Mixed amphetamine salts
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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. "Adderall" was approved by the FDA in 1996, and has since become one of the most popular medicines 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.
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
Typical Adult+1
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).Effects
- Attention and focus 100% +83.5 (n=2) ~80% +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=2) ~50% +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% +83.5 (n=2) ~80% +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)
- Motivation and drive 100% +66.5 (n=2) ~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 50% +100.0 (n=2) ~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)
- Decreased appetite/Anorexia 100% +50.0 (n=2) ~50% +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)
- Dry mouth 50% -33.0 (n=2) ~66% -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 50% +0.0 (n=2) ~50% -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 50% -33.0 (n=2) ~33% -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)
- Insomnia 0% — (n=2) ~5% -67.0 (n=1)(with proper am 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)
- Irritability 50% -33.0 (n=2) ~20% -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=2) ~20% -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)
- Headache 0% — (n=2) ~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)
- Weight loss 0% — (n=2) ~20% +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)
- Palpitations 0% — (n=2) ~20% -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)
- Stereotyped behaviors 50% -67.0 (n=2) ~5% -67.0 (n=1)Repetitive movements, e.g. skin picking, muscle twitches, ticsDid 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=2) ~0% -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)
- Agitation 0% — (n=2) ~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=2) ~5% -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)
- Mania 0% — (n=2) ~5% -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)
- Dependence / misuse 0% — (n=2) ~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)
- Tolerance 50% -33.0 (n=2) ~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)
- Growth suppression 0% — (n=2) ~0% -67.0 (n=1)(well documented effect with chronic use in 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=2) ~0% -100.0 (n=1)Especially in combination with MAOIsDid 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=2) ~5% -33.0 (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)
- Seizure/Epileptic fit 0% — (n=2) ~0% -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)
- Hyperthermia 0% — (n=2) ~0% -67.0 (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/Discontinuation Syndrome 50% -33.0 (n=2) ~50% -67.0 (n=1)Low motivation, low mood, 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)
Urinary Retention 50% -33.0 (n=2) ~33% -33.0 (n=1)
Difficult/slow urination
Did you experience this?
How often have you seen this?
How was it? (-100 worst, +100 best)How was it? (-100 worst, +100 best)
Confusion no reports yet no reports yet
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.
Relevant anecdote
⚕️ Provider +1
I've started warning people about increased bowel motility with this medicine, encouraging people to not trust their farts too much :)
Relevant Literature
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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
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
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
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.[2] 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.
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.
Indications
- 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
Typical Adult+1
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).