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| structure        = Amphetamine-white.svg
| structure        = Amphetamine-white.svg
| classes          = Psychostimulant, Amphetamine
| classes          = Psychostimulant, Amphetamine
| mechanism        = TAAR1 agonism, VMAT2 substrate, DAT/NET reverse transport — net release of dopamine and norepinephrine
| uses              = <vote slug="inattention">Inattention</vote>, <vote slug="narcolepsy">Narcolepsy</vote>, <vote slug="hyperactivity">Hyperactivity</vote>, <vote slug="impulsivity">Impulsivity</vote>, <vote slug="irritability">Irritability</vote>
| uses              = <vote slug="Inattention">Inattention</vote>, <vote slug="narcolepsy">Narcolepsy</vote>
| starting_dose    = 2.5 mg IR, 5 mg XR, or 12.5mg Mydayis
| formula          = C<sub>9</sub>H<sub>13</sub>N (parent amphetamine)
| 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
| fda_max          = XR = 40 or 60 mg/d; IR = 40 or 60 mg/d<ref name="carlat">S0</ref>
| 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
Line 14: Line 15:
| pregnancy        = Category C
| pregnancy        = Category C
| legal            = Schedule II
| legal            = Schedule II
| 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.
| 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.<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.
| 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).  
| pharmacodynamics  = Amphetamine produces its effects through several converging mechanisms at monoaminergic terminals:
Amphetamine was first synthesized in 1887 by Lazăr Edeleanu, then developed as a med in the late 1920s. "Adderall" was approved by the FDA in 1996, and has since become one of the most popular meds 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.
* '''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.
| indications      = <problem ref="adhd" author="MDElliottMD"/>
* '''VMAT2 substrate''' — enters the presynaptic terminal, displaces dopamine and norepinephrine from vesicles into the cytoplasm.
<problem ref="narcolepsy" author="MDElliottMD"/>
* '''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.'''
<problem ref="trd-augment" author="MDElliottMD">
* '''Weak reuptake inhibition''' at DAT and NET (secondary to release).
Off-label.
* '''MAO inhibition''' at higher concentrations, slowing presynaptic catabolism of monoamines.
</problem>
* '''Serotonergic effects''' at high or supratherapeutic doses (relevant to overdose and serotonin syndrome risk).
<problem ref="shift-work" author="MDElliottMD">
Off-label.
</problem>
<problem ref="chronic-illness-cog" author="MDElliottMD">
Off-label.
</problem>
 
<problem ref="impulsivity" author="MDElliottMD"/>
 
<problem ref="distractibility" author="MDElliottMD">
Impoved sustained attention by decreasing distractibility
</problem>
| dosing            = <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.
 
Occasionally can go higher if no notable effects (good or bad) at 60 mg, proceed with caution.


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.
If not long enough acting: add a tail dose of Adderall IR at [XR dose]/2.
| indications      = * Attention-deficit hyperactivity disorder (ADHD) in children, adolescents, and adults
If too long acting (e.g. disrupting sleep): switch to IR entirely (again at half the XR dose).
* Narcolepsy
</titration>
* Off-label: treatment-resistant depression (augmentation), excessive daytime sleepiness in shift-work disorder, cognitive symptoms in chronic illness
| effects           =
| dosing            = '''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.
* <effect ref="attention" author="MDElliottMD">Improved sustained attention, particularly on uninteresting things.</effect>
'''Adderall XR (children 6–12, ADHD):''' Start 5–10 mg AM; max 30 mg/day.
* <effect ref="reduced-impulsivity" author="MDElliottMD"/>
'''Adderall IR:''' Start 5 mg once or twice daily; titrate by 5 mg/week; max 40 mg/day in 2–3 divided doses.
* <effect ref="wakefulness" author="MDElliottMD"/>
'''Mydayis (long-acting, ≥13 y):''' 12.5 mg AM; max 25 mg/day (adults), 12.5 mg/day (adolescents).
* <effect ref="motivation" author="MDElliottMD"/>
'''Narcolepsy:''' 5–60 mg/day in divided doses.
* <effect ref="euphoria" author="MDElliottMD"/>
'''Renal/hepatic impairment:''' caution; reduce dose. Avoid in severe renal impairment.
* <effect ref="decreased-appetite" author="MDElliottMD"></effect>
| effects          = | effects =  
* <effect ref="dry-mouth" author="MDElliottMD"/>
* <effect ref="hr-bp-elevation" author="MDElliottMD"/>
* <effect ref="bruxism" author="MDElliottMD"/>
* <effect ref="insomnia" author="MDElliottMD">(with proper am dosing)</effect>
* <effect ref="irritability" author="MDElliottMD"/>
* <effect ref="anxiety" author="MDElliottMD"/>
* <effect ref="headache" author="MDElliottMD"/>
* <effect ref="weight-loss" author="MDElliottMD"/>
* <effect ref="palpitations" author="MDElliottMD"/>
* <effect ref="stereotypies" author="MDElliottMD">Repetitive movements, e.g. skin picking, muscle twitches, tics</effect>
* <effect ref="cardiac-event" author="MDElliottMD"></effect>
* <effect ref="agitation" author="MDElliottMD"/>
* <effect ref="psychosis" author="MDElliottMD"></effect>
* <effect ref="mania" author="MDElliottMD"></effect>
* <effect ref="dependence" author="MDElliottMD"></effect>
* <effect ref="tolerance" author="MDElliottMD"></effect>
* <effect ref="growth-suppression" author="MDElliottMD">(well documented effect with chronic use in children)</effect>
* <effect ref="serotonin-syndrome" author="MDElliottMD">Especially in combination with MAOIs</effect>
* <effect ref="vasculopathy" author="MDElliottMD">Raynaud-like phenomenon, rare digital ischemia.</effect>
* <effect ref="seizure" author="MDElliottMD"></effect>
* <effect ref="hyperthermia" author="MDElliottMD">Risk in hot environments or with vigorous exercise.</effect>
* <effect ref="withdrawal" author="MDElliottMD">Low motivation, low mood, hypersomnia, increased appetite on abrupt discontinuation.</effect>
* <effect ref="urinary-retention" author="MDElliottMD">Difficult/slow urination</effect>


==== Therapeutic ====
<effect ref="focus-intensification"/>
* <effect slug="attention" label="Attention and focus">Improved attention, executive function, and working memory.</effect>
* <effect slug="reduced-impulsivity" label="Reduced impulsivity and hyperactivity"/>
* <effect slug="wakefulness" label="Wakefulness"/>
* <effect slug="motivation" label="Motivation and drive"/>
* <effect slug="euphoria" label="Mild euphoria"/>


==== Common ====
<effect ref="appetite-suppression"/>
* <effect slug="decreased-appetite" label="Decreased appetite">Often dose-limiting; may produce weight loss over time.</effect>
* <effect slug="insomnia" label="Insomnia">Especially with late-afternoon dosing.</effect>
* <effect slug="dry-mouth" label="Dry mouth"/>
* <effect slug="irritability" label="Irritability"/>
* <effect slug="anxiety" label="Anxiety"/>
* <effect slug="hr-bp-elevation" label="Elevated heart rate / blood pressure">Usually mild but dose-dependent.</effect>
* <effect slug="headache" label="Headache"/>
* <effect slug="bruxism" label="Jaw clenching / bruxism">May produce TMJ symptoms over time.</effect>
* <effect slug="weight-loss" label="Weight loss"/>


==== Cardiovascular ====
<effect ref="alertness"/>
* <effect slug="palpitations" label="Palpitations"/>
* <effect slug="cardiac-event" label="Serious cardiac event">Rare reports of sudden cardiac death in patients with structural heart disease (FDA warning).</effect>


==== Psychiatric ====
<effect ref="executive-functioning"/>
* <effect slug="agitation" label="Agitation"/>
| pk_absorption    = Excellent oral bioavailability, sources report ">75%" to "~90%". Food does not significantly affect total absorption but can delay peak concentration.
* <effect slug="psychosis" label="Psychosis">Rare; higher risk in patients with bipolar predisposition.</effect>
| pk_distribution  = Volume of distribution ~4 L/kg; plasma protein binding less than 20%. Crosses the blood–brain barrier and placenta.
* <effect slug="mania" label="Mania">Rare; higher risk in patients with bipolar predisposition.</effect>
| pk_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>S1</ref>
| pk_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:''' D-enantiomer 9 h (children 6–12 y), 11 h (adolescents 13–17 y), 10 h (adults); L-enantiomer 11 h, 13–14 h, 13 h respectively.
| pharmacodynamics  = Amphetamine purportedly works via 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).


==== Other adverse ====
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.
* <effect slug="dependence" label="Dependence / misuse">Schedule II controlled substance; high abuse liability, particularly when crushed, insufflated, or injected.</effect>
| interactions      = Minimal in practice. Caution with other psychostimulants, including caffeine. metabolized by 2D6, so relevant caution applies.
* <effect slug="tolerance" label="Tolerance">To therapeutic effects, with chronic high-dose use.</effect>
<pharmaInteractions/>
* <effect slug="growth-suppression" label="Growth suppression">Modest reduction in height/weight velocity in chronically-treated children.</effect>
| pregnancy_details = [https://www.ncbi.nlm.nih.gov/books/NBK501307/ 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.
* <effect slug="serotonin-syndrome" label="Serotonin syndrome">Especially in combination with serotonergic agents or MAOIs.</effect>
| monitoring        = * Baseline: cardiovascular history, weight/height, mental health history (especially for psychosis/bipolar/substance use risk), (optional) blood pressure, (optional) heart rate,
* <effect slug="stereotypies" label="Stereotyped behaviors">Skin-picking, repetitive movements at higher doses.</effect>
* At each visit: efficacy, side effects, general well-being
* <effect slug="vasculopathy" label="Peripheral vasculopathy">Raynaud-like phenomenon, rare digital ischemia.</effect>
* Periodically reassess continued need; consider med holidays to assess ongoing benefit
* <effect slug="seizure" label="Lowered seizure threshold">Caution in epilepsy.</effect>
* <effect slug="hyperthermia" label="Hyperthermia">Risk in hot environments or with vigorous exercise.</effect>
* <effect slug="withdrawal" label="Withdrawal / "crash"">Fatigue, depression, hypersomnia, increased appetite on abrupt discontinuation.</effect>
| contraindications = * Hypersensitivity to amphetamines
* Concurrent MAOI use, or within 14 days of MAOI discontinuation
* Symptomatic cardiovascular disease, advanced atherosclerosis, moderate–severe hypertension
* Hyperthyroidism
* Glaucoma
* Agitated states
* History of substance use disorder (relative contraindication; careful risk-benefit)
* Caution: structural cardiac abnormalities, bipolar disorder, psychotic disorders, Tourette syndrome / tic disorders
| 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_details = 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)
* Sleep quality (insomnia is dose-limiting)
| counseling        = * Take in the morning to minimize insomnia; avoid afternoon dosing.
| counseling        = * Take first thing in the morning to minimize insomnia; avoid (late) 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.)
* '''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.
* Take with or without food; high-acid beverages (orange juice, vitamin C) may reduce absorption.
* Stay well-hydrated, especially in heat or during exercise.
* Stay well-hydrated, especially in heat or during exercise.
* Eat regular meals despite appetite suppression.
* Eat regular meals despite appetite suppression.
* Do not combine with alcohol — masks effects of both, increases cardiac strain.
* Report any chest pain, palpitations, severe agitation, hallucinations, or signs of poor circulation in extremities.
* Do not share or sell — federal Schedule II controlled substance; serious legal and clinical consequences.
* Sudden discontinuation can cause a fatigue/depression "crash", plan for it.
* Report chest pain, palpitations, severe agitation, hallucinations, or signs of poor circulation in extremities.
* Take caution: make increase bowel motility and increase risk of expelled fecal content.
* Sudden discontinuation can cause a fatigue/depression "crash" — taper or plan for it.
| anecdotes        =  
| anecdotes        =  
| seealso          = [[Dextroamphetamine]], [[Lisdexamfetamine]], [[Methylphenidate]], [[Dexmethylphenidate]], [[Modafinil]], [[Atomoxetine]], [[Methamphetamine]]
| seealso          = [[Dextroamphetamine]], [[Lisdexamfetamine]], [[Methylphenidate]], [[Dexmethylphenidate]], [[Modafinil]], [[Atomoxetine]], [[Methamphetamine]]
| references        =  
| references        =  
}}
}}
[[Category:Psychostimulants]]
[[Category:Amphetamines]]

Latest revision as of 03:16, 19 May 2026

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 med in the late 1920s. "Adderall" was approved by the FDA in 1996, and has since become one of the most popular meds 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.

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
⚕ No clinical reports yet

Log in to add your own experience.

Problems

Impaired persistent attention4.0n=2
Narcolepsy4.0n=1
Treatment-resistant depression (augmentation)2.0n=1
Off-label.
Excessive daytime sleepiness in shift-work disorder4.0n=1
Off-label.
Cognitive symptoms in chronic illness3.0n=1
Off-label.
Impulsivity3.0n=1
Distractibility4.0n=1
Impoved sustained attention by decreasing distractibility
+ Add a problem

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).

+ Add a titration strategy

Effects

  • Attention and focus👤 100% +83.5 (n=2)⚕️ ~80% +100.0 (n=1)
    Improved sustained attention, particularly on uninteresting things.
  • Reduced impulsivity and hyperactivity👤 100% +33.0 (n=2)⚕️ ~50% +67.0 (n=1)
  • Wakefulness👤 100% +83.5 (n=2)⚕️ ~80% +100.0 (n=1)
  • Motivation and drive👤 100% +66.5 (n=2)⚕️ ~66% +100.0 (n=1)
  • Mild euphoria👤 50% +100.0 (n=2)⚕️ ~66% +100.0 (n=1)
  • Decreased appetite/Anorexia👤 100% +50.0 (n=2)⚕️ ~50% +33.0 (n=1)
  • Dry mouth👤 50% -33.0 (n=2)⚕️ ~66% -33.0 (n=1)
  • Elevated heart rate / blood pressure👤 50% +0.0 (n=2)⚕️ ~50% -33.0 (n=1)
  • Jaw clenching / bruxism👤 50% -33.0 (n=2)⚕️ ~33% -33.0 (n=1)
  • Insomnia👤 0% — (n=2)⚕️ ~5% -67.0 (n=1)
    (with proper am dosing)
  • Irritability👤 50% -33.0 (n=2)⚕️ ~20% -67.0 (n=1)
  • Anxiety👤 0% — (n=2)⚕️ ~20% -67.0 (n=1)
  • Headache👤 0% — (n=2)⚕️ ~5% -67.0 (n=1)
  • Weight loss👤 0% — (n=2)⚕️ ~20% +67.0 (n=1)
  • Palpitations👤 0% — (n=2)⚕️ ~20% -67.0 (n=1)
  • Stereotyped behaviors👤 50% -67.0 (n=2)⚕️ ~5% -67.0 (n=1)
    Repetitive movements, e.g. skin picking, muscle twitches, tics
  • Serious cardiac event👤 0% — (n=2)⚕️ ~0% -100.0 (n=1)
  • Agitation👤 0% — (n=2)⚕️ ~5% -67.0 (n=1)
  • Psychosis👤 0% — (n=2)⚕️ ~5% -100.0 (n=1)
  • Mania👤 0% — (n=2)⚕️ ~5% -100.0 (n=1)
  • Dependence / misuse👤 0% — (n=2)⚕️ ~5% -67.0 (n=1)
  • Tolerance👤 50% -33.0 (n=2)⚕️ ~5% -33.0 (n=1)
  • Growth suppression👤 0% — (n=2)⚕️ ~0% -67.0 (n=1)
    (well documented effect with chronic use in children)
  • Serotonin syndrome👤 0% — (n=2)⚕️ ~0% -100.0 (n=1)
    Especially in combination with MAOIs
  • Peripheral vasculopathy👤 0% — (n=2)⚕️ ~5% -33.0 (n=1)
    Raynaud-like phenomenon, rare digital ischemia.
  • Seizure/Epileptic fit👤 0% — (n=2)⚕️ ~0% -100.0 (n=1)
  • Hyperthermia👤 0% — (n=2)⚕️ ~0% -67.0 (n=1)
    Risk in hot environments or with vigorous exercise.
  • Withdrawal/Discontinuation Syndrome👤 50% -33.0 (n=2)⚕️ ~50% -67.0 (n=1)
    Low motivation, low mood, hypersomnia, increased appetite on abrupt discontinuation.
  • Urinary Retention👤 50% -33.0 (n=2)⚕️ ~33% -33.0 (n=1)
    Difficult/slow urination
Focus intensification👤 100% +67.0 (n=1)⚕️ no reports yet
Appetite Suppression👤 100% +33.0 (n=1)⚕️ no reports yet
Alertness👤 100% +33.0 (n=1)⚕️ no reports yet
Executive Functioning👤 100% +67.0 (n=1)⚕️ no reports yet

+ Add an effect

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: D-enantiomer 9 h (children 6–12 y), 11 h (adolescents 13–17 y), 10 h (adults); L-enantiomer 11 h, 13–14 h, 13 h respectively.

Pharmacodynamics

Amphetamine purportedly works via 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

Minimal in practice. Caution with other psychostimulants, including caffeine. metabolized by 2D6, so relevant caution applies.

No interactions reported yet.

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, weight/height, mental health history (especially for psychosis/bipolar/substance use risk), (optional) blood pressure, (optional) heart rate,
  • At each visit: efficacy, side effects, general well-being
  • Periodically reassess continued need; consider med holidays to assess ongoing benefit
  • Sleep quality (insomnia is dose-limiting)

    Patient counseling

  • Take first thing in the morning to minimize insomnia; avoid (late) 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.
  • Report any chest pain, palpitations, severe agitation, hallucinations, or signs of poor circulation in extremities.
  • Sudden discontinuation can cause a fatigue/depression "crash", plan for it.
  • Take caution: make increase bowel motility and increase risk of expelled fecal content.

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See also

Dextroamphetamine, Lisdexamfetamine, Methylphenidate, Dexmethylphenidate, Modafinil, Atomoxetine, Methamphetamine
Structure of Mixed amphetamine salts
Summary
Classes
Psychostimulant, Amphetamine
Common uses
+ 2 more uses →
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
US FDA Max
XR = 40 or 60 mg/d; IR = 40 or 60 mg/d[1]
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
  1. ↑ S0
  2. ↑ S1
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