Does Cannabidiol Attenuate the Acute Effects of ∆9-tetrahydrocannabinol Intoxication in Individuals Diagnosed With Schizophrenia? A Double-blind, Randomised, Placebo-controlled Experimental Study
Phase: NA
Conditions: Schizophrenia, Cannabis Use
Sponsor: King's College London

 
 
Integrate Study 
 
Statistical Analysis Plan 
 
 
Does cannabidiol attenuate the acute effects of ∆9-tetrahydrocannabinol intoxication in 
individuals diagnosed with schizophrenia? A double-blind, randomised, placebo-controlled 
experimental study 
 
 
 
 
 
 
 
 
 
 
 
 
Version: 1.0 
Date: 28/07/2023 
 
 
IRAS: 278595 
ClinicalTrials.gov: NCT04605393 
 
 
Authors: Edward Chesney, Dominic Oliver, Will Lawn, Tom Freeman, Amir Englund, John 
Strang, Philip McGuire 

Study Design 
Integrate is a double-blind, randomised, placebo-controlled, crossover, experimental study 
assessing whether pre-treatment with oral cannabidiol (CBD) can attenuate the negative 
effects of acute delta-9-tetrahydrocannabinol (THC) intoxication in individuals with 
schizophrenia or schizoaffective disorder who use cannabis. 
 
Population 
The study will recruit 30 participants with a diagnosis of schizophrenia or schizoaffective 
disorder, who smoke cannabis regularly, are currently receiving treatment with 
antipsychotic medication, and are clinically stable (no inpatient or intensive community care 
for at least three months). Full inclusion and exclusion criteria are described in the study 
protocol. 
 
Drug conditions 
There are two drug conditions: 
 
i) 
CBD 1000mg oral & THC inhaled 
ii) 
Placebo oral & THC inhaled 
 
Each participant will complete two experiments so that they receive each treatment once. 
The order of CBD/placebo is randomised and double-blind. CBD/placebo capsules are 
administered with food (two yoghurts). 
 
After completing trial experiments at 10mg and 15mg, the starting dose of THC was set at 
20mg (101mg of 19.8% THC ground cannabis flos). 
 
The THC is administered three hours after CBD administration using a medical grade 
vaporiser device. 
 
Dose escalation 
If a participant completes two experimental visits and does not demonstrate a significant 
response (defined as a PANSS positive subscale score increase of 3 or more), they will be 
invited to complete another pair of experiments with a higher dose of THC. The dose of CBD 
will always be 1000mg. 
 
Experiments 1 & 2: 20mg THC inhaled & oral CBD 1000mg/placebo 
 
Experiments 3 & 4: 40mg THC inhaled & oral CBD 1000mg/placebo 
 
Experiments 5 & 6: 60mg THC inhaled & oral CBD 1000mg/placebo 

 
With each pair of experiments participants will be re-randomised to treatment with 
CBD/placebo. 
Flowchart 
 
 
 
 
Baseline visit 
- assess inclusion/exclusion criteria 
- collect demographic and clinical data 
- rehearse study procedures
Randomise
CBD 1000mg PO 
&
THC 20mg inh
CBD 1000mg PO 
&
THC 20mg inh
Placebo PO 
&
THC 20mg inh
Placebo PO 
&
THC 20mg inh
Significant response during either
experiment 
(i.e. PANSS-P increase 3+)
Repeat experiments with THC
40mg and then THC 60mg
Yes
No

Study objective 
To assess the extent to which, in individuals with schizophrenia, the presence of CBD 
attenuates the acute effects of THC on cognitive impairment and psychotic symptoms. 
 
Primary hypotheses and outcome measures 
Hypothesis 1: CBD will reduce the impairment in delayed verbal recall compared with 
placebo. 
Outcome measure: Hopkins verbal learning task – delayed verbal recall. The total number of 
words correctly recalled at 20-25 minutes. 
 
Hypothesis 2: CBD will reduce the severity of positive psychotic symptoms compared with 
placebo.  
Outcome measure: Positive and Negative Syndrome Scale (PANSS) - Positive subscale. 
Change from pre-CBD/placebo to post-THC. 
Secondary hypotheses and outcome measures 
Hypothesis 3: CBD will reduce state anxiety compared with placebo. 
Outcome measure: State-Trait Anxiety Inventory (STAI-S). Change from pre-CBD/placebo to 
post-THC. 
 
Hypothesis 4: CBD will reduce the impairment in working memory compared with placebo. 
Outcome measure: Forward and reverse digit span. The total number of numbers correctly 
repeated. 
 
Data processing and statistical analysis 
Data processing and missing data 
Multiple imputation chain equations (MICE) will be used to impute missing values in 
psychopathological, cognitive, physiological, and pharmacokinetic outcomes using the mice 
package in R. We will complete sensitivity analyses to assess the effect of data imputation. 
 
Analysis population 
Primary analyses will be per-protocol (i.e. data where participants completed a pair of 
experiments). For participants who completed more than one pair of experiments, the data 
from the experiments where the highest THC dose was administered will be used. We will 
complete sensitivity analyses i) using the data from all participants who completed pairs of 
experiments with 20mg THC; and ii) intention to treat analyses. 
 

Order effects 
It will be assumed that there are no carryover effects from the previous experimental 
session as there was sufficient time for drug washout between session. A period effect may 
be present due to learning and because participants become more comfortable with the lab 
environment over time. We will therefore include visit number in all models to account for 
potential order effects. 
 
Correction for multiple comparisons 
Benjamini Hochberg correction will be conducted across outcomes locally i.e. across 
secondary cognitive outcomes, secondary psychopathological outcomes, visual analogue 
scales and physiological outcomes. 
 
Analysis of primary and secondary outcome measures 
Continuous outcomes will be reported as means with standard deviation. Categorical 
outcomes will be reported as frequencies. 
 
We will use linear mixed models to assess the effect of CBD on all continuous outcomes. 
Treatment allocation (CBD/placebo) and visit number will be included as categorical fixed 
effects, with participant as a random effect to account for the dependency between 
repeated measures. Estimated marginal means will be calculated and compared in a 
pairwise test. If residuals do not fit a normal distribution, values will be transformed to fit a 
normal distribution.   
 
P values below 0.05 will be considered significant. All tests will be two-tailed. 
 
Analysis of VAS  
Two comparisons will be made for each outcome: i) effect at 10mins post-THC; and ii) total 
effect over time (AUC from pre-THC timepoint to End of Study timepoint). For calculation of 
AUC, the pre-THC timepoint will be set at -20mins and the end of study visit will be set at 
+135mins post-THC. We will use a linear mixed-model for this comparison. 
 
Analysis of STAI-S 
The STAI-state scale was administered at three timepoints during each experiment: pre-
CBD/placebo, pre-THC and post-THC. Here, the outcome of primary interest is the difference 
between baseline anxiety and post-THC anxiety. An additional and separate analysis will be 
completed to assess whether CBD can reduce anxiety prior to THC intoxication. We will use 
a linear mixed-model for this comparison. 
 

Pharmacokinetic analyses 
Pharmacokinetic parameters will be summarized descriptively. We will report the geometric 
mean of the AUCt and Cmax. THC’s AUC will calculated be from 0mins – 90mins. 
 
To compare the Cmax and AUCt of THC and its metabolites across treatment arms, we will 
used a paired sample t-test or a Wilcoxon rank sum test, depending on the distribution of 
the data. 
 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
1 
 
DOES CANNABIDIOL ATTENUATE THE ACUTE EFFECTS OF ∆9-
TETRAHYDROCANNABINOL INTOXICATION IN INDIVIDUALS 
DIAGNOSED WITH SCHIZOPHRENIA? A DOUBLE-BLIND, 
RANDOMISED, PLACEBO-CONTROLLED EXPERIMENTAL STUDY 
 
 
Study Acronym: INTEGRATE 
 
Academic Sponsor 
Prof Reza Razavi, King's College London 
Room 5.31, James Clerk Maxwell Building, 57 Waterloo Road, London SE1 8WA 
0207 8483224, reza.razavi@kcl.ac.uk 
 
NHS Sponsor: 
Gill Dale, South London and Maudsley NHS Foundation Trust 
R&D Department, Room W1.08, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), De 
Crespigny Park, London, SE5 8AF 
slam-ioppn.research@kcl.ac.uk , 020 7848 0339 
 
Chief Investigator  
Professor Sir John Strang 
Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, SE5 8AF, London 
john.strang@kcl.ac.uk 
 
Co-Investigators 
Dr Edward Chesney 
Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, SE5 8AF, London 
edward.chesney@kcl.ac.uk 
 
Professor Philip McGuire 
Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, SE5 8AF, London 
philip.mcguire@kcl.ac.uk 
 
Dr Amir Englund 
Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, SE5 8AF, London 
amir.englund@kcl.ac.uk 
 
Dr Tom P Freeman 
Department of Psychology, University of Bath, Bath, BA2 7AY 
T.P. Freeman@bath.ac.uk 
 
Dominic Oliver 
Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, SE5 8AF, London 
dominic.a.oliver@kcl.ac.uk 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
2 
 
Statistician  
Dr John Hodsoll  
Institute of Psychiatry, Psychology and Neuroscience, De Crespigny Park, SE5 8AF, London 
john.hodsoll@kcl.ac.uk 
 
 
Protocol Synopsis 
Study title 
Does cannabidiol attenuate the acute effects of ∆9-tetrahydrocannabinol 
intoxication in individuals diagnosed with schizophrenia? A double-blind, 
randomised, placebo-controlled experimental study 
Study acronym 
INTEGRATE 
Study type 
Non-CTIMP Experimental Study 
Sponsor 
King's College London 
Chief Investigator 
Prof John Strang 
REC number 
Health & Social Care Research Ethics Committee A (HSC REC A) 
Reference Number: 20/NI/0074 
 
Study design 
A randomised, double-blind, placebo-controlled, two-arm cross-over 
experimental study 
Primary Objective 
 
To assess the extent to which, in individuals with schizophrenia, the 
presence of CBD attenuates the acute effects of THC on cognitive 
impairment and psychotic symptoms. 
Secondary Objectives 
The secondary aims are to compare CBD pre-treatment with placebo pre-
treatment on the following outcomes:  
1. Cognition (including verbal learning, delayed recall, working 
memory) 
2. Psychotic symptoms (positive and negative)

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
3 
 
3. Specific psychotic phenomena (auditory hallucinations, persecutory 
beliefs) 
4. Anxiety 
5. Other subjective experiences 
6. THC, CBD and metabolite plasma levels 
7. Plasma endocannabinoid levels and potential biomarkers and 
inflammatory markers 
Primary Endpoint 
Difference in delayed verbal recall, as measured by the Hopkins Verbal 
Learning Test between placebo/THC and CBD/THC. 
 
Secondary Endpoints 
All measures will be collected at baseline and then during both test 
conditions.  Endpoints will be the difference between the test conditions.  
 
1. Cognition 
o HVLT-R Immediate verbal recall 
o Forward and reverse digit span 
2. Psychotic symptoms 
o Positive and Negative Syndrome Scale (PANSS) 
 Positive subscale 
 Negative subscale 
o State Social Paranoia Scale (SPSS) 
 
3. White Noise Task 
 
4. Advice Taking Task 
 
5. Psychotomimetic States Inventory (PSI) 
 
6. State-Trait Anxiety Inventory (STAI-S) 
 
7. Visual analogue scales: Feel drug effect, Like drug effect, Want 
more drug, Thinking clearly, Tired, Excited, Want to talk, Anxious, 
Relaxed, Happy, Irritable, Suspicious, Hearing voices, Dry mouth, 
Hungry, Vulnerable, Threatened. 
 
8. Preference for overall drug experience and opinion on CBD as a 
potential harm reduction treatment 
 
9. The difference in plasma levels of THC, CBD, and their metabolites 
  
10. The difference in plasma endocannabinoid levels and potential 
biomarkers and inflammatory markers

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
4 
 
Sample size 
The study aims to achieve 30 complete datasets. Accounting for an 
estimated 25% drop-out rate it is expected to recruit 40 participants.  
Summary of 
eligibility criteria 
Inclusion: 
i. 
Age 18-65 years. 
ii. 
Clinical diagnosis of schizophrenia or schizoaffective disorder (i.e. 
documented as such in the patient’s clinical records and satisfying 
ICD-10 criteria for F20 or F25) 
iii. 
Clinically stable for at least three months (since discharge from 
hospital, home treatment team, or prior clinical deterioration, and 
with agreement from the patient’s responsible clinician) 
iv. 
Regular (at least weekly) cannabis use for the past 3 months or 
more 
v. 
Evidence from either clinicians or from the patient that cannabis use 
exacerbates their symptoms or increases their risk of relapse 
vi. 
Treatment with regular doses of antipsychotic medication for at 
least 1 month, confirmed by a blood test at the baseline visit if the 
participant is not prescribed an injectable formulation, and with the 
participant agreeing to be maintained at a stable dose over the 
course of the experiment 
vii. 
The participant agrees to abstain from cannabis use for at least 
24hours prior to study visits 
viii. 
The participant is willing to have an intravenous cannula inserted to 
collect blood samples on experimental visits 
ix. 
Sufficiently fluent English 
x. 
Providing written informed consent 
 
Exclusion: 
xi. 
Extreme cannabis use: participant is estimated to be using over 2 
grams of cannabis/day 
xii. 
Dependence on alcohol or illicit substances other than cannabis as 
defined by ICD-10 
xiii. 
Pregnancy (current or planned) or breastfeeding 
xiv. 
Physical health disorder or another mental health disorder that the 
study psychiatrist judges may influence the patient’s ability to 
tolerate the procedure, or that may alter the results of the study. 
xv. 
Taken part in any drug study within the last 3 months or taking part 
in another study over the course of the trial 
xvi. 
Drug sensitivity/allergy to cannabis or Lorazepam 
xvii. 
Unlikely to be able to complete the study sessions for any reason, as 
judged by the study psychiatrist 
 
Additional criteria which must be met on experimental visits 
xviii. 
Negative alcohol breath test 
xix. 
Negative urine drug screen (apart from cannabis and prescribed 
medication)

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
5 
 
xx. 
Negative urine pregnancy test 
xxi. 
Stable mental state as judged by the study psychiatrist
Study drug, dosage 
and administration 
 
Participants will be administered 1000mg CBD orally or a matching 
placebo. 
 
3 hours later they will inhale a dose of THC (initially set at 20mg, with 
potential increases to 40mg and 60mg on subsequent visits) or a matching 
placebo. The THC and placebo cannabis will be GMP approved (or 
equivalent standards) and be administered using a Volcano Medic 
Vaporizer (Storz & Bickel), Germany. 
Version and date of 
final protocol 
Version 1.0 [10/02/2020] 
Version 1.1 [03/03/2020] 
Version 1.2 [21/05/2020] 
Version 1.3 [15/06/2020] 
Version and date of 
Protocol Amendments
Version 2.0 [27/10/2020] 
Version 2.1 [05/02/2021] 
Version 3.0 [05/05/2021] 
Version 4.0 [01/12/2021] 
Version 5.0 [08/11/2022]
 
Table of Contents 
Protocol Synopsis ....................................................................................................................................... 2 
1. 
Summary ....................................................................................................................................... 6 
2 Objectives........................................................................................................................................... 7 
2.1. Primary objective ................................................................................................................................... 7 
2.2. Secondary objectives .............................................................................................................................. 7 
3 Trial Design ....................................................................................................................................... 7 
3.1 Trial Design ............................................................................................................................................. 8 
3.2 Study Flowchart ...................................................................................................................................... 8 
3.3 Recruitment ............................................................................................................................................. 8 
3.3.1 Inclusion Criteria ................................................................................................................................. 9 
3.3.2 Exclusion Criteria ................................................................................................................................ 9 
3.3.3 Withdrawal of Subjects ..................................................................................................................... 10 
3.4 Baseline visit .......................................................................................................................................... 10 
3.4.1 Consent ........................................................................................................................................................ 10 
3.4.2 Assessment for Study Eligibility ................................................................................................................. 10 
3.4.3 Collection of additional demographic and clinical information .................................................................. 10 
3.4.4 Assessment for eligibility to continue with baseline and experimental visits.............................................. 11 
3.4.5 Baseline Antipsychotic Level ...................................................................................................................... 12 
3.4.6 Practice of Experimental Procedures and Collection of Baseline Outcome Data ........................................ 12 
3.5 Randomisation & Blinding ................................................................................................................... 12 
3.5 Experimental visits ................................................................................................................................ 13 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
6 
 
3.5.1 Timetable ..................................................................................................................................................... 13 
3.5.2 Preparation ................................................................................................................................................... 14 
3.5.3 Administration of oral CBD/Placebo ........................................................................................................... 14 
3.5.4 Inhalation Procedure .................................................................................................................................... 14 
3.6 Outcome measures ................................................................................................................................ 15 
3.6.1 Burden to participants ............................................................................................................................. 15 
3.6.2 Blood collection and analysis ................................................................................................................. 15 
3.6.3 Cognitive measures ................................................................................................................................. 16 
3.6.4 Intermediate measures ............................................................................................................................ 16 
3.6.5 Psychotic symptom measures ................................................................................................................. 17 
3.6.5 Other outcome measures ......................................................................................................................... 17 
3.6.6 Next day effects ...................................................................................................................................... 18 
3.7 Safety ...................................................................................................................................................... 18 
3.7.1 Baseline safety measures ............................................................................................................................. 18 
3.7.1 Pre-THC Inhalation ..................................................................................................................................... 19 
3.7.2 Post-THC Inhalation .................................................................................................................................... 19 
3.7.3 Sobriety testing ............................................................................................................................................ 19 
3.7.4 Follow-up .................................................................................................................................................... 20 
3.7.5 Covid-19 ...................................................................................................................................................... 20 
4. Trial Statistics................................................................................................................................. 21 
4.1 Sample Size ............................................................................................................................................ 21 
4.2 Analysis .................................................................................................................................................. 21 
5 Participant reimbursement ............................................................................................................ 22 
6. Trial Steering Committee .............................................................................................................. 22 
7. Access to Source Data and Documents ........................................................................................ 22 
8. Ethics & Regulatory Approvals .................................................................................................... 22 
9. Data Handling ................................................................................................................................ 23 
10. Publication .................................................................................................................................... 23 
11. Finance .......................................................................................................................................... 23 
12. Addendum: Rationale for THC and CBD doses and routes of administration ..................... 24 
13. References ......................................................................................... Error! Bookmark not defined. 
14. Signature ....................................................................................................................................... 29 
 
1. Summary  
 
Psychotic disorders cause distressing symptoms and severely impact quality of life (Packer et al., 
1997).  Many patients with schizophrenia smoke cannabis recreationally (Hunt et al., 2018), a 
behaviour which is associated with negative outcomes including increased risk of relapse 
(Schoeler et al., 2016) and more severe psychotic symptoms (Henquet et al., 2010). The 
compound found in cannabis which is responsible for these effects is ∆9-tetrahydrocannabinol 
(THC). Experimental studies in healthy controls have shown that pre-treatment with cannabidiol 
(CBD), another compound produced by the cannabis plant, can counteract THC induced 
psychotic symptoms and cognitive impairment without significantly modifying other subjective 
effects (Englund et al., 2013) (Haney et al., 2016). No previous study has investigated whether 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
7 
 
CBD is able to moderate the effects of acute THC intoxication in individuals diagnosed with a 
psychotic disorder such as schizophrenia. 
 
The present study will recruit participants with a diagnosis of schizophrenia who use cannabis 
regularly. Participants will attend the laboratory on three occasions: an initial visit to check that 
they are safe to join the study, and two experiments. On the morning of experimental visits, each 
participant will be administered either an oral dose of CBD (1000mg) or a matching placebo. The 
order of CBD/placebo administration will be randomised across the two visits. Three hours later, 
they will be administered a dose of vaporised cannabis containing THC. The THC cannabis 
administration will follow a standardised inhalation procedure using a medical-grade vaporizer 
device. 
 
Once intoxicated, participants will complete a series of standard cognitive tasks as well as tasks 
exploring specific psychotic phenomena: the White Noise Task (Galdos et al., 2010) and the 
Advice Taking Task (Diaconescu et al., 2019). Finally, measures of subjective and objective 
psychotic phenomena as well as measures of other relevant subjective states (i.e. mood, anxiety, 
pleasure, hunger) will be collected. 
 
The study will be carried out at the NIHR-Wellcome Trust Clinical Research Facility at King’s 
College Hospital by researchers who have experience of testing cannabinoid compounds in the 
acute setting and working with people with psychotic disorders. All participants will be 
individuals who already use cannabis regularly so that they are not exposed to any additional 
harm. The researchers will closely monitor those taking part to make sure that they are well, both 
during the visits and for several weeks afterwards. The study will comply with the Declaration of 
Helsinki and will be conducted in the principles of Good Clinical Practice (GCP). It will be 
reviewed and approved by a relevant Research Ethics Committee (REC). 
2 Objectives 
2.1. Primary objective 
To assess the extent to which, in individuals with schizophrenia, the presence of CBD attenuates the 
acute effects of THC on cognitive impairment and psychotic symptoms. 
 
2.2. Secondary objectives 
The secondary aims are to compare THC administration following CBD pre-treatment with placebo 
pre-treatment on the following outcomes:  
 
1. Cognition (including verbal learning, delayed recall, working memory) 
2. Psychotic symptoms (positive and negative) 
3. Specific psychotic phenomena (auditory hallucinations, persecutory beliefs) 
4. Anxiety 
5. Other subjective experiences 
6. THC, CBD and metabolite plasma levels 
7. Plasma endocannabinoid levels and potential biomarkers and inflammatory markers 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
8 
 
3 Trial Design  
3.1 Trial Design 
Randomised, double-blind, placebo-controlled, two-arm, cross-over, within-subjects study. 
 
The study includes one baseline visit followed by two experimental visits, separated by at least one 
week. 
 
3.2 Study Flowchart 
 
Initial Brief 
Screening  
Baseline Visit 
Experimental Visits 1 &2
Informed consent 
 
x 
 
Physical examination 
 
X 
 
Demographic and clinical 
information 
X 
X 
 
Physical Observations 
 
X 
X 
Alcohol, Drug and Pregnancy 
Tests 
 
X 
X 
Blood sampling 
 
X 
 (antipsychotic level only) 
X 
Cannula 
 
 
X 
CBD/placebo administration 
 
 
X 
THC administration 
 
 
X 
Cognitive and psychopathological 
testing 
 
X 
X 
Sobriety test 
 
 
X 
Follow-up call (+ 1 day) 
 
 
X 
Follow-up call (+7-10 days) 
 
 
X 
 
3.3 Recruitment 
The research team will contact local clinical services (ie. inpatient wards and community mental 
health teams (CMHTs)) and ask them to identify patients who are likely to meet the study’s inclusion 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
9 
 
criteria. Clinicians will then ask potential participants if they agree to be contacted by the study team. 
The researchers will also utilise the South London and Maudsley NHS Foundation Trust (SLaM) 
Consent for Contact initiative in order to recruit Trust patients and will follow the related Trust 
policy. The researchers will then contact potential participants by telephone or in person to explore 
their eligibility for the study and answering any questions they have about what participation in the 
study entails. The researchers will also obtain consent from the participant for the research team to 
review their clinical notes and discuss their history with their clinical team. If the participants’ 
responses to the initial questions are satisfactory, and there are no issues identified from the review 
of their clinical notes or discussion with the clinical team, the participant will be invited for a 
Baseline visit and be provided with a Participant Information Sheet (PIS).  
 3.1 Inclusion Criteria  
Each participant must meet ALL of the following criteria:  
i. 
Age 18-65 years 
ii. 
Clinical diagnosis of schizophrenia or schizoaffective disorder (i.e. documented as such in the 
patient’s clinical records and satisfying ICD-10 criteria for F20 or F25) 
iii. 
Clinically stable for at least three months (since discharge from hospital, home treatment 
team, or prior clinical deterioration, and with agreement from the patient’s responsible 
clinician) 
iv. 
Regular (at least weekly) cannabis use for the past 3 months or more 
v. 
Evidence from either clinicians or from the patient that cannabis use exacerbates their 
symptoms or increases their risk of relapse 
vi. 
Treatment with regular doses of antipsychotic medication for at least 1 month, confirmed by 
a blood test at the baseline visit if the participant is not prescribed an injectable formulation, 
and with the participant agreeing to be maintained at a stable dose over the course of the 
experiment 
vii. 
The participant agrees to abstain from cannabis use for at least 24hours prior to study visits 
viii. 
The participant is willing to have an intravenous cannula inserted to collect blood samples on 
experimental visits 
ix. 
Sufficiently fluent English 
x. 
Providing written informed consent 
 
3.3.2 Exclusion Criteria  
If the participants ONE OR MORE of the following criteria they will be excluded from the study: 
i. 
Extreme cannabis use, participant is estimated to be using over 2 grams of cannabis/day 
ii. 
Dependence on alcohol or illicit substances (other than cannabis) as defined by ICD-10 
iii. 
Pregnancy (current or planned) or breastfeeding 
iv. 
Physical health disorder or another mental health disorder that the study psychiatrist judges 
may influence the patient’s ability to tolerate the procedure, or that may alter the results of 
the study. 
v. 
The participant has taken part in any drug study within the last 3 months or taking part in 
another study over the course of the trial 
vi. 
Drug sensitivity/allergy to cannabis or Lorazepam 
vii. 
Unlikely to be able to complete the series of procedures and study sessions for any reason, as 
judged by the study psychiatrist 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
10 
 
3.3.3 Withdrawal of Subjects  
Participants are free to withdraw from the study at any stage for any reason. The researchers may 
withdraw the participant from the study up until they complete their final experimental visit if it 
becomes apparent that they do not meet all inclusion and exclusion criteria. The researchers may also 
withdraw the participant due to adverse or serious adverse effects, protocol violations, administrative 
or other reasons.  
 
The researchers will ask the participant why they have decided to withdraw and will explain that this 
data will be recorded anonymously. The participant will not be obliged to disclose their reasons for 
withdrawal.  The participant will be able to withdraw their data until two weeks after the final study 
visit but will not be able to withdraw their data after this point. 
 
3.4 Baseline visit 
3.4.1 Consent 
The baseline visit will be held at either the participant’s CMHT or at the King’s Clinical Research 
Facility (CRF). At the start of the visit the researchers will explain to the participant the aims and 
procedures of the study once more. The participant will be given time to re-read the PIS and to ask 
questions about the study. The participant will be informed about what will happen during the rest of 
baseline visit and experimental sessions including requirements regarding alcohol and other drug use 
during and between study visits as well as data protection and confidentiality issues. If consenting, 
the participant and researcher will then read and sign the consent form. 
3.4.2 Assessment for Study Eligibility 
To assess for eligibility the following assessments will be completed by the study psychiatrist: 
i. 
Mini-International Neuropsychiatric Interview to screen for co-morbid (non-schizophrenia) 
mental illness 
ii. 
Clinical interview covering medical, psychiatric and substance use histories 
iii. 
Review of electronic health records (electronic Patient Journey System) 
iv. 
Discussion with the participant’s Responsible Clinician 
v. 
Mental state examination 
vi. 
A targeted physical examination depending on physical co-morbidities identified during the 
assessment 
 
3.4.3 Collection of additional demographic and clinical information 
The following information will also be collected through interview of the participant and assessment 
of their electronic health records: 
 
i. 
Demographics: age, gender, ethnicity, education level, employment, marital status 
 
ii. 
Clinical information 
a. Current and past diagnosed psychiatric and medical illnesses 
b. Current and past substance use 
c. Current and past prescribed medications including long-acting injectable formulations 
and clozapine 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
11 
 
d. Admissions to psychiatric hospital, their legal status under the Mental Health Act, 
their duration, and admission to psychiatric intensive care wards 
e. History of being subject to a Community Treatment Order 
f. Management by forensic mental health services 
g. Custodial/prison sentences 
h. Health of the Nation Outcomes Scale score (most recent) 
 
iii. 
Cannabis-Experiences Questionnaire (CEQ). A questionnaire concerned with subjective 
experiences of cannabis (Barkus et al., 2006). It has 13 questions divided into three subscales: 
Pleasurable Experiences, Psychosis-Like Experiences and After-Effects.  
 
iv. 
Timeline Follow-back (Cannabis). This questionnaire obtains a variety of quantitative 
estimates of substance use. 
 
v. 
The Cannabis Use Disorder Identification Test – Revised (CUDIT-R) (Adamson 2010) 
 
vi. 
Substance Use Awareness and Insight Scale (SAS) (Kim 2021) 
 
vii. 
Psychotomimetic States Inventory (PSI). A 48-item questionnaire that measures psychotic-
like experiences. The PSI was developed for use in drug studies, particularly cannabis and 
ketamine studies (Mason et al., 2008).  Items are rated on a 4-point scale (from 0 = never to 3 
= strongly). The PSI has subscales of delusionary thinking, perceptual disorders, cognitive 
disorganisation 
 
viii. 
Drug Use Disorders Identification Test (DUDIT). An 11-item self-administered screening 
instrument for drug-related problems. 
 
ix. 
Alcohol Use Disorders Identification Test (AUDIT). 10 question alcohol harm screening tool. 
 
x. 
Wechsler Test of Adult Reading (WTAR). This tool is used to provide a measure of 
premorbid intelligence (Wechsler, 2001). 
 
xi. 
Revised-Green Paranoid Thoughts Scale. A scale which comprises an eight-item ideas of 
reference and 10-item ideas of persecution subscale (Freeman et al., 2019). 
 
xii. 
State Trait Anxiety Scale.  This scale differentiates between the temporary condition of "state 
anxiety" and the more general and long-standing quality of "trait anxiety." The trait scale will 
also be used as an outcome measure (Spielberger 1983). 
 
xiii. 
Carbon monoxide breath test. This test uses a simple handheld device. Carbon monoxide 
levels can be used as a measure of nicotine dependence. 
 
xiv. 
Height, weight, body mass index, body fat content (%). 
3.4.4 Assessment for eligibility to continue with baseline and experimental visits 
As well as meeting the study’s inclusion and exclusion criteria, participants must fulfil a number of 
additional criteria at the baseline and experimental visits before completing any outcome measures. 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
12 
 
If a participant does not meet these criteria the visit will be postponed. Depending on the individual 
circumstances, the investigators will consider whether failing these criteria will mean that a 
participant has to be withdrawn from the study.  
 
i. 
Negative alcohol breath test 
ii. 
Negative urine drug screen (apart from cannabis and prescribed medication) 
iii. 
Negative urine pregnancy test 
iv. 
Stable mental state, as judged by the investigator and in light of the participant’s normal 
baseline symptomatology 
 
3.4.5 Baseline Antipsychotic Level 
During the baseline visit, a single blood sample will be collected to measure plasma levels of 
prescribed antipsychotic medication in those prescribed an oral formulation. The sample will be 
collected by the study doctor or CRF nurses in a 5ml EDTA vacutainer. Staff will aim to take a 
trough sample (i.e. at least 6 hours post dose). The samples will be processed locally at the King’s 
College Hospital/ViaPath Toxicology Unit. If the result of the test implies poor or non-compliance 
with prescribed antipsychotic medication, the participant will be withdrawn from the study. If a 
participant is prescribed a long-acting injectable formulation of an antipsychotic, and has been 
adherent to it for at least the previous three months, they will be able to participate in the study 
without obtaining plasma antipsychotic levels in advance of experiments. 
 
3.4.6 Practice of Experimental Procedures and Collection of Baseline Outcome Data 
At the baseline visit, if no reasons for exclusion are identified, the participant will then practice the 
inhalation procedure (with air only) and complete the cognitive and psychological test batteries. The 
cognitive and psychological test batteries are completed at baseline to familiarise the participant with 
the outcome measures. 
 
3.5 Randomisation & Blinding 
On each experimental visit the participant will receive one of the two drug conditions (placebo/THC; 
CBD/THC). The order in which they are given the two conditions will be randomised across 
experimental visits. The randomisation will be double blinded to both researchers and participants. 
The Maudsley Pharmacy will prepare study drug and dispense it to a blinded researcher. A 
statistician at King’s College London who is not otherwise connected to the study in any other way 
will produce a randomisation list which will be held at the Maudsley Pharmacy. Information on the 
allocation of participants to experimental arms will concealed from the study team until the study is 
completed. 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
13 
 
3.5 Experimental visits 
 
After successfully completing the baseline visit, the participant will be asked to attend experimental 
visits. To complete the study, a participant must attend two experimental visits (placebo/THC; 
CBD/THC). To allow for washout of the study drug, there is a minimum of one week between 
experimental visits. 
  
3.5.1 Timetable 
Experimental Visit Timetable 
Event 
Time post-completion 
of THC administration 
Expected Time 
Preparation & Baseline Psychopathological 
Testing 
Pregnancy, Alcohol & Drug Testing 
-3.5hrs 
10am-10.30am 
  
Mental state review 
  
  
Cannula Insertion 
  
  
Blood sampling I 
  
 
Visual Analogue Scales I 
 
 
 
STAI-S I
SSPS I 
PANSS I 
PSI 
 
 
CBD/Placebo 
Oral CBD/Placebo Administration 
-3hrs 
 10.30am 
Light lunch 
Light lunch
Visual Analogue Scales II 
Blood sampling II 
-90min 
 
 12pm-12.30pm 
 
THC Administration 
Visual Analogue Scales III (pre-dosing)
STAI-S II (pre-dosing) 
-30mins 
1pm-1.30pm 
  
Inhalation Procedure 
  
Initial Assessments 
Blood sampling III 
0min 
  
  
Blood sampling IV 
+5min 
  
  
Visual Analogue Scales IV
PANSS II (initial assessments) 
+10min 
  
  
Blood sampling V 
+15min 
  
Cognitive and Psychopathological Testing 
Hopkins Verbal Learning Test (5min) 
+20min 
1.50pm 
  
Digit Span (5min) 
  
  
White Noise Task (7min) 
  
  
Advice Taking Task (8 min) 
  
  
Hopkins VLT - delayed recall (2min) 
+45min 
2.15pm 
  
Visual Analogue Scales V (2min) 
  
  
Blood sampling VI 
+90min 
3pm 
  
Visual Analogue Scales VI
STAI-S III 
  
  
End of day review and final outcome measures 
Visual Analogue Scales VII  
+3.5hrs 
5pm 
  
SSPS II 
  
  
PANSS II (final interview and scoring)
PSI 
 
  
Sobriety Assessment 
Sobriety Assessment 
Discharge 
Discharge 
4hrs 
5.30pm 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
14 
 
STAI-S: State-Trait Anxiety Inventory-State Scale
SSPS: State Social Paranoia scale 
PANSS: Positive and Negative Syndrome Scale 
PSI: Psychotomimetic States Inventory 
 
3.5.2 Preparation 
Before experimental visits the participant will be asked to: 
 abstain from alcohol and cannabis for at least 24 hours before experimental visits 
 abstain from other illicit drugs for at least 7 days before experimental visits 
 eat their normal breakfast 
 have their normal morning caffeine and nicotine 
 take their normally prescribed medications 
 
Upon arrival the participant will complete the eligibility tests described in section 3.3.4. If there is no 
reason to postpone the experimental visit the participant will have an intravenous cannula inserted for 
blood sampling and a baseline blood sample will be collected. Baseline vital signs (heart rate, blood 
pressure and, temperature) will also be recorded. 
 
3.5.3 Administration of oral CBD/Placebo 
The participant will then be administered oral CBD or a matching placebo. Previous studies have 
shown that oral CBD reaches peak plasma concentrations within 3 hours. Administration of vaporized 
THC will therefore be timed to occur 3 hours after administration of the CBD/placebo. The CBD and 
placebo will be administered with food to improve bioavailability. 
 
3.5.4 Inhalation Procedure  
The cannabis will be provided by a manufacturer which adheres to Good Manufacturing Practice (or 
equivalent standards) and meet the European Medicines Agency’s contaminant levels for products 
used in the respiratory tract (or equivalent regulations).  
 
Participants will be administered 20mg THC for their first two experiments. Those who do not 
demonstrate a significant response on the PANSS-positive scale (increase 3) on either visit will be 
invited to repeat the two experiments where they are administered 40mg THC. If no PANSS-P 
response is observed at this dose, they will be invited to return to complete fifth and sixth 
experiments with 60mg THC. Both the participant and study psychiatrist must approve the dose 
increases. If it has been a substantial period of time since their last assessment (>3 months) 
participants will be asked to repeat the parts of the baseline visit to confirm study eligibility and re-
familiarise them with the study’s procedures and assessments. Participants who completed the study 
at a lower dose (i.e. 10mg or 15mg on an earlier version of this protocol) will also be invited to 
complete experiments at 20mg if they did not previously experience a significant PANSS-P 
response. 
 
The cannabis will be administered via the intra-pulmonary route using a standardised inhalation 
protocol which has been used in previous comparable studies. The cannabis is prepared and 
vaporized by nursing staff separate from the study team to maintain blinding to the type of cannabis 
being administered. The cannabis preparations will be vaporized at 210°C using the Storz-Bickel 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
15 
 
Volcano® Medic Vaporizer. This will vaporize the cannabis into a transparent polythene bag with a 
valve mouthpiece which prevents loss of drug between inhalations.  
 
The inhalation procedure will start when the participant is standing. Participants will be instructed to 
inhale a medium size breath from the bag, hold their breath for 8 seconds, and then exhale. They will 
then wait another 8 seconds before taking another breath. They will repeat this process until the 
balloon has been emptied.  
 
To ensure that the study drug is delivered to the participant this process will be repeated for a second 
time. The same cannabis plant material will be heated and vaporized for a second time and a second 
balloon with be filled with the remnants of the study drug. There will be a 1-2minute break between 
balloons. Once both balloons have been inhaled the participant will be seated or lying down in a bed.  
 
Throughout the inhalation procedure the investigator will monitor the participant for adverse effects 
or over-intoxication. The details of the safety protocols and procedures are described below (section 
3.7). 
3.6 Outcome measures 
3.6.1 Burden to participants 
Together, the cognitive and psychological outcome measures are expected take around 40minutes. 
Inhalation of 20mg THC leads to a reasonable or high level of intoxication for at least 90minutes. 
There is therefore no pressure to complete the tasks in rapid succession and participants will be able 
to take short breaks between measures. 
 
3.6.2 Blood and urine collection, handling and analysis 
Urine will be tested using a bedside drug screen and a bedside pregnancy test. One urine sample, 
collected at the screening or baseline visit will be stored for laboratory analysis of cannabinoids. 
Urine samples will be decanted into screw-cap collection tubes and be placed in a -20oC freezer and 
then -80oC freezer as soon as possible. The stored samples will be anonymised with participant ID, 
visit number and time point of collection and freezing. Samples will be analysed and processed 
according to standard procedures. All other urine samples will be disposed of immediately.  
 
At the baseline visit, a blood sample will be taken to test for prescribed antipsychotic levels. The test 
will be completed by ViaPath and be processed according to standard clinical procedures. 
 
On experimental visits, participants will have a venous cannula inserted for collection of blood 
samples. Blood samples will be taken before administration of CBD/placebo, 1.5 hours post CBD 
administration (30mins pre-THC inhalation) and at 0, 5, 15 and 90minutes after the end of the 
THC/placebo inhalation procedure. Each sample will be collected in a 5ml EDTA tube (green). 
Within 10min of collection, the samples will be centrifuged (3000rpm for 10minutes). The plasma 
will be decanted from the EDTA tube into two screw-cap collection tubes and immediately placed in 
a -20oC freezer. The stored samples will be anonymised with participant ID, visit number and time 
point. Only the research team will be able to link ID number to participant details. The samples will 
be moved to a -80oC freezer for longer term storage as soon as possible. Only plasma will be stored 
so that analyses can be completed. No human tissue will be stored at the end of the research, all 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
16 
 
tissues will have been disposed of in accordance with the Human Tissue Authority’s Code of 
Practice 
 
Plasma samples will later be analysed for the levels of prescribed antipsychotic, 9-THC, 11-OH-
9-THC, 11-COOH-9-THC, CBD, 6-OH-CBD and 7-OH-CBD, potential biomarkers and 
inflammatory markers using high performance liquid chromatography–mass spectrometry at King’s 
College Hospital and at the University of Turku, Finland. 
 
 
3.6.3 Cognitive measures 
Hopkins verbal learning task – Revised 
The investigator reads a list of 12 words to the participant. The participant is then asked to recall as 
many of the words from the list as they can remember. They repeat this process three times. 20-25 
minutes later the participant is asked to recall as many of the words from the list as they can 
remember. Repetitions and intrusions (words recalled not part of the original list) are recorded for 
each trial. A different version of the task (i.e. a different list of nouns) will be used on each occasion. 
(Brandt 1991). 
 
Forward and reverse digit span 
In the forward digit span the investigator reads a string of numbers to the participant which the 
participant repeats back in the same order. If the participant is correct the length of the string of 
numbers increases by one. The task is ended when the participant fails to give the answer on two 
consecutive attempts. For the reverse task the participant must recall the list of numbers in reverse 
order. 
 
3.6.4 Intermediate measures 
White Noise Task 
This task is designed to provoke illusions of speech in white noise (Galdos et al., 2010).  Participants 
listen to 75 consecutive 1-second audio clips of three different types: white noise only, white noise + 
barely audible speech, white noise + clearly audible speech. Following each 1-second stimuli, 
participants indicate whether they heard something, nothing or if they are not sure.  
 
Modified Advice Taking Task  
This laptop task is a modified version of the advice-taking task used by Behrens and colleagues 
(Behrens et al., 2008) (Diaconescu et al., 2019). It provides a measure of social inference which is 
believed to play a key role in the development of persecutory delusions.  On each trial participants 
try to predict a binary outcome (blue vs. green). They are offered two sources of information with 
each trial: a social cue (human advisor) and a non-social cue (pie-chart).  The pie-chart displays 
different green-blue ratios (50:50, 55:45, 60:40, and 75:25) thus varying its certainty. Participants are 
informed that the advisor will vary their intentions to either help or obstruct the participant. They 
will also be told that the adviser does not have full information and could therefore make 
unintentional mistakes. Players accrued points with every correct prediction and are provided a 
reward depending on their overall success.  
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
17 
 
3.6.5 Psychotic symptom measures 
State social paranoia scale (SSPS) 
This is a 10-item instrument which measures persecutory thoughts (Freeman et al., 2007). The 
persecutory items (e.g. ‘someone had bad intentions towards me’) are presented among 10 neutral 
items and scored on a 5-point scale (do not agree – totally agree).  
 
Positive and negative syndrome scale (PANSS) – positive subscale and negative subscales 
The PANSS is the most common scale to measure psychotic symptoms and commonly used in 
schizophrenia research (Kay et al., 1987). The positive subscale includes the following symptoms: 
delusions, conceptual disorganisation, hallucinations, hyperactivity, grandiosity, suspiciousness and 
hostility. The negative subscale contains these symptoms: blunted affect, emotional withdrawal, poor 
rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and 
flow of conversation, and stereotyped thinking. The symptoms are scored on a 7-point scale from 
absent-severe. The PANSS is an investigator rated scale and is scored following a semi-structured 
interview and through observation of the participant during the experimental visit. 
 
3.6.5 Other outcome measures 
 
Psychotomimetic States Inventory (PSI). 
A 48-item questionnaire that measures psychotic-like experiences. The PSI was developed for use in 
drug studies, particularly cannabis and ketamine studies (Mason et al., 2008).  Items are rated on a 4-
point scale (from 0 = never to 3 = strongly). The PSI has subscales of delusionary thinking, 
perceptual disorders, cognitive disorganisation 
 
State-Trait Anxiety Inventory-State (STAI-S)  
This is a 20-item scale which measures current state of anxiety (Spielberger 1983). Each item is 
scored from 1 (not at all) to 4 (very much). 
 
Visual analogue scales (VAS)  
These will be used to measure contemporary subjective experiences. The scales ranges will range 
from 0 to 10. The following scales will be used: 
 Feel drug effect 
 Like drug effect 
 Want more drug 
 Thinking clearly 
 Tired 
 Excited 
 Want to talk 
 Anxious 
 Relaxed 
 Happy 
 Irritable 
 Suspicious 
 Hearing voices 
 Dry mouth 
 Hungry 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
18 
 
 Vulnerable 
 Threatened 
 
As the study progresses, additional visual analogue scales may be added if it becomes apparent that 
relevant symptoms are not accounted for.  
 
Preference for overall drug experience 
At the end of the second experimental visit, participants will be asked which of the two drug 
experiences they preferred. They will be asked to describe the reasons for this decision.  
 
Opinion on CBD as a potential harm reduction treatment 
Participants will be asked to discuss their thoughts regarding CBD as a novel treatment. Before 
answering questions, they will be asked to assume that CBD is effective at reducing psychosis 
symptoms and the risk of relapse. They will then answer a series of specific and open-box questions 
regarding: 
 
- 
Indication for treatment (psychosis treatment vs. cannabis harm-reduction vs. other indications) 
- 
Polypharmacy with antipsychotic medication (ie. an adjunct to antipsychotic medication vs. to 
enable antipsychotic dose to be reduced vs. CBD monotherapy) 
- 
Concerns regarding adverse effects 
- 
Formulation (tablets, capsules, oil, other) 
- 
Natural vs. synthetically derived CBD 
 
3.6.6 Next day effects 
The day after each experimental visit, participants will be contacted by an investigator to review 
mental state and adverse effects. 
 
3.7 Safety  
The research group at KCL has extensive experience in the experimental administration of 
cannabinoids and well-established procedures to manage adverse effects. The study will at the CRF 
which is based within King’s College Hospital, a large teaching hospital. It is a short walk away 
from A&E and has access to all on-call acute medical support. 
 
3.7.1 Baseline safety measures 
At the baseline assessment, the participant will be assessed by a psychiatrist who is experienced in 
working with patients with schizophrenia and with using cannabis preparations in an experimental 
setting. The psychiatrist will also review the participant’s electronic clinical record and discuss the 
inclusion of the participant with their responsible clinician (ie. Community Mental Health Team 
Consultant) and their care-coordinator. The care-coordinator and responsible clinician will be 
provided with the study’s PIS and be able to discuss the study with the study psychiatrist. They will 
also be made aware of the dates of the experimental visits which their patient will be attending the 
study on. If the participant provides consent, the study team will also inform relevant friends, family 
or carers of the dates of their experimental visits. 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
19 
 
3.7.1 Pre-THC Inhalation 
On arrival at the laboratory, participants will complete the assessments described in section 3.3.4. 
Before the inhalation procedure, the investigator will talk to the participant about what to expect over 
the rest of the experimental visit. 
3.7.2 Post-THC Inhalation 
During inhalation the participant will stand next to a chair or bed so that if they feel lightheaded they 
are able to sit or lie down easily. If this occurs, the inhalation procedure will be paused and the 
participant will have their physical observations checked.  
 
Physical observations (HR, BP, Temp) will also be collected at baseline, at 0, 5, 15 and 90minutes 
post-inhalation, and before discharge. If physical observations are of clinical concern, a study doctor, 
who will be present throughout testing, will continue to monitor their physical observations and 
overall well-being closely and seek appropriate specialist advice as required 
 
Throughout the inhalation, the investigator continuously monitors for physical and psychological 
effects of the drug. If the participant appears to be experiencing unpleasant side effects or is unlikely 
to tolerate the full dose of the study drug, the administration can be paused or halted at any time. 
 
In the unlikely event of distressing side effects (e.g. paranoia, anxiety), rescue medication 
(lorazepam) will be made available. If symptoms are severe, antipsychotic medication can also be 
used.  
 
SLaM Pharmacy will serve as the emergency code breaker. In the extremely unlikely case that a 
clinician requires blinded information from a participants’ experimental visit, they can contact SLaM 
Pharmacy switchboard where they can speak to the on-call pharmacist for code breaking information 
at all times including out-of-hours. Out of hours, there may be a delay of up to three hours before the 
pharmacist is able to obtain the relevant information. The contact details for the SLaM switchboard 
will also be made available to participants. 
 
3.7.3 Sobriety testing 
At the end of experimental visits, participants will complete a series of sobriety tests. These will 
include examination of mental state by a psychiatrist and completion of the Standardized 
Field Sobriety Test Battery (heel-toe walking and turn, horizontal nystagmus, one leg stand test). 
These tests will also be completed at baseline to assess participants ability to complete them when 
sober and make reasonable adjustments on experimental visits if required.  
 
Participants who are not considered to have fully recovered will be permitted to stay in the facility 
for as long as necessary. In the unlikely event that a participant’s symptoms do not resolve by the 
end of the study session Participants who are not considered to have fully recovered will be 
permitted to stay in the facility for as long as necessary. In the unlikely event that a participant’s 
symptoms do not resolve by the end of the study session, the following protocol will be adhered to: 
 
1. The participant fails the sobriety test. 
2. The study team will explain to the participant that they have failed the test and that 
they will have to remain under observation until the study psychiatrist agrees that they 
are psychologically fit to return home. 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
20 
 
3. The participant will be able to repeat the sobriety tests and assessment with the study 
psychiatrist at regular intervals. 
4. If it is likely that the participant will need to remain under observation for a 
significant period of time, the study team will inform the nurse in charge of the CRF 
of this issue. They will discuss how long the CRF is likely to remain open for.  
5. The study team will also offer to contact a family member, carer or friend so that they 
can be informed that the participant remains under observation in hospital. The study 
team may contact the family member, carer, or friend without the participant’s 
consent, if the participant had previously provided consent for such contact, they 
currently lack the mental capacity to make this decision and such action would be in 
their best interests. 
6. If the participant does not agree to remain under observation, the importance of safety 
and continued observation will be explained to them. If they disagree with study 
psychiatrists assessment, and request discharge from the unit, the study psychiatrist 
will consider assessing the participant for section 5.2 of the Mental Health Act. 
7. If the CRF closes, the study team will transfer the participant to the A&E department 
at King’s College Hospital. They will inform the Psychiatric Liaison Nurses in A&E 
and the on-call psychiatry SpR and consultant 
8. Once the participant has been transferred to A&E, responsibility for their care will be 
taken over by SLaM. 
9. If the participant is transferred to A&E or another inpatient ward, or is detained under 
the Mental Health Act, the study’s Chief Investigator will be informed at the earliest 
opportunity. 
 
3.7.4 Follow-up 
Participants will receive two follow-up phone calls from the study team on day 1 and between days 
7-10 after each experimental visit. The participants will be asked questions relating to their general 
well-being, sleep, mood, anxiety, psychotic symptoms, and adverse events. Normal clinical care will 
continue during the course of participation. If a patient becomes unwell during the study or its 
follow-up period, the study team will inform the participant’s community mental health team to 
request appropriate clinical follow-up. 
 
If a participant doesn’t respond to an initial phone call from the study team, the following escalation 
protocol will be adhered to: 
1. Repeat phone calls x2 
2. Text message asking the participant to call the study team 
3. If the participant has provided consent, the team will contact a family member, carer 
or friend and ask them to check that the participant is well, and request that the 
participant contacts the study team 
4. If there has been no contact with the participant to confirm that they are well, the 
study team will contact the participant’s care-coordinator and responsible clinician on 
the morning of the next working day. The study team will ask the care-coordinator 
and responsible clinician to follow their usual clinical protocol in such circumstances. 
At this point, the follow-up will be handed over to the Community Mental Health 
Team. 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
21 
 
3.7.5  Covid-19 
Local guidance (SLaM and King’s College Hospital) on the management of SARS-CoV-2 will be 
followed throughout the study. 
4. Cannabis use outcomes in volunteers who do not meet inclusion criteria 
To allow a broader range of participants to be involved in the research study, those who do not meet 
the criteria described in section 3.3, will be invited to participate in a limited part of the study as long 
as they meet the following criteria: 
 
1. Diagnosis of a psychotic disorder (including psychosis spectrum (ICD-10: F20-29), bipolar 
affective disorder (F31), cannabis-induced psychotic disorders (F12.x) and clinical high-risk 
for psychosis) or control (ie. regular cannabis user without a psychosis diagnosis) 
2. Regular cannabis use (at least weekly) 
3. Has used cannabis within the past 7 days (self-report) 
4. Urine dipstick test positive for cannabis 
5. Providing written informed consent 
 
They will be asked to read through the relevant parts of the Participant Information Sheet and sign a 
consent form (as per section 3.4.1). They will not be required to sign to sections 9, 10 or 14 of the 
consent form. 
 
They will then answer questions regarding their medical and psychiatric history and substance use  
(as per section 3.4.3, subsections i-ix). They will provide a single urine sample which will be stored 
and analysed (as per section 3.6.2). They will also answer questions regarding CBD as a potential 
harm reduction treatment (section 3.6.5) and complete a PANSS interview. All data will be collected 
in accordance with the study’s ethical standards and data handling protocols (sections 9 and 10). 
Participants will be reimbursed £20 for their contribution. 
5. Trial Statistics 
5.1 Sample Size 
The relative effects of THC and CBD/THC have never been compared in this population previously. 
We chose a sample size (n=30) which we believe has adequate power to detect meaningful effects. In 
a two-tailed paired sample t-test, a sample size of n=30 has 80% power, at alpha=0.05 to detect an 
effect size of 0.53.In a study comparing the effect of THC relative to CBD/THC on psychotic 
symptoms in healthy volunteers[27], the effect size for increase in State Social Paranoia Scale was 
d=0.64. Assuming a drop-out rate of 25% (as in previous studies using this methodology), we plan to 
initially enrol n=40 patients.  
 
5.2 Analysis 
Study data will be analysed following the completion of data collection and database lock. For the 
primary analysis linear mixed models will be used, with fixed effects of experimental condition and 
random intercept for repeated measures within participants. Differences in the frequency of 
categorical data will be analysed using Pearson’s Chi-square test or multilevel logistic regression as 
appropriate. Relationships between cognitive, intermediate and psychosis data will be analysed using 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
22 
 
Pearson’s or Spearman’s rank correlation coefficient. If data do not fit a normal distribution they will 
be analysed after appropriate transformation. We will present both effect sizes and tests addressing 
study hypotheses with statistical significance set at p <0.05. All tests will be two-tailed. 
6 Participant reimbursement   
Participants will be reimbursed for their time at a rate equivalent to the London Living Wage 
(£10.55/hour). The baseline assessment is expected to take 4 hours and each experimental visit is 
expected to take up to 8 hours, a total of 20 hours. The total payment for completing the study (ie. 
two experiments with THC 20mg) will be £200. The participant will be paid £30 for the baseline, 
£70 for experimental visit 1 and £100 for experimental visit 2. Further reimbursement will be 
provided if a participant attends experimental visits 3 (£70), 4 (£100), 5 (£70) and 6 (£100). The total 
payment for attending all visits will be £540. Participants who do not complete all study visits will be 
reimbursed for the number of study visits they have attended. Participant will be paid either in cash 
or via bank transfer as per their preference. For bank transfers, bank details will be taken from the 
participant at the end of the study and payment will be processed 2-4 weeks after the final study visit. 
7. Trial Steering Committee  
The trial steering committee will supervise the trial on behalf of the sponsor, ensuring that the study 
is conducted under good clinical practice (GCP). In addition the trial steering committee will monitor 
progress of the trial, monitor adherence to the protocol and monitor participant safety. The trial 
steering committee will include Professor Philip McGuire, Professor John Strang, Dr Amir Englund 
and Dr Edward Chesney. 
8. Access to Source Data and Documents 
The researchers will permit study-related monitoring, audits, REC review, and regulatory inspections 
by providing the Sponsor(s), Regulators and REC direct access to source data and other documents. 
9. Ethics & Regulatory Approvals 
The trial will be conducted in compliance with the principles of the Declaration of Helsinki (1996), 
the principles of Good Clinical Practice (GCP) and in accordance with all applicable regulatory 
requirements. The study protocol, informed consent form, and participant information sheet will be 
submitted to an appropriate Research Ethics Committee (REC) and R&D for approval.  
 
Should the protocol require a major amendment, the amended protocol will be sent to the REC and 
R&D for approval before the changes in the protocol will be implemented. Minor amendments 
(administrative or logistic) may be implemented immediately, and the REC will be informed of this 
in writing.  
 
Written informed consent will be obtained from each participant before the initiation of any data 
collection or study related activity. Consent will be obtained in accordance with REC guidance and 
GCP and be performed by Edward Chesney or another psychiatrist. 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
23 
 
10. Data Handling 
The study will adhere to KCL’s policy on data management, security and sharing.  
 
Participants will provide written informed consent for the study team to access their medical records. 
The study team will review their electronic health record (ePJS) for the South London and Maudsley 
Trust and will also review the Local Care Record which accesses their primary care notes and 
records across King's Health Partners (ie. Guys, St Thomas, King's Hospitals). 
 
We will ask participants to provide mobile phone numbers and/or email addresses so that we can 
contact them during the study. We will not request personal address details unless we are booking a 
taxi for them. If a participant requests, they will be contacted with the study outcome. 
 
The Chief Investigator will act as custodian for the study data and all participant data will be 
anonymised. Data will be collected using source data questionnaires (pen and paper) and laptop 
computers (cognitive tasks) on study visits. Each study participant will be given a study ID 
consisting of a 3 digit number preceded by the study acronym “INTG” (e.g. INTG002). Source 
documents and electronic data records (SPSS or Excel) will be named with this ID. The source 
documents will be kept in locked cabinets within access-card locked rooms; electronic data will be 
backed up onto encrypted external hard-drives.  
 
Only the study research team will have access to participant's non-anonymised personal data during 
the study. Study data will be analysed at the IoPPN, King's College London, by the research team 
including study statistician. Data files which will be analysed will contain the participant ID number 
and contain no identifiable personal data. If participant’s bank details are used to provide payment, 
the information will be not be stored for any longer than necessary and will be destroyed at the 
earliest opportunity according to standard departmental procedures. 
 
Research data will be stored for a minimum of 10 years following the completion of the study. Case 
report forms will be scanned so that they can stored electronically along with other data from the 
study. We plan to store the data on King's Research Data Management system. 
11. Publication 
The trial protocol will be published in advance on Open Science Framework (www.osf.io/) and 
clinicaltrials.gov. Hypotheses for each outcome measure will also be pre-registered. It is intended 
that the results of the study will be reported and disseminated at international conferences and in 
peer-reviewed scientific journals. Where appropriate, the results will be disseminated to the general 
public by means of press releases, posts on social media and at public engagement event. As the 
results of the study may be valuable to public policy, the results may also be shared with 
governmental advisory groups such as the ACMD. Individual participants will not be identifiable in 
publications. 
12. Finance 
The trial is being funded by the National Institute of Health Research Award NIHR300273 
(£412,000). 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
24 
 
 
13. Addendum: Rationale for THC and CBD doses and routes of 
administration 
 
Rationale for CBD dosing and administration route 
Intravenous administration of CBD is not an established route. Inhalation of CBD is ineffective at higher 
doses due to coughing(Solowij et al. 2019). We therefore chose to administer CBD orally.   
 
A recent systematic review of the pharmacokinetics of cannabidiol highlighted the paucity of data from 
human studies(Millar et al. 2018). The best data, is probably from submissions for EMA approval of epidiolex 
(cannabidiol oral solution) which says: 
 
 ‘Bioavailability of CBD was approximately 6.5 % following oral administration in fasting conditions. 
Due to significant food effect observed the bioavailability following administration with food can be 
expected around 14-25%.’ 
(https://www.ema.europa.eu/en/documents/assessment-report/epidyolex-epar-public-
assessment-report_en.pdf) 
 
We are aware of the food effect of CBD and are requesting that our participants ensure that they eat 
their normal breakfast before experiments. 
 
In a study of healthy volunteers, 600mg oral CBD led to a significant reduction in the proportion of subjects 
who developed psychotic symptoms (Englund et al. 2013). There have been two randomized controlled 
clinical trials of CBD as an add-on treatment for schizophrenia. In one 600mg daily was not effective at 
reducing psychotic symptoms(Boggs et al. 2018), in the other 1000mg was effective(McGuire et al. 2018). 
We therefore decided to administer 1000mg of CBD orally. 
 
CBD reaches peak plasma concentration after around 3 hours after oral administration. We will therefore 
administer the CBD 2 ½ hours before the start of the inhalation procedure which takes up to 30 minutes. 
 
 
Rationale for THC dosing and administration route 
THC can be administered orally, inhaled or intravenously. During the preparation for this study, the study 
team interviewed patients who said that inhalation of vapor was the most acceptable route as it is the most 
similar to smoking, the standard route of administration for almost all users. Familiarity with smoking will 
mean that users are less likely to become over-intoxicated as they are able to titrate the study in their usual 
manner. There is also significantly less variability in absorption between individuals compared to oral 
administration. Vaporization is expected to deliver around 30-40% of the total THC dose to the participant 
(i.e. 3-4mg.)   
 
Regular users to have a much higher tolerance to THC. For example, in one study of frequent cannabis users 
(53% daily users, mean 21days/month), compared to placebo, a dose of 2.5mg THC IV caused a slight 
improvement delayed verbal recall, suggesting that these participants experienced withdrawal symptoms 
during the placebo arm(D’Souza et al. 2008). 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
25 
 
Five previous studies have administered THC to people  with a psychosis diagnosis in an experimental 
setting, three of which are discussed here (D’Souza et al. 2005)(Kuepper et al. 2013)(Henquet et al. 2006), 
while two neuroimaging studies unfortunately provide little information on either the psychological effects 
or safety of THC in this population (Whitfield-Gabrieli et al. 2018)(Vadhan et al. 2017). 
 
D’Souza et al. used an IV preparation of THC in patients with schizophrenia who did not use cannabis 
regularly and were prescribed a regular antipsychotic (D’Souza et al. 2005). They compared two doses of 
THC: 2.5mg and 5mg, equivalent to around 7mg and 14mg of vaporized THC, with placebo. It is important to 
note that in this study, the IV THC was administered over only 2minutes. Unlike in the INTEGRATE study, this 
would have prevented early termination of drug administration due to over-intoxication. 
 
There study reported two adverse events related to the study drug: 
 
 ‘One subject who failed to disclose a remote history of untreated hypertension at screening 
experienced hypertension, anxiety, and paranoia after receiving 5 mg delta-9-THC’.  
 
‘One subject diagnosed with paranoid schizophrenia who did not like the effects of delta-9-THC 
withdrew consent after completing 2 test days and became paranoid about research staff and 
his clinicians.’ 
 
An increase in PANNS-positive score of 3 or more was considered significant. The 2.5mg dose triggered such 
a reaction in 80% percent of the patient participants (mean increase: 5, range: -2 – 11). The 5mg dose 
triggered a significant reaction in 75% of participants (mean increase: 5, range: 0 – 12) 
 
Kuepper et al. administered 8mg THC via a vaporizer to 9 medication-free patients with a psychotic 
disorder(Kuepper et al. 2013). Six participants were daily cannabis users, one was a weekly user and two 
used it monthly or less. They reported no serious adverse events or drop-outs. There was little data on the 
psychological effects of the drug, but the study reported that THC induced significant increases in visual 
analogue scales, such as ‘feeling high’, and that there were no differences in these outcomes compared to 
two control groups (relatives of patients and healthy controls). 
 
Henquet et al. administered THC to 30 patients with a psychotic disorder, 8 of whom were not prescribed an 
antipsychotic(Henquet et al. 2006). The dose used was 300ug THC/kg, equivalent to 21mg in a 70kg person. 
The THC was smoked in cigarettes containing tobacco. In another study comparing smoking of THC with 
vaporization, the subjective effects of 25mg smoked THC were similar to a 10mg vaporized dose (Spindle et 
al. 2018). Henquet et al. combined two other groups (relatives of patients and healthy controls) with the 
patients for all analyses preventing group specific inferences. The study did not report any adverse events. 
 
Using earlier versions of this protocol we administered THC 10mg, 15mg and then 20mg as the starting dose. 
A total of 19 experiments have been completed by 10 participants. There have been no serious adverse 
events and no significant episodes of over-intoxication, nausea, drowsiness, dizziness, anxiety, agitation or 
hostility. All participants who received the study drug completed all study procedures successfully. All 
participants said that they are willing to enter the study again at a higher dose, except one who didn’t want 
to be cannulated again. We asked participants who completed the study to estimate the dose of THC that 
they believe they could tolerate without difficulty. Six participants were confident they could tolerate at 
least 40mg (study psychiatrist agreed in four cases) and two said they could tolerate 60mg THC or more. We 
have amended the protocol to allow participants who have safely completed experiments to re-enter the 
study at a higher dose (40mg and then 60mg). We hope that this approach will mean that more participants 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
26 
 
will demonstrate a significant response to THC during their experiments, increasing the number of chances 
that CBD has to block its effects. 
 
The mean daily use of cannabis in the population who either completed a baseline assessment for the main 
experiment or the substudy (protocol section 4) is 1g per day (n=22).  Almost all participants smoked strong 
cannabis (roughly 15% THC content). A reasonable estimate for average THC consumption in the local 
schizophrenia population is therefore 150mg daily. 
 
During recruitment around half of potential participants were excluded as their cannabis consumption was 
too high (i.e. >1g day). We have amended the inclusion criteria to allow participants who use as much as 
2g/day (300mg THC/day) to enter the study. We expect that this will immediately provide us with another 
10-15 recruits. It is likely that those with a higher cannabis tolerance (i.e. using 1-2g/day) will only 
demonstrate a psychotic response at higher doses.  
 
We will continue to take a cautious approach to experiments, for example, by first administering higher 
doses of THC to those who demonstrated the least response to lower doses.  
14 References 
Adams, R.A., Stephan, K.E., Brown, H.R., Frith, C.D., Friston, K.J., 2013. The computational anatomy of 
psychosis. Front. psychiatry 4, 47. 
Adamson SJ, Kay-Lambkin FJ, Baker AL, Lewin TJ, Thornton L, Kelly BJ, Sellman JD. An improved brief measure 
of cannabis misuse: the Cannabis Use Disorders Identification Test-Revised (CUDIT-R). Drug and alcohol 
dependence. 2010 Jul 1;110(1-2):137-43. 
Barkus, E.J., Stirling, J., Hopkins, R.S., Lewis, S., 2006. Cannabis-induced psychosis-like experiences are 
associated with high schizotypy. Psychopathology 39, 175–178. 
Behrens, T.E., Hunt, L.T. and Rushworth, M.F., 2009. The computation of social behavior. science, 324(5931), 
pp.1160-1164. 
Brandt, J., 1991. The Hopkins Verbal Learning Test: Development of a new memory test with six equivalent 
forms. The Clinical Neuropsychologist, 5(2), pp.125-142. 
Englund, A., Morrison, P.D., Nottage, J., Hague, D., Kane, F., Bonaccorso, S., Stone, J.M., Reichenberg, A., 
Brenneisen, R., Holt, D., Feilding, A., Walker, L., Murray, R.M., Kapur, S., 2013. Cannabidiol inhibits THC-elicited 
paranoid symptoms and hippocampal-dependent memory impairment. J. Psychopharmacol. 27, 19–27. 
https://doi.org/10.1177/0269881112460109 
Freeman, D., Loe, B.S., Kingdon, D., Rosebrock, L., Brown, P., Sheaves, B., Waite, F., Bird, J.C., 2019. The revised 
Green et al paranoid thoughts scale (R-GPTS): Psychometric properties, severity ranges, and clinical cut-offs. 
Psychol. Med. 
Heatherton, T.F., Kozlowski, L.T., Frecker, R.C., FAGERSTROM, K., 1991. The Fagerström test for nicotine 
dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br. J. Addict. 86, 1119–1127. 
Diaconescu, A.O., Hauke, D.J. and Borgwardt, S., 2019. Models of persecutory delusions: a mechanistic insight 
into the early stages of psychosis. Molecular psychiatry, 24(9), pp.1258-1267. 
Galdos, M., Simons, C., Fernandez-Rivas, A., Wichers, M., Peralta, C., Lataster, T., Amer, G., Myin-Germeys, I., 
Allardyce, J., Gonzalez-Torres, M.A., 2010. Affectively salient meaning in random noise: a task sensitive to 
psychosis liability. Schizophr. Bull. 37, 1179–1186. 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
27 
 
Haney M, Malcolm RJ, Babalonis S, et al. Oral cannabidiol does not alter the subjective, reinforcing or 
cardiovascular effects of smoked cannabis. Neuropsychopharmacology 2016; 41: 1974. 
Hunt, G.E., Large, M.M., Cleary, M., Lai, H.M.X. and Saunders, J.B., 2018. Prevalence of comorbid substance 
use in schizophrenia spectrum disorders in community and clinical settings, 1990–2017: systematic review and 
meta-analysis. Drug and alcohol dependence, 191, pp.234-258. 
Kay, S.R., Fiszbein, A. and Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophrenia bulletin, 13(2), pp.261-276. 
Kim J, Kambari Y, Taggar A, Quilty LC, Selby P, Caravaggio F, Ueno F, Torres E, Song J, Pollock BG, Graff-Guerrero 
A. A measure of subjective substance use disorder awareness–Substance Use Awareness and Insight Scale 
(SAS). Drug and Alcohol Dependence. 2021 Oct 27:109129. 
Mason, O. J. et al. (2008) The psychotomimetic states inventory (PSI): measuring psychotic-type experiences 
from ketamine and cannabis. Schizophrenia Research. 
McCarthy-Jones, S., Thomas, N., Strauss, C., Dodgson, G., Jones, N., Woods, A., Brewin, C.R., Hayward, M., 
Stephane, M., Barton, J., 2014. Better than mermaids and stray dogs? Subtyping auditory verbal hallucinations 
and its implications for research and practice. Schizophr. Bull. 40, S275–S284. 
Moritz, S., Woodward, T.S., 2005. Jumping to conclusions in delusional and non-delusional schizophrenic 
patients. Br. J. Clin. Psychol. 44, 193–207. 
Packer, S., Husted, J., Cohen, S., Tomlinson, G., 1997. Psychopathology and quality of life in schizophrenia. J. 
Psychiatry Neurosci. 22, 231. 
Paparelli, A., Di Forti, M., Morrison, P.D., Murray, R.M., 2011. Drug-induced psychosis: how to avoid star gazing 
in schizophrenia research by looking at more obvious sources of light. Front. Behav. Neurosci. 5, 1. 
Selzer, M.L., Vinokur, A., van Rooijen, L., 1975. A self-administered short Michigan alcoholism screening test 
(SMAST). J. Stud. Alcohol 36, 117–126. 
Spielberger, C.D., 1983. State-trait anxiety inventory for adults. 
Treadway, M.T., Buckholtz, J.W., Schwartzman, A.N., Lambert, W.E. and Zald, D.H., 2009. Worth the ‘EEfRT’? 
The effort expenditure for rewards task as an objective measure of motivation and anhedonia. PloS one, 4(8), 
p.e6598. 
Volkow, N.D., Swanson, J.M., Evins, A.E., DeLisi, L.E., Meier, M.H., Gonzalez, R., Bloomfield, M.A.P., Curran, 
H.V., Baler, R., 2016. Effects of cannabis use on human behavior, including cognition, motivation, and 
psychosis: a review. JAMA psychiatry 73, 292–297. 
Waters, F., Fernyhough, C., 2017. Hallucinations: a systematic review of points of similarity and difference 
across diagnostic classes. Schizophr. Bull. 43, 32–43. 
Wechsler, D., 2001. Wechsler Test of Adult Reading: WTAR. Psychological Corporation. 
Boggs, Douglas L, Toral Surti, Aarti Gupta, Swapnil Gupta, Mark Niciu, Brian Pittman, Ashley M. Schnakenberg 
Martin, et al. 2018. “The Effects of Cannabidiol (CBD) on Cognition and Symptoms in Outpatients with Chronic 
Schizophrenia a Randomized Placebo Controlled Trial.” Psychopharmacology 235 (7): 1923–32.  
D’Souza, Deepak Cyril, Walid Michel Abi-Saab, Steven Madonick, Kimberlee Forselius-Bielen, Anne Doersch, 
Gabriel Braley, Ralitza Gueorguieva, Thomas B. Cooper, and John Harrison Krystal. 2005. “Delta-9-
Tetrahydrocannabinol Effects in Schizophrenia: Implications for Cognition, Psychosis, and Addiction.” 
Biological Psychiatry 57 (6): 594–608.  

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
28 
 
D’Souza, Deepak Cyril, Mohini Ranganathan, Gabriel Braley, Ralitza Gueorguieva, Zoran Zimolo, Thomas 
Cooper, Edward Perry, and John Krystal. 2008. “Blunted Psychotomimetic and Amnestic Effects of Δ-9- 
Tetrahydrocannabinol in Frequent Users of Cannabis.” Neuropsychopharmacology 33 (10): 2505–16. 
Henquet, Cécile, Araceli Rosa, Lydia Krabbendam, Sergi Papiol, Lourdes Faňanás, Marjan Drukker, Johannes G. 
Ramaekers, and Jim Van Os. 2006. “An Experimental Study of Catechol-O-Methyltransferase Val158Met 
Moderation 
of 
Δ-9-Tetrahydrocannabinol-Induced 
Effects 
on 
Psychosis 
and 
Cognition.” 
Neuropsychopharmacology 31 (12): 2748–57.  
Kuepper, Rebecca, Jenny Ceccarini, Johan Lataster, Jim van Os, Marinus van Kroonenburgh, Joop M.A. van 
Gerven, Machteld Marcelis, Koen van Laere, and Cécile Henquet. 2013. “Delta-9-Tetrahydrocannabinol-
Induced Dopamine Release as a Function of Psychosis Risk: 18F-Fallypride Positron Emission Tomography 
Study.” PLoS ONE 8 (7): 1–11.  
Mason, N.L., Theunissen, E.L., Hutten, N.R., Desmond, H.Y., Toennes, S.W., Stiers, P. and Ramaekers, J.G., 2019. 
Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal 
connectivity. European Neuropsychopharmacology, 29(2), pp.247-256. 
McGuire, Philip, Philip Robson, Wieslaw Jerzy Cubala, Daniel Vasile, Paul Dugald Morrison, Rachel Barron, 
Adam Taylor, and Stephen Wright. 2018. “Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A 
Multicenter Randomized Controlled Trial.” American Journal of Psychiatry 175 (3): 225–31.  
Millar, Sophie Anne, Nicole Louise Stone, Andrew Stephen Yates, and Saoirse Elizabeth O’Sullivan. 2018. “A 
Systematic Review on the Pharmacokinetics of Cannabidiol in Humans.” Frontiers in Pharmacology. Frontiers. 
Schoeler, T., Monk, A., Sami, M.B., Klamerus, E., Foglia, E., Brown, R., Camuri, G., Altamura, A.C., Murray, R. 
and Bhattacharyya, S., 2016. Continued versus discontinued cannabis use in patients with psychosis: a 
systematic review and meta-analysis. The Lancet Psychiatry, 3(3), pp.215-225.  
Solowij, Nadia, Samantha Broyd, Lisa-marie Greenwood, Hendrika van Hell, Dave Martelozzo, Kuna Rueb, 
Juanita Todd, Zheng Liu, Peter Galettis, and Jennifer Martin. 2019. “A Randomised Controlled Trial of 
Vaporised Δ 9-Tetrahydrocannabinol and Cannabidiol Alone and in Combination in Frequent and Infrequent 
Cannabis Users: Acute Intoxication Effects.” European Archives of Psychiatry and Clinical Neuroscience 269 (1): 
17–35. 
Spindle, Tory R, Edward J Cone, Nicolas J Schlienz, John M Mitchell, George E Bigelow, Ronald Flegel, Eugene 
Hayes, and Ryan Vandrey. 2018. “Acute Effects of Smoked and Vaporized Cannabis in Healthy Adults Who 
Infrequently Use Cannabis: A Crossover Trial.” JAMA Network Open 1 (7): e184841–e184841. 
Stone JM, Morrison PD, Brugger S, Nottage J, Bhattacharyya S, Sumich A, Wilson D, Tunstall N, Feilding A, 
Brenneisen R, McGuire P. Communication breakdown: delta-9 tetrahydrocannabinol effects on pre-speech 
neural coherence. Molecular psychiatry. 2012 Jun;17(6):568-9. 
Vadhan, Nehal P., Cheryl M. Corcoran, Gill Bedi, John G. Keilp, and Margaret Haney. 2017. “Acute Effects of 
Smoked Marijuana in Marijuana Smokers at Clinical High-Risk for Psychosis: A Preliminary Study.” Psychiatry 
Research 257 (August): 372–74.  
Whitfield-Gabrieli, Susan, Adina S. Fischer, Angela M. Henricks, Jibran Y. Khokhar, Robert M. Roth, Mary F. 
Brunette, and Alan I. Green. 2018. “Understanding Marijuana’s Effects on Functional Connectivity of the 
Default Mode Network in Patients with Schizophrenia and Co-Occurring Cannabis Use Disorder: A Pilot 
Investigation.” Schizophrenia Research 194: 70–77.  
 
 

INTEGRATE Study Protocol 
Version 5.0 04/10/2022 
IRAS ID: 278595 
 
 
 
 
29 
 
14. Signature 
 
 
 
 
 
______________________________________  
 
_________________________ 
Chief Investigator 
 
 
 
 
 
Date 
Print name