Phase 3 SUMMIT Trial Tests AXS-05 for Smoking Cessation

Axsome Therapeutics has initiated the phase 3 SUMMIT trial evaluating AXS-05 (dextromethorphan-bupropion) as a potential smoking cessation treatment in adults, with the first participant now dosed.¹

SUMMIT—Studying NMDA and Sigma-1 in Smoking Cessation Treatment—is a randomized, double-blind, active- and placebo-controlled multicenter trial. Adults who currently smoke will be randomly assigned in a 1:1:1 ratio to AXS-05, bupropion, or placebo for approximately 12 weeks. The primary endpoint is smoking abstinence at the end of the treatment period.¹

Including bupropion as an active comparator should help determine whether the dextromethorphan-bupropion combination offers efficacy beyond bupropion alone, an established pharmacologic option for smoking cessation.

The company did not disclose the planned enrollment, specific eligibility criteria, study locations, dosing regimen, method used to verify abstinence, or secondary endpoints. No efficacy or safety results are available because the trial has only recently begun.

AXS-05 Targets Multiple CNS Pathways

AXS-05 is an oral combination of dextromethorphan and bupropion. The treatment acts through several central nervous system pathways, with dextromethorphan functioning as an N-methyl-D-aspartate receptor antagonist and sigma-1 receptor agonist and bupropion acting as an aminoketone and cytochrome P450 2D6 inhibitor.¹

The combination is marketed in the US as Auvelity for major depressive disorder in adults and agitation associated with dementia due to Alzheimer disease. It is not approved by the US Food and Drug Administration for smoking cessation.¹

Although bupropion is already used for smoking cessation, SUMMIT is designed to examine whether combining it with dextromethorphan improves abstinence outcomes. Detailed results will be needed to determine the magnitude and durability of any benefit, as well as the treatment’s safety and tolerability in adults attempting to quit smoking.

Persistent Need for More Effective Treatments

Axsome cited federal estimates indicating that approximately 34 million US adults smoke cigarettes and more than half have a smoking-related disease.² Cigarette smoking accounts for approximately 1 in 5 deaths in the US and generates more than $300 billion in annual health care spending and lost productivity.²˒³

Nearly 70% of adults who smoke report wanting to quit, but sustained cessation remains difficult. Only an estimated 3% to 5% of people who attempt to stop smoking without assistance remain abstinent for 6 to 12 months.²˒⁴

Primary care clinicians routinely identify tobacco use, counsel patients on cessation, and initiate evidence-based behavioral and pharmacologic interventions. If SUMMIT demonstrates that AXS-05 improves abstinence compared with both placebo and bupropion, the findings could inform whether the combination offers another treatment option for patients who smoke. However, the clinical relevance of the program will depend on the absolute quit rates, definition and biochemical confirmation of abstinence, treatment adherence, adverse events, and durability of cessation after therapy ends.

References

1. Axsome Therapeutics initiates SUMMIT phase 3 trial of AXS-05 in smoking cessation. News release. August 31, 2026. Accessed September 11, 2026.
2. US Department of Health and Human Services. Smoking Cessation: A Report of the Surgeon General. US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2020.
3. Centers for Disease Control and Prevention. Tobacco-related mortality. 2020.
4. Hughes JR, Keely J, Naud S. Shape of the relapse curve and long-term abstinence among untreated smokers. Addiction. 2004;99(1):29-38. doi:10.1111/j.1360-0443.2004.00540.x