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Northwestern scientists have identified, for the first time, a specific group of neurons — cells in the brain — that appear to contribute to anxiety caused by cannabinoid drugs, particularly when those drugs are combined with stressful conditions. Cannabinoids are a category of substances that includes THC, the main psychoactive ingredient in cannabis.

To investigate how cannabinoids influence fear and anxiety, researchers exposed mice to a threatening smell derived from fox urine. Before encountering the odor, the animals were given either a placebo or a synthetic cannabinoid drug.

Mice that received the cannabinoid froze more frequently and spent less time exploring the predator scent. Researchers traced these anxiety related behaviors to increased activity in a small population of brain cells known as somatostatin neurons. These neurons are located in the central amygdala, an area of the brain involved in processing fear and stress.

When the researchers genetically silenced the somatostatin neurons, the mice that received the cannabinoid became less likely to avoid the predator odor. The result suggested that these cells play an important role in producing the anxious response.

“The results of this study could explain why a good trip can turn bad pretty quickly if people consume too much cannabis or the situation they are in turns stressful or scary,” said study senior author Dr. Sachin Patel, chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine.

The study was published on Oct. 2 in Nature Communications.

Tracking the Brain During a Threat

Patel and his colleagues gave mice several different doses of the synthetic cannabinoid and measured their reactions to the predator odor. The researchers recorded how much time the animals spent near the scent and whether they responded by freezing or fleeing.

At the same time, the team monitored activity inside the brain by implanting a small microscope into the mice’s brain.

Researchers also studied brain tissue to determine how cannabinoids changed communication between neurons. Their experiments showed that the drug weakened a natural brain mechanism that normally acts as a “brake” on somatostatin neurons. With that restraint reduced, the neurons became more active.

“Higher doses of cannabinoids and environmental stress worked together to synergistically release the ‘brake’ on the central amygdala, which in turn drove excessive anxiety,” Patel explained.

Why Cannabis and Anxiety Matter

Cannabis use in the U.S. has steadily increased in recent years. At the same time, emergency department visits involving adverse effects from the drug have also risen.

Previous studies have found an association between cannabis use and a higher long term risk of anxiety. Anxiety and mood disorders are also on the rise globally.

“Understanding how cannabis affects brain function to generate its psychoactive effects could ultimately reveal new ways to counteract negative consequences should they arise in some people,” Patel said.

The researchers believe the findings may also have relevance beyond cannabis related side effects. Patel said the same neurons could potentially represent a broader target for understanding or reducing anxiety.

“Suppressing the activity of somatostatin neurons in the central amygdala could represent a final pathway for reducing anxiety symptoms, not just in the context of cannabis side effects,” he explained.

Nightmares can be one of the most distressing symptoms of post-traumatic stress disorder (PTSD), a condition that may develop after a person experiences a disaster, serious accident, violence, combat, or another severe trauma. During sleep, people with PTSD may feel as though they are living through the event again in vivid detail. These repeated episodes can cause severe sleep loss and make some people afraid to go to bed.

Available medications often provide limited relief from trauma-related nightmares. Researchers at Charité — Universitätsmedizin Berlin therefore examined whether a prescription drug containing THC, one of the active compounds found in cannabis, could help. The findings, published in Nature Medicine, showed that more than half of the participants responded to the treatment. More than one-third said their nightmares disappeared completely.

Why PTSD Nightmares Are So Difficult to Treat

The effects of a terrifying or life-threatening experience can continue long after the immediate danger has passed. In post-traumatic stress disorder (PTSD), the brain has difficulty processing overwhelming events. The memories may be stored in a way that makes them return involuntarily and without conscious control.

This can happen during the day and at night. While sleeping, people with PTSD may repeatedly relive the trauma until they wake in panic. Antidepressants and medications that lower blood pressure are among the treatments sometimes used, but their effectiveness is limited. They also often do little to relieve the nightmares themselves. Germany has not yet approved a medication specifically for trauma-related nightmares.

Prof. Stefan Röpke studies trauma-related disorders at the Department of Psychiatry and Neurosciences on the Benjamin Franklin Campus of Charité. While exploring possible new treatments, he and his team, working with additional research partners, turned their attention to tetrahydrocannabinol, commonly known as THC. It is the primary psychoactive compound in cannabis.

THC interacts with the body’s endocannabinoid system, which helps regulate sleep, stress, and the way emotional memories are processed. Stefan Röpke explains: “There is evidence suggesting that during REM sleep — the intense dream phases in which the brain processes experiences and regulates emotions — THC reduces dream activity and thereby alleviates nocturnal stress responses.”

Testing Dronabinol for PTSD Nightmares

Cannabis-based medicines are already used in pain treatment, especially when standard therapies do not work well enough or cause intolerable side effects. In Germany, access became easier after the so-called “Cannabis for medical purposes” law went into effect in 2017. The legislation expanded the medical and scientific use of cannabinoids derived from plants or produced synthetically.

For the study, the researchers used Dronabinol, a prescription medication containing THC obtained directly from the cannabis plant and administered as drops. They wanted to find out whether the drug could safely reduce nightmares linked to PTSD.

More than 170 people with post-traumatic stress disorder and frequent, severe nightmares took part. For ten weeks, participants received either Dronabinol or a cannabis-flavored placebo that looked identical. They took the drops each evening before going to bed.

Neither the participants nor the healthcare professionals knew who received the medication and who received the placebo. This double-blind, placebo-controlled design is considered the gold standard for testing medical treatments.

Nightmares Declined More With THC Treatment

At the end of the ten weeks, nightmare severity had fallen significantly more in the Dronabinol group than in the placebo group. On a scale ranging from zero to eight, the average nightmare burden dropped by 3.7 points among participants taking Dronabinol. The placebo group experienced an average decrease of 2.2 points. For the people affected, the difference was clearly noticeable.

“More than a third of the patients treated with Dronabinol reported that they no longer experienced any nightmares after ten weeks. Another 21 percent reported that their nightmare burden had been at least halved,” as Stefan Röpke stated. “And about five out of six patients in the dronabinol group felt their health had markedly improved.”

No Severe Side Effects or Signs of Dependence

The cannabinoid appeared to act specifically on nightmares and sleep rather than on every aspect of PTSD. The researchers could not conclusively show that it reduced the overall severity of post-traumatic stress disorder or any accompanying depression.

Even so, most participants experienced meaningful relief. By interrupting the repeated nighttime reliving of trauma, the treatment allowed many of them to sleep more peacefully.

No severe side effects were reported. Mild and moderate effects, including dizziness, headaches, and increased appetite, occurred more frequently among those receiving Dronabinol. The researchers also found no withdrawal symptoms after participants stopped taking the evening doses at the end of the study.

Future studies will examine whether the treatment remains safe and effective when used for longer periods. Researchers also want to determine whether patients may gradually develop tolerance to the drug.

Stress does more than influence how we feel. It can also change what we remember, particularly when an experience is emotionally intense or personally meaningful. Scientists have long known that cortisol, a hormone released during stressful situations, can strengthen emotional memories. What has been less clear is exactly how this happens inside the brain.

Researchers at Yale University have now uncovered important clues. Their study reveals that cortisol strengthens emotional memories by changing how brain networks involved in emotion and memory function and communicate with one another. The findings offer a deeper understanding of why certain experiences leave such powerful impressions while others quickly fade.

“We all experience stress, and my lab is interested in understanding how stress can be helpful,” said corresponding author Elizabeth Goldfarb, an assistant professor of psychiatry at Yale School of Medicine and of psychology in the Faculty of Arts and Sciences.

The findings were published in the journal Science Advances.

How Stress Hormones Influence Memory

Previous research involving both humans and rodents has shown that stress and cortisol can improve memory for emotional events. Scientists also know that certain brain regions, including the amygdala, play an essential role in this process. The amygdala is particularly important for processing emotions and identifying experiences that may be significant.

However, understanding precisely how cortisol strengthens memories has been challenging. Many brain regions participate in several mental functions, making it difficult to determine whether the hormone is influencing emotional responses, memory formation, or both.

“Forming memories for emotional experiences involves different processes in the brain: first, perceiving an experience as emotional or intense, and second, encoding that experience into long-term memory,” said Goldfarb, who is also a member of Yale’s Wu Tsai Institute, an interdisciplinary research initiative that explores cognition.

The researchers wanted to examine these processes separately to determine how cortisol affects the brain’s ability to recognize emotional significance and preserve an experience as a lasting memory.

Watching the Brain Form Emotional Memories

To investigate, the Yale team conducted an experiment in which participants took a pill containing either hydrocortisone, a form of cortisol, or an inactive placebo. They then viewed a series of pictures while undergoing functional MRI (fMRI) scanning.

This imaging technique measures changes in blood flow and oxygen levels associated with brain activity, allowing researchers to identify which areas of the brain are more active during different tasks.

As participants examined the pictures, they reported their emotional reactions to each image. The following day, researchers tested how well they remembered what they had seen.

Each person completed the experiment twice, once after receiving hydrocortisone and once after receiving the placebo. The study used a double blind design, meaning neither the participants nor the experimenter knew which substance had been administered during a particular session.

This approach allowed the scientists to compare how the same person’s brain responded with and without the additional cortisol.

A Five-Second Look at Brain Network Activity

One of the study’s most important advances came from the way researchers analyzed the brain scans.

Scientists often study a measurement called functional connectivity, which describes how closely activity in different parts of the brain fluctuates together. When two regions show synchronized patterns of activity, it can indicate that they are participating in related processes.

Traditionally, examining these relationships requires several minutes of brain imaging data. The Yale team instead analyzed functional connectivity during individual trials lasting only around five seconds.

Using these brief snapshots, the researchers tested whether patterns of brain activity could predict two different outcomes: how emotionally intense participants found a picture and whether they would remember that picture the following day.

The approach worked for both. By identifying patterns associated with emotional intensity and memory formation separately, the scientists were able to examine how cortisol influenced each network and the interactions between them.

This gave the researchers a more detailed picture of the changing brain activity associated with emotional memory formation.

Cortisol Changes How Brain Networks Work Together

The results revealed two major effects.

First, cortisol improved participants’ ability to remember emotionally significant experiences, confirming what earlier research had suggested.

Second, and more importantly, the hormone strengthened emotional memory through distinct changes in the brain networks responsible for processing emotion and forming memories.

In networks associated with emotion, cortisol produced more consistent patterns of activity and increased their engagement. This suggests that the hormone helped the brain respond more strongly and reliably to the emotional significance of an experience.

In memory networks, cortisol had a different effect. It made their activity patterns more specialized for emotional information, suggesting that the brain was adjusting how it encoded emotionally meaningful experiences.

The hormone also increased coordination between the networks involved in emotion and memory. In other words, cortisol appeared to help these different brain systems work together more effectively when processing experiences that carried emotional weight.

Together, these findings suggest that stress strengthens emotional memories through several interacting brain mechanisms rather than through a single region or process.

Why Emotional Experiences Can Be So Memorable

The results help explain why stress does not necessarily improve memory for everything. Instead, its benefits appear to be selective, making experiences that feel particularly intense or meaningful more likely to be remembered.

The researchers believe this reflects the brain’s ability to adapt to stressful situations by prioritizing information that may be important.

“Stress responses are fundamentally adaptive and can help you form strong memories — but this is specific to experiences that you find to be emotionally intense or meaningful,” Goldfarb said. “This is in part related to your brain increasing engagement of networks that track emotional intensity. So, if you are stressed out and trying to learn something new, it might help to think about exciting elements or strong feelings connected to what you are learning.”

The findings also point to a potentially useful insight about learning. Connecting information to something exciting, personally important, or emotionally engaging could make it easier to remember, particularly during stressful situations.

Rather than simply disrupting memory, stress can sometimes help the brain identify which experiences deserve special attention and strengthen the networks involved in preserving them.

Scientists at Mount Sinai have identified three important brain connections associated with long-term improvement in patients receiving deep brain stimulation (DBS) for severe depression that has not responded to conventional treatments. The discovery could help researchers make this experimental therapy more precise and effective.

Published October 1 in the American Journal of Psychiatry, the research examined the largest group of patients assembled across multiple independent cohorts to date who had received subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression.

The researchers found that lasting improvements were consistently associated with electrical stimulation reaching three specific white matter pathways: the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

These findings strengthen the case for using detailed maps of the brain’s connections to determine exactly where electrodes should be implanted, rather than choosing their positions based primarily on anatomical landmarks. Known as connectome-based targeting, this strategy has already helped shape the ongoing Abbott TRANSCEND clinical trial, a randomized, controlled study that uses individualized brain connectivity maps to guide SCC DBS treatment.

“This study underscores the importance of individualized surgical targeting for achieving optimal outcomes with deep brain stimulation for depression,” said Helen Mayberg, MD, Mount Sinai Professor in Neurotherapeutics and founding Director of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai. “In any randomized controlled trial of a neuromodulation treatment, precise lead placement and confirmation that the intended brain target has been engaged are essential first steps. We still have much to learn about which patients are most likely to benefit from stimulation of this particular target, but developing imaging-based signatures that can match patients to their optimal treatment remains a central goal of our research.”

How Deep Brain Stimulation Targets Severe Depression

For people with treatment-resistant depression, standard therapies have failed to provide adequate relief. Researchers are investigating deep brain stimulation as a possible treatment for individuals living with severe, persistent symptoms.

The procedure involves surgically placing electrodes inside the brain to deliver controlled electrical signals to circuits involved in depression. However, positioning the electrodes correctly remains one of the greatest challenges.

Electrical stimulation does not simply affect the brain tissue closest to an implanted electrode. It can also influence larger networks through the white matter pathways that connect different brain regions. As a result, two patients with electrodes implanted in nearly identical locations may experience very different outcomes depending on which connections are actually stimulated.

Earlier research from Mount Sinai and Emory University helped establish the importance of these networks. In studies published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry, and Nature, the teams identified white matter pathways associated with successful SCC DBS treatment and developed a method for planning electrode placement using brain connectivity maps.

The latest investigation sought to determine whether those connections were also important in patients treated at other research centers. Scientists also wanted to understand whether differences in the pathways reached by stimulation could help account for patients who did not benefit.

Three Brain Connections Linked to Lasting Improvement

To investigate, the researchers examined information from several clinical studies, including the BROADEN trial and a patient cohort at the University of Toronto, where SCC DBS was originally developed.

They used computer models of the electrical fields generated by implanted electrodes alongside maps of brain connectivity. This allowed them to estimate which pathways received stimulation and compare those patterns across different patient groups.

The results showed a consistent relationship between sustained improvement and stimulation of the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

One finding was especially notable. Across the study sites, patients who had not responded to treatment after two years showed a lack of stimulation engagement with the left cingulum bundle.

The researchers did not investigate whether moving electrodes to reach this pathway would improve those patients’ symptoms. Nevertheless, the pattern offers a possible explanation for why apparently similar electrode placements can produce different results. An electrode might be positioned in the correct general region but still fail to activate all the connections associated with lasting improvement.

“This study addresses an important question in DBS: not simply which area of the brain to stimulate, but which connections within that area need to be engaged,” said Brian Kopell, MD, Director of the Center for Neuromodulation at Mount Sinai. “For a network disorder such as depression, millimeters can determine whether stimulation reaches the pathways we intend to modulate. Identifying and reproducibly engaging those pathways gives us a more precise surgical target and a framework for understanding why otherwise similar electrode placements may produce different clinical outcomes.”

Toward More Personalized Depression Treatments

Although reaching these three pathways appears important, the researchers emphasize that electrode placement alone is unlikely to determine whether a patient improves.

The investigation concentrated on identifying the brain connections that should receive stimulation. Additional studies are needed to determine which individuals are most likely to benefit from SCC DBS and how electrical stimulation should be adjusted as treatment continues.

There were also limitations to the brain imaging data. Individual diffusion MRI scans, which can provide information about a person’s white matter connections, were not available for every participant. Consequently, much of the analysis used generalized maps of brain connectivity rather than maps created specifically for each patient.

For the Emory patient group, the researchers were able to compare results obtained from generalized connectivity maps with those based on individual diffusion imaging. Both approaches produced consistent findings, providing further support for the importance of the identified pathways. However, more research is needed to establish the value of patient-specific imaging.

Future investigations will explore whether additional brain imaging measurements, including white matter integrity and functional connectivity, can help identify suitable patients, improve electrode placement, and guide treatment settings.

“Our findings show precisely engaging these white matter pathways is a critical first step toward sustained response,” said Ki Sueng Choi, PhD, Associate Professor, Imaging Core Leader at the Center for Advanced Circuit Therapeutics at Mount Sinai, and corresponding author of the study. “The next step is to characterize abnormal functional and structural brain states along these pathways to build more detailed models for setting patient-specific stimulation parameters, including amplitude, frequency, and pulse width, for precision medicine.”

By combining increasingly detailed brain maps with personalized stimulation settings, scientists hope to better understand why some people experience lasting relief while others do not. The findings represent another step toward developing more targeted treatments for severe depression, although further clinical research is necessary to establish how much these approaches can improve outcomes.