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.

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.”

Authors: Madeline M. Pantoni, Jinah L. Kim, Kaitlin R. Van Alstyne & Stephen G. Anagnostaras

Summary

Abstract

A systematic review of existing literature found no evidence in animals that MDMA impairs memory at low doses, but mixed results at high doses. An empirical dose-ranging study is warranted.

MDMA is a widely used recreational drug that shows substantial promise as a psychotherapeutic agent. It increases extracellular levels of serotonin, norepinephrine, and dopamine by reversing their transporters and also exhibits some affinity for 5-HT, DA, muscarinic, histamine, and adrenergic receptors.

MDMA has prosocial effects that distinguish it from psychostimulants and hallucinogens. MDMA may enhance the effectiveness of psychotherapy for psychiatric conditions such as social anxiety and autism spectrum disorders or even improve social behavior as a stand-alone treatment.

Despite MDMA’s apparent therapeutic promise, there is some concern regarding its behavioral toxicity, such as the potential to elicit memory impairments, addiction, and depressed mood. A dose-ranging study is warranted to further understand the dose-effect relationship of MDMA on behavioral assays of memory, addiction, and depression.

We have argued that doses should be scaled between animals and humans directly by body weight, but that temporal scaling should be used instead of dose scaling. Here, 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 in mice.

Psychostimulants enhance fear memory at low, clinically relevant doses, but impair it at high, abused doses. Citalopram, a highly selective serotonin reuptake inhibitor, has no effect at low doses, but enhances fear memory at high, abused doses.

Behavioral sensitization, conditioned place preference, and conditioned responding are behaviors that reflect the addictive potential of a drug. These behaviors are dose-dependent and are caused by the action of high-dose psychostimulants at DAT and the ensuing increase in extracellular DA levels.

In the forced swim test, animals are placed into a tank filled with water and their time spent mobile versus immobile is measured. Common antidepressants decrease immobility behavior.

MDMA has been shown to produce behavioral sensitization and fear memory impairments in rodents at doses of 2 to 40 mg/kg, but not at doses lower than 4 mg/kg.

In a previous study, mice treated with 3 mg/kg or 10 mg/kg of MDMA showed conditioned place preference, but not at 1 mg/kg or 3.3 mg/kg. In the present study, we examined the effects of low-dose MDMA on several behavioral tasks.

Methods

184 hybrid C57BL/6Jx129S1/SvImJ (129B6) mice were used for fear conditioning, 45 were used for behavioral sensitization, conditioned place preference, and conditioned responding, and 79 were used for the forced swim test. All animal care and experimental procedures were approved by the UCSD IACUC.

Four mice were tested concurrently in individual conditioning chambers that consisted of stainless-steel sidewalls and rod floors, white acrylic back walls, and clear polycarbonate front and top walls. The chambers were transformed across multiple sensory dimensions to create two distinct contexts.

Mice were given an injection of MDMA 30 min before a 10-min training session, which consisted of a 3-min baseline period followed by a single tone-shock pairing. The mice were then given a 5-min post-shock test to measure on-drug short-term memory.

Mice were tested for long-term context memory and long-term tone memory seven days after training.

Eight mice were tested concurrently in individual place preference chambers. They were separated by a black wall with a removable insert and were visually and tactilely distinct as they differed by flooring and wall combinations.

Forty-five mice were randomly assigned to four groups by dose of MDMA administered: 0 (n = 12), 0.1 (n = 10), 1 (n = 11) or 10 (n = 12) mg/kg. They were habituated to the testing chamber, off drug, for 30 min per side per day for 2 consecutive days prior to training.

Twenty-four hours after the last training day, mice were tested for conditioned place preference. Place preference was calculated as the difference between responses on the paired side versus the unpaired side.

Mice were injected with saline and then a high dose of MDMA 48 hours after the last training day. Locomotor, stereotyped, and vertical activity were scored to evaluate conditioned responding to the drug-paired side.

Five mice were tested concurrently in individual cylindrical beaker-like glass tanks filled with water to a depth of 15 cm. Immobility was measured using an HD USB video camera and behavioral tracking software.

Seventy-nine mice were randomly assigned to different groups and given a dose of MDMA 30 min before testing. The time spent immobile was scored during the last 4 min to evaluate potential antidepressant effects.

Statistical analyses were performed on data from repeated measures, within-subjects and between-subjects experiments. Fisher’s least significant difference tests were used to compare group differences against the saline control group.

Results

MDMA weakly dose-dependently modulated locomotor activity during the training baseline period, and dose-dependently modulated freezing during the on-drug post-shock, off-drug context, and off-drug tone tests. Only mice previously given 3 or 10 mg/kg MDMA exhibited reduced freezing during the post-shock test.

Mice were trained for 7 days in a two-sided chamber and then injected with MDMA. On day 7, MDMA significantly increased locomotor, stereotyped, and vertical activity compared to saline controls.

Mice receiving 10 mg/kg MDMA showed significantly increased locomotor, stereotypic, and vertical activity compared to saline controls, and these effects were observed on the last 5 days of training but not the first 2 days.

Only mice receiving 10 mg/ kg MDMA exhibited a significant increase in locomotion, stereotypy, and vertical activity from day 1 to day 7 when compared to saline controls.

Twenty-four hours after the last training day, no significant group differences were found in distance traveled or time spent between sides. Additionally, none of the groups exhibited place preference in locomotor activity.

Mice trained with 10 mg/kg MDMA exhibited a conditioned response (CR) or sensitization (S) as measured by increased locomotion following the saline challenge and the high-dose MDMA challenge.

MDMA dose-dependently modulated immobility in the forced swim test. Only mice given 3 or 10 mg/kg MDMA exhibited reduced immobility relative to saline controls.

Discussion

The present study provides further evidence for the critical role of dose selection in the behavioral effects of MDMA. High doses of MDMA should be avoided for their amnesic effects and addictive potential, while low doses are likely safe.

A dose-effect analysis of MDMA showed that 3 mg/kg MDMA impairs memory at low, clinically relevant doses, but that 10 mg/kg MDMA impairs memory at high doses. Further investigation is required to isolate the nature of the observed memory impairments.

We did not detect any MDMA-induced fear memory enhancements at low, clinically relevant doses, but high-dose MDMA has been reported to enhance fear memory extinction. Further research should investigate the effects of low-dose MDMA on fear extinction.

High-dose psychostimulants such as MDMA have been shown to elicit dramatic locomotor stimulation, behavioral sensitization, conditioned place preference, and conditioned responding, but not acute locomotor stimulation or conditioned place preference. Females are more sensitive than males to the psychological effects of MDMA.

The place preference observed in mice treated with MDMA at high doses is inconsistent with previous reports that MDMA induces place preference at high doses. The place preference observed in mice treated with MDMA is also far weaker than that observed in previous psychostimulant studies.

There are opposing views regarding how MDMA modulates depressive symptoms. Recent clinical studies suggest that MDMA has antidepressant properties.

Acute MDMA-induced antidepressant effects were detected at high, memory-impairing doses of 3 and 10 mg/kg but not at lower doses of 0.1, 0.5, and 1 mg/kg. Low-dose MDMA may also have other therapeutic effects such as increased sociality or openness that facilitate the clinical improvements observed following MDMA-assisted psychotherapy.

MDMA’s therapeutic effects are mediated by the serotonergic system, whereas its addiction-related effects are primarily mediated by the dopaminergic system. MDMA binding at DAT and the consequent increase in DA release are required for MDMA’s rewarding effects.

At low doses, MDMA stimulates 5-HT release and little to no dopamine release, whereas at high doses, MDMA stimulates both 5-HT and DA release. MDMA induces addiction-related behaviors at high doses that correlate with substantial dopamine release.

We found that therapeutic use of MDMA below 3 mg/kg is less likely to produce significant adverse cognitive effects. However, future studies should consider exploring ultra-low doses of MDMA, which may be even safer and as effective compared to low doses.