Project Grant F32DA063281

CANNABIDIOL AND BUPRENORPHINE: A POLY-PHARMACY APPROACH TO TREAT OPIOID USE DISORDER - PROJECT SUMMARY EACH YEAR, MILLIONS OF AMERICANS ARE DIAGNOSED WITH OPIOID USE DISORDER (OUD), AND OPIOID OVERDOSE CLAIMS OVER 80,000 LIVES. THESE STAGGERING STATISTICS PERSIST DESPITE THE AVAILABILITY OF BUPRENORPHINE, A HIGHLY EFFECTIVE AND THE MOST WIDELY PRESCRIBED OUD MEDICATION. HOWEVER, AS MANY AS HALF OF OUD PATIENTS MAINTAINED ON BUPRENORPHINE DISCONTINUE TREATMENT WITHIN ONE YEAR, IN PART BECAUSE OF UNDERDOSING. PARTICULARLY IN PATIENTS WHO USED FENTANYL, DOSES OF BUPRENORPHINE LARGER THAN THE DOSE RECOMMENDED BY THE FOOD AND DRUG ADMINISTRATION (FDA) CAN IMPROVE TREATMENT RETENTION; HOWEVER, LARGE DOSES CAN HAVE ADVERSE EFFECTS INCLUDING VENTILATORY DEPRESSION AND SEDATION. MOREOVER, PHYSICAL DEPENDENCE CAN DEVELOP FROM LONG-TERM MAINTENANCE WITH LARGE DOSES, THEREFORE ABRUPT DISCONTINUATION CAN RESULT IN WITHDRAWAL WHICH INCREASES THE RISK OF RELAPSE. OUTCOMES FOR THE THOUSANDS OF OUD PATIENTS PRESCRIBED BUPRENORPHINE COULD BE SIGNIFICANTLY IMPROVED BY IDENTIFYING A SAFE AND EFFECTIVE ADJUVANT TREATMENT THAT ENHANCES THE THERAPEUTIC EFFECTS OF SMALLER DOSES OF BUPRENORPHINE WITHOUT INCREASING THE ADVERSE EFFECTS OBSERVED WITH LARGER DOSES OF BUPRENORPHINE. THE CANNABINOID CANNABIDIOL (CBD) HAS BEEN TOUTED AS A POTENTIAL ADJUVANT AS IT CAN ATTENUATE CUE-INDUCED CRAVING IN OUD PATIENTS MAINTAINED ON BUPRENORPHINE. CBD IS APPROVED BY THE FOOD AND DRUG ADMINISTRATION FOR EPILEPTIC SEIZURES, AND IS NON-PSYCHOACTIVE, NON-ADDICTIVE AND HAS A WIDE THERAPEUTIC WINDOW AND DESIRABLE SAFETY PROFILE. THE OVERARCHING GOAL OF THE PROPOSED STUDY IS TO EVALUATE CBD AS A POTENTIAL ADJUVANT TO BUPRENORPHINE. AIM 1 WILL USE A FENTANYL-FOOD CHOICE PROCEDURE WITH MALE AND FEMALE RHESUS MACAQUES TO EXAMINE HOW CHRONICALLY ADMINISTERED CBD MODIFIES THE EFFECTS OF BUPRENORPHINE ON FENTANYL CHOICE. IN AIM 2, THE SAFETY OF CHRONICALLY CO-ADMINISTERING CBD AND BUPRENORPHINE WILL BE CHARACTERIZED BY MEASURING THEIR EFFECTS ON OXYGEN SATURATION, HEART RATE AND ACTIVITY. WITH THE USE OF NHPS, A PREDICTIVE DRUG-CHOICE PROCEDURE AND BY MEASURING CLINICALLY RELEVANT PHYSIOLOGICAL EFFECTS, THE PROPOSED STUDIES ARE TRANSLATIONAL AND HAVE A HIGH DEGREE OF PREDICTIVE VALIDITY. BECAUSE CBD AND BUPRENORPHINE ARE FDA-APPROVED MEDICATIONS THESE FINDINGS COULD BE PARTICULARLY IMPACTFUL AS THEY COULD BE RAPIDLY TRANSLATED TO CLINICAL TRIALS. TAKEN TOGETHER, THESE STUDIES COULD IDENTIFY CBD AS A NON-PSYCHOACTIVE, NON-ADDICTIVE AND SAFE ADJUVANT TO BUPRENORPHINE THAT IMPROVES ITS EFFECTIVENESS, AND, ULTIMATELY, OUTCOMES FOR THE THOUSANDS OF OUD PATIENTS MAINTAINED ON BUPRENORPHINE. IMPORTANTLY, THE RIGOROUS RESEARCH TRAINING AND MANY PROFESSIONAL DEVELOPMENT ACTIVITIES PROPOSED IN THIS APPLICATION (E.G., WRITING GRANTS AND MANUSCRIPTS, ATTENDING AND PRESENTING AT SCIENTIFIC MEETINGS) WILL ENHANCE THE APPLICANT'S RESEARCH REPERTOIRE TO ENCOMPASS NEW SCIENTIFIC KNOWLEDGE, SKILLS AND EXPERIENCE. ACHIEVING THE TRAINING GOALS DESCRIBED HEREIN WILL CONTRIBUTE SIGNIFICANTLY TO HER SUCCESS IN TRANSITIONING FROM A POSTDOCTORAL FELLOW TO AN INDEPENDENT INVESTIGATOR DEDICATED TO STUDYING SUBSTANCE USE DISORDERS.