Cotinine is an

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...

found in tobacco and is also the predominant metabolite of

nicotine Nicotine is a naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and '' Duboisia hopwoodii'') and is widely used recreationally as a stimulant and anxiolytic. As a pharmaceutical drug, it is use ...

. An anagram of the word "nicotine", it is used as a biomarker for exposure to tobacco smoke. Cotinine is currently being studied as a treatment for depression, PTSD,

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

, Alzheimer's disease and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

. 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 Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...

in comparison. It has demonstrated nootropic and

antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of ...

-like effects in animal models. Cotinine treatment has also been shown to reduce depression,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, and

fear Fear is an intensely unpleasant emotion in response to perceiving or recognizing a danger or threat. Fear causes physiological changes that may produce behavioral reactions such as mounting an aggressive response or fleeing the threat. Fear ...

-related behavior as well as memory impairment in animal models of depression, PTSD, 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

Pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

Cotinine has an

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ...

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 Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...

, 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 <10 ng/mL are considered to be consistent with no active smoking. Values of 10 ng/mL to 100 ng/mL are associated with light smoking or moderate passive exposure, and levels above 300 ng/mL are seen in heavy smokers - more than 20 cigarettes a day. In urine, values between 11 ng/mL and 30 ng/mL may be associated with light smoking or passive exposure, and levels in active smokers typically reach 500 ng/mL or more. In saliva, values between 1 ng/mL and 30 ng/mL may be associated with light smoking or passive exposure, and levels in active smokers typically reach 100 ng/mL or more. Cotinine assays provide an objective quantitative measure that is more reliable than smoking histories or counting the number of cigarettes smoked per day. Cotinine also permits the measurement of exposure to second-hand smoke (passive smoking). 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-cigarette An electronic cigarette is an electronic device that simulates tobacco smoking. It consists of an atomizer, a power source such as a battery, and a container such as a cartridge or tank. Instead of smoke, the user inhales vapor. As such ...

s, 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 The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georg ...

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

{{Nicotinic acetylcholine receptor modulators Pyrrolidones Alkaloids found in Nicotiana Nicotinic agonists Pyridine alkaloids Recreational drug metabolites Biomarkers 3-Pyridyl compounds