Clinical Psychopharmacology · Paper A
Substance pharmacology (stimulants)
Cocaine and amphetamines both raise synaptic dopamine, but by different mechanisms with different clinical consequences. For example, imagine two patients with acute stimulant intoxication, one on cocaine develops chest pain from coronary vasospasm, while the other on amphetamine is more likely to show a clear-consciousness psychosis from prolonged dopamine release. In practice, this means naming the specific drug, not just 'stimulant', is needed to predict which complication is more likely.
Cocaine is a pure reuptake inhibitor at the dopamine, noradrenaline and serotonin transporters, producing sympathomimetic intoxication and, via coronary vasospasm, a recognised cause of cardiac ischaemia even in young patients with normal coronary arteries. Amphetamines instead enter the presynaptic terminal and drive transporter-mediated reverse efflux, releasing dopamine directly, on top of reuptake blockade. Take a young patient with chest pain and normal coronary arteries on angiography, found to have used cocaine that day. The upshot: amphetamine's extra releasing action is why its psychotomimetic and dependence-related effects differ from cocaine's, despite both drugs raising synaptic dopamine.
Cocaine and amphetamines both raise dopamine (a driving reward, motivation, and movement) in the , but they do it through different mechanisms, and that difference has real clinical consequences.
A stimulant, in this context, is a drug that increases (and often and ) activity in the brain, producing arousal, euphoria, and increased alertness. What makes cocaine and amphetamines pharmacologically distinct, despite both being called "stimulants," is exactly how each one increases dopamine at the .
For example, imagine two patients with acute stimulant intoxication: the one who used cocaine develops chest pain from coronary vasospasm (sudden narrowing of a heart artery from spasm rather than blockage), while the one who used amphetamine is more likely to show a clear-consciousness psychosis from prolonged, active dopamine release. Naming the specific drug, not just the umbrella term "stimulant," is what predicts which complication is more likely: treating "stimulant intoxication" as one uniform picture is the single biggest mistake in this topic.
Cocaine is a pure reuptake inhibitor (a drug that blocks a transporter protein from removing from the , letting it build up) at the dopamine, noradrenaline, and serotonin transporters. It has no direct releasing action of its own; it simply stops the normal process. Amphetamines go a step further: they enter the presynaptic nerve terminal and drive transporter-mediated reverse efflux (using the same transporter, in reverse, to actively push dopamine out into the synapse), on top of blocking reuptake in the usual way. This "blocks removal only" versus "blocks removal and actively pumps more out" distinction is the mechanistic root of everything else in this topic.
Acute stimulant intoxication produces a sympathomimetic toxidrome (a recognisable pattern of physical signs caused by overactivity of the sympathetic nervous system), including agitation, a racing heart, high blood pressure, and a raised body temperature. Because cocaine drives coronary vasospasm directly, it is a recognised cause of cardiac ischaemia (reduced blood flow to heart muscle) even in young patients with structurally normal coronary arteries and no underlying atherosclerosis. This is an important diagnosis to consider in any young patient presenting with chest pain and a history of recent cocaine use, since the mechanism, and therefore the urgent investigation and management pathway, differs from typical plaque-related angina.
Two look-alike pairs matter most here. First, cocaine versus amphetamine: both are "stimulants" and both can cause agitation and a racing heart, but cocaine's specific complication is coronary vasospasm from pure reuptake blockade, while amphetamine's active dopamine release makes prolonged clear-consciousness psychosis relatively more prominent. Second, stimulant-induced psychosis versus : heavy or prolonged use of either drug can precipitate a psychosis with clear consciousness (the patient remains alert and oriented, unlike a delirium), and the key discriminator from a primary psychotic illness is the timeline: stimulant-induced psychosis typically resolves within days of abstinence, whereas schizophrenia persists regardless of ongoing substance use.
Acute intoxication is diagnosed clinically from the sympathomimetic toxidrome plus a history or urine toxicology consistent with stimulant use. Stimulant-induced psychosis is diagnosed by that same clear-consciousness presentation combined with the timeline: if psychotic symptoms resolve within days of abstinence, that supports a substance-induced picture rather than , which would persist. On the licensed side, (attention-deficit hyperactivity disorder) is diagnosed through a structured clinical assessment against recognised diagnostic criteria, under NICE guidance, before methylphenidate or lisdexamfetamine is ever considered.
A patient with stimulant-induced psychosis needs supportive care and abstinence support rather than long-term antipsychotic treatment aimed at a chronic illness, since the picture is expected to resolve with time off the drug. Stimulant withdrawal itself looks very different from withdrawal from sedative drugs such as alcohol or benzodiazepines: it is driven by monoamine depletion (a temporary shortage of like dopamine and noradrenaline after heavy use) and produces a "crash" of dysphoria (low mood and unease), hypersomnia (excessive sleepiness), and increased appetite. This is fundamentally different from the -rebound hyperexcitability and seizure risk seen in alcohol or benzodiazepine withdrawal, so stimulant withdrawal is managed supportively, with no equivalent life-threatening seizure risk requiring a structured detoxification regime. On the licensed side, methylphenidate is used first-line, alongside psychological and educational support, in the management of under NICE guidance. Lisdexamfetamine is a related option, but with an important pharmacological difference: it is an inactive prodrug (a compound with no effect on its own until the body converts it into the active drug) that must be enzymatically cleaved before it releases active dexamfetamine, which blunts the peak plasma level compared with immediate-release dexamfetamine and gives it a lower misuse potential while still being an effective ADHD treatment.
If a vignette gives you psychosis with clear consciousness that has fully resolved within a few days of stopping a stimulant, do not reach for : the resolving timeline is the deliberate clue pointing to a substance-induced picture instead.
Cocaine blocks dopamine reuptake while amphetamines both block reuptake and actively push dopamine out, and that mechanistic difference is exactly why cocaine intoxication is remembered for coronary vasospasm, amphetamine use for clear-consciousness psychosis, and why the same system is deliberately exploited more cautiously, slower onset, design, when prescribed therapeutically as methylphenidate or lisdexamfetamine for .