Taking tiny, frequent amounts of the psychedelic drug lysergic acid diethylamide (LSD) might temporarily elevate mood for people diagnosed with major depressive disorder. In a small pilot study, participants taking low, precise doses reported feeling more energetic, creative, and connected on days they took the drug. The research was published in the journal Progress in Neuropsychopharmacology & Biological Psychiatry.
Classic psychedelic compounds such as LSD are known for inducing profound changes in perception at high amounts. For decades, strict legal restrictions largely halted clinical research on these substances. Recently, scientific interest has renewed, and a practice called microdosing has gained popularity globally.
This practice involves taking very small amounts of a psychedelic substance. The amount is high enough to potentially alter brain chemistry but low enough to avoid causing hallucinations or severe cognitive disruptions. Many individuals practice microdosing on their own to self-medicate for mental health conditions, particularly depression.
Despite widespread anecdotal reports of psychological benefits, clinical trial data evaluating microdosing remain limited. Prior tests involving healthy volunteers suggested that low doses of LSD can acutely improve mood and increase feelings of sociability. This prompted researchers to investigate whether similar acute mood elevations occur in people actively experiencing depression. Dimitri Daldegan-Bueno, a pharmacy researcher at the University of Auckland in New Zealand, led the investigation along with several colleagues.
Major depressive disorder is a leading cause of disability worldwide. Symptoms go beyond sadness, encompassing a loss of interest in pleasurable activities, fatigue, and feelings of isolation. Standard psychiatric treatments frequently take weeks to become fully effective and do not relieve symptoms for everyone. Emerging research suggests that activating specific serotonin receptors in the brain with psychedelics might promote flexibility in brain signaling, offering a novel approach to treatment.
To test this approach, the research team enrolled nineteen adults who all met diagnostic criteria for major depression. They underwent an eight-week treatment regimen. The first session took place in a clinical laboratory. Participants were given a precise, eight-microgram dose of liquid LSD in a sublingual format. Sublingual administration involves holding the liquid under the tongue for about thirty seconds before swallowing.
During this initial session, scientists took multiple blood samples over six hours. This process allowed the research team to track the drug’s pharmacokinetics. Pharmacokinetics is a branch of pharmacology that focuses on how the body absorbs, distributes, and clears a drug from the bloodstream.
For the next phase of the trial, participants took the drug home. They consumed the sublingual liquid twice a week for the remainder of the eight weeks, totaling fifteen home doses. At home, they had the option to slowly raise or lower the amount of the drug they were taking. The permitted range for the drug was strictly capped between four and twenty micrograms.
To determine their individual ideal dose, participants answered daily questions on a customized smartphone application. If they felt the drug was interfering with their regular daily functioning, they were instructed to decrease the dose the next time. If they felt no psychological effects, they could slightly increase the dose during the next scheduled session.
The smartphone program also tracked a variety of psychiatric metrics. Every evening, participants filled out a short survey evaluating their sleep quality from the night before. They rated their mental state using visual analog scales. A visual analog scale is a measuring tool that asks users to specify their level of agreement along a continuous line rather than selecting a rigid multiple-choice option. Within the program, participants rated how connected, creative, energetic, happy, irritable, and jittery they felt that day.
Looking at the data across the eight weeks, daily mood improved in specific patterns. On the specific days they consumed the microdose, participants logged higher levels of creativity, energy, and social connectedness compared to the days immediately following the dose. On the first and second days after taking the drug, participants reported feeling happier. In addition, irritability scores dropped two days after consuming the dose.
These acute improvements in mood could theoretically counter some of the core symptoms of major depressive disorder. A common feature of depression is anhedonia, which is an inability to feel pleasure or find motivation to engage in social activities. If a patient feels a temporary surge in creative energy and social connection, they might be more likely to participate in positive social behaviors. Engaging in rewarding activities can create a positive feedback loop that helps lift a depressed mood over time.
Despite these daily mood boosts, the daily depression questionnaire used in the app did not yield statistically significant changes based on the dosing schedule. The researchers suspect this was a measurement issue. The specific questionnaire they used asked participants to evaluate their depression symptoms over the preceding three days. Because they filled this out every single day, the answers overlapped, making it difficult to isolate the effect of a single dosing day. A separate, formal clinical interview conducted at the end of the entire trial showed an average drop in depression severity of sixty percent across the group.
The blood analysis from the laboratory sessions provided detailed data on how the human body processes microdoses of this specific substance. On average, the drug reached its peak concentration in the blood just over an hour after sublingual administration. This timing aligns closely with the onset of psychological effects reported by the participants.
The pharmacokinetic data also revealed individual variations in how the drug was metabolized. When researchers compared the blood test results to the home dosing adjustments, they noticed a physiological pattern. Participants who naturally processed the drug faster, resulting in lower peak concentrations in their blood, were more likely to gradually increase their home doses over the eight weeks.
Conversely, those with higher blood concentrations from the standard lab dose tended to keep their home doses lower. This suggests that participants were successfully adjusting their drug intake to achieve a consistent subjective effect, compensating for their unique internal metabolism.
The daily surveys also asked participants to rate the strength of the drug’s effects across the fifteen home sessions. Participants did not report the drug feeling weaker or stronger over the eight weeks. This finding is notable in pharmacology. Many psychiatric substances cause tolerance, where the brain adapts and requires more of the drug to achieve the same effect. Other drugs cause sensitization, where repeated use leads to stronger reactions. In this trial, the perceived effects remained entirely stable, indicating no rapid tolerance or sensitization to the repeated low doses of the drug.
While these results might appear promising for the field of psychiatric research, the study design has severe limitations. It was an uncontrolled, open-label pilot trial. Every single participant knew they were diagnosed with depression and knew they were receiving LSD. In psychiatric research, participant expectations often exert a massive influence on the reported outcomes. A participant hoping for relief from depression might unconsciously report better moods simply because they believe the treatment will work.
This psychological phenomenon is known as the placebo effect. Without a control group receiving an inactive substance for comparison, scientists cannot definitively isolate the chemical effects of the drug from the psychological effects of undergoing a novel treatment. The excitement of participating in a supportive clinical trial can elevate a person’s mood independently of any pharmacological intervention.
Additionally, the demographics of the group were limited. The trial included only nineteen individuals, most of whom identified as male. A larger sample size is required to ensure these behavioral patterns hold true for the general adult population. Most of the participants were also taking standard prescription antidepressants simultaneously, meaning the drug’s effects were interacting with existing medications.
Because of these limitations, the research team emphasized that these findings must be viewed as strictly exploratory. The data successfully proved that patients can safely manage their own microdosing regimen at home with remote monitoring. However, proving the clinical efficacy of this treatment will require randomized, double-blind trials. In those future studies, researchers will compare an active drug group against a placebo group. Only then can scientists determine if tiny amounts of psychedelics are a true medical asset for treating major depressive disorder.
The study, “LSD microdosing for major depressive disorder: Mood and pharmacokinetic outcomes from a Phase 2a trial,” was authored by Dimitri Daldegan-Bueno, Carina Joy Donegan, Rachael Sumner, Anna Forsyth, Soo Hee Jeong, William Evans, Malak Alshakhouri, Robin J. Murphy, Lisa Reynolds, Nicholas Hoeh, Nathan Allen, Frederick Sundram, David B. Menkes, and Suresh Muthukumaraswamy.