Basic Science Study of the Mechanisms of Attentional Enhancement by Compounds Acting on the Nicotinic Receptor
Conditions
Keywords
nicotine, galantamine, attention, cognition, non-smoker
Brief summary
The aim of this study is to test whether the attention-enhancing effects of low-dose nicotine can be enhanced by the drug galantamine, FDA-approved for the treatment of Alzheimer's disease. This proof-of-principle study is performed in healthy non-smokers and involves two single exposures to a nicotine patch (7 mg/24 hrs) and two single exposures to galantamine (4 mg). The dose of galantamine is substantially lower than the clinical dose range of 16-24 mg/day. The hypothesis is that performance-enhancing effects of nicotine are greater in the presence of this low dose of galantamine.
Detailed description
Healthy non-smokers will be screened for study eligibility and receive training on three different attention tasks. Over four test session, participants will then perform these tasks after receiving (1) a placebo patch and a placebo capsule, (2) a nicotine patch (7 mg/24 hrs) and a placebo capsule, (3) a placebo patch and a galantamine capsule, and (4) a nicotine patch and a galantamine capsule. The four test session are performed on separate days and take approximately 7 hours each. During the first 5 hours, the participant may read or watch TV while nicotine and/or galantamine are being absorbed. During the last two hours, the participant will perform the attention tasks on a computer. The investigators hypothesize that performance-enhancing effects of nicotine, which were documented in previous research, will be larger in the presence than in the absence of galantamine. This proof-of-concept would have implications for the development of drugs for the treatment of conditions such as Alzheimer's disease or schizophrenia.
Interventions
DRUGNicotine patch and galantamine capsule
On this test day, cognition is assessed after administration of a nicotine patch (7 mg/24 hrs) and a galantamine capsule (4 mg p.o.).
DRUGPlacebo patch & placebo capsule
On this test day, cognition is assessed after administration of a placebo patch and a placebo capsule.
DRUGPlacebo patch & galantamine capsule
On this test day, cognition is assessed after administration of a placebo patch and a galantamine capsule (4 mg p.o.).
DRUGNicotine patch & placebo capsule
On this test day, cognition is assessed after administration of a nicotine patch (7 mg/24 hrs) and a placebo capsule.
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Aged 21 to 55 years. * No exposure to any nicotine-containing product in the last year. * Smoked no more that 40 cigarettes, cigars or cigarillos in lifetime. * Normal or corrected to normal vision (at least 20/80). * Body weight 110-220 lbs.
Exclusion criteria
* Pregnant or breast-feeding. * Drug or alcohol abuse or dependence currently or in the last 2 years. * DSM Axis I mood, anxiety or psychotic disorder. * Cardiovascular or cerebrovascular disease, such as history of myocardial infarction and ischemia, heart failure, angina, stroke, severe arrhythmias, or EKG abnormalities (Wolf-Parkinson-White syndrome, Complete left bundle branch block, PR interval \<120 ms or \>200 ms, Prolonged QT interval (corrected) \>500 ms, Cardiac arrhythmias as defined by PACs \>3 per min or PVCs \>1 per min). * Uncontrolled hypertension (resting systolic BP above 140 or diastolic above 90 mm Hg). * Hypotension (resting systolic BP below 90 or diastolic below 60). * Significant kidney or liver impairment. * Moderate to severe asthma. * Obstructive pulmonary disease. * Type I or II diabetes. * Use of any centrally active medications; any peripherally acting cholinergic medications; cimetidine; ketoconazole; erythromycin; quinidine, or chronic nonsteroidal anti-inflammatory drugs. * History of or current neurological illnesses, such as stroke, seizure disorders, neurodegenerative diseases, or organic brain syndrome. * Learning disability, mental retardation, or any other condition that impedes cognition. * Heart rate \<55 bpm. * Current or history of gastric ulcer disease. * Any surgeries requiring full anesthesia scheduled within 2 weeks of any of the study test sessions. * Anemia. * Inability to perform the Rapid Visual Information Processing Task.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change Detection Task Accuracy | 15 min | The task requires encoding the color of 1 or 5 shape items and reporting whether or not one of the items changed color. Accuracy refers to the percentage of all trials in which a correct response was given. One participant's data were excluded from this task because of excessive no-response trials. |
| Spatial Attentional Resource Allocation Task Predictive Trials Reaction Time | 45 min | The task requires detecting brief target stimuli presented at one of four locations in the four corner of the screen. On predictive trials, a central cue predicts the target location. |
| Rapid Visual Information Processing Task Hit Rate | 30 min | The task requires following a stream of digits and detecting three consecutive odd or even numbers. The Hit Rate reflects the percentage of all target sequences that were detected. |
| Change Detection Task Reaction Time | 15 min | The task requires encoding the color of 1 or 5 shape items and reporting whether or not one of the items changed color. One participant's data were excluded from this task because of excessive no-response trials. |
| Spatial Attentional Resource Allocation Task (SARAT) Non-predictive Trial Reaction Time | 45 min | The task requires responding to brief target stimuli presented randomly in one of four locations in the four corners of the screen. On non-predictive trial, the cue does not provide any advance information about where the target will occur. |
| Rapid Visual Information Processing Task Reaction Time | 30 min | The task requires the detection of three consecutive odd or three consecutive even digits in a stream of sequentially presented digits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Profile of Mood Scale - Total Mood Disturbance | 5 min | Participants rate their current subjective state on a list of adjectives, which contribute to six factors/subscales. Total Mood Disturbance is a composite measure, obtained by summing the scores of all subscales, each with a range of 0-4, weighting the one positively valenced factor negatively. Thus, smaller or more negative values represent a more positive mood state. The theoretical range of the Total Mood Disturbance measure is from -4 to +20. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Healthy Adults All participants receive the following four interventions, on separate days, in a counterbalanced order:
1. placebo patch and placebo capsule
2. placebo patch and galantamine capsule
3. nicotine patch and placebo capsule
4. nicotine patch and galantamine capsule
Placebo patch & placebo capsule: On this test day, cognition is assessed after administration of a placebo patch and a placebo capsule.
Placebo patch & galantamine capsule: On this test day, cognition is assessed after administration of a placebo patch and a galantamine capsule (4 mg p.o.).
Nicotine patch & placebo capsule: On this test day, cognition is assessed after administration of a nicotine patch (7 mg/24 hrs) and a placebo capsule.
Nicotine patch and galantamine capsule: On this test day, cognition is assessed after administration of a nicotine patch (7 mg/24 hrs) and a galantamine capsule (4 mg p.o.). | 43 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 7 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Pregnancy | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | Healthy Adults |
|---|---|
| Age, Continuous | 33.3 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 18 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 43 participants |
| Sex: Female, Male Female | 27 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 34 | 0 / 30 | 0 / 32 |
| other Total, other adverse events | 1 / 32 | 5 / 34 | 0 / 30 | 4 / 32 |
| serious Total, serious adverse events | 0 / 32 | 0 / 34 | 0 / 30 | 0 / 32 |
Outcome results
Primary
Change Detection Task Accuracy
The task requires encoding the color of 1 or 5 shape items and reporting whether or not one of the items changed color. Accuracy refers to the percentage of all trials in which a correct response was given. One participant's data were excluded from this task because of excessive no-response trials.
Time frame: 15 min
Population: Healthy adult non-smokers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Change Detection Task Accuracy | 83 percentage of all trials | Standard Deviation 6 |
| Nicotine Patch and Placebo Capsule | Change Detection Task Accuracy | 83 percentage of all trials | Standard Deviation 6 |
| Placebo Patch and Galantamine Capsule | Change Detection Task Accuracy | 84 percentage of all trials | Standard Deviation 6 |
| Nicotine Patch and Galantamine Capsule | Change Detection Task Accuracy | 84 percentage of all trials | Standard Deviation 6 |
Primary
Change Detection Task Reaction Time
The task requires encoding the color of 1 or 5 shape items and reporting whether or not one of the items changed color. One participant's data were excluded from this task because of excessive no-response trials.
Time frame: 15 min
Population: Healthy adult non-smokers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Change Detection Task Reaction Time | 1018 ms | Standard Deviation 241 |
| Nicotine Patch and Placebo Capsule | Change Detection Task Reaction Time | 1023 ms | Standard Deviation 216 |
| Placebo Patch and Galantamine Capsule | Change Detection Task Reaction Time | 1043 ms | Standard Deviation 239 |
| Nicotine Patch and Galantamine Capsule | Change Detection Task Reaction Time | 973 ms | Standard Deviation 225 |
Primary
Rapid Visual Information Processing Task Hit Rate
The task requires following a stream of digits and detecting three consecutive odd or even numbers. The Hit Rate reflects the percentage of all target sequences that were detected.
Time frame: 30 min
Population: Healthy adult non-smokers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Rapid Visual Information Processing Task Hit Rate | 50 percentage of all targets | Standard Deviation 19 |
| Nicotine Patch and Placebo Capsule | Rapid Visual Information Processing Task Hit Rate | 54 percentage of all targets | Standard Deviation 18 |
| Placebo Patch and Galantamine Capsule | Rapid Visual Information Processing Task Hit Rate | 49 percentage of all targets | Standard Deviation 21 |
| Nicotine Patch and Galantamine Capsule | Rapid Visual Information Processing Task Hit Rate | 54 percentage of all targets | Standard Deviation 19 |
Primary
Rapid Visual Information Processing Task Reaction Time
The task requires the detection of three consecutive odd or three consecutive even digits in a stream of sequentially presented digits.
Time frame: 30 min
Population: Healthy adult non-smokers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Rapid Visual Information Processing Task Reaction Time | 463 ms | Standard Deviation 59 |
| Nicotine Patch and Placebo Capsule | Rapid Visual Information Processing Task Reaction Time | 459 ms | Standard Deviation 64 |
| Placebo Patch and Galantamine Capsule | Rapid Visual Information Processing Task Reaction Time | 473 ms | Standard Deviation 70 |
| Nicotine Patch and Galantamine Capsule | Rapid Visual Information Processing Task Reaction Time | 459 ms | Standard Deviation 63 |
Primary
Spatial Attentional Resource Allocation Task Predictive Trials Reaction Time
The task requires detecting brief target stimuli presented at one of four locations in the four corner of the screen. On predictive trials, a central cue predicts the target location.
Time frame: 45 min
Population: 27 healthy adult non-smokers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Spatial Attentional Resource Allocation Task Predictive Trials Reaction Time | 420 ms | Standard Deviation 66 |
| Nicotine Patch and Placebo Capsule | Spatial Attentional Resource Allocation Task Predictive Trials Reaction Time | 408 ms | Standard Deviation 56 |
| Placebo Patch and Galantamine Capsule | Spatial Attentional Resource Allocation Task Predictive Trials Reaction Time | 416 ms | Standard Deviation 61 |
| Nicotine Patch and Galantamine Capsule | Spatial Attentional Resource Allocation Task Predictive Trials Reaction Time | 413 ms | Standard Deviation 63 |
Primary
Spatial Attentional Resource Allocation Task (SARAT) Non-predictive Trial Reaction Time
The task requires responding to brief target stimuli presented randomly in one of four locations in the four corners of the screen. On non-predictive trial, the cue does not provide any advance information about where the target will occur.
Time frame: 45 min
Population: Healthy adult non-smokers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Spatial Attentional Resource Allocation Task (SARAT) Non-predictive Trial Reaction Time | 472 ms | Standard Deviation 71 |
| Nicotine Patch and Placebo Capsule | Spatial Attentional Resource Allocation Task (SARAT) Non-predictive Trial Reaction Time | 455 ms | Standard Deviation 62 |
| Placebo Patch and Galantamine Capsule | Spatial Attentional Resource Allocation Task (SARAT) Non-predictive Trial Reaction Time | 465 ms | Standard Deviation 66 |
| Nicotine Patch and Galantamine Capsule | Spatial Attentional Resource Allocation Task (SARAT) Non-predictive Trial Reaction Time | 449 ms | Standard Deviation 64 |
Secondary
Profile of Mood Scale - Total Mood Disturbance
Participants rate their current subjective state on a list of adjectives, which contribute to six factors/subscales. Total Mood Disturbance is a composite measure, obtained by summing the scores of all subscales, each with a range of 0-4, weighting the one positively valenced factor negatively. Thus, smaller or more negative values represent a more positive mood state. The theoretical range of the Total Mood Disturbance measure is from -4 to +20.
Time frame: 5 min
Population: Healthy adult non-smokers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo Patch and Placebo Capsule | Profile of Mood Scale - Total Mood Disturbance | -0.32 score on a scale | Standard Deviation 0.91 |
| Nicotine Patch and Placebo Capsule | Profile of Mood Scale - Total Mood Disturbance | -0.48 score on a scale | Standard Deviation 0.98 |
| Placebo Patch and Galantamine Capsule | Profile of Mood Scale - Total Mood Disturbance | -0.60 score on a scale | Standard Deviation 0.99 |
| Nicotine Patch and Galantamine Capsule | Profile of Mood Scale - Total Mood Disturbance | -0.43 score on a scale | Standard Deviation 1.16 |