Randomized Placebo Controlled Cross-over Study Investigating the Influence of CBD on Episodic Memory in Healthy Subjects
Phase: NA
Conditions: Healthy
Sponsor: Prof. Dominique de Quervain, MD



CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 4 of 38 
Table of Contents 
STUDY SYNOPSIS ........................................................................................................................................7 
ABBREVIATIONS ....................................................................................................................................... 10 
STUDY SCHEDULE ................................................................................................................................... 11 
1. 
STUDY ADMINISTRATIVE STRUCTURE ........................................................................................ 12 
1.1 
Sponsor-Investigator ............................................................................................................... 12 
1.2 
Subinvestigator ....................................................................................................................... 12 
1.3 
Statistician ("Biostatistician") ................................................................................................... 12 
1.4 
Laboratory .............................................................................................................................. 12 
1.5 
Monitoring institution ............................................................................................................... 13 
1.6 
Data Safety Monitoring Committee .......................................................................................... 13 
1.7 
Any other relevant Committee, Person, Organisation, Institution .............................................. 13 
2. 
ETHICAL AND REGULATORY ASPECTS ...................................................................................... 14 
2.1 
Study registration .................................................................................................................... 14 
2.2 
Categorisation of study ........................................................................................................... 14 
2.3 
Competent Ethics Committee (CEC) ....................................................................................... 14 
2.4 
Competent Authorities (CA)..................................................................................................... 14 
2.5 
Ethical Conduct of the Study ................................................................................................... 14 
2.6 
Declaration of interest ............................................................................................................. 14 
2.7 
Patient Information and Informed Consent............................................................................... 14 
2.8 
Participant privacy and confidentiality ...................................................................................... 15 
2.9 
Early termination of the study .................................................................................................. 15 
2.10 Protocol amendments ............................................................................................................. 15 
3. 
BACKGROUND AND RATIONALE .................................................................................................. 16 
3.1 
Background and Rationale ...................................................................................................... 16 
3.2 
Investigational Product (treatment, device) and Indication ....................................................... 16 
3.3 
Preclinical Evidence ................................................................................................................ 16 
3.4 
Clinical Evidence to Date ........................................................................................................ 16 
3.5 
Dose Rationale / Medical Device: Rationale for the intended purpose in study (pre-market MD)17 
3.6 
Explanation for choice of comparator (or placebo) ................................................................... 17 
3.7 
Risks / Benefits ....................................................................................................................... 17 
3.8 
Justification of choice of study population ................................................................................ 17 
4. 
STUDY OBJECTIVES ........................................................................................................................ 18 
4.1 
Overall Objective..................................................................................................................... 18 
4.2 
Primary Objective.................................................................................................................... 18 
4.3 
Secondary Objectives ............................................................................................................. 18 
4.4 
Safety Objectives .................................................................................................................... 18 
5. 
STUDY OUTCOMES........................................................................................................................... 19 
5.1 
Primary Outcome .................................................................................................................... 19 
5.2 
Secondary Outcomes.............................................................................................................. 19 
5.3 
Other Outcomes of Interest ..................................................................................................... 19 
5.4 
Safety Outcomes .................................................................................................................... 19 
6. 
STUDY DESIGN .................................................................................................................................. 20 
6.1 
General study design and justification of design ...................................................................... 20 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 5 of 38 
6.2 
Methods of minimising bias ..................................................................................................... 20 
6.2.1 Randomisation ................................................................................................................ 20 
6.2.2 Blinding procedures ........................................................................................................ 20 
6.2.3 Other methods of minimising bias.................................................................................... 20 
6.3 
Unblinding Procedures (Code break) ....................................................................................... 20 
7. 
STUDY POPULATION........................................................................................................................ 22 
7.1 
Eligibility criteria ...................................................................................................................... 22 
7.2 
Recruitment and screening ..................................................................................................... 22 
7.3 
Assignment to study groups .................................................................................................... 22 
7.4 
Criteria for withdrawal / discontinuation of participants ............................................................. 23 
8. 
STUDY INTERVENTION .................................................................................................................... 24 
8.1 
Identity of Investigational Products (treatment / medical device) .............................................. 24 
8.1.1 Experimental Intervention (treatment / medical device) .................................................... 24 
8.1.2 Control Intervention (standard/routine/comparator treatment / medical device) ................ 24 
8.1.3 Packaging, Labelling and Supply (re-supply) ................................................................... 24 
8.1.4 Storage Conditions.......................................................................................................... 24 
8.2 
Administration of experimental and control interventions ......................................................... 25 
8.2.1 Experimental Intervention ................................................................................................ 25 
8.2.2 Control Intervention ......................................................................................................... 25 
8.3 
Dose / Device modifications .................................................................................................... 25 
8.4 
Compliance with study intervention ......................................................................................... 25 
8.5 
Data Collection and Follow-up for withdrawn participants ........................................................ 25 
8.6 
Trial specific preventive measures .......................................................................................... 25 
8.7 
Concomitant Interventions (treatments) ................................................................................... 25 
8.8 
Study Drug / Medical Device Accountability ............................................................................. 25 
8.9 
Return or Destruction of Study Drug / Medical Device ............................................................. 25 
9. 
STUDY ASSESSMENTS .................................................................................................................... 26 
9.1 
Study flow chart(s) / table of study procedures and assessments ............................................ 26 
9.2 
Assessments of outcomes ...................................................................................................... 26 
9.2.1 Assessment of primary outcome ..................................................................................... 26 
9.2.2 Assessment of secondary outcomes ............................................................................... 26 
9.2.3 Assessment of other outcomes of interest ....................................................................... 26 
9.2.4 Assessment of safety outcomes ...................................................................................... 26 
9.2.5 Assessments in participants who prematurely stop the study ........................................... 26 
9.3 
Procedures at each visit .......................................................................................................... 26 
9.3.1 Screening visit ................................................................................................................ 26 
9.3.1 Cognitive testing visit 1 and visit 2 ................................................................................... 27 
10. SAFETY ............................................................................................................................................... 28 
10.1 Drug studies ........................................................................................................................... 28 
10.2 Medical Device Category C studies ......................................................................................... 28 
10.3 Medical Device Category A studies ......................................................................................... 28 
10.4 Other clinical studies Category A ............................................................................................. 28 
10.4.1 Serious adverse events ................................................................................................... 28 
10.4.2 Adverse events ............................................................................................................... 28 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 6 of 38 
11. STATISTICAL METHODS .................................................................................................................. 29 
11.1 Hypothesis .............................................................................................................................. 29 
11.2 Determination of Sample Size ................................................................................................. 29 
11.3 Statistical criteria of termination of trial .................................................................................... 29 
11.4 Planned Analyses ................................................................................................................... 29 
11.4.1 Datasets to be analysed, analysis populations ................................................................. 29 
11.4.2 Primary Analysis ............................................................................................................. 30 
11.4.3 Secondary Analyses ....................................................................................................... 30 
Interim analyses......................................................................................................................... 30 
11.4.4 Safety analysis ................................................................................................................ 30 
11.4.5 Deviation(s) from the original statistical plan .................................................................... 30 
11.5 Handling of missing data and drop-outs................................................................................... 30 
12. QUALITY ASSURANCE AND CONTROL........................................................................................ 31 
12.1 Data handling and record keeping / archiving .......................................................................... 31 
12.1.1 Case Report Forms ......................................................................................................... 31 
12.1.2 Specification of source documents .................................................................................. 31 
12.1.3 Record keeping / archiving .............................................................................................. 31 
12.2 Data management .................................................................................................................. 31 
12.2.1 Data Management System .............................................................................................. 31 
12.2.2 Data security, access and back-up .................................................................................. 31 
12.2.3 Analysis and archiving .................................................................................................... 31 
12.2.4 Electronic and central data validation .............................................................................. 32 
12.3 Monitoring ............................................................................................................................... 32 
12.4 Audits and Inspections ............................................................................................................ 32 
12.5 Confidentiality, Data Protection ............................................................................................... 33 
12.6 Storage of biological material and related health data .............................................................. 33 
13. PUBLICATION AND DISSEMINATION POLICY ............................................................................. 34 
14. FUNDING AND SUPPORT ................................................................................................................ 35 
14.1 Funding .................................................................................................................................. 35 
14.2 Other Support ......................................................................................................................... 35 
15. INSURANCE ........................................................................................................................................ 35 
16. REFERENCES .................................................................................................................................... 36 
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 7 of 38 
STUDY SYNOPSIS  
Sponsor-Investigator 
Prof. Dominique de Quervain, MD 
Study Title: 
Randomized placebo controlled cross-over study investigating the 
influence of CBD on episodic memory in healthy subjects  
Short Title / Study ID: 
CoIL-Basel 
Protocol Version and 
Date: 
Version 2 11/07/2018 
Trial registration: 
Trial will be registered on clinicaltrials.gov and www.kofam.ch 
Study category and 
Rationale 
Other clinical trial with persons category A 
We will use Cannabidiol (CBD) e-liquid compliant to foodstuff and 
commodities regulation in usual amounts available on Swiss market. Low 
dose of CBD e-liquid and experimental setting bear only minimal risks for 
participants.  
Clinical Phase: 
Basic research 
Background and 
Rationale: 
The primary “non-psychoactive” phytochemical in cannabis CBD, is thought 
to have a broad range of therapeutic properties, including amelioration of 
the adverse psychological effects of THC, like impaired cognition (Osborne, 
Solowij, & Weston-Green, 2017; Zuardi, 2008). Here, we aim at 
investigating the effect of CBD on episodic memory. 
 
Objective(s): 
Primary objective of the study: Influence of CBD on episodic memory 
functions in healthy subjects 
Secondary objectives: Influence on working memory 
Outcome(s): 
The primary endpoints will be performance in a verbal memory task (de 
Quervain, Henke et al. 2003). 
The secondary endpoints will be performance in a working memory test.  
Study design: 
Placebo controlled, randomized, double blind, cross-over design.  
Inclusion / Exclusion 
criteria: 
Inclusion criteria 
• 
Normotensive (BP between 90/60mmHg and 140/90mmHg) 
• 
BMI between 18 and 30 kg/m2 
• 
Male or female 
• 
Aged between 18 and 30 years  
• 
Native or fluent German-speaking  
Exclusion criteria 
• 
Acute or chronic psychiatric disorder including drug or alcohol 
abuse  
• 
Known hypersensitivity or allergy to propylene glycol 
• 
Women who are pregnant or breast feeding  
• 
Smoking (> 5 cigarettes per day) 
• 
Participation in one of our previous studies using the same verbal 
test in the past 2 years 
• 
Participation in a study with investigational drug within the 30 days 
preceding and during the present study  
• 
Intake of CBD / THC within the 7 days preceding and during the 
present study in any application form 
• 
Long-term systemic medication or topical steroids to treat an 
underlying disease within last 3 months 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 8 of 38 
Measurements and 
procedures: 
• 
Screening visit with questionnaires.  
• 
Visit 1, 2 (Visit 2 2 week + 8 week after visit 1): 
A urine sample will be taken to control for pre-visit cannabis 
consumption. Subject will learn a list of 15 words followed by an 
immediate recall. Then they will be randomized to vape (verum or 
placebo) for 15min. They will perform a working memory test (n-
back) and rate different VAS (mood, arousal, motivation, tiredness, 
headache, tolerance). And then the episodic memory test words 
short delay will be performed.  
 
Assessment of safety: AE recording 
Study Product / 
Intervention:  
Single vape of 0.25ml 5% CBD e-liquid Citrus Fruits, Pharma Hemp 
(12.5mg CBD). We estimate 15min vape time.   
Control Intervention 
(if applicable): 
Single vape of 0.25ml e-liquid La Baronne Jaune, BORDO2 tastes like 
lemon and madeleine. 15min vape time. 
Number of 
Participants with 
Rationale: 
We are interested to detect cannabidiol effects with at least medium effect 
sizes. The estimation of N=34 is based on a power analysis using 
dependent t-tests assuming to detect a medium effect size (dz = 0.5) with a 
power of 80% at α=0.05 (software: G-power 3). 
Study Duration: 
Study duration is estimated 6 months 
Study Schedule: 
First participant in 10/2018 (planned) 
Last participant out 03/2019 (planned) 
Investigator(s): 
Sponsor-Investigator 
Prof. Dominique de Quervain, MD  
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel  
Tel: 
+41 61 207 0237 
Fax: 
+41 61 207 0241 
Email: dominique.dequervain@unibas.ch 
Subinvestigator 
Janine Hotz 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel  
Tel: 
+41 61 207 0249 
Fax: 
+41 61 207 0241 
Email: j.hotz@unibas.ch 
Study Centre(s): 
Division of Cognitive Neuroscience  
University of Basel 
Statistical 
Considerations: 
A significance level of p < 0.05 (two-sided) will be considered as significant. 
All analyses will be done in R. The differences between the experimental 
conditions will be analyzed using linear mixed models in combination with 
analysis of variance (SS II). 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 9 of 38 
GCP Statement: 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as 
far as applicable) as well as all national legal and regulatory requirements.  
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 10 of 38 
ABBREVIATIONS 
AE 
Adverse Event  
BASEC 
Business Administration System for Ethical Committees, 
(https://submissions.swissethics.ch/en/) 
BMI 
BP 
CA 
Body mass index 
Blood pressure 
Competent Authority (e.g. Swissmedic) 
CB1 receptors 
CB1 receptors 
CBD 
CEC 
Cannabinoid 1 receptors 
Cannabinoid 2 receptors 
Cannabidiol 
Competent Ethics Committee 
CRF 
Case Report Form  
ClinO 
Ordinance on Clinical Trials in Human Research (in German: KlinV, in French: OClin, 
in Italian: OSRUm) 
eCRF 
Electronic Case Report Form  
CTCAE 
Common terminology criteria for adverse events 
DSUR 
Development safety update report 
EKNZ 
GCP 
Ethikkommission Nordwestschweiz 
Good Clinical Practice  
IB 
Investigator’s Brochure 
Ho 
Null hypothesis 
H1 
Alternative hypothesis 
HRA 
Federal Act on Research involving Human Beings (in German: HFG, in French: LRH, 
in Italian: LRUm) 
IMP 
Investigational Medicinal Product 
IIT 
Investigator-initiated Trial 
ISO 
International Organisation for Standardisation 
ITT 
Intention to treat 
MADRS-S 
MD 
Montgomery-Asperg Depression Self-rating Scale 
Medical Device  
MedDO 
NA 
NG/ML 
Medical Device Ordinance (in German: MepV, in French: ODim) 
Not applicable 
Nanogram per millilitre 
PI 
SD 
Principal Investigator  
Source Data 
SDV 
Source Data Verification  
SOP 
Standard Operating Procedure 
SPC 
Summary of product characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
THC 
TMF 
Delta-9-tetrahydrocannabinol 
Trial Master File  

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 11 of 38 
VAS 
               Visual analogue scales 
STUDY SCHEDULE  
Procedure 
Visit 
Duration 
(min) 
Starting time Visit 1  
1 day (+ 3 month) after 
Tel. Screening 
Starting time Visit 2  
2 week (+ 8 week) after 
Visit 1  
Telephonescreening  
Inclusion / Exclusion criteria 
  
10 
- 
- 
Screening 
Informed consent 
Visit 1 
10 
00:10 
- 
MADRS-S 
5 
00:20 
- 
Sociodemographic questionnaire 
2 
00:25 
- 
Mental - Health questionnaire 
5 
00:27 
- 
Concomitant medication 
2 
00:32 
- 
Inclusion / Exclusion criteria  
1 
00:34 
- 
Test battery 1, 2 
Urine sample 
Visit 1, Visit 2 
(cross-over)  
8 
00:35 
00:00 
AE / Medication Log 
1 
00:43 
00:08 
Primary Endpoint: Words learning 
and immediate recall  
2 
00:44 
00:09 
Vape 
15 
00:46 
00:11 
Secondary Endpoint: n-back 
15 
01:01 
00:26 
VAS of mood, arousal  
Confounding factors: VAS of 
motivation, tiredness, headache, 
tolerance 
1 
01:16 
00:41 
Primary Endpoint: Words short 
delay recall 
3 
01:17 
00:42 
Overall time  
  
80min 
45min 
End Visit 1 and Visit 2 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 12 of 38 
1. STUDY ADMINISTRATIVE STRUCTURE  
1.1 Sponsor-Investigator  
Principal Investigator / 
Sponsor 
Prof. Dominique de Quervain, MD 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel 
 
Tel.: 
+41 61 267 0237 
Fax: 
+41 61 267 0241 
Email: dominique.dequervain@unibas.ch 
 
 
1.2 Subinvestigator  
Subinvestigator 
Janine Hotz 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel  
 
Tel.: 
+41 61 207 0249 
Fax: 
+41 61 207 0241 
Email: j.hotz@unibas.ch 
 
 
1.3 Statistician ("Biostatistician")  
Statistician and data manager 
 
 
 
 
Nathalie Schicktanz, Dr. 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel  
Tel.:     +41 61 267 0228 
Fax: 
+41 61 267 0241 
Email: Nathalie.schicktanz@unibas.ch 
 
 
1.4 Laboratory 
Not applicable 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 13 of 38 
1.5 Monitoring institution 
Monitor 
 
 
 
 
Bernhard Fehlmann 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel  
 
Tel.:    +41 61 207 0226 
Fax: 
+41 61 207 0241 
Email: bernhard.fehlmann@unibas.ch 
 
 
1.6 Data Safety Monitoring Committee  
A data safety monitoring will not be formed due to the fact that no extended or unexpected safety 
concerns are anticipated. 
 
1.7 Any other relevant Committee, Person, Organisation, Institution  
Not applicable 
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 14 of 38 
2. ETHICAL AND REGULATORY ASPECTS  
The decision of the CEC authority concerning the conduct of the study will be made in writing to the 
Sponsor-Investigator before commencement of this study. The clinical study can only begin once 
approval from all required authorities has been received. Any additional requirements imposed by the 
authorities shall be implemented. 
 
2.1 Study registration  
The study will be registered on clinicaltrial.gov and kofam.ch. 
 
2.2 Categorisation of study  
This study is classified as other clinical trial with persons. 
The use of CBD e-liquid classified as foodstuff and commodities (according to Swissmedics: 
https://www.swissmedic.ch/swissmedic/de/home/news/mitteilungen/produkte-mit-cannabidiol--cbd----
ueberblick.html) in usual quantity and dose entails only minimal risks and burdens and justifies the risk 
categorization A. CBD e-liquids are available on the Swiss market. The experimental setting entails 
only minimal risks and burdens to the well-being of subjects. 
 
2.3 Competent Ethics Committee (CEC)  
The sponsor/investigator will obtain approval from CEC (EKNZ) before the start of the clinical trial. 
The sponsor/investigator will report all changes in the research activity and all unanticipated problems 
involving risks to humans; including in case of planned or premature study end and the final report and 
no changes are made to the protocol without prior EKNZ approval, except where necessary to 
eliminate apparent immediate hazards to study participants. 
Premature study end or interruption of the study is reported within 15 days. The regular end of the 
study is reported to the EKNZ within 90 days, the final study report shall be submitted within one year 
after study end. Amendments are reported according to chapter 2.10. 
 
2.4 Competent Authorities (CA)  
Not applicable 
 
2.5 Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the 
current version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by 
ICH, in case of medical device: the European Regulation on medical devices 2017/745 and the ISO 
Norm 14155 and ISO 14971, the Swiss Law and Swiss regulatory authority’s requirements. The CEC 
and regulatory authorities will receive annual safety and interim reports and be informed about study 
stop/end in agreement with local requirements. 
 
2.6 Declaration of interest  
The authors certify that they have no intellectual, financial or proprietary conflict and are independent. 
 
2.7 Patient Information and Informed Consent 
During the telephone screening the subinvestigator will explain to each participant the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits and 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 15 of 38 
any discomfort it may entail. Each participant will be informed that the participation in the study is 
voluntary and that he/she may withdraw from the study at any time.  
The participant must be informed that his/her medical records may be examined by authorised 
individuals other than their treating physician. 
All participants for the study will be provided a participant information sheet and a consent form 
describing the study and providing sufficient information for participant to make an informed decision 
about their participation in the study. The information will be sent by e-mail to interested voluntary 
participants after telephone screening. Details see chapter 9.3. The interested voluntary will be given 
time between telephone screening and screening (at least one day) for his/her decision to participate. 
The participant information sheet and the consent form will be submitted to the CEC to be reviewed 
and approved. The formal consent of a participant, using the approved consent form, must be 
obtained before the participant is submitted to any study procedure.   
The participant should read and consider the statement before signing and dating the informed 
consent form, and should be given a copy of the signed document. The consent form must also be 
signed and dated by the investigator (or his designee) at the same time as the participant sign, and it 
will be retained as part of the study records. 
 
2.8 Participant privacy and confidentiality  
The investigator affirms and upholds the principle of the participant's right to privacy and that they 
shall comply with applicable privacy laws. Especially, anonymity of the participants shall be 
guaranteed when presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilising 
subject identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorised representatives of the Sponsor-Investigator or an ethics 
committee may require direct access to parts of the medical records relevant to the study, including 
participants’ medical history. 
 
2.9 Early termination of the study  
The Sponsor-Investigator may terminate the study prematurely according to certain circumstances, for 
example: 
• 
Insufficient participant recruitment 
  
2.10 Protocol amendments 
Substantial amendments are only implemented after approval of the CEC. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-
being of human subjects may proceed without prior approval of the sponsor and the CEC. Such 
deviations shall be documented and reported to the sponsor and the CEC as soon as possible. 
All non-substantial amendments are communicated to the CEC within the Annual Safety Report (ASR).  
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 16 of 38 
3. BACKGROUND AND RATIONALE  
3.1 Background and Rationale  
Cannabis is thought to be the most commonly used illicit substance (Hall & Degenhardt, 2007). Delta-
9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two major constituents of cannabis. THC 
is psychoactive and binds to cannabinoid 1 (CB1) receptors located in brain and the periphery, as well 
as to cannabinoid 2 (CB2) receptors which are located exclusively on nonneural tissue, such as 
immune cells (Pertwee, 1997) or glial cells (Nunez et al., 2004). In contrast, CBD has little affinity to 
CB1 and CB2 receptors (Bisogno et al., 2001; Showalter, Compton, Martin, & Abood, 1996) and is not 
psychoactive.  
Prolonged frequent of THC, has been associated with deleterious effects on psychological functions, 
including increased risk of developing schizophrenia-related psychotic episodes (Di Forti et al., 2015; 
Moore et al., 2007), impaired cognition (Broyd, van Hell, Beale, Yucel, & Solowij, 2016; Solowij & 
Michie, 2007), and alteration in brain structure (Lorenzetti, Solowij, & Yucel, 2016) and function 
(Bhattacharyya, Crippa, Martin-Santos, Winton-Brown, & Fusar-Poli, 2009; Martin-Santos et al., 2012). 
Furthermore, acute exposure to high doses of THC can also produce psychotic episodes in healthy 
individuals that largely resemble positive symptoms of schizophrenia (Henquet, Di Forti, Morrison, 
Kuepper, & Murray, 2008). 
In contrast, the primary “non-intoxicating” phytochemical in cannabis, CBD, is thought to have a broad 
range of therapeutic properties, including amelioration of the adverse psychological effects of THC. 
Moreover, CBD shows pro-cognitive effects and has, in multiple studies, been shown to protect 
against the detrimental cognitive effects of THC (Osborne et al., 2017; Zuardi, 2008). Regarding the 
effect of CBD on episodic memory, naturalistic human studies found that THC was associated with 
impaired learning and memory, but that the amount of CBD within cannabis was correlated with less 
impaired cognition (Morgan et al., 2012; Morgan, Schafer, Freeman, & Curran, 2010). A placebo-
controlled between-subject study using participants with the diagnosis of schizotyp found reduced 
performance in an emotional recognition task in the THC groups as compared to a THC plus CBD 
group. Interestingly, CBD administration significantly improved accuracy in the emotional recognition 
task beyond placebo levels (Hindocha et al., 2015). However, an imaging study in healthy subjects 
found no effect of THC (10mmg), CBD (600 mg) or placebo on cognitive task performance, but only on 
brain activations (Bhattacharyya et al., 2010).  
 
Although the precise pharmacological mechanisms and neurocircuitry responsible for the deleterious 
vs. therapeutic properties are still being investigated, it is assumed that CBD indirectly influence CB1 
receptors as CBD has low affinity for CB1 and CB2 receptors (McPartland, Duncan, Di Marzo, & 
Pertwee, 2015). Moreover, CBD interacts with the 5-HT1A as an agonist (Russo, Burnett, Hall, & 
Parker, 2005). In general, neurotransmission through the brain’s endocannabinoid system has been 
shown to influence emotional memory processing through changes in dopamine signaling within the 
mesolimbic system (for a review see (Hudson, Rushlow, & Laviolette, 2018)). Here, we aim at 
investigating the effects of CBD on episodic memory. 
 
3.2 Investigational Product (treatment, device) and Indication  
Refer to chapter 8.1. 
 
3.3 Preclinical Evidence  
N/A 
 
3.4 Clinical Evidence to Date  
Only a few studies investigated the effect of CBD alone on episodic memory (see 3.1). In summary, 
animals and a few human studies showed that CBD has the potential to limit THC induced cognitive 
impairments. However, we are interested to investigate the effect of CBD on episodic memory in 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 17 of 38 
humans.  
 
3.5 Dose Rationale / Medical Device: Rationale for the intended purpose in 
study (pre-market MD)  
The CBD doses used in describes studies in chapter 3.1 varies from 16 mg to 600 mg of CBD. Due to 
practical reasons and reasons of compliance, we have chosen a dose of 12.5 mg dose of CBD based 
on the estimated time taking to vape such a dose (15 minutes).  
 
3.6 Explanation for choice of comparator (or placebo)  
We will use a placebo vaping product (does not include CBD) tasting similar to intervention vaping 
product as a comparator. 
 
3.7 Risks / Benefits  
Benefits: current evidences suggests that CBD has the ability to reduce psychotic, anxiety and 
withdrawal symptoms (Mandolini et al., 2018) and amelioration of the adverse psychological effects of 
THC (Osborne et al., 2017). 
 
Risks: sedative actions like somnolence and increase of sleep duration (for review see (Zuardi, 2008)). 
Therefore, subjects will not be allowed to drive home by a vehicle after study participation. 
 
3.8 Justification of choice of study population  
This study aims to gain knowledge about memory processes in healthy participants. We will include 
male and female subjects between 18 and 30 years. 
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 18 of 38 
4. STUDY OBJECTIVES  
4.1 Overall Objective 
The purpose of this study is to evaluate whether CBD has an influence on episodic memory functions 
in healthy participants. 
 
4.2 Primary Objective 
The study seeks primarily to determine the effect of CBD on episodic memory functions. 
 
4.3 Secondary Objectives 
The secondary objects are to assess the Influence of CBD on working memory. 
 
4.4 Safety Objectives 
The study aims to assess tolerability of CBD in terms of incidence of side effects e.g. headache, 
gastrointestinal side effects etc. 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 19 of 38 
5. STUDY OUTCOMES  
5.1 Primary Outcome 
The primary endpoint will be the performance in a verbal memory task (de Quervain, Henke et al. 
2003), i.e. number of correctly recalled words (hits). Participants will view three series of five 
semantically unrelated nouns with the instruction to learn the words for immediate (after each series) 
and delayed (30 minutes after learning) free recall. Words are presented at a rate of 2 seconds.  
 
5.2 Secondary Outcomes 
Working memory will be assessed by means of a letter 0-back and 2-back task (Papassotiropoulos 
et al., 2011). The 0-back condition serves as a low-load control condition, measuring general attention 
and does not require the manipulation of information within working memory. In the 2-back condition, 
participants have to compare the currently presented letter with the one presented 2 steps before and 
have to indicate whether they are identical or not. The 2-back condition requires online monitoring, 
updating and manipulation of remembered information and therefore is assumed to involve key 
processes of working memory (Owen, McMillan, Laird, & Bullmore, 2005). Accuracy and reaction time 
will be measured. The tasks lasts about 15 minutes. 
 
5.3 Other Outcomes of Interest 
Current mood and arousal will be assessed by means of 10 cm visual analog scales (VAS) with the 
two end points—“lowest level” (0) and “highest level” (10). 
 
VAS of motivation, tiredness, headache and tolerance will be assessed to control for possible 
confounders ranging between 0 and 10 each.    
 
5.4 Safety Outcomes 
Safety outcome variables will consist of rate of adverse events in general. 
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 20 of 38 
6. STUDY DESIGN  
6.1 General study design and justification of design  
This is a single center clinical study comparing effects of CBD e-liquid versus a perfumed e-liquid on 
physiological processes (episodic memory) in healthy subjects using the following design 
- 
Randomized 
- 
Double-blind  
- 
Placebo-controlled 
- 
Cross-over design 
- 
Approx. equal number of male and female subjects in each group 
The duration of the study - from first participant in to last participant out - lasts approximately 6 months. 
The duration for a participant will be approximately 80 minutes for visit 1, and 45 min for visit 2. 
Dropouts will be replacement until data of total needed sample size is completed. 
 
The wash-out period between the two testing days lasts 14 days (approximately 10 half-lives of CBD 
(Ujvary & Hanus, 2016)) to 56 days (due to flexible recruiting). 
 
6.2 Methods of minimising bias  
6.2.1 
Randomisation  
By time of visit 1 eligible participants will be randomly allocated to receive either CBD or placebo 
(perfumed e-liquid) first. To minimise allocation bias, a randomization list will be prepared by a team 
member of the division of cognitive neuroscience. Block randomization will be used to achieve balance 
between number of participants starting with CBD and number of participants starting with placebo. A 
separate list will be used for males and females. The randomization number will be listed in the SD 
and in the eCRF. 
 
6.2.2 
Blinding procedures  
CBD e-liquid and perfumed e-liquid will be filled in identically looking vaporization tanks and labelled 
with a randomization number. Furthermore, tanks are wrapped with transparent colorized tape to 
cover e-liquid colour. Both vapes taste like citrus fruits. Participants will vape under supervision of a 
study member on a quiet balcony to avoid contaminating the air in the examination room with CBD 
vapours.  
 
6.2.3 
Other methods of minimising bias  
The investigators of the test days will be trained personal and will follow detailed instructions to ensure 
that each test day will be conducted in a highly standardized way. 
All study team members will be blinded to ensure that task evaluation by raters will be unbiased. 
In order to minimise time of days effect, the time of day of all main visits will be keep constant (e.g. 
morning or afternoon) for each participant.  
 
6.3 Unblinding Procedures (Code break)  
Unblinding will be permitted under these circumstances  
• 
SAE 
• 
AE if knowledge is crucial for further medical approach  
Unblinding procedures:  
Randomization list containing unblinding information of each participant will be kept under the 
responsibility of the Sponsor-Investigator and unblinding of the participant can be performed by the 
Sponsor-Investigator at any time. The Sponsor-Investigator documents the unblinding. The 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 21 of 38 
subinvestigator and other members of the team will not be informed about the result.  
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 22 of 38 
7. STUDY POPULATION  
7.1 Eligibility criteria  
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
- 
Healthy 
- 
Normotensive (BP between 90/60mmHg and 140/90mmHg) 
- 
BMI between 18 and 30 kg/m2 
- 
Male or female 
- 
Aged between 18 and 30 years  
- 
Native or fluent German-speaking  
- 
Able and willing to give written informed consent as documented by signature and comply with 
the requirements of the study protocol 
- 
Willing to donate urine sample to control for pre-Visit CBD/THC consume 
 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant, for 
example: 
- 
Acute or chronic psychiatric disorder including drug or alcohol abuse 
- 
Women who are pregnant or breast feeding  
- 
Intention to become pregnant during the course of the study  
- 
Smoking (> 5 cigarettes per day) 
- 
Participation in one of our previous studies using the same verbal test in the past 2 years 
- 
Participation in a study with CBD / THC within the 30 days preceding and during the present 
study  
- 
Known hypersensitivity or allergy to propylene glycol 
- 
Intake of CBD / THC within the 7 days preceding and during the present study in any 
application form 
- 
Long-term systemic medication or topical steroids to treat an underlying disease within last 3 
months 
- 
Inability to follow the procedures of the study, e.g. due to language problems, psychological 
disorders, dementia, etc. of the participant 
- 
Enrolment of the investigator, his/her family members, employees and other dependent 
persons 
 
7.2 Recruitment and screening  
Study participants will be searched at the University of Basel, Bern and Zurich by mean of flyers as 
well as advertisements via the websites psycho.unibas.ch, markt.unibas.ch and marktplatz.uzh.ch, 
newspapers, Basler Verkehrsbetriebe (BVB) and Facebook. We will also invite former participants of 
unrelated studies in our Division of Cognitive Neuroscience by e-mail. 
After contacting our subinvestigator via e-mail, a study team member will call the volunteer to inform 
him/her about the study. If the person meets all inclusion criteria and none of the exclusion criteria and 
is interested in participating, a date for the first visit will be fixed, the informed consent 
(Probandeninformation und Einverständniserklärung) will be sent, and the telephone screening 
documents will be filed as part of the SD in the participant’s dossier. The telephone screening 
documents of participants, who are not eligible for the screening, will be shredded. 
A study compensation of CHF 70 including travel expenses will be paid during visit 2.  
 
7.3 Assignment to study groups  
After informed consent, each participant will be assigned to a participant number. Eligible participants 
will be randomly allocated to either receive CBD or placebo first at visit 1 (see 6.1.3).  

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 23 of 38 
7.4 Criteria for withdrawal / discontinuation of participants  
Participants have the right to withdraw from the study at any time for any reason without being obliged 
to give reason. There will be a final interview regarding their actual wellbeing after withdrawal for 
whatever reason. The subinvestigator also has the right to withdraw participants from the study if it is 
in the best interest of the participant.  
The following reasons result in withdrawal: 
• 
Adverse events prohibiting cognitive testing (e.g. nausea, headache) 
• 
Single administration of psychoactive drug within 5 days before visit 2  
• 
Non-Compliance  
• 
Severe protocol violations 
• 
Administrative problems 
• 
Impossibility to vape 0.25mL e-Liquid 
• 
Alcohol intake within 12 hours before visit 2  
 
Withdrawal date and reason (if known) will be listed in the participant enrolment log. Safety data will 
be analysed for all participants, who received study medication. 
A team member, who is not involved in the data sampling procedure, will provide the study leader with 
replacement e-liquid tanks, in case drop-outs have to be replaced. This way, the randomization order 
of the randomization list can be maintained. Drop-outs will be replaced until data of 34 participants are 
completed. 
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 24 of 38 
8. STUDY INTERVENTION  
8.1 Identity of Investigational Products (treatment / medical device)  
8.1.1 
Experimental Intervention (treatment / medical device) 
Single vape of 0.25mL of CBD e-Liquid containing: 5% CBD (low-temperature extracted Cannabidiol 
from Cannabis sativa L., purity 99%), Glycerine (vegetable), Propylene glycol, water 
Brant: Pharma Hemp, Slovenia, https://pharmahemp.store/shop/e-liquids/cbd-e-liquid-5-10ml/ 
Label: CBD E LIQUID 5% Citrus Fruits 
Color: Light orange 
Taste: Citrus Fruits 
Vaporizer: Canna Vape Kit   
 
8.1.2 
Control Intervention (standard/routine/comparator treatment / medical 
device)  
Single vape of 0.25mL of La Baronne Jaune e-Liquid containing: Foodstuff fragrance additives, 80% 
Glycerine (vegetable), 20%Propylene glycol 
Brant: BORDO2, France, https://www.bordo2.com/oh-my-god/la-baronne-jaune-oh-my-god 
Label: LA BARONNE JAUNE 
Color: Colorless 
Taste: Lemon and madeleines 
Vaporizer: Canna Vape Kit   
 
8.1.3 
Packaging, Labelling and Supply (re-supply)  
We will use commercially available e-liquids: 
 
• 
CBD e-liquid provided with a Certificate of Analysis 
containing 5.079% w/w CBD and < 0.05% w/w THC  
 
• 
La Baronne Jaune e-liquid  
 
In 
preparing 
the 
Vaporization 
tanks 
we 
shall 
adhere 
to 
the 
Schweizerische 
Hygieneverordnung: https://www.admin.ch/opc/de/classified-compilation/20143394/index.html, 
concerning especially: 
 
• 
Cleanliness of work surface and all used utensils 
• 
Use of products before date of expiry  
• 
New vaporization tanks for each participant 
• 
Protection from contamination by using new syringes to fill the tanks 
• 
Temperature control  
 
8.1.4 
Storage Conditions  
Filled tanks are kept at room temperature between 15°C and 25°C (controlled by Logtag® data logger) 
in a dark with badge restricted room until consumption.  
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 25 of 38 
8.2 Administration of experimental and control interventions  
8.2.1 
Experimental Intervention  
It takes approximate 15 minutes to vape 0.25mL of an e-Liquid. We use a CBD e-Liquid with a high 
amount of CBD to reach a low dose (12.5mg CBD). This vape time is reasonable for e.g. students 
vaping before an exam.  
Pharma Hemp produces CBD-Liquids with CO2 fluid extraction. This procedure gentle extract CBD 
from Cannabis sativa L. yielded purest CBD oil. 
 
8.2.2 
Control Intervention 
Bord’O2 is a French e-Liquid brand from Bordeaux. It is rated as the top 3 e-Liquid brands according 
to the website vapoteurs.net. La Baronne Jaune tastes similar to CBD e-Liquid. So the use of this e-
Liquid seems very suitable as comparator.  
 
8.3 Dose / Device modifications  
The filled tank (0.25mL) has to be vaped. 
 
8.4 Compliance with study intervention  
Participants will vape e-liquid under supervision of a study member. 
 
8.5 Data Collection and Follow-up for withdrawn participants  
Withdrawn participants will be paid off the compensation. In case of an AE it will be followed up until 
resolution. 
 
8.6 Trial specific preventive measures 
One week before and during the entire Study participants are not allowed to consume CBD in any 
form like smoking, vaping, eating (e.g. sweets, ice cream, chocolate containing CBD, CBD capsules), 
drinking (e.g. teas, beer, milk containing CBD), or using CBD lotions, massage oil, tinctures, sprays or 
joss-sticks. 
We will register possible consumption. Coffee and black tea is permitted in the individual amount. 
Subjects should keep regular sleep habits. 
Alcohol, psychoactive drugs are not permitted within the above (7.4) specified time period. 
 
8.7 Concomitant Interventions (treatments)  
Concomitant medication other than psychoactive medication and alcohol are not allowed but will not 
result in withdrawal. 
 
8.8 Study Drug / Medical Device Accountability  
Not applicable 
 
8.9 Return or Destruction of Study Drug / Medical Device  
Not applicable 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 26 of 38 
9. STUDY ASSESSMENTS  
9.1 Study flow chart(s) / table of study procedures and assessments 
See study schedule. 
 
9.2 Assessments of outcomes  
9.2.1 
Assessment of primary outcome  
See primary outcome 5.1. 
 
9.2.2 
Assessment of secondary outcomes 
See secondary outcome 5.2. 
 
9.2.3 
Assessment of other outcomes of interest 
See chapter 5.3. 
 
9.2.4 
Assessment of safety outcomes 
9.2.4.1 
Adverse events  
All (S)AEs occurring after IC confirmation until visit 2 will be fully recorded in the participants eCRF. 
Description of (S)AE includes time of onset, duration and resolution, assessment of intensity, 
relationship to study drug, and measures taken. All (S)AEs are post-investigated until resolution.   
 
9.2.4.2 
Laboratory parameters 
No laboratory parameters will be assessed. 
 
9.2.5 
Assessments in participants who prematurely stop the study 
If participants stopped the study prematurely for whatever reason, a final examination will take place. 
The examination aims at recording any adverse events.  
 
9.3 Procedures at each visit 
9.3.1 
Screening visit 
During the screening – that is the first part of the first visit- the subinvestigator will again explain the 
nature of the study, its purpose, the procedures involved, the expected duration, the potential risks 
and benefits, and any discomfort it may entail. Furthermore, each subject will be informed that 
participation in the study is completely voluntary and that they can withdraw from the study at any time. 
Subjects will be informed that authorized individuals, other than the investigators, may analyse the 
observational data.  
Thereafter, participants must read and confirm the informed consent. They will be given a copy of the 
signed document. The consent form must also be signed and dated by the investigator. It will be kept 
as part of the participants study records.  
Written informed consent will be obtained from all participants without limiting time for signature. 
Participants who are candidates for enrolment into the study will be evaluated for eligibility during the 
screening visit (inclusion, exclusion criteria). Screening visit will consist of 
• 
Assessment of medication history 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 27 of 38 
• 
Vital signs (blood pressure / heart rate) will be taken with the participant having been in a 
seated position for at least 5 minutes.  
• 
Height / weight (for calculation of BMI)  
 
A pregnancy test will follow in case participants are not sure whether they are pregnant or not. 
Pregnancy testing will be performed in a urine sample according to instructions of AxaClear®, 
Axapharm.  
 
The following questionnaires will be used to assess possible psychiatric disorders: 
• 
Sociodemographic questionnaire 
• 
Mental health questionnaire  
• 
Depressive symptoms will be assessed with the self-rating questionnaire MADRS-S 
(Schmidtk1988). This scale consists of 9 items assessing participants' mood, feelings of 
unease, sleep, appetite, ability to concentrate, initiative, emotional involvement, pessimism 
and zest for life. Each item is scored between 0 and 3. The total score is calculated by 
summing the answers of the nine items, ranging between 0 and 27 (higher scores indicate 
increased impairment). 
Screening failures equal to participants not meeting all inclusion criteria or meeting one or more of the 
exclusion criteria. Excluded participants will be listed on a screening failure log.  
 
9.3.1 
Cognitive testing visit 1 and visit 2 
There will be a short examination consisting of a THC test, concomitant medication and adverse 
events. A THC test will be performed in a urine sample according to instructions of THC-Test, 
MedicTest. The test strip detects THC consummation with a sensitivity of 25 NG/ML. The detection 
time from last consummation least 3-5 days depending of the consumed amount. (The THC tests will 
be stored with IMP at the same conditions). Participants eligible for the study will start with the verbal 
memory task, i.e. learning a list of 15 words (for details see chapter 5.1), followed by an immediate 
free recall. 
Then the participant vape 0.25mL of the e-Liquid (CBD or perfumed e-Liquid on visit 1 or visit 2 
according to the randomization list). After approx. 15 minutes of vaping he/she will perform on the 0-, 
and 2-back task, followed by some VAS (for details see chapter 5.2). Then, short delay recall of the 
words will be assessed (for detail see study schedule table).  
At the end of each test day participants will be interviewed regarding their actual wellbeing. If there are 
no complaints / symptoms they can be dismissed. In case of minor health problems, the participant will 
have to stay in the study centre under medical control until recovery.  
The same memory/cognitive test battery will be administered in test days 1 and 2 using parallel 
versions of the primary and the main secondary outcome measures. 
 
A study compensation of CHF 70 will be paid at the end of visit 2. Screening Failures and Drop-Outs 
receive a pro rata compensation.  

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 28 of 38 
10. SAFETY  
10.1 Drug studies 
Not applicable. 
 
10.2 Medical Device Category C studies 
Not applicable. 
 
10.3 Medical Device Category A studies 
Not applicable. 
 
10.4 Other clinical studies Category A 
10.4.1  Serious adverse events 
A serious adverse event is defined as any adverse event where it cannot be excluded that the event is 
attributed to study, and which 
- 
Requires inpatient treatment not envisage in the protocol or extends a current hospital stay; 
- 
results in permanent or significant incapacity or disability; or 
- 
is life-threatening or results in death. 
The Sponsor Investigator is immediately notified (within 24 hours) if urgent safety and protective 
measures have to be taken during the conduct of the study. If a serious event occurs, the research 
project will be interrupted. The Ethics Committee will be notified via BASEC of these measures and of 
the circumstances necessitating them within 15 days.  
10.4.2 Adverse events  
We will document all adverse events following the vaporization of the e-Liquids until end of visit 2 
assessing causality and severity. 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 29 of 38 
11. STATISTICAL METHODS  
A within-subject design is performed to achieve more Power than a between-subject design by 
partitioning between-subject variance out of the error variance. No carryover-effects (e.g. practice, 
fatigue) are expected.  
 
A significance level of p < 0.05 (two-sided) will be considered as significant. As there is only one 
primary outcome measure, no Bonferroni correction will be applied. 
 
11.1 Hypothesis 
Cannabidiol has an influence on episodic memory. 
 
11.2 Determination of Sample Size  
We are interested to detect cannabinol effects with at least medium effect sizes. The estimation of 
N=34 is based on a power analysis using dependent t-tests assuming to detect a medium effect size 
(dz = 0.5) with a power of 80% at α=0.05 (software: G-power 3). 
 
11.3 Statistical criteria of termination of trial  
The study will be terminated, as soon as 34 participants will have completed the entire study.  
 
11.4 Planned Analyses  
All analyses will be done in R. Episodic memory performance (memory free recall) and secondary 
variables of interest will be analyzed by calculating linear mixed models with subject as random effect, 
experimental condition (Cannabidiol versus placebo) as contrast of interest (fixed effect) as well as the 
interaction term between experimental condition and covariates (sex, age). In case of significant 
interactions between covariates and experimental condition, post-hoc tests will be applied to describe 
the interaction. 
 
Furthermore, to control for possible confounders, possible confounders (words immediate recall, 
MADRS-S, sociodemographic variables, VAS for mood / arousal / motivation / tiredness / headache / 
tolerance), subjects' believe about group allocation, will be entered into the model as covariates (each 
covariate entering the statistical analyses separately).  
In case of no significant influence of covariates on dependent variables and in case of no significant 
interaction of covariate and experimental condition, we will consider to remove covariates out of the 
statistical model in order to reduce model complexity as far as possible (calculate t-tests in the 
simplest case).  
 
To illustrate the influence on episodic memory change between experimental conditions, the delta 
values will be calculated and used dependent variable in an additional analyses. The delta values 
correspond to the difference in task performance between experimental conditions.  
 
For interim analyses refer to 11.4.3. 
 
11.4.1 Datasets to be analysed, analysis populations 
Analysis of the primary and secondary outcome measures will be only performed with those 
participants, who completed all tests and investigations. There will be replacement of Drop-Outs until 
data of 34 participants are completed. Furthermore, subject performance will be analysed regarding 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 30 of 38 
statistical outliers and might be removed from analyses. Drop-outs and statistical outliers will be 
thoroughly described.  
 
11.4.2 Primary Analysis 
Primary outcome analyses will be performed after completed data sampling (see 11.3, 11.4) by study 
statistician. 
11.4.3 Secondary Analyses 
Secondary outcome analyses will be analysed analogue to primary analyse (see 11.3, 11.4). 
Subgroup analyses will be performed in case of significant interactions between covariates and 
experimental condition in order to describe the interaction (see 11.4). 
 
Interim analyses 
No interim analyses will be applied. 
 
11.4.4 Safety analysis 
Safety analyses will be performed after data sampling completion analogue to the analyses of primary 
and secondary analyses. 
11.4.5 Deviation(s) from the original statistical plan  
Deviation from the original statistical plan will be performed, if reviewers demand specific analyses. If 
in the meantime other studies find important effects or confounding effects related to our study, we will 
include these found confounders (if we have those) as an additional analysis in our statistical plan 
beside our planned analyses.  
All encoded data from participants who withdraw after enrollment are evaluated and anonymized 
afterwards. 
11.5 Handling of missing data and drop-outs  
Missing data will be recorded as NA. For drop-outs will be replaced (see 11.4.1). 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 31 of 38 
12. QUALITY ASSURANCE AND CONTROL  
The Principal investigator has an overall responsibility for the implementation and conduct of the study. 
He is allowed to delegate tasks to the research team as specified in the authorization list. Adequate 
information and training of the involved staff is in his charge and will be documented. 
For quality assurance the Ethics Committee may visit the research sites. Direct access to the source 
data and all project related files and documents must be granted on such occasions. 
 
12.1 Data handling and record keeping / archiving  
Documentation of all study relevant source data of every study participant will be done by completing 
the project specific electronic case report forms (eCRF). Entries in the CRF must be consistent with 
information recorded in the source documents. CRF data should be accurate, consistent, complete 
and reliable. For confidentiality reasons CRFs must not contain any personal data of study participants. 
 
12.1.1 Case Report Forms  
As eCRF we will use LabKey®, a validated software provided with an audit trail. Words are imported 
from logfiles and automatically rated. Rated words are checked for correctness by the subinvestigator. 
Single data entry for the other parameters.  
 
12.1.2 Specification of source documents  
Source data will consist of telephone screening forms, screening questionnaires and checklists, 
demographic data, visit dates such as memory test dates and scales, Informed Consent Forms, 
randomisation number, SAEs, AEs and concomitant medication. 
 
12.1.3 Record keeping / archiving  
All study data must be archived for a minimum of (10 years) after study termination or premature 
termination of the clinical trial. Study data will be archived in the archives of Division of Cognitive 
Neuroscience. 
 
12.2 Data management  
12.2.1 Data Management System  
Each subject will be assigned to a numeric code in the following way: 58-0001-BS. The first two digits 
identify the study, the 4 four digits in the middle the subject number and the last two digits are 
reserved for marking the centre. First subject will receive the number 58-0101-BS as the first 100 
numbers are kept for testing purposes.  
The coding list will be kept under lock and key. 
 
12.2.2 Data security, access and back-up  
Study team members will have access only to anonymized source data. All source data will be kept 
under lock and key. Electronical data will be stored on the server with back-up of the Division of 
Cognitive Neuroscience accessible only for study team members. The access to the sever room is a 
batch restricted only for authorized people. 
 
12.2.3 Analysis and archiving 
The log-files (data) will be stored on a linux or macintosh file-system with restricted user access (main 
file-system). The meta-information of each log-file (SHA-1 hashes as file id, file modification time, path 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 32 of 38 
to the file on the file-system, date and time information logged in the log-file) is stored in LabKey 
(https://www.labkey.com/) in a study specific folder (main study folder). The relevant content of the 
log-files that is necessary for creating an analytical database is additionally uploaded to LabKey (main 
study folder). Data that needs a manual data entry is entered directly in LabKey (data entry folder); 
after quality control the final data will again be stored in the main study folder within LabKey, and 
additionally as text-files in the file-system. 
The analytical database is created based on the uploaded or manually entered raw data as text-files 
with time-stamps. These text-files are stored within the LabKey file-system in the main study folder. 
 
LabKey is a SQL database in combination with a file-system (linux file-system) with a web-based 
graphical user interface (GUI). LabKey provides a user-management and a data-access management. 
Within LabKey each study has its own study folders (main study folder, data entry folder) with 
restricted user access. Subject specific data is stored in these study folders only. Within these study 
folders the access to the LabKey file-system is also handled. Additional information (like design tables 
of tasks, no subject specific information) is stored also in common folders within LabKey. 
The LabKey instance is deployed by SciCORE (https://scicore.unibas.ch/) within a virtual machine, the 
main file-system is deployed by the IT-department of Psychology. 
 
For log-files we don’t expect that any changes will be done. Therefore, we store the meta-information 
of each log-file to be able to verify that the file is in the original state. All other information is 
documented and stored within LabKey. LabKey provides an audit trail that allows the tracking of 
changes over time.  
After database closure all eCRF will be printed and archived in paper form. Archiving for all data 
(electronic or paper form and film sequences) will be for at least 10 years. 
 
12.2.4 Electronic and central data validation  
For log-files we use different levels of validation: As a first step we evaluate for each subject, visit and 
computer if all expected log-files are available and stored in the correct sequence; this check is done 
via the modification time of the files. We furthermore check if the log-files have an expected number of 
lines (if applicable, fixed task designs only). If the basis checks fail, we manually curate the log-files, if 
possible; manual data curation is documented in text-files stored together with the log-files or in 
LabKey. After performing these basic checks, the data is copied and stored in the final storage space 
of a study in the main file-system (see above). At the same time-point the meta-information of each file 
(see above) is stored in LabKey. When uploading the relevant content of the raw data, we further 
validate if the file-content corresponds to the expected design of a task, if possible (this is task-
dependent). Furthermore within LabKey we track for each subject, visit and task if there are exclusion 
reasons (filter-variables). While creating the final analytical database we apply these filter-variables to 
the data.  
 
12.3 Monitoring  
The aim of monitoring is to evaluate the progress of the study, to verify the accuracy and 
completeness of CRFs, to ensure that all protocol requirements, applicable local authority regulations 
and investigator’s obligations are being fulfilled, and to resolve any inconsistencies in the study 
records. The investigator will allow the sponsor to periodically monitor the study. 
Monitoring will be performed by an independent team member. Monitoring will consist of 20% of safety 
parameters, primary endpoint, inclusion and exclusion criteria, and 100% informed consent. (See 
Monitoring Plan). 
 
12.4 Audits and Inspections  
Audits by the CEC during study or after study closure may be performed to ensure proper study 
conduct and data handling procedures according to ICH-GCP guidelines and regulatory requirements. 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 33 of 38 
Audits and inspections may include verification of all source documents, check of CRFs and site files 
and a visual inspection of the study site. Direct access to all documents and places at study site is 
mandatory. In case of an announced audit or inspection immediate notification of the respective other 
party is necessary. 
 
12.5 Confidentiality, Data Protection  
Participant’s confidentiality will be maintained at all times. Personnel from the sponsor, members of 
CEC are obliged to respect medical secrecy and to refrain from divulging the participant’s identity or 
any other personal information they might fortuitously be aware of.  
 
12.6 Storage of biological material and related health data  
Not applicable. 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 34 of 38 
13. PUBLICATION AND DISSEMINATION POLICY  
The main publication will be created by Prof. Dominique de Quervain. Subsequent publications of 
subgroups can follow thereafter and will have to be approved by Prof. de Quervain. 
No unpublished data given to the investigator may be transmitted to a third party without prior written 
approval by Prof. de Quervain. No publication or communication involving the results of the study is 
authorized without prior written consent from the Prof. de Quervain. In view of patent and 
confidentiality issues, however, the investigator must accept requirements on the timing of early 
publication. The investigator’s name should not be used in any publication without the prior written 
permission of Prof. de Quervain.  
 
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 35 of 38 
14. FUNDING AND SUPPORT  
14.1 Funding  
Funding of trial conduct phase: Funds of the Division of Cognitive Neuroscience, University of Basel. 
 
14.2 Other Support  
Not applicable 
 
15. INSURANCE  
In the event of study-related damage or injuries, the liability of the University Basel provides 
compensation, except for claims that arise from misconduct or gross negligence.  
 
 
 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 36 of 38 
16. REFERENCES  
1. Declaration of Helsinki, Version October 2013, 
(http://www.wma.net/en/30publications/10policies/b3/index.html )  
2. International Conference on Harmonization (ICH, 1996) E6 Guideline for Good Clinical 
Practice. 
(http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf) 
3. International Conference on Harmonization (ICH, 1997) E8 Guideline: General Considerations 
for Clinical Trials 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8
_Guideline.pdf) 
4. Humanforschungsgesetz, HFG Bundesgesetz über die Forschung am Menschen 
(Bundesgesetz über die Forschung am Menschen, HFG) vom 30. September 2011/ Loi 
fédérale relative à la recherche sur l’être humain (loi relative à la recherche sur l’être humain, 
LRH) du 30 septembre 2011 / Legge federale concernente la ricerca sull'essere umano 
(Legge sulla ricerca umana, LRUm) del 30 settembre 2011  
5. Verordnung über klinische Versuche in der Humanforschung (Verordnung über klinische 
Versuche, KlinV) vom 20. September 2013 / Ordonnance sur les essais cliniques dans le 
cadre de la recherche sur l’être humain (Ordonnance sur les essais cliniques, OClin) du 20 
septembre 2013. Ordinanza sulle sperimentazioni cliniche nella ricerca umana 
(Ordinanza sulle sperimentazioni cliniche, OSRUm) del 20 settembre 2013  
6. Heilmittelgesetz, HMG Bundesgesetz über Arzneimittel und Medizinprodukte (Heilmittelgesetz, 
HMG) vom 15. Dezember 2000 / Loi fédérale sur les médicaments et les dispositifs médicaux 
(Loi sur les produits thérapeutiques, LPT) du 15 décembre 2000 / Legge federale sui 
medicamenti e i dispositivi medici (Legge sugli agenti terapeutici, LATer)   
7. ISO 14155:2011 Clinical investigation of medical devices for human subjects -- Good clinical 
practice (www.iso.org) 
8. ISO 10993 Biological evaluation of medical devices (www.iso.org) 
9. MEDDEV 2.7/3 revision 3, May 2015 
10. Medizinprodukteverordnung (MepV) vom 17. Oktober 2001 / Ordonnance sur les dispositifs 
médicaux (ODim) du 17 octobre 2001 / Ordinanza relativa ai dispositivi medici (ODmed) del 
17 ottobre 2001. 
11. WHO, International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/)  
Bhattacharyya, S., Crippa, J. A., Martin-Santos, R., Winton-Brown, T., & Fusar-Poli, P. (2009). 
Imaging the neural effects of cannabinoids: current status and future opportunities for 
psychopharmacology. Curr Pharm Des, 15(22), 2603-2614.  
Bhattacharyya, S., Morrison, P. D., Fusar-Poli, P., Martin-Santos, R., Borgwardt, S., Winton-Brown, 
T., . . . McGuire, P. K. (2010). Opposite effects of delta-9-tetrahydrocannabinol and 
cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 35(3), 
764-774. doi:10.1038/npp.2009.184 
Bisogno, T., Hanus, L., De Petrocellis, L., Tchilibon, S., Ponde, D. E., Brandi, I., . . . Di Marzo, V. 
(2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 
receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol, 
134(4), 845-852. doi:10.1038/sj.bjp.0704327 
Broyd, S. J., van Hell, H. H., Beale, C., Yucel, M., & Solowij, N. (2016). Acute and Chronic Effects of 
Cannabinoids on Human Cognition-A Systematic Review. Biol Psychiatry, 79(7), 557-567. 
doi:10.1016/j.biopsych.2015.12.002 
Di Forti, M., Marconi, A., Carra, E., Fraietta, S., Trotta, A., Bonomo, M., . . . Murray, R. M. (2015). 
Proportion of patients in south London with first-episode psychosis attributable to use of high 
potency cannabis: a case-control study. Lancet Psychiatry, 2(3), 233-238. doi:10.1016/S2215-
0366(14)00117-5 
Hall, W., & Degenhardt, L. (2007). Prevalence and correlates of cannabis use in developed and 
developing 
countries. 
Curr 
Opin 
Psychiatry, 
20(4), 
393-397. 
doi:10.1097/YCO.0b013e32812144cc 
Henquet, C., Di Forti, M., Morrison, P., Kuepper, R., & Murray, R. M. (2008). Gene-environment 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 37 of 38 
interplay 
between 
cannabis 
and 
psychosis. 
Schizophr 
Bull, 
34(6), 
1111-1121. 
doi:10.1093/schbul/sbn108 
Hindocha, C., Freeman, T. P., Schafer, G., Gardener, C., Das, R. K., Morgan, C. J., & Curran, H. V. 
(2015). Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on 
facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis 
users. Eur Neuropsychopharmacol, 25(3), 325-334. doi:10.1016/j.euroneuro.2014.11.014 
Hudson, R., Rushlow, W., & Laviolette, S. R. (2018). Phytocannabinoids modulate emotional memory 
processing through interactions with the ventral hippocampus and mesolimbic dopamine 
system: implications for neuropsychiatric pathology. Psychopharmacology (Berl), 235(2), 447-
458. doi:10.1007/s00213-017-4766-7 
Lorenzetti, V., Solowij, N., & Yucel, M. (2016). The Role of Cannabinoids in Neuroanatomic Alterations 
in Cannabis Users. Biol Psychiatry, 79(7), e17-31. doi:10.1016/j.biopsych.2015.11.013 
Mandolini, G. M., Lazzaretti, M., Pigoni, A., Oldani, L., Delvecchio, G., & Brambilla, P. (2018). 
Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical 
overview. Epidemiol Psychiatr Sci, 1-9. doi:10.1017/S2045796018000239 
Martin-Santos, R., Crippa, J. A., Batalla, A., Bhattacharyya, S., Atakan, Z., Borgwardt, S., . . . McGuire, 
P. K. (2012). Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and 
cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Des, 18(32), 4966-4979.  
McPartland, J. M., Duncan, M., Di Marzo, V., & Pertwee, R. G. (2015). Are cannabidiol and Delta(9) -
tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic 
review. Br J Pharmacol, 172(3), 737-753. doi:10.1111/bph.12944 
Moore, T. H., Zammit, S., Lingford-Hughes, A., Barnes, T. R., Jones, P. B., Burke, M., & Lewis, G. 
(2007). Cannabis use and risk of psychotic or affective mental health outcomes: a systematic 
review. Lancet, 370(9584), 319-328. doi:10.1016/S0140-6736(07)61162-3 
Morgan, C. J., Gardener, C., Schafer, G., Swan, S., Demarchi, C., Freeman, T. P., . . . Curran, H. V. 
(2012). Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like 
symptoms 
and 
psychological 
well-being. 
Psychol 
Med, 
42(2), 
391-400. 
doi:10.1017/S0033291711001322 
Morgan, C. J., Schafer, G., Freeman, T. P., & Curran, H. V. (2010). Impact of cannabidiol on the acute 
memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study 
[corrected]. Br J Psychiatry, 197(4), 285-290. doi:10.1192/bjp.bp.110.077503 
Nunez, E., Benito, C., Pazos, M. R., Barbachano, A., Fajardo, O., Gonzalez, S., . . . Romero, J. (2004). 
Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: 
an immunohistochemical study. Synapse, 53(4), 208-213. doi:10.1002/syn.20050 
Osborne, A. L., Solowij, N., & Weston-Green, K. (2017). A systematic review of the effect of 
cannabidiol on cognitive function: Relevance to schizophrenia. Neurosci Biobehav Rev, 72, 
310-324. doi:10.1016/j.neubiorev.2016.11.012 
Papassotiropoulos, A., Henke, K., Stefanova, E., Aerni, A., Muller, A., Demougin, P., . . . de Quervain, 
D. J. (2011). A genome-wide survey of human short-term memory. Mol Psychiatry, 16(2), 184-
192. doi:mp2009133 [pii] 
10.1038/mp.2009.133 
Pertwee, R. G. (1997). Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther, 74(2), 
129-180.  
Russo, E. B., Burnett, A., Hall, B., & Parker, K. K. (2005). Agonistic properties of cannabidiol at 5-
HT1a receptors. Neurochem Res, 30(8), 1037-1043. doi:10.1007/s11064-005-6978-1 
Showalter, V. M., Compton, D. R., Martin, B. R., & Abood, M. E. (1996). Evaluation of binding in a 
transfected cell line expressing a peripheral cannabinoid receptor (CB2): identification of 
cannabinoid receptor subtype selective ligands. J Pharmacol Exp Ther, 278(3), 989-999.  
Solowij, N., & Michie, P. T. (2007). Cannabis and cognitive dysfunction: parallels with endophenotypes 
of schizophrenia? J Psychiatry Neurosci, 32(1), 30-52.  
Ujvary, I., & Hanus, L. (2016). Human Metabolites of Cannabidiol: A Review on Their Formation, 
Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res, 1(1), 90-101. 
doi:10.1089/can.2015.0012 

CoIL-Basel, Version 2 of date 11/07/2018 
 
Page 38 of 38 
Zuardi, A. W. (2008). Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. 
Rev Bras Psiquiatr, 30(3), 271-280.