Milk Thistle in Pathological Gambling

Study Overview
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Brief Summary
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The goal of the proposed study is to evaluate the efficacy and safety of silymarin in individuals with gambling disorder. The hypothesis to be tested is that silymarin will be more effective and well tolerated in subjects with gambling disorder compared to placebo. The proposed study will provide needed data on the treatment of a disabling disorder that currently lacks a clearly effective treatment.

Detailed Description
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Gambling disorder is a significant public health problem that often results in a distinctive pattern of persistent and disabling psychological symptoms. Although once thought to be relatively uncommon, studies estimate that gambling disorder has a lifetime prevalence among adults of 1.6% and past-year prevalence of 1.1%. Patients with gambling disorder also experience significant social and occupational impairment as well as financial and legal difficulties. Individuals with gambling disorder report chronically high levels of stress, and vulnerability to gambling addiction is enhanced by stressful events (4), particularly as stress may result cognitive problems leading to impulsive and unhealthy decisions. A stress response is elicited when sensations and Observations do not match existing or anticipated expectations. A primary endocrine response to stress is the secretion of glucocorticoids through the activation of the hypothalamic-pituitary-adrenal axis. Although their release serves to maintain homeostasis during acute episodes of stress, prolonged stress responses have been associated with structural brain damage both in humans and animals. In humans, stress also enhances addictive craving, and relapse to addiction is more likely to occur in individuals exposed to high levels of stress. Since oxidative stress may be implicated in the etiology of addictive behaviors, use of antioxidants to reduce relapse, improve cognitive functioning, and reduce addictive urges may be a sensible step. Silymarin, a flavonoid and a member of the Asteraceae family, is extracted from the seeds of milk thistle (Silybum marianum) and is known to own antioxidative and anti-apoptotic properties. Silymarin has been reported to decrease lipid peroxidation. Furthermore, it has been demonstrated that its anti-oxidative activity is related to the scavenging of free radicals and activation of anti-oxidative defenses: increases in cellular glutathione content and superoxide dismutase activity. Milk thistle has been used for a range of psychiatric disorders including methamphetamine abuse and obsessive compulsive disorder, two psychiatric disorders with similarities to gambling disorder. The flavanoid complex silymarin in preclinical studies has been found to increase serotonin levels in the cortex, and ameliorate decreases in dopamine and serotonin in the prefrontal cortex and hippocampus associated with methamphetamine abuse. In the frontal cortex one of the functions of dopamine is to increase the signal to noise ratio, increased dopamine correlating with increased frontal performance. Studies have shown that the higher cortical dopamine levels are associated with improved frontal cortical cognitive performance. Cortical inhibition is felt to be the basis for top-down control of motivated behaviors. A recent randomized controlled study with milk thistle was conducted in Iran Thirty five participants with moderate OCD were randomly assigned to 200 mg of milk thistle leaf extract or 10 mg of fluoxetine three times daily for eight weeks. Results revealed no significant difference in treatment effects between milk thistle and fluoxetine from baseline to endpoint as both interventions provided a highly significant reduction in symptoms. Silymarin or Milk Thistle may therefore offer promise for the treatment of individuals with gambling disorder. Pharmacological management of gambling symptoms has produced mixed results, with some studies showing a superiority of medication to placebo. The current pilot study examines the tolerability and efficacy of milk thistle in the treatment of gambling disorder. We hypothesize that milk thistle will reduce the severity of gambling symptoms and improve patients' overall functioning.

Official Title
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Silymarin Treatment of Pathological Gambling: A Double-Blind, Placebo-Controlled Study

Conditions
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Pathological Gambling, Gambling Disorder

Intervention / Treatment
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* Drug: Placebo
* Drug: Milk Thistle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women age 18-75; Diagnosis of current gambling disorder based on DSM-5 criteria and confirmed using the clinician-administered Structured Clinical Interview for Pathological Gambling (SCI-PG) (12); Gambling behavior within 2 weeks prior to enrollment; Women of child bearing age are required to have a negative result on a beta-human chorionic gonadotropin pregnancy test; Women of childbearing potential utilizing a medically accepted form of contraception defined as double barrier, oral contraceptive, injectable contraceptive, implantable contraceptive devices, and abstinence Exclusion Criteria: Infrequent gambling (i.e. less than one time per week) that does not meet DSM-5 criteria for gambling disorder; Unstable medical illness or clinically significant abnormalities on laboratory tests, EKG, or physical examination at screen as determined by the investigator; History of seizures; Myocardial infarction within 6 months; Current pregnancy or lactation, or inadequate contraception in women of childbearing potential; A need for medication other than milk thistle with possible psychotropic effects or unfavorable interactions as determined by the investigator; Clinically significant suicidality (defined by the Columbia Suicidal Scale); Lifetime history of bipolar disorder type I or II, schizophrenia, or any psychotic disorder; Initiation of psychotherapy or behavior therapy within 3 months prior to study baseline; Previous treatment with milk thistle

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matched dosage of milk thistle daily. | Drug: Placebo<br>* Taken as two 150mg capsules BID for 2 weeks, then 300mg BID for remainder of the study.<br>* Other names: Sugar Pill;|
| Active Comparator: Milk Thistle<br>Capsule form, 150mg BID to 300mg BID | Drug: Milk Thistle<br>* Taken as two 150mg capsules BID for 2 weeks, then 300mg BID for remainder of the study.<br>* Other names: Silymarin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) | The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the PG-YBOCS for the duration of the 8 weeks. At each of these visits the outcome will be assessed. The scale itself assess severity of gambling. | Once every two weeks for the 8 weeks of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression-Improvement and Severity scales (CGI) | The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the CGI for the duration of the 8 weeks. At each of these visits the outcome will be assessed. The scale itself assess overall disorder severity. | Once every two weeks for the 8 weeks of the study | 
| Gambling Symptom Assessment Scale (G-SAS) | The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the G-SAS for the duration of the 8 weeks. At each of these visits the outcome will be assessed. The scale itself assess severity of gambling symptoms. | Once every two weeks for the 8 weeks of the study | 
| Hamilton Anxiety Rating Scale (HAM-A) | The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the HAM-A for the duration of the 8 weeks. At each of these visits the outcome will be assessed. The scale itself assess levels of anxiety. | Once every two weeks for the 8 weeks of the study | 
| Sheehan Disability Scale (SDS) | The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the SDS for the duration of the 8 weeks. At each of these visits the outcome will be assessed. The scale itself assess level of disability resulting from gambling (or target disorder) | Once every two weeks for the 8 weeks of the study | 
| Hamilton Depression Rating Scale (HAM-D) | The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the HAM-D for the duration of the 8 weeks. At each of these visits the outcome will be assessed. The scale itself assess level of depression. | Once every two weeks for the 8 weeks of the study | 
| Perceived Stress Scale (PSS) | The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the PSS for the duration of the 8 weeks. At each of these visits the outcome will be assessed. The scale itself assesses the level of perceived stress the individual experiences. | Once every two weeks for the 8 weeks of the study | 
| Quality of Life Inventory (QOLI) | The entire study for an individual subject will last 8 weeks. This inventory will be completed at the first and last visit of the study, with only these two points being assessed. The scale itself assess the subjects overall perceived quality of life. | Once every two weeks for the 8 weeks of the study |