Milk Thistle in Pathological Gambling

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02337634

Enrollment

Registered

2015-01-13

Start date

2015-01-31

Completion date

2022-12-31

Last updated

2024-09-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pathological Gambling, Gambling Disorder

Brief summary

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

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.

Interventions

DRUGPlacebo

Taken as two 150mg capsules BID for 2 weeks, then 300mg BID for remainder of the study.

DRUGMilk Thistle

Taken as two 150mg capsules BID for 2 weeks, then 300mg BID for remainder of the study.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS)	Once every two weeks for the 8 weeks of the study	Every 2 weeks the subject will take the PG-YBOCS for the duration of the 8-week study. At each of these visits the outcome will be assessed, but only one value (change from baseline to week 8) will be reported. The scale itself assesses severity of gambling, with higher scores indicating worse outcomes. The scale includes two subscales: a thought/urge subscale and a behavior subscale. Each subscale contains 5 items to be rated with a score of 0-4. Subscale scores are summed to get a total score. Possible total scores range from 0-40.

Secondary

Measure	Time frame	Description
Gambling Symptom Assessment Scale (G-SAS)	Once every two weeks for the 8 weeks of the study	Every 2 weeks the subject will take the G-SAS for the duration of the 8-week study. This is a 12-item, reliable and valid, self-rated scale assessing gambling urges, thoughts, and behaviors during the previous seven days. At each of these visits the outcome will be assessed, but only one value (change from baseline to week 8) will be reported. The scale itself assess severity of gambling symptoms, with a higher score indicating a worse outcome. Each item can be rated with a score of 0-4, with the sum of the 12 items equaling the total score. Possible total scores range from 0-48.
Hamilton Anxiety Rating Scale (HAM-A)	Once every two weeks for the 8 weeks of the study	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. Results are reported as the change in Week 8-Week 0 scores. The scale itself assess levels of anxiety, with higher scores indicating worse outcomes. Possible total scores range from 0-56.
Sheehan Disability Scale (SDS)	Once every two weeks for the 8 weeks of the study	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. Results are reported as the change in Week 8-Week 0 scores. The scale itself assesses level of disability resulting from gambling (or target disorder), with higher scores indicating worse outcomes. Possible total scores range from 0-30.
Clinical Global Impression-Improvement and Severity Scales (CGI-I and CGI-S)	Once every two weeks for the 8 weeks of the study	The entire study for an individual subject will last 8 weeks. Every 2 weeks the subject will take the CGIs for the duration of the 8 weeks. Results are reported as the change in Week 8-Week 0 scores. The scales themselves assess overall disorder severity, with higher scores indicating worse outcomes (i.e., less improvement or greater severity). Possible total scores range from 1-7.
Perceived Stress Scale (PSS)	Once every two weeks for the 8 weeks of the study	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. Results are reported as the change in Week 8-Week 0 scores. The scale itself assesses the level of perceived stress the individual experiences, with higher scores indicating worse outcomes. Possible total scores range from 0-40.
Quality of Life Inventory (QOLI)	Once every two weeks for the 8 weeks of the study	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. Results are reported as the change in Week 8-Week 0 scores. The scale itself assess the subjects overall perceived quality of life, with higher scores indicating better outcomes. Possible total scores range from 1-77.
Hamilton Depression Rating Scale (HAM-D)	Once every two weeks for the 8 weeks of the study	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. Results are reported as the change in Week 8-Week 0 scores. The scale itself assesses level of depression, with higher scores indicating worse outcomes. Possible total scores range from 0-52.

Countries

United States

Participant flow

Pre-assignment details

12 enrolled participants were excluded from the study prior to randomization because they did not meet the inclusion criteria.

Participants by arm

Arm	Count
Placebo Matched dosage of milk thistle daily. Placebo: Taken as two 150mg capsules BID for 2 weeks, then 300mg BID for remainder of the study.	25
Milk Thistle Capsule form, 150mg BID to 300mg BID Milk Thistle: Taken as two 150mg capsules BID for 2 weeks, then 300mg BID for remainder of the study.	17
Total	42

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	0
Overall Study	Protocol Violation	3	1

Baseline characteristics

Characteristic	Placebo	Milk Thistle	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	1 Participants	1 Participants	2 Participants
Age, Categorical Between 18 and 65 years	24 Participants	16 Participants	40 Participants
Age, Continuous	50.48 years STANDARD_DEVIATION 12.99	48.25 years STANDARD_DEVIATION 13.64	49.6 years STANDARD_DEVIATION 13.24
Race/Ethnicity, Customized African American	17 Participants	13 Participants	30 Participants
Race/Ethnicity, Customized Caucasian	5 Participants	4 Participants	9 Participants
Race/Ethnicity, Customized Hispanic/Latino	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Native American	1 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Not reported	1 Participants	0 Participants	1 Participants
Region of Enrollment United States	25 participants	17 participants	42 participants
Sex: Female, Male Female	7 Participants	10 Participants	17 Participants
Sex: Female, Male Male	18 Participants	7 Participants	25 Participants
Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) Score	20.62 units on a scale STANDARD_DEVIATION 3.4	21.17 units on a scale STANDARD_DEVIATION 3.1	20.84 units on a scale STANDARD_DEVIATION 3.36

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 26	0 / 17
other Total, other adverse events	3 / 26	4 / 17
serious Total, serious adverse events	0 / 26	0 / 17

Outcome results

Primary

Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS)

Every 2 weeks the subject will take the PG-YBOCS for the duration of the 8-week study. At each of these visits the outcome will be assessed, but only one value (change from baseline to week 8) will be reported. The scale itself assesses severity of gambling, with higher scores indicating worse outcomes. The scale includes two subscales: a thought/urge subscale and a behavior subscale. Each subscale contains 5 items to be rated with a score of 0-4. Subscale scores are summed to get a total score. Possible total scores range from 0-40.