Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers

The study recruited 24 recreational psychedelic users who passed medical screening and provided informed consent. Test days were separated by at least five days and each participant received placebo and the three active low LSD doses in unique treatment orders under double‑blind, within‑subject conditions. Doses of 5, 10 and 20 mcg LSD base (administered orally in 96% ethanol) were given at 10:00 AM; placebo was ethanol alone. The equivalent tartrate values are noted by the investigators but analyses use mcg LSD base. Venous blood was drawn at −0.5h (baseline), +2h, +4h and +6h relative to dosing via a peripheral catheter into lithium heparin tubes. Plasma was separated and frozen at −20°C until assay. Plasma BDNF was quantified using a commercial ELISA (Biosensis Mature BDNF Rapid ELISA kit); samples were diluted 1:20, run in duplicate, and analysed blind to condition. The assay’s intra‑assay and inter‑assay coefficients of variation were reported below 10% (intra 4.29%, inter 7.14%). LSD plasma concentrations were measured by UHPLC‑MS/MS with an alternate extraction used for samples below 5 pg/mL, yielding a lower limit of quantification (LLOQ) of 2.5 pg/mL. The investigators calculated trapezoidal areas under the curve (AUC) for BDNF and for LSD plasma concentrations per dose. Statistical analyses used complete within‑subject cases in SPSS v25.0. Non‑parametric Wilcoxon signed‑rank tests compared placebo versus each LSD dose on BDNF AUCs and on BDNF levels at each timepoint. Friedman tests were run per treatment condition to test within‑condition time effects; significant Friedman tests were followed by Dunn’s pairwise comparisons (baseline v 2h, 4h, 6h; 2h v 4h; 4h v 6h) with sequential Bonferroni correction. Effect sizes and 95% confidence intervals were reported for significant effects (point‑biserial r for Wilcoxon, Cramer’s V for Friedman). The study was approved by the local ethics committee and registered in the Dutch trial registry, and a permit for handling LSD was obtained.

Peripheral catheter problems led to substantial missing BDNF data: one participant provided no blood samples, and among the remaining 23 participants the proportion of available samples across timepoints ranged from 6% to 100%. Only five participants (21.7%) had a complete dataset across all four timepoints. Because of these missing data, analyses were performed on complete within‑subject cases per dose (placebo versus each LSD dose) to allow the planned statistical tests. The investigators report that low LSD doses produced acute increases in plasma BDNF levels at specific post‑dose times. Compared with placebo, BDNF was increased at 4 hours after 5 mcg LSD, and at 6 hours after both 5 mcg and 20 mcg LSD; no clear increase was observed after the 10 mcg dose. The authors note a dose‑dependent pattern in time course, with the 5 mcg condition showing an earlier peak (4h) than the 20 mcg condition (6h). Some group comparisons of AUCs did not reach statistical significance in the extracted text (one reported comparison showed Z = −1.01, p = 0.31), and LSD plasma AUCs increased with dose as expected, illustrated by the authors’ figures. The Results section in the provided extraction does not supply full tables of test statistics, effect sizes, or exact sample sizes per comparison beyond the statements above.

Hutten and colleagues interpret their findings as preliminary evidence that single low doses of LSD can acutely raise plasma BDNF in healthy volunteers within a 6‑hour window, a result the authors consider relevant for therapeutic and cognitive effects that depend on enhanced neuroplasticity. They place these observations alongside prior reports that a single high dose of ketamine or ayahuasca can elevate peripheral BDNF and relate such changes to rapid antidepressant effects, suggesting a possible shared final pathway for induction of plasticity. The discussion highlights the differing time courses observed between the 5 mcg and 20 mcg doses and notes that dose and timing can markedly influence BDNF responses, citing animal work with ketamine that showed dose‑ and time‑dependent changes in BDNF and other plasticity markers. The authors therefore recommend that future human studies extend sampling beyond the 6‑hour window used here and include additional molecular markers (for example cFos, pERK) to better map the signalling cascades involved. Mechanistically, they refer to previously proposed roles for TrkB, mTOR and 5‑HT2A signalling in psychedelic‑induced structural changes, and describe ketamine’s upstream NMDA/GABA/glutamate/mTOR/BDNF cascade as a possible analogue to LSD’s downstream effects. Limitations acknowledged by the investigators include the small effective sample size for complete‑case analyses owing to blood‑draw difficulties, and the fact that only acute, single‑dose effects were assessed rather than repeated dosing typical of microdosing regimens. The within‑subject design and multiple post‑dose assessments are cited as strengths that reduce inter‑individual variability. Finally, the authors recommend replication and extension in patient populations to determine whether LSD‑induced increases in peripheral BDNF translate into clinically meaningful therapeutic effects.