Testing the combination of bupropion and extended-release naltrexone for methamphetamine use disorder
Despite dozens of clinical trials costing many millions of dollars there are no FDA-approved medications for stimulant use disorders, such as cocaine or methamphetamine. This study investigated whether the combination of bupropion – which has shown promise in reducing stimulant use – and extended-release naltrexone – FDA-approved for both alcohol and opioid use disorder – improves outcomes for people with methamphetamine use disorder.
The past decade has seen a rise in prevalence of methamphetamine use and overdoses involving methamphetamine, particularly in conjunction with the synthetic opioid, fentanyl. Despite the public health impact of methamphetamine use, and many large-scale studies, there are no medications approved by the Food and Drug Administration (FDA) for treating methamphetamine use disorder. Recently, researchers have demonstrated that bupropion and extended-release naltrexone (medications commonly used for other substance use disorders) may be effective for reducing methamphetamine use when used in combination.
Extended-release naltrexone is a monthly injection (also known by the brand name “Vivitrol”) that blocks opioid receptors (an “antagonist”) and may help reduce methamphetamine use by blunting feelings of reward and euphoria associated with its use, which may then also help reduce craving. Bupropion is an antidepressant with stimulant-like qualities; a norepinephrine reuptake inhibitor, it is hypothesized to work by reducing the dysphoria associated with methamphetamine withdrawal.
To test the efficacy of extended-release naltrexone in combination with bupropion, researchers designed a multi-site, double-blind placebo-controlled trial with two stages. In the first 6-week stage, 403 participants were randomized to receive either combination extended-release naltrexone and bupropion or placebo. Participants in the placebo condition that did not demonstrate a response – 3 of 4 negative methamphetamine drug screens in the last 2 weeks of the trial – were re-randomized to receive either combination extended-release naltrexone and bupropion or placebo in the second stage. In the first stage, 18 of 109 participants (16.5%) in the naltrexone–bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone–bupropion group and 2 of 111 (1.8%) in the placebo group had a response. These results provided initial evidence for efficacy of combination extended-release naltrexone and bupropion over 6 weeks.
In this study, those initially randomized to the active medication condition in stage 1 continued to receive combination extended-release naltrexone and bupropion throughout stage 2. Although combination extended-release naltrexone and bupropion showed efficacy across the first 6 weeks of the trial, it is unknown whether continued naltrexone/bupropion use for an additional 6 weeks results in further improvements in methamphetamine use outcomes at the end of the 12 week medication period.
This study was a secondary analysis of a multi-site, two-staged, double-blind placebo-controlled trial to determine whether an additional 6 weeks of combination extended-release naltrexone and bupropion was associated with further improvements in methamphetamine outcomes at the 12 week follow up.
HOW WAS THIS STUDY CONDUCTED?
The primary study, known as the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial, used a randomized placebo-control sequential parallel design that was carried out across 8 sites throughout the United States.
This design randomized participants in 2 stages, each lasting 6 weeks. First, all participants were randomized to receive either combination extended-release naltrexone and bupropion or placebo. In stage 2, participants in the placebo condition that did not demonstrate a response in stage 1 – negative methamphetamine results (consistent with no use) on 3 out of 4 drug tests — were re-randomized to receive either combination extended-release naltrexone and bupropion or placebo. Researchers enrolled 403 treatment-seeking adults between the ages of 18 and 65 who met DSM-5 criteria for moderate or severe methamphetamine use disorder. Participants were required to be capable of understanding study procedures, report recent methamphetamine use (at least 18 of the last 30 days), and were opioid-free. There were many reasons people were excluded as is typical in clinical trials to give the medication the best chance of success (e.g., undergoing current substance use disorder treatment, seizure risk, or taking contraindicated medications). The initial study published 6 week outcomes. This secondary analysis of data also included an additional 6 weeks of medication efficacy data (12 weeks total). The trial defined a treatment response as screening negative for methamphetamine on at least 3 of 4 possible urine drugs screens in weeks 5 to 6 and 11 to 12. Participants were no longer given medication or placebo after week 12 but continued providing urine screens through week 16.
The researchers wanted to know whether the combination extended-release naltrexone and bupropion or placebo continued to improve through week 12 relative to the group that received placebo throughout the duration of the study. The researchers calculated change in percentage of methamphetamine-negative urine tests over time by treatment condition and examined significant change from the beginning of the treatment period, and incremental improvement from week 7 to week 12.
Among the 403 participants in the trial, 68.7% were male, 78.2% were White, 35.2% had a high school diploma, GED, or equivalent of a lower education level, and 23.1% were married. The average age was 41. Participants used methamphetamine on an average of 26.7 days in the past month.
WHAT DID THIS STUDY FIND?
Continued combination extended-release naltrexone and bupropion incrementally improved methamphetamine use outcomes
From week 1 to week 12, there was a 27.1% increase in negative methamphetamine urine screens for the medication group. Within the placebo group, there was a 11.4% increase in negative methamphetamine urine screens. From week 1 to week 6, there was an initial 18.4% increase in negative methamphetamine urine screens, followed by an additional 9.2% increase from week 7 to week 12. In the placebo group, there was an initial 7.0% increase in negative methamphetamine urine screens from week 1 to week 6, followed by a modest 3.9% increase from week 7 to week 12. Both groups remained relatively stable from week 13 to week 16 when no medication or placebo was administered.
WHAT ARE THE IMPLICATIONS OF THE STUDY FINDINGS?
The results from this clinical trial found that the combination of extended-release naltrexone and bupropion reduced methamphetamine use over 6 weeks. Further, this secondary analysis found that an additional 6 weeks of the medication combination was associated with an incremental improvement in outcomes. These findings are particularly important given decades of medications trials failing to show benefits for stimulant use disorder generally and methamphetamine use specifically. Though many medication classes have lacked efficacy at treating stimulant use disorder, including cannabidiol, Vigabatrin, various antipsychotics, anticonvulsants, antidepressants, dopamine agonists, opioids, and other psychostimulants, novel directions in medication development have shifted toward targeting multiple neurobiological mechanisms, with the hope that more comprehensive coverage may be associated with greater efficacy. This clinical trial seems to support this general premise and may encourage similar trials for other drug combinations.
It is also important to highlight that medications are not the only option. Contingency management, which is a broadly defined collection of programs that systematically use incentives to reward (i.e., positively reinforce) stimulant abstinence (e.g., by providing monetary vouchers to patients for testing negative for stimulant use via urinalysis), has very useful in the treatment of stimulant use disorder. Increasing access to contingency management may improve public health management of stimulant use disorder more broadly, though many health care providers have concerns about its utility in real world settings including its focus on external motivation and issues with monetary rewards. Psychosocial interventions including 12-step facilitation approaches have also been shown to improve outcomes for other stimulant use disorders, such as cocaine. These treatments actively link patients with community-based 12-step mutual-help organizations while providing recovery psychoeducation and helping them to develop skills to initiate and maintain abstinence.
There have also been increasing calls for alternative efficacy outcomes in medication development. Abstinence is the traditional outcome in medications trials and has the greatest individual and public health impact; however, other harm reduction targets such as reductions in substance use are increasingly considered as they can still result in increases in psychosocial functioning and quality of life. Although the combination of extended-release naltrexone and bupropion does appear promising as a potential medication for increasing abstinence outcomes, future studies might consider examining outcomes along a spectrum, such as percent days abstinent from methamphetamine use as has been done for alcohol use disorder.
Although these results are promising, it should be remembered that at peak medication benefit in this study, 70% of urine toxicology screens were still positive for methamphetamine. Also, the research excluded participants who also used opioids, reducing the overall generalizability of the study. There has been a rapid increase in methamphetamine use among people with opioid use disorder, fueling concerns of an emerging “twin epidemic”. In a nationally representative sample, rates of co-use increased from 9.0% in 2015 to 30.2% in 2017. Given the growing emergence of this population, it is important to demonstrate efficacy for this medication combination amongst people who use both opioids and methamphetamine.
The trial excluded individuals who use opioids, which is a growing population increasingly common among people who use methamphetamine.
BOTTOM LINE
The combination of extended-release naltrexone and bupropion improved methamphetamine use over 6 weeks, and an additional, incremental improvement in negative methamphetamine urine screens with an additional 6 weeks of medication. This study suggests the combination of extended-release naltrexone and bupropion may be useful for the treatment for methamphetamine use disorder.
For individuals and families seeking recovery: If you or a family member are seeking help for methamphetamine use disorder, the combination of extended-release naltrexone and bupropion may be potentially promising option. However, it is not currently FDA-approved. Other psychosocial treatments, such as contingency management, are helpful at increasing abstinence in dozens of studies. It is also important to mention that scientists continue to explore other medication options, with some emerging as potential therapeutics that will be tested in further clinical trials.
For treatment professionals and treatment systems: These results highlight a potential new medication treatment for patients with methamphetamine use disorder. It is important to be aware of other substance use, however, and opioid use in particular, as simultaneous opioid and methamphetamine use is on the rise and the current study did not test efficacy in a population of people who use opioids.
For scientists: This study represents a key breakthrough in medications development for stimulant use disorder. However, further research is necessary to establish efficacy and safety necessary to meet criteria for FDA approval. Further, a substantial portion of the population of people who use methamphetamines also use opioids, and future clinical trials exploring differential efficacy amongst those who also use opioids may help determine the generalizability of these findings. Additional studies measuring the additive benefit of medications for opioid use disorder with other treatments or recovery support services may also improve rates of initiation and sustained recovery in this co-use population.
For policy makers: This study suggests some promise in the combination of extended-release naltrexone and bupropion for the treatment of methamphetamine use disorder. However, more research is necessary. Policy that increases funding to continue investigating this drug combination, or perhaps other drug combinations, may help improve treatment of methamphetamine use disorder. Funding for trials testing combination of medications in addition to psychosocial treatments, such as contingency management, may also be useful.
The past decade has seen a rise in prevalence of methamphetamine use and overdoses involving methamphetamine, particularly in conjunction with the synthetic opioid, fentanyl. Despite the public health impact of methamphetamine use, and many large-scale studies, there are no medications approved by the Food and Drug Administration (FDA) for treating methamphetamine use disorder. Recently, researchers have demonstrated that bupropion and extended-release naltrexone (medications commonly used for other substance use disorders) may be effective for reducing methamphetamine use when used in combination.
Extended-release naltrexone is a monthly injection (also known by the brand name “Vivitrol”) that blocks opioid receptors (an “antagonist”) and may help reduce methamphetamine use by blunting feelings of reward and euphoria associated with its use, which may then also help reduce craving. Bupropion is an antidepressant with stimulant-like qualities; a norepinephrine reuptake inhibitor, it is hypothesized to work by reducing the dysphoria associated with methamphetamine withdrawal.
To test the efficacy of extended-release naltrexone in combination with bupropion, researchers designed a multi-site, double-blind placebo-controlled trial with two stages. In the first 6-week stage, 403 participants were randomized to receive either combination extended-release naltrexone and bupropion or placebo. Participants in the placebo condition that did not demonstrate a response – 3 of 4 negative methamphetamine drug screens in the last 2 weeks of the trial – were re-randomized to receive either combination extended-release naltrexone and bupropion or placebo in the second stage. In the first stage, 18 of 109 participants (16.5%) in the naltrexone–bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone–bupropion group and 2 of 111 (1.8%) in the placebo group had a response. These results provided initial evidence for efficacy of combination extended-release naltrexone and bupropion over 6 weeks.
In this study, those initially randomized to the active medication condition in stage 1 continued to receive combination extended-release naltrexone and bupropion throughout stage 2. Although combination extended-release naltrexone and bupropion showed efficacy across the first 6 weeks of the trial, it is unknown whether continued naltrexone/bupropion use for an additional 6 weeks results in further improvements in methamphetamine use outcomes at the end of the 12 week medication period.
This study was a secondary analysis of a multi-site, two-staged, double-blind placebo-controlled trial to determine whether an additional 6 weeks of combination extended-release naltrexone and bupropion was associated with further improvements in methamphetamine outcomes at the 12 week follow up.
HOW WAS THIS STUDY CONDUCTED?
The primary study, known as the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial, used a randomized placebo-control sequential parallel design that was carried out across 8 sites throughout the United States.
This design randomized participants in 2 stages, each lasting 6 weeks. First, all participants were randomized to receive either combination extended-release naltrexone and bupropion or placebo. In stage 2, participants in the placebo condition that did not demonstrate a response in stage 1 – negative methamphetamine results (consistent with no use) on 3 out of 4 drug tests — were re-randomized to receive either combination extended-release naltrexone and bupropion or placebo. Researchers enrolled 403 treatment-seeking adults between the ages of 18 and 65 who met DSM-5 criteria for moderate or severe methamphetamine use disorder. Participants were required to be capable of understanding study procedures, report recent methamphetamine use (at least 18 of the last 30 days), and were opioid-free. There were many reasons people were excluded as is typical in clinical trials to give the medication the best chance of success (e.g., undergoing current substance use disorder treatment, seizure risk, or taking contraindicated medications). The initial study published 6 week outcomes. This secondary analysis of data also included an additional 6 weeks of medication efficacy data (12 weeks total). The trial defined a treatment response as screening negative for methamphetamine on at least 3 of 4 possible urine drugs screens in weeks 5 to 6 and 11 to 12. Participants were no longer given medication or placebo after week 12 but continued providing urine screens through week 16.
The researchers wanted to know whether the combination extended-release naltrexone and bupropion or placebo continued to improve through week 12 relative to the group that received placebo throughout the duration of the study. The researchers calculated change in percentage of methamphetamine-negative urine tests over time by treatment condition and examined significant change from the beginning of the treatment period, and incremental improvement from week 7 to week 12.
Among the 403 participants in the trial, 68.7% were male, 78.2% were White, 35.2% had a high school diploma, GED, or equivalent of a lower education level, and 23.1% were married. The average age was 41. Participants used methamphetamine on an average of 26.7 days in the past month.
WHAT DID THIS STUDY FIND?
Continued combination extended-release naltrexone and bupropion incrementally improved methamphetamine use outcomes
From week 1 to week 12, there was a 27.1% increase in negative methamphetamine urine screens for the medication group. Within the placebo group, there was a 11.4% increase in negative methamphetamine urine screens. From week 1 to week 6, there was an initial 18.4% increase in negative methamphetamine urine screens, followed by an additional 9.2% increase from week 7 to week 12. In the placebo group, there was an initial 7.0% increase in negative methamphetamine urine screens from week 1 to week 6, followed by a modest 3.9% increase from week 7 to week 12. Both groups remained relatively stable from week 13 to week 16 when no medication or placebo was administered.
WHAT ARE THE IMPLICATIONS OF THE STUDY FINDINGS?
The results from this clinical trial found that the combination of extended-release naltrexone and bupropion reduced methamphetamine use over 6 weeks. Further, this secondary analysis found that an additional 6 weeks of the medication combination was associated with an incremental improvement in outcomes. These findings are particularly important given decades of medications trials failing to show benefits for stimulant use disorder generally and methamphetamine use specifically. Though many medication classes have lacked efficacy at treating stimulant use disorder, including cannabidiol, Vigabatrin, various antipsychotics, anticonvulsants, antidepressants, dopamine agonists, opioids, and other psychostimulants, novel directions in medication development have shifted toward targeting multiple neurobiological mechanisms, with the hope that more comprehensive coverage may be associated with greater efficacy. This clinical trial seems to support this general premise and may encourage similar trials for other drug combinations.
It is also important to highlight that medications are not the only option. Contingency management, which is a broadly defined collection of programs that systematically use incentives to reward (i.e., positively reinforce) stimulant abstinence (e.g., by providing monetary vouchers to patients for testing negative for stimulant use via urinalysis), has very useful in the treatment of stimulant use disorder. Increasing access to contingency management may improve public health management of stimulant use disorder more broadly, though many health care providers have concerns about its utility in real world settings including its focus on external motivation and issues with monetary rewards. Psychosocial interventions including 12-step facilitation approaches have also been shown to improve outcomes for other stimulant use disorders, such as cocaine. These treatments actively link patients with community-based 12-step mutual-help organizations while providing recovery psychoeducation and helping them to develop skills to initiate and maintain abstinence.
There have also been increasing calls for alternative efficacy outcomes in medication development. Abstinence is the traditional outcome in medications trials and has the greatest individual and public health impact; however, other harm reduction targets such as reductions in substance use are increasingly considered as they can still result in increases in psychosocial functioning and quality of life. Although the combination of extended-release naltrexone and bupropion does appear promising as a potential medication for increasing abstinence outcomes, future studies might consider examining outcomes along a spectrum, such as percent days abstinent from methamphetamine use as has been done for alcohol use disorder.
Although these results are promising, it should be remembered that at peak medication benefit in this study, 70% of urine toxicology screens were still positive for methamphetamine. Also, the research excluded participants who also used opioids, reducing the overall generalizability of the study. There has been a rapid increase in methamphetamine use among people with opioid use disorder, fueling concerns of an emerging “twin epidemic”. In a nationally representative sample, rates of co-use increased from 9.0% in 2015 to 30.2% in 2017. Given the growing emergence of this population, it is important to demonstrate efficacy for this medication combination amongst people who use both opioids and methamphetamine.
The trial excluded individuals who use opioids, which is a growing population increasingly common among people who use methamphetamine.
BOTTOM LINE
The combination of extended-release naltrexone and bupropion improved methamphetamine use over 6 weeks, and an additional, incremental improvement in negative methamphetamine urine screens with an additional 6 weeks of medication. This study suggests the combination of extended-release naltrexone and bupropion may be useful for the treatment for methamphetamine use disorder.
For individuals and families seeking recovery: If you or a family member are seeking help for methamphetamine use disorder, the combination of extended-release naltrexone and bupropion may be potentially promising option. However, it is not currently FDA-approved. Other psychosocial treatments, such as contingency management, are helpful at increasing abstinence in dozens of studies. It is also important to mention that scientists continue to explore other medication options, with some emerging as potential therapeutics that will be tested in further clinical trials.
For treatment professionals and treatment systems: These results highlight a potential new medication treatment for patients with methamphetamine use disorder. It is important to be aware of other substance use, however, and opioid use in particular, as simultaneous opioid and methamphetamine use is on the rise and the current study did not test efficacy in a population of people who use opioids.
For scientists: This study represents a key breakthrough in medications development for stimulant use disorder. However, further research is necessary to establish efficacy and safety necessary to meet criteria for FDA approval. Further, a substantial portion of the population of people who use methamphetamines also use opioids, and future clinical trials exploring differential efficacy amongst those who also use opioids may help determine the generalizability of these findings. Additional studies measuring the additive benefit of medications for opioid use disorder with other treatments or recovery support services may also improve rates of initiation and sustained recovery in this co-use population.
For policy makers: This study suggests some promise in the combination of extended-release naltrexone and bupropion for the treatment of methamphetamine use disorder. However, more research is necessary. Policy that increases funding to continue investigating this drug combination, or perhaps other drug combinations, may help improve treatment of methamphetamine use disorder. Funding for trials testing combination of medications in addition to psychosocial treatments, such as contingency management, may also be useful.
The past decade has seen a rise in prevalence of methamphetamine use and overdoses involving methamphetamine, particularly in conjunction with the synthetic opioid, fentanyl. Despite the public health impact of methamphetamine use, and many large-scale studies, there are no medications approved by the Food and Drug Administration (FDA) for treating methamphetamine use disorder. Recently, researchers have demonstrated that bupropion and extended-release naltrexone (medications commonly used for other substance use disorders) may be effective for reducing methamphetamine use when used in combination.
Extended-release naltrexone is a monthly injection (also known by the brand name “Vivitrol”) that blocks opioid receptors (an “antagonist”) and may help reduce methamphetamine use by blunting feelings of reward and euphoria associated with its use, which may then also help reduce craving. Bupropion is an antidepressant with stimulant-like qualities; a norepinephrine reuptake inhibitor, it is hypothesized to work by reducing the dysphoria associated with methamphetamine withdrawal.
To test the efficacy of extended-release naltrexone in combination with bupropion, researchers designed a multi-site, double-blind placebo-controlled trial with two stages. In the first 6-week stage, 403 participants were randomized to receive either combination extended-release naltrexone and bupropion or placebo. Participants in the placebo condition that did not demonstrate a response – 3 of 4 negative methamphetamine drug screens in the last 2 weeks of the trial – were re-randomized to receive either combination extended-release naltrexone and bupropion or placebo in the second stage. In the first stage, 18 of 109 participants (16.5%) in the naltrexone–bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone–bupropion group and 2 of 111 (1.8%) in the placebo group had a response. These results provided initial evidence for efficacy of combination extended-release naltrexone and bupropion over 6 weeks.
In this study, those initially randomized to the active medication condition in stage 1 continued to receive combination extended-release naltrexone and bupropion throughout stage 2. Although combination extended-release naltrexone and bupropion showed efficacy across the first 6 weeks of the trial, it is unknown whether continued naltrexone/bupropion use for an additional 6 weeks results in further improvements in methamphetamine use outcomes at the end of the 12 week medication period.
This study was a secondary analysis of a multi-site, two-staged, double-blind placebo-controlled trial to determine whether an additional 6 weeks of combination extended-release naltrexone and bupropion was associated with further improvements in methamphetamine outcomes at the 12 week follow up.
HOW WAS THIS STUDY CONDUCTED?
The primary study, known as the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial, used a randomized placebo-control sequential parallel design that was carried out across 8 sites throughout the United States.
This design randomized participants in 2 stages, each lasting 6 weeks. First, all participants were randomized to receive either combination extended-release naltrexone and bupropion or placebo. In stage 2, participants in the placebo condition that did not demonstrate a response in stage 1 – negative methamphetamine results (consistent with no use) on 3 out of 4 drug tests — were re-randomized to receive either combination extended-release naltrexone and bupropion or placebo. Researchers enrolled 403 treatment-seeking adults between the ages of 18 and 65 who met DSM-5 criteria for moderate or severe methamphetamine use disorder. Participants were required to be capable of understanding study procedures, report recent methamphetamine use (at least 18 of the last 30 days), and were opioid-free. There were many reasons people were excluded as is typical in clinical trials to give the medication the best chance of success (e.g., undergoing current substance use disorder treatment, seizure risk, or taking contraindicated medications). The initial study published 6 week outcomes. This secondary analysis of data also included an additional 6 weeks of medication efficacy data (12 weeks total). The trial defined a treatment response as screening negative for methamphetamine on at least 3 of 4 possible urine drugs screens in weeks 5 to 6 and 11 to 12. Participants were no longer given medication or placebo after week 12 but continued providing urine screens through week 16.
The researchers wanted to know whether the combination extended-release naltrexone and bupropion or placebo continued to improve through week 12 relative to the group that received placebo throughout the duration of the study. The researchers calculated change in percentage of methamphetamine-negative urine tests over time by treatment condition and examined significant change from the beginning of the treatment period, and incremental improvement from week 7 to week 12.
Among the 403 participants in the trial, 68.7% were male, 78.2% were White, 35.2% had a high school diploma, GED, or equivalent of a lower education level, and 23.1% were married. The average age was 41. Participants used methamphetamine on an average of 26.7 days in the past month.
WHAT DID THIS STUDY FIND?
Continued combination extended-release naltrexone and bupropion incrementally improved methamphetamine use outcomes
From week 1 to week 12, there was a 27.1% increase in negative methamphetamine urine screens for the medication group. Within the placebo group, there was a 11.4% increase in negative methamphetamine urine screens. From week 1 to week 6, there was an initial 18.4% increase in negative methamphetamine urine screens, followed by an additional 9.2% increase from week 7 to week 12. In the placebo group, there was an initial 7.0% increase in negative methamphetamine urine screens from week 1 to week 6, followed by a modest 3.9% increase from week 7 to week 12. Both groups remained relatively stable from week 13 to week 16 when no medication or placebo was administered.
WHAT ARE THE IMPLICATIONS OF THE STUDY FINDINGS?
The results from this clinical trial found that the combination of extended-release naltrexone and bupropion reduced methamphetamine use over 6 weeks. Further, this secondary analysis found that an additional 6 weeks of the medication combination was associated with an incremental improvement in outcomes. These findings are particularly important given decades of medications trials failing to show benefits for stimulant use disorder generally and methamphetamine use specifically. Though many medication classes have lacked efficacy at treating stimulant use disorder, including cannabidiol, Vigabatrin, various antipsychotics, anticonvulsants, antidepressants, dopamine agonists, opioids, and other psychostimulants, novel directions in medication development have shifted toward targeting multiple neurobiological mechanisms, with the hope that more comprehensive coverage may be associated with greater efficacy. This clinical trial seems to support this general premise and may encourage similar trials for other drug combinations.
It is also important to highlight that medications are not the only option. Contingency management, which is a broadly defined collection of programs that systematically use incentives to reward (i.e., positively reinforce) stimulant abstinence (e.g., by providing monetary vouchers to patients for testing negative for stimulant use via urinalysis), has very useful in the treatment of stimulant use disorder. Increasing access to contingency management may improve public health management of stimulant use disorder more broadly, though many health care providers have concerns about its utility in real world settings including its focus on external motivation and issues with monetary rewards. Psychosocial interventions including 12-step facilitation approaches have also been shown to improve outcomes for other stimulant use disorders, such as cocaine. These treatments actively link patients with community-based 12-step mutual-help organizations while providing recovery psychoeducation and helping them to develop skills to initiate and maintain abstinence.
There have also been increasing calls for alternative efficacy outcomes in medication development. Abstinence is the traditional outcome in medications trials and has the greatest individual and public health impact; however, other harm reduction targets such as reductions in substance use are increasingly considered as they can still result in increases in psychosocial functioning and quality of life. Although the combination of extended-release naltrexone and bupropion does appear promising as a potential medication for increasing abstinence outcomes, future studies might consider examining outcomes along a spectrum, such as percent days abstinent from methamphetamine use as has been done for alcohol use disorder.
Although these results are promising, it should be remembered that at peak medication benefit in this study, 70% of urine toxicology screens were still positive for methamphetamine. Also, the research excluded participants who also used opioids, reducing the overall generalizability of the study. There has been a rapid increase in methamphetamine use among people with opioid use disorder, fueling concerns of an emerging “twin epidemic”. In a nationally representative sample, rates of co-use increased from 9.0% in 2015 to 30.2% in 2017. Given the growing emergence of this population, it is important to demonstrate efficacy for this medication combination amongst people who use both opioids and methamphetamine.
The trial excluded individuals who use opioids, which is a growing population increasingly common among people who use methamphetamine.
BOTTOM LINE
The combination of extended-release naltrexone and bupropion improved methamphetamine use over 6 weeks, and an additional, incremental improvement in negative methamphetamine urine screens with an additional 6 weeks of medication. This study suggests the combination of extended-release naltrexone and bupropion may be useful for the treatment for methamphetamine use disorder.
For individuals and families seeking recovery: If you or a family member are seeking help for methamphetamine use disorder, the combination of extended-release naltrexone and bupropion may be potentially promising option. However, it is not currently FDA-approved. Other psychosocial treatments, such as contingency management, are helpful at increasing abstinence in dozens of studies. It is also important to mention that scientists continue to explore other medication options, with some emerging as potential therapeutics that will be tested in further clinical trials.
For treatment professionals and treatment systems: These results highlight a potential new medication treatment for patients with methamphetamine use disorder. It is important to be aware of other substance use, however, and opioid use in particular, as simultaneous opioid and methamphetamine use is on the rise and the current study did not test efficacy in a population of people who use opioids.
For scientists: This study represents a key breakthrough in medications development for stimulant use disorder. However, further research is necessary to establish efficacy and safety necessary to meet criteria for FDA approval. Further, a substantial portion of the population of people who use methamphetamines also use opioids, and future clinical trials exploring differential efficacy amongst those who also use opioids may help determine the generalizability of these findings. Additional studies measuring the additive benefit of medications for opioid use disorder with other treatments or recovery support services may also improve rates of initiation and sustained recovery in this co-use population.
For policy makers: This study suggests some promise in the combination of extended-release naltrexone and bupropion for the treatment of methamphetamine use disorder. However, more research is necessary. Policy that increases funding to continue investigating this drug combination, or perhaps other drug combinations, may help improve treatment of methamphetamine use disorder. Funding for trials testing combination of medications in addition to psychosocial treatments, such as contingency management, may also be useful.
