MDMA appears to confer resilience in a stress rodent model of chronic social defeat

A new experiment in Japan has shown that when mice are exposed to a state of chronic stress linked to social defeat, they develop a number of detrimental health problems. But these adverse health conditions were absent in mice that were repeatedly injected with MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy. The study was published in Psychiatric research.

MDMA is one of the most widely used recreational drugs in the world. It produces prosocial feelings and improves empathy and sociability. However, it is also known to produce hallucinogenic effects and facilitate a host of adverse mental health consequences with prolonged use. First created in Germany as part of the search for a possible appetite suppressant, it is now banned in most of the world.

On the other hand, a recent large study of American adults found that ecstasy use was associated with a reduced risk of psychological distress and suicidal thoughts. Another study that took place between 2015 and 2020 and included over 200,000 American adults linked ecstasy use to a decreased likelihood of severe psychological distress, depression and suicidal thoughts. This contrasts with use of the hallucinogenic drug LSD (lysergic acid diethylamide), which was linked to an increased likelihood of depression and suicidal thoughts in the same study.

Recent studies have also shed light on the potential use of MDMA as a treatment for post-traumatic stress disorder (PTSD). One study reported that ecstasy could produce a significant reduction in symptom intensity in patients with severe post-traumatic stress disorder compared to placebo. In their new study, lead researcher Youge Qu and her colleagues set out to examine whether repeatedly administering MDMA to mice would help them become resilient to the effects of chronic social defeat stress.

Chronic Social Defeat Stress (CSDS) is a protocol (scientific procedure) in which a mouse is exposed to a larger aggressive mouse in an enclosed space. This is followed by a confrontation between the two mice in which the mouse undergoing this treatment is defeated and forced into a subordinate position (social defeat).

As a rule, this procedure is repeated daily for 10 days. The chronic social defeat stress protocol is known to produce depression-like effects in mice exposed to it as well as a number of easily detectable effects, such as increased spleen weight and decreased preference for sucrose. This is the reason why it is widely used in mouse research.

This study was conducted on 7-week-old mice, while 13-week-old (thus larger) mice were used as aggressors. The mice had water and food available at all times. They were divided into three groups. The first group was a control. He received saline (instead of MDMA) and was not exposed to chronic social defeat stress. The second group was exposed to chronic social defeat stress for 10 days, each day using a different aggressive mouse and receiving saline solution. The third group was subjected to the chronic social defeat protocol and received MDMA.

At specific time points, the researchers assessed whether the mice lost the ability to feel pleasure (anhedonia) using a sucrose preference test (one of the expected effects of chronic social defeat stress treatment ). They also drew blood from their hearts at the end of treatment, stool samples to analyze the composition of microorganisms in their intestines, and measured levels of several compounds known to be indicators of adverse effects from the stress protocol. of chronic social defeat.

Mice that were exposed to the chronic social defeat protocol but were injected with saline instead of MDMA had increased spleen weight, which is one of the known adverse consequences of this protocol. These mice also had a reduced preference for sucrose, indicating anhedonia. Levels of other adverse effect indicators of chronic social defeat stress protocols were all elevated in mice that were injected with saline. All of these undesirable changes were absent in mice that received MDMA injections.

Additionally, the researchers found changes in the composition of gut microbes in mice that were subjected to the chronic social defeat stress protocol and injected with a saline protocol. These changes were absent in mice that underwent the same protocol, but were injected with MDMA. The researchers attributed these changes to the so-called gut-microbiota-brain axis, a mechanism of chemical pathways that enables the interaction between brain activity and gut microorganisms.

“The present study suggests that repeated MDMA use may be associated with resilience in mice subjected to CSDS via the gut-microbiota-brain axis. It is likely that abnormalities in the gut-microbiota-brain axis, including microbial-derived metabolites, may contribute to susceptibility to stress-related disorders. Finally, MDMA would be a prophylactic and therapeutic drug to prevent the onset of stress-related disorders”, conclude the researchers.

The study sheds light on the biochemical mechanisms of stress. However, it also has limitations that must be taken into account. Notably, the study did not provide evidence supporting the role of the gut-microbiota-brain axis in the development of stress resilience in mice given MDMA. Furthermore, it is unclear whether the mechanism by which the effects of MDMA were achieved in mice can be replicated in humans, and if so, whether it would be desirable.

The observed effect could just as well be drug-induced indifference to social situations instead of resilience. Indifference and neglect of social situations (such as jobs, family obligations, financial responsibilities, and other social responsibilities) in humans who use drugs is generally considered an adverse effect of drug use, even though it prevents the person from the effects of the stress that these situations could cause.

The article, “Repeated use of 3,4-methylenedioxymethamphetamine is associated with resilience in mice after chronic social defeat stress: a role of the gut-microbiota-brain axis”, was authored by Youge Qu, Akifumi Eguchi, Xiayun Wan, Li Ma, Lijia Chang, Jiajing Shan, Yong Yang, Chisato Mori, and Kenji Hashimoto.

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