Michael Bewernitz, Daniela Conrado, OJ Ganesh, Yi Zhang Diet and Leptin Combination Therapy in Addiction Recovery (R21 Group Proposal) Michael Bewernitz, Daniela Conrado, OJ Ganesh, Yi Zhang

Overall Significance Post addiction weight gain Individual problems Health Psychosocial Society problems Higher health costs, NIDDK says more than 40% higher Burden to health and social care system

Hypothesis and Innovation Central Hypothesis: Leptin with diet therapy will curb weight gain and improve midbrain food responses more effectively than either intervention in addiction recovering patients. Innovation: A comprehensive approach to tackle the complex weight gain Nutritional intervention: physiological & psychosocial aspects Leptin: neuroendocrine, neuropsychological & neurocognitive aspects Linking brain functionality to physiological weight change via fMRI analysis.

fMRI-Imaging of Reward-System Describes Neurobiological Effects Midbrain reward center: linking appetitive activity to behavioral psychology and neurocognition. Ventral Tegmental Area (VTA) in midbrain: heightened reactivity to high-calorie foods in obesity; implication in drug addiction & motivation. Leptin: regulation of both ingestive behaviors and energy expenditure; an anti-obesity agent undergoing multiple clinical trials. Brain tells us what and how much we eat, and the midbrain reward circuitry provides important neural control mechanisms. Drugs and foods can activate similar midbrain reward pathways. Obese individuals exhibit exaggerated reactivity to stimuli associated with high-calorie foods in the VTA (and insula, hippo and etc.). VTA: widely implicated in drug/food rewards, motivation and cognition. Leptin functions in the VTA to attenuate food intake, preference for high-fat foods, and reduce dietary weight gain. 4

Specific Aims Specific Aim 1: Determine the synergistic weight reducing effect of a low carb/low fat diet and leptin combination therapy - Primary Outcome: reduction of weight gain in addiction recovery Specific Aim 2: Examine the midbrain food responses by fMRI analysis post diet-leptin combination therapy or monotherapy - Secondary Outcome: improve midbrain reward responses to food stimulation

Study Design Population n=20 Prospective, randomized, double-blind pilot study in veterans whom successfully completed the post-addiction recovery program at multiple NF/SG VHS VA clinics Population n=20 Action Timeline SA1/SA2 measures Study Onset No therapy n=5 Dietary only n=5 Leptin only n=5 Leptin & Dietary together n=5 SA1 measures Month 1 SA1/SA2 measures Mid-intervention SA1 measures Month 2 Ending SA1/SA2 measures Efficacy Measures (SA1): Metabolic Panel, Physical assessments Neural Response Measures (SA2): fMRI images

Experimental Timeline study onset month 1 mid month 2 ending Day 28 42 56 84 Randomization X Patient history Dispense therapy (multiple doses) Leptin assay Metabolic panel Physiological assessment fMRI Data Analysis Analysis Plan: 2x2 factorial ANOVA

Pitfalls and Alternatives Interference of nicotine in measured outcomes. Consider nicotine as a covariate. Intra-group variation: responders vs. non-responders. Extra blood sample: genotype data to compare with pharmacogenomics studies. Injection site reactions. Compliance assistance. Dietary intervention (open-label). No clinically significant adverse effects were observed on major organ systems. Mild-to-moderate reactions at the injection site were the most commonly reported adverse effects. 8 8

Future Directions Proof of concept and feasibility demonstrated by this pilot study: Protocol adjustment. Follow-up study. Further analysis of covariates. Post recovery follow-up physiological assessments and fMRI analysis. To compare with fMRI in healthy volunteers. -With this pilot study, we expect to build foundation (in other words, to demonstrate proof of concept and feasibility) to conduct a follow-up study 9 9

Thank you! Thanks and Acknowledgements Dr. Keith Muller Dr. Philipp Dahm Beth Auten CTSI Thank you!