PROJECT SUMMARY Few therapeutics are available for individuals trying to recover from opioid use disorder. Buprenorphine and methadone, opioid receptor agonists, are approved by the FDA to treat Opioid Use Disorder (OUD) but long- term efficacy and treatment adherence are sub-optimal. Extended-release naltrexone (Vivitrol®, Alkermes), a full µ-opioid receptor antagonist, was approved by the FDA in 2010 for the prevention of relapse to opioid dependence but initiation and adherence to treatment are low. There is an urgent need for improved treatments for chronic relapsing opioid use disorder that has serious public health consequences. For the treatment of chronic relapsing OUD, we propose to develop an extended-release combination of low- dose naltrexone and cannabidiol (CBD) by nanoencapsulating them in biodegradable polymer nanospheres using an environmental-friendly proprietary SuperFluids™ technology. CBD has been shown to inhibit cue- induced heroin seeking in animals, and subsequent human clinical trial studies have revealed its potential utility and safety. Animal studies have shown that low-dose naltrexone, when combined with CBD, is better than either of the two in isolation to improve motivation and alcohol consumption in mice. This combination is promising, considering that naltrexone primarily targets the μ opioid receptor, and CBD binds the μ and δ opioid receptors. Lowering the dose of naltrexone will be impactful since it will reduce the side effects of Vivitrol®, and improve safety and compliance. This novel formulation will significantly enhance the bioavailability and pharmacodynamics of the two therapeutics, reduce dose frequency, and improve addiction treatment adherence. In Phase I, we will develop nanoformulations of CBD and low-dose naltrexone/CBD in biodegradable polymer nanospheres, and assess the intramuscular administration of the nanoparticles to reduce OUD relapse compared to Vivitrol® in an animal model of OUD relapse. In Phase II, we will conduct a more extensive R&D program that includes scale-up of cGMP manufacturing, GLP in vitro and in vivo product characterization, and establish the regulatory pathway for clinical development. In Phase III, with strategic corporate partners and/or investors, we will conduct clinical trials of CBD/naltrexone PLGA nanoparticles in patients suffering from chronic relapsing opioid use disorder.

PROJECT NARRATIVE Opioid use disorder has reached epidemic proportions, primarily driven by the desire of the medical industry to alleviate pain symptoms for a vast array of medical conditions in all age groups. Current treatments for opioid use disorder use opioid agonists such as methadone, buprenorphine, and the opioid antagonist naltrexone, a treatment intended only for people who are no longer dependent on narcotics or alcohol. The side-effects of naltrexone often make it difficult to maintain adherence. Unlike current treatments, cannabidiol (CBD), a bioactive ingredient of marijuana, is not an opioid and is non-psychoactive. CBD has been shown to inhibit cue-induced opioid-seeking behaviors, cravings and withdrawals. Together with low-dose naltrexone, CBD encapsulated in nanoparticles will improve therapeutic efficacy for opioid use disorder relapse while reducing side-effects, and increasing adherence and accessibility. A medication that can reduce opioid withdrawal symptoms will improve the chances of success of going through withdrawal without relapse, thereby significantly impacting personal well-being, future health care costs and economic burdens.