Lipophilicity

Lipophilicity describes how strongly a compound is attracted to fats and oils relative to water. It is usually expressed as log P — the logarithm of the ratio of a compound's concentration in an oily phase versus a water phase — where higher positive values indicate a preference for fats and negative values a preference for water.

The property sits at the centre of pharmacokinetics, the study of how the body absorbs, distributes, and eliminates drugs. Along with molecular size, ionisation state, and protein binding, lipophilicity is one of the key factors that determines how far a substance travels through the body and how quickly it reaches its site of action.

How it works · its role

Cell membranes are built from a lipid bilayer — a double sheet of fatty molecules with a hydrophobic core. Compounds that dissolve readily in fats pass through this barrier by passive diffusion; compounds that prefer water are largely blocked and must rely on protein transporters to cross.

The blood-brain barrier is a particularly selective version of this membrane. Many psychoactive substances must cross it to produce any effect at all, which is why a disproportionate number of neuroactive drugs are moderately to highly lipophilic.

Very high lipophilicity creates a secondary effect: accumulation in fatty tissue throughout the body. Once stored, a compound releases slowly back into circulation, extending its effective presence. This can prolong effects, delay full clearance, or produce a secondary peak well after the initial dose.

Relevance to substances & effects

The contrast between heroin and morphine illustrates the effect on onset. Heroin is considerably more lipophilic than morphine; it crosses the blood-brain barrier faster, producing a sharper initial rush before converting to morphine in the brain. The subjective difference in onset between the two is largely explained by this single property.

THC, the primary psychoactive compound in cannabis, is strongly lipophilic. It accumulates in fat stores throughout the body and releases gradually — which accounts for its unusually long detection window in urine tests and the variability in onset when taken orally, where fat content in a meal aids absorption.

Classic psychedelics such as LSD and psilocin are moderately lipophilic, supporting efficient transfer across the blood-brain barrier to their receptor targets. Many benzodiazepines are highly lipophilic, entering the central nervous system rapidly for quick onset before redistributing into peripheral fat stores — a pattern that shortens the sedative window even as the compound remains in the body considerably longer.

Lipophilicity is one predictor among several; molecular size, ionisation, active transport, and metabolism all shape how a substance ultimately behaves. Log P gives a useful first approximation, not a complete picture.