Pharmacodynamics<unk>  exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain. The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by<unk>  because of its effects on monoamine transporters. The reinforcing and motivational salience-promoting effects of<unk>  are due mostly to enhanced dopaminergic activity in the mesolimbic pathway. The euphoric and locomotor-stimulating effects of<unk>  are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.<unk>  has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a and G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines. Activation of increases production via adenylyl cyclase activation and inhibits monoamine transporter function. Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. Notably,<unk>  and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. Imaging studies indicate that monoamine reuptake inhibition by<unk>  and trace amines is site specific and depends upon the presence of TAAR1 in the associated monoamine neurons. In addition to the neuronal monoamine transporters,<unk>  also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5. SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.<unk>  is known to strongly induce cocaine- and<unk> -regulated transcript (CART) gene expression, a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro. The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique .<unk>  also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines. In humans, the only post-synaptic receptor at which<unk>  is known to bind is the receptor, where it acts as an agonist with low micromolar affinity. The full profile of<unk> 's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine, serotonin, norepinephrine, epinephrine, histamine, CART peptides, endogenous opioids, adrenocorticotropic hormone, corticosteroids, and glutamate, which it affects through interactions with , , , , , , and possibly other biological targets.<unk>  also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain. Dextroamphetamine is a more potent agonist of than levoamphetamine. Consequently, dextroamphetamine produces greater stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects. Dopamine In certain brain regions,<unk>  increases the concentration of dopamine in the synaptic cleft.<unk>  can enter the presynaptic neuron either through or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake,<unk>  produces competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron,<unk>  activates which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization ( reuptake inhibition), but phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux).<unk>  is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux. Through direct activation of G protein-coupled inwardly-rectifying potassium channels, reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state.<unk>  is also a substrate for the presynaptic vesicular monoamine transporter, . Following<unk>  uptake at VMAT2,<unk>  induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2. Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at . Norepinephrine Similar to dopamine,<unk>  dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine. Based upon neuronal expression,<unk>  is thought to affect norepinephrine analogously to dopamine. In other words,<unk>  induces TAAR1-mediated efflux and reuptake inhibition at phosphorylated , competitive NET reuptake inhibition, and norepinephrine release from . Serotonin<unk>  exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine.<unk>  affects serotonin via and, like norepinephrine, is thought to phosphorylate via . Like dopamine,<unk>  has low, micromolar affinity at the human 5-HT1A receptor. Other neurotransmitters, peptides, hormones, and enzymes + Human carbonic anhydraseactivation potency Enzyme KA () Sources hCA4 94 hCA5A 810 hCA5B 2560 hCA7 910 hCA12 640 hCA13 24100 hCA14 9150 Acute<unk>  administration in humans increases endogenous opioid release in several brain structures in the reward system. Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to<unk> . This increase in extracellular glutamate presumably occurs via the<unk> -induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons.<unk>  also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through . Acute<unk>  administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis. In December 2017, the first study assessing the interaction between<unk>  and human carbonic anhydrase enzymes was published; of the eleven carbonic anhydrase enzymes it examined, it found that<unk>  potently activates seven, four of which are highly expressed in the human brain, with low nanomolar through low micromolar activating effects. Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma. Pharmacokinetics The oral bioavailability of<unk>  varies with gastrointestinal pH; it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.<unk>  is a weak base with a pKa of 9.9; consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium. Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. Approximately of<unk>  circulating in the bloodstream is bound to plasma proteins. Following absorption,<unk>  readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue. The half-lives of<unk>  enantiomers differ and vary with urine pH. At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are hours and hours, respectively. Highly acidic urine will reduce the enantiomer half-lives to 7 hours; highly alkaline urine will increase the half-lives up to 34 hours. The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.<unk>  is eliminated via the kidneys, with of the drug being excreted unchanged at normal urinary pH. When the urinary pH is basic,<unk>  is in its free base form, so less is excreted. When urine pH is abnormal, the urinary recovery of<unk>  may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively. Following oral administration,<unk>  appears in urine within 3 hours. Roughly 90% of ingested<unk>  is eliminated 3 days after the last oral dose. CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize<unk>  or its metabolites in humans.<unk>  has a variety of excreted metabolic products, including , , , benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are , , and norephedrine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following: Pharmacomicrobiomics The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions), there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile. The field that studies these interactions is known as pharmacomicrobiomics. Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs),<unk>  is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream. The first<unk> -metabolizing microbial enzyme,
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