Greater subjective effects of a low dose of LSD in participants with depressed mood

Depression remains a common, disabling condition for which many patients do not respond to standard treatments. Recent clinical and preclinical work has focused on high, single-dose psychedelic treatments (for example psilocybin or LSD combined with psychotherapy), but these approaches are resource intensive and carry risks. Anecdotal reports and surveys have suggested that very low ‘‘microdoses’’ of psychedelics can improve mood, mental health and creativity without overt perceptual disruption, yet controlled studies in healthy volunteers have mostly failed to confirm robust benefits. One important gap is that prior placebo-controlled microdose trials have largely tested healthy adults; it remains possible that low doses produce detectable effects only in individuals who have baseline negative mood or depressive symptoms. Molla and colleagues set out to test whether a single low dose of LSD (26 µg) produces stronger acute and short-term mood effects in volunteers with elevated depressive symptoms compared with non-depressed volunteers. The study used a randomized, double-blind, placebo-controlled, crossover design to compare subjective, physiological, behavioural and 48-hour follow-up mood measures in two groups defined by Beck Depression Inventory-II (BDI) scores at screening (high BDI ≥17, low BDI <17). The investigators aimed to capture both in-session effects and sub-acute changes 48 hours after dosing.

The study employed a two-group, double-blind, placebo-controlled crossover design. Thirty-nine healthy volunteers aged 18–35 were recruited and split into two groups on the basis of BDI screening scores: High BDI (≥17; n = 20) and Low BDI (<17; n = 19). Participants had to be English fluent, have at least high-school education, BMI 19–30 kg/m2, not be taking medications other than oral contraceptives, and have some prior psychedelic experience without adverse reactions. Screening included a physical exam, ECG, semi-structured psychiatric interview and drug history; participants were not formally assessed for Major Depressive Disorder, and most in the high BDI group reported only depressed mood in the mild range. Each participant completed two 5-hour laboratory sessions (09:00–14:00), at least 7 days apart, receiving 26 µg LSD tartrate in 0.4 mL solution sublingually (held 60 s) on one session and 0.4 mL distilled water placebo on the other, with randomized order. To reduce expectancy effects participants were told they might receive placebo, a stimulant, a sedative or a hallucinogen. Urine drug screens, breath alcohol tests and pregnancy tests (when applicable) were performed prior to sessions. A single plasma sample for LSD concentration was collected 60 minutes post-administration at expected peak effect. Outcome measures included momentary and peak subjective drug effects (Drug Effects Questionnaire, DEQ), standard drug-effect inventories (ARCI), Profile of Mood States (POMS) with nine subscales, 5D-ASC to assess altered states of consciousness, an End of Session Questionnaire (ESQ) to probe drug identification and liking, behavioural tasks of creativity (Divergent Association Task, Forward Flow, Remote Associates, Alternative Uses) at expected peak, an emotional face recognition task, cardiovascular monitoring (blood pressure and heart rate), and BDI and POMS completed online 48 hours after each session. Data analysis used mixed-model ANOVAs with drug condition (LSD, placebo) as a within-subject factor and BDI group (high, low) as a between-subject factor. Peak change scores from baseline were computed for in-session measures and change scores for 48-h outcomes; drug order was included as a between-subject factor where relevant. Statistical significance was set at p < 0.05, and the Benjamini–Hochberg false discovery rate (5%) was applied for multiple comparisons except for primary outcomes (BDI and POMS depression change scores).

Sample characteristics: Thirty-nine participants completed the study (age 18–35). The High BDI group had mean BDI at orientation 18.7 (SD 7.4) and the Low BDI group 3.9 (SD 4.3). The groups did not differ on most demographic variables or past drug use history. Subjective ‘‘feel drug’’ and liking: LSD increased ‘‘feel drug’’ ratings relative to placebo across both groups (drug × time, F(4,148) = 31.9, p < 0.001), with peak effects at 60–255 minutes. End-of-session liking was greater after LSD than placebo (drug F(1,37) = 20.7, p < 0.001, ηp2 = 0.4); there was a trend for the high BDI group to like LSD more than the low BDI group (drug × group F(1,37) = 3.7, p = 0.06, ηp2 = 0.1). Mood (POMS) and depression (BDI): At baseline the high BDI group scored higher on POMS anxiety, confusion, depression and fatigue and lower on positive mood. Across both groups LSD increased peak POMS anxiety (F(1,37) = 4.6, p = 0.04, ηp2 = 0.11) and friendliness (F(1,37) = 5.7, p = 0.02, ηp2 = 0.13), and decreased fatigue (F(1,37) = 4.6, p < 0.001, ηp2 = 0.30) relative to placebo. Crucially, LSD increased elation and vigor on the POMS only in the High BDI group (drug × group interactions: elation F(1,37) = 6.1, p = 0.02, ηp2 = 0.14; vigor F(1,37) = 7.6, p = 0.009, ηp2 = 0.17). For the primary 48-h outcome, BDI scores in the High BDI group decreased 48 hours after LSD compared with placebo (drug × group F(1,35) = 4.3, p < 0.05, ηp2 = 0.11; post-hoc p < 0.05 for High BDI LSD vs placebo). There were no drug-order effects on BDI change scores. ARCI and 5D-ASC: Relative to placebo, LSD increased ARCI scales associated with stimulant and euphoric effects across groups: amphetamine (A) F(1,37) = 15.8, p < 0.001, ηp2 = 0.30; BG F(1,37) = 8.3, p = 0.006, ηp2 = 0.18; LSD-like F(1,37) = 14.7, p < 0.001, ηp2 = 0.28; and MBG (euphoria) F(1,37) = 13.3, p = 0.001, ηp2 = 0.26. The marijuana (M) scale showed a larger LSD effect in the High BDI group (drug × group F(1,37) = 4.8, p = 0.03, ηp2 = 0.12). On the 5D-ASC, LSD increased many subscales in both groups (experience of unity, impaired control/cognition, anxiety, complex and elementary imagery, audio-visual synaesthesia, changed meaning of percepts, and visionary restructuralization), and produced greater increases in the High BDI group for spiritual experience (drug × group F(1,37) = 4.8, p = 0.04, ηp2 = 0.12), blissful state (F(1,37) = 6.9, p = 0.01, ηp2 = 0.16), insightfulness (F(1,37) = 5.9, p = 0.02, ηp2 = 0.14), oceanic boundlessness (F(1,37) = 5.0, p = 0.03, ηp2 = 0.12), and disembodiment (F(1,37) = 4.8, p = 0.04, ηp2 = 0.12). Physiology and plasma levels: LSD raised systolic (F(1,37) = 7.7, p = 0.009, ηp2 = 0.17) and diastolic blood pressure (F(1,37) = 10.3, p = 0.003, ηp2 = 0.22), with no effect on heart rate. Mean plasma LSD concentrations at 60 minutes did not differ significantly between groups (Low BDI 410.8 pg/mL ± SEM 21.6; High BDI 509.8 pg/mL ± SEM 44.9; p > 0.05) and were not correlated with peak ‘‘feel drug’’ or liking ratings (p > 0.5). Behavioural measures and emotion recognition: LSD did not significantly alter performance on the creativity measures (DAT, FF, RAT, AUT) in either group. On the emotional faces task, the High BDI group rated happy faces lower on valence and arousal relative to the Low BDI group regardless of drug. LSD increased positive valence ratings for happy faces across groups (F(1,35) = 5.7, p = 0.02) but did not affect ratings for angry or neutral faces. ESQ drug identification was near chance: about half of participants correctly identified receiving a hallucinogen during LSD sessions (42% Low BDI, 50% High BDI) and similar proportions correctly identified placebo. Sub-acute POMS at 48 h: Fatigue scores were higher 48 h after placebo than after LSD in both groups (drug F(1,35) = 4.8, p = 0.03, ηp2 = 0.12). Anxiety scores were lower 48 h after LSD relative to placebo (drug × order F(1,35) = 7.2, p = 0.01, ηp2 = 0.17). An interaction indicated a reduction in anger in the High BDI group that depended on drug order (drug × group × order F(1,35) = 5.6, p = 0.02). The investigators noted that change scores tended to be larger when LSD was administered first.

Molla and colleagues interpret their findings as evidence that a single low dose of LSD (26 µg) produces greater positive mood and certain stimulant-like subjective effects in individuals who report mild-to-moderate depressive symptoms compared with non-depressed volunteers. The high BDI group showed larger increases in POMS elation and vigor during the session and greater scores on positively valenced 5D-ASC subscales (for example oceanic boundlessness, spiritual experience, blissful state and insightfulness). Importantly, BDI scores in the high-symptom group were lower 48 hours after LSD than after placebo, suggesting a short-term sub-acute benefit on depressive symptoms in this sample. The authors position these results relative to prior microdose studies by emphasising that most previous controlled trials recruited healthy volunteers; testing individuals with baseline negative mood may explain why anecdotal reports of mood benefit have not been reproduced in healthy-sample laboratory studies. They also draw attention to the specificity of effects: the high and low BDI groups did not differ in feeling ‘‘a drug effect’’, cardiovascular responses, ARCI stimulant-like scales overall, or the ability to identify the drug, indicating that the enhanced sensitivity in the high BDI group was limited to particular positive mood and altered-consciousness measures rather than reflecting a global increased sensitivity to LSD. Several limitations are acknowledged. The high BDI group manifested only mild symptoms and participants’ depressive scores tended to decline over the roughly two weeks of the study irrespective of drug, which complicates interpretation. Only a single dose and a single post-dose plasma sample (at 60 minutes) were obtained, limiting pharmacokinetic–pharmacodynamic inferences; the investigators did not find a relationship between plasma level and subjective ratings. The sample was demographically homogeneous and comprised individuals with prior psychedelic experience, which may reduce generalisability. Finally, the study did not assess clinical Major Depressive Disorder, and the durability of the observed 48-hour mood effects remains unknown. The authors suggest several directions for future research: replicate the finding in larger and more clinically depressed samples, test repeated low-dose regimens and lower doses that may avoid perceptual effects, combine dosing with psychotherapeutic support, collect multiple plasma samples and biological measures (for example BDNF) to probe neuroplasticity mechanisms, and include more diverse participant populations. They conclude that baseline mood may moderate subjective and short-term antidepressant responses to low-dose LSD, a factor that could reconcile some discrepancies between anecdotal reports and prior controlled trials.