Lisdexamfetamine

Source: Wikipedia, the free encyclopedia.
Not to be confused with Levoamphetamine.

Lisdexamfetamine
Clinical data
Trade namesVyvanse, Tyvense, Elvanse, others
Other namesL-Lysine-d-amphetamine; (2S)-2,6-Diamino-N-[(2S)-1-phenylpropan-2-yl]hexanamide
N-[(2S)-1-Phenyl-2-propanyl]-L-lysinamide
AHFS/Drugs.comMonograph
MedlinePlusa607047
License data
Pregnancy
category
  • AU: B3
Dependence
liability		Moderate[1][2]
Addiction
liability		Moderate[1][2]
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: 96.4%[9]
Protein binding20% (as dextroamphetamine)[10]
MetabolismHydrolysis by enzymes in red blood cells initially, subsequent metabolism follows
MetabolitesDextroamphetamine (and its metabolites) and L-lysine
Onset of actionOral: <2 hours[11][12]
Elimination half-lifeLisdexamfetamine: <1 hour[13]
Dextroamphetamine: 10–12 h[13][7]
Duration of action10–12 hours[14][11][12]
ExcretionKidney: ~2%
Identifiers
  • (2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide
JSmol)
  • O=C(N[C@H](Cc1ccccc1)C)[C@@H](N)CCCCN
  • InChI=1S/C15H25N3O/c1-12(11-13-7-3-2-4-8-13)18-15(19)14(17)9-5-6-10-16/h2-4,7-8,12,14H,5-6,9-11,16-17H2,1H3,(H,18,19)/t12-,14-/m0/s1 checkY
  • Key:VOBHXZCDAVEXEY-JSGCOSHPSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a

by mouth. Its effects generally begin within two hours and last for up to 14 hours.[15] In the United Kingdom, it is usually less preferred to methylphenidate for the treatment of children.[16]

Common side effects of lisdexamfetamine include

United States Food and Drug Administration.[15] Serotonin syndrome may occur if used with certain other medications.[15] Its use during pregnancy may result in harm to the baby and use during breastfeeding is not recommended by the manufacturer.[17][15][18]

Lisdexamfetamine is an inactive

attached to dextroamphetamine.[20]

Lisdexamfetamine was approved for medical use in the United States in 2007, and in the European Union in 2012.

Schedule II controlled substance in the United States.[17][24]

Uses

Medical

30mg Vyvanse capsules
Part of this section is transcluded from amphetamine. (edit | history)

Lisdexamfetamine is used primarily as a treatment for

adult ADHD.[25]
Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,[26][27] but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth.[28][29][30] 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.[28][29][30]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.[31][32][33] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety.[31][32] 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 1] 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.[31][33] 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.[32] 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.[31]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's

mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.[34] Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.[35][34][36] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.[37] 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.[38][39] The Cochrane reviews[note 2] 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.[41][42] 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.[43]

Enhancing performance

This section is transcluded from Amphetamine. (edit | history)

Cognitive performance

In 2015, a

task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.[35][48][49] 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.[35][49][50] 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.[51][52][53] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.[35][49]

Physical performance

Amphetamine is used by some athletes for its psychological and

release of dopamine in the central nervous system.[58][59][60] 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.[59][61][62] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;[54][58] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.[63][58]

Available forms

Lisdexamfetamine is available as the

dextroamphetamine sulfate or to 15 mg dextroamphetamine free-base in terms of the amount of dextroamphetamine contained.[13][64][65] Lisdexamfetamine capsules can be swallowed intact, or they can be opened and mixed into water, yogurt, or applesauce and consumed in that manner.[7][66]

Contraindications

Pharmaceutical lisdexamfetamine is

heart disease, or severe agitation or anxiety, or in those currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[68] However, a European consensus statement on adult ADHD noted that stimulants do not worsen substance misuse in adults with ADHD and comorbid substance use disorder and should not be avoided in these individuals.[69] In any case, the statement noted that immediate-release stimulants should be avoided in those with both ADHD and substance use disorder and that slower-release stimulant formulations like OROSTooltip osmotic-controlled release oral delivery system methylphenidate (Concerta) and lisdexamfetamine should be preferred due to their lower misuse potential.[69] Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.[70]

Adverse effects

Products containing lisdexamfetamine have a comparable

sudden cardiac death in those with underlying heart problems, stimulant psychosis, and serotonin syndrome.[15][7]

Interactions

Pharmacology

Main section: Amphetamine § Pharmacodynamics

Mechanism of action

Pharmacodynamics of amphetamine in a dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.
CAMKIIα-dependent pathway, in turn producing dopamine efflux.[77][78]

Lisdexamfetamine is an

inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug's activity.[79] After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine.[7] The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.[7][80]

The

synaptic cleft.[72][73]

Lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine.

diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.[80]

Pharmacokinetics

tmax (4.6 hours vs. 3.3 hours) were longer for lisdexamfetamine than with dextroamphetamine.[64]
This section is transcluded from Amphetamine. (edit | history)

The oral

plasma proteins.[10] Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.[84]

The half-lives of amphetamine enantiomers differ and vary with urine pH.[83] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.[83] Highly acidic urine will reduce the enantiomer half-lives to 7 hours;[84] highly alkaline urine will increase the half-lives up to 34 hours.[84] 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.[83] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[83] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.[83] 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.[83] Following oral administration, amphetamine appears in urine within 3 hours.[84] Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.[84] 

Lisdexamfetamine is a

parenteral use does not enhance the subjective effects of lisdexamfetamine.[13][64] Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.[13][64]

sympathomimetics are 4-hydroxyamphetamine,[87] 4-hydroxynorephedrine,[88] and norephedrine.[89] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[83][90]
The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans[sources 1]
Graphic of several routes of amphetamine metabolism
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[86] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).[83] The remaining 10–20% is excreted as the active metabolites.[83] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA, which is then metabolized by GLYAT into hippuric acid.[96]

Chemistry

Lisdexamfetamine is a

IUPAC nomenclature, but it is usually named as N-[(2S)-1-phenyl-2-propanyl]-L-lysinamide or (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide.[100]
The condensation reaction occurs with loss of water:

(S)-PhCH
2CH(CH
3)NH
2   +   (S)-HOOCCH(NH
2)CH
2CH
2CH
2CH
2NH
2   →   (S,S)-PhCH
2CH(CH
3)NHC(O)CH(NH
2)CH
2CH
2CH
2CH
2NH
2   +   H
2O

water-soluble (792 mg mL−1) powder with a white to off-white color.[7]

PhCH
2CH(CH
3)NHC(O)CH(NH
2)CH
2CH
2CH
2CH
2NH
2   +   2 CH
3SO
3H   →   [PhCH
2CH(CH
3)NHC(O)CH(NH+
3)CH
2CH
2CH
2CH
2NH+
3][CH
3SO−
3]
2

Comparison to other formulations

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.

Amphetamine base in marketed amphetamine medications
drug formula molar mass
[note 4] 		amphetamine base
[note 5] 		amphetamine base
in equal doses 		doses with
equal base
content
[note 6]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[103][104] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
22.0 mg
—
30.0 mg
amphetamine sulfate[105] (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[103][104] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
—
25% amphetamine sulfate[105] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[106] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
—
25% amphetamine aspartate monohydrate[107] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[85]
 C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
—
8.9 mg
—
74.2 mg
amphetamine base suspension[108] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

History

See also: History and culture of substituted amphetamines

Lisdexamfetamine was

red blood cells delays its onset of action, regardless of the route of administration.[109]

In February 2007, the US Food and Drug Administration (FDA) approved lisdexamfetamine for the treatment of ADHD.[110] In August 2009, Health Canada approved the marketing of lisdexamfetamine for prescription use.[111]

In January 2015, lisdexamfetamine was approved by the FDA for treatment of binge eating disorder in adults.[112]

The FDA gave tentative approval to

patent protection of lisdexamfetamine in the US was 24 February 2023.[113] The Canadian patent expires 20 years from the filing date of 1 June 2004.[114]

Production quotas for 2016 in the United States were 29,750 kg.[115]

Society and culture

Name

Elvanse Adult capsules 50mg and 70mg laid on the packaging (German)

Lisdexamfetamine is the

International Nonproprietary Name (INN) and is a contraction of L-lysine-dextroamphetamine.[116]

As of November 2020, lisdexamfetamine is sold under the following brand names: Aduvanz, Elvanse, Juneve, Samexid, Tyvense, Venvanse, and Vyvanse.[117]

Research

Depression

Some clinical trials that used lisdexamfetamine as an

third-line adjunctive agents.[120]

In February 2014, Shire announced that two late-stage

network meta-analysis, lisdexamfetamine was significantly effective as an antidepressant augmentation for treatment-resistant depression.[120]

Although lisdexamfetamine has shown limited effectiveness in the treatment of depression in clinical trials, a

clinical study found that the addition of lisdexamfetamine to an antidepressant improved executive dysfunction in people with mild major depressive disorder but persisting executive dysfunction.[124][125]

While development of lisdexamfetamine for major depressive disorder and

bipolar depression was discontinued, the drug remains in phase II clinical trials for treatment of mood disorders as of October 2021.[122]

Explanatory notes

  1. 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).[33]

    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.[33]
  2. ^ Cochrane reviews are high quality meta-analytic systematic reviews of randomized controlled trials.[40]
  3. ^ 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.[91][95] 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;[95][97] however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in synaptic vesicles within noradrenergic neurons in the brain.[98][99]
  4. ^ For uniformity, molar masses were calculated using the Lenntech Molecular Weight Calculator[102] and were within 0.01 g/mol of published pharmaceutical values.
  5. ^ Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  6. ^ 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.

Reference notes

  1. ^ a b [83][91][92][93][94][86][95][96]

References

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    Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
    Adderall [Peak:2–3 h] [Duration:5–7 h]
    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
    Adderall XR [Peak:7–8 h] [Duration:12 h]
    Vyvanse [Peak:3–4 h] [Duration:12 h]
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    . Several other studies,[97-101] including a meta-analytic review[98] and a retrospective study,[97] suggested that stimulant therapy in childhood is associated with a reduced risk of subsequent substance use, cigarette smoking and alcohol use disorders. ... Recent studies have demonstrated that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for more than 2-year treatment periods with few and tolerable adverse effects. The effectiveness of long-term therapy includes not only the core symptoms of ADHD, but also improved quality of life and academic achievements. The most concerning short-term adverse effects of stimulants, such as elevated blood pressure and heart rate, waned in long-term follow-up studies. ... The current data do not support the potential impact of stimulants on the worsening or development of tics or substance abuse into adulthood. In the longest follow-up study (of more than 10 years), lifetime stimulant treatment for ADHD was effective and protective against the development of adverse psychiatric disorders.
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    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
  55. ISBN 9780071624428
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  56. ^ Bracken NM (January 2012). "National Study of Substance Use Trends Among NCAA College Student-Athletes" (PDF). NCAA Publications. National Collegiate Athletic Association. Archived (PDF) from the original on 9 October 2022. Retrieved 8 October 2013.
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    . 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.
  59. ^
    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.
  60. 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.
  61. 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)
  62. S2CID 22782401
    . 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.
  63. ^ a b c "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.
  64. ^
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    . Inactive lisdexamfetamine is completely (>98%) converted to its active metabolite D-amphetamine in the circulation (Pennick, 2010; Sharman and Pennick, 2014). When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al., 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al., 2011) thus reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine. Intravenous lisdexamfetamine use also produced significantly lower increases in "drug liking" and "stimulant effects" compared with D-amphetamine in intravenous substance users (Jasinski and Krishnan, 2009a).
  65. ^ "Elvanse Adult 30mg Hard Capsules". Retrieved 26 February 2022. 2. Qualitative and quantitative composition. 30 mg Capsules: Each capsule contains 30 mg lisdexamfetamine dimesylate, equivalent to 8.9 mg of dexamfetamine. 50 mg Capsules: Each capsule contains 50 mg lisdexamfetamine dimesylate, equivalent to 14.8 mg of dexamfetamine. 70 mg Capsules: Each capsule contains 70 mg lisdexamfetamine dimesylate, equivalent to 20.8 mg of dexamfetamine.
  66. PMID 27661399
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  67. ^ Heedes G, Ailakis J. "Amphetamine (PIM 934)". INCHEM. International Programme on Chemical Safety. Retrieved 24 June 2014.
  68. ^ a b c d "Adderall XR- dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate and amphetamine aspartate capsule, extended release". DailyMed. 25 October 2023. Retrieved 18 March 2024.
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    . VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC).
  74. PMID 27141430
    . Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
  75. PMID 21772817
    . Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
  76. ^ "TAAR1". GenAtlas. University of Paris. 28 January 2012. Retrieved 29 May 2014.  • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
  77. PMID 25033183
    . AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
  78. PMID 23968642
    . AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
  79. ^ a b Wishart DS, Djombou Feunang Y, Guo AC, Lo EJ, Marcu A, Grant JR, et al. "Lisdexamfetamine | DrugBank Online". DrugBank. 5.0.
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  81. S2CID 53183893
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  82. ISBN 978-3-030-92391-4
    . Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound's absorption (Markowitz and Patrick 2017).
  83. ^ a b c d e f g h i j k l m n "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Retrieved 30 December 2013.
  84. ^ a b c d e "Metabolism/Pharmacokinetics". Amphetamine. Hazardous Substances Data Bank. United States National Library of Medicine – Toxicology Data Network. 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
  85. ^ a b c d e "Vyvanse- lisdexamfetamine dimesylate capsule Vyvanse- lisdexamfetamine dimesylate tablet, chewable". DailyMed. Shire US Inc. 30 October 2019. Retrieved 22 December 2019.
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  88. ^ "Compound Summary". p-Hydroxynorephedrine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
  89. ^ "Compound Summary". Phenylpropanolamine. PubChem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 15 October 2013.
  90. ^ "Pharmacology and Biochemistry". Amphetamine. Pubchem Compound Database. United States National Library of Medicine – National Center for Biotechnology Information. Retrieved 12 October 2013.
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    . 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.
  92. 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.
  93. PMID 15922018.
    Table 5: N-containing drugs and xenobiotics oxygenated by FMO
  94. PMID 10027866
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  95. ^
    PMID 13977820
    . Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
  96. ^
    S2CID 23738007
    . Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
  97. S2CID 28641000
    . The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
  98. PMID 4457764
    . In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.
    The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
  99. PMID 2600821
    . The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.
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  108. ^ "Dyanavel XR Prescribing Information" (PDF). United States Food and Drug Administration. Tris Pharma, Inc. May 2017. pp. 1–14. Retrieved 4 August 2017. 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. The amphetamine base contains dextro- to levo-amphetamine in a ratio of 3.2:1, which is approximately the ratio in Adderall. The product uses an ion exchange resin to achieve extended release of the amphetamine base.
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