Naltrexone + Bupropion for Methamphetamine Addiction

Recruiting at 9 trial locations

Overseen By Tara Chowdhury, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Institute on Drug Abuse (NIDA)

Must not be taking: Tricyclics, MAOIs, Stimulants, others

Disqualifiers: Epilepsy, Heart block, Hypertension, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 11

Duration: 12 weeks

360 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary objective of this study is to evaluate the efficacy of extended release naltrexone plus bupropion XL (XR-NTX/BUP-XL) compared to matched injectable and oral placebo (iPLB/oPLB) in reducing methamphetamine (MA) use in individuals with moderate or severe methamphetamine use disorder (MUD) seeking to stop or reduce MA use.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, you cannot be on tricyclic antidepressants, certain asthma medications, some steroids, and other drugs that might interact with the study medications. It's best to discuss your current medications with the study team to see if any changes are needed.

What data supports the effectiveness of the drug combination of naltrexone and bupropion for methamphetamine addiction?

Research shows that the combination of naltrexone and bupropion can help reduce methamphetamine use and cigarette smoking in people with methamphetamine addiction, as seen in the ADAPT-2 trial. ^{1 2 3 4 5}

Is the combination of Naltrexone and Bupropion generally safe for humans?

Research has shown that the combination of naltrexone and bupropion has been used safely in humans for conditions like smoking cessation and weight management. However, specific safety data for methamphetamine addiction is limited. ^{1 2 4 5 6}

How is the drug combination of naltrexone and bupropion unique for treating methamphetamine addiction?

The combination of naltrexone and bupropion is unique because it targets both methamphetamine addiction and the common co-occurring issue of tobacco smoking, potentially improving overall treatment outcomes. This dual approach is not well-studied for methamphetamine use disorder, making it a novel option compared to other treatments. ^{2 5 7 8 9}

Research Team

Shwe Gyaw, MD

Principal Investigator

NIDA/NIH

Eligibility Criteria

This trial is for adults aged 18-65 with moderate to severe methamphetamine use disorder who want to reduce or stop using. Participants must have tested positive for methamphetamine twice, be willing to follow study procedures and medication instructions, and use a smartphone app for daily video dosing. Women of childbearing potential must agree to birth control measures.

Inclusion Criteria

I agree to use a smartphone app for daily medication videos.

I have provided at least 2 positive urine tests for methamphetamine.

I am between 18 and 65 years old.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive extended-release naltrexone injections and bupropion XL tablets or placebo for 12 weeks

12 weeks

4 visits (in-person) for injections at Weeks 1, 4, 7, and 10

Evaluation

Participants undergo urine drug screen tests to evaluate methamphetamine use reduction

2 weeks

4 visits (in-person) for urine drug screens

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person) at Weeks 14 and 16

Treatment Details

Interventions

• Naltrexone/Bupropion

Trial Overview The trial tests if extended-release naltrexone combined with bupropion XL (XR-NTX/BUP-XL) is more effective than placebo in reducing methamphetamine use among individuals seeking treatment. It compares the drug combination against matched injectable and oral placebos.

Participant Groups

Group I: XR-NTX/BUP-XL Experimental Treatment 2 Interventions

Participants randomized to the (XR-NTX/BUP-XL) arm will receive 450 mg of once-daily oral extended-release bupropion tablets and once every three weeks (Weeks 1, 4, 7, and 10) injections of extended-release naltrexone (Vivitrol®)

Group II: PLB/PLB Placebo Group 2 Interventions

Participants randomized to the PLB arm will receive once-daily placebo tablets and once every three weeks (Weeks 1, 4, 7, and 10) placebo injections.

Naltrexone/Bupropion is already approved in United States, European Union for the following indications:

Approved in United States as Vivitrol (naltrexone) / Wellbutrin (bupropion) for:

• Alcohol dependence (naltrexone)
• Major depressive disorder (bupropion)
• Seasonal affective disorder (bupropion)
• Smoking cessation (bupropion)

Approved in European Union as Vivitrol (naltrexone) / Wellbutrin (bupropion) for:

• Alcohol dependence (naltrexone)
• Major depressive disorder (bupropion)
• Seasonal affective disorder (bupropion)
• Smoking cessation (bupropion)

Who Is Running the Clinical Trial?

National Institute on Drug Abuse (NIDA)

Lead Sponsor

Trials

2,658

Recruited

3,409,000+

Findings from Research

In a study involving 302 participants with cocaine dependence and a history of opioid dependence, buprenorphine + naloxone (BUP) combined with extended-release injectable naltrexone (XR-NTX) showed a significant reduction in cocaine use for those receiving 16 mg/day of BUP compared to placebo, indicating its potential effectiveness in this population.

However, no significant differences were observed in the primary outcome for the 4 mg/day BUP group compared to placebo, suggesting that higher doses may be necessary for efficacy, while adherence, retention, and adverse events were similar across all groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine + naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study. Ling, W., Hillhouse, MP., Saxon, AJ., et al.[2018]

In a trial involving 403 adults with methamphetamine use disorder, the combination of extended-release injectable naltrexone and oral bupropion showed a higher response rate (13.6%) compared to placebo (2.5%) over 12 weeks, indicating some efficacy in reducing methamphetamine use.

While the treatment was more effective than placebo, the overall response rate was still low, and adverse events such as gastrointestinal issues and tremors were reported in some participants, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupropion and Naltrexone in Methamphetamine Use Disorder. Trivedi, MH., Walker, R., Ling, W., et al.[2021]

In a study of 570 patients with opioid use disorder (OUD) treated for 24 weeks, 18.4% reported methamphetamine/amphetamine (MA/A) use at baseline, and this usage did not significantly decline over time.

While there was no significant difference in MA/A use between those treated with buprenorphine/naloxone (BUP-NX) and extended-release naltrexone (XR-NTX), BUP-NX subjects had about half the odds of MA/A use compared to XR-NTX, suggesting a potential benefit that warrants further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methamphetamine/amphetamine use over time among persons with opioid use disorders treated with buprenorphine/naloxone versus extended-release naltrexone. Tsui, JI., Campbell, ANC., Pavlicova, M., et al.[2022]

Combining low doses of naltrexone (NTX) and bupropion (BUP) significantly reduced alcohol consumption in alcohol-preferring rats, while neither drug was effective when used alone, highlighting the potential of combination therapy.

This approach not only enhances efficacy but also minimizes side effects associated with higher doses, which can improve patient compliance and outcomes in treating alcohol use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-Administration of Low-Dose Naltrexone and Bupropion Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats. Nicholson, ER., Dilley, JE., Froehlich, JC.[2019]

In the ADAPT-2 study involving 403 participants with moderate to severe methamphetamine use disorder, 290 were current cigarette smokers, and those treated with naltrexone plus bupropion (NTX-BUP) showed significant improvements in smoking cessation outcomes compared to placebo.

NTX-BUP treatment led to greater reductions in the number of cigarettes smoked per week and increased nonsmoking days, suggesting that this combination therapy could be an effective strategy for addressing both methamphetamine and tobacco use disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone plus bupropion reduces cigarette smoking in individuals with methamphetamine use disorder: A secondary analysis from the CTN ADAPT-2 trial. Schmitz, JM., Stotts, AL., Yoon, JH., et al.[2023]

A new RP-HPLC method was developed and validated for accurately measuring the release of bupropion hydrochloride and naltrexone hydrochloride from compounded bilayer tablets, ensuring effective monitoring of these medications in weight management.

The method met all ICH guidelines for specificity, accuracy, and precision, making it reliable for analyzing dissolution samples of these drugs, which are used as adjunct therapy for obesity in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dissolution Assay of Bupropion/Naltrexone Hydrochloride Salts of Bilayer Composition Tablets Following the Development and Validation of a Novel HPLC Method. Apostolidi, A., Protopapa, C., Siamidi, A., et al.[2022]

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]

In a study involving 7 participants, neither naltrexone, bupropion, nor their combination significantly reduced methamphetamine self-administration or altered the subjective effects of methamphetamine, indicating that these medications may not be effective for treating methamphetamine use disorder.

The study suggests that the strong reinforcing effects of methamphetamine could make it resistant to treatment with these drugs, highlighting the need for further research on longer treatment durations and potential combinations with behavioral therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naltrexone and bupropion, alone or combined, do not alter the reinforcing effects of intranasal methamphetamine. Stoops, WW., Pike, E., Hays, LR., et al.[2018]

In a study involving 204 participants with methamphetamine dependence, bupropion did not significantly improve abstinence rates compared to a placebo, indicating it may not be effective for less-than-daily users of methamphetamine.

Despite 47% of participants adhering to the bupropion treatment protocol, the lack of difference in abstinence rates suggests that psychosocial therapy remains the primary treatment for methamphetamine dependence, and further research is needed to identify subgroups that might benefit from bupropion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial. Anderson, AL., Li, SH., Markova, D., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Buprenorphine + naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Bupropion and Naltrexone in Methamphetamine Use Disorder. [2021]

3. Ireland pubmed.ncbi.nlm.nih.gov

Methamphetamine/amphetamine use over time among persons with opioid use disorders treated with buprenorphine/naloxone versus extended-release naltrexone. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Co-Administration of Low-Dose Naltrexone and Bupropion Reduces Alcohol Drinking in Alcohol-Preferring (P) Rats. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Naltrexone plus bupropion reduces cigarette smoking in individuals with methamphetamine use disorder: A secondary analysis from the CTN ADAPT-2 trial. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Dissolution Assay of Bupropion/Naltrexone Hydrochloride Salts of Bilayer Composition Tablets Following the Development and Validation of a Novel HPLC Method. [2022]

7. Netherlands 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. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Naltrexone and bupropion, alone or combined, do not alter the reinforcing effects of intranasal methamphetamine. [2018]

9. Ireland pubmed.ncbi.nlm.nih.gov

Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial. [2022]