3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.2.9 Psychostimulants

3 min read2 figures

Written by Resident Doctor Committee · Published

Reuptake blockade versus release

The dopamine transporter (DAT) and noradrenaline transporter (NET) are sodium-coupled pumps that clear released catecholamines. Stimulants used in attention-deficit hyperactivity disorder (ADHD) act on both together.

  • Methylphenidate blocks DAT and NET from outside, without entering the terminal or emptying vesicles, so it raises synaptic catecholamines, especially in prefrontal cortex, only as neurones fire.

  • Amfetamine enters the terminal through DAT and NET, disrupts vesicular storage through vesicular monoamine transporter 2 (VMAT2) so monoamines move into the cytosol, and runs the transporters in reverse.

  • Amfetamine therefore releases monoamines rather than acting mainly by blocking reuptake.

Compare the vesicles: methylphenidate blocks DAT and NET from outside and leaves them full, whereas amfetamine is carried in, disrupts VMAT2 and pushes monoamines out through the transporter running in reverse. Drawn for MRCPsychiatrist

Agents

Drug

Main action

Misuse liability

Methylphenidate

Blocks DAT and NET

Depends on formulation and route

Dexamfetamine

Releases monoamines; active as swallowed

Substantial

Lisdexamfetamine

Inactive prodrug that red blood cells hydrolyse to dexamfetamine

Reduced by slower delivery, not removed

Atomoxetine

Selective noradrenaline reuptake inhibitor

Low; not a controlled drug

Modafinil

Weak, atypical DAT blockade

Low, with little euphoria

Atomoxetine and the prefrontal cortex

  • The prefrontal cortex has few dopamine transporters, so NET clears its dopamine.

  • Atomoxetine's NET blockade therefore raises prefrontal dopamine but not nucleus accumbens dopamine, which is why it has little misuse potential.

  • Prefrontal catecholamines follow an inverted U: moderate levels support attention, while too little or too much impairs control, so excessive doses can worsen ADHD.

  • Atomoxetine has a UK adult licence for ADHD, whereas some other ADHD medicines are licensed only for ages 6 to 17.

Prefrontal dopamine terminals have few dopamine transporters, so NET clears much of the dopamine there, while dense transporters clear striatal dopamine directly; this is why NET blockade by atomoxetine raises prefrontal dopamine but not accumbens dopamine. Drawn for MRCPsychiatrist

Alpha-2 agonists

Drug

Receptors

Consequence

Guanfacine

Selective alpha-2A agonist

Strengthens prefrontal network firing for attention and working memory; brainstem action cuts sympathetic outflow, so check blood pressure and pulse

Clonidine

All three alpha-2 subtypes alike, plus brainstem imidazoline sites

Sedation and hypotension limit it; unlicensed for ADHD in the UK, used on specialist advice when tics or sleep problems coexist

Wake-promoting drugs

  • Modafinil is the first-line drug for the excessive daytime sleepiness of narcolepsy.

  • Caffeine competitively blocks adenosine receptors, and the A2A subtype carries its wake-promoting effect.

Methylphenidate formulations

Immediate-release methylphenidate lasts about 3 to 4 hours and modified-release products often 8 to 12, with differing immediate to modified-release splits.

Product

Immediate : modified release

Equasym XL

30:70

Medikinet XL

50:50

Concerta XL and its tablet equivalents

22:78

Reward and misuse

  • Large dopamine surges in the pathway from ventral tegmental area to nucleus accumbens reinforce drug taking and its cues.

  • Faster brain delivery is more reinforcing, so smoking and injection carry more risk than oral use, and crushing modified-release products changes exposure.

  • Amfetamine-type drugs and methylphenidate are the 'smart drugs' healthy students most often misuse as study aids, unlike non-stimulant ADHD drugs.

Adverse effects

Adverse effects follow from raised dopamine and noradrenaline, so effects running against that action are not expected.

Drug

Very common (1 in 10 or more)

Common

Methylphenidate

Insomnia (most common), decreased appetite

Headache, nausea, abdominal pain, tachycardia

Lisdexamfetamine

Decreased appetite (most frequent), insomnia, dry mouth

Weight loss, headache, irritability

Atomoxetine

Headache (most frequent), insomnia, nausea, abdominal pain

Raised pulse and blood pressure

  • Appetite suppression comes from raised hypothalamic noradrenaline and dopamine, so monitor weight and childhood growth.

  • Peripheral catecholamine effects include tachycardia, hypertension, sweating and tremor, so monitor pulse and blood pressure.

  • Of all psychotropic classes, psychostimulants are the one most associated with bruxism.

  • Narrow-angle glaucoma contraindicates both stimulants and atomoxetine, because raised noradrenaline dilates the pupil and can close a narrow drainage angle.

Toxicity, psychosis and withdrawal

  • Catecholamine excess causes agitation, tachycardia, hypertension, arrhythmia and hyperthermia, and severe cases bring seizures, rhabdomyolysis, myocardial infarction or intracerebral haemorrhage.

  • Stimulant psychosis often brings persecutory ideas and tactile or visual hallucinations; sleep deprivation raises the risk, and many episodes settle within days or weeks.

  • Withdrawal brings fatigue, hypersomnia, increased appetite, dysphoria and anhedonia over days or weeks, so assess depression and suicidality.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.