Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity

Interest in classic psychedelics as treatments for psychiatric disorders has resurged, with prior clinical trials suggesting that single, relatively high doses of agents such as LSD or psilocybin can relieve mood and anxiety symptoms. Psychedelics principally act as serotonin (5-HT2A) agonists and, in the case of LSD, also engage dopamine systems implicated in reward processing. Deficits in neural reward processing are a prominent feature of depressive disorders, and electrophysiological markers of reward feedback (e.g., the Reward-Positivity, RewP) are often blunted in depression. Separately, anecdotal reports and popular interest in repeated very low doses of LSD (“microdosing”) claim improvements in mood and cognition, but controlled data on low-dose effects — especially on neural measures of reward — remain limited. Glazer and colleagues set out to test whether single, low doses of LSD alter neural indices of reward processing in healthy adults. Using scalp electroencephalography (EEG) and the electrophysiological monetary incentive delay (eMID) task, the investigators focused on three feedback-related event-related potentials (ERPs): the frontocentral Reward-Positivity (RewP), the parietal Feedback-P3 (FB-P3), and the Late-Positive Potential (LPP). The primary hypothesis was that single low doses of LSD (13 or 26 μg) would increase reward-related ERP amplitudes during feedback processing, consistent with effects that might be relevant to antidepressant mechanisms.

The study used a within-subject, double-blind design. Eighteen healthy young adults (N = 18; 6 women; age range 18–35) completed three 5-hour sessions in randomized order, receiving sublingual placebo (LSD-0), 13 μg LSD (LSD-13), and 26 μg LSD (LSD-26). EEG was recorded while participants performed the electrophysiological monetary incentive delay (eMID) task between approximately 120 and 180 minutes after drug administration. The extracted STUDY DESIGN text contained a small omission in one sentence about the 26 μg dose, but the 26 μg dose is reported elsewhere in the document. Participants underwent medical and psychiatric screening (physical exam, ECG, modified SCID-5, self-report health and drug history). Inclusion criteria included English fluency, right-handedness, at least high-school education, BMI 18–29 kg/m2, and at least one prior use of a classic psychedelic or MDMA. Exclusions included history of psychosis, severe PTSD or panic disorder, past-year substance use disorder (except nicotine), pregnancy or nursing, night-shift work, regular medications other than birth control, adverse reaction to psychedelics, or unwillingness to use such drugs again. None of the participants met criteria for major depressive disorder, although this was not an exclusion. The eMID task presented reward or neutral cues, a target requiring a speeded response, and feedback indicating 'Win' or 'Lose'. Reward trials signalled the possibility of gaining US$1.50; neutral trials carried no monetary consequence though feedback still conveyed performance information. Positive and negative feedback were presented approximately 50% of the time via an adaptive algorithm that adjusted target duration; this equiprobability was used to control for frequency effects on ERPs but complicates interpretation of behavioural performance. The full task comprised 180 trials (30 of each feedback type: Reward Win, Reward Lose, Neutral Win, Neutral Lose). EEG preprocessing used EEGLAB and ERPLAB in MATLAB. Data were resampled to 250 Hz, re-referenced to average mastoids, and 64 channels retained. Line noise and noisy channels were removed, then ICA (after a 1.0 Hz high-pass filter and removal of large-amplitude segments) was applied to correct ocular and muscle artifacts; ICA weights were then applied to the unfiltered data. After artifact correction, data were bandpass filtered 0.1–30 Hz and epoched into feedback-related segments. Participants with fewer than 20 trials per feedback condition were excluded; the retained sample (N = 18) had an average of 28.577 trials per feedback bin (SD = 2.970). ERP measurement focused on three components: the RewP (measured as mean amplitude 250–350 ms at FCz as the difference between positive and negative feedback), the FB-P3 (a parietal component indexing motivational salience), and the LPP (indexing affective value of feedback). Statistical analyses employed repeated-measures ANOVAs with Greenhouse-Geisser correction where appropriate; Cohen’s d was used to report t-test effect sizes. The paper notes that related analyses on anticipatory ERPs showed no significant dose associations (details in Supplementary Materials). Subjective measures were collected and analysed but most detailed analyses are reported in supplementary material.

The extracted results text is fragmentary, but the main findings are reported in the Results and Discussion sections. A repeated-measures ANOVA showed a significant three-way interaction of drug dose × feedback condition × feedback valence (F(2,34) = 3.631, p = 0.047, partial η2 = 0.176). Follow-up analyses indicated dose-specific effects on the feedback-related ERPs. In the reward feedback condition, LSD-13 (13 μg) significantly increased RewP difference-wave amplitudes for positive versus negative feedback compared with placebo, indicating enhanced hedonic impact of reward feedback. LSD-13 also increased LPP amplitudes for reward (vs. neutral) feedback, suggesting an increased affective response to feedback. Both LSD-13 and LSD-26 increased FB-P3 amplitudes for positive (vs. negative) feedback relative to placebo, consistent with greater motivational salience of positive outcomes under drug conditions. The paper notes that in the placebo condition negative feedback slightly increased FB-P3 amplitudes, a pattern that was reversed after LSD doses. Subjective measures indicated that LSD-13 and LSD-26 produced modest stimulant-like subjective effects, including increased energy, positive mood, elation, anxiety, intellectual efficiency, and ratings of 'bliss'. Most subjective ratings were not associated with ERP amplitudes. The investigators also report that ERPs during reward anticipation showed no significant associations with LSD dose (details referred to the Supplementary Materials). Trial counts and ERP measurement details were reported: 18 participants were retained with an average of ~28.6 trials per feedback bin (SD ~3). The extracted text does not provide complete numerical effect sizes or confidence intervals for each ERP comparison beyond the ANOVA statistic noted above.

Glazer and colleagues interpret their results as the first evidence in humans that single, low doses of LSD can increase neural sensitivity to reward feedback. Specifically, a 13 μg dose enhanced hedonic (RewP) and affective (LPP) responses to reward feedback in the eMID task, while both 13 μg and 26 μg doses increased the motivational salience of positive versus negative feedback (FB-P3). The investigators note these ERP components are attenuated in depressive disorders, and therefore the observed increases could be relevant to antidepressant mechanisms if replicated in symptomatic samples or with repeated dosing. The authors place their findings within existing mechanistic literature, emphasising that LSD interacts with both serotonin and dopamine systems. They note preclinical and human studies suggesting LSD can affect frontostriatal dopamine signalling directly and indirectly via 5-HT pathways, and that such actions could plausibly modulate neural indices of reward. However, the role of specific 5-HT receptors in reward processing remains incompletely understood, and the authors frame dopamine–serotonin interactions as a possible mechanism rather than a demonstrated pathway in this study. Several limitations are acknowledged. The sample was small and relatively homogeneous in terms of mental health, body weight, education and prior psychedelic exposure; all participants had prior psychedelic experience. Menstrual cycle phase was not controlled in female participants, and the interval since participants’ last psychedelic use was not assessed biochemically (urine testing for recent psychedelic use was not performed). EEG recordings were made at a time when effects were expected to peak, but the full time course of neural effects relative to administration is not characterised. Low baseline depression scores prevented analyses in a clinical population. The small sample size limited statistical power and the ability to assess individual differences, dose–response relationships, or effects on anticipatory ERPs. The authors recommend future research with larger, more heterogeneous samples, controlled assessment of recent psychedelic exposure, explicit examination of repeated low-dose regimens, and investigation of the durability, optimal dosing, tolerance, interactions and safety profile of low-dose LSD. Overall, the investigators stress cautious interpretation: while single low doses altered reward-related ERPs in healthy adults, further work is required to determine whether repeated dosing produces clinically meaningful benefits for depressive symptoms and to elucidate the underlying neuropharmacology.

The study provides initial evidence that single, low doses of LSD (13 μg and 26 μg) increase neural sensitivity to reward feedback in healthy adults, affecting ERP components (RewP, FB-P3, LPP) that are commonly attenuated in depression. These doses produced modest subjective effects and did not affect ERPs during reward anticipation. Most subjective effects were not related to the observed changes in neural activity. The authors conclude that if these findings generalise to repeated low-dose administration and translate to symptomatic populations, they could help explain reported benefits of microdosing and inform future therapeutic investigations. They recommend studies of repeated dosing, larger samples, and broader outcome measures to evaluate durability, optimal dosing, individual variability, and safety.