Brixadi for Stimulant Use Disorder: Evolving Pharmacologic Considerations and Clinical Implications

Substance use disorders are an increasing concern globally, causing a tremendous uptick in public health burden in recent years. Despite the growing attention these disorders receive, there remain no approved pharmacotherapies for stimulant use disorder, thereby contributing a major portion of this burden. This review examines the potential use of Brixadi, an extended-release injectable formulation of the widely used pharmacotherapy buprenorphine, indicated for opioid use disorder, in the treatment of stimulant use disorder. Psychostimulants, including cocaine, methamphetamine, and designer stimulants, all exert their effects by inhibiting or reversing the directionality of the monoamine transporters in the synaptic cleft. Inhibition or reversal of these transporters in the synaptic cleft allows dopamine, serotonin, and norepinephrine to remain in the synapse, which ultimately enhances their activity and contributes to the reinforcement of substance use. The reinforcement loop driven by excess neurotransmitters, particularly dopamine, provides a pharmacotherapeutic target via receptor interactions. Brixadi is an injectable extended-release buprenorphine primarily used to treat opioid use disorder. The extended-release mechanism enables sustained drug-receptor interaction, resulting in stable plasma drug concentrations. Buprenorphine is as a dual-acting agent, a partial μ-opioid receptor (MOR) agonist and a κ-opioid receptor (KOR) antagonist. KOR antagonism modulates symptoms of withdrawal in OUD, including dysphoria, stress, and drug cravings. Therefore, Brixadi's KOR antagonism may offer a promising pharmacologic target for stimulant use disorder recovery by mitigating these negative affective states. Additionally, the bimodal mechanism suggests that Brixadi may be a beneficial pharmacologic candidate for people who suffer from polysubstance use involving opioids and psychostimulants. While there is promise behind these developments, current studies are limited to preclinical trials and have not yet advanced toward clinical trials. However, Brixadi's extended-release profile and potential capability to minimize withdrawal-related dysphoria and stress-induced drug seeking present promise for further clinical investigation.