Auvelity for Opioid Use Disorder

Overseen By Lori Keyser-Marcus, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Virginia Commonwealth University

Must be taking: Buprenorphine

Must not be taking: Antidepressants, Antiepileptics, CNS stimulants

Disqualifiers: Pregnancy, Uncontrolled psychiatric disorders, others

Compensation: Varies

Number of Visits: 8

Duration: 8 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combining two drugs, dextromethorphan and bupropion (known as Auvelity), for individuals with opioid use disorder (OUD) who are already using buprenorphine. The researchers aim to assess the safety of this combination with buprenorphine and its effectiveness in reducing negative feelings, cravings, and withdrawal symptoms. Participants will receive either the actual treatment or a placebo. This trial may suit those who have maintained a steady dose of buprenorphine for at least two weeks and are experiencing moderate OUD symptoms. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as antidepressants, antiepileptics, and CNS stimulants, at least two weeks before starting the study medication. If you are on these medications, you will need to discontinue them to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that Auvelity, a combination of dextromethorphan and bupropion, is generally safe and well-tolerated. Studies have found it effective for treating major depressive disorder, indicating its safety for people.

In these studies, some patients experienced side effects such as dry mouth, dizziness, and nausea, but these were usually mild. Since Auvelity is already approved for depression, this approval provides some confidence about its safety. However, this trial is in the early stages and primarily aims to assess its interaction with opioids like buprenorphine and to ensure it remains safe in this new context. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for opioid use disorder?

Unlike the standard treatments for opioid use disorder, which often include medications like methadone or buprenorphine, Auvelity offers a novel approach. This treatment combines dextromethorphan and bupropion, leveraging their unique mechanisms. Dextromethorphan acts on the brain's NMDA receptors, while bupropion is known for its antidepressant effects. Together, they may provide a new way to address the condition, potentially improving mood and reducing cravings more effectively. Researchers are excited about this combination because it targets different pathways than traditional therapies, which could lead to better outcomes for patients.

What evidence suggests that Auvelity might be an effective treatment for opioid use disorder?

Research has shown that the combination of dextromethorphan and bupropion, known as Auvelity, effectively treats major depressive disorder (MDD). Studies have found that it works quickly and is generally well tolerated, with higher remission rates compared to other treatments. This combination affects the NMDA receptor, which plays a role in mood regulation, and may also influence the opioid system, potentially reducing mental pain. In this trial, participants will receive either Auvelity or a placebo to evaluate its potential benefits for opioid use disorder (OUD). While Auvelity is mainly used for depression, these effects suggest it might help with symptoms like negative mood and cravings in OUD. Since using Auvelity for OUD is a new area of research, more data is needed to confirm its effectiveness for this condition. ^{1 2 6 7 8}

Who Is on the Research Team?

Frederick G Moeller

Principal Investigator

Virginia Commonwealth University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with moderate to severe Opioid Use Disorder (OUD) who are currently on stable buprenorphine treatment. They must have a positive urine test for buprenorphine, mild depression symptoms or greater, and agree to use contraception if applicable. Excluded are those on certain medications like antidepressants, with serious health issues, significant heart abnormalities, or recent suicidal behavior.

Inclusion Criteria

I am currently being treated for opioid use disorder with specific medications.

Quick Inventory of Depressive Symptomatology (16-Item) (QIDS-SR16) score of mild or greater (>6)

Understand the study procedures and provide written informed consent in the English language

Exclusion Criteria

Current severe alcohol use disorder or current benzodiazepine use or recent (within last 3 months) discontinuation of alcohol with severe alcohol use disorder or discontinuation of benzodiazepines with severe benzodiazepine use disorder

Current DSM-5 diagnosis of any psychoactive substance use disorder other than opioids, cocaine, marijuana, or nicotine, or mild or moderate alcohol use disorder. Diagnosis of mild to moderate use disorder for alcohol will not be considered exclusionary

Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Auvelity or placebo as an adjunctive treatment to buprenorphine/naloxone for opioid use disorder

8 weeks

Multiple PK study visits, each lasting up to 8 hours

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Phase Ib/2a Drug-drug Interaction Study of a Combination of 45mg Dextromethorphan With 105 mg Bupropion

Trial Overview The study tests the combination of Dextromethorphan and Bupropion (Auvelity) against a placebo in people with OUD. It aims to assess drug interactions and early signs of effectiveness in reducing negative feelings, cravings, and withdrawal symptoms associated with opioid addiction.

How Is the Trial Designed?

Group I: Auvelity Experimental Treatment 1 Intervention

Orally-administered combination of dextromethorphan with Bupropion (trade name Auvelity)

Group II: Placebo Placebo Group 1 Intervention

Subjects who are randomized to placebo will receive identical capsules to the test product at the same time periods noted above, administered orally.

Who Is Running the Clinical Trial?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Published Research Related to This Trial

In a study of 426 smokers, those with a decreased activity variant of the CYP2B6 gene experienced more intense cravings and higher relapse rates when trying to quit smoking with bupropion, indicating that genetic factors can influence treatment outcomes.

Bupropion appeared to lessen these negative effects, particularly in female smokers, suggesting that gender and genetic makeup may play important roles in the effectiveness of smoking cessation treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacogenetic investigation of smoking cessation treatment. Lerman, C., Shields, PG., Wileyto, EP., et al.[2021]

In a pilot study involving 49 participants with severe methamphetamine use disorder, the combination of naltrexone and bupropion showed potential efficacy, with 11 participants meeting the predefined responder criteria for treatment success.

The study's design indicated that while the combination therapy did not meet the statistical success threshold of 9 responders, the results suggest enough promise to justify further investigation into this pharmacotherapy approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utilizing a Two-stage Design to Investigate the Safety and Potential Efficacy of Monthly Naltrexone Plus Once-daily Bupropion as a Treatment for Methamphetamine Use Disorder. Mooney, LJ., Hillhouse, MP., Thomas, C., et al.[2019]

A survey of 1,291 Australian physicians revealed that while most recognized and advised patients on harmful alcohol and smoking behaviors, only a small percentage used formal screening tools or had training in smoking cessation strategies.

Physicians generally viewed pharmacotherapies like bupropion, acamprosate, and naltrexone as effective for treating nicotine and alcohol dependence, but there is significant room for improvement in their prescribing practices and counseling skills to enhance treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of pharmacotherapies for the management of addictive behaviours in Australian clinical practice. Doran, CM., Duszynski, KM., Beilby, JJ., et al.[2018]

In a rat model of opiate self-administration, the combination of bupropion and dextromethorphan significantly reduced remifentanil self-administration in rats with high baseline use, suggesting potential efficacy for treating severe opiate addiction.

Conversely, in rats with lower baseline remifentanil self-administration, bupropion increased self-administration, indicating that the effects of these drugs can vary based on the level of existing addiction, highlighting the need for tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dextromethorphan and bupropion reduces high level remifentanil self-administration in rats. Blair, G., Wells, C., Ko, A., et al.[2021]

A physiologically-based pharmacokinetic (PBPK) model developed for bupropion and its metabolites showed that these metabolites significantly contribute to drug-drug interactions (DDIs) with CYP2D6 substrates, indicating the importance of considering metabolites in DDI predictions.

The study found that the inhibitory potency of bupropion's metabolites varies, with hydroxybupropion being the strongest inhibitor, suggesting that caution and potential dosage adjustments are necessary when prescribing bupropion alongside other medications that are metabolized by CYP2D6.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model. Xue, C., Zhang, X., Cai, W.[2020]

In a 12-week clinical trial involving 149 methadone-maintained subjects, bupropion HCL (300 mg/day) did not show significant efficacy compared to placebo in treating cocaine dependence.

However, exploratory analyses indicated that bupropion may have a beneficial effect for individuals who were depressed at the start of the study, suggesting that targeting specific subgroups could improve treatment outcomes in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter trial of bupropion for cocaine dependence in methadone-maintained patients. Margolin, A., Kosten, TR., Avants, SK., et al.[2019]

In a rat model of nicotine addiction, combining lower doses of varenicline with higher doses of bupropion significantly reduced nicotine self-administration more than either drug alone, suggesting a potential benefit of combination therapy for tobacco cessation.

Higher doses of varenicline alone did not enhance the effects of bupropion, indicating that specific dose combinations are crucial for maximizing the efficacy of these medications in reducing tobacco addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupropion-varenicline interactions and nicotine self-administration behavior in rats. Hall, BJ., Slade, S., Wells, C., et al.[2018]

A comprehensive physiologically based pharmacokinetic (PBPK) model for bupropion was developed using data from 67 clinical studies, which accurately predicts drug-gene and drug-drug interactions involving its metabolites.

The model effectively accounts for the impact of genetic variations in the CYP2B6 enzyme, demonstrating strong predictive performance for interactions with other drugs, making it a valuable tool for understanding bupropion's metabolism and safety in diverse patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physiologically Based Pharmacokinetic Modeling of Bupropion and Its Metabolites in a CYP2B6 Drug-Drug-Gene Interaction Network. Marok, FZ., Fuhr, LM., Hanke, N., et al.[2023]

The active metabolite of bupropion, (2S,3S)-hydroxybupropion, was found to reduce nicotine intake in rats, indicating its potential role in smoking cessation by modifying the positive reinforcing effects of nicotine.

This metabolite did not affect the aversive properties of nicotine, suggesting that bupropion's effectiveness as a smoking cessation aid may stem from its ability to enhance dopamine and noradrenaline levels in the brain's reward centers while not altering the negative effects of nicotine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examination of the metabolite hydroxybupropion in the reinforcing and aversive stimulus effects of nicotine in rats. Malcolm, E., Carroll, FI., Blough, B., et al.[2018]

In a 48-week study involving 588 smokers, maintenance treatment with bupropion significantly extended the time to relapse compared to a placebo, with a median of 136 days for bupropion users versus 71 days for those on double placebo.

While bupropion showed a modest benefit in preventing relapse, the advantage diminished after stopping the medication, and the use of nicotine gum was low, indicating the need for further research on its effectiveness and optimal treatment duration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized trial of bupropion and/or nicotine gum as maintenance treatment for preventing smoking relapse. Covey, LS., Glassman, AH., Jiang, H., et al.[2018]

Bupropion (BUP) shows a clear dose-dependent inhibition of the CYP2D6 enzyme, which is important for metabolizing certain medications, as evidenced by a study of 221 patients combining BUP with venlafaxine.

Patients taking a higher dose of BUP (300 mg/d or greater) had a significantly higher rate of phenoconversion to poor metabolizers (50%) compared to those on a lower dose (19%), highlighting the need for careful monitoring and potential dose adjustments for CYP2D6 substrates in patients on BUP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression. Hole, K., Arnestad, M., Molden, E., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10591164/

Dextromethorphan-bupropion (Auvelity) for the Treatment of ... These data suggest that dextromethorphan-bupropion is an effective, fast-acting, and well tolerated option for depression treatment and produced remission in a ...

2. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.20220434

Where Does It Fit in the NMDA Versus mu-Opioid Story? In the Tabuteau et al. study, the combination of 90 mg of dextromethorphan with 210 mg of bupropion proved significantly more effective than 210 ...

3. auvelity.com auvelity.com/

For Major Depressive Disorder (MDD) - AUVELITY ... AUVELITY is a treatment for adults with MDD. Learn more about how AUVELITY is thought to work, side effects, and see dosing information.

4. annals-general-psychiatry.biomedcentral.com annals-general-psychiatry.biomedcentral.com/articles/10.1186/s12991-025-00549-x

Can dextromethorphan-bupropion reduce mental pain in ... We hypothesized that dextromethorphan-bupropion could impact the reduction of mental pain in MDD patients by targeting the opioid system.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12370225/

Efficacy and safety of dextromethorphan–bupropion ... The findings indicate superior efficacy of the dextromethorphan–bupropion combination, with remission rates of 46.5% and 39.5%, compared to 16.2 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05976646

NCT05976646 | Phase Ib/2a Drug-drug Interaction Study of ... Taken together, providing AUVELITY as an adjunctive treatment to buprenorphine could be an avenue to target crucial underlying mechanisms of OUD and improve OUD ...

7. accessdata.fda.gov accessdata.fda.gov/spl/data/ed41b2a2-19c2-4357-8818-712d09c8ba79/ed41b2a2-19c2-4357-8818-712d09c8ba79.xml

ed41b2a2-19c2-4357-8818-712d09c8ba79.xml ... AUVELITY is a combination of dextromethorphan and bupropion. Bupropion inhibits the metabolism of dextromethorphan via CYP2D6. Dextromethorphan when co ...

8. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp.21080800

Effect of AXS-05 (Dextromethorphan-Bupropion) in Major ... In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally ...