Mixed amphetamine salts
Psychostimulant, Amphetamine
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.
Typical Adult+1
Start at 5mg XR, can increase by 5 mg every day until the desired effect is reached, up to 30mg XR to start, up to 60 mg XR eventually if necessarily, in 10 mg increments.
Can occasionally go higher if no notable effects, good or bad, at 60 mg. Proceed with caution.
If not long enough acting: can add tail dose of Adderall IR at [XR dose]/2.
If too long acting (e.g. disrupting sleep), can switch to IR entirely (again at half the XR dose)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
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