Post-traumatic stress disorder (PTSD) is a widespread mental health condition – especially in Israel that has regularly been assailed by terrorism, missiles and all-out war, in addition to aging Holocaust survivors exposed to years of loss and suffering – that’s triggered by experiencing or witnessing terrifying events. Symptoms may include flashbacks, nightmares and severe anxiety, as well as uncontrollable thoughts about what they endured. 

Most people who go through traumatic events may have temporary difficulty adjusting and coping, but with time and good self-care, they usually get better. If the symptoms get worse, last for months or even years, and interfere with your day-to-day functioning, you may have PTSD.

Post-traumatic stress disorder symptoms may start within one month of a traumatic event, but sometimes symptoms may not appear until years after the event. These symptoms cause significant problems in social or work situations and in relationships and can also interfere with one’s ability to go about your normal daily tasks.

PTSD symptoms include intrusive memories, avoidance, negative changes in thinking and mood and changes in physical and emotional reactions. Symptoms can vary over time or vary from person to person; one may have more PTSD symptoms when stressed in general or when coming across reminders of what occurred. For example, you may hear a car backfire and relive combat experiences. Or you may see a report on the news about an assault and feel overcome by memories of what happened to you. 

PTSD is an incapacitating disorder in susceptible persons with no therapy that is effective for all. Especially puzzling is how transient exposure to trauma creates persistent long-term suffering from PTSD and why some people are susceptible to PTSD while others that were exposed to the same trauma remain resilient.

Epigenetic modifications are chemical marks written into DNA during fetal development to correctly program how our genes function in different organs that program their activity. However, research in the last two decades has suggested that these marks could also be affected and adjusted by experiences and exposures at different point of time during one’s life. 

Studies on humans have suggested that perhaps the initial trauma exposure results in “epigenetic alterations” that in turn mediate and embed the PTSD disorder. These ideas were based on analysis of blood DNA of humans with PTSD, but it was not known whether epigenetic changes play a causal role in the brain regions that are considered important for PTSD. 

A team of scientists from Bar-Ilan University (BIU) in Ramat gan (near Tel Aviv), led by Prof. Gal Yadid of the Goodman Faculty of Life Sciences and Gonda (Goldschmied) Multidisciplinary Brain Research Center, examined this question using an animal model for PTSD and discovered a new way for treating PTSD that might be applied to humans. Their findings were recently published in the prestigious Nature journal Molecular Psychiatry under the title “Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy.” 

The researchers first mapped “epigenetic DNA methylation marks” in a brain region that is important for PTSD. They found distinct epigenetic differences between animals that were exposed to trauma and were resilient and those animals that were exposed to trauma and were susceptible and developed PTSD-like behavior.

They found that an important “epigenetic” enzyme that transfers methyl groups onto DNA, called DNMT3A, is reduced in animals that are susceptible to PTSD. The researchers also searched for groups of genes whose methylation is altered in the PTSD susceptible animals and found that one group of genes is controlled by the retinoic acid receptor which is activated by vitamin A. Indeed, delivering DNMT3A or retinoic acid orphan receptor gene into the animal brains reverses the PTSD-like phenotypes, suggesting that these genes that are differentially methylated are responsible for PTSD behavior. 

Injecting human or even animal brains with genes is still not a feasible therapeutic option. Therefore, the authors tested whether nutritional supplements that mimic the activity of these genes could treat and reverse PTSD in susceptible animals. Since DNMT3A increases DNA methylation, the researchers used a natural product that donates methyl groups S-adenosylmethionine (SAMe) and to activate the retinoic acid receptor they treated the animals with vitamin A.  They found that combined treatment with the methyl donor SAM and retinoic acid reversed PTSD-like behaviors. 

The data suggest a novel approach to treatment of PTSD, which involves combining two natural products that modulate the epigenome. Importantly, epigenetic treatments reverse the underlying causes of the disorder on DNA and thus serve as a “cure” rather than temporary relief of symptoms. “Since these nutritional supplements are relatively nontoxic, they offer hope for a nontoxic treatment of PTSD that reverses the underlying genomic cause of the disease,” said Yadid. “Our data point to a novel approach to the treatment of PTSD, which is potentially translatable to humans.”