Mechanism of Action of Amphetamine
Amphetamine primarily works by blocking the reuptake of dopamine and norepinephrine transporters, while also directly stimulating the release of these monoamines from presynaptic terminals, making it a potent central nervous system stimulant. 1, 2
Primary Mechanisms
- Amphetamine inhibits dopamine and norepinephrine transporters, preventing reuptake of these neurotransmitters from the synaptic cleft 1, 3
- Amphetamine directly stimulates the release of norepinephrine and dopamine from presynaptic terminals, increasing extracellular levels of these monoamines 1, 4
- Amphetamine inhibits vesicular monoamine transporter 2 (VMAT-2), causing depletion of synaptic vesicles and increasing intracellular monoamine levels 5, 3
- Amphetamine inhibits monoamine oxidase activity, which further increases monoamine levels by preventing their breakdown 2, 3
- Amphetamine shows agonist activity at serotonin type 1A receptors, contributing to its overall effects 1, 3
Molecular Actions
- Amphetamine acts as a substrate for monoamine transporters, entering the presynaptic neuron where it disrupts vesicular storage of monoamines 5, 4
- Once inside neurons, amphetamine causes reverse transport (efflux) of dopamine and norepinephrine through their respective transporters 5, 4
- Amphetamine's weak base properties allow it to disrupt the pH gradient necessary for proper vesicular storage of monoamines 4
- At the trace amine receptor 1 (TA1), amphetamine acts as an agonist with pEC50 values of 6.0-6.7 for the human receptor, contributing to its stimulant effects 6
Pharmacodynamic Effects
- Amphetamine significantly enhances executive function, working memory, and inhibitory control in the prefrontal cortex 1, 7
- Amphetamine occupies a high proportion of dopamine transporter sites in the striatum when given orally 1
- The facilitative effects on locomotor activity and reinforcement processes are mediated by dopaminergic effects at the nucleus accumbens 7
- Effects on delayed responding and working memory are mediated by noradrenergic afferents from the locus coeruleus to prefrontal cortex 7
Clinical Implications
- Amphetamine produces stronger stimulant effects with greater impact on neurotransmitter systems than other stimulants like caffeine 1
- Amphetamine's mechanism of action makes it effective for treating ADHD, narcolepsy, and obesity 5, 8
- The rewarding and potentially addictive properties of amphetamine rely on its ability to increase extracellular levels of monoamines, particularly dopamine 5, 8
- Lisdexamfetamine, a prodrug of dextroamphetamine, works through the same mechanisms after conversion to the active form 9
Pharmacokinetic Considerations
- Amphetamine's immediate-release forms act within 30 minutes with effects lasting 3-4 hours 1
- Amphetamine's plasma half-life ranges from 3 hours to 11 hours 1
- Lisdexamfetamine, as a prodrug, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro until converted to dextroamphetamine 9
Side Effects Related to Mechanism
- Amphetamine can cause pronounced side effects including decreased appetite, sleep disturbances, increased blood pressure and heart rate due to its sympathomimetic actions 1, 3
- Long-term use can lead to growth suppression in children, likely related to its effects on appetite and metabolic processes 1
- Amphetamine's mechanisms may contribute to neurotoxicity through the production of reactive oxygen and nitrogen species 4
Understanding amphetamine's complex mechanism of action helps explain both its therapeutic efficacy in conditions like ADHD and its potential for abuse and addiction.