There are no FDA approved medications for individuals with methamphetamine use disorder. This pilot study tested early indicators of safety and efficacy for Ifenprodil, a medication that blocks receptors for the excitatory neurotransmitter glutamate.
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Despite dozens of clinical trials, there are currently no FDA approved medications to treat methamphetamine use disorder directly. While psychosocial approaches such as cognitive-behavioral therapy, 12-step facilitation, contingency management, and the Matrix Model which combines several elements of these therapies with a family component, improve outcomes among individuals with methamphetamine use disorder. Escalating prevalence and public health harms of methamphetamine use, however, highlight the need for additional treatments that can help.
A critical step in the careful process of developing new medications – or identifying existing medications used for other conditions – are early pilot treatment studies that test safety and examine early indicators of efficacy. This study investigated a medication called Ifenprodil which blocks brain receptors that bind with glutamate, an excitatory neurotransmitter with roles in memory, cognition, and mood regulation. The medication is thought to help block the rewarding effects of substance use (including but not limited to methamphetamine use). While acamprosate, an FDA-approved medication for alcohol use disorder, modulates actions at these same NMDA receptors, psychologically, Ifenprodil’s blockade mechanism would be similar to naltrexone’s ability to block the rewarding effects of alcohol and opioid use.
As a pilot study of this medication, which is currently approved and shown to be helpful and safe for other uses (e.g., to treat dizziness after reduced blood flow to the brain, a condition known as ischemia), the current study focused on determining the safety and helpfulness of this medication for individuals with methamphetamine use disorder.
This double-blind randomized controlled trial (i.e., neither study staff administering the treatment nor participants knew their study group assignment) included 33 adults with methamphetamine use disorder (based on Diagnostic and Statistical Manual fifth edition [DSM-5]) diagnosis) receiving placebo, or either 60mg or 120mg of Ifenprodil (hereafter referred to as “medication” or “study medication”), and assessed every 4 weeks for 24 weeks.
Participants were referred to the study by outpatient providers from a large hospital in a suburb of Tokyo, Japan. The participants were 30 males and 3 females with an average age approximately 40-years-old. Exclusion criteria included severe physical/health concerns, determined to be ineligible to participate in the study by their physician, or the use of medications contraindicated with the study medication.
Participants were assessed every 4 weeks via self-report questionnaires on substance use (based on the Timeline Follow Back Procedure), stimulant relapse risk (via the Stimulant Relapse Risk Scale), and drug craving on a 0 to 10 scale. Urine toxicology screens for methamphetamine use was likewise performed at all these visits but . Safety was monitored throughout the study.
The primary outcome of the study was use or nonuse of methamphetamine during the administration period measured with a 28-day calendar (i.e., timeline follow-back) where participants retrospectively indicated any methamphetamine use each day, which was then aggregated into a measure of any methamphetamine use during the 12-week medication trial. Additional outcomes included the days of amphetamine use during the administration period, the days of amphetamine use during only the follow-up period after the medication was discontinued, relapse risk based on the Stimulant Relapse Risk Scale, drug craving, and methamphetamine detection via urinalysis.
Study medication was well tolerated
The study medication was generally well tolerated and there was not a discernable pattern of differences in side effects among the medication and placebo groups. The most common side effect were symptoms of the common cold.
Study medication was generally no better than placebo
The study medication with the higher dose (120 mg/day) and placebo groups had similar rates of methamphetamine abstinence during the drug administration period. The smaller 60mg dose, descriptively, had the worst methamphetamine use outcomes of the three conditions.
There were some advantages for the medication on some substance use related outcomes. First, it is worth mentioning out of 84 days of medication administration, the 120mg medication group reported methamphetamine use on 22 days versus 28 days in the placebo group, though this did not reach statistical significance given the smaller sample size of this pilot study. Also, during the follow-up period only (the 12 weeks after discontinuing the medication), only 4 of the 10 patients initially assigned to the 120mg group were successfully followed up, though these 4 participants had 100% abstinence rates (compared to abstinence on 97% of days among the 8 followed up in the placebo group). As such, there is little confidence that this potentially positive indicator for the study medication was actually due to the medication itself, rather than other helpful individual factors that also made it more likely for them to make it to all study assessments during follow-up.
Finally, compared to placebo, the study medication also demonstrated improvement on the portion of the relapse risk scale relating to emotion regulation while receiving the medication and during the 12-week follow-up. However, there were no group differences on relapse risk overall, nor was there any improvement seen for other measured outcomes, including drug craving or methamphetamine detection via toxicology screen.
In this small pilot study of Ifenprodil for methamphetamine use disorder, overall, most indicators suggest the medication is unlikely to help individuals with methamphetamine use disorder. Where there were a few positive indicators, the study design lowers confidence that the medication itself accounted for these improvements. This pilot study had a very small sample size (only 33 participants) which was split among three treatment groups making it unlikely that randomizing participants to groups would create equivalence on all possible key variables highly suspect. Nevertheless, the medication was well-tolerated with no discernable pattern in side effects attributable to the study medication. Overall, Ifenprodil may be safe and well tolerated, but based on these data seems unlikely to help.
Ultimately, through a careful process of considering new medications through studies like this, scientists and clinicians can better determine whether specific medications can serve as a helpful and safe treatment to be integrated into clinical care for methamphetamine use disorder. This particular treatment however, requires more research. Psychosocial interventions such as contingency management, cognitive-behavioral therapy and 12-step facilitation constitute first-line approaches for the treatment of methamphetamine use disorder.
The current pilot study investigated the medication Ifenprodil as a potential treatment for methamphetamine use disorder. The results of the study provided early indications this medication was generally well tolerated and safe for use in patients with methamphetamine use disorder, though there was little evidence of benefit on methamphetamine use or related processes like craving. Psychosocial interventions such as contingency management, cognitive-behavioral therapy and 12-step facilitation constitute first-line approaches for the treatment of methamphetamine use disorder.
Kotajima-Murakami, H., Takano, A., Hirakawa, S., Ogai, Y., Funada, D., Tanibuchi, Y., Ban, E., Kikuchi, M., Tachimori, H., Maruo, K., Kawashima, T., Tomo, Y., Sasaki, T., Oi, H., Matsumoto, T., & Ikeda, K. (2022). Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology Reports, 42(1), 92–104. doi: 10.1002/npr2.12232
l
Despite dozens of clinical trials, there are currently no FDA approved medications to treat methamphetamine use disorder directly. While psychosocial approaches such as cognitive-behavioral therapy, 12-step facilitation, contingency management, and the Matrix Model which combines several elements of these therapies with a family component, improve outcomes among individuals with methamphetamine use disorder. Escalating prevalence and public health harms of methamphetamine use, however, highlight the need for additional treatments that can help.
A critical step in the careful process of developing new medications – or identifying existing medications used for other conditions – are early pilot treatment studies that test safety and examine early indicators of efficacy. This study investigated a medication called Ifenprodil which blocks brain receptors that bind with glutamate, an excitatory neurotransmitter with roles in memory, cognition, and mood regulation. The medication is thought to help block the rewarding effects of substance use (including but not limited to methamphetamine use). While acamprosate, an FDA-approved medication for alcohol use disorder, modulates actions at these same NMDA receptors, psychologically, Ifenprodil’s blockade mechanism would be similar to naltrexone’s ability to block the rewarding effects of alcohol and opioid use.
As a pilot study of this medication, which is currently approved and shown to be helpful and safe for other uses (e.g., to treat dizziness after reduced blood flow to the brain, a condition known as ischemia), the current study focused on determining the safety and helpfulness of this medication for individuals with methamphetamine use disorder.
This double-blind randomized controlled trial (i.e., neither study staff administering the treatment nor participants knew their study group assignment) included 33 adults with methamphetamine use disorder (based on Diagnostic and Statistical Manual fifth edition [DSM-5]) diagnosis) receiving placebo, or either 60mg or 120mg of Ifenprodil (hereafter referred to as “medication” or “study medication”), and assessed every 4 weeks for 24 weeks.
Participants were referred to the study by outpatient providers from a large hospital in a suburb of Tokyo, Japan. The participants were 30 males and 3 females with an average age approximately 40-years-old. Exclusion criteria included severe physical/health concerns, determined to be ineligible to participate in the study by their physician, or the use of medications contraindicated with the study medication.
Participants were assessed every 4 weeks via self-report questionnaires on substance use (based on the Timeline Follow Back Procedure), stimulant relapse risk (via the Stimulant Relapse Risk Scale), and drug craving on a 0 to 10 scale. Urine toxicology screens for methamphetamine use was likewise performed at all these visits but . Safety was monitored throughout the study.
The primary outcome of the study was use or nonuse of methamphetamine during the administration period measured with a 28-day calendar (i.e., timeline follow-back) where participants retrospectively indicated any methamphetamine use each day, which was then aggregated into a measure of any methamphetamine use during the 12-week medication trial. Additional outcomes included the days of amphetamine use during the administration period, the days of amphetamine use during only the follow-up period after the medication was discontinued, relapse risk based on the Stimulant Relapse Risk Scale, drug craving, and methamphetamine detection via urinalysis.
Study medication was well tolerated
The study medication was generally well tolerated and there was not a discernable pattern of differences in side effects among the medication and placebo groups. The most common side effect were symptoms of the common cold.
Study medication was generally no better than placebo
The study medication with the higher dose (120 mg/day) and placebo groups had similar rates of methamphetamine abstinence during the drug administration period. The smaller 60mg dose, descriptively, had the worst methamphetamine use outcomes of the three conditions.
There were some advantages for the medication on some substance use related outcomes. First, it is worth mentioning out of 84 days of medication administration, the 120mg medication group reported methamphetamine use on 22 days versus 28 days in the placebo group, though this did not reach statistical significance given the smaller sample size of this pilot study. Also, during the follow-up period only (the 12 weeks after discontinuing the medication), only 4 of the 10 patients initially assigned to the 120mg group were successfully followed up, though these 4 participants had 100% abstinence rates (compared to abstinence on 97% of days among the 8 followed up in the placebo group). As such, there is little confidence that this potentially positive indicator for the study medication was actually due to the medication itself, rather than other helpful individual factors that also made it more likely for them to make it to all study assessments during follow-up.
Finally, compared to placebo, the study medication also demonstrated improvement on the portion of the relapse risk scale relating to emotion regulation while receiving the medication and during the 12-week follow-up. However, there were no group differences on relapse risk overall, nor was there any improvement seen for other measured outcomes, including drug craving or methamphetamine detection via toxicology screen.
In this small pilot study of Ifenprodil for methamphetamine use disorder, overall, most indicators suggest the medication is unlikely to help individuals with methamphetamine use disorder. Where there were a few positive indicators, the study design lowers confidence that the medication itself accounted for these improvements. This pilot study had a very small sample size (only 33 participants) which was split among three treatment groups making it unlikely that randomizing participants to groups would create equivalence on all possible key variables highly suspect. Nevertheless, the medication was well-tolerated with no discernable pattern in side effects attributable to the study medication. Overall, Ifenprodil may be safe and well tolerated, but based on these data seems unlikely to help.
Ultimately, through a careful process of considering new medications through studies like this, scientists and clinicians can better determine whether specific medications can serve as a helpful and safe treatment to be integrated into clinical care for methamphetamine use disorder. This particular treatment however, requires more research. Psychosocial interventions such as contingency management, cognitive-behavioral therapy and 12-step facilitation constitute first-line approaches for the treatment of methamphetamine use disorder.
The current pilot study investigated the medication Ifenprodil as a potential treatment for methamphetamine use disorder. The results of the study provided early indications this medication was generally well tolerated and safe for use in patients with methamphetamine use disorder, though there was little evidence of benefit on methamphetamine use or related processes like craving. Psychosocial interventions such as contingency management, cognitive-behavioral therapy and 12-step facilitation constitute first-line approaches for the treatment of methamphetamine use disorder.
Kotajima-Murakami, H., Takano, A., Hirakawa, S., Ogai, Y., Funada, D., Tanibuchi, Y., Ban, E., Kikuchi, M., Tachimori, H., Maruo, K., Kawashima, T., Tomo, Y., Sasaki, T., Oi, H., Matsumoto, T., & Ikeda, K. (2022). Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology Reports, 42(1), 92–104. doi: 10.1002/npr2.12232
l
Despite dozens of clinical trials, there are currently no FDA approved medications to treat methamphetamine use disorder directly. While psychosocial approaches such as cognitive-behavioral therapy, 12-step facilitation, contingency management, and the Matrix Model which combines several elements of these therapies with a family component, improve outcomes among individuals with methamphetamine use disorder. Escalating prevalence and public health harms of methamphetamine use, however, highlight the need for additional treatments that can help.
A critical step in the careful process of developing new medications – or identifying existing medications used for other conditions – are early pilot treatment studies that test safety and examine early indicators of efficacy. This study investigated a medication called Ifenprodil which blocks brain receptors that bind with glutamate, an excitatory neurotransmitter with roles in memory, cognition, and mood regulation. The medication is thought to help block the rewarding effects of substance use (including but not limited to methamphetamine use). While acamprosate, an FDA-approved medication for alcohol use disorder, modulates actions at these same NMDA receptors, psychologically, Ifenprodil’s blockade mechanism would be similar to naltrexone’s ability to block the rewarding effects of alcohol and opioid use.
As a pilot study of this medication, which is currently approved and shown to be helpful and safe for other uses (e.g., to treat dizziness after reduced blood flow to the brain, a condition known as ischemia), the current study focused on determining the safety and helpfulness of this medication for individuals with methamphetamine use disorder.
This double-blind randomized controlled trial (i.e., neither study staff administering the treatment nor participants knew their study group assignment) included 33 adults with methamphetamine use disorder (based on Diagnostic and Statistical Manual fifth edition [DSM-5]) diagnosis) receiving placebo, or either 60mg or 120mg of Ifenprodil (hereafter referred to as “medication” or “study medication”), and assessed every 4 weeks for 24 weeks.
Participants were referred to the study by outpatient providers from a large hospital in a suburb of Tokyo, Japan. The participants were 30 males and 3 females with an average age approximately 40-years-old. Exclusion criteria included severe physical/health concerns, determined to be ineligible to participate in the study by their physician, or the use of medications contraindicated with the study medication.
Participants were assessed every 4 weeks via self-report questionnaires on substance use (based on the Timeline Follow Back Procedure), stimulant relapse risk (via the Stimulant Relapse Risk Scale), and drug craving on a 0 to 10 scale. Urine toxicology screens for methamphetamine use was likewise performed at all these visits but . Safety was monitored throughout the study.
The primary outcome of the study was use or nonuse of methamphetamine during the administration period measured with a 28-day calendar (i.e., timeline follow-back) where participants retrospectively indicated any methamphetamine use each day, which was then aggregated into a measure of any methamphetamine use during the 12-week medication trial. Additional outcomes included the days of amphetamine use during the administration period, the days of amphetamine use during only the follow-up period after the medication was discontinued, relapse risk based on the Stimulant Relapse Risk Scale, drug craving, and methamphetamine detection via urinalysis.
Study medication was well tolerated
The study medication was generally well tolerated and there was not a discernable pattern of differences in side effects among the medication and placebo groups. The most common side effect were symptoms of the common cold.
Study medication was generally no better than placebo
The study medication with the higher dose (120 mg/day) and placebo groups had similar rates of methamphetamine abstinence during the drug administration period. The smaller 60mg dose, descriptively, had the worst methamphetamine use outcomes of the three conditions.
There were some advantages for the medication on some substance use related outcomes. First, it is worth mentioning out of 84 days of medication administration, the 120mg medication group reported methamphetamine use on 22 days versus 28 days in the placebo group, though this did not reach statistical significance given the smaller sample size of this pilot study. Also, during the follow-up period only (the 12 weeks after discontinuing the medication), only 4 of the 10 patients initially assigned to the 120mg group were successfully followed up, though these 4 participants had 100% abstinence rates (compared to abstinence on 97% of days among the 8 followed up in the placebo group). As such, there is little confidence that this potentially positive indicator for the study medication was actually due to the medication itself, rather than other helpful individual factors that also made it more likely for them to make it to all study assessments during follow-up.
Finally, compared to placebo, the study medication also demonstrated improvement on the portion of the relapse risk scale relating to emotion regulation while receiving the medication and during the 12-week follow-up. However, there were no group differences on relapse risk overall, nor was there any improvement seen for other measured outcomes, including drug craving or methamphetamine detection via toxicology screen.
In this small pilot study of Ifenprodil for methamphetamine use disorder, overall, most indicators suggest the medication is unlikely to help individuals with methamphetamine use disorder. Where there were a few positive indicators, the study design lowers confidence that the medication itself accounted for these improvements. This pilot study had a very small sample size (only 33 participants) which was split among three treatment groups making it unlikely that randomizing participants to groups would create equivalence on all possible key variables highly suspect. Nevertheless, the medication was well-tolerated with no discernable pattern in side effects attributable to the study medication. Overall, Ifenprodil may be safe and well tolerated, but based on these data seems unlikely to help.
Ultimately, through a careful process of considering new medications through studies like this, scientists and clinicians can better determine whether specific medications can serve as a helpful and safe treatment to be integrated into clinical care for methamphetamine use disorder. This particular treatment however, requires more research. Psychosocial interventions such as contingency management, cognitive-behavioral therapy and 12-step facilitation constitute first-line approaches for the treatment of methamphetamine use disorder.
The current pilot study investigated the medication Ifenprodil as a potential treatment for methamphetamine use disorder. The results of the study provided early indications this medication was generally well tolerated and safe for use in patients with methamphetamine use disorder, though there was little evidence of benefit on methamphetamine use or related processes like craving. Psychosocial interventions such as contingency management, cognitive-behavioral therapy and 12-step facilitation constitute first-line approaches for the treatment of methamphetamine use disorder.
Kotajima-Murakami, H., Takano, A., Hirakawa, S., Ogai, Y., Funada, D., Tanibuchi, Y., Ban, E., Kikuchi, M., Tachimori, H., Maruo, K., Kawashima, T., Tomo, Y., Sasaki, T., Oi, H., Matsumoto, T., & Ikeda, K. (2022). Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology Reports, 42(1), 92–104. doi: 10.1002/npr2.12232
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