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.