Low-dose hydrocortisone improves attention, learning in women with HIV, trial finds

A single 10 mg dose of oral hydrocortisone improved attention and verbal learning within hours in virally suppressed women with HIV, and daily dosing over four weeks was linked to gains in delayed memory recall, according to a randomized clinical trial published recently in JAMA Network Open.

Why researchers targeted the stress hormone system

Women with HIV report high rates of trauma, chronic stress and depression, all of which are linked to persistent cognitive impairment, particularly in verbal learning and memory. A possible cause of impairment is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the body's central stress-response system. The HPA axis governs cortisol, the hormone that shapes learning, memory and attention through its effects on the hippocampus and prefrontal cortex. Hydrocortisone is chemically identical to cortisol, and researchers hypothesized that a low, controlled dose could help modulate the HPA axis and glucocorticoid receptor signaling, potentially through reduced inflammation among other pathways. Currently, no interventions directly target that pathway in women with HIV.

The study was conducted by a group of researchers, including Leah H. Rubin, Ph.D., M.P.H., professor at Johns Hopkins University. Rubin and her colleagues enrolled 81 virally suppressed women with HIV, who were an average of 55 years old. Most participants identified as Black or African American (90.1%) and all participants self-reported stress, a mood or anxiety disorder or both and had measurable impairment in at least 1 cognitive domain, such as attention or executive function, the study says.

This study had two phases. The first was a double-blind, placebo-controlled crossover phase that tested the cognitive effects of a single 10-mg oral dose of low-dose hydrocortisone (LDH) at 30 minutes and at 4 hours. In the second phase, participants took daily LDH or placebo for four weeks.

What the trial found

At 30 minutes after dosing, Rubin and her team found no significant cognitive benefit on the trial's primary verbal learning and memory measures, working memory or visuospatial abilities. However, by hour four, verbal learning improved significantly, while the gain in delayed recall fell just short of statistical significance. Attention improved at both the 30-minute mark and the 4-hour mark. Cortisol peaked 75 minutes after the dose.

After four weeks of daily dosing, women taking LDH daily saw their delayed recall improve significantly, while the placebo group did not see a significant increase. However, the direct comparison between the two groups' improvement over time did not reach statistical significance, so the study cannot confidently say LDH outperformed placebo on this measure, Rubin and her team noted. The researchers also tracked neuroendocrine, inflammatory, glucocorticoid receptor and HIV reservoir markers to explain the cognitive changes but found no biomarker that accounted for the improvements.

“Together, these findings suggest that transient modulation of the HPA axis can enhance domain-specific cognitive function, particularly verbal learning, memory, and attention, in populations affected by chronic stressors, psychiatric comorbidities and cognitive impairment,” Rubin and her team wrote in the study.

The regimen was safe and well tolerated, the authors noted: “The time-limited, 4-week dosing of LDH was safe and well tolerated, with no serious adverse events or clinically meaningful changes in metabolic, hepatic or HIV-related indices.”

LDH is not intended to replace existing nonpharmacologic approaches such as cognitive behavioral therapy, exercise, sleep interventions or stress reduction strategies, the authors noted, but rather to help clarify modifiable neurobiological pathways that could inform future multimodal treatments.