New Study: Immune System Changes Caused by Childhood Adversity Increase Susceptibility to Substance Use Disorders

I observed in a previous post  that  genetics, trauma, and substance-related changes in the brain are the “usual suspects” behind many substance use disorders.  The heritability of substance use disorders has been established through family, adoption, and twin studies that suggest  an individual’s risk tends to increase along with the degree of genetic relationship to an addicted relative and ranges from 0.39 for hallucinogens to 0.72 for cocaine. The impact  of substances on the brain is increasingly clear due to the proliferation of neuroimaging studies  that track changes in brain structure and function caused by psychoactive substances–changes that perpetuate continued use despite adverse consequences.

Now there is  a  study published in Biological Psychiatry in  May 2018,  conducted by researchers at the IRCCS Santa Lucia Foundation and University of Rome “La Sapienza,” Italy, that  focuses on the traumatic roots of substance use disorders and identifies a specific way in which   high levels of childhood stress   increase an individual’s sensitivity to psychoactive substances.

First a word about ACES:  Adverse Childhood Events

We’ve known for some time that adverse events that occur in childhood increase the likelihood of physical and mental disorders later in life. A study conducted by the Centers for Disease Control and Prevention (CDC) and Kaiser Permanente  and published in 1998 demonstrated that toxic  childhood stress leads to a myriad of  dramatic and highly destructive outcomes in adults, including a number  of life-threatening health conditions such as  obesity, heart disease, alcoholism, and drug use.  Subsequent research has reinforced these findings. Adverse childhood events  can include emotional abuse, physical abuse, sexual abuse, neglect, exposure to domestic violence, mental illness in the household and other highly stressful experiences. They may be acute events that occur between birth and age 18 or they may occur over a sustained period of time. While adverse events  can happen to anyone, they are far more frequent among children who live in poverty.

The American Pediatric Society observed in 2014 that  “ACEs may become toxic when there is “strong, frequent, or prolonged activation of the body’s stress response systems in the absence of the buffering protection of a supportive, adult relationship”  and affirmed that these impacts can last a lifetime.  The current study illuminates one of the ways in which  toxic stress  can permanently transform key biological processes  and predispose affected children to later problems with psychoactive substances. This interesting and important discovery concerns the impact of toxic stress on the immune system. The researchers used both animal and human subjects to demonstrate “that exposure to social stress at an early age permanently sensitizes… peripheral and brain immune responses to cocaine in mice”.

First, the authors explained that, because the human immune system is not fully developed at birth, it can change in significant ways during childhood, so that people have a greater response when they experience psychological and immune challenges later in life.  Then, they posed three questions:

  1. Does child maltreatment (CM) cause individuals to develop greater immune responses to cocaine?
  2. What are the acute effects of early stress on the immune system in the brain?
  3. Do these effects cause long-lasting susceptibility to cocaine?

Then, they  performed a series of  experiments in mice and humans in an attempt to answer these questions.

The animal studies showed that mice who were exposed to psychosocial stress (an intimidating adult mouse)   produced permanent changes in the peripheral and central immune system, rendering them more sensitive to a potent tumor promoter as well as  cocaine in adulthood.

Next, the researchers recruited individuals with a diagnosis of  cocaine use disorders who were currently abstinent and undergoing treatment for their disorders.  They assessed these subjects for exposure to childhood and/or adolescent maltreatment and used blood tests to evaluate whether genes that are mediators of innate immunity (and which were  significantly modulated in the experimental mice) were also altered in the human subjects.

The researchers observed significantly higher messenger RNA expression levels of these three genes in all cocaine-addicted individuals when they compared them with control subjects who did not have cocaine use disorders, “suggesting that chronic cocaine use has persistent inflammatory effects”. Most importantly though, when  the cocaine-dependent population was further  categorized by level of their  exposure to childhood maltreatment, differences in gene expression were driven  primarily by the group that reported exposure to severe maltreatment at an early age. The authors observed that, “These findings corroborate and expand earlier data on altered immune system in individuals who experience CM, demonstrating that an early life stress experience permanently changes the responsiveness of the peripheral immune system to a substance of abuse, such as cocaine. Moreover, if immune activation during early life stress was blocked using antibiotics, affected mice did not demonstrate cellular change or drug-seeking behavior.

According to senior researcher Valeria Carola, PhD:

 “Our work emphasizes once again the importance of the emotional environment where our children are raised and how much a serene and stimulating environment can provide them with an extra ‘weapon’ against the development of psychopathologies,”

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