Daily cannabis in adolescent mice leads to lasting changes in brain immune cells

Microglia responses to infection, social stress blunted


Philadelphia June 14, 2022

Research suggests that cannabis use in adolescence is not detrimental to health or behavior, although it carries some risks. Now a new study in mice shows that daily exposure to THC, the primary psychoactive ingredient in marijuana, can have subtle yet far-reaching consequences involving immune cells of the brain.

The study, led by Daniele Piomelli, PhD, appears in Biological Psychiatry, published by Elsevier.

Dr. Piomelli said, “More than 20% of teenagers who use cannabis do so daily. Our study, which was carried out in mice, suggests that this pattern of cannabis use causes lasting transcriptional changes in microglia – the main immune cell type found in the brain.”

John Krystal, MD, Editor of Biological Psychiatry, said of the work, "We are inclined to think that low doses of cannabis are benign, particularly among adolescents. However, this study, conducted in rodents, highlights a potential unappreciated risk. Microglia are the immune cells of the brain, and they are involved in the brain's response to infection and other insults. They also play a role in eliminating the synaptic connections of the brain during both development and aging.”

The researchers treated mice with delta9-tetrahydrocannabinol (THC) daily during a two-week period of adolescence and later assessed the effects on the brain’s microglia by performing transcriptomics, a method to see which genes cells are making into proteins. Thousands of genes were expressed differently in microglia from mice treated with THC compared to untreated mice even into adulthood, most of which were related to immune signaling.

In another experiment, some mice were exposed as adults to lipopolysaccharide (LPS), a bacterial endotoxin that raises a substantial immune response, before their microglia were collected. LPS caused transcriptional changes in microglial in normal mice, but this response was blunted in mice treated with THC.

“The changes [caused by THC] weaken microglia’s ability to mount an appropriate response to certain microbes, which could be detrimental to adult brain health,” said Dr. Piomelli.

In yet another arm of the study, the researchers exposed young adult male mice to a repeated social defeat protocol, a type of psychosocial stress that is known to activate microglia. As expected, control mice responded to this stress with microglial transcriptional changes related to stress hormones and inflammatory molecules, and the mice displayed behavioral changes. But THC-treated mice did not exhibit these changes.

“Even more strikingly,” said Dr. Piomelli, “the THC-evoked changes also cause microglia to become unresponsive to psychosocial stress. In normal mice, and probably in humans, psychosocial stress activates microglia, triggers the release of stress hormones and proinflammatory cytokines, increases anxiety, and reduces sociability. In mice treated with THC in adolescence, this response disappears. The inability to react appropriately to stress could be problematic in young adults whose neuroimmune system is still learning to cope with stressful events.”

Dr. Krystal concluded, “This study conducted in rodents suggests that even though individual low doses of cannabis may not have obvious negative effects on behavior, repeated exposure to its principal constituent, THC, may disrupt microglial function in the brain. Because these cells are involved in both immune responses and in synaptic elimination, there could be important implications of regular low doses of cannabis during adolescence for brain and behavioral health."

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Notes for editors

The article is "Frequent low-dose Δ9 -tetrahydrocannabinol in adolescence disrupts microglia homeostasis and disables responses to microbial infection and social stress in young adulthood," by Hye-Lim Lee, Kwang-Mook Jung, Yannick Fotio, Erica Squire, Francesca Palese, Lin Lin, Alexa Torrens, Faizy Ahmed, Alex Mabou Tagne, Jade Ramirez, Shiqi Su, Christina Renee Wong, Daniel Hojin Jung, Vanessa Scarfone, Pauline Nguyen, Marcelo Wood, Kim Green, and Daniele Piomelli (https://doi.org/10.1016/j.biopsych.2022.04.017). It appears as an Article in Press in Biological Psychiatry, published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at Biol.Psych@sobp.org or +1 254 522 9700. Journalists wishing to interview the authors may contact Daniele Piomelli at piomelli@hs.uci.edu or Anne Ward at awarde@hs.uci.edu or +1 949 824 6357.

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article. The study was supported by a Center of Excellence grant from the National Institute on Drug Abuse (P50DA044118).

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry

Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

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Rhiannon Bugno, Editorial Office
Biological Psychiatry
+1 254 522 9700
Biol.Psych@sobp.org