Dextromethorphan and Bupropion (AUVELITY): A Bad Choice for Agitation Due to Alzheimer’s Disease Dementia

In 2022 the Food and Drug Administration (FDA) approved dextromethorphan-buproprion (AUVELITY), an oral combination drug, for major depressive disorder in adults.[1] In April 2026 the FDA extended the approval to include agitation associated with dementia due to Alzheimer’s disease. Dextromethorphan-bupropion is the second drug approved for this indication — in 2023 the FDA extended the approval of the antipsychotic brexpiprazole (REXULTI and generic) to include agitation from Alzheimer’s disease dementia.[2]

Dextromethorphan-bupropion has serious risks and only marginal benefits for agitation associated with dementia due to Alzheimer’s disease. Public Citizen’s Health Research Group has designated it as a Do Not Use drug. Importantly, dextromethorphan-bupropion is not approved for “as-needed” (often referred to as pro re nata or “PRN”) use.[3] A month’s supply of dextromethorphan-bupropion costs about $1,250.

Dextromethorphan (DELSYM and generic) is an over-the-counter cough suppressant that we previously designated as Do Not Use because studies show that it is no more effective than placebo in suppressing nighttime cough in children.[4] Dextromethorphan is also approved in combination with quinidine (NUEDEXTA and generic) for the treatment of pseudobulbar affect (a neurological condition that causes sudden and uncontrollable outbursts of laughing or crying).[5] Of note, the mechanism by which dextromethorphan contributes to the treatment of agitation associated with Alzheimer’s disease dementia is not known.[6]

In 1985 the FDA approved bupropion (APLENZIN, FORFIVO, WELLBUTRIN and generics), an antidepressant, for the treatment of major depressive disorder.[7] Bupropion has a boxed warning — the agency’s most prominent warning — because it increases the risk of suicidal thoughts and behavior in children, adolescents and young adults. At a lower dose, bupropion (generic only)[8] is approved as a smoking cessation aid, as well as for weight management in combination with the opioid disorder drug naltrexone (CONTRAVE).[9] We previously designated bupropion as Limited Use for either depression or smoking cessation and as Do Not Use for weight management.[10],[11]

Antipsychotics are frequently prescribed to manage agitation associated with dementia due to Alzheimer’s disease, including antipsychotics not specifically approved for this indication (off-label use).[12] However, antipsychotics are associated with serious risks, including an increased risk of death among elderly patients with dementia-related psychosis. Because the limited benefits of antipsychotics do not outweigh the serious harms,[13] we designated brexpiprazole as Do Not Use for agitation associated with dementia due to Alzheimer’s disease.

Agitation due to Alzheimer’s disease dementia

In addition to the decline in thinking, memory and the ability to perform daily activities associated with Alzheimer’s disease, more than 90% of patients develop behavioral and psychological symptoms, such as irritability, sleep disturbances, hallucinations, depression, apathy and agitation.[14] Symptoms of agitation such as hitting, pacing, complaining, being verbally aggressive and restlessness are distressing for patients and their caregivers. Agitation symptoms become more prevalent in the later stages of the disease.[15] Nonpharmacological approaches (such as exercise or music therapy) are recommended as initial treatments.

Effectiveness of dextromethorphan-bupropion

Dextromethorphan-bupropion was assessed in two randomized controlled trials in adults who were diagnosed with probable Alzheimer’s disease and associated agitation.[16] Only limited data about the results of the trials are available; as of July 2026, the trial results had not been published in a peer-reviewed journal.

According to dextromethorphan-bupropion’s label, one study was a double-blind, placebo-controlled study in which 357 participants were randomized to receive the approved dose twice daily, 105 mg of bupropion alone, or placebo.[17],[18],[19] Due to limited effectiveness, treatment for the 49 participants in the bupropion-only group was stopped early.

After five weeks, the participants in the dextromethorphan-bupropion group showed some improvements on two measurement tools.[20] The primary endpoint was improvement on a clinician-rated questionnaire called the Cohen Mansfield Agitation Inventory, which measures how frequently patients show agitated behavior on a scale from 29 to 203 points (with lower scores indicating fewer agitation symptoms).

On average, participants who had received the drug combination had a reduction of 15 points on this scale, whereas those in the placebo group had a reduction of 12 points. This three-point difference between the groups was statistically significant, but it is unlikely to be clinically meaningful to patients and caregivers. Moreover, a significantly greater proportion of participants in the combination-drug group were rated to have “minimally improved” scores on a secondary measurement tool (called the Clinical Global Impression of Change) than those in the placebo group.

The second trial was a long-term withdrawal study of 456 adults.[21],[22] All participants first received the approved dose of dextromethorphan-bupropion twice daily for up to 52 weeks (open-label phase). The 456 participants who responded then continued with a double-blind withdrawal phase of up to 24 weeks, in which they were randomized to either continue the drug or switch to placebo. Compared with the placebo group, participants who continued with drug treatment had significantly longer periods free of agitation symptoms before relapsing. After 24 weeks, agitation symptoms relapsed in about 10% of the 54 participants who continued drug treatment, compared with a relapse rate of about 30% in the 39 participants switched to placebo.

Safety

Like bupropion alone, dextromethorphan-bupropion has a boxed warning regarding the increased risk of suicidal thoughts and behaviors in children and youths.[23] The combination drug is associated with additional serious adverse events, including an increased risk of seizures, hypertension (high blood pressure), the precipitation of manic episodes, psychosis or other neuropsychiatric reactions, and serotonin syndrome (which can be life-threatening and cause symptoms such as hallucinations, loss of coordination, fast heartbeat, diarrhea, coma, nausea and vomiting).

Older patients are at an increased risk of hyponatremia (low blood sodium), which can cause symptoms such as confusion, weakness, memory impairment and headaches. Dextromethorphan-bupropion should not be taken during pregnancy, because it may harm the fetus.

Based on the results of the first of the two trials discussed above, participants treated with the combination drug for agitation were more likely than those who received a placebo to experience dizziness (9% vs. 3%), somnolence (8% vs. 4%), dyspepsia (indigestion; 6% vs. 1%), fatigue (6% vs. 3%) and nausea (5% vs. 3%).[24]

Importantly, for both drug components, life-threatening overdoses, misuse and abuse have been reported.[25]

What You Can Do

Agitation associated with dementia due to Alzheimer’s disease is a frequent and challenging clinical problem for which better treatments are needed. However, we have classified dextromethorphan-bupropion as Do Not Use because it is associated with serious adverse events that outweigh its marginal benefits.

Discuss the best approach to address agitation due to Alzheimer’s disease dementia with the patient’s clinician. Other possible causes for agitation (including other prescription drugs or medical conditions) should be considered,[26] and nonpharmacological approaches tried. If the patient is already taking dextromethorphan-bupropion, do not discontinue the drug without discussing it with the clinician first.
 

References

[1] Axsome Therapeutics. Label: dextromethorphan and bupropion extended release (AUVELITY). April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215430s009s018lbl.pdf. Accessed July 4, 2026.

[2] Brexpiprazole: Do not use for agitation due to Alzheimer’s dementia. Worst Pills, Best Pills News. October 2023. https://www.worstpills.org/newsletters/view/1559. Accessed July 4, 2026.

[3] Axsome Therapeutics. Label: dextromethorphan and bupropion extended release (AUVELITY). April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215430s009s018lbl.pdf. Accessed July 4, 2026.

[4] Drug profile: dextromethorphan. February 2026. https://www.worstpills.org/monographs/view/206. Accessed July 4, 2026.

[5] Otsuka America Pharmaceutical. Label: dextromethorphan and quinidine (NUEDEXTA). December 2022. https://www.otsuka-us.com/media/static/NUEDEXTA-PI.pdf. Accessed July 4, 2026.

[6] Axsome Therapeutics. Label: dextromethorphan and bupropion extended release (AUVELITY). April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215430s009s018lbl.pdf. Accessed July 4, 2026.

[7] GlaxoSmithKline. Label: bupropion (WELLBUTRIN SR). November 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/020358s070lbl.pdf. Accessed July 4, 2026.

[8] Teva. Label: bupropion hydrochloride extended release (generic). September 2025. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a591e33a-52f0-41c8-a00b-4a1afcc3dc4c&type=display. Accessed July 4, 2026.

[9] Currax Pharmaceuticals. Label: naltrexone and bupropion (CONTRAVE). November 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/200063s024s026lbl.pdf. Accessed July 4, 2026.

[10] Drug profile: bupropion. January 2026. https://www.worstpills.org/monographs/view/66. Accessed July 4, 2026.

[11] Naltrexone-bupropion (CONTRAVE): Another dangerous weight-loss drug. Worst Pills, Best Pills News. September 2017. https://www.worstpills.org/newsletters/view/1149. Accessed July 4, 2026.

[12] Brexpiprazole: Do not use for agitation due to Alzheimer’s dementia. Worst Pills, Best Pills News. October 2023. https://www.worstpills.org/newsletters/view/1559. Accessed July 4, 2026.

[13] Teixeira AL, Kim Y, Cordeiro TM, et al. Agitation in Alzheimer's disease: From assessment to therapeutics. World J Psychiatry. 2025;15(11):109581.

[14] Rogowska M, Thornton M, Creese B, et al. Implications of adverse outcomes associated with antipsychotics in older patients with dementia: A 2011–2022 Update. Drugs Aging. 2023;40(1):21-32.

[15] Teixeira AL, Kim Y, Cordeiro TM, et al. Agitation in Alzheimer's disease: From assessment to therapeutics. World J Psychiatry. 2025;15(11):109581.

[16] Axsome Therapeutics. Label: dextromethorphan and bupropion extended release (AUVELITY). April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215430s009s018lbl.pdf. Accessed July 4, 2026.

[17] Ibid.

[18] O'Gorman C, Jones A, Cummings JL, et al. Efficacy and safety of AXS‐05, a novel, oral, NMDA‐receptor antagonist with multimodal activity, in agitation associated with Alzheimer’s disease: Results from ADVANCE‐1, a phase 2/3, double‐blind, active and placebo‐controlled trial. Alzheimer's & Dementia. 2020;16(S9):e047684.

[19] Clinicaltrials.gov. Addressing dementia via agitation-centered evaluation (ADVANCE) trial. September 13, 2023. https://clinicaltrials.gov/study/NCT03226522. Accessed July 4, 2026.

[20] Axsome Therapeutics. Label: dextromethorphan and bupropion extended release (AUVELITY). April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215430s009s018lbl.pdf. Accessed July 4, 2026.

[21] Ibid.

[22] Clinicaltrials.gov. A study to assess the long-term safety and efficacy of AXS-05 in subjects with Alzheimer's disease agitation (ACCORD-2). December 8, 2025. https://clinicaltrials.gov/study/NCT04947553. Accessed July 4, 2026.

[23] Axsome Therapeutics. Label: dextromethorphan and bupropion extended release (AUVELITY). April 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215430s009s018lbl.pdf. Accessed July 4, 2026.

[24] Ibid.

[25] Dextromethorphan/bupropion (Auvelity) for depression. Med Lett Drugs Ther. 2022;64(1666):201-203.

[26] Herrmann N, Wang HJ, Song BX, et al. Risks and benefits of current and novel drugs to treat agitation in Alzheimer’s disease. Expert Opin Drug Saf. 2022;21(10):1289-1301.