Biological roots of PTSD differ strikingly between men and women

A new analysis of blood samples from patients with posttraumatic stress disorder reveals that the condition may be driven by fundamentally different biological mechanisms in men compared to women. Researchers found that men with the disorder primarily exhibit deficits in specific stress-regulating lipids, whereas women exhibit heightened signs of systemic inflammation. These results were published in the journal Progress in Neuropsychopharmacology & Biological Psychiatry.

Posttraumatic stress disorder, or PTSD, is a psychiatric condition that develops in some individuals following exposure to severe or life-threatening events. It is well established that the disorder does not affect the population uniformly. Women are diagnosed with the condition at nearly twice the rate of men. Women also tend to suffer from longer-lasting symptoms and have higher rates of co-occurring health issues, such as autoimmune diseases. Despite these clear disparities, the biological reasons for this gender gap have remained elusive.

Medical researchers have historically focused on two specific internal networks when studying the effects of trauma. The first is the endocannabinoid system. This network functions as a physiological buffer against stress. It utilizes lipid-based messengers to help the brain process fear, regulate emotional behavior, and return the body to a state of calm after a threat has passed. When this system is working correctly, it aids in the extinction of fear memories.

The second network of interest is the immune system. In times of acute stress or injury, the body releases inflammatory proteins known as cytokines. While this is a protective measure in the short term, chronic inflammation can become maladaptive. Sustained immune activation is known to negatively influence brain circuits that regulate mood and arousal.

Most prior investigations into the biology of trauma have studied these two systems in isolation. Many older studies also combined data from male and female participants, which can obscure sex-specific patterns. To address these gaps, a team led by Primavera A. Spagnolo at the Department of Psychiatry, Brigham and Women’s Hospital and Harvard Medical School designed a study to analyze both systems simultaneously. The researchers aimed to determine if the molecular fingerprints of the disorder differ based on biological sex.

The research team utilized data and samples from the Mass General Brigham Biobank. They retrospectively selected a cohort of 173 individuals for analysis. This group was engineered to be balanced, consisting of 90 men and 83 women. Approximately half of the participants had a confirmed medical diagnosis of PTSD. The other half served as a healthy control group with no history of psychiatric illness.

The investigators analyzed serum samples to measure the circulating concentrations of key molecules. To assess the stress-buffering system, they measured levels of endocannabinoids. These included anandamide, a molecule essential for mood regulation, and 2-arachidonoylglycerol. They also measured related lipids like oleoylethanolamide and arachidonic acid. To assess immune status, the team quantified levels of several pro-inflammatory markers, including C-reactive protein and various interleukins.

The analysis revealed distinct molecular profiles that varied significantly by sex. Men diagnosed with PTSD showed a marked depletion of endocannabinoids compared to healthy men. Specifically, they had lower levels of anandamide, arachidonic acid, and oleoylethanolamide. This suggests that in males, the pathophysiology of the disorder is linked to a breakdown in the body’s natural ability to chemically buffer stress.

The male patients did not exhibit widespread immune dysregulation. When compared to the healthy male control group, the men with PTSD showed normal levels for most inflammatory markers. The only exception was tumor necrosis factor-alpha, which was elevated.

A completely different biological picture emerged among the female participants. Women with PTSD did not show the depletion of anandamide or arachidonic acid seen in the male group. Their endocannabinoid levels remained largely comparable to healthy women. In fact, one lipid called 2-arachidonoylglycerol was found at slightly higher levels in the female patient group.

Instead of a lipid deficit, the female patients displayed a profile characterized by overactive inflammation. Women with the disorder had significantly higher concentrations of interleukin-6 and interleukin-8 compared to healthy women. They also showed elevated levels of tumor necrosis factor-alpha. This indicates that for women, the disorder is more closely associated with a persistent state of immune activation.

The researchers performed additional statistical checks to ensure the robustness of these findings. They accounted for a common genetic variation in the FAAH gene. This gene produces an enzyme responsible for breaking down anandamide. Even after controlling for participants’ genotypes, the sex-based divergence remained clear.

The team also examined a subgroup of patients who suffered from major depressive disorder alongside their PTSD. Depression is a common comorbidity that shares many biological features with trauma disorders. The study found that the sex-specific patterns held true in this subgroup as well. Men with both conditions showed low endocannabinoids, while women with both conditions showed high inflammation.

These findings offer a potential explanation for why certain experimental treatments for PTSD have failed in the past. Several clinical trials have tested drugs designed to boost endocannabinoid levels by inhibiting the enzyme that destroys them. These trials have largely been unsuccessful. Spagnolo and her colleagues note that these trials often enrolled a majority of female participants.

If women with PTSD do not suffer from a deficit of endocannabinoids, treatments aimed at replenishing them would likely be ineffective. Conversely, such treatments might be highly beneficial for men, who show a clear deficiency. This study suggests that future therapeutic approaches must be tailored to the sex of the patient. Treatments for women might need to focus on dampening the inflammatory response.

There are limitations to this study that contextualize the results. The researchers used a retrospective design based on electronic health records. They did not conduct real-time clinical interviews to assess the current severity of symptoms. They also lacked data on the timing of the original trauma or childhood adversity.

Additionally, the study did not measure levels of sex hormones like estradiol at the time of blood collection. Estradiol is known to influence both the immune system and endocannabinoid signaling. Spagnolo and her team hypothesize that hormonal fluctuations may play a role in the “multiple-hit” mechanism that makes women more vulnerable to these changes.

The authors recommend that future research should track these biological markers prospectively. They suggest utilizing stress-provoking experimental tasks to see how these systems react in real time. Confirming these distinct pathways could pave the way for precision medicine in psychiatry. The study highlights the necessity of moving beyond a “one size fits all” approach to mental health treatment.

The study, “Sex differences in endocannabinoid and inflammatory markers associated with posttraumatic stress disorder,” was authored by Therese A. Rajasekera, Anna Joseph, Hui Pan, Jonathan M. Dreyfuss, Doruntina Fida, Julia C. Wilson, Madeline Behee, Raina N. Fichorova, Resat Cinar, and Primavera A. Spagnolo.