BXCL501 for Treatment of Opioid Withdrawal: Positive Phase 2 Topline Results

BioXcel Therapeutics today announced positive topline results from a phase 2 investigator-sponsored trial evaluating BXCL501 for the treatment of opioid withdrawal symptoms in adults with opioid use disorder (OUD) undergoing a methadone taper. Study data suggest that BXCL501 may be as effective as or superior to lofexidine (Lucemyra) for reducing the symptoms of opioid withdrawal during a methadone taper, while also possessing a more convenient dosing regimen and a favorable tolerability profile.¹

In this study, BXCL501 240 µg twice daily reduced opioid withdrawal symptoms compared with placebo during a 7-day methadone taper, as measured by the Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop). After receiving BXCL501 240 µg, participants experienced a more than 30% reduction in SOWS-Gossop scores, with investigators observing peak symptom improvement on days 3 and 4. BXCL501 also demonstrated superiority over lofexidine; reduction in withdrawal symptoms with BXCL501 numerically exceeded that observed with lofexidine 0.54 mg administered 4 times daily. Additionally, BXCL501 demonstrated a favorable tolerability profile, with rates of key adverse events comparable with or lower than those reported for lofexidine in the Lucemyra FDA label.

BXCL501 also had similar or lower overall rates of cardiovascular (CV) effects than lofexidine. Orthostatic hypotension, the most common CV adverse event for Lucemyra, was significantly lower for the 180 µg twice daily BXCL501 dose group (18% vs 50% lofexidine, P<0.05) and remained lower in the highest 240 µg twice daily BXCL501 dose group (37%) over the 7-day dosing period. Notably, there were no reports of sedation or somnolence in the BXCL501 treatment arms (5% reported sedation in the lofexidine arm). Investigators believe these results support the future development of BXCL501 in opioid withdrawal.

“As we continue to face a worldwide crisis encompassing a large patient population suffering from opioid use disorder, these results showcase an encouraging therapeutic milestone demonstrating the significant potential of BXCL501 as a therapy for meaningfully reducing opioid withdrawal symptoms,” said Sandra Comer, PhD, the principal investigator of the study and professor of neurobiology in the department of psychiatry at Columbia University. “Opioid withdrawal remains a significant burden on the health care system and patients, and despite available therapies, there is still a substantial unmet need for safe and more effective treatment options that can help patients successfully transition to other medications such as buprenorphine or naltrexone for long-term benefits.”¹

BXCL501 differs from other available treatments: it a nonopioid, orally dissolving thin film formulation of dexmedetomidine administered twice daily.

This study was funded by the National Institute on Drug Abuse, while BioXcel Therapeutics supplied BXCL501. Investigators designed the study as a 4-arm trial: BXCL501 180 µg twice daily or 240 µg twice daily, placebo, and lofexidine 0.54 mg 4 times daily as a positive control. It enrolled participants who were predominantly exposed to fentanyl and included a high proportion of participants exposed to fentanyl adulterated or associated with xylazine. Xylazine in particular has been designated as an emerging threat by the White House Office of National Drug Control Policy. The trial was completed after 80 participants were enrolled.²

The findings of this study build on the earlier BioXcel-sponsored phase 1b/2 study, RELEASE, which established the tolerability profile of selected BXCL501 doses in patients dependent on opioids. It also extends those results into a clinically distinct setting that included a methadone taper and an active comparator.³

BXCL501 is also being evaluated in phase 3 pivotal studies for the treatment of acute agitation associated with bipolar disorder, schizophrenia, and Alzheimer disease.^4,5

References

1. BioXcel Therapeutics announces positive phase 2 topline results from columbia university-led study of BXCL501 for treatment of opioid withdrawal. News release. March 5, 2026. Accessed March 5, 2026. https://www.globenewswire.com/news-release/2026/03/05/3250004/0/en/BioXcel-Therapeutics-Announces-Positive-Phase-2-Topline-Results-from-Columbia-University-Led-Study-of-BXCL501-for-Treatment-of-Opioid-Withdrawal.html

2. Fentanyl adulterated or associated with xylazine implementation report. White House Office of National Drug Control Policy. June 2024. Accessed March 5, 2026. https://www.whitehouse.gov/wp-content/uploads/2025/03/ONDCP-2024-FAAX-Implementation-Report.pdf

3. Jones JD, Rajachandran L,Yocca F, et al. Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial. Am J Drug Alcohol Abuse. 2023;49(1):109-122.

4. Kuntz L. Primary end point of phase 3 trial met: BXCL501 for agitation associated with bipolar disorders or schizophrenia. Psychiatric Times. August 27, 2025. https://www.psychiatrictimes.com/view/primary-endpoint-of-phase-3-trial-met-bxcl501-for-agitation-associated-with-bipolar-disorders-or-schizophrenia

5. O’Brien E. Phase 3 study on treatment of agitation in Alzheimer disease doses first patient. Psychiatric Times. May 3, 2022. https://www.psychiatrictimes.com/view/phase-iii-study-on-treatment-of-agitation-in-alzheimer-disease-doses-first-patient