Low doses of LSD alter emotional brain responses in people with mild depression

A new study suggests that low doses of the psychedelic drug lysergic acid diethylamide, better known as LSD, can enhance how the human brain processes emotional rewards. The research, published in the Journal of Psychopharmacology, points to specific shifts in electrical brain activity following the administration of a small dose in patients experiencing mild depression. These neural changes corresponded with an improved mood that lasted for days after the initial exposure.

For years, public interest has grown around the practice of taking very small, barely perceptible amounts of psychedelic drugs. Often referred to as microdosing, this habit is frequently touted by advocates as a way to elevate mood, enhance creativity, and improve mental focus. Taking tiny amounts of LSD every few days has become especially popular among those seeking alternative ways to manage depression.

Yet proving the benefits of microdosing under controlled laboratory conditions has proven difficult. Subjective self-reported mood questionnaires sometimes fail to capture subtle biological changes happening beneath the surface. To bypass these limitations, researchers are turning to direct measurements of electrical activity in the brain. They suspect that tracking exact neural responses to rewards might reveal biological shifts that typical subjective measures easily overstate or miss completely.

James Glazer, a researcher in the Department of Psychiatry at Northwestern University, led the investigation alongside colleagues from the University of Chicago. The research team included Hanna Molla, Royce Lee, Robin Nusslock, and Harriet de Wit. The group recently discovered that low doses of LSD altered brain responses to monetary rewards in healthy adults. Relying on that prior work, they designed a new experiment to see if the drug might have specific neurobiological effects on individuals already experiencing depressed mood.

People suffering from depression often experience a blunted capacity to process rewards. When they win something or receive positive feedback, their brains do not react as strongly as the brains of healthy individuals. This reduced emotional processing can sap motivation and make it difficult to learn from mistakes or adapt behavior effectively. The researchers wanted to know if a small amount of LSD could help normalize this disturbed reward processing.

To measure these subtle brain adjustments, the team utilized electroencephalography. This technique involves placing a net of sensors over a person’s scalp to record the electrical signals fired by neurons communicating with one another. Because these sensors measure activity in real time, they offer an incredibly precise look at how the brain reacts moment to moment.

The researchers broke down the brain’s reaction to feedback into three chronological stages. First, an immediate electrical wave encodes the initial shock of winning or losing. Second, a motivational wave updates the brain’s working memory with contextual information, categorizing the size of the reward. Finally, a prolonged wave of electrical activity reflects the deeper emotional value of the outcome.

This final, prolonged pattern of electrical activity is known to correspond with activation in the amygdala, an almond-shaped cluster of neurons deep within the brain. The amygdala regulates emotional processing and often functions abnormally in people suffering from depression. Because earlier studies showed that psychedelics can alter the amygdala’s connectivity, the researchers suspected this final emotional brain wave might be particularly sensitive to the drug.

The experiment involved thirty-four healthy volunteers between the ages of 18 and 35. The participants had a range of scores on a standard depression inventory. Some volunteers reported minimal symptoms, while others reported mild to moderate feelings of depression at the time of the study. This dimensional approach allowed the researchers to look at depression as a spectrum rather than a rigid category.

Each participant attended two separate five-hour laboratory sessions spaced at least a week apart. In one session, they received a low dose of 26 micrograms of LSD. In the alternative session, they received an inactive placebo. The study was double-blind, meaning neither the participants nor the researchers running the sessions knew which substance was administered on any given day.

The 26-microgram dose utilized in the study was specifically chosen to fall within the realm of microdosing. A standard recreational or therapeutic dose of LSD meant to induce full hallucinogenic experiences typically ranges from 75 to 200 micrograms. By using a fraction of that amount, the researchers aimed to observe changes in basic brain function without subjecting the volunteers to intense perceptual distortions or visual hallucinations that could interfere with playing a computerized testing game.

During the time of peak drug effect, the volunteers completed a computerized game designed to test their reaction to rewards. First, the screen displayed a cue indicating whether the upcoming round offered a chance to win money. Next, the participants had to quickly press a button when a target shape appeared. Finally, the screen flashed feedback telling the player if their reaction was fast enough to win a small financial reward or if they were too slow.

While the participants played the game, the scalp sensors tracked the specific electrical patterns as the volunteers digested their performance. The scientists were particularly interested in the prolonged emotional wave, which typically occurs a fraction of a second after a person receives negative feedback compared to positive feedback. In healthy brains, experiencing a monetary loss triggers a robust electrical response that dwarfs the usual response to winning.

This heightened reaction to losing serves a specific evolutionary purpose. By prompting an amplified emotional response to negative outcomes, the brain drives individuals to adapt, focus harder, and avoid future mistakes. A robust reaction to failure helps people assign higher emotional stakes to the task, which naturally improves their overall performance during subsequent attempts.

During the placebo sessions, the researchers observed exactly what they expected from participants reporting higher depression levels. Without the influence of the active drug, individuals with worse depressive moods showed a smaller electrical response to losing the game. Their capacity to process the emotional sting of a missed reward appeared stunted, fitting the classic profile of depressive blunting.

The dynamics changed noticeably during the experimental drug session. The administration of the low-dose psychedelic altered the brain’s reaction to negative feedback in the game. In volunteers with higher baseline symptoms of depressed mood, the drug widened the gap in electrical activity between losing and winning scenarios. Their brains generated a much larger late emotional response to missing the reward.

This biological reaction suggests that the substance temporarily restored a more typical emotional response to feedback. The individuals with mild to moderate depression started processing unearned rewards with the same type of neurological intensity typically seen in people without mood disorders. The drug seemed to reverse the blunted neural responses usually associated with depressive symptoms, boosting their emotional engagement with the task.

These shifts in brain wave activity corresponded directly with actual improvements in how the volunteers felt. Participants who exhibited the strongest increase in this electrical response to negative feedback also reported the highest increases in positive mood during the drug session. The direct biological measurements precisely mirrored their subjective experiences while playing the game under the influence of the trace psychedelic dose.

The apparent benefits extended beyond the time spent inside the laboratory. The researchers tested the participants’ depression levels again two days after each session. Volunteers who showed the elevated electrical response to losing the reward game during the active drug session reported lower overall depressed mood forty-eight hours later. The neural adjustment within the lab predicted a lingering elevation in their everyday emotional state.

The scientists also noted broader alterations in how the participants’ brains engaged with the overall game. When examining the entire group, the low dose of LSD reduced the difference in brain activity between rounds that offered money and neutral rounds that offered nothing. The psychedelic seemed to equalize the motivational processing of the game, making the unrewarded trials just as engaging as the trials with a financial prize.

Not all measured electrical brain signals changed during the experiment. An earlier study by the same laboratory found that an even lower dose of 13 micrograms amplified the most immediate brain wave associated with catching a reward. In this current experiment using 26 micrograms, that immediate response remained unaffected, and the changes between drug and placebo were not statistically significant. This hints that different doses might produce uniquely tailored effects on the nervous system.

The authors note several limitations to the current investigation. The participants only experienced momentary symptoms of depressed mood, rather than established long-term clinical diagnoses. A larger trial involving patients with formally diagnosed, severe major depressive disorder would be necessary to confirm if these brain activity patterns hold true for clinical populations. The sample size was relatively modest, which can limit the ability to detect distinct individual differences.

Future research must explore exactly how different doses manipulate neural circuitry. There may be a distinct developmental sweet spot for achieving desired emotional outcomes without causing unwanted psychological disruption. Determining whether repeated microdosing over several weeks builds upon these acute neurological changes remains an important next step. Scientists need to investigate if the brain continues to adapt or if a tolerance develops to the low-dose regimen.

These results provide an initial biological foundation for understanding how trace amounts of psychedelics interact with the human brain. The changes in reward valuation suggest that these substances might offer targeted interventions for people whose neurophysiological state is depressed. By highlighting precise electrical shifts in emotional processing, the study opens new avenues for evaluating potential next-generation therapies.

The study, “Reward-related neural activity after low doses of LSD in participants with depressed mood,” was authored by James Glazer, Hanna Molla, Royce Lee, Robin Nusslock, and Harriet de Wit.