Abstract
Recent studies and anecdotal reports suggest that psychedelics can improve mood states, even at low doses. However, few placebo-controlled studies have examined the acute effects of low doses of LSD in individuals with psychiatric symptoms. In the current study, we examined the acute and sub-acute effect of a low dose of LSD (26 µg) on subjective effects and mood in volunteers with mild depressed mood. The study used a randomized, double-blind, crossover design to compare the effects of LSD in two groups of adults: participants who scored high (≥17; n = 20) or low (<17; n = 19) on the Beck Depression-II inventory (BDI) at screening. Participants received a single low dose of LSD (26 µg) and placebo during two 5-h laboratory sessions, separated by at least one week. Subjective, physiological, and mood measures were assessed at regular intervals throughout the sessions, and behavioral measures of creativity and emotion recognition were obtained at expected peak effect. BDI depression scores and mood ratings were assessed 48-h after each session. Relative to placebo, LSD (26 µg) produced expected, mild physiological and subjective effects on several measures in both groups. However, the high BDI group reported significantly greater drug effects on several indices of acute effects, including ratings of vigor, elation, and affectively positive scales of a measure of psychedelic effects (5D-ASC). The high BDI group also reported a greater decline in BDI depression scores 48-h after LSD, compared to placebo. These findings suggest that an acute low dose of LSD (26 µg) elicits more pronounced positive mood and stimulant-like effects, as well as stronger altered states of consciousness in individuals with depressive symptoms, compared to non-depressed individuals.
Subject terms: Depression, Translational research
Introduction
Depression is a debilitating and highly prevalent mental health condition, affecting over 8% of the US population [1], and millions more worldwide [2]. Because many patients fail to respond to standard medications, there is an urgent need for alternative therapeutics. One promising new candidate treatment is administration of single high doses of psychedelic compounds such as psilocybin and lysergic acid diethylamide (LSD), combined with supportive psychotherapy [3–7]. Yet, high doses of psychedelics also have risks and they require substantial time and effort from trained personnel [8]. One interesting alternative therapeutic approach is to use very low doses, or “microdoses” of psychedelic drugs, which reportedly have some anti-depressant effects.
Microdosing is a popular, but medically unsanctioned practice. Users report that repeated ingestion of LSD at doses 1/10 to 1/20th of a full “tripping” dose, improves depression, mental health and enhances cognitive functions including creativity, without producing disruptive perceptual effects [9–11]. However, the claims are based mainly on anecdotal reports which provide little information about the characteristics of the users, their expectancies, or the drug they self-administer. Several recent placebo-controlled studies have examined the effects of microdoses of LSD in healthy adults, either using “citizen-science” naturalistic designs or laboratory based studies with healthy adults [12–21]. With the exception of one study that found transient mood-enhancing effects [15], these studies have by and large failed to support the claims of beneficial psychiatric effects. Until now, however, most of these studies have been conducted in healthy adults without significant psychiatric symptoms. It is possible that low doses of LSD only produce detectable effects in individuals with negative mood symptoms at baseline.
In the current study, we assessed the effects of a single low dose of LSD (26 µg) or placebo in participants who scored above average on a standardized measure of depression. Participants who scored high (17 or higher) on the Beck Depression Inventory-II (BDI) were compared to participants with low scores (<17) in their mood, cardiovascular and behavioral responses to a single dose of LSD or placebo. Measures of depression were obtained both during the drug effect and also 48-h later.
Methods and materials
Design
We used a two-group, double-blind, placebo-controlled, cross-over design in which participants high or low on depression received LSD (26 µg) and placebo on two laboratory sessions. (We refer to the “high” depression group here only to contrast the two study groups; the symptoms reported by the depressed group were in the mild range, relative to patients meeting diagnostic criteria for depression). The order was randomized and the sessions were separated by at least 7 days. The two groups were formed based on participants’ Beck Depression Inventory-II (BDI) scores at screening: Low BDI (<17; n = 19) and High BDI (≥17; n = 20). For both groups, mood, subjective drug effects, behavioral tasks, cardiovascular measures, and single plasma samples were obtained to measure LSD levels. EEG data was also collected (not reported here). The primary outcome measures were the change in BDI scores from pre-study (orientation session) to 48 h after each session, and mood ratings during sessions.
Participants
Thirty-nine healthy volunteers (age 18–35 years) participated in the study (See CONSORT Diagram, Fig S1). They were recruited from the University of Chicago, via posters and internet advertisements on social media. Ads for the depressed group included the heading “Are you depressed?”. Study inclusion criteria were fluency in English, minimum high school education, BMI 19–30 kg/m2, no current medications aside from oral contraceptives, and some previous experience with a psychedelic (e.g., psilocybin, LSD, mescaline, dimethyltryptamine, or MDMA) with no adverse reactions. Screening included a physical exam, electrocardiogram, semi-structured psychiatric interview, and detailed drug use history questionnaire. Exclusion criteria were psychiatric conditions including current suicidal ideation, severe post-traumatic stress disorder, obsessive-compulsive disorder, or panic disorder, lifetime psychotic disorder, past year history of substance use disorder or adverse responses to psychoactive drugs, medical conditions contraindicating study participation and pregnancy or planned pregnancy in women. Participants were not explicitly evaluated for Major Depressive Disorder, but most reported only depressed mood.
Drugs
LSD tartrate (Organix Inc) in a tartaric acid solution was prepared by the University of Chicago Investigational Pharmacy. The 26 µg dose of LSD was administered in 0.4 mL of solution sublingually, and 0.4 mL of distilled water was administered during placebo sessions. The 26 µg dose of LSD produces modest subjective and cardiovascular effects in some individuals [13, 22].
Procedure
Orientation
During an orientation session, participants were given information about the study and provided written, informed consent. The study was approved by the Institutional Review Board of the Biological Sciences Division of the University of Chicago. To minimize drug-specific expectancies, participants were informed that they might receive a placebo, a stimulant such as amphetamine, a sedative such as valium, or a hallucinogenic drug such as LSD. They were instructed to fast for at least 8 h prior to the sessions, abstain from drug use for at least 48 h, cannabis use for at least 7 days, and alcohol use for 24 h before the sessions.
Study sessions
The two 5 h in-lab sessions were conducted from 9:00 a.m. to 2:00 p.m., separated by at least 7 days. Upon arrival, abstention from drugs and alcohol was verified by urinalysis (CLIAwaived Instant Drug Test Cup) and breathalyzer tests (Alco-Sensor III, Intoximeters, St Louis, MO). Women were tested for pregnancy. Participants then provided baseline subjective mood and cardiovascular measures (see below). At 9:30 am, participants ingested a dose of LSD (26 µg) or placebo under double-blind conditions. They were instructed to hold the solution sublingually for 60 s before swallowing. Plasma samples for LSD detection were obtained 60 min after administration, when levels were expected to peak [23, 24]. Participants completed subjective mood and drug effects measures at regular intervals throughout the session, and blood pressure and heart rate were recorded.
Participants completed the BDI and Profile of Mood States (POMS) questionnaires online 48 h after each in-lab session.
Depression measure
Beck Depression Inventory-II [BDI] [25]
The BDI is a 21-item inventory that assesses the severity of depression, from 0 to 63. Although cutoff scores for depressed mood vary across studies [26–29], the manual suggests scores of 0–13 indicate no depression, 14–19 indicates mild-moderate depression, 20–28 indicates moderate-severe depression, and 29–63 indicates severe depression. Participants completed this inventory during screening, orientation, and 48-h after each drug session. Although this questionnaire usually refers to how individuals are feeling during the past week, we asked participants to respond to the questionnaire based on how they felt at the moment they were completing the questionnaire.
Subjective measures taken during study sessions
Drug Effects Questionnaire [DEQ]: [30, 31]
The DEQ consists of questions presented on a visual analog scale about the subjective effects of drugs. For the present analysis, participants rated on a 100 mm line, ranging from “not at all” to “very much” (0–100), the extent to which they felt a drug effect.
Addiction Research Center Inventory [ARCI]:[32]
The ARCI is a 53-item true or false questionnaire with the following scales measuring typical drug effects: amphetamine (A); benzedrine group (BG; energy and intellectual efficiency); morphine-benzedrine group (MBG; euphoric effects); LSD (hallucinogen-like effects); pentobarbital-chlorpromazine-alcohol group (PCAG; sedative effects); and marijuana (M).
Profile of Mood States [POMS]:[33]
The POMS consists of 72 adjectives commonly used to describe momentary mood states. The POMS is sensitive to the effects of drugs in similar samples of healthy volunteers [34]. It has 9 subscales: anger, anxiety, confusion, depression, elation, fatigue, friendliness, vigor, positive mood.
5-Dimensional Altered States of Consciousness [5D-ASC]: [35, 36]
The 5D-ASC is sensitive to psychedelics [37], and assesses altered states of consciousness across three broad domains: oceanic boundlessness, anxious ego dissolution, and visionary restructuralization. Within these domains are eleven subscales: experience of unity, spiritual experience, blissful state, insightfulness, disembodiment, impaired control/cognition, anxiety, complex imagery, elementary imagery, audio-visual synesthesiae, and changed meaning of percepts..
End of session questionnaire [ESQ]
The ESQ was completed at the end of each drug session. Participants were asked to identify what they believed they received during the session by selecting from one of four drug classes: placebo, hallucinogen, stimulant, or sedative. They also completed a visual analog scale rating on how much they “liked the drug effect” (“dislike” [−50] to “like very much” [+50]).
Behavioral measures taken during study sessions
Creativity tasks and emotional faces recognition task
Participants completed four creativity-related tasks at the expected time of peak drug effects: divergent association (DAT), forward flow (FF), remote associations (RAT), and alternative uses (AUT) tasks. They also completed an emotion recognition task (see supplementary materials for detailed methodology).
Physiological measures taken during study sessions
Cardiovascular measures
Blood pressure and heart rate were monitored using portable blood pressure cuffs (Omron BP791IT, Omron Healthcare).
Plasma LSD
Plasma samples to detect LSD levels were collected 60 min after drug administration at expected peak effect. They were immediately stored at −80 °C. The samples were analyzed by the Mass Spectrometry Core at the University of Illinois Chicago for detection of LSD concentrations (see supplementary materials for detailed methodology).
Data analysis
Mixed model analysis of variance (ANOVA) was conducted using drug condition (LSD, placebo) as a within-subject variable, and BDI group (high, low) as a between-subject factor (SPSS Version 25). Change scores were calculated to assess lasting changes for BDI (orientation to post session 1 and 2), and POMS (just prior to drug administration to post session 1 and 2). For these change score analyses, drug order (LSD-placebo or placebo-LSD) was included as a between-subject factor to determine whether order had an effect on lasting depression and mood ratings. Changes scores were also calculated for subjective and cardiovascular measures taken within the sessions. For these, we calculated the peak change from baseline (i.e., before drug or placebo was administered) to the highest or lowest value during the session. The exception to this was ratings of “feel drug” effect, for which we analyzed both peak values and all time points during the session). The criterion for significance was p < 0.05.
The Benjamini-Hochberg method using a false discovery rate of 5% was applied to control for multiple comparisons on all outcome measures, excluding the primary outcome measures (BDI and POMS depression change scores).
Results
Demographics
High and low BDI groups did not differ on most variables including age, education level, and past drug use history. The two groups differed on BDI scores at orientation: High BDI group mean of 18.7 (SD ± 7.4) and low BDI group 3.9 (SD ± 4.3) (Table 1).
Table 1.
Demographic characteristics and drug use histories of the Low BDI Group (N = 19) and High BDI Group (N = 20).
| Low BDI Group n (%) or Mean (± SD) |
High BDI Group n (%) or Mean (± SD) |
|
|---|---|---|
| Male, Female, Other | 10, 9, 0 | 11, 8, 1 |
| Race/ Ethnicity | ||
| African American | 1 (5%) | 2 (10%) |
| Asian | 1 (5%) | 5 (25%) |
| Caucasian | 14 (74%) | 9 (45%) |
| Hispanic | 1 (5%) | 1 (5%) |
| Other/More than one | 2 (10%) | 3 (15%) |
| Age, Years | 25.5 ( ± 3.6) | 26.9 ( ± 3.6) |
| BMI | 23.1 ( ± 2.2) | 23.2 ( ± 2.7) |
| Education in years | 15.8 ( ± 1.3) | 15.6 ( ± 1.8) |
| BDI score at orientation | 3.9 ( ± 4.3) | 18.7 ( ± 7.4)*** |
| Drug Use in Past Month | ||
| Caffeinated drinks per day | 1.3 ( ± 1.3) | 1.5 ( ± 1.3) |
| Daily nicotine users | 1 (5.3%) | 4 (20%) |
| Alcoholic drinks per week | 4.3 ( ± 5.9) | 4.6 ( ± 5.0) |
| Cannabis use in past 30 days | 8.0 ( ± 10.5) | 7.3 ( ± 10.0) |
| Lifetime Nonmedical Drug Use (n never used, 1–10, > 11 times) | ||
| Cannabis | 0, 2, 17 | 0, 1, 19, |
| Sedatives | 15, 3, 1 | 19,1,0 |
| Stimulants | 16, 1, 2 | 17,1,2 |
| Opiates | 10, 8, 1 | 8, 8, 4 |
| Psychedelics | 2, 14, 3 | 3, 15, 2 |
| MDMA | 6, 10, 3 | 9, 9, 2 |
Independent samples t-test, High BDI Group vs. Low BDI Group, ***p < 0.001.
Subjective measures taken during study sessions
Drug-effect ratings
LSD significantly increased “feel drug” ratings relative to placebo in both low and high BDI groups (drug × time, F(4,148) = 31.9, p < 0.001, at 60, 120, 195, and 255 min post-drug administration). The groups did not differ on this measure (Fig. 1A). At the end of the sessions, participants rated liking the drug effect significantly more after LSD, relative to placebo (drug, F(1,37) = 20.7, p < 0.001, ƞp2 = 0.4; Fig. 1B). The high BDI group showed a trend for liking the effects of LSD more than the low BDI group (drug × group, F(1,37) = 3.7, p = 0.06, ƞp2 = 0.1).
Fig. 1. Subjective effects after LSD in the Low and High BDI groups.
A Mean (SEM) ratings for “feeling a drug effect” at specified time intervals after administration of LSD (solid lines) and placebo (dashed lines) in the low BDI (green square) and high BDI (blue diamond) groups. B End of session ratings of drug-liking after placebo (hatched bars) or LSD (solid bars) in the low (green) and high (blue) BDI groups. Bars depict mean ratings ± SEM. C Scatterplot represents the relationship between peak “feel drug effect” ratings after LSD (LSD minus placebo) and LSD concentrations (pg/mL) from plasma obtained 60 min after drug administration. p < 0.0005***.
Baseline ARCI and POMS scores
Before examining peak change scores in the two groups, we examined baseline (pre-drug) subjective self-reports in the two BDI groups. Baseline scores from LSD and placebo sessions were averaged to determine possible group differences in mood states at baseline. On POMS measures, participants in the high BDI group scored higher on anxiety, confusion, depression and fatigue, and lower on positive mood (Table S1).
Peak change from baseline ARCI and POMS scores
POMS
In the two BDI groups combined, LSD increased peak change POMS scores on anxiety (F(1,37) = 4.6, p = 0.04, ƞp2 = 0.11), and friendliness (F(1,37) = 5.7, p = 0.02, ƞp2 = 0.13) scales, and LSD significantly decreased ratings on the fatigue scale (F(1,37) = 4.6, p < 0.001, ƞp2 = 0.30) compared to placebo. LSD significantly increased elation and vigor (POMS) scores only in high BDI participants (drug × group, elation F(1,37) = 6.1, p = 0.02, ƞp2 = 0.14; vigor F(1,37) = 7.6, p = 0.009, ƞp2 = 0.17), and a trend was observed for a greater effect of the drug in the high BDI group on positive mood (drug × group, F(1,37) = 3.3, p = 0.08, ƞp2 = 0.08) (Fig. 2A, B). The high BDI group reported a greater decrease in POMS depression than the low BDI group, for both drug and placebo sessions (main effect of group, F(1,37) = 8.9, p = 0.005, ƞp2 = 0.20) (Table S2).
Fig. 2. Acute subjective and mood effects after LSD in the Low and High BDI groups.
Acute effects of LSD (26 µg) in the low (green) and high (blue) BDI groups on the following subjective measures: (A) POMS positive mood scale, (B) POMS vigor scale, (C) ARCI MBG (euphoria) scale, and (D) ARCI LSD scale. All points depict mean scores ± SEM. Pre-values indicate baseline (pre-drug) scores and post-values indicate peak ratings after drug-administration. Main effect of drug, p < 0.005**, p < 0.0005***; drug × group interaction, &p < 0.08, #p < 0.05.
ARCI
Regardless of group, LSD significantly increased ARCI scores on A (amphetamine; F(1,37) = 15.8, p < 0.001, ƞp2 = 0.30), BG (energy and intellectual efficiency; F(1,37) = 8.3, p = 0.006, ƞp2 = 0.18), LSD (F(1,37) = 14.7, p < 0.001, ƞp2 = 0.28), and MBG (euphoric effects; F(1,37) = 13.3, p = 0.001, ƞp2 = 0.26) scales. LSD had a greater effect on the M (marijuana) scale in the high BDI group relative to the low BDI group (drug × group, F(1,37) = 4.8, p = 0.03, ƞp2 = 0.12) (Table S2 and Fig. 2C, D).
Physiological measures taken during study sessions
Cardiovascular measures
LSD increased systolic (F(1,37) = 7.7, p = 0.009, ƞp2 = 0.17) and diastolic (F(1,37) = 10.3, p = 0.003, ƞp2 = 0.22) blood pressure, and had no effect on heart rate (p = 0.7). These effects were similar for both BDI groups (Table S2).
Plasma LSD
Mean LSD concentrations (60 min post-drug administration) are shown in Table S2. Plasma levels did not differ in the two groups (low BDI group, 410.8 pg/mL ± SEM: 21.6; high BDI group, 509.8 pg/mL ± SEM: 44.9; independent t-test, two-tailed, p > 0.05). Plasma levels were not related to either peak “feel drug” ratings (LSD minus placebo session; Fig. 1) or drug liking ratings (p > 0.5).
Behavioral measures taken during study sessions
Creativity Tasks
LSD, relative to placebo, did not significantly alter performance on the DAT, FF, RAT, or AUT measures of fluency, flexibility, and originality, for either BDI group (Table S3).
Emotional Facial Recognition Task
Regardless of drug, participants in the high BDI group rated happy faces significantly lower on positive valence (F(1,35) = 6.3, p = 0.02, ƞp2 = 0.15) and arousal (F(1,35) = 8.0, p = 0.008, ƞp2 = 0.19), relative to the low BDI group. LSD significantly increased positive valence ratings for happy faces (F(1,35) = 5.7, p = 0.02, ƞp2 = 0.14) in both groups, but did not alter arousal ratings for happy faces. LSD, relative to placebo, did not significantly affect valence or arousal ratings for angry or neutral faces in either BDI group (Table S3).
End of study session measures
5D-ASC
In both BDI groups, LSD increased scores on the following scales relative to placebo: experience of unity (drug, F(1,37) = 15.2, p < 0.001, ƞp2 = 0.29), impaired control and cognition (drug, F(1,37) = 7.1, p = 0.01, ƞp2 = 0.16), anxiety (drug, F(1,37) = 15.2, p < 0.001, ƞp2 = 0.29), anxious ego dissolution (drug, F(1,37) = 6.5, p = 0.02, ƞp2 = 0.15), complex imagery (drug, F(1,37) = 18.0, p < 0.001, ƞp2 = 0.33), elementary imagery (drug, F(1,37) = 18.4, p < 0.001, ƞp2 = 0.33), audio-visual synesthesiae (drug, F(1,37) = 6.3, p = 0.02, ƞp2 = 0.15), changed meaning of percepts (drug, F(1,37) = 15.1, p < 0.001, ƞp2 = 0.29), and visionary restructuralization (drug, F(1,37) = 25.7, p < 0.001, ƞp2 = 0.41).
LSD had a greater effect in the high BDI group relative to the low BDI group on the following scales: spiritual experience (drug × group, F(1,37) = 4.8, p = 0.04, ƞp2 = 0.12), blissful state (drug × group, F(1,37) = 6.9, p = 0.01, ƞp2 = 0.16), insightfulness (drug × group, F(1,37) = 5.9, p = 0.02, ƞp2 = 0.14), oceanic boundlessness (drug × group, F(1,37) = 5.0, p = 0.03, ƞp2 = 0.12), and disembodiment (drug × group, F(1,37) = 4.8, p = 0.04, ƞp2 = 0.12) (Fig. 3).
Fig. 3. Effects of LSD on the 5-Dimensional Altered States of Consciousness measure in the Low (green) and High (blue) BDI groups.
Results are shown for the following domains: A Oceanic Boundlessness, B Anxious Ego Dissolution, and C Visionary Restructuralization. Bars depict mean ratings ± SEM for placebo (hatched bars) and LSD (solid bars) conditions. Main effect of drug, *p < 0.05, ***p < 0.0005; drug × group interaction: high BDI - LSD vs placebo, #p < 0.05, ##p < 0.005; low BDI - LSD vs placebo, $p < 0.05.
ESQ
About half the participants correctly identified receiving a hallucinogen during their LSD session, in both groups (42 percent correct in the low BDI group, and 50 percent correct in the high BDI group. Similarly about half correctly identified placebo in both groups (Fig. S2).
48-hrs post-session measures
BDI
In the high BDI group, but not the low BDI group, BDI scores decreased 48 h after the LSD session, compared to placebo (drug × group F(1,35) = 4.3, p < 0.05, ƞp2 = 0.11; post-hoc t-test, p < 0.05, high BDI group LSD vs. placebo). There were no effects of drug order on BDI change scores (p = 0.3) (Fig. 4).
Fig. 4. Effect of LSD (26 µg) on Beck Depression Inventory-II (BDI) ratings 48 h after drug administration sessions in low BDI (green) and high BDI (blue) groups.
Participants responded to BDI items based on how they felt in the moment. BDI difference scores were calculated by subtracting 48 h post-session scores from orientation scores. Bars depict mean difference scores (±SEM) 48 h after placebo (hatched bars) and LSD (solid bars) sessions. drug × group interaction, post-hoc t-tests, p < 0.05*, p < 0.0005***.
POMS
Change scores were calculated for all POMS scales 48 h after the session minus pre-drug baseline. In both BDI groups, fatigue scores were higher 48 h after placebo sessions compared to after LSD sessions (drug F(1,35) = 4.8, p = 0.03, ƞp2 = 0.12), and anxiety scores were significantly lower 48 h after LSD relative to placebo (drug × order, F(1,35) = 7.2, p = 0.01, ƞp2 = 0.17). In the high BDI group, but not the low BDI group, there was a reduction in anger (drug × group × order, F(1,35) = 5.6, p = 0.02, ƞp2 = 0.14) and depression (drug × group × order, F(1,35) = 4.4, p = 0.04) 48 h after the LSD session compared to placebo, along with an increase in positive mood (drug × group × order, F(1,35) = 4.4, p = 0.04, ƞp2 = 0.11) (Table S4). Examination of order effects revealed that the change scores from before to after sessions were greater when participants received LSD first. There were no significant effects of drug or BDI group on confusion, elation, friendliness, or vigor.
Discussion
In this study we examined the effects of a low dose of LSD in participants who scored higher than average on a measure of depression. Participants with mild to moderate depression (BDI score ≥17; range of scores at screening: 17–32) formed the "high” depression group and individuals who scored in the non-depressed range (BDI score <17; range of scores at screening: 0–14) formed the low depression group. LSD produced its expected effects on subjective ratings and blood pressure. As hypothesized, the two groups differed on several measures of subjective responses to LSD: the high BDI group reported greater increases on mood measures of "vigor” and "elation” (POMS) after LSD, and they reported greater psychoactive effects on some measures of the 5D-ASC. On BDI depression ratings obtained two days after each session, the high BDI group reported lower depression scores after LSD than after placebo sessions (relative to scores at orientation). The low BDI group scored low on BDI at orientation and after both sessions. Interestingly, the high BDI group did not report greater drug effects on all measures: The groups did not differ on ratings of "feeling a drug effect”, cardiovascular measures, increases in "friendliness” and "anxiety” (POMS), or LSD or stimulant-like scales on the ARCI. Thus, the high BDI group were not more sensitive to LSD overall, but preferentially were more sensitive to only certain measures of subjective response to the drug.
The finding that the more depressed participants reported greater effects from LSD than non-depressed participants on certain subjective measures is novel, and may provide some insight as to why previous studies have failed to detect beneficial effects from the drug. Until now, most studies have tested low doses of LSD in healthy volunteers, or in un-screened members of the general population. In contrast, this study focused on individuals with some symptoms of depression. The group differences observed here may help to explain the apparent discrepancy between users” anecdotal reports in surveys and the findings from controlled studies. Baseline scores revealed differences in mood prior to receiving the drug, including higher anxiety, fatigue, depression, and confusion in the high BDI group. The drug produced greater increases in "elation” and "vigor” on the POMS, in the high BDI group. On the 5DASC, participants in the high BDI group reported greater increases within the Oceanic Boundlessness dimension, which captures spiritual and positively-felt experiences. A greater increase was also observed on the marijuana scale of the ARCI, which was primarily driven by higher ratings on items related to somatic changes. In contrast to these group differences in drug responses, the groups reported similar levels of feeling a drug effect, feeling anxious, less fatigued, more friendly, or stimulated (as measured by the ARCI), and they were similar in their ability to identify what they had received. The specificity of the group differences suggests that individuals with greater levels of depressed mood may experience more positive, and more stimulant-like subjective effects from LSD.
The difference in response to LSD was also evident in the measure taken two days after the sessions. There was a significant difference in BDI scores 48 h after the high BDI group received LSD compared to when they received placebo, suggesting that the drug had lasting effects on depression. This finding is consistent with our hypothesis, and with users’ claims that the drug has some lasting anti-depressant effects. This finding supports the idea that the drug may have anti-depressant effects in some people. The potential mechanism behind these lasting effects remain unclear. Imaging studies show depression is linked to decreased cortical volume [38]. Preclinical research has demonstrated that LSD promotes neuroplasticity in cortical neurons, and this can be seen 24 h after treatment [39]. The cortical changes induced by psychedelics have recently been shown to depend on known neuroplasticity mediators, BDNF and TrkB [40]. However, it is uncertain whether these mechanisms contribute to the observed anti-depressant effects in this study, where a single low dose of LSD was administered. Future studies should examine structural or functional changes in relevant cortical regions, and monitor BDNF levels in the days following treatment.
It will also be important to determine in future studies if this observation is replicable, how long the effect lasts, and if it is more pronounced when combined with psychotherapy, or in individuals with more severe depression or after repeated doses of the drug. It is difficult to compare the changes in depression between the two groups in the present study because depression was near-zero in the low depression group at all times. We note that the BDI scores in the high BDI group declined over the roughly two weeks of the study: ratings were highest at screening and orientation and lowest at the last measure of the study. This decline in symptoms has been reported in many other psychiatric treatment studies [41].
We detected a decrease in depression scores 48 h after the sessions in the high BDI group, but LSD did not decrease POMS depression scores during the sessions. In the high BDI group, depression scores declined 48 h after the LSD session, relative to placebo. This was measured by both the BDI and the POMS. However, during the sessions, we did not observe an LSD related decrease in POMS depression. It is possible that the anti-depressant effects of LSD are not immediately detectable.
In the present study, LSD did not affect measures of cognition or creativity, including measures of divergent association, remote associations or alternative uses. The lack of effect on these measures is largely consistent with the findings of Cavanna et al. [17] who reported that low doses of psilocybin also did not alter these measures of creativity. Murphy et al. [15] found that low doses of LSD produced small increases in self-reported creativity, but the drug did not significantly alter any standard measures of cognition (e.g., memory or inhibitory control). Creativity is a complex construct [42], and it is not clear that the existing objective measures of creativity reflect the same constructs that elicit self-reports of increased creativity. It remains an interesting future challenge to determine how low doses of psychedelic drugs change perception or cognition in ways that lead to the self-reported experience of creativity.
The present study had both strengths and limitations. Strengths include the use of double-blind procedures and a broad range of standardized outcome measures, including self-report as well as objective measures. It is also among the first to test the effects of a low dose of psychedelic drug in individuals who report some depressive symptoms. One limitation of the study is the relatively modest level of symptoms reported by the high BDI group, and the fact that these participants’ scores declined over the course of the study regardless of drug administration. It will be important to extend the study with participants who report more severe symptoms of depression. Another limitation is that only a single dose was administered. This was a first step to detect any effect in this population. Future studies are needed to examine effects of microdoses of psychedelic drugs taken repeatedly. There is also a need to test the potential antidepressant effect of lower doses, including doses that do not elicit any perceptual and subjective effects. Another limitation is that only one plasma sample was obtained after drug administration for LSD level analysis. These samples were collected at expected peak drug effect [23, 24], and notably, we did not find a significant relationship between subjective feel drug ratings and plasma concentrations of LSD. To gain a better understanding of this relationship, future studies should involve the collection of plasma at multiple time points after drug administration. Finally, our subject sample was demographically homogeneous, consisting of adults who had some experience with a psychedelic in the past with minimal negative experiences. Future studies should assess whether similar findings are obtained in diverse populations with more psychiatric symptoms and past drug use history.
In summary, participants who scored higher than average on the BDI reported greater increases in ratings of elation and vigor after a single low dose of LSD, compared to volunteers whose scores were in the normal range. LSD was administered under double blind conditions, and responses were compared to placebo control. The participants were mainly healthy young adults, half of whom reported mild symptoms of depression, as assessed by the BDI. Interestingly, the increased sensitivity to the drug were limited to elation and positive mood, and the high and low BDI groups did not differ on ratings of feeling the drug, or on other subjective or physiological measures. The findings suggest that baseline mood and psychiatric symptoms may enhance certain responses to the drug in some individuals. This is important because many survey studies and anecdotal reports suggest that low doses of LSD improve mood, but controlled studies have found little support for this. The controlled studies to date have included mainly healthy adults, and the present findings raise the possibility that the drug differentially affects individuals with pre-existing psychiatric symptoms. The findings raise interesting questions about the specificity of this effect, its relevance to the popular practice of microdosing and its neurobiological basis.
Supplementary information
Acknowledgements
The authors acknowledge the support of the Mass Spectrometry Core in Research Resources Center of University of Illinois at Chicago. Clinical trials registry: Clinicaltrials.gov, Mood Effects of Serotonin Agonists (NCT03790358).
Author contributions
HdW, HM, and RL contributed to the design and implementation of the study. IT carried out the data collection. HM analyzed the data. HdW and HM prepared the manuscript. All authors reviewed and edited the final manuscript.
Funding
This work was supported by National Institutes of Health (grant DA02812). HM was supported by T32GM07019.
Competing interests
HdW is on the Board of Directors of PharmAla Biotech and consultant to Awakn Life Sciences and Gilgamesh Pharmaceuticals. These were unrelated to the present research. HM, RL, and IT report no conflicts.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41386-023-01772-4.
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