The pharmacology of amphetamine and methylphenidate: Relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities

Abstract

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.

Keywords: Amphetamine; Attention-deficit/hyperactivity disorder; Methylphenidate; Pharmacology.

Figure 1.. Brain Mechanisms in ADHD*

(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, the ventromedial 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 (ie, 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. *Reprinted with permission from Macmillan Publishers Ltd: [NAT REV DIS PRIMERS] (Faraone SV, Asherson P, Banaschewski T, Biederman J, Buitelaar JK, Ramos-Quiroga JA, et al. Nat Rev Dis Primers. 2015 Aug 6;1:15020), copyright 2015.

Figure 2.. PRISMA Flow Diagram of the Literature Search

*Publications were excluded if they did not focus on the mechanism of action or pharmacologic effects of amphetamine or methylphenidate or if the publications were imaging studies in individuals who were not healthy (ie, studies in those with psychiatric disorders were not included).