Rate-Limiting Step - PsychonautWiki

Rate-Limiting Step

In chemistry, many catalytic reactions have a rate-limiting step.[1] The catalyst is necessary for the reaction to happen, and if there are no spare catalysts, the process has achieved maximum efficiency, whereby adding more of the chemical to be converted does not speed up proceedings or increase total concentrations of the end result.

In drug chemistry, this is often an enzyme involved in the metabolism of a drug. Once there are no more free catalysts available, the reaction has reached its maximum speed. This is especially relevant for prodrugs, which are inert when ingested, but metabolized into an active form. If the enzymes required to transform the drug into the (more) active form are satiated, the production of active substance can go no faster. This leads to a slower buildup of active substance, and can occasion a ceiling effect where adding more drugs does not get the user any higher, although it may prolong the experience and exacerbate side effects.[citation needed]

Prodrugs affected by rate-limiting steps


Codeine (3-methylmorphine) is a prodrug for morphine. While codeine has some activity of its own, the vast majority of its pharmacological activity comes from its conversion to morphine. Codeine is metabolized into morphine in the liver by the enzyme P450 CYP2D6. Too much codeine will saturate these enzymes, leading to a "ceiling effect" around 400mg, where further dosage will not increase blood morphine concentrations. For this reason, codeine is relatively safe in overdose compared to other opiates, which is not to say that caution isn't warranted.

The same holds for codeine (3-methylmorphine)'s closely related chemical cousin, 3-ethylmorphine. Ethylmorphine is also metabolized by CYP2D6.[2]


Another prodrug is lisdexamfetamine, which is metabolized by red blood cells into dextroamfetamine. Dosing higher quickly reaches diminishing returns as the necessary catalysts become saturated. At that stage, ingesting more will only prolong the duration, and not the intensity of the high. Lisdexamfetamine is therefore a less intensive, longer-lasting experience than its active form, dexamfetamine.


Psilocybin is a prodrug for psilocin, the active ingredient in magic mushrooms. The conversion from psilocybin to psilocin takes place in the stomach, which can delay the onset of the trip. Some people soak the mushrooms in lemon juice prior to ingestion. This "lemon tek" is supposed to kickstart the conversion from psilocybin to psilocin and thus facilitate a faster comeup. Unfortunately, evidence suggests that lemon juice is not sufficient to catalyze this reaction, and so the Lemon tek appears to be an urban drug myth.

Alcohol Metabolism

Alcohol is metabolized to acetaldehyde in the liver, but this is a complex system and several of the steps may be self-limiting, such that introducing an agent that improves the conversion rate of one component may cause other steps of the conversion to become rate-limiting. Thus there is no certain way to increase alcohol metabolism in the liver.[3]