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Mixed amphetamine salts: Difference between revisions

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| 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).  
| 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. "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.
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.
| pk_absorption    = Excellent oral bioavailability — sources report ">75%" to "~90%". Food does not significantly affect total absorption but can delay peak concentration.
| pk_distribution  = Volume of distribution ~4 L/kg; plasma protein binding less than 20%. Crosses the blood–brain barrier and placenta.
| 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>https://www.ncbi.nlm.nih.gov/sites/books/NBK507808/</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).
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      = <indication slug="adhd" title="ADHD in children, adolescents, and adults" author="MDElliottMD"/>
| indications      = <indication slug="adhd" title="ADHD in children, adolescents, and adults" author="MDElliottMD"/>
<indication slug="narcolepsy" title="Narcolepsy" author="MDElliottMD"/>
<indication slug="narcolepsy" title="Narcolepsy" author="MDElliottMD"/>
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Difficult/slow urination
Difficult/slow urination
</effect>
</effect>
| pk_absorption    = Excellent oral bioavailability — sources report ">75%" to "~90%". Food does not significantly affect total absorption but can delay peak concentration.
| pk_distribution  = Volume of distribution ~4 L/kg; plasma protein binding less than 20%. Crosses the blood–brain barrier and placenta.
| 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>https://www.ncbi.nlm.nih.gov/sites/books/NBK507808/</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).


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.
| contraindications = * Hypersensitivity to amphetamines
| contraindications = * Hypersensitivity to amphetamines
* Concurrent MAOI use, or within 14 days of MAOI discontinuation
* Concurrent MAOI use, or within 14 days of MAOI discontinuation
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