Genetic polymorphism

A genetic polymorphism is a variation in a DNA sequence that is common enough in a population — conventionally above 1% frequency — to be considered a normal alternative form rather than a rare defect. The word polymorphism describes variation at the population level: it says something about how a gene is distributed across a group, not what any one individual carries. That individual-level fact is called a genotype.

In pharmacology, the most consequential polymorphisms affect genes encoding drug-metabolising enzymes, particularly the cytochrome P450 family. These variants produce distinct metaboliser phenotypes — poor, intermediate, extensive, and ultra-rapid — that reflect how efficiently a person's enzyme clears a given compound. Which phenotype predominates varies between ancestral populations, so a dose that works well on average may not behave the same way across different groups.

How it works · its role

A polymorphism changes the DNA sequence of a gene, which may alter how the protein it encodes folds or functions. In a metabolising enzyme, the effect can range from subtly reduced activity to near-complete loss — or, when extra functional gene copies are inherited, to unusually high activity.

The four phenotypes reflect this spectrum. Poor metabolisers carry alleles that produce a sluggish or non-functional enzyme; a drug that depends on that enzyme accumulates rather than being cleared. Ultra-rapid metabolisers carry additional functional copies and process the drug faster than a standard dose assumes. Intermediate and extensive metabolisers fall between these poles, with extensive (also called normal) metaboliser being the most common phenotype in most populations.

Allele frequencies are not uniform across ancestry groups. Certain loss-of-function alleles in CYP2C19, for example, are considerably more prevalent in East Asian populations than in European ones. This means that epidemiological safety data gathered on one population may not transfer cleanly to another.

Relevance to substances & effects

The enzymes most often discussed in this context — CYP2D6 and CYP2C19 — metabolise a wide range of psychoactive compounds, including opioids, many antidepressants, and some stimulants.

Codeine is the textbook example. It must be converted to morphine by CYP2D6 to produce its effect. Poor metabolisers gain very little from a standard dose. Ultra-rapid metabolisers can reach unexpectedly high morphine levels from the same amount, which has prompted safety advisories around opioid prescribing in several countries.

MDMA is also partially metabolised by CYP2D6, and polymorphisms here affect how the compound accumulates during a session. Many antidepressants — including SSRIs and tricyclics — rely heavily on CYP2C19, making metaboliser status relevant to both how well the drug works and how tolerable it is.

More broadly, any compound that depends on a single enzyme pathway for clearance will behave differently in people who carry loss-of-function alleles. The interaction data elsewhere on this site assumes an average metaboliser; individuals at the poor or ultra-rapid extremes may experience greater effects in either direction, and should interpret standard dose and duration estimates accordingly.