The scale of the problem is staggering. According to the review, an estimated 4.3 million people in the United States meet diagnostic criteria for stimulant use disorder, nearly a quarter of them aged 25 or younger. National overdose deaths involving stimulants rose nearly 34-fold between 2002 and 2022, and 182,502 stimulant-related overdose deaths were reported between 2021 and 2024. More than 60,000 stimulant-related overdose deaths have been recorded annually in recent years, with 43.1 percent of stimulant-involved deaths between January 2021 and June 2024 also involving opioids. Black or African American and American Indian or Alaska Native communities have experienced disproportionately steep increases in stimulant-involved deaths, adding an urgent health equity dimension to the crisis.

Yet while medications exist for opioid, alcohol, and tobacco use disorders, stimulant use disorder remains one of the few major substance use disorders with no FDA-approved drug therapy, leaving clinicians dependent on behavioral interventions with limited long-term efficacy. It is against this backdrop that the LSU team examined the theoretical potential of Brixadi. Brixadi is an extended-release injectable buprenorphine that uses a fluid-crystal depot delivery system: after subcutaneous injection, the solution solidifies into a viscous crystalline gel that gradually releases the drug over one week or one month, producing stable plasma concentrations and sustained receptor occupancy. Peak plasma levels occur roughly 20 hours after injection, and steady state is reached by the fourth dose, with half-lives ranging from 3 to 5 days for weekly injections and 19 to 26 days for monthly ones.

Buprenorphine’s pharmacology is what makes the hypothesis plausible. The drug is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor, binding with exceptionally high affinity—reported inhibition constants of approximately 0.2 nanomolar at the mu receptor and 0.07 nanomolar at the kappa receptor—and dissociating slowly. That ceiling effect on respiratory depression and euphoria underpins its favorable safety profile, while its high affinity allows it to displace full agonists such as fentanyl and heroin from receptors. But for stimulant addiction, the kappa receptor is the critical piece. Kappa-opioid receptors respond to dynorphins, endogenous peptides that suppress dopamine signaling in the mesolimbic reward pathway and generate dysphoria, stress responses, and drug craving. Chronic stimulant use upregulates prodynorphin transcription, elevating dynorphin levels and pushing the brain into a low-dopamine state that drives further drug seeking in a self-reinforcing loop.

Animal research supports this framework. Methamphetamine exposure increases dynorphin expression in the nucleus accumbens and preclinical cortex, and in mouse studies by Whitfield and colleagues, kappa receptor activation during abstinence appeared to create neuroadaptations that made methamphetamine more appealing, essentially fueling relapse through negative reinforcement. Conversely, pharmacologic blockade of the kappa receptor has, in some animal models, reduced drug-seeking behavior or methamphetamine self-administration, although the effects have not been uniform across species and paradigms. In rodents and rhesus monkeys, buprenorphine has also been shown to decrease cocaine self-administration and cocaine-seeking behavior, and rodent studies suggest buprenorphine reduces methamphetamine consumption and drug seeking partly through activation of the nociceptin/orphanin FQ peptide receptor.

Human evidence remains thin but intriguing. A double-blind randomized clinical trial by Ahmadi and Razeghian Jahromi found that buprenorphine reduced methamphetamine craving during withdrawal more effectively than methadone, though the 17-day trial could not determine whether the effect persisted or prevented relapse. Trials of concurrent opioid and cocaine dependence have reported reductions in cocaine use and craving with buprenorphine, and a combination of buprenorphine and naltrexone blocked compulsive cocaine intake in rodents without producing opioid dependence. Buprenorphine’s antidepressant-like effects in animal models—mediated through kappa receptors and stress modulation—further suggest it may blunt the hyperkatifeia, the intensified negative emotional state, that fuels relapse during stimulant withdrawal.

The strongest practical argument, however, may lie in polysubstance use. Toxicologic data show that 89.6 percent of individuals presenting for opioid use disorder treatment test positive for more than one substance, with a mean of 3.3 substances per person and up to 11 detected in some cases. Approximately one-third of individuals with opioid use disorder use stimulants concurrently, methamphetamine use in this population has risen by more than 80 percent, and over half of US overdose deaths from 2018 to 2024 involved concurrent opioid and stimulant use. Because opioid and stimulant use disorders converge on overlapping dopamine, reward, and stress circuitry—psychostimulants acting directly on dopaminergic transporters and opioids disinhibiting dopamine release indirectly—stabilizing the opioid component may disrupt the reinforcing environment sustaining stimulant use. Notably, when patients remained in buprenorphine treatment, one study found a 15 percent absolute reduction in methamphetamine use at six months, even though methamphetamine use predicted lower treatment retention overall.

Brixadi’s depot formulation may add distinct advantages in this population. Long-acting buprenorphine formulations have achieved treatment retention rates above 60 to 70 percent at six months, and maintenance on buprenorphine is associated with a greater than 50 percent reduction in all-cause mortality compared with no treatment. Monthly or weekly injections remove the daily adherence burden that trips up patients experiencing housing instability or limited transportation, minimize peak-to-trough fluctuations, and keep patients engaged in care long enough to benefit from behavioral therapies such as contingency management, the intervention with the best evidence for stimulant use disorder. The authors frame this as harm reduction: buprenorphine does not directly treat stimulant craving, but stabilizing opioid dependence may reduce chaotic polysubstance patterns, lower overdose risk, and create openings for broader therapeutic engagement.

The review is candid about its limitations. Brixadi is not approved for any stimulant use disorder, no clinical trial has demonstrated that buprenorphine reduces methamphetamine or cocaine use as a primary outcome, and much of the kappa-antagonism rationale rests on preclinical models and neurobiologic theory. Larger, well-controlled clinical trials are needed to determine whether the proposed mechanisms translate into meaningful reductions in stimulant use, craving, and relapse. Still, the convergence of an unmet clinical need, a well-characterized safety profile, plausible stress-and-craving pharmacology, and enormous polysubstance overlap makes the proposition difficult to ignore. With more than 60,000 stimulant-related deaths each year and no approved medication in sight, the authors argue that Brixadi’s extended-release profile and potential to counter withdrawal-related dysphoria and stress-induced drug seeking present a compelling case for accelerated clinical investigation.

Subject of Research: Evaluation of extended-release injectable buprenorphine (Brixadi) as a potential pharmacotherapy for stimulant use disorder

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

Article References: Brixadi for Stimulant Use Disorder: Evolving Pharmacologic Considerations and Clinical Implications. (n.d.). https://doi.org/10.1007/s12325-026-03772-4

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03772-4

Keywords: Brixadi, buprenorphine, stimulant use disorder, methamphetamine, cocaine, kappa-opioid receptor, dynorphin, polysubstance use, opioid use disorder, harm reduction, pharmacotherapy, addiction