Central Stimulants

Central stimulants raise dopamine and noradrenaline signalling and increase alertness. Methylphenidate and amphetamine-based drugs (dexamfetamine, lisdexamfetamine, mixed amphetamine salts) treat attention deficit hyperactivity disorder and narcolepsy. Modafinil and armodafinil treat narcolepsy and other sleepiness, and caffeine citrate treats apnoea of prematurity.

Mechanism. Methylphenidate blocks the dopamine and noradrenaline transporters. Amphetamines block reuptake, reverse transporter flow, and inhibit vesicular storage and monoamine oxidase. Modafinil weakly inhibits the dopamine transporter. Caffeine antagonises adenosine receptors.

Pharmacokinetics. Methylphenidate immediate release half-life 2 to 3 hours with effect for 3 to 4 hours; extended release 8 to 12 hours. Dexamfetamine half-life 10 hours. Lisdexamfetamine is a prodrug converted in red blood cells, with a smoother effect and lower misuse risk.

Methylphenidate. Immediate release 5 to 10 mg two to three times daily; extended release 18 to 72 mg each morning. Narcolepsy 10 mg two to three times daily.

Dexamfetamine and lisdexamfetamine. Dexamfetamine 5 to 60 mg daily in divided doses; lisdexamfetamine 30 to 70 mg each morning (binge eating disorder 50 to 70 mg).

Modafinil. 200 to 400 mg each morning for narcolepsy and shift work sleep disorder; armodafinil 150 to 250 mg.

Caffeine citrate. Loading 20 mg/kg then 5 to 10 mg/kg daily for apnoea of prematurity.

Differences. Amphetamines are more potent and have more misuse and psychosis risk. Modafinil has fewer cardiovascular effects.

• Attention deficit hyperactivity disorder: titrate to the lowest effective dose; drug holidays can limit growth effects.
• Narcolepsy: modafinil first; methylphenidate or dexamfetamine second-line.
• Binge eating disorder: lisdexamfetamine.
• Resistant depression, apathy, cancer-related fatigue: specialist use, off-label.
• Missed doses: do not take late in the day to avoid insomnia.

Special groups. Pregnancy: limited data, with a small increase in pre-eclampsia and preterm birth with amphetamines. Breastfeeding: methylphenidate low exposure; avoid amphetamines. Children: from 6 years for attention deficit hyperactivity disorder. Older adults: cardiovascular risk. Kidney impairment: reduce doses. Liver impairment: reduce doses. Regional: strict control limits supply; misuse and cathinone use from khat add stimulant exposure.

Adverse effects. Appetite loss, insomnia, anxiety, irritability, headache, raised blood pressure (2 to 5 mmHg) and heart rate (3 to 6 beats each minute), tics, growth slowing, rarely psychosis, seizures, priapism (methylphenidate), peripheral vasculopathy, and rebound or crash on stopping. Rare sudden death occurs in structural heart disease.

Contraindications. Structural cardiac abnormality, severe hypertension, arrhythmia, hyperthyroidism, glaucoma, psychosis, drug misuse (relative), and monoamine oxidase inhibitors within 14 days.

Interactions. Monoamine oxidase inhibitors (hypertensive crisis), antihypertensives (opposed), phenytoin and warfarin (levels rise), SSRIs and bupropion (CYP2D6 effects on amphetamines).

Monitoring. Blood pressure, pulse, height and weight, sleep, mood and psychotic symptoms, and misuse or diversion.

Referral and escalation. Chest pain, palpitations or syncope, psychosis, or misuse.