Healthy Adult Male and Female VolunteersEarly Phase 1NCT07742631
Neurocognitive Effects of Extended-Release Methylphenidate in Healthy Adults
A Early Phase 1 study testing Methylphenidate Stimulant medication therapy in people with Healthy Adult Male and Female Volunteers, run by University of Witwatersrand, South Africa at 1 site in South Africa.
Trial summary
This study evaluated the effects of methylphenidate (MPH), a stimulant medication commonly used to treat attention deficit hyperactivity disorder (ADHD), in healthy adults without ADHD. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Adult Male and Female Volunteers
- What is being tested?
- Methylphenidate Stimulant medication therapy
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteSouth Africa
- Study dates
- 6 Feb 2023to 15 Apr 2024
- Phase
- Early Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy adults without a diagnosis of ADHD
- Age 18 to 50 years
- Willing to participate after being informed about the study
- Willing to receive both methylphenidate and placebo during the study period
- Willing to undergo non-invasive physiological, cognitive, cardiovascular, balance, and physical performance assessments
- Able to comply with all study procedures and visits
Who cannot join
- Current use of any medication that may affect cognitive performance, physical performance, electrocardiogram (ECG) findings, cardiovascular function, or balance
- Any medical, neurological, musculoskeletal, psychiatric, or other condition that may interfere with the safe or successful completion of study assessments and physical performance testing
- Any contraindication to methylphenidate administration
Trial locations and contacts
1 site in 1 country.
South Africa1 site
University of the Witwatersrand
Johannesburg, Gauteng, 2193
About this study
Official title: The Neurocognitive Effects of Extended-Release Methylphenidate in Healthy Adults: A Review and Placebo-Controlled Randomized Controlled Trial
This study evaluated the effects of methylphenidate (MPH), a stimulant medication commonly used to treat attention deficit hyperactivity disorder (ADHD), in healthy adults without ADHD. Although MPH is sometimes used by students and athletes to improve concentration or performance, its true benefits and risks in healthy individuals are uncertain.
The purpose of this study was to determine whether short-term use of MPH improves thinking ability, physical performance, cardiovascular function, balance, muscle strength, or heart safety in healthy adults.
In this randomized, double-blind, placebo-controlled crossover study, 28 healthy adult participants received either MPH (20 mg daily) or a placebo for 14 days, followed by a washout period and then the alternate treatment. Participants underwent repeated testing of heart rate, blood pressure, exercise capacity, balance, muscle strength, cognitive function, and heart electrical activity (ECG).
Read the detailed description
Methylphenidate (MPH) is a central nervous system stimulant widely prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). In addition to its clinical use, there has been increasing interest in the use of MPH by healthy individuals for potential cognitive enhancement, academic performance, and physical performance. Despite this growing use, there is limited high-quality evidence on its effects across multiple physiological and functional domains in healthy adults. This study was designed to address these gaps.
This investigation used a randomized, double-blind, placebo-controlled crossover design to evaluate the effects of short-term MPH administration in healthy, drug-naïve adults. A crossover design was selected to allow each participant to serve as their own control, thereby reducing variability and improving the precision of comparisons between treatment conditions. Participants were randomly assigned to receive either extended-release MPH (20 mg daily) or a placebo for 14 days, followed by a washout period and subsequent crossover to the alternate treatment.
The study was conducted in a controlled laboratory setting to ensure consistency in testing conditions and measurement accuracy. Participants underwent a comprehensive assessment battery at baseline and repeated assessments after each treatment phase. These evaluations were selected to provide a multidimensional understanding of MPH's effects across several key domains:
Physiological and cardiovascular function: Resting heart rate and blood pressure were measured to assess potential stimulant-related cardiovascular effects. In addition, cardiopulmonary exercise testing (CPET) was used to evaluate exercise capacity, aerobic fitness (including maximum oxygen consumption, VO₂ peak), ventilatory efficiency, and overall cardiopulmonary performance.
Neurocognitive function: Cognitive performance was assessed using a validated computerized neurocognitive test battery (CNS Vital Signs®). This evaluated domains such as attention, memory, processing speed, executive function, and reaction time. These measures were included because MPH is known to influence dopaminergic and noradrenergic pathways involved in cognitive processing.
Postural balance: Objective balance testing was conducted using the Biodex® Balance System, which evaluates stability under different sensory conditions. This allowed assessment of visual, vestibular, and somatosensory contributions to balance control.
Muscle strength: Handgrip strength, a reliable indicator of overall muscular strength and physical performance, was measured using a calibrated dynamometer.
Cardiac electrical activity: Electrocardiography (ECG) was recorded at rest and during exercise to monitor cardiac rhythm and electrical conduction, ensuring detection of any potential stimulant-related cardiac effects.
Participants were instructed to maintain their usual diet and physical activity throughout the study to minimize confounding factors. All assessments were performed at similar times of day across testing sessions to reduce the effects of diurnal variation.
The study also incorporated rigorous safety and screening procedures. Participants underwent pre-participation health screening, including standardized questionnaires and cardiovascular risk assessment, to ensure suitability for exercise testing and stimulant exposure. Continuous monitoring during exercise testing ensured participant safety.
This study specifically targeted healthy adults without ADHD to isolate the effects of MPH independent of its therapeutic role. By integrating physiological, cognitive, neuromuscular, and cardiovascular measures within a single study design, the research provides a comprehensive evaluation of MPH's potential for performance enhancement or health risk in this population.
- Conditions
- Healthy Adult Male and Female Volunteers
- Being tested
- Methylphenidate Stimulant medication therapy, Placebo Capsule(s)
- Keywords
- methylphenidate, central nervous system stimulants, cognitive function, exercise performance, cardiopulmonary exercise testing, cardiovascular effects, electrocardiography, postural balance, randomized crossover study
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Methylphenidate Stimulant medication therapyDrug
Also called Methylphenidate
Extended-release methylphenidate 20 mg administered orally once daily for 14 days.
Placebo Capsule(s)Other
Also called Inactive comparator
Matching placebo capsules containing inert sucrose, identical in appearance to the active medication capsules.
| Study group | Role | What they receive |
|---|---|---|
| Mehylphenidate -> Placebo | Active comparator | Participants received extended-release methylphenidate 20 mg once daily for 14 days, followed by a washout period, then matching placebo capsules once daily for 14 days. Receives: Drug: Methylphenidate Stimulant medication therapy; Other: Placebo Capsule(s) |
| Placebo -> Methylphenidate | Placebo comparator | Matching placebo capsules administered orally once daily for 14 days. Capsules were identical in appearance to methylphenidate capsules to maintain blinding. Receives: Drug: Methylphenidate Stimulant medication therapy; Other: Placebo Capsule(s) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Peak Oxygen Consumption (VO₂peak)
Maximal oxygen uptake (VO₂peak) measured during cardiopulmonary exercise testing (CPET)
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate (post-intervention, following crossover design)
Secondary outcomes (19)
Attention (CNS Vital Signs)
Neurocognitive attention performance assessed using the CNS Vital Signs® computerized test battery.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate
Postural Balance Performance (Biodex Balance System)
Postural balance assessed using the Biodex Balance System® under four conditions (eyes open/closed and firm/unstable surfaces), measuring sway and stability indices.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate
Ventilatory Threshold (VT1)
Ventilatory threshold measured during CPET as an indicator of aerobic capacity
Measured: Baseline, after 14 days placebo, after 14 days methylphenidate
Handgrip Strength
Muscle strength measured using a handgrip dynamometer, assessing maximal grip force of the dominant hand as an indicator of neuromuscular performance.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate
Resting Heart Rate
Resting heart rate (beats per minute) measured using standardised procedures following a 5-minute rest period.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate
Electrocardiogram (ECG) Rhythm Parameters
Cardiac electrical activity assessed using electrocardiography, including measurements of heart rhythm.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate
Oxygen Pulse
Oxygen pulse (mL/beat) measured during cardiopulmonary exercise testing (CPET) as the ratio of oxygen consumption (VO₂) to heart rate, serving as a surrogate marker of stroke volume and cardiovascular efficiency during exercise.
Measured: Baseline, after 14 days placebo, after 14 days methylphenidate
Ventilatory Efficiency (VE/VCO₂ Slope)
Ventilatory efficiency assessed by the VE/VCO₂ slope during CPET, representing the relationship between minute ventilation (VE) and carbon dioxide production (VCO₂). This parameter reflects ventilatory efficiency and pulmonary gas exchange.
Measured: Baseline, after 14 days placebo, after 14 days methylphenidate
Oxygen Uptake Efficiency Slope (OUES)
Oxygen uptake efficiency slope (OUES) measured during CPET as the relationship between oxygen consumption (VO₂) and ventilation (VE), reflecting the efficiency of oxygen uptake during exercise, including at submaximal effort levels.
Measured: Baseline, after 14 days placebo, after 14 days methylphenidate
Oxygen Consumption to Work Rate Ratio (VO₂/Work Rate)
Ratio of oxygen consumption (VO₂) to work rate (mL/min/watt) measured during CPET, indicating the efficiency of oxygen utilisation relative to external workload and overall cardiopulmonary performance.
Measured: Baseline, after 14 days placebo, after 14 days methylphenidate
Reaction Time (CNS Vital Signs)
Neurocognitive reaction time assessed using the CNS Vital Signs® computerized test battery.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Executive Function (CS Vital Signs)
Executive function performance assessed using the CNS Vital Signs® computerized test battery.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Complex Attention (CS Vital Signs)
Complex attention performance assessed using the CNS Vital Signs® computerized test battery.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Processing Speed
Processing speed assessed using the CNS Vital Signs® computerized test battery.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Memory Domains (CNS Vital Signs)
Memory performance (including composite memory domains as defined by CNS Vital Signs®) assessed using the computerized test battery.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Electrocardiogram Tracing PR intervals
Electrocardiogram PR intervals
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Electrocardiogram tracing QRS intervals
Measurement of QRS intervals on electrocardiogram tracings
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Electrocardiogram QT/QTc measurement
Measurement of QT/QTc intervals on electrocardiogram
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate.
Blood Pressure
Brachial arterial blood pressure (mmHg) measured using standardised procedures following a 5-minute rest period.
Measured: Baseline (pre-intervention), after 14 days of placebo, and after 14 days of methylphenidate
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Aug 2026
- Study start6 Feb 2023
- Primary completion15 Apr 2024
- Study completion15 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (32)Papers the sponsor has linked to this study.
- Other trials for Healthy Adult Male and Female VolunteersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomised, double-blind, placebo-controlled cross-over design.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Witwatersrand, South Africa
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Demitri Constantinou, University of Witwatersrand, South Africa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07742631
- Sponsor's protocol ID
- 180611
- Other IDs
- PACTR202011697726048
- Status last verified
- Jul 2026
- First submitted
- 13 May 2026
- Last updated
- 3 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: The study dataset (de-identified) is securely archived at the University of the Witwatersrand. Ethical restrictions prevent public release of participant data; however, access may be granted to qualified researchers upon reasonable request to the corresponding author and with appropriate institutional approvals.
Publications
World Anti Doping Agency. (2016). 2015 Anti-Doping Testing Figures Samples Analyzed and Reported by Accredited Laboratories in ADAMS. Montreal: World Anti Doping Agency.
Winterstein AG, Gerhard T, Kubilis P, Saidi A, Linden S, Crystal S, Zito J, Shuster JJ, Olfson M. Cardiovascular safety of central nervous system stimulants in children and adolescents: population based cohort study. BMJ. 2012 Jul 18;345:e4627. doi: 10.1136/bmj.e4627.
PubMed 22809800Westover AN, Nakonezny PA, Barlow CE, Vongpatanasin W, Adinoff B, Brown ES, Mortensen EM, Halm EA, DeFina LF. Exercise outcomes in prevalent users of stimulant medications. J Psychiatr Res. 2015 May;64:32-9. doi: 10.1016/j.jpsychires.2015.03.011. Epub 2015 Mar 21.
PubMed 25840827Swart J, Lamberts RP, Lambert MI, St Clair Gibson A, Lambert EV, Skowno J, Noakes TD. Exercising with reserve: evidence that the central nervous system regulates prolonged exercise performance. Br J Sports Med. 2009 Oct;43(10):782-8. doi: 10.1136/bjsm.2008.055889. Epub 2008 Dec 3.
PubMed 19052141Stiefel G, Besag FM. Cardiovascular effects of methylphenidate, amphetamines and atomoxetine in the treatment of attention-deficit hyperactivity disorder. Drug Saf. 2010 Oct 1;33(10):821-42. doi: 10.2165/11536380-000000000-00000.
PubMed 20812768Shorer Z, Bachner Y, Guy T, Melzer I. Effect of single dose methylphenidate on walking and postural stability under single- and dual-task conditions in older adults--a double-blind randomized control trial. J Gerontol A Biol Sci Med Sci. 2013 Oct;68(10):1271-80. doi: 10.1093/gerona/glt035. Epub 2013 Apr 11.
PubMed 23580740Rapoport JL, Buchsbaum MS, Weingartner H, Zahn TP, Ludlow C, Mikkelsen EJ. Dextroamphetamine. Its cognitive and behavioral effects in normal and hyperactive boys and normal men. Arch Gen Psychiatry. 1980 Aug;37(8):933-43. doi: 10.1001/archpsyc.1980.01780210091010.
PubMed 7406657Potocnjak I, Degoricija V, Vukicevic Baudoin D, Culig J, Jakovljevic M. Cardiovascular side effects of psychopharmacologic therapy. Int J Cardiol. 2016 Sep 15;219:367-72. doi: 10.1016/j.ijcard.2016.06.057. Epub 2016 Jun 20.
PubMed 27352209Martinez-Raga J, Knecht C, Szerman N, Martinez MI. Risk of serious cardiovascular problems with medications for attention-deficit hyperactivity disorder. CNS Drugs. 2013 Jan;27(1):15-30. doi: 10.1007/s40263-012-0019-9.
PubMed 23160939Lee SH, Song DH, Kim BN, Joung YS, Ha EH, Cheon KA, Shin YJ, Yoo HJ, Shin DW. Variability of response time as a predictor of methylphenidate treatment response in korean children with attention deficit hyperactivity disorder. Yonsei Med J. 2009 Oct 31;50(5):650-5. doi: 10.3349/ymj.2009.50.5.650. Epub 2009 Oct 21.
PubMed 19881968Kim H, Heo HI, Kim DH, Ko IG, Lee SS, Kim SE, Kim BK, Kim TW, Ji ES, Kim JD, Shin MS, Choi YW, Kim CJ. Treadmill exercise and methylphenidate ameliorate symptoms of attention deficit/hyperactivity disorder through enhancing dopamine synthesis and brain-derived neurotrophic factor expression in spontaneous hypertensive rats. Neurosci Lett. 2011 Oct 17;504(1):35-9. doi: 10.1016/j.neulet.2011.08.052. Epub 2011 Aug 31.
PubMed 21907264Karpuz D, Hallioglu O, Toros F, Tasdelen B. The effect of metilpheniydate, risperidone and combination therapy on ECG in children with attention-deficit hyperactivity disorder. J Electrocardiol. 2017 Jul-Aug;50(4):410-415. doi: 10.1016/j.jelectrocard.2017.02.012. Epub 2017 Feb 20.
PubMed 28274540Jacobi-Polishook T, Shorer Z, Melzer I. The effect of methylphenidate on postural stability under single and dual task conditions in children with attention deficit hyperactivity disorder - a double blind randomized control trial. J Neurol Sci. 2009 May 15;280(1-2):15-21. doi: 10.1016/j.jns.2009.01.007. Epub 2009 Feb 13.
PubMed 19217632Huang YS, Wang LJ, Chen CK. Long-term neurocognitive effects of methylphenidate in patients with attention deficit hyperactivity disorder, even at drug-free status. BMC Psychiatry. 2012 Nov 9;12:194. doi: 10.1186/1471-244X-12-194.
PubMed 23140464Guskiewicz KM. Balance assessment in the management of sport-related concussion. Clin Sports Med. 2011 Jan;30(1):89-102, ix. doi: 10.1016/j.csm.2010.09.004.
PubMed 21074084