MDMA and memory, addiction, and depression: dose-effect analysis
This rodent study (2022) assessed the effects of varying doses of MDMA (0.01 to 10mg/kg) on a number of fear conditioning variables. High doses of MDMA (≥ 3mg/kg) produced amnesia of fear conditioning memory, some evidence of addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1mg/kg) had no effect on these behaviours. These findings suggest that the therapeutic use of MDMA below 3mg/kg is less likely to produce significant adverse cognitive effects.
Authors
- Pantoni, M. M.
- Kim, J. L.
- Van Alstyne, K. R.
Published
Abstract
Rationale
±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that shows substantial promise as a psychotherapeutic agent. Still, there is some concern regarding its behavioural toxicity, and its dose-effect relationship is poorly understood. We previously explored the role of dose in the cognitive effects of MDMA in a systematic review of existing literature and found no evidence in animals that MDMA impairs memory at low doses (< 3 mg/kg) but mixed results at high doses (≥ 3 mg/kg). Since this review is comprised mostly of single-dose studies and an assortment of methodologies, an empirical dose-ranging study on this topic is warranted.
Objectives
The current study aims to evaluate the conclusion from our systematic review that 3 mg/kg may be the threshold for MDMA-induced amnesia and to further understand the dose-effect relationship of MDMA on behavioural assays of memory, addiction, and depression.
Methods
We systematically examined the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioural sensitization conditioned place preference and conditioned responding, and the Porsolt forced swim test in mice.
Results
High doses of MDMA (≥ 3 mg/kg) produced amnesia of fear conditioning memory, some evidence of addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) had no effect on these behaviours.
Conclusions
The present dose-ranging study provides further evidence that 3 mg/kg is the threshold for MDMA-induced amnesia. These findings, in addition to our systematic review, demonstrate that careful selection of MDMA doses is critical. High doses (≥ 3 mg/kg) should likely be avoided due to evidence that they can produce amnesia and addiction. Conversely, there is little evidence to suggest that low doses, which are usually administered in clinical studies (approximately 1-2 mg/kg), will lead to these same adverse effects. Ultra-low doses (< 1 mg/kg) are likely even safer and should be investigated for therapeutic effects in future studies.
Research Summary of 'MDMA and memory, addiction, and depression: dose-effect analysis'
Introduction
MDMA (±3,4-methylenedioxymethamphetamine) is described as a recreational drug with growing evidence for psychotherapeutic utility, notably for disorders where prosocial effects (increased empathy, trust and sociality) may aid treatment. However, there remain concerns about behavioural toxicity, specifically potential effects on memory, addiction liability and mood, and a persistent gap in dose–response data. Pantoni and colleagues previously conducted a systematic review that found no evidence of memory impairment at low doses (< 3 mg/kg) in animal studies but mixed findings at higher doses (≥ 3 mg/kg); that review largely comprised single-dose and heterogeneous studies, motivating a controlled, empirical dose-ranging investigation. This study set out to test the hypothesis that 3 mg/kg represents a threshold for MDMA-induced amnesia and to characterise dose–effect relationships of MDMA across assays modelling memory (Pavlovian fear conditioning), addiction-related behaviours (behavioural sensitization, conditioned place preference, conditioned responding) and depressive-like behaviour (Porsolt forced swim test) in mice. Doses spanned 0.01–10 mg/kg to cover approximately one-tenth to ten times the doses used in recent clinical studies, and the authors justify direct body-weight scaling between rodents and humans for dose selection unless pharmacokinetic evidence dictates otherwise.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Create a free account to open full-text PDFs.
Study Details
- Study Typemeta
- Journal
- Compound
- Topics
- APA Citation
Pantoni, M. M., Kim, J. L., Van Alstyne, K. R., & Anagnostaras, S. G. (2022). MDMA and memory, addiction, and depression: dose-effect analysis. Psychopharmacology, 239(3), 935-949. https://doi.org/10.1007/s00213-022-06086-9
References (23)
Papers cited by this study that are also in Blossom
Bershad, A. K., Miller, M. A., Baggot, M. J. et al. · Journal of Psychopharmacology (2016)
Bouso, J. C., Doblin, R., Farré, M. et al. · Journal of Psychoactive Drugs (2008)
Danforth, A. L., Grob, C. S., Struble, C. et al. · Psychopharmacology (2018)
Dolder, P. C., Müller, F., Schmid, Y. et al. · Psychopharmacology (2017)
Feduccia, A. A., Mithoefer, M. C. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2018)
Feduccia, A. A., Jerome, L., Yazar-Klosinski, B. et al. · Frontiers in Psychiatry (2019)
Heifets, B. D., Malenka, R. C. · Cell (2016)
Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)
Kamilar-Britt, P., Bedi, G. · Neuroscience and Biobehavioral Reviews (2015)
Liechti, M. E., Gamma, A., Vollenweider, F. X. · Psychopharmacology (2001)
Show all 23 referencesShow fewer
Mitchell, J., Bogenschutz, M. P., Lilienstein, A. et al. · Nature Medicine (2021)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2010)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2012)
Mithoefer, A. T., Mithoefer, M. C., Feduccia, A. A. et al. · Lancet Psychiatry (2018)
Mithoefer, M. C., Feduccia, A. A., Jerome, L. et al. · Psychopharmacology (2019)
Nichols, D. E. · Journal of Psychoactive Drugs (1986)
Oehen, P., Traber, R., Widmer, V. et al. · Journal of Psychopharmacology (2012)
Ot'alora G, M., Grigsby, J., Poulter, B. et al. · Journal of Psychopharmacology (2018)
Sessa, B., Nutt, D. J. · British Journal of Psychiatry (2015)
Wagner, M. T., Mithoefer, M. C., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2017)
Yazar-Klosinski, B., Mithoefer, M. C. · Clinical Pharmacology and Therapeutics (2016)
Young, M. B., Andero, R., Ressler, K. J. et al. · Translational Psychiatry (2015)
Young, M. B., Norrholm, S. D., Khoury, L. M. et al. · Psychopharmacology (2017)
Cited By (3)
Papers in Blossom that reference this study
Sarmanlu, M., Kuypers, K. P. C., Vizeli, P. et al. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2023)
Warner-Schmidt, J., Pittenger, C., Stogniew, M. et al. · Frontiers in Psychiatry (2023)
Sottile, R. J., Vida, T. · Frontiers in Psychiatry (2022)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.