Mixed Amphetamine Salts

Indications

• FDA-approved for attention-deficit/hyperactivity disorder; immediate-release tablets are labeled from age 3 and Adderall XR from age 6 years.
• Mydayis, the triple-bead extended-release capsule, is approved for ADHD in patients age 13 years and older with about 16 hours of coverage.
• Immediate-release mixed amphetamine salts are FDA-approved for narcolepsy in patients age 6 years and older.
• Used off-label for treatment-resistant depression augmentation and for apathy or fatigue in medically ill, cancer, or geriatric patients.
• Used off-label for binge eating disorder, where lisdexamfetamine rather than mixed salts holds the actual FDA indication.
• Chosen over methylphenidate when a longer duration or a stronger dopamine-releasing effect is wanted, since the classes are not interchangeable.

Mechanism of action

• Acts as a substrate at the dopamine and norepinephrine transporters, reversing transporter flux so catecholamines are pushed out into the synapse.
• Blocks vesicular monoamine transporter 2 packaging and inhibits monoamine oxidase weakly, raising the cytoplasmic pool available for release.
• Release is not activity-dependent, which explains greater potency and higher abuse liability than the methylphenidate class.
• The dextro isomer favors dopaminergic effects while the levo isomer is relatively more noradrenergic, giving a mixed clinical profile.
• Increased prefrontal catecholamine tone improves working memory and impulse control, while striatal effects drive both benefit and reinforcement.

Pharmacokinetics

• Immediate-release Tmax is about 3 hours; Adderall XR is bimodal with a second bead release near 7 hours and Mydayis adds a third pulse.
• Half-life is roughly 9-11 hours for d-amphetamine and 11-14 hours for l-amphetamine in adults, and shorter in children.
• Partly metabolized by CYP2D6 to 4-hydroxyamphetamine and by deamination, but a large fraction is excreted unchanged in urine.
• Renal elimination is strongly pH dependent: alkaline urine slows excretion and raises levels, while acidic urine shortens duration.
• Food delays Tmax of the extended-release capsules by about 2.5 hours without changing total exposure, so timing consistency matters more than fasting.

Dosing

• Immediate-release for ADHD in patients 6 and older: start 5 mg PO once or twice daily, increase by 5 mg/day weekly, usual max 40 mg/day.
• Adderall XR: children 6-12 start 5-10 mg each morning to a maximum of 30 mg/day; adults typically use 20 mg once daily in the morning.
• Mydayis: adults start 12.5-25 mg each morning with a maximum of 50 mg/day; patients 13-17 years should not exceed 25 mg/day.
• Give the last immediate-release dose by early afternoon and Mydayis on waking, since late dosing is the usual cause of treatment-emergent insomnia.
• Extended-release capsules may be opened onto applesauce and swallowed without chewing; do not divide the contents of a single capsule across doses.
• No taper is pharmacologically required, but abrupt cessation after high chronic doses produces crash fatigue, hypersomnia, and dysphoria.

Adverse effects

• Anorexia and weight loss, insomnia, dry mouth, headache, irritability, and emotional lability are common and largely dose related.
• Blood pressure rises about 2-5 mmHg and heart rate 3-6 bpm on average, with a minority developing sustained hypertension or palpitations.
• Late-day rebound with irritability or tearfulness is common as levels fall and often responds to a small afternoon immediate-release dose.
• Psychosis or mania can emerge at usual doses in about 0.1 percent of patients, requiring the stimulant to be stopped rather than covered.
• Peripheral vasculopathy including Raynaud phenomenon, priapism, and rare serious cardiovascular events including sudden death are labeled risks.
• Growth suppression in children of roughly 1-2 cm and 1-3 kg over the first years of continuous treatment warrants growth chart tracking.

Monitoring

• Baseline height, weight, pulse, blood pressure, cardiac and family history of sudden death, and screening for tics, psychosis, and substance misuse.
• Repeat pulse, blood pressure, and weight at every visit; plot height at least twice yearly in children on continuous treatment.
• Use a validated ADHD rating scale at baseline and after each titration step and document target symptoms rather than global impressions.
• Assess sleep onset, evening appetite, mood in the late afternoon, and any cardiac symptoms such as exertional chest pain or syncope.
• Review the prescription drug monitoring program at each refill and ask directly about sharing, selling, or nonoral use of the medication.

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 levels, while ascorbic acid and acidic urine lower them.
• CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, and quinidine raise exposure and increase the risk of serotonin syndrome per the label.
• Additive pressor effects with decongestants, other stimulants, SNRIs, and thyroid hormone; avoid duplicate stimulant therapy without a clear plan.
• Amphetamines can blunt the antihypertensive effect of guanethidine and similar agents and can raise the risk of arrhythmia with halogenated anesthetics.

Special populations

• Pregnancy: associated with lower birth weight and preterm birth in observational data; use only when benefit clearly outweighs risk and document the discussion.
• Lactation: amphetamine concentrates in breast milk with a relative infant dose of about 2-14 percent, so monitor the infant for irritability and poor feeding.
• Pediatric: immediate-release is labeled from age 3, but treatment before age 6 is rarely appropriate before behavioral parent training is tried.
• Geriatric: reduce starting dose, avoid in uncontrolled hypertension or recent cardiac events, and watch for insomnia, delirium, and appetite loss.
• Renal impairment: clearance falls, so cap doses in severe impairment and avoid in end-stage renal disease, where amphetamines are not dialyzable.

Clinical pearls

• Amphetamines are roughly twice as potent per milligram as methylphenidate; do not convert doses one for one.
• Rebound at 4 pm usually needs a small immediate-release booster, not a bigger morning dose.
• Baking soda, antacids, and alkaline urine prolong the dose; acidic drinks shorten it.