Mixed amphetamine salts
Psychostimulant, Amphetamine, CNS stimulant
Mixed amphetamine salts
Adderall, Adderall XR, Mydayis
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.
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.[1] Elimination: Primarily renal — ~30–40% recovered as unchanged amphetamine, the rest as metabolites. Due to its pKa 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.
Dextroamphetamine, Lisdexamfetamine, Methylphenidate, Dexmethylphenidate, Modafinil, Atomoxetine, Methamphetamine
Experience
2 personal reports · avg efficacy 90.0/100 · avg side-effect burden 30.0/100 · median use 8 months · median dose 17.5 mg/day · 100% still taking it
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Problems
- Attention-deficit hyperactivity disorder (ADHD) in children, adolescents, and adults
- Narcolepsy
- Off-label: treatment-resistant depression (augmentation), excessive daytime sleepiness in shift-work disorder, cognitive symptoms in chronic illness
Titration strategies
Adderall XR (adults, ADHD): Start 5–10 mg first thing in the morning. Titrate by 5 mg every 4–7 days as tolerated, up to 30 mg/day (FDA labeling). Some clinicians titrate further; doses >40 mg/day are off-label. Adderall XR (children 6–12, ADHD): Start 5–10 mg AM; max 30 mg/day. Adderall IR: Start 5 mg once or twice daily; titrate by 5 mg/week; max 40 mg/day in 2–3 divided doses. Mydayis (long-acting, ≥13 y): 12.5 mg AM; max 25 mg/day (adults), 12.5 mg/day (adolescents). Narcolepsy: 5–60 mg/day in divided doses. Renal/hepatic impairment: caution; reduce dose. Avoid in severe renal impairment.
Effects
Therapeutic
- Attention and focus 100% +100.0 (n=1) ~95% +100.0 (n=1)Improved attention, executive function, and working memory.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Reduced impulsivity and hyperactivity 100% +33.0 (n=1) ~66% +67.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Wakefulness 100% +100.0 (n=1) ~80% +67.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Motivation and drive 100% +100.0 (n=1) ~66% +100.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Mild euphoria 100% +100.0 (n=1) ~80% +67.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
Common
- Decreased appetite 100% +33.0 (n=1) ~50% +33.0 (n=1)Often dose-limiting; may produce weight loss over time.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Insomnia 0% — (n=1) ~20% -67.0 (n=1)Especially with late-afternoon dosing.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Dry mouth 100% -33.0 (n=1) ~66% -67.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Irritability 0% — (n=1) ~5% -67.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Anxiety 0% — (n=1) ~20% -33.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Elevated heart rate / blood pressure 100% -33.0 (n=1) ~50% -33.0 (n=1)Usually mild but dose-dependent.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Headache 0% — (n=1) ~5% -33.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Jaw clenching / bruxism 100% -33.0 (n=1) ~33% -33.0 (n=1)May produce TMJ symptoms over time.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Weight loss 0% — (n=1) ~20% +33.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
Cardiovascular
- Palpitations 0% — (n=1) ~5% -33.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Serious cardiac event 0% — (n=1) ~0% — (n=1)Rare reports of sudden cardiac death in patients with structural heart disease (FDA warning).Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
Psychiatric
- Agitation 0% — (n=1) ~5% -67.0 (n=1)Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Psychosis 0% — (n=1) ~5% -100.0 (n=1)Rare; higher risk in patients with bipolar predisposition.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Mania 0% — (n=1) ~5% -100.0 (n=1)Rare; higher risk in patients with bipolar predisposition.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
Other adverse
- Dependence / misuse 0% — (n=1) ~5% -67.0 (n=1)Schedule II controlled substance; high abuse liability, particularly when crushed, insufflated, or injected.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Tolerance 0% — (n=1) ~5% -33.0 (n=1)To therapeutic effects, with chronic high-dose use.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Growth suppression 0% — (n=1) ~0% — (n=1)Modest reduction in height/weight velocity in chronically-treated children.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Serotonin syndrome 0% — (n=1) ~0% — (n=1)Especially in combination with serotonergic agents or MAOIs.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Stereotyped behaviors 100% -33.0 (n=1) ~5% -67.0 (n=1)Skin-picking, repetitive movements at higher doses.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Peripheral vasculopathy 0% — (n=1) ~5% — (n=1)Raynaud-like phenomenon, rare digital ischemia.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Lowered seizure threshold 0% — (n=1) ~0% — (n=1)Caution in epilepsy.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Hyperthermia 0% — (n=1) ~5% -33.0 (n=1)Risk in hot environments or with vigorous exercise.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
- Withdrawal / 100% — (n=1) ~50% -67.0 (n=1)Fatigue, depression, hypersomnia, increased appetite on abrupt discontinuation.Did you experience this?How often have you seen this?How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
Pharmacokinetics
Pharmacodynamics
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).
Interactions
- MAOIs (phenelzine, tranylcypromine, selegiline, linezolid) — hypertensive crisis, serotonin syndrome; contraindicated
- Serotonergic agents (SSRIs, SNRIs, triptans, tramadol) — serotonin syndrome risk
- Tricyclic antidepressants — additive cardiovascular effects
- Acidifying agents (ammonium chloride, ascorbic acid in large doses, fruit juices) — increase urinary clearance, reduce efficacy
- Alkalinizing agents (sodium bicarbonate, acetazolamide, antacids) — decrease clearance, prolong/intensify effects
- CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) — elevated amphetamine levels
- Antihypertensives — may be antagonized by amphetamine's pressor effects
- Sympathomimetics (pseudoephedrine, phenylephrine) — additive cardiovascular effects
- Alcohol — may mask intoxication; cardiac risk
- Caffeine — additive stimulant effects, anxiety
Pregnancy and lactation
Monitoring
- Baseline: cardiovascular history, blood pressure, heart rate, weight/height, mental health history (especially for psychosis/bipolar/substance use 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
- Periodically reassess continued need; consider drug holidays in children to assess ongoing benefit and minimize growth effects
- Sleep quality (insomnia is dose-limiting)
Patient counseling
- Take in the morning to minimize insomnia; avoid 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.)
- 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.
- Do not share or sell — federal Schedule II controlled substance; serious legal and clinical consequences.
- 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.
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See also
Summary
Classes
Psychostimulant, Amphetamine, CNS stimulant
Common uses
- Distractibility4.0n=1
- Excessive daytime sleepiness in shift-work disorder4.0n=1
- Impaired persistent attention4.0n=2
- Cognitive symptoms in chronic illness3.0n=1
- Impulsivity3.0n=1
Pharmacy
Pharmacology
Routes
Oral
Onset
IR: 30–60 min; XR: 1–2 h to peak effect
Duration
IR 4–6 h; XR 10–12 h; Mydayis 14–16 h
Half-life
D-amphetamine ~10 h; L-amphetamine ~13 h (adults)
Bioavailability
~75–90% (oral)
Pregnancy
Category C
Legal status
Schedule II
Purported mechanism
TAAR1 agonism, VMAT2 substrate, DAT/NET reverse transport — net release of dopamine and norepinephrine