General Investigational Plan
Hypotheses:
Aim 1: Measure the impact of daily oral riboflavin supplementation on blood Glu levels.
Hypothesis 1: Patients receiving riboflavin will have significant reductions in blood
Glu levels, as compared to placebo.
Aim 2: Observe the impact of oral riboflavin on CIWA-AR scale scoring. Hypothesis 2:
Riboflavin will significantly reduce the active group's CIWA-AR scores, and will result
in fewer symptom triggered benzodiazepine doses, as compared to placebo.
Plan: The proposed study would apply a recently identified method using vitamin B2
(riboflavin) to reduce excess brain Glu activity in veterans in acute alcohol withdrawal.
This method of "glutamate scavenging", was identified in a 2018 as a way to reduce glutamate
associated brain damage which typically occurs after stroke. When tested in human patients
immediately following stroke, the intervention demonstrated efficacy through better
structural and functional outcomes when compared to placebo. Improvements persisted at 3
months after the initial stroke, and were not associated with any known side effects.
Administration of riboflavin quickly decreases Glu levels in both the blood and brain, as
measured using chromatography and Magnetic Resonance Imaging (MRI), respectively. As
riboflavin's Glu reducing properties have just been discovered, this method has only been
applied to the treatment of stroke, and has yet to be studied outside of the field of
neurology. Further, oral riboflavin has not been investigated as a method of glutamate
reduction. The hyperglutamatergic state in patients with alcohol withdrawal provides one
opportunity for such an investigation, one that may lead to future studies improving
treatments of alcohol withdrawal. Chronic, as well as acute alcohol users have both elevated
extracellular glutamate as well as changes to glutamate receptors and transporters. These
changes appear play a role in the rewarding effects of alcohol, and contribute to the
symptoms of withdrawal. A positive correlation exists between CSF levels of glutamate and the
severity of alcohol dependence, and patients in acute withdrawal have measurably increased
levels of glutamate in their peripheral blood. During early withdrawal, elevated glutamate
levels have been observed in the hippocampus and anterior cingulate cortex, returning to
normal 3 days after symptom resolution. Given this information, riboflavin may provide a
safe, effective, and affordable intervention to normalize the hyperglutamatergic state
associated with alcohol withdrawal. The proposed study would investigate this hypothesis in
patients admitted to the inpatient psychiatry unit in acute alcohol withdrawal.
Methods: Participants would be recruited on the inpatient psychiatry unit as they were
admitted. The primary teams/on call residents would be asked to page a study member if a
patient was admitted on the standard protocol for alcohol withdrawal: the Clinical Institute
Withdrawal Assessment for Alcohol-Revised (CIWA-Ar). The study coordinator would consent the
patient, and they would be randomized to either the placebo or riboflavin group. They would
then receive TID oral dosing of either 100mg riboflavin or placebo, in addition to treatment
as usual. The primary outcome would be daily blood glutamate levels, obtained with the normal
morning labs. Secondary outcomes would CIWA scores, number of symptom-triggered
benzodiazepines given, anxiety, and alcohol craving scores (using standardized measures).