Cotinine

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Alkaloid found in tobacco

title: "Cotinine" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["pyrrolidones", "alkaloids-found-in-nicotiana", "nicotinic-agonists", "pyridine-alkaloids", "recreational-drug-metabolites", "biomarkers", "3-pyridyl-compounds", "human-drug-metabolites"] description: "Alkaloid found in tobacco" topic_path: "general/pyrrolidones" source: "https://en.wikipedia.org/wiki/Cotinine" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Alkaloid found in tobacco ::

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Cotinine is an alkaloid found in tobacco and is also the predominant metabolite of nicotine, typically used as a biomarker for exposure to tobacco smoke. Cotinine is currently being studied as a treatment for depression, post-traumatic stress disorder (PTSD), schizophrenia, Alzheimer's disease and Parkinson's disease. Cotinine was developed as an antidepressant as a fumaric acid salt, cotinine fumarate, to be sold under the brand name Scotine, but it was never marketed.

Similarly to nicotine, cotinine binds to, activates, and desensitizes neuronal nicotinic acetylcholine receptors, though at much lower potency in comparison. It has demonstrated nootropic and antipsychotic-like effects in animal models. Cotinine treatment has also been shown to reduce depression, anxiety, and fear-related behavior as well as memory impairment in animal models of depression, post-traumatic stress disorder, and Alzheimer's disease. Nonetheless, treatment with cotinine in humans was reported to have no significant physiologic, subjective, or performance effects in one study, though others suggest that this may not be the case.

Because cotinine is the main metabolite to nicotine and has been shown to be pharmacologically active, it has been suggested that some of nicotine's effects in the nervous system may be mediated by cotinine and/or complex interactions with nicotine itself.

Pharmacology

A few studies indicate that the affinity for cotinine to the nicotinic acetylcholine receptors (nAChRs) is about 100 times lower than nicotine's. Some work suggests that cotinine may be a positive allosteric modulator of α7 nAChRs. If this is true, cotinine would facilitate endogenous neurotransmission without directly stimulating nAChRs.

Pharmacokinetics

Cotinine has an in vivo half-life of approximately 20 hours, and is typically detectable for several days (up to one week) after the use of tobacco. The level of cotinine in the blood, saliva, and urine is proportionate to the amount of exposure to tobacco smoke, so it is a valuable indicator of tobacco smoke exposure, including secondary (passive) smoke. People who smoke menthol cigarettes may retain cotinine in the blood for a longer period because menthol can compete with enzymatic metabolism of cotinine. African American smokers generally have higher plasma cotinine levels than Caucasian smokers. Males generally have higher plasma cotinine levels than females. These systematic differences in cotinine levels were attributed to variation in CYP2A6 activity. At steady state, plasma cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genetic variation, cotinine accumulates in individuals with slower CYP2A6 activity, resulting in substantial differences in cotinine levels for a given tobacco exposure.

Detection in body fluids

Drug tests can detect cotinine in the blood, urine, or saliva. Salivary cotinine concentrations are highly correlated to blood cotinine concentrations, and can detect cotinine in a low range, making it the preferable option for a less invasive method of tobacco exposure testing. Urine cotinine concentrations average four to six times higher than those in blood or saliva, making urine a more sensitive matrix to detect low-concentration exposure.

Cotinine levels

However, tobacco users attempting to quit with the help of nicotine replacement therapies (i.e., gum, lozenge, patch, inhaler, and nasal spray) will also test positive for cotinine, since all common NRT therapies contain nicotine that is metabolized in the same way. Therefore, the presence of cotinine is not a conclusive indication of tobacco use. Cotinine levels can be used in research to explore the question of the amount of nicotine delivered to the user of e-cigarettes, where laboratory smoking machines have many problems replicating real-life conditions.

Serum cotinine concentration has been used for decades in US population surveys of the Centers for Disease Control and Prevention to monitor tobacco use, to monitor levels and trends in exposure to environmental tobacco smoke, and to study the relationship between tobacco smoke and chronic health conditions. An estimated one in four nonsmokers (approximately 58 million persons) were exposed to secondhand smoke during 2013-2014. Nearly 40% of children aged 3–11 years were exposed as were 50% of non-Hispanic blacks.

References

References

  1. (November 2022). "Fractionation and Extraction Optimization of Potentially Valuable Compounds and Their Profiling in Six Varieties of Two ''Nicotiana'' Species". Molecules.
  2. (1996). "Dictionary of Pharmacological Agents". Chapman & Hall/CRC.
  3. (March 1999). "(S)-(-)-Cotinine, the major brain metabolite of nicotine, stimulates nicotinic receptors to evoke [3H]dopamine release from rat striatal slices in a calcium-dependent manner". The Journal of Pharmacology and Experimental Therapeutics.
  4. (March 1994). "Nicotinic receptor binding of [3H]cytisine, [3H]nicotine and [3H]methylcarbamylcholine in rat brain". European Journal of Pharmacology.
  5. (September 1998). "Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists". Neuropharmacology.
  6. (February 2007). "Disconnection between activation and desensitization of autonomic nicotinic receptors by nicotine and cotinine". Neuroscience Letters.
  7. (October 2009). "A reversible model of the cognitive impairment associated with schizophrenia in monkeys: potential therapeutic effects of two nicotinic acetylcholine receptor agonists". Biochemical Pharmacology.
  8. (February 2009). "Desensitization of nicotinic acetylcholine receptors as a strategy for drug development". The Journal of Pharmacology and Experimental Therapeutics.
  9. (October 2015). "New Insights into the Mechanisms of Action of Cotinine and its Distinctive Effects from Nicotine". Neurochemical Research.
  10. (August 1997). "Safety of cotinine in humans: physiologic, subjective, and cognitive effects". Pharmacology, Biochemistry, and Behavior.
  11. (Oct 2012). "Cotinine: Beyond that Expected, More than a Biomarker of Tobacco Consumption". Frontiers in Pharmacology.
  12. (October 1997). "Contribution of CNS nicotine metabolites to the neuropharmacological effects of nicotine and tobacco smoking". Biochemical Pharmacology.
  13. (September 2008). "Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site". Proceedings of the National Academy of Sciences of the United States of America.
  14. (February 2009). "Methods for quantification of exposure to cigarette smoking and environmental tobacco smoke: focus on developmental toxicology". Therapeutic Drug Monitoring.
  15. (December 2002). "Signs of smoking linger longer in menthol smokers". Science Blog.
  16. (September 1990). "Racial differences in serum cotinine levels among smokers in the Coronary Artery Risk Development in (Young) Adults study". American Journal of Public Health.
  17. (August 2008). "Sex-related differences in serum cotinine concentrations in daily cigarette smokers". Nicotine & Tobacco Research.
  18. (April 2013). "The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex". Cancer Epidemiology, Biomarkers & Prevention.
  19. Avila-Tang, Erika et al (September 2012). "Assessing secondhand smoke using biological markers" - Nicotine and metabolites [http://tobaccocontrol.bmj.com/content/early/2012/09/01/tobaccocontrol-2011-050298.full]. Retrieved 10 June 2013
  20. (September 2008). "Assessing smoking status in children, adolescents and adults: cotinine cut-points revisited". Addiction.
  21. "Reasons for False Positives for Nicotine on a Blood Test". LiveStrong.com.
  22. (2015). "E-cigarettes: an evidence update. A report commissioned by Public Health England". Public Health England.
  23. (December 2018). "Exposure to Secondhand Smoke Among Nonsmokers - United States, 1988-2014". MMWR. Morbidity and Mortality Weekly Report.

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pyrrolidonesalkaloids-found-in-nicotiananicotinic-agonistspyridine-alkaloidsrecreational-drug-metabolitesbiomarkers3-pyridyl-compoundshuman-drug-metabolites