Drug abuse liability

Abuse liability refers to the tendency of a drug to be used in non-medical situations, even sporadically, due to underlying psychoactive effects it produces (such as euphoria, sedation, or mood changes)¹.

The ability to detect/refute drug abuse liability is critical in product development, licensing, and for post-marketing surveillance.

Comprehensive understanding of abuse liability contributes to accurate risk-benefit analysis and internal decision-making, as well as accurate product labelling. In academic settings, detection of abuse liability is important when considering new projects, and when making Institutional Review Board (IRB) / Ethics Committee applications.

Abuse liability is dependent not only on the drug properties (including neurochemical effects on the brain, formulation, and pharmacokinetics) but also on the population being studied (age, vulnerability for addiction, psychiatric and physical health morbidities)².

Abuse liability has critical public health implications – for example, the US Drug Enforcement Administration (DEA) has highlighted the growing problem of prescription drug abuse, and that the economic cost of non-medical use of prescription opioids is >$53 billion per year³.

Examples of drugs with high abuse liability include certain opioids and morphine derivatives, central nervous system depressants, and stimulants⁴.

 

Pathology and functional impact of drug abuse

Medications can cause untoward cognitive effects both via direct effects on the brain (by crossing the blood-brain barrier) and via indirect actions (peripheral mechanisms in the body). Research indicates that several brain mechanisms are implicated in abuse liability:

1. direct effects on the reward pathway (prefrontal cortex and ventral striatum, i.e. nucleus accumbens)
2. indirect effects on stress-related pathways (amygdala)
3. activation of ventral tegmentum and amygdala through exposure to drug-related cues^{5, 6}.

These circuits are under the neuromodulatory influence of dopamine, GABA, opioids, glutamate, nicotinic, and cannabinoid systems.

Translational studies indicate that the opioid system may be more involved in ‘liking’ and the dopamine system in ‘wanting’⁷; and that drug addiction involves a shift from behaviour that is initially impulsive, to later more ingrained habitual behaviour that is compulsive⁸.

The integrity of the blood-brain barrier is not static, but is affected by dynamic brain regulatory mechanisms⁹, and also by brain pathologies and advancing age, helping to emphasise that abuse liability is dependent not only on drug properties but also the population being considered.

Due to extensive cross-talk between the body and brain, drug compounds designed for non-CNS indications can still cause human abuse liability.

Not all untoward cognitive effects of interventions can be predicted from pre-clinical data; furthermore, medications can have multiple pharmacological effects, some of which may be ‘off target’.

 

You might also be interested in…

Almutairi MM, Gong C, Xu YG, Chang Y, Shi H. Factors controlling permeability of the blood-brain barrier. Cell Mol Life Sci. 2016 Jan;73(1):57-77.

Assessment of Abuse Potential of Drugs. Draft Guidance. US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), 2010.

Carter LP, Griffiths RR. Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend. 2009 Dec 1;105 Suppl 1:S14-25.

Hindmarch I. Instrumental assessment of psychomotor functions and the effects of psychotropic drugs. Acta Psychiatr Scand Suppl. 1994;380:49-52.

 

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1. _{Adapted from Guidance For Industry: Assessment of Abuse Potential of Drugs. Draft Guidance. US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), 2010.}
2. _{Carter LP, Griffiths RR. Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend. 2009 Dec 1;105 Suppl 1:S14-25.}
3. _{National Drug Threat Assessment Summary. U.S. Drug Enforcement Administration, 2013.}
4. _{Commonly Abused Prescription Drugs. National Institute on Drug Abuse, October 2011.}
5. _{Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry. 2005 Aug;162(8):1403-13.}
6. _{Volkow ND, Wang GJ, Fowler JS, Tomasi D. Addiction circuitry in the human brain. Annu Rev Pharmacol Toxicol. 2012;52:321-36.}
7. _{Berridge KC, Robinson TE, Aldridge JW. Dissecting components of reward: 'liking', 'wanting', and learning. Curr Opin Pharmacol. 2009 Feb;9(1):65-73.}
8. _{Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ. High impulsivity predicts the switch to compulsive cocaine-taking. Science. 2008 Jun 6;320(5881):1352-5.}
9. _{Almutairi MM, Gong C, Xu YG, Chang Y, Shi H. Factors controlling permeability of the blood-brain barrier. Cell Mol Life Sci. 2016 Jan;73(1):57-77.}