How do Glutathione Levels Affect Compulsivity? A Double-blind, Placebo-controlled Study

Anorexia nervosa is a psychiatric disorder with a high mortality rate and for which there is very little evidence for pharmacological interventions of value. The picture is similar in bulimia nervosa, with a high mortality rate and with mixed outcomes from studies testing Selective Serotonin Reuptake Inhibitors (SSRIs). It is possible to conceptualise eating disorders as akin to compulsive disorders, especially noting that repetitive weighing, calorie counting and compulsive exercise and compensatory mechanisms might fit into a hypothetic obsessive-compulsive spectrum (OC spectrum). Some disorders on this OC spectrum are associated with oxidative stress. This may also be true in eating disorders: it has recently been found in a meta-analysis that there is evidence of increased oxidative stress markers in AN.

Glutathione is the main cellular anti-oxidant in mammals and it is possible to increase glutathione levels (and thus potentially combat oxidative stress) with a dietary supplement called N-Acetyl Cysteine (NAC). NAC is an acetylated form of the naturally occurring amino acid cysteine, and is converted to cysteine in the body. Cysteine is a key precursor of glutathione. Oral administration of cysteine itself does not increase brain glutathione levels because cysteine is poorly absorbed from the gastro-intestinal tract. However NAC is bioavailable and thus administration of it does increase glutathione in the brain.

Using NAC to increase glutathione levels has been shown to be beneficial in some compulsive disorders such as addictions, Obsessive-Compulsive Disorder (OCD) and related disorders such as trichotillomania in preliminary studies. There have been positive indications for use and evidence in pathological gambling, trichotillomania, OCD and cocaine addiction. However, NAC has not to our knowledge ever been considered for the treatment of eating disorders. This research therefore aims to investigate whether increasing glutathione can reduce neuropsychological markers of compulsivity in a group at risk for eating disorders.

The researchers have chosen to use a female non-patient group which is thought to be highly compulsive, but which will also be without the possible confounds of medication (as in OCD or addiction disorders) and without malnutrition (as in clinical eating disorders). Those recruited will be females, because there is evidence that there may be different risk factors and thus mechanisms underlying the development of eating disorders in males and females, such that recruiting both might produce a confound. The investigators have also chosen to use a short duration of NAC administration. This not only allows the use of a cross-over design without fears of high attrition rates and non-compliance, but it also will allow the detection of subtle and early changes in compulsivity. The hypothesis is thus that improvements will be seen in tasks measuring compulsivity, and also potentially in tasks which measure related constructs such as impulsivity, habit-based learning, and delay discounting. The researchers do not expect improvement in self-report symptom questionnaires. However, a possible future study would be a randomized clinical trial looking at increasing glutathione in a clinical group over time and how it affects clinical symptomatology.

The questionnaires chosen will identify eating disorder symptom levels (the Eating Attitudes Test - 26 (EAT-26) is a validated way of doing this) and look at compulsive starvation using the self-starvation scale (Godier & Park 2015). The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV (SCID) will be used to rule out those with a current Axis I diagnosis including an eating disorder, to prevent the complications of starvation and medication in this initial pilot study. The Eysenck Personality Questionnaire (EPQ) will be used to ascertain personality traits, and the National Adult Reading Test (NART) will be used to estimate Intelligence Quotient (IQ).