Nicotine and cotinine concentrations in serum and milk of nursing smokers

Analysis of 44 milk samples from 23 nursing smokers revealed that there was a linear correlation between nicotine concentrations in serum and in milk (r = 0.70). The nicotine concentrations in milk were considerably higher than the corresponding serum concentrations: milk/serum concentration ratio = 2.92 +/- 1.09; (n = 44). There was also a linear correlation between the cotinine concentrations in serum and in milk (r = 0.89). The cotinine concentrations in milk were lower than the corresponding serum concentrations: milk/serum concentration ratio = 0.78 +/- 0.19; (n = 44). The direct comparison between the half-lives of nicotine in serum and in milk was possible in five nursing smokers. The half-life of nicotine in milk was determined in four additional smoking mothers. The half-life of nicotine in milk t 1/2 = 97 +/- 20 min slightly exceeded the half-life of nicotine in serum t 1/2 = 81 +/- 9 min; the difference between these two values was not statistically significant (P greater than 0.05). Cotinine concentrations remained fairly consistent during a 4 h interval without smoking.     

ADHD medication reduces cotinine levels and withdrawal in smokers with ADHD

Individuals with ADHD may self-medicate with nicotine, the main psychoactive ingredient in tobacco smoke, in order to reduce symptoms and negative moods associated with ADHD. ADHD medication (e.g., methylphenidate and atomoxetine) may mimic some of the effects of nicotine and may aid smoking cessation in smokers with ADHD. The present study examined if ADHD medication reduces smoking and withdrawal in non-treatment seeking smokers with ADHD. Fifteen adult smokers with ADHD participated in the study, which consisted of an experimental phase and field monitoring phase to examine the acute and extended effects, respectively, of ADHD medication. During the experimental phase, smokers were asked to complete a Continuous Performance Task (CPT) and the Shiffman-Jarvik smoking withdrawal questionnaire during the following four conditions: (1) ADHD medication + cigarette smoking, (2) ADHD medication + overnight abstinence, (3) placebo + cigarette smoking, and (4) placebo + overnight abstinence. During the field monitoring phase, participants were asked to provide salivary cotinine samples and complete electronic diaries about smoking, smoking urge, ADHD symptoms, and stress in everyday life for two days on ADHD medication and for two days on placebo. Results of the experimental phase showed that ADHD medication improved task performance on the CPT and reduced withdrawal during overnight abstinence. During the field monitoring phase, ADHD medication reduced salivary cotinine levels compared to placebo. In addition, the electronic diary revealed that ADHD medication improved difficulty concentrating during no smoking events and stress. The findings of the present study suggest that, along with other strategies, ADHD medication may be used to aid smoking withdrawal and cessation in smokers with ADHD.     

Saliva cotinine and exhaled carbon monoxide levels in natural environment waterpipe smokers

The purpose of this study is to evaluate the variations in exhaled CO and saliva cotinine in natural environment waterpipe smokers and compare them with cigarette smokers and absolute nonsmokers. Three groups were included in the study: nonsmokers (n = 20), waterpipe smokers (n = 15), and cigarette smokers (n = 20). A questionnaire was completed for each participant, exhaled CO was measured before and after waterpipe or cigarette smoking, and saliva cotinine was measured immediately after. We excluded from our study mixed smokers of both waterpipe and cigarettes. Mean values of saliva cotinine in waterpipe and cigarette smokers were very close: 77.8 ng/ml (SD = 110.4) and 87.1 (SD = 82.7) respectively. The weight and height of the persons as well as the size of the waterpipe bottle affected saliva cotinine. However, in waterpipe smokers, CO increased by 300% after 1 h of smoking, while in cigarette smokers, it only increased by 60%. In nonsmokers, exhaled CO was similar to environmental CO (10.2 ppm). The results of our study confirm that waterpipe device water does not filter nicotine and that the smoker him- or herself, by the frequency and the depth of inhalation, controls smoke inhalation. Like cigarette smokers, waterpipe smokers are exposed to harmful substances, such as CO, which was found to be quite high. The levels of expired CO and salivary cotinine could be good tools to detect exposure to waterpipe smoking.     

Decreased serum cotinine levels in smokers of both tobacco and marijuana as compared with smokers of tobacco only

Serum and salivary cotinine levels were determined in tobacco smokers (n=125) tobacco (n=47) or who smoked both marijuana and tobacco (n=78) as part of a field study of the pulmonary effects of heavy, habitual use of marijuana alone or with tobacco. After adjustment for current daily amount of tobacco use and time since the last tobacco cigarette was smoked, the smokers of both marijuana and tobacco were found to have lower levels of cotinine then those who smoked only tobacco, in serum [258±113 ng/ml (S.D.) and 332±109, respectively; P=0.003] and in saliva (331±170 and 395±170, respectively; P=0.058). Serum cotinine showed a significantly negative relationship to the daily amount of marijuana currently smoked (p=0.026). Possible explanations include inhibition by marijuana component(s) of the enzymes that participate in the conversion of nicotine to cotinine, differences in nicotine absorption patterns between the two groups of tobacco smokers, and acceleration of cotinine metabolism by marijuana smoking. Carefully controlled pharmacokinetic studies, not possible in a large-scale survey such as this one, are required both to confirm the differences in blood cotinine levels observed between the dual smokers of tobacco only and to define more clearly nicotine-marijuana interactions.     

Nicotine discrimination in male and female smokers

Discriminative stimulus effects of nicotine were evaluated in humans using formal behavioral drug discrimination procedures. Male and female smokers (n=9 each) were trained on day 1 to reliably discriminate 0 versus 12 µg/kg nicotine administered by measured-dose nasal spray. All subjects were able to reach criterion performance (at least 80% correct). Generalization of responding across nicotine doses of 0, 2, 4, 8, and 12 µg/kg (approximately 0–0.8 mg for typical subject) was then examined on day 2. Nicotine-appropriate responding was linearly related to dose, and subjects were able to distinguish the smallest dose (2 µg/kg) from placebo. Although there were no differences between males and females in behavioral discrimination, subjective effects were correlated with nicotine discrimination in females but not in males. These findings indicate that humans are able to discriminate among low doses of nicotine per se, that males and females may differ in the stimuli used to discriminate nicotine, and that drug discrimination procedures may be more sensitive than traditional subjective effects measures in distinguishing among low doses of nicotine.This research was supported by grant DA-08578 from the National Institute on Drug Abuse. J.E.G. was supported in part by predoctoral training grant HL-07560 from the National Heart, Lung, and Blood Institute.     

Salivary cotinine levels in human tobacco smokers predict the attentional validity effect size during smoking abstinence

Abstract. Rationale. The link between attention and brain cholinergic neurotransmission is widely accepted. Human chronic tobacco smokers maintain high levels of nicotine in plasma and body tissues and show enhanced attentional orienting and other attentional tasks. Objective. We wished to test whether abstinence from smoking caused levels of the nicotine metabolite cotinine to decline and attentional enhancement to be reduced in a correlated manner. Methods. The levels of salivary cotinine and behavioral performance on a cued target detection task were measured in chronic, adult tobacco smokers over a 5-day abstinence period. Control groups assessed over the same time period include non-smokers, smokers that did not abstain from tobacco, and smokers that abstained for 4 days and smoked on the last day. Results. In all groups with tobacco exposure, the levels of cotinine declined steadily with time after abstinence, reaching near zero levels at day 5. During this period, reaction times declined as well for all groups, due in part to task practice effects. In contrast, the validity effect, which indexes attentional allocation, increased with abstinence and was inversely related to cotinine levels in groups exposed to tobacco. Conclusions. We conclude that 1) nicotine abstinence increases the attentional validity effect, and 2) this increase is indexed by salivary cotinine, and 3) that control levels of attentional performance are achieved after 3–4 days of tobacco abstinence. Electronic Publication     

Nicotine elimination and tolerance in non-dependent cigarette smokers

Although most smokers are nicotine-dependent, recent studies suggest that some very light smokers (chippers, who smoke fewer than five cigarettes per day) may smoke for decades without developing dependence. It was considered that slowed nicotine elimination and/or reduced nicotine tolerance might underlie chippers' ability to maintain smoking at such low levels. To evaluate this hypothesis, we studied the elimination kinetics and pharmacodynamics of nicotine in chippers and matched regular smokers. Plasma nicotine levels and cardiovascular responses were observed for several hours after subjects were administered uniform doses of tobacco smoke. Chippers did show less chronic nicotine tolerance, but only on some response measures. Their rates of nicotine elimination equaled those of regular smokers. This finding, when coupled with other data about chippers' smoking patterns and nicotine absorption, establish that chippers cannot maintain substantial plasma nicotine levels between cigarettes, and thus suggest that attempts to maintain minimal trough levels of nicotine do not underlie chippers' smoking.     

Nicotine and cotinine effects on development of two-cell mouse embryos in vitro

The independent and interactive effects of nicotine and cotinine on the development of cultured two-cell embryos were investigated. Cultures were maintained for 120 h and developmental stages of embryos were scored after 72 h and at the termination of culture. Concentrations of nicotine at or below 0.5 mM, and concentrations of cotinine at or below 0.008 mM, did not adversely affect development. In addition, neither nicotine nor cotinine produced synergistic effects at higher concentrations at which both independently impaired development. These data show, therefore, that nicotine and its major metabolite, cotinine, significantly interfere with preimplantation development of mouse embryos only at concentrations far in excess of those anticipated to be present in the blood of an "average" smoker. Thus, we conclude that the well documented adverse effects of smoking during pregnancy are unlikely to be attributable to a direct effect of nicotine or cotinine on the preimplantation embryo.     

Nicotine and cotinine effects on development of two-cell mouse embryos in vitro

The independent and interactive effects of nicotine and cotinine on the development of cultured two-cell embryos were investigated. Cultures were maintained for 120 h and developmental stages of embryos were scored after 72 h and at the termination of culture. Concentrations of nicotine at or below 0.5 mM, and concentrations of cotinine at or below 0.008 mM, did not adversely affect development. In addition, neither nicotine nor cotinine produced synergistic effects at higher concentrations at which both independently impaired development. These data show, therefore, that nicotine and its major metabolite, cotinine, significantly interfere with preimplantation development of mouse embryos only at concentrations far in excess of those anticipated to be present in the blood of an “average” smoker. Thus, we conclude that the well documented adverse effects of smoking during pregnancy are unlikely to be attributable to a direct effect of nicotine or cotinine on the preimplantation embryo.     

Nicotine replacement to reduce cigarette consumption in smokers who are unwilling to quit: a randomized trial

The objective of this study was to assess whether nicotine replacement therapy, administered in a real-life situation, could reduce cigarette consumption in smokers who were not prepared to quit smoking. Daily smokers of more than 20 cigarettes per day who had no intention to quit smoking in the next 6 months were recruited from the general population and randomly assigned to either a 6-month treatment of nicotine (choice among a 15-mg nicotine patch, a 4-mg nicotine gum, a 10-mg nicotine inhaler, or a combination of these, N = 265), matching placebo products (N = 269), or no intervention (N = 389). Products were sent to participants by mail. Education was limited to a booklet. Of 923 participants, 879 (95%) were followed up after 6 months. Mean baseline consumption was 30 cigarettes per day in all groups. At 6 months, cigarette consumption decreased by a median of 10 cigarettes per day in the nicotine group, 7.5 in the placebo group, and 2.5 among controls ( < 0.04 for all pair-wise comparisons). Smoking cessation rates were low (2%-4%) and did not differ significantly between groups. Quit attempts were less frequent among controls (21%) than among the nicotine (28%, = 0.04) and placebo (27%, = 0.08) subjects. In conclusion, nicotine replacement therapy helped smokers reduce their cigarette consumption and maintain this reduction over 6 months, but a large part of this reduction was attributable to a placebo effect. Nicotine treatment for smoking reduction had no detectable impact on smoking cessation.     

Recovery cycle of the Hoffmann reflex of tobacco smokers and nonsmokers: relationship to plasma nicotine and cotinine levels

Ten normal adult tobacco smokers and 10 non-smoking volunteers 20–31 years of age were the subjects of this study. The tobacco smokers all had a history of daily tobacco smoking. They were asked to stop smoking for 12 hours prior to testing. The Hoffmann (H) reflex and its recovery cycle were measured on different days before and just after smoking one nonfiltered 0 mg, low (0.27 mg), or high (2.16 mg) nicotine containing cigarette in a randomized order. Blood samples were drawn immediately after the H reflex recordings in the tobacco smokers. The blood samples were centrifuged, the plasma removed, frozen, and later assayed for nicotine and cotinine levels.Nonsmokers compared to tobacco smokers before smoking only had a tendency for enhanced amplitude of the recovery cycle. After smoking the nicotine containing cigarettes, the tobacco smokers had a depression of the amplitude of the H reflex recovery cycle. The amplitude of the H reflex recovery cycle at 160 ms was reduced. This decreased significantly with increasing plasma nicotine and cotinine concentrations. Individual differences were marked.The data obtained are consistent with evidence in animals that nicotine and tobacco smoke stimulate Renshaw inhibitory neurons in the spinal cord, either directly or indirectly which leads to a skeletal muscle relaxant effect.     

Nicotine signaling and progression of chronic kidney disease in smokers

The deleterious health effects of cigarette smoking are far reaching, and it remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular disease and lung disease, there is strong evidence, both from human and animal studies, demonstrating a role for cigarette smoking in the progression of chronic kidney disease (CKD). Clinical studies have shown a strong correlation between cigarette smoking and worsening CKD in patients with diabetes, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to its role in the addictive properties of cigarette smoking, has other biological effects via activation of non-neuronal nicotinic acetylcholine receptors (nAChRs). Several nAChR subunits are expressed in the normal kidney and blockade of the α7-nAChR subunit ameliorates the effects of nicotine in animal models of CKD. Nicotine increases the severity of renal injury in animal models including acute kidney injury, diabetes, acute nephritis and subtotal nephrectomy. The renal effects of nicotine are also linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In summary, clinical and experimental evidence indicate that nicotine is at least in part responsible for the deleterious effects of cigarette smoking in the progression of CKD. The mechanisms involved are the subject of active investigation and may result in novel strategies to ameliorate the effects of cigarette smoking in CKD.     

High dose transdermal nicotine therapy for heavy smokers: safety,tolerability and measurement of nicotine and cotinine levels

Transdermal nicotine has been shown to relieve nicotine withdrawal and to double smoking cessation rates compared to placebo in clinical trials. A 21 or 22 mg/day dose provides a steady state serum nicotine that is less than obtained from smoking. Limited information is available about higher nicotine patch doses. To define better the optimal dosing of nicotine patch therapy, we undertook an open-label study to determine the safety and tolerability of 44 mg/day dose for smoking cessation in subjects smoking 20 cigarettes per day. Forty smokers received 44 mg/day of transdermal nicotine for 4 weeks followed by 4 weeks of 22 mg/day. Of the 40 subjects enrolled, 38 (95%) completed the 4 weeks of 44 mg patch therapy and 36 (90%) completed the entire 8 weeks of patch therapy. Non-smokers at week 4 had a mean serum nicotine level of 23.4±11.7 ng/ml and cotinine of 152.2±87.3 ng/ml. Percent replacement was calculated by dividing the steady state level at week 4 by the baseline level while the subjects were smoking their usual number of cigarettes. Percent nicotine replacement for non-smokers at week 4 (while on 44 mg nicotine patch) averaged 158%±108.4, and for cotinine was 112.0±73.8. For nicotine, 33% of non-smokers at week 4 had 100% nicotine replacement and for cotinine 63% 100% replacement. Biochemically confirmed point prevalence smoking cessation rates were 65% and 55% at weeks 4 and 8 of patch therapy, respectively, and self-reported smoking cessation at 3 months was 50%. The most common effect was skin irritation at the patch site. A single subject was admitted for myocardial infarction following step-down from 44 to 22 mg of replacement nicotine. The subject was not smoking and the adverse event was deemed to be not related to the patch therapy. Sleep complaints were reported in 33% of subjects during the 44 mg phase. Other complaints were infrequent. We conclude that 44 mg per 24-h nicotine patch therapy in heavy smokers is safe, tolerable, and without significant adverse events.     

Psychophysiological effects of nicotine abstinence and behavioral challenges in habitual smokers

We tested the hypothesis that psychophysiological responses to behavioral challenges are enhanced by short-term abstinence from smoking. Blood pressure (BP), salivary cortisol levels, and withdrawal symptoms were measured after a period of smoking abstinence (18 h) or ad libitum smoking, during rest, and in response to acute behavioral challenges. Thirty habitual smokers (15 women and 15 men) participated in two laboratory sessions conducted on two separate days (after abstinence or ad libitum smoking). Cotinine concentrations in saliva and expired carbon monoxide were measured in both conditions. Abstinence produced significant withdrawal symptoms in all participants, with women reporting greater desire to smoke than men. Participants showed greater systolic BP responses to the behavioral challenges in the abstinence condition than the control condition. They also showed worse cognitive performance on the challenges in the abstinence than in the ad libitum condition. Men had greater salivary cortisol levels than women, and both men and women showed the expected decline in cortisol levels across time, but showed no difference between the abstinence and ad libitum smoking conditions in the laboratory or during ambulatory measurements. These results indicate that abstinence alters mood, performance, and BP responses to acute challenges but not adrenocortical responses. It is possible that these changes mediate stress-related vulnerability to smoking relapse.     

Nicotine from cigarette smoking increases circulating levels of cortisol,growth hormone,and prolactin in male chronic smokers

Results of this study indicate that nicotine from cigarette smoking increases circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers. Previous studies have not addressed the question of whether the stimulus for smoking-related hormone release is the stress of smoking or a pharmacologic action of nicotine and other tobacco substrates. Nicotine exposure is controlled in this study by allowing each subject to smoke only two 2.0 mg nicotine cigarettes during one experimental session and two 0.2 mg nicotine cigarettes in another session. Plasma levels of cortisol, growth hormone, and prolactin for the higher nicotine session were found to be significantly elevated over those for the low-nicotine session, indicating that nicotine itself plays a predominate role in smoking-induced hormone increases. All hormone levels for the 2.0 mg nicotine session had not returned to baseline 60 min after smoking.     

Effect of exercise on transdermal nicotine release in healthy habitual smokers

OBJECTIVE: Transdermal nicotine patches have become a frequently prescribed tool in smoking cessation programs during the past years. However, there is circumstantial evidence that transdermal nicotine release substantially varies with physical activity producing toxic plasma concentrations that may account for severe adverse events. METHODS: We, therefore, compared nicotine release from two different transdermal nicotine systems (TDNS) at rest and during strenuous physical activity in a two-period crossover study in healthy smokers (n = 10). The subjects were randomly assigned to receive either 21 mg/day of formulation A or B on study Day 1 and 2. Patches were applied eight hours before starting standardized physical activity, and nicotine concentrations were measured in plasma and topically in the tissue layers underneath the application site by microdialysis. RESULTS: There was no difference between groups in the mean values for area under the time-concentration curve at rest from 0 - 8 hours AUC(0-8) (p < 0.799) and during exercise from 8 - 11 hours AUC(8-11) (p < 0.878). C(max) values between groups with C(max) values of 16.4 +/- 9.5 ng/ml and 16.0 +/- 10.7 ng/ml at rest (p < 0.919, NS) and 10.05 +/- 6.8 ng/ml and 10.2 +/- 6.9 ng/ml (p < 0.959, NS) during exercise did not differ significantly. Nicotine tissue concentrations increased two-fold during exercise versus baseline (p < 0.878). Skin blood flow increased significantly during exercise compared with baseline (p < 0.001). No adverse events were observed. CONCLUSION: The present study provides evidence that transdermal nicotine release from TDNS increases during exercise. However, this increase has no significant effect on overall plasma pharmacokinetics. Our pharmacokinetic data further indicate that the two TDNS formulations are equivalent during conditions of rest and exercise.     

Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia.

The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.