Intermittent adaptation. A theory of drug tolerance, dependence and addiction

Pharmacopsychiatry. 2009 May:42 Suppl 1:S129-43. doi: 10.1055/s-0029-1202848. Epub 2009 May 11.


A mathematical model of drug tolerance and its underlying theory is presented. The model is essentially more complex than the generally used model of homeostasis, which is demonstrated to fail in describing tolerance development to repeated drug administrations. The model assumes the development of tolerance to a repeatedly administered drug to be the result of a regulated adaptive process. The oral detection and analysis of endogenous substances is proposed to be the primary stimulus for the mechanism of drug tolerance. Anticipation and environmental cues are in the model considered secondary stimuli, becoming primary only in dependence and addiction or when the drug administration bypasses the natural--oral--route, as is the case when drugs are administered intravenously. The model considers adaptation to the effect of a drug and adaptation to the interval between drug taking autonomous tolerance processes. Simulations with the mathematical model demonstrate the model's behaviour to be consistent with important characteristics of the development of tolerance to repeatedly administered drugs: the gradual decrease in drug effect when tolerance develops, the high sensitivity to small changes in drug dose, the rebound phenomenon and the large reactions following withdrawal in dependence. Simulations of different ways withdrawal can be accomplished, demonstrates the practical applicability of the model.

MeSH terms

  • Adaptation, Physiological*
  • Computer Simulation*
  • Dose-Response Relationship, Drug
  • Drug Tolerance / physiology*
  • Homeostasis / physiology
  • Humans
  • Illicit Drugs / pharmacology
  • Models, Biological*
  • Substance-Related Disorders*


  • Illicit Drugs