Inter-individual variability in neural response to low doses of LSD

Authors: Nadia R. P. W. Hutten, Conny W. E. M. Quaedflieg, Natasha L. Mason, Eef L. Theunissen, Matthias E. Liechti, Urs Duthaler, Kim P. C. Kuypers, Valerie Bonnelle, Amanda Feilding & Johannes G. Ramaekers

Background

Microdosing research to date has shown little solid evidence to meet claims often reported anecdotally. Although some studies have reported small improvements in attention, emotional processing, and mood after administration of a low dose of a psychedelic in healthy volunteers, other studies have failed to replicate these findings.  

This prompted researchers at Maastricht University to become curious about what might be causing this disparity in results. They devised a study, in collaboration with The Beckley Foundation, to explore what may lead different people to respond in different ways to low doses of LSD. They aimed to test the hypothesis that effects of low doses of LSD on arousal, attention and memory depend on an individual’s cognitive state at baseline. 

The results of this research were recently published by Nature in the journal of Translational Psychiatry. Among other findings (outlined in more detail below) it is the first perfectly blinded study to demonstrate that microdoses of LSD can have prolonged effects on the brains of healthy volunteers, following the completion of a dosing regimen. 

The Principal Investigator of the study, Prof. Jan Ramaeckers, said of the results: ‘I’m very pleased with these findings as they show individualized responses to low doses of LSD as well as (prolonged) neural adaptations that underlie improved attention and arousal, in a fully blinded study. These findings provide evidence that microdosing entails more than mere expectation effects.’ 

Methods

The study was placebo-controlled and ‘double blinded’ meaning that both participants and researchers were unaware of which individuals received the LSD vs the placebo. Healthy participants received either a low dose of LSD (15mcg) or a placebo, a total of 4 times, over two weeks. Unlike some previous microdosing research undertaken, this study was perfectly blinded meaning that the subjects were unable to successfully guess, to a degree greater than chance, which condition (LSD or placebo) they had been assigned to. 

Neurophysiological data was collected from the participants using EEG, or ‘electroencephalography’, a non-invasive method of measuring the electrical activity of the brain by using electrodes placed on the scalp. Different kinds of brain waves with different frequencies can be identified based on the signals that are picked up. These include delta (0.5-4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-100 Hz) waves. Assessing the ‘power’ or strength of the brain’s electrical activity within each of these different frequency bands can provide insights into different brain states and cognitive processes. For example, high power in low frequency bands (delta and theta) is generally associated with sleep, drowsiness, and meditative states whereas low power within these frequency bands is typical during wakefulness or active mental states.  

Results

MICRODOSES OF LSD HAVE STIMULATORY EFFECTS IN HEALTHY VOLUNTEERS

The results of the study demonstrated an increase in alertness and wakefulness in the individuals who received microdoses of LSD, as indicated by decreases in EEG power in low frequency bands.’ These stimulant effects were shown to be higher in those who had low arousal levels at baseline.  

The researchers suggest that these stimulatory effects may be a result of the effect of LSD on the neurotransmitter dopamine, which is known to be involved in the regulation of the sleep-wake cycle and influence levels of alertness. They may also be perpetuated by the action of LSD to release cortisol, a hormone released by the adrenal glands that plays a large role in the stress response, thereby increasing alertness. 

Interestingly, increases in arousal and wakefulness for the LSD group were sustained at the 1-week follow-up, during which the participants did not receive any further LSD. The researchers suggest that these findings may reflect persisting alterations in neuroplasticity or immune profile.  

MICRODOSES OF LSD IMPROVED SENSORY PROCESSING IN HEALTHY VOLUNTEERS

Study participants took part in something called an ‘oddball task’, an experiment commonly used to assess brain responses to unexpected stimuli. In this case, subjects were exposed to a series of different sounds. The researchers wanted to explore the effects of LSD on pre-attentive processing, which refers to the brain’s ability to automatically detect and rapidly analyse basic features of sensory information, such as sound, before conscious attention is directed towards it.   

The results of the oddball task demonstrated that pre-attentive processing was increased by microdoses of LSD, suggesting that low doses of LSD may subtly accelerate and improve the processing of auditory sensory information in healthy volunteers. Additionally, the stimulatory effects of LSD were most pronounced in those with poorer pre-attentive processing at baseline. 

This evidence conflicts with some previous research indicating that low doses of LSD reduce pre-attentive processing during an oddball task where participants were shown images of emotional faces. The researchers suggest that this discrepancy may be due to the greater complexity of this task compared to the auditory task.  

In terms of the potential mechanisms underlying this result, the researchers suggest that low dose psychedelics may alter the balance between ‘top-down’ and ‘bottom-up’ processing by the brain. Top-down processing refers to the ability of the brain to use pre-existing knowledge and expectations to interpret sensory information, whereas bottom-up processing refers to the ability of the brain to process sensory information from the external environment from lower to higher levels of the sensory hierarchy (i.e. from raw sensory information such as sound waves, to more complex interpretation of elements such as the specific qualities of different instruments or voices).  

MICRODOSES OF LSD IMPAIRED LEARNING AND MEMORY IN HEALTHY VOLUNTEERS

Long term potentiation (LTP) is a process by which the connection between two neurons is strengthened by them having been triggered simultaneously. It’s one of the major processes that underlies learning and memory.  

The researchers discovered that perceptual learning and memory were impaired in the LSD group, as indicated by reductions in long-term potentiation in these individuals. These effects were strongest in those with higher levels of perceptual learning and memory at baseline.  

The researchers suggest that these effects may be due to alterations to the balance of the neurotransmitters glutamate and GABA. Glutamate is the central nervous system’s main excitatory neurotransmitter, meaning that it increases the activity of the neurons it interacts with, whereas GABA is its main inhibitory neurotransmitter, which means it decreases the activity of the neurons it interacts with. Glutamate and GABA both play an important role in processes underlying long-term potentiation.  

Although this study demonstrated an impairment in learning and memory due to microdoses of LSD, other research suggests that the effects of LSD upon memory are transient. At larger doses, some evidence even points to longer-term improvements, via the mechanism of neuroplasticity.  

Conclusions

Taken together, these findings demonstrate that the effects produced by microdoses of LSD differ between individuals. These differences were found to relate to the cognitive state of the participants at baseline and were most pronounced in individuals with the largest capacity for improvement (in arousal, wakefulness, and auditory processing) or impairment (in learning and memory) in their performance.  

Decreases in in EEG power in low frequency bands (related to arousal and wakefulness) were still noticeable at the 1 week follow up. This finding suggests these effects may persist beyond dosing, possibly by increasing neuroplasticity. Indeed, earlier research has already shown that low doses of LSD may increase neuroplasticity within 2-6 hours of administration due to increases in a protein called BDNF (or Brain Derived Neurotrophic Factor), which plays an important role in the survival of existing neurons, and growth of new ones.  

The authors of this research hope that these findings may additionally offer potential new horizons for research into ADHD and OCD, which are characterised by increased activity in the same frequency bands that appear to have been reduced by microdoses of LSD in this study. To back this theory up, the researchers point to evidence taken from a previous survey of ‘microdosers’ with ADHD, which indicated that these people did notice a reduction in their symptoms as a result of their self-treatment with low dose psychedelics.

References

Hutten, N.R.P.W., Quaedflieg, C.W.E.M., Mason, N.L. et al. Inter-individual variability in neural response to low doses of LSD. Transl Psychiatry 14, 288 (2024). https://doi.org/10.1038/s41398-024-03013-8