Amphetamine

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Amphetamine
INN: Amfetamine
Racemic amphetamine 2.svg
D-Amphetamine molecule ball from xtal.png
Clinical data
Pronunciation /æmˈfɛtəmn/ ( Loudspeaker.svg listen )
Trade names Evekeo, Adderall [note 1] , others
Other namesα-methylphenethylamine
AHFS/Drugs.com Monograph
MedlinePlus a616004
License data
Pregnancy
category
  • US:C (Risk not ruled out) [1]
    Dependence
    liability
    Moderate [2]
    Addiction
    liability
    Moderate
    Routes of
    administration
    Medical: oral, intravenous [3]
    Recreational: oral, insufflation, rectal, intravenous, intramuscular
    Drug class CNS stimulant, anorectic
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability Oral: 75–100% [4]
    Protein binding 20% [5]
    Metabolism CYP2D6, [6] DBH, [7] [8] FMO3 [7] [9] [10]
    Metabolites 4-hydroxyamphetamine , 4-hydroxynorephedrine , 4-hydroxyphenylacetone , benzoic acid, hippuric acid, norephedrine, phenylacetone [6] [11]
    Onset of action IR dosing: 30–60 minutes [12]
    XR dosing: 1.5–2 hours [13] [14]
    Elimination half-life D-amph: 9–11 hours [6] [15]
    L-amph: 11–14 hours [6] [15]
    pH-dependent: 7–34 hours [16]
    Duration of action IR dosing: 3–6 hours [2] [13] [17]
    XR dosing: 8–12 hours [2] [13] [17]
    Excretion Primarily renal;
    pH-dependent range: 1–75% [6]
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    NIAID ChemDB
    CompTox Dashboard (EPA)
    ECHA InfoCard 100.005.543 OOjs UI icon edit-ltr-progressive.svg
    Chemical and physical data
    Formula C9H13N
    Molar mass 135.210 g·mol−1
    3D model (JSmol)
    Chirality Racemic mixture [18]
    Density .936 g/cm3 at 25 °C [19]
    Melting point 11.3 °C (52.3 °F) (predicted) [20]
    Boiling point 203 °C (397 °F) at 760  mmHg [21]
       (verify)

    Amphetamine [note 2] (contracted from alpha-methylphenethylamine) is a central nervous system (CNS) stimulant marketed under the brand name Evekeo, among others. It is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers: [note 3] levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use. [sources 1]

    Contents

    The first amphetamine pharmaceutical was Benzedrine, a brand which was used to treat a variety of conditions. Currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall, [note 4] dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems. [sources 2]

    At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness, and improved cognitive control. It induces physical effects such as improved reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., delusions and paranoia) which rarely occurs at therapeutic doses even during long-term use. Recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects. [sources 3]

    Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines, [note 5] which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N-methylphenethylamine , both of which are produced within the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group. [sources 4]

    Uses

    Medical

    Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (a sleep disorder), and obesity, and is sometimes prescribed off-label for its past medical indications, particularly for depression and chronic pain. [2] [35] [49] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage, [50] [51] but, in humans with ADHD, pharmaceutical amphetamines, at therapeutic dosages, appear to improve brain development and nerve growth. [52] [53] [54] 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. [52] [53] [54]

    Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD. [43] [55] [56] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety. [43] [55] 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 6] 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. [43] [56] 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. [55] 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. [43]

    Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems; [57] 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. [57] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. [26] [57] [58] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms. [59] 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. [60] [61] The Cochrane reviews [note 7] 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. [63] [64] 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. [65]

    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; [66] [67] 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. [26] [66] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information. [68] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. [26] [69] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. [26] [70] [71] 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. [26] [71] [72] 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. [73] [74] [75] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control. [26] [71]

    Physical performance

    Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness; [27] [39] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. [76] [77] 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. [27] [78] [79] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system. [78] [79] [80] 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. [79] [81] [82] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; [27] [78] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature. [28] [78]

    Contraindications

    According to the International Programme on Chemical Safety (IPCS) and the United States Food and Drug Administration (USFDA), [note 8] amphetamine is contraindicated in people with a history of drug abuse, [note 9] cardiovascular disease, severe agitation, or severe anxiety. [35] [28] [84] 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. [35] [28] [84] 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, [35] [28] [84] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented. [85] [86] 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. [28] [84] 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. [84] Amphetamine has also been shown to pass into breast milk, so the IPCS and the USFDA advise mothers to avoid breastfeeding when using it. [28] [84] Due to the potential for reversible growth impairments, [note 10] the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical. [28]

    Adverse effects

    The adverse side effects of amphetamine are many and varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects. [28] [39] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use. [36] [28] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes. [39]

    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). [28] [39] [87] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections. [28] Gastrointestinal side effects may include abdominal pain, constipation, diarrhea, and nausea. [2] [28] [88] 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 5] Dangerous physical side effects are rare at typical pharmaceutical doses. [39]

    Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths. [39] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident. [39] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating. [39] This effect can be useful in treating bed wetting and loss of bladder control. [39] The effects of amphetamine on the gastrointestinal tract are unpredictable. [39] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); [39] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. [39] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids. [2] [39]

    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 6] However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease. [sources 7]

    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. [28] [39] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness; [sources 8] these effects depend on the user's personality and current mental state. [39] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users. [28] [40] [41] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. [28] [41] [42] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility. [28]

    Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses, [63] [95] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine. [95] [96]

    Reinforcement disorders

    Addiction

    Addiction and dependence glossary [96] [97] [98] [99]
    • 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 promotionincrease the rate of gene transcription
    • downregulation , repression, or suppressiondecrease 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
    Interactive icon.svg
    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, [100] [101] 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. [100] [102] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors; [100] [103] [104] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron. [105] 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. [103] [104] 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. [103] [104]

    Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses; [43] [44] [45] in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult. [43] 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. [106] [107] 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. [97] [108] [109] 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. [108] [110] 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. [111] [112] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction; [sources 9] exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction. [111] [113]

    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. [109] [114] [115] The most important transcription factors [note 11] 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). [109] 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 12] for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration) involved in addiction. [97] [108] [109] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. [97] [108] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others. [sources 10]

    ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression. [97] [109] [119] 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). [109] 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 11] which occurs via H3K9me2-mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5). [109] [119] [120] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. [110] [109] [123] 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. [110] [109] 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. [110] [124] [125] These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs. [110] [123]

    The effects of amphetamine on gene regulation are both dose- and route-dependent. [115] Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. [115] 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. [115] This suggests that medical use of amphetamine does not significantly affect gene regulation. [115]

    Pharmacological treatments

    As of December 2019, there is no effective pharmacotherapy for amphetamine addiction. [126] [127] [128] Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; [38] [129] however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs. [38] [129] Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors [note 13] in the nucleus accumbens; [107] magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel. [107] [130] One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain. [107] Supplemental magnesium [note 14] 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. [107]

    A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction; [127] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. [127] 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. [127]

    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). [131] 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. [131]

    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 9] Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. [111] [113] [132] 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. [110] [132] This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. [110] 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. [112]

    Summary of addiction-related plasticity
    Form of neuroplasticity
    or behavioral plasticity
    Type of reinforcer Sources
    OpiatesPsychostimulantsHigh fat or sugar food Sexual intercourse Physical exercise
    (aerobic)
    Environmental
    enrichment
    ΔFosB expression in
    nucleus accumbens D1-type MSNs
    [110]
    Behavioral plasticity
    Escalation of intakeYesYesYes [110]
    Psychostimulant
    cross-sensitization
    YesNot applicableYesYesAttenuatedAttenuated [110]
    Psychostimulant
    self-administration
    [110]
    Psychostimulant
    conditioned place preference
    [110]
    Reinstatement of drug-seeking behavior [110]
    Neurochemical plasticity
    CREB phosphorylation
    in the nucleus accumbens
    [110]
    Sensitized dopamine response
    in the nucleus accumbens
    NoYesNoYes [110]
    Altered striatal dopamine signaling DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD1, ↓DRD2, ↑DRD3 DRD2 DRD2 [110]
    Altered striatal opioid signaling No change or
    μ-opioid receptors
    μ-opioid receptors
    κ-opioid receptors
    μ-opioid receptors μ-opioid receptors No changeNo change [110]
    Changes in striatal opioid peptides dynorphin
    No change: enkephalin
    dynorphin enkephalin dynorphin dynorphin [110]
    Mesocorticolimbic synaptic plasticity
    Number of dendrites in the nucleus accumbens [110]
    Dendritic spine density in
    the nucleus accumbens
    [110]

    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. [133] [134] 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." [135] 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. [135] 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. [135] The review indicated that the severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. [135] Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose. [2]

    Overdose

    An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. [2] [84] [136] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine. [39] [84] 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. [84] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma. [28] [39] 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 15] [137]

    Overdose symptoms by system
    SystemMinor or moderate overdose [28] [39] [84] Severe overdose [sources 12]
    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. [139] [140] There is no evidence that amphetamine is directly neurotoxic in humans. [141] [142] 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 13] 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. [140] 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. [140]

    Psychosis

    An amphetamine overdose can result in a stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia. [40] [41] A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely. [40] [145] According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. [40] Psychosis rarely arises from therapeutic use. [28] [41] [42]

    Drug 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. [28] Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer. [9] [28] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine); [28] therefore, concurrent use of both is dangerous. [28] 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. [28] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively. [28] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD. [note 16] [150]

    In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively. [28] Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do the opposite. [28] Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H2 antihistamines, which increase gastrointestinal pH (i.e., make it less acidic). [28]

    Pharmacology

    Pharmacodynamics

    Pharmacodynamics of amphetamine in a dopamine neuron
    TAAR1 Dopamine.svg
    via AADC
    Interactive icon.svg
    Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. [37] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. [37] [151] 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. [151] [152] 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. [37] [153] [154] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. [37] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport. [37] 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. [155] [156]

    Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of the brain. [37] [58] The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on monoamine transporters. [37] [58] [151] The reinforcing and motivational salience-promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway. [26] The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum. [3]

    Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines. [37] [157] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits monoamine transporter function. [37] [158] Monoamine autoreceptors (e.g., D2 short, presynaptic α2, and presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. [37] [38] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. [37] [38] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons. [37]

    In addition to the neuronal monoamine transporters, amphetamine also inhibits both vesicular monoamine transporters, VMAT1 and VMAT2, as well as SLC1A1, SLC22A3, and SLC22A5. [sources 14] SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter. [sources 14] Amphetamine is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression, [5] [164] a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro . [5] [165] [166] The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique Gi/Go-coupled GPCR. [166] [167] Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines. [22] [168] In humans, the only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor, where it acts as an agonist with low micromolar affinity. [169] [170]

    The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine, [37] serotonin, [37] norepinephrine, [37] epinephrine, [151] histamine, [151] CART peptides, [5] [164] endogenous opioids, [171] [172] [173] adrenocorticotropic hormone, [174] [175] corticosteroids, [174] [175] and glutamate, [155] [160] which it effects through interactions with CART, 5-HT1A, EAAT3, TAAR1, VMAT1, VMAT2, and possibly other biological targets. [sources 15] Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in the human brain. [176]

    Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine. [177] Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects. [39] [177]

    Dopamine

    In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft. [37] Amphetamine can enter the presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly. [37] As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter. [37] Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. [37] Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces the reversal of dopamine transport through DAT (i.e., dopamine efflux). [note 16] [37] [178] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux. [157] [155] [156] Through direct activation of G protein-coupled inwardly-rectifying potassium channels, TAAR1 reduces the firing rate of dopamine neurons, preventing a hyper-dopaminergic state. [153] [154] [179]

    Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter, VMAT2. [151] [152] Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2. [151] [152] Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT. [37] [151] [152]

    Norepinephrine

    Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine. [46] [58] Based upon neuronal TAAR1mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine. [37] [151] [178] In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET, competitive NET reuptake inhibition, and norepinephrine release from VMAT2. [37] [151]

    Serotonin

    Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine. [37] [58] Amphetamine affects serotonin via VMAT2 and, like norepinephrine, is thought to phosphorylate SERT via TAAR1. [37] [151] Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor. [169] [170]

    Other neurotransmitters, peptides, hormones, and enzymes

    Human carbonic anhydrase
    activation potency
    Enzyme KA (nM)Sources
    hCA4 94 [176]
    hCA5A 810 [176] [180]
    hCA5B 2560 [176]
    hCA7 910 [176] [180]
    hCA12 640 [176]
    hCA13 24100 [176]
    hCA14 9150 [176]

    Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system. [171] [172] [173] Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase in the striatum following exposure to amphetamine. [155] This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3, a glutamate reuptake transporter, in dopamine neurons. [155] [160] Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2. [151] Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating the hypothalamic–pituitary–adrenal axis. [35] [174] [175]

    In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published; [176] of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the human brain, with low nanomolar through low micromolar activating effects. [176] Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; [181] but, based upon the clinical use of carbonic anhydrase inhibitors, carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma. [181]

    Pharmacokinetics

    The oral bioavailability of amphetamine varies with gastrointestinal pH; [28] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine. [4] Amphetamine is a weak base with a pKa of 9.9; [6] 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. [6] [28] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. [6] Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins. [5] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue. [16]

    The half-lives of amphetamine enantiomers differ and vary with urine pH. [6] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively. [6] Highly acidic urine will reduce the enantiomer half-lives to 7 hours; [16] highly alkaline urine will increase the half-lives up to 34 hours. [16] 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. [6] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. [6] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. [6] 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. [6] Following oral administration, amphetamine appears in urine within 3 hours. [16] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose. [16]  

    The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract; [182] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis. [182] The elimination half-life of lisdexamfetamine is generally less than 1 hour. [182]

    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 16] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine , 4-hydroxynorephedrine , 4-hydroxyphenylacetone , benzoic acid, hippuric acid, norephedrine, and phenylacetone. [6] [11] Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, [183] 4-hydroxynorephedrine, [184] and norephedrine. [185] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. [6] [186] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

    Metabolic pathways of amphetamine in humans [sources 16]
    Amph Pathway.png
    Amphetamine
    Para-
    Hydroxylation
    Para-
    Hydroxylation
    Para-
    Hydroxylation
    unidentified
    Beta-
    Hydroxylation
    Beta-
    Hydroxylation
    DBH
    Oxidative
    Deamination
    Oxidation
    unidentified
    Glycine
    Conjugation
    Interactive icon.svg
    The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine; [11] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row). [6] The remaining 10–20% is excreted as the active metabolites. [6] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid. [188]

    Pharmacomicrobiomics

    The human metagenome (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. [192] [193] Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions), [note 18] [192] [194] there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the human microbiome, drug metabolism by microbial enzymes modifying the drug's pharmacokinetic profile, and microbial drug metabolism affecting a drug's clinical efficacy and toxicity profile. [192] [193] [195] The field that studies these interactions is known as pharmacomicrobiomics. [192]

    Similar to most biomolecules and other orally administered xenobiotics (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by human gastrointestinal microbiota (primarily bacteria) prior to absorption into the blood stream. [195] The first amphetamine-metabolizing microbial enzyme, tyramine oxidase from a strain of E. coli commonly found in the human gut, was identified in 2019. [195] This enzyme was found to metabolize amphetamine, tyramine, and phenethylamine with roughly the same binding affinity for all three compounds. [195]

    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. [37] [46] [196] 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). [37] [46] [197] 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. [46] [197] In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, the same enzyme that metabolizes norepinephrine into epinephrine. [46] [197] Like amphetamine, both phenethylamine and N-methylphenethylamine regulate monoamine neurotransmission via TAAR1; [37] [196] [197] unlike amphetamine, both of these substances are broken down by monoamine oxidase B, and therefore have a shorter half-life than amphetamine. [46] [197]

    Chemistry

    Racemic amphetamine
    Interactive icon.svg
    The skeletal structures of L-amph and D-amph
    Amphetamine Freebase.png
    A vial of the colorless amphetamine free base
    Amphetamine and P2P.png
    Amphetamine hydrochloride (left bowl)
    Phenyl-2-nitropropene (right cups)

    Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C 9 H 13 N . The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers. [23] This racemic mixture can be separated into its optical isomers: [note 19] levoamphetamine and dextroamphetamine. [23] At room temperature, the pure free base of amphetamine is a mobile, colorless, and volatile liquid with a characteristically strong amine odor, and acrid, burning taste. [21] Frequently prepared solid salts of amphetamine include amphetamine adipate, [198] aspartate, [28] hydrochloride, [199] phosphate, [200] saccharate, [28] sulfate, [28] and tannate. [201] Dextroamphetamine sulfate is the most common enantiopure salt. [47] Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives. [7] [23] In organic chemistry, amphetamine is an excellent chiral ligand for the stereoselective synthesis of 1,1'-bi-2-naphthol . [202]

    Substituted derivatives

    The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone"; [7] [48] [203] specifically, this chemical class includes derivative compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with substituents. [7] [48] [204] The class includes amphetamine itself, stimulants like methamphetamine, serotonergic empathogens like MDMA, and decongestants like ephedrine, among other subgroups. [7] [48] [203]

    Synthesis

    Since the first preparation was reported in 1887, [205] numerous synthetic routes to amphetamine have been developed. [206] [207] The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the Leuckart reaction (method 1). [47] [208] In the first step, a reaction between phenylacetone and formamide, either using additional formic acid or formamide itself as a reducing agent, yields N-formylamphetamine . This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt. [208] [209]

    A number of chiral resolutions have been developed to separate the two enantiomers of amphetamine. [206] For example, racemic amphetamine can be treated with d-tartaric acid to form a diastereoisomeric salt which is fractionally crystallized to yield dextroamphetamine. [210] Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale. [211] In addition, several enantioselective syntheses of amphetamine have been developed. In one example, optically pure (R)-1-phenyl-ethanamine is condensed with phenylacetone to yield a chiral Schiff base. In the key step, this intermediate is reduced by catalytic hydrogenation with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the benzylic amine bond by hydrogenation yields optically pure dextroamphetamine. [211]

    A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions. [206] [207] One example is the Friedel–Crafts alkylation of benzene by allyl chloride to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2). [212] Another example employs the Ritter reaction (method 3). In this route, allylbenzene is reacted acetonitrile in sulfuric acid to yield an organosulfate which in turn is treated with sodium hydroxide to give amphetamine via an acetamide intermediate. [213] [214] A third route starts with ethyl 3-oxobutanoate which through a double alkylation with methyl iodide followed by benzyl chloride can be converted into 2-methyl-3-phenyl-propanoic acid. This synthetic intermediate can be transformed into amphetamine using either a Hofmann or Curtius rearrangement (method 4). [215]

    A significant number of amphetamine syntheses feature a reduction of a nitro, imine, oxime, or other nitrogen-containing functional groups. [207] In one such example, a Knoevenagel condensation of benzaldehyde with nitroethane yields phenyl-2-nitropropene . The double bond and nitro group of this intermediate is reduced using either catalytic hydrogenation or by treatment with lithium aluminium hydride (method 5). [208] [216] Another method is the reaction of phenylacetone with ammonia, producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6). [208]

    Amphetamine synthetic routes
    Amphetamine Leukart synthesis.svg
    Method 1: Synthesis by the Leuckart reaction 
    Amphetamine resolution and chiral synthesis.svg
    Top: Chiral resolution of amphetamine 
    Bottom: Stereoselective synthesis of amphetamine 
    Amphetamine Friedel-Crafts alkylation.svg
    Method 2: Synthesis by Friedel–Crafts alkylation 
    Amphetamine Ritter Synthesis.svg
    Method 3: Ritter synthesis
    Amphetamine Hofmann Curtius Synthesis.svg
    Method 4: Synthesis via Hofmann and Curtius rearrangements
    Amphetamine Knoevenagel synthesis.svg
    Method 5: Synthesis by Knoevenagel condensation
    Amphetamine p2p ammonia synthesis.svg
    Method 6: Synthesis using phenylacetone and ammonia

    Detection in body fluids

    Amphetamine is frequently measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics. [sources 17] Techniques such as immunoassay, which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs. [220] Chromatographic methods specific for amphetamine are employed to prevent false positive results. [221] Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g., selegiline), over-the-counter drug products that contain levomethamphetamine, [note 20] or illicitly obtained substituted amphetamines. [221] [224] [225] Several prescription drugs produce amphetamine as a metabolite, including benzphetamine, clobenzorex, famprofazone, fenproporex, lisdexamfetamine, mesocarb, methamphetamine, prenylamine, and selegiline, among others. [3] [226] [227] These compounds may produce positive results for amphetamine on drug tests. [226] [227] Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for 2–4 days. [220]

    For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay for amphetamine and methamphetamine may produce more false positives than liquid chromatography–tandem mass spectrometry. [224] Gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(−)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine. [221] GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride allows for the detection of both dextroamphetamine and dextromethamphetamine in urine. [221] Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug. [221]

    History, society, and culture

    Global estimates of drug users in 2016
    (in millions of users) [228]
    SubstanceBest
    estimate
    Low
    estimate
    High
    estimate
    Amphetamine-
    type stimulants
    34.1613.4255.24
    Cannabis 192.15165.76234.06
    Cocaine 18.2013.8722.85
    Ecstasy 20.578.9932.34
    Opiates 19.3813.8026.15
    Opioids 34.2627.0144.54

    Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine; [205] [229] [230] its stimulant effects remained unknown until 1927, when it was independently resynthesized by Gordon Alles and reported to have sympathomimetic properties. [230] Amphetamine had no medical use until late 1933, when Smith, Kline and French began selling it as an inhaler under the brand name Benzedrine as a decongestant. [29] Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain, among others. [49] [29] During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects. [205] [231] [232] As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine. [205] For example, during the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act. [233] [234] In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors, [235] musicians, [236] mathematicians, [237] and athletes. [27]

    Amphetamine is still illegally synthesized today in clandestine labs and sold on the black market, primarily in European countries. [238] Among European Union (EU) member states in 2018, 11.9 million adults of ages 15–64 have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the last year. [239] During 2012, approximately 5.9  metric tons of illicit amphetamine were seized within EU member states; [240] the "street price" of illicit amphetamine within the EU ranged from 6–38 per gram during the same period. [240] Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA. [238]

    As a result of the United Nations 1971 Convention on Psychotropic Substances, amphetamine became a schedule II controlled substance, as defined in the treaty, in all 183 state parties. [30] Consequently, it is heavily regulated in most countries. [241] [242] Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use. [243] [244] In other nations, such as Canada (schedule I drug), [245] the Netherlands (List I drug), [246] the United States (schedule II drug), [28] Australia (schedule 8), [247] Thailand (category 1 narcotic), [248] and United Kingdom (class B drug), [249] amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment. [238] [31]

    Pharmaceutical products

    Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis, [note 1] Adzenys ER, Adzenys XR-ODT, Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose active moiety can be accurately referred to simply as "amphetamine". [2] [35] [88] Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only enantiopure amphetamine product currently available. A prodrug form of dextroamphetamine, lisdexamfetamine, is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine. [36] [182] The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine. [3] Levoamphetamine was previously available as Cydril. [3] Many current amphetamine pharmaceuticals are salts due to the comparatively high volatility of the free base. [3] [36] [47] However, oral suspension and orally disintegrating tablet (ODT) dosage forms composed of the free base were introduced in 2015 and 2016, respectively. [88] [250] [251] Some of the current brands and their generic equivalents are listed below.

    Amphetamine pharmaceuticals
    Brand
    name
    United States
    Adopted Name
    (D:L) ratio
    Dosage
    form
    Marketing
    start date
    US consumer
    price data
    Sources
    Adderall3:1 (salts)tablet1996 GoodRx [3] [36]
    Adderall XR3:1 (salts)capsule2001 GoodRx [3] [36]
    Mydayis3:1 (salts)capsule2017 GoodRx [252] [253]
    Adzenys ERamphetamine3:1 (base)suspension2017 GoodRx [254]
    Adzenys XR-ODTamphetamine3:1 (base) ODT 2016 GoodRx [251] [255]
    Dyanavel XRamphetamine3.2:1 (base)suspension2015 GoodRx [88] [250]
    Evekeoamphetamine sulfate1:1 (salts)tablet2012 GoodRx [35] [256]
    Evekeo ODTamphetamine sulfate1:1 (salts) ODT 2019 GoodRx [257]
    Dexedrinedextroamphetamine sulfate1:0 (salts)capsule1976 GoodRx [3] [36]
    Zenzedidextroamphetamine sulfate1:0 (salts)tablet2013 GoodRx [36] [258]
    Vyvanselisdexamfetamine dimesylate1:0 (prodrug)capsule2007 GoodRx [3] [182] [259]
    tablet
    Amphetamine base in marketed amphetamine medications
    drugformula molecular mass
    [note 21]
    amphetamine base
    [note 22]
    amphetamine base
    in equal doses
    doses with
    equal base
    content
    [note 23]
    (g/mol)(percent)(30 mg dose)
    totalbasetotaldextro-levo-dextro-levo-
    dextroamphetamine sulfate [261] [262] (C9H13N)2•H2SO4
    368.49
    270.41
    73.38%
    73.38%
    22.0 mg
    30.0 mg
    amphetamine sulfate [263] (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 [261] [262] (C9H13N)2•H2SO4
    368.49
    270.41
    73.38%
    73.38%
    25%amphetamine sulfate [263] (C9H13N)2•H2SO4
    368.49
    270.41
    73.38%
    36.69%
    36.69%
    25%dextroamphetamine saccharate [264] (C9H13N)2•C6H10O8
    480.55
    270.41
    56.27%
    56.27%
    25%amphetamine aspartate monohydrate [265] (C9H13N)•C4H7NO4•H2O
    286.32
    135.21
    47.22%
    23.61%
    23.61%
    lisdexamfetamine dimesylate [182] C15H25N3O•(CH4O3S)2
    455.49
    135.21
    29.68%
    29.68%
    8.9 mg
    74.2 mg
    amphetamine base suspension [note 24] [88] C9H13N
    135.21
    135.21
    100%
    76.19%
    23.81%
    22.9 mg
    7.1 mg
    22.0 mg

    Notes

    1. 1 2 Adderall and other mixed amphetamine salts products such as Mydayis are not racemic amphetamine - they are a mixture composed of equal parts racemate and dextroamphetamine.
      See Mixed amphetamine salts for more information about the mixture, and this section for information about the various mixtures of amphetamine enantiomers currently marketed.
    2. Synonyms and alternate spellings include: 1-phenylpropan-2-amine (IUPAC name), α-methylphenethylamine, amfetamine (International Nonproprietary Name [INN]), β-phenylisopropylamine, and speed. [22] [23] [24]
    3. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation. [25]
      Levoamphetamine and dextroamphetamine are also known as L-amph or levamfetamine (INN) and D-amph or dexamfetamine (INN) respectively. [22]
    4. The brand name Adderall is used primarily throughout this article to refer to the amphetamine salt mixture it contains because the four-salt composition of the drug makes its nonproprietary name (dextroamphetamine sulfate 25%, dextroamphetamine saccharate 25%, amphetamine sulfate 25%, and amphetamine aspartate 25%) excessively lengthy. [36]
    5. The term "amphetamines" also refers to a chemical class, but, unlike the class of substituted amphetamines, [7] the "amphetamines" class does not have a standardized definition in academic literature. [18] One of the more restrictive definitions of this class includes only the racemate and enantiomers of amphetamine and methamphetamine. [18] The most general definition of the class encompasses a broad range of pharmacologically and structurally related compounds. [18]
      Due to confusion that may arise from use of the plural form, this article will only use the terms "amphetamine" and "amphetamines" to refer to racemic amphetamine, levoamphetamine, and dextroamphetamine and reserve the term "substituted amphetamines" for its structural class.
    6. 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). [56]

      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). [56]

      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. [56]
    7. Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials. [62]
    8. 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. [83]
    9. 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. [3]
    10. 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. [43] [55] [87] The average reduction in final adult height from 3 years of continuous stimulant therapy is 2 cm. [87]
    11. Transcription factors are proteins that increase or decrease the expression of specific genes. [116]
    12. 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.
    13. 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. [130]
    14. The review indicated that magnesium L-aspartate and magnesium chloride produce significant changes in addictive behavior; [107] other forms of magnesium were not mentioned.
    15. The 95% confidence interval indicates that there is a 95% probability that the true number of deaths lies between 3,425 and 4,145.
    16. 1 2 The human dopamine transporter (hDAT) contains a high-affinity, extracellular, and allosteric Zn2+ (zinc ion) binding site which, upon zinc binding, inhibits dopamine reuptake, inhibits amphetamine-induced hDAT internalization, and amplifies amphetamine-induced dopamine efflux. [146] [147] [148] [149] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites. [148]
    17. 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 . [7] [187] 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; [187] [189] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain. [190] [191]
    18. There is substantial variation in microbiome composition and microbial concentrations by anatomical site. [192] [193] Fluid from the human colon – which contains the highest concentration of microbes of any anatomical site – contains approximately one trillion (10^12) bacterial cells/ml. [192]
    19. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation. [25]
    20. The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine. [222] [223]
    21. For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator [260] and were within 0.01g/mol of published pharmaceutical values.
    22. Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
    23. 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.
    24. 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. [88] The product uses an ion exchange resin to achieve extended release of the amphetamine base. [88]
    Image legend
    1.   (Text color) Transcription factors

    Reference notes

    1. [3] [18] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35]
    2. [3] [15] [26] [29] [35] [37] [38]
    3. [15] [26] [27] [28] [32] [39] [40] [41] [42] [43] [44] [45]
    4. [46] [47] [48]
    5. [2] [28] [39] [87] [88] [89]
    6. [90] [91] [92] [93]
    7. [28] [84] [90] [92]
    8. [32] [28] [39] [94]
    9. 1 2 [110] [111] [112] [113] [132]
    10. [108] [110] [109] [117] [118]
    11. [109] [120] [121] [122]
    12. [24] [28] [39] [136] [138]
    13. [50] [140] [143] [144]
    14. 1 2 [151] [155] [159] [160] [161] [162] [163]
    15. [37] [151] [159] [160] [164] [169]
    16. 1 2 [6] [7] [8] [9] [10] [11] [187] [188]
    17. [27] [217] [218] [219]

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    References

    1. "Amphetamine / dextroamphetamine Use During Pregnancy". Drugs.com. 23 September 2019. Retrieved 22 December 2019.
    2. 1 2 3 4 5 6 7 8 9 10 Stahl SM (March 2017). "Amphetamine (D,L)". Prescriber's Guide: Stahl's Essential Psychopharmacology (6th ed.). Cambridge, United Kingdom: Cambridge University Press. pp. 45–51. ISBN   9781108228749 . Retrieved 5 August 2017.
    3. 1 2 3 4 5 6 7 8 9 10 11 12 13 Heal DJ, Smith SL, Gosden J, Nutt DJ (June 2013). "Amphetamine, past and present – a pharmacological and clinical perspective". Journal of Psychopharmacology. 27 (6): 479–496. doi:10.1177/0269881113482532. PMC   3666194 . PMID   23539642. The intravenous use of d-amphetamine and other stimulants still pose major safety risks to the individuals indulging in this practice. Some of this intravenous abuse is derived from the diversion of ampoules of d-amphetamine, which are still occasionally prescribed in the UK for the control of severe narcolepsy and other disorders of excessive sedation. ... For these reasons, observations of dependence and abuse of prescription d-amphetamine are rare in clinical practice, and this stimulant can even be prescribed to people with a history of drug abuse provided certain controls, such as daily pick-ups of prescriptions, are put in place (Jasinski and Krishnan, 2009b).
    4. 1 2 "Pharmacology". Dextroamphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013.
    5. 1 2 3 4 5 "Pharmacology". Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 5 November 2013.
    6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.
    7. 1 2 3 4 5 6 7 8 9 Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN   9781609133450. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
    8. 1 2 Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). Journal of Biological Chemistry. 249 (2): 454–458. PMID   4809526 . Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
    9. 1 2 3 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
    10. 1 2 Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". Journal of Pharmacology and Experimental Therapeutics. 288 (3): 1251–1260. PMID   10027866.
    11. 1 2 3 4 Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". Journal of Pharmaceutical and Biomedical Analysis. 30 (2): 247–255. doi:10.1016/S0731-7085(02)00330-8. PMID   12191709.
    12. "Pharmacology". amphetamine/dextroamphetamine. Medscape. WebMD. Retrieved 21 January 2016. Onset of action: 30–60 min
    13. 1 2 3 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]
    14. Brams M, Mao AR, Doyle RL (September 2008). "Onset of efficacy of long-acting psychostimulants in pediatric attention-deficit/hyperactivity disorder". Postgraduate Medicine. 120 (3): 69–88. doi:10.3810/pgm.2008.09.1909. PMID   18824827. S2CID   31791162.
    15. 1 2 3 4 "Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet". DailyMed. Teva Pharmaceuticals USA, Inc. 8 November 2019. Retrieved 22 December 2019.
    16. 1 2 3 4 5 6 "Metabolism/Pharmacokinetics". Amphetamine. United States National Library of Medicine – Toxicology Data Network. Hazardous Substances Data Bank. Archived from the original on 2 October 2017. Retrieved 2 October 2017. Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34 hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine). ... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3 hours following oral administration. ... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine
    17. 1 2 Mignot EJ (October 2012). "A practical guide to the therapy of narcolepsy and hypersomnia syndromes". Neurotherapeutics. 9 (4): 739–752. doi:10.1007/s13311-012-0150-9. PMC   3480574 . PMID   23065655.
    18. 1 2 3 4 5 Yoshida T (1997). "Chapter 1: Use and Misuse of Amphetamines: An International Overview". In Klee H (ed.). Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. p.  2. ISBN   9789057020810. Amphetamine, in the singular form, properly applies to the racemate of 2-amino-1-phenylpropane. ... In its broadest context, however, the term [amphetamines] can even embrace a large number of structurally and pharmacologically related substances.
    19. "Density". Amphetamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. 5 November 2016. Retrieved 9 November 2016.
    20. "Properties: Predicted – EPISuite". Amphetamine. ChemSpider. Royal Society of Chemistry. Retrieved 6 November 2013.
    21. 1 2 "Chemical and Physical Properties". Amphetamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 13 October 2013.
    22. 1 2 3 "Compound Summary". Amphetamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. 11 April 2015. Retrieved 17 April 2015.
    23. 1 2 3 4 "Identification". Amphetamine. DrugBank. University of Alberta. 8 February 2013. Retrieved 13 October 2013.
    24. 1 2 Greene SL, Kerr F, Braitberg G (October 2008). "Review article: amphetamines and related drugs of abuse". Emergency Medicine Australasia. 20 (5): 391–402. doi:10.1111/j.1742-6723.2008.01114.x. PMID   18973636. S2CID   20755466.
    25. 1 2 "Enantiomer". IUPAC Compendium of Chemical Terminology. IUPAC Goldbook. International Union of Pure and Applied Chemistry. 2009. doi:10.1351/goldbook.E02069. ISBN   9780967855097. Archived from the original on 17 March 2013. Retrieved 14 March 2014. One of a pair of molecular entities which are mirror images of each other and non-superposable.
    26. 1 2 3 4 5 6 7 8 9 10 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.
    27. 1 2 3 4 5 6 7 Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". Primary Care: Clinics in Office Practice. 40 (2): 487–505. doi:10.1016/j.pop.2013.02.009. PMID   23668655. Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training ...
      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
    28. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 "Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release". DailyMed. Shire US Inc. 17 July 2019. Retrieved 22 December 2019.
    29. 1 2 3 4 Rasmussen N (July 2006). "Making the first anti-depressant: amphetamine in American medicine, 1929–1950". Journal of the History of Medicine and Allied Sciences. 61 (3): 288–323. doi:10.1093/jhmas/jrj039. PMID   16492800. S2CID   24974454. However the firm happened to discover the drug, SKF first packaged it as an inhaler so as to exploit the base's volatility and, after sponsoring some trials by East Coast otolaryngological specialists, began to advertise the Benzedrine Inhaler as a decongestant in late 1933.
    30. 1 2 "Convention on psychotropic substances". United Nations Treaty Collection. United Nations. Archived from the original on 31 March 2016. Retrieved 11 November 2013.
    31. 1 2 Wilens TE, Adler LA, Adams J, Sgambati S, Rotrosen J, Sawtelle R, Utzinger L, Fusillo S (January 2008). "Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature". Journal of the American Academy of Child & Adolescent Psychiatry. 47 (1): 21–31. doi:10.1097/chi.0b013e31815a56f1. PMID   18174822. Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile) ...

      Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
    32. 1 2 3 Montgomery KA (June 2008). "Sexual desire disorders". Psychiatry. 5 (6): 50–55. PMC   2695750 . PMID   19727285.
    33. "Amphetamine". Medical Subject Headings. United States National Library of Medicine. Retrieved 16 December 2013.
    34. "Guidelines on the Use of International Nonproprietary Names (INNS) for Pharmaceutical Substances". World Health Organization. 1997. Retrieved 1 December 2014. In principle, INNs are selected only for the active part of the molecule which is usually the base, acid or alcohol. In some cases, however, the active molecules need to be expanded for various reasons, such as formulation purposes, bioavailability or absorption rate. In 1975 the experts designated for the selection of INN decided to adopt a new policy for naming such molecules. In future, names for different salts or esters of the same active substance should differ only with regard to the inactive moiety of the molecule. ... The latter are called modified INNs (INNMs).
    35. 1 2 3 4 5 6 7 8 9 "Evekeo- amphetamine sulfate tablet". DailyMed. Arbor Pharmaceuticals, LLC. 14 August 2019. Retrieved 22 December 2019.
    36. 1 2 3 4 5 6 7 8 "National Drug Code Amphetamine Search Results". National Drug Code Directory. United States Food and Drug Administration. Archived from the original on 16 December 2013. Retrieved 16 December 2013.
    37. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". Journal of Neurochemistry. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC   3005101 . PMID   21073468.
    38. 1 2 3 4 5 Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug and Alcohol Dependence. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMC   4724540 . PMID   26644139. When considered together with the rapidly growing literature in the field a compelling case emerges in support of developing TAAR1-selective agonists as medications for preventing relapse to psychostimulant abuse.
    39. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York, USA: McGraw-Hill. ISBN   9780071624428.
    40. 1 2 3 4 5 Shoptaw SJ, Kao U, Ling W (January 2009). Shoptaw SJ, Ali R (ed.). "Treatment for amphetamine psychosis". Cochrane Database of Systematic Reviews (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMC   7004251 . PMID   19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
      About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
      Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
      psychotic symptoms of individuals with amphetamine psychosis may be due exclusively to heavy use of the drug or heavy use of the drug may exacerbate an underlying vulnerability to schizophrenia.
    41. 1 2 3 4 5 Bramness JG, Gundersen ØH, Guterstam J, Rognli EB, Konstenius M, Løberg EM, Medhus S, Tanum L, Franck J (December 2012). "Amphetamine-induced psychosis—a separate diagnostic entity or primary psychosis triggered in the vulnerable?". BMC Psychiatry. 12: 221. doi:10.1186/1471-244X-12-221. PMC   3554477 . PMID   23216941. In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine ... Secondly, psychosis has been viewed as an adverse event, although rare, in children with ADHD who have been treated with amphetamine
    42. 1 2 3 Greydanus D. "Stimulant Misuse: Strategies to Manage a Growing Problem" (PDF). American College Health Association (Review Article). ACHA Professional Development Program. p. 20. Archived from the original (PDF) on 3 November 2013. Retrieved 2 November 2013.
    43. 1 2 3 4 5 6 7 8 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. S2CID   3449435. 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.
    44. 1 2 Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN   9780071827706. Such agents also have important therapeutic uses; cocaine, for example, is used as a local anesthetic (Chapter 2), and amphetamines and methylphenidate are used in low doses to treat attention deficit hyperactivity disorder and in higher doses to treat narcolepsy (Chapter 12). Despite their clinical uses, these drugs are strongly reinforcing, and their long-term use at high doses is linked with potential addiction, especially when they are rapidly administered or when high-potency forms are given.
    45. 1 2 Kollins SH (May 2008). "A qualitative review of issues arising in the use of psycho-stimulant medications in patients with ADHD and co-morbid substance use disorders". Current Medical Research and Opinion. 24 (5): 1345–1357. doi:10.1185/030079908X280707. PMID   18384709. S2CID   71267668. When oral formulations of psychostimulants are used at recommended doses and frequencies, they are unlikely to yield effects consistent with abuse potential in patients with ADHD.
    46. 1 2 3 4 5 6 7 Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID   19948186.
    47. 1 2 3 4 "Amphetamine". European Monitoring Centre for Drugs and Drug Addiction. Retrieved 19 October 2013.
    48. 1 2 3 4 Hagel JM, Krizevski R, Marsolais F, Lewinsohn E, Facchini PJ (2012). "Biosynthesis of amphetamine analogs in plants". Trends in Plant Science. 17 (7): 404–412. doi:10.1016/j.tplants.2012.03.004. PMID   22502775. Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. ... For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
      [Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
    49. 1 2 Bett WR (August 1946). "Benzedrine sulphate in clinical medicine; a survey of the literature". Postgraduate Medical Journal. 22 (250): 205–218. doi:10.1136/pgmj.22.250.205. PMC   2478360 . PMID   20997404.
    50. 1 2 Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L (August 2012). "Toxicity of amphetamines: an update". Archives of Toxicology. 86 (8): 1167–1231. doi:10.1007/s00204-012-0815-5. PMID   22392347. S2CID   2873101.
    51. Berman S, O'Neill J, Fears S, Bartzokis G, London ED (October 2008). "Abuse of amphetamines and structural abnormalities in the brain". Annals of the New York Academy of Sciences. 1141 (1): 195–220. doi:10.1196/annals.1441.031. PMC   2769923 . PMID   18991959.
    52. 1 2 Hart H, Radua J, Nakao T, Mataix-Cols D, Rubia K (February 2013). "Meta-analysis of functional magnetic resonance imaging studies of inhibition and attention in attention-deficit/hyperactivity disorder: exploring task-specific, stimulant medication, and age effects". JAMA Psychiatry. 70 (2): 185–198. doi: 10.1001/jamapsychiatry.2013.277 . PMID   23247506.
    53. 1 2 Spencer TJ, Brown A, Seidman LJ, Valera EM, Makris N, Lomedico A, Faraone SV, Biederman J (September 2013). "Effect of psychostimulants on brain structure and function in ADHD: a qualitative literature review of magnetic resonance imaging-based neuroimaging studies". The Journal of Clinical Psychiatry. 74 (9): 902–917. doi:10.4088/JCP.12r08287. PMC   3801446 . PMID   24107764.
    54. 1 2 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. S2CID   25954331. 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.
    55. 1 2 3 4 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. pp. 121–123, 125–127. ISBN   9781441913968. Ongoing research has provided answers to many of the parents' concerns, and has confirmed the effectiveness and safety of the long-term use of medication.
    56. 1 2 3 4 5 Arnold LE, Hodgkins P, Caci H, Kahle J, Young S (February 2015). "Effect of treatment modality on long-term outcomes in attention-deficit/hyperactivity disorder: a systematic review". PLOS ONE. 10 (2): e0116407. doi:10.1371/journal.pone.0116407. PMC   4340791 . PMID   25714373. The highest proportion of improved outcomes was reported with combination treatment (83% of outcomes). Among significantly improved outcomes, the largest effect sizes were found for combination treatment. The greatest improvements were associated with academic, self-esteem, or social function outcomes.
      Figure 3: Treatment benefit by treatment type and outcome group
    57. 1 2 3 Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. pp. 154–157. ISBN   9780071481274.
    58. 1 2 3 4 5 Bidwell LC, McClernon FJ, Kollins SH (August 2011). "Cognitive enhancers for the treatment of ADHD". Pharmacology Biochemistry and Behavior. 99 (2): 262–274. doi:10.1016/j.pbb.2011.05.002. PMC   3353150 . PMID   21596055.
    59. Parker J, Wales G, Chalhoub N, Harpin V (September 2013). "The long-term outcomes of interventions for the management of attention-deficit hyperactivity disorder in children and adolescents: a systematic review of randomized controlled trials". Psychology Research and Behavior Management. 6: 87–99. doi:10.2147/PRBM.S49114. PMC   3785407 . PMID   24082796. Only one paper53 examining outcomes beyond 36 months met the review criteria. ... There is high level evidence suggesting that pharmacological treatment can have a major beneficial effect on the core symptoms of ADHD (hyperactivity, inattention, and impulsivity) in approximately 80% of cases compared with placebo controls, in the short term.
    60. 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. pp. 111–113. ISBN   9781441913968.
    61. "Stimulants for Attention Deficit Hyperactivity Disorder". WebMD. Healthwise. 12 April 2010. Retrieved 12 November 2013.
    62. Scholten RJ, Clarke M, Hetherington J (August 2005). "The Cochrane Collaboration". European Journal of Clinical Nutrition. 59 (Suppl 1): S147–S149, discussion S195–S196. doi:10.1038/sj.ejcn.1602188. PMID   16052183. S2CID   29410060.
    63. 1 2 Castells X, Blanco-Silvente L, Cunill R (August 2018). "Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults". Cochrane Database of Systematic Reviews. 8: CD007813. doi:10.1002/14651858.CD007813.pub3. PMC   6513464 . PMID   30091808.
    64. Punja S, Shamseer L, Hartling L, Urichuk L, Vandermeer B, Nikles J, Vohra S (February 2016). "Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents". Cochrane Database of Systematic Reviews. 2: CD009996. doi:10.1002/14651858.CD009996.pub2. PMID   26844979.
    65. Osland ST, Steeves TD, Pringsheim T (June 2018). "Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders". Cochrane Database of Systematic Reviews. 6: CD007990. doi:10.1002/14651858.CD007990.pub3. PMC   6513283 . PMID   29944175.
    66. 1 2 Spencer RC, Devilbiss DM, Berridge CW (June 2015). "The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex". Biological Psychiatry. 77 (11): 940–950. doi:10.1016/j.biopsych.2014.09.013. PMC   4377121 . PMID   25499957. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2 and dopamine D1 receptors. ... This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 versus α1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). ... In particular, in both animals and humans, lower doses maximally improve performance in tests of working memory and response inhibition, whereas maximal suppression of overt behavior and facilitation of attentional processes occurs at higher doses.
    67. Ilieva IP, Hook CJ, Farah MJ (June 2015). "Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis". Journal of Cognitive Neuroscience. 27 (6): 1069–1089. doi:10.1162/jocn_a_00776. PMID   25591060. S2CID   15788121. Specifically, in a set of experiments limited to high-quality designs, we found significant enhancement of several cognitive abilities. ... The results of this meta-analysis ... do confirm the reality of cognitive enhancing effects for normal healthy adults in general, while also indicating that these effects are modest in size.
    68. Bagot KS, Kaminer Y (April 2014). "Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review". Addiction. 109 (4): 547–557. doi:10.1111/add.12460. PMC   4471173 . PMID   24749160. Amphetamine has been shown to improve consolidation of information (0.02  P  0.05), leading to improved recall.
    69. Devous MD, Trivedi MH, Rush AJ (April 2001). "Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers". Journal of Nuclear Medicine. 42 (4): 535–542. PMID   11337538.
    70. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 10: Neural and Neuroendocrine Control of the Internal Milieu". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 266. ISBN   9780071481274. Dopamine acts in the nucleus accumbens to attach motivational significance to stimuli associated with reward.
    71. 1 2 3 Wood S, Sage JR, Shuman T, Anagnostaras SG (January 2014). "Psychostimulants and cognition: a continuum of behavioral and cognitive activation". Pharmacological Reviews. 66 (1): 193–221. doi:10.1124/pr.112.007054. PMC   3880463 . PMID   24344115.
    72. Twohey M (26 March 2006). "Pills become an addictive study aid". JS Online. Archived from the original on 15 August 2007. Retrieved 2 December 2007.
    73. Teter CJ, McCabe SE, LaGrange K, Cranford JA, Boyd CJ (October 2006). "Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration". Pharmacotherapy. 26 (10): 1501–1510. doi:10.1592/phco.26.10.1501. PMC   1794223 . PMID   16999660.
    74. Weyandt LL, Oster DR, Marraccini ME, Gudmundsdottir BG, Munro BA, Zavras BM, Kuhar B (September 2014). "Pharmacological interventions for adolescents and adults with ADHD: stimulant and nonstimulant medications and misuse of prescription stimulants". Psychology Research and Behavior Management. 7: 223–249. doi:10.2147/PRBM.S47013. PMC   4164338 . PMID   25228824. misuse of prescription stimulants has become a serious problem on college campuses across the US and has been recently documented in other countries as well. ... Indeed, large numbers of students claim to have engaged in the nonmedical use of prescription stimulants, which is reflected in lifetime prevalence rates of prescription stimulant misuse ranging from 5% to nearly 34% of students.
    75. Clemow DB, Walker DJ (September 2014). "The potential for misuse and abuse of medications in ADHD: a review". Postgraduate Medicine. 126 (5): 64–81. doi:10.3810/pgm.2014.09.2801. PMID   25295651. S2CID   207580823. Overall, the data suggest that ADHD medication misuse and diversion are common health care problems for stimulant medications, with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.
    76. Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes" (PDF). NCAA Publications. National Collegiate Athletic Association. Retrieved 8 October 2013.
    77. Docherty JR (June 2008). "Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)". British Journal of Pharmacology. 154 (3): 606–622. doi:10.1038/bjp.2008.124. PMC   2439527 . PMID   18500382.
    78. 1 2 3 4 Parr JW (July 2011). "Attention-deficit hyperactivity disorder and the athlete: new advances and understanding". Clinics in Sports Medicine. 30 (3): 591–610. doi:10.1016/j.csm.2011.03.007. PMID   21658550. In 1980, Chandler and Blair47 showed significant increases in knee extension strength, acceleration, anaerobic capacity, time to exhaustion during exercise, pre-exercise and maximum heart rates, and time to exhaustion during maximal oxygen consumption (VO2 max) testing after administration of 15 mg of dextroamphetamine versus placebo. Most of the information to answer this question has been obtained in the past decade through studies of fatigue rather than an attempt to systematically investigate the effect of ADHD drugs on exercise.
    79. 1 2 3 Roelands B, de Koning J, Foster C, Hettinga F, Meeusen R (May 2013). "Neurophysiological determinants of theoretical concepts and mechanisms involved in pacing". Sports Medicine. 43 (5): 301–311. doi:10.1007/s40279-013-0030-4. PMID   23456493. S2CID   30392999. In high-ambient temperatures, dopaminergic manipulations clearly improve performance. The distribution of the power output reveals that after dopamine reuptake inhibition, subjects are able to maintain a higher power output compared with placebo. ... Dopaminergic drugs appear to override a safety switch and allow athletes to use a reserve capacity that is 'off-limits' in a normal (placebo) situation.
    80. 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.
    81. 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)
    82. Roelands B, De Pauw K, Meeusen R (June 2015). "Neurophysiological effects of exercise in the heat". Scandinavian Journal of Medicine & Science in Sports. 25 (Suppl 1): 65–78. doi:10.1111/sms.12350. PMID   25943657. This indicates that subjects did not feel they were producing more power and consequently more heat. The authors concluded that the "safety switch" or the mechanisms existing in the body to prevent harmful effects are overridden by the drug administration (Roelands et al., 2008b). Taken together, these data indicate strong ergogenic effects of an increased DA concentration in the brain, without any change in the perception of effort.
    83. Kessler S (January 1996). "Drug therapy in attention-deficit hyperactivity disorder". Southern Medical Journal. 89 (1): 33–38. doi:10.1097/00007611-199601000-00005. PMID   8545689. S2CID   12798818. statements on package inserts are not intended to limit medical practice. Rather they are intended to limit claims by pharmaceutical companies. ... the FDA asserts explicitly, and the courts have upheld that clinical decisions are to be made by physicians and patients in individual situations.
    84. 1 2 3 4 5 6 7 8 9 10 11 Heedes G, Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014.
    85. Feinberg SS (November 2004). "Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication". The Journal of Clinical Psychiatry. 65 (11): 1520–1524. doi:10.4088/jcp.v65n1113. PMID   15554766.
    86. Stewart JW, Deliyannides DA, McGrath PJ (June 2014). "How treatable is refractory depression?". Journal of Affective Disorders. 167: 148–152. doi:10.1016/j.jad.2014.05.047. PMID   24972362.
    87. 1 2 3 4 Vitiello B (April 2008). "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function". Child and Adolescent Psychiatric Clinics of North America. 17 (2): 459–474. doi:10.1016/j.chc.2007.11.010. PMC   2408826 . PMID   18295156.
    88. 1 2 3 4 5 6 7 8