survivors of torture; cultural competency in medicine; patient-centered medical homes; integrated medical and behavioral health care

Phone:  716-816-7248

Email:  [email protected]

Head shot of Javid Bayandor.

Javid Bayandor

Associate Professor of Mechanical and Aerospace Engineering

Expertise:  Mid-air collisions; crashes involving drones (unmanned aircraft systems); space exploration and missions; crashworthiness; ballistics; advanced aerospace design

Phone:  716-645-1422

Email: [email protected]

Head shot of Peter Winkelstein, University at Buffalo faculty expert on electronic health records.

Peter Winkelstein

Executive Director of the Institute for Healthcare Informatics

Expertise: electronic health/medical records; medical informatics; ethics and informatics; computer modeling

Phone:  716-881-7546. Winkelstein can also be reached through Ellen Goldbaum in University Communications at 716-645-4605 or [email protected] , or Douglas Sitler in University Communications at 716-645-9069 or [email protected] .

Email: [email protected]

Head shot of Thomas Ramming.

Thomas Ramming

Clinical Associate Professor Emeritus of Educational Leadership and Policy

Expertise:  K-12 school and district leadership, educational policy, organizational development, human resources, labor relations, collective bargaining, leadership recruitment and development, shared services, inter-district collaboration

Phone: 716-645-1099

Email: [email protected]

Head shot of John D. Atkinson, University at Buffalo sustainability and air pollution expert.

John D. Atkinson

Associate Professor of Civil, Structural and Environmental Engineering

Expertise:  sustainability, greenhouse gas emissions, air and water pollution control, materials science and engineering, adsorption, life-cycle assessment

Phone:  716-645-4001

Email:  [email protected]

Head shot of Elizabeth Otto, University at Buffalo faculty expert on art history, including Bauhaus, modern art, Dada, surrealism, cubism, and gender.

Elizabeth Otto

Professor of Modern and Contemporary Art History

Expertise: the Bauhaus, history of photography, European and American Art, visual culture, theories of montage, gender issues, art and religion

Phone:  716-645-5334

Email: [email protected]

Portrait of Kelly Patterson, University at Buffalo housing and urban development expert.

Kelly Patterson

Associate Professor of Social Work

Expertise: social welfare policy; cannabis policy; residential segregation; fair housing; gentrification; homelessness; poverty and economic inequality; race and class

Phone:  716-645-1248

Email: [email protected]

Head shot of Alan Rabideau, University at Buffalo groundwater pollution and hazardous waste management expert.

Alan Rabideau

Professor and Chair of Civil, Structural and Environmental Engineering

Expertise: pollution, groundwater contamination, radioactive and hazardous waste management, mathematical modeling

Phone: 716-645-4003

Email:  [email protected]

Head shot of Mary McVee, University at Buffalo expert on literacy instruction.

Director of the Center for Literacy and Reading Instruction

Expertise: literacy instruction; diversity and literacy; technology and literacy; narrative

Phone:  716-645-2458

Email: [email protected]

Portrait of Carine Mardorossian, University at Buffalo medical humanities and sexual violence expert.

Carine Mardorossian

Professor of English, and Global Gender and Sexuality Studies

Expertise:  medical humanities, death and dying, feminism, sexism, sexual violence, Caribbean literature

Phone:  716-645-0711

Email:  [email protected]

Portrait of Dhaval Shah, University at Buffalo targeted drugs and biologics expert.

Dhaval Shah

Associate Professor of Pharmaceutical Sciences

Expertise:  targeted drugs; biologics; anticancer medications; tumor growth; pediatric drug dosing; drug discovery and development

Phone:  716-645-4819

Email:  [email protected]

Head shot of Avto Kharchilava.

Avto Kharchilava

Professor of Physics

Expertise: Higgs boson search, particle detectors, phenomena beyond the Standard Model

Phone: 716-645-6251

Email: [email protected]

Head shot of Mark Karwan, University at Buffalo expert on sports scheduling.

Mark H. Karwan

Praxair Professor of Operations Research

Expertise: sports scheduling, especially in the NFL

Phone: 716-645-2422

Email: [email protected]

Head shot of Stuart Evans, University at Buffalo weather, climate and atmospheric science expert.

Stuart M. Evans

Assistant Professor of Geography

Expertise: climate change, dust and dust storms, weather, atmospheric science, precipitation, monsoons, lake effect snow

Phone:  716-645-0491

Email: [email protected]

Head shot of Richard D. Blondell.

Richard D. Blondell

Professor Emeritus of Family Medicine

Expertise:  addiction, substance abuse, opioids

Contact: Richard Blondell can be reached most quickly through Ellen Goldbaum in University Communications at 716-645-4605 or  [email protected] , or Douglas Sitler in University Communications at 716-645-9069 or  [email protected] .

Portrait of Holly Buck, University at Buffalo environmental policy and climate change policy expert.

Holly Jean Buck

Assistant Professor of Environment and Sustainability

Expertise: environmental policy, climate change policy, geoengineering, carbon capture, climate adaptation, environmental justice

Phone:  716-645-0135

Email:  [email protected]

Head shot of Beata Csatho.

Beata Csatho

Professor of Geology

Expertise: climate change, sea level rise, Greenland Ice Sheet, Antarctic ice loss, glaciers, remote sensing, using satellite data and laser altimetry to measure the Earth

Phone:  716-645-4325

Email: [email protected]

Head shot of Jessica Kruger, University at Buffalo faculty expert on consumption and addictive behaviors.

Jessica Kruger

Clinical Associate Professor of Community Health and Health Behavior

Expertise:  cannabis, binge-watching, consumption, addictive behaviors, substance use and abuse, health behavior decision-making

Phone:  716-829-6748

Email: [email protected]

Head shot of Nicholas Rajkovich, University at Buffalo climate change expert.

Nicholas Rajkovich

Associate Professor of Architecture

Expertise: climate change and cities; climate adaptation in the Great Lakes region; energy efficiency; renewable energy; climate refuge cities

Phone:  716-829-6910

Email: [email protected]

Head shot of Machiko Tomita, University at Buffalo aging and caregiving expert.

Machiko R. Tomita

Clinical Professor of Rehabilitation Science

Expertise: aging, falls and frailty prevention in older adults, caregiving for older adults, smart home technology, virtual group exercise

Phone:  716-829-6740

Email: [email protected]

Head shot of Ndubueze L. Mbah, University at Buffalo West Africa and Atlantic World expert.

Ndubueze L. Mbah

Associate Professor of History

Expertise:  African history; the Atlantic World; colonialism; gender in West Africa; history of slavery and emancipation; Boko Haram

Phone:  716-645-8415

Email:  [email protected]

Head shot of Zhen Wang, University at Buffalo medicinal plant and synthetic biology expert.

Assistant Professor of Biological Sciences

Expertise: plant natural products, medicinal plants, synthetic biology, metabolic engineering

Phone:  716-645-4969

Email: [email protected]

Portrait of Laura Rusche, University at Buffalo genetics and yeast biology expert.

Laura Rusche

Professor of Biological Sciences

Expertise:  yeast, genomics, genetics, gene expression, chromosomes, DNA, RNA, chromatin, sirtuins

Phone:  716-645-5198

Email:  [email protected]

Head shot of Robert Adelman, University at Buffalo immigration and U.S. Census expert.

Robert Adelman

Chair and Professor of Sociology

Expertise:  urban sociology, segregation, race, immigration, U.S. Census

Phone:  716-645-8478

Email: [email protected]

Headshot of Joseph Gardella Jr., industrial pollution and plastics expert.

Joseph A. Gardella Jr.

SUNY Distinguished Professor Emeritus of Chemistry

Expertise: industrial pollution; hazardous waste; microbeads; surface chemistry of plastics; controlled release of pharmaceuticals; wound healing; tissue engineering; STEM education

Phone: 716-645-1499

Email: [email protected]

Head shot of Jamie Ostrov, University at Buffalo bullying and victimization expert.

Jamie Ostrov

Professor of Psychology

Expertise: subtypes of aggression and victimization, developmental psychopathology, media effects on children, peer relationships, applied developmental psychology

Phone: 716-645-3680

Email: [email protected]

Head shot of Johannes Hachmann, University at Buffalo computational chemistry and materials design expert.

Johannes Hachmann

Associate Professor of Chemical and Biological Engineering

Expertise: computational chemistry; molecular and materials modeling; cheminformatics; machine learning; big data; materials discovery and design

Phone:  716-645-1524

Email:  [email protected]

Head shot of James Battista.

James Coleman Battista

Expertise: national, state and legislative politics  

Phone:  716-645-8438

Email: [email protected]

Portrait of Charlotte Lindqvist.

Amanda Aykanian

Assistant Professor of Social Work

Expertise:  homelessness, including how social policies and programs affect unhoused people; homeless service systems and workforce issues; social welfare history and policy; social service program implementation

Phone:  716-645-1270

Email:  [email protected]

Portrait of Guyora Binder, University at Buffalo criminal law expert.

Guyora Binder

SUNY Distinguished Professor of Law and Hodgson Russ Faculty Scholar

Expertise:  criminal law, felony murder, homicide, jurisprudence, legal theory, international law

Phone:  716-645-2673

Email:  [email protected]

Head shot of Yu-Ping Chang, University at Buffalo caregiving and dementia expert.

Yu-Ping Chang

Patricia H. and Richard E. Garman Endowed Professor of Nursing

Expertise: mental health; substance abuse and addiction; family caregiving and dementia

Phone:  716-829-2015

Email: [email protected]

Portrait of David M. Holmes, University at Buffalo global health equity and medicine and spirituality expert.

David M. Holmes

Clinical Associate Professor of Family Medicine

Expertise:  global health, health care for underserved communities and human trafficking victims, spirituality in health, religious exemptions for vaccines, addiction medicine, wilderness medicine, travel medicine

Email:  [email protected]

Contact:  David M. Holmes can be reached through Ellen Goldbaum in University Communications at 716-645-4605 or  [email protected] , or Douglas Sitler in University Communications at 716-645-9069 or  [email protected] .

Head shot of Min-Hsuan Tu, University at Buffalo leadership and abuse of power expert.

Min-Hsuan Tu

Assistant Professor of Organization and Human Resources

Expertise: abusive leadership; power and influence; leader identity and development

Contact:  Min-Hsuan Tu can be reached most quickly through Jackie Ghosen in the School of Management Communications Office at 716-645-2833 or [email protected] .

Head shot of Edward Bednarczyk standing in a pharmacy.

Edward Bednarczyk

Clinical Associate Professor of Pharmacy Practice

Expertise: medical marijuana, tobacco sales in pharmacies, headaches and migraines, pharmacy practice

Phone:  716-645-4805

Email: [email protected]

Head shot of Nadine "Shaanta" Murshid, University at Buffalo faculty expert on social policy, intimate partner violence and microfinance.

Nadine Shaanta Murshid

Associate Dean for Diversity, Equity and Inclusion

Expertise:  microfinance, mobile financial services, domestic violence, street harassment, women’s health, trauma

Phone:  716-645-5749

Email:  [email protected]

Portrait of Susan Spierre Clark, University at Buffalo sustainability, climate change, infrastructure and community resilience expert.

Susan Spierre Clark

Expertise:  climate change and sustainable development; resilient infrastructure; power outages due to extreme events; sustainability education; community resilience

Phone:  716-645-1403

Email:  [email protected]

Head shot of Frank Scannapieco, University at Buffalo oral health and dental plaque expert.

Frank A. Scannapieco, DMD, PhD

Chair of Oral Biology

Expertise: link between oral and overall health; oral health care in hospitals and nursing homes; dental plaque

Phone:  716-829-3373

Email: [email protected]

Head shot of Stefan Ruhl, University at Buffalo saliva and oral biology expert.

Stefan Ruhl

Professor of Oral Biology

Expertise:  saliva, oral bacteria, glycobiology of bacterial adhesion, oral microbiome, oral health

Phone:  716-829-6073

Email:  [email protected]

Portrait of LaGarrett J. King, University at Buffalo Black history education expert.

LaGarrett J. King

Director of the Center for K-12 Black History and Racial Literacy Education

Expertise:  Black history education, social studies, history of education, teacher education, racism and anti-Blackness

Email:  [email protected]

Head shot of Surajit Sen, University at Buffalo professor of physics.

Surajit Sen

Expertise: wave behavior, granular systems, quasi-equilibrium, nonequilibrium and chaotic phenomena, collisions, shock mitigation, sociophysics

Phone:  716-645-6151, 716-907-4961

Email: [email protected]

Head shot of Sameer Honwad, University at Buffalo education access and equity expert.

Sameer Honwad

Assistant Professor of Learning and Instruction

Expertise: access, equity and diversity in education; cultural studies; international education; science and environmental education

Email: [email protected]

Diana Aga.

Director of the UB RENEW Institute

Expertise:  chemicals of emerging concern; industrial pollution; wastewater treatment; environmental impact of PFAS ("forever chemicals"), PCBs, PBDEs (flame retardants), pesticides, nanomaterials, antimicrobials, pharmaceuticals and personal care products; antibiotic resistance in the environment; target and non-target analysis; Great Lakes pollution

Phone:  716-645-4220

Email: [email protected]

Photo of Nallan Suresh.

Nallan Suresh

UB Distinguished Professor and Chair of Operations Management and Strategy

Expertise:  global supply networks; supply chain disruptions; U.S. and global manufacturing; international trade; logistics; infrastructure; economic development

Contact: Nallan Suresh can be reached most quickly through Jackie Ghosen in the School of Management Communications Office at 716-645-2833 or [email protected] .

Dominic Sellitto.

Dominic Sellitto

Clinical Assistant Professor of Management Science and Systems

Expertise: cybersecurity; data breaches; data privacy and security regulations; ethical data usage; cyberwarfare; artificial intelligence and its interplays with cybersecurity; data analytics; health care analytics; automation technologies

Contact:  Dominic Sellitto can be reached most quickly through Jackie Ghosen in the School of Management Communications Office at 716-645-2833 or [email protected] .

Head shot of Daniel Antonius.

Daniel Antonius

Associate Professor of Psychiatry

Expertise: terrorism, violence, aggression, CTE and behavior, mental health and the legal system

Phone:  716-898-5290

Email: [email protected]

Portrait of Luis A. Colón, University at Buffalo separation science, analytical chemistry, and STEM diversity expert.

Luis A. Colón

A. Conger Goodyear Professor of Chemistry

Expertise: analytical chemistry, separation science, liquid chromatography, diversity in STEM, mentoring students of color

Phone:  716-645-4213

Email: [email protected]

Portrait of Joanna Pepin, University at Buffalo family sociology, family policy and gender and work expert.

Joanna Pepin

Assistant Professor of Sociology

Expertise:  family sociology, inequality, gender and work, ​childcare, paid family leave

Phone:  716-645-2417

Email:  [email protected]

Portrait of Allison Brashear, University at Buffalo medical education and spasticity and dystonia expert.

Allison Brashear

Vice President for Health Sciences and Dean of the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo

Expertise:  medical education and research, diversity in medicine, women in medicine, community engagement and health equity, clinical trials, treatment of rare neurologic disorders, spasticity and dystonia.

Contact: Allison Brashear can be reached through Ellen Goldbaum in University Communications at 716-645-4605 or [email protected] .

Mike Mingcheng Wei.

Mike Mingcheng Wei

Associate Professor of Operations Management and Strategy

Expertise: supply chain management; dynamic pricing; revenue management; strategic consumer behavior; online learning and decision-making; online recommendation systems; assortment optimization; high-dimensional machine learning

Contact: Mike Mingcheng Wei can be reached most quickly through Jackie Ghosen in the School of Management Communications Office at 716-645-2833 or [email protected] .

Head shot of Panayotis (Peter) K. Thanos, University at Buffalo addiction and reward pathways expert.

Panayotis (Peter) K. Thanos

Senior Research Scientist of Pharmacology and Toxicology

Expertise:  ADHD treatment, addiction; brain imaging; alcohol and drug abuse, obesity, binge eating disorder, bariatric surgery, prenatal nicotine use, prenatal cannabis

Phone:  716-881-7520

Email:  [email protected]

Head shot of Joana Gaia, University at Buffalo digital security and privacy expert.

Expertise: health information systems; business intelligence; digital security and privacy; data analytics; emergency management; girls and STEM careers

Contact: Joana Gaia can be reached most quickly through Jackie Ghosen in the School of Management Communications Office at 716-645-2833 or [email protected] .

Head shot of Praveen Arany.

Praveen Arany

Associate Professor of Oral Biology

Expertise: therapeutic uses of lasers and light, particularly in wound healing and tooth regeneration

Phone:  716-829-3479

Email: [email protected]

Portrait of Hua (Helen) Wang, University at Buffalo communication and health promotion expert.

Hua (Helen) Wang

Professor of Communication

Expertise:  communication strategies for health promotion and social change; entertainment-education; communication technology; social networks; digital media literacy; health interventions

Phone:  716-645-1501

Email:  [email protected]

Portrait of David A. Mmilling, University at Buffalo medical education expert.

David A. Milling

Senior Associate Dean for Student and Academic Affairs in the Jacobs School of Medicine and Biomedical Sciences

Expertise:  medical education; clinical skills; multicultural affairs and cultural competency in medicine; diversity in the medical profession

Phone:  716-829-2802

Email:  [email protected]

Contact:  Milling can also be reached through Ellen Goldbaum in University Communications at 716-645-4605 or  [email protected] , or Douglas Sitler in University Communications at 716-645-9069 or  [email protected] .

Portrait of Joanne Song McLaughlin, University at Buffalo labor economics and age discrimination expert.

Joanne Song McLaughlin

Associate Professor of Economics

Expertise: labor economics; health insurance mandates; age discrimination; older workers; AI and the future of work

Phone:  716-645-8685

Email: [email protected]

Head shot of Gregory Homish, University at Buffalo substance use and mental health expert.

Gregory Homish

Professor and Chair of Community Health and Health Behavior

Expertise: substance use and misuse; substance use among military personnel; substance use and families; emergency preparedness and response; health of emergency responders

Phone:  716-829-6959

Email: [email protected]

Head shot of Sarah Muldoon.

Sarah Muldoon

Associate Professor of Mathematics

Expertise:  brain activity, brain networks, network neuroscience

Phone:  716-645-6284

Email: [email protected]

Head shot of Peter Bush.

Director of the South Campus Instrument Center

Expertise: forensic dentistry, bite mark analysis, victim identification

Phone:  716-829-3561

Email: [email protected]

Head shot of Kristin Stapleton, University at Buffalo faculty expert on modern China.

Kristin Stapleton

Professor and Chair of History

Expertise: modern China; U.S.-China relations; Chinese cities; history of the family, socialism and humor in China

Phone:  716-645-5645

Email: [email protected]

Portrait of Donald A. Grinde Jr., University at Buffalo Native American studies expert.

Donald A. Grinde Jr.

Professor Emeritus in the Department of Africana and American Studies

Expertise:  Native American studies, Native American thought, Haudenosaunee/Iroquois history, U.S. Indian Policy since 1871, American Indian activism

Phone:  716-645-0828

Email:  [email protected]

Head shot of David Schmid.

David Schmid

Associate Professor of English

Expertise: popular culture, cultural studies, celebrity, crime, manhood, the monstrous, contemporary British and American fiction, American literary and cultural treatments of the city

Phone: 716-645-0679

Email: [email protected]

Head shot of Chunming Qiao.

Chunming Qiao

SUNY Distinguished Professor of Computer Science and Engineering

Expertise: Self-driving and connected cars, specifically the computing systems for these technologies

Phone:  716-645-4751

Email: [email protected]

Head shot of Lillian S. Williams, University at Buffalo U.S. social and urban history expert.

Lillian S. Williams

Associate Professor of Africana and American Studies

Expertise:  U.S. social and urban history; African American history in the U.S. and Western New York; women’s history

Phone:  716-645-0798

Email:  [email protected]

Head shot of Marion Werner, University at Buffalo international trade expert.

Marion Werner

Professor of Geography

Expertise:  global trade; agriculture, food, labor rights and trade; agri-business; development in Latin America and the Caribbean

Phone:  716-645-0475

Email:  [email protected]

Portrait of Sarah Cercone Heavey.

Sarah Cercone Heavey

Clinical Assistant Professor of Community Health and Health Behavior

Expertise:  opioid use disorder, medication-assisted treatment for opioid use disorder, naloxone, overdose, veterans’ mental health, suicide prevention, mental health 

Phone:  716-829-6752

Email:  [email protected]

Head shot of Michael LaMonte, University at Buffalo expert on healthy aging.

Michael LaMonte

Expertise: healthy aging, cardiovascular disease, physical activity, women’s health, menopause, cancer, the microbiome, periodontal disease

Phone:  716-829-5379

Email: [email protected]

Portrait of Sama Waham, University at Buffalo filmmaking, cinematography, documentary and storytelling expert.

Assistant Professor of Media Study

Expertise:  filmmaking; cinematography; narrative, documentary, experimental and hybrid films; storytelling

Phone:  716-645-0954

Email:  [email protected]

Head shot of Jeffrey Miecznikowski.

Jeffrey Miecznikowski

Interim Chair and Associate Professor of Biostatistics

Expertise: statistical analysis

Phone:  716-881-8953

Email: [email protected]

Portrait of Isok Kim, University at Buffalo mental health and refugee-related trauma expert.

Expertise:  mental health and wellbeing among Asian Americans; refugee-related trauma; post-resettlement challenges; culturally responsive mental health services

Phone:  716-645-1252

Email:  [email protected]

Ning Dai.

Associate Professor of Civil, Structural and Environmental

Expertise: wastewater reuse, disinfection and disinfection byproducts; seawater desalination; algal blooms; pesticides

Phone:  716-645-4015

Email: [email protected]

Head shot of Lora Park, University at Buffalo expert on psychology, including self, self-esteem and interpersonal processes.

Associate Professor of Psychology

Expertise: self, self-esteem, motivation, interpersonal processes

Phone: 716-645-0228

Email: [email protected]

Head shot of Lynn Shanahan, University at Buffalo literacy expert.

Lynn Shanahan

Associate Professor of of Learning and Instruction

Expertise: childhood literacy; literacy, technology and multimodality; STEM and urban education

Phone:  716-645-4028

Email: [email protected]

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Association of Coffee Consumption and Prediagnostic Caffeine Metabolites With Incident Parkinson Disease in a Population-Based Cohort


  • 1 From the Institute for Risk Assessment Sciences (Y.Z., H.K., S. Peters, R.V.), Utrecht University, the Netherlands; Department of Environmental Health Sciences (Y.L., G.W.M.), Mailman School of Public Health, Columbia University, New York, NY; Department of Epidemiology (J.M.H.), Murcia Regional Health Council-IMIB, Murcia; CIBER Epidemiología y Salud Pública (CIBERESP) (J.M.H., M.G.), Madrid; Movement Disorders Unit (A.V.-A.), Department of Neurology, University Hospital Donostia; BioDonostia Health Research Institute (A.V.-A.), Neurodegenerative Diseases Area, San Sebastián, Spain; Division of Cancer Epidemiology (J.A.S.), German Cancer Research Center (DKFZ), Heidelberg, Germany; Danish Cancer Institute (J.H.), Danish Cancer Society, Copenhagen, Denmark; Escuela Andaluza de Salud Pública (EASP) (D.P.); Instituto de Investigación Biosanitaria-ibs.GRANADA (D.P.), Granada; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP) (D.P.), Madrid, Spain; Unit of Cancer Epidemiology (C.S.), Città della Salute e della Scienza University-Hospital, Turin, Italy; Unit of Nutrition and Cancer (R.Z.-R.), Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Epidemiology and Prevention Unit (V.P.), Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy; Department of Epidemiology and Biostatistics (A.K.H., M.G.), School of Public Health, Imperial College London, United Kingdom; School of Medicine (S. Panico), Federico II University, Naples, Italy; de Salud Pública y Laboral de Navarra (M.G.), Pamplona; Navarra Institute for Health Research (IdiSNA) (M.G.), Pamplona, Spain; Institute for Cancer Research (G.M.), Prevention and Clinical Network (ISPRO), Florence, Italy; Institute of Epidemiology and Social Medicine (C.M.L.), University of Münster, Germany; Ageing Epidemiology Research Unit (AGE) (C.M.L.), School of Public Health, Imperial College London, United Kingdom; and University Medical Centre Utrecht (R.V.), the Netherlands.
  • PMID: 38513162
  • DOI: 10.1212/WNL.0000000000209201

Background and objectives: Inverse associations between caffeine intake and Parkinson disease (PD) have been frequently implicated in human studies. However, no studies have quantified biomarkers of caffeine intake years before PD onset and investigated whether and which caffeine metabolites are related to PD.

Methods: Associations between self-reported total coffee consumption and future PD risk were examined in the EPIC4PD study, a prospective population-based cohort including 6 European countries. Cases with PD were identified through medical records and reviewed by expert neurologists. Hazard ratios (HRs) and 95% CIs for coffee consumption and PD incidence were estimated using Cox proportional hazards models. A case-control study nested within the EPIC4PD was conducted, recruiting cases with incident PD and matching each case with a control by age, sex, study center, and fasting status at blood collection. Caffeine metabolites were quantified by high-resolution mass spectrometry in baseline collected plasma samples. Using conditional logistic regression models, odds ratios (ORs) and 95% CIs were estimated for caffeine metabolites and PD risk.

Results: In the EPIC4PD cohort (comprising 184,024 individuals), the multivariable-adjusted HR comparing the highest coffee intake with nonconsumers was 0.63 (95% CI 0.46-0.88, p = 0.006). In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary metabolites, paraxanthine and theophylline, were inversely associated with PD risk. The ORs were 0.80 (95% CI 0.67-0.95, p = 0.009), 0.82 (95% CI 0.69-0.96, p = 0.015), and 0.78 (95% CI 0.65-0.93, p = 0.005), respectively. Adjusting for smoking and alcohol consumption did not substantially change these results.

Discussion: This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis.

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Caffeine in Children and Adolescents

Photo of a cup of coffee and coffee beans.

Caffeine is the most widely used psychoactive substance in the world and its use is increasing among children. Although considered safe, the majority of empirical data on the effects of caffeine have been collected in adults.

Principal Investigator : Jennifer L. Temple, PhD

Funding Agency : National Institute on Drug Abuse

Period : 04/2011-02/2016 Abstract : Caffeine is the most widely used psychoactive substance in the world and its use is increasing among children. Although considered safe, the majority of empirical data on the effects of caffeine have been collected in adults. Our previous studies, supported by a KO1 from NIDA, have demonstrated that caffeine has dose-dependent effects on physiological, mood and energy intake in adolescents and that boys appear to be more sensitive to the effects of caffeine than girls. This series of laboratory studies aims to investigate the mechanisms underlying these gender differences, including pubertal development, steroid hormone concentrations, menstrual cycle phase and adenosine receptor genotypes. These studies are important because they will provide much needed information on the effects of caffeine in children and adolescents, as well as identify mechanisms that influence gender differences in response to caffeine and, perhaps, other drugs of abuse.

Faculty Spotlight

Jennifer L. Temple, PhD and Amanda Ziegler.

Jennifer L. Temple, PhD Associate Professor 

Dave Hostler.

Dave Hostler, PhD Chair and Professor

Todd Rideout, PhD.

Todd Rideout, PhD Assistant Professor

Todd Rideout, PhD.

Elizabeth G. Mietlicki-Baase, PhD  Assistant Professor

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  • Open access
  • Published: 24 January 2024

Caffeine supplementation improves the cognitive abilities and shooting performance of elite e-sports players: a crossover trial

  • Shih-Hao Wu 1 , 2 ,
  • Yu-Chun Chen 3 ,
  • Che-Hsiu Chen 4 ,
  • Hou-Shao Liu 5 , 6 ,
  • Zhi-Xin Liu 5 &
  • Chih-Hui Chiu 5  

Scientific Reports volume  14 , Article number:  2074 ( 2024 ) Cite this article

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  • Neuroscience

We explored the effect of 3 mg/kg of caffeine supplementation on the cognitive ability and shooting performance of elite e-sports players. Nine e-sports players who had received professional training in e-sports and had won at least eighth place in national-level e-sports shooting competitions. After performing three to five familiarization tests, we employed a single blind, randomized crossover design to divide participants into caffeine trial (CAF) and placebo trial (PL). The CAF trial took capsules with 3 mg/kg of caffeine, whereas the PL trial took a placebo capsule. After a one-hour rest, the Stroop task, the visual search ability test, and the shooting ability test were conducted. The CAF trial’s performance in the Stroop task in terms of congruent condition ( P  = 0.023) and visual search reaction time with 20 items ( P  = 0.004) was significantly superior to those of the PL trial. In the shooting test, the CAF trial’s kill ratio ( P  = 0.020) and hit accuracy ( P  = 0.008) were significantly higher, and the average time to target ( P  = 0.001) was significantly shorter than those of the PL trial. Caffeine supplementation significantly improves e-sports players’ reaction times and shooting performance.

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Owing to the popularity of e-sports, numerous countries have recognized e-sports as a formal sport. E-sports were also included as a demonstration event at the 2018 Asian Games in Jakarta and as an official event at the Hangzhou Asian Games in 2023. Professional e-sports leagues have been founded in several countries. E-sports include multiplayer online battlefield arena games (e.g., League of Legends ), first-person shooter games (e.g., Counter-Strike: Global Offensive , and Valorant ), real-time strategy games, and sports games 1 . For example, Game for Peace is a first-person shooting game and an official sport of the 2023 Hangzhou Asian Games. Studies on first-person shooters have revealed that players with experience in competitions had shorter reaction times in a Stroop test 2 and stronger visual search abilities 3 . Therefore, improving cognitive abilities that relate to e-sports competitions may be critical for participants in first-person shooter competitions, and external nutrients that enhance cognitive abilities may be crucial to their success.

Caffeine is a popular and effective ergogenic supplementation for athletes of all levels 4 , 5 . It is typically consumed through food and drink, and the mechanism through which low-dose caffeine acts as a psychostimulant is based on central antagonism at the A 1 and A 2A adenosine receptors. The capacity of caffeine to bind adenosine receptors facilitates the inhibition of the brake that endogenous adenosine imposes on the ascending dopamine and arousal systems, which facilitates cholinergic and dopaminergic transmission 6 , 7 . Therefore, caffeine consumption may improve energy, mood, cognitive function, attention, simple reaction time, choice reaction time, and memory and alleviate fatigue 8 , 9 . The consumption of caffeine 1 h before playing a first-person shooter can improve players’ visual search ability and speed in a state of alertness 10 . A dosage of 3 mg/kg of caffeine before a game can increase players’ typing speed 11 , shorten their reaction times and increase their shooting accuracy 12 . However, few studies have explored the ergogenic effects of caffeine on problem-solving abilities by Stroop task 13 on Esports players.

This is because visual search ability and the presence of decoys that distract the player's attention both affect performance in first-person shooting games. When investigating the effect of caffeine on shooting accuracy, it is not sufficient to use simple reaction time as an indicator of cognitive ability. Therefore, the purpose of this study was to explore the effect of caffeine intake 1 h before a first-person shooting game on players' performance by using the Stroop task and testing their visual search and shooting abilities.

The study was a single blind, repeated-measure, crossover design where participants were randomized to ingest a caffeine capsule (CAF) and a placebo capsule (PL) separated by 7 days, 1 h before performing cognitive function tests. We used computerized randomization to arrange the order of participants in the experiment. At least 1 week before the formal experiment, all subjects participated in three to five familiarization tests, such as cognitive function and shooting tests. The primary outcome was the results of the cognitive function tests, and the secondary outcome was shooting performance. The study started on 01/01/2022 and ended on 30/04/2022.


We recruited nine healthy male adults (age: 20.8 ± 0.9 years; height: 172.3 ± 1.2 cm; mass: 72.8 ± 8.3 kg; training age: 2.8 ± 0.3 years). All participants have experienced international first-person shooting and are recruited from national Esports training centers. We did not recruit female participants to eliminate the effect of their menstrual cycle, which could have increased the confounding factors of the experiment 14 , 15 . The inclusion criteria were: (i) healthy male adults, those individuals who are free of pain, insomnia, or other injuries recently, without any medication used in recent 2 months, (ii) underwent training (more than 5 days per week) in first-person shooters, are a type of shooter game 16 that relies on a first-person point of view with which the player experiences the action through the eyes of the character, more than two years. The exclusion criteria were: (i) females, (ii) below 20 years old, (iii) did not have sufficient training/competitions experience (for example, did not have experienced international first-person shooting), (iv) with cardiovascular diseases or any disease that made subjects feel ill, (v) participants with daily caffeine intake below 80 mg 12 . According to the pre-test dietary recorded by photos, the participants had an average daily caffeine intake of 44.1 ± 32.9 mg. Among the participants, the lowest mean daily caffeine intake was 0 mg and the highest was 78 mg.

Two weeks before the main trial, all the participants were asked to avoid ingestion of more than 80 mg of caffeine a day. Before the experiment, all participants were fully informed of the experimental procedures and risks and provided informed consent. All the study was executed in the eSports room. This study received approval from the Institutional Review Board of Jen-Ai Hospital-Dali Branch (111-06) and registered in the ClinicalTrials.gov (Date: 30/08/2022; ID “NCT05521347”; https://register.clinicaltrials.gov ). This study was conducted following the Declaration of Helsinki.

Experimental procedure

All tests were conducted in a professional e-sports classroom, and the indoor ambient temperature was set at 26 °C. All participants' computers and chairs were equipped with the equipment they were most accustomed to training on. Participants’ diet and mealtimes were recorded for the 3 days before the first formal experiment, and the participants were required to follow the same diet 3 days before the next formal experiment. Nutrient composition on Day 1 included 11.7 ± 4.1% protein, 42.6 ± 13.3% carbohydrate, 28.9 ± 6.8% lipid and 2265.0 ± 265.6 kcal. Nutrient composition on Day 2 included 11.4 ± 2.3% protein, 40.0 ± 10.6% carbohydrate, 28.9 ± 6.1% lipid and 2050.0 ± 454.4 kcal. They were also required to avoid food and beverages with caffeine (e.g., coffee, energy drinks, chocolate, chocolate drink, and tea) 3 days before the formal experiment.

On the day of the formal experiment, participants had breakfast and lunch at 8:00 a.m. and 12:00 p.m., respectively. The nutritional composition of breakfast and lunch was 10.9 ± 3.5% protein, 42.9 ± 15.9% carbohydrate, 26.3 ± 7.8% lipid, and 1190.2 ± 235.4 kcal. The participants arrived at the classroom at approximately 3:00 p.m. for the experiment. The participants took capsules with 3 mg/kg of caffeine (CAF trial) (caffeine, Wako Pure Chemical Industries, Ltd., Osaka, Japan) and or a placebo capsule (PL trial) with 200 mL of water. The placebo capsule contained flour. All the capsules used for the placebo and caffeine trials are identical in size, shape, color, and taste. Each participant had a computer with a frame rate of at least 240 Hz and a mouse with a scrolling speed of 1 ms. After the participants remained in the room for 1 h, during which time they were asked to take any form of rest other than engaging in e-sports, they took the Stroop task, the visual search test, and the shooting ability test. All participants completed all tests without adverse effects.

Outcome measure

The color-word Stroop task and visual search test were conducted using Psych/Lab for Windows. Measures used in the literature have satisfactory reliability and validity 17 . The Stroop task involved four base colors, namely red, green, blue, and yellow, and the names of the base colors were presented in Chinese characters and in diverse colors to confuse the participants. The participants were required to press a key corresponding to the base color name they saw on the screen (“R” for red, “G” for green, “B” for blue, and “Y” for yellow). In each test, eighty trials lasting 5 min each were conducted. The test results comprised a congruent condition, in which the key pressed corresponded correctly to the color on screen, and an incongruent condition, in which the key pressed corresponded incorrectly to the color name on screen.

In the visual search test, participants identified orange “T” s on the screen from upside-down orange “T” s, blue “T” s, and upside-down blue “T” s. When an orange “T” would appear, the participants were required to press the spacebar as quickly as possible. If no orange “T” appeared, the participants were required to not react. A total of 80 search displays were presented in 5 min. In each display, 5, 10, 15, or 20 items were presented.

The shooting ability test involved a three-dimensional aim trainer, which was proposed in a previous study 12 . Participants used the mouse to shoot the electronic targets on the computer screen. The test comprised sixty targets and could be completed in 2 min. It was performed on a static map with medium difficulty. In each round, three targets appeared at once, and participants were required to shoot them within 2 s, ideally eliminating each target with a one-shot kill. Participants’ kill ratio (number of targets hit/60), hit accuracy (60/number of shooting), and average time to target were noted.

Statistical analysis

All data are presented as averages ± standard deviations. The Shapiro–Wilk test was used to examine the normality of the data. Cognitive performance, accuracy, and hit reaction time were analyzed through a paired sample t test. We used G*power 3 software 24 to achieve an alpha value of 5% and a power of 0.8; a sample of six was considered sufficient for this study. Effect sizes were calculated using Cohen's D. All data were calculated using SPSS (version 20, Chicago, IL, USA), and the significance level was α < 0.05.

Stroop task

The reaction time in the congruent condition of the Stroop task (Fig.  1 A) of the caffeine trial was significantly shorter than that in the placebo trial ( P  = 0.023). The reaction time in the incongruent condition of the Stroop task (Fig.  1 B) did not significantly differ between the trials ( P  = 0.478). The effect size (Cohen’s D) was 1.2 for the congruent condition. The correct rates were not significantly different in congruent condition (CAF: 89.2 ± 18.6%; PLA: 87.3 ± 9.2%; P  = 0.715) and incongruent condition (CAF: 93.8 ± 5.7%; PLA: 86.7 ± 5.3%; P  = 0.273).

figure 1

The reaction time in the congruent condition of the Stroop task ( A ) and the reaction time in the incongruent condition of the Stroop task ( B ). *CAF was significantly higher than those for the PLA ( P  = 0.023) in the congruent condition of the Stroop task.

Visual search reaction time

The visual search reaction time (Table 1 ) in the caffeine trial was significantly shorter than that in the placebo trial ( P  = 0.020) with 20 items. The effect size (Cohen’s D) was 0.95. The visual search reaction time did not differ significantly between the trials ( P  > 0.05) with 5, 10, and 15 items.

Shooting performance

In the caffeine trial, the kill ratio ( P  = 0.020) and accuracy ( P  = 0.008) were significantly higher than those in the placebo trial, and average time to target ( P  = 0.001) was significantly shorter (Fig.  2 ). The effect size (Cohen’s D) was 0.96 for kill ratio, 1.6 for accuracy, and 1.96 for average time to target.

figure 2

The kill ratio ( A ), kill accuracy ( B ), and the average time to target ( C ) of the shooting ability test. *CAF was significantly higher than those for the PLA in the kill ratio ( P  = 0.020), kill accuracy ( P  = 0.008), and the average time to target ( P  = 0.001).

The aim of this study was to investigate the effect of supplementary caffeine with 3 mg/kg on improving performance of E-sport players in Stroop task, visual search reaction time, kill ratio, hit accuracy, and average time to target. Caffeine supplementation improved reaction times in the congruent condition of the Stroop task, visual search reaction time with twenty items, kill ratio, accuracy, and average time to target, but the effects on reaction time in the incongruent condition of the Stroop task were insignificant.

Caffeine exhibits dose-dependent effects with desirable effects at lower doses (i.e., ≤ 400 mg) and detrimental effects above this level, although there is considerable inter-individual variation. For example, at doses of 250 mg, increased arousal, alertness, concentration, and well-being have been noted in human subjects 18 . Concentrations of 3–6 mg/kg caffeine are considered safe 19 and helpful for the performance of E-sport players 12 . In our study, caffeine supplementation at 3 mg/kg showed a clear benefit on the various measures described above. In contrast, increased tension, nervousness, anxiety, excitement, irritability, nausea, paresthesia, tremor, perspiration, palpitations, restlessness, and possibly dizziness occur at a dose of 500 mg 20 . These effects may interfere with E-sports athlete performance, especially under fast-paced, high-stress visual and auditory stimuli. Ebrahimi et al. had proved that taking 5 mg/kg of caffeine can increase the blood pressure and heart rate of the shooters that leads to a decrease in shooting performance 21 . Sub-lethal doses of 7–10 mg/kg produce symptoms such as nausea, headache, chills, flushing, palpitations, and tremor, although individuals’ responses may vary significantly 18 . In extremely high doses, especially for some vulnerable populations, caffeine consumption could be harmful, including seizure or impairments in cardiovascular function, such as hemodynamic collapse and refractory arrhythmia 22 , however, it is extremely rare 23 . In 2017, the American Association of Poison Control Centers reported 3765 cases of caffeine overdose, of which 650 were intentional and none resulted in death from caffeine alone. Ingestion of 5 g (80–100 mg/kg) is likely to prove fatal 24 . Therefore, caffeine with 3 mg/kg is a safe psychomotor-activating supplementation for general populations, and a popular and effective ergogenic supplementation among athletes.

To the best of our knowledge, only one study has explored the effect of caffeine supplementation on e-sports players’ cognitive and shooting abilities. That study revealed that caffeine can improve attention, reaction time, and shooting ability, which is consistent with our results 12 . However, that study only involved a reaction test, the results of which might not explain improvements in cognitive function. The results of the Stroop task and visual search test in our study explain why caffeine improves shooting ability. We discovered that caffeine increases cognitive speed and shortens reaction times. The test with the aim trainer also revealed significant differences, indicating that caffeine can improve shooting ability in e-sports. Our results suggest that caffeine supplementation affects not only reaction time but also complex visual search ability in first-person shooters.

In our study, caffeine supplementation with 3 mg/kg showed clear benefits in the reaction time of the Stroop task-congruent, however, insignificant effects in the reaction time of the Stroop task-incongruent in elite players of E-sports. Dixit et al. conducted a study on 30 male undergraduate students through tests before and 40 min after the students consuming 3 mg/kg caffeine. The caffeine did not affect performance in a Stroop task, but significant decreases in reaction time were observed 25 . Yuan et al. conducted a behavioral experiment on thirty-one healthy participants through a Stroop task before and after the participants drank approximately 210 mL of coffee. The response time in the incongruent stimulus condition was longer than that in the congruent and neutral stimulus conditions both before and after the participants consumed the coffee. A decrease in interference in the incongruent stimulus and an increase in facilitation in the congruent were evidenced by decreases in reaction time after caffeine consumption 26 . Hasenfratz and Battig observed short reaction times in a Stroop task after participants consumed 250 mg of caffeine 27 . These results are consistent with ours, indicating that caffeine supplementation can shorten reaction times.

In our study, caffeine supplementation with 3 mg/kg showed an obvious reduction in the visual search reaction time in twenty items, however, insignificant effects in the visual search reaction time in 5, 10, 15 times in elite players of E-sports. Lorist et al. administered 3 mg/kg of coffee to undergraduate students, which shortened response times, as in our study 28 . Significant effects were only noted in tasks with more items, which may be related to cognitive processing demands; a higher number of items would require more concentration. The caffeine facilitated concentration, and differences between the caffeine and placebo trials were only observed under certain cognitive processing demands. Durlach also revealed that 60 mg of caffeine from a cup of tea significantly shortened reaction times in a sample visual search 29 . Marsden and Leach revealed that caffeine can improve visual search abilities but not chart search abilities in experienced navigators 30 . Therefore, caffeine reduces visual search reaction times. Our results indicate that the effect of caffeine on reaction time is related to improvements in perceptual attentional processes rather than motor processes, as indicated by Saville et al. 31 . The results also suggest that caffeine is effective in improving performance in e-sports that require attention, accuracy and short reaction times.

This study revealed that caffeine can increase e-sports players’ accuracy in shooting moving targets and reduce their response times. This might be attributable to the 3-mg/kg dosage, which reduced reaction times in the congruent condition of the Stroop task and visual search tasks with more items. This might also be related to the ergogenic effects of caffeine on dynamic visual acuity and problem-solving abilities. Redondo et al. discovered that the effects of caffeine on visual search reaction times may be related to the ergogenic effect on dynamic visual acuity 32 . This is particularly relevant to our tasks, which require the accurate and rapid detection of moving targets. In first-person shooters, players use various strategies to react to quick processions of visual and auditory stimuli and adapt to changing environments 33 . Our tasks required the identification of stimuli and the appropriate responses, motor plans, and actions.

The metabolism of caffeine is highly variable among individuals due to different genotype expressions at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested 34 . Southward et al. suggested that there might be up to 33% of those who do not enhance performance following caffeine ingestion (i.e., non-responders) 35 . Minaei et al. found that the ingestion of 6 mg/kg of caffeine improved peak power output only in participants with the AA genotype compared with the placebo trial; however, expression of the CYP1A2 did not influence average or minimum power output or fatigue index 36 . However, in our study, all our subjects could observe the effect of caffeine on those specific measurements.

This study used a rigorous, two-arm crossover, randomized, controlled design. All outcomes were measured using a computer to ensure reliability. Despite these strengths, this study has several limitations. The main limitation is the low external validity and that the AIM trainer needs to be assembled. However, the inclusion of participants with previous experience increased the external validity. To our knowledge, only one study used the aim trainer to evaluate the effect of caffeine on e-sports performance 12 . By using a computer-based aim trainer, this study ensured that the outcome measures accurately represented participants’ performance. The computers we used may have influenced the results. Each participant used dedicated computers, and we used rigorous criteria for frame rates and mouse speeds. Therefore, the results accurately represent changes in performance due to caffeine supplementation. In addition, there is considerable inter-individual variation in the effects of different doses of caffeine. Even at the same dose, some subjects may experience adverse effects such as palpitations, anxiety, or tremors, which can interfere with the performance of eSports, especially during fast-paced, high-stress visual and auditory stimuli. In our study, however, the dosage of caffeine was adjusted according to the subjects' body mass, and the method was accurate enough for a medical experiment. We did not measure caffeine levels during the experiment. However, we controlled the food diary for 3 days at both experimental visits and avoided food and drinks with caffeine during this period. Furthermore, there is a significant lack of female athletes in e-sports 37 , 38 . Although this makes it difficult for us to recruit female athletes, a woman's menstrual cycle may be one of the variables affecting experimental control 14 , 15 . For this reason, gender was specifically included as an exclusion criterion in this study. The fact that we only had male subjects did not affect the results of this study and its external validity.

In future studies, we may be able to differentiate between participants who consume caffeine and those who do not. In addition, we can supplement caffeine in different ways, such as chewing gum, sublingual tablets, etc., to see if these methods of consuming caffeine without drinking water are more beneficial to performance.

Caffeine supplementation improved cognitive abilities, decreased reaction times in the congruent condition and visual search reaction times in tasks with more items, increased kill ratio and accuracy, and reduced average time to target among elite e-sport players. A dosage of 3 mg/kg of caffeine supplementation ingested 1 h before the game may have a positive effect on players’ performance in a first-person shooter by using a Stroop task and testing the players’ visual search and shooting abilities. Such findings may encourage coaches and athletes to consider the use of caffeine as a nutritional supplement prior to important competitions to further enhance competitive performance.

Data availability

All relevant materials are presented in the present manuscript.

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Thanks for Overseas Chinese University to provide the equipment for this study.

This study was funded by the National Taiwan University of Sport in Taiwan (111DG00102).

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Shih-Hao Wu

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Yu-Chun Chen

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Che-Hsiu Chen

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S.-H.W. (Shih-Hao Wu) and Y.-C.C. (Yu-Chun Chen) assisted the data analysis and manuscript preparation. C.-C.H. (Che-Hsiu, Chen) and Z.-X.L. (Zhi Xin, Liu) assisted the experimental design and manuscript preparation. C.-H.C. (Chih-Hui Chiu) carried out the experiment, data analysis and assisted in the manuscript preparation.

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Wu, SH., Chen, YC., Chen, CH. et al. Caffeine supplementation improves the cognitive abilities and shooting performance of elite e-sports players: a crossover trial. Sci Rep 14 , 2074 (2024). https://doi.org/10.1038/s41598-024-52599-y

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buffalo case study caffeine

chemical formula for caffeine with three coffee beans on the side

Many of us can’t imagine starting the day without a cup of coffee. One reason may be that it supplies us with a jolt of caffeine, a mild stimulant to the central nervous system that quickly boosts our alertness and energy levels. [1] Of course, coffee is not the only caffeine-containing beverage. Read on to learn more about sources of caffeine, and a review of the research on this stimulant and health.

Absorption and Metabolism of Caffeine

The chemical name for the bitter white powder known as caffeine is 1,3,7 trimethylxanthine. Caffeine is absorbed within about 45 minutes after consuming, and peaks in the blood anywhere from 15 minutes to 2 hours. [2] Caffeine in beverages such as coffee, tea, and soda is quickly absorbed in the gut and dissolves in both the body’s water and fat molecules. It is able to cross into the brain. Food or food components, such as fibers, in the gut can delay how quickly caffeine in the blood peaks. Therefore, drinking your morning coffee on an empty stomach might give you a quicker energy boost than if you drank it while eating breakfast.

Caffeine is broken down mainly in the liver. It can remain in the blood anywhere from 1.5 to 9.5 hours, depending on various factors. [2] Smoking speeds up the breakdown of caffeine, whereas pregnancy and oral contraceptives can slow the breakdown. During the third trimester of pregnancy, caffeine can remain in the body for up to 15 hours. [3]

People often develop a “caffeine tolerance” when taken regularly, which can reduce its stimulant effects unless a higher amount is consumed. When suddenly stopping all caffeine, withdrawal symptoms often follow such as irritability, headache, agitation, depressed mood, and fatigue. The symptoms are strongest within a few days after stopping caffeine, but tend to subside after about one week. [3] Tapering  the amount gradually may help to reduce side effects.

Sources of Caffeine

Caffeine is naturally found in the fruit, leaves, and beans of coffee , cacao, and guarana plants. It is also added to beverages and supplements. There is a risk of drinking excess amounts of caffeinated beverages like soda and energy drinks because they are taken chilled and are easy to digest quickly in large quantities.

  • Coffee. 1 cup or 8 ounces of brewed coffee contains about 95 mg caffeine. The same amount of instant coffee contains about 60 mg caffeine. Decaffeinated coffee contains about 4 mg of caffeine. Learn more about coffee .
  • Espresso. 1 shot or 1.5 ounces contains about 65 mg caffeine.
  • Tea. 1 cup of black tea contains about 47 mg caffeine. Green tea contains about 28 mg. Decaffeinated tea contains 2 mg, and herbal tea contains none. Learn more about tea .
  • Soda. A 12-ounce can of regular or diet dark cola contains about 40 mg caffeine. The same amount of Mountain Dew contains 55 mg caffeine.
  • Chocolate (cacao) . 1 ounce of dark chocolate contains about 24 mg caffeine, whereas milk chocolate contains one-quarter of that amount.
  • Guarana. This is a seed from a South American plant that is processed as an extract in foods, energy drinks, and energy supplements. Guarana seeds contain about four times the amount of caffeine as that found in coffee beans. [4] Some drinks containing extracts of these seeds can contain up to 125 mg caffeine per serving.
  • Energy drinks. 1 cup or 8 ounces of an energy drink contains about 85 mg caffeine. However the standard energy drink serving is 16 ounces, which doubles the caffeine to 170 mg. Energy shots are much more concentrated than the drinks; a small 2 ounce shot contains about 200 mg caffeine. Learn more about energy drinks .
  • Supplements. Caffeine supplements contain about 200 mg per tablet, or the amount in 2 cups of brewed coffee.

Recommended Amounts

In the U.S., adults consume an average of 135 mg of caffeine daily, or the amount in 1.5 cups of coffee (1 cup = 8 ounces). [5] The U.S. Food and Drug Administration considers 400 milligrams (about 4 cups brewed coffee) a safe amount of caffeine for healthy adults to consume daily. However, pregnant women should limit their caffeine intake to 200 mg a day (about 2 cups brewed coffee), according to the American College of Obstetricians and Gynecologists.

The American Academy of Pediatrics suggests that children under age 12 should not consume any food or beverages with caffeine. For adolescents 12 and older, caffeine intake should be limited to no more than 100 mg daily. This is the amount in two or three 12-ounce cans of cola soda.

Caffeine and Health

Caffeine is associated with several health conditions. People have different tolerances and responses to caffeine, partly due to genetic differences. Consuming caffeine regularly, such as drinking a cup of coffee every day, can promote caffeine tolerance in some people so that the side effects from caffeine may decrease over time. Although we tend to associate caffeine most often with coffee or tea, the research below focuses mainly on the health effects of caffeine itself. Visit our features on coffee , tea , and energy drinks for more health information related to those beverages.

Caffeine can block the effects of the hormone adenosine, which is responsible for deep sleep . Caffeine binds to adenosine receptors in the brain, which not only lowers adenosine levels but also increases or decreases other hormones that affect sleep, including dopamine, serotonin, norepinephrine, and GABA. [2] Levels of melatonin, another hormone promoting sleep, can drop in the presence of caffeine as both are metabolized in the liver. Caffeine intake later in the day close to bedtime can interfere with good sleep quality. Although developing a caffeine tolerance by taking caffeine regularly over time may lower its disruptive effects, [1] those who have trouble sleeping may consider minimizing caffeine intake later in the day and before going to bed.

In sensitive individuals, caffeine can increase anxiety at doses of 400 mg or more a day (about 4 cups of brewed coffee). High amounts of caffeine may cause nervousness and speed up heart rate, symptoms that are also felt during an anxiety attack. Those who have an underlying anxiety or panic disorder are especially at risk of overstimulation when overloading on caffeine.

Caffeine stimulates the heart, increases blood flow, and increases blood pressure temporarily, particularly in people who do not usually consume caffeine. However, strong negative effects of caffeine on blood pressure have not been found in clinical trials, even in people with hypertension, and cohort studies have not found that coffee drinking is associated with a higher risk of hypertension. Studies also do not show an association of caffeine intake and atrial fibrillation (abnormal heart beat), heart disease , or stroke. [3]

Caffeine is often added to weight loss supplements to help “burn calories.” There is no evidence that caffeine causes significant weight loss. It may help to boost energy if one is feeling fatigued from restricting caloric intake, and may reduce appetite temporarily. Caffeine stimulates the sympathetic nervous system, which plays a role in suppressing hunger, enhancing satiety, and increasing the breakdown of fat cells to be used for energy. [6] Cohort studies following large groups of people suggest that a higher caffeine intake is associated with slightly lower rates of weight gain in the long term. [3] However, a fairly large amount of caffeine (equivalent to 6 cups of coffee a day) may be needed to achieve a modest increase in calorie “burn.” Additional calories obtained from cream, milk, or sweetener added to a caffeinated beverage like coffee or tea can easily negate any calorie deficit caused by caffeine.

Caffeine can cross the placenta, and both mother and fetus metabolize caffeine slowly. A high intake of caffeine by the mother can lead to prolonged high caffeine blood levels in the fetus. Reduced blood flow and oxygen levels may result, increasing the risk of miscarriage and low birth weight. [3] However, lower intakes of caffeine have not been found harmful during pregnancy when limiting intakes to no more than 200 mg a day. A review of controlled clinical studies found that caffeine intake, whether low, medium, or high doses, did not appear to increase the risk of infertility. [7]

Most studies on liver disease and caffeine have specifically examined coffee intake. Caffeinated coffee intake is associated with a lower risk of liver cancer, fibrosis, and cirrhosis. Caffeine may prevent the fibrosis (scarring) of liver tissue by blocking adenosine, which is responsible for the production of collagen that is used to build scar tissue. [3]

Studies have shown that higher coffee consumption is associated with a lower risk of gallstones. [8] Decaffeinated coffee does not show as strong a connection as caffeinated coffee. Therefore, it is likely that caffeine contributes significantly to this protective effect. The gallbladder is an organ that produces bile to help break down fats; consuming a very high fat diet requires more bile, which can strain the gallbladder and increase the risk of gallstones. It is believed that caffeine may help to stimulate contractions in the gallbladder and increase the secretion of cholecystokinin, a hormone that speeds the digestion of fats.

Caffeine may protect against Parkinson’s disease. Animal studies show a protective effect of caffeine from deterioration in the brain. [3] Prospective cohort studies show a strong association of people with higher caffeine intakes and a lower risk of developing Parkinson’s disease. [9]

Caffeine has a similar action to the medication theophylline, which is sometimes prescribed to treat asthma. They both relax the smooth muscles of the lungs and open up bronchial tubes, which can improve breathing. The optimal amount of caffeine needs more study, but the trials reviewed revealed that even a lower caffeine dose of 5 mg/kg of body weight showed benefit over a placebo. [10] Caffeine has also been used to treat breathing difficulties in premature infants. [3]

Caffeine stimulates the release of a stress hormone called epinephrine, which causes liver and muscle tissue to release its stored glucose into the bloodstream, temporarily raising blood glucose levels. However, regular caffeine intake is not associated with an increased risk of diabetes . In fact, cohort studies show that regular coffee intake is associated with a lower risk of type 2 diabetes , though the effect may be from the coffee plant compounds rather than caffeine itself, as decaffeinated coffee shows a similar protective effect. [3] Other observational studies suggest that caffeine may protect and preserve the function of beta cells in the pancreas, which are responsible for secreting insulin. [11]

Signs of Toxicity

Caffeine toxicity has been observed with intakes of 1.2 grams or more in one dose. Consuming 10-14 grams at one time is believed to be fatal. Caffeine intake up to 10 grams has caused convulsions and vomiting, but recovery is possible in about 6 hours. Side effects at lower doses of 1 gram include restlessness, irritability, nervousness, vomiting, rapid heart rate, and tremors.

Toxicity is generally not seen when drinking caffeinated beverages because a very large amount would need to be taken within a few hours to reach a toxic level (10 gm of caffeine is equal to about 100 cups of brewed coffee). Dangerous blood levels are more often seen with overuse of caffeine pills or tablets. [3]

Did You Know?

  • Caffeine is not just found in food and beverages but in various medications. It is often added to analgesics (pain relievers) to provide faster and more effective relief from pain and headaches. Headache or migraine pain is accompanied by enlarged inflamed blood vessels; caffeine has the opposite effect of reducing inflammation and narrowing blood vessels, which may relieve the pain.
  • Caffeine can interact with various medications. It can cause your body to break down a medication too quickly so that it loses its effectiveness. It can cause a dangerously fast heart beat and high blood pressure if taken with other stimulant medications. Sometimes a medication can slow the metabolism of caffeine in the body, which may increase the risk of jitteriness and irritability, especially if one tends to drink several caffeinated drinks throughout the day. If you drink caffeinated beverages daily, talk with your doctor about potential interactions when starting a new medication.

cup of coffee

Energy Drinks

  • Clark I, Landolt HP. Coffee, caffeine, and sleep: A systematic review of epidemiological studies and randomized controlled trials. Sleep medicine reviews . 2017 Feb 1;31:70-8. *Disclosure: some of HPL’s research has been supported by Novartis Foundation for Medical-Biological Research.
  • Institute of Medicine (US) Committee on Military Nutrition Research. Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington (DC): National Academies Press (US); 2001. 2, Pharmacology of Caffeine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223808/
  • van Dam RM, Hu FB, Willett WC. Coffee, Caffeine, and Health.  NEJM .  2020 Jul 23; 383:369-378
  • Moustakas D, Mezzio M, Rodriguez BR, Constable MA, Mulligan ME, Voura EB. Guarana provides additional stimulation over caffeine alone in the planarian model. PLoS One . 2015 Apr 16;10(4):e0123310.
  • Drewnowski A, Rehm CD. Sources of caffeine in diets of US children and adults: trends by beverage type and purchase location. Nutrients . 2016 Mar;8(3):154.
  • Harpaz E, Tamir S, Weinstein A, Weinstein Y. The effect of caffeine on energy balance. Journal of basic and clinical physiology and pharmacolog y. 2017 Jan 1;28(1):1-0.
  • Bu FL, Feng X, Yang XY, Ren J, Cao HJ. Relationship between caffeine intake and infertility: a systematic review of controlled clinical studies.  BMC Womens Health . 2020;20(1):125.
  • Zhang YP, Li WQ, Sun YL, Zhu RT, Wang WJ. Systematic review with meta‐analysis: coffee consumption and the risk of gallstone disease. Alimentary pharmacology & therapeutics . 2015 Sep;42(6):637-48.
  • Hong CT, Chan L, Bai CH. The Effect of Caffeine on the Risk and Progression of Parkinson’s Disease: A Meta-Analysis. Nutrients . 2020 Jun;12(6):1860.
  • Welsh EJ, Bara A, Barley E, Cates CJ. Caffeine for asthma.  Cochrane Database Syst Rev . 2010;2010(1):CD001112.
  • Lee S, Min JY, Min KB. Caffeine and Caffeine Metabolites in Relation to Insulin Resistance and Beta Cell Function in US Adults. Nutrients . 2020 Jun;12(6):1783.

Last reviewed July 2020

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REVIEW article

The safety of ingested caffeine: a comprehensive review.

\r\nJennifer L. Temple,*&#x;

  • 1 Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY, USA
  • 2 Department of Community Health and Health Behavior, University at Buffalo, Buffalo, NY, USA
  • 3 Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France
  • 4 Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit, MI, USA

Caffeine is the most widely consumed psychoactive drug in the world. Natural sources of caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to promote arousal, alertness, energy, and elevated mood. Over the past decade, the introduction of new caffeine-containing food products, as well as changes in consumption patterns of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies about the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to the negative effects of caffeine consumption: pregnant and lactating women, children and adolescents, young adults, and people with underlying heart or other health conditions, such as mental illness. Here, we review the research into the safety and safe doses of ingested caffeine in healthy and in vulnerable populations. We report that, for healthy adults, caffeine consumption is relatively safe, but that for some vulnerable populations, caffeine consumption could be harmful, including impairments in cardiovascular function, sleep, and substance use. We also identified several gaps in the literature on which we based recommendations for the future of caffeine research.


Caffeine is the most widely consumed psychoactive drug in the world ( 1 ) and one of the most comprehensively studied ingredients in the food supply. It occurs naturally in the leaves and seeds of many plants and has a taste bitter enough to deter pests ( 2 ). Natural sources of dietary caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to enhance their stimulant properties. Historically, this addition was limited to soda-type beverages, but over the past decade, caffeine has been added to a diverse variety of foods and non-food items to promote arousal, alertness, energy, and elevated mood ( 3 – 5 ). This recent increase in caffeine-containing food products, as well as changes in patterns of consumption of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies of the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to its negative effects. Health and regulatory authorities have recently highlighted the risk of consumption among pregnant and lactating women, children, adolescents, young adults, and people with underlying heart and other health conditions.

In light of these concerns, we conducted a comprehensive review of all relevant published clinical and intervention trials, observational studies, systematic reviews, meta-analyses, and expert reviews on the use and safety of caffeine in humans, complemented where needed (e.g., for aspects of safety or mechanisms of action) with evidence from animal studies. We evaluated the strengths and limitations of the evidence on the safety of ingested caffeine, specifically focusing on the safety of caffeine-containing foods (e.g., beverages and solid foods). We summarize here what is known and what remains to be learned about caffeine intake and safety in healthy and vulnerable populations and highlight needed research.

Dietary Sources of Caffeine

Adults commonly consume caffeine in coffee and tea, both of which contain natural caffeine in their leaves or beans ( 6 ). Energy drinks often contain caffeine from natural products such as extracts from guarana leaves. In addition to coffee, tea, and energy drinks, caffeine is also naturally present in cocoa beans and thus in chocolate. The amount of caffeine in chocolate varies by the percentage of cocoa it contains, with 100% cocoa chocolate (unsweetened baking chocolate) containing around 240 mg caffeine/100 g, 55% cocoa (bittersweet) containing 124 mg caffeine/100 g, and 33% cocoa (milk chocolate) containing 45 mg caffeine/100 g ( 7 ). Synthetic caffeine is also added to soda and energy drinks ( 8 ), which are commonly consumed by children and adolescents worldwide, and to other food and non-food products with niche markets for subsets of consumers, such as juice, chewing gum, water, cookies, hot sauce, candy, beef jerky, mints, syrup, waffles, shampoo, soap, lip balm, eye cream, body scrub, and body lotion. These products are primarily marketed with claims that they provide energy, alertness, or are “age-defying.” Last year, the FDA announced that it will begin investigating the safety of caffeine added to food products, with a special emphasis on children and adolescents. 1

Caffeine is a constituent of many over-the-counter pain relievers and prescription drugs because the vasoconstricting and anti-inflammatory effects of caffeine act as a compliment to analgesics, in some cases increasing the effectiveness of pain relievers by up to 40% ( 9 – 14 ). Caffeine is used for general pain relief in medications such as Midol™ and Vanquis™, which contain doses ranging from 33 to 60 mg. It is used therapeutically in combination with ergotamine to treat migraine headaches and in combination with non-steroidal anti-inflammatory analgesics. Anacin™, Excedrin™, Goody’s™ headache powder, and pain reliever plus contain between 32 and 65 mg of caffeine, and prescription headache medications, including Fiorinal, Orphenadrine, and Synalgos, contain between 30 and 60 mg of caffeine.

Alone, caffeine is used as a somnolytic to counteract drowsiness (e.g., NoDoze™ and Vivarin™ each contain 200 mg of caffeine), to enhance seizure duration in electroconvulsive therapy, and to treat respiratory depression in neonates, postprandial hypotension, and obesity ( 15 – 18 ). Similar synergistic additive effects of caffeine and medications also occur in treatments for asthma and gall bladder disease, attention deficit-hyperactivity disorder, shortness-of-breath in newborns, low blood pressure, and weight loss ( 19 – 24 ). Between 50 and 200 mg of caffeine is added to some weight-loss supplements (Dexatrim™, Hydroxycut™, and Nutrisystem™ Energi-Zing Shake) for its purported effects on appetite suppression and increased metabolism ( 25 ).

Estimates of Caffeine Consumption

Recent estimates in adults suggest that more than 85% of adults in the U.S. regularly consume caffeine, with an average daily intake of about 180 mg/day, about the amount of caffeine in up to two cups of coffee ( 6 , 26 ). Among children and adolescents, caffeine use appears to be either stable or slightly decreasing over time, despite the influx of new caffeine-containing products on the market. For example, a study by Ahluwalia and Herrick using NHANES data reports that about 75% of U.S. children between 6 and 19 years old consume caffeine, with an average consumption of 25 mg/day in children 2–11 years old and 50 mg/day in children 12–17 years old ( 8 ). Another study also using the NHANES dataset reports average caffeine consumption in children and adolescents as 35 mg/day, with 4–8 years old consuming 15 mg/day, 9–13 years old consuming 26 mg/day, and 14–19 years old consuming 61 mg/day ( 27 ).

Coffee consumption varies worldwide: Finland and Norway are at the top of the list, with averages of 9.6 and 7.2 kg of coffee consumed per capita per year. The U.S. ranks 22nd, with 3.1 kg. A 1984 study showed that Canada and the U.S. had per capita rates of caffeine consumption that were triple the worldwide average but that were still half of what was consumed in countries such as Sweden and the United Kingdom (U.K.) ( 28 ). A more recent study from the Canadian Community Health Survey found that coffee was the second most popular drink among Canadian adults, with water being the first ( 29 ). The U.K.’s National Diet and Nutrition Survey also collected information on caffeine consumption through foods and beverages from adults and children. These data show that, on average, adults in the U.K. consume about 130 mg/day of caffeine and that children consume about 35 mg/day ( 30 ). A study from Japan using 4-day food diaries reported average daily caffeine consumption as about 260 mg/day in adults ( 31 ). Finally, people in Finland, Norway, the Netherlands, and Sweden are consistently reported to drink the most caffeine, primarily from coffee. However, these estimates are derived from sales of coffee and not from surveys of individual intake.

Trends in Caffeine Consumption

Trends in caffeine consumption have been stable among adults for the past two decades ( 6 ). Among children aged 2–19 years old, caffeine consumption increased significantly from the 1970s through the 1990s ( 5 , 32 ). This increase was also marked by a decrease in dairy consumption and an increase in soda consumption ( 32 ). More recent data suggest that caffeine consumption has remained stable among this age group since the 1990s ( 8 , 33 ), a finding similar to that in adults. This stability is somewhat surprising, given the marked increase in the number, variety, and availability of caffeinated beverages introduced in the past decade. Some researchers speculate that this stability reflects a lag in data collection or in consumption trends from when products are introduced to the market to when data are collected (for example, the most recent NHANES data on caffeine consumption are from 2011). Another potential explanation is that a possible decline in consumption among younger children has been offset by increased consumption among older adolescents and young adults attracted to the increasing number of new caffeine-containing products. Targeted marketing strategies seem to support this explanation. Advertisements for caffeinated energy drinks, the fastest growing segment of the beverage market ( 34 , 35 ), are specifically aimed at adolescent and young adult males ( 36 , 37 ). Given the popularity and prevalence of energy drinks, caffeine consumption could reasonably be expected to increase quickly among children and adolescents.

Caffeine intake usually begins in childhood, most often in the form of chocolate, soda, and chocolate milk ( 8 ). As children become adolescents, they increase consumption of soda and begin to add beverages with greater caffeine content, such as coffee and energy drinks ( 8 ). Average caffeine intakes increase from about 50 mg/day in childhood (aged 2–11 years) to 180 mg/day in adulthood ( 6 ). This amount is about 2 mg/kg/day in children, 2.4 mg/kg/day in women, and 2.0 mg/kg/day in men. This shift in absolute caffeine intake from childhood to adulthood is related to changes in the pattern of consumption, with adults adopting a more regular, daily pattern of consumption relative to children ( 6 ). In addition, the dietary sources of caffeine shift over the lifespan: adults primarily consume coffee and tea, whereas children and adolescents consume primarily soda and chocolate, which contain much lower amounts of caffeine.

The pattern of caffeine use changes across the lifespan has not been studied, but tolerance to the effects of caffeine has been speculated to increase the desire for larger doses to reverse the impact of overnight caffeine withdrawal ( 38 ). In addition, once caffeine intake is great enough to disrupt sleep, or if sleep duration is shortened by other factors, caffeine is often used to promote morning arousal, which can further disrupt sleep, creating a pattern in which caffeine is both the cause and the cure for too little sleep ( 38 , 39 ). Variations in caffeine sensitivity and consumption may relate to polymorphisms in enzymes that degrade caffeine and in adenosine receptors, which are the primary targets of caffeine ( 40 ).

The Pharmacokinetics of Caffeine

Caffeine works by binding to adenosine receptors located in the central and peripheral nervous systems as well as in various organs, such as the heart, and blood vessels. Adenosine is a molecule involved in numerous biochemical pathways, mostly for energy transfer (in the form of adenosine triphosphate, the basic fuel of cells) and signaling. Adenosine is a neuromodulator that can promote sleep, affect memory and learning, and protect cells after insults. Adenosine can also act on several types of cognate receptors: for example, A1, A2a, A2b, and A3, which are G-coupled proteins. In the central nervous system, activating A1 receptors inhibits the release of neurotransmitters, whereas activating A2a receptors promotes their release ( 41 ). During early stages of brain development, the predominant effect of caffeine is to antagonize type 2A adenosine receptors, slowing down the migration speed of some neurons ( 42 ). At toxic doses (i.e., extreme doses that humans rarely absorb), caffeine can alter other cellular functions, releasing Ca 2+ from intracellular stores at lethal levels ( 43 ). The toxic dose effects are not considered here because, although they are of great concern to the medical profession and may be on the rise, they are still rare compared to other, non-lethal caffeine effects and the precise mechanism of caffeine toxicity has not been investigated in humans.

Absorption and Metabolism

Caffeine is usually ingested. Caffeine is soluble in water and lipids, easily crosses the blood–brain barrier, and can be found in all body fluids, including saliva and cerebrospinal fluid. Importantly, caffeine ingested by women perinatally will be present in the umbilical cord and breast milk. Hence, it will also be present in the fetus and in breastfed infants. Caffeine is absorbed rapidly and totally in the small intestine in less than 1 h ( 44 ) and diffuses rapidly in other tissues ( 45 ). Absorption by the small intestine does not seem to vary by sex, genetic background, environmental factors, or other variables ( 46 ), although specific studies are still needed to confirm this premise. Caffeine concentrations peak in saliva 45 min after ingestion ( 47 ) and in serum after about 2 h ( 48 ). Caffeine has a relatively long half-life of 3–7 h in adults. In neonates, the half-life is even longer—between 65 and 130 h—because of their immature kidneys and liver. Peak concentrations are important because the effects of caffeine depend in part on the length of time it remains in tissues. Clearly, the effects are age dependent and depend on complex genetic and environmental interactions.

Caffeine is primarily metabolized in the liver by the cytochrome P450 oxidase enzyme system; in particular, by the CYP1A2 enzyme. However, this oxidase enzyme system is also present in other tissues, including the brain ( 49 ). Caffeine metabolism is affected by several factors, described in detail below.

Genetic Variation

The CYP1A2 gene, which encodes for a cytochrome P450 enzyme, has a large genetic variability. At least 150 single-nucleotide polymorphisms can accelerate caffeine clearance ( 50 ). The metabolic consequences of this polymorphism on caffeine downstream effects should be studied in humans. Genetic variation (i.e., increased or decreased activity of the cytochrome P450 oxidase enzyme) may increase or decrease the possible harmful effects of caffeine (e.g., during pregnancy) and any beneficial effects (e.g., on memory and learning during aging or in pathologies, such as Alzheimer’s disease). The half-life of caffeine may also be increased in liver diseases, which decreases P450 activity ( 50 ).

The molecular targets of caffeine, namely the adenosine receptors, also have great genetic variability. For example, common variants of the gene encoding for the A2a receptor can disrupt sleep ( 51 ) or cause anxiety in some individuals ( 52 ) after ingesting caffeine. More studies are needed to determine the effects of genetic variants on the consequences of caffeine consumption ( 53 ), not only in the central nervous system but also in other organs, such as the heart ( 40 ).

Circadian Rhythms

The expression of the cytochrome P450 epoxygenases is regulated in a circadian manner ( 54 ). Although this effect was discovered in cultured rodent cells, it may apply to many species, including humans ( 55 ). The implications are particularly important because the effects of caffeine (at least the duration of its activity) will differ during the circadian cycle. Because caffeine can alter sleep, it may also change the circadian rhythm, leading to a change in expression patterns for the cytochrome P450. One interesting hypothesis is whether caffeine consumption in adolescents and adults disrupts the expression of P450 in relation to its circadian rhythm. If the expression is downregulated, the effects of caffeine could be prolonged and produce a negative feedback loop.

Steroid Hormones

The cytochrome P450 oxidase enzyme system is the same enzyme that metabolizes steroid hormones ( 56 ). Thus, steroid hormones slow caffeine metabolism. In women, this effect slows the metabolism of caffeine during pregnancy and when taking oral contraceptives ( 57 ). However, studies have not found marked differences in caffeine metabolism between the luteal and follicular phases of the menstrual cycle ( 57 , 58 ). Oral contraceptives tend to double the half-life of caffeine ( 59 ).

The half-life of caffeine is on average 8.3 h longer during pregnancy and may be as much as 16 h longer than usual ( 60 , 61 ). This longer half-life means that the effects of caffeine will be longer lasting in women and in the fetus. Given the effects that caffeine may have on brain development, this increased half-life in pregnant women should be taken into account when considering safety issues.

Caffeine is eliminated more slowly during early infancy, requiring perhaps 80 h in preterm and healthy-term neonates, because of the reduced efficiency of cytochrome P450 ( 62 , 63 ). Elimination is likely to be at least as slow in the fetus. Fetal exposure to caffeine during pregnancy may potentially have long-lasting effects, especially in the brain. By age 6 months, infants eliminate caffeine at the same rate as that of adults ( 62 ).

Substance Use

Cigarette smoking doubles the rate of caffeine clearance by increasing liver enzyme activity, which may explain the higher rate of caffeine consumption among smokers ( 64 ). Substantial alcohol intake increases the half-life of caffeine and decreases its clearance ( 65 ).

Central and Peripheral Effects of Caffeine

The general effects of caffeine on body functions are summarized in Table 1 .


Table 1. Summary of outcome measures investigated .

Cognitive Effects

Caffeine can influence objective and perceived cognitive performance by increasing alertness and wakefulness ( 66 – 68 ). Acute caffeine can also improve performance on memory tasks ( 69 , 70 ). Finally, caffeine improves psychomotor vigilance, such as reaction time ( 71 – 73 ). The impact of caffeine appears to be greater under conditions that would negatively impact performance, such as acute caffeine withdrawal ( 74 – 76 ) or sleep deprivation ( 71 , 77 ). In fact, studies that have employed long-term caffeine withdrawal methodology have consistently failed to find cognitive enhancing effects of acute caffeine ( 78 – 82 ). Nevertheless, in 2001, the Institute of Medicine’s Food and Nutrition Board Committee on Military Nutrition Research reported that ingesting 150 mg of caffeine enhances cognitive performance for at least 10 h ( 83 ), and this recommendation has not been updated in light of more recent empirical findings.

Numerous preclinical studies have found that antagonizing adenosine receptors, including with caffeine, has neuroprotective effects during aging and in neurological disorders by slowing cognitive decline and the progression of the disorders [reviewed in Ref. ( 84 , 85 )]. Based on these animal studies, several large longitudinal clinical studies in different countries have established an inverse relationship between coffee consumption and memory decline during normal aging ( 86 – 88 ). However, a study of 4,200 women and 1,800 men reported that caffeine consumption reduced cognitive decline only in women ( 69 ). In addition, a more recent study in a small group of women ( 89 ) failed to replicate the findings of the Ritchie study, demonstrating that more work is needed to understand the relationship between habitual caffeine consumption and cognitive performance. Finally, large cohort studies of men and women have also found an inverse relationship between caffeine consumption and the risk of Parkinson’s disease ( 90 – 92 ) and Alzheimer’s disease ( 93 – 95 ).

Pain Relief

Caffeine has long been used to treat pain. However, its pain-reduction effects were not properly studied until 1984, when Lachance ( 96 ) documented that additive caffeine reduced the dose of acetaminophen necessary to achieve the target of a 40% reduction in pain scores ( 96 ). Since then, the vasoconstricting action of caffeine, secondary to adenosine receptor antagonism, has been associated with pain relief ( 97 ). Several studies have reported that acute dietary caffeine consumption can reduce pain ( 98 , 99 ). In addition, caffeine in doses of between 300 and 500 mg can soothe post-dural puncture headaches, which is the most common complication of lumbar puncture procedures ( 100 ).

Cardiovascular Effects

In general, acute intake of caffeine stimulates a modest increase in blood pressure (both systolic and diastolic), effects on heart rate (bradycardia or tachycardia, depending on dose), and neuroendocrine effects (release of epinephrine, norepinephrine, and renin) ( 101 ). These effects suggest that the mechanism of action is an increase in intracellular calcium concentrations, the release of norepinephrine, and the sensitization of dopamine receptors. These events may lead to supraventricular and ventricular tachyarrhythmias, especially at high doses. One proposed mechanism for caffeine-related cardiac arrhythmias is, again, the blockade of adenosine receptors ( 102 , 103 ).

Patients with cardiac disease are often warned about the potential harmful effects of caffeine. For example, 94% of several hundred physicians from Minnesota and Vermont recommended reducing or stopping caffeine for patients reporting heart palpitations ( 104 ). However, this advice has been based primarily on anecdote and folklore ( 105 , 106 ). Many of caffeine’s health effects occur after sympathetic excitation. Today, however, data suggest that caffeine does have cardiac effects, and arrhythmia is among them ( 107 ). Moreover, effects that do exist differ by dose and between habitual and non-habitual users. This severity of these threats often depends on such factors as preexisting medical conditions as well as the quantity of the ingredients taken and the length of time a person has been exposed to these substances. Many of the ingredients that include caffeine alone or in combination with other active substances have the potential to interact with prescription and over-the-counter medications. At typical caffeine doses, however, studies have documented mild changes in heart rate and blood pressure, a slight increase in sympathetic activity, and small changes in cardiac electrophysiological properties ( 105 , 108 – 110 ).

Vascular System Effects

Caffeine is believed to improve endothelial cell function at rest by increasing intracellular calcium concentrations, which stimulates the expression of endothelial nitric oxide synthase, which in turn stimulates the endothelial cells to produce nitric oxide. The nitric oxide then diffuses into vascular smooth muscle, which lies just underneath the endothelial cells, causing vasodilation ( 111 ). Caffeine can also bind directly to the vascular smooth muscle cell receptors and, through similar mechanisms, cause vasoconstriction ( 112 ).

The above information not withstanding, consuming caffeine immediately before or during exercise can be harmful and may increase the risk for myocardial ischemia ( 113 ). Indirect laboratory measures indicate that caffeine consumed immediately before exercising substantially reduces myocardial blood flow in healthy individuals ( 114 ). Several mechanisms may explain this reduction ( 114 ), including the ability of caffeine to block adenosine receptors that modulate coronary vasomotor tone. This vasoconstrictive effect might be more pronounced among caffeine-naïve individuals or in those who quickly ingest higher amounts of caffeine: for example, by consuming energy drinks. When caffeine blocks adenosine receptors, it reduces the ability of the coronary arteries to improve their flow commensurate with the increased myocardial demand of exercise, which could result in supply demand ischemia ( 114 ).

Caffeine Toxicity

Seifert et al. ( 115 ) examined data from calls to the U.S. National Poison Data System made between October 1, 2010 and September 30, 2011 related to caffeine exposure and energy drink consumption ( 115 ). Of 2.3 million calls, 4,854 (0.2%) were energy drink related. Of the 1,480 calls related to exposures not involving alcohol, 51% concerned children under the age of 6, and 77% were the result of unintentional ingestion. The overall incidence of moderate-to-major adverse effects of energy drink-related toxicity was 15.2% for non-alcoholic energy drinks. The seven cases with major adverse effects consisted of three with seizure, two with non-ventricular dysrhythmia, one with ventricular dysrhythmia, and one with tachypnea. Of the same 1,480 calls, 946 concerned products containing caffeine only and 534 concerned products with caffeine-containing additives, such as guarana (a plant whose seeds are high in caffeine) or taurine (a naturally occurring organic acid often used as a nutritional supplement). Compared to energy drinks with additives, caffeine-only exposures involved a significantly greater proportion of cases less than 6 years old (50.7%) and a greater proportion of unintentional exposures (76.7%). The proportion of cases involving additives referred to a health-care facility was also significantly greater, as was the incidence of toxic effects of any severity. One caveat to this study is that information on preexisting medical conditions was not available for the cases studied. Research in this area should attempt to include and account for preexisting health conditions.

Researchers have also expressed concern about unintentional caffeine consumption and an increase in overconsumption of caffeinated energy drinks in children and young adults. For example, Bronstein et al. ( 116 ) identified 48,177 poison center calls related to caffeine consumption and 6,724 calls related specifically to energy drink consumption. Seifert et al. ( 115 ) also reported that 55% of calls regarding caffeine consumption were related to unintentional exposures ( 115 , 116 ). A study of 13- to 17-year olds admitted to urban emergency rooms in the U.S. found that more than half reported consuming energy drinks in the past month, and those who had were also more likely to report that they had “gotten into trouble at home, school, or work” than those who consumed other types of caffeinated beverages [OR: 3.12 (1.24–7.88)] ( 117 ).

In March 2013, 18 scientific and medical experts sent the FDA commissioner a report summarizing the research findings on energy drink consumption in children. This report concluded “… there is neither sufficient evidence of safety nor a consensus of scientific opinion to conclude that the high levels of added caffeine in energy drinks are safe under the conditions of their intended use, as required by the FDA’s Generally Recognized As Safe standards for food additives. To the contrary, the best available scientific evidence demonstrates a robust correlation between the caffeine levels in energy drinks and adverse health and safety consequences, particularly among children, adolescents, and young adults” ( 118 ). Furthermore, the Institute of Medicine has recommended that drinks containing caffeine should not be sold to children at school ( 119 ). In addition, The American Academy of Pediatrics’ Committee on Nutrition and the Council on Sports Medicine and Fitness recently concluded that “rigorous review and analysis of the literature reveal that caffeine and other stimulant substances contained in energy drinks have no place in the diet of children and adolescents” ( 120 ).

Death from caffeine ingestion appears to be rare. This rarity may be related, in part, to the marked gastric irritation from caffeine that results in spontaneous emesis. Nevertheless, several hospitalizations and some deaths from caffeine toxicity have been reported ( 121 ). For example, between 2005 and 2011, there were 79,438 emergency room visits attributable to overconsumption of energy products containing high levels of caffeine in patients aged 12 years and older ( 121 ). In most of these cases, the mechanism seems to be tachyarrhythmia and involves unusually high doses of caffeine (>3 mg/kg) ( 121 ). Most deaths after caffeine intoxication were caused by overdoses of diet pills and stimulants, and most have occurred in young patients without known underlying heart disease or any variant of normal, such as mitral valve prolapse. In one non-fatal adverse event report, no predisposing factors or structural cardiac abnormality were associated with atrial fibrillation ( 122 ). In this case, caffeine-induced atrial fibrillation spontaneously reverted to normal sinus rhythm.

Reproductive Effects

Caffeine consumption is associated with fertility indices in some studies but not in others. An extensive literature review by the Oak Ridge National Laboratory concluded that chronic caffeine intake in humans is related to adverse effects on conception and reproduction, such as delayed conception and decreased fecundity. These effects appeared at caffeine doses above 200 mg/day ( 121 ). A separate review concluded that for healthy adults, intakes below 400 mg/day were not associated with adverse reproductive effects; however, the authors recommended consumption below 300 mg/day for women of reproductive age ( 123 ). In addition, some researchers argue that any association between caffeine intake and reproductive outcomes may be explained by other variables, such as maternal smoking or substance use and that research should address confounding, as well as errors in measuring exposure ( 124 ).

Reports regarding caffeine consumption and spontaneous abortions have also been conflicting. Weng et al. ( 125 ) reported a hazard ratio of 2.23 for spontaneous abortion among 164 women who consumed 200 mg/day or more of caffeine and of 1.34 for 899 women who consumed less than 200 mg/day ( 125 ). After adjusting for pregnancy symptoms, such as nausea and vomiting, other researchers found that consuming doses of 200 mg/day or more still almost doubled the risk of spontaneous abortion. A meta-analysis by Chen et al. ( 126 ) reported that, compared to a no or very low caffeine intake reference group (0–50 mg/day during pregnancy), every additional 100 mg/day of caffeine (about the amount contained in a typical cup of coffee) increased the risk of pregnancy loss (both miscarriage and stillbirth) by 7% ( 126 ). In addition, among women consuming more than 700 mg/day, the risk of pregnancy loss was increased by 72%. Similar findings were reported by Li et al. ( 127 ), who found in a separate meta-analysis of 26 studies that the risk of pregnancy loss increased by 19% for every additional 150 mg of caffeine consumed per day and by 8% for every additional 2 cups of coffee (about 200 mg) per day ( 127 ). However, Savitz et al. ( 128 ) reported no association among 2407 women who were interviewed regarding caffeine intake before experiencing spontaneous abortion ( 128 ). This finding suggests that recall bias may explain the increased hazards of spontaneous abortion reported by Weng et al. ( 125 ) and potentially other researchers ( 125 ). Other comprehensive reviews have reported some evidence that caffeine intakes of more than 300 mg/day have been associated with spontaneous abortion and low birth weight, but all have stressed the need for further research before a causal relationship can be established ( 129 , 130 ). A recent study from the Nurses Health Study shows pre-pregnancy coffee consumption at levels ≥4 serving/day is associated with an increased risk of spontaneous abortions, particularly at 8–19 weeks gestational age ( 131 ).

Congenital Anomalies

No clear association has been found in humans between moderate doses of caffeine ingestion during pregnancy and birth defects, including congenital heart disease ( 132 ). For example, the National Birth Defects Prevention Study found variable results for this possible association ( 133 ). In another study of 2,030 malformed infants, the risk of congenital anomalies was not related to the total maternal daily caffeine ingestion below 400 mg/day (or up to 4 cups of coffee) during pregnancy ( 134 ). Other studies have found that the frequency of all congenital malformations, including congenital heart defects, was no higher than expected among women who drank between four and eight cups of coffee daily during their pregnancy ( 135 , 136 ). The Institute of Medicine’s Workshop on Potential Health Hazards Associated with Consumption of Caffeine in Food and Dietary Supplements found that risk of congenital defects from caffeine was not increased in the range of amounts women typically consumed during pregnancy ( 121 ).

The consequences of caffeine consumption during pregnancy on offspring have recently been studied in mice ( 137 ). Caffeine consumption by the dam (the human equivalent of two to three cups of coffee per day) was associated with caffeine concentrations in the offspring brain that were similar to those in the umbilical cords of women drinking two to three cups of coffee per day ( 138 ). At early stages of development, specific types of neurons arise in particular brain regions and then migrate to their target areas. Caffeine slowed the migration of these neurons by 50% by antagonizing adenosine type 2A receptors. As a result, these neurons were late at being incorporated into the circuitry, with negative consequences: pups were more susceptible to seizures, and in adulthood, in utero exposed mice had mild cognitive deficits. This study was the first to document that caffeine exposure during pregnancy could harm the offspring. Generalizing the results of animal studies to humans is always speculative, but these results strongly justify conducting prospective studies in humans. Interestingly, in keeping with animal data, greater exposure to caffeine during pregnancy is associated with a lower IQ in children at age 5.5 years ( 139 ). This finding again supports the need for additional studies in humans.

Birth Weight Effects

Several studies have reported a significant negative association between maternal caffeine consumption and birth weight ( 84 , 85 , 140 – 142 ). However, two other large prospective cohort studies reported a dose-dependent positive association between caffeine intake during pregnancy and the risk of adverse birth weight-related outcomes, such as fetal growth restriction and small for gestational age babies ( 143 , 144 ). In these studies, caffeine intake and adverse birth weight-related outcomes were found at all amounts of maternal caffeine intake. In both studies, the risk for adverse birth-related outcomes increased notably at a caffeine dose of 200 mg/day from all nutritional sources. In addition, one study of 1,207 pregnant women reported that, although they tended to reduce consumption of caffeine during pregnancy, a moderate decrease in caffeine intake to 100 mg/day in the third trimester of pregnancy did not decrease the risk of adverse birth weight-related outcomes ( 145 ).

Two separate meta-analyses of different sets of studies by Rhee et al. ( 142 ) and Chen et al. ( 146 ) reported odds ratios of having a newborn classified as low-birth weight (less than 2,500 g) for maternal caffeine consumption above 50 mg/day when compared to intakes below 50 mg/day. Furthermore, both meta-analyses found an increased risk of low-birth weight offspring for every 100 mg/day increase in maternal caffeine consumption (OR, 1.03–1.62). Another study by Hoyt et al. ( 140 ) found the odds ratios of having a low-birth weight baby increased to a range of 1.3–2.1 in women consuming more than 300 mg/day of caffeine during pregnancy ( 140 ).

Taken together, these studies provide substantial evidence of a negative association between maternal caffeine consumption and infant birth weight. Even so, the studies all relied on maternal self-report about caffeine intake; thus, the data may not be accurate. Furthermore, it is possible that additional variables, not controlled for in the analyses, could explain these relationships. For example, chronic sleep loss during pregnancy is also associated with poor birth outcomes, including low birth weight ( 147 ). Thus, pregnant women with disrupted sleep might use more caffeine to increase alertness, so the impact on birth weight could be related to short sleep duration and not to caffeine. Although this conclusion is speculative, it highlights the importance of considering additional variables when interpreting correlational data.

Caffeine may cause irritability and sleep disruption in nursing infants whose mothers consume caffeine ( 148 ), but the findings are equivocal ( 149 ). In addition, some evidence indicates that caffeine intake can reduce production of breast milk ( 148 ). Mothers are often advised by their doctors to reduce or eliminate caffeine intake if they feel that their infant shows signs of caffeine sensitivity, but there is no evidence in the literature of detrimental effects of caffeine ingestion during lactation in the general population. Behavioral issues, such as fussiness, jitteriness, and poor sleep patterns, have been reported among infants breastfed by mothers who consumed 10 or more cups of coffee (~1 g of caffeine) per day ( 121 ). The effects of caffeine in breast milk can be amplified in preterm infants or infants less than 5 months old because they metabolize caffeine so slowly ( 121 ). In addition, an intake of more than 450 mL (about two cups) of coffee per day may decrease breast milk iron concentrations, which could contribute to infant anemia ( 150 ). However, the European Food Safety Authority concluded that a single dose of 200 mg or less of caffeine (about two cups) consumed by lactating women, as well as chronic intakes at or below 200 mg, pose no safety concerns for breastfed infants ( 151 ).

Outcomes after Infancy

Few studies have examined the impact of maternal caffeine intake on outcomes after infancy. One study by Klebanoff and Keim ( 152 , 153 ) using 2,197 mother–child dyads measured child IQ and problem behaviors and examined correlations with maternal paraxanthine concentrations (a metabolite of caffeine) taken between 20 and 26 weeks of gestation ( 152 , 153 ). This study found no meaningful relationship between maternal caffeine intake during pregnancy and a range of behavioral and cognitive measures in children 4–7 years old. However, another study of 1,083 mother–child pairs revealed that children who were born to mothers who estimated caffeine intake >200 mg/day during pregnancy had an odds ratio of 2.3 (95% confidence interval of 1.13–4.69) of having a child with a lower IQ at age of 5.5 years compared to the reference population of mothers reporting <100 mg/day of caffeine consumption ( 139 ). A study by Li et al. ( 154 ) reported that maternal caffeine intake was associated with increased odds of childhood obesity, with each 100-mg increase in daily maternal caffeine intake being associated with a 23% higher odds of obesity at age 15 years ( 127 ), although a study by Klebanoff and Keim found no relationships between maternal caffeine consumption and childhood obesity ( 152 , 153 ).

The above studies are correlational; thus, causation cannot be determined. In addition, the maternal caffeine intake in these studies was estimated based on self-reports. One potential explanation for the discrepancies described above is the method used to determine caffeine use. In the study by Klebanoff and Keim ( 152 , 153 ), which found no significant relationship between maternal caffeine intake and outcomes after infancy, measured serum caffeine concentrations and did not use self-report ( 152 , 153 ). By contrast, the studies that found significant relationships between maternal intake and measures in the offspring after infancy relied exclusively on retrospective self-reports, several years after the fact, about prenatal caffeine consumption by mothers after they gave birth and during the first two trimesters of pregnancy, respectively. Caffeine intake was estimated from food-frequency questionnaires or interviews in which women reported how often and how much they consumed coffee, tea, and soda. Other variables affecting self-reported caffeine consumption and offspring behavioral outcomes might explain these relationships, but in the study that relied entirely on serum concentrations, such variables were not identified. These studies also measured different outcomes in the offspring. Klebanoff and Keim ( 152 , 153 ) had the most comprehensive battery of cognitive and behavioral outcomes, but Galera et al. ( 139 ) only measured IQ (The Wechsler Preschool and Primary Scale of Intelligence Third Edition), and Li et al. ( 127 ) only measured weight and weight gain in the offspring ( 139 , 152 – 154 ). Meaningful comparisons of studies are difficult when the methods for assessing caffeine intake and the outcomes are different. Research with objective measures of caffeine intake and standard outcomes is needed.

Other Existent, Emerging, or Minor Issues

Most of the research examining linkages between caffeine and cancer has been conducted on coffee and tea and not on caffeine specifically, which makes it difficult to determine the mechanism. The International Agency for Research on Cancer has concluded that the evidence is insufficient to conclude that caffeine, as consumed by a typical coffee drinker, is carcinogenic ( 121 ). Several large prospective trials have reached the same conclusion ( 123 , 155 , 156 ). Furthermore, Nawrot et al. ( 123 ) concluded in their review of the research that caffeine is unlikely to be a human carcinogen at levels less than 500 mg/day, to the equivalent of five cups of coffee ( 123 ).

Unstable Bladder

Excessive caffeine intake (more than 400 mg/day) may increase the risk of detrusor instability (unstable bladder) in women ( 157 ). For women with preexisting bladder symptoms, even moderate caffeine intake (200–400 mg/day) may increase the risk for unstable bladder ( 157 ). This finding was confirmed in another case–control study of women who were given 200 mg of caffeine citrate ( 158 ). In addition, caffeine intake of 4.5 mg/kg/day caused early urgency and frequency of urination in men and women with overactive bladder ( 159 ). However, these studies did not examine whether a decrease in caffeine intake was associated with improvements in overactive bladder symptoms. Studies should address this issue.

Caffeine–Drug Interactions

According to www.drugs.com (a site owned by The Drugsite Trust, a privately held Trust administered by two New Zealand Pharmacists), 85 drugs (430 brand and generic names) are known to interact with caffeine, of which 11 can lead to major interactions. 2 Because caffeine consumption is at an all-time high and prescription drug use is more prevalent than ever, the risk of negative caffeine and prescription drug interactions is increasing ( 160 , 161 ). Because of the popularity of caffeine, clinicians should be conscious of the pharmacokinetic interactions between dietary caffeine and over-the-counter and prescription medications, and they should provide the necessary guidance to the patient including dietary restrictions. We also recommend that the potential interaction with these drugs be appropriately addressed on the labeling.

Hydration and Diuresis

Caffeine has a diuretic effect ( 123 , 162 , 163 ). However, in one clinical trial, different doses of caffeine (up to 6 mg/kg body weight) consumed by 59 habitual caffeine consumers after a 6-day run-in period of 3 mg/kg of caffeine did not markedly change hydration-related biomarkers, suggesting that increasing doses of caffeine did not induce hypohydration in these participants ( 164 ). These findings are supported by two similar studies, one in which 5 mg/kg body weight of caffeine was consumed daily for 4 consecutive days by 30 men who normally consumed less than 100 mg/day ( 42 ) and one in which 4 mg/kg body weight/day of caffeine from coffee was consumed for 3 consecutive days by 50 adult male habitual coffee consumers who usually consumed 3–6 cups of coffee/day ( 165 ). These findings suggest that the diuretic effects from consuming between 4 and 6 mg/kg body weight/day of caffeine are not likely to have adverse consequences for healthy adults who are habitual consumers of caffeine. Similar studies should be conducted in populations that vary by health status, age, and sex.

Populations At-Risk for Harmful Effects of Caffeine

Pregnant and lactating women.

Pregnant women and fetuses may be particularly vulnerable to the effects of caffeine. Caffeine is a biologically active molecule that can act on multiple targets and affect numerous functions positively or negatively. At early stages of fetal development, caffeine may have deleterious effects ( 137 ). A recent prospective study suggests that preconception caffeine consumption may also pose a risk to pregnancy, with pre-pregnancy consumption of >400 mg of caffeine/day increasing the risk of spontaneous abortion by 11% compared with women who consumed <50 mg of caffeine/day ( 131 ). Many psychoactive compounds can cross the placental barrier and alter the development of the fetal brain. Once caffeine enters the fetal circulation, it is metabolized slowly because neither the placenta nor the fetus itself has cytochrome P450, the enzyme that metabolizes caffeine ( 166 ). This reduced caffeine metabolism results in a longer half-life and increased caffeine exposure to the fetus ( 141 , 167 ). The American College of Obstetricians and Gynecologists recommends limiting caffeine consumption during pregnancy to less than 200 mg/day ( 168 ). In the late 1970s, most women maintained their intake during pregnancy at an average of about 190 mg/day 3 ( 5 ). In the 1980s and 1990s, the average maternal caffeine consumption declined to about 125 mg/day ( 5 ). Consumption was reported to be about 123 mg/day between 1997 and 2007 ( 84 , 85 ) and was even lower (58 mg/day) in a 1999 survey ( 169 ). This decline has been attributed to FDA warnings that excess caffeine consumption during pregnancy may adversely affect neonates ( 170 ). Interestingly, however, in a small cohort of 105 women who drank coffee before pregnancy, 65% reported an aversion to coffee during the first trimester, and 95% voluntarily reduced their consumption during this trimester ( 171 ), so perhaps women might be naturally averse to caffeinated products during pregnancy.

Data on caffeine consumption during lactation are limited. One small study from Poland reported that average caffeine intake in a sample of lactating women ranged from 127 to 163 mg/day ( 172 ).

Children and Adolescents

Young children may be vulnerable to the effects of caffeine because they weigh less. For example, a typical can of soda contains about 45 mg of caffeine on average. In an adult weighing 70 kg, the effective dose is 0.6 mg/kg, but in a child weighing 20 kg, the effective dose of the same soda would be 2.25 mg/kg. In comparison, the average caffeine intake in adults is 180 mg/day, resulting in an average effective dose of 2.5 mg/kg. Thus, the physiological impact of a single soda in a child may be equivalent to the impact of two cups of coffee in an average-sized adult. Adolescents may also be particularly vulnerable to the sleep-disrupting effects of caffeine because they may also use caffeinated beverages to stay awake ( 173 , 174 ).

Data have been collected in children and adolescents using dose–response and placebo-controlled research methods. Outcomes, such as cardiovascular function ( 175 – 178 ), mood ( 179 – 181 ), and cognitive performance ( 82 , 182 ), have all been measured at caffeine doses ranging from 50 to 300 mg. None of the results suggest that caffeine at these doses is acutely harmful to children and adolescents ( 183 ).

Some studies suggest an association between caffeine consumption and longer term behavioral problems in youth, such as anger, violence, sleep disturbances, and alcohol and drug use ( 180 , 184 ). Researchers in Iceland surveyed 7,400 adolescents (aged 14 and 15 years) and found that most reported consuming caffeine on a typical day and that caffeine intake (primarily from soda and energy drinks) was related to daytime sleepiness and anger for both sexes ( 185 ). In a 2013 study of 3,747 15- to 16-year olds, self-reported caffeine intake was strongly associated with self-reported violent behavior and conduct disorders ( 186 ). In this study, 21% of participants consumed at least one energy drink per day.

Other studies have found that anxiety can be produced at a wide range of doses (200–2,000 mg of caffeine/day), but many of these studies have used psychiatric patients or patients with a preexisting anxiety disorder ( 123 ). Other effects in these studies included nervousness, fidgeting, jitteriness, restlessness, hyperactivity, and sleeplessness ( 123 , 187 , 188 ). When children were stratified by prestudy caffeine intake, emotions and behaviors differed between low- and high-dose consumers ( 187 , 188 ). Children consuming high doses were more easily frustrated and were more nervous during baseline tests than were the children consuming lower doses. Other studies have found that children with attention-deficit/hyperactivity disorder have higher rates of caffeine abuse, perhaps due to the additive effects of caffeine on dopamine action at the dopamine D2 dopamine receptor, similar to the way guanfacine works for children with this disorder ( 189 , 190 ).

The safety of high-dose caffeine and energy drinks in younger individuals and caffeine-naïve individuals has not yet been determined. The consumption of highly caffeinated energy drinks has been associated with elevated blood pressure, altered heart rates, and severe cardiac events in children, adolescents, and young adults, especially those with underlying cardiovascular diseases ( 115 , 177 , 191 , 192 ). For example, a study of 50 young adults found that consuming a sugar-free energy drink containing 80 mg of caffeine (slightly less than the caffeine contained in one cup of coffee) was associated with changes in platelet and endothelial function great enough to increase the risk for severe cardiac events in susceptible individuals ( 193 ). These findings show how the acute effects of caffeine on heart rate might result in cardiovascular events requiring hospitalization, especially in at-risk young adults. In addition, caffeine’s effects on blood pressure are more pronounced among African-American children than among Caucasian children (mean difference in blood pressure averaging 6.5 mm Hg) ( 175 , 194 ). High doses of caffeine may exacerbate cardiac conditions for which stimulants are contraindicated ( 195 – 198 ). In particular, ion channelopathies and hypertrophic cardiomyopathy, which is the most prevalent genetic cardiomyopathy in children and young adults (0.2% of the population), are of concern because of the risk of hypertension, syncope, arrhythmias, and sudden death ( 197 , 199 ).

Patients with Mental Illness

Another population that may be at risk for adverse effects of caffeine are patients with mental illness. Caffeine antagonism of adenosine receptors can result in enhanced dopaminergic signaling, thought to be due to a combination of increased dopamine release ( 200 , 201 ), upregulation of dopamine receptors, and increased affinity of dopamine receptors for dopamine in the striatum and nucleus accumbens ( 202 ). Furthermore, adenosine receptors can form heterodimers with dopamine receptors ( 203 ), which can modulate dopamine signaling. For some psychiatric illness, such as Parkinson’s disease, Alzheimer’s disease, and depression, caffeine antagonism of adenosine receptors may improve symptoms ( 204 , 205 ) and slow the progression of neurodegeneration ( 206 , 207 ), although these findings are equivocal with some studies reporting caffeine increases depressive symptoms ( 208 ). For other mental illness, such as schizophrenia, caffeine may exacerbate psychotic symptoms ( 209 ), although the majority of this literature is informed by case studies, with very few double-blind placebo-controlled studies ( 210 ). There is also good evidence that higher caffeine use is associated with greater reporting of anxiety symptoms ( 211 , 212 ) and may increase risk of symptom relapse ( 213 ) and suicide among bipolar disorder patients ( 214 ). Finally, there is strong empirical evidence that caffeine potentiates the rewarding effects of drugs of abuse ( 215 – 217 ), which suggests that caffeine use can increase vulnerability to substance use disorder ( 218 ). The lack of randomized control trials on the impact of caffeine in patients with mental illness makes it difficult to determine safe doses, effects of acute and chronic caffeine, and potential interactions between caffeine and medications. Currently, there are no specific recommendations for caffeine consumption for individuals with mental or psychiatric illness, but it may be worth consideration by physicians and psychologists treating patients with mental illness.

Caffeine and Alcohol

Another increasingly popular form of caffeine consumption is to mix alcohol with energy drinks. In fact, there are several recent reviews on this topic ( 219 – 221 ). We will briefly highlight this literature here. In 2010, the FDA removed pre-mixed alcohol-energy drinks from the market because caffeine was determined to be an unsafe additive to alcohol, 4 in part because it promoted excessive drinking ( 222 ). However, energy drinks can be legally mixed with alcohol in the U.S. if they are sold separately. In fact, this practice is popular among college students, as suggested by the increase in self-reports over the past 5–10 years ( 223 – 229 ). The research on alcohol-mixed energy drinks is still developing, and the vast majority has been conducted in the U.S. and Australia. Much of this research consists of surveys of college-age young adults immediately after they leave bars where they have been drinking ( 230 – 233 ). Self-report is often unreliable, but self-report while intoxicated may be particularly problematic. Similarly, intoxication may confound retrospective assessments of alcohol consumption and related behaviors and attitudes.

More recently, several well-controlled, objective, laboratory-based studies on the impact of alcohol-mixed energy drinks have been conducted. In many studies, the combination of alcohol and energy drinks results in higher rates of binge drinking, reductions in perceived intoxication, faster rates of self-paced alcohol consumption, or increases in risk taking behavior ( 225 , 234 – 239 ). These data are equivocal, however, with studies showing that caffeine combined with alcohol does not always increase the amount of alcohol consumed ( 240 ) or does not have an impact on risk taking behavior ( 235 , 241 ). Potential reasons for these discrepancies may be difference in the doses of caffeine and alcohol, differences in the administration paradigm, and an influence of expectancy of caffeine effects on alcohol intoxication ( 241 ). More work is needed in this area to be able to draw stronger conclusions.

Caffeine-Related Diagnoses

The American Psychiatric Association’s Diagnostic and Statistical Manual-IV ( 242 ) included four caffeine-related diagnoses: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified ( 242 ). Caffeine intoxication is diagnosed if clinically significant impairment results from the following criteria: (1) recent consumption of caffeine, usually in excess of 250 mg, (2) five (or more) of the following: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, periods of inexhaustibility, psychomotor agitation, and (3) the symptoms in criteria (2) have to cause clinically significant distress or impairment in social, occupational, or other important areas of functioning and these symptoms cannot be attributable to another medical condition or mental disorder. Caffeine-induced anxiety and sleep disorder retain the diagnosis for substance/medication-induced anxiety and sleep disorders, but require that clinically significant symptoms occur in association with caffeine intoxication or withdrawal ( 243 ). Caffeine-related disorder not otherwise specified classifies symptoms related to caffeine use or withdrawal that do not fit into the aforementioned categories.

The latest edition of the DSM ( 243 ) has officially recognized caffeine withdrawal disorder and outlines guidelines for criteria for caffeine use disorder in a section on emerging measures and models ( 243 ). The diagnosis of caffeine withdrawal syndrome is empirically based on detailed analyses of decades of studies of symptoms [reviewed by Juliano and Griffiths ( 244 )]. Caffeine withdrawal disorder is diagnosed when an individual experiences clinically significant impairment related to withdrawal symptoms after abrupt cessation of caffeine intake, including headache, difficulty concentrating, fatigue, nausea, flu-like symptoms, and changes in mood. These symptoms typically begin 12–24 h after caffeine cessation and may continue for 3–7 days. Ongoing research on caffeine withdrawal suggests that this continues to be an important problem and will help refine and clarify this diagnosis ( 245 , 246 ). Avoidance of caffeine withdrawal, with or without a diagnosis of caffeine withdrawal disorder, may motivate individuals to consume more caffeine. This could result in chronic, excessive consumption of caffeine. When this excess consumption results in clinically significant impairment, an individual may meet the criteria for caffeine use disorder ( 247 – 249 ). Although not an official DSM diagnosis, the proposed criteria for caffeine use disorder include having all three of the following criteria met: (1) persistent desire or unsuccessful effort to control caffeine use, (2) “use despite harm,” and (3) withdrawal. Having these proposed criteria outlined will allow researchers to collect data to provide reliable and valid empirical studies of the prevalence of this phenomenon ( 250 ). This is critical because the progression of inclusion of caffeine-related diagnoses is directly related to an increase in empirical support for such disorders.

Recommendations on Safe Intake Levels and Limits on Intake

Caffeine reaches maximum plasma concentration 15–120 min after ingestion ( 251 ), which might explain why energy drink-related adverse events are usually reported a few hours after consumption. The threshold of caffeine toxicity appears to be around 400 mg/day in healthy adults (19 years or older), 100 mg/day in healthy adolescents (12–18 years old), and 2.5 mg/kg/day in healthy children (less than 12 years old) ( 123 , 192 ). For comparison, one standard sized can of a popular energy drink provides 77 mg of caffeine (or 1.1 mg/kg/day) for a 70-kg male and twice that, 2.2 mg/kg/day, for a 35-kg pre-teen ( 252 ). Recommended safety thresholds vary, however. For example, the European Food and Safety Authority considers 3-mg/kg body weight/day of habitual caffeine consumption to be safe for children and adolescents ( 253 ). 5

A comprehensive review of the effects of caffeine consumption on human health concluded that for healthy adults, moderate chronic intakes of caffeine up to 400 mg/day are not associated with adverse effects on cardiovascular health, calcium balance and bone status, behavior, cancer risk, or male fertility ( 123 ). However, the recommended intake is much lower for pregnant or nursing mothers. The European Commission’s Scientific Committee of Food Safety Authority and Health Canada both recommend that women consume no more than 300 mg of caffeine/day during pregnancy ( 121 , 253 ). In addition, despite conflicting results regarding the association between caffeine consumption and spontaneous abortion, the American College of Obstetricians and Gynecologists recommends that pregnant women restrict their caffeine intake to less than 200 mg/day ( 121 ).

For most children, adolescents, and young adults, safe levels of caffeine consumption have not been established. Because deleterious effects of heavy caffeine use have been documented in those who have cardiovascular issues, studies of safe doses and the effects of chronic use are paramount in understanding the implications of caffeine. This research should seek to better characterize the effects of caffeine use before, during, and after exercise, the interactions of caffeine use with alcohol and medications, such as stimulants, and the effects of prolonged caffeine use. A better understanding of caffeine’s effects in individuals with cardiac problems will better equip health-care providers to screen and identify at-risk individuals, and in turn, to better educate and counsel these cardiac patients. Such information will also help health-care leaders to work with families, schools, and other community services to change marketing strategies, improve the dissemination of information, and identify at-risk behaviors and age groups. Finally, the health-care providers and regulatory agencies must begin collecting and archiving better data on the adverse events and health effects of caffeine consumption to improve estimates about its scope, effects, and outcomes. Analyses of a comprehensive, centralized database would help direct research, education, and funding to support these populations. In addition, agencies like the U.S. FDA and Health Canada need to initiate programs to educate consumers, especially children and adolescents, about the dangers of highly caffeinated products, to reconsider applying the U.S. FDA’s Generally Recognized as Safe standard to energy drinks and other beverages with added caffeine, and requiring manufacturers to include the caffeine content on product labels. Because of the potentially harmful adverse effects and developmental effects of caffeine, the consensus among the research and medical communities is that any dietary intake of caffeinated energy drinks should be discouraged for all children ( 123 , 192 ).

One of the primary concerns about energy drinks is that the actual caffeine content is not often given on the product’s packaging or on its website ( 120 ). The total amount of caffeine contained in some energy drinks can exceed 500 mg (equivalent to 14 cans of common caffeinated soft drinks or 5 cups of coffee) and is high enough to be toxic in children and young adults ( 34 ). Given these concerns, the American Academy of Pediatrics released the following recommendation to the United States Senate Committee on Commerce, Science, and Transportation:

Due to the potentially harmful health effects of caffeine, dietary intake should be discouraged for all children. Because the actual stimulant content of energy drinks is hard to determine, energy drinks pose an even greater health risk than simple caffeine. Therefore, energy drinks are not appropriate for children and adolescents and should never be consumed (2014).

In 2010, Health Canada convened an Expert Panel 6 on Caffeinated Energy Drinks to develop a plan to more effectively address the safety concerns related to caffeinated energy drinks currently marketed in Canada. The Panel issued their recommendations to Health Canada in the fall of 2010. 7 Health Canada analyzed the recommendations, completed a health risk assessment, and continued to gather and exchange information with major food safety regulators within the country and internationally. This initiative resulted in a proposed management approach that was consistent with the strategies in the Panel’s recommendations. Components of this approach include regulating product formulation and labeling, addressing potential health risks and adverse effects, providing enhanced education and communication to consumers, and addressing uncertainties and data gaps through research on long-term effects. Long-term research was made a priority, to further investigate risks to consumers, to identify serious adverse event signals (such as cardiac events and to a lesser extent, seizures), and finally to better manage caffeine labeling and dosing limits. The data have reconfirmed that moderate daily caffeine intake at dosages of up to 400 mg/day are not associated with adverse effects. However, the data show that women of childbearing age and children may be at higher risk from caffeine, which has therefore led to separate guidelines for these at-risk groups. However, several products containing stimulant drugs do not have a natural health product license and exemption numbers that clearly describe their caffeine content. Therefore, the Panel recommended that Health Canada ensure that all products meet strict labeling that includes a full disclosure of the exact caffeine dose. Finally, the Panel recommended that Health Canada, in collaboration with the provinces and territories, consider beginning a surveillance system in sentinel emergency rooms across the country to actively search for serious adverse drug reactions associated with consuming drinks containing stimulant drugs with or without alcohol or other products. The proposal details how this system could be modeled after the nation’s long-running IMPACT system that monitors immunizations and related adverse events through a network of 12 Canadian centers, representing 90% of all tertiary care pediatric beds. A similar database, The Canadian Health Measures Survey, 8 launched in 2007, contains data from voluntary household interviews that collects important health information (e.g., physical measurements, nutrition, and blood and urine samples).

Future Research

Several questions remain about caffeine consumption and patterns of intake. First, it is not clear how much caffeine is being consumed from “uncommon” or unidentified sources of caffeine, such as foods and medications. These sources are often overlooked in large national surveys and, thus, caffeine intake may be underestimated. Second, caffeine may be indirectly harmful because it is consumed with other substances that are harmful. For example, coffee drinking may promote donut eating or cigarette smoking, or energy drink consumption may promote alcohol intake. Third, future studies need to investigate absorption, distribution, metabolism, and excretion of caffeine occurring in non-natural forms (such as encapsulated forms), which may influence pharmacokinetics, and thus effects. Finally, most research has relied on self-report and correlational analysis, which limits the ability to determine causality and directionality.

Despite all that is known about caffeine intake and safety of caffeine consumption, certain gaps in our knowledge need to be addressed:

(1) Identifying at-risk populations for caffeine toxicity . We already know that small children and pregnant women, as well as individuals with cardiac or vascular disease, are likely to be particularly vulnerable to the harmful effects of caffeine. Furthermore, there is some evidence that individuals with mental illness may also be at risk for harmful effects of caffeine on symptoms, but the majority of these relationships have been described in case studies. More randomized control trials need to be conducted in patients with mental illness to determine safe doses for caffeine ingestion. In addition to the known vulnerable populations, there may be individuals, such as the elderly or individuals with underlying medical conditions, who are not part of any vulnerable population but who, for genetic or metabolic reasons, may be susceptible to harmful effects. The Federal Substance Abuse and Mental Health Services Administration reported that from 2007 to 2011, the number of emergency room visits involving energy drinks doubled across the U.S., from 10,068 to 20,783. However, for adults aged 40 years and older, emergency room visits involving energy drinks nearly quadrupled during that same period (from 1,382 to 5,233). 9 This finding suggests that energy drink consumption in older people is increasing with perhaps a greater risk of negative outcomes. Identifying and warning at-risk individuals to avoid caffeine-containing products would be desirable.

(2) Determining how best to disseminate information about caffeine content in a meaningful and truthful way without causing alarm . Although the preponderance of evidence suggests that caffeine is safe for most people, there may be reasons to limit caffeine use in some populations. Providing more information about safe levels may be useful, but the information must be understandable to the population and based on evidence, rather than on supposition. Adding information about caffeine content on the products themselves may not be enough. The best way to educate consumers about safe levels of caffeine consumption needs to be determined. For example, evidence suggests that “natural frequencies” are an effective way to communicate risk. For example, one could explain “For every 1,000 children who consume energy drinks, XX will have CNS symptoms.” However, research is necessary to fill in the blank in this statement ( 254 ).

(3) Conducting prospective, longitudinal studies to determine how caffeine use relates to behavioral and health-related outcomes , such as the duration and quality of sleep, potential for abuse, and impact on the use of other substances, including controlled (cigarettes and e-cigarettes) and uncontrolled (marijuana, cocaine) drugs. Cross-sectional data suggest that caffeine use is generally safe, but rigorous longitudinal studies have not yet determined the effect of chronic caffeine consumption on development in children and adolescents.

(4) Further exploring the potential health benefits of caffeine . Although much of this document has focused on potential harmful effects of caffeine, some health benefits of caffeine remain under explored. In particular, some research suggests that caffeine may slow age-related cognitive decline ( 255 , 256 ), reduce risk of some neurological disorders ( 90 , 257 , 258 ), and promote longevity ( 156 ).

(5) Developing better systems of documenting and sharing adverse events . In addition to identifying at-risk or vulnerable populations, as mentioned earlier, and potentially dangerous combinations of caffeine with other substances (e.g., alcohol), we need a better system of documenting adverse events and sharing that documentation among scientists and clinicians. Systematically collecting all adverse events, poison center data, and emergency room visits associated with caffeine consumption (for example, energy drink consumption), together with more comprehensive evaluation of additional risk factors, is necessary to accurately determine the risks of toxicity for youth and other vulnerable individuals.

(6) Improving knowledge of the potential dangers from consuming energy drinks before, during, and after athletic activity will be essential to identify the potential dangers of direct and implied claims of enhanced athletic performance, which is common in energy drink marketing. Long-term systematic assessment of energy drink and general caffeine intake at the population level, specifically intake by youth, should be a priority.

When taken together, the literature reviewed here suggests that ingested caffeine is relatively safe at doses typically found in commercially available foods and beverages. There are some trends in caffeine consumption, such as alcohol-mixed energy drinks, that may increase risk of harm. There are also some populations, such as pregnant women, children, and individuals with mental illness, who may also be considered vulnerable for harmful effects of caffeine. Excess caffeine consumption is increasingly being recognized by health-care professionals and by regulatory agencies as potentially harmful. More research needs to be conducted to address these emerging concerns and provide empirical support for the recommendations.

Author Contributions

JT, CB, and SL contributed equally to the preparation of this comprehensive review. JC, JW, and MM helped gather additional references and prepare the manuscript after the initial major review of the literature was conducted.

Conflict of Interest Statement

The authors prepared this comprehensive review at the request of the American Association for the Advancement of Science. Once the draft was completed, we were given permission to publish the manuscript. SL has served as an expert for legal cases involving caffeine-containing energy drinks.

CB is funded by l’Agence Nationale de la Recherche (ANR, ANR-14-CE13-0032-02 ADONIS), JT is funded by the National Institutes of Health (DA021759, DA030386, and DK106265). SL is funded by the National Institutes of Health (HL111459, HL109090, HL078522, HL053392, HL079233, HL087000, HL095127, HD060325, NR012885, CA127642, CA068484, and HD052104).

  • ^ https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm350570.htm .
  • ^ https://www.drugbank.ca/drugs/DB00201#pharmacology .
  • ^ It is difficult to calculate the caffeine intake relative to body weight during pregnancy because women begin pregnancy at a broad range of weights, gain weight at different rates, and gain different amounts of weight. Because of this, only absolute caffeine intake is shown in this section.
  • ^ https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm234900.htm .
  • ^ http://www.efsa.europa.eu/en/efsajournal/pub/4102 .
  • ^ http://www.hc-sc.gc.ca/dhp-mps/prodnatur/activit/groupe-expert-panel/index-eng.php .
  • ^ http://www.hc-sc.gc.ca/fn-an/securit/addit/caf/ced-response-bec-eng.php .
  • ^ http://www23.statcan.gc.ca/imdb/p2SV.pl?Function=getSurvey&SDDS=5071 .
  • ^ http://www.samhsa.gov/data/sites/default/files/DAWN126/DAWN126/sr126-energy-drinks-use.pdf .

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Keywords: caffeine, energy drinks, pregnancy, children, adolescence

Citation: Temple JL, Bernard C, Lipshultz SE, Czachor JD, Westphal JA and Mestre MA (2017) The Safety of Ingested Caffeine: A Comprehensive Review. Front. Psychiatry 8:80. doi: 10.3389/fpsyt.2017.00080

Received: 30 January 2017; Accepted: 24 April 2017; Published: 26 May 2017

Reviewed by:

Copyright: © 2017 Temple, Bernard, Lipshultz, Czachor, Westphal and Mestre. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jennifer L. Temple, jltemple@buffalo.edu

† These authors have contributed equally to this work.

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Here's exactly when to stop drinking caffeine for the best chance of a great night's sleep

Discover a good caffeine cutoff time, plus when and why it’ll vary

A espresso with late art on the top in a white coffee cup and saucer next to a hessian sack and coffee beans

Can’t start your day without a hearty dose of coffee? Regularly brew a cup of green tea after lunch? While these caffeinated drinks offer health benefits that go beyond helping you perk up and stay focused, relying on them in high quantities and/or drinking up too late in the day could mean bad news for your shuteye come nightfall, and having even the very best mattress may not be enough to lull you off to sleep.

If you can’t bear to part ways with your go-to sources of caffeine, it’ll be in your best interest to at least cap off intake at a certain point in the day; it's also useful to know that the best time in the morning to drink coffee is 10am, not first thing.

We spoke to a dietician to discover if there’s an ideal time to stop caffeinating for the sake of better sleep, and also learned why caffeine and sleep are at odds with each other, as well as finding out about some surprising sources of the stimulant you may also want to steer clear of.

When should I stop drinking caffeine before bed?

“It is suggested that most people should stop consuming caffeine at least six hours before bedtime [to avoid] disruptive effects on sleep,” says Amy Shapiro, MS, RD, CDN, founder and director of Real Nutrition in New York City.

According to a 2013 study published in the Journal of Clinical Sleep Medicine , participants who consumed 400 milligrams of caffeine 0, 3, or 6 hours before their regular bedtime led to significantly disturbed sleep compared to placebo groups.

People who are sensitive to caffeine and/or have ongoing sleep issues may want to cease caffeinating even earlier than the six-hour mark. On the other hand, some may take to a post-dinner shot of espresso just fine and have no difficulty catching their ZZZs within a few hours’ time.

A cup of black coffee surrounded by coffee beans

In short, the ideal caffeine cutoff time will be based on the individual, so the six-hour mark is a decent general guideline. “The timing may vary due to the high variability of individual responses to caffeine consumption based on sex, age, diet, health, metabolism etc.,” Shapiro explains. “Depending on the individual, the effects of caffeine consumption can last up to 12 hours.”

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The amount of caffeine present in the beverage will also play a role, she adds. For example, a large cup of coffee can pack over 400 milligrams of caffeine, while a bottle of iced tea can offer 20 to 50 milligrams per serving. Caffeine content will vary based on factors such as the size of the drink, brands, and brewing times.

What caffeine does to your body

“Caffeine is a stimulant that increases activity in your brain and nervous system, and increases circulation of neurotransmitters including cortisol and adrenaline,” Shapiro explains. (Cortisol is known as the stress hormone yet it also helps us stay alert. Similarly, adrenaline helps prepare us for fight-or-flight mode and allows us to react quickly.)

A scoop of ground coffee

Short-term effects of caffeine, she continues, typically include:

  • Mental alertness
  • Physical energy
  • Increased breathing
  • Faster heart rate

Caffeine isn’t without its risks. Shapiro warns that high doses, frequent use, or potential adverse effects may include:

  • Restlessness
  • Physical and/or psychological dependence

Why caffeine disrupts sleep

Most people reach for caffeine since it helps them stay awake, so it makes sense that it’d be at odds with falling asleep.

“Caffeine acts primarily on receptors in the body that are related to functions of the brain associated with sleep, arousal, and cognition,” Shapiro explains. “Adenosine receptor agonists in the brain generally promote sleep, and caffeine promotes wakefulness by antagonizing [i.e., inhibiting or counteracting] those receptors.”

A person in bed at night, unable to sleep

In other words, caffeine disallows certain sleepiness cues to kick in when they should—which is how coffee, caffeinated tea and the like can prevent a good night’s rest.

In addition to affecting sleep latency (i.e., the time it takes to fall asleep), caffeine may also worsen sleep quality. In a 2021 randomized controlled trial in healthy men, published in the Journal of Biological Rhythms, those who had 150 milligrams of caffeine three times in the daytime over 10 days experienced the following sleep issues compared to a placebo group:

  • Delays in REM sleep (a sleep stage that heavily influences subjective sleep quality)
  • Greater difficulty waking up
  • Feeling more tired upon arising

What foods and drinks contain caffeine?

You likely already know that coffee, some teas (namely black and green tea), and energy drinks contain caffeine. However, they’re not the only dietary items that pack the stimulant.

According to Shapiro, additional sources of caffeine you may want to cut off by the afternoon include:

  • Soft drinks, such as soda
  • Some protein bars
  • Chocolate/cacao
  • Some medications

Moreover, it’s worth remembering that the terms ‘decaf’ and ‘caffeine-free’ aren’t interchangeable. The former indicates that caffeine was removed from a given product and trace amounts will likely remain present. Meanwhile, the latter indicates that caffeine wasn’t in a given product (such as the majority of herbal teas ) to begin with.

The takeaway

If you struggle to fall asleep at night, you may find relief by ceasing caffeine intake 6 hours before bedtime. However, since caffeine tolerance varies by the individual, you might need to extend this timeline, sometimes to as long as 12 hours.

It could also benefit your ZZZs to reduce the amount of caffeine you consume (i.e., going from two cups to one cup daily) or perhaps even slowly taper off caffeine entirely.

Last but not least, you can always add items that promote better rest—such as chamomile tea and tart cherry juice—into your nightly regimen.

Amy Shapiro

Amy Shapiro MS, RD, CDN, has been the founder and director of Real Nutrition, an NYC-based private practice, for over 15 years. She is dedicated to healthfully and successfully guiding clients to their optimal nutrition, weight, and overall wellness. Recognized for her individualized, lifestyle-focused approach, which integrates realistic food plans, smart eating habits, and active living. 

Michele Ross

Michele Ross is a freelance wellness, beauty, and lifestyle writer based in Los Angeles. She contributes to publications including Well+Good, Editorialist, and RealSelf; has worked with brands including HUM Nutrition, Goldfaden MD, and Beast Health; and has served as a content strategist and ghostwriter for doctors and dietitians. Her goal is to empower readers to make informed decisions about their routines that work for their specific needs and concerns.

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Effects of Caffeine Intake on Cognitive Performance Related to Total Sleep Deprivation and Time on Task: A Randomized Cross-Over Double-Blind Study

Michael quiquempoix.

1 Department of Operational Environments, Fatigue and Vigilance Team, French Armed Forces Biomedical Research Institute (IRBA), Paris, France

2 VIFASOM Team (EA 7330), University of Paris - Hôtel Dieu AP-HP Hospital, Paris, France

Fabien Sauvet

Mégane erblang.

3 LBEPS, Univ Evry, IRBA, University of Paris-Saclay, Paris, France

Pascal Van Beers

Mathias guillard, catherine drogou, aurélie trignol, anita vergez, damien léger.

4 Centre du sommeil et de la vigilance, Hôpital Hôtel Dieu AP-HP, Paris, 75004, France

Mounir Chennaoui

Danielle gomez-merino, arnaud rabat, introduction.

It is widely admitted that both total sleep deprivation (TSD) and extended task engagement (Time-On-Task, TOT) induce a cognitive fatigue state in healthy subjects. Even if EEG theta activity and adenosine both increase with cognitive fatigue, it remains unclear if these modifications are common mechanisms for both sustained attention and executive processes.

We performed a double-blind counter-balanced (placebo (PCBO) and caffeine (CAF) - 2×2.5 mg/kg/24 h)) study on 24 healthy subjects (33.7 ± 5.9 y). Subjects participated in an experimental protocol including an habituation/training day followed by a baseline day (D0 and D1) and a total sleep deprivation (TSD) day beginning on D1 at 23:00 until D2 at 21:00. Subjects performed the psychomotor vigilance test (PVT) assessing sustained attention, followed by the executive Go-NoGo inhibition task and the 2-NBack working memory task at 09:15 on D1 and D2.

We showed differential contributions of TSD and TOT on deficits in sustained attention and both executive processes. An alleviating effect of caffeine intake is only observed on sustained attention deficits related to TSD and not at all on TOT effect. The caffeine dose slows down the triggering of sustained attention deficits related to TOT effect.

These results suggest that sustained attention deficits induced by TSD rely on the adenosinergic mechanism whereas TOT effect observed for both sustained attention and executive would not.

Cognitive/Mental fatigue, a general process associated with a sensation of exhaustion and lack of energy and resulting in a decrease of cognitive capacity, 1 is involved in 4 to 50% of accidents (eg road, aviation, railway, etc.) when human error is engaged (for review see 2 ). The longer subjects are engaged in a demanding cognitive task (Time-On-Task – TOT - effect), the more impaired they will be on sustained attention or other attention and executive processes (for review 1 , 3 ). Cognitive/mental fatigue could be the outcome of an imbalance between energy demand/mental resource 4 , 5 and/or the outcome of a personal evaluation concerning the cognitive demand of the task. 1 , 6

Accidents related to cognitive fatigue are often observed with sleepy subjects. 2 Sleep, a well-regulated physiological process, is under the control of two factors: 1) the homeostatic factor (the longer the time spent awake the greater the drive for sleep) and 2) the circadian one that varies with a 24-hour periodicity independently of the amount of preceding sleep or wakefulness (for review see 7 ). Total sleep deprivation (TSD), which is characterized as a non-physiological prolonged duration of wakefulness is an extreme situation inducing both subjective (complaint) and objective (reduction in latency to fall asleep) sleepiness state (for review see 8 ). TSD is also responsible for deficits both on sustained attention, executive and higher cognitive processes (such as planning, reasoning, etc.) in healthy individuals 9 , 10 (for review see 8 ).

Time on task (TOT) and sleepiness (ie, TSD) both contribute to cognitive/mental fatigue. Sustained attention deficits related to TOT during 20-min of the Psychomotor vigilance test (PVT) have been observed in well-rested subjects, with significant increase of self-reported sleepiness and mental fatigue. 11 , 12 In addition, Gui et al found that impaired spontaneous activity and connectivity in the resting-state DMN (default mode network) are associated with TOT effects and mental fatigue during a PVT of 20 minutes. 12 However subjective fatigue and sleepiness were shown increased and driving performance deteriorated during a simulate monotonous night-time rural driving, concomitantly to increased EEG delta, theta and alpha activity, while breaks improved driving and fatigue ratings but did not affect EEG activity and sleepiness. 13 During a neuropsychological test battery of approximately 90 minutes, significant increase of EEG-relative power of theta activity was evidenced in frontal-central and parietal regions 14 and a positive correlation was found between PVT deficits related to TSD and changes in EEG theta activity particularly in centro-posterior brain areas. 15 The effects of TOT and TSD are evidenced in overlapping brain areas at least for sustained attention tasks. 16–18 Wascher et al have also observed an increase of frontal theta power of subjects cognitively fatigued (ie, a sensorimotor decision making during 4 hours). 16 The same results have also been observed in TSD situations. 19–21

Both cognitive deficits related to TSD and TOT are also dependent of brain metabolic resources and this was shown in the frontal cortex notably for TSD. 19 , 22 Interestingly, Martin et al, proposed that mental fatigue causes localized changes in cerebral fuel stores, which in turn contribute to changes in cerebral adenosine that acts on motivation during a prolonged and demanding cognitive task through the interaction between adenosine and dopamine receptors. 23 It is interesting to note that TOT effects were firstly revealed during a 20-min PVT task with an increase of response time, and secondly evidenced as associated with the dopamine system (the DAT1 transporter precisely). 11 Adenosine is a neuromodulator that reduces neural activity via binding to adenosine receptors, mainly the A 1 and A 2A receptors. 24 , 25 Adenosinergic mechanisms have been repeatedly shown to regulate sustained and selective attention deficits associated with TSD, sometimes using caffeine, the non-selective competitive adenosine receptor antagonist. 25–27 Caffeine administration was evidenced both to reduce subjective sleepiness and to limit the cognitive impairment on sustained attention induced by TSD (for review see 25 ). Nevertheless, we found no data 1) relative to TOT effects during TSD on executive tasks such as inhibition and working memory and 2) regarding caffeine effects on cognitive deficits related to TOT under TSD.

In this study, we sought to (i) determine the effects of TSD and TOT on three different cognitive processes (sustained attention, motor inhibition, and working memory) and EEG theta power, and (ii) further examine their underlying mechanisms through the influence of caffeine intake. Our interest in EEG theta power originates from our previous study, which showed significant positive correlations between theta power in the centro-temporal brain region and the number of PVT lapses after TSD under caffeine or placebo conditions, whereas no significant correlation was observed for alpha power. 28


24 healthy subjects (33.7±5.9 years), after giving their informed written consent, were included in this randomized cross-over and double-blind study that received the agreement of the Cochin–CPP Ile de France IV (Paris) Ethics Committee and of the French National Agency for Medicines and Health Products Safety (ANSM, ID RCB Number: 2017-A02793-50). It was also conducted according to the principles expressed in the Declaration of Helsinki of 1975 as revised in 2001 and in accordance with the full trial protocol (PERCAF) that has been recorded ( {"type":"clinical-trial","attrs":{"text":"NCT03859882","term_id":"NCT03859882"}} NCT03859882 , 25/02/2019). Subjects had not travelled between time zones within 7 days prior the study. They were free from medical, psychiatric and sleep disorders and were excluded if they self-reported any use of medications with sleep related side effects and illicit drugs. Subjects were also excluded if they reported a daily caffeine intake greater than 500 mg in order to minimize caffeine withdrawal effects during the protocol, and they were asked to reduce their caffeine intake 48 hours before the protocol. Exclusion criteria additionally included physical or mental health troubles based on (I) Hospital Anxiety and Depression scale, HAD ≥ 16, (II) significant medical history, (III) Epworth Sleepiness Scale, ESS > 11, (IV) Pittsburg sleep quality index, PSQI > 6, (V) morningness-eveningness questionnaire < 31 or > 69, (VI) habitual time in bed per night < 6 hours. 10

Subjects completed a sleep/wake schedule for one week prior to the study. Their average daily caffeine consumption was 254 ± 190 mg (mean ± SD). The characteristics of our subjects are summarized in Table 1 .

Subjects Characteristics

Notes : The main characteristics of our subjects with their mean (± s.e.m.) age, the number (proportion) of male gender, their mean (± s.e.m.) weight, their mean (± s.e.m.) height, their mean (± s.e.m.) daily caffeine consumption, their mean (± s.e.m.) total sleep time, their mean (± s.e.m.) weekly physical exercise and their mean (± s.e.m.) Epworth Sleepiness Score.

Behavioural Tests and Parameters

Karolinska sleeping scale (kss) for sleepiness.

Subjective sleepiness was assessed on a single-item scale using the Karolinska Sleepiness Scale (KSS). This 9-points scale, based on a self-reported, assess awake/sleepiness rating. 29 The different levels used for ratings were: 1 = very alert, 3 = alert, 5 = neither alert nor sleepy, 7 = sleepy (but not fighting sleep), 9 = very sleepy (fighting sleep). Our computer version enables subject to choose out of the nine given options just before starting the PVT.

Psychomotor Vigilance Task (PVT) for Sustained Attention

We utilized a computer-based version of the 10-min PVT, 9 that is detailed in previous studies. 9 , 10 Results are expressed as Response Time (RT) and number of lapses. Lapses were defined as Response Time (RT) > 500 ms and RT were ranged from 150 to 500 ms. We have also analyzed both 10% fast and 10% slow RT. 30

Executive Task N°1: Go-NoGo for Motor Inhibition

In this first executive task, 10 subjects were required either to respond or not to respond when a visual stimulus (a white arrow) arrived on a screen (black). A detailed version of this task is described in a previous studies. 10 In our study, the proportion of “Go” and “No-Go” responses were respectively 75% and 25% of total trials. The total duration of the task is 10 min. Results are expressed with the rate of errors by commission (ie, responding “Go” on a “No-Go” trial) or the rate of omission (ie, no response on a “Go” trial) and the Response Time (RT).

Executive Task N°2: 2N-Back for Working Memory

In this second executive (visual working memory) task, pseudo-random sequences of letters appeared in the center of the screen and subjects have to respond to specified letters. A detailed version of this task is described in a previous studies. 10 Briefly this task combined two conditions: (I) a control condition “0N-Back” consisting in responding to a specific letter (ie, letter W, also permanently displayed at the bottom of the screen during the block) and (II) a working memory “2N-Back” condition where participants had to respond whenever the current letter is identical to the letter presented two trials back (ie, M-X-M). The total duration is around 10 min. Results are expressed as response time (RT) and percentage of correct responses (CR). 10

Time on Task (TOT) Analysis

Time on task (TOT) effect was visually inspected minute by minute and quantitatively assessed by comparing the first 3 and the last 3 minutes on PVT (RT and number of lapses but not for RT 10% fastest and 10% slowest due to insufficient number of trials), Go/No-Go (RT, rate of No-Go errors) and 2N-Back tasks (TR, rate of correct responses). This was chosen i) to approximately estimate time on task kinetic and ii) because a 3-minute task is often used to evaluate cognitive fatigue. 31

Study Design and Testing Conditions

This is a laboratory-based, double-blind, placebo-controlled, and crossover study, with participants randomly assigned to either a caffeine or a placebo condition ( Figure 1 ). The full trial protocol can be accessed by request to the corresponding author. The assignment of participants (caffeine (CAF) or placebo (PCBO)) has been made using the order of inscription to the study by an independent member of the staff following a random list. The randomized plan has been made in order to have 2 subjects with caffeine and 2 subjects with placebo in each session. Participant and staff members were blind for treatments. The in-laboratory experimental protocol included: (I) a habituation/training day (D0), (II) a baseline day (D1), (III) a total sleep deprivation (TSD) day beginning on D1 at 23:00 until D2 at 21:00, and (IV) a recovery night (from 21:00 until 09:00) for safety reasons so that the subjects can recover before returning to their usual life. Caffeine or placebo was administrated at 08:30 and 14:30 on D1 and at 08:30 on D2. The psychomotor vigilance task (PVT) was performed and the sleepiness scale (KSS) was completed at 09:15 at baseline (D1) and on the day of TSD (D2). The executive Go-NoGo test was performed just after each PVT on D1 and D2, followed by the 2-NBack task.

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Object name is NSS-14-457-g0001.jpg

Experimental design. It includes an habituation/training day followed by a baseline day (D0 and D1) and a total sleep deprivation (TSD) day beginning on D1 at 23:00 until D2 at 21:00. Subjects completed the Karolinska Sleepiness Scale (KSS) and then performed cognitive tests at 09:15 on D1 and D2 (26h of awakening), and EEG was recorded during each test. (↓) 08:30 and 14:30, Placebo or caffeine (2.5 mg/kg).

Subjects were maintained in an individual temperature-controlled (22 ± 1°C) room. Restroom and bathroom facilities were collectively available in the sleep-laboratory flat that contains a main living room (34 m 2 ). Illumination was maintained between 150 and 300 lux during the entire experimental period (lights off during sleep periods). Subjects were prohibited from practicing exercise, taking tobacco, alcohol, or other psychoactive substances during the study. When not engaged in any specific testing or meals, subjects followed a standardized activity program (reading, watching videos, and playing games). In addition to the portable or wrist actimeters, investigators were systematically present in the laboratory with at least 1 of them with subjects. When subjects were about to fall asleep (eyes closed, head down), they were gently and immediately woken up (ie, no period of sleep > 30 seconds). During testing periods (morning D1 and morning D2), subjects were individually equipped (electrophysiological measurement) and monitor by an experimenter. All subjects had a systematic habituation/training period (D0 day) for behavioral tests in order to reduce learning or misunderstanding bias during the first set of tests.

Caffeine Administration

Caffeine (CAF) or placebo (PCBO) was administrated in decaffeinated beverage. During caffeine condition, caffeine powder was pre-measured by the project supervisor and amounted to 2.5 mg per kg body mass for each participant, then mixed with decaffeinated beverage. After review of literature, this amount of caffeine powder was chosen because a range from 0.2 to 5.5 mg/kg has been found to enhance response time in sleep-deprived conditions. 32

Electrophysiological Measurements

Eeg procedure.

EEG was recorded at 19 scalp sites, according to the international 10–20 system (Fp1, Fp2, F7, F3, Fz, F4, F8, T7, C3, Cz, C4, T8, P7, P3, Pz, P4, P8, O1, O2), with a Siesta 802 (Compumedics Limited, Victoria, Australia). EEG was recorded continuously at a sampling rate of 512 Hz referenced with bridged mastoidal electrodes. Data were re-referenced during preprocessing with a common average. Electrodes were interfaced with the scalp using EC2 gel (Grass Technologies, Astro-Med, Inc., West Warwick, RI, USA), and impedances were kept below 10 kOhm during the whole session. EEG was installed approximately 20–30 min before the first cognitive task (PVT), and supplemented with EC2 gel if needed, to prevent dry electrodes during recordings.

EEG Analysis

EEG data were analyzed in MatLab (MathWorks, Natick, MA, USA) with Fieldtrip toolbox 33 and custom codes. Data were bandstop filtered between 48 and 52 Hz to remove electrical noise, high pass filtered above 0.1 Hz and locally detrended.

Blink and saccade artefacts were removed by computing an Independent Component Analysis (ICA, Fieldtrip) and visually discarding components that had either prefrontal distribution and blink-related waveform or a fronto-temporal distribution and a saccade-related waveform. Movement artefacts were removed by visual inspection on a 10 seconds time window basis. If the first 3 min or last 3 min of each cognitive test presented more than 30 seconds of movement artifacts, the electrode was rejected. If during the 10 min of each cognitive test there were more than 120 seconds of cumulated artifacts, the electrode was rejected. Finally, if more than 3 (out of 19) electrodes were removed, the subject was excluded from EEG analysis. EEG theta power (4–8 Hz) was assessed by using continuous Morlet wavelets transform during the entire period of each cognitive test (10 min each). Regions of interest (ROI) represent the mean of grand averaged (all subjects) theta power over frontal (Fp1, Fp2, F7, F3, Fz, F4, F8), Centro-Temporal (T7, C3, Cz, C4, T8) and Parieto-Occipital (P7, P3, Pz, P4, P8, O1, O2) regions. We assessed effects of CAF and TOT (first 3 min vs last 3 min of test, see Time on Task (TOT) Analysis) during D2 for all cognitive tasks.

Statistical Analysis

Data has been collected in the French armed forces biomedical institute (IRBA) in Brétigny sur Orge. All data in text, tables and figures are presented as mean ± standard error of the mean (SEM). Statistical analyses were performed using Statistica 10.0 (StatSoft R). All value’s distributions were tested for their normality (Kolmogorov–Smirnov, Shapiro–Wilk and Lilliefors tests). The primary objective was to investigate the efficacy of caffeine (CAF) compared to placebo (PCBO) for improving sustained attention during a total sleep deprivation (TSD) protocol in healthy subjects, using the psychomotor vigilance test (PVT). In the literature, the 09:15 hour corresponds to the highest decrease of sustained attention during total sleep deprivation, due to a continuous awakening period (sleep pressure) and the nadir of circadian rhythm. 34 Secondary objectives were to assess efficacy of CAF on executive functions with Go-NoGo and 2N-Back performances and interaction between CAF and time on task (TOT). With 24 subjects, the study has at least 80% power to detect a significant difference in the primary endpoint when comparisons are made at the unadjusted 2‐sided 5% level. Powering was made assuming an effect size equal to 1.3 and a true within subject standard error of 37.9 ms in response time in the PVT, as reported for placebo treatment in our laboratory. 34 When the value’s distribution was normal (at least two negative tests), a two-way repeated measures ANOVAs were conducted in order to test 1) treatment condition (CAF or PCBO), TSD effect and their interaction and 2) treatment condition (CAF or PCBO), Time-On-Task (TOT) effect and their interaction. When value’s distribution was not normal, we used a one way non-parametric ANOVA test with repeated measures (ANOVA of Friedman and Wilcoxon test for post hoc comparison: W) to identify differences inside and between each factor (ie, treatment condition and TOT).

We measured mean response time (RT) and number of lapses during PVT, RT and percentage of errors during Go-NoGo and RT and percentage of correct responses during 2N-Back tasks while performing EEG measurements for each test.

Effect of TSD and CAF on Subjective Sleepiness: Karolinska Sleepiness Scale (KSS)

We observed global day and treatment effects on KSS score that resulted in a significant increase of KSS score after TSD (D2) compared to Baseline (D1) for both PCBO and CAF conditions ( Table 2 ). We did not observe any significant difference between PCBO and CAF at D1 and D2 (respectively p>0.11 and p>0.24).

Global Effects of Total Sleep Deprivation (Day Effect, D2 vs D1) and Treatment (CAF vs PCBO) on Cognitive Performances

Notes : A Friedman’s ANOVA analysis was performed for KSS, PVT Lapses, Go-NoGo Error Rate, 2-NBack Correct Responses, and global (ie all ROIs) EEG during the 10 min of each test respectively. A 2-Way ANOVA analysis was performed for Response Time (RT) during the three cognitive tasks (PVT, Go-NoGo and 2N-Back) with a looking at Day, Treatment and interaction effects. Data are expressed as means ± sem. Note that Post hoc analysis have been made when there was a global effect on Friedman’s ANOVA, or main effects with interaction on the 2-way ANOVA. Anova p-values   a  p<0.05,   b  p<0.01,  c  p<0.001. D2 vs D1 post-hoc:  **p<0.01, ***p<0.001. CAF vs PCBO post-hoc (at the same day):  # p <0.05, ### p<0.001.

Effects of TSD, CAF and TOT on PVT Lapses

Concerning the number of lapses accumulated during 10 min of PVT, we observed a global day and/or treatment effect ( Table 2 ). Post hoc analyses showed a significant increase in the number of lapses at D2 compared to D1 both in PCBO and CAF conditions ( Table 2 ). We also observed significantly lower lapses in CAF compared to PCBO at D2 ( Table 2 ). Since the number of lapses was affected by TSD in both PCBO and CAF conditions, we looked at Time-On-Task (TOT) and treatment effects and their interaction. To differentiate TSD effects from a mixture of TSD and TOT on the number of lapses, we compared the first 3 min (0–3 min, TSD effect) of PVT with the last 3 min (7–10 min, TSD + TOT effects) ( Figure 2A , shaded areas). There was a significant TSD effect (D2 vs D1) during the first 3 min of test in both PBCO and CAF conditions (p<0.001 for PCBO and p=0.015 for CAF condition). Significant TOT and treatment effects were observed on the number of lapses. More precisely at D2, the number of lapses per minute was significantly higher at the last 3 min (7–10min) compared to the first 3 min (0–3min) for both PCBO and CAF conditions ( Table 3, Figure 2B ). In contrast, we observed that the number of lapses is significantly lower at D2 in the CAF compared to PCBO condition for both the first 3 and the last 3 min of PVT ( Figure 2B ). We approximately estimated the kinetic of TOT by computing the difference of the number of lapses between 0–3 min and 7–10 min (Delta [7–10 min] – [0–3 min]), and found no significant difference between PCBO and CAF at D2 (p = 1.0; Figure 2C ).

Effects of Time on Task (TOT, First 3 Min vs Last 3 Min) and Treatment (CAF vs PCBO) on Cognitive Performances at D2 Day (After Total Sleep Deprivation)

Notes : A Friedman’s ANOVA analysis was performed for PVT Lapses, Go-NoGo Error Rate and 2-NBack Correct Responses, assessing a global effect of treatment and TOT. A 2-way ANOVA analysis of Reaction Times was performed for the three cognitive tasks (PVT, Go-NoGo and 2N-Back) with a looking at TOT, treatment and interaction effects. b  p<0.01,  c  p<0.001.

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Caffeine reduces TSD-related sustained attention deficits without any effects on TOT ( A ) Kinetic of the number of lapses min −1 as a function of time during the psychomotor vigilance task (PVT) at D2 (after total sleep deprivation (TSD)) for both placebo (PCBO, black) and caffeine (CAF, red) conditions, fitted with a linear regression. Shaded areas show time points of interest further analyzed: the first 3 min (0–3 min) and the last 3 min (7–10 min) of test. ( B ) Number of lapses min −1 during the first and the last 3 min of PVT at D2 for PCBO and CAF conditions. Error bars show s.e.m. *Significant difference between 0–3 min and 7–10 min of the test (*p<0.05; **p<0.01). # Significant difference between PCBO and CAF conditions ( # p<0.05). ( C ) Algebraic difference in the number of lapses min −1 between 0–3 min and 7–10 min of the task for both PCBO and CAF conditions.

Effects of TSD, CAF and TOT on No-Go Errors

We observed a global day and/or treatment effect for the rate of No-Go errors over the 10 minutes of test ( Table 2 ). More precisely, a significant increase in the rate of No-Go errors was observed at D2 compared to D1 both for PCBO and CAF conditions with no statistical difference between the two conditions ( Table 2 ). We then looked at the influence of TOT and treatment factors and their interaction. Interestingly, we observed no significant increase in the rate of No-Go errors in the first 3 min at D2 compared to D1 for both PBCO and CAF groups (p=0.47 for PCBO and p=0.17 for CAF). At D2 (after TSD), we observed a significant increase of No-Go errors between the first and the last 3 min of the task ( Figure 3A , shaded areas) for both PCBO and CAF conditions ( Table 3, Figure 3B ) but with no statistical difference in the estimated kinetic of TOT between the two conditions (p = 0.98; Figure 3C ) even if there was a significantly higher rate of No-Go errors in the first 3 min for CAF compared to PCBO condition ( Figure 3B ).

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Lack of alleviating effects of caffeine on inhibition impairments related to TSD and TOT. ( A ) Kinetic of rate of No-Go errors (response on « No-Go » trials) during the Go/No-Go task at D2 (after TSD) for both placebo (PCBO, black) and caffeine (CAF, red) conditions, fitted with a linear regression. Shaded areas show the first 3 min (0–3 min) and the last 3 min (7–10 min) of test. ( B ) Rate of No-Go errors during the first and the last 3 min of test at D2 for both PCBO and CAF. Error bars show s.e.m. *Significant difference between 0–3 min and 7–10 min of the test (**p<0.01; ***p<0.001). # Significant difference between PCBO and CAF conditions ( # p<0.05). ( C ) Algebraic difference in the rate of No-Go errors between the first and the last 3 min for both PCBO and CAF conditions.

Effects of TSD, CAF and TOT on 2N-Back Correct Responses

We observed a global day and/or treatment effect for the percentage of correct answers in 2N condition ( Table 2 ) in PCBO and CAF conditions. A significant decrease of the percentage of correct responses (% CR) at D2 compared to D1 for CAF condition was observed but not for PCBO condition, with a significant difference between PCBO and CAF conditions at D2 ( Table 2 ). We then looked at the influence of TOT and treatment factors and their interaction. We observed no significant increase in the 2N-Back correct responses in the first 3 min at D2 compared to D1 for both PBCO and CAF groups (p=0.261 for PCBO and p=0.215 for CAF). At D2 (after TSD), a significant effect of TOT and/or treatment was noticed ( Table 3 ; Figure 4A ). More precisely, a significant decrease of the % of CR in the last 3 min of the task compared to the first 3 min occurred in both PCBO and CAF conditions ( Figure 4A and ​ andB) B ) but with no significant difference between PCBO and CAF conditions during the first and the last 3 minutes (respectively p>0.10 and p>0.08; Figure 4B ). Finally, with the approximated kinetic of TOT, we observed no statistical difference between PCBO and CAF at D2 (p = 0.48; Figure 4C ).

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No beneficial effects of caffeine on working memory decrement after TSD and TOT ( A ) Kinetic of percentage of correct answers for the 2N-Back conditions at D2 (after TSD) for both placebo (PCBO, black) and caffeine (CAF, red) conditions, fitted with a linear regression. Shaded areas show the first 3 min (0–3 min) and the last 3 min (7–10 min) of test. ( B ) Percentage of correct answers during the first and last 3 min of test at D2 for both PCBO and CAF conditions. Error bars show s.e.m. *Significant difference between 0–3 min of 7–10 min (*p<0.05; **p<0.01). ( C ) Algebraic difference of rate of correct answers between the first 3 min and the last 3 min for PCBO and CAF conditions.

Effects of TSD, CAF and TOT on Response Time (RT) During PVT, Go-NoGo and 2N-Back

Significant main day effects and/or treatment effects on mean RT for these three cognitive tasks and also for the 10% fastest and the 10% slowest RT (just below lapses time period) for PVT were noticed ( Table 2 ). More precisely, we showed that mean RT increased at D2 compared to D1 both for PCBO and CAF conditions during the three tasks ( Table 2 ). We also observed a significant treatment main effect but only for mean RT and the 10% slowest RT for PVT, without any interaction ( Table 2 ). Since all these behavioral parameters were affected by TSD, we looked at TOT and treatment effects and their interaction. We observed significant increase for PVT in the first 3 min at D2 compared to D1 for both PBCO and CAF groups (p<0.001 for PCBO and CAF respectively) and for Go-NoGo (p=0.015 for PCBO and p=0.048 for CAF respectively), and no significance for 2N-Back (p=0.628 for PCBO and p=0.876 for CAF). We observed a TOT effect on mean RT for both PVT and Go-NoGo but not for 2N-Back ( Table 3 ). We also saw a significant treatment effect on mean RT but only for PVT and with any interaction with day ( Table 2 ) or TOT ( Table 3 ). More precisely, we showed at D2 that mean RT (ms) increased with TOT both for PCBO and CAF conditions during PVT (PCBO-D2 0-3min =301±7 vs PCBO-D2 7-10min =316±6; CAF-D2 0-3min =278±6 vs CAF-D2 7-10min =306±7) and Go-NoGo (PCBO-D2 0-3min =333±9 vs PCBO-D2 7-10min =335±9; CAF-D2 0-3min =328±11 vs CAF-D2 7-10min =330±12) but with a significant global decrease of PVT mean RT with caffeine (PCBO-D2 0-3min/7-10min =308±5 vs CAF-D2 0-3min/7-10min =292±5).

Effects of TSD, CAF and TOT on 0N-Back Correct Responses and RT

We observed a day effect for the percentage of % CR in 0N condition (Chi 2 (24,3) =26.5, p=1.3*10 −5 , Concordance Coeff. = 0.37, Aver. Rank = 0.34) in PCBO and CAF conditions. There was a significant decrease of correct responses at D2 compared to D1 for both PCBO (PCBO-D2=96.3±0.7% vs PCBO-D1=98.8±0.2%, p=1.9*10 −3 ) and CAF conditions (CAF-D2=95.5±0.7% vs CAF-D1=98.3±0.4%, p=2.6*10 −4 ), with no significant difference between conditions at D2 (PCBO-D2=96.3±0.7% vs CAF-D2=95.5±0.7%, p>0.20). At D2, no significant effect of TOT and treatment on the percentage of % CR was seen (Chi 2 (24,3) =5.0, p>0.17, Concordance Coeff.=0.07, Aver. Rank=0.03). Concerning mean RT, a significant day effect (F (1,23) =22,13; p=1.10 −4 ) with no significant treatment effect (F (1,23) =0.905; p>0.35) and no interaction (F (1,23) =1,31; p>0.26) were noticed. More precisely, we showed that mean RT increased at D2 both for PCBO and CAF conditions (PCBO D2 =465±18 vs PCBO D1 =409±14, p<1.10 −4 ; CAF D2 =453±15 vs CAF D1 =409±12, p<1.10 −4 ).

Effects of TSD, TOT and CAF on EEG Theta Power

A global effect of day and/or treatment over the 10 min of the 3 tests was observed for EEG theta power in the 3 ROIs (Parieto-Occipital (PO), Centro-Temporal (CT) and Frontal (F)) ( Table 4 ). Additional statistical effects of day and treatment on Alpha and Beta power are shown in the Supplementary Table S1 .

Global Effects of Total Sleep Deprivation (Day Effect, D2 vs D1), Treatment (CAF vs PCBO) and Region of Interest (ROIs: Parieto-Occipital, Centro-Temporal, Frontal) on EEG Theta Power During the 3 Cognitive Tasks

Notes : A Friedman’s ANOVA analysis was performed for EEG theta power during PVT, Go-NoGo and 2-NBack, assessing a global effect of total sleep deprivation, treatment and ROIs. Post hoc analysis has been made when there was a global effect on Friedman’s ANOVA. D2 vs D1 post-hoc: *p <0.05, **p<0.01, ***p<0.001. CAF vs PCBO post-hoc (at the same day): # p <0.05 CAF. Bold numbers underline a total sleep deprivation effect.

During the PVT Task

The theta power increase significantly in the 3 ROIs during PVT in the PCBO condition and only in the F brain area in the CAF condition ( Table 4 ). At D2 (after TSD), a significant difference between PCBO and CAF is observed in the PO brain region. We then look at influence of TOT and treatment factors and their interaction among the three scalp ROI at D2 ( Figure 5 ). Concerning PO brain region, we observed a TOT effect (F (1,20) =4,55; p <0.05), with no treatment (caffeine) effect (F (1,20) =3,62; p=0.07) and no interaction (F (1,20) =0,18; p=0.67). Concerning CT and F brain regions, we observed no effect of TOT (respectively, F (1,20) =1,46; p=0.24; F (1,20) =3,94; p=0.06) or treatment (caffeine) (respectively, F (1,20) =3,46; p=0.07; F (1,20) =1,18; p=0.29), and not interaction (respectively, F (1,20) =0,76; p>0.39; F (1,20) =0,15; p>0.70) ( Figure 5A and ​ andD D ).

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Caffeine and TOT effects on theta activity during the three cognitive tasks after TSD. On the left panel ( A – C ), topographical EEG representation of Time-On-Task (TOT) and caffeine significant (black in bold) or not significant (grey) effects at D2 (after TSD), and on the right panel ( D – F ), bar histograms of raw theta power in the 3 regions of interest (ROI) of the first 3 min and of the last 3 min, for PVT (upper), Go-NoGo (middle) and 2N-Back (lower). Anova p-values; a p<0.05, b p<0.01.

During the Go-NoGo Task

The theta power increase significantly in the PO and CT brain regions during Go-NoGo in the PCBO condition, and a significant difference between PCBO and CAF is observed in the two regions at D2 (after TSD) ( Table 4 ). We then look at influence of TOT and treatment factors and their interaction among the three scalp ROI at D2 ( Figure 5 ). Concerning PO, CT and F brain ROIs, we observed a TOT effect (respectively, F (1,20) =8,16; p <0.01; F (1,20) =11,94; p <0.01 and F (1,20) =5,29; p<0.05), with no treatment (caffeine) effect (respectively, F (1,20) =2,87; p>0.10; F (1,20) =2,94; p>0.10 and F (1,20) =0,97; p>0.33) and no interaction (respectively, F (1,20) =0,32; p>0.58; F (1,20) =0,83; p>0.37 and F (1,20) =0,19; p>0.66) ( Figure 5B and ​ andE E ).

During the 2N-Back Task

The theta power increase significantly in the PO and CT brain regions during 2N-Back in the PCBO condition and in the F region in the CAF condition ( Table 4 ). A significant difference between PCBO and CAF is observed in the CT region at D2 (after TSD). We then look at influence of TOT and treatment factors and their interaction among the three scalp ROI at D2 ( Figure 5 ). Concerning CT brain region, we observed a treatment (caffeine) effect (F (1,20) =7,98; p<0.05), with no TOT effect (F (1,20) =3,87; p>0.06) and no interaction (F (1,20) =1,61; p>0.22). Concerning F brain region, we observed no treatment (caffeine) effect (F (1,20) =1,16; p>0.29), but a TOT effect (F (1,20) =6,14; p<0.05) and no interaction (F (1,20) =0,01; p>0.91). Concerning PO brain region, we observed neither treatment (caffeine) effect (F (1,20) =0,19; p>0.66) nor TOT effect (F (1,20) =0.001; p>0.97) and no interaction (F (1,20) =1,11; p>0.30) ( Figure 5C and ​ andF F ).

Aims of our study were to determine the contribution of both TSD (Total Sleep Deprivation) and TOT (Time-On-Task) on sustained attention and executive processes (ie, inhibition and working memory) using caffeine and the contribution of EEG theta activity in such modifications. In this double-blind counter-balanced (PCBO placebo and CAF caffeine - 2.5 mg/kg) study, we demonstrate for the first-time differential effects of TSD and TOT on deficits of sustained attention and of two executive processes (inhibition and working memory). These cognitive capabilities were impaired by TSD and TOT when expressed in number of lapses (PVT), rate of errors (NoGo) and percentage of correct responses (2N-Back) tasks. More precisely, at the D2 day compared to the D1 day (corresponding to 26 hours of prolonged wakefulness), we observed a significant increase in the number of PVT lapses, the rate of No-Go errors and a decrease in the percentage of 2N-Back correct responses (only significant in the caffeine condition). In addition, we found a TSD per-se effect (D2 compared to D1 on the first three minutes of test) and a TOT effect (last vs first three minutes of the 10-min testing) in placebo and caffeine condition but differently regarding the three cognitive tasks. More precisely, the deleterious effect of TSD per-se was only observed for the increase in the number of Lapses (PVT) whereas the deleterious effect of TOT was observed for all the three cognitive tasks parameters (number of lapses, rate of No-Go errors and percentage of correct responses). This TOT effect is confirmed by the significant increase of theta power in at least one of the three brain regions of interest (ROI) during the three cognitive tasks and in the three ROIs during the Go-NoGo task, as previously shown in subjects engaged in sustained attention and executive tasks and fatigued with TOT. 15 , 16 When we looked at response time, subjects under TSD presented a TOT effect only during PVT and Go-NoGo tasks.

Caffeine consumption significantly reduced sustained attention deficits (number of Lapses) related to TSD and the corresponding EEG theta spectral power without any reduction due to TOT (the last minus the first three minutes). Indeed, the linear downward shift of the number of lapses in the caffeine condition as shown in Figure 2A ) and no caffeine effect on kinetics (slopes of regression lines that tend to be similar) suggested that under caffeine a subject that has not slept will degrade at the same rate but starting from a lower level, so caffeine delays the onset of sustained attention deficits due to TOT. The caffeine alleviating effect on the median and the 10% slowest RT (just below lapses time period) confirmed the delayed effect of caffeine on sustained attention deficits with also a significant decrease of theta power (during PVT) on the whole scalp. No such beneficial effect of caffeine was observed 1) on executive (inhibition and working memory) deficits related to TOT under TSD associated with just a global decrease of the EEG theta power on the whole scalp and 2) on the increase of subjective sleepiness.

All these results are in accordance with previous ones showing that a continuous period of wakefulness (upper than 24 hours) is associated with deficits of sustained attention and executive capacities (ie, inhibition and working memory) with higher sleepiness ratings 9 , 10 , 15 , 35 , 36 (for review see 8 ). We added the information that TOT contributes to sustained attention and executive processes deficits related to TSD as previously evidenced with studies using a 10-min PVT task. 34–37 Even if post-hoc analysis showed that working memory capabilities were not significantly affected by TSD in the placebo condition as previously described, 38 , 39 our results revealed a TOT effect under TSD. In agreement with Frenda and Fenn (2016), we argue that TSD impairs cognitive processes by primarily inhibiting the ability of individuals to be alert and to sustain their attention and allows other higher executive functions under compensatory mechanisms, explaining why working memory deficits observed in this study are mainly related to TOT (under TSD). 40 This differential effect of caffeine on cognitive processes under TSD with a benefit for sustained attention deficits and not for two executive ones (inhibition and working memory) are also in accordance with our previous studies showing that countermeasures such as sleep extension and regular physical activity are ineffective to limit such executive deficits related to TSD. 9 , 10 , 41 Lack of beneficial effect of caffeine on executive deficits and corresponding EEG theta power related to TSD and also on sleepiness could be due to the lower dose used (175 mg compared to 200–600 mg in other studies 42 , 43 ) (for review see 25 ). In any case, caffeine was found to be rarely or not at all effective in counteracting executive deficits related to TSD 42 (for review see 25 ). In contrast, previous studies have reported, as for us with RT during PVT, an improvement of response time for both simple and choice reaction time task related to TSD with caffeine. 44

Sleep pressure that increases with TSD (for review see 7 ) exert a deleterious effect on the capacity of subjects to stay awake, to be alert and thus to sustain their attention. With sustained attention, while waiting for the occurrence of a stimulus, subjects will be more easily distracted by their internal thoughts. 45 Indeed, sleepy subjects that are often unaware of their own environment have a higher frequency of self-reported mind-wandering, an experience of thoughts both stimulus-independent and task-unrelated that seems to frequently co-occur with sleepiness. 46 Interestingly, the brain default mode network (DMN) – a brain network whose activity is high when the mind is not engaged in specific behavioral tasks and low during focused attention on the external environment 47 – is both associated with mind-wandering state 47 , 48 and anti-correlated with a fronto-parietal network (central executive network: CEN) associated with cognitive control, 49 especially in TSD situations. 45 , 50 As we found a specific caffeine alleviating effect on the number of lapses related to TSD, we can make the assumption that under TSD, caffeine may help the brain of sleepy subjects to less often switch from a goal-directed to a goal-irrelevant brain function (ie, DMN) and to be less often mind wandered. This hypothesis is reinforced by our observation that caffeine alleviates TSD increases on i) the mean RT, ii) the 10% slowest RT on PVT, a behavioural parameter which has been linked to an activation of DMN 30 and iii) the theta power of the subject’s brain during PVT (D2 vs D1). The increase of theta power during PVT following TSD has already been observed in sleepy subjects accompanied with sustained attention decrements 15 , 51 or in a state of mind-wandering. 52 Furthermore, a recent study demonstrated that taking a 200 mg caffeine pill increases brain entropy nearly in the entire cerebral cortex with higher effects in DMN and sensorimotor networks. 53 These authors suggested that such pharmacological effects of caffeine on the human brain may result in an improvement of vigilance, attention and others functions which are mainly sub-served by the aforementioned brain regions.

In our study, the benefit of a low dose of caffeine (175 mg), a well-known antagonist of adenosine receptors, on the number of lapses, response time (mean and 10% slower) and theta power of subjects engaged in a PVT highlights the involvement of adenosinergic systems in sustained attention deficits related to TSD per-se. 54 Executive deficits observed with this TSD protocol were mainly revealed with TOT. It thus seems that TSD per-se and TOT differentially contribute to cognitive deficits related to TSD. These results are in accordance with studies showing that TOT is responsible for inducing a mental fatigue state of subjects engaged in an executive task 55–57 (for review see 1 ). Furthermore, it has been observed that 35 hours of continuous wakefulness are associated with an increase of cerebral responses within parieto-frontal networks and with better working memory performance at most difficult load in a verbal learning or in logical reasoning. 35 , 58 , 59 The frontal increase of theta power on the scalp related to TOT for both executive tasks is also in accordance with studies showing an increase of theta power of subjects engaged in an executive task and fatigued with TOT. 14 The lack of beneficial effects of caffeine on such cognitive deficits (ie, executive) and on theta power related to TSD suggests that the neurobiological mechanisms implicated would be different and/or less sensitive to the subsequent increase of extracellular adenosine classically related to sustained attention deficits. 25 , 54 Nevertheless, since working memory deficits related to TSD were worsen under caffeine consumption we can exclude the implication of adenosine on such executive process. Indeed, in a previous study with healthy subjects, caffeine administration (6 mg/kg) lowered the increase of perceived exertion (RPE) and amplitude of motor-related cortical potential observed in the second half compared with the first half of a 15-min sub-maximal intermittent isometric knee-extension exercise protocol (ie, as a TOT effect in a physical task). 60 In the herein presented study, we can at least suggest that TOT effects themselves do not depend directly on the adenosinergic mechanisms. It would be interesting in future studies to look at potential benefit of higher doses of caffeine (> 3 mg per kg of body mass) to counteract cognitive deficits of totally sleep-deprived subjects related to TOT. With respect to sustained attention, sleep pressure (ie, TSD) may thus be considered as a threshold modulator of TOT mechanisms. Longer duration tasks (60 min) are generally used to reveal a cognitive fatigue when subjects are not submitted to TSD. 61 In our conditions, a task of 10 minutes is sufficient to elicit TOT effect after TSD, suggesting that sleep pressure may trigger TOT earlier by an additive modulation of an input-output linear relationship (for instance, the number of lapses per min as a function of time).

Some limitations in the present study must be taken into consideration when interpreting our results. Indeed, the sample size is small and may have masked subtle results on the effects of caffeine on cognitive performance related to the TOT effect for example. In addition, there is variability in daily caffeine consumption that cannot be accounted for with the creation of subgroups given the sample size.

This study demonstrated that cognitive deficits (sustained attention and executive processes) related to TSD are under the influence not only of the lack of sleep itself (TSD) but also of Time-On-Task (TOT). A low dose of caffeine (2.5 mg/kg) is only beneficial for sustained attention deficits related to TSD per-se, by slowing down the trigger due to the TOT factor. Such dose of caffeine was neither efficient to counteract sustained attention deficits related to TOT nor executive processes deficits that seem mainly affected by TOT and thus less dependent to the wakefulness instability state due to an increase of the homeostatic sleep pressure. Finally, the increase of global EEG theta power during TSD and increase in three brain regions during TOT highlighted the implication of brain theta rhythm in revealing a mental/cognitive fatigue state.

Our results demonstrated, to our knowledge for the first time, that cognitive deficits related to a continuous wakefulness of 26 hours are not only due to a lack of sleep itself but also to a time on task (TOT) effect putting forward the idea 1) to look more carefully at the commitment time of a subject under sleep debt that is engaged in a cognitive task and 2) to question for a common psychophysiological substrate of a mental/cognitive fatigue state. Our results also pointed out a differential benefit of a low dose of caffeine (175 mg) that only slows down the triggering of sustained attention deficits related to TOT. They reinforce the idea that caffeine effectiveness in counteracting sleepiness and sustained attention deficits related to TSD would rely on the adenosinergic mechanism whereas TOT effect observed for both sustained attention and executive would not.


The authors thank Philippe Colin, Benoît Lepetit, Cyprien Bourrilhon, Pierre Fabriès, Rodolphe Dorey and Bruno Schmid for their technical and logistic contribution to this work.

Funding Statement

Financial supports were provided by the French General Directorate for Armament (Direction Générale de l’Armement), Department of Defense, Contract N°: PDH-1-SMO-2-509/SAN-1-509.


BMI, body mass index; CAF, caffeine; EFs, executive functions; KSS, Karolinska sleepiness scale; PCBO, placebo; PSQI, Pittsburgh Sleep Quality Index; PVT, psychomotor vigilance test; ROI, region of interest; TSD, total sleep deprivation; TOT, time-on-task.

Clinical Trials Details

Clinical Trials Brief Title: Protocol PERCAF 2018. Clinical Trials Number: {"type":"clinical-trial","attrs":{"text":"NCT03859882","term_id":"NCT03859882"}} NCT03859882 . Clinical Trials, First submission date: 25/02/2019.

Statement of Significance

It is widely admitted that total sleep deprivation (TSD) is responsible for a large range of cognitive deficits in healthy adults. However, the contribution of sleep debt per se, time on task and benefit of caffeine on cognitive deficits have received little investigation. Here we showed that the contribution of sleep debt per se, time on task and caffeine were not equivalent depending on the cognitive process engaged (ie, sustained attention versus executive processes). These results suggest that cognitive fatigue 1) would be differently supplied by sleep debt and time on task and 2) would not rely on the same neurophysiological changes according to the process involved. They would also open discussion upon concepts of cognitive fatigue and fatigability.

Data Sharing Statement

The authors do not intend to share individual data from de-identified participants, and no study documents will be made available.

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. Damien Léger reports grants from Sanofi, grants from Idorsia, grants from Jazz, grants from Bioserenity, outside the submitted work. The authors report no other potential conflicts of interest for this work.

buffalo case study caffeine

The Nespresso Coffee Pod That Has The Most Caffeine

N espresso pods are great for making coffee at home, especially since they're compatible with some of the best coffee pod machines available, but sometimes, you prefer a pure caffeine kick over a smooth taste. While Nespresso pods' levels of intensity are reflected on the brand's website, the precise caffeine content is not, begging the question, which pod provides the biggest caffeine boost?

This appears to be a fairly common question, appearing as a top-five FAQ on Nespresso's website . The FAQ explains that, while most coffee pods have a similar caffeine level, those meant for higher volume beverages consequently have a higher level of caffeine. The FAQ specifically mentions the Carafe Pour-Over Style pod, which contains "over 200mg of caffeine per complete capsule serving." A double shot of espresso will usually have between 58 and 185 milligrams of caffeine, so caffeine content exceeding 200 milligrams is pretty impressive.

Of course, this is based on a slight technicality. Because the pour-over pods are intended to be served in an 18-ounce carafe or 12-ounce cup, a significantly larger measurement than the 1.35-ounce cup recommended for an espresso pod, the caffeine is distributed throughout a much larger volume of liquid. The FAQ states that an espresso pod normally contains between 50 and 100 milligrams of caffeine, so if served correctly, the pour-over pod won't feel quite like the adrenaline shot you'd expect.

Read more: How To Get More Flavor From Your Coffee Pods & Other Keurig Hacks

Which Single-Serving Nespresso Pods Have The Most Caffeine?

While there's no reason you can't use the pour-over pod in a single serving, it won't do your taste buds or your wallet any favors. Espresso pods cost between 85 and 90 cents per capsule, whereas pour-over pods come in at $1.65, almost double the price. The pour-over pods are optimized for higher volumes of liquid, so the taste may seem overly strong and bitter if used for a short drink. In theory, you could reuse the pod , but the quality of the drink takes something of a nosedive.

Luckily, there are some single-serving exceptions to the 50 to 100-milligram rule (although they don't surpass 200 milligrams like pour-over capsules). According to Nespresso's FAQ, Vertuo coffees contain a caffeine content ranging between 170 and 200 milligrams. They're best served as 2.7-ounce double shots, but if you use Nespresso pods for the energy boost rather than to sample the best flavors , you're likely well acquainted with double shots already. These pods are naturally more expensive than single-shot capsules and will set you back between $1.15 and $1.25, depending on which pod you choose.

Read the original article on Mashed .

Coffee pods and espresso beans


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    known literature exists describing caffeine intake among case workers. ... This cross-sectional study was approved by Buffalo State College, State University of New York Institutional Review Board. Case workers in the United States were recruited with the intent of snowball sampling. A brief study description with a link to the

  7. Caffeine Use Disorder: A Comprehensive Review and Research Agenda

    Introduction. C affeine is the most widely used drug in the world. 1 In the United States, more than 90% of adults use it regularly, and, among them, average consumption is more than 200 mg of caffeine per day 2 —more caffeine than is contained in two 6-ounce cups of coffee or five 12-ounce cans of soft drinks. 3,4 Although consumption of low to moderate doses of caffeine is generally safe ...

  8. Study finds no association between caffeine ...

    BUFFALO, N.Y. — Researchers from the University at Buffalo conducted a study of nearly 80,000 postmenopausal women in the U.S. to determine whether caffeine consumption from coffee and tea has any association with invasive breast cancer. ... "The overlap of age at diagnosis of breast cancer and age with high consumption of caffeine, and the ...

  9. PDF Dangerous mistake: an accidental caffeine overdose

    Caffeine (1,3,7-trimethylxanthine) is a natural product commonly presented in food's composition, beverages and medicinal products. Generally, it is thought to be safe under normal dosage, yet it can be fatal in case of severe intoxication. We report a case of a healthy 32-year-old woman who went to the local emergency department (eD) 30 min ...

  10. Coffee genome sheds light on the evolution of caffeine

    The study was led by the French Institute of Research for Development, the French National Sequencing Center (CEA-Genoscope) and the University at Buffalo. The findings appear in the journal Science. BUFFALO, N.Y. — The newly sequenced genome of the coffee plant reveals secrets about the evolution of man's best chemical friend: caffeine.

  11. How much caffeine you should actually have—and when

    Published January 10, 2024. The Wall Street Journal quoted Jennifer Temple, in a story on how much caffeine is appropriate for adults. Government and health groups recommend that healthy adults consume no more than 400 milligrams of caffeine daily, which, Temple said, comes out to about four 8-ounce cups of coffee.

  12. New Insight into Caffeine Use Disorder

    About 90% of adults in the United States use caffeine regularly, says Griffiths, and their average consumption exceeds 200 milligrams of caffeine per day — more caffeine than is contained in two 6-ounce cups of coffee, or five 12-ounce cans of soft drinks. This latest research study, notes Sweeney, is the most thorough evaluation to date of ...

  13. Association of Coffee Consumption and Prediagnostic Caffeine

    This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine and its metabolites years before diagnosis. ... In the nested case-control study, which included 351 cases with incident PD and 351 matched controls, prediagnostic caffeine and its primary ...

  14. Caffeine in Children and Adolescents

    Abstract: Caffeine is the most widely used psychoactive substance in the world and its use is increasing among children. Although considered safe, the majority of empirical data on the effects of caffeine have been collected in adults. Our previous studies, supported by a KO1 from NIDA, have demonstrated that caffeine has dose-dependent effects ...

  15. Caffeine supplementation improves the cognitive abilities and ...

    The aim of this study was to investigate the effect of supplementary caffeine with 3 mg/kg on improving performance of E-sport players in Stroop task, visual search reaction time, kill ratio, hit ...

  16. Caffeine

    In the U.S., adults consume an average of 135 mg of caffeine daily, or the amount in 1.5 cups of coffee (1 cup = 8 ounces). [5] The U.S. Food and Drug Administration considers 400 milligrams (about 4 cups brewed coffee) a safe amount of caffeine for healthy adults to consume daily. However, pregnant women should limit their caffeine intake to ...

  17. The Safety of Ingested Caffeine: A Comprehensive Review

    Cognitive Effects. Caffeine can influence objective and perceived cognitive performance by increasing alertness and wakefulness (66-68).Acute caffeine can also improve performance on memory tasks (69, 70).Finally, caffeine improves psychomotor vigilance, such as reaction time (71-73).The impact of caffeine appears to be greater under conditions that would negatively impact performance ...

  18. PDF A Case Study Investigating a Behavioural Intervention to Reduce

    A Case Study Investigating a Behavioural Intervention to Reduce Caffeine Consumption.

  19. Dark roasted and dangerous: Everything you should know about caffeine

    Caffeine intoxication occurs when a person has dangerously high levels of caffeine in the system. It creates a spectrum of unpleasant and severe symptoms, such as trouble breathing and seizures ...

  20. Caffeine Intake and Mental Health in College Students

    College students use very high doses of caffeine, an average of over 800 mg/day, which is approximately double the recommended safe dosage [ 3 ]. The short-term and long-term effects of caffeine on the human body have been studied. Research to date has primarily focused on caffeine's exacerbation of anxiety, sleep disorders, and depression in ...

  21. Health Effects of Caffeine

    And Cooper notes that if you consume 10 grams (or 10,000 milligrams) of caffeine - equivalent to what would be found in about 100 cups of coffee - that amount of caffeine can be fatal.

  22. Nespresso's Decaf Coffee Pods Aren't As Caffeine-Free As We Thought

    For many of us, that's the case upon discovering that decaf coffee isn't strictly devoid of caffeine. Nespresso, to its credit, doesn't simply avoid discussing the misconception of zero caffeine ...

  23. Buffalo Case Study Caffeine

    Buffalo Case Study Caffeine. Please don't hesitate to contact us if you have any questions. Our support team will be more than willing to assist you. Remember, the longer the due date, the lower the price. Place your order in advance for a discussion post with our paper writing services to save money!

  24. Here's exactly when to stop drinking caffeine for the best chance of a

    According to a 2013 study published in the Journal of Clinical Sleep Medicine, participants who consumed 400 milligrams of caffeine 0, 3, or 6 hours before their regular bedtime led to ...

  25. Buffalo Case Study Caffeine

    Buffalo Case Study Caffeine, Esl Best Essay Writer Service Usa, Great Expectation Pip Essay, Cover Letter Deputy Manager, Stand Up For Life Essay Contest, Explain The Steps In Writing An Effective Exam Essay, 5 Paragraph Essay And Outline The Hazard Of Moviegoing User ID: 104293

  26. Your New EV Could Do With a Shot of Caffeine. And AI

    Your New EV Could Do With a Shot of Caffeine. And AI. Novel breakthroughs, with the help of powerful computers, are bringing us closer to an emissions-free future. March 31, 2024 at 3:00 PM PDT ...

  27. 23 Caffeinated Drinks Ranked by Caffeine Levels

    Caffeine. Celsius Original (12 fluid ounces) 200 mg. Monster Energy - The Original Green Monster Energy (16 fluid ounces) 160 mg. Rockstar Energy Drink, Origina l (16 fluid ounces) 160 mg. Red ...

  28. Effects of Caffeine Intake on Cognitive Performance Related to Total

    In any case, caffeine was found to be rarely or not at all effective in counteracting executive deficits related to TSD42 (for review see25). In contrast, previous studies have reported, as for us with RT during PVT, an improvement of response time for both simple and choice reaction time task related to TSD with caffeine.44

  29. Buffalo Case Study Caffeine

    Buffalo Case Study Caffeine. 100% Success rate. Our team of paper writers consists only of native speakers coming from countries such as the US or Canada. But being proficient in English isn't the only requirement we have for an essay writer. All professionals working for us have a higher degree from a top institution or are current university ...

  30. The Nespresso Coffee Pod That Has The Most Caffeine

    The FAQ states that an espresso pod normally contains between 50 and 100 milligrams of caffeine, so if served correctly, the pour-over pod won't feel quite like the adrenaline shot you'd expect ...