Clinical trial NCT02902081
Conditions: Drug Addiction
Sponsor: University of Chicago
Start date: 2013-02-01; Completion date: 2017-03-01
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this research is to examine the effect of cannabidiol (CBD), a cannabinoid compound found in marijuana, on responses to emotional stimuli. Both preclinical and clinical studies indicate that CBD may act to reduce anxiety without excessive sedative side-effects. Thus the investigators hypothesize that CBD may reduce responses specifically to negative emotional and social stimuli, including pictures and emotional faces, without altering responses to positive stimuli. To examine this, the investigators will administer placebo, 300mg, 600mg, and 900mg CBD to healthy normal adults in a double-blind within-subjects study. The investigators will measure subjective and subtle physical responses to positive and negative stimuli using measures that have been characterized with classic anxiety-reducing drugs and drugs of abuse. Further, the investigators will examine whether CBD-induced changes in these measures of emotional response relate to changes in actual behavior in a controlled social interaction. These results will allow the investigators to examine the potential usefulness of CBD as an anxiety-reducing drug, and suggest mechanisms by which CBD may reduce anxiety.

Detailed description:

Arms: arm 1: Oral placebo administered once prior to subjective drug effects questionnaires and behavioral tasks. arm 2: (300 mg, 600 mg, 900 mg) cannabidiol administered once prior to subjective drug effects questionnaires and behavioral tasks.
Interventions: intervention 1: Cannabidiol intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Detailed Protocol 
 
Title: Effects of cannabidiol on responses to emotional stimuli (“Effects of drugs on 
mood and behavior” on the consent form) 
 
P.I.: Harriet de Wit 
 
Co-Investigators: Anya Bershad, Emma Childs, Royce Lee 
 
May 11, 2016 
 
Objectives: To study the effects of cannabidiol (CBD), a constituent of marijuana, 
on responses to emotional stimuli in healthy young adults. 
 
Aim 1.  We will assess the effects of CBD on subjective and psychophysiological 
responses to images with positive (rewarding) vs. negative (aversive) emotional content. 
Our working hypothesis is that CBD will reduce subjective and psychophysiological 
responses to negative images without affecting responses to positive images. 
 
Aim 2. We will examine the effect of CBD on responses to the socially rewarding and 
aversive information conveyed by emotional facial expressions.  We will measure speed 
of identification for positive (rewarding) and negative (aversive) emotional expressions 
as they dynamically develop, psychophysiological reactions to emotional expressions and 
direction of attention to emotional expressions. Our working hypothesis is that CBD will 
slow identification of negative expressions, reduce psychophysiological responses to 
negative expressions, and reduce direction of attention to negative expressions without 
affecting responses to positive expressions. 
  
Aim 3. We will examine the effect of cannabidiol on a controlled social interaction with a 
research assistant.  Our working hypothesis is that the reduction in responses to negative 
emotional and social stimuli produced by CBD will result in greater talkativeness in a 
controlled social interaction. 
 
Exploratory Aim.  We will additionally measure the effects of CBD on subjective mood, 
including anxiety, euphoria and sedation, to determine whether the CBD’s effects on 
responses to emotional stimuli are mediated by effects on subjective mood, or occur 
above and beyond CBD-induced changes in mood.  
 
Significance 
 
The purpose of this project is to investigate the effects of cannabidol (CBD) on 
responses to emotional stimuli in humans. CBD is one of the primary constituents in 
whole plant marijuana (Ashton 2001). Such cannabinoid compounds are of interest for 
two reasons.  First, understanding the effects of these compounds may shed light on the 
phenomena of marijuana use and abuse.  Second, studying the effects of cannabinoids 
may be informative about the purposes and functioning of the brain’s endocannabinoid 


system. This system has recently been the focus of much therapeutic interest due to its 
involvement in stress and eating disorders (Felder 2006). Most research on cannabinoids 
has focused on delta-9-tetrahydrocannabidiol, the primary psychoactive ingredient in 
marijuana and the chemical that appears to be most responsible for the typical subjective 
effects of marijuana (Ilan et al. 2005). However, cannabidiol has recently become a focus 
of interest for two reasons. First, it appears to dampen some of the anxiogenic effects of 
THC, which may contribute to the reinforcing effects of whole plant marijuana (Zuardi et 
al. 1982).  Second, cannabidiol may have anxiolytic effects in and of itself (Bergamaschi 
et al. 2011b; Crippa et al. 2011; Fusar-Poli P and et al. 2009; Zuardi et al. 1993). At this 
point, the neural mechanisms by which cannbidiol produces these effects are unknown. 
Cannabidiol does not appear to have direct actions at either of the endocannabinoid 
receptors, although it can antagonize the effects of cannabinoid agonists. It may act as an 
antagonist at the putative new cannabinoid receptor, GPR55, and it may act as a 5-HT1A 
receptor agonist as well as a modulator at opioid receptor sites (Pertwee 2008).  
 
Our primary interest here is in the potential anxiolytic properties of CBD. In 
animals, CBD increases exploratory behavior in the elevated plus maze, and reduces 
freezing in a conditioned environment and in response to exposure to a predator, 
suggesting anxiolysis  (Schier et al. 2012).  These effects were comparable to those of 
diazepam, a benzodiazepine and known anxiolytic, but were mediated by different 
neurochemical mechanisms (Schier et al. 2012).  In humans, CBD reduced anxiety in 
responses to public speaking in both healthy volunteers and individual with social anxiety 
disorder (Bergamaschi et al. 2011b; Zuardi et al. 1993), reduced amygdala responses to 
fearful faces (Bhattacharyya et al. 2009; Fusar-Poli P and et al. 2009), and reduced 
subjective anxiety in response to a stressful imaging procedure (Crippa et al. 2003).  
Importantly, CBD also produced less sedation when compared to the traditional 
anxiolytic diazepam (Zuardi et al. 1993).  Together, these findings suggest CBD has 
anxiolytic properties that may be comparable to those of traditional drugs, but that are 
mediated through different neural mechanisms and potentially produce fewer sedative 
side-effects.  
 
In the current study we intend to examine the effect of CBD on responses to both 
positive and negative emotional and social stimuli. We will characterize both subjective 
responses and subtle psychophysiological responses to these stimuli. These measures of 
emotional response have been used to characterize many other drugs, including  
traditional anxiolytics like diazepam (Bitsios et al. 1999; Murphy et al. 2008; Patrick et 
al. 1996) and drugs of abuse such as amphetamine and THC (Ballard et al. 2012; Wardle 
and de Wit 2012).  This investigation will allow us to determine whether cannabidiol 
dampens responses to aversive stimuli in a manner comparable to traditional anxiolytics 
(Patrick et al. 1996). Importantly, in contrast to previous studies that have examined only 
anxiety-provoking stimuli, we can also examine whether CBD affects responses to 
positive stimuli. Ideally, to consider CBD as a novel anxiolytic, CBD should produce a 
decrease in negative responses without affecting positive responses. If CBD dampens 
responses to positive stimuli also, this might suggest general sedation (Grillon and Baas 
2003). In contrast, enhancement of responses to positive stimuli might suggest CBD 
contributes to the rewarding and potentially addictive effects of whole plant marijuana 


(e.g. Wardle and de Wit 2012). In addition, we will examine the relationship between 
effects on responses to emotional stimuli and social behavior in a controlled talking task.  
It has been suggested that CBD may be an effective treatment for social anxiety, and this 
will provide a model of how CBD’s effects may contribute to changes in actual social 
behavior.  If CBD does dampen responses to negative stimuli without interfering with 
positive responses, and these changes contribute to measurable changes in actual social 
behavior, this would contribute to mounting evidence that CBD should be considered as a 
novel treatment for anxiety disorders (Schier et al. 2012). 
 
Finally, we will examine on an exploratory basis the extent to which any changes 
in responses to emotional stimuli and social behavior are accounted for by CBD’s 
subjective effects. Specifically, we will examine the extent to which observed effects of 
CBD on responses to emotional stimuli and behavior can be accounted for by changes in 
subjective anxiety, sedation and euphoria. A growing literature suggests that both abused 
and therapeutic drugs may produce subtle changes in perception and responses to 
emotional stimuli that are independent of more commonly measured subjective changes 
(Harmer 2008; Harmer et al. 2003; Harmer et al. 2008; Wardle and de Wit 2012).  
 
 
In a four-session within-subjects study we will compare a placebo control to 300, 
600 and 900mg of cannabidiol.  In Aim 1 we will explore how cannabidiol affects 
reactions to rewarding vs. aversive pictures.  Participants will view pleasant pictures (e.g. 
of parties, pets, sunsets), neutral pictures (e.g. of household objects, neutral landscapes) 
and unpleasant pictures (e.g. medical imagery, war scenes and disgusting objects) drawn 
from the standardized International Affective Picture Set (IAPS) while we measure 
subjective responses to these pictures using self-reports.  We predict that cannabidiol will 
reduce subjective and psychophysiological responses to negative pictures without 
affecting responses to positive pictures. In Aim 2 we will examine responses to emotional 
facial expressions, which are an ecologically relevant category of rewarding and aversive 
stimuli. We will measure how quickly individuals are able to perceive happy vs. negative 
facial expressions using dynamically developing expressions of happiness, fear, anger 
and sadness.  We predict that cannabidiol will blunt perception of, psychphysiological 
responses to and attentional bias towards negative facial expressions without affecting 
responses to positive facial expressions. In Aim 3 we will examine the relationship of 
responses to emotional stimuli with talkativeness in a controlled social interaction.  We 
predict that cannabidiol will increase talkativeness, and this effect will be mediated by the 
decreased responses to negative social and emotional stimuli measured in the previous 
aims.  Finally, on an exploratory basis we will measure the subjective effects of 
cannabadiol, and specifically the its effects on anxiety, sedation and euphoria, with the 
aim of determining whether CBD’s effects on responses to emotional stimuli are related 
to, or independent of, its subjective effects. 
 
Methods: 
Design: The study will use a 4-session within-subjects double-blind design in which 
participants will receive three doses (300, 600mg and 900mg oral) of cannabidol and a 
placebo in randomized order. All 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:  We will recruit 50 healthy volunteers, with the expectation (based on previous 
retention rates) that 36 healthy volunteers (18 male, 18 female; age range 18-35 years) 
will complete all experimental procedures. All 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. Because 
CBD will be administered as part of the study, the following populations are excluded for 
safety reasons: Individuals with a medical condition contraindicating study participation, 
as determined by our physician, individuals regularly using any medications aside from 
hormonal contraception in women, individuals with a current (active in the past year) 
DSM-IV Axis I mood, anxiety, eating, or substance dependence disorder or a lifetime 
history of a psychotic disorder or mania; women who are pregnant, nursing, or planning 
to become pregnant in the next 3 months; anyone reporting a known or suspected allergy 
to cannabinoids.  The self-report questionnaires we use require fluency in English, and 
have not been translated and validated in other languages, thus individuals with less than 
a high-school education or those not fluent in English will be excluded, as lack of English 
familiarity at a high school level may compromise our ability to interpret their self-
reports. Individuals with a BMI below 19 or above 30 will also be excluded, as this 
would change dosing requirements. Last, for scientific reasons, we will include only 
individuals who report using marijuana < 100 times in their lifetime, to reduce variation 
in possible developed tolerance to CBD. 
 
Drug and Doses: We will administer placebo, 300mg, 600mg and 900mg CBD in 
counterbalanced order under double-blind conditions. Plasma levels peak approximately 
1 - 4 hr after oral administration, with mean peak concentration at 90min, and remain 
elevated up to 12 hr after an acute dose. The 300mg, 600mg and 900mg doses have been 
effective doses for reducing anxiety in previous studies (Bergamaschi et al. 2011b; Fusar-
Poli P and et al. 2009; Zuardi et al. 1993). Using three doses will help establish a dose-
response curve for any effects. Doses will be separated by at least 7 days  
 
CBD will be obtained in pure form from GW Pharmaceuticals (GW Pharmaceuticals 
2012).  Our IND has been approved (IND 125302). CBD is currently in Phase II studies 
for several indications including MS neuropathic pain and spasticity, and a 1:1 ratio 
combined CBD and THC oral spray is approved in several countries in Europe and in 
Canada for MS related spasticity (GW Pharmaceuticals 2012). Preclinical toxicity data 
suggest a good safety margin between the clinical dose proposed and a toxic dose, and 
doses of up to 1500mg CBD per day in humans are reported to be well-tolerated (Zuardi 
et al. 2006). Adverse effects of CBD/THC combined products have been subject to 
greater study that CBD alone, and these include dizziness, nausea, fatigue, dry mouth, 
somnolence, anxiety, mood changes, transient hypotension or tachycardia, delusional 
ideas, disorientation, and hallucinations. Most of these effects are likely attributable to 
the THC present in these combinations (GW Pharmaceuticals 2012).  Indeed, one review 


of the safety and side-effects of CBD alone noted no adverse effects across several 
studies (Bergamaschi et al. 2011a). However, we will take precautions against these 
possible adverse effects in our CBD alone study. See “Risks” for complete safety 
precautions. CBD alone may produce mild sedation, but does not appear to produce 
subjective intoxication, marked negative effects on mood or changes in cardiovascular 
functioning (GW Pharmaceuticals 2012).  
 
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. We 
will record psychophysiological facial EMG responses during a 1s baseline recording 
period will precede each picture, and during the 6s presentation of each (see 
“Psychophysiological Measures”). An Evaluative Space Grid rating will follow each 
picture to collect subjective reactions (see “Subjective Measures”).   
2. Dynamic Emotion Identification Task (DEIT) – In a task created for use in our 
laboratory (Wardle et al. 2012a), participants will view dynamically developing facial 
expressions composed of 2% morphs between a neutral face and a 100% expression 
of an emotion presented sequentially. The emotions will be happiness, sadness, anger, 
fear and disgust.  Participants will be instructed to respond as soon as they believe 
they can correctly identify the emotion expressed.  In this way both sensitivity (% of 
emotion expressed at time of identification) can be measured. Accuracy is usually 
near ceiling with this paradigm, and thus is not a primary dependent variable.  EMG 
measurements will also be taken while participants view the facial expressions to 
examine psychophysiological reactions to the expressions (see “Psychophysiological 
Measures”). 
3. Attentional Bias Task (ABT) – In a task adapted from Garner and colleagues (Garner 
et al. 2006) participants will be presented with pairs of faces, one on each side of a 
computer screen.  Each pair will contain one neutral face and one 100% emotional 
expression taken using the same actor.  The emotional expressions used will be from 
the standardized Karolinska set (Goeleven et al. 2008). Participants will be shown a 
central fixation cross for 1,000 ms, then the pairs of faces side by side for 500 ms. To 
distract participant attention from the primary purpose of the task, and reduce 
response bias, a probe (either an up arrow or a down arrow) will be presented in the 
same location as one of the previous pictures after each trial.  Participants must 
respond to the direction the arrow is pointing by pressing a key. After a response, or 
after 10s have elapsed with no response, an intertrial interval of 750 to 1,250 ms will 
begin, followed by the presentation of another trial.  
4. Interpersonal Speech Task (IST) – This is a controlled interaction task previously 
validated in our lab (Wardle et al. 2011) The IST is a semi-structured dialog task 
designed to model certain aspects of the psychotherapeutic encounter. During the 
IST, participants will be asked to describe a significant person in their life. They will 
be given 5 minutes to speak about this person with the research assistant, who will be 
trained in basic active listening skills (Sommers-Flanagan and Sommers-Flanagan 
2009). Transcription and textual analysis by the Linguistic Word Count and Inquiry 


Program will be used to examine the total number of words as an index of social 
activity, and the amount of positivity and the amount of negativity expressed in each 
speech task, as a behavioral index of affect (Pennebaker et al. 2007). 
 
 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 in similar samples of 
healthy volunteers (de Wit & Griffiths, 1991; Johanson & Uhlenhuth, 1980), and will 
be used to assess mood effects of the drug during the study sessions. 
2. 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 is also be used to assess the pharmcodynamics of 
the drug effect during the study 
3. The Addiction Centre Research Inventory – ARCI (Martin et al. 1971). The ARCI is 
a true-false questionnaire that consists of empirically derived scales sensitive to the 
effects of a variety of classes of psychoactive drugs (Haertzen 1966). We used a 53-
item version, which yields scores for six scales that include: sedation (Pentobarbital-
Chlorpromazine Group; PCAG), stimulant-like effects (Amphetamine; A, and 
Benzedrine Group; BG), somatic and dysphoric effects (Lysergic Acid; LSD), 
euphoria (Morphine-Benzedrine Group; MBG), and marijuana-like effects (M). 
4. The Evaluative Space Grid – ESG (Larsen et al. 2009). The Evaluative Space Grid is 
validated measure consisting of a two dimensional grid that provides a single item 
measure of positivity and negativity.  This will be used to measure subjective 
reactions to the IAPS pictures. 
 
Psychophysiological Measures: 
 
1. Cardiovascular measures – Blood pressure and heart rate will be periodically 
monitored 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 the capsules used in the study 
may contain a placebo, a stimulant drug (e.g. amphetamine, methylphenidate), a sedative 
drug (e.g. diazepam, alprazolam), or a cannabinoid drug, which is a component of 
marijuana (e.g. THC or cannabidiol).  In previous studies we have found this procedure 
reduces expectancy effects. 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.  
 
Study Session: Please see below for a full timeline of the study session. Participants will 
be asked to fast overnight. On study session days, participants will arrive at 9am, and 
consume a standardized snack.  Participants will then complete a urine and breath 
screening for recent alcohol and drug use, and a pregnancy test (for women).  We will 
then take Time 1 measures of subjective mood, drug effects and cardiovascular variables. 
We will continue to take these same measures periodically throughout the study (see 
below).  Participants will be administered the drug or placebo at 1:30pm.  While waiting 
for the drug effect to reach peak, participants will be allowed to relax and watch a movie 
or read a book, but will not be allowed to do work. At 2:15 pm, 3 pm, 3:45 pm, we will 
reassess mood. The task portion of the study will begin approximately 90min after 
administration of the drug, and will last for approximately 1 hour, to coincide with the 
peak effect of the drug. The IAPS, DEIT, ABT tasks will be presented in a 
counterbalanced order. The psychophysiological equipment will then be disconnected 
and the IST task will be completed. Participants will then remain in the lab completing 
subjective measures of the drug effect every half-hour until at least 5:45 pm (when we 
expect drug effects will be decreased sufficiently to permit participants to leave safely), 
or until drug effects decrease sufficiently to permit participants to leave safely (as 
measured by both subjective report and cardiovascular variables). Some drug effects may 
persist for up to 12hrs after the end of the study session, but based on the literature on 
CBD given chronically to an ambulatory population, these should be mild and non-
impairing (Cunha et al. 1980). Sessions will be separated by at least 5 days. 
 
Timeline 
1:00pm  
- Arrival, snack, breath and urine tests 
1:15pm  
- Mood (POMS), drug effect (DEQ, ARCI) and cardiovascular measures 
1:30pm  
- Capsule administered 
2:15pm  
- Mood (POMS), drug effect (DEQ, ARCI) and cardiovascular measures 
3:00pm 
- Mood (POMS), drug effect (DEQ, ARCI) and cardiovascular measures 
3:45pm  
- Mood (POMS), drug effect (DEQ, ARCI) and cardiovascular measures 
4:00pm 
- IAPS, DEIT, ABT tasks, counterbalanced 
4:45pm  
- IST task 
5:00pm 
- Mood (POMS), drug effect (DEQ, ARCI) and cardiovascular measures 
5:45pm  
- Mood (POMS), drug effect (DEQ, ARCI) and cardiovascular measures 
5:50pm  
- Leave laboratory 
 
Debriefing: Participants will return to the lab for a final session at which they will 
complete a final DEQ rating of how much they liked each study drug and how much they 
would want to take each study session drug again.  Participants will also be asked to 
report which type or types of drugs they think they received at each session.  Finally, 
participants will be fully debriefed with regard to the study hypotheses, methods and the 
types of drugs that they received, and will be given a chance to ask any final questions. 
 


Data Analysis 
 
IAPS: We hypothesize that participants will react less to negative pictures while taking 
CBD, while reactions to positive and neutral slides will be unchanged. We will conduct a 
Mixed Linear Model analysis in R using lme4 on each dependent variable (subjective 
ratings, corrugator and startle responses) using Drug (0, 300, 600 and 900mg) and picture 
type (positive, neutral, negative) as independent variables, and including random 
variables for Subject and Drug. 
 
DEIT: We hypothesize that participants will show decreased sensitivity to negative facial 
expressions (anger, sadness and fear) on CBD, as measured by a greater intensity of 
expression required to identify negative facial expressions, but unchanged intensity for 
happy facial expressions.  We also hypothesize that CBD will reduce negative 
psychophysiological responses to negative facial expressions, but not happiness. We will 
conduct a Mixed Linear Model analysis in R using lme4 on each dependent variable 
(expression intensity and corrugator responses) using Drug (0, 300, 600 and 900mg) and 
expression type (happy, angry, fearful, sad) as independent variables, and including 
random variables for Subject, Drug and Actor. 
 
ABT: We hypothesize that participants will show reduced attentional bias to negative 
facial expressions (anger, sadness and fear) on CBD, as measured by increased reaction 
times for probe response for negative faces, without any change in responses to happy 
faces. We will conduct a Generalized Mixed Linear Model analysis in R using lme4 on 
the binomial variable of initial gaze direction with Drug (0, 300, 600 and 900mg) and 
expression type (happy, angry, fearful, sad) as independent variables, and including 
random variables for Subject and Drug.  We will conduct a Mixed Linear Model analysis 
in R using lme4 on total dwell time on each face, using Drug (0, 300, 600 and 900mg) 
and expression type (happy, angry, fearful, sad) as independent variables, and including 
random variables for Subject and Drug. 
 
IST: We hypothesize that participants will show increased talkativeness on the IST, as 
measured by total word count and further, that this increased talkativeness will be 
mediated by reduced negative responses to negative emotional and social cues (as 
measured in the IAPS, DEIT and ABT). We will first derive per-participant estimates of 
the effect of drug on responses to negative stimuli from the Mixed Linear Model analyses 
described above. We will then conduct a Mixed Linear Model analysis in R using lme4 
on total word count with Drug (0, 300, 600 and 900mg) as an independent variable, and 
including random variables for Subject and Drug (per Wardle et al. 2012b). Following 
criteria for within-subject mediation (Judd et al. 2001), we will first establish whether 
drug has the hypothesized effect on talkativeness. We will then include the per-
participant estimates of the effect of drug on responses to negative stimuli as covariates, 
and examine 1. Whether changes in responses to negative stimuli account for a 
significant proportion of changes in talkativeness, and 2. Whether the effect of drug on 
talkativeness is still significant after inclusion of the changes in responses to negative 
stimuli.  If the effect of drug on effort is wholly mediated by changes in responses to 
negative stimuli, we would expect the effect of drug on talkativeness to no longer be 


significant after including drug-induced changes in responses to negative stimuli as a 
covariate (see Wardle and de Wit 2012 for an example of this type of analysis). 
 
Exploratory Analysis of Relationship to Mood: We will conduct similar within-subject 
mediational Mixed Linear Model analyses in R using lme4 on our primary outcomes of 
responses to negative stimuli, using subjective measures of anxiety (from the POMS), 
sedation (from the ARCI) and euphoria (from the POMS, ARCI and DEQ) as covariates.  
Following the procedure described above, we will determine whether the effects of the 
drug on responses to negative stimuli are partially or wholly mediated by its effects on 
subjective mood. 
 
Human Subjects Information 
 
Recruiting methods: We will place print ads in newspapers and on online job search 
sites such as craigslist.org, and flyer in the Chicago area.  Healthy 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: Written informed 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 CBD include: dizziness, nausea, fatigue, dry 
mouth, somnolence, anxiety, mood changes, transient hypotension or tachycardia, 
delusional ideas, disorientation, and hallucinations. This list of effects is derived from 
study of CBD/THC combined medicines, and most of these effects are likely 
attributable to the THC present in these combinations. However, we will still take 
precautions to minimize these possible effects in our CBD-alone study. Subjects are 
carefully screened to exclude those who are physically or psychiatrically at risk for these 
side effects (e.g., any Axis I disorders or history of psychosis, high blood pressure or 
cardiovascular risk factors). 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 and blood pressure throughout the sessions. In 
addition, on-call physicians will be available in the case of medical emergencies. 
Subjects will be told not to drive following the sessions and, if necessary, will be 
reimbursed for public transportation costs. 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. There have been no clinical reports of drug-drug interactions 
(GW Pharmaceuticals 2012), but participants regularly taking medication aside from 
birth control will be excluded, and participants will also be told to refrain from using 
any other recreational or medical drugs (aside from birth control) for at least 12 hours 
after the study to minimize any chance of interaction effects with other drugs. Because 
CBD is contraindicated in pregnant or nursing women, women must not be pregnant or 
planning to become pregnant within three months of the study. They will be tested for 
pregnancy at each session. Last, we will exclude any individuals reporting a known or 
suspected allergy to cannabinoids. 
 
Because the subjects are normal healthy adults participating voluntarily, there are no 
alternative treatments to the study drug. They will be fully debriefed following the 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 factors 
influencing drug use.  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 screening portion of the study takes 
approximately 2 hours. The orientation typically takes approximately 1 hour.  The study 
sessions are estimated to last 5 hrs each, and the debriefing is .5 hours, for a total of 21.5 
hours spent in study sessions. Participants are compensated $35 for each study session, 
with a bonus of $110 for completion of all study sessions, giving a total of $250.  
 
Data and Safety Monitoring: The PI 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 an unanticipated problem 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 submit written notification of the problem to the problem to the IRB using the 
“Unanticipated Problem” report within 10 working days.  The PI would then determine, 
in collaboration with the IRB whether the problem requires further reporting to the 
federal funding agency or FDA.  If a life-threatening adverse event were to occur, the PI 
would communicate the event to the IRB chair immediately, and halt further study 
sessions and participant enrollment.  
 
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