Clinical trial NCT03934710
Conditions: Healthy
Sponsor: University of Chicago
Start date: 2019-04-20; Completion date: 2021-06-07
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study we are examining the effects of repeated very low doses of serotonin agonists on mood individuals with negative mood.

Detailed description:
Here, we are examining the effects of four repeated low doses of lysergic acid diethylamide (LSD), compared to placebo, administered to healthy adults at 3-4 day intervals, on mood, cognitive performance and responses to emotional tasks

Arms: arm 1: Placebo arm 2: 13ug of serotonin agonist arm 3: 26ug of serotonin agonist
Interventions: intervention 1: Placebo intervention 2: Serotonin agonist - 13ug intervention 3: Serotonin agonist - 26ug
Intervention descriptions: intervention 1: Drug will be administered in solution form intervention 2: 13ug lysergic acid diethylamide intervention 3: 26ug lysergic acid diethylamide

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
 
Title: Mood effects of serotonin agonists Extended (“Effects of drugs on mood and 
behavior – MESA-E” on the consent form) 
 
ID: IRB18-1183  
 
 
 
 
 
NCT03934710 
Date: 2/20/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
Protocol 
 
Title: Mood effects of serotonin agonists Extended (“Effects of drugs on mood and 
behavior – MESA-E” on the consent form) 
 
P.I.: Harriet de Wit 
 
Protocol 18-1183 
 
Co-Investigators: Royce Lee, Anya Bershad 
 
Feb 20, 2019 
 
Objectives: To study the effects of very low doses of lysergic acid diethylamide 
administered at 3-day intervals for two weeks, on affect and responses to emotional 
stimuli in young adults with depressed mood. 
 
Background:  
 
The purpose of this study is to determine the effects of very low, sub-
hallucinogenic doses of lysergic acid diethylamide (LSD) on negative mood states in 
human volunteers. The serotonergic system is critically involved in the neurobiology of 
depression, and specifically 5HT2A signaling is thought to underlie the effectiveness of 
standard selective-serotonin reuptake inhibitor (SSRI) antidepressants (Celada et al., 
2004). LSD acts directly at 5HT2A and other serotonin receptors, and may have mood-
enhancing effects.  In the 1950s and 1960s, over 1,000 studies were published 
supporting therapeutic effects of LSD in combination with psychotherapy (Savage, 
1952; Vollenweider and Kometer, 2010). However, many of these early studies lacked 
adequate control groups, and did not isolate drug effects from effects of the 
psychotherapy itself. Recent preclinical studies show that LSD exerts antidepressant 
effects in animal models (Buchborn et al., 2014), and a small number of recent studies 
in humans have shown that moderate to high doses of the drug (200-800μg) are 
effective in reducing end-of-life anxiety in terminally ill patients, and may also be 
effective in the treatment of addictive disorders (Gasser et al., 2014; Krebs and 
Johansen, 2012). Anecdotal reports suggest that very low doses of LSD, below those 
that produce standard “hallucinatory” effects (100-200 μg), reduce depressed mood, 
and such “microdosing” is reported to improve cognitive function and positive outlook 
(Nichols, 2013). A Google search of “LSD microdosing” reveals over 900 blog posts and 
articles reporting that low doses of LSD (10-30 μg) improve mood and cognition, without 


producing noticeable hallucinogenic effects. However, the idea that sub-threshold doses 
of LSD may have anti-depressant properties has never been tested in humans.  
In an ongoing study (Protocol 15-1311) we are testing the effects of single low 
doses (“microdoses”) of LSD on subjective ratings and behavioral markers of 
depression (e.g., negative processing bias) in young adults. In the ongoing study, 
participants receive single doses at one-week intervals, and we are examining their 
direct effects during the laboratory sessions.  Thus far, the doses are well tolerated and 
initial findings are promising. We have identified a dose that would be suitable for 
repeated administration (i.e., one dose every 3 days), as described in the present 
protocol.  Figure 1 shows the mean (and sem) ratings of “feel” a drug effect, scored 
from 0 (not at all) to 100 (strong drug effect), in 20 participants (unpublished data from 
Protocol 15-1311).  The lines correspond to placebo (lowest) 6.3, 13, and 26 
micrograms.  The dose to be used here (13 micrograms) produces ratings of ‘feeling a 
drug effect” of about 20 on a scale of 100.  No adverse effects were reported at any of 
the three doses tested. Based on this and other unpublished reports (see attached 
review), in the present protocol we propose to test effects of a low dose (13 μg LSD) 
administered four times, once each day at 3-day intervals.  Participants will participate 
in two, two-week phases in which they receive either drug or placebo at 3-day intervals.  
The two phases will be presented in counterbalanced order and will be separated by 2 
weeks.  Thus subjects will attend four 5-h laboratory sessions to consume the drug (or 
placebo) on Days 1, 4, 7 and 10, and a 1-hour nondrug followup session at day 13.  
After a 2-week washout period, this sequence will be repeated with the other substance 
(drug or placebo). Participants will complete mood questionnaires on the days between 
the sessions to monitor the subacute effects of the drug. We hypothesize that low doses 
of LSD will alleviate both subjective and behavioral dimensions of depression in adult 
volunteers, during the sessions and in the days following.  
 
Methods: 
Design: Participants will be healthy adults who report moderate negative mood states, 
and some prior use of hallucinogen drugs or MDMA.  The study will consist of two 
blocks of 4 laboratory sessions involving either low-dose LSD (13 ug) or placebo 
administration. Within each block, four 5-hour sessions will be conducted at 3-day 
intervals, with at least two weeks separating the blocks.  At each 5-hour laboratory 
session participants will receive single low doses of LSD or placebo (13 ug in one block, 
placebo in the other). Following each block they will attend a 1-hour nondrug behavioral 
testing session. Screening, orientation, and study session procedures will take place in 
the Human Behavioral Pharmacology Laboratory suite in the L4 wing of 5841 S. 
Maryland Ave.  
 
Subjects:  Forty volunteers (20 male, 20 female; age range 18-35 years except 
undergraduates at U of C who must be 21 or older) who score in the minimal-to-
moderate range (0-28) on the Beck Depression Inventory (BDI-II; Beck et al., 1996) will 
participate in the experiment. The BDI-II contains 21 questions, each scored from 0 to 3. 
Higher total scores indicate more severe depressive symptoms. The standardized 
cutoffs are: 0–13: minimal depression, 14–19: mild depression, 20–28: moderate 
depression and 29–63: severe depression.  All subjects will have previous experience 


with a hallucinogenic drug (e.g. psilocybin, LSD, mescaline, dimethyltryptamine or 
MDMA). Based on our previous rates of participants completing multi-session drug 
studies, to recruit 40 complete subjects we will need to consent 55 participants. 
Participants will be recruited without regard to race, religion or ethnicity through posters, 
advertisements and word-of-mouth referrals. Candidates will be screened in accordance 
with our general screening protocol, approved by the IRB under Protocol #13681B, 
which includes a physical, EKG, psychiatric screening interview and detailed drug use 
history questionnaire. The following populations are excluded for safety reasons: 
Individuals with a medical condition contraindicating study participation, as determined 
by our physician (e.g. liver or kidney disease), individuals with current or past drug 
abuse or dependence, individuals with serious psychiatric conditions (e.g., PTSD or 
Panic Disorder), any lifetime PTSD or psychotic disorder, or a first degree relative with a 
psychotic disorder, women who are pregnant, nursing, or planning to become pregnant 
in the next 3 months.  The self-report questionnaires we use require fluency in English 
and a high-school education so lack of either of these are further exclusionary criteria. 
Individuals with a BMI below 19 or above 30 will also be excluded to minimize variability 
due to body weight.  Women not on hormonal birth control will be scheduled only in the 
follicular phase of the menstrual cycle.  
 
Drug and Doses: The 13 μg dose of LSD does not produce hallucinatory or perceptual 
effects. Other recent studies have used substantially higher doses (100 – 200 μg (Krebs 
and Johansen, 2012; Schmid et al., 2014) or 20-80 μg administered intravenously 
(Carhart-Harris et al. 2014) with no adverse effects. We will administer the drug in 
accordance with the published safety guidelines for hallucinogen research in humans 
(Johnson et al., 2008). The onset of action after oral LSD is 30 minutes, with a peak 
plasma concentration at 1.5-3 hours (Dolder et al., 2015). Our preliminary findings 
indicate that the subjective effects of the drug have returned to baseline by 4 hours 
(Figure 1 above).  Doses will be separated by three days. The drug is obtained from 
Organix Inc, under IND 127547, and placed in solution with assistance from the U of 
Chicago Investigational Pharmacy Service. The drug is administered sublingually in a 
volume of 0.2 ml; placebo consists of 0.2 ml distilled water.  See “Risks” for complete 
safety information. 
 
Study Tasks: 
 
1. International Affective Picture System (IAPS) – (Lang et al., 1999) Participants will 
view standardized positive, negative and neutral pictures from the IAPS.  The 
negative and positive images will be matched on degree of valence and arousal. An 
Evaluative Space Grid rating will follow each picture to allow for ratings on both 
emotional valence (positive, negative, neutral), and arousal.  
2. Dynamic Affect Recognition Evaluation – (DARE; Porges et al., 2007) Participants 
will view dynamically developing facial expressions depicting one of six emotions: 
Happiness, sadness, anger, fear, surprise or disgust. Participants will be instructed 
to respond as soon as they are able to identify the emotion depicted. The variables 
of interest are accuracy and latency to response.   


3. Cyberball (Williams and Jarvis 2006). This task simulates social acceptance and 
exclusion. Subjects participate in two 4-min computer games in which they play 
“catch” with two computer avatars. In each game subjects are included (63 ± 3% of 
the tosses) and then excluded (10 ± 3% of the tosses). They complete 
questionnaires assessing their mood and estimate the percentage of tosses (0-
100%) they receive, and to rate their desire to play again (0-100). 
4. N-back Task – This continuous performance task is a standard measure of working 
memory. Individuals with major depression have been shown to exhibit slower 
reaction times and reduced accuracy on this task, and who routinely use very low 
doses of LSD report experiencing cognitive enhancement. We will also include a 
questionnaire assessing how well the participants think they performed on this task, 
to obtain a measure of meta-cognition of agency. 
5. Digit Symbol Substitution Test (DSST) – This task requires subjects to match as 
many numbers to symbols as they can in a 90 second interval.  
 
 Subjective Measures: 
 
1. Profile of Mood States – (POMS: McNair et al., 1971) The POMS is a validated 
measure consisting of 72 adjectives commonly used to describe momentary mood 
states. The POMS is highly sensitive to the effects of drugs, and will be used to 
assess mood effects of the drug during the study sessions. 
2. Positive and Negative Affect Scale (PANAS; Watson, Clark and Tellegen, 1988). 
The PANAS will be used to monitor subjects’ mood states on the days between 
sessions. 
3. Drug Effects Questionnaire - (DEQ: Fischman and Foltin, 1991) The DEQ is a 
validated measure consisting of questions on a visual analog scale about the 
subjective effects of drugs. Subjects are asked to rate the extent they feel a drug 
effect, whether they like or dislike the drug effect, and if given a choice would they 
want to take more of the drug.  This will also be used to assess the 
pharmacodynamics of the drug effect during the study. 
4. Visual Analogue Scale (VAS) – This includes adjectives assessing commonly 
reported effects of LSD, such as “stimulated”, “happy”, “closeness”, “openness”, and 
“trust” (Schmid et al., 2014). This will also be used to assess the effect of the drug 
during the sessions. 
5. 5 Dimensions of Altered States of Consciousness (5D-ASC) scale (Dittrich, 1998) 
assesses altered states of consciousness in five domains, and is sensitive to LSD 
administration (Schmid et al. 2014). This will be completed once at the end of each 
drug session. 
6. The Columbia Suicide-Severity Rating Scale (C-SSRS; Posner et al. 2008) defines 5 
subtypes of suicide ideation and will be administered at the start of each session for 
safety reasons.  
 
Physiological Measures: 
 


Blood pressure and heart rate will be monitored every 30 min using portable blood 
pressure cuffs, to track the cardiovascular effects of the drug, and ensure participant 
safety.  
 
Procedure  
 
Orientation: Participants who meet criteria will first be scheduled for an orientation 
session.  During this session, subjects will be informed that during the sessions, they 
may be given a placebo, a stimulant drug used to treat ADHD (e.g. methylphenidate), a 
sedative drug used to treat sleep disorders (e.g. diazepam), or a “hallucinogenic” drug 
(e.g. LSD). This procedure minimizes expectancy effects that may obscure the true 
pharmacological effects of drugs. We and others (Mitchell et al, 1996; Kirk et al, 1998; 
Metric et al, 2009; 2012; Heinz et al, 2013) have demonstrated that participants’ 
expectancies can strongly influence responses to drugs, and this is especially true for 
this current project. That is, there is a strong expectation among users about the 
effectiveness of microdosing.  This sentiment is evident in numerous accounts and 
claims on the internet.  Until now, these claims have not been put to the test.  If our 
participants know or expect to be receiving this particular drug then it will be impossible 
to determine whether the results were due to their expectancies or to the 
pharmacological effects of the drug.  Even with these instructions, there is a possibility 
that expectations will influence the outcome, but as researchers we need to make a 
best effort. At the end of the study we will ask subjects what they thought they received, 
before providing them with the information.  Participants will be given an oral description 
of the study procedures and the written consent form. After the experimenter reviews 
this information and the consent form with the subject, and answers any questions 
he/she may have, subjects will answer questions confirming their understanding of the 
study, and sign the informed consent document. The subject will then practice 
completing the tasks and questionnaires to be used in the study.  This will help reduce 
practice effects across the study sessions. Abstention from recent drug and alcohol use 
will verified by breathalyzer and urine drug tests.  Women will also be urine tested for 
pregnancy.  
 
Study Session: The study consists of two 2-week blocks, each with 4 sessions, 
conducted at 3-day intervals.  The blocks can be separated by 2-4 weeks. The timeline 
of each session is summarized below. On study session days, participants will arrive at 
9am, and consume a standardized snack. Research assistants will conduct urine and 
breath screening for recent alcohol and drug use, and a pregnancy test (for women).  
We will then take pre-drug measures of subjective mood, drug effects, body 
temperature, and cardiovascular variables; these measures are repeated every 30 min 
throughout the session (see below).  Participants will ingest the drug or placebo at 
9:30am.  While waiting for the drug effect to reach peak, they will be allowed to relax 
and watch a movie or read a book, but will not be allowed to do work. At 2 hrs after drug 
ingestion subjects will complete behavioral tasks, lasting about 1 hour, coinciding with 
the peak effect of the drug. They will complete the tasks in a counterbalanced order. 
The subjects will then be given a standardized lunch. Research assistants will check on 
participants every half hour, and they will be in an adjacent room with a video monitor 


throughout the sessions. A psychiatrist will be on call and on the premises throughout 
each session.  A procedure is in place to handle adverse drug responses (see SOP 
below).  Participants will remain in the lab until 2 pm, or if needed until effects of the 
drug return to baseline, as measured by both subjective report and cardiovascular 
variables.  Our laboratory is located in a hospital setting, with medical assistance readily 
available.  In the unlikely event that subjects are still affected by the drug at 2:00 pm, we 
can retain them in our comfortable testing rooms (couches, tv, blankets) until the effects 
dissipate. A research assistant will be in the adjacent room at all times, and will obtain 
approval from the physician before releasing the subject.  Sessions will be separated by 
3 days. 
 
Timeline 
9:00am – Arrival, snack, breath and urine tests 
9:15am – subjective and cardiovascular measures 
9:30am – Drug administered 
10:30am - subjective and cardiovascular measures 
11:00am - subjective and cardiovascular measures 
11:30am – Tasks, counterbalanced 
1:00pm – subjective and cardiovascular measures  
1:15pm-  Standardized lunch  
1:30pm - subjective and cardiovascular measures 
2:00pm - subjective and cardiovascular measures, end of session questionnaire; Leave 
Laboratory 
 
Post drug session.  Three days after each block of four sessions subjects will attend a 
1-hour non-drug laboratory session to assess their post-drug mood and behavioral 
responses. During this session they will complete the DASS, BDI, the IAPS ratings, and 
the n-back memory test.  During the second post-drug session (i.e., after the second 4-
session blocks) will also complete an end-of-study questionnaire, on which they will be 
asked to report which type or types of drugs they think they received at each session.  
They will also re-complete the State of Consciousness Questionnaire (Griffiths et al., 
2006). Finally, participants will be told about the study hypotheses, methods and the 
types of drugs that they received, and will be given a chance to ask any final questions 
in person, via phone, or via email. 
 
Data Analysis 
 
The effects of the drug will be assessed using three-way repeated measures analysis of 
variance (ANOVA), with drug (drug vs placebo), session (days 1-4) dose and time 
(within sessions) as within-subject factors. We hypothesize LSD will reduce depressed 
mood, compared to placebo, that this effect will increase over the 4 drug administration 
days, and that it will be evident three days after the 4th drug administration. Our primary 
mood measure will be negative affect scores on the PANAS.  Behavioral tasks will also 
be analyzed with two-way repeated measures ANOVAs, with drug, session and 
stimulus valence (negative, positive, neutral) as within-subjects factors.  
 


Human Subjects Information 
 
Recruiting methods: We will place print ads in newspapers and on online job search 
sites such as craigslist.org, Facebook, and flyers in the Chicago area.  Volunteers who 
respond to our ads are screened using our standard screening protocol for all studies in 
the Human Behavioral Psychopharmacology Laboratory, which is separately approved 
by the IRB under Protocol #13681B 
 
Obtaining consent: Consent for the screening session only is obtained at the 
screening according to procedures outlined in Protocol #13681B.  Written informed 
consent for the study procedures is obtained at the orientation session, after a verbal 
explanation of study procedures, check of comprehension, and an opportunity for the 
participant to ask any questions they may have.  Consent is verbally re-verified at the 
beginning of each study session.   
   
Risk to subjects: 
 
1. Diagnostic procedures and questionnaires: Some of the questions asked during the 
screening may be considered sensitive information, including drug use history and 
psychiatric history. We have rigorous procedures in place to ensure confidentiality of 
data, including locked cabinets for confidential files, subject coding, secure computer 
systems, and rigorous training of personnel. Please see screening protocol #13681B for 
full information on steps taken to protect information gathered as part of the screening.   
 
2. Study drug: The possible side effects of LSD include: dizziness, weakness, tremors, 
nausea, drowsiness, paraesthesia, blurred vision, dilated pupils and increased tendon 
reflexes, increase in blood pressure, although these effects are minimal even at doses 
much higher than we plan to administer. The risk of these effects is low at the 13 
microgram dose used in this study (Passie et al., 2008). In addition, to protect against, 
or minimize any possible risks with LSD, we will administer the drug according to the 
guidelines set forth by Johnson et al. 2008. Subjects are carefully screened to exclude 
those who are physically or psychiatrically at risk (e.g., current AXIS I disorders or 
history of psychosis). The studies are conducted in a hospital, where emergency 
assistance, including the psychiatry resident on-call, and the psychiatrist connected 
with the study are close at hand. A research assistant will be present throughout the 
procedures and will monitor heart rate, blood pressure, and respiratory rate throughout 
the sessions. In addition, on-call physicians will be available in the case of medical 
emergencies. Subjects will be provided with transportation home after the sessions. 
Subjects will be told that small amounts of the drugs or their metabolites will be 
detectable in the body for several weeks and to advise the experimenter if they intend 
to undergo a drug screening within one month of participating in the study.  
The PI holds an IND to study LSD (IND127547) and we submitted an amendment to 
the original protocol on September 29, 2018, to conduct this study.   
 
3. Tasks: Some of the tasks (emotional pictures, pictures of facial expressions) employ 
stimuli that are designed to elicit short-term positive and negative emotional reactions. 


Although the pictures used are designed to elicit emotional reactions, these reactions 
are typically brief, and similar methods to have previously been used in a wide range of 
studies without evidence of any long-term adverse reactions.  Further, participants are 
screened for any psychiatric conditions that might make them vulnerable to 
experiencing adverse reactions to brief alterations in mood.  Any participants who are 
unduly distressed will be counseled by a trained staff member. 
 
Benefits to subjects: There is no direct benefit to the participants, although we hope 
that the information learned from this study will contribute to our knowledge of potential 
novel treatments for mood disorders.  Additionally, participating in research may be an 
educational experience for participants, and we attempt to facilitate this by providing a 
thorough debriefing including an explanation of study hypotheses and procedures at the 
conclusion of participation. 
 
Subject time commitment and compensation:  The study sessions (8 sessions) are 
estimated to last 5 hrs each, plus two 1-hour followup sessions for a total of 42 hours 
spent in study sessions. Participants are compensated $40 for each study session, $10 
for each of the 1-hour sessions and a bonus of $110 for completion of all study 
sessions, giving a total of $450.  
 
Data and Safety Monitoring: The PI and the psychiatrist associated with the study will 
monitor data collection and safety at weekly staff meetings.  During these meetings, the 
PI will review and respond appropriately to (1) data collection and storage practices and 
(2) any adverse or unexpected effects from the study drugs.  Both the study physician 
and PI will monitor the safety of study participants on an ongoing basis. The physician 
connected with this study will be on call during the experimental sessions and for 24 
hours after sessions.  Subjects will be given telephone numbers for the study physician 
and investigators in case they experience unpleasant effects after leaving the 
laboratory. If a serious or unexpected adverse event were to occur, the staff member 
most closely involved with the subject at that time or the physician would notify the PI 
immediately. The PI would then take appropriate action and communicate with all 
necessary offices within the University and the FDA. 
 
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Standard Operating Procedure for psychiatric symptoms in MESA study (IND12747) 
August 7, 2018 
H. de Wit, PI 
 
The studies will be conducted in a comfortable, living-room like environment located in 
the Department of Psychiatry, at the University of Chicago Hospital.  The rooms are 
quiet, and have couches, subdued lighting and carpets.   Subjects are encouraged to 
bring calming music or reading material. A research assistant or post doctoral fellow will 
be present during all sessions, in a room adjacent to the participant.  Participants can 
contact the research assistant at all times.  The psychiatrist connected with the study 
will be on call, and notified in advance that a session is scheduled.  The psychiatrist can 
be telephoned (home and work numbers) or paged. If he is not available he will 
delegate this responsibility to a colleague. The emergency room is a 5 minute walk from 
the laboratory.   
 
The research assistant will check on the subject at least every 30 minutes to obtain 
cardiovascular measures and administer questionnaires.  If the subject describes 
discomfort that does not require further assistance, the research assistant will visit the 
subject every 10 minutes. 
 
The research assistant will page the psychiatrist immediately if any of the following 
events occur: 
1. If the subject’s heart rate increases to 120 bpm or higher or if blood pressure 
rises over 180/105. 
 
2. If the subject exhibits psychotic symptoms, or severe depression, or 
expresses thoughts or intentions to hurt self or others.  
 
If the intentions to hurt self or others are immediate, the research assistant will call 
Hospital Security to transport the subject to the Emergency Room.  A wheelchair is 
available, and the ER is a 5 minute walk from the testing rooms. 
 
Treatment for drug-induced psychiatric symptoms will be treated mainly by reassurance, 
and if necessary, with a 1 mg lorazepam tablet.  Lorazepam will be available in the 
laboratory but only administered with instruction from the psychiatrist or the PI.   
 
At the scheduled end of the sessions (2:00 pm), subjects will be queried about residual 
drug effects, and the research assistant, in consultation with the PI and the psychiatrist, 
will determine whether the subject can be released.  The research assistant will remain 
with the subject until it is safe for the participant to leave.  Subjects will not be permitted 
to drive after sessions, and will be provided with transportation home.