New research suggests that taking low doses of the hallucinogen lysergic acid diethylamide, known as LSD, can enhance the way the human brain processes emotional rewards. The study, published in the Journal of Psychopharmacology, points to specific changes in brain electrical activity after administering small doses to patients suffering from mild depression. These neural changes were consistent with an improvement in mood that lasted several days after the initial exposure.
For years, there has been growing public interest in the act of ingesting very small, barely perceptible amounts of psychedelic drugs. This practice, often referred to as microdosing, is frequently touted by proponents as a way to lift your mood, increase creativity, and improve mental focus. Taking small amounts of LSD every few days is especially popular among people looking for another way to manage depression.
However, proving the benefits of microdosing under controlled laboratory conditions has proven difficult. Subjective, self-reported mood surveys may not capture the subtle biological changes occurring beneath the surface. To get around these limitations, researchers are turning to direct measurements of electrical activity in the brain. They believe that tracking precise neural responses to reward could reveal biological changes that are easily exaggerated or missed entirely by typical subjective measurements.
James Glaser, a researcher in Northwestern University’s Department of Psychiatry, led the study along with colleagues at the University of Chicago. The research team included Hannah Mora, Lois Lee, Robin Nussrock, and Harriet de Witt. The same group recently found that low doses of LSD change the brain’s response to monetary rewards in healthy adults. Building on that previous study, they designed new experiments to see if the drug had specific neurobiological effects in individuals already experiencing depressed mood.
People who suffer from depression often experience a slowed down in their ability to process rewards. When they win something or receive positive feedback, their brains don’t respond as strongly as the brains of healthy people. This reduced emotional processing can reduce motivation and make it difficult to learn from mistakes and adapt behavior effectively. Researchers wanted to know if small doses of LSD could help normalize this impaired reward processing.
To measure these subtle brain adjustments, the research team used electroencephalography. The technique involves placing a web of sensors over a person’s scalp to record electrical signals emitted by neurons communicating with each other. These sensors measure activity in real time, giving us a very accurate picture of how our brains react from moment to moment.
Researchers categorized the brain’s response to feedback into three chronological stages. First, the immediate radio waves encode the initial shock of winning or losing. Second, the motivational waves update the brain’s working memory with contextual information to categorize the magnitude of the reward. Finally, long-lasting waves of electrical activity reflect the deeper emotional value of the results.
This last, extended pattern of electrical activity is known to correspond to activation of the amygdala, an almond-shaped collection of neurons deep in the brain. The amygdala regulates emotional processing and often functions abnormally in people suffering from depression. Previous studies have shown that psychedelic drugs can alter connections in the amygdala, so the researchers wondered if this last emotional brainwave might be particularly sensitive to drugs.
The experiment involved 34 healthy volunteers between the ages of 18 and 35. Participants had varying scores on standard depression items. Some volunteers reported mild symptoms, while others reported mild to moderate depression at the time of the study. This multidimensional approach allowed researchers to view depression as a spectrum rather than a strict category.
Each participant participated in two separate 5-hour lab sessions at least 1 week apart. In one session, they received a low dose of 26 micrograms of LSD. In the alternative session, an inert placebo was administered. This study was double-blind. That is, neither the participants nor the researchers conducting the sessions knew which substances were administered on any given day.
The 26 microgram dose used in the study was specifically chosen to fall within the microdosing range. Standard doses of recreational or therapeutic LSD, intended to induce a full hallucinatory experience, usually range from 75 to 200 micrograms. By using some of that dose, the researchers aimed to observe changes in basic brain function without exposing volunteers to the severe perceptual distortions and hallucinations that can interfere with playing computerized test games.
During the period when the drug’s effects were at their peak, the volunteers completed a computerized game designed to test their response to reward. First, the screen displayed a cue indicating whether there was a chance to win a prize in the next round. Next, participants had to press a button quickly when the target shape appeared. Finally, the screen flashed feedback telling the player if their reactions were fast enough to earn a small monetary reward, or too slow.
While participants played the game, scalp sensors tracked specific electrical patterns as the volunteers digested their performance. Scientists were particularly interested in the long-lasting waves of emotion that occur within seconds after a person receives positive and negative feedback. In a healthy brain, experiencing a financial loss triggers a powerful electrical response that dwarfs the normal response to victory.
This heightened response to losing serves a specific evolutionary purpose. By prompting an amplified emotional response to negative outcomes, the brain encourages individuals to adapt, improve focus, and avoid future mistakes. Strong reactions to failure help people assign higher emotional stakes to the task, which naturally improves overall performance on subsequent attempts.
During the placebo session, the researchers observed exactly what they expected from participants who reported higher levels of depression. Without the influence of active drugs, people with more severe depressive mood had a smaller electrical response when losing a match. The ability to process the emotional pain of missed rewards appears to be impaired, which fits the typical blunting features of depression.
The dynamics changed markedly during the drug experiment session. Low doses of hallucinogens changed the brain’s response to negative feedback in games. In volunteers with higher baseline symptoms of depressed mood, the drug widened the difference in electrical activity between losing and winning scenarios. Their brains triggered a later, larger emotional response to missed rewards.
This biological response suggests that the substance temporarily restored a more typical emotional response to feedback. People with mild to moderate depression began processing unearned rewards with the same type of neurological intensity typically seen in people without mood disorders. The drug appeared to reverse the slowed neural responses typically associated with depressive symptoms and increase emotional engagement with the task.
These changes in brain wave activity directly corresponded to actual improvements in the volunteers’ mood. Participants who showed the strongest increase in electrical response to negative feedback also reported the largest increase in positive mood during the drug session. Direct biological measurements accurately reflected the subjective experience while playing the game under the influence of trace psychedelic doses.
The clear benefits extended beyond the time spent in the lab. Researchers retested participants’ depression levels two days after each session. Volunteers who showed an elevated electrical response to losing a reward game during an active drug session reported lower overall depressive mood 48 hours later. Neuromodulation in the laboratory predicted a prolonged increase in their daily emotional state.
The scientists also noted widespread changes in how participants’ brains engaged throughout the game. Across the group, low doses of LSD reduced the difference in brain activity between rounds that offered money and neutral rounds that offered nothing. Psychedelics seemed to equalize the game’s motivational process, making trials without rewards just as appealing as those with prizes.
Not all of the measured brain electrical signals changed during the experiment. Previous research from the same lab found that even a lower dose of 13 micrograms amplified the most immediate brain waves associated with receiving a reward. In this current experiment using 26 micrograms, that immediate response was not affected and the change between drug and placebo was not statistically significant. This suggests that different doses may produce uniquely tailored effects on the nervous system.
The authors note that the current study has several limitations. Participants experienced only episodic symptoms of depressed mood rather than an established long-term clinical diagnosis. Larger studies in patients with officially diagnosed severe major depressive disorder will be needed to confirm whether these brain activity patterns apply to clinical populations. The sample size was relatively modest, which may limit our ability to detect clear individual differences.
Future studies should investigate exactly how different doses manipulate neural circuits. There may be a distinct developmental sweet spot for achieving desired emotional outcomes without causing undesirable psychological turmoil. Determining whether repeated microdosing over several weeks is underlying these acute neurological changes remains an important next step. Scientists need to investigate whether the brain continues to adapt or develops tolerance to low-dose therapy.
These results provide the first biological basis for understanding how trace amounts of psychedelic substances interact with the human brain. Changes in reward valuation suggest that these substances may provide targeted intervention for people with depressed neurophysiological status. This study opens new avenues for evaluating potential next-generation therapies by highlighting precise electrical changes in emotional processing.
The study, “Reward-related neural activity after low-dose LSD administration in participants with depressed mood,” was authored by James Glazer, Hanna Molla, Royce Lee, Robin Nusslock, and Harriet de Wit.
