A new experiment in Japan showed that when mice are exposed to a chronic social defeat stress condition, they develop a number of adverse health conditions. But these adverse health conditions were absent in mice that were repeatedly injected with MDMA (3,4-Methylenedioxymethamphetamine), also known as the club drug ecstasy. The study was published in Psychiatry Research.
MDMA is one of the most widely used recreational drugs in the world. It produces prosocial feelings and enhances empathy and sociability. However, it is also known to produce hallucinogenic effects and to facilitate a host of adverse mental health consequences through prolonged use. Created first in Germany in the scope of researching a possible appetite suppressor, it is now banned in most of the world.
On the other hand, a large recent study of U.S. adults found that ecstasy use was associated with lowered odds of psychological distress and suicidal thoughts. Another study that ran between 2015-2020 and included over 200,000 U.S. adults linked the use of ecstasy with decreased likelihood of serious psychological distress, depression and suicidal thinking. This was in contrast with the use of hallucinogenic drug LSD (lysergic acid diethylamide), which was linked to increased likelihood of depression and suicidal thinking in the same study.
Recent studies have also brought into focus the potential use of MDMA as a treatment for post-traumatic stress disorder (PTSD). A study reported that ecstasy could produce significant reduction in the intensity of symptoms in patients with severe posttraumatic stress disorder compared to placebo. In their new study, lead researcher Youge Qu and her colleagues wanted to examine whether repeatedly giving 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).
Typically, this procedure is repeated daily over 10 days. The chronic social defeat stress protocol is known to produce effects similar to depression in mice exposed to it along with a number of easily detectable effects, such as increased weight of spleen and lower preference for sucrose. That is the reason it is extensively used in research on mice.
This study was conducted on mice aged 7 weeks, while mice aged 13 weeks (therefore larger) were used as aggressors. Mice had water and food available at all times. They were divided into three groups. The first group was a control. It was given a saline solution (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 larger aggressor mouse and given a saline solution. The third group was subjected to the chronic social defeat protocol and given MDMA.
At specific points, the researchers assessed whether mice lost the ability to feel pleasure (anhedonia) using a sucrose preference test (one of the expected effects of the chronic social defeat stress treatment). They also collected blood from their hearts at the end of the treatment, stool samples to analyze the composition of microorganisms in their guts, and measured levels of several compounds that are known to be indicators of adverse effects of the chronic social defeat stress protocol.
Mice that were exposed to the chronic social defeat protocol, but received a saline injection instead of MDMA had increased spleen weights, which is one of the known adverse consequences of this protocol. These mice also had reduced preference for sucrose, indicating anhedonia. Levels of other indicators of adverse effects of the chronic social defeat stress protocols were all elevated in mice that were injected with a saline solution. All these adverse changes were absent in mice that were receiving MDMA injections.
Additionally, the researchers found changes in the composition of the gut microbes in mice that were subjected to the chronic social defeat stress protocol and injected with saline protocol. These changes were absent in mice that underwent the same protocol, but were being injected with MDMA. The researchers attributed these changes to the so-called gut-microbiota-brain axis, a mechanism of chemical pathways that allow interaction between brain activity and microorganisms in the gut.
“The present study suggests that repeated use of MDMA might be associated with resilience in mice subjected to CSDS through gut–microbiota–brain axis. It is likely that abnormalities in gut–microbiota–brain axis including microbes-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,” the researchers concluded.
The study sheds light on the biochemical mechanisms of stress. However, it also has limitations that need to be taken into account. Notably, the study did not provide evidence supporting the role of the gut-microbiota-brain axis in developing stress resilience in mice that received MDMA. Additionally, it remains unknown whether the mechanism through which the effects of MDMA were achieved in mice can be reproduced in humans and if they can, whether they would be desirable.
The observed effect might 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 consuming drugs is generally seen as an undesirable effect of drug use even if it does save the person from the effects of stress that these situations might cause.
The paper, “Repeated use of 3,4-methylenedioxymethamphetamine is associated with the resilience in mice after chronic social defeat stress: A role of 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.