Trials in rats have renewed hope for the first treatment to reverse the lasting effects of prenatal opioid exposure.
New UNSW research published in Translational Psychiatry shows a gut supplement can repair opioid-related damage in rat pups, raising hopes for a future treatment for babies exposed to opioids in the womb.
The pups of pregnant rats given methadone, a type of opioid often used to manage withdrawal symptoms, showed behavioural and health issues similar to those associated with babies exposed to opioids before birth.
However, pups simultaneously treated with sodium butyrate, a compound naturally produced in the gut when dietary fibre is broken down, showed marked improvements. In some tests, they performed as well as pups that had never been exposed to methadone.
“For the first time, we've shown it may be possible to reverse some of the lasting effects of opioid exposure before birth,” says Associate Professor Kelly Clemens from UNSW Sydney’s School of Psychology.
The study is part of a broader research project, led by A/Prof Clemens, aimed at improving the life outcomes of babies born to mothers using opioids.
“Opioids affect multiple internal systems in both a pregnant mother and her baby, including the brain, as well as the gut, where they disrupt the microbiota,” says A/Prof. Clemens.
The microbiota, a community of microbes in the gut, plays a vital role in producing short-chain fatty acids like butyrate, which help regulate immune function, and brain development.
“Beyond the immediate withdrawal symptoms seen after birth, growing evidence suggests that opioid exposure in utero can lead to subtle but lasting developmental challenges, including difficulties with attention, anxiety, learning, and impulse control,” says A/Prof. Clemens.
“The animal studies are the first to show that butyrate can repair damage across a broad spectrum of these outcomes.”
While A/Prof. Clemens cautions that further research is needed before human trials begin, she says the results raise the possibility for one day developing the first ever treatment to prevent or reverse harm from opioid exposure in children.
Dr Isobel Williams, who led the experiments as part of her doctoral research at UNSW, explains: “In people using opioids, the balance of gut bacteria is disrupted, and butyrate production drops. We wanted to see if replacing that missing butyrate could make a difference in rats because their biology closely mimics our own.”
Testing butyrate's potential
Pregnant rats were divided into groups. About half received methadone from mid-pregnancy through birth and early nursing, simulating prenatal opioid exposure. Some were also given sodium butyrate, either alone or alongside methadone.
Their offspring were monitored from birth through adolescence and adulthood.
Those pups and mothers exposed to methadone showed significant disruptions in their microbiota, and the genetic codes needed to produce butyrate. Supplementing with sodium butyrate reversed some of these disruptions.
As the pups grew, they took a series of tests designed to simulate the learning and behaviour effects observed in children exposed to opioids in the womb.
“We were honestly surprised by how broad the improvements were,” Dr Williams says. “It wasn’t just one area, we saw benefits across memory, attention, and even brain structure.”
When placed in the centre of a plastic tub, the methadone-exposed pups showed more signs of fear and stress. While sodium butyrate didn’t eliminate all signs of anxiety, it restored exploratory behaviours linked to learning and curiosity.
In cognitive tests, rats had to remember and identify which of two lights appeared in a grid, challenging their working memory and ability to distinguish similar patterns. Methadone-exposed rats struggled, especially with closely spaced lights or delayed cues.
Another task measured attention and impulse control by training rats to poke their noses into specific holes only when a light appeared to receive food. Methadone-exposed rats missed more cues and responded prematurely - signs of poor attention and increased impulsivity.
Methadone-exposed pups showed brain tissue damage, with reduced levels of myelin - a fatty substance that insulates nerve fibres, supporting brain communication. But those treated in tandem with sodium butyrate showed large improvements in their myelin levels.
However, the study found butyrate appeared to do more harm than good when administered to healthy pregnant rats not receiving methadone.
In these healthy pregnant rats, butyrate disrupted the gut microbiome, immune system, and maternal behaviour, leading to small but lasting impacts on the learning and behaviour of their pups.
“Butyrate appears to counteract some of the effects of opioids across multiple systems in both the mother and her baby. However, these interactions are complex, and introducing the supplement could potentially disrupt the balance in otherwise healthy systems,” says A/Prof. Clemens.
She adds that the study sheds new light on a growing body of research linking gut microbiome disturbances to various disorders, like autism and schizophrenia.
The next step for A/Prof. Clemens and her team will be securing funding for further animal trials, and she says there are still plenty of questions as to how butyrate could be used in a treatment.
“Is early pregnancy the key window? Can it help if given after birth? Or even in adolescence, when brain development undergoes another major reorganisation?
“These are big questions. But if we can answer them, we might finally have a way to help a group of children who’ve been left behind for far too long.”
Opioid’s long shadow
The team is currently working with clinicians at hospitals in Sydney and Brisbane to monitor gut health and developmental outcomes in babies born to mothers using opioids. The hope is that one day, sodium butyrate, or a related therapy, could protect these babies from the worst outcomes.
Senior Neonatologist Professor Ju Lee Oei is a clinical partner on the project, who works at The Royal Hospital for Women in Sydney and the Mater Research Institute in Brisbane.
In the mid-1990s, amid a heroin crisis, her team established the world’s first outpatient clinic to prescribe methadone to opioid-exposed newborns after hospital discharge. Methadone helps ease withdrawal symptoms in affected babies, allowing them to be gradually weaned off opioids under medical supervision.
“In the past, if a baby was withdrawing and no one recognised it, they’d likely be sent home and die,” says Prof Oi.
“These children often came from poorer parts of the community and were invisible.”
While methadone can be a lifesaving treatment for babies experiencing withdrawal, Prof. Oei says clinicians are increasingly recognising the broader long-term challenges associated with prenatal opioid exposure.
“Now that we know how to treat withdrawal, we’re more aware, and we’re seeing other long-term issues.”
Including, she says, eye problems, infections, and neurodevelopmental issues.
“It’s like having a chronic health condition, like being born premature or with cancer. You manage and support the child, but the condition is still there.
“Right now, our interventions are very prolonged and intensive - we’re talking about years of therapy for babies at risk of neurodevelopmental problems.
“But in our population, that’s often not possible. Families are mobile, unstable, and by the time the child is five, about half are already in out-of-home care.
“Having a “magic bullet” treatment that could repair or protect the brain before the baby is even born would be incomparable.”
And, she says, even though that treatment might still be some time away, there is a lot to celebrate from the recent animal study.
“Isobel’s animal study brings together so many aspects of the disruption opioids cause in the developing brain. It shows us what's happening and gives us a potential path forward.”
Ends
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