In a breakthrough for climate science, a team of U.S. researchers has identified the oldest directly dated ice and air ever discovered on Earth. The samples were found in the Allan Hills region of East Antarctica, an area long known to preserve ancient ice near the surface.

A research team at the Institute for Neurosciences (IN), led by Juan Lerma, has uncovered how a distinct group of neurons in the amygdala — a region of the brain involved in processing emotions — contributes to anxiety, depression, and changes in social behavior. The discovery, published in iScience, shows that restoring the balance of neuronal excitability within a precise part of the amygdala can reverse these behavioral changes in mice.

• Scientists have discovered that the human brain has its own built-in pain map, activating different regions when easing pain in the face, arms, or legs.
• Placebo pain relief only works in the exact area where the brain expects it to happen.
• Understanding this system could lead to safer, more precise treatments that target pain exactly where it occurs.

Mapping the Brain’s Hidden System for Pain

Researchers at the University of Sydney have revealed a brainstem network that manages pain differently depending on where it occurs in the body. Using placebo pain relief, they discovered a map-like system that fine-tunes pain control for specific regions, such as the face, arms, or legs. The findings could lead to safer and more precise pain therapies that avoid the risks of opioid-based treatments.

The brainstem functions as the main communication pathway between the brain and spinal cord, directing signals that control thought, sensation, and survival responses. It also produces most of the brain’s vital neurochemicals, making it a central hub for regulating both physical and emotional states.

Published in Science, the study used 7-Tesla functional magnetic resonance imaging (fMRI) (one of the most advanced brain scanners available, with only two in Australia) to identify how two major regions of the brainstem coordinate pain relief through placebo responses.

Dr. Lewis Crawford, lead author and research fellow at the School of Medical Sciences and the Brain and Mind Centre, explained, “This is the first time we’ve seen such a precise and detailed pain map in the human brainstem, showing us that it tailors pain relief to the specific part of the body that’s experiencing it.”

This breakthrough builds on decades of research led by co-author Professor Kevin Keay, Deputy Head of the School of Medical Sciences, who has long studied the brain’s role in pain regulation.

How the Placebo Effect Reveals the Brain’s Pain Control

To explore how the brain organizes pain relief, researchers tested 93 healthy volunteers by applying heat to different parts of their bodies. A placebo cream was used on some areas, but scientists secretly lowered the temperature to convince participants that the cream was reducing pain.

Each participant’s heat level was personalized to reach a moderate level of discomfort, based on a scale from 0 (no pain) to 100 (worst pain imaginable), typically between 40 and 50 degrees Celsius.

When the same heat stimulus was later reapplied, participants continued to feel less pain in the areas where the placebo cream had been used, even though the temperature was no longer reduced. About 61 percent reported this effect, a strong indication of genuine placebo-driven pain relief.

Dr. Crawford noted, “We found that upper parts of the brainstem were more active when relieving facial pain, while lower regions were engaged for arm or leg pain.”

Pinpointing the Brain’s Pain-Relief Centers

Two major brainstem regions, the periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM), were identified as central to this system. Each showed distinct patterns of activity depending on where the pain occurred. Upper sections of the PAG and RVM responded to facial pain, while lower sections activated for pain in the limbs.

According to Dr. Crawford, “The brain’s natural pain relief system is more nuanced than we thought. Essentially, it has a built-in system to control pain in specific areas. It’s not just turning pain off everywhere; but working in a highly coordinated, anatomically precise system.”

A Blueprint for Targeted Pain Therapies

Understanding which brainstem areas are linked to different parts of the body may open new avenues for developing non-invasive therapies that reduce pain without widespread side effects.

“We now have a blueprint for how the brain controls pain in a spatially organized way,” said Professor Luke Henderson, senior author and Professor in the School of Medical Sciences and the Brain and Mind Centre. “This could help us design more effective and personalized treatments, especially for people with chronic pain in a specific area of their body.”

The study also challenges long-held assumptions about how placebo pain relief works. Instead of relying on the brain’s opioid system, experts say a different part of the brainstem — the lateral PAG — is not only responsible but works without using opioids and could instead be linked to cannabinoid activity.

“Opioid-based pain relief typically activates central areas of the brain and can affect the whole body, whereas the cannabinoid circuit that we identified appears to operate in more targeted regions of the brainstem,” said Dr. Crawford. “This supports the idea that cannabinoids may play a role in localized, non-opioid pain control.”

“Knowing exactly where pain relief is happening in the brain means we can target that area or assess whether a drug is working in the right place,” said Dr. Crawford. “This could lead to more precise treatments for chronic pain that don’t rely on opioids and work exactly where the brain expects pain relief to occur — a huge step forward for pain management.”

• A large review of health data from more than 130,000 adults with insomnia found that people who took melatonin for a year or longer were more likely to develop heart failure, be hospitalized for the condition, or die from any cause compared to those who didn’t take the supplement.
• While the study cannot prove that melatonin directly causes these outcomes, the strong association raises important safety questions about long-term use of this popular sleep aid. Researchers emphasize that more studies are needed to fully understand melatonin’s impact on heart health and ensure it can be used safely.

Long-Term Melatonin Use Linked to Higher Heart Failure Risk

People who regularly take melatonin to improve sleep may face serious health risks. A preliminary study presented at the American Heart Association’s Scientific Sessions 2025 found that adults with chronic insomnia who used melatonin for a year or longer were more likely to develop heart failure, be hospitalized for heart failure, and die from any cause than those who did not take the supplement. The findings will be discussed at the AHA’s annual meeting, taking place Nov. 7-10 in New Orleans, a leading international event for cardiovascular science and clinical research updates.

Melatonin is a hormone produced by the pineal gland that regulates the body’s sleep-wake cycle. Its levels naturally rise in the dark and drop during daylight hours. Synthetic melatonin, which is chemically identical to the natural hormone, is widely used to treat insomnia (difficulty falling and/or staying asleep) and jet lag. In many countries, including the U.S., melatonin supplements can be purchased over the counter. However, because they are not regulated in the U.S., products can differ widely in purity and dosage.

How the Study Was Conducted

Researchers divided participants into two groups based on their medical records. Those who had taken melatonin for at least one year were classified in the “melatonin group,” while individuals with no record of melatonin use were placed in the “non-melatonin group.”

“Melatonin supplements may not be as harmless as commonly assumed. If our study is confirmed, this could affect how doctors counsel patients about sleep aids,” said Ekenedilichukwu Nnadi, M.D., lead author of the study and chief resident in internal medicine at SUNY Downstate/Kings County Primary Care in Brooklyn, New York.

Investigating Heart Failure and Sleep Aid Safety

Although melatonin is marketed as a safe and natural sleep remedy, little evidence exists on its long-term cardiovascular effects. The research team wanted to know whether long-term use could influence heart failure risk in people with chronic insomnia. According to the American Heart Association’s 2025 Heart Disease and Stroke Statistics, heart failure occurs when the heart cannot pump enough oxygen-rich blood to sustain the body’s organs. The condition affects about 6.7 million U.S. adults.

To explore this question, scientists used data from the TriNetX Global Research Network, an international database of de-identified medical records. They reviewed five years of data on adults diagnosed with chronic insomnia who had documented melatonin use for more than a year. Each was matched with another person who also had insomnia but had never used melatonin. Individuals with a previous diagnosis of heart failure or who had been prescribed other sleep medications were excluded.

The main analysis found:

• Among adults with insomnia, those whose electronic health records indicated long-term melatonin use (12 months or more) had about a 90% higher chance of incident heart failure over 5 years compared with matched non-users (4.6% vs. 2.7%, respectively).
• There was a similar result (82% higher) when researchers analyzed people who had at least 2 melatonin prescriptions filled at least 90 days apart. (Melatonin is only available by prescription in the United Kingdom.)

A secondary analysis found:

• Participants taking melatonin were nearly 3.5 times as likely to be hospitalized for heart failure when compared to those not taking melatonin (19.0% vs. 6.6%, respectively).
• Participants in the melatonin group were nearly twice as likely to die from any cause than those in the non-melatonin group (7.8% vs. 4.3%, respectively) over the 5-year period.

“Melatonin supplements are widely thought of as a safe and ‘natural’ option to support better sleep, so it was striking to see such consistent and significant increases in serious health outcomes, even after balancing for many other risk factors,” Nnadi said.

Expert Reactions and Caution From Sleep Researchers

“I’m surprised that physicians would prescribe melatonin for insomnia and have patients use it for more than 365 days, since melatonin, at least in the U.S., is not indicated for the treatment of insomnia. In the U.S., melatonin can be taken as an over-the-counter supplement and people should be aware that it should not be taken chronically without a proper indication,” said Marie-Pierre St-Onge, Ph.D., C.C.S.H., FAHA, chair of the writing group for the American Heart Association’s 2025 scientific statement, Multidimensional Sleep Health: Definitions and Implications for Cardiometabolic Health. St-Onge, who was not involved in this study, is a professor of nutritional medicine in the division of general medicine and director of the Center of Excellence for Sleep & Circadian Research in the department of medicine at Columbia University Irving Medical Center in New York City.

The study has several limitations. First, the database includes countries that require a prescription for melatonin (such as the United Kingdom) and countries that don’t (such as the United States), and patient locations were not part of the de-identified data available to the researchers. Since melatonin use in the study was based only on those identified from medication entries in the electronic health record, everyone taking it as an over-the-counter supplement in the U.S. or other countries that don’t require a prescription would have been in the non-melatonin group; therefore, the analyses may not accurately reflect this. Hospitalization figures were also higher than those for initial diagnosis of heart failure because a range of related diagnostic codes may be entered for the hospitalization, and they may not always include the code for a new diagnosis of heart failure. The researchers also lacked information on the severity of insomnia and the presence of other psychiatric disorders.

“Worse insomnia, depression/anxiety or the use of other sleep-enhancing medicines might be linked to both melatonin use and heart risk,” Nnadi said. “Also, while the association we found raises safety concerns about the widely used supplement, our study cannot prove a direct cause-and-effect relationship. This means more research is needed to test melatonin’s safety for the heart.”

Study details, background and design:

• The study included 130,828 adults (average age of 55.7 years; 61.4% women) diagnosed with insomnia.
• The study data was from TriNetX, established in 2013, a growing global network of real-world, de-identified patient data available for research.
• 65,414 participants had been prescribed melatonin at least once and reported taking it for at least a year.
• A second group of people were examined for comparison (control group) — those who had never been prescribed melatonin and were matched to the group taking melatonin on 40 factors including demographic information, health conditions and medications.
• Participants were excluded if they had already been diagnosed with heart failure or had been prescribed other types of sleeping pills such as benzodiazepines.
• The melatonin and control groups were matched for age, sex, race/ethnicity, heart and nervous system diseases, medications for heart and nervous system diseases, blood pressure and body mass index. Researchers looked at electronic medical records from the five years after the matching date.
• For the main findings, records were searched for codes related to an initial diagnosis of heart failure. Secondary findings included codes for hospitalization related to heart failure or death.
• Following the initial analyses, researchers validated the credibility of their findings by conducting a sensitivity analysis. This involved slightly changing the criteria: they required participants in the melatonin group to have filled at least two melatonin prescriptions that were at least 90 days apart. This adjustment aimed to determine whether the extended duration of confirmed melatonin prescriptions influenced the outcomes.

Note: The study featured in this article is a research abstract. Abstracts presented at American Heart Association’s scientific meetings are not peer-reviewed, and the findings are considered preliminary until published as full manuscripts in a peer-reviewed scientific journal.