Effects of Nicotine in Tobacco Smokers

Compulsive ritualistic behavior and negative reinforcement are core features of tobacco
dependence (TD) and obsessive-compulsive symptoms (OCS; intrusive thoughts or impulses that
cause distress and rituals executed to alleviate such distress). OCS levels vary along a
continuum and an appreciable portion of the general population and smoker samples experience
significant levels of OCS. The investigators found that OCS levels are high in smokers and
predict TD severity, tobacco withdrawal symptoms, and barriers to quitting. Yet, there are no
cessation treatment studies focused on smokers with OCS and few data on the mechanisms
linking OCS and TD that can guide treatment for this comorbidity.

To address this gap, the investigators propose an experimental medicine translational
research study that will test a novel theoretical model of the mechanisms linking OCS and
persistent TD. By doing so, this study will advance the long-term goal of research program of
improving cessation treatment for smokers with OCS. The model purports that, in daily
smokers, OCS perpetuates TD because smoking has negatively reinforcing pharmacological and
behavioral effects that are uniquely salient to smokers with OCS. Pharmacological: People
with OCS become cognitively and affectively absorbed by obsessions and aversive cues due to
deficits in cognitive control. Nicotine enhances cognitive control and buffers distraction by
aversive cues. Thus, in smoking abstinence, pre-existing cognitive control deficits could be
unmasked and exacerbated in smokers with OCS, leaving them vulnerable to aversive stimuli
that cue intrusive obsessive thoughts and other general sources of distress from withdrawal.
Behavioral: The tobacco self-administration ritual (i.e., sequence of lighting a cigarette,
hand-to-mouth movements, puffing, inhalation, and exhalation) acquires negatively reinforcing
distress-alleviating properties independent of nicotine. Because people with OCS are prone to
compulsive ritualistic acts to quell distress, smoking may serve as a substitute ritual that
compensates for compulsions. Upon smoking abstinence, loss of the smoking ritual may allow
formerly suppressed urges to engage in compulsive acts to become unchecked, and in turn
amplify distress and drive to reinstate the smoking ritual.

In the proposed study, smokers (5+ cigarettes/day; N=220) will attend a baseline visit
involving multi-measure assessment of past-month OCS levels. They will then complete 4 lab
visits each after 12-hr smoking abstinence. At each visit, they will be administered 1 of 4
experimental manipulations used to isolate pharmacological and behavioral causal influences
on the putative mechanisms liking OCS to persistent TD. The manipulations will also inform
candidate treatments worthy of future inquiry. The within-subject experimental conditions
are: (i) conventional cigarettes to offset loss of nicotine and the smoking ritual, (ii)
denicotinized cigarettes to offset loss of the smoking ritual only, (iii) 21milligram
nicotine transdermal patch without smoking to offset loss of nicotine only, and (iv) a
placebo patch without smoking. Outcomes will be assessed at each visit using an innovative
multi-method strategy. Intermediate outcomes assess putative mechanisms linking OCS to
smoking: cognitive control impairment, general distress (i.e., withdrawal symptoms, negative
affect), OCS-specific distress (i.e., affective/attentional reactivity to obsession-related
cues, state OCS), and urge to smoke for distress relief. The 'distal' outcome is smoking
reinstatement behavior measured by a task occurring at the end of each visit. Data will be
used to model behavioral and pharmacological effects on a negative reinforcement pathway
(momentary increases in general and OCS-specific distress states --> urge to smoke for relief
--> smoking reinstatement), which will service the primary aim of testing of whether baseline
visit OCS level amplifies (i.e., statistically moderates) each component path in the pathway.

The primary aims are to test the following key hypotheses derived from the model:

1. Smokers with higher OCS levels will exhibit greater amplification of the negative
reinforcement pathway (OCS-specific and general distress --> urge to smoke --> smoking
reinstatement) due to the behavioral effects of losing the self-administration ritual,
which will be modeled by the no smoking vs. denicotinized cigarette smoking pairwise
contrast.

2. Smokers with higher OCS levels will exhibit greater amplification of cognitive control
deficits, and in turn, amplification of the negative reinforcement pathway due to the
pharmacological effects of nicotine reduction, regardless of whether the smoking ritual
is present (denicotinized cigarette vs. conventional cigarette smoking) or absent
(placebo patch + no smoking vs. nicotine patch + no smoking).

The secondary aim is to test model specificity by comparing the amplifying (moderating)
effects of OCS to the corresponding moderating effects of other syndromes (i.e., ADHD,
depression, generalized anxiety, panic, psychosis, PTSD, alcohol/drug problems, and
personality disorder symptoms) and studying whether effects persist after simultaneously
adjusting for multiple moderating pathways.

In addition to innovating theory, this project will elucidate mechanisms of TD in high-OCS
smokers that can be targeted in subsequent treatment development research (e.g., support for
Aim 2 --> nicotine agonist treatments, Aim 1 --> treatments to replace or suppress impulses
to execute ritualistic behavior).

Inclusion Criteria:

- At least 21 years old

- Daily smoking at least 2 years

- Currently smoke 5 - 40 cigarettes/day

Exclusion Criteria:

- Breath Carbon Monoxide levels above 10 ppm at study intake.

- Currently pregnant or breastfeeding. Contraindications for nicotine patch (i.e. angina
pectoris, cardiac arrhythmias, heart attack, stroke, type-I diabetes, hypertension,
hyperthyroidism, pheochromocytoma, skin diseases that increase sensitivity to patch
irritation).

- Use of bupropion