Psychedelics pharmacologically alter the wakefulness experience in humans. These changes are conceptualised in terms of subjective changes, but not a distinct vigilance state. On this basis, we decided to investigate the effects of psychedelics through the scope of sleep research.
The Psychedelic Journey
The project behind this paper started as a simple question we asked in 2018. Psychedelics alter wake in humans, but what happens to the subsequent sleep? As they seem to profoundly change the subjective experience, can we even call the psychedelic experience wake?
A paper published in Translational psychiatry by Thomas et al., explored this question and revealed that psilocin alters the subsequent sleep states. However, psilocin is a long-acting psychedelic. The doubt remains that what was measured then could still be due to the substance in the body, and not a direct result of the experience itself.
This thought led us to 5-MeO-DMT. This compound has a very short half-life, with most of the behavioural effects on mice gone within 45 minutes. Thus, by injecting 5-MeO-DMT at light onset (i.e. the beginning of night time for the mice), we could leave them be and analyse the sleep episodes immediately after, answering the thrilling question: Could a strong but short-lasting psychedelic alter wake so much that the following sleep is also changed?
A Paradoxical state of wakefulness
Classical sleep studies rely on manual scoring of vigilance states. A trained scorer looks at EEG & EMG recordings and determines whether the animal is awake (fast EEG activity + high EMG activity) or asleep and, if asleep, whether it is in NREM sleep (non rapid eye mouvement sleep, with slow oscillations of high amplitude + low to no EMG activity) or REM sleep (rapid eye mouvement sleep, high EEG theta activity + muscle atonia). Although trivial in principle, it quickly became apparent that mice injected with 5-MeO-DMT did not follow this simple rule.
Within 5 minutes of the injection, the EEG shows large slow waves of high amplitude together with high EMG activity. Because high EMG activity (and video recordings) confirmed that the animal was behaviourally active, we deemed it reasonable to classify these episodes as "wake." Further analyses confirmed what we saw: 5-MeO-DMT transiently increases slow wave activity while suppressing theta activity, the latter being associated with memory and mouvement.
In the field of sleep research, REM sleep is also known as paradoxical sleep (PS) as one of its discoverers, French neuroscientist Michel Jouvet, was puzzled by the paradoxical co-occurrence of an active brain state in the deepest behavioural stage of sleep described. Jokingly, and because we observed the exact mirrored state (i.e. sleep signals in an awake animal), we labelled this state Paradoxical wake. I still call it that way; it is surprisingly catchy with larger audiences (and unsurprisingly satisfies my Frenchness).
Down into the rabbit hole
We then started to dig. Talking with several sleep researchers led to interesting questions (and puzzled looks). "Uh?" "But, how does it feel, being in this state?" "Are these slow waves true sleep slow waves?" "What nucleus does 5-MeO-DMT activate?" During my limited time as a PhD student, I decided to focus on the sleep-likeness of this brain state.
This followed three axes: 1. Sleep regulation (if these are sleep oscillations, we would expect changes in sleep pressure), 2. the aspect of the slow waves, and 3. levels of arousal (if the brain enters a sleep-like state, levels of arousal should decrease).
Regarding sleep regulation, we saw an increased latency to enter REM sleep, a common effect of psychedelics. This delay far outlasted the clearance of the drug. Regarding NREM sleep, sleep deprivation has been shown to increase the amplitude of slow waves in the subsequent sleep episode (i.e., slow wave amplitude is a common read-out of sleep pressure). In our case, sleep deprivation did not increase the amplitude of 5-MeO-DMT-induced slow waves during wake. However, after sleep deprivation, 5-MeO-DMT did reduce the amplitude of slow waves during NREM sleep, bringing them to pre-sleep deprivation levels. 5-MeO-DMT slow waves, although seemingly not impacted by sleep pressure, might have the ability to reduce it. This could be because these slow waves share similarities with sleep slow waves, which could help dissipate sleep pressure.
Regarding levels of arousal, our main concern regarded the handling of the animals. We wanted to investigate pupil size but did not want to disrupt our animals too much by going head-fixed or taking pictures regularly. We therefore designed the occulometer, a device capable of monitoring eye mouvement and pupil size in freely-moving mice, based on a device made for birds. Our results suggest a high level of cortical arousal, despite the occurrence of global slow waves.
What to make of it?
This project diverted the psychedelic experience away from psychedelic research and instead decided to use psychedelics to help understand brain and vigilance states, as classically studied in the field of sleep research. We speculate that the occurrence of this paradoxical wake state could be the basis for the psychedelic experience or even the potential therapeutic effects. In sleep research, slow waves are thought to help mediate some of sleep's recovery function. Although no consensus has been reached on the underlying mechanisms, their effects are tied to sleep homeostasis and synaptic plasticity. The possibility remains that slow waves occurring outside of sleep could also have potential effects on plasticity and thus might be the basis of the psychedelic effects.
Link to the paper: https://doi.org/10.1038/s42003-025-09412-x