Clinical trial NCT01954966: Progesterone and Brain Imaging Study
Official title: Multimodal Imaging of Progesterone/Neurosteroid Effects in Nicotine Addiction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Nicotine Dependence
Nicotine Withdrawal
Keywords: Nicotine
Smoking
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2013-10-07
Enrollment: 81
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Male and female smokers were recruited to undergo 2 phases of smoking cessation. Each phase was 4 days long and involved 3 brain-imaging scans, blood draws and an intervention involving progesterone or a matched placebo.

Detailed description: The purpose of this study is to learn whether a sex hormone called progesterone is helpful in reducing cigarette smoking and craving for cigarettes. This study also includes brain imaging to measure possible effects of progesterone on certain neurochemicals. These neurochemicals are called gamma-aminobutyric acid (or GABA for short) and glutamate. Both nicotine and progesterone affect these brain chemicals.

Individuals wishing to participate in this study must be medically healthy men or women who smoke at least 10 cigarettes per day or greater. Participants must not suffer from a mental illness or use drugs other than nicotine and marijuana. Participants cannot have any implanted metallic devices such as pacemakers, orthodontic braces, or shrapnel. Participants must not have peanut allergies and must never have had a reaction to progesterone. Finally, participants cannot be taking any medications for anxiety, depression or insomnia.

Eligibility criteria: Inclusion Criteria:

* Female and male smokers, aged 18 to 50 years;
* History of smoking greater than or equal to 10 cigarettes daily for the past year, as per self-report (periods of smoking abstinence within the last year will be exclusionary at PI discretion);
* Not seeking treatment at the time of the study for nicotine dependence;
* Have a Fagerstrom Test for Nicotine Dependence (FTND) score of at least 3 and a Carbon Monoxide (CO) level greater than or equal to 11 ppm;
* Clean urine drug screen (marijuana is permissible);
* In good health as verified by medical history;
* For women, not pregnant as determined by pregnancy screening, nor breast feeding.

Exclusion Criteria:

* History of major medical illness: including liver diseases, abnormal vaginal bleeding, suspected or known malignancy; thrombophlebitis; deep vein thrombosis; pulmonary embolus; clotting or bleeding disorders; heart disease; diabetes; history of stroke or other medical conditions that the physician investigator deems as contraindicated for the patient to be in the study;
* Regular use of psychotropic medication (antidepressants, antipsychotics, or anxiolytics) and recent (within previous year) psychiatric diagnosis and treatment for Axis I disorders including major depression, bipolar affective disorder, generalized anxiety disorder, post-traumatic stress disorder and panic disorder;
* Lifetime history of schizophrenia or other psychotic disorder;
* Lifetime substance dependence disorder, excepting nicotine, alcohol and marijuana, as per SCID interview
* Substance use disorders within the previous 2 years, excepting nicotine, as per SCID interview
* Regular use of any other tobacco products than cigarettes, including smokeless tobacco and nicotine products;
* Known allergy to progesterone or peanuts (vehicle for micronized progesterone).

Primary outcomes:
measure: GABA Pre and Post Progesterone Administration (Dorsal Anterior Cingulate Cortex [DACC])
timeFrame: Test Day #2 and Test Day #5 - 6 total scans over the period of 2-3 months.
measure: GABA Pre and Post Progesterone Administration (Dorsolateral Pre-Frontal Cortex [DLPFC])
timeFrame: Test Day #2 and Test Day #5 - 6 total scans over the period of 2-3 months.
Secondary outcomes:
measure: Symptoms During Nicotine Abstinence (NWSC)
timeFrame: Day 1 (pre and post smoking session, day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Brief Questionnaire on Smoking Urges (BQSU)
timeFrame: Day 1 (pre and post smoking session, day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Tiffany Questionnaire on Smoking Urges (TQSU)
timeFrame: Day 1 (pre smoking session, day 3 (PM), day 4 (PM), day 5 (pre smoking session)
measure: Profile of Mood States (POMS) Subscale: Tension-Anxiety
timeFrame: Day 2 (pre and post scan), Day 5 (pre smoking session)
measure: Profile of Mood States (POMS) Subscale: Depression-Dejection
timeFrame: Day 2 (pre and post scan), Day 5 (pre smoking session)
measure: Profile of Mood States (POMS) Subscale: Anger-Hostility
timeFrame: Day 2 (pre and post scan), Day 5 (pre smoking session)
measure: Profile of Mood States (POMS) Subscale: Fatigue
timeFrame: Day 2 (pre and post scan), Day 5 (pre smoking session)
measure: Profile of Mood State (POMS) Subscale: Vigor
timeFrame: Day 2 (pre and post scan), Day 5 (pre smoking session)
measure: Profile of Mood States (POMS) Subscale: Confusion-Bewilderment
timeFrame: Day 2 (pre and post scan), Day 5 (pre smoking session)
measure: Visual Analog Scale (VAS) Question: Headache
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Hunger
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Nauseous
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Heartburn.
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Tired
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Irritable
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Energetic
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Relaxed
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Talkative
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Happy
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Nervous
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Sad
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Calm
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Depressed
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Drowsy
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Visual Analog Scale (VAS) Question: Anxious
timeFrame: Day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Positive and Negative Affect Schedule (PANAS) Negative Affect
timeFrame: Day 1 (pre and post smoking session, day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Positive and Negative Affect Schedule (PANAS) Positive Affect
timeFrame: Day 1 (pre and post smoking session, day 2 (pre and post scan), day 3 (AM and PM), day 4 (AM and PM), day 5 (pre and post smoking session)
measure: Nicotine Effects Questionnaire (NEQ) Question: Feels Strength of Nicotine
timeFrame: Day 1 (pre smoking session), Day 5 (post smoking session)
measure: Nicotine Effects Questionnaire (NEQ) Question: Feels Good Effects of Nicotine
timeFrame: Day 1 (pre smoking session), Day 5 (post smoking session)
measure: Nicotine Effects Questionnaire (NEQ) Question: Feels Bad Effects of Nicotine
timeFrame: Day 1 (pre smoking session), Day 5 (post smoking session)
measure: Nicotine Effects Questionnaire (NEQ) Question: Head Rush
timeFrame: Day 1 (pre smoking session), Day 5 (post smoking session)
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Penn Center for Women's Behavioral Wellness
state: Pennsylvania
Study officials:
affiliation: Associate Professor of Psychiatry, University of Pennsylvania
name: Cynthia N Epperson, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Epperson CN, O'Malley S, Czarkowski KA, Gueorguieva R, Jatlow P, Sanacora G, Rothman DL, Krystal JH, Mason GF. Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy. Biol Psychiatry. 2005 Jan 1;57(1):44-8. doi: 10.1016/j.biopsych.2004.09.021.
citation: Cai K, Nanga RP, Lamprou L, Schinstine C, Elliott M, Hariharan H, Reddy R, Epperson CN. The impact of gabapentin administration on brain GABA and glutamate concentrations: a 7T (1)H-MRS study. Neuropsychopharmacology. 2012 Dec;37(13):2764-71. doi: 10.1038/npp.2012.142. Epub 2012 Aug 8.
citation: Epperson CN, Toll B, Wu R, Amin Z, Czarkowski KA, Jatlow P, Mazure CM, O'Malley SS. Exploring the impact of gender and reproductive status on outcomes in a randomized clinical trial of naltrexone augmentation of nicotine patch. Drug Alcohol Depend. 2010 Nov 1;112(1-2):1-8. doi: 10.1016/j.drugalcdep.2010.04.021. Epub 2010 Jun 19.
citation: Mason GF, Petrakis IL, de Graaf RA, Gueorguieva R, Guidone E, Coric V, Epperson CN, Rothman DL, Krystal JH. Cortical gamma-aminobutyric acid levels and the recovery from ethanol dependence: preliminary evidence of modification by cigarette smoking. Biol Psychiatry. 2006 Jan 1;59(1):85-93. doi: 10.1016/j.biopsych.2005.06.009. Epub 2005 Nov 14.
citation: Cosgrove KP, Mitsis EM, Bois F, Frohlich E, Tamagnan GD, Krantzler E, Perry E, Maciejewski PK, Epperson CN, Allen S, O'malley S, Mazure CM, Seibyl JP, van Dyck CH, Staley JK. 123I-5-IA-85380 SPECT imaging of nicotinic acetylcholine receptor availability in nonsmokers: effects of sex and menstrual phase. J Nucl Med. 2007 Oct;48(10):1633-40. doi: 10.2967/jnumed.107.042317. Epub 2007 Sep 14.
citation: Novick AM, Duffy KA, Johnson RL, Sammel MD, Cao W, Strasser AA, Sofuoglu M, Kuzma A, Loughead J, Morrow AL, Epperson CN. Effect of progesterone administration in male and female smokers on nicotine withdrawal and neural response to smoking cues: role of progesterone conversion to allopregnanolone. Biol Sex Differ. 2022 Oct 23;13(1):60. doi: 10.1186/s13293-022-00472-w.
citation: Novick AM, Duffy KA, Johnson RL, Sammel MD, Cao W, Strasser AA, Sofuoglu M, Kuzma A, Loughead J, Epperson CN. Progesterone Increases Nicotine Withdrawal and Anxiety in Male but Not Female Smokers During Brief Abstinence. Nicotine Tob Res. 2022 Nov 12;24(12):1898-1905. doi: 10.1093/ntr/ntac146.