Safety of Cotinine in Humans: Physiologic, Subjective, and Cognitive Effects

doi:10.1016/S0091-3057(97)80001-9

Pharmacology Biochemistry and Behavior

Volume 57, Issue 4, August 1997, Pages 643-650

https://doi.org/10.1016/S0091-3057(97)80001-9 Get rights and content

Abstract

Preliminary data suggest that cotinine, the major metabolite of nicotine, may be behaviorally active. Studies involving the administration of cotinine at doses that produce high blood concentrations (in excess of those produced by cigarette smoking) may be of interest. This inpatient, 10-day human study examined the safety and the effects from several high doses of oral cotinine fumarate (40, 80, or 160 mg) or placebo in abstinent cigarette smokers. All subjects smoked cigarettes ad lib during the first 2 days of the study, then were required to be abstinent beginning on the third day. All subjects were given placebo on this day to wash out nicotine before the administration of cotinine. Subjects were subsequently randomly assigned in a double-blind manner to cotinine or placebo for the next 3 days to determine the safety profile of cotinine. All subjects were given placebo on the final 3 days to examine cotinine withdrawal symptoms. The results showed no significant physiologic, subjective, or performance effects across the various doses of cotinine and placebo. Furthermore, no cotinine withdrawal effects were observed. This study demonstrates that short-term administration of cotinine to humans at levels as high as 10 times that attained from cigarette smoking is safe with no observable acute or withdrawal effects from cotinine in this setting.

Section snippets

Subjects

Subjects (37 male and female smokers) were recruited from the Minneapolis–St. Paul metropolitan area via newspaper advertisements. Subjects were initially screened over the telephone. If they met the telephone screening criteria, they were seen by the research coordinator and physician. At this screening session, informed written consent was obtained. Subjects were required to complete a smoking history and Fagerstrom Nicotine Tolerance Questionnaire [13]. Alveolar carbon monoxide (CO) and

Demographics, Smoking History, and Cotinine Levels

Thirty-seven subjects entered the study and 35 subjects completed it. Two of the subjects were discharged before assignment to the medication. One subject experienced family problems while on the unit, and the other experienced a reoccurrence of peptic ulcer disease. Nine subjects completed the protocol in each group except the 160-mg one, in which eight subjects completed the study. The demographic and smoking history variables are shown in Table 2. Significant differences were observed in age

Discussion

This study shows that the short-term administration of cotinine at doses that result in mean serum concentration over 2500 ng/ml (almost 10 times higher than the concentration observed during smoking cigarettes) is well tolerated by normal subjects during nicotine abstinence. Ten subjects had elevations in their ALT during the study, but their clinical importance is unclear. Elevations occurred in all treatment groups, including placebo. Most elevations were small, and in all cases where

Acknowledgements

This study was funded by LEC TEC Corporation and in part by NIDA Grant P50-DA09259, and Clinical Research Center Grant M01-RR00400. The authors acknowledge the major contributions of Donna Rafael, Mahmoud Mahmoud, David Rolf, John Bennek, Professor Ed Leete.

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Cited by (72)

The involvement of dopamine and D2 receptor-mediated transmission in effects of cotinine in male rats
2023, Neuropharmacology
Previous studies indicated that cotinine, the major metabolite of nicotine, supported intravenous self-administration and exhibited relapse-like drug-seeking behaviors in rats. Subsequent studies started to reveal an important role of the mesolimbic dopamine system in cotinine's effects. Passive administration of cotinine elevated extracellular dopamine levels in the nucleus accumbens (NAC) and the D1 receptor antagonist SCH23390 attenuated cotinine self-administration. The objective of the current study was to further investigate the role of mesolimbic dopamine system in mediating cotinine's effects in male rats. Conventional microdialysis was conducted to examine NAC dopamine changes during active self-administration. Quantitative microdialysis and Western blot were used to determine cotinine-induced neuroadaptations within the NAC. Behavioral pharmacology was performed to investigate potential involvement of D2-like receptors in cotinine self-administration and relapse-like behaviors. NAC extracellular dopamine levels increased during active self-administration of cotinine and nicotine with less robust increase during cotinine self-administration. Repeated subcutaneous injections of cotinine reduced basal extracellular dopamine concentrations without altering dopamine reuptake in the NAC. Chronic self-administration of cotinine led to reduced protein expression of D2 receptors within the core but not shell subregion of the NAC, but did not change either D1 receptors or tyrosine hydroxylase in either subregion. On the other hand, chronic nicotine self-administration had no significant effect on any of these proteins. Systemic administration of eticlopride, a D2-like receptor antagonist attenuated both cotinine self-administration and cue-induced reinstatement of cotinine seeking. These results further support the hypothesis that the mesolimbic dopamine transmission plays a critical role in mediating reinforcing effects of cotinine.
The involvement of mesolimbic dopamine system in cotinine self-administration in rats
2022, Behavioural Brain Research
Cotinine is the major metabolite of nicotine and has recently been shown to be self-administered intravenously by rats. However, mechanisms underlying cotinine self-administration remained unknown. Mesolimbic dopamine system projecting from the ventral tegmental area (VTA) to nucleus accumbens (NAC) is closely implicated in drug reinforcement, including nicotine. The objective of the current study was to determine potential involvement of mesolimbic dopamine system in cotinine self-administration. An intracranial self-administration experiment demonstrates that cotinine at 0.88 and 1.76 ng/100 nl/infusion was self-infused into the VTA by rats. Rats produced more infusions of cotinine than vehicle and responded more on active than inactive lever during acquisition, reduced responding when cotinine was replaced by vehicle, and resumed responding during re-exposure to cotinine. Microinjection of cotinine at 1.76 ng/100 nl/infusion into the VTA increased extracellular dopamine levels within the NAC. Subcutaneous injection of cotinine at 1 mg/kg also increased extracellular dopamine levels within the NAC. Administration of the D₁-like receptor antagonist SCH 23390 attenuated intravenous cotinine self-administration. On the other hand, bupropion, a catecholamine uptake inhibitor, did not significantly alter intravenous cotinine self-administration. These results suggest that activation of mesolimbic dopamine system may represent one cellular mechanism underlying cotinine self-administration. This shared mechanism between cotinine and nicotine suggests that cotinine may play a role in nicotine reinforcement.
Nicotine and its derivatives in healthy brain aging
2021, Factors Affecting Neurological Aging: Genetics, Neurology, Behavior, and Diet
Aging is a multifaceted process affecting all aspects of the human psyche and body. Brain aging is one of the vital aspects of human aging manifested by memory and learning impairment. It is caused by impaired mitochondrial function, excessive production and scavenging of oxidants, diminished neurotrophic factors levels, and cholinergic hypofunction, eventually leading to neuroinflammation, excitotoxicity, and neuronal death. A myriad of therapeutic strategies has been tried to ameliorate at least partially age-induced cognitive decline. However, not all these options have yielded fruitful results in the clinic. Nicotine and its major cerebral metabolites, i.e., cotinine and nornicotine, have shown procognitive effects in disorders of cognition and healthy aging, in both experimental studies and clinical trials. These effects result from their antioxidant, antiapoptotic, antiinflammatory, and neuroprotective properties. A wider therapeutic window and lack of abuse potential make the latter a superior option over the former, though. This chapter tries to shed light on the procognitive impacts of nicotine and its major bioproduct cotinine on age-related cognitive decline.
Cotinine ameliorates memory and learning impairment in senescent mice
2020, Brain Research Bulletin
This study aimed to assess the effects of cotinine on age-induced memory and learning impairment and related downstream pathways in mice. Thirty aged (18-month old) and 10 young mice (8-week old) were randomly divided into 4 groups (n = 10 each) and subjected to cotinine at 5 mg/kg dose and/or methyllycaconitine (MLA) at 1 mg/kg, i.p. dose (α₇ nAChRs antagonist) for 4 weeks. Morris water maze (MWM) and novel object recognition (NOR) tasks were used to assess spatial and recognition learning and memories of the mice, respectively. Levels of oxidative stress, apoptosis, neuroinflammation, and structural synaptic plasticity, and also neurotrophic factors and α₇ nAChRs were assessed in the hippocampus using either ELISA or Western blotting. Aging was associated with learning and memory disabilities and dysregulation of the assessed pathways in the hippocampus of mice. Chronic cotinine treatment improved learning and memory in aged animals, indicated by decreased latency time, and increased time spent in the target quadrant and discrimination index (DI) in the MWM and NOR tasks. Also, chronic cotinine injection increased total antioxidant capacity (TAC), SOD and GSH-px activity, PSD-95, GAP-43, SYN, brain-derived neurotrophic factor, and neural growth factor levels and decreased malondialdehyde, TNF-α, and IL-1β in the hippocampus of aged mice. Conversely, MLA treatment reversed most of the mentioned effects via the blockade of α₇ nAChRs. Cotinine improves age-induced memory and learning impairment via its modulatory effects on α₇ nAChRs and subsequent activation/deactivation of the mentioned pathways in the hippocampus of aged mice.
Estrogen-progestin oral contraceptive and nicotine exposure synergistically confers cardio-renoprotection in female Wistar rats
2020, Biomedicine and Pharmacotherapy
Approximately fifty percent of premenopausal women who smoke cigarettes or on nicotine replacement therapy are also on hormonal contraceptives, especially oral estrogen-progestin. Oral estrogen-progestin therapy has been reported to promote insulin resistance (IR) which causes lipid influx into non-adipose tissue and impairs Na⁺/K⁺ -ATPase activity, especially in the heart and kidney. However, the effects of nicotine on excess lipid and altered Na⁺/K⁺ -ATPase activity associated with the use of estrogen-progestin therapy have not been fully elucidated. This study therefore aimed at investigating the effect of nicotine on cardiac and renal lipid influx and Na⁺/K⁺ -ATPase activity during estrogen-progestin therapy. Twenty-four female Wistar rats grouped into 4 (n = 6/group) received (p.o.) vehicle, nicotine (1.0 mg/kg) with or without estrogen-progestin steroids (1.0 μg ethinyl estradiol and 5.0 μg levonorgestrel) and estrogen-progestin only daily for 6 weeks. Data showed that estrogen-progestin treatment or nicotine exposure caused IR, hyperinsulinemia, increased cardiac and renal uric acid, malondialdehyde, triglyceride, glycogen synthase kinase-3, plasminogen activator inhibitor-1, reduced bilirubin and circulating estradiol. Estrogen-progestin treatment led to decreased cardiac Na⁺/K⁺-ATPase activity while nicotine did not alter Na⁺/K⁺-ATPase activity but increased plasma and tissue cotinine. Renal Na⁺/K⁺-ATPase activity was not altered by the treatments. However, all these alterations were reversed following combined administration of oral estrogen-progestin therapy and nicotine. The present study therefore demonstrates that oral estrogen-progestin therapy and nicotine exposure synergistically prevents IR-linked cardio-renotoxicity with corresponding improvement in cardiac and renal lipid accumulation, oxidative stress, inflammation and Na⁺/K⁺-ATPase activity.
Cotinine and memory: Remembering to forget
2019, Neuroscience of Nicotine: Mechanisms and Treatment
Cotinine, the main derivative of nicotine, has remarkable beneficial effects on learning and memory. Cotinine pharmacokinetics and pharmacodynamics in mammals have been investigated for half of a century. However, only few years ago, it was discovered that cotinine is a positive allosteric modulator (PAM) of the α7 nicotinic acetylcholine receptors (nAChRs). Cotinine prevented memory loss and restored working memory in rodent models of Alzheimer's disease (AD), posttraumatic stress disorder (PTSD), and autism and after chemotherapy. Cotinine also facilitated fear extinction in rodents by stimulating signaling pathways that promotes synaptic plasticity and protects neurons and astrocytes against neuroinflammation. Clinical trials, performed with subjects from 2 months to 65 years of age, revealed that cotinine is safe and not addictive at doses equivalent to the ones improving brain functions in mammals. Clinical trials to determine cotinine beneficial effects on memory are guarantee.

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ArticlesSafety of Cotinine in Humans: Physiologic, Subjective, and Cognitive Effects

Abstract

Section snippets

Subjects

Demographics, Smoking History, and Cotinine Levels

Discussion

Acknowledgements

Life Sci.

Addict. Behav.

J. Subst. Abuse

J. Chromatogr.

J. Biol. Chem.

Int. J. Neuropharmacol.

Diagnostic and statistical manual of mental disorders

A possible relationship between pKa1 and lipid solubility and the amounts excreted in urine of some tobacco alkaloids given to man

J. Pharm. Pharmacol.

Cotinine disposition and effects

Clin. Pharmacol. Ther.

Inverse relation between serum cotinine concentration and blood pressure in cigarette smokers

Circulation

Studies on the respiratory and cardiovascular effects of (−)-cotinine

J. Pharmacol. Exp. Ther.

−)-Cotinine

Studies on the metabolism of (−)-cotinine in the human

J. Pharmacol. Exp. Ther.

Self-report vs. sleep lab findings in 122 drug-free subjects with complaints of chronic insomnia

Am. J. Psychiatry

The pharmacokinetics of cotinine in plasma and saliva from nonsmoking healthy volunteers

Eur. J. Clin. Pharmacol.

Articles
Safety of Cotinine in Humans: Physiologic, Subjective, and Cognitive Effects