Lisdexamfetamine

Indications

• FDA-approved for attention-deficit/hyperactivity disorder in children age 6 years and older, adolescents, and adults as a once-daily morning dose.
• FDA-approved for moderate to severe binge eating disorder in adults, the only stimulant with this indication, based on binge-day reduction trials.
• Explicitly not approved and not recommended for weight loss or obesity, a limitation stated in the label and often ignored in practice.
• Favored when abuse or diversion risk is a concern, since the prodrug must be hydrolyzed systemically and is not activated by snorting or injection.
• Used off-label for treatment-resistant depression augmentation and for cognitive fatigue in medically ill or post-traumatic brain injury patients.
• Chewable tablets and dispersible capsule contents make it useful off-label as a stimulant option for patients who cannot swallow capsules.

Mechanism of action

• The lysine conjugate is pharmacologically inert until peptide bond hydrolysis in red blood cells releases active d-amphetamine.
• Released d-amphetamine reverses dopamine and norepinephrine transporter flux and disrupts vesicular storage, producing sustained catecholamine release.
• Rate-limited enzymatic conversion flattens the plasma curve, which reduces euphoria and gives a longer, smoother clinical effect.
• Increased prefrontal norepinephrine and dopamine tone improves sustained attention, working memory, and impulse control.
• In binge eating disorder the benefit is thought to come from dopaminergic effects on reward-driven eating and on impulsivity rather than appetite alone.

Pharmacokinetics

• Prodrug Tmax is about 1 hour while d-amphetamine Tmax is roughly 3.5 hours with capsules and 4.4 hours with chewable tablets.
• Prodrug half-life is under 1 hour; the liberated d-amphetamine half-life is about 11-12 hours in adults, supporting once-daily dosing.
• Conversion occurs by hydrolysis in blood rather than by hepatic CYP enzymes, so CYP-based drug interactions are minimal.
• Food does not affect exposure, though a high-fat meal delays Tmax by about an hour; capsules can be dissolved in water, juice, or yogurt.
• Elimination is largely renal as amphetamine and metabolites, and urinary pH shifts alter amphetamine clearance as with other amphetamines.

Dosing

• ADHD: start 30 mg PO each morning, increase by 10-20 mg at weekly intervals to a maximum of 70 mg/day; give as a single morning dose.
• Binge eating disorder in adults: start 30 mg each morning, titrate by 20 mg weekly to the target range of 50-70 mg/day, maximum 70 mg/day.
• Renal impairment: maximum 50 mg/day when eGFR is 15 to under 30 mL/min/1.73 m2 and 30 mg/day in end-stage disease; not removed by dialysis.
• Capsule contents may be emptied into water, orange juice, or yogurt and consumed immediately; a single capsule must not be split between doses.
• Chewable tablets are milligram-equivalent to capsules and must be chewed completely before swallowing with adequate fluid.
• No taper is required pharmacologically, but abrupt withdrawal after chronic high doses causes fatigue, hypersomnia, and dysphoria for several days.

Adverse effects

• Decreased appetite in about 27 percent, insomnia in 19-27 percent, dry mouth, weight loss, irritability, anxiety, and headache are common.
• Blood pressure and pulse rise modestly, averaging 2-5 mmHg and 3-7 bpm, with occasional clinically important hypertension or tachycardia.
• Late-day dysphoria or rebound is less common than with immediate-release amphetamine but still occurs, especially at higher milligram doses.
• New psychosis, mania, or aggression can develop at usual doses and requires stopping the stimulant rather than adding an antipsychotic.
• Peripheral vasculopathy including Raynaud phenomenon, priapism, and rare sudden cardiac death in structural heart disease are labeled warnings.
• Growth suppression occurs in children, with expected slowing of about 1-2 cm and 1-3 kg over the first years of continuous treatment.

Monitoring

• Baseline height, weight, pulse, blood pressure, cardiac and family sudden-death history, and screening for psychosis, tics, and substance misuse.
• Recheck vital signs and weight at each visit and plot height at least every 6 months in children and adolescents on continuous treatment.
• Track ADHD symptoms with a validated scale, or binge days per week in binge eating disorder, at baseline and after each dose change.
• Reassess renal function periodically in older adults or those on nephrotoxic agents, since dose caps apply below an eGFR of 30.
• Review the prescription drug monitoring program at each refill and ask directly about early refills, sharing, and nonoral use.

Interactions

• Contraindicated within 14 days of an MAOI, including phenelzine, tranylcypromine, selegiline, and linezolid, because of hypertensive crisis risk.
• Urinary alkalinizers such as sodium bicarbonate and acetazolamide raise amphetamine exposure, while acidifying agents shorten its effect.
• Serotonergic drugs including SSRIs, SNRIs, triptans, and tramadol raise the risk of serotonin syndrome when combined with amphetamines.
• Additive pressor effect with decongestants, thyroid hormone, and other stimulants; avoid duplicate stimulant therapy without a specific plan.
• CYP interactions are minimal because activation depends on red blood cell hydrolysis rather than hepatic oxidation.

Special populations

• Pregnancy: amphetamine exposure is linked to lower birth weight and preterm birth in observational data, so reserve for clear clinical need.
• Lactation: amphetamine concentrates in milk with a relative infant dose near 2-14 percent; monitor the infant for agitation and poor weight gain.
• Pediatric: approved from age 6 for ADHD but not for binge eating disorder, which remains an adult indication only.
• Geriatric: no dedicated studies; start at 30 mg or lower, check blood pressure, and reassess cardiovascular risk before continuing.
• Renal impairment requires the labeled dose caps, whereas no hepatic adjustment is specified since activation is not hepatic.

Clinical pearls

• Onset takes 1.5-2 hours; patients expecting an immediate lift often mislabel it as ineffective.
• It is the only stimulant approved for binge eating disorder, and it is not approved for weight loss.
• Dissolving the capsule in liquid does not speed onset, since red blood cells still gate activation.