**1. Introduction**

Attention Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed and treated mental disorder during childhood [1] and it is increasingly diagnosed and treated in during adulthood [2]. ADHD is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity, persisting no less than six months, that is inconsistent with developmental level and has negative impact in at least two settings (academic, occupational or social) [3]. Inattention refers to important difficulties in sustaining attention to tasks that do not deliver a high level of stimulation or regular rewards, distractibility, and difficulties with organisation. Hyperactivity refers to disproportionate motor activity and difficulties with remaining still, most manifest in structured situations that involve behavioral self-control. Finally, impulsivity is a propensity to behave in response to immediate stimuli, without consideration of the risks and consequences [4]. Specific manifestations vary across individuals, and may change over the course of development. Depending on the symptoms presented, three different types of ADHD can be diagnosed: predominantly inattentive presentation, predominantly hyperactive-impulsive presentation, or combined presentation [3,4]. Although ADHD onset occurs during childhood and it often persists into adulthood, there is an important knowledge gap concerning

**Citation:** 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

Academic Editors: Edward D. Barker and Marilyn Cornelis

Received: 23 December 2021 Accepted: 8 February 2022 Published: 10 February 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

ADHD lifespan aspects [5]. Population surveys suggest that ADHD occurs in most cultures in about 5% of children and about 2.5% of adults [6] and, as of 2019, it was estimated to affect 84.7 million people worldwide [7]. ADHD management recommendations depend on the country [8–10] and usually include psychotherapy (essentially Cognitive Behavior Therapy, CBT), lifestyle changes and medications [11]. ADHD medication treatment, however, has been historically considered controversial [12], particularly due to its side effects [13–15]. In the face of these controversies and high rates of diagnosis, alternative/complementary pharmacological therapeutic approaches for ADHD are needed.

Although larger ADHD models containing supplementary pathways have been suggested [16,17], it is widely accepted that ADHD impairments, including selective and sustained attention, impulsivity, and motor activity, arise from abnormalities in different circuits involving the prefrontal cortex [18]: sustained attention is modulated by a cortico-striato-thalamocortical (CSTC) loop that comprises the dorsolateral prefrontal cortex (DLPFC) projecting to the striatal complex. Selective attention is modulated by a cortico-striato-thalamo-cortical (CSTC) loop ascending from the dorsal anterior cingulate cortex (dACC) and projecting to the striatal complex, followed by the thalamus, and back to the dACC. Impulsivity is related to a cortico-striato-thalamocortical (CSTC) loop that contains the orbitofrontal cortex (OFC), the striatal complex, and the thalamus. Finally, motor activity, including hyperactivity and psychomotor agitation or retardation, can be modulated by a cortico-striato-thalamo-cortical (CSTC) loop arising from the prefrontal motor cortex to the lateral striatum to the thalamus and back to the prefrontal motor cortex. ADHD patients cannot activate prefrontal cortex areas in an appropriate manner when responding to cognitive tasks requiring attention and executive control, and show a dysfunction in reward and motivation, hindering cognitive control of behaviour [19,20]. Children diagnosed with ADHD, in this regard, need stronger incentives to adapt their behaviour [21], showing impaired responses to partial schedules of reinforcement and difficulties in delaying gratification [22,23].

In ADHD, inefficient information processing and arousal-related behaviours are hypothetically caused by imbalances mainly in the dopamine (DA) and norepinephrine (NE) circuits [24,25] and the serotonin (5-HT), glutamate (GLU), and acetylcholine (ACh) pathways within these areas of the brain [26–28].

Different genes are associated with the disorder, including the serotonin transporter (SERT), the synaptosomal-associated protein (SNAP-25), and the brain-derived neurotrophic factor (BDNF) [29,30], while some genes directly affect DA neurotransmission, including the DA transporter (DAT) or the DA receptor 4 (DRD4) [31,32]. In this respect, the ventral tegmental area (VTA) and locus coeruleus (LC) neurons have different targets, although their efferent fibers converge into the PFC: DA is released into the nucleus accumbens (NAcc), facilitating reward; NE is released in different posterior cortical areas, optimizing the organism reaction to significant stimuli; and both organic compounds are released into the PFC, enhancing working memory and attention in the face of significant stimuli [33].

Animal studies have provided insights into the pathological and neurochemical basis of ADHD through different types of animal model (see Figure 1) [34]. Among these, the spontaneously hypertensive rat (SHR) is considered an excellent and validated hyperactive model to study ADHD. Concerning its behavioral profile, SHR presents anomalies in DA neurotransmission [35] and, importantly, in adenosine neurotransmission [36].

**Figure 1.** Animal models of Attention Deficit Hyperactivity Disorder. Key for abbreviations used: SHR: spontaneously hypertensive rat, low-density lipoprotein receptor, SI: social isolated, 6-OHDA: 6-hydroxy-dopamine, ADHD: Attention Deficit Hyperactivity Disorder.

Caffeine, in this respect, is an adenosine A1 and A2A receptor antagonist controlling synaptic plasticity [37]. These receptors are functionally paired with certain postsynaptic DA receptors, such as D2 receptors, where DA binds and has a stimulatory effect. When adenosine binds to its receptors, this causes reduced sensitivity of D2 receptors. Antagonism of adenosine receptors by caffeine prevents adenosine from binding, enhancing dopaminergic actions [18,24]. In addition to these dopaminergic effects, it has been shown that caffeine also produces secondary effects on ACh and NE [37–39]. Moreover, caffeine's effects on the non-selective antagonism of adenosine receptors also generate vasoconstriction in the nervous system. In this respect, it has been shown that caffeine modifies the blood perfusion signal, measured by fMRI, due to its neural and vascular effects, depending on the cerebral distribution of its receptors [40]. Similarly, the effect that caffeine may have at the cognitive level could depend on its regional effects on vascular response [41].

Nevertheless, the potential of caffeine consumption as a treatment for ADHD remains largely controversial, with studies showing efficacy in relieving ADHD-related symptoms [42], and studies failing to find superior effects when compared to first-line ADHD medication [43]. Beyond ADHD, there is an existing correlation between the daily consumption of moderate doses of caffeine and related benefits in different psychiatric disorders linked with adenosine A2A receptor blockade controlling synaptic plasticity [44], mainly at the glutamatergic synapses [45]. Moreover, regular coffee consumption improves children's performance in comparison to decaffeinated coffee or placebo [46]. However, some studies have reported that caffeine consumption improvement is not significantly superior to placebo [47] or methylphenidate (MPD) [48], while hyperactivity has been strongly associated with higher coffee consumption among adolescents [49].

The number of publications that study the potential effects of caffeine consumption on ADHD treatment has accumulated since 1975 (see Figure 2) and, over the last few years, caffeine has been used in ADHD research in the context of animal models. Surprisingly, an updated evidence-based systematic review on the effects of caffeine on ADHD-like symptoms in animal studies is lacking.

**Figure 2.** Caffeine/Attention Deficit Hyperactivity Disorder-related articles since 1975 (Source: MEDLINE).

Consequently, to provide insight and value at the preclinical level, we sought to produce a comprehensive compilation and systematically review all the relevant scientific publications that make reference to the underlying effects of caffeine intake on treating ADHD-like symptoms in animal studies.
