Initial Screening of Gemfibrozil as a Novel Treatment for Tobacco Addiction

Animal studies have shown that drugs acting as agonists at alpha-type peroxisome proliferator-activated receptors (PPARα) suppress nicotine self-administration, attenuate relapse to nicotine-seeking behavior in the reinstatement model, and block nicotine-induced neuronal firing and dopamine release in reward pathways of the brain. These results have been demonstrated with synthetic PPARα agonists and with fibrate drugs (clofibrate, fenofibrate), which are used clinically to treat elevated cholesterol and triglycerides levels. Thus, PPARα is a potential target for the treatment of tobacco addiction. This is the first human study to investigate whether a fibrate drug (gemfibrozil, Lopid®) can reduce nicotine reward and aid smokers in becoming tobacco abstinent.

The objectives of this study are:

1. to investigate the effect of gemfibrozil on laboratory measures of nicotine reinforcement and cue-elicited craving
2. to screen for the ability of gemfibrozil to aid smoking abstinence during a brief quit attempt
3. to examine the validity of using laboratory measures of tobacco dependence to predict smoking abstinence and possible gemfibrozil-related increases in smoking abstinence

This outpatient study will be conducted at the Center for Addiction and Mental Health (CAMH) in Toronto, Canada. This site will enroll 40 adult smokers who intend to quit smoking in the next 3 months.

The study is a double-blind, placebo-controlled, crossover design comparing the effects of gemfibrozil and placebo. The study will comprise two 2-week medication phases with a washout period of at least one week. At the end of the first medication week laboratory measures will be taken and during the second medication week participants will make a quit attempt and abstinence will be assessed.

Outcome measures include laboratory assessments of nicotine reinforcement and smoking cue reactivity. The measure of nicotine reinforcement is the percentage of nicotine cigarette puffs chosen during a forced-choice task. Measures of cue reactivity include tobacco craving, mood, and autonomic responsivity. Other measures are days of smoking abstinence during the quit-attempt weeks. Abstinence is assessed by self-reports of no smoking and by breath carbon monoxide < 5 ppm on clinic visits. Other assessments of abstinence include self-reported tobacco craving and withdrawal.

• Gemfibrozil (Drug), also known as Lopid: 600 mg of gemfibrozil (one capsule) twice daily for two weeks.
• Placebo (Drug), also known as Lactose: One lactose pill twice a day for two weeks.

Primary outcomes

• Number of Days With Self-report of No Smoking and Breath Carbon Monoxide of <5 PPM During Quit-attempt Weeks [1 week in each phase]: the number of days of no smoking was calculated for each participant. Abstinence was verified by daily Self-reports of no smoking and breath carbon monoxide < 5 ppm

Secondary outcomes

• The Percentage of Choice of Nicotinized Cigarettes After 1 Week of Treatment [during the lab forced choice paradigm after 1 week of treatment]: Percentage of choice of Nicotinized cigarettes was calculated for each participant during the lab session which took place after 1 week of treatment. Each session started with participants taking four puffs of their preferred-brand cigarette to standardize the time from last nicotine exposure. Participants were asked to complete some questionnaires at baseline. Then, they were asked to relax for 30 min listening to music or reading. Four exposure trials followed that were separated by 30 min of relaxation. In each exposure trial, participants took four puffs of a Nicotinized (A) or Denicotinized (less than 0.05 mg nicotine.) (B) cigarette in the order of ABAB or BABA. Cigarettes were color-coded. Participants then began four choice trials separated by 30 min of relaxation. In each trial, participants chose any combination of 4 puffs from the two cigarettes.

Other outcomes

• Cue- Reactivity Visual Analogue Scale for Craving After 1 Week of Treatment [during the lab Cue- reactivity paradigm after 1 week of treatment]: In this study, each session started with participants taking four puffs of their preferred-brand cigarette to standardize the time from last nicotine exposure. Participants were then seated in a comfortable chair and completed the baseline Visual Analogue Scale for craving 0-100 mm (The higher the number the more is the craving). The smoking cue was a pack of cigarettes and a lighter. Participants were instructed to light the cigarette without puffing and hold it for 30 sec while the physiological recordings were measured. Then the participant was asked to extinguish the cigarette. The neutral cue was an unsharpened pencil, a notepad, and a sharpener. Participants were instructed to sharpen the pencil and hold it as if writing for 30 sec. Participants completed the Visual Analogue Scale for craving during the cue, and 15 and 30 min after cue presentation.

Sex: All, ages: 19 Years to 65 Years

Inclusion Criteria:

* 19-65 year old males and females
* smoking at least 10 cigarettes per day for at least 2 years
* intend to quit smoking within the next 3 months
* medically and psychologically healthy as determined by screening criteria

Exclusion Criteria:

* currently attempting to quit smoking
* treatment for tobacco addiction in the past 3 months
* use of nicotine replacement products, bupropion, or varenicline in the past 3 months as an aid to quit or reduce smoking
* use of any oral tobacco product in the past 3 months
* history of drug or alcohol dependence within last 5 years
* consumption of more than 15 alcoholic drinks per week on average during the past month
* use of any illicit drug more than once per week on average during the past month
* current use of gemfibrozil or other fibrate medication
* current use of any medication that is contraindicated for gemfibrozil or that would interfere with the protocol in the opinion of MAI/QI. This includes, but is not limited to, anticoagulants, statins, other fibrates, other lipid-lowering agents such as niacin or herbal remedies, and any oral or injected medications for diabetes.
* any pre-existing gall-bladder disease or operation in the past 12 months
* any history of or current cardiovascular, liver, hepatic or renal disease
* diabetes
* pregnant, nursing, or become pregnant during the study
* use of psychoactive drugs or medications as revealed by urine toxicology

Participant flow

Outcome results

• Number of Days With Self-report of No Smoking and Breath Carbon Monoxide of <5 PPM During Quit-attempt Weeks (Primary), Mean, days: Gemfibrozil 0.2 +/- 0.1; Placebo 0 +/- 0 (p 0.1)
• The Percentage of Choice of Nicotinized Cigarettes After 1 Week of Treatment (Secondary), Mean, percentage of choice of nicotinized ciga: Gemfibrozil 0.775 +/- 0.034; Placebo Group 0.77 +/- 0.05 (p 0.9)
• Cue- Reactivity Visual Analogue Scale for Craving After 1 Week of Treatment (Other pre specified), Mean, units on a scale: from 0-100 mm: Gemfibrozil 51 +/- 32.7; Placebo Group 44 +/- 27.4 (p 0.4)

Adverse events

Time frame: The side effects were collected for each participant over six weeks from the start of treatment (2 weeks gemfibrozil/or placebo), 1 week washout period, (2 weeks gemfibrozil/or placebo), and 1 week after completion of the study.

Other adverse events by term

• Bernard Le Foll, MD, PhD, Principal investigator, Centre for Addiction and Mental Health