Dextroamphetamine

Dextroamphetamine[note 1] is a central nervous system (CNS) stimulant and an amphetamine enantiomer[note 2] that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.[17][18] It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine was also used in the past by some countries' military forces to fight fatigue during extended combat operations.

For the racemate, see Amphetamine. For the prodrug marketed under the brand name Vyvanse, see Lisdexamfetamine.

Dextroamphetamine
INN: Dexamfetamine
Clinical data
Pronunciation/ˌdɛkstroʊæmˈfɛtəmiːn/
Trade namesDexedrine, DextroStat, Metamina, Attentin, Zenzedi, Procentra, Amfexa
Other namesD-Amphetamine
AHFS/Drugs.comMonograph
MedlinePlusa605027
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Dependence
    liability    		Moderate[1][2]
    Addiction
    liability    		High
    Routes of
    administration    		By mouth
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilityOral: 75–100%[3]
    Protein binding15–40%[4]
    MetabolismCYP2D6,[5] DBH,[6] FMO3[7]
    Onset of actionIR dosing: 0.5–1.5 hours[8][9]
    XR dosing: 1.5–2 hours[10][11]
    Elimination half-life9–11 hours[5][12]
    pH-dependent: 7–34 hours[13]
    Duration of actionIR dosing: 3–6 hours[10][14]
    XR dosing: 8–12 hours[2][10][14]
    ExcretionRenal (45%);[15] urinary pH-dependent
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.000.103
    Chemical and physical data
    FormulaC9H13N
    Molar mass135.210 g·mol−1
    3D model (JSmol)
    Density0.913 g/cm3
    Boiling point201.5 °C (394.7 °F)
    Solubility in water20 mg/mL (20 °C)
     NY (what is this?)  (verify)

    The amphetamine molecule exists as two enantiomers,[note 2] levoamphetamine and dextroamphetamine. Dextroamphetamine is the dextrorotatory, or 'right-handed', enantiomer and exhibits more pronounced effects on the central nervous system than levoamphetamine. Pharmaceutical dextroamphetamine sulfate is available as both a brand name and generic drug in a variety of dosage forms. Dextroamphetamine is sometimes prescribed as the inactive prodrug lisdexamfetamine dimesylate, which is converted into dextroamphetamine after absorption.

    Dextroamphetamine, like other amphetamines, elicits its stimulating effects via several distinct actions: it inhibits or reverses the transporter proteins for the monoamine neurotransmitters (namely the serotonin, norepinephrine and dopamine transporters) either via trace amine-associated receptor 1 (TAAR1) or in a TAAR1 independent fashion when there are high cytosolic concentrations of the monoamine neurotransmitters[20] and it releases these neurotransmitters from synaptic vesicles via vesicular monoamine transporter 2.[21] It also shares many chemical and pharmacological properties with human trace amines, particularly phenethylamine and N-methylphenethylamine, the latter being an isomer of amphetamine produced within the human body.

    Uses

    Medical
    Dexedrine IR tablets
    Dexedrine Spansule 5, 10 and 15 mg capsules

    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]

    Enhancing performance

    Cognitive performance

    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]

    Physical performance

    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]

    Recreational

    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]

    Contraindications

    According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug Administration (USFDA),[note 5] amphetamine is contraindicated in people with a history of drug abuse,[note 6] cardiovascular disease, severe agitation, or severe anxiety.[64][59][65] It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension.[64][59][65] These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine,[64][59][65] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.[66][67] These agencies also state that anyone with anorexia nervosa, bipolar disorder, depression, hypertension, liver or kidney problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette syndrome should monitor their symptoms while taking amphetamine.[59][65] Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a human teratogen), but amphetamine abuse does pose risks to the fetus.[65] Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it.[59][65] Due to the potential for reversible growth impairments,[note 7] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.[59]

    Adverse effects

    Physical

    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]

    Psychological

    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]

    Reinforcement disorders

    Addiction
    Addiction and dependence glossary[81][82][83][84]
    • addiction – a biopsychosocial disorder characterized by compulsively seeking to achieve a desired effect, such as intoxication, despite harm and adverse consequences to self and others
    • addictive behavior – a behavior that is both rewarding and reinforcing
    • addictive drug – a drug that is both rewarding and reinforcing
    • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
    • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
    • drug withdrawal – symptoms that occur upon cessation of repeated drug use
    • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
    • psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
    • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
    • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
    • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
    • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
    • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
    Transcription factor glossary
    • gene expression – the process by which information from a gene is used in the synthesis of a functional gene product such as a protein
    • transcription – the process of making messenger RNA (mRNA) from a DNA template by RNA polymerase
    • transcription factor – a protein that binds to DNA and regulates gene expression by promoting or suppressing transcription
    • transcriptional regulation – controlling the rate of gene transcription for example by helping or hindering RNA polymerase binding to DNA
    • upregulation, activation, or promotion – increase the rate of gene transcription
    • downregulation, repression, or suppression – decrease the rate of gene transcription
    • coactivator – a protein that works with transcription factors to increase the rate of gene transcription
    • corepressor – a protein that works with transcription factors to decrease the rate of gene transcription
    • response element – a specific sequence of DNA that a transcription factor binds to
    Signaling cascade in the nucleus accumbens that results in amphetamine addiction
    Note: colored text contains article links.
    Nuclear membrane
    Plasma membrane
    Cav1.2
    DARPP-32
    PP2B
    CREB
    HDAC1
    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]

    Biomolecular mechanisms

    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]

    Pharmacological treatments
    Further information: Addiction § Research

    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]

    Behavioral treatments

    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]

    Summary of addiction-related plasticity
    Form of neuroplasticity
    or behavioral plasticity    		 Type of reinforcer Sources
    Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
    (aerobic)    		 Environmental
    enrichment
    ΔFosB expression in
    nucleus accumbens D1-type MSNs    		 ↑↑↑↑↑↑[98]
    Behavioral plasticity
    Escalation of intake YesYesYes[98]
    Psychostimulant
    cross-sensitization    		 YesNot applicableYesYesAttenuatedAttenuated[98]
    Psychostimulant
    self-administration    		 ↑↑↓↓↓[98]
    Psychostimulant
    conditioned place preference    		 ↑↑↓↑↓↑[98]
    Reinstatement of drug-seeking behavior ↑↑↓↓[98]
    Neurochemical plasticity
    CREB phosphorylation
    in the nucleus accumbens    		 ↓↓↓↓↓[98]
    Sensitized dopamine response
    in the nucleus accumbens    		 NoYesNoYes[98]
    Altered striatal dopamine signaling ↓DRD2, ↑DRD3↑DRD1, ↓DRD2, ↑DRD3↑DRD1, ↓DRD2, ↑DRD3↑DRD2↑DRD2[98]
    Altered striatal opioid signaling No change or
    ↑μ-opioid receptors    		↑μ-opioid receptors
    ↑κ-opioid receptors    		↑μ-opioid receptors↑μ-opioid receptorsNo changeNo change[98]
    Changes in striatal opioid peptides ↑dynorphin
    No change: enkephalin    		↑dynorphin↓enkephalin↑dynorphin↑dynorphin[98]
    Mesocorticolimbic synaptic plasticity
    Number of dendrites in the nucleus accumbens ↓↑↑[98]
    Dendritic spine density in
    the nucleus accumbens    		 ↓↑↑[98]

    Dependence and withdrawal

    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]

    Overdose

    An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.[1][65][125] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.[51][65] Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose.[65] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.[59][51] In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an "amphetamine use disorder" resulted in an estimated 3,788 deaths worldwide (3,425–4,145 deaths, 95% confidence).[note 12][126]

    Overdose symptoms by system
    System Minor or moderate overdose[59][51][65] Severe overdose[sources 8]
    Cardiovascular
    Central nervous
    system
    Musculoskeletal
    Respiratory
    • Rapid breathing
    Urinary
    Other

    Toxicity

    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]

    Psychosis
    See also: Stimulant psychosis

    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]

    Interactions

    Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[5][136] Inhibitors of the enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.[7][136] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[136] therefore, concurrent use of both is dangerous.[136] Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants.[136] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[136] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 13][140]

    Pharmacology

    Pharmacodynamics
    Main section: Amphetamine § Pharmacodynamics
    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 phosphorylate 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]

    Further information on related compounds: Trace amine

    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]

    Pharmacokinetics

    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 pKa 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 15–40% 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]
    Para-
    Hydroxylation
    Para-
    Hydroxylation
    Para-
    Hydroxylation
    unidentified
    Beta-
    Hydroxylation
    Beta-
    Hydroxylation
    Oxidative
    Deamination
    Oxidation
    unidentified
    Glycine
    Conjugation
    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]

    History, society, and culture

    Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu. It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline & French (now known as GlaxoSmithKline) introduced it in the form of the Benzedrine inhaler for use as a bronchodilator. Notably, the amphetamine contained in the Benzedrine inhaler was the liquid free-base,[note 15] not a chloride or sulfate salt.

    Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets under the tradename Dexedrine.[167] In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, and obesity. In Canada indications once included epilepsy and parkinsonism.[168] Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule").[169] Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.[170]

    It quickly became apparent that dextroamphetamine and other amphetamines had a high potential for misuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dextroamphetamine, along with other sympathomimetics, was eventually classified as Schedule II, the most restrictive category possible for a drug with a government-sanctioned, recognized medical use.[171] Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine/GSK (US & Canada), Dexedrine/UCB (United Kingdom), Dextropa (Portugal), and Stild (Spain).[172] It became popular on the mod scene in England in the early 1960s, and carried through to the Northern Soul scene in the north of England to the end of the 1970s.

    In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).[173]

    The U.S. Air Force uses dextroamphetamine as one of its "go pills", given to pilots on long missions to help them remain focused and alert. Conversely, "no-go pills" are used after the mission is completed, to combat the effects of the mission and "go-pills".[174][175][176][177] The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. The military did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications or awakeness promoting agents with different side effect profiles, such as modafinil, are being investigated and sometimes issued for this reason.[175]

    Formulations
    Dextroamphetamine pharmaceuticals and prodrugs[note 16]
    Brand
    name    		 United States
    Adopted Name    		 (D:L) ratio Dosage
    form    		 Marketing
    start date    		 US consumer
    price data    		 Sources
    Adderall–3:1 (salts)tablet1996GoodRx[18][186]
    Adderall XR–3:1 (salts)capsule2001GoodRx[18][186]
    Mydayis–3:1 (salts)capsule2017GoodRx[187]
    Adzenys XR-ODTamphetamine3:1 (base)ODT2016GoodRx[188][189]
    Dyanavel XRamphetamine3.2:1 (base)suspension2015GoodRx[69][190]
    Evekeoamphetamine sulfate1:1 (salts)tablet2012GoodRx[64] [191]
    Dexedrinedextroamphetamine sulfate1:0 (salts)capsule1976GoodRx[18][186]
    Zenzedidextroamphetamine sulfate1:0 (salts)tablet2013GoodRx[186]
    Vyvanselisdexamfetamine dimesylate1:0 (prodrug)capsule2007GoodRx[18][192]
    tablet

    Dextroamphetamine sulfate
    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]

    Lisdexamfetamine
    Main article: Lisdexamfetamine

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

    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]

    Amphetamine base in marketed amphetamine medications
    drug formula molecular mass
    [note 18]    		 amphetamine base
    [note 19]    		 amphetamine base
    in equal doses    		 doses with
    equal base
    content
    [note 20]
    (g/mol) (percent) (30 mg dose)
    total base total dextro- levo- dextro- levo-
    dextroamphetamine sulfate[207][208] (C9H13N)2•H2SO4
    368.49
    270.41
    73.38%
    73.38%
    —
    22.0 mg
    —
    30.0 mg
    amphetamine sulfate[209] (C9H13N)2•H2SO4
    368.49
    270.41
    73.38%
    36.69%
    36.69%
    11.0 mg
    11.0 mg
    30.0 mg
    Adderall
    62.57%
    47.49%
    15.08%
    14.2 mg
    4.5 mg
    35.2 mg
    25% dextroamphetamine sulfate[207][208] (C9H13N)2•H2SO4
    368.49
    270.41
    73.38%
    73.38%
    —
    25% amphetamine sulfate[209] (C9H13N)2•H2SO4
    368.49
    270.41
    73.38%
    36.69%
    36.69%
    25% dextroamphetamine saccharate[210] (C9H13N)2•C6H10O8
    480.55
    270.41
    56.27%
    56.27%
    —
    25% amphetamine aspartate monohydrate[211] (C9H13N)•C4H7NO4•H2O
    286.32
    135.21
    47.22%
    23.61%
    23.61%
    lisdexamfetamine dimesylate[192] C15H25N3O•(CH4O3S)2
    455.49
    135.21
    29.68%
    29.68%
    —
    8.9 mg
    —
    74.2 mg
    amphetamine base suspension[note 21][69] C9H13N
    135.21
    135.21
    100%
    76.19%
    23.81%
    22.9 mg
    7.1 mg
    22.0 mg

    Notes
    1. Synonyms and alternate spellings include: (2S)-1-phenylpropan-2-amine (IUPAC name), dexamfetamine (INN),[16] dexamphetamine, (S)-amphetamine, (+)-amphetamine, and D-amphetamine.
    2. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[19]
    3. The ADHD-related outcome domains with the greatest proportion of significantly improved outcomes from long-term continuous stimulant therapy include academics (≈55% of academic outcomes improved), driving (100% of driving outcomes improved), non-medical drug use (47% of addiction-related outcomes improved), obesity (≈65% of obesity-related outcomes improved), self-esteem (50% of self-esteem outcomes improved), and social function (67% of social function outcomes improved).[29]

      The largest effect sizes for outcome improvements from long-term stimulant therapy occur in the domains involving academics (e.g., grade point average, achievement test scores, length of education, and education level), self-esteem (e.g., self-esteem questionnaire assessments, number of suicide attempts, and suicide rates), and social function (e.g., peer nomination scores, social skills, and quality of peer, family, and romantic relationships).[29]

      Long-term combination therapy for ADHD (i.e., treatment with both a stimulant and behavioral therapy) produces even larger effect sizes for outcome improvements and improves a larger proportion of outcomes across each domain compared to long-term stimulant therapy alone.[29]
    4. Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[36]
    5. The statements supported by the USFDA come from prescribing information, which is the copyrighted intellectual property of the manufacturer and approved by the USFDA. USFDA contraindications are not necessarily intended to limit medical practice but limit claims by pharmaceutical companies.[63]
    6. According to one review, amphetamine can be prescribed to individuals with a history of abuse provided that appropriate medication controls are employed, such as requiring daily pick-ups of the medication from the prescribing physician.[18]
    7. In individuals who experience sub-normal height and weight gains, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted.[27][28][68] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm.[68]
    8. Transcription factors are proteins that increase or decrease the expression of specific genes.[104]
    9. In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
    10. NMDA receptors are voltage-dependent ligand-gated ion channels that requires simultaneous binding of glutamate and a co-agonist (D-serine or glycine) to open the ion channel.[119]
    11. The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior;[95] other forms of magnesium were not mentioned.
    12. The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
    13. The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[137][138][139] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[139]
    14. 4-Hydroxyamphetamine has been shown to be metabolized into 4-hydroxynorephedrine by dopamine beta-hydroxylase (DBH) in vitro and it is presumed to be metabolized similarly in vivo.[159][162] Evidence from studies that measured the effect of serum DBH concentrations on 4-hydroxyamphetamine metabolism in humans suggests that a different enzyme may mediate the conversion of 4-hydroxyamphetamine to 4-hydroxynorephedrine;[162][164] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[165][166]
    15. Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.
    16. These represent the current brands in the United States, except Dexedrine instant release tablets. Dexedrine tablets, introduced in 1937, is discontinued but available as Zenzedi and generically;[178][179] Dexedrine listed here represents the extended release "Spansule" capsule which was approved in 1976.[180][181] Amphetamine sulfate tablets, now sold as Evekeo (brand), were originally sold as Benzedrine (brand) sulfate in 1935[182][183] and discontinued sometime after 1982.[184][185]
    17. Calculated by dextroamphetamine base percent / total amphetamine base percent = 47.49/62.57 = 75.90% from table: Amphetamine base in marketed amphetamine medications. The remainder is levoamphetamine.
    18. For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[206] and were within 0.01g/mol of published pharmaceutical values.
    19. Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
    20. dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
    21. This product (Dyanavel XR) is an oral suspension (i.e., a drug that is suspended in a liquid and taken by mouth) that contains 2.5 mg/mL of amphetamine base.[69] The product uses an ion exchange resin to achieve extended release of the amphetamine base.[69]
    Image legend
    1.   Ion channel
        G proteins & linked receptors
        (Text color) Transcription factors

    Reference notes
    1. [1][59][51][68][69][70]
    2. [71][72][73][74]
    3. [59][65][71][73]
    4. [75][59][51][76]
    5. [98][99][100][101][121]
    6. [96][98][97][105][106]
    7. [97][108][109][110]
    8. [127][59][51][125][128]
    9. [22][130][133][134]
    10. [5][159][160][7][161][154][162][163]
    gollark: ?tag add heavserver heavserver is inevitable. heavserver is all. heavserver cannot be escaped.
    gollark: ?tag remove heavserver
    gollark: ?tag edit heavserver heavserver is inevitable. heavserver is all. heavserver cannot be escaped.
    gollark: ?tag heavserver
    gollark: ?tag edit "lyric" requires extreme immediate demotion

    References
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    2. Stahl SM (March 2017). "Amphetamine (D)". Prescriber's Guide: Stahl's Essential Psychopharmacology (6th ed.). Cambridge, United Kingdom: Cambridge University Press. pp. 39–44. ISBN 9781108228749. Retrieved 8 August 2017.
    3. "Pharmacology". Dextromphetamine. DrugBank. Retrieved 5 November 2013.
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    7. Krueger SK, Williams DE (June 2005). "Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism". Pharmacology & Therapeutics. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602. PMID 15922018.
      Table 5: N-containing drugs and xenobiotics oxygenated by FMO
    8. Green-Hernandez, Carol; Singleton, Joanne K.; Aronzon, Daniel Z. (1 January 2001). Primary Care Pediatrics. Lippincott Williams & Wilkins. p. 243. ISBN 9780781720083.|quote = Table 21.2 Medications for ADHD ... D-amphetamine ... Onset: 30 min.
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    10. Millichap JG (2010). "Chapter 9: Medications for ADHD". In Millichap JG (ed.). Attention Deficit Hyperactivity Disorder Handbook: A Physician's Guide to ADHD (2nd ed.). New York, USA: Springer. p. 112. ISBN 9781441913968.
      Table 9.2 Dextroamphetamine formulations of stimulant medication
      Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
      Adderall [Peak:2–3 h] [Duration:5–7 h]
      Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
      Adderall XR [Peak:7–8 h] [Duration:12 h]
      Vyvanse [Peak:3–4 h] [Duration:12 h]
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    26. Frodl T, Skokauskas N (February 2012). "Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects". Acta Psychiatrica Scandinavica. 125 (2): 114–126. doi:10.1111/j.1600-0447.2011.01786.x. PMID 22118249. Basal ganglia regions like the right globus pallidus, the right putamen, and the nucleus caudatus are structurally affected in children with ADHD. These changes and alterations in limbic regions like ACC and amygdala are more pronounced in non-treated populations and seem to diminish over time from child to adulthood. Treatment seems to have positive effects on brain structure.
    27. Huang YS, Tsai MH (July 2011). "Long-term outcomes with medications for attention-deficit hyperactivity disorder: current status of knowledge". CNS Drugs. 25 (7): 539–554. doi:10.2165/11589380-000000000-00000. PMID 21699268. Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
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      Figure 3: Treatment benefit by treatment type and outcome group
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    31. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 13: Higher Cognitive Function and Behavioral Control". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 318, 321. ISBN 9780071481274. Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in normal subjects and those with ADHD. ... stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks ... through indirect stimulation of dopamine and norepinephrine receptors. ...
      Beyond these general permissive effects, dopamine (acting via D1 receptors) and norepinephrine (acting at several receptors) can, at optimal levels, enhance working memory and aspects of attention.
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      Physiologic and performance effects
       • Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
       • Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
       • Improved reaction time
       • Increased muscle strength and delayed muscle fatigue
       • Increased acceleration
       • Increased alertness and attention to task
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    56. Parker KL, Lamichhane D, Caetano MS, Narayanan NS (October 2013). "Executive dysfunction in Parkinson's disease and timing deficits". Frontiers in Integrative Neuroscience. 7: 75. doi:10.3389/fnint.2013.00075. PMC 3813949. PMID 24198770. Manipulations of dopaminergic signaling profoundly influence interval timing, leading to the hypothesis that dopamine influences internal pacemaker, or "clock," activity. For instance, amphetamine, which increases concentrations of dopamine at the synaptic cleft advances the start of responding during interval timing, whereas antagonists of D2 type dopamine receptors typically slow timing;... Depletion of dopamine in healthy volunteers impairs timing, while amphetamine releases synaptic dopamine and speeds up timing.
    57. Rattray B, Argus C, Martin K, Northey J, Driller M (March 2015). "Is it time to turn our attention toward central mechanisms for post-exertional recovery strategies and performance?". Frontiers in Physiology. 6: 79. doi:10.3389/fphys.2015.00079. PMC 4362407. PMID 25852568. Aside from accounting for the reduced performance of mentally fatigued participants, this model rationalizes the reduced RPE and hence improved cycling time trial performance of athletes using a glucose mouthwash (Chambers et al., 2009) and the greater power output during a RPE matched cycling time trial following amphetamine ingestion (Swart, 2009). ... Dopamine stimulating drugs are known to enhance aspects of exercise performance (Roelands et al., 2008)
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      Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
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      Figure 2: Psychostimulant-induced signaling events
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      Figure 4: Epigenetic basis of drug regulation of gene expression
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