Reverse tolerance

Addiction and dependence glossary^[1]^[2]^[3]
Addiction and dependence glossary
	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., fatigue and delirium tremens); psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome); 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; tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose;
	v; t; e;

Reverse tolerance or drug sensitization is a pharmacological phenomenon describing subjects' increased reaction (positive or negative) to a drug following its repeated use.^[4] Not all drugs are subject to reverse tolerance.

This is the opposite of drug tolerance, in which the effect or the subject's reaction decreases 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 as excessive drinking can cause liver damage, this can then put this group at risk of intoxication when drinking even very small amounts of alcohol.^[5] Sensitization, a form of reverse tolerance, develops rapidly to the positive, euphoric effects of alcohol, but not to the physical effects, such as sedation and respiratory depression, which diminish with prolonged use. This sensitization does not occur, however, with administration of benzodiazepines or neuroactive steroids, which only exhibit weakening of effect with repeated use.

Reverse tolerance can also occur in users of stimulants such as cocaine or amphetamines. A previously recreational dose may become enough to cause psychosis in regular users, or users who previously had a psychotic episode may be more likely to have one in the future and at lower doses once drug usage continues.^[6]

In some cases drug sensitization may also refer to medical interventions (e.g. a drug holiday) that aim to reduce the insensitivity caused by drug tolerance.

References

^ 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.
^ 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.
^ 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.
^ "Reverse tolerance and drug sensitization".
^ "What Is Reverse Tolerance?".
^ "Chronic Amphetamine Use and Abuse".

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[Addiction_glossary-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.

[Cellular_basis-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.

[Brain_disease-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] "Reverse tolerance and drug sensitization".

[5] "What Is Reverse Tolerance?".

[6] "Chronic Amphetamine Use and Abuse".

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See also

References