What is the primary difference between the mechanisms of action of methylphenidate and amphetamine?

The primary difference between the mechanisms of action of methylphenidate and amphetamine lies in how they increase dopamine and norepinephrine levels in the synapse. Methylphenidate primarily functions as a norepinephrine-dopamine reuptake inhibitor (NDRI). It binds to and blocks the dopamine transporter (DAT) and norepinephrine transporter (NET), preventing the reuptake of dopamine and norepinephrine from the synapse back into the presynaptic neuron. By blocking reuptake, methylphenidate increases the concentration of these neurotransmitters in the synapse, enhancing neurotransmission. Amphetamine, in contrast, acts both as a reuptake inhibitor and, more importantly, as a releasing agent. Like methylphenidate, amphetamine can inhibit DAT and NET. However, amphetamine also enters the presynaptic neuron and disrupts the vesicular monoamine transporter 2 (VMAT2), leading to an increase in cytosolic dopamine and norepinephrine. This increase, combined with amphetamine's interactions with DAT and NET, causes the transporters to reverse their direction, actively pumping dopamine and norepinephrine out of the neuron and into the synapse. Therefore, while both drugs increase dopamine and norepinephrine levels, methylphenidate primarily does so by blocking reuptake, whereas amphetamine both blocks reuptake and actively promotes neurotransmitter release through transporter reversal. This difference in mechanism contributes to the distinct pharmacological and clinical profiles of these two stimulants.