Tolerance and Dependence Tolerance and Dependence Studies


Another factor in the evaluation of drug abuse liability is the assessment of whether the test substance will produce tolerance, sensitisation or physical dependence. Tolerance and sensitisation (when the effects of a drug either diminish or increase on repeated administration) are biological phenomena that have been associated with known drugs of abuse for many years. Physical dependence is manifest by the occurrence of time-dependent biochemical, behavioural and physiological changes (ie the withdrawal syndrome) that may occur on termination of chronic drug administration and indicates that adaptation to administration of the drug has occurred. The reason why it is important to examine the possibility that adverse effects may occur on the termination of drug treatment as part of the abuse liability assessment package is because such a syndrome could result in drug-seeking behaviour to alleviate the unpleasant effects of drug withdrawal.


RenaSci have developed a model for evaluating drug tolerance and dependence in rats. Animals are treated chronically with the novel substance before abrupt cessation of drug treatment (spontaneous drug withdrawal).  Drug effects and physical and behavioural symptoms of tolerance (during treatment) and dependence (following withdrawal) are recorded using detailed checklists of over 40 different parameters. Observations are compared to those produced by an appropriate reference compound/postive control. Physiological responses such as body weight, food and water intake and body temperature are also measured.


Drugs are typically administered for up to 28 days and animals observed during a withdrawal phase of up to 7 days. Plasma samples can be taken from satellite groups of rats for DMPK analysis. 


The model has been validated using the μ-opioid receptor agonist and controlled drug, morphine. 


Detailed Checklists for Assessing Tolerance and Dependence Liability


Studies performed to GLP.  


All tolerance and dependence studies are designed and conducted by experts with extensive experience of interactions with the FDA and EMA on abuse liability. Results supplied as fully-audited reports prepared to regulatory standards.


Please get in touch for further information about the evaluation of tolerance and physical dependence in rats.




Heal et al. 2016. A preclinical evaluation of the potential of the κ-opioid receptor agonist CR845 to induce tolerance and a syndrome of dependence on withdrawal. Poster No. 0077. Presented at the Joint Meeting of the Safety Pharmacology Society, Japanese Safety Pharmacology Society and Canadian Society of Pharmacology and Therapeutics, Vancouver, British Columbia, Canada, 18th-21st September 2016.



Calderon et al. 2015. Chapter 10. Regulatory framework and guidance to the evaluation of the abuse liability of drugs in the United States and Europe. In: Nonclinical Assessment of Abuse Potential for New Pharmaceuticals, 1st Edition. Carrie G Markgraf, Thomas J Hudzik and David J  Compton (Eds). Academic Press, Elsevier, pp 245-268, 2015.


Heal et al. 2018. Evaluation of the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans. Neuropharmacology 142: 89-115, 2018. doi: 10.1016/j.neuropharm.2018.01.049. [Epub 2018 Feb 8]. [PubMed]