Adderall pathway

Rotor: the dopamine transporter (DAT; NET in noradrenergic terminals), turning backward = effluxCanisters: IR beads (left) and delayed-release beads behind a 4 h timer (right)Column: plasma amphetamine, d-isomer (dark) under l-isomer (pale), 0–60 ng/mLTray: the presynaptic terminal: vesicles on VMAT2 collars, cytosol pool, TAAR1 leverFront: liver cartridge (CYP2D6, deamination) and kidney with urine pH knob, each to a beaker (% of dose)Mixed amphetamine salts are 3:1 d- to l-amphetamine; 20 mg of salts is about 12.5 mg of base. XR releases half its beads at once and half about 4 h later, so XR 20 mg once (model Cmax 35 ng/mL at 7.1 h) tracks IR 10 mg twice 4 h apart; IR 20 mg peaks at 3.0 h. Amphetamine is a lipophilic weak base: it crosses the blood-brain barrier, rides DAT and NET into the terminal as a substrate (competing with reuptake), enters vesicles through VMAT2 and collapses their pH gradient so dopamine leaks into the cytosol, and activates intracellular TAAR1, whose PKA/PKC signalling phosphorylates DAT. Phosphorylated DAT runs in reverse: dopamine leaves without an action potential and the cleft rises several-fold. Effect fades before plasma does (acute tolerance), so XR covers ~10–12 h though levels persist. In prefrontal cortex D1 and α2A tone sharpens working memory and attention; in the accumbens the same surge is reward and abuse liability; in the periphery noradrenaline raises heart rate and blood pressure. About 30–40 % leaves unchanged in urine at usual pH; acid urine traps the ionised drug (t½ 5.2 h in this model), alkaline urine lets it back (t½ 15.1 h). The rest is oxidised: CYP2D6 4-hydroxylation and deamination to benzoic then hippuric acid. Readout: hours · formulation · plasma d+l ng/mL · synaptic dopamine × baseline · heart rate bpm and systolic mmHg above baseline. Teaching model, calibrated to the label; hover scrubs 0–24 h.

Formulation

Urine pH

CYP2D6

1. What is in the pill

Adderall is mixed amphetamine salts: equal parts dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate. Net result is 3:1 d- to l-amphetamine. 20 mg of salts is about 12.5 mg of amphetamine base (about 63 %).

Product	Release	Tmax	Notes
Adderall IR tablet	Immediate	~3 h	Duration ~4–6 h clinically; usually given once or twice daily, first dose on waking, next 4–6 h later.
Adderall XR capsule	Two bead populations: 50 % immediate, 50 % enteric-coated delayed (~4 h)	~7 h (d), ~8 h (l)	XR 20 mg once is bioequivalent to IR 10 mg twice, 4 h apart. High-fat meal delays Tmax ~2.5 h, AUC unchanged. Capsule may be opened onto applesauce; do not chew beads.

Label PK, XR 20 mg in adults: d-amphetamine Cmax 28.1 ng/mL, AUC 567 ng·h/mL; l-amphetamine Cmax 8.7 ng/mL, AUC 203 ng·h/mL. Half-life d 10 h, l 13 h in adults; 9 and 11 h in children 6–12 (faster weight-adjusted clearance, so children reach lower exposure per mg/kg).

2. The pathway, step by step

Absorption. Well absorbed from the small intestine. Amphetamine is a weak base (pKa 9.9): gut alkalinisers (antacids, sodium bicarbonate, and PPIs for XR) raise the un-ionised fraction and speed absorption; acidifiers (ascorbic acid, fruit juice) lower it.
Distribution. Lipophilic, low plasma protein binding, large apparent volume (~3.4 L/kg for d, back-calculated from label AUC). Crosses the blood-brain barrier and the placenta and enters breast milk.
Entry into the terminal. A substrate of DAT and NET (and weakly SERT), so it is carried into dopamine and noradrenaline terminals and competitively blocks reuptake of the native transmitter. It also diffuses across membranes.
Vesicle emptying. Enters synaptic vesicles through VMAT2 and, as a weak base, buffers the acidic vesicle interior. The proton gradient that drives catecholamine storage collapses and dopamine leaks into the cytosol. Cytosolic dopamine climbs.
TAAR1 and transporter reversal. Intracellular amphetamine activates trace amine-associated receptor 1 (Gs- and G13-coupled). PKA, PKC and CaMKII phosphorylate the DAT N-terminus. Phosphorylated DAT runs in reverse (efflux) and is internalised. With a high cytosolic gradient, dopamine is pumped out into the synapse independent of action potentials and calcium-triggered exocytosis. This is the key difference from methylphenidate, which only blocks DAT/NET.
Minor actions. Weak MAO inhibition at high concentrations; d-isomer is roughly 3–5× more potent than l at releasing dopamine, while the two are closer at noradrenaline, so l-amphetamine adds relatively more peripheral sympathomimetic effect.
Receptors and circuits. Prefrontal cortex: dopamine at D1 and noradrenaline at α2A strengthen persistent firing in working-memory networks (α2A closes HCN channels on dendritic spines). Effect follows an inverted U: therapeutic doses move tone toward the optimum, excess impairs flexibility. Striatum and nucleus accumbens: phasic-like dopamine surge drives reinforcement, which is the basis of abuse liability, greatest with rapid rise (intranasal, IV, crushed). Hypothalamus: anorexia. Reticular activating system: wakefulness (narcolepsy indication).
Periphery. Noradrenaline release at sympathetic terminals: α1 vasoconstriction and β1 chronotropy and inotropy. Mean changes in trials are small (about +2–4 mmHg, +3–6 bpm) but some patients rise much more. Also mydriasis, bronchodilation, dry mouth, sphincter tone.
Elimination. Hepatic oxidation: CYP2D6 4-hydroxylation to 4-hydroxyamphetamine (then dopamine β-hydroxylase to 4-hydroxynorephedrine), α-carbon oxidation and deamination via FMO3 to phenylacetone, then benzoic acid, conjugated with glycine to hippuric acid. Renal: 30–40 % unchanged at usual urine pH. Ion trapping makes urinary recovery 1–75 % depending on urine pH and flow.

3. Targets at a glance

Target	What amphetamine does	Result
DAT, NET	Substrate; competitive inhibitor; reverses transport after phosphorylation	Reuptake blocked; non-exocytotic efflux of DA and NE
VMAT2	Substrate; weak base dissipates vesicular ΔpH	Vesicular DA moves into cytosol
TAAR1	Agonist (intracellular)	PKA/PKC signalling; DAT phosphorylation, efflux, internalisation
SERT	Weak substrate	Minor 5-HT release at therapeutic dose; relevant to serotonin syndrome with serotonergic drugs
MAO	Weak inhibitor at high levels	Small; clinically the MAOI interaction is the opposite direction

4. What the figure models

Part	Stands for	Driven by
Bead canisters, timer	Gut: first pulse, second pulse (XR delayed beads, or the second IR tablet)	First-order absorption, ka 0.95/h (IR beads), 0.6/h after a 4 h lag (DR beads)
Plasma column	d (dark) and l (pale) amphetamine, ng/mL	One compartment, V/F 240 L (d), 290 L (l), calibrated to label Cmax and AUC
Slotted plate	Blood-brain barrier	Effect compartment, keo 1/h
Vesicles, cytosol pool, lever	VMAT2 emptying, cytosolic DA, TAAR1 activation	Sigmoid Emax of brain concentration (EC50 16 ng/mL, Hill 2.5; d weighted 4× l at DA) with acute tolerance: EC50 rises as exposure persists (0.12/h), so effect fades by ~10–12 h on XR while plasma is still a third of Cmax
Lit rotor	DAT: forward = reuptake, backward = efflux	Same Emax
Cleft tank	Synaptic DA, fold over baseline	1 + 5 × Emax (microdialysis-scale, 2–5× at therapeutic exposure)
Dials	PFC D1/α2A tone; heart rate rise	DA and NE Emax; HR max +10 bpm, SBP max +7 mmHg; cardiovascular tolerance half the central
Liver, kidney, beakers	Metabolised vs excreted unchanged, % of dose	Metabolic k fixed (×0.7 with a strong CYP2D6 inhibitor); renal k from urine pH by ion trapping

5. Indications and dosing (US label)

Use	IR	XR
ADHD, age 3–5	Start 2.5 mg daily, +2.5 mg weekly	Not labelled
ADHD, age 6–12	Start 5 mg once or twice daily, +5 mg weekly; rarely above 40 mg/day	Start 10 mg (or 5 mg) each morning, +5–10 mg weekly, max 30 mg
ADHD, age 13–17	As above	Start 10 mg; may go to 20 mg after 1 week
ADHD, adults	Individualise; divided doses	20 mg each morning
Narcolepsy	5–60 mg/day in divided doses (age 6+)	Not labelled

Give in the morning; late doses cause insomnia. Use the lowest effective dose and reassess periodically, including drug holidays in children with growth concerns.

6. Safety

Boxed warning: high potential for abuse and misuse, which can lead to substance use disorder including addiction; misuse and abuse can cause overdose and death. Assess risk before prescribing, counsel on safe storage and not sharing, check the PDMP, reassess regularly.
Contraindications: hypersensitivity to amphetamine; MAOI now or within 14 days (hypertensive crisis). Older labels also listed symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, glaucoma, agitated states and history of drug abuse; these remain clinical cautions.
Cardiovascular: sudden death reported in patients with structural cardiac abnormalities or cardiomyopathy; stroke and MI in adults. Screen personal and family history (sudden death, arrhythmia, syncope, exertional chest pain), examine; ECG or cardiology if findings. Monitor BP and HR.
Psychiatric: new psychosis or mania (screen for bipolar history), aggression, anxiety, tics may worsen.
Growth: weight and height suppression in children; track on growth charts.
Other: lowered seizure threshold, peripheral vasculopathy including Raynaud's, visual accommodation difficulty, serotonin syndrome with serotonergic drugs or CYP2D6 inhibitors.
Common effects: decreased appetite and weight loss, insomnia, dry mouth, headache, abdominal pain, nausea, irritability, anxiety, tachycardia.

7. Interactions that follow from the pathway

Drug or state	Mechanism	Effect
MAOIs (incl. linezolid, IV methylene blue)	More releasable catecholamine, less degradation	Hypertensive crisis; contraindicated within 14 days
CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine)	Less 4-hydroxylation	Higher exposure; serotonin syndrome risk with SSRIs. Start low, monitor
Serotonergic drugs (SSRIs, SNRIs, TCAs, triptans, tramadol, fentanyl, lithium, St John's wort)	Additive 5-HT	Serotonin syndrome
Urinary alkalinisers (acetazolamide, thiazides, bicarbonate)	Less ionised drug in tubule, more reabsorbed	Longer t½, higher levels
Urinary acidifiers (ammonium chloride, ascorbic acid)	Ion trapping in urine	Shorter t½, lower levels
Gut alkalinisers, PPIs (XR)	Faster absorption	Earlier Tmax with XR
Antihypertensives	Sympathomimetic opposition	Reduced BP control

8. Overdose

Sympathomimetic toxidrome: agitation, tremor, hyperreflexia, mydriasis, diaphoresis, tachycardia, hypertension, hyperthermia, psychosis, seizures, arrhythmia; complications include rhabdomyolysis, AKI, ICH, MI, aortic dissection. Treat with benzodiazepines first (agitation, tachycardia, hypertension, seizures), active cooling, IV fluids, and supportive care. Severe persistent hypertension: phentolamine or nitroprusside; avoid unopposed β-blockade. Activated charcoal only early and with a protected airway. Do not acidify urine (worsens myoglobinuric AKI). Serotonin toxicity: cyproheptadine.

9. Testing

Immunoassay urine screens detect amphetamine for about 2–4 days after therapeutic use (longer with alkaline urine). Chiral analysis separates d from l: Adderall gives a mixed d/l pattern, dextroamphetamine products give d only, and selegiline gives l-amphetamine and l-methamphetamine.