Psychedelic medicine: The biology underlying the persisting psychedelic effects

This paper presents an alternative hypothesis of how psychedelics work with a focus on sleep (macrodose) and the microbiome (microdose). The author proposes ways of testing this hypothesis.

Abstract

“Psychedelic substances have regained interest as therapeutic agents in the treatment of stress-related disorders. The effects seem to be of persisting nature even after a single dose. Also in lower than ‘regular’ recreational doses, so-called micro-doses, without the typical effects on consciousness, users report beneficial effects on cognitive processes and well-being. The exact neurobiological mechanism underlying these persisting effects is not clear. While previous research has mainly focused on the central nervous system including the immune system and the neuroendocrine system, I propose a central role for sleep and the microbiome in the effects of regular and low doses of psychedelics respectively. It will be explained why this is hypothesized and studies to test this idea proposed. It is concluded that while these studies are needed to understand the biology underlying psychedelic medicine, it is also important to approach it in a holistic way, including all the above mentioned biological processes psychedelics are known to affect, and explore the role of other substance-related factors like route of administration and form, and factors like diet and lifestyle which are part of the psychedelic experience.“

Author: Kim P. C. Kuypers

Notes

“I suggest that a regular [macro] dose targets directly the central level, more specifically sleep and that a low [micro] dose indirectly targets central level processes via the gut. I acknowledge that all the mentioned biological systems work in an interactive way to produce the persisting effects though this will not be discussed as this is beyond the scope of this paper.”

These novel hypotheses look at how psychedelics have a persistent effect (so not focusing on the immediate effect). As noted, also in the abstract, this paper looks only at this aspect within a wider model of psychedelic use (how it’s administered, therapy (or not), type of mental disorder, etc).

“I suggest that a single dose of a psychedelic causes a reset of the biological clock underlying sleep/wake cycles and thereby enhances cognitive-emotional processes in depressed people but also improving feelings of well-being and enhancing mood in healthy individuals.”

If the disturbance of sleep is an underlying cause (or effect?) of mental disorders (e.g. depression), then maybe psychedelics have their long-lasting effects via resetting the biological clock. Kuypers proposes testing this with both a placebo and ketanserin (which blocks the psychedelic effects) in a double-blind study design.

One could also look at how different psychedelics have an effect on sleep/biological clock. If this hypothesis turns out to be true, one would expect ketamine to have a shorter lasting effect on this than other (classical) psychedelics.

“I suggest that low doses of psychedelics induce their effects via alterations in the microbiome and related pathways to the brain. Again, placebo-controlled experimental studies both in animals and humans are suggested to study this.”

Kuypers states that the effect of psychedelics at microdosages may not have a significant effect on the brain itself directly, but can have this via the microbiome and it’s connection to our brain (via the kynurenine pathway). A very interesting hypothesis that may make a bridge between psychedelic research and that of our gut (another quickly developing field).

Although our knowledge is still very limited, other studies (e.g. Foster & McVey Neufeld (2013)↗, Kelly et al (2016)↗, Dash et al (2015)↗) have been studying the (bidirectional) influence of the gut on our brain (specifically related to depression).