The effects of three low morning and evening doses of LSD on mood, biological and psychological measures of sleep, neuroplasticity, and well-being

Psychedelic research has seen a revival in the past decades, leading to a wave
of new studies investigating the effects of psychedelic substances in clinical
populations as well as in healthy volunteers. Psychedelics, such as psilocybin
and LSD, have shown to be a potential alternative treatment option for
psychiatric conditions, such as stress-related disorders and addiction. Also in
healthy volunteers, a psychedelic acutely induced positive effects on mood and
participants described it as being among the most personally meaningful
experiences of their lives. Recently, the practice of repeatedly using small
doses of a psychedelic has received increasing scientific interest and is
better known as *microdosing*. Both healthy and clinical populations who
microdose do this to enhance cognitive performance and mood.
To understand the full potential of microdosing, knowledge about the underlying
neurobiological mechanism of the positive effects on mood and behavior are
pivotal. A potential mechanism underlying these positive effects that has not
been investigated yet is the effect of microdosing on sleep. Nearly all of the
successful treatments for mood disorders seem to affect circadian rhythms
(sleep) and enhance neuroplasticity (brain-derived neurotrophic factor, BDNF),
the present project seeks to investigate the effect of small doses of a
psychedelic (LSD, 20 µg) on these parameters in healthy volunteers.
Studies have suggested the involvement of serotonin 1A and 2C receptors in the
normalization of the circadian rhythm, and LSD is a potent agonist of these
receptors, it is therefore expected that LSD affects sleep. Additionally, a
recent study from our lab showed that low doses of LSD, positively influenced
mood and enhance BDNF levels, a marker of neuroplasticity. We hypothesize that
the aforementioned effects on sleep and BDNF underlie the positive effects of
LSD on mood and well-being.
Another finding is that psychedelics* effects on sleep are dependent on the
time of administration. To understand the effect of the timing of LSD
administration on mood, sleep and neuroplasticity, the effect of three repeated
small morning and evening doses of LSD will be compared in healthy volunteers
on assessments of mood, sleep and neuroplasticity.

To understand the effect of microdosing on mood, sleep and neuroplasticity, the
effect of three repeated low doses of LSD in the morning and evening in healthy
volunteers will be compared to placebo on measures of mood, sleep and
neuroplasticity (BDNF). Secondly, the effects of daytime and evening low-dose
LSD administration will be examined on cognitive performance, emotion
regulation, well-being and immune system response.

The study follows a 2 (LSD vs placebo) by 2 (morning doses vs evening doses)
double-blind, randomized, placebo-controlled, within-subject design.

All participants will undergo four conditions. Each condition includes three
occasions of administering LSD (20 µg) or placebo in the morning, or in the
evening. The three dosing days within one condition will be interspersed with
one day. Between the conditions, there will be a washout period of minimal five
days. All participants will go through all four conditions.

Volunteers will be enrolled for minimally eight weeks, undergoing four
conditions in total. Before starting in one of the conditions, participants
will undergo a full medical screening (blood and urine samples will be taken)
by a licensed physician ensuring their safety and a short training session will
be held to familiarize them with the testing procedures. Each condition will
include four lab visits, of which three include drug administration (LSD or
placebo) in the morning or evening and cognitive testing. The remaining lab
visit only includes collecting a blood sample. Every day during the four
conditions, participants keep a diary assessing their sleep and mood. Dosing
days are interspersed by one day and between each condition, a washout of at
least five days is included. On the first and last test day of each condition,
four blood samples will be taken. The first blood sample will be taken just
before treatment administration, the remaining three blood samples will be
taken every hour after treatment administration. The blood samples will serve
to determine markers of neuroplasticity, well-being (i.e. cytokines), LSD
concentration, cortisol and endocannabinoid concentrations. Other blood samples
will be taken 24 hours and 48 hours after the first treatment administration.
Over the course of the medical examination and the lab visits, participants
will give a total of 492ml of blood. In case they experience complaints, the
medical supervisor will be contacted. The total discomfort experienced by the
volunteer is minimal when all precautions are taken into account.