Poster No:
834
Submission Type:
Abstract Submission
Authors:
Robin Murphy1, Kate Godfrey2, Anna Forsyth3, Suresh Muthukumaraswamy1, Rachael Sumner4
Institutions:
1University of Auckland, Auckland, Auckland, 2Imperial College, London, London, 3University of Auckland, Auckland, AK, 4The University of Auckland, Auckland, Auckland
First Author:
Co-Author(s):
Introduction:
Repeatedly taking low doses of psychedelics such as lysergic acid diethylamide (LSD), or 'microdosing', is an increasingly prevalent practice for self-treatment of mental health disorders. Current research into the efficacy and mechanism of these protocols is limited, however research in our laboratory has shown that microdosing LSD can produce subtle improvements to mood in healthy populations (Murphy et al., 2023), and may have long-lasting benefits for people with major depressive disorder (Daldegan-Bueno et al.). Alterations to predictive coding have been proposed as a driver of psychedelic effects (Carhart-Harris & Friston, 2019), and auditory predictive coding has been altered under full doses of psychedelics (Timmermann et al., 2018). The roving mismatch negativity (rMMN) electroencephalography (EEG) paradigm (Garrido et al., 2008) is a task which has been shown to be sensitive to predictive coding alterations under full doses of ketamine (Sumner et al., 2020), but has not been investigated under microdoses of LSD. In this task, prediction error is thought to be indexed by the magnitude of MMN response, and model updating by repetition suppression.
Methods:
Participants were 80 healthy males who underwent six weeks of microdosing LSD or inactive placebo every third day (14 doses total). Participants completed the rMMN EEG protocol at a drug-free baseline, and at a Treatment session one week later, ~2.5 hours after taking their first microdose. Participants then returned for a drug-free Final session two days after their final microdose. Doses administered in the Treatment session were 10 μg, and subsequent doses were titrated down to 5-9 μg for 6 participants in the LSD group and one in the placebo group. Separate analyses were conducted for acute (Baseline vs Treatment; placebo n = 38; LSD n = 40) and durable (Baseline vs Final; placebo n = 26; LSD n = 25) effects. rMMN consists of 250 trains of 6-11 repeated sinusoidal tones. The first tone in a train is then a 'deviant', which typically triggers an MMN response, which then is suppressed following repetition, such that the sixth tone can be treated as the 'standard'. In contrast to typical oddball paradigms, this allows for the deviant and standard to be identical stimuli.
MMN response was analysed in a 2x2 ANOVA (Group x Time) of the difference waves of the average of the deviant tone subtracted from the standard in SPM12. Repetition suppression was analysed in R by comparing the amplitude of cluster peaks of the MMN and P3 evoked response potentials (ERPs) in a 2 x 2 x 5 linear mixed effects model of Group x Time x Tone.
Results:
Analysis of the acute deviant tone difference wave showed no interaction effect of Group by Time, nor main effect of Group, and a significant main effect of Time (F(1,152) = 21.14, FWE-c p = 0.024). This effect peaked at 317 ms in the posterior right section of the P3 component, with greater amplitude at Baseline than Treatment, regardless of Group.
Analysis of the durable deviant tone difference wave showed no main effect of Group or Time and a significant interaction effect of Group by time peaking at 184 ms on the left (F(1,98) = 13.16, uncorrected p = 0.0005) and 183 ms on the right (F(1,98) = 12.32, uncorrected p = 0.0007). Comparing these clusters to the average effect of condition showed that they are most likely modulations of the MMN's dipole, and therefore not indicative of altered MMN.
No significant difference was found in repetition suppression in the acute, nor the durable analysis.
Conclusions:
We found no measurable effects of 10 μg LSD microdoses on ERP indexes of prediction error or model updating during the rMMN task in the acute phase of the drug, or two days after the final of 14 doses taken regularly over six weeks. This contrasts with full doses of both LSD and psilocybin, which have demonstrated suppressive effects on MMN responses in oddball tasks (Duerler et al., 2022; Timmermann et al., 2018).
Learning and Memory:
Neural Plasticity and Recovery of Function
Learning and Memory Other 1
Modeling and Analysis Methods:
EEG/MEG Modeling and Analysis
Perception, Attention and Motor Behavior:
Perception: Auditory/ Vestibular
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission 2
Keywords:
Electroencephaolography (EEG)
Learning
Perception
Pharmacotherapy
Seretonin
Other - Psychedelics
1|2Indicates the priority used for review
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Please indicate below if your study was a "resting state" or "task-activation” study.
Task-activation
Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Healthy subjects
Was this research conducted in the United States?
No
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel?
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Please indicate which methods were used in your research:
EEG/ERP
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SPM
Other, Please list
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FieldTrip
Provide references using APA citation style.
Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 71(3), 316-344. https://doi.org/10.1124/pr.118.017160
Daldegan-Bueno, D., et al. LSD microdosing in major depressive disorder: results from an open-label trial. In review.
Duerler, P. et al. (2022). Psilocybin induces aberrant prediction error processing of tactile mismatch responses—a simultaneous EEG–fMRI study. Cerebral Cortex, 32(1), 186-196. https://doi.org/10.1093/cercor/bhab202
Garrido, M. I. et al. (2008). The functional anatomy of the MMN: a DCM study of the roving paradigm. Neuroimage, 42(2), 936-944.
Murphy, R. J. et al. (2023). Acute mood-elevating properties of microdosed LSD in healthy volunteers: a home-administered randomised controlled trial. Biological Psychiatry, 94(6), 511-521. https://doi.org/10.1016/j.biopsych.2023.03.013
Sumner, R. L. et al. (2020). Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors. European Neuropsychopharmacology, 38, 73-85. https://doi.org/10.1016/j.euroneuro.2020.07.009
Timmermann, C. et al. (2018). LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm. Neuropharmacology, 142, 251-262. https://doi.org/10.1016/j.neuropharm.2017.10.039
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