Mixed amphetamine salts: Difference between revisions

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 | structure         = Amphetamine-white.svg
 | classes           = Psychostimulant, Amphetamine
-| uses              = <vote slug="inattention">Inattention</vote>, <vote slug="narcolepsy">Narcolepsy</vote>
+| uses              = <vote slug="inattention">Inattention</vote>, <vote slug="narcolepsy">Narcolepsy</vote>, <vote slug="hyperactivity">Hyperactivity</vote>, <vote slug="impulsivity">Impulsivity</vote>, <vote slug="irritability">Irritability</vote>
-| starting_dose     = 5 mg XR
+| starting_dose     = 2.5 mg IR, 5 mg XR, or 12.5mg Mydayis
 | preparations      = IR tabs 5, 7.5, 10, 12.5, 15, 20, 30 mg; XR caps 5, 10, 15, 20, 25, 30 mg; Mydayis caps 12.5, 25, 37.5, 50 mg
+| fda_max           = XR = 40 or 60 mg/d; IR = 40 or 60 mg/d<ref name="carlat">S0</ref>
 | routes            = Oral
 | onset             = IR: 30–60 min; XR: 1–2 h to peak effect
@@ Line 14: / Line 15: @@
 | pregnancy         = Category C
 | legal             = Schedule II
-| mechanism         = TAAR1 agonism, VMAT2 substrate, DAT/NET reverse transport — net release of dopamine and norepinephrine
+| mechanism         = TAAR1 agonism, VMAT2 substrate, DAT/NET reverse transport, net release of dopamine and norepinephrine
-| intro             = '''Mixed amphetamine salts (MAS)''' — marketed primarily as '''Adderall''' — is a 3:1 mixture of dextroamphetamine and levoamphetamine salts (dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate, and amphetamine aspartate). Amphetamine was first synthesized in 1887 by Lazăr Edeleanu, then developed as a medicine in the late 1920s. It has a chiral center and two enantiomers, levoamphetamine and dextroamphetamine; the latter is significantly more centrally psychoactive, while the levo enantiomer contributes more to peripheral noradrenergic effects. MAS is FDA-approved for attention-deficit hyperactivity disorder and narcolepsy. As a Schedule II controlled substance it carries substantial dependence and misuse potential, particularly in academic and occupational settings where it is frequently used off-label as a cognitive enhancer.
+| intro             = '''Mixed amphetamine salts (MAS)''', marketed primarily as '''Adderall''', is a 3:1 mixture of dextroamphetamine and levoamphetamine salts (dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate, and amphetamine aspartate).
-| pharmacokinetics  = '''Absorption:''' Excellent oral bioavailability — sources report ">75%" to "~90%". Food does not significantly affect total absorption but can delay peak concentration. '''Distribution:''' Volume of distribution ~4 L/kg; plasma protein binding less than 20%. Crosses the blood–brain barrier and placenta. '''Metabolism:''' Amphetamine is oxidized to 4-hydroxyamphetamine, α-hydroxyamphetamine, or norephedrine. Norephedrine and 4-hydroxyamphetamine are active metabolites and are further metabolized to 4-hydroxy-norephedrine. Deamination of α-hydroxyamphetamine yields phenylacetone, which is metabolized to benzoic acid and conjugated to its glucuronide and hippuric acid. '''CYP2D6''' is crucial for amphetamine metabolism; genetic polymorphism causes significant inter-patient variability in clearance. Amphetamine itself inhibits monoamine oxidase (MAO), and both CYP1A2 and CYP3A4 contribute to its metabolism.<ref>https://www.ncbi.nlm.nih.gov/sites/books/NBK507808/</ref> '''Elimination:''' Primarily renal — ~30–40% recovered as unchanged amphetamine, the rest as metabolites. Due to its pK<sub>a</sub> of 9.9, urinary elimination is highly pH-dependent: alkaline urine reduces ionization and decreases renal clearance, while acidic urine and high flow rates accelerate clearance via active tubular secretion. '''Half-life:''' The D-enantiomer has a half-life of 9 hours in children (6–12 y), 11 hours in adolescents (13–17 y), and 10 hours in adults. The L-enantiomer is consistently longer-lived: 11 hours in children, 13–14 hours in adolescents, 13 hours in adults.
+Amphetamine was first synthesized in 1887 by Lazăr Edeleanu, then developed as a med in the late 1920s. "Adderall" was approved by the FDA in 1996, and has since become one of the most popular meds in the United States. Adderall/MAS is FDA-approved for attention-deficit hyperactivity disorder and narcolepsy. It is listed in Schedule II of the Controlled Substances Act, and so is tightly regulated in the United States as well as many other countries around the world.
-| pharmacodynamics  = Amphetamine produces its effects through several converging mechanisms at monoaminergic terminals:
+| indications       = <problem ref="adhd" author="MDElliottMD"/>
-* '''Trace amine-associated receptor 1 (TAAR1) agonism''' — activates TAAR1 in monoaminergic neurons, triggering PKA/PKC signaling that phosphorylates the dopamine and norepinephrine transporters (DAT, NET), causing them to internalize and reverse direction.
+<problem ref="narcolepsy" author="MDElliottMD"/>
-* '''VMAT2 substrate''' — enters the presynaptic terminal, displaces dopamine and norepinephrine from vesicles into the cytoplasm.
+<problem ref="trd-augment" author="MDElliottMD">
-* '''Reverse transport via DAT/NET''' — the elevated cytoplasmic monoamine pool is then ejected into the synaptic cleft via the now-reversed transporters. '''This is the primary mechanism of action — release, not reuptake inhibition.'''
+Off-label.
-* '''Weak reuptake inhibition''' at DAT and NET (secondary to release).
+</problem>
-* '''MAO inhibition''' at higher concentrations, slowing presynaptic catabolism of monoamines.
+<problem ref="shift-work" author="MDElliottMD">
-* '''Serotonergic effects''' at high or supratherapeutic doses (relevant to overdose and serotonin syndrome risk).
+Off-label.
+</problem>
+<problem ref="chronic-illness-cog" author="MDElliottMD">
+Off-label.
+</problem>
+<problem ref="impulsivity" author="MDElliottMD"/>
-The net result is a robust increase in synaptic dopamine and norepinephrine in prefrontal cortex, striatum, and nucleus accumbens — underlying both therapeutic (attention, executive function, wakefulness) and reinforcing (euphoria, abuse liability) effects.
+<problem ref="distractibility" author="MDElliottMD">
-| indications       = * Attention-deficit hyperactivity disorder (ADHD) in children, adolescents, and adults
+Impoved sustained attention by decreasing distractibility
-* Narcolepsy
+</problem>
-* Off-label: treatment-resistant depression (augmentation), excessive daytime sleepiness in shift-work disorder, cognitive symptoms in chronic illness
 | dosing            = <titration slug="typical-adult" title="Typical Adult" author="MDElliottMD">
 Start at 5 mg XR; may increase by 5 mg each day until the desired effect is reached, up to 30 mg XR to start, and up to 60 mg XR eventually if necessary, in 10 mg increments.
-Occasionally can go higher if no notable effects (good or bad) at 60 mg — proceed with caution.
+Occasionally can go higher if no notable effects (good or bad) at 60 mg, proceed with caution.
 If not long enough acting: add a tail dose of Adderall IR at [XR dose]/2.
@@ Line 38: / Line 44: @@
 </titration>
 | effects           =
-* <effect ref="attention" author="MDElliottMD">Improved attention, executive function, and working memory.</effect>
+* <effect ref="attention" author="MDElliottMD">Improved sustained attention, particularly on uninteresting things.</effect>
 * <effect ref="reduced-impulsivity" author="MDElliottMD"/>
 * <effect ref="wakefulness" author="MDElliottMD"/>
@@ Line 66: / Line 72: @@
 * <effect ref="hyperthermia" author="MDElliottMD">Risk in hot environments or with vigorous exercise.</effect>
 * <effect ref="withdrawal" author="MDElliottMD">Low motivation, low mood, hypersomnia, increased appetite on abrupt discontinuation.</effect>
-| contraindications = * Hypersensitivity to amphetamines
+* <effect ref="urinary-retention" author="MDElliottMD">Difficult/slow urination</effect>
-* Concurrent MAOI use, or within 14 days of MAOI discontinuation
-* Symptomatic cardiovascular disease, advanced atherosclerosis, moderate–severe hypertension
+<effect ref="focus-intensification"/>
-* Hyperthyroidism
-* Glaucoma
+<effect ref="appetite-suppression"/>
-* Agitated states
-* History of substance use disorder (relative contraindication; careful risk-benefit)
+<effect ref="alertness"/>
-* Caution: structural cardiac abnormalities, bipolar disorder, psychotic disorders, Tourette syndrome / tic disorders
-| interactions      = * '''MAOIs''' (phenelzine, tranylcypromine, selegiline, linezolid) — hypertensive crisis, serotonin syndrome; contraindicated
+<effect ref="executive-functioning"/>
-* '''Serotonergic agents''' (SSRIs, SNRIs, triptans, tramadol) — serotonin syndrome risk
+| pk_absorption     = Excellent oral bioavailability, sources report ">75%" to "~90%". Food does not significantly affect total absorption but can delay peak concentration.
-* '''Tricyclic antidepressants''' — additive cardiovascular effects
+| pk_distribution   = Volume of distribution ~4 L/kg; plasma protein binding less than 20%. Crosses the blood–brain barrier and placenta.
-* '''Acidifying agents''' (ammonium chloride, ascorbic acid in large doses, fruit juices) — increase urinary clearance, reduce efficacy
+| pk_metabolism     = Amphetamine is oxidized to 4-hydroxyamphetamine, α-hydroxyamphetamine, or norephedrine. Norephedrine and 4-hydroxyamphetamine are active metabolites and are further metabolized to 4-hydroxy-norephedrine. Deamination of α-hydroxyamphetamine yields phenylacetone, which is metabolized to benzoic acid and conjugated to its glucuronide and hippuric acid. '''CYP2D6''' is crucial for amphetamine metabolism; genetic polymorphism causes significant inter-patient variability in clearance. Amphetamine itself inhibits monoamine oxidase (MAO), and both CYP1A2 and CYP3A4 contribute to its metabolism.<ref>S1</ref>
-* '''Alkalinizing agents''' (sodium bicarbonate, acetazolamide, antacids) — decrease clearance, prolong/intensify effects
+| pk_elimination    = Primarily renal, ~30–40% recovered as unchanged amphetamine, the rest as metabolites. Due to its pK<sub>a</sub> of 9.9, urinary elimination is highly pH-dependent: alkaline urine reduces ionization and decreases renal clearance, while acidic urine and high flow rates accelerate clearance via active tubular secretion. '''Half-life:''' D-enantiomer 9 h (children 6–12 y), 11 h (adolescents 13–17 y), 10 h (adults); L-enantiomer 11 h, 13–14 h, 13 h respectively.
-* '''CYP2D6 inhibitors''' (fluoxetine, paroxetine, bupropion) — elevated amphetamine levels
+| pharmacodynamics  = Amphetamine purportedly works via several converging mechanisms at monoaminergic terminals:
-* '''Antihypertensives''' — may be antagonized by amphetamine's pressor effects
+* '''Trace amine-associated receptor 1 (TAAR1) agonism''', activates TAAR1 in monoaminergic neurons, triggering PKA/PKC signaling that phosphorylates the dopamine and norepinephrine transporters (DAT, NET), causing them to internalize and reverse direction.
-* '''Sympathomimetics''' (pseudoephedrine, phenylephrine) — additive cardiovascular effects
+* '''VMAT2 substrate''', enters the presynaptic terminal, displaces dopamine and norepinephrine from vesicles into the cytoplasm.
-* '''Alcohol''' — may mask intoxication; cardiac risk
+* '''Reverse transport via DAT/NET''', the elevated cytoplasmic monoamine pool is then ejected into the synaptic cleft via the now-reversed transporters. '''This is the primary mechanism of action, release, not reuptake inhibition.'''
-* '''Caffeine''' — additive stimulant effects, anxiety
+* '''Weak reuptake inhibition''' at DAT and NET (secondary to release).
-| pregnancy_details = Category C. Crosses the placenta. Prenatal amphetamine exposure has been associated with low birth weight, premature delivery, and neonatal withdrawal (agitation, dysphoria, lassitude). Long-term neurodevelopmental outcomes from prescribed therapeutic exposure are less clear and likely modest, but illicit-dose exposure is associated with significant developmental impact. Decision should be individualized; many patients defer ADHD treatment during pregnancy. Excreted in breast milk in clinically significant amounts — breastfeeding generally discouraged.
+* '''MAO inhibition''' at higher concentrations, slowing presynaptic catabolism of monoamines.
-| monitoring        = * Baseline: cardiovascular history, blood pressure, heart rate, weight/height, mental health history (especially for psychosis/bipolar/substance use risk)
+* '''Serotonergic effects''' at high or supratherapeutic doses (relevant to overdose and serotonin syndrome risk).
-* Consider ECG if cardiac risk factors present
-* At each visit: blood pressure, heart rate, weight (and height in children), efficacy, side effects, signs of misuse or diversion
+The net result is a robust increase in synaptic dopamine and norepinephrine in prefrontal cortex, striatum, and nucleus accumbens, underlying both therapeutic (attention, executive function, wakefulness) and reinforcing (euphoria, abuse liability) effects.
-* Periodically reassess continued need; consider drug holidays in children to assess ongoing benefit and minimize growth effects
+| interactions      = Minimal in practice. Caution with other psychostimulants, including caffeine. metabolized by 2D6, so relevant caution applies.
+<pharmaInteractions/>
+| pregnancy_details = [https://www.ncbi.nlm.nih.gov/books/NBK501307/ Category C]. Crosses the placenta. Prenatal amphetamine exposure has been associated with low birth weight, premature delivery, and neonatal withdrawal (agitation, dysphoria, lassitude). Long-term neurodevelopmental outcomes from prescribed therapeutic exposure are less clear and likely modest, but illicit-dose exposure is associated with significant developmental impact. Decision should be individualized; many patients defer ADHD treatment during pregnancy. Excreted in breast milk in clinically significant amounts, breastfeeding generally discouraged.
+| monitoring        = * Baseline: cardiovascular history, weight/height, mental health history (especially for psychosis/bipolar/substance use risk), (optional) blood pressure, (optional) heart rate,
+* At each visit: efficacy, side effects, general well-being
+* Periodically reassess continued need; consider med holidays to assess ongoing benefit
 * Sleep quality (insomnia is dose-limiting)
-| counseling        = * Take in the morning to minimize insomnia; avoid afternoon dosing.
+| counseling        = * Take first thing in the morning to minimize insomnia; avoid (late) afternoon dosing.
-* '''Do not crush, chew, or split Adderall XR or Mydayis capsules''' — disrupts the controlled-release mechanism. (Capsules may be opened and sprinkled on applesauce if needed.)
+* '''Do not crush, chew, or split Adderall XR or Mydayis capsules''', disrupts the controlled-release mechanism. (Capsules may be opened and sprinkled on applesauce if needed.)
 * Take with or without food; high-acid beverages (orange juice, vitamin C) may reduce absorption.
 * Stay well-hydrated, especially in heat or during exercise.
 * Eat regular meals despite appetite suppression.
-* Do not combine with alcohol — masks effects of both, increases cardiac strain.
+* Report any chest pain, palpitations, severe agitation, hallucinations, or signs of poor circulation in extremities.
-* Do not share or sell — federal Schedule II controlled substance; serious legal and clinical consequences.
+* Sudden discontinuation can cause a fatigue/depression "crash", plan for it.
-* Report chest pain, palpitations, severe agitation, hallucinations, or signs of poor circulation in extremities.
+* Take caution: make increase bowel motility and increase risk of expelled fecal content.
-* Sudden discontinuation can cause a fatigue/depression "crash" — taper or plan for it.
+| anecdotes         =
-| anecdotes         = <anecdote slug="2026-05-12" perspective="provider" author="MDElliottMD">
-I've started warning people about increased bowel motility with this medicine, encouraging people to not trust their farts too much :)
-</anecdote>
 | seealso           = [[Dextroamphetamine]], [[Lisdexamfetamine]], [[Methylphenidate]], [[Dexmethylphenidate]], [[Modafinil]], [[Atomoxetine]], [[Methamphetamine]]
 | references        =
-}}<h2 id="Pharmacokinetics">Pharmacokinetics</h2><span></span>
+}}
-'''Absorption:''' Excellent oral bioavailability — sources report ">75%" to "~90%". Food does not significantly affect total absorption but can delay peak concentration. '''Distribution:''' Volume of distribution ~4 L/kg; plasma protein binding less than 20%. Crosses the blood–brain barrier and placenta. '''Metabolism:''' Amphetamine is oxidized to 4-hydroxyamphetamine, α-hydroxyamphetamine, or norephedrine. Norephedrine and 4-hydroxyamphetamine are active metabolites and are further metabolized to 4-hydroxy-norephedrine. Deamination of α-hydroxyamphetamine yields phenylacetone, which is metabolized to benzoic acid and conjugated to its glucuronide and hippuric acid. '''CYP2D6''' is crucial for amphetamine metabolism; genetic polymorphism causes significant inter-patient variability in clearance. Amphetamine itself inhibits monoamine oxidase (MAO), and both CYP1A2 and CYP3A4 contribute to its metabolism.<ref>https://www.ncbi.nlm.nih.gov/sites/books/NBK507808/</ref> '''Elimination:''' Primarily renal — ~30–40% recovered as unchanged amphetamine, the rest as metabolites. Due to its pK<sub>a</sub> of 9.9, urinary elimination is highly pH-dependent: alkaline urine reduces ionization and decreases renal clearance, while acidic urine and high flow rates accelerate clearance via active tubular secretion. '''Half-life:''' The D-enantiomer has a half-life of 9 hours in children (6–12 y), 11 hours in adolescents (13–17 y), and 10 hours in adults. The L-enantiomer is consistently longer-lived: 11 hours in children, 13–14 hours in adolescents, 13 hours in adults.<h2 id="Pharmacodynamics">Pharmacodynamics</h2><span></span>
-Amphetamine produces its effects through several converging mechanisms at monoaminergic terminals:
-*'''Trace amine-associated receptor 1 (TAAR1) agonism''' — activates TAAR1 in monoaminergic neurons, triggering PKA/PKC signaling that phosphorylates the dopamine and norepinephrine transporters (DAT, NET), causing them to internalize and reverse direction.
-*'''VMAT2 substrate''' — enters the presynaptic terminal, displaces dopamine and norepinephrine from vesicles into the cytoplasm.
-*'''Reverse transport via DAT/NET''' — the elevated cytoplasmic monoamine pool is then ejected into the synaptic cleft via the now-reversed transporters. '''This is the primary mechanism of action — release, not reuptake inhibition.'''
-*'''Weak reuptake inhibition''' at DAT and NET (secondary to release).
-*'''MAO inhibition''' at higher concentrations, slowing presynaptic catabolism of monoamines.
-*'''Serotonergic effects''' at high or supratherapeutic doses (relevant to overdose and serotonin syndrome risk).
-The net result is a robust increase in synaptic dopamine and norepinephrine in prefrontal cortex, striatum, and nucleus accumbens — underlying both therapeutic (attention, executive function, wakefulness) and reinforcing (euphoria, abuse liability) effects.<h2 id="Indications">Indications</h2>
+[[Category:Psychostimulants]]
-*Attention-deficit hyperactivity disorder (ADHD) in children, adolescents, and adults
+[[Category:Amphetamines]]
-*Narcolepsy
-*Off-label: treatment-resistant depression (augmentation), excessive daytime sleepiness in shift-work disorder, cognitive symptoms in chronic illness<h2 id="Titration">Titration strategies</h2>
-<span></span><titration slug="typical-adult" title="Typical Adult" author="MDElliottMD">
-Start at 5 mg XR; may increase by 5 mg each day until the desired effect is reached, up to 30 mg XR to start, and up to 60 mg XR eventually if necessary, in 10 mg increments.
-Occasionally can go higher if no notable effects (good or bad) at 60 mg — proceed with caution.
-If not long enough acting: add a tail dose of Adderall IR at [XR dose]/2.
-If too long acting (e.g. disrupting sleep): switch to IR entirely (again at half the XR dose).
-</titration>

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