Dextroamphetamine

Dextroamphetamine 5mg tablets

Dexedrine Spansule 5, 10 and 15 mg capsules, a sustained-release dosage form of dextroamphetamine

Dextroamphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder), and is sometimes prescribed off-label for its past medical indications, such as depression and obesity.[17][18] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[22][23] but, in humans with ADHD, pharmaceutical amphetamines, at therapeutic dosages, appear to improve brain development and nerve growth.[24][25][26] Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.[24][25][26]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[27][28][29] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[27][28] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes[note 3] across 9 categories of outcomes related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.[27][29] One review highlighted a nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.[28] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.[27]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;[30] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[30] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[31][30][32] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[33] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.[34][35] The Cochrane reviews[note 4] on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.[37][38] A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.[39]

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;[40][41] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D₁ and adrenoceptor α₂ in the prefrontal cortex.[31][40] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.[42] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.[31][43] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[31][44][45] Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.[31][45][46] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs.[47][48][49] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[31][45]

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;[50][51] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.[52][53] In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time.[50][54][55] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system.[54][55][56] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.[55][57][58] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[50][54] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[59][54]

Dextroamphetamine is also used recreationally as a euphoriant and aphrodisiac, and like other amphetamines is used as a club drug for its energetic and euphoric high. Dextroamphetamine is considered to have a high potential for misuse in a recreational manner since individuals typically report feeling euphoric, more alert, and more energetic after taking the drug.[60][61][62] Large recreational doses of dextroamphetamine may produce symptoms of dextroamphetamine overdose.[62] Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate it or subsequently dissolve it in water and inject it.[62] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[62] Chronic overuse of dextroamphetamine can lead to severe drug dependence, resulting in withdrawal symptoms when drug use stops.[62]

Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate).[59][51][68] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.[59] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea.[1][59][69] Other potential physical side effects include appetite loss, blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, tics (a type of movement disorder), and weight loss.[sources 1] Dangerous physical side effects are rare at typical pharmaceutical doses.[51]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.[51] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.[51] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.[51] This effect can be useful in treating bed wetting and loss of bladder control.[51] The effects of amphetamine on the gastrointestinal tract are unpredictable.[51] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);[51] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.[51] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.[1][51]

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of amphetamine or other ADHD stimulants.[sources 2] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease.[sources 3]

At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness, apprehension, concentration, initiative, self-confidence and sociability, mood swings (elated mood followed by mildly depressed mood), insomnia or wakefulness, and decreased sense of fatigue.[59][51] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;[sources 4] these effects depend on the user's personality and current mental state.[51] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.[59][77][78] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.[59][78][79] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.[59]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,[37][80] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.[80][81]

Signaling cascade in the nucleus accumbens that results in amphetamine addiction Note: colored text contains article links. Nuclear pore Nuclear membrane Plasma membrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB ΔFosB JunD c-Fos SIRT1 HDAC1 [Color legend 1] This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[85][86] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[85][87][88] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[85][89][90] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[91] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[89][90] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[89][90]

Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses;[27][92][93] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult.[27] Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction.[94][95] Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.[82][96][97] Once nucleus accumbens ΔFosB is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression.[96][98] While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction.[99][100] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;[sources 5] exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction.[99][101]

Chronic use of amphetamine at excessive doses causes alterations in gene expression in the mesocorticolimbic projection, which arise through transcriptional and epigenetic mechanisms.[97][102][103] The most important transcription factors[note 8] that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor-kappa B (NF-κB).[97] ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces a pronounced gene-related phenotype) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 9] for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction.[82][96][97] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[82][96] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[sources 6]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression.[82][97][107] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[97] Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation (H3K9me2) and blocks the induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use,[sources 7] which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5).[97][107][108] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[98][97][111] Since both natural rewards and addictive drugs induce the expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[98][97] Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[98][112][113] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs.[98][111]

The effects of amphetamine on gene regulation are both dose- and route-dependent.[103] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses.[103] The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor.[103] This suggests that medical use of amphetamine does not significantly affect gene regulation.[103]

As of December 2019, there is no effective pharmacotherapy for amphetamine addiction.[114][115][116] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions;[117][118] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.[117][118] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors[note 10] in the nucleus accumbens;[95] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel.[95][119] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain.[95] Supplemental magnesium[note 11] treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for amphetamine addiction.[95]

A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction;[115] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[115] There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.[115]

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[120] Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.[120]

Additionally, research on the neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction.[sources 5] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions.[99][101][121] In particular, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D₂ (DRD2) density in the striatum.[98][121] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density.[98] One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system.[100]

Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect.[122][123] According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[124] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week.[124] Amphetamine withdrawal symptoms can include anxiety, drug craving, depressed mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and lucid dreams.[124] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence.[124] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose.[1]

In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity, or damage to dopamine neurons, which is characterized by dopamine terminal degeneration and reduced transporter and receptor function.[129][130] There is no evidence that amphetamine is directly neurotoxic in humans.[131][132] However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia, the excessive formation of reactive oxygen species, and increased autoxidation of dopamine.[sources 9] Animal models of neurotoxicity from high-dose amphetamine exposure indicate that the occurrence of hyperpyrexia (i.e., core body temperature ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity.[130] Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability.[130]

An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia.[77][78] A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely.[77][135] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[77] Psychosis rarely arises from therapeutic use.[59][78][79]

Pharmacodynamics of amphetamine in a dopamine neuron via AADC Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[20] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[20][21] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[21][141] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylates DAT.[20][142][143] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[20] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[20] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[144][145]

Amphetamine and its enantiomers have been identified as potent full agonists of trace amine-associated receptor 1 (TAAR1), a GPCR, discovered in 2001, that is important for regulation of monoaminergic systems in the brain.[146][147] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits the function of the dopamine transporter, norepinephrine transporter, and serotonin transporter, as well as inducing the release of these monoamine neurotransmitters (effluxion).[20][146][148] Amphetamine enantiomers are also substrates for a specific neuronal synaptic vesicle uptake transporter called VMAT2.[21] When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.[21]

Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary.[147][149] Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[147] Consequently, dextroamphetamine produces roughly three to four times more central nervous system (CNS) stimulation than levoamphetamine;[147][149] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[149]

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring neuromodulator molecules produced in the human body and brain.[20][150][151] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., it has an identical molecular formula).[20][150][152] In humans, phenethylamine is produced directly from L-phenylalanine by the aromatic amino acid decarboxylase (AADC) enzyme, which converts L-DOPA into dopamine as well.[150][152] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine.[150][152] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1;[20][151][152] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine.[150][152]

The oral bioavailability of amphetamine varies with gastrointestinal pH;[59] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[153] Amphetamine is a weak base with a pK_a of 9.9;[5] 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.[5][59] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.[5] Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins.[4] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[13]

The half-lives of amphetamine enantiomers differ and vary with urine pH.[5] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[5] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[13] highly alkaline urine will increase the half-lives up to 34 hours.[13] 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.[5] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[5] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[5] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.[5] Following oral administration, amphetamine appears in urine within 3 hours.[13] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[13]

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 amphetamine or its metabolites in humans.[sources 10] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[5][154] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine,[155] 4-hydroxynorephedrine,[156] and norephedrine.[157] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[5][158] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 10] 4-Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4-Hydroxyamphetamine 4-Hydroxynorephedrine Para- Hydroxylation Para- Hydroxylation Para- Hydroxylation CYP2D6 CYP2D6 unidentified Beta- Hydroxylation Beta- Hydroxylation DBH DBH [note 14] Oxidative Deamination FMO3 Oxidation unidentified Glycine Conjugation XM-ligase GLYAT The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[154] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[5] The remaining 10–20% is excreted as the active metabolites.[5] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[163]

Dexamphetamine 5 mg generic name tablets

In the United States, immediate release (IR) formulations of dextroamphetamine sulfate are available generically as 5 mg and 10 mg tablets, marketed by Barr (Teva Pharmaceutical Industries), Mallinckrodt Pharmaceuticals, Wilshire Pharmaceuticals, Aurobindo Pharmaceutical USA and CorePharma. Previous IR tablets sold by the brand names of Dexedrine and Dextrostat have been discontinued but in 2015 IR tablets became available by the brand name Zenzedi, offered as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets.[193] Dextroamphetamine sulfate is also available as a controlled-release (CR) capsule preparation in strengths of 5 mg, 10 mg, and 15 mg under the brand name Dexedrine Spansule, with generic versions marketed by Barr and Mallinckrodt. A bubblegum flavored oral solution is available under the brand name ProCentra, manufactured by FSC Pediatrics, which is designed to be an easier method of administration in children who have difficulty swallowing tablets, each 5 mL contains 5 mg dextroamphetamine.[194] The conversion rate between dextroamphetamine sulfate to amphetamine free base is .728.[195]

In Australia, dexamphetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug.[196] or slow release dextroamphetamine preparations may be compounded by individual chemists.[197] In the United Kingdom, it is available in 5 mg instant release sulfate tablets under the generic name dexamfetamine sulfate as well as 10 mg and 20 mg strength tablets under the brand name Amfexa. It is also available in generic dexamfetamine sulfate 5 mg/ml oral sugar-free syrup.[198] The brand name Dexedrine was available in the United Kingdom prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).[199]

Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand name Vyvanse (Elvanse in the European market) (lisdexamfetamine dimesylate). Dextroamphetamine is liberated from lisdexamfetamine enzymatically following contact with red blood cells. The conversion is rate-limited by the enzyme, which prevents high blood concentrations of dextroamphetamine and reduces lisdexamfetamine's drug liking and abuse potential at clinical doses.[200][201] Vyvanse is marketed as once-a-day dosing as it provides a slow release of dextroamphetamine into the body. Vyvanse is available as capsules, and chewable tablets, and in seven strengths; 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate between lisdexamfetamine dimesylate (Vyvanse) to dextroamphetamine base is 29.5%.[202][203][204]

Adderall 20 mg tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom

Another pharmaceutical that contains dextroamphetamine is commonly known by the brand name Adderall. It is available as immediate release (IR) tablets and extended release (XR) capsules. Adderall contains equal amounts of four amphetamine salts:

• One-quarter racemic (d,l-)amphetamine aspartate monohydrate
• One-quarter dextroamphetamine saccharate
• One-quarter dextroamphetamine sulfate
• One-quarter racemic (d,l-)amphetamine sulfate

Adderall has a total amphetamine base equivalence of 63%.[205] While the enantiomer ratio by dextroamphetamine salts to levoamphetamine salts is 3:1, the amphetamine base content is 75.9% dextroamphetamine, 24.1% levoamphetamine. [note 17]