Milk Thistle in Pathological Gambling

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.

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