Adderall

SKIP-FOR-NOW for Dylan at 20 — the brain-development concern (real for stimulants in <25yo with chronic use), appetite suppression (problematic for MMA cardio + recovery calories), peak-and-crash dependence trajectory, and the inconvenient fact that d-amphetamine showed no significant cognitive enhancement in healthy adults in the Roberts 2020 meta-analysis make this a wrong-tool-for-the-job pick when modafinil is available. Adderall is excellent for clinical ADHD with appropriate Rx — Dylan does not have that diagnosis.

Adderall is mixed amphetamine salts in a 3:1 (75%:25%) ratio of d-amphetamine to l-amphetamine (the four salt components — dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and amphetamine sulfate — were chosen historically for solubility and PK smoothing, not for distinct CNS effects).

The four-step releaser mechanism:

1. Substrate uptake. Amphetamine enters the presynaptic neuron via DAT/NET/SERT (acting as a substrate, not just a blocker) and crosses the membrane directly via lipid diffusion. This is fundamentally different from modafinil's pure DAT inhibition.

2. TAAR1 agonism (intracellular receptor). Amphetamine activates the trace amine-associated receptor 1 (TAAR1), a Gs/Gq-coupled GPCR located on the intracellular membrane. TAAR1 activation raises cAMP via adenylyl cyclase and triggers PKA/PKC phosphorylation cascades that reverse the polarity of DAT and NET, converting them from reuptake pumps into outward-facing efflux channels. This is the "reverse transport" step central to amphetamine's dopamine-flooding profile.

3. VMAT2 disruption. Amphetamine enters synaptic vesicles via VMAT2 and collapses the proton gradient that holds monoamines in vesicular storage. Cytosolic dopamine, norepinephrine, and serotonin concentrations rise sharply — this is the substrate that DAT/NET will then push out via the reversed transporter.

4. MAO-A inhibition (weak). Mild reversible MAO-A inhibition slows monoamine catabolism, raising the cytosolic pool further.

Net result: The synapse is flooded with dopamine and norepinephrine via non-vesicular efflux. This is mechanistically distinct from a normal action potential (which dumps a quantal vesicle of NT) — amphetamine releases dopamine continuously and dose-dependently rather than in spike-locked pulses. This is what produces the characteristic "amped" subjective state, and also what predicts the abuse liability and dependence profile.

d-amphetamine vs l-amphetamine functional split:

• d-amphetamine (75% of Adderall): Stronger central nervous system effects — more potent DA releaser in striatum, more euphoric, more cognitive amped-ness, more drive. Half-life ~10 hr.
• l-amphetamine (25%): Slightly weaker CNS profile per mg, but disproportionately stronger peripheral cardiovascular and norepinephrine effects — more BP elevation, more HR, more peripheral vasoconstriction. Half-life ~13 hr (longer tail).
• This is why Dexedrine (pure d-amphetamine) has a "cleaner" peripheral profile per mg of CNS effect, and why some clinicians prefer Dexedrine when the cardiovascular load on Adderall is intolerable.

Modern mechanistic caveat (2024-2025): The simple "amphetamine = pure reverse-transporter efflux" model has been challenged. Recent work (Daws lab, Sulzer lab) suggests therapeutic-dose amphetamine may also work by augmenting exocytotic (vesicular) dopamine release and enhancing phasic over tonic signaling — i.e., the dopaminergic burst-to-baseline contrast that drives salience attribution and ADHD-relevant attention. Recreational/high-dose amphetamine pushes the system further into pure reverse-transport mode. Practical implication: low-dose ADHD prescribing may be subtly different mechanistically from high-dose abuse pharmacology.