Adderall - Mechanism of Action

Mechanism of Action

With respect to central stimulant actions, the S(+) isomer (i.e., dextroamphetamine) is several times more potent than its R(-)enantiomer (i.e., levoamphetamine); this is not necessarily the case with other actions produced by amphetamine, in particular those produced in the periphery such as cardiovascular actions. Dextroamphetamine induces more euphoria, whereas levoamphetamine induces more depression. The overall greater potency of the dextro form to central actions suggests that this form may have a higher potential for abuse.

Adderall’s inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals formulated exclusively of dextroamphetamine. Although it seems the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported that certain children have a better clinical response to levoamphetamine. Amphetamines are believed to exert their effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine, and serotonin .

It is hypothesized that D-amphetamine acts primarily on the dopaminergic (DA) systems, while L-amphetamine is comparatively norepinephrinergic (NE). The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic dopaminergic pathway. Amphetamine binds to the dopamine transporter (DAT) and blocks the transporter's ability to clear DA from the synaptic space. In addition, amphetamine is transported into the cell, which leads to dopamine efflux (DA is transported out of the cell and into the synaptic space via reverse transport of the DAT).

Amphetamine also possesses the ability to inhibit the enzymes monoamine oxidase-A and -B (MAO-A and MAO-B) in high doses. MAO-A is responsible for the breakdown of serotonin, dopamine, norepinephrine, and epinephrine. MAO-B is responsible for breaking down dopamine (more potently than MAO-A) and phenylethylamine (PEA), which has actions similar to those of amphetamine itself, and is thought to be involved in feelings of lust, confidence, obsession, and sexuality. Some of the first antidepressants successfully marketed are, in fact, monoamine oxidase inhibitors. However, MAO inhibition seen with amphetamine is not substantial enough in duration and quantity to entail the need for a tyramine-limited diet, unlike the more potent and long-lived MAO-inhibiting antidepressants.

Amphetamine's ability to cause the inhibition of MAO results in the accumulation of monoamines: Amphetamine directly stimulates the release of these neurochemicals, resulting in a potent elevation in monoamine neurotransmission. In sum, the effect of amphetamines is to increase neurotransmitter availability in the synapse, by both releasing more neurotransmitters and prolonging their availability in the synapse by slowing their removal.