Modulation of long-term potentiation following microdoses of LSD captured by thalamo-cortical modelling in a randomised, controlled trial

Abstract

Background: Microdosing psychedelics is a phenomenon with claimed cognitive benefits that are relatively untested clinically. Pre-clinically, psychedelics have demonstrated enhancing effects on neuroplasticity, which cannot be measured directly in humans, but may be indexed by non-invasive electroencephalography (EEG) paradigms. This study used a visual long-term potentiation (LTP) EEG paradigm to test the effects of microdosed lysergic acid diethylamide (LSD) on neural plasticity, both acutely while on the drug and cumulatively after microdosing every third day for six weeks. Healthy adult males (n = 80) completed the visual LTP paradigm at baseline, 2.5 h following a dose of 10 µg of LSD or inactive placebo, and 6 weeks later after taking 14 repeated microdoses. Visually induced LTP was used as indirect index of neural plasticity. Surface level event-related potential (ERPs) based analyses are presented alongside dynamic causal modelling of the source localised data using a generative thalamocortical model (TCM) of visual cortex to elucidate underlying synaptic circuitry.

Results: Event-related potential (ERP) analyses of N1b and P2 components did not show evidence of changes in visually induced LTP by LSD either acutely or after 6 weeks of regular dosing. However modelling the complete timecourse of the ERP with the TCM demonstrated changes in laminar connectivity in primary visual cortex. This primarily included changes to self-gain and inhibitory input parameters acutely. Layer 2/3 to layer 5 excitatory connectivity was also different between LSD and placebo groups. After regular dosing only excitatory input from layer 2/3 into layer 5 and inhibitory input into layer 4 were different between groups.

Conclusions: Without modulation of the ERPs it is difficult to relate the findings to other studies visually inducing LTP. It also indicates the classic peak analysis may not be sensitive enough to demonstrate evidence for changes in LTP plasticity in humans at such low doses. The TCM provides a more sensitive approach to assessing changes to plasticity as differences in plasticity mediated laminar connectivity were found between the LSD and placebo groups.

Trial registration: ANZCTR registration number ACTRN12621000436875; Registered 16/04/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 .

Keywords: Dynamic causal modelling; Long-term potentiation; Lysergic acid diethylamide; Neuroplasticity; Psychedelics.

Fig. 1

Diagram of the LTP paradigm timing and sequence. Adapted from Sumner, McMillan et al. (2020)

Fig. 2

TCM architecture and connectivity with six cortical column neural populations and two thalamic populations. Cortical populations include layer 2/3 superficial pyramidal (SP) and superficial interneuron (SI) cells, layer 4 spiny stellate cells (SS), layer 5 deep pyramidal (DP) and deep interneuron (DI) cells, and layer 6 thalamic projection (TP) cells. Thalamic populations include reticular (RT) and relay cells (RL). Connectivity between cells include ascending (in green) and descending (in orange) connections between excitatory cell populations, and inhibitory (in red) and excitatory (in blue) connections between excitatory and inhibitory cell populations. Solid lines indicate connectivity parameters which were allowed to change within the model, and dashed lines indicate fixed parameters. The model also parameterises the decay constants of AMPA, NMDA, GABA-A, GABA-B, M- and H-channels

Fig. 3

Interaction of Group x Session in the Early Baseline to Treatment analysis as illustrated at electrode P6. ERPs shown are pre-tetanus and early post-tetanus, arrow shows peak of interaction significance, blue shaded area shows time window cluster around peak, grey shaded area shows the analysis parameter window. P6 here is illustrative only, analysis was conducted on a 19 electrode occipital-parietal ROI.

Fig. 4

Interaction of Group x Session in the Late Baseline to Final analysis as illustrated at electrode Oz. ERPs shown are pre-tetanus and late post-tetanus, arrow shows peak of interaction significance, blue shaded area shows time window cluster around peak, grey shaded area shows the analysis parameter window. Oz here is illustrative only, analysis was conducted on a 19 electrode occipital-parietal ROI.

Fig. 5

Parameter estimates of difference in LSD group relative to placebo in the Baseline to Treatment and Baseline to Final visits. Coloured bars indicate very strong evidence (> 0.99 poster probability) with pink (positive values) indicating a greater visual LTP mediated change in that parameter for the LSD group over placebo and yellow bars (negative values) indicating greater visual LTP mediated change in that parameter in placebo over LSD. Error bars indicate standard deviation

Fig. 6

Parameters with very strong evidence of the difference between LSD and placebo groups in the PEB of PEBs for the Baseline vs. Treatment and Baseline vs. Final analyses