Effects of Caffeine Consumption on Attention Deficit Hyperactivity Disorder (ADHD) Treatment: A Systematic Review of Animal Studies
2. Materials and Methods
2.1. Search Strategy
2.2. Study Selection Criteria
2.3. Study Selection
2.4. Data Extraction and Analyses
3.1. Study Selection
3.1.1. Species, Animal Model, Sex, and Treatment
3.1.2. Animal Models of ADHD
3.1.3. Behavioral Tests
3.2. Study Outcomes
Attention and Behavioral Flexibility
3.2.2. Hyperactivity and Impulsivity
3.2.3. Learning and Memory
Spatial Short-Term Memory
3.2.4. Olfactory Discrimination
3.2.5. Blood Pressure
3.2.6. Body Weight
Brain Levels of Synaptosomal-Associated Protein-25
Brain Levels of Syntaxin
Brain Levels of Serotonin
Brain Levels of Dopamine
Dopamine Transporter Density
AdenosineA2A Receptor Density
Colocalization of Dopamine Transporter and Adenosine A2A Receptors
Brain-Derived Neurotrophic Factor
Neuronal Development In Vitro
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Species, Strain, Sex|
& Sample (n)
|Animal Model||Age||Independent Variables||Caffeine|
Type of Stress
|Dependent Variables||Main Results|
|Szczepanik et al., 2016||Mice|
|Genetic (LDLr)||3 months|
(total distance travelled)
(time in the center)
(visual inspection of
the occupation plot)
|- LDLr mice travelled greater distances than the C57BI/6 wild type mice during the 5 min period of analysis.|
- Caffeine treatment induced a renormalization effect in 8 month-old mouse locomotion.
- Caffeine treatment was unable to modify the hyperlocomotion observed in 3 month-old LDLr mice.
- All animal groups spent a similar amount of time in the center of an open field.
- Similar exploratory behavior between groups.
et al., 2007
(LE or CD)
omissions, premature and
perseverative responses, choice
and magazine latency)
|- Caffeine, SCH 412348 and KW-6002 augmented time reaction in LE and CD, without effect on accuracy.|
- Effects of SCH 412348 were at doses that were not overtly psychostimulatory.
- CGS-21680 reduced speed reaction and augmented omissions. A CGS-21680 lower dose reduced the increased premature response caused by amphetamine.
- Caffeine’s attentional-enhancing effects were facilitated through A2A receptor blockade. Selective A2A receptor antagonists could be included as a potential therapy for ADHD.
et al., 2019
|Not used||4 months||Treatment|
|Conditioned learning ability (average swimming speed,|
intergroup freezing, maximum speed, time spent in each area,
latency to enter each area)
|- 0 and 10 mg/L caffeine groups spent most of the time close to the target.|
- 10 mg caffeine group had the shortest latency to reach the target.
- 0 and 10 mg/L caffeine groups increased the average speed and distance travelled.
- Caffeine exposure at low doses seems to enhance visual cue discrimination and zebrafish performance.
et al., 2005
|Genetic (SHR)||3 months||Treatment|
(WKY or SHR)
|Water maze task||Spatial learning|
Mean arterial pressure
|- SHR needed a larger amount of trials during the training session to learn the spatial information, although a similar profile to that of WKY rats during the test session, showing a selective spatial learning deficit.|
- Caffeine’s pre-training administration enhanced SHRs’ spatial learning deficit.
- Caffeine’s post-training administration did not enhance SHRs’ test performance, although it improved WKY rats’ memory retention.
- Mean blood pressure was not altered by caffeine.
et al., 2009
|Genetic (SHR)||3 months||Treatment|
(WKY or SHR)
Mean arterial pressure
|- SHR only discriminated between the most structurally distinct pairs of objects.|
- Pre-training administration of MPD, caffeine, the selective adenosine receptor antagonists DPCPX and ZM241385, or the association of ineffective doses of DPCPX and ZM241385, improved the performance of SHR in the object-recognition task.
- The administration of the same doses of MPD and caffeine did not significantly alter the mean arterial pressure of either WKYs or SHRs.
et al., 2010
(WKY or SHR)
Chronic treatment (14 days)
|- WKY rats distinguished all the items. SHRs were unable to distinguish pairs of items with slight structural alterations.|
- Caffeine or MPD chronic treatment enhanced SHR item-recognition deficits. The same treatments impaired the adult WKY rats’ short-term object recognition ability.
- Effects were independent of variations in locomotion, arterial blood pressure, and body weight.
et al., 2011
(number of arms crossed)
(total number of arms
walked, and total number
of arms walked until
one was repeated)
|- Caffeine treatment significantly improved 6-OHDA lesioned rats’ attention deficit.|
- After caffeine consumption, no changes were found in motor activity.
et al., 2013
|Genetic (SHR)||24 days||Treatment|
(WKY or SHR)
for 21 days)
behavior; Y maze;
locomotion -related behavior
(regressive and never-
reinforced errors, perseverative
errors, total number of trials
required before reaching 10
correct consecutive choices)
Locomotion and anxiety
(number of peripheral squares crossed, number of central
squares crossed, percentage of
(number of entries; time spent
per arm; random exploration)
|- SHRs were hyperactive and showed poorer performance in the attentional set-shifting and Y-maze paradigms, displayed increased dopamine transporter density, and increased dopamine uptake in frontocortical and striatal terminals.|
- Chronic caffeine treatment improved memory and attention deficits, and normalized dopaminergic function in SHR.
- First indication of adenosine A2A receptors (A2AR) in nerve terminals in frontal cortex.
- First evidence that A2AR density is improved in SHR.
et al., 2013
modified Y-maze test; novel object
recognition test; fear-conditioning test
(entering & drinking latency)
(duration of wrestling)
(time spent in the new arm;
total time exploring objects)
|- SI rats showed deficits in spatial attention on the water-finding test. Re-socialized did not reduce deficit in spatial attention. SI effect on spatial attention revealed no difference in gender or correlation with aggressive behaviour.|
- SI impaired conditional and contextual fear memory.
- MPD and caffeine enhanced deficits in SI-induced latent learning in a manner that was reversible with cholinergic but not dopaminergic antagonists.
et al., 2018
|Genetic (SHR)||15 days|
(caffeine/water, caffeine/caffeine or water)
(WKY or SHR)
Until PND 28
|Open-field test; Novel object|
Y maze task
|Open field test|
(travel distance periphery)
(total travelled distance in the open field)
Spatial recognition- Y maze and object recognition
(exploration, discrimination ratio, number of entries, time spent in novel arm, total number of entries
in three arms)
|- Adolescent SHR from both sexes displayed hyperlocomotion, recognition, and spatial memory disturbances. Females displayed a lack of habituation and deteriorated spatial memory.|
- Caffeine was effective at improving recognition memory damage in both sexes.
- Spatial memory was improved only in female SHRs.
- Female SHRs displayed impaired hyperlocomotion following caffeine treatment.
- SHRs of both sexes presented increases in BDNF, truncated and phospho-TrkB receptors, and phospho-CREB levels in the hippocampus.
- Caffeine normalized BDNF in males and truncated TrkB receptor in both sexes.
et al., 2019
|Genetic (SHR)||60/65 days|
(WIN, AM251, caffeine or
(WKY or SHR)
|2 or 5 mg/kg|
Chronic treatment (21 days)
delay of reward;
(tolerance to delay of
|- WIN treatment decreased large reward choices and AM251 treatment increased large reward choices in SHR.|
- Acute caffeine pretreatment blocked WIN effects.
- Chronic caffeine treatment increased the impulsive phenotype and potentiated the WIN effects.
- Cannabinoid and adenosine receptors modulate impulsive behavior in SHR.
et al., 2020
|Genetic (SHR)||In vitro||Treatment|
(WKY or SHR)
(singling, neurite branching)
|- SHR neurons displayed less neurite branching, shorter maximal neurite length and decreased axonal outgrowth.|
- Caffeine recovered neurite branching and elongation from SHR neurons via PKA and PI3K signaling,
- A2AR agonist (CGS 21680) promoted more neurite branching via PKA signaling.
- The selective A2AR antagonist (SCH 58261) was efficient at recovering axonal outgrowth from SHR neurons through PI3K and not PKA signaling.
et al., 2020
|Genetic (SHR)||30 days|
(WKY or SHR)
discrimination; Open field;
(time spent in compartments, numbers of crossings)
(total distance, time spent in
the central zone)
(total time spent exploring the
objects, discrimination index)
Working and procedural
memories (escape latency)
|- SHR showed olfactory and short-term recognition memory deficiencies from adolescence to adulthood, accompanied by lower prefrontal cortex and hippocampus SNAP-25 levels.|
- Caffeine and physical exercise during adolescence or adulthood repaired the olfactory discrimination ability and enhanced short-term recognition memory in SHRs.
- Caffeine consumption and physical exercise during adolescence augmented hippocampus and prefrontal cortex SNAP-25, syntaxin, and serotonin levels, as well as SHRs’ striatal dopamine levels.
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Vázquez, J.C.; Martin de la Torre, O.; López Palomé, J.; Redolar-Ripoll, D. Effects of Caffeine Consumption on Attention Deficit Hyperactivity Disorder (ADHD) Treatment: A Systematic Review of Animal Studies. Nutrients 2022, 14, 739. https://doi.org/10.3390/nu14040739
Vázquez JC, Martin de la Torre O, López Palomé J, Redolar-Ripoll D. Effects of Caffeine Consumption on Attention Deficit Hyperactivity Disorder (ADHD) Treatment: A Systematic Review of Animal Studies. Nutrients. 2022; 14(4):739. https://doi.org/10.3390/nu14040739Chicago/Turabian Style
Vázquez, Javier C., Ona Martin de la Torre, Júdit López Palomé, and Diego Redolar-Ripoll. 2022. "Effects of Caffeine Consumption on Attention Deficit Hyperactivity Disorder (ADHD) Treatment: A Systematic Review of Animal Studies" Nutrients 14, no. 4: 739. https://doi.org/10.3390/nu14040739