Studies of the impact of gender on the pharmacodynamics of nicotine have resulted in mixed findings. One study39 found that men had significantly greater clearance of nicotine than women, but a second study40 found no effect of gender on nicotine clearance. As male subjects usually weigh more and have larger liver mass and partal vein capacity, it is to be expected that men will usually have greater total nicotine clearance than women. The possibility of changes in nicotine metabolism during the menstrual cycle has not been examined. There is some evidence of an increase in nicotine withdrawal symptoms and greater cigarette craving during menses;4142 however these data are inconclusive due to the overlap of symptoms attributable to menses and symptoms attributable to nicotine withdrawal.
Nicotinic agents have been studied in subjects of all ages. Children as young as 10 have participated in studies of nicotine patch in Tourette's syndrome,43 and elderly subjects as old as 80 have participated in AD studies.16 The question of age affecting nicotine tolerance and absorption has not been directly studied. It is obvious that the variability in body mass associated with different age groups (children vs. adults vs. elderly subjects) will impact the effect of a given dose of nicotine. However, subjects of all ages have been successfully used in nicotinic investigations when issues of dosing and side effect management have been addressed.
Newhouse and colleagues44 demonstrated that there are varying cognitive effects associated with the age of normal volunteer subjects. This study demonstrated that elderly (60 +) subjects were more susceptible to the cognitive effects of nicotinic blockade than were young (18 to 30) subjects; presumably this was associated with the loss of nicotinic receptors, which comes with age.19 The finding that the age of the subject impacts the magnitude of the cognitive effects in normal volunteers has implications for subject selection. One strategy for managing this finding is to use subjects in a similar age range. If this is not feasible, it will be important to examine a subset or even individual results of subjects, based upon age.
One consistent finding regarding subject characterization in the study of nicotine and cognition indicates that there are individual differences in subjects' response to nicotine. Perkins45 reviewed a large body of literature in support of the theory that baseline state may account for a significant portion of variability in results of nicotinic studies. The effects of baseline performance may explain why studies using normal volunteers show small or no improvements following nicotine administration,46 while studies using impaired subjects (either from sleep deprivation, tobacco withdrawal, or diagnosis of AD, ADHD, Schizophrenia, etc.) show larger improvements following nicotine administration.16,18 26 47 48 The effects of baseline performance on the magnitude and direction of the effects of nicotine administration can be seen on a number of dependant variables including mood, behavioral ratings, and tests of cognition, and have been shown in subjects using a wide variety of methodologies.45 One investigator demonstrated that subjects who had lower initial arousal levels experienced a greater stimulant effect of nicotine than subjects whose baseline arousal was already high.49 Although it is possible that this may represent "ceiling" or "floor" effects, due to the finding that many effects involving responding exist well within the upper and lower limits of the dependent measure,50 this explanation does not explain away the findings relevant to baseline dependency. Individual variability has been explored in primates by individually dose-ranging subjects and their cognitive changes in order to compare individuals.51
The practical implications of these findings include examining data based on individuals as well as on group means. Traditionally, data from pharmacological studies are collapsed to compare means (of differing treatments, or of treatment vs. placebo). Baseline dependency may influence the response to the drugs such that a subgroup of subjects (with low baseline mood scores) may experience elevations of mood ratings, while another subgroup (with high baseline mood ratings) may experience declines of mood ratings. Collapsing the data would results in a finding of no significant difference, but examination of subgroups or even individual subjects data could provide a more complete picture of the effect of the drug.
Another important methodological implication from this body of research is to characterize the subject pool carefully, using baseline measures comparable to the dependant measures of study. This allows for post-hoc characterization of the effects of nicotinic agents on the dependent variable that accounts for the subjects' baseline performance on this variable. These findings also underscore the importance of controlling for baseline conditions (either within or between subjects) to reduce the baseline variability and, thus, potential variability in the effects seen from nicotine administration.
Several considerations contribute to the decision of which preparation and route of administration to use for nicotine and/or nicotinic agents in human cognitive investigations. Nicotine is available and has been used in many forms including inhaled, iv, subcutaneous, transdermal patch, nasal spray, and gum. These have all been used successfully in human studies of performance. Issues to address in this determination include the speed of nicotinic effects, the side effects profile, the dosing accuracy required by the investigation, and practical issues of dose preparation and blinding.
IV administration of nicotine has been used successfully in cognitive studies using patients diagnosed with AD and PD.52 53 This route of administration results in a steady rise in plasma levels over the first 30 minutes of drug administration; plasma levels decline rapidly when drug administration ceases.54
The primary advantage of iv administration is the precision with which a dose can be administered (based upon the weight of the subject). This allows for greater control over the drug and, presumably, plasma nicotine levels. Another advantage of the increased control with iv preparation is that drug administration can be rapidly adjusted or discontinued if side effects occur. This can reduce the discomfort experienced by patients and lead to greater compliance and higher completion rates in this type of protocol.
The main drawback to using an iv preparation of nicotine involves the creation of the pharmaceutical. IV nicotine is not commercially available and thus must be prepared by a pharmacy (in accordance with an IND from the FDA) and administered by a physician. This is in contrast to commercially available forms of nicotine (patch, gum, and nasal spray) that can be purchased over the counter and administered by other study personnel (or self-administered by the subject). IV nicotine must be prepared by a pharmacy for each subject because the doses are based upon the weight of the subject. The rapid absorption and continuous administration in iv dosing lead to the possibility of the rapid onset of nicotine toxicity. This can be managed by frequent monitoring of subjective symptoms and discontinuation of the infusion at the onset of symptoms of nicotine toxicity. IV administration of nicotine also necessitates cardiac monitoring during the infusion; cardiac telemetry has been used successfully5253 in several studies using iv administration of nicotine. Other drawbacks to this route of administration include subject discomfort due to the insertion of the iv, occasional arm pain during the infusion, and the need to remain stationary during the infusion. These problems are largely manageable and should not prevent subjects from completing a protocol.
Nicotine inhaled from cigarette smoking reaches the brain in 10 to 19 seconds.55 Cigarette smokers vary individually in the actual dose of nicotine they get from each cigarette by changes in how they puff their cigarette (rate, volume, and intensity) and changes in depth of inhalation.35 For these reasons, it is difficult to control the nicotine dosage used in smoking studies. Standard methodologies in studies using cigarette smoking as a route of nicotine delivery dictate smoking rate and length of inhalation to subjects in an attempt to control the nicotine dose; however, precise dosing is difficult to attain using inhaled cigarette smoke.
The primary advantage to cigarette smoking in nicotine research is that it is a prime model for addiction studies where subjects control their own dosing and investigators control contributing variables. Cigarette smoking is naturalistic, and these laboratory studies can provide a useful link to real-life uses of nicotine. However, for the study of cognition and clinical disorders, smoking is not typically used to deliver nicotine. The loss of precise dosing is the primary drawback of this method of drug delivery. In addition, smoking cigarettes is quite noxious to nicotine-naïve subjects, and creating placebo cigarettes with a similar taste and abrasiveness to the airways, while possible, is labor intensive and expensive.
Oral nicotine is usually administered via nicotine gum. This preparation of nicotine is absorbed through the oral mucosa and results in a slow rise of plasma nicotine levels that peak at approximately 30 minutes.35 There is substantial variability in the amount of nicotine actually extracted from the gum due to variations in chewing between subjects.56 Nicotine is also swallowed with this administration method, leading to inaccuracies in determining how much nicotine reaches the brain.56
Nicotine gum is readily available in standard doses and is easy to administer to subjects. It is portable, allowing for dosing in virtually any setting. Drawbacks include inaccuracies in dosing cited earlier, as well as difficulties in creating placebo gum due to the distinct taste of nicotine gum.
Subcutaneous administration has been used in several studies of the cognitive effects of acute nicotine administration. Pharmacokinetic studies show that, following administration, plasma levels rise steadily with peak plasma levels reached approximately 15 minutes following injection.57 Advantages to this method of administration include the speed of administration and nicotine absorption. Unlike intravenous administration, the subjects' exposure to a needle is brief and, with the use of pH neutralization, the site of the injection is relatively painless following the injection.57 Subcutaneous preparations of nicotine are prepared individually for each subject, allowing for precise dosing based on the weight of the subject.
Drawbacks to this route of administration include the same problems in drug manufacturing as for iv preparations. Specifically, these include the necessity of a pharmacy to create the nicotine preparation (in accordance with an IND from the FDA), and a physician to administer it. An additional drawback to subcutaneous administration is that side effects cannot be managed by adjusting or discontinuing the nicotine dose. Some subjects may experience pain and irritation at the site of the injections, and others may find the procedure itself to be unpleasant. Subcutaneous administration has not been widely used in cognitive studies of nicotine; when compared with iv administration, it appears that the drawbacks are similar, and iv administration has the added advantage of continuous administration and the ability to adjust or discontinue the drug rapidly.
Nicotine patches have been successfully used in studies of cognition and nicotine in patients with AD, PD, and ADHD; they deliver nicotine continuously while worn. The absorption of nicotine is slow, with peak plasma levels achieved approximately six hours after the patch is applied.40 These levels remain generally steady for 7 to 8 hours and then decline over the next 6 hours.40
Nicotine patches are well suited for clinical studies for several reasons. They offer steady rates of nicotine delivery unlike smoking, nasal spray, or nicotine gum. This helps with the control of dosing that is problematic in many administration methods. There are many conveniences associated with use of the nicotine patch, including ease of application, and the unobtrusive nature of the transdermal patch. Nicotine patches are relatively easy to blind and are commercially available. Some brands are constructed so that it is possible to cut the patch to control the amount of nicotine administered, allowing for some flexibility in dosing.
There are several drawbacks to the use of patches as well. The onset of peak plasma levels occurs relatively slowly while the onset of side effects is often seen within 1 hour.57 Due to the slow rise in plasma levels, nicotine continues to accumulate after the patch is first removed. This can be problematic for subjects who become symptomatic because the drug cannot be rapidly discontinued. While using the nicotine patch provides a convenience of premade doses, it is difficult to make dosage adjustments because it is available in limited dosage forms. Nicotine patches also produce skin irritation in some subjects.
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Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.