Mixed amphetamine salts: Difference between revisions
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| structure = Amphetamine-white.svg | | structure = Amphetamine-white.svg | ||
| classes = Psychostimulant, Amphetamine | | classes = Psychostimulant, Amphetamine | ||
| uses = <vote slug="inattention">Inattention</vote>, <vote slug="narcolepsy">Narcolepsy</vote> | |||
| uses = <vote slug=" | | starting_dose = 5 mg XR | ||
| | | preparations = IR tabs 5–30 mg; XR caps 5–30 mg; Mydayis caps 12.5–50 mg | ||
| routes = Oral | | routes = Oral | ||
| onset = IR: 30–60 min; XR: 1–2 h to peak effect | | onset = IR: 30–60 min; XR: 1–2 h to peak effect | ||
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| pregnancy = Category C | | pregnancy = Category C | ||
| legal = Schedule II | | legal = Schedule II | ||
| 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). 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. | ||
| 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. | | 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. | ||
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* Narcolepsy | * Narcolepsy | ||
* Off-label: treatment-resistant depression (augmentation), excessive daytime sleepiness in shift-work disorder, cognitive symptoms in chronic illness | * Off-label: treatment-resistant depression (augmentation), excessive daytime sleepiness in shift-work disorder, cognitive symptoms in chronic illness | ||
| dosing = | | dosing = <titration slug="typical-adult" title="Typical Adult" author="MDElliottMD"> | ||
<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. | ||
Start at | |||
Occasionally can go higher if no notable effects (good or bad) at 60 mg — proceed with caution. | |||
If not long enough acting: | If not long enough acting: add a tail dose of Adderall IR at [XR dose]/2. | ||
If too long acting (e.g. disrupting sleep) | If too long acting (e.g. disrupting sleep): switch to IR entirely (again at half the XR dose). | ||
</titration> | </titration> | ||
| effects = | | effects = ==== Therapeutic ==== | ||
* <effect slug="attention" label="Attention and focus" author="MDElliottMD">Improved attention, executive function, and working memory.</effect> | |||
==== Therapeutic ==== | * <effect slug="reduced-impulsivity" label="Reduced impulsivity and hyperactivity" author="MDElliottMD"/> | ||
* <effect slug="attention" label="Attention and focus">Improved attention, executive function, and working memory.</effect> | * <effect slug="wakefulness" label="Wakefulness" author="MDElliottMD"/> | ||
* <effect slug="reduced-impulsivity" label="Reduced impulsivity and hyperactivity"/> | * <effect slug="motivation" label="Motivation and drive" author="MDElliottMD"/> | ||
* <effect slug="wakefulness" label="Wakefulness"/> | * <effect slug="euphoria" label="Mild euphoria" author="MDElliottMD"/> | ||
* <effect slug="motivation" label="Motivation and drive"/> | |||
* <effect slug="euphoria" label="Mild euphoria"/> | |||
==== Common ==== | ==== Common ==== | ||
* <effect slug="decreased-appetite" label="Decreased appetite">Often dose-limiting; may produce weight loss over time.</effect> | * <effect slug="decreased-appetite" label="Decreased appetite" author="MDElliottMD">Often dose-limiting; may produce weight loss over time.</effect> | ||
* <effect slug="insomnia" label="Insomnia">Especially with late-afternoon dosing.</effect> | * <effect slug="insomnia" label="Insomnia" author="MDElliottMD">Especially with late-afternoon dosing.</effect> | ||
* <effect slug="dry-mouth" label="Dry mouth"/> | * <effect slug="dry-mouth" label="Dry mouth" author="MDElliottMD"/> | ||
* <effect slug="irritability" label="Irritability"/> | * <effect slug="irritability" label="Irritability" author="MDElliottMD"/> | ||
* <effect slug="anxiety" label="Anxiety"/> | * <effect slug="anxiety" label="Anxiety" author="MDElliottMD"/> | ||
* <effect slug="hr-bp-elevation" label="Elevated heart rate / blood pressure">Usually mild but dose-dependent.</effect> | * <effect slug="hr-bp-elevation" label="Elevated heart rate / blood pressure" author="MDElliottMD">Usually mild but dose-dependent.</effect> | ||
* <effect slug="headache" label="Headache"/> | * <effect slug="headache" label="Headache" author="MDElliottMD"/> | ||
* <effect slug="bruxism" label="Jaw clenching / bruxism">May produce TMJ symptoms over time.</effect> | * <effect slug="bruxism" label="Jaw clenching / bruxism" author="MDElliottMD">May produce TMJ symptoms over time.</effect> | ||
* <effect slug="weight-loss" label="Weight loss"/> | * <effect slug="weight-loss" label="Weight loss" author="MDElliottMD"/> | ||
==== Cardiovascular ==== | ==== Cardiovascular ==== | ||
* <effect slug="palpitations" label="Palpitations"/> | * <effect slug="palpitations" label="Palpitations" author="MDElliottMD"/> | ||
* <effect slug="cardiac-event" label="Serious cardiac event">Rare reports of sudden cardiac death in patients with structural heart disease (FDA warning).</effect> | * <effect slug="cardiac-event" label="Serious cardiac event" author="MDElliottMD">Rare reports of sudden cardiac death in patients with structural heart disease (FDA warning).</effect> | ||
==== Psychiatric ==== | ==== Psychiatric ==== | ||
* <effect slug="agitation" label="Agitation"/> | * <effect slug="agitation" label="Agitation" author="MDElliottMD"/> | ||
* <effect slug="psychosis" label="Psychosis">Rare; higher risk in patients with bipolar predisposition.</effect> | * <effect slug="psychosis" label="Psychosis" author="MDElliottMD">Rare; higher risk in patients with bipolar predisposition.</effect> | ||
* <effect slug="mania" label="Mania">Rare; higher risk in patients with bipolar predisposition.</effect> | * <effect slug="mania" label="Mania" author="MDElliottMD">Rare; higher risk in patients with bipolar predisposition.</effect> | ||
==== Other adverse ==== | ==== Other adverse ==== | ||
* <effect slug="dependence" label="Dependence / misuse">Schedule II controlled substance; high abuse liability, particularly when crushed, insufflated, or injected.</effect> | * <effect slug="dependence" label="Dependence / misuse" author="MDElliottMD">Schedule II controlled substance; high abuse liability, particularly when crushed, insufflated, or injected.</effect> | ||
* <effect slug="tolerance" label="Tolerance">To therapeutic effects, with chronic high-dose use.</effect> | * <effect slug="tolerance" label="Tolerance" author="MDElliottMD">To therapeutic effects, with chronic high-dose use.</effect> | ||
* <effect slug="growth-suppression" label="Growth suppression">Modest reduction in height/weight velocity in chronically-treated children.</effect> | * <effect slug="growth-suppression" label="Growth suppression" author="MDElliottMD">Modest reduction in height/weight velocity in chronically-treated children.</effect> | ||
* <effect slug="serotonin-syndrome" label="Serotonin syndrome">Especially in combination with serotonergic agents or MAOIs.</effect> | * <effect slug="serotonin-syndrome" label="Serotonin syndrome" author="MDElliottMD">Especially in combination with serotonergic agents or MAOIs.</effect> | ||
* <effect slug="stereotypies" label="Stereotyped behaviors">Skin-picking, repetitive movements at higher doses.</effect> | * <effect slug="stereotypies" label="Stereotyped behaviors" author="MDElliottMD">Skin-picking, repetitive movements at higher doses.</effect> | ||
* <effect slug="vasculopathy" label="Peripheral vasculopathy">Raynaud-like phenomenon, rare digital ischemia.</effect> | * <effect slug="vasculopathy" label="Peripheral vasculopathy" author="MDElliottMD">Raynaud-like phenomenon, rare digital ischemia.</effect> | ||
* <effect slug="seizure" label="Lowered seizure threshold">Caution in epilepsy.</effect> | * <effect slug="seizure" label="Lowered seizure threshold" author="MDElliottMD">Caution in epilepsy.</effect> | ||
* <effect slug="hyperthermia" label="Hyperthermia">Risk in hot environments or with vigorous exercise.</effect> | * <effect slug="hyperthermia" label="Hyperthermia" author="MDElliottMD">Risk in hot environments or with vigorous exercise.</effect> | ||
* <effect slug="withdrawal" label="Withdrawal / " | * <effect slug="withdrawal" label="Withdrawal / "crash"" author="MDElliottMD">Fatigue, depression, hypersomnia, increased appetite on abrupt discontinuation.</effect> | ||
| contraindications = * Hypersensitivity to amphetamines | | contraindications = * Hypersensitivity to amphetamines | ||
* Concurrent MAOI use, or within 14 days of MAOI discontinuation | * Concurrent MAOI use, or within 14 days of MAOI discontinuation | ||
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* Report chest pain, palpitations, severe agitation, hallucinations, or signs of poor circulation in extremities. | * Report chest pain, palpitations, severe agitation, hallucinations, or signs of poor circulation in extremities. | ||
* Sudden discontinuation can cause a fatigue/depression "crash" — taper or plan for it. | * Sudden discontinuation can cause a fatigue/depression "crash" — taper or plan for it. | ||
| anecdotes = | | anecdotes = <anecdote slug="2026-05-12" perspective="provider" author="MDElliottMD"> | ||
<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 :) | I've started warning people about increased bowel motility with this medicine, encouraging people to not trust their farts too much :) | ||
</anecdote> | </anecdote> | ||