Drug tolerance

This article is about human resistance to the effects of drugs. For pathogenic resistance to the effects of drugs, see Drug resistance.
Addiction and dependence glossary[1][2][3]
  • addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., delirium tremens and nausea)
  • psychological dependence – dependence that is characterised by emotional-motivational withdrawal symptoms (e.g., anhedonia and anxiety) that affect cognitive functioning.
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • – the diminishing effect of a drug resulting from repeated administration at a given dose

Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Drug tolerance develops gradually over time. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, further reducing the drug's effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction.[4] The process of tolerance development is reversible (e.g., through a drug holiday[5]) and can involve both physiological factors and psychological factors.[6]

One may also develop drug tolerance to side effects,[7] in which case tolerance is a desirable characteristic. A medical intervention that has an objective to increase tolerance (e.g., allergen immunotherapy, in which one is exposed to larger and larger amounts of allergen to decrease one's allergic reactions) is called drug desensitization.[8]

The opposite concept to drug tolerance is reverse tolerance, in which case the subject's reaction or effect will increase following its repeated use. The two notions are not incompatible and tolerance may sometimes lead to reverse tolerance. For example, heavy drinkers initially develop tolerance to alcohol (requiring them to drink larger amounts to achieve a similar effect) but excessive drinking can cause liver damage, which then puts them at risk of intoxication when drinking even very small amounts of alcohol.[9]

Drug tolerance should not be confused with drug tolerability, which refers to the degree to which overt adverse effects of a drug can be tolerated by a patient.

  1. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
  2. ^ Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
  3. ^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
    Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
  4. ^ Miller, NS; Dackis, CA; Gold, MS (1987). "The relationship of addiction, tolerance, and dependence to alcohol and drugs: a neurochemical approach". J Subst Abuse Treat. 4 (3–4): 197–207. doi:10.1016/s0740-5472(87)80014-4. PMID 3325655.
  5. ^ Weiner, WJ; Koller, WC; Perlik, S; Nausieda, PA; Klawans, HL (1980). "Drug holiday and management of Parkinson disease". Neurology. 30 (12): 1257–61. doi:10.1212/wnl.30.12.1257. PMID 7192805. S2CID 23029500.
  6. ^ Schöneberg, Torsten (2008). "Tolerance and Desensitization". Encyclopedia of Molecular Pharmacology. pp. 1203–1207. doi:10.1007/978-3-540-38918-7_140. ISBN 978-3-540-38916-3.
  7. ^ Swift, CG; Swift, MR; Hamley, J; Stevenson, IH; Crooks, J (1984). "Side-effect 'tolerance' in elderly long-term recipients of benzodiazepine hypnotics". Age Ageing. 13 (6): 335–43. doi:10.1093/ageing/13.6.335. PMID 6440434.
  8. ^ "Rapid Drug Desensitization for Hypersensitivity Reactions to Chemotherapy and Monoclonal Antibodies in the 21st Century" (PDF).
  9. ^ "What Is Reverse Tolerance?".
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