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05. Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder

Published on December 1, 2021 Expired on April 1, 2025

Andrew Saxon, M.D.

Professor, Department of Psychiatry and Behavioral Sciences - University of Washington School of Medicine

Key Points

Amphetamines as a replacement pharmacotherapy for methamphetamine use disorder do not show benefit.
MPH shows a positive signal, particularly for patients who have underlying ADHD.
There is a need to study MPH in larger studies before it can be considered the go-to medication for methamphetamine use disorder.

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Slides and Transcript

Slide 1 of 16

So, we're going to turn on replacement pharmacotherapy to treat methamphetamine and amphetamine use disorder.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 1 of 16

Slide 2 of 16

There have been several studies that have looked at this option. The outcome for almost all of these studies that we'll be talking about is the percent of urine specimens positive for methamphetamine or cocaine. In this case, the patients were treated with dexamphetamine 60 mg per day compared to placebo with 30 patients per condition. And what you can see is over eight weeks of study, there's really no difference in methamphetamine use. So, the idea of substituting amphetamines for methamphetamine use disorder does not seem to hold much merit.

References:

Galloway, G. P., Buscemi, R., Coyle, J. R., Flower, K., Siegrist, J. D., Fiske, L. A., Baggott, M. J., Li, L., Polcin, D., Chen, C. Y., & Mendelson, J. (2010). A randomized, placebo-controlled trial of sustained-release dextroamphetamine for treatment of methamphetamine addiction. Clinical Pharmacology & Therapeutics, 89(2), 276-282.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 2 of 16

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Slide 3 of 16

I want to take just a side step for a moment to mention more about attention deficit hyperactivity disorder. And in this study, it was an in-depth study of 51 patients who had methamphetamine use disorder. And the instrument called the Wender Utah Rating Scale which was designed to screen for ADHD, it asks about a lot of childhood behaviors, was administered to all of these patients. And you can see that 70% of them screened positive for ADHD. Now, this doesn't absolutely confirm the diagnosis of ADHD but it makes it very likely.

References:

Jaffe, C., Bush, K. R., Straits-Troster, K., Meredith, C., Romwall, L., Rosenbaum, G., Cherrier, M., & Saxon, A. J. (2005). A comparison of methamphetamine-dependent inpatients with and without childhood attention deficit hyperactivity disorder symptomatology. Journal of Addictive Diseases, 24(3), 133-152.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 3 of 16

Slide 4 of 16

And so those that screened positive for ADHD, reported much higher rates of methamphetamine use in the prior 30 days.

References:

Jaffe, C., Bush, K. R., Straits-Troster, K., Meredith, C., Romwall, L., Rosenbaum, G., Cherrier, M., & Saxon, A. J. (2005). A comparison of methamphetamine-dependent inpatients with and without childhood attention deficit hyperactivity disorder symptomatology. Journal of Addictive Diseases, 24(3), 133-152.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 4 of 16

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Slide 5 of 16

So, we know that these two disorders travel together and can influence each other. And it's relevant because of the idea of using stimulant treatment for stimulant use disorder.

References:

Jaffe, C., Bush, K. R., Straits-Troster, K., Meredith, C., Romwall, L., Rosenbaum, G., Cherrier, M., & Saxon, A. J. (2005). A comparison of methamphetamine-dependent inpatients with and without childhood attention deficit hyperactivity disorder symptomatology. Journal of Addictive Diseases, 24(3), 133-152.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 5 of 16

Slide 6 of 16

This amphetamine use disorder study compared aripiprazole to methylphenidate. Methylphenidate, is a stimulant medication which is indicated for the treatment of ADHD, and that primarily acts similarly to cocaine. These two active medications were compared to placebo and they were treated for 20 weeks. The aripiprazole dose was 15 mg per day, and this was a slow-release form of methylphenidate that was titrated upward to 54 mg per day.

References:

Tiihonen, J., Kuoppasalmi, K., Föhr, J., Tuomola, P., Kuikanmäki, O., Vorma, H., Sokero, P., Haukka, J., & Meririnne, E. (2007). A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. American Journal of Psychiatry, 164(1), 160-162.

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Slide 7 of 16

So in the table, we're looking at the outcome as the percentage of urine drug screens that were positive for amphetamines. And you can see for placebo that was 82%. Whereas, for aripiprazole, it was even worse. It was 90% were positive which was a significant difference from placebo. And so, aripiprazole is not only not effective, it may make people worse. And then the methylphenidate actually outperformed placebo.

References:

Tiihonen, J., Kuoppasalmi, K., Föhr, J., Tuomola, P., Kuikanmäki, O., Vorma, H., Sokero, P., Haukka, J., & Meririnne, E. (2007). A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. American Journal of Psychiatry, 164(1), 160-162.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 7 of 16

Slide 8 of 16

So, there is a signal there that treating amphetamine use disorder with methylphenidate which has a slightly different mechanism of action may be somewhat beneficial.

References:

Tiihonen, J., Kuoppasalmi, K., Föhr, J., Tuomola, P., Kuikanmäki, O., Vorma, H., Sokero, P., Haukka, J., & Meririnne, E. (2007). A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. American Journal of Psychiatry, 164(1), 160-162.

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Slide 9 of 16

This study again looked at methylphenidate. In this case, it was for people who had co-occurring attention deficit hyperactivity disorder and amphetamine use disorder. In the study, they used much higher doses than were used in the study we just presented. So, this was osmotic-release methylphenidate, and they went between 96 mg per day up to 180 mg per day. There were 27 patients in each condition.

References:

Konstenius, M., Jayaram‐Lindström, N., Guterstam, J., Beck, O., Philips, B., & Franck, J. (2013). Methylphenidate for attention deficit hyperactivity disorder and drug relapse in criminal offenders with substance dependence: A 24‐week randomized placebo‐controlled trial. Addiction, 109(3), 440-449.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 9 of 16

Slide 10 of 16

And we're looking on the Y axis at the proportion of negative urine toxicology screens for amphetamine over the 24 study weeks. And you can see that the methylphenidate group performed, twice the number that the placebo group was getting. So, methylphenidate at higher doses is beginning to look really good.

References:

Konstenius, M., Jayaram‐Lindström, N., Guterstam, J., Beck, O., Philips, B., & Franck, J. (2013). Methylphenidate for attention deficit hyperactivity disorder and drug relapse in criminal offenders with substance dependence: A 24‐week randomized placebo‐controlled trial. Addiction, 109(3), 440-449.

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Slide 11 of 16

Here's one more methamphetamine use disorder study on methylphenidate that did not really look at whether people had attention deficit hyperactivity disorder or not. So, there were 28 people in each condition. In this case, they also used the 54 mg per day.

References:

Rezaei, F., Emami, M., Zahed, S., Morabbi, M., Farahzadi, M., & Akhondzadeh, S. (2015). Sustained-release methylphenidate in methamphetamine dependence treatment: A double-blind and placebo-controlled trial. DARU Journal of Pharmaceutical Sciences, 23(1).

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 11 of 16

Slide 12 of 16

Now, we're looking at percent positive urine drug screen. The black bars represent the methylphenidate group. The gray bars represent placebo. And you can see initially there wasn't much difference but as time goes on the patients treated with methylphenidate on average were giving a lower percentage of positive urine drug screens.

References:

Rezaei, F., Emami, M., Zahed, S., Morabbi, M., Farahzadi, M., & Akhondzadeh, S. (2015). Sustained-release methylphenidate in methamphetamine dependence treatment: A double-blind and placebo-controlled trial. DARU Journal of Pharmaceutical Sciences, 23(1).

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Slide 13 of 16

So, we have sufficient data now to suggest that methylphenidate may be a very useful treatment for methamphetamine use disorder. And we will need larger, multi-site, really well-performed randomized trials to confirm that because you see these studies are small studies. But in the meantime, it's something worth considering as an off-label treatment if nothing else is working.

References:

Konstenius, M., Jayaram‐Lindström, N., Guterstam, J., Beck, O., Philips, B., & Franck, J. (2013). Methylphenidate for attention deficit hyperactivity disorder and drug relapse in criminal offenders with substance dependence: A 24‐week randomized placebo‐controlled trial. Addiction, 109(3), 440-449.
Rezaei, F., Emami, M., Zahed, S., Morabbi, M., Farahzadi, M., & Akhondzadeh, S. (2015). Sustained-release methylphenidate in methamphetamine dependence treatment: A double-blind and placebo-controlled trial. DARU Journal of Pharmaceutical Sciences, 23(1).

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 13 of 16

Slide 14 of 16

So amphetamines as a replacement pharmacotherapy for methamphetamine use disorder do not show much benefit. In contrast, methylphenidate does show a positive signal for some extent for people who don't have ADHD but definitely for those who do have underlying ADHD which of course is common in this population.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 14 of 16

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Slide 15 of 16

And we need to study methylphenidate further in much larger studies before we could ever say that's your go-to medication for methamphetamine use disorder but there's certainly some promise there.

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 15 of 16

Slide 16 of 16

Stimulant Replacement Therapies for Methamphetamine and Amphetamine Use Disorder Slide 16 of 16

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Next Section

06. Antidepressants and Naltrexone for Methamphetamine Use Disorder

Learning Objectives:

After completing this activity, the learner will be able to:

Review the pathophysiology and clinical course of stimulant use disorder.
Discuss the appropriate use of psychotropic medications for the management of stimulant use disorder.
Cite specific strategies in the management of specific stimulant use disorders, such as methamphetamine and cocaine use disorders.

Original Release Date: 12/01/2021

Review and Re-release Date: 03/01/2024

Expiration Date: 04/01/2025

Expert: Andrew Saxon, M.D.

Medical Editor: Melissa Mariano, M.D

Relevant Financial Disclosures:

The following planners, faculty, and reviewers have the following relevant financial relationships with commercial interests to disclose:

Dr. Saxon has disclosed the following relationships:

Indivior, Inc.: Advisory board
UpToDate, Inc.: Section Editor
Indivior, Inc.: Advisory board
UpToDate, Inc.: Editor

All of the relevant financial relationships listed for these individuals have been mitigated.

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