MDMA and memory, addiction, and depression: dose-effect analysis

Madeline M. Pantoni,Stephan G. Anagnostaras,Kaitlin R. Van Alstyne,Jinah L. Kim

doi:10.1007/s00213-022-06086-9

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 behavioral 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 comprised mostly of single-dose studies and an assortment of methodologies, an empirical dose-ranging study on this topic is warranted.ObjectivesThe 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 behavioral assays of memory, addiction, and depression.MethodsWe systematically examined the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioral sensitization, conditioned place preference, and conditioned responding; and the Porsolt forced swim test in mice.ResultsHigh doses of MDMA (≥ 3 mg/kg) produced amnesia of fear conditioning memory, some evidence of an addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) had no effect on these behaviors.ConclusionsThe 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 dose 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.

Highlights

±3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational drug that shows substantial promise as a psychotherapeutic agent (Feduccia et al 2018; Sessa and Nutt 2015; UNODC 2020)
The current study aims to evaluate the conclusion from our systematic review that 3 mg/kg may be the threshold for MDMAinduced amnesia, and to further understand the dose-effect relationship of MDMA on behavioral assays of memory, addiction, and depression
We found that high doses of MDMA produced fear memory impairments, some evidence of an addictive potential, and antidepressant effects, while low doses of MDMA (≤ 1 mg/kg) did not

Summary

Introduction

±3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational drug that shows substantial promise as a psychotherapeutic agent (Feduccia et al 2018; Sessa and Nutt 2015; UNODC 2020). Low-dose MDMA (about 1 to 2 mg/kg) produces equivalent increases in plasma drug concentration and monoamine release in humans (oral administration) and rodents (parenteral administration) (Baumann et al 2007; Green et al 2012), but time of peak drug exposure is shorter in rodents (10 to 45 min; Baumann et al 2009) than in humans (about 145 min; Kolbrich et al 2008) This data justifies temporal scaling but not dose scaling between rodent and human MDMA studies (for further discussion, see Pantoni and Anagnostaras 2019). We systematically examine the effects of 0.01 to 10 mg/kg MDMA on Pavlovian fear conditioning; behavioral sensitization, conditioned place preference, and conditioned responding; and the Porsolt forced swim test in mice This range captures doses from one-tenth to ten times those used in recent clinical studies (approximately 1–2 mg/kg MDMA; Bouso et al 2008; Danforth et al 2018; Mithoefer et al 2011, 2013, 2018; Oehen et al 2013; Ot’alora et al 2018). Additional evidence suggests that psychostimulant-induced memory enhancement requires the combination of both DAT and NET inhibition (see Carmack et al 2014; Pantoni et al 2020)

Methods

Results

Conclusion