Mixed amphetamine salts

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Psychostimulant, Amphetamine, CNS stimulant

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.

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

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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.

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Effects

Therapeutic: improved attention and executive function, reduced impulsivity and hyperactivity, increased wakefulness, mild euphoria, increased motivation, mild appetite suppression. Common adverse: decreased appetite (often dose-limiting), insomnia, dry mouth, irritability, anxiety, mild elevation of heart rate and blood pressure, headache, jaw clenching/bruxism, mild weight loss.

Cardiovascular: tachycardia, hypertension, palpitations; rare but reported cases of sudden cardiac death in patients with structural heart disease (FDA warning)
Psychiatric: anxiety, agitation, insomnia, irritability; rarely psychosis or mania (especially in patients with bipolar predisposition)
Dependence and misuse — Schedule II controlled substance; high abuse liability, particularly when crushed/insufflated/injected
Tolerance to therapeutic effects can develop with chronic high-dose use
Growth suppression in children — modest reduction in height/weight velocity with chronic stimulant use
Serotonin syndrome — especially in combination with serotonergic agents or MAOIs
Stereotyped behaviors (skin-picking, repetitive movements) at higher doses
Bruxism and TMJ symptoms
Peripheral vasculopathy — Raynaud-like phenomenon, rare digital ischemia
Lowered seizure threshold (caution in epilepsy)
Hyperthermia — risk in hot environments or with vigorous exercise
Withdrawal on abrupt discontinuation — fatigue, depression, hypersomnia, increased appetite ("crash")

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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.^[1] Elimination: Primarily renal — ~30–40% recovered as unchanged amphetamine, the rest as metabolites. Due to its pK_a 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.

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).

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.

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

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, 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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Mixed amphetamine salts

Experience

Problems

Titration strategies

Effects

Pharmacokinetics

Pharmacodynamics

Interactions

Pregnancy and lactation

Monitoring

Patient counseling

Relevant anecdote

Relevant Literature

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