The Pharmacology of ADHD

This review from Stephen V. Faraone on the pharmacology of Methylphenidate and Amphetamines provides an in-depth understanding on the pharmacology of ADHD medication.

(Faraone, 2018)


Psychostimulants, including amphetamines and methylphenidate, are first-line pharmacotherapies for individuals with attention-deficit/hyperactivity disorder (ADHD).

This review aims to educate physicians regarding differences in pharmacology and mechanisms of action between amphetamine and methylphenidate, thus enhancing physician understanding of psychostimulants and their use in managing individuals with ADHD who may have comorbid psychiatric conditions.

A systematic literature review of PubMed was conducted in April 2017, focusing on cellular- and brain system–level effects of amphetamine and methylphenidate.

The primary pharmacologic effect of both amphetamine and methylphenidate is to increase central dopamine and norepinephrine activity, which impacts executive and attentional function.

Amphetamine actions include dopamine and norepinephrine transporter inhibition, vesicular monoamine transporter 2 (VMAT-2) inhibition, and monoamine oxidase activity inhibition.

Methylphenidate actions include dopamine and norepinephrine transporter inhibition, agonist activity at the serotonin type 1A receptor, and redistribution of the VMAT-2.

There is also evidence for interactions with glutamate and opioid systems.

Clinical implications of these actions in individuals with ADHD with comorbid depression, anxiety, substance use disorder, and sleep disturbances are discussed.


Attention-deficit/hyperactivity disorder (ADHD) was initially identified in children (Lahey et al., 1994) but is now understood to persist into adulthood in about two thirds of cases (Barkley et al., 2002Weiss et al., 1985Faraone et al., 2006).

In a 2007 meta-analysis that included more than 100 studies, the estimated worldwide prevalence of ADHD in individuals <18 years old was 5.29% (Polanczyk et al., 2007).

The estimated prevalence in adults was 4.4% in a national survey in the United States (Kessler et al., 2006), 3.4% in a 10-nation survey (Fayyad et al., 2007), and 2.5% in a meta-regression analysis of 6 studies (Simon et al., 2009).

A large body of evidence suggests that multiple neurotransmitters and brain structures play a role in ADHD (Purper-Ouakil et al., 2011Cortese, 2012Faraone et al., 2015).

Although a substantial amount of research has focused on dopamine (DA) and norepinephrine (NE), ADHD has also been linked to dysfunction in serotonin (5hydroxytryptamine [5-HT]), acetylcholine (ACH), opioid, and glutamate (GLU) pathways (Cortese, 2012Maltezos et al., 2014Blum et al., 2008Potter et al., 2014Elia et al., 2011).

The alterations in these neurotransmitter systems affect the function of brain structures that moderate executive functionworking memory, emotional regulation, and reward processing (Fig. 1) (Faraone et al., 2015).

Figure 1

(a) The cortical regions (lateral view) of the brain have a role in attention-deficit/hyperactivity disorder (ADHD). The dorsolateral prefrontal cortex is linked to working memory, theventromedial prefrontal cortex to complex decision making and strategic planning, and the parietal cortex to orientation of attention.

(b) ADHD involves the subcortical structures (medial view) of the brain. The ventral anterior cingulate cortex and the dorsal anterior cingulate cortex subserve affective and cognitive components of executive control. Together with the basal ganglia (comprising the nucleus accumbens, caudate nucleus, and putamen), they form the frontostriatal circuit. Neuroimaging studies show structural and functional abnormalities in all of these structures in patients with ADHD, extending into the amygdala and cerebellum.

(c) Neurotransmitter circuits in the brain are involved in ADHD. The dopamine
system plays an important part in planning and initiation of motor responses, activation, switching, reaction to novelty, and processing of reward. The noradrenergic system influences arousal modulation, signal-to-noise ratios in cortical areas, state-dependent cognitive processes, and cognitive preparation of urgent stimuli.

(d) Executive control networks are affected in patients with ADHD. The executive control and cortico-cerebellar networks coordinate executive functioning (i.e., planning, goal-directed behavior, inhibition, working memory, and the flexible adaptation to context). These networks are underactivated and have lower internal functional connectivity in individuals with ADHD compared with individuals without the disorder.

(e) ADHD involves the reward network. The ventromedial prefrontal cortex, orbitofrontal cortex, and ventral striatum are at the center of the brain network that responds to anticipation and receipt of reward. Other structures involved are the thalamus, the amygdala, and the cell bodies of dopaminergic neurons in the substantia nigra, which, as indicated by the arrows, interact in a complex manner. Behavioral and neural responses to reward are abnormal in ADHD.

(f) The alerting network is impaired in ADHD. The frontal and parietal cortical areas and the thalamus intensively interact in the alerting network (indicated by the arrows), which supports attentional functioning and is weaker in individuals with ADHD than in controls.

(g) ADHD involves the default-mode network (DMN). The DMN consists of the medial prefrontal cortex and the posterior cingulate cortex (medial view) as well as the lateral
parietal cortex and the medial temporal lobe (lateral view). DMN fluctuations are 180° out of phase with fluctuations in networks that become activated during externally oriented tasks, presumably reflecting competition between opposing processes for processing resources. Negative correlations between the DMN and the frontoparietal control network are weaker in patients with ADHD than in people who do not have the disorder.

Individuals with ADHD are often diagnosed with additional psychiatric comorbidities, including anxiety, mood, substance use, sleep disturbances, and antisocial personality disorders (Mao and Findling, 2014Kooij et al., 2012Konofal et al., 2010).

Importantly, the neurobiological substrates that mediate behaviors associated with ADHD share commonalities to some extent with those involved in these comorbid disorders (Farb and Ratner, 2014Sternat and Katzman, 2016Schwartz and Kilduff, 2015).

Genetic studies have also identified shared genetic risk factors between ADHD and associated comorbid disorders (Sharp et al., 2014Carey et al., 2016). As such, comorbidities need to be taken into account when considering pharmacotherapy in an individual with ADHD.

Although stimulants (including amphetamine [AMP]–based and methylphenidate [MPH]–based agents) and nonstimulants (e.g., atomoxetineclonidine, and guanfacine) are approved for the treatment of ADHD (Thomas et al., 2013), stimulants are considered first-line therapy in children, adolescents, and adults with ADHD because of their greater efficacy (Atkinson and Hollis, 2010Subcommittee on Attention-Deficit/Hyperactivity Disorder et al., 2011Rostain, 2008Bolea-Alamanac et al., 2014Kooij et al., 2010Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA), 2011).

AMP and MPH have been shown to exhibit comparable efficacy in 2 meta-analyses (Faraone and Glatt, 2010Catala-Lopez et al., 2017), with other analyses reporting that AMP has moderately greater effects than MPH (Faraone and Buitelaar, 2010Joseph et al., 2017Stuhec et al., 2015).

The tolerability and safety profiles of AMP and MPH in terms of adverse events, treatment discontinuation, and cardiovascular effects are also generally comparable (Duong et al., 2012Vaughan and Kratochvil, 2012Martinez-Raga et al., 2017), although weight loss and insomnia have been reported to be more common with AMP than with MPH (Catala-Lopez et al., 2017).

Additional work is planned that will further compare the efficacy, tolerability, and safety profiles of different pharmacologic interventions in children, adolescents, and adults with ADHD (Cortese et al., 2017).

Although increased synaptic availability of DA and NE is a key result of exposure to both AMP and MPH (dela Pena et al., 2015Zhu and Reith, 2008), differences in the specific cellular mechanisms of action of AMP and MPH may influence their effects on the neurobiological substrates of ADHD and response to treatment in individuals with ADHD as well as their effects on common comorbidities, such as depression and anxiety.

The objective of this review is to educate physicians about the mechanisms of action of AMP and MPH and the implications of these actions on the management of ADHD and its comorbidities.

To achieve this goal, a systematic review of the published literature was conducted to obtain articles describing the cellular- and brain system–level effects of AMP and MPH.

The results of relevant studies are described and interpreted in the context of the treatment of ADHD and in light of the comorbidities associated with ADHD.

The Pharmacology of Psychostimulants


The main mechanism of action of AMP is to increase synaptic extracellular DA and NE levels (Avelar et al., 2013Covey et al., 2013Finnema et al., 2015Floor and Meng, 1996Jedema et al., 2014Joyce et al., 2007Kuczenski and Segal, 1997May et al., 1988Mukherjee et al., 1997Pum et al., 2007Ren et al., 2009Schiffer et al., 2006Xiao and Becker, 1998Young et al., 2011Wall et al., 1995).

This effect is mediated by inhibition of DA transporters (DAT) and NE transporters (NET) (Avelar et al., 2013Covey et al., 2013Easton et al., 2007bb), which reduces the reuptake of these molecules from the synapse.

In wild-type mice, AMP initially increases surface trafficking of DAT and DA uptake, but continued AMP exposure results in decreased surface expression of the DAT and decreases in DA uptake (Chen et al., 2009).

In a dose-dependent and region-specific manner, AMP also increases vesicular DA release via inhibition of the vesicular monoamine transporter 2 (VMAT-2), which releases DA from vesicular storage, and the concomitant release of cytosolic DA via reverse transport by the DAT (Easton et al., 2007bb; Riddle et al., 2007Sulzer et al., 1995).

Furthermore, AMP inhibits monoamine oxidase (MAO) activity (Miller et al., 1980Robinson, 1985), which decreases cytosolic monoamine breakdown.

A wide array of studies using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) have demonstrated that AMP produced reductions in the binding potential of ligands for DA receptors (al-Tikriti et al., 1994Carson et al., 1997Castner et al., 2000Chou et al., 2000Dewey et al., 1993Drevets et al., 1999Gallezot et al., 2014Ginovart et al., 1999Howlett and Nahorski, 1979Laruelle et al., 1997Le Masurier et al., 2004Lind et al., 2005Mukherjee et al., 1997Pedersen et al., 2007Saelens et al., 1980Schiffer et al., 2006Seneca et al., 2006Sun et al., 2003Tomic et al., 1997Tomic and Joksimovic, 2000van Berckel et al., 2006) and NE receptors (Finnema et al., 2015Landau et al., 2012), which is an indirect indicator of increased competition for binding sites resulting from increased extracellular DA or NE.

The striatum, which contains most of the DATs in the brain (Volkow et al., 1996bb; Fischman et al., 1997), appears to be a principal site of action of AMP (Avelar et al., 2013Kilbourn and Domino, 2011), but direct effects in the cortex and the ventral tegmental area have also been reported (Pum et al., 2007Ren et al., 2009Schwarz et al., 2007bb).

The effects of AMP extend to and are modulated by other neurotransmitter systems (Choe et al., 2002Duttaroy et al., 1992Inderbitzin et al., 1997Konradi et al., 1996Liu et al., 2003Pum et al., 2007Quelch et al., 2014Ritz and Kuhar, 1989Shaffer et al., 2010Smith et al., 2005Yin et al., 2010Yu et al., 2003), including ACH, 5-HT, opioid, and GLU, either directly through enhanced release from presynaptic terminals or via downstream effects.

Reductions in ligand binding in PET (Boileau et al., 2007Buckholtz et al., 2010Cardenas et al., 2004Cropley et al., 2008Drevets et al., 2001Leyton et al., 20022004Martinez et al., 2003Narendran et al., 20092010Oswald et al., 20052015Riccardi et al., 2006aa,b, 2011Shotbolt et al., 2012Slifstein et al., 2010Wand et al., 2007Willeit et al., 2008Woodward et al., 2011) and SPECT (Kegeles et al., 1999Laruelle et al., 1995Laruelle and Innis, 1996Schouw et al., 2013) studies in healthy humans indicate that AMP increases DA release across multiple brain regions, including the dorsal and ventral striatum, substantia nigra, and regions of the cortex.

AMP also has been shown to alter regional CBF to areas of the brain with DA innervation, including the striatum, anterior cingulate cortex, prefrontal and parietal cortex, inferior orbital cortex, thalamuscerebellum, and amygdala (Devous et al., 2001Rose et al., 2006Schouw et al., 2013Vollenweider et al., 1998Wolkin et al., 1987).

The effects of AMP on regional CBF appear to be dependent on the dose, with lower doses decreasing rates of blood flow in the frontal and temporal cortices and in the striatum (Wolkin et al., 1987) and higher doses increasing blood flow in the anterior cingulate cortex, caudate nucleusputamen, and thalamus (Vollenweider et al., 1998).

In fMRI studies in healthy adults, AMP increased BOLD signal variability (Garrett et al., 2015) and exerted an “equalizing” effect on ventral striatum activity during incentive processing (Knutson et al., 2004). In addition, AMP was shown to strengthen amygdalar responses during the processing of angry and fearful facial expressions (Hariri et al., 2002).

Changes in neuronal activity have been shown to correlate with various behavioral traits (Buckholtz et al., 2010Drevets et al., 2001Leyton et al., 2002Woodward et al., 2011).

In PET studies, changes in the binding potential of [11C]raclopride (a D2 receptor antagonist) in regions of the ventral striatum of healthy adults associated with AMP binding have been reported to be negatively correlated with changes in AMP-associated euphoria (Drevets et al., 2001) and with increases in drug wanting and novelty seeking (Leyton et al., 2002).


The direct effects of MPH include inhibition of the DAT and NET (Dresel et al., 1999Federici et al., 2005Gatley et al., 1996Markowitz et al., 2006Nikolaus et al., 2007Wall et al., 1995), an affinity for and agonist activity at the 5-HT1A receptor (Markowitz et al., 2009Markowitz et al., 2006), and redistribution of VMAT-2 (Riddle et al., 2007Sandoval et al., 2002).

As a consequence of these interactions, MPH elevates extracellular DA and NE levels (Easton et al., 2007bb; Kuczenski and Segal, 1997Schiffer et al., 2006Young et al., 2011).

The enhanced efflux of DA and NE associated with MPH exposure results in increased availability of DA and NE to bind to their respective transporters (i.e., the DAT or NET) or to DA or NE receptors, as evidenced by reductions in ligand binding in PET and SPECT studies (Ding et al., 1997Dresel et al., 1999Gatley et al., 1999Nikolaus et al., 2005Nikolaus et al., 2007, 2011; Volkow et al., 1999a).

Methylphenidate has also been shown to increase striatal DA availability, as measured by reductions in ligand binding potential in PET studies (Booij et al., 1997Clatworthy et al., 2009Montgomery et al., 2007Spencer et al., 20062010Udo de Haes et al., 2005Volkow et al., 199420012004Wang et al., 1999), with evidence to indicate that this effect is related to binding to the DAT (Volkow et al., 1998Volkow et al., 1999aVolkow et al., 1999b2002a).

MPH-induced reductions in striatal [11C]raclopride binding were associated with MPH-induced changes in euphoria and anxiety and were correlated to age (Udo de Haes et al., 2005Volkow et al., 1994).

In addition, NE systems have been implicated as key targets for MPH, with MPH dose-dependently blocking the NET in the thalamus and other NET-rich regions; the estimated occupancy of the NET at therapeutic doses of 0.35–0.55 mg/kg MPH is 70%–80% (Hannestad et al., 2010).

Assessments of functional activity using fMRI have provided evidence for the widespread functional effects of MPH (Costa et al., 2013Moeller et al., 2014Mueller et al., 2014Ramaekers et al., 2013Schlosser et al., 2009Tomasi et al., 2011).

Using fMRI, it has been shown that MPH increases activation of the parietal and prefrontal cortices and increases deactivation of the insula and posterior cingulate cortex during visual attention and working memory tasks (Tomasi et al., 2011).

Another fMRI study reported MPH-induced activation in the putamen during a go/no-go task when a response inhibition error occurred but not when a response was successfully inhibited (Costa et al., 2013), suggesting that the effects of MPH are context dependent.

Furthermore, MPH exposure altered connectivity strength across various cortical and subcortical networks (Mueller et al., 2014) and shifted brain activation under conditions of uncertainty to higher levels of activation in left and right parahippocampal regions and cerebellar regions (Schlosser et al., 2009).

Lastly, MPH-associated decreases in task-related errors on the Stroop color-word task were associated with concurrent decreases in anterior cingulate cortex activity (Moeller et al., 2014).

MPH has also been shown to reduce regional CBF in the prefrontal cortex and increase regional CBF in the thalamus and precentral gyrus (Schweitzer et al., 2004).

In another study that used functional near-infrared spectroscopy, MPH-associated improvements in the performance of a working memory task corresponded with decreased oxy-hemoglobin levels in the right lateral prefrontal cortex, which is a surrogate for decreased neural activation (Ramasubbu et al., 2012).

Structural alterations in ADHD

meta-analysis of imaging data from individuals with ADHD across all age groups revealed altered white matter integrity in diverse brain areas, including the striatum and the frontal, temporal, and parietal lobes (van Ewijk et al., 2012).

In a meta-analysis of imaging data from children and adults (Nakao et al., 2011), global gray matter volume was significantly smaller in those with ADHD, especially in basal ganglia structures integral to executive function.

In adults with ADHD, reduced gray matter volume in the caudate and parts of the dorsolateral prefrontal cortex, inferior parietal lobe, anterior cingulate cortexputamen, and cerebellum were observed; increased volume was noted in other parts of the dorsolateral prefrontal cortex and inferior parietal lobe (Seidman et al., 2011).

A meta-analysis of 1713 persons with ADHD and 1529 controls found volumetric reductions in the accumbens, amygdala, caudate, hippocampus, and putamen (Hoogman et al., 2017).

Functional alterations in ADHD

A meta-analysis of imaging data focusing specifically on timing function, which is important for impulsiveness in ADHD, showed consistent deficits in the left inferior prefrontal, parietal, and cerebellar regions of individuals with ADHD (Hart et al., 2012).

A meta-analysis of 24 task-related fMRI studies coupled with functional decoding based on the BrainMap database reported hypoactivation in the left putamen, inferior frontal gyrus, temporal pole, and right caudate of individuals with ADHD (Cortese et al., 2016).

When examining these deficits in regard to the BrainMap database, it was suggested that individuals with ADHD may exhibit deficits in the cognitive aspects of music, perception and audition, speech and language, and executive function (Cortese et al., 2016).

Co-occurring psychiatric conditions and ADHD

Attention-deficit/hyperactivity disorder is often associated with comorbid psychiatric disorders (Mao and Findling, 2014Kooij et al., 2012Konofal et al., 2010), such as anxiety and mood disorders.

Importantly, the same brain regions and neurotransmitter systems that underlie ADHD are also implicated in the psychiatric disorders that are frequently comorbid with ADHD (Farb and Ratner, 2014Sternat and Katzman, 2016Schwartz and Kilduff, 2015).

Thus, it is important to understand how ADHD therapies might influence psychiatric comorbidities.

Anxiety disorders

In healthy human volunteers, AMP has been reported to potentiate amygdalar activity in response to the processing of angry and fearful facial expressions (Hariri et al., 2002). These data provide a potential neurobiologic basis for the anxiogenic effects of AMP (Hariri et al., 2002). However, it has been theorized that stimulant-associated augmentation of serotonergic drive could ameliorate the comorbid anxiety associated with ADHD (Heal et al., 2013). In practice, the effects of stimulants on anxiety can be complex, with acute administration of MPH reducing anxiety in adults and chronic treatment during early life increasing anxiety during adulthood (Sanchez-Perez et al., 2012).

Depressive disorders

Psychostimulants have been used in the treatment of major depressive disorder (MDD) since the early 1950s, when the use of MPH was first examined for MDD (Robin and Wiseberg, 1958). The rationale for examining the potential utility of psychostimulants in depressive disorders is based on preclinical and clinical evidence implicating DA in depressive symptomatology (Treadway and Zald, 2011). However, the rapid onset of action of psychostimulants suggests the mechanisms by which they may influence depressive symptoms is likely to differ from that of antidepressants (Malhi et al., 2016).

Substance use disorders

The neurobiology of reward and addiction and the key role of mesolimbic DA systems have been described in great detail (Volkow and Morales, 2015Koob, 2006). Although associations have been made between ADHD and substance abuse, their relationship is complex. Several reviews have emphasized that substance use disorders can be comorbid with ADHD (Mao and Findling, 2014Kooij et al., 2012).

For example, in a study of 208 adults diagnosed with ADHD and treated with psychostimulants as youths, the relative risk of having a diagnosis of substance use disorder or alcohol abuse, respectively, compared with the general population was 7.7 or 5.2 (Dalsgaard et al., 2014).

Furthermore, a 2012 review noted that there was evidence for increased rates of substance abuse in individuals with ADHD treated with psychostimulants (Nelson and Galon, 2012). Given the known abuse liability of psychostimulants and data indicating that psychostimulant medications are associated with misuse and diversion (Rabiner et al., 2009Garnier et al., 2010), it is not surprising that psychostimulant medications approved for use in ADHD are schedule II medications with black box warnings for potential drug dependence (Panagiotou et al., 2011).

Some treatment guidelines suggest that nonstimulant alternatives be considered as therapies for ADHD when issues related to abuse and dependence are a concern (Atkinson and Hollis, 2010Bolea-Alamanac et al., 2014Pliszka and AACAP Work Group on Quality Issues, 2007).

Sleep disturbances

The neurobiologic substrates of sleep are diverse and distributed throughout the brain, with monoaminergic systems playing an important role in wakefulness (Schwartz and Kilduff, 2015). Substantial literature exists regarding the sleep disturbances associated with ADHD, which include insomnia, disordered sleep, difficulty falling asleep, sleep apneadaytime somnolence, and increased nocturnal motor activity (see (Konofal et al., 2010Cohen-Zion and Ancoli-Israel, 2004Lecendreux and Cortese, 2007Snitselaar et al., 2017) for reviews).

Evidence suggests that impaired and/or disordered sleep is present in individuals not being treated with psychostimulants (Konofal et al., 2010). For example, in a study of the effects of MPH on sleep in children with ADHD, parents reported that approximately 10% of study participants had sleep problems before starting their medication (Becker et al., 2016).

However, in regard to the reported effects of psychostimulants on sleep in individuals with ADHD, there are some discrepancies. In a meta-analysis of 9 articles, the use of psychostimulant medication was associated with longer sleep latency, worse sleep efficiency, and shorter sleep duration (Kidwell et al., 2015).

A review of the safety and tolerability of ADHD medications noted that insomnia was one of the most commonly reported adverse events associated with psychostimulant treatment (Duong et al., 2012). In contrast, some studies have shown that psychostimulants have no significant negative impact on sleep (Becker et al., 2016Owens et al., 2016Surman and Roth, 2011).

A post hoc analysis of the effects of lisdexamfetamine or SHP465 mixed amphetamine salts in adults with ADHD demonstrated that the proportions of participants exhibiting a worsening of sleep during treatment, as measured by the Pittsburgh Sleep Quality Index, did not differ from that of placebo (Surman and Roth, 2011).

Discrepancies in the effects of stimulants on sleep in individuals with ADHD might be attributable to various factors, including sleep quality prior to treatment, the stimulant formulation, the length of treatment, and the method of sleep assessment (Cohen-Zion and Ancoli-Israel, 2004Becker et al., 2016Kidwell et al., 2015).

For example, in a study of MPH in children with ADHD, 23% of participants without preexisting sleep problems developed sleep problems while taking MPH, whereas 68.5% of those with preexisting sleep problems no longer experienced sleep problems after taking MPH (Becker et al., 2016).


Based on the published literature, the primary pharmacologic effects of both AMP and MPH are related to increased central DA and NE activity in brain regions that include the cortexand striatum. These regions are involved in the regulation of executive and attentional function (Faraone et al., 2015).

In ADHD, dysfunction in the DA and NE systems, which are critical to proper cortical and striatal function, likely account for some of the pathophysiology of ADHD (Cortese, 2012Faraone et al., 2015Arnsten, 2009). Although it is a limitation of the review that the only database searched was PubMed, it is unlikely that important studies were not captured.

It has been speculated that the moderately greater efficacy of AMP-based agents compared with MPH-based agents in ADHD may be related to differences in their molecular actions (Faraone and Buitelaar, 2010), but to date there is no conclusive clinical evidence to support this speculation.

Furthermore, there is no conclusive clinical evidence supporting a prospective choice for an AMP-based agent over an MPH-based agent (or vice versa) based on the mechanisms of action of these drug classes. As such, the current understanding of differences in the mechanisms of action of AMP and MPH has not led to clinical guidelines regarding their use in specific patient populations.

Furthermore, it is possible that differences in the pharmacologic profile between AMP and MPH, in combination with the complexities associated with the etiology of ADHD (Faraone et al., 2015), contribute to individual differences in treatment response to AMP-based agents or MPH-based agents in individuals with ADHD. Interactions among these factors might explain why some patients have a differential response to these drugs.

When contemplating pharmacotherapy for ADHD, in addition to taking into account the potential for adverse cardiovascular outcomes (Westover and Halm, 2012), the presence of comorbid psychiatric disorders should be considered.

Multiple psychiatric comorbidities, including depression and anxiety (Mao and Findling, 2014Kooij et al., 2012), are thought to be mediated in part by shared neurobiological pathways that are also implicated in the pathophysiology of ADHD (Farb and Ratner, 2014Sternat and Katzman, 2016).

As such, the effect of psychostimulant treatment on the symptoms of these disorders and the potential interactions with medications used to treat these disorders need to be considered.


Faraone, S. V. (2018). The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neuroscience and Biobehavioral Reviews87, 255–270.

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