Generic Name:
mixed amphetamine salts

Trade Name:
Adderall ® [
Shire]

Drug Constituents:
dextroamphetamine saccharate; d,l-amphetamine aspartate monohydrate; dextroamphetamine sulfate; d,l-amphetamine sulfate

Dosage Forms/Routes:
Tablet/oral;
Extended release capsule/oral

Major Metabolite:
p-hydroxyamphetamine;
p-hydroxynorephedrine; norephedrine

Database Search Links:
[PubMed]

[Search PubMed for
Randomized Controlled Trials
]

[
PubChem]
[PDSP Ki database]

Initial Approval:
01/19/1960


Manufacturers:

[FDA Search]

Product Insert:
[Tablet]
[Extended Release Capsule]

RxList:
[Link 1]
[Link 2] (XR)

Epocrates:
[Link]

Indications:
ADHD

Possible Mechanisms of Action:
At plasmalemmal catecholamine transporters, amphetamine indirectly increases the efflux of cytosolic catecholamines so that they are released into the synaptic cleft (1). The drug causes the release of norepinephrine more potently than it causes the release of dopamine; it is much less effective as a serotonin releasing agent (1) The drug also directly inhibits norepinephrine and dopamine reuptake at higher concentrations (1). Amphetamine- induced activation of protein kinase C (PKC) beta(II) is responsible for the drug's effect on dopamine efflux (2). Na+ is cotransported with amphetamine as it enters neurons via catecholamine transporters; amphetamine-induced increases in intracellular Na+ may stimulate Na+/Ca2+ antiporters, resulting in an influx of Ca2+ into the cytosol (3). The activity of a Ca2+ dependent enzyme, phospholipase C (PLC), is increased by amphetamine, and PLC may be responsible for the increase in PKC beta(II) activity associated with amphetamine (3). Intracellular dopamine is also required for amphetamine- induced increases in PKC activity (3). Amphetamine increases the activity of phospholipase A2 (PLA2), perhaps by increasing intracellular pH (3). Low PLA2 activity may increase the activation of PKC, while high PLA2 activity may decrease the activation of PKC by amphetamine (3).

Amphetamine, a weak base, increases cytosolic dopamine and norepinephrine through two mechanisms. First, amphetamine inhibits vesicular sequestration of dopamine and norepinephrine into vesicles by directly interacting with vesicular monoamine transporter-2 (VMAT-2) (4). Second, amphetamine decreases VMAT-2 activity by reducing the pH gradients that drive monoamine uptake into vesicles (5).

At higher concentrations, amphetamine may act as a competitive antagonist at NMDA receptors (6). In addition, the drug is an agonist at TA1, a trace amine receptor (7).

Chemical Class:
amphetamine

1. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS.
Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin.
Synapse 2001 Jan;39(1):32-41
[Abstract]

2. Johnson LA, Guptaroy B, Lund D, Shamban S, Gnegy ME.
Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta.
J Biol Chem. 2005 Mar 25;280(12):10914-9. [Abstract]

3. Giambalvo CT.
Mechanisms underlying the effects of amphetamine on particulate PKC activity.
Synapse. 2004 Feb;51(2):128-39. [Abstract]

4. Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E.
Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.
Proc Natl Acad Sci U S A. 1996 May 14;93(10):5166-71. [Full Text]

5. Sulzer D, Rayport S.
Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: a mechanism of action.
Neuron. 1990 Dec;5(6):797-808. [Abstract]

6. Yeh GC, Chen JC, Tsai HC, Wu HH, Lin CY, Hsu PC, Peng YC.
Amphetamine inhibits the N-methyl-D-aspartate receptor-mediated responses by directly interacting with the receptor/channel complex.
J Pharmacol Exp Ther. 2002 Mar;300(3):1008-16. [Full Text]

7. Miller GM, Verrico CD, Jassen A, Konar M, Yang H, Panas H, Bahn M, Johnson R, Madras BK.
Primate trace amine receptor 1 modulation by the dopamine transporter.
J Pharmacol Exp Ther. 2005 Jun;313(3):983-94. [Abstract]